United States Patent (19) 11 Patent Number: 4,952,690 Gosteli et al. 45) Date of Patent: Aug. 28, 1990

(54) 6-SUBSTITUTED THIA-AZA COMPOUNDS 4,447,360 5/1984 Gosteli et al...... 260/239 A 4,500,457 2/1985 Gosteli et al. . ... 260/245.2 R 75 Inventors: Jacques Gosteli, Basel; Ivan Ernest, 4,515,717 5/1985 Gosteli et al...... as a s 260/239 A Birsfelden, both of Switzerland; 4,518,533 5/1985 Gosteli et al...... 260/245.4 Marc Lang, Mulhouse, France; 4,524,028 6/1985 Gosteli et al...... 260/239 A Robert B. Woodward, Cambridge, 4,543,257 9/1985 Cama et al...... 540/310 ... 540/359 Mass. 4,614,614 9/1986 Ernest et al. 4,616,007 10/1986 Lang ...... 514/192 73) Assignee: Ciba-Geigy Corporation, Ardsley, 4,656,165 4/1987 Lang ...... 514/192 N.Y. 4,826,832 5/1989 Lang ...... 540/310 21 Appl. No.: 396,783 Primary Examiner-Mark L. Berch (22 Filed: Aug. 21, 1989 Attorney, Agent, or Firm-JoAnn Villamizar 57) ABSTRACT Related U.S. Application Data The invention relates to azetidin-2-ones of the formula 60 Continuation of Ser. No. 152,526, Feb. 5, 1988, aban doned, which is a division of Ser. No. 57,082, Jun. 3, 1987, abandoned, which is a division of Ser. No. 208,105, Nov. 18, 1980, Pat. No. 4,692,442, which is a continuation of Ser. No. 7,453, Jan. 29, 1979, aban doned. (30) Foreign Application Priority Data Feb. 2, 1978 CH) Switzerland...... 1140/78-3 51) Int. C.’...... C07D 205/09; CO7D 205/08; CO7D 499/00; A61K 31/425 wherein Ra represents hydroxy-lower alkyl, R1 repre 52 U.S. C...... 540/357 sents hydrogen, an organic radical bonded by a carbon 58) Field of Search ...... 540/357 atom to the ring carbon atom or an etherified mercapto group, R2 together with the carbonyl group to which (56) References Cited it is attached is a protected carboxyl group and Z' is U.S. PATENT DOCUMENTS oxygen, sulfhur or an optionally substituted methyli 4,123,539 10/1978 DiNinno ...... 424/270 dene group, functional groups in the radicals Ra, R1 and 4,168,314 9/1979 Christensen et al...... 424/270 Z' optionally being in protected form. The azetidinones 4,260,618 4/1981 Christensen ...... 424/263 are useful intermediates for the preparation of penem 4,272,437 6/1981 Menard ...... 540/30 antibiotics. 4,331,676 5/1982 Gosteli et al...... 424/270 4,364,865 12/1982 Ernest et al...... 260/239 A 4,431,588 2/1984 Pfaender ...... 540/310 12 Claims, No Drawings 4,952,690 1. 6SUBSTITUTED THAAZA COMPOUNDS CROSS REFERENCE TO RELATED APPLICATION This application is a continuation application of appli 7 1 cation Ser. No. 152,526 filed Feb. 5, 1988, now aban doned; which is a divisional application of application and may systematically be called 7-oxo-4-thia-l- Ser. No. 057,082, filed June 3, 1987, now abandoned, 10 azabicyclo3,2,0hept-2-ene. For the sake of simplicity it which is a divisional application of application Ser. No. is referred to hereinafter as "2-penem', wherein the 208,105 filed Nov. 18, 1980 now U.S. Pat. No 4,692,442, following numbering derived from penam and custom which is a continuation application of application Ser. ary in penicillin chemistry shall be used: No. 007,453 filed Jan. 29, 1979, now abandoned. 15 The present invention relates to new bicyclic thia-aza 6 s S compounds containing a £8-lactam ring substituted in 2 the 3-position and having antibiotic properties. Since the discovery of penicillin, numerous bicyclic 7 4. thia-aza compounds having a B-lactam structure have of 3 become known. A survey of earlier works is made by E. H. Flynn, "Cephalosporins and Penicillins', Academic The present invention relates to 2-penem-3-carboxy Press, New York and London, 1972. More recent devel lic acid compounds of the formula opments are described by J. Cs. Jászberényi et al., Progr.Med. Chem, Vol. 12, 1975, 395-477, and a P. G. 25 Ra s (I) Sammes, Chem. Rev. 1976, Vol. 76, No. 1, 113-155 and V by various authors at an international symposium of the C-R Chemical Society held in Cambridge, England in June, O N / 1976, (subsequent publication: J. Elks, "Recent Ad vances in the Chemistry of S-lactam Antibiotics', The 30 Chemical Society, Burlington House, London, 1977). in which Apart from the usual penam and cephen compounds Ra represents an organic radical bonded by a carbon carrying an acylamino group in the 6- or 7-position, atom to the ring carbon atom, a free, etherified or such compounds that are unsubstituted in these posi 35 esterified hydroxy or mercapto group or a halogen tions have also become known, for example 3-carboxy aton, 2,2-dimethylpenam (J. P. Clayton, J. Chem. Soc., 1969, R represents hydrogen, an organic radical bonded by a 2123) and 3-methyl-4-carboxy-3-cephem (K. Kiihlein, carbon atom to the ring carbon atom, or an etherified Liebigs Ann., 1974, page 369 and D. Bormann, ibid., mercapto group, and page 1391). 3-carboxy-2,2-dimethylpenam compounds, R2 represents a hydroxy group or an radical that to gether with the carbonyl grouping-CO=O)-forms that instead of the customary 6,8-acylamino group have a protected carboxyl group, a 6a-chloro or 6a-bromo group, have been described by and to salts of such compounds with salt-forming I. McMillan and R.J. Stoodley, Tetrahedron Lett. 1205 groups, processes for the manufacture of such com (1966), and J. Chem. Soc. C 2533 (1968), whilst corre 45 pounds, pharmaceutical preparations containing com sponding 6a-hydroxy-, 6a-acetoxy- and 6a-phenox pounds of the formula I with pharmacological proper yacetoxy-2,2-dimethylpenam-3-carboxylic acids have ties, and the use of the new compounds either as phar been described by D. Hauser and H. P. Sigg, Helv. macologically active substances, preferably in the form Chimica Acta 50, 1327 (1967). None of these com of pharmaceutical preparations, or as intermediates. pounds, however, has any, or any substantial, antibiotic 50 An organic radical Rabonded by a carbon atom to activity. the ring carbon atom is especially a saturated or unsatu 6-acylamino-2-penem-3-carboxylic acid compounds rated, optionally substituted, aliphatic, cycloaliphatic, having an antibiotic activity that contain the novel 2 cycloaliphatic-aliphatic, aromatic or aliphatic hydro penem ring system are described in DOS No. 2655298. carbon radical having up to 18, preferably up to 10, 2-penem compounds carrying in the 6-position sub 55 carbon atoms, or an optionally substituted heterocyclor stituents other than acylamino are not so far known. heterocyclyl-lower alkyl radical having up to 10 carbon atoms and up to 4 ring hetero atoms selected from the The problem underlying the present invention is to group nitrogen, oxygen and/or sulphur, especially op produce bicyclic thia-aza compounds containing a B tionally substituted lower alkyl or lower alkenyl, op lactam ring that possess the 2-penem ring system substi tionally functionally modified carboxyl, or optionally tuted in the 6-position and that are active against both substituted cycloalkyl, cycloalkenyl, cycloalkyl-lower penicillin-sensitive and penicillin-resistant bacteria. alkyl, cycloalkyl-lower alkenyl, cycloalkenyl-lower The manufacture according to the invention of the alkyl, phenyl, phenyl-lower alkyl or phenyl-lower alke novel compounds and the new intermediates required nyl. Examples of substituents of such radicals are op therefor open up new fields in which research into other 65 tionally functionally modified, such as optionally etheri commercially valuable compounds can be carried out. fied or esterified hydroxy or mercapto groups, for ex The ring system of the compounds of the present ample hydroxy, lower alkoxy, for example methoxy or invention has the formula ethoxy, lower alkanoyloxy, for example acetoxy or 4,952,690 3 4. propionoxy, hydroxysulphonyloxy present in said form, cyclopentyl or cyclohexyl, whereas a cyloalkyl-lower halogen atoms, for example chlorine or bromine, or alkyl radical Ra contains, for example, 4 to 7 carbon lower alkylthio groups, for example methylthio; option atoms and is, for example, cyclopropylmethyl, cy ally functionally modified carboxyl groups, such as clobutylmethyl, cyclopentylmethyl or cyclohexyl carboxyl, lower alkoxycarbonyl, for example:methoxy methyl. carbonyl or ethoxycarbonyl groups, carbamoyl or cy A cycloalkenyl radical Rais a corresponding cycloal ano; also nitro; sulpho present in salt form, or optionally kyl radical having one or optionally two C-C double substituted amino, such as amino mono-substituted or bonds, such as cyclohexenyl, for example cyclohexenyl, di-substituted by lower alkyl, for example methyl or or cyclohexadienyl, for example cyclohexa-1,4-dienyl ethyl or by acyl, such as lower alkanoyl, for example 10 A cycloalkyl-lower alkenyl radical or cycloalkenyl acetyl, or amino di-substituted by lower alkylene, for lower alkyl radical Rais, for example, cyclohexylvinyl, example 1,4-butylene or 1,5-pentylene. cyclohexylally, or cyclohexenylmethyl or cyclohexa A lower alkyl radical Ra contains up to 7, especially 1,4-dienylmethyl. up to 4, carbon atoms, and is, for example, methyl, A phenyl or a phenyl-lower alkyl radical, for example ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or 15 a benzyl or 1- or 2-phenylethyl radical Ramay be substi pentyl. Substituted lower alkyl R is especially substi tuted, preferably in the aromatic radical, for example by tuted methyl, ethyl or propyl, the substituents standing lower alkyl, such as methyl or ethyl, by lower alkoxy, especially in the 1-, but also in the 2- or 3-position, and such as methoxy, or by halogen, such as fluorine or is, for example, hydroxy-lower alkyl, such as hydroxy chlorine, further by nitro or by amino, wherein phenyl methyl, hydroxyethyl or hydroxypropyl; lower alkoxy 20 lower alkyl may be substituted in the position, for exam lower alkyl, such as lower alkoxymethyl, lower alkox ple, by hydroxy, hydroxysulphonyloxy, carboxy, sul yethyl or lower alkoxypropyl, for example methox pho or amino ymethyl, methoxyethyl or methoxypropyl; lower al In a heterocyclyl or heterocyclyl-lower alkyl radical kanoyloxy-lower alkyl, such as lower alkanoylox Ra, a heterocyclyl radical is a radical that is preferably ymethyl, lower alkanoyloxyethyl or lower alkanoylox 25 of aromatic nature and is bonded by a carbon atom, ypropyl, for example acetoxymethyl, propionox such as pyridyl, for example pyridyl, pyrid-3-yl or py ymethyl, acetoxyethyl, acetoxypropyl, in salt form, for rid-4-yl, thienyl, for example thien-2-yl, or furyl, for example in the form of an alkali metal salt, such as a example fur-2-yl, or a corresponding pyridyl-, thienyl sodium salt; or hydroxysulphonyloxy-lower alkyl, such or furyl-lower alkyl, especially-methyl radical, wherein as hydroxysulphonyloxymethyl, hydroxysulphonylox 30 heterocyclyl-lower alkyl may be substituted in the a yethyl or hydroxysulphonyloxypropyl, present in the position, for example, by hydroxy, hydroxysul form of an ammonium salt; halo-lower alkyl, such as phonyloxy, carboxy, sulpho or amino. halomethyl, haloethyl or halopropyl, for example chlo A phenyl- or heterocyclyl-lower alkenyl radical Rais roethyl or bromoethyl or chloropropyl or bromopro a lower alkenyl radical, for example phenylvinyl or pyl; lower alkylthio-lower alkyl, such as methylthi 35 furylallyl, substituted in the same manner as a corre omethyl, methylthioethyl, methylthiopropyl or tert sponding lower alkyl radical butylthiomethyl; lower alkoxycarbonyl-lower alkyl, A phenyl-, naphthyl- or heterocyclyl-lower alkenyl such as lower alkoxycarbonylmethyl or lower alkox radical Ra is a lower alkenyl radical, for example phe ycarbonylethyl, for example, methoxycarbonylmethyl, nylvinyl or furylally, substituted in the same manner as methoxycarbonylethyl, ethoxycarbonylmethyl or a corresponding lower alkyl radical. ethoxycarbonylethyl; cyano-lower alkyl, such as cyano An etherified hydroxy group Ra is etherified by an methyl or cyanoethyl; sulpho-lower alkyl, such as sul optionally substituted aliphatic, cycloaliphatic, cy phomethyl, sulphoethyl or sulphopropyl, in which the cloaliphatic-aliphatic, aromatic or araliphatic hydrocar sulpho group is present in salt form, for example in the bon radical having up to 18, especially up to 10 carbon form of an alkali metal salt, such as a sodium salt, or in 45 atoms, and is especially optionally substituted lower the form of an ammonium salt; or optionally protected, alkoxy, cycloalkoxy, cycloalkyllower alkoxy, phenoxy, for example acetylated, amino-lower alkyl, such as ami naththyloxy or phenyl-lower alkoxy. Examples of sub nonethyl, aminoethyl or aminopropyl. stituents of such radicals are optionally functionally A lower alkenyl radical Ra contains 2 to 7, especially modified, such as optionally etherified or esterified, 2 to 4 carbon atoms, and is, for example, vinyl, allyl or hydroxy or mercapto groups, for example hydroxy, but-2-enyl or but-3-enyl. Substituted lower alkenyl may lower alkoxy, for example methoxy or ethoxy, lower carry the same substituents as substituted lower alkyl. alkanoyloxy, for example acetoxy or propionoxy, halo An optionally functionally modified carboxyl group gen, for example chlorine or bromine, or lower alkyl Ra is a free carboxyl group or one of the, for example thio, for example methylthio; or optionally functionally esterified or amidated, carboxyl groups mentioned 55 modified carboxyl groups, such as carboxyl, lower alk under the -CO=O)-R21 groups, such as lower alk oxycarbonyl, for example methoxycarbonyl or ethox oxycarbonyl, for example methoxycarbonyl, ethoxy ycarbonyl, carbamoyl or cyano; also nitro; or optionally henoxycarbonyl optionally substituted, for example, by substituted amino, such as amino mono-substituted or halogen, such as chlorine, by lower alkoxy, such as di-substituted by lower alkyl, for example methyl or methoxy, or by nitro, such as phenoxycarbonyl, o-, m ethyl, or by acyl, such as lower alkanoyl, for example or p-chlorophenoxycarbonyl, pentachlorophenoxycar acetyl, or amino di-substituted by lower alkylene, for bonyl, o-, m- or p-methoxyphenoxycarbonyl or p-nitro example 1,4-butylene or 1,5-pentylene. phenoxycarbonyl; aminocarbonyl; or substituted A lower alkoxy radical R contains up to 7, especially aminocarbonyl, such as aminocarbonyl mono-sub up to 4, carbon atoms, and is, inter alia, methoxy, eth stituted or di-substituted by a lower alkyl group, for 65 oxy, propoxy, isopropoxy, butoxy, isobutoxy, tert.- example methyl or ethyl. butoxy or pentoxy. Substituted lower alkoxy R is espe A cycloalkyl radical Rahas, for example, 3 to 7 car cially substituted methoxy, ethoxy or propoxy, the sub bon atoms and is, for example, cyclopropyl, cyclobutyl, stituents standing in the 1-, 2- or 3-position, such as 4,952,690 5 6 methoxymethoxy, ethoxymethoxy, methoxyethoxy or A benzoyloxy or phenyl-lower alkanoyloxy radical methoxypropoxy; lower alkanoyloxymethoxy, lower Ra, for example a phenylacetoxy radical, may be substi alkanoyloxyethoxy or lower alkanoyloxypropoxy, such tuted, preferably in the aromatic radical, for example, as acetoxymethoxy, acetoxyethoxy or acetoxypropoxy; by lower alkyl, such as methyl or ethyl, by lower alk halomethoxy; haloethoxy or halopropoxy, such as chlo oxy, such as methoxy, by halogen, such as fluorine or roethoxy or bromoethoxy or chloropropoxy or chlorine, by nitro or by optionally protected hydroxy or bromopopoxy; lower alkoxycarbonylmethoxy or lower amino. In the phenyl-lower alkanoyloxy radical, option r alkoxycarbonylethoxy, for example methoxycar ally substituted, for example protected, hydroxy or bonylmethoxy, ethoxycarbonylmethoxy or methoxycr optionally substituted, for example protected, amino, bonylethoxy; cyanomethoxy, cyanoethoxy, or option 10 may also stand in the aliphatic moiety, especially in the ally protected aminomethoxy, aminoethoxy or amino 2-position. propoxy. An etherified mercapto group R is etherified by an A cycloalkoxy group Ra has, for example, 3 to 7. optionally substituted aliphatic, cycloaliphatic, cy carbon atoms and is, for example, cyclopropoxy, cy cloaliphatic-aliphatic, aromatic or araliphatic hydrocar clobutoxy, cyclopentoxy or cyclohexyloxy. 15 bon radical having up to 18, especially up to 10 carbon A cycloalkyl-lower alkoxy radical Rahas, for exam atoms, and is especially optionally substituted lower ple, 4 to 7 carbon atoms and is, for example, cyclo alkylthio, cycloalkylthio, cycloalkyl-lower alkylthio, propylmethoxy, cyclobutylmethoxy, cyclopentylme phenylthio or phenyl-lower alkylthio. Examples of sub thoxy or cyclohexylmethoxy. stituents of such radicals are optionally functionally A phenoxy or phenyl-lower alkoxy radical Ra, for modified, such as optionally etherified or esterified, example a benzyl- or 1- or 2-phenylethoxy radical may hydroxy or mercapto, for example, hydroxy, lower be substituted, preferably in the aromatic radical, for alkoxy, for example methoxy or ethoxy, lower al example by lower alkyl, such as methyl or ethyl, by kanoyloxy, for example acetoxy or propionoxy, halo lower alkoxy, such as methoxy, by halogen, such as gen, for example chlorine or bromine, lower alkylthio, fluorine or chlorine, or by nitro or amino. 25 An esterified hydroxy group Ra is a hydroxy group for example methylthio; or optionally functionally mod esterified by an acyl radical of an optionally substituted ified carboxyl groups, such as carboxyl, lower alkoxy aliphatic, cycloaliphatic, cycloaliphaticaliphatic, aro carbonyi, for example methoxycarbonyl or ethoxycar matic or araliphatic carboxylic acid having up to 18 bonyl, carbamoyl or cyano; also nitro; or optionally carbon atoms. Such groups are especially optionally 30 substituted amino, such as amino mono-substituted or substituted lower alkanoyloxy, cycloalkanoyloxy, cy di-substituted by lower alkyl, for example methyl or cloalkyl-lower alkanoyloxy, benzoyloxy, or phenyl ethyl, or by acyl, such as lower alkanoyl, for example lower alkanoyloxy. Substituents of such radicals are, for acetyl, or amino di-substituted by lower alkylene, for example, optionally functionally modified, such as op example by 1,4-butylene or 1,5-pentylene. tionally etherified or esterified, hydroxy or mercapto 35 A lower alkylthio radical Ra contains up to a espe groups, for example hydroxy, lower alkoxy, for exam cially up to 4, carbon atoms, and is, inter alia meth ple methoxy or ethoxy, aryloxy, for example phenoxy, ylthio, ethylthio, propylthio, isopropylthio, butylthio, lower alkanoyloxy, for example acetoxy or propionoxy, isobutylthio, tert-butylthio or pentylthio. Substituted halogen, for example chlorine or bromine, or lower lower alkylthio Ra is especially substituted methylthio, alkylthio, for example methylthio: or optionally func ethylthio or propylthio, the substituents standing in the tionally modified carboxyl groups, such as carboxyl, 1-, 2- or 3-position, such as methoxymethylthio, ethox lower alkoxycarbonyl, for example methoxycarbonyl ymethylthio, methoxyethylthio or methoxypropylthio; or ethoxycarbonyl, carbamoyl or cyano; also nitro; or lower alkanoyloxymethylthio, lower alkanoyloxyeth optionally substituted amino, for example amino mono ylthio or lower alkanoyloxypropylthio, such as acetox substituted or di-substituted by lower alkyl, for example 45 ymethylthio, acetoxyethylthio or acetoxypropylthio; methyl or ethyl, or by acyl, such as lower alkanoyl, for halomethylthio, haloethylthio or halopropylthio, for example acetyl, or amino disubstituted by lower alkyl example chloroethylthio or bromoethylthio, or chloro ene, for example 1,4-butylene or 1,5-pentylene. propylthio or bromopropylthio; lower alkoxycarbonyl A lower alkanoyloxy radical Ra contains up to 7, methylthio or lower alkoxycarbonylethylthio, for ex especially up to 4, carbon atoms, and is, for example, 50 ample methoxycarbonylethylthio; cyanomethylthio; formyloxy, acetoxy, propionoxy or butyryloxy. Substi cyanoethylthio; or optionally protected, for example tuted lower alkanoyloxy Ra is especially substituted N-acylated, aminomethylthio, aminoethylthio or acetoxy, for example, hydroxyacetoxy, methox aminopropylthio. yacetoxy, phenoxyacetoxy, haloacetoxy, for example A cycloalkylthio group Rahas, for example, 3 to 7 chloroacetoxy or bromoacetoxy, cyanoacetoxy or op 55 carbon atoms and is, for example, cyclopropylthio, tionally protected glycyloxy. cyclobutylthio, cyclopentylthio or cyclohexylthio. A cycloalkanoyloxy radical Ra has 4 to 8 carbon A cycloalkyl-lower alkylthio radical Rahas, for ex atoms and is, for example, cyclopropylcarbonyloxy, ample, 4 to 7 carbon atoms and is, for example, cyclo cyclobutylcarbonyloxy, cyclopentylcarbonyloxy or propylmethylthio, cyclobutylmethylthio, cyclopentyl cyclohexylcarbonyloxy, or a corresponding radical methylthio or cyclohexylmethylthio. substituted, for example, in the 1-position, for example A phenylthio or phenyl-lower alkylthio radical Ra, by hydroxy or amino. for example a benzylthio or 1- or 2-phenyl-lower alkyl A cycloalkyl-lower alkanoyloxy radical Rahas 5 to 9 thio radical, for example a benzylthio or 1- or 2 carbon atoms and is, for example, cyclopropylacetoxy, phenylethylthio radical, may be substituted, preferably cyclobutylacetoxy, cyclohexylacetoxy or cyclohexyl 65 in the aromatic radical, for example may lower alkyl, propionoxy, or a corresponding radical substituted, for such as methyl or ethyl, by lower alkoxy, such as me example, in the 1-position, for example by hydroxy or thoxy, by halogen, such as fluorine or chlorine, by nitro 2. or by amino. 4,952,690 7 8 An esterified mercapto group Rais a mercapto group nyl, optionally functionally modified carboxyl, or op esterified by an acyl radical of an optionally substituted tionally substituted cycloalkyl, cycloalkenyl, cycloal aliphatic, cycloaliphatic, cycloaliphaticaliphatic, aro kyll-lower alkyl, cycloalkyl-lower alkenyl, cycloalke matic or araliphatic carboxylic acid having up to 18 nyl-lower alkyl, phenyl, phenyl-lower alkyl or phenyl carbon atoms. Such radicals are especially optionally lower alkenyl. Examples of substituents such radicals substituted lower alkanoylthio, cycloalkanoylthio, cy are optionally functionally modified, such as optionally cloalkyl-lower alkanoylthio, benzoylthio or phenyl etherified or esterified, hydroxy or mercapto groups, lower alkanoylthio. Substituents of such radicals are, for example hydroxy, lower alkoxy, for example me for example, optionally functionally modified, such as thoxy or ethoxy, or lower alkanoyloxy, for example optionally etherified or esterified, hydroxy or mercapto 10 acetoxy or propionoxy groups, halogen atoms, for ex groups, for example hydroxy, lower alkoxy, for exam ample chlorine or bromine, or lower alkylthio groups, ple methoxy or ethoxy, aryloxy, for example phenoxy, for example methylthio, or a heterocyclylthio radical; lower alkanoyloxy, for example acetoxy or propionoxy, this heterocyclyl radical is optionally substituted, has halogen, for example chlorine or bromine, or lower aromatic properties or is partially saturated; substituents alkylthio, for example methylthio; or optionally func 15 are, inter alia, lower alkyl, especially methyl; hydroxy tionally modified carboxyl groups, such as carboxyl, lower alkyl, for example hydroxymethyl; carboxy lower alkoxycarbonyl, for example methoxycarbonyl lower alkyl, for example carboxymethyl or 1- or 2-car or ethoxycarbonyl, carbamoyl or cyano; also nitro; or boxyethyl; optionally N-substituted amino-lower alkyl, optionally substituted amino, such as amino mono-sub such as di-lower alkylamino-lower alkyl, for example stituted or di-substituted for example by lower alkyl, for dimethylaminoethyl; sulpho-lower alkyl present in salt example methyl or ethyl, by acyl, such as lower alkan form, for example sulphomethyl or 1- or 2-sulphoethyl oyl, for example acetyl, or amino di-substituted by present in the form of a sodium salt; cycloalkyl, for lower alkylene, for example 1,4-butylene or 1,5-penty example cyclopentyl or cyclohexyl; aryl, such as phenyl lene. optionally substituted by halogen, for example chlorine, A lower alkanoylthio radical Ra contains up to 7, 25 or by nitro; aryl-lower alkyl, for example benzyl; or especially up to 4, carbon atoms and is, for example, functional group, such as halogen, for example fluorine, formylthio, acetylthio, propionylthio or butyrylthio. chlorine or bromine; optionally substituted amino, such Substituted lower alkanoylthio Ra or Ra is especially as amino optionally mono-substituted or di-substituted substituted acetylthio, for example hydroxyacetylthio, by lower alkyl, for example amino, methylamino or methoxyacetylthio or phenoxyacetylthio; haloacet 30 dimethylamino; nitro; hydroxy; lower alkoxy, for exam ylthio, for example chloroacetylthio or bromoacet ple methoxy or ethoxy; or optionally functionally modi ylthio; cyanoacetylthio or optionally protected gly fied carboxyl, such as carboxyl, esterified carboxyl, cylthio. such as lower alkoxycarbonyl, for example methoxycar A cycloalkanoylthio radical R has 4 to 8 carbon bonyl or ethoxycarbonyl, optionally substituted, such as atoms and is, for example, cyclopropylcarbonylthio, 35 N-mono-lower alkylated or N,N-di-lower alkylated cyclobutylcarbonylthio, cyclopentylcarbonylthio or carbamoyl, for example N-methylcarbamoyl, or N,N- cyclohexylcarbonylthio, or a corresponding radical dimethylcarbamoyl, or cyano; as well as oxo or oxido; substituted, for example, in the 2-position, for example wherein one or more such substituents are present and by hydroxy or amino. these are bonded especially to ring carbon atoms, but A cycloalkyl-lower alkanoylthio radical Rahas 5 to 9 alternatively, especially lower alkyl and oxido, are carbon atoms and is, for example, cyclopropylacet bonded to ring carbon atoms; such heterocyclic radicals ylthio, cyclobutylacetylthio, cyclohexylacetylthio or are especially monocyclic, five-membered, diaza-, tria cyclohexylpropionylthio, or a corresponding radical za-, tetraza-, thiaza-, tiadiaza, thiatriaza-, oxaza- or ox substituted, for example, in the 2-position, for example adiazacyclic radicals of aromatic nature optionally con by hydroxy or amino. 45 taining the above-mentioned substitutents, or corre A benzoylthio or phenyl-lower alkanoylthio radical sponding radicals that are optionally substituted, for Ra, for example a phenylacetylthio radical, may be example by the above-mentioned substituents, having a substituted, preferably in the aromatic radical, for exam fused benzene ring, such as benzodiaza- or benzooxaza ple by lower alkyl such as methyl or ethyl, by lower cyclic radicals; monocyclic, six-membered monoazacy alkoxy, such as methoxy, by halogen, such as fluorine or clic or diazacyclic radicals of aromatic nature option chlorine, by nitro or by optionally protected hydroxy or ally containing the above-mentioned substituents, espe amino. In the phenyl-lower alkanoylthio radical, op cially oxido; or corresponding partially saturated radi tionally substituted, for example protected hydroxy or cals optionally substituted, for example by the above optionally substituted for example protected amino may mentioned substituents, especially oxo; or bicyclic, also stand in the aliphatic moiety, especially in the 2 55 triazacyclic or tetrazacyclic radicals of aromatic nature position. optionally substituted, for example by the above-men Ra in the meaning of a halogen atom is iodine or tioned substitutents; or corresponding partially satu especially fluorine, chlorine or bromine. rated radicals optionally substituted, for example by the An organic radical R1 bonded by a carbon aton to above-mentioned substitutents, especially oxo. Exam the ring carbon atom is especially a saturated or unsatu ples of such heterocyclyl radicals are imidazolyl, for rated, optionally substituted aliphatic, cycloaliphatic, example imidazol-2-yl; triazolyl optionally substituted cycloaliphatic-aliphatic, aromatic or araliphatic hydro by lower alkyl and/or phenyl, for example 1,2,3-triazol carbon radical having up to 18, preferably up to 10, 4-yl, 1-methyl-1H-1,2,3-triazol-4-yl, 1H-1,2,4-triazol carbon atoms, or an optionally substituted heterocyclyl 3-yl, 5-methyl-1H-1,2,4-triazol-3-yl, 3-methyl-1-phenyl or heterocyclyl-lower alkyl radical having up to 10 65 1H-1,2,4-triazol-5-yl, 4,5-dimethyl-4H-1,2,4-triazol-3-yl carbon atoms and up to 4 ring hetero atoms selected or 4-phenyl-4H-1,2,4-triazol-3-yl; tetrazolyl optionally from the group nitrogen, oxygen and/or sulphur, espe substituted by lower alkyl, -phenyl or halo-phenyl, for cially optionally substituted lower alkyl or lower alke example 1H-tetrazol-5-yl, 1-methyl-1H-tetrazol-5-yl, 4,952,690 9 10 1-phenyl-1H-tetrazol-5-yl, 1-(4-chlorophenyl)-1H-tet acetoxypropyl; halomethyl, haloethyl or halopropyl, razol-5-yl, 1-carboxymethyl-1H-tetrazol-5-yl, 1-(2- for example chloroethyl or bromoethyl, or chloropro dimethylaminoethyl)-1H-tetrazol-5-yl or 1-sodium sul pyl or bromopropyl; methylthiomethyl, methylthio phomethyl-1H-tetrazol-5-yl; thiazolyl or isothiazolyl ethyl, methylthiopropyl, tert-butylthiomethyl, 1,2,3- optionally substituted by lower alkyl or thienyl, for triazol-4-ylthiomethyl, 1H-tetrazol-5-ylthiomethyl, 1 example thiazol-2-yl, 4-(thien-2-yl)-thiazol-2-yi, 4,5- methyl-1H-tetrazol-5-ylthiomethyl, 1-carboxymethyl dimethylthiazol-2-yl, isothiazol-3-yl, isothiazol-4-yl or 1H-tetrazol-5-ylthiomethyl, 1-(2-dimethylaminoethyl)- isothiazol-5-yl; thiadiazolyl optionally substituted by 1H-tetrazol-5-ylthiomethyl or 1-sodium sulphomethyl lower alkyl, for example 1,2,3-thiadiazol-4-yl, 1,2,3- 1H-tetrazol-5-ylthiomethyl, 1H-tetrazol-5-ylthioethyl, thiadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 2-methyl-1,3,4- 10 (1-methyl-1H-tetrazol-5-ylthio)-ethyl, 2-methyl-1,3,4- thiadiazol-5-yl, 1,2,4-thiadiazol-5-yl or 1,2,5-thiadiazol thiadiazol-5-ylthiomethyl; lower alkoxycarbonylmethyl 3-yl; thiatriazolyl, for example 1,2,3,4-thiatriazol-5-yl; or lower alkoxycarbonylethyl, for example methox oxazolyl or isoxazolyl optionally substituted by lower ycarbonylmethyl, ethoxycarbonylmethyl or methoxy alkyl or phenyl, for example oxazol-5-yl, 4-methylox carbonylethyl; cyanomethyl, cyanoethyl; or optionally azol-5-yl, oxazol-2-yl, 4,5-diphenyloxazol-2-yl or 3 15 protected aminomethyl, aminoethyl or aminopropyl. methylisoxazol-5-yl oxadiazolyl optionally substituted by lower alkyl, -phenyl, nitro-phenyl or thienyl, for A lower alkenyl radical R1 contains 2 to 7, especially example 1,2,4-oxadiazol-5-yl, 2-methyl-1,3,4-oxadiazol 2 to 4, carbon atoms, and is, for example, vinyl, allyl or 5-yl, 2-phenyl-1,3,4-oxadiazol-5-yl, 5-(4-nitrophenyl)- but-2-enyl or but-3-enyi. Substituted lower alkenyl may 1,3,4-oxadiazol-2-yl or 2-(thienyl)-1,3,4-oxadiazol-5-yl; 20 carry the same substituents as substituted lower alkyl benzimidazolyl optionally substituted by halogen, for and is, for example, 2-aminovinyl or 2-acylaninovinyl, example benzimidazol-2-yl or 5-chlorobenzimidazol such as 2-acetylaminovinyl. 2-yl; or benzoxazolyl optionally substituted by halogen An optionally functionally modified carboxyl group or nitro, for example benzoxazol-2-yl, 5-nitrobenzox R1 is a free carboxyl group or one of the, for example azol-2-yl or 5-chlorobenzoxazol-2-yl; 1-oxidopyridyl, 25 esterified or oxidated, carboxyl groups mentioned for example 1-oxidopyrid-2-yl or 4-chloro-1-oxidopy under the groups -C(=O)-R2?, such as lower alk rid-2-yl; pyridazinyl optionally substituted by hydroxy, oxycarbonyl, for example methoxycarbonyl ethoxycar for example 3-hydroxypyridazin-6-yl; N-oxidopyridazi bonyl or tert-butoxycarbonyl; aryl-lower alkoxycar nyl optionally substituted by lower alkyl, lower alkoxy bonyl, such as benzyloxycarbonyl, p-nitrobenzylox or halogen, for example 2-oxido pyridazin-6-yi, 3 ycarbonyl or diphenylmethoxycarbonyl; aryloxycarbo chloro-1-oxidopyridazin-6-yl, 3-methyl-2-oxidopyrida nyl, such as phenoxycarbonyl optionally substituted, for zin-6-yl, 3-methoxy-1-oxidopyridazin-6-yl, 3-ethoxy-1- example, by halogen, such as chlorine, by lower alkoxy, oxidopyridazin-6-yl, 3-n-butoxy-1-oxidopyridazin-6-yl such as methoxy, or by nitro, such as phenoxycarbonyl, or 3-(2-ethylhexyloxy)-1-oxidopyridazin-6-yl; or 2-oxo o-, m- or p-chlorophenoxycarbonyl, pentachloro 1,2-dihydropyrimidinyl, optionally substituted by lower 35 phenoxycarbonyl, o-, m- or p-methoxyhenoxycarbonyl alkyl, amino, di-lower alkylamino or carboxy, for exam or p-nitrophenoxycarbonyl; or aminocarbonyl or substi ple 2-oxo-1,2-dihydropyrimidin-4-yl, 6-methyl-2-oxo tuted aminocarbonyl such as aminocarbonyl mono- or 1,2-dihydropyrimidin-4-yl, 5-methyl-2-oxo-1,2-dihy disubstituted by, for example lower alkyl, for example dropyrimidin-4-yl, 6-amino-2-oxo-1,2-dihydropyrimi methyl or ethyl. din-4-yl, 6-dimethylamino-2-oxo-1,2-dihyiropyrimidin A cycloalkyl radical R1 has, for example, 3 to 7 car 4-yl, 5-carboxy-2-oxo-1,2-dihydropyrimidin-4-yl or 6 bon atoms and is, for example, cyclopropyl, cyclobutyl, carboxy-2-oxo-1,2-dihydropyrimidin-4-yl; triazolopyri cyclopentyl or cyclohexyl, whilst a cycloalkyllower dyl, for example s-triazolo4,3-alpyrid-3-yl or 3H-v- alkyl radical R1 has, for example, 4 to 7 carbon atoms triazolo.4,5-b]pyrid-5-yl; or purinyl optionally substi and is, for example, cyclopropylmethyl, cyclobutyl tuted by halogen and/or lower alkyl, for example purin 45 methyl, cyclopentylmethyl or cyclohexylmethyl. 2-yl, purin-6-yl or 8-chloro-2-methylpurin-6-yi; also A cycloalkenyl radical R1 is a corresponding cycloal 2-oxo-1,2-dihydropurinyl, for example 2-oxo-1,2-dihy kyl radical having one or optionally two C-C double dropurin-6-yl); or optionally functionally modified car bonds, such as cyclohexenyl, for example cyclohex-1- boxyl groups, such as carboxyl, lower alkoxy carbonyl, enyl, or cyclohexadienyl, for example cyclohexa-1,4- for example methoxycarbonyl or ethoxycarbonyl, car SO dienyl. bamoyl or cyano; also nitro; or optionally substituted A cycloalkyl-lower alkenyl radical or cycloalkenyl amino, for example amino mono-substituted or di-sub lower alkyl radical R1 is, for example, cyclohexylvinyl stituted by lower alkyl, for example methyl or ethyl, by or cyclohexylallyl, or cyclohexenylmethyl or cyclohex acyl, such as lower alkanoyl, for example acetyl, or a-1,4-dienylmethyl respectively. amino di-substituted by lower alkylene, for example 55 A phenyl or phenyl-lower alkyl radical R1, for exam 1,4-butylene or 1,5-pentylene. ple a benzyl or 1- or 2-phenylethyl radical, may be A lower alkyl radical R1 contains up to 7, especially substituted, preferably in the aromatic radical, for exam up to 4, carbon atoms, and is, for example, methyl, ple by lower alkyl, such as methyl or ethyl, by lower ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or alkoxy, such as methoxy, or by halogen, such as fluorine pentyl. Substituted lower alkyl is especially substituted or chlorine, or also by nitro or amino. methyl, ethyl or propyl, the substituents standing espe A radical R1 may alternatively represent a heterocy cially in the 1-, but also in the 2- or 3-position, such as clic or heterocyclic-aliphatic radical bonded by a car hydroxymethyl, hydroxyethyl or hydroxypropyl; bon atom and preferably of aromatic nature, such as lower alkoxymethyl, lower alkoxyethyl or lower alkox pyridyl, for example pyrid-2-yl, pyrid-3-yl or pyrid ypropyl, for example methoxmethyl, methoxyethyl or 65 4-yl; thienyl, for example thien-2-yl, or furyl, for exam methoxypropyl; lower alkanoyloxymethyl, lower al ple fur-2-yl; a corresponding pyridyl-lower alkyl, thie kanoyloxyethyl or lower alkanoyloxypropyl, for exam nyl-lower alkyl or furyl-lower alkyl radicals, especially ple, acetoxymethyl, propionoxymethyl, acetoxyethyl or pyridylmethyl, thienylmethyl or furylmethyl radicals, 4,952,690 11 12 A phenyl- or heterocyclyl-lower alkenyl radical Ris A phenylthio radical R1 or a phenyl-lower alkylthio a lower alkenyl radical substituted in the same manner radical R1, for example a benzyl- or 1- or 2-phenyleth as a corresponding lower alkyl radical, for example ylthio radical, may be substituted, preferably in the phenylvinyl or furylallyl. aromatic radical, for example by lower alkyl, such as An etherified mercapto group R1 is etherified by an methyl or ethyl, by lower alkoxy, such as methoxy, by optionally substituted aliphatic, cycloaliphatic, cy halogen, such as fluorine or chlorine, or by nitro or cloaliphatic-aliphatic, aromatic or araliphatic hydrocar amino. bon radical having up to 18, especially up to 10 carbon Heterocyclically etherified mercapto groups R1 are atoms, or a heterocyclic radical and is optionally substi especially etherified by an optionally substituted hetero tuted lower alkylthio, lower alkenylthio, cycloal O cyclic radical that has 1 to 4 ring nitrogen atoms and kylthio, cycloalkyl-lower alkylthio, phenylthio, phenyl optionally a further ring hetero atom selected from lower alkylthio or heterocyclylthio. Substituents of oxygen and sulphur and that is bonded to the mercapto such radicals are, for example, optionally functionally group by a ring carbon atom. modified, such as optionally etherified or esterified, Such heterocyclic radicals are especially optionally hydroxy or mercapto, for example hydroxy, lower alk 15 substituted, for example by the substituents mentioned oxy, for example methoxy or ethoxy, lower al below, monocyclic, five-membered diaza-, triaza-, tet kanoyloxy, for example acetoxy or propionoxy, halo raza-, thiaza-, thiadiaza-, thiatriaza-, oxaza- or oxadiaza gen, for example chlorine or bromine, or lower alkyl cyclic radicals of aromatic nature, or optionally substi thio, for example methylthio; or optionally functionally tuted monocyclic six-membered aza- or diaza-cyclic 20 radicals of aromatic or partially saturated character. - modified carboxyl groups, such as carboxyl, lower alk Substituents of such heterocyclyl radicals are, inter oxycarbonyl, for example methoxycarbonyl or ethox alia, lower alkyl, especially methyl, as well as ethyl, ycarbonyl, carbamoylor cyano; also nitro; or optionally n-propyl, isopropyl or straight-chained or branched substituted amino, such as amino mono- or di-sub butyl: or lower alkyl substituted by hydroxy, as lower stituted such as by lower alkyl, for example methyl or 25 alkoxycarbonyl, sulpho, amidated sulphomono- or di ethyl, or by acyl, such as lower alkanoyl, for example lower alkylamino, acylamino, as lower alkanoylamino, acetyl, or amino di-substituted by lower alkylene, for or by substituted lower alkanoylamino, such as lower example by 1,4-butylene or 1,5-pentylene; or the substit alkanoylamino substituted by carboxy or halogen, for uents listed below in the case of the individual etherified example, 2-hydroxyethyl, 2-acetoxyethyl, 2-chloro mercapto groups R1. 30 ethyl, carboxymethyl, 2-carboxyethyl, ethoxycarbonyl A lower alkylthio radical R1 contains up to 7, espe methyl, 2-ethoxycarbonylethyl, sulphomethyl, 2-sul cially up to 4, carbon atoms, and is, for example, meth phoethyl, sulphamylmethyl, 2-sulphamylethyl, 2 ylthio, ethylthio, propylthio, isopropylthio, butylthio, aminoethyl, 2-dimethylaminoethyl, or 2-acetylamino isobutylthio, tert-butylthio or pentylthio. Substituted ethyl. Further substituents of the heterocyclic radical lower alkylthio R1 is, primarily, substituted methylthio, 35 are cycloalkyl, for example cyclopenty or cyclohexyl; ethylthio or propylthio, the substituents standing in the aryl, such as phenyl optionally substituted by halogen, 1-, 2- or 3-position such as methoxymethylthio, ethox for example chlorine, or by nitro; aryl-lower alkyl, for ymethylthio, methoxyethylthio or methoxypropylthio; example benzyl; or a heterocyclyl radical such as furyl, lower alkanoyloxymethylthio, lower alkanoyloxyeth for example fur-2-yl, thienyl, for example thien-2-yl, or ylthio or lower alkanoyloxypropylthio, such as acetox oxazolyl, for example oxazol-2-yl or oxazol-5-yl; or ymethylthio, acetoxyethylthio or acetoxypropylthio; functional groups, such as: halogen, for example fluo halomethylthio, haloethylthio or halopropylthio, for rine, chlorine or bromine; optionally substituted amino example chloroethylthio or bromoethylthio, or chloro such as amino optionally mono-substituted or di-sub propylthio or bromopropylthio; lower alkoxycarbonyl stituted by lower alkyl, for example, amino, me methylthio or lower alkoxycarbonylethylthio, for ex 45 thylamino or dimethylamino; acylamino, such as lower ample methoxycarbonylethylthio; cyanomethylthio; alkanoylamino or lower alkanoylamino substituted by cyanoethylthio; or optionally protected, for example halogen or carboxy, such as acetylamino, 3-chloropric acetylated, aminomethylthio, aminoethylthio or amin pionylamino or 3-carboxypropionylanino; nitro; hy propylthio. droxy; lower alkoxy, for example methoxy, ethoxy, A lower alkenylthio radical R1 contains 2 to 7, espe n-butoxy or 2-ethylhexyloxy; or optionally functionally cially 2 to 4, carbon atoms and is especially 1-lower modified carboxyl, such as carboxy, esterified carboxy, alkynylthio, for example, vinylthio, prop-1-enylothio, such as lower alkoxycarbonyl, for example methoxycar but-1-enylthio or pent-1-enylthio or also 2-lower alke bonyl or ethoxycarbonyl, optionally substituted, for nylthio, for example allylthio. Substituted lower alke example N-mono- or N,N-di-lower alkylated carban nylthio R is especially substituted in the 2-position, 55 cyl, for example, N-methylcarbamoyl or N,N-dimethyl wherein the substituents that chiefly come into consid carbamoyl; or cyano; as well as oxo or oxido; wherein eration are lower alkoxy, lower alkanoyloxy and op one or more such substituents are present and these are tionally protected amino. Thus R1 is, for example, 2 bonded especially to ring carbon atoms, but alterna methoxyvinylthio, 2-acetoxyvinylthio, 2 tively, especially lower alkyl and oxido, are bonded to acetylaminovinylthio or correspondingly substituted ring nitrogen atoms. prop-1-enylthio. Preferred heterocyclically etherified mercapto A cycloalkylthio group R1 has, for example, 3 to 7 groups R1 in which the heterocyclic radical is a corre carbon atoms, and is, for example, cyclopropylthio, sponding monocyclic, five-membered radical, are inter cyclobutylthio, cyclopentylthio or cyclohexylthio. alia imidazolylthio, for example imidazol-2-ylthio; A cycloalkyl-lower alkylthio radical R1 has, for ex 65 triazolylthio optionally substituted by lower alkyl and ample, 4 to 7 carbon atoms and is, for example, cyclo /or phenyl, for example, H-1,2,3-triazol-4-ylthio, 1 propylmethylthio, cyclobutylmethylthio, cyclopentyl methyl-1H-1,2,3-triazol-4-ylthio, 1H-1,2,4-triazol methylthio or cyclohexylmethylthio. 3-ylthio, 5-methyl-1H-1,2,4-triazol-3-ylthio, 3-methyl-1- 4,952,690 13 14 phenyl-1H-1,2,4-triazol-5-ylthio, 4,5-dimethyl -4H convertible into another functionally modified carboxyl 1,2,4-triazol-3-ylthio or 4-phenyl -4H-1,2,4-triazol group, such as into another esterified carboxyl group or 3-ylthio; especially tetrazolylthio optionally substituted into a hydrazinocarbonyl group. Such a group R2? is, as stated, for example 1-tetrazol-5-ylthio, 1-methyl for example, 2-halo-lower alkoxy, in which the halogen 1H-tetrazol-5-ylthio, 1-carboxymethyl-1H-tetrazol preferably has an atomic weight of more than 19, for 5-ylthio, 1-(2-carboxyethyl)-1H-tetrazol-5-ylthio, 1-sul example 2,2,2-trichloroethoxy or 2-iodoethoxy, also phomethyl-1H-tetrazol-5-ylthio, 1-(2-sulphoethyl)-1H 2-chloroethoxy or 2-bromoethoxy which may readily tetrazol-5-ylthio, 1-(2-dimethylaminoethyl)H-tetrazol be converted into the latter, or 2-lower alkylsulphonyl 5-ylthio, 1-phenyl-1H-tetrazol-5-ylthio or 1-(4-chloro lower alkoxy, for example, 2-methylsulphonylethoxy. phenyl)-1H-tetrazol-5-ylthio; thiazolylthio or isothiazo 10 The group R21 is optionally substituted hydrocarbon lylthio optionally substituted by lower alkyl or thienyl, radicals, especially saturated aliphatic or aromatic hy for example thiazol-2-ylthio, 4-(thien-2-yl)-thiazol drocarbon radicals, such as lower alkyl, for example 2-ylthio, 4,5-dimethylthiazol-2-ylthio, isothiazol methyl, and/or phenyl, or is a methoxy group mono 3-ylthio, isothiazol-4-ylthio or isothiazol-5-ylthio; espe substituted by an unsaturated aliphatic hydrocarbon cially thiadiazolylthio optionally substituted as stated, 15 radical, such as lower alkenyl, for example 1-lower for 5-ylthio, 1,3,4-thiadiazol-2-ylthio, 2-methyl-1,3,4- alkenyl, such as vinyl, by a carbocyclic aryl group hav thiadiazol-5-ylthio 2-(3-carboxypropionylamino)-1,3,4- ing electron-donating substituents, or by a heterocyclic thiadiazol-5-ylthio, 1,2,4-thiadiazol-5-ylthio or 1,2,5- group of aromatic nature having oxygen or sulphur as thiadiazol-3-ylthio; thiatriazolylthio, for example ring member. Examples of such groups R2 are tert 1,2,3,4-thiatriazol-5-ylthio; oxazolylthio or isoxazo 20 lower alkoxy, for example tert-butoxy or tert-pentoxy; lylthio optionally substituted as stated, for example optionally substituted diphenylmethoxy, for example oxazol-5-ylthio, 4-methyloxoazol-5-ylthio, oxazol diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy; 2-ylthio, 4,5-diphenyloxazol-2-ylthio or 3-methylisox lower alkenyloxy, especially 2-lower alkenyloxy, for azol-5-ylthio; or oxadiazolylthio optionally substituted example allyloxy; lower alkoxyphenyl-lower alkoxy, as stated, for example 1,2,4-oxadiazol-5-ylthio, 2-meth 25 yl-1,3,4-oxadiazol-5-ylthio, 2-phenyl-1,3,4-oxadiazol for example lower alkoxybenzyloxy, such as methox 5-ylthio, 5-(4-nitrophenyl)-1,3,4-oxadiazol-2-ylthio or ybenzyloxy (in which methoxy is especially in the 3-, 4 2-(thien-2-yl)-1,3,4-oxadiazol-5-ylthio. and/or 5-position), especially 3- or 4-methoxyben Preferred heterocyclically etherified mercapto zyloxy or 3,4-dimethoxybenzyloxy; or, above all, ni groups R, in which the heterocyclic radical is a corre 30 trobenzyloxy, for example, 4-nitrobenzyloxy, 2 sponding monocyclic, six-membered radical or a corre nitrobenzyloxy or 4,5-dimethoxy-2-nitrobenzyloxy; or sponding partially saturated radical, are, inter alia, 1 furfuryloxy, such as 2-furfuryloxy. The group R2? is oxidopyridylthio, optionally substituted by halogen, for furthermore a 2-oxoethoxy group that is optionally example 1-oxidopyrid-2-ylthio or 4-chloro-1-oxidopy substituted in the 2-position by lower alkyl, such as rid-2-ylthio; pyridazinylthio optionally substituted by 35 methyl, by lower alkoxy, such as methoxy or ethoxy, by hydroxy, for example 3-hydroxypyridazin-6-ylthio; N aralkyl, such as benzyl, or by aryl, such as phenyl, and oxidopyridazinylthio optionally substituted by lower is substituted in the 1-position by lower alkyl, such as alkyl, lower alkoxy or halogen, for example 2 methyl, lower alkoxycarbonyl, such as methoxycar oxidopyridazin-6-yilthio, 3-chloro-1-oxidopyridazin bonyl, lower alkylcarbonyl, such as methylcarbonyl, 6-ylthio, 3-methyl-2-oxidopyridazin-6-ylthio, 3 aralkylcarbonyl, such as benzylcarbonyl, or arylcarbo methoxy-i-oxidopyridazin-6-ylthio, 3-ethoxy-1- nyl, such as benzoyl. Thus R21 represents, for example, oxidopyridazin- 6-ylthio, 3-n-butoxy-1-oxidopyridazin acetonyloxy, phenacyloxy, 2,4-dioxo-3-pentoxy, 1 6-ylthio or 3-(2-ethylhexyloxy)-1-oxidopyridazin methoxycarbonyl-2-oxopropoxy or 1-ethoxycarbonyl 6-ylthio; or 2-oxo-1,2-dihydropyrimidinylthio option 2-oxopropoxy. The group R21 is alternatively a 2 ally substituted by lower alkyl, amino, di-lower alkyl 45 cyanoethoxy group that is optionally substituted in the anino 4-ylthio, 6-methyl-2-oxo-1,2-dihydropyrimidin 1- and/or in the 2-position, for example by lower alkyl, 4-ylthio, 5-methyl-2-oxo-1,2-dihydropyrimidin-4-ylthio, such as methyl, or by aryl, such as optionally substituted 6-amino-2-oxo-1,2-dihydropyrimidin-4-ylthio, 6-dime phenyl, and represents, for example, 2-cyanoethoxy or thylamino-2-oxo-1,2-dihydropyrimidin-4-ylthio, 5-car 2-cyano-2-phenylethoxy, R21 is alternatively a 2 boxy-2-oxo-1,2-dihydropyrimidin-4-ylthio or 6-car 50 (S1)(S2)(S3)-silylethoxy group, in which each of the boxy-2-oxo-1,2-dihydropyrimidin-4-ylthio. substituents S1, S2 and S3 independently of one another A protected carboxyl group of the formula -CO represents an optionally substituted hydrocarbon radi =O)-R21 is especially an esterified carboxyl group in cal and the individual radicals may be linked by a single which R21 represents a hydroxy group etherified by an C-C bond A hydrocarbon radical S1, S2, S3 is, for organic radical or an organic silyl or stannyl group. 55 example, an alkyl radical, a cycloalkyl radical or an aryl Organic radicals, also as substituents in organic silyl or radical, preferably such a radical having a maximum of stannyl groups, are aliphatic, cycloaliphatic, cycloali 12 carbon atoms, wherein the radical of one kind may phatic-aliphatic, aromatic or araliphatic radicals, espe be substituted by a radical of a different kind, or by cially optionally substituted hydrocarbon radicals of lower alkoxy, such as methoxy, or by halogen, such as this type, and heterocyclic or heterocyclic-aliphatic 60 fluorine or chlorine; and is especially lower alkyl hav radicals, preferably having up to 18 carbon atoms. ing up to 7, preferably up to 4, carbon atoms, such as An etherified hydroxy group R1 forms together methyl, ethyl, propyl or butyl cycloalkyl having up to 7 with the carbonyl grouping an esterified carboxyl carbon atoms, such as cyclopropyl or cyclohexyl; cy group that can preferably be readily split, for example cloalkylalkyl, such as cyclopentylmethyl; aryl having by reduction, such as by hydrogenolysis, or by solvoly 65 up to 10 carbon atoms, such as phenyl, tolyl or xylyl; or sis, such as acid hydrolysis or, especially, basic or neu aryl-lower alkyl, such as benzyl or phenylethyl. Radi tral hydrolysis, oxidatively, or under physiological con cals R24 of this kind to be given special mention are ditions, or an esterified carboxyl group that is readily 2-tri-lower alkylsilylethoxy, such as 2-trimethylsilyle- . 4,952,690 15 16 thoxy or 2-(dibutylmethylsilyl)-ethoxy, and 2-triaryl ycarbonyloxyethoxy, for example 1-ethoxycarbonylox silylethoxy, such as 2-triphenylsilylethoxy. yethoxy; lower alkanoylthiomethoxy, for example ace R21 may alternatively be 2-oxa- or 2-thia-cycloalkoxy tylthiomethoxy or pivaloylthiomethoxy; lower al or -cycloalkenyloxy having 5-7 ring members, such as kanoylaminomethoxy, in which lower alkanoyl may 2-tetrahydrofuryloxy, 2-tetrahydropyranyloxy or 2,3- optionally be substituted by halogen, such as chlorine, dihydro-2-pyranyloxy or a corresponding thia group, or for example acetylaminomethoxy or 2,2- R21 forms together with the -CO-O)- grouping an dichloroacetylaninonethoxy; aroylaminomethoxy, for activated ester group and is, for example, nitrophenoxy, example benzoylaminomethoxy; or, as an example of for example 4-nitrophenoxy or 2,4-dinitrophenoxy, or R21 containing lactone, phthalidyloxy. The etherified polyhalo-phenoxy, for example pentachlorophenoxy. 10 hydroxymethoxy group R21 is, for example, lower al R21 may, however, alternatively be lower alkoxy, for koxymethoxy, especially methoxymethoxy. A 2 example methoxy or ethoxy. aminoaliphatyloxy group R21 is, for example, a 2 An organic silyloxy or organic stannyloxy group R21 amino-lower alkoxy group, such as a 2-aminoethoxy is especially a silyloxy or stannyloxy group substituted group, in which amino is substituted by two lower alkyl by 1 to 3 optionally substituted hydrocarbon radicals, 15 groups or by alkylene optionally containing an oxa preferably having up to 18 carbon atoms. It contains as group, and represents, for example, 2-dimethylaminoe substituents preferably optionally substituted, for exam thoxy, 2-diethylaminoethoxy or 2-(1-morpholino)e- ple by lower alkoxy, such as methoxy, or by halogen, thoxy, or 2-aminocycloalkyloxy, for example 2-dime such as chlorine, aliphatic, cycloaliphatic, aromatic or thylaminocyclohexyloxy. araliphatic hydrocarbon radicals, such as lower alkyl, 20 A radical R21 forming with a -COO)- grouping halo-lower alkyl, cycloalkyl, phenyl or phenyl-lower an optionally substituted hydrazinocarbonyl group is, alkyl and represents especially tri-lower alkylsilyloxy, for example, hydrazino or 2-lower alkylhydrazino, for for example, trimethylsilyloxy, halo-lower alkoxy example 2-methylhydrazino. lower alkylsilyloxy, for example, chloromethoxyme Preferred groups R1 are those that can be converted thylsilyloxy; or tri-lower alkylstannyloxy, for example 25 into a free hydroxy group under neutral, basic or physi tri-n-butylstannyloxy. ological conditions. The group R21 may alternatively be an etherified Salts are especially those of compounds of the for hydroxy group that together with the carbonyl group mula I with an acid grouping such as a carboxyl group, ing-C(=O)- forms an esterified carboxyl group that or alternatively a hydroxysulphonyloxy group or sul can be split under physiological conditions. 30 pho group, especially metal or ammonium salts, such as These ester groups impart to the inherently active alkali metal and alkaline earth metal salts, for example carboxylic acids improved absorption for oral adminis sodium, potassium, magnesium or calcium salts; as well tration and/or prolonged activity. Numerous such ester as ammonium salts with annonia or suitable organic groups are known in the field of penicillins and cephalo amines, especially aliphatic, cycloaliphatic, cycloali sporins. There may be mentioned, for example, -CO 35 phatic-aliphatic or araliphatic primary, secondary or =O)-R21 groups in which R21 represents a methoxy tertiary mono-, di- or polyamines, or heterocyclic bases group substituted by acyl, acyloxy, acylthio, acylamino being suitable for the salt formation, such as lower al or etherified hydroxy and optionally a further organic kylamines, for example triethylamine; hydroxy-lower radical, in which the methyl group may be bonded to alkylamines, for example 2-hydroxyethylamine, di-(2- the carbonyl of the acyl group also by means of a bridge hydroxyethyl)amine or tri-(2-hydroxyethyl)-amine; containing carbon, or represents a 2-amino-aliphatyloxy basic aliphatic esters of carboxylic acids, for example group. In such groups acyl represents the radical of an 4-aminobenzoic acid 2-diethylaminoethyl ester; lower organic carboxylic acid having up to approximately 18 alkyleneamines, for example 1-ethylpiperidine; cy carbon atoms, and is, for example, optionally substituted cloalkylamines, for example bicyclohexylamine; or ben alkanoyl, cycloalkanoyl, aroyl, heterocyclylcarbonyl, 45 zylamines, for example N,N'-dibenzylethylenediamine; for example also the heterocyclylcarbonyl radical of a and also, bases of the pyridine type, for example pyri carboxylic acid of the formula I, or of a biologically dine, collidine or quinoline. Compounds of the formula active penam-3- or cephen-4-carboxylic acid, or is the I that have a basic group may likewise form acid addi acyl radical of a semi-seter of carbonic acid. Etherified tion salts, for example with inorganic acids, such as hydroxy in the methoxy group is etherified by a hydro hydrochloric acid, sulphuric acid orphosphoric acid, or carbon radical, especially by lower alkyl. The organic with suitable organic carboxylic or sulphonic acids, for radical that optionally additionally substitutes the me example trifluoroacetic acid or p-toluenesulphonic acid. thoxy group has up to 7 carbon atoms and is especially Compounds of the formula I having an acid and a basic lower alkyl, such as methyl, or aryl, such as phenyl. The group may also occur in the form of inner salts, that is said carbon bridge contains one to three, especially two, 55 in the zwitterion form. Pharmaceutically acceptable carbon atoms, so that a lactone, especially a y-lactone, is salts are preferred. present. The aliphatyl group in the said 2-aminoalipha In the penem compounds of the formula I the two tyl group may be of aliphatic or cycloaliphatic nature asymmetric carbon atoms in the 5- and 6-positioned and is saturated or unsaturated. The 2-amino group is may occur in the R-, the S- or the racemic RS-configu preferably substituted by alkylene containing two lower ration. Preferred are the compounds in which the con alkyl groups or optionally an oxa group. In such ester figuration of the 5-carbon atom corresponds to that of groups -CO-O)-R21 that can be split physiologi natural penicillin (5R-configuration). The substituents cally, R21 is, for example, lower alkanoyloxymethoxy, in the 5- and 6-positions may be in the cis- or trans-posi for example acetoxymethoxy or pivaloyloxymethoxy; tion in relation to one another. amino-lower alkanoyloxymethoxy, especially a-amino The compounds of the present invention have valu lower alkanoyloxymethoxy, for example glycyloxyme able pharmacological properties or may be used as in thoxy, L-valyloxymethoxy, L-leucyloxymethoxy; termediate for the manufacture of compounds having lower alkoxycarbonyloxymethoxy or 1-lower alkox such properties. Compounds of the formula I in which 4,952,690 17 18 Ra and R have the meanings given above and R2 repre nyl-lower alkanoyloxy substituted by hydroxy or sents hydroxy or an etherified hydroxy group R21 form amino; R1 represents hydrogen, lower alkyl, hydroxy ing together with the carbonyl group an esterified car lower alkyl, lower alkoxy-lower alkyl, lower al boxyl group that can be readily split preferably under kanoyloxy-lower alkyl, lower alkylthio-lower alkyl, physiological conditions, or pharmacologically accept heterocyclylthio-lower alkyl, amino-lower alkyl, able salts of such compounds having salt-forming acylamino-lower alkyl, carboxy-lower alkyl, lower al groups have anti-bacterial activities. They inhibit, for koxycarbonyl-lower alkyl, phenyl-lower alkyl, phenyl: example, the growth, of gram-positive and gram-nega phenyl substituted by lower alkyl, lower alkoxy, hy tive bacteria, such as Staphylococcus aureus and penicil droxy, halogen, nitro or by amino; furyl, thienyl, pyri lin-resistant Staphylococcus aureus, Escherichia coli, Pro O dyl; lower alkenylthio or lower alkylthio optionally teus vulgaris, Pseudomonas aeruginosa and Pseudomonas substituted by hydroxy, lower alkoxy, lower al aeruginosa R. Using the compounds of the formula I kanoyloxy, lower alkylthio, lower alkoxycarbonyl, car according to the invention in the disc-plate test with the bamoyl, cyano, nitro, amino or by amino mono-sub specific bacteria with a 0.5% strength solution on filter stituted or di-substituted by lower alkyl or lower alkan paper (6 mm diameter) inhibiting zones of approxi 15 oyl; or triazolylthio, tetrazolylthio, thiazolylthio, thia mately 12 to 33 mm diameter are found. triazolylthio, thiadiazolylthio, oxazolylthio or ox Penicillin V tested analogously at the same time, in adiazolylthio, in which the heterocyclic rings may ope the case of penicillin-sensitive Staphylococcus aureus tionally be substituted, for example by lower alkyl, bacteria causes inhibiting zones of 29 to 33 mm diameter N,N-di-lower alkylamino-lower alkyl, carboxy-lower and in the case of penicillin-resistant bacteria inhibiting 20 alkyl, sulpho-lower alkyl, amino, carboxy-lower al zones of a maximum of 9 to 12 mm. Neither Penicillin V kanoylamino or by carbamoyl; and R2 represents hy nor Penicillin G is effective against Pseudomonas aerugi droxy, a hydroxy group etherified by an easily, espe OS cially physiologically, splittable organic radical or an The anti-bacterial activity in vitro may also be ascer organic silyl or stannyl group, or an optionally substi tained in the Agar Dilution Test (according to Erics 25 tuted hydrazino group R24, and relates to salts of such son) in which against gram-positive and gram-negative compounds with salt-forming groups. cocci MIC values of 0.06 to 8 mcg/ml are ascertained In a 2-penem compound of the formula I or in a salt and against gram-negative bacilli, such as entero bac of such a compound having salt-forming groups, Ra teria, Pseudomonas and Haemophilus, MIC values of especially represents lower alkyl having up to 4 carbon from 2 to 128 mcg/ml are ascertained 30 atoms, for example methyl, ethyl, propyl or butyl; hy In vivo, in the systemic infection of mice with Strepto droxy-lower alkyl especially 1-hydroxylower alkyl, coccus pyogenes Aronson, on subcutaneous administra having up to 4 carbon atoms, for example hydroxy tion of the compounds according to the invention ED50 methyl, hydroxyethyl or hydroxypropyl; lower alkoxy values of approximately S1 to approximately 50 mg/kg lower alkyl, especially 1-lower alkoxy-lower alkyl, in result. 35 which lower alkyl contains up to 4 carbon atoms, for Attention is drawn in particular to the activity against example 1-methoxymethyl, 1-methoxyethyl or methox Pseudomonas aeruginosa. ypropyl; lower alkanoyloxy-lower alkyl, especially The compounds inhibit g-lactamases and have a syn 1-lower alkanoyloxy-lower alkyl, in which lower al ergistic effect in combination with other f3-lactam anti kanoyloxy and lower alkyl each contain up to 4 carbon biotics. atoms, for example acetoxymethyl, propionoxymethyl These new compounds, especially the preferred ones, or 1-acetoxyethyl; hydroxysulphonyloxy-lower alkyl in or their pharmacologically acceptable salts, may there salt form, in which lower alkyl contains up to 4 carbon fore be used, alone or in combination with other antimi atoms, especially 1-hydroxysulphonyloxy-lower alkyl, crobica, for example, in the form of antibiotically-active for example hydroxysulphonyloxymethyl, 1-hydrox preparations, in the treatment of corresponding sys 45 ysulphonyloxyethyl or 1-hydroxysulphonyloxypropyl; temic or organ infections, as fodder additives, for pre hydroxy; lower alkoxy containing up to 4 carbon atoms, serving foodstuffs or as disinfectants. for example methoxy, ethoxy, propoxy or butoxy; Compounds of the formula I, in which Ra and R1 lower alkanoyloxy having up to 4 carbon atoms, for have the meanings given above, in which functional example formyloxy, acetoxy or propionoxy, or such a groups optionally present may be protected, and in SO lower alkanoyloxy substituted by phenoxy, hydroxy, which R2 represents a radical R21 forming together halogen, amino or cyano, for example phenoxyacetoxy, with the -CO-O)- grouping a protected carboxyl hydroxyacetoxy, haloacetoxy, aminoacetoxy or group that can preferably be readily split, wherein a cyanoacetoxy; phenyl-lower alkanoyloxy, in which carboxyl group protected in this manner is different lower alkanoyloxy contains up to 4 carbon atoms, for from a carboxyl group that can be split physiologically, 55 example phenylacetoxy, or phenyl-lower alkanoyloxy are valuable intermediates that can be converted in a substituted by hydroxy or amino, in which lower alkan simple manner, for example as described below, into the oyl contains up to 4 carbon atoms, for example hydrox above-mentioned, pharmacologically active com yphenylacetoxy or aminophenylacetoxy, in which hy pounds. droxy or amino is preferably in the p-position, or a The invention relates especially to the 2-penem com hydroxyphenylacetoxy or a-aminophenylacetoxy; R1 pounds of the formula I, in which Ra represents lower especially represents hydrogen; lower alkyl having up alkyl, hydroxy-lower alkyl, especially 1-hydroxy-lower to 4 carbon atoms, for example methyl, ethyl, propyl or alkyl, lower alkoxy-lower alkyl, lower alkanoyloxy butyl; hydroxy-lower alkyl, especially co-hydroxy lower alkyl, hydroxysulphonyloxy-lower alkyl in salt lower alkyl, having up to 4 carbon atoms, for example form, especially 1-hydroxysulphonyloxy-lower alkyl, 65 hydroxymethyl, hydroxyethyl or hydroxypropyl; hydroxy, lower alkoxy, lower alkanoyloxy or lower lower alkoxy-lower alkyl, especially co-lower alkoxy alkanoyloxy substituted by phenoxy, hydroxy, halogen, lower alkyl, in which lower alkoxy and lower alkyl amino or cyano, or phenyl-lower alkanoyloxy or phe contain up to 4 carbon atoms, for example methox 4,952,690 19 20 ymethyl, methoxyethyl or methoxypropyl; lower al ible into the 2-iodoethoxy; or phenacyloxy; 1-phenyl kanoyloxy-lower alkyl, especially o-lower al lower alkoxy having 1-3 phenyl radicals optionally kanoyloxy-lower alkyl, in which lower alkanoyloxy substituted by lower alkoxy and/or nitro, for example and lower alkyl each contain up to 4 carbon atoms, for 4-methoxybenzyloxy, 4-nitrobenzyloxy, 2-nitro-4,5- example acetoxymethyl, acetoxyethyl or acetoxypro dimethoxybenzyloxy, diphenylmethoxy, 4,4'-dimethox pyl; lower alkylthio-lower alkyl, especially op-lower ydiphenylmethoxy or trityloxy; acetonyloxy; 2-cyanoe alkylthio-lower alkyl, in which lower alkyl contains up thoxy; 2-tri-lower alkylsilylethoxy, for example 2-trime to 4 carbon atoms, for example methylthiomethyl, tert thylsilylethoxy; lower alkancyloxymethoxy, for exam butylthiomethyl, methylthioethyl or methylthiopropyl; ple acetoxymethoxy or pivaloyloxymethoxy; aamino heterocyclylthio-lower alkyl, in which lower alkyl con 10 lower alkanoyloxymethoxy, for example glycyloxyme tains up to 4 carbon atoms and heterocyclyl represents thoxy, phthalidyloxy, pentachlorophenoxy; also tri a five-membered aromatic diaza-, thiaza-, tetraza-, thia lower alkylsilyloxy, for example trimethylsilyloxy; and Za-, thiadiaza-, thiatriaza-, oxaza- or oxadiaza-cyclic lower alkenyloxy, such as 2-lower alkenyloxy, for ex radical optionally substituted by lower alkyl, such as ample allyloxy. methyl, carboxy-lower alkyl, for example carboxy 15 The invention relates especially to 2-R-6-R2-2- methyl or 1- or 2-carboxyethyl, optionally N-sub penem-3-carboxylic acid compounds in which stituted amino-lower alkyl, such as di-lower Rarepresents lower alkyl having up to 4 carbon atom, alkylamino-lower alkyl, for example dimethylamino especially methyl, ethyl, propyl, isopropyl, or butyl; ethyl, sulpho-lower alkyl in salt form, for example sul 1-hydroxy-lower alkyl having up to 4 carbon atom, phomethyl or 1- or 2-sulphoethyl in the form of a so 20 dium salt, for example imidazol-2-ylthiomethyl, 1,2,3- especially hydroxymethyl, 1-hydroximethyl; 1-hydroxy triazol-4-ylthiomethyl, 1-methyl-1H-1,2,3-triazol-4- propyl or 1-hydroxyisopropyl; phenyl-lower alkyl hav ylthiomethyl, 1-tetrazol-5-ylthiomethyl, 1-methyl ing up to 10 carbon atoms, especially benzyl; phenoxy 1H-tetrazol-5-ylthiomethyl, 1-carboxymethyl-1H-tet lower alkanoyloxy having up to 10 carbon atoms, espe razol-5-ylthiomethyl, 1-(2-dimethylaminoethyl)-1H-tet 25 cially phenoxyacetoxy; or lower alkoxy having up to 4 razol-5-ylthiomethyl, 1-sodium sulphomethyl-1H-tet carbon atoms, especially methoxy; razol-5-ylthiomethyl or 2-methyl-1,3,4-thiadiazol-5- and R1 represents hydrogen; lower alkyl having up to ylthiomethyl or an ethyl radical correspondingly substi 4 carbon atoms, especially methyl: amino- lower alkyl, tuted in the 2-position; amino-lower alkyl, especially especially co-amino-lower alkyl, in which lower alkyl o-amino-lower alkyl in which lower alkyl contains up 30 contains up to 4 carbon atoms, for example amino to 4 carbon atoms, for example aminomethyl, amino methyl, aminoethyl or aminopropyl; acylamino-lower ethyl or aminopropyl; acylamino-lower alkyl, in which alkyl, in which acyl is lower alkanoyl or a substituted acyl is lower alkanoyl or a substituted oxycarbonyl oxycarbonyl group that can be used as an amino-protec group that can be used as an amino-protective group, tive group, for example acetylaminomethyl for example acetylaminomethyl, acetylaminoethyl, 35 acetylaminoethyl, acetylaminopropyl or tert-butyl-, acetylaminopropyl or tert-butyl-, 2,2,2-trichloroethyl-, 2,2,2-trichloroethyl-, diphenylmethyl- or p-nitroben diphenylmethyl- OT p-nitrobenzyloxycar zyloxycarbonylaminomethyl, -ethyl or -propyl; lower bonylaninomethyl, -ethyl or -propyl; carboxy-lower alkylthio, especially ethylthio; lower alkylthio or lower alkyl, in which lower alkyl contains up to 4 carbon alkenylthio substituted, especially in the O-position, by atoms and carboxy is especially carbonyl-lower alkyl amino, mono- or di-lower alkylamino or lower al each contain up to 4 carbon atoms, for example, me kanoylamino, for example 2-aminoethylthio, 2 thoxy-, ethoxy- or tert-butoxycarbonylmethyl or methylaminoethylthio, 2-dinathylaminoethylthio, 2 -ethyl; or phenyl-lower alkyl, in which lower alkyl acetylaminoethylthio, 3-aminopropylthio, 3 contains up to 4 carbon atoms, for example benzyl, methylamincipropylthio, 3-dimethylaminopropylthio or phenylethyl or phenylpropyl; phenyl; hydroxyphenyl; 45 3-acetylaninopropylthio, 2-acetylaninovinylthio, 1 aminophenyl; furyl, thienyl or pyridyl, such as fur-2-yl; methyl-1H-tetrazol-5-ylthio, 1-(2-dimethylaminoethyl)- thien-2-yl, pyrid-2-yl; pyrid-3-yl; pyrid-4-yl; lower al 1H-tetrazol-5-ylthio, 2-methyl-1,3,4-thiadiazol-5-ylthio kylthio, for example methyl-, ethyl- or propylthio, or 1,3,4-thiadiazol-2-ylthio; and to the esters, especially lower alkenylthio, for example vinylthio or allylthio, or the esters that can be split under neutral or basic condi lower alkylthio or lower alkenylthio substituted, espe tions, such as nitrobenzyl esters, for example 4-nitroben cially in the O-position, by amino, mono- or di-lower zyl, diphenylmethyl, pentachlorophenyl, acetonyl, 2 alkylamino or lower alkanoyl amino, for example 2 cyanoethyl or 2-trimethylsilylethyl ester, and to esters aminoethylthio, 2-methylaminoethylthio, 2-dime of such compounds that can be split under physiological thylaminoethylthio, 2-acetylaminoethylthio, 3-amino conditions, and to the salts, especially the pharmacolog propylthio, 3-methylaminopropylthio, 3-dime 55 ically acceptable salts, of such compounds having salt thylaminopropylthio or 3-acetylaminopropylthio, 2 forming groups, acetylaminoethylthio; tetrazolylthio or thiadiazolthio The invention relates especially to the compounds of optionally substituted by lower alkyl, sulfo-lower alkyl, the formula I mentioned in the Examples, to the salts carboxy-lower alkyl, or by di-lower alkylamino-lower thereof, especially the -pharmaceutically acceptable alkyl, especially 1-methyl-1H-tetrazol-5-ylthio, 1-sul salts, and to the new starting materials and intermedi phomethyl-1H-tetrazol-5-ylthio, 1-carboxymethyl-1H ates that can be used for their manufacture. tetrazol-5-ylthio, 1-(2dimethylaminoethyl)-1H-tetrazol On account of its particularly good antibacterial ac 5-ylthio; 2-methyl-1,3,4-thiadiazol-5-ylthio or 1,3,4- tivity, 6-ethyl-2-(3-aminopropyl)-2-penem 3-carboxylic thiadiazol-1-ylthio; and R2 especially represents hy acid, especially the corresponding 5R-compound, and droxy, optionally o-polybranched lower alkoxy, for the pharmacologically acceptable salts and physiologi example, methoxy or tert-butoxy; or 2-halo-lower alk cally split-table esters are to be given special attention. oxy, for example 2,2,2-trichloroethoxy, 2-iodoethoxy, The new compounds are produced by ring closing an or 2-chloroethoxy or 2-bromoethoxy readily convert ylid compound of the formula 4,952,690 21 22 group esterified twice by lower alkyl, for example Z. (II) ethyl, wherein the symbol Xeb in the case of the phos R H phono group additionally includes the cation of a strong H S-C-R1 r base, especially a suitable metal, for example a lithium sodium or potassium, ion. Preferred as group Xb is in O N one case triphenylphosphonio and in the other case Yoe-x8 diethylphosphono together with an alkali metalion, for Osc-R1 example a sodium ion. In phosphonio compounds of the formula II, which in in which 10 the isomeric ylene form are alternatively called phos Ra R1 and R21 have the meanings given, wherein the phorane compounds, the negative charge is neutralised functional groups in these radicals are preferably by the positively charged phosphonio group. In phos present in protected form, Z represents oxygen or phono compounds of the formula II, which in their sulphur, isomeric form can alternatively be called phosphonate and in which 15 XB represents either a phosphonio group substituted compounds, the negative charge is neutralised by the three times or a phosphono group esterified twice, cation of a strong base, which cation, depending on the together with a cation method of production of the phosphono starting mate and, if desired or necessary, converting the protected rial, may be, for example, an alkali metalion, for exam carboxyl group of the formula -CG=O)-R21 in a 20 ple, a sodium, lithium or potassium ion. The phospho compound of the formula I obtained into the free or into nate starting substances are therefore used as salts in the a different protected carboxyl group, and/or, if desired, reaction. in a compound of the formula I obtained, converting a Formula II shows the starting material in the form in group Rand/or R1 within the definition into a different which the ring closure takes place. Normally the corre group Ra and/or R1, and/or, if desired, converting a 25 sponding phosphoranylidene compound of the formula compound obtained having a salt-forming group into a salt, or a salt obtained into the free compound or into a different salt, and/or, if desired, separating a mixture of (IIA) isomeric compounds obtained into the individual iso H f es. 30 H S-C-R1 In the starting material of the formula II R, R1 and R2? have especially the preferred meanings, wherein N functional groups are usually present in the protected form, amino, for example, is present in the form of the nitro or azido group. 35 In a starting material of the formula II, R2 prefera in which X represents a tri-substituted, especially a bly represents an etherified hydroxy group forming triaryl-, for example triphenyl-, or a tri-lower alkyl-, for together with the -CO-O)-grouping an esterified car example tri-n-butyl-phosphoranylidene radical, or the boxyl group that can readily be split, especially under corresponding phosphono compound of the formula mild conditions, wherein functional groups that are optionally present in a carboxyl protective group R21 Z. (IIB) may be protected in a manner known per se, for exam H ple as indicated above. A group R24 is inter alia lower H. S-C-R1 alkoxy, especially a-polybranched lower alkoxy, for example methoxy or tert-butoxy; lower alkenyloxy, 45 O N especially 2-lower alkenyloxy, for example allyloxy; or 2-halo-lower alkoxy, for example 2,2,2-trichloroethoxy, 2-bromoethoxy, or 2-iodoethoxy; 2-lower alkylsulpho nyllower alkoxy, for example 2-methylsulphonyle thoxy; or an optionally substituted, such as lower alk which X2 represents a phosphono-, especially a dialkyl oxy, for example methoxy-, or nitro-containing, 1-phe phosphono-, for example a diethylphosphono group, is nyl-lower alkoxy group, such as diphenylmethoxy or used, wherein a phosphono starting material of the benzyloxy optionally substituted, for example as men formula IIB is converted into the form suitable for the tioned, for example benzyloxy, 4-methoxybenzyloxy,4- ring closure that is into the compound of the formula II, nitrobenzyloxy, diphenylmethoxy or 4,4'-dimethoxydi 55 by treating with a suitable basic reagent, such as an phenylmethoxy: pentachlorophenoxy; acetonyloxy; inorganic base, for example an alkali metal carbonate, 2-cyanoethoxy; a 2-(S1)(S2)(S3)-silylethoxy group, such such as sodium or potassium carbonate, or with an or as 2-trimethylsilylethoxy, 2-(dibutylmethylsilyl)-ethoxy ganic base, such as a tri-lower alkylamine, for example or 2-triphenylsilylethoxy; also an organic silyloxy or triethylamine, or a cyclic base of the amidine type, such stannyloxy group, such as tri-lower alkylsilyloxy, for as an appropriate diaza-bicycloalkene compound, for example trimethylsilyloxy; or one of the mentioned example 1,5-diaza-bicycloS,4,0undec-5-ene. etherified hydroxy groups that can be split physiologi Preferred starting materials are the phosphoranyli cally. dene compounds of the formula IIA. The group X69 in the starting material of the formula The ring closure can take place spontaneously, that is II is one of the phosphonio or phosphono groups cus 65 to say during the production of the starting materials, or tomary in the Wittig condensation reaction, especially a by heating, for example in a temperature range of ap triaryl-, for example triphenyl-, or trilower alkyl-, for proximately 30' C. to approximately 160 C, preferably example tributylphosphonio group, or a phosphono of approximately 50° C. and approximately 100 C. 4,952,690 23 24 The reaction is preferably carried out in the presence sulphide, into a formylmethoxycarbonyl group, from of a suitable inert solvent, such as in an aliphatic, cyclo which the carboxyl group can be released by treating aliphatic or aromatic hydrocarbon, for example hexane, with a base, such as a secondary amine, for example cyclohexane, benzene, toluene, xylene or mesitylene; a dimethylamine; or a 2-lower alkenyloxycarbonyl group, halogenated hydrocarbon, for example methylene chlo for example allyloxycarbonyl, can be isomerised, for ride; an ether, for example diethyl ether; a lower alkyl example by treating with tristriphenylohosphine rho ene glycol di-lower alkyl ether, for example dimethoxy dium chloride, palladium-on-carbon, or an alkali metal ethane or diethylene glycol dimethyl ether, or a cyclic lower alkanolate, for example potassium tert-butylate, ether, for example dioxan or tetrahydrofuran; a carbox in dimethylsulphoxide to form a 1-lower alkenylox ylic acid amide, for example dimethylformamide; a 10 ycarbonyl group and this can be split hydrolytically di-lower alkyl sulphoxide, for example dimethylsulph under weakly acidic or weakly basic conditions. A 2 oxide; or a lower alkanol, for example methanol, etha oxoethoxycarbonyl or 2-cyanoethoxycarbonyl group no or tert-butanol; or in a mixture thereof, and, if nec optionally substituted in the 2-position by lower alkyl or essary, in an inert gas atmosphere, for example an argon by aryl, for example the acetonyloxycarbonyl or 2 or nitrogen atmosphere. 15 cyanoethoxycarbonyl group, can be converted under In a compound of the formula I obtainable according mild conditions, that is at room temperature or while to the invention having a protected, especially an esteri cooling, by treatment with a suitable base, into the cor fied, carboxyl group of the formula-C(=O)-R21, the responding salt of this carboxyl group, from which the latter can be converted in a manner known per se, for free carboxyl group can be obtained by acidification. example depending on the type of protective group, 20 Suitable bases are nucleophilic-reacting metal, such as into the free carboxyl group. For example, a carboxyl alkaline earth metal, and especially alkali metal, bases, group esterified by a suitable 2-halo-lower alkyl group, such as corresponding hydroxides, carbonates, bicar an arylcarbonylmethyl group or a 4-nitrobenzyl group bonates, alkoxides, phenolates, mercaptides, thiopheno can be converted into the free carboxyl group for exam lates or amides, for example sodium hydroxide, sodium ple by treating with a chemical reducing agent, such as 25 carbonate, sodium bicarbonate, sodium ethanolate, so a metal, for example zinc, or a reducing metal salt, such dium thiophenolate, sodium amide or sodium morpho as a chronium(II) salt, for example chromium(II) chlo lide, or corresponding lithium or potassium compounds, ride, usually in the presence of a hydrogen-yielding which are used in water or in aqueous or hydroxyl agent, which together with the metal enables nascent group-containing or alternatively polar inert solvents hydrogen to be produced, such as an acid, especially 30 with subsequent treatment with water. To split the acetic or formic acid, or an alcohol, wherein water is 2-cyanoethoxycarbonyl groups, it is also possible to use preferably added; a carboxyl group esterified by an tertiary amines, such as tri-lower alkylamine, for exam arylcarbonylmethyl group can be converted into the ple triethylamine or Hinig base, or cyclic or bicyclic free carboxyl group by treating with a nucleophilic, amines or imines such as N-methylmorpholine or 1,5- preferably salt-forming reagent, such as sodium thio 35 diazabicyclo5,4,0undec-5-ene, in an inert solvent, such phenolate or sodium iodide; and also a carboxyl group as methylene chloride or tetrahydrofuran, wherein the esterified by 4-nitrobenzyl can be converted into the corresponding ammonium salts of the carboxyl com free carboxyl group by treating with an alkali metal pound are obtained directly A substituted silylethox dithionite, for example sodium dithionite. A carboxyl ycarbonyl group can be converted into the free car group esterified by a 2-lower alkylsulphonyl-lower boxyl group by treatment with a salt of hydrofluoric alkyl group can be split and released, for example by acid that yields fluoride anions, such as an alkali metal treating with a basic agent, for example one of the nu fluoride, for example sodium or potassium fluoride, in cleophilic-reacting bases mentioned further below; a the presence of a macrocyclic polyether ("crown carboxyl group esterified by a suitable arylmethyl ether'), or with a fluoride of an organic quaternary base grouping can be split and released, for example by radi 45 such as tetraalkylammonium fluoride or trialkylarylam ation, preferably with ultra-violet light, for example of monium fluoride, for example tetraethylammonium less than 290 mu when the arylmethyl group is, for fluoride or tetrabutylammonium fluoride, in the pres example, a benzyl radical optionally substituted in the ence of an aprotic polar solvent, such as dimethyl sulph 3-, 4- and/or 5-position, for example by lower alkoxy oxide or N,N-dimethylacetamide. A pentachloro and/or nitro groups, or with longer-wave ultraviolet phenoxycarbonyl group can be converted into a free light, for example of above 290 mu, when the aryl carboxyl group under mild conditions, for example by methyl group is, for example, a benzyl radical substi dilute sodium carbonate solution or sodium bicarbonate tuted in the 2-position by a nitro group; a carboxyl solution or by an organic base in the presence of water. group esterified by a suitably substituted methyl group, A carboxyl group protected, for example, by silyla such as tert-butyl or di-phenylmethyl, can be split and 55 tion or stannylation, can be released in the usual manner released, for example, by treating with a suitable acid by solvolysis, for example by treating with water or an agent, such as formic acid or trifluoroacetic acid, op alcohol. tionally with the addition of a nucleophilic compound, If there is more than one protected carbcxyl group such as phenol or anisole; and an esterified carboxyl present in a compound obtainable in accordance with group that can be split by hydrogenolysis, for example the invention these may be converted into free carboxyl benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl, can groups either jointly or selectively. be split and released by hydrogenolysis, for example by In a compound of the formula I obtainable in accor treating with hydrogen in the presence of a noblemetal, dance with the process that contains a free carboxyl for example a palladium, catalyst. In addition, a car group, such a group can be converted in a manner boxyl group esterified with a lower alkenyl group, such known per se into a protected carboxyl group. For as with 2-lower alkenyl, especially ally, can be con example, esters are obtained, for example, by treating verted oxidatively, for example by treating with ozone, with a suitable diazo compound, such as a diazo-lower followed by a reducing agent, for example dimethyl alkane, for example diazomethane or diazobutane, or a 4,952,690 25 26 phenyldiazo-lower alkane, for example diphenyl form of 1-lower alkoxycarbonyl-2-propylideneamino diazomethane, if necessary in the presence of a Lewis groups or of the o-nitrophenoxyacetylamino groups, or acid, such as, for example, boron trifluoride, or by re of acyloxy groups, such as those mentioned above, for acting with an alcohol suitable for esterification in the example the tert-butoxycarbonyloxy group, 2,2,2tri presence of an esterifying agent, such as a carbodiimide, chloroethoxycarbonyloxy group, 2-bromoethoxycar for example dicyclohexylcarbodiimide, or carbonyl bonyloxy group or p-hitrobenzyloxycarbonyloxy dinidazole, or further with an N,N'-disbustituted O- or group, or corresponding acylthio groups, or in the form S-substituted isourea or isothiourea, in which an O- and of esterified carboxy groups, such as those mentioned S-substituent is, for example, lower alkyl, especially above, for example the tert-butoxycarbonyloxy group, tert-butyl, phenyl-lower alkyl or cycloalkyl, and N- or O 2,2,2-trichloroethoxycarbonyl group, 2-bromoethox N"-substituents are, for example, lower alkyl, especially ycarbonyloxy group or p-nitrobenzyloxycarbonyloxy isopropyl, cycloalkyl or phenyl, or according to any group, or corresponding acylthio groups, or in the form other known and suitable method of esterification, such of esterified carboxy groups, such as those mentioned as reacting a salt, optionally produced in situ, of the acid above, for example the diphenylmethoxycarbonyl with a reactive ester of an alcohol and a strong inor 15 group, p-nitrobenzyloxycarbonyl group, acetonylox ganic acid or strong organic sulphonic acid. Further, ycarbonyl group or 2-cyanoethoxycarbonyl group, or acid halides, such as acid chlorides (produced, for ex of substituted sulpho groups, such as the above-men ample, by treating with oxalyl chloride), activated es tioned lower alkylsulpho groups, for example the me ters (formed, for example, with N-hydroxy nitrogen thylsulcho group, and when the reaction is complete compounds, such as N-hydroxysuccinimide) or mixed 20 may be released, where applicable after converting the anhydrides (obtained, for example, with haloformic protective group. For example, a 2,2,2-trichloroethox acid lower alkyl esters, such as chloroformic acid ethyl ycarbonylamino group or 2-iodoethoxycarbonylamino ester or chloroformic acid isobutyl ester, or with haloa group or alternatively a p-nitrobenzyloxycar cetic acid halides, such as trichloroacetic acid chloride) bonylamino group may be split by treating with suitable can be converted into an esterified carboxyl group by 25 reacting with alcohols, optionally in the presence of a reducing agents, such as zinc in the presence of aqueous base, such as pyridine. acetic acid or hydrogen in the presence of a palladium In a compound of the formula I having an esterified catalyst a diphenylmethoxycarbonylamino group or carboxyl group, this group can be converted into a tert-butylcarbonylamino group may be split by treating different esterified carboxyl group, for example 2 30 with formic acid or trifluoroacetic acid: an aryl- or chloroethoxycarbonyl or 2-bromoethoxycarbonyl can aryl-lower alkylthioamino group may be split by treat be converted into 2-iodoethopxycarbonyl by treating ing with a nucleophilic reagent such as sulphurouse with an iodine salt, such as sodium iodide, in the pres acid; an arylsulphonylamino group may be split by ence of a suitable solvent, such as acetone. means of electrolytic reduction; a 1-lower alkoxycarbo In a compound having a free carboxyl group obtain 35 nyl-2-propylideneamino group by treating with aqueous able according to the process, such a group can also be mineral acid, and a tert-butoxycarbonyloxy group by converted into an optionally substituted hydrazinocar treating with formic or trifluoroacetic acid or a 2,2,2-tri bonyl group, by reacting preferably reactive function chloroethoxycarbonyloxy group or p-nitrobenzylox ally modified derivatives, such as the above-mentioned ycarbonyloxy group may be split by treating with a activated esters, or mixed anhydrides of the correspond chemical reducing agent, such as zinc in the presence of ing acid with hydrazines. aqueous acetic acid, or with hydrogen in the presence A carboxyl group protected by an organic silyl or of a palladium catalyst; and a diphenylmethoxycarbonyl stannyl group can be formed in a manner known perse, group may be split by treating with formic or trifluoro for example by treating the compound containing car acetic acid or by hydrogenolysis: an acetonyloxy- or boxyl or a salt thereof, such as an alkali metal salt, for 45 cyanoethoxycarbonyl group may be split by treating example a sodium salt, thereof, with a suitable silylation with bases, such as sodium bicarbonate or 1,5-diazabicy or stannylation agent. cloS,4,0undec-5-ene, and a substituted sulpho group In the process according to the invention, and in by treating with an alkali metal halide; the splitting may, additional steps to be carried out where applicable or if desired, in each case be carried out in stages. where necessary, if required free functional groups that Furthermore, in a resulting compound functional do not participate in the reaction are transiently pro substituents, such as free amino, hydroxy, mercapto, tected in a manner known per se: for example, free carboxy or sul-oho groups, may be functionally modi amino groups are transiently protected, for example, by fied by processes known per se, for example by alkyla acylation, tritylation or silylation; free hydroxy and, tion, acylation or esterification or substitution. mercapto groups, for example by etherification or ester 55 Thus, an amino, hydroxy, mercapto, carboxy or sul ification, inclusive of silylation; and can, if desired, be pho group may be alkylated, for example methylated, released individually or jointly in a manner known per by treating with an alkylating reagent, such as a diazo se after the reaction. For example amino, hydroxy, compound, for example diazomethane, or with a reac mercapto, carboxyl or sulpho groups present in a start tive ester of an alcohol, for example dimethyl sulphate, ing material may be protected, for example in the form or amino, hydroxy or mercapto groups may be acyl of acylamino groups, such as those mentioned above, ated, for example, acetylated, by treating with a reac for example the 2,2,2-trichloroethoxycarbonylamino tive functional derivative of an acid, for example an group, 2-bromoethoxycarbonylamino group, 4-methox anhydride or acid chloride, such as acetic anhydride or ybenzyloxycarbonylamino group or tert-butoxycar acetyl chloride. Further, for example an amino group bonylamino group, or in the form of aryl- or aryl-lower 65 may be converted into a sulphoamino group by treating alkylthioamino groups, for example the 2-nitro-phenyl with sulphur trioxide, preferably in the form of a com thioamino group or arylsulphonylamino group, for ex plex with an organic base such as a tri-lower alkyla ample the 4-methylphenylsulphonylamino group, in the mine, for example triethylamine. 4,952,690 27 28 A hydroxy group in the substituent Ra, especially the as acid addition salts to the isoelectric point, for exam hydroxy group in a 1-hydroxy-lower alkyl radical, may ple with weak bases, or by treating with liquid ion ex be converted into a hydroxysulphonyloxy group pres ent in corresponding salt form by treating with a sul changers. Salts of 1-oxides of compounds of the formula phur trioxide complex, for example the complex with I with salt-forming groups may be produced in an anal dioxan or with a tertiary nitrogen base, such as tri-lower ogous manner. alkylamine, for example triethylamine, N,N-di-lower Salts may be converted in the usual manner into the alkylaniline, for example, N,N-dimethylaniline, or espe free compounds: metal and ammonium salts, for exam cially with pyridine, or alternatively by treating with ple, by treating with suitable acids, and acid addition the amidosulphonic acid, optionally in the presence of 10 salts, for example, by treating with a suitable basic pyridine, and the hydroxysulphonyloxy group in salt agent. form can be converted into a hydroxysulphonyloxy Mixtures of isomers obtained may be separated into group present in metal salt form by double reaction the individual isoners by methods known per se: mix with a corresponding metal hydroxide, metal carbonate, tures of diastereoisomeric isomers, for example, by frac or metal bicarbonate, such as an alkali metal, for exam 15 ple sodium, hydroxide, carbonate or bicarbonate. tional crystallisation, adsorption chromatography (col In compounds obtainable according to the invention, unn or thin-layer chromatography) or other suitable in a manner known per se, primary and secondary hy separating processes. Resulting racenic compounds can droxy groups may also be converted into aldehyde or be separated into the antipodes in the usual manner, keto groups by oxidation, for example according to optionally after introducing suitable salt-forming group Pfitzner-Moffatt, or, if necessary after acylation, may be ings, for example by forming a mixture of diastereoiso split off together with an adjacent removable hydrogen meric salts and converting the optically active salts into atom to form a C-C double bond. Aldehyde or keto the free compounds, or by fractional crystallisation groups may be converted into hydroxy groups by re from optically active solvents. duction, for example with complex metal hydrides, or 25 In all subsequent conversions of the compounds ob into acetals or ketals by treating with alcohols, into the corresponding imines, oximes or hydrazones by treating tained, the reactions that are preferred are those carried with an amine, hydroxylamine or hydrazine, or into the out under neutral, alkaline or weakly basic conditions. corresponding methylidene compounds by treating The process also includes those embodiments accord with a Wittig reagent. Resulting acetals or ketals may 30 ing to which compounds produced as intermediates are be converted into the corresponding aldehydes or ke used as starting substances and the remaining process tones, for example by treating with trimethyliodosilane. steps are carried out with these, or according to which In compounds obtained according to the invention, the process is interrupted at any stage; furthermore, furthermore, in a manner known per se, C-C double starting substances may be used in the form of deriva bonds may be reduced, for example with catalytically 35 tives or may be formed in situ, optionally under the activated hydrogen. Halogen, such as bromine or io conditions of the reaction. For example, a starting mate dine, substituents may be replaced by hydrogen by rial of the formula II in which Z is oxygen may be treating, for example, with zincMsilver in methanol or produced in situ from a compound of the formula II in methanol/acetic acid, or may be converted into 1-sub stituted 1-hydroxymethyl groups, for example the 1 which Z is an optionally substituted methylidene group, hydroxyethyl group, by treating with an organometal by ozonisation and subsequent reduction of the ozonide compound, such as methyl magnesium bromide or butyl formed, analogously to the method given in stage 2.5, lithium, followed by an aldehyde, for example acetalde whereupon, especially when R1 is hydrogen, the cycli hyde. A nitro or azido group may be converted into an sation to the compound of the formula I takes place in amino group, for example by treating with catalytically 45 the reaction solution. activated, for example by a palladium or platinum oxide The starting compounds of the formula II and the catalyst, hydrogen. The mentioned subsequent reac preliminary stages may be produced, for example, ac tions can be carried out both at the appropriate places in cording to the following reaction schemes 1, 2 and 3. the radicals Ra and in the radicals R1. Salts of compounds of the formula I may be produced in a manner known per se. For example, salts of such Reaction scheme 1 compounds with acid groups can be formed for example Z by treating with metal compounds such as alkali metal H W H R. H -C-R1 salts of suitable carboxylic acids, for example the so Stage 1.1 G dium salt of a-ethylcaproic acid, or with ammonia or a 55 O NH II O NH IV suitable organic anine, wherein preferably stoichiomet ric amounts or only a small excess of the salt-forming agent is used. Salts of carboxylic acids of the formula I r 1.2 may also be obtained by splitting under basic conditions the mentioned esters of such compounds that can be 60 split under such conditions, for example 2-cyanoethyl or acetonyl esters. Acid addition salts of compounds of the formula I with basic groupings are obtained in the usual manner, for example by treating with an acid or a suitable anion exchange reagent. Inner salts of con pounds of the formula I that contain, for example, a salt-forming amino group and a free carboxyl group may be formed, for example, by neutralising salts such 4,952,690 29 30 -continued vent. The basic conditions may be established, for exam Reaction scheme ple, by the addition of an inorganic base such as an alkali Z. -----> metal or an alkaline earth metal hydroxide, carbonate or bicarbonate, for example sodium, potassium or calcium S-C-R hydroxide, carbonate or bicarbonate. The organic sol vents that may be used are, for example, water-miscible O N alcohols, for example, lower alkanols such as methanol Yoe-xe or ethanol; ketones, for example lower alkanones such O=c-R1 as acetone; amides, for example lower alkanecarboxylic 10 acid amides such as dimethylformamide, and the like. In the compounds of the formulae IV, V, VI and II in The reaction is usually carried out at room temperature the reaction scheme I and in the compounds of the but can be carried out at elevated or reduced tempera formulae Xa, XI, XII and IVa in the reaction scheme 2, ture. The reaction can be accelerated by adding a salt of Z' is oxygen, sulphur or alternatively, especially when hydriodic acid or thiocyanic acid, for example an alkali R1 is hydrogen, a methylidene group optionally substi 15 metal salt, such as a sodium salt. tuted by ono or two substituents Y, which group can be Both optically inactive cis- or trans-compounds of the converted by oxidation into an oxo group Z. A substitu formula III and mixtures thereof, or corresponding ent Y of this methylidene group is an organic radical, optically active compounds, can be used in the reaction for example one of the organic radicals mentioned The group R1-C(=Z)-S- which is introduced is under R1, such as one of the mentioned, optionally 20 directed by the group R, especially into the trans-posi substituted, lower alkyl, cycloalkyl, cycloalkyl-lower tion, irrespective of whether W is in the cis- or trans alkyl, phenyl or phenyl-lower alkyl radicais, and espe position with respect to the Ra group. Although pre cially one of the functionally modified, such as esteri dominantly the trans-isomers are formed, occasionally fied, carboxyl groups. Esterification with an optically also cis-isomers are isolated. The separation of the cis active alcohol such as 1-menthol is included. This me 25 and trans-isomers is carried out according to conven thylidene group preferably carries one of the substitu tional methods, especially by chromatography and/or ents mentioned. The methoxycarbonylmethylidene and by crystallisation. the (1)-menthyloxycarbonylmethylidene group Z are The subsequent ozonisation of a methylidene group given special mention. The latter can be used for the Z can be carried out as described further below. A production of optically active compounds of the formu 30 resulting racemate of the formula IV can be separated iae IV to VI and II. into the optically active compounds. Stage 1.1 The compounds of the formula IV are new. A thioazetidinone of the formula IV is obtained by The optically active compounds of the formula IV a treating a 4-W-azetidinone of the formula III, in which 35 covered by the formula IV can also be produced ac W represents a nucleofuge leaving group with a mer cording to the reaction scheme 2 given below capto compound R1-C(=Z)-SH or with a salt, for Azetidinones of the formula III, in which Ra is example an alkali metal salt such as a sodium or potas methyl and W is acetyl, phenylsulphonyl or camphor sium salt thereof, and, if desired, separating an isomeric 10-sulphonyl, are known (German Offenlegungsschrift mixture obtained into the individual isomers, and/or if 40 No. 1906 401 or K. Clauss et. al., Liebigs Ann. Chen. desired converting a group Ra or R1 in a compound 974, 539-560). The remaining compounds of the for obtained into a different group Ra or LR respectively, mula III are new. They can be produced according to and/or, if desired, converting an optionally substituted methods that are known per se. methylidene group Z' into an oxo group Z. The azetidinones of the formula III are produced, for The nucleofuge leaving group W in a starting mate 45 example, by the addition of chlorosulphonyl isocyanate rial of the formula III is a radical that can be replaced by to correspondingly substituted vinyl esters and subse the nucleophilic radical R1-C(=Z)-S-. Such quently splitting off the chlorosulphonyl group. In this groups Ware, for example, acyloxy radicals, sulphonyl synthesis, usually mixtures of cis- and trans-isomers are radicals R-SO2-, in which R is an organic radical, obtained, which if desired can be separated into the pure azido or halogen. In an acyloxy radical W, acyl is the 50 cis- or trans-isomers, for example by chromatography radical or an organic carboxylic acid, including an opti and/or crystallisation or distillation. The pure cis- and cally active carboxylic acid, and has, for example, the trans-isomers are present in the form of racemic com same meaning as the acyl radicai R1-CO-, in which pounds and can be separated into their optical antipo R1 is hydrogen or one of the mentioned organic radicals des, for example when the acyl in the acyloxy radical W bonded by a carbon atom, for example, one of the men 55 in compounds of the formula III stems from an optically tioned, optionally substituted lower alkyl, cycloalkyl, active acid The optically active compounds of the for cycloalkyl-lower alkyl, phenyl or phenyl-lower alkyl mula IIIa covered by the formula III can be produced radicals. In a sulphonyl radical R-SO2-, R is, for according to reaction scheme 3 given below. example, an optionally substituted aliphatic, araliphatic or aromatic hydrocarbon radical having up to 12 car Stage 1.2 bonatoms, and is especially lower alkyl, such as methyl, An a-hydroxycarboxylic acid compound of the for ethyl or a methyl substituted by an optically active mula V is obtained by reacting a compound of the for radical, such as camphoryl, or benzyl, phenyl or toluyl. mula IV with a glyoxylic acid compound of the formula A halogen radical W is bromine, iodine or especially OHC-C(EC)-R21 or a suitable derivative such as a chlorine. W is preferably acetoxy or chlorine. 65 hydrate, hemihydrate or semiacetal, for example a The nucleophilic substitution may be carried out semiacetal with a lower alkanol, for example, methanol under neutral or weakly basic conditions in the presence or ethanol, and, if desired, separating a so obtained of water and optionally a water-miscible organic sol isomeric mixture into the individual isomers, and/or, if 4,952,690 31. 32 desired, converting a group Ra or R1 in a compound the reaction is carried out in the presence of a suitable obtained into a different group Ra or R1 respectively, solvent, for example dioxane or tetrahydrofuran, or of a and/or, if desired, converting an optionally substituted solvent mixture, if necessary while cooling and/or in an methylidene group Z' into an oxo group Z. inert gas atmosphere, such as a nitrogen atmosphere. The compound V is usually obtained as a mixture of 5 In a compound of the formula VI obtainable in this the two isomers (with reference to the grouping manner, a reactive esterified hydroxy group X can be converted into a different reactive esterified hydroxy na group in a manner known per se. For example, a chlo CHV- OH). rine atom can be exchanged for a bromine or iodine O aton by treating the corresponding chlorine compound It is possible, however, also to isolate the pure isomers with a suitable bromine or iodine reagent, especially therefron. with an inorganic bromide or iodide salt such as lithium The addition reaction of the glyoxylic acid ester com bromide, preferably in the presence of a suitable sol pound to the nitrogen atom of the lactam ring takes vent such as ether. place at room temperature or, if necessary, while heat 15 Both pure optically inactive cis- or trans-compounds ing, for example up to approximately 100 C., and in the of the formula V and mixtures thereof, or correspond absence of an actual condensation agent and/or without ing optically active compounds, can be used in the reac the formation of a salt. When using the hydrate of the tion. A racemic compound of the formula VI obtained glyoxylic acid compound, water is formed which, if can be separated into the optically active compounds. necessary, is removed by distillation, for example azeo 20 tropically, or by using a suitable dehydration means Stage 1.4 such as a molecular sieve. Preferably the process is A starting material of the formula II is obtained by carried out in the presence of a suitable solvent, such as, treating a compound of the formula VI in which So for example, dioxan, toluene or dimethylformamide, or 25 represents a reactive esterified hydroxy group, with a of a solvent mixture, if desired or necessary in an inert suitable phosphine compound such as a tri-lower alkyl gas atmosphere, such as a nitrogen atmosphere. phosphine, for example tri-n-butylphosphine, or a tria Both pure optically inactive cis- or trans-compounds ryl-phosphine, for example triphenylphosphine, or with of the formula TV and mixtures thereof, or correspond a suitable phosphite compound such as a tri-lower alkyl ing optically active compounds, can be used in the reac 30 phosphite, for example triethyl phosphite, or an alkali tion. A racenic compound of the formula V obtained metal dimethyl phosphite, wherein depending on the can be separated into the optically active compounds. choice of reagent a compound of the formula IIA or IIB Stage 1.3 can be obtained, and if desired converting a group Raor Compounds of the formula VI, in which X repre R1 in a compound obtained into a different group R or sents a reactive esterified hydroxy group, especially 35 R1 respectively, and/or if desired converting an option halogen or organic sulphonyloxy, are produced by con ally substituted methylidene group Z' into an oxo group verting the secondary hydroxy group in a compound of Z. the formula Vinto a reactive esterified hydroxy group, The above reaction is preferably carried out in the especially into halogen, for example chlorine or bro presence of a suitable inert solvent such as a hydrocar mine, or into an organic sulphonyloxy group such as bon, for example hexane, cyclohexane, benzene, toluene lower alkylsulphonyloxy, for example methylsul or xylene; or an ether, for example dioxan, tetrahydro phonyloxy, or arylsulphonyloxy, for example 4-methyl furan or diethylene glycol dimethyl ether, or of a sol phenylsulohonyloxy, if desired separating an isomeric vent mixture. Depending on the reactivity, the opera mixture obtained into the individual isomers, and, if tion is carried out while cooling or at elevated tempera desired, converting a group Ra or R1 in a compound ture, approximately between -10' + 100', preferably at obtained into a different group R or R1 respectively, approximately 20 to 80, and/or in an inert gas atmo and/or, if desired, converting an optionally substituted sphere, such as a nitrogen atmosphere. In order to pre methylidene group Z' into an oxo group Z. vent oxidative processes, catalytic announts of an antiox The compound VI may be obtained in the form of idant, for example hydroquinone, may be added. mixtures of the isomers (with reference to the grouping SO When using a phosphine compound the reaction is usually carried out in the presence of a basic agent, such as an organic base, for example an amine, such as trieth na ylamine, diisopropylethylamine or "polystyrene-Hinig cCH-X.) 55 base', and thus the phosphoranylidene starting material of the formula IIA, which is formed from the corre or in the form of pure isomers. sponding phosphonium salt, is obtained directly. The above reaction is carried out by treating with a Both pure optically inactive cis- or trans-compounds suitable esterifying agent, using, for example, a haloge of the formula VI and mixtures thereof, be used in the nating agent such as a thionyl halide, for example the reaction. A racenic compound of the formula II ob chloride, a phosphorus oxyhalide, especially the chlo tained can be separated into the optically active com ride, or a halophosphonium halide such as triphenyl pounds. phosphine dibromide or diiodide, and a suitable organic In the compounds of the formulae II to VIR prefera sulphonic acid halide such basic, especially an organic bly represents one of the mentioned organic radicals basic, agent such as an aliphatic tertiary amine, for ex 65 bonded by a carbon atom to the ring carbon atom, or ample triethylamine, diisopropylethylamine or "polys alternatively an etherified hydroxy group, in which tyrene-Hinig base', or a heterocyclic base of the pyri functional groups optionally present in such a radical dine type, for example pyridine or collidine. Preferably Ra are preferably in protected form. 4,952,690 33 34 The separation of the above-mentioned cis- trans Racenic compounds containing hydroxy groups may compounds into the pure cis- and trans-isoners is ef fected according to customary separation methods, for be converted into a mixture of diastereoisomeric ure example by chromatography and/or by distillation or thanes, for example by reacting with optically active crystallisation. isocyanates, such as with (--)- or (-)-1-phenylethyl The above-mentioned racemic compounds are split isocyanate. into their optical antipodes by methods known per se. Basic racemic compounds can form diastereoisomeric One of these methods consists in reacting a racemic salts with the optically active acids. Racemic com compound with an optically active auxiliary, separating pounds containing double bonds may be converted, for the resulting mixture of two diastereoisomeric com O example by platinum chloride and (+)-1-phenyl-2- pounds by means of suitable physical/chemical methods and then splitting the individual diastereoisoneric com aminopropane, into mixtures of diastereoisomeric com pounds into the optically active compounds. plex salts. Particularly suitable racemic compounds for separat Physical/chemical methods, especially fractional ing into antipodes are those that possess an acidic group, 15 crystallisation, are suitable for separating the diastereo for example racemic compounds of the compounds of isomeric mixtures. It is also possible, however, to use the formula I. Others of the described racemic con chromatographic methods, above all solid-liquid chro pounds can be converted into acidic racemic com matography. Readily volatile diastereoisoneric mix pounds by simple reactions. For example, racemic com pounds carrying aldehyde or keto groups react with a 20 tures may also by separated by distillation or gas chro hydrazine derivative carrying acid groups, for example matography. 4-(4-carboxyphenyl)-semicarbazide to form the corre Splitting the separated diastereoisomers into the opti sponding hydrazone derivatives, or compounds con cally active starting materials is likewise carried out taining alcohol groups react with a dicarboxylic acid according to customary methods. The acids or the bases anhydride, for example phthalic acid anhydride, to form 25 are freed from the salts, for example by treating with the racenic compound of an acidic semiester. stronger acids or bases respectively than those origi These acidic racemic compounds may be reacted nally used. The desired optically active compounds are with optically active bases, for example esters of opti cally active amino acids, or (-)-brucine, (--)-quinidine, obtained from the esters and urethanes, for example by (-)-quinine, (+)-cinchonine, (--)-dehydroabietyla 30 alkaline hydrolysis or by reduction with a complex mine, (+)- and (-)-ephedrine, (--)- and (-)-1-phenyle hydride such as lithium aluminium hydride. thylamine or their N-mono- or N,N-dialkylated deriva A further method of separating the racemic com tives, to form mixtures consisting of two diastereoiso pounds consists in the chromatography on optically meric salts. 35 active absorption layers, for example on cane sugar. In racemic compounds containing carboxyl groups, According to a third method, the racemic com for example in racemic compounds that contain a func tionally modified carboxymethylidene group Z, this pounds can be dissolved in optically active solvents and carboxyl group may already be esterified by, or esterifi the more sparingly soluble optical antipode is crystal cation may be carried out by, an optically active alcohol lised out. such as (-)-menthol, (+)-borneol, (+)- or (-)-2- In a fourth method the different reactivity of the octanol, whereupon after subsequent isolation of the optical antipodes in comparison with the biological desired diastereoisoner, the carboxyl group is released, material, such as microorganisms or isolated enzymes, is or the part of the molecule containing the esterified used. carboxyl group, for example the esterified carboxyme 45 thylidene radical, is split off. According to a fifth method, the racemic compounds Racemic compounds containing hydroxy groups may are dissolved and one of the optical antipodes is crystal likewise be split into their optical antipodes, for which lised out by injecting a small amount of an optically especially optically active acids or their reactive func active product obtained according to the above meth tional derivatives that form diastereoisomeric esters 50 ods. with the said alcohols are used. Such acids are, for Optically active trans-compounds of the formula IVa example (-)-abietic acid, D(+)- and L(-)-malic acid, N-acylated optically active amino acids, (+)- and (-)- that can be used according to the invention may also be camphanic acid, (+)- and (-)-ketopinic acid, L(--)- produced in accordance with the following reaction ascorbic acid, (-)-camphoric acid, (--)-camphor-10 55 scheme: sulphonic acid.(3), (--)- or (-)-a-bromocamphor-T-sul phonic acid, D(-)-quinic acid, D(-)-isoascorbic acid, Reaction scheme 2 D(-)- and L(--)-mandelic acid, (--)-1-menthoxyacetic acid, D(-)- and L(--)-tartaric acid and their di-O-benz oyl- and di-O-p-toluy derivatives. The acyl radicals of 60 the optically active acids mentioned may be present, for Ra s S example, as acyl in compounds of the formula III or as H Stage 2.1 G H R1-C(=O)- in compounds of the formulae II and IV O N O N to VI, and render possible the splitting of the racemates of such compounds. If desired or necessary, when the 65 splitting of the racemic compound is complete the opti cally active group R1-C(=O)- can be converted into (VII) Stage 2.2 . a desired optically inactive group R1-C(=O)-. 4,952,690 35 36 -continued VII, in which R is hydroxy, have also been described Reaction scheme 2 by J. C. Sheehan et al., J. Org. Chem. 39, 1444 (1974) H (manufacture from the corresponding 6-diazopenicil Es-s-re s-s-R lanic acid compounds). Further starting materials of the H e23 formula VII, in which Ra is optionally protected 1 T NN-CH3 O N CH2 hydroxyethyl, bromine or iodine, are described by =C- H-CC DiNinno et al. (J. Org. Chem. 42 (1967), 2960). In a CH3 CH3 resulting compound of the formula VIII, an Ra group O=c-R1 O=C-R1 can be converted into a different Ra group. (X) r 2.4 (IX) r 2.4a. O Stage 2.2 A 3-methylenebutyric acid compound of the formula R. H. f R. H. f IX is obtained by treating a 1-oxide of a penicillanic acid Hanss' s S-C-R1 sis H e S-C-R1 compound of the formula VIII with a mercapto com C 49 15 pound R-SH, and if desired, converting a group Rain O N - CH3 O N eCH2 a resulting compound into a different group Ra. =C- H-CC In the mercapto compound R-SH and in the reac CH3 CH3 tion product of the formula IX, R is an optionally sub o=c-R1 O=C-R1 stituted aromatic heterocyclic radical having up to 15, 20 preferably up to 9, carbon atoms, and at least one ring (XI) r 2.5 (Xa) nitrogen atom, and optionally a further ring hetero atom, such as oxygen or sulphur, which radical is bonded to the thio group -S- by one of its ring car Ra e S-C-R1f R HES-C-R1 f bon atoms that is bonded to a ring nitrogen atom by a H Bism 25 double bond. Radicals of this type are monocyclic or O N Stage 2.6 O NH bicyclic and may be substituted, for example by lower seCD alkyl, such as methyl or ethyl, lower alkoxy, such as (XII) O=C-R4 (IVa) methoxy or ethoxy, halogen, such as fluorine or chlo rine or aryl, such as phenyl. Radicals Rof this type are, for example, monocyclic Stage 2.1 five-membered thiadiazacyclic, thiatriazacyclic, ox An oxide of a penicillanic acid compound of the for adiazacyclic or oxatriazacyclic radicals of aromatic mula VIII is obtained by oxidizing a penicillanic acid character, especially monocyclic five-membered diaza compound of the formula VII in the 1-position and if 3 cyclic, oxazacyclic and thiazacyclic radicals of aro desired converting an R group in a resulting compound matic character, and/or especially the corresponding into a different Ragroup. The oxidation is carried out in benzdiazacyclic, benzoxazacyclic or benzthiazacyclic a manner known per se with suitable oxidising agents, radicals, in which the heterocyclic part is five-mem such as hydrogen peroxide or inorganic or organic bered and has an aromatic character, wherein in R peracids. Suitable inorganic peracids are, for example, radicals a substitutable ring nitrogen atom may be sub periodic or persulphuric acid. Suitable organic peracids stituted, for example, by lower alkyl. Representative of are, for example, percarboxylic acids, such as performic such R9 groups are 1-methylimidazol-2-yl, 1,3-thiazol acid, peracetic acid, trifluoroperacetic acid, permaleic 2-yl, 1,3,4-thiadiazol-2-yl, 1,3,4,5-thiatriazol-2-yl, 1,3- acid, perbenzoic acid, 3-chloroperbenzoic acid or oxazol-2-yl, 1,3,4-oxadiazol-2-yl, 1,3,4,5-oxatriazol-2-yl, monoperphthalic acid, or persulphonic acids, for exam 2-quinolyl, 1-methylbenzimidazol-2-yl, benzoxazol-2-yl ple p-toluenepersulphonic acid. The peracids may also and especially benzthiazol-2-yl. be produced in situ from hydrogen peroxide and the corresponding acids. The oxidation is carried out under The reaction is carried out in an inert solvent, such as mild conditions, for example attemperatures of approxi an aliphatic or aromatic hydrocarbon, for example ben mately -50' to approximately --100', preferably at zene or toluene, while warming up to the reflux temper approximately - 10 to approximately --40', in an inert ature of the solvent used. solvent. Stage 2.3 Racemic 1-oxides of the formula VIII, in which Ris phenoxy or methoxy, and R21 is methoxy, are known A 3-methylcrotonic acid compound of the formula X A. K. Bose et al., Tetrahedron 28, 5977 (1972). The is obtained by isomerising a 3-methylenebutyric acid optically active compounds of the formula VIII are new 55 compound of the formula IX by treating with a suitable and are also part of the present invention. basic agent and, if desired, converting a group Rain a Starting compounds of the formula VII are known or resulting compound into a different group Ra. can be produced according to known processes. For Suitable basic agents are, for example, organic nitro example, they may be obtained according to D. Hauser gen bases such as tertiary amines, for example tri-lower and H. P. Sigg, Helv. Chinica Acta 50, 1327 (1967), by alkylamines such as triethylamine or Hinig base, or reacting a 6-diazopenicillanic acid ester, which is op inorganic bases, which are used in an inert solvent, such tionally produced in situ from a 6-amino-penicillanic as an optionally halogenated hydrocarbon, for example acid ester and nitrous acid, with water or an alcohol or methylene chloride, at room temperature or optionally an acid of the formula H-Ra. Compounds of the formula slightly reduced or elevated temperature. VII, in which Ra is an acyloxy group, may likewise be 65 obtained according to D. Hauser, by pyrolysing a corre Stage 2.4 sponding 6a- or 66-N-nitrosoacylaminopenicillanic A thio compound of the formula XI is obtained by acid ester in an inert solvent. Compounds of the formula treating a compound of the formula X with a suitable 4,952,690 37 38 reducing agent and simultaneously or subsequently or R1 in a compound obtained into a different group Ra reacting with an acylation derivative of an acid of the or R1 respectively, and/or, if desired, converting an formula R1-C(=Z)-OH, or, when Z represents a optionally substituted methylidene group Z' into an oxo methylidene group optionally substituted by Y, reacting group Z. with an alkyne of the formula R1-CC-Y, and, if desired, converting a group Ra or R1 in a compound so Stage 2.5 obtained into a different group Ra or R1 respectively, A 2-oxoacetic acid compound of the formula XII is and/or, if desired, converting an optionally substituted obtained by ozonising a compound of the formula XI methylidene group Z' into an oxo group Z. and splitting the ozonide formed to the oxo compound Suitable reducing agents are, for example, hydride O by means of reduction, and if desired converting a reducing agents such as alkali metal borohydrides, for group Ra or R1 in a compound obtained into a different example sodium borohydride, or also zinc in the pres group Ra or R respectively, and/or, if desired, convert ence of a carboxylic acid, for example a carboxylic acid ing an optionally substituted methylidene group Z' into of the formula R1-C(=O)-OH. The hydride reduc an oxo group Z. ing agents are usually used in the presence of suitable 15 The ozonisation is usually carried out with an solvents, such as dimethylformamide. The hydride re ozone/oxygen mixture in an inert solvent, such as a duction is preferably carried out in dimethylformamide lower alkanol, for example methanol or ethanol, a lower with sodium borohydride at temperatures of approxi alkanone, for example acetone, an optionally haloge mately -50" to approximately -10', preferably at ap nated aliphatic, cycloaliphatic or aromatic hydrocar proximately -20, whereupon at the same temperature 20 bon, for example a halogen-lower alkane, such as meth the acylating agent and optionally a tertiary base, such ylene chloride or carbon tetrachloride, or in a solvent as pyridine, are added. The reduction with zinc and a mixture, including an aqueous mixture, preferably while carboxylic acid is optionally carried out in a solvent, for cooling, for example at temperatures of approximately which the carboxylic acid, if liquid, can itself be used, at -90 to approximately 0'. temperatures of approximately - 10 to approximately 25 An ozonide obtained as intermediate is, usually with --50", preferably at approximately 0' to room tempera out being isolated, split reductively to form a compound ture. The acylating agent can be added to the reduction of the formula XII, wherein catalytically activated hy mixture from the beginning or when reduction is com drogen, for example hydrogen in the presence of a plete and optionally after evaporating off the carboxylic heavy metal hydrogenating catalyst, such as a nickel acid used and/or the solvent. Suitable acylating agents 30 catalyst or palladium catalyst, preferably on a suitable are especially anhydrides of the carboxylic acids men carrier material, such as calcium carbonate or carbon, is tioned, such as symmetric anhydrides, for example used; or chemical reducing agents, such as reducing acetic anhydride, or mixed anhydrides, preferably those heavy metals, including heavy metal alloys or amal with hydrohalic acids, that is the corresponding carbox gams, for example zinc, in the presence of a hydrogen ylic acid halides, for example the chlorides and bro 35 donor such as an acid, for example acetic acid, or of an mides, such as acetyl bromide. For example a com alcohol, for example a lower alkanol, are used; or reduc pound of the formula X may be converted with zinc in ing inorganic salts, such as alkali metal iodides, for ex a mixture of acetic acid and acetic anhydride at 0 to ample sodium iodide, or alkali metal bisulphites, for approximately 20' into a compound of the formula XI, example, sodium bisulphite, in the presence of a hydro in which R1 is methyl. Owing to the reduced risk of 40 gen donor, such as an acid, for example acetic acid, or racemisation, the zinc/carboxylic acid reduction is pre water, are used; or reducing organic compounds such as ferred. The alkyne can also be added to the reduction formic acid are used. It is also possible to use as reduc mixture from the beginning or when reduction is con ing agents compounds that may readily be converted plete. The addition of the 4-mercaptoazetidin-2-one, into corresponding epoxy compounds or oxides, produced as an intermediate in the reduction, to the 45 wherein the epoxide formation can take place on ac triple bond of the alkyne takes place spontaneously at count of a CC-double bond and the oxide formation on the reduction temperature. account of an oxide-forming hetero atom, such as a sulphur, phosphorus or nitrogen atom. Compounds of Stage 2.3a this type are, for example, suitably substituted ethylene A thio compound of the formula XI is also obtained 50 compounds (which are converted into ethylene oxide by isomerising a compound of the formula Xa in accor compounds in the reaction), such as tetracyanoethylene, dance with the reaction conditions of stage 2.3 by treat in particular suitable sulphide compounds (which in the ing with a suitable basic agent, if desired converting a reaction are converted into sulphoxide compounds), group Ra or R1 in a compound obtained into different such as di-lower alkyl sulphides, especially dimethyl group Ra or R1 respectively, and/or, if desired, convert 55 sulphide, suitable organic phosphorus compounds, such ing an optionally substituted methylidene group Z' into as a phosphine, which contains optionally substituted an oxo group Z. aliphatic or aromatic hydrocarbon radicals as substitu ents (and which in the reaction is converted into a phos Stage 2.4a phine oxide), such as tri-lower alkylphosphines, for A compound of the formula Xa is obtained by treat example tri-n-butylphosphine, or triarylphosphines, for ing a 3-methylenebutyric acid compound of the formula example triphenylphosphine, or phosphites, which con IX in accordance with the reaction conditions of stage tain optionally substituted aliphatic hydrocarbon radi 2.4 with a suitable reducing agent, and simultaneously cals as substituents (and in the reaction are converted or subsequently reacting with an acylating derivative of into phosphoric acid triesters), such as tri-lower alkyl a carboxylic acid of the formula R1-C(=Z)-OH, or, 65 phosphites, usually in the form of corresponding alco when Z represents a methylidene group optionally hol adduct compounds, such as trimethyl phosphite, or substituted by Y, with an alkyne of the formula phosphorous acid triamides, which contain optionally R1-CC-Y, and, if desired, converting a group Ra substituted aliphatic hydrocarbon radicals as substitu 4,952,690 39 40 ents, such as hexa-lower alkyl phosphorous acid tria -continued mides, for example hexamethylphosphorous acid triam Reaction scheme 3 ide, the latter preferably in the form of a methanol ad duct, or suitable nitrogen bases (which in the reaction H- w; H w are converted into the corresponding N-oxides), such as Stage 3.4 heterocyclic nitrogen bases of aromatic nature, for ex O N CStage 3. O NN CH3 ample bases of the pyridine types and especially pyri EO =C- dine itself. The splitting of the usually unisolated ozo (xv) o=c-R? (XIV) o-l-r" nide is normally carried out under the conditions used 10 Stage 3.5 for its manufacture, that is to say, in the presence of a Stage 3.3 suitable solvent or solvent mixture, and while cooling or heating gently, wherein preferably temperatures of Ra W Ra H S approximately - 10" C. to approximately --25' C. are used and the reaction usually terminates at room tem- 15 L. - perature. O NH O N X (IIIa)Ia (VII) O-C-RA Stage 2.6 W = Acyloxy or Halogen A compound of the formula IVa is obtained by solvo lysing a compound of the formula XII and, if desired, 20 converting a group Ra or R1 in a compound so obtained Stage 3.1 into a different group Ra or R1, and/or, if desired, con A 3-methylenebutyric acid compound of the formula verting an optionally substituted methylidene group Z' XIII is obtained by treating a 1-oxide of a penicillanic into an oxo group Z. acid compound of the formula VIII in the presence of a The solvolysis may be carried out by hydrolysis alco- 25 tri-lower alkyl phosphite with an organic carboxylic holysis or hydrazinolysis. The hydrolysis is carried out acid acyl-OH, if desired converting a group R in a with water, optionally in a water-miscible solvent. The resulting compound into a different group Ra and/or alcoholysis is usually carried out with a lower alkanol, isolating the cis- and/or the trans-compound from a for example methanol or ethanol, preferably in the pres resulting cis-trans compound. ence of water and an organic solvent, such as a lower 30 A suitable tri-lower alkyl phosphite is, for example, alkanecarboxylic acid lower alkyl ester, for example trimethylphosphite. A suitable organic carboxylic acid ethyl acetate, preferably at room temperature, if neces acyl-OH is, for example, a carboxylic acid R1-COOH, sary while cooling or heating. The hydrazinolysis is in which R1 represents hydrogen or one of the men carried out in a conventional manner with a substituted 35 tioned organic radicals bonded by a carbon atom, for hydrazine, for example with phenylhydrazine or a ni example one of the mentioned lower alkyl, cycloalkyl, trophenylhydrazine, such as 2-nitrophenylhydrazine, cycloalkyl-lower alkyl, phenyl or phenyl-lower alkyl 4-nitro-phenylhydrazine or 2,4-dinitrophenylhydrazine, radicals. Preferred are lower alkanecarboxylic acids, which is preferably used in an approximately equimolar including formic acid, especially acetic acid. amount, in an organic solvent, such as an ether, for 40 The reaction is effected, analogously to A. Suaratoet. example tetrahydrofuran, dioxan, diethyl ether, an aro al., Tetrahedron Letters, 42,4059-4062, 1978, in an inert matic hydrocarbon, such as benzene or toluene, a halo organic solvent, for example a hydrocarbon, such as genated hydrocarbon, such as methylene chloride, chlo benzene, toluene or xylene, or an ether-type solvent, robenzene or dichlorobenzene, an ester, such as ethyl such as dioxan or tetrahydrofuran, or a solvent mixture, acetate, or the like, at temperatures between approxi- 45 at elevated temperature, approximately up to the reflux mately room temperature and approximately 65' C. The temperature of the solvent used, at approximately 50' to a-keto. compound of the formula XII does not necessar 150 C., preferably at approximately 80" to approxi ily have to be isolated. If, for example, the ozonide is mately 100' C. split in the presence of a solvolysing agent, such as, for In the reaction a mixture of the cis- and trans-com example, water, a compound of the formula IVa can be 50 pounds is obtained. By means of customary separating obtained directly. methods, such as crystallisation or chromatography, the Optically active cis-, trans- and cis-trans compounds cis- and/or trans- compound can be obtained in pure of the formula IIIa may also be obtained in accordance form. with the following reaction scheme: 55 Stage 3.2 A 3-methylcrotonic acid compound of the formula Reaction scheme 3 XIV, in which W' represents acyloxy, is obtained by isomerising a 3-methylenebutyric acid compound of the R formula XIII by treating with a suitable basic agent, and Ea g S O-Acyl 60 if desired converting a group Ra in a resulting com H Stage 3.1 G H pound into a different group Ra, and/or, if desired iso N Oda N CH2 lating the cis- and/or trans-compound from a resulting cis-trans compound. (VIII) o=c-R4 (XIII) o--Rth-ce 6s The basic isomerisation is carried out as described in stage 2.3. The subsequent separation into pure com pounds, to be carried out if desired, is effected as de scribed in stage 3.1. 4,952,690 41 42 separation into pure compounds carried out subse Stage 3.3 quently if desired, is effected as described in stage 3.1. A compound of the formula XIV, in which W' repre sents halogen, is obtained by treating a penicillanic acid Stage 3.5 compound of the formula VII with a halogenating A compound of the formula IIIa, in which W has the agent yielding positive halogen ions and, if necessary, meaning given under formula III, is obtained by solvo treating a possibly resulting intermediate with a base, lysing a compound of the formula XV, in which W and if desired converting a group Rain a resulting con represents acyloxy or halogen, and if desired converting pound of the formula XIV into a different group Ra, a group Ra in a resulting compound into a different and/or isolating the cis- and/or the trans-compound O group Ra, and/or, if desired, converting a group Winto from a resulting cis-trans compound. a different group W or W, and/or if desired isomerising Halogenating agents that yield positive halogen ions a resulting cis-compound to form the corresponding are for example elemental halogens, such as chlorine, trans-compound, and/or isolating the cis- and/or trans bromine or iodine; mixed halogens, such as BrC1, Clor compound from a resulting cis-trans compound. 15 The solvolysis is carried out as described in stage 2.6. Br; sulphuryl halides, such as sulphuryl chloride or When W is hadogen, hydrazinolysis is preferably used. sulphuryl bromide; N-haloamides or N-haloimides, In this case too it is not necessary to isolate the interme such as N-chloroacetamide, N-bromoacetamide, N diate of the formula XV after the ozonisation and reduc chlorosuccinimide, N-bromosuccinimide or N,N'- tion reaction, but it can be produced in situ and solvo dibromohydantoine; or organic hypohalites, especially lysed directly. lower alkanoyl hypohalites, such as acetyl hypochlo In a resulting compound of the formula IIIain which rite, propionyl hypochlorite, butyryl hypochlorite, ace W represents acyloxy or halogen, this group can be tyl hypobromite, propionyl hypcbromite, butyryl hypo converted into a different group W by nucleophilic bromite and the like. exchange, wherein the group W being introduced must The reaction is carried out analogously to U.S. Pat. 25 be more nucleophilic than that leaving. This exchange No. 3,920,696 or St. Kukolja, Journ. Am. Chem. Soc. may be carried out analogously to stage 1.1, for exam 93, 6267 (1971), in an inert aprotic solvent, especially in ple, by treating with an alkali metal salt, such as a so a halogenated hydrocarbon, such as methylene chloride dium or potassium salt of an acid H.-W. or carbon tetrachloride, at temperatures between ap In this exchange of W for a different W, and in the proximately -80' and approximately --80' C., prefera subsequent exchange for a group R1-C(=Z)-S- bly at approximately -76. C. to approximately room according to stage 1.1, the optically active trans-com temperature. pounds of the formula IIIa and IVa respectively are The molar ratio of halogenating agent to compound obtained in excess, irrespective of whether a cis- or of the formula VII is between 1:1 and 3:1 or even trans-compound was used as starting material. higher. If the molar ratio is approximately 1:1, a con 35 By isomerisation, for example by treating with a mild pound of the formula Lewis acid in catalytic amounts, a resulting cis-com pound can be converted into a trans-compound. The isomerisation with a Lewis acid is carried out in an inert Hal (XIV) solvent at elevated temperature, approximately at 50 to H r 150' C., for example under reflux in benzene. In the compounds II, IV to XV, IIIa and IVa, a group YCH-C3s Hil Ra, R1 or R21 can be converted according to methods oc-R4 CH3 known per se into a different Ra R1 or R24 group re is obtained as intermediate, which can be converted into spectively, wherein, taking into consideration the vari 45 ous functional groups, it is possible to use the same a compound of the formula XIV by treating with a base, methods as are given for converting these substituents such as a tertiary amine, for example triethylamine. By in the compounds of the formula I. using at least 2 moles of halogenating agent or more per In the compounds IV (including IVa) to VI and II, an mole of penicillanic acid compound, the desired com optionally substituted methylidene group Z may be pound of the formula XIV is obtained even without 50 converted into an oxo group Z by ozonisation and sub subsequent treatment with a base. sequent reduction of the ozonide formed, according to In the ring opening reaction a mixture of the cis- and the process described in stage 2.5. trans-compound is obtained, the trans-compound pref The invention likewise includes the new intermedi erably being formed. By customary separating methods, ates, such as those of the formulae IIIa and IV (includ such as crystallisation or chromatography, the cis-and 55 ing IVa) to XV and especially of the formula II, and the /or the trans-compounds can be obtained in pure form. processes for their production. The pharmacologically acceptable compounds of the Stage 3.4 invention may be used, for example, for the production A 2-oxoacetic acid compound of the formula XV, in of pharmaceutical preparations that contain an effective which W' represents acyloxy or halogen, is obtained by amount of the active substance together or in admixture ozonising a compound of the formula XIV and splitting with inorganic or organic, solid or liquid, pharmaceuti the ozonide formed by reduction to form the oxo group, cally acceptable carriers that are suitable for enteral or and, if desired, converting a group Ra in a resulting parenteral administration. For example, tablets or gela compound into a different group Ra, and/or, if desired, tin capsules that contain the active substance together isolating the cis- and/or trans- compound from a result 65 with diluents, for example lactose, dextrose, sucrose, ing cis-trans compound. mannitol, sorbitol, cellulose and/or glycine, and lubri The ozonisation and the reduction of the ozonide cants, for example silica, talcum, stearic acid or salts formed are carried out as described in stage 2.5. The thereof, such as magnesium or calcium stearate, and/or 4,952,690 43 44 polyethylene glycol; tablets also contain binders, for 4.93, 1H, d (J-2.5 Hz); 3.0-3.4, 1H, m; 2.4, 3H, s; 1.42, example magnesium aluminium silicate, starches such as 3H, d. maize, wheat, rice or arrowroot starch, gelatin, traga canth, methylcellulose, sodium carboxymethylcellulose EXAMPLE 2 and/or polyvinylpyrrollidone, and, if desired, disinte 2-(4-acetylthio-3-methyl-2-oxoazetidin-1-yl)-2-hydrox grating agents, for example starches, agar, alginic acid or a salt thereof, such as sodium alginate, and/or effer yacetic acid p-nitrobenzyl ester (racemic cis-trans vescing mixtures, or adsorbents, dyestuffs, flavouring mixture) substances and sweeteners. Also, the new pharmacolog A solution of 500 mg of 2-ethoxy-2-hydroxyacetic ically active compounds can be used in the form of 10 acid p-nitrobenzyl ester in a mixture of 10 ml of toluene injectable, for example intravenously administrable, and 2.5 ml of dimethylformamide is added at room preparations or in the form of infusion solutions. Solu tions of this type are preferably isotonic aqueous solu temperature to 129 mg (0.81 mmole) of 4-acetylthio-3- tions or suspensions, wherein these can be produced methyl-2-oxoazetidine (racemic cis-trans mixture). before use, for example, from lyophilised preparations 15 After adding freshly dried molecular sieves, the mixture that contain the active substance alone or together with is stirred under nitrogen for 15 hours at room tempera a carrier, for example mannitol. The pharmaceutical ture and subsequently for 2 hours at 50'. The molecular preparations may be sterilised and/or contain auxilia sieves are filtered off, washed with toluene and the ries, for example preservatives, stabilisers, wetting filtrate and washing liquid are together ccncentrated by agents and/or emulsifiers, solubilisers, salts for regulat evaporation in vacuo. The residue is dried under high ing the osmotic pressure and/or buffers. The pharma vacuum and chromatographed over silica gel with ceutical preparations of the invention which, if desired, toluene/ethyl acetate (9:1 to 8:2). After elution of the may contain other pharmacologically valuable sub unreacted 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl stances are produced in a manner known per se, for example by means of conventional mixing, granulating, 25 ester a mixture of the cis-trans isomers of the title con pill-coating, dissolving or lyophilising processes and pound having the following physico-chemical proper contain from approximately 0.1% to 100%, especially ties is eluted: from approximately 1% to approximately 50%, in the TLC: Rys 0.38 (toluene/ethyl acetate 2:3); IR spec case of the lyophilisates up to 100%, of the active sub trum (CH2Cl2): absorption bands at 2.85, 5.62, 5.7, 5.9, Stance. 6.2, 6.55, 7.4 and 8.25. Referring to the present description, organic radicals referred to as "lower', unless expressly defined, contain EXAMPLE 3 up to 7, preferably up to 4, carbon atoms; acyl radicals 2-(4-acetylthio-3-methyl-2-oxoazetidin-1-yl)-2-tri contain up to 20, preferably up to 12, and especially up phenylphosphoranylideneacetic acid p-nitrobenzyl to 7, carbon atoms. 35 The following Examples serve to illustrate the inven ester (racemic cis-trans mixture) tion; temperatures are in degrees Centigrade. The foll (a) A solution of 225 mg of 2-(4-acetylthio-3-methyl lowing abbreviation is used: TLC=thin layer chro 2-oxoazetidin-1-yl)-2-hydroxyacetic acid p-nitrobenzyl matogram over silica gel ester (racemic cis-trans mixture) in 5 ml of absolute EXAMPLE 1. dioxan is added to a solution of 1 g of poly-Hinig base in 2.5 ml of absolute dioxan that has already been stirred 4-acetylthio-3-methyl-2-oxoazetidine (racemic cis and for 30 minutes. After adding a solution of 0.175 ml of trans compound) thionyl chloride in 1.5 ml of absolute dioxan, the reac A solution of 0.33 ml of thioacetic acid in 4.5 ml of 1N tion mixture is stirred for 100 minutes at room tempera sodium hydroxide solution is added dropwise at room ture under nitrogen The poly-Hinig base is filtered off temperature under a nitrogen atmosphere to a solution and washed with dioxan and the filtrate is concentrated of 438 mg (3.06 mmoles) of 4-acetoxy-3-methylazetidin by evaporation in vacuo. TLC of the crude 2-(4-acetvl 2-one (produced according to K. Clauss et al., Lieb, thi-o-3-methyl-2-oxoazetidin-1-yl)-2-chloroacetic acid Ann. Chem., 1974, 539; racenic mixture of cis- and 50 trans-isomer in a ratio of 3:1; Mp 53'-65) in 1.13 ml of p-nitrobenzyl ester (racemic cis-trans mixture): water and 0.27 ml of acetone, and the mixture is stirred R?so.62 (toluene/ethyl acetate 2:3). at the same temperature for 3 hours. The reaction mix (b) The crude 2-(acetylthio-3-methyl-2-oxo-azetidin ture is exhaustively extracted with methylene chloride. 1-yl)-2-chloroacetic acid p-nitrobenzyl ester obtained is The combined organic phases are dried over sodium 55 dissolved in 12 ml of absolute dioxan, 1 g of poly-Hinig sulphate and concentrated by evaporation in vacuo. base is added and the mixture is stirred for 30 minutes, The residue is chromatographed over silica gel with then 312 mg of triphenylphosphine are added and the toluene/ethyl acetate (4:1 to 3:2) and yields first of all mixture is stirred under nitrogen for 15 hours at 50'. the pure trans-compound, then a mixture of the cis- and The poly-Hinig base is filtered off, washed with dioxan trans-isomers of the title compound and subsequently the pure cis-compound. and the filtrate and washing liquid are together concen TLC: Rf-0.31 (cis-isomer); 0.36 (trans-isoner) trated by evaporation in vacuo. The residue is chro (toluene/ethyl acetate 2:3); IR spectrum (CH2Cl2): ab matographed over silica gel with toluene/ethyl acetate sorption bands at 2.95, 5.6, 5.87, 8.65, 8.85 and 10.45p. and yields a cis-trans mixture of the title compound NMR spectrum (in CDCl3/100 Mc, in ppm): cis-com having the following physico-chemical properties: pound: 6.2, 1H, wide (exchange with D2O); 5.45, 1H, TLC: Rf-0.28 (toluene/ethyl acetate 2:3; IR spec d(J-5.5 Hz); 3.5-3.9, 1H, m; 2.4, 3H, s; 1.3, 3H, d; trum (CH2Cl2): absorption bands at 5.67, 5.9, 6.15, 6.55, trans-compound 6.5, 1H, wide (exchange with D2O); 6.95, 7.4, 9.0 and 9.25. 4,952,690 45 46 hours. The reaction mixture is exhaustively extracted EXAMPLE 4 with methylene chloride. The combined organic phases 2,6-dimethyl-2-penem-3-carboxylic acid p-nitrobenzyl are dried over sodium sulphate and concentrated by ester (racemic cis-trans mixture) evaporation in vacuo. The residue is chromatographed A catalytic amount of p-hydroxyquinone is added to 5 over 150 g of silica gel with toluene/ethyl acetate (9:1) a solution of 118 mg of 2-(4-acetylthio-3-methyl-2- and yields the almost pure trans-isomer of the title com oxoazetidin-1-yl)-2-triphenylphosphoranylideneacetic pound with the following physico-chemical properties: acid p-nitrobenzyl ester (racemic cis-trans mixture) in TLC: 0.38 (toluene/ethyl acetate 2:3); IR spectrum 50 ml of absolute toluene, and the mixture is stirred for (CH2Cl2): absorption bands at 2.95, 5.6, 5.87, 7.37, 7.45, 48 hours at 90' under nitrogen. The solvent is evapo 10 8.62 and 8.82. NMR spectrum (in CD Cl3/100 Mc, in rated offin vacuo and the residue is chromatographed ppm) 6.55, 1H, m (exchange with D2O); 4.9, 1H, d, J-2 over silica gel with toluene/ethyl acetate (19:1). A cis Hz; 3.35-3.05, 1H, m; 2.38, 3H, s; 1.4, 3H, d, J = 7 Hz. trans mixture (1:4) of the title compound is obtained in Subsequently a mixture of the cis- and trans-isomers is the form of a yellowish oil having the following physi isolated. co-chemical properties: 15 TLC: Ry=0.59 (toluene/ethyl acetate 2:3); IR spec EXAMPLE 8 trum (CH2Cl2): absorption bands at 5.6, 5.85 6.3, 6.55, 2-(4-acetylthio-3-methyl-2-oxoazetidin-1-yl)-2-hydrox 7.4, 7.6, 8.3 and 9.25p; NMR spectrum (in CDCl3/100 yacetic acid p-nitrobenzyl ester (racemic Mc, in ppm): 8.4–8.2, 2H; 7.75-7.76, 2H, m; 5.7-5.2, 3H, trans-compound) 20 m; 4.1-3.6, 1H, m; 2.4, 2.43, 3H, 2s; 1.6-1.4, 3H, 2d. At room temperature a solution of 5 g of 2-ethoxy-2- EXAMPLES hydroxyacetic acid p-nitrobenzyl ester in a mixture of 2,6-dimethyl-2-penem-3-carboxylic acid (racemic 100 ml of toluene and 25 ml of dimethylformamide is cis-trans mixture) added to 1.35 g (8.49 mmole) of 4-acetylthio-3-methyl 25 2-oxoazetidine (racemic trans-compound). After adding 2 ml of 0.2M aqueous sodium bicarbonate solution freshly dried molecular sieves the mixture is stirred and 100 mg of 10% palladium/carbon catalyst are under nitrogen for 15 hours at room temperature and added to a solution of 47 mg (0.14 mmole) of 2,6- dimethyl-2-penem-3-carboxylic acid p-nitrobenzyl ester then for 2 hours at 50'. The molecular sieves are filtered (racemic cis-trans mixture 1:4) in 3 ml of absolute ethyl off, washed with toluene and the filtrate and washing acetate and the mixture is stirred at normal pressure for 30 liquid are together concentrated by evaporation in 40 minutes under hydrogen. The catalyst is filtered off vacuo. The residue is dried under high vacuum and from the hydrogenated mixture over diatomaceous chromatographed over 100 g of silica gel with toluene earth, the residue is washed with 0.2M sodium bicar /ethyl acetate (9:1). After elution of the unreacted 2 bonate solution and several times with ethyl acetate. ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester, the The aqueous phase is washed with methylene chloride, 35 title compound having the following physicochemical acidified with 5% aqueous citric acid solution and ex properties is eluted: haustively extracted with methylene chloride. The TLC: Rf-0.33 (toluene/ethyl acetate 2:3); IR spec combined organic phases are dried over sodium sul trum (CH2Cl2): absorption bands at 2.85, 5.6, 5.7, 5.87, phate, filtered, concentrated by evaporation in vacuo 6.2, 6.52, 7.4, 8.28 and 9-9.2. and dried under high vacuum. The title compound EXAMPLE 9 obtained (cis-trans mixture ~ 1:4) has the following physico-chemical properties: 2-(4-acetylthio-3-methyl-2-oxoazetidin-1-yl)-2-tri TLC : Rf=0.28 (toluene/ethyl acetate/acetic acid phenylph-os-phoranylideneacetic acid p-nitrobenzyl 60:40:5); IR spectrum (CH2Cl2): absorption bands at 3.5, ester racemic trans-compound 5.6, 5.95 and 6.3; NMR spectrum (DMSO d6/100 Mc, 45 (a) A solution of 3 g of 2-(4-acetylthio-3-methyl-2- in ppm): 5.65, 1H, q; 3.3-3.9, 2H, m (--H2O); 2.28, 3H, oxoazetidin-1-yl)-2-hydroxyacetic acid p-nitrobenzyl s, melting point 119. ester (racemic trans-compound) in 75 ml of absolute EXAMPLE 6 dioxan is added to a solution of 13.5g of poly-Hinig 50 base in 35 ml of absolute dioxan that has already been Sodium salt of 2,6-dimethyl-2-penem-3-carboxylic acid stirred for 30 minutes. After adding a solution of 2.4 ml (racenic cis-trans mixture) of thionyl chloride in 22.4 ml of absolute dioxan, the A solution of 50 mg of 2,6-dimethyl-2-penem-3-car reaction mixture is stirred for 100 minutes at room tem boxylic acid in the equivalent amount of aqueous so perature under nitrogen. The poly-Hinig base is filtered dium bicarbonate solution is concentrated by evapora 55 off, washed with dioxan and the filtrate is concentrated tion in vacuo and dried under high vacuum. by evaporation in vacuo. TLC of the crude 2-(4-acetylthio-3-methyl-2- EXAMPLE 7 oxoazetidin-1-yl)-2-chloroacetic acid p-nitrobenzyl 4-acetylthio-3-methyl-2-oxoazetidine (racenic ester (racemic trans-compound): Rs 0.59 (toluene trans-compound) 60 Methyl acetate 2:3). A solution of 1.5 ml of thioacetic acid in 20.5 ml of 1N (b) The resulting crude 2-(4-acetylthio-3-methyl-2- sodium hydroxide solution is added dropwise at room oxoazetidin-1-yl)-2-chloroacetic acid p-nitrobenzyl temperature, under nitrogen, to a solution of 2 g of ester is dissolved in 175 ml of absolute dioxan, 13.5g of 4-acetoxy-3-methyl-azetidin-2-one (produced accord poly-Hinig base are added, then 4.2 mg of triphenyl ing to K. Clauss et. al., Lieb. Ann. Chem., 1974, 539; 65 phosphine, and the mixture is stirred for 15 hours at 50 racemic mixture of cis- and trans-isomer in a ratio of 3:1, under nitrogen. The poly-Hinig base is filtered off, Mp. 53-65) in 5.16 ml of water and 1.25 mi of acetone, washed with dioxan and the filtrate and washing liquid and the mixture is stirred at the same temperature for 3 are together concentrated by evaporation in vacuo. The 4,952,690 47 48 residue is chromatographed oversilica gel with toluene are dried over sodium sulphate and concentrated by /ethyl acetate and yields the trans-title compound with evaporation in vacuo. The residue is chromatographed the following physico-chemical properties: over 40 g of silica gel with toluene/ethyl acetate (4:1) TLC: Rf=0.24 (toluene/ethyl acetate 2:3); IR spec and yields the trans-title compound. trum (CH2Cl2) absorption bands at 5.67, 5.9, 6.15, 6.55, TLC: R=0.4 (toluene/ethyl acetate 2:3); IR spec 7.4 and 9.0. trum (CH2Cl2): absorption bands at 2.95, 3.37, 5.62, 5.87 EXAMPLE 10 and 8.8l. NMR spectrum (in CDCl3/100 Mc, in ppm): 2,6-dimethyl-2-penem-3-carboxylic acid p-nitrobenzyl 6.35, 1H, m (exchange with D2O); 5.04, 1H, d (J-2.5 Hz); 3.0, 1H, m; 2.37, 3H, s; 2.1, 1H, m; 1.05, 3H, m. ester (racemic trans-compound) 10 The starting material is produced as follows: (a) A A catalytic amount of p-hydroxyquinone is added to mixture of 172.28 g (216.5 ml, 2 mole) of isovaleralde a solution of 363 mg of 2-(4-acetylthio-3-methyl-2- hyde, 306 g (283 ml) of acetic anhydride and 24 g of oxoazetidin-1-yl)-3-triphenylphospohoranylideneacetic freshly molten potassium acetate is refluxed for 17 acid p-nitrobenzyl ester (racemic trans-compound) in hours. The cooled mixture is washed with 5% sodium 180 ml of absolute toluene and the mixture is stirred 15 under nitrogen for 48 hours at 90'. The solventis evapo carbonate solution until the organic phase reacts neu rated off in vacuo and the residue is chromatographed trally. After washing with water and drying over mag over 20 g of silica gel with toluene/ethyl acetate (19:1). nesium sulphate the oil obtained is distilled. 3-methyl The trans-title compound is obtained in the form of but-l-enyl acetate (cis-trans mixture 1:4) having a boil yellowish crystals having a melting point of 141-143' 20 ing point of 135-140/760 mmHg is obtained. (b) A and the following physico-chemical properties: solution of 8.72 ml of N-chlorosulphonyl isocyanate in TLC: Ry-0.6 (toluene/ethyl acetate 2:3); IR spec 10 ml of absolute methylene chloride is added dropwise trum (CH2Cl2) absorption bands at 3.4, 5.57, 5.82, 6.27, to a solution of 12.8 g (0.1 mole) of 3-methylbut-1-enyl 6.55, 7.4, 7.6, 8.3 and 9.22; NMR spectrum (in acetate (cis-trans mixture 1:4) in 40 ml of absolute meth CDCl3/100 Mc, in ppm): 8.25-8.15, 2H, m; 7.65-7.56, 25 ylene chloride at room temperature under nitrogen. 2H, m; 5.55-5.12, 3H, n+d (J-1.5 Hz); 3.9-3.6 lh, m; After 4 hours the reaction mixture is slowly poured into 2.36, 3H, s: 1.5, 3H, d. a mixture of 10 ml of water, 45g of ice, 24 g of sodium bicarbonate and 8.3 g of sodium sulphite, the tempera EXAMPLE 11 ture being maintained between 0' and 5' by the occa 2,6-dimethyl-2-penem-3-carboxylic acid (racemic sional addition of ice. After approximately 30 minutes trans-compound) the organic phase reacts neutrally, whereupon it is sepa 3 ml of 0.2N aqueous sodium bicarbonate solution rated off. The aqueous phase is extracted with methy and 150 mg of 10% palladium/carbon catalyst are added lene chloride. The organic phases are combined, dried to a solution of 80 mg (0.24 mmole) of 2,3-dimethyl-2- over sodium sulphate and concentrated by evaporation penen-3-carboxylic acid p-nitrobenzyl ester (racemic 35 in vacuo. The residue is chromatographed over silica trans-compound) in 5 ml of absolute ethyl acetate, and gel with toluene/ethyl acetate and yields a cis-trans the mixture is stirred at normal pressure for 50 minutes mixture of 4-acetoxy-3-isopropylazetidin-2-one in a under hydrogen. The catalyst is filtered off from the ratio of approximately 1:3. hydrogenated mixture over diatomaceous earth and TLC: R=0.3 (toluene/ethyl acetate 2:3); IR spec washed with 0.2N sodium bicarbonate solution and trum (in methylene chloride): absorption bands at 2.95, several times with ethyl acetate. The aqueous phase is 3.37, 5.6, 5.72, 7.32, 8.1, 9.7 and 10.2i; NMR spectrum washed with methylene chloride, acidified with 5% (CDCl3/100 Mc, in ppm): 6.75, 1H, m (exchange with aqueous citric acid solution and exhaustively extracted D2O); 5.85, d, J = 4.5 Hz (cis) and 5.6, d, J = 1.5 Hz with methylene chloride. The combined organic phases 45 (trans), 1H; 3.03, 1H, m; 2.1, 3H, 2s; 2.3-1.8, 1H, m; 1.1, are dried over sodium sulphate, filtered, concentrated 6H, m. by evaporation in vacuo and dried in a high vacuum. The resulting title compound has the following physi EXAMPLE 13 co-chemical properties: 2-(4-acetylthio-3-isopropyl-2-oxoazetidin-1-yl)-2- Melting Point 119 (decomposition): TLC: R=0.3 hydroxyacetic acid p-nitrobenzyl ester (racemic (toluene/ethyl acetate/acetic acid 60:40:5); IR spectrum trans-compound) (KBr): absorption bands at 3.3-3.5, 5.62, 6.0, 6.35, 6.95, 7.55 and 7.85u; NMR spectrum (DMSO d6/100 Mc, in 1.9 g of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ppm): 5.38, 1H, d, (J-1.5 Hz); 3.7, 1H, m: 3.4, 1H, m ester are added at room temperature to a solution of 616 (exchange with D2O); 2.28, 3H, s; 1.34, 3H, d. mg (3.3 mmole) of 4-acetylthio-3-isopropyl-2-oxoazeti 55 dine (racemic trans-compound) in 48 ml of toluene and EXAMPLE 12 10.5 ml of dimethylformamide. After adding freshly 4-acetylthio-3-isopropyl-2-oxoazetidine (racemic dried molecular sieves the mixture is stirred under nitro trans-compound) gen for 15 hours at room temperature and then for 2 A solution of 0.52 ml of thioacetic acid in 7 ml of 1N hours at 50'. The molecular sieves are filtered off, sodium hydroxide solution is added dropwise at room washed with toluene and the filtrate and washing liquid temperature under a nitrogen atmosphere to a solution are together concentrated by evaporation in vacuo. The of 750 mg (4.38 mmole) of 4-acetoxy-3-isopropylazeti residue is dried in a high vacuum and chromatographed din-2-one (racemic mixture of cis- and trans-isomer in over 60 g of silica gel with toluene/ethyl acetate (9:1). the ratio of 1:3) in 3.6 ml of water and 0.9 ml of acetone 65 The two transisomers of the title compound, contami and the mixture is stirred at the same temperature for 75 nated slightly by unreacted 2-ethoxy-2-hydroxyacetic minutes. The reaction mixture is exhaustively extracted acid p-nitrobenzyl ester, are obtained with the follow with methylene chloride. The combined organic phases ing physicochemical properties: 4,952,690 49 50 TLC: R-04 and 0.37 (toluene/ethyl acetate 2:3); IR trans-compound) in 7 ml of absolute ethyl acetate, and spectrum (CH2Cl2): absorption bands at 5.62, 5.68, 6.55 the mixture is stirred at normal pressure for 30 minutes and 7.42. under hydrogen. The catalyst is filtered off from the hydrogenated mixture over diatomaceous earth and EXAMPLE 4 washed with 0.2N sodium bicarbonate solution and 2-(4-acetylthio-3-isopropyl-2-oxoazetidin-1-yl)-2-tri several times with ethyl acetate. The aqueous phase is phenylphosphoranylideneacetic acid p-nitrobenzyl washed with methylene chloride, acidified with 5% ester (racemic trans-compound) aqueous citric acid solution and exhaustively extracted (a) A solution of 1.175 g of 2-(4-acetylthio-3-isopro with methylene chloride. The combined organic phases pyl-2-oxoazetidin-1-yl)-2-hydroxyacetic acid p-nitro O are dried over sodium sulphate, filtered, concentrated benzyl ester (racemic trans-compound) in 21 ml of abso by evaporation in vacuo and dried in a high vacuum. lute dioxan is added to a solution of 3.8g of poly-Hinig The resulting title compound has the following physi base in 10 ml of absolute dioxan that has already been co-chemical properties: stirred for 30 minutes. After the dropwise addition of a Melting Point 140-143 (decomposition); TLC: solution of 0.67 ml of thionyl chloride in 6.3 ml of abso 15 Rf-0.37 (toluene/ethyl acetate/acetic acid 60:40:5); IR lute dioxan, the reaction mixture is stirred for 90 min spectrum (KBr): absorption bands at 3.5, 5.62, 6.0, 6.35, utes at room temperature under nitrogen. The poly 6.9, 7.52, 7.8 and 8.0p; NMR spectrum (DMSO d6/100 Hinig base is filtered off, washed with dioxan and the Mc, in ppm): 5.52, 1H, d, J = 1.5 Hz; 3.56, 1H-2 H2O, filtrate is concentrated by evaporation in vacuo. The dd, J = 1.5 and 7.5 Hz; 2.26, 3H; s; 2.04, 1H, m: 1-0.9, resulting crude 2-(4-acetylthio-3-isopropyl-2-oxoazeti 20 6H, m. din-1-yl)-2-chloroacetic acid p-nitrobenzyl ester (race mic trans-compound) can be used in the next step with EXAMPLE 17 out further purification. 4-acetylthio-3-benzyl-2-oxoazetidine (racemic (b) The resulting crude 2-(4-acetylthio-3-isopropyl-2- trans-compound) oxoazetidin-1-yl)-2-chloroacetic acid p-nitrobenzyl 25 ester is dissolved in 50 ml of absolute dioxan, 3.8g of A solution of 0.76 g (10 mmole) of thioacetic acid in poly-Hinig base are added, the mixture is stirred for 30 10 ml of 1N sodium hydroxide solution is added drop minutes, then 1.18 g of triphenylphosphine are added wise to a solution of 2.19 g (10 mmole) of 4-acetoxy-3- and the mixture is stirred for 15 hours at 50' under benzylazetidin-2-one (racemic mixture of cis- and trans nitrogen. The poly-Hinig base is filtered off, washed 30 isomer in the ratio of 9:13) in 10 ml of dioxan at room with dioxan and the filtrate and washing liquid are to temperature under a nitrogen atmosphere, and the mix gether concentrated by evaporation in vacuo. The resi ture is stirred at the same temperature for 3 hours. The due is chromatographed over 60 g of silica gel with reaction mixture is exhaustively extracted with methy toluene/ethyl acetate 7:3 and yields the trans-title com lene chloride. The combined organic phases are dried 35 over sodium sulphate and concentrated bv evaporation pound with the following physico-chemical properties: in vacuo. The residue is chromatogra.ohed over silica TLC: Rf-0.25 (toluene/ethyl acetate 2:3); IR spec gel with toluene/ethyl acetate (9:1) and yields a cis trum (CH2Cl2): absorption bands at 5.7, 5.9, 6.17, 6.55, trans mixture of the title compound in the ratio of 2:10. 7.42 and 9.05. By recrystallisation from methylene chloride/hexane at EXAMPLE 1.5 - 10 the pure trans-compound having a melting point 2-methyl-6-isoprooyl-2-penem-3-carboxylic acid of 42-43 is obtained. p-nitrobenzyl ester (racemic trans-compound) TLC: RA=0.52 (toluene/ethyl acetate 1:1); IR spec trum (CH2Cl2) absorption bands at 2.95, 5.65, 5.95, 7.40, A catalytic amount of p-hydroxyquinone is added to 8.8 and 10.5u; NMR spectrum (in CDCl3/100 Mc, in a solution of 660 mg of 2-(4-acetylthio-3-isopropyl-2- 45 ppm): 7.24, 5 H, m; 16.60, 1H, b; 4.99, 1H, d, J = 2 Hz; oxoazetidin-1-yl)-2-triphenylphosphoranylideneacetic 3.45, 1H, dd, JB=8 Hz, Jo-6 Hz, JD=2 Hz; 3.18, 1H, acid p-nitrobenzyl ester (racemic trans-compound) in q, JA= 15 Hz, Jc=6 Hz; 3.00, 1H, q, JA= 15 Hz, JB=8 300 ml of absolute toluene, and the mixture is stirred for Hz: 2.30, 3H, s. 48 hours at 90 under nitrogen. The solvent is evapo The starting material is produced as follows rated off in vacuo and the residue is chromatographed 50 (a) A mixture of 25 g (0.186 mole) of 3-phenylpro over 30 g of silica gel with toluene/ethyl acetate (19:1). pionaldehyde, 50 ml of acetic anhydride and 50 ml of The trans-title compound is obtained, by crystallisation pyridine is stirred for 15 hours at 100 and then concen from diethyl ether/methylene chloride, in the form of trated by evaporation in a water jet vacuum. The resi colourless crystals having the following -physico due is dissolved in methylene chloride, washed with 5% chemical properties: melting point: 138-139"; TLC: 55 aqueous sodium bicarbonate solution and citric acid Rfs=0.59 (toluene/ethyl acetate 2:3): IR spectrum solution, dried over sodium sulphate and freed of sol (CH2Cl2) absorption bands at 5.57, 5.82, 6.27, 6.55, 7.4 vent in vacuo. The residue is distilled in vacuo. 3 and 7.6; NMR spectrum (in CDCl3/100 Mc, in ppm): phenylprop-1-enyl acetate (cis-trans mixture 1:1) having 8.3-8.2, 2H, m; 7.5-7.4, 2H, m1 5.75-5.1, 3H, m; 3.6-3.5, a boiling point of 61-65/1 mm Hg is obtained. 1H, dd, J = 8 and 1.5 Hz; 2.35, 3H, s; 1.07, 6H, m. (b) A mixture, prepared at 0, of 17.6 g (0.1 mole) of EXAMPLE 16 3-phenylprop-1-enyl acetate (cis-trans mixture 1:1) and 14.15 g (0.1 mmole) of N-chlorosulphonyl isocyanate is 2-methyl-6-isopropyl-2-penem-3-carboxylic acid stirred for 6 hours at 10-15. The reaction mixture is (racemic trans-compound) diluted with 100 ml of cold methylene chloride and is 4 ml of 0.2N aqueous sodium bicarbonate solution 65 slowly poured into a mixture of 10 ml of water, 45g of and 50 mg of 10% palladium/carbon catalyst are added ice, 24 g of sodium bicarbonate and 17 g of sodium to a solution of 100 mg of 2-methyl-6-isopropyl-2- sulphite. After filtering, the organic phase is separated penem-3-carboxylic acid p-nitrobenzyl ester (racemic off. The aqueous phase is extracted with methylene 4,952,690 51 52 chloride. The organic phases are combined, dried over TLC: R-0.50 (toluene/ethyl acetate 1:1); IR spec sodium sulphate and concentrated by evaporation in trum (CH2Cl2): absorption bands at 5.7, 5.9, 6.2, 6.55, vacuo. The residue is chromatographed over silica gel 7.00, 7.42, 9.05 and 11.75l. with toluene/ethyl acetate 9:1 to 8:2, and yields a cis trans mixture of 4-acetoxy-3-benzylazetidin-2-one in a 5 EXAMPLE 20 ratio of 9:13. 2-methyl-6-benzyl-2-penem-3-carboxylic acid TLC: Rf-0.5 (toluene/ethyl acetate 1:1); IR spec p-nitrobenzyl ester (racemic trans-compound) trum (in methylene chloride): absorption bands at 2.95, A catalytic amount of p-hydroxyquinone is added to 5.6, 5.75, 7.35, 8.15, 8.65, 9.6, and 10.25p; NMR spec a solution of 0.90 g (1.3 mmole) of 2-(4-acetylthio-3-ben trum (CDCl3/100 Mc, in ppm): 2.04, s and 2.08, s, 3H; 10 zyl-2-oxoazetidin-1-yl)-2-triphenylphosphoranylidenea 2.95-3.15, 2H, m: 3.35-3.8 1H, m 5.50, 0.6H, d, J = 2 Hz cetic acid p-nitrobenzyl ester (racemic trans-compound) (trans); 5.86, 0.4 H, d, J =4 Hz (cis); further signals at in 50 ml of dry toluene and the mixture is stirred under 6.807.4S. nitrogen for 2 days at 90'. The solvent is evaporated off EXAMPLE 18 in vacuo and the residue is chromatographed over silica 15 gel with toluene/ethyl acetate (9:1). The trans-title 2-(4-acetylthio-3-benzyl-2-oxoazetidin-1-yl)-2-hydrox compound is obtained by crystallisation from methy yacetic acid p-nitrobenzyl ester (racemic lene chloride/diethyl ether and has the following physi trans-compound) co-chemical properties: 2 g of 2-ethoxy-2-hydroxyacetic acid p-nitropenzyl 20 Melting Point: 182'-183; TLC: R=0.85 (toluene ester are added at room temperature to a solution of /ethyl acetate 1:1): IR spectrum (CH2Cl2): absorption 0.73 g (3.1 mmole) of 4-acetylthio-3-benzyl-3-oxoazeti bands at 5.60, 5.85, 6.30, 6.55, 7.4, 7.6, 8.25, 8.55, 9.25 dine (racemic trans-compound) in 50 ml of toluene and and 11.70; NMR spectrum (CDCl3/100 Mc, in ppm): 20 ml of dimethylformamide. After adding freshly dried 2.36, 3H, s; 3.12, 1H, dd, J= 14 Hz, JB =9 Hz, 3.34, 1H, molecular sieves, the mixture is stirred under nitrogen 25 dd, JA = 14 Hz, Jo-6 Hz; 4.03, 1H, dd, JB=9 Hz, Jc=6 overnight at room temperature and then for 2 hours at Hz, JD=2 Hz: 5.40, 1H, d, JD=2 Hz; 5.25, 1H, d, J = 14 50'. The molecular sieves are filtered off, washed with Hz; 5.45, 1H, d, J = 14 Hz; 7.30, 5H, m; 7.66, 2H, d, J =9 toluene and the filtrate and washing liquid are together Hz; 8.27, 2H, d, J =9 Hz. concentrated by evaporation in vacuo. The residue is EXAMPLE 21 dried in a high vacuum and chromatographed over 30 silica gel with toluene/ethyl acetate (9:1 to 4:1). The 2-methyl-6-benzyl-2-penem-3-carboxylic acid (racemic two trans-isomers of the title compound, slightly con trans-compound) taninated with unreacted 2-ethoxy-2-hydroxyacetic 8 ml of 0.2M aqueous sodium bicarbonate solution acid p-nitrobenzyl ester, are obtained with the follow and 400 mg of 10% palladium/carbon catalyst are ing physico-chemical properties: TLC: Rf-0.57 35 added to a solution of 200 mg of 2-methyl-6-benzyl-2- (toluene/ethyl acetate 1:1); IR spectrum (CH2Cl2); ab penem-3-carboxylic acid p-nitrobenzyl ester (racemic sorption bands at 2.85, 5.60, 5.70, 6.00, 6.20, 6.55, 7.40, trans-compound) in 12 ml of absolute ethyl acetate and 8.25, 9.00 and 11.75l. the mixture is stirred at normal pressure for 60 minutes EXAMPLE 19 under hydrogen. The catalyst is filtered off from the 2-(4-acetylthio-3-benzyl-2-oxoazetidin-1-yl)-2-tri 40 hydrogenated mixture over diatomaceous earth. The chenylphosphoranylideneacetic acid p-nitrobenzyl aqueous phase is separated off, acidified with 5% aque ester (racemic trans-compound) ous citric acid solution and exhaustively extracted with methylene chloride. The combined organic phases are (a) 6 g of poly-Hinig base are added to a solution of dried over sodium sulphate, filtered, concentrated by 1.5 g of 2-(4-acetylthio-3-benzyl-2-oxoazetidin-1-yl)-2- 45 evaporation in vacuo and dried in a high vacuum. The hydroxyacetic acid p-nitrobenzyl ester (racemic trans resulting title compound has the following physico compound) in 20 ml of dry dioxan. After dropwise chemical properties: addition of a solution cf 1.5 ml of thionyl chloride in 10 TLC: Rf=0.31 (toluene/ethyl acetate/acetic acid ml of dioxan, the reaction mixture is stirred for 60 min 60:40:5);IR spectrum (KBr): absorption bands at utes at room temperature under nitrogen. The poly 50 Hinig base is filtered off, washed with dioxan and the 3.204.30 b, 5.65, 6.0, 6.35, 6.9, 7.5, 7.9 and 8.2. filtrate is concentrated by evaporation in vacuo. The EXAMPLE 22: resulting crude 2-(4-acetylthio-3-benzyl-2-oxoazetidin 4-ethylthiothiocarbonylthio-3-isopropyl-2-oxoazetidine 1-yl)-2-chloroacetic acid -p-nitrobenzyl ester (racemic (racemic trans-compound) trans-compound) can be used in the next step without 55 further purification. A solution of 230 mg of potassium ethyl trithiocar (b) The crude 2-(4-acetylthio-3-isopropyl-2-oxoazeti bonate in 1.5 ml of water is added dropwise at room din-1-yl)-2-chloroacetic acid p-nitrobenzyl ester ob temperature, in a nitrogen atmosphere, to a solution of tained is dissolved in 20 ml of dry dioxan, 6 g of poly 195 mg (1.14 mmole) of 4-acetoxy-3-isopropylazetidin Hinig base are added, the mixture is stirred for 30 min 2-one (racemic mixture of cis- and trans-isoner in the utes, then 1.5g of triphenylphosphine are added and the ratio of 1:3) in 1 ml of water and 0.2 ml of acetone and mixture is stirred overnight at 50' under nitrogen. The the mixture is stirred at the same temperature for 120 poly-Hinig base is filtered off, washed with dioxan and minutes. The reaction mixture is exhaustively extracted the filtrate and washing liquid are together concen with methylene chloride. The combined organic phases trated by evaporation in vacuo. The residue is chro 65 are dried over sodium sulphate and concentrated by matographed over silica gel with toluene/ethyl acetate evaporation in vacuo. The residue is chromatographed (9:1 to 1:1) and yields the trans-title compound with the over 12 g of silica gel with toluene/ethyl acetate (9:1) following physico-chemical properties: and yields the trans-title compound. Melting point: 4,952,690 53 54 65-66 TLC: R-0.5 (toluene/ethyl acetate 2:3; IR spectrum (CH2Cl2): absorption bands at 2.95, 3.37, 5.62 EXAMPLE 25 and 9.25. NMR spectrum (in CDCl3/100Mc, in ppm): 2-ethylthio-6-isopropyl-2-penem-3-carboxylic acid 6.65, 1H, m (exchange with D2O); 5.4, 1H, d (J-2.5 p-nitrobenzyl ester (racemic transcompound) Hz): 3.39, 2H, q; 3.05, 1H, m; 2.15, 1H, m: 1.38, 3H, t; A catalytic amount of p-hydroxyquinone is added to 1.1, 6H, m. a solution of 600 mg (0.855 mmole) of 2-(4-ethylthiothi EXAMPLE 23 ocarbonylthio-3-isopropyl-2-oxoazetidin-1-yl)-2-tri 2-(4-ethylthiothiocarbonylthio-3-isopropyl-2-oxoazeti phenylphosphoranylideneacetic acid p-nitrobenzyl din-1-yl)-2-hydroxyacetic acid p-nitrobenzyl ester O ester (racemic trans-compound) in 250 ml of absolute o-xylene and the mixture is stirred under reflux in a (racemic trans-compound) nitrogen atmosphere for 48 hours. The solvent is evapo 311 mg of 2-ethoxy-2-hydroxyacetic acid p-nitroben rated off in vacuo and the residue is chromatographed zyl ester are added at room temperature to a solution of over 35 g of silica gel with toluene/ethyl acetate (19:1). 137 mg (0.55 mmole) of 4-ethylthiothiocarbonyltho-3- 5 The trans-title compound is obtained in the form of isopropyl-2-oxoazetidine (racemic trans-compound) in colourless crystals by crystallisation from diethyl 8 ml of toluene and 2 ml of dimethylformanide. After ether/methylene chloride; adding freshly dried molecular sieves, the mixture is TLC: Rf=0.62 (toluene/ethyl acetate 2:3); IR spec stirred under nitrogen for 15 hours at room temperature 20 trum, (CH2Cl2): absorption bands at 5.57, 5.9, 6.55, 7.4 and then for 2 hours at 50. The molecular sieves are and 7.52. filtered off, washed with toluene and the filtrate and washing liouid are together concentrated by evapora EXAMPLE 26 tion in vacuo. The residue is dried in a high vacuum and 2-ethylthio-6-isopropyl-2-penem-3-carboxylic acid chromatographed over 80 g of silica gel with toluene 25 (racemic trans-compound) Methyl acetate (9:1). The two trans-isomers of the title compound, contaminated slightly by unreacted 2 4 ml of 0.2N aqueous sodium bicarbonate solution ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester are and 150 mg of 10% palladium/carbon catalyst are obtained with the following physico-chemical proper added to a solution of 100 mg of 2-ethylthio-6-isopro ties: 30 pyl-2-penem-3-carboxylic acid p-nitrobenzyl ester (ra TLC: Rf-0.4 (toluene/ethyl acetate 2:3); IR spec cemic trans-compound) in 6 ml of absolute ethyl acetate trum (CH2Cl2): absorption bands at 5.62, 5.7, 6.55, 7.42, and the mixture is stirred at normal pressure for 240 minutes under hydrogen. The catalyst is filtered off 8.2 and 9.2. from the hydrogenated mixture over diatomaceous EXAMPLE 24 35 earth, then washed once with 0.2N sodium bicarbonate 2-(4-ethylthiothiocarbonylthio-3-isopropyl-2-oxoazeti solution and several times with ethyl acetate. The aque din-1-yl)-2-triphenylphosohoranylideneacetic acid ous phase is washed with methylene chloride, acidified p-nitrobenzyl ester (racemic transcompound) with 5% aqueous citric acid solution and exhaustively extracted with methylene chloride. The combined or A solution of 606 mg of 2-(4-ethylthiothiocarbo ganic phases are dried over sodium sulphate, filtered, nylthio-3-isopropyl-2-oxoazetidin-1-yl)-2-hydroxya concentrated by evaporation in vacuo and dried in a cetic acid p-nitrobenzyl ester (racemic trans-compound) high vacuum. The resulting title compound has the in 6 ml of absolute tetrahydrofuran is cooled to -15, following physicochemical properties: while stirring 0.16 ml (2.23 mmole) of thionyl chloride and then, slowly, a solution of 0.31 ml of triethylamine 45 TLC: R?=0.35 (toluene/ethyl acetate/acetic acid in 0.3 ml of absolute tetrahydrofuran are added. The 60:40:5); IR spectrum (KBr): absorption bands at 3.5, reaction mixture is stirred for 1 hour at 0, 30 ml of cold 5.62, 6.0, 6.75, 6.9, 7.52, 7.9, 8.15 and 8.9L. methylene chloride are added and the mixture is washed EXAMPLE 27 with ice-cold 2N hydrochloric acid. The organic phase 50 6-diazopenicillanic acid methyl ester is washed with water until there is neutral reaction, then is dried with sodium sulphate and concentrated by Analogously to German Offenegungsschrift No. 2 evaporation in vacuo. The resulting crude 2-(4-ethylthi 305 972, 1.01 g of crude 66-(N-nitroso)phenox othiocarbonylthio-3-isopropyl-2-oxoazetidin-1-yl)-2- yacetamidopenicillanic acid methyl ester (produced chloroacetic acid p-nitrobenzyl ester is dissolved in 1.5 55 according to U.S. Pat. No. 3,880,837) are dissolved at ml of dry tetrahydrofuran, 0.71 g of triphenylphosphine room temperature in 75 ml of absolute chloroform and is added and the mixture is stirred overnight at room aftcr adding 200 ml of saturated aqueous sodium bicar temperature under a nitrogen atomsphere. The reaction bonate solution the mixture is stirred for 9 hours at a mixture is diluted with methylene chloride, washed in temperature of between 10 and 20. The chloroform succession with saturated aqueous sodium bicarbonate solution is separated off, washed with water and dried solution and water, dried over sodium sulphate and over sodium sulphate. After evaporating off the solvent concentrated by evaporation in vacuo. The residue in vacuo at room temperature, the crude diazo com yields the title compound by chromatography over pound is obtained in the form of an oil. It can be used in silica gel with toluene/ethyl acetate (9:1). 65 the next reaction without further purification. TLC: Rf-0.5 (toluene/ethyl acetate 2:3); IR spec IR spectrum (in methylene chloride): characteristic trum (CH2Cl2): absorption bands at 3.4, 5.7, 6.15, 6.55, absorption bands at 3.40, 4.80, 5.55, 5.70, 6.23, 6.50, 6.68, 7.45, 9.05 and 9.25. 7.75, 8.22, 8.85, 10.6 and 11.42. 4,952,690 55 56 with toluene/ethyl acetate (9:1 and 4:1) and yields the EXAMPLE 28 title compound in the form of an oil. 6a-methoxypenicillanic acid methyl ester IR spectrum (in methylcne chloride): characteristic 5 ml of methanol and a few drops of 30% aqueous absorption bands at 3.40, 5.63, 5.78, 6.85, 7.03, 7.23, 7.32, perchloric acid are added to a solution of 2 g of crude 5 7.70, 8.15, 8.87, 9.00, 9.25 and 9.92. 6-diazopenicillanic acid methyl ester in 15 ml of abso lute methylene chloride and the mixture is stirred for 15 EXAMPLE 32 minutes at room temperature. The reaction mixture is 2-(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl)- diluted with 30 ml of methylene chloride and washed in O 3-methylcrotonic acid methyl ester succession with aqueous sodium bicarbonate solution, water and sodium chloride solution, dried over sodium A solution of 372 mg of 2-((3S,4R)-4-(benzthiazol-2- sulphate and concentrated by evaporation in vacuo. yldithio)-3-methoxy-2-oxoazetidin-1-yl)-3-methylcro The residue is chromatographed over silica gel with tonic acid methyl ester in 10 ml of dimethylformamide toluene/ethyl acetate (9:1 and 4:1) and yields the 15 is cooled to -20, 10 ml of a solution of 2 g of sodium slightly contaminated title compound. borohydride in 200 ml of dimethylformamide are added IR spectrum (in methylene chloride): characteristic and the mixture is stirrcd at the same temperature for 30 bands at 3.40, 5.63, 5.70, 6.90, 7.30, 7.68, 8.25, 8.47, 8.90, minutes. 5 ml of freshly distilled acetyl bromide are 9.15, 9.70 and 9.86. added to the reaction mixture and the mixture is further EXAMPLE 29 20 stirred for 110 minutes at 0'. After adding 150 ml of benzene, the reaction mixture is washed in succession 6a-methoxypenicillanic acid methyl ester 1-oxide with sodium bicarbonate solution and water, dried over A solution of 473 mg of 6a-methoxypenicillanic acid sodium sulphate and concentrated by evaporation in methyl ester in 10 ml of methylene chloride is cooled to vacuo. The residue yields, after chromatography over 0', 334 ng of m-chloroperbenzoic acid are added and 25 silica gel with toluene/ethyl acetate (9:1), the title com the resulting suspension is stirred for 1 hour at the same pound in the form of a slightly yellowish oil. temperature. The reaction mixture is diluted with 50 ml of methylene chloride, washed twice with aqueous IR spectrum (in methylene chloride); characteristic sodium bicarbonate solution and with water, and dried absorption bands at 3.40, 5.63, 5.77, 5.83, 6.10, 6.95, 7.20, over sodium sulphate. The solvent is evaporated off in 7.30, 7.70, 8.12, 8.90, 9.20,990, 10.20, 10.50 and 11.83. vacuo and the residue is chromatographed over silica Example 33 gel. With toluene/ethyl acetate (9:1 and 4:1) the title compound is obtained in the form of a white powder. 2-(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl 2-oxoacetic acid methyl ester An analytical sample is recrystallised from methylene 35 chloride/diethyl ether/pentane and has the following 3 equivalents of ozone are conveyed through a solu physico-chemical properties: tion, cooled to -30', of 87 mg (0.31 mmole) of 2 Mp. 121; ap= -281E1"; IR spectrum (in methy (3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl)-3- lene chloride); characteristic absorption bands at 3.40, methylcrotonic acid methyl ester in 5 ml of ethyl ace 5.58, 5.70, 6.85, 6.97, 7.75, 8.20, 8.90 and 9.45p. tate. The reaction mixture is diluted with 30 ml of meth EXAMPLE 30 ylene chloride and is shaken for 2 minutes with a 10% 2-(3S,4R)-4-(benzthiazol-2-yldithio)-3-methoxy-2- aqueous sodium bisulphite solution. The organic phase oxoazetidin-1-yl)-3-methylenebutyric acid methyl ester is separated off, washed with saturated sodium chloride A solution of 307 mg of 6a-methoxypenicillanic acid 45 solution, dried over sodium sulphate and concentrated methyl ester 1-oxide is dissolved in 10 ml of toluene, by evaporation in vacuo. 196.57 mg of 2-mercaptobenzthiazole are added and the IR spectrum of the resulting oily title compound (in mixture is refluxed for 90 minutes. The solvent is dis methylene chloride): characteristic bands at 3.40, 5.47, tilled off in vacuo and the residue is chromatographed 5.67, 5.82, 6.97, 7.33, 8.10, 8.92, 9.88 and 10.40p. The over silica gel. By elution with toluene/ethyl acetate 50 resulting product can be used in the next step without (9:1) the title compound is obtained in the form of a further purification. colourless oil. IR spectrum (in methylene chloride): characteristic bands at 3.40, 5.62, 5.72, 6.68, 6.85, 7.02, EXAMPLE 34 (3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidine 7.25, 7.50, 8.10, 8.20, 8.60, 8.95, 9.55, 9.92 and 10.92. 55 EXAMPLE 31 A solution of 71.20 mg of 2(3S,4R)-4-acetylthio-3- 2-((3S,4R)-4-(benzthiazol-2-yldithio)-3-methoxv-2- methoxy-2-oxoazetidin-1-yl-2-oxoacetic acid methyl oxoazetidin-1-yl)-3-methylcrotonic acid methyl ester ester (crude product) in 10 ml of 1% aqueous methanol 0.1 ml of triethylamine is added to a solution of 432 is stirred overnight at room temperature. The reaction ng of 2-((3S,4R)-4-(benzthiazol-2-yldithio)-3-methoxy mixture is diluted with methylene chloride, washed 2-oxoazetidin-1-yl-3-methylenebutyric acid methyl with water, dried over sodium sulphate and concen ester in 25 ml of methylene chloride and the mixture is trated by evaporation in vacuo. The residue is chro stirred at room temperature for 100 minutes. The reac matographed over silica gel with toluene/ethyl acetate tion mixture is diluted with methylene chloride, washed 65 (9:1) and yields the title compound. twice with aqueous citric acid solution and water, dried IR spectrum (in methylene chloride); characteristic over sodiun sulphate and freed of solvent in vacuo. The absorption bands at 2.95, 3.40, 5.60, 5.88, 7.00, 7.37, 7.52, residue is purified by chromatography over silica gel 8.25, 8.70, 8.85, 10.5 and 12.15. 4,952,690 57 58 EXAMPLE 35 EXAMPLE 38 2-C3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl)- (5R,6S)-2-methyl-6-methoxy-2-penem-3-carboxylic 2-hydroxyacetic acid p-nitrobenzyl ester acid 714 mg of 2-ethoxy-2-hydroxyacetic acid p-nitroben- 5 75 mg of 10% palladium/carbon catalyst are added to zyl ester and 4 g of molecular sieve A4 are added to a a solution of 34 mg of (5R,6S)-2-methyl-6-methoxy-2- solution of 245 mg of (3S,4R)-4-acetylthio-3-methoxy-2- penem-3-carboxylic acid p-nitrobenzyl ester in a mix oxoazetidine in a mixture of 8 ml of toluene and 2 ml of ture of 2 ml of ethyl acetate and 2 ml of 2M sodium dimethylformamide and the mixture is stirred overnight bicarbonate solution, and the mixture is hydrogenated at room temperature. The molecular sieves are filtered at room temperature for 1.5 hours under atmospheric off from the mixture and the filtrate is concentrated by pressure. The hydrogenated mixture is filtered through evaporation in vacuo. The residue is chromatographed diatomaceous earth and the filter residue is washed with over silica gel, and by elution with toluene/ethyl ace 1 ml of 2M aqueous sodium bicarbonate solution and tate (9:1 and 4:1) the title compound, contaminated with 15 ethyl acetate. The aqueous phase is separated off from some glyoxylate, is obtained. the filtrate, acidified with 0.1M aqueous citric acid and extracted several times with methylene chloride. The EXAMPLE 36 combined methylene chloride extracts are dried over 2-((3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl)- sodium sulphate and concentrated by evaporation in 2-triphenylphosphoranylideneacetic acid p-nitrobenzyl 20 WCO ester IR spectrum (in methylene chloride) of the resulting (a) A suspension of 2 g of poly-Hinig base in 8ml of crude title compound: characteristic absorption bands dioxan is stirred for 30 minutes at room temperature, at 3.40, 5.57, 5.80, 5.95, 6.30, 7.00, 8.20 and 9.90. 832 mg of 2-((3S,4R)-4-acetylthio-3-methoxy-2- EXAMPLE 39 oxoazetidin-1-yl)-2-hydroxyacetic acid p-nitrobenzyl 25 6a-phenoxyacetoxypenicillanic acid methyl ester ester dissolved in 12 ml of dioxan are added and then Analogously to D. Hauser and H. P. Sigg, Helv. slowly a solution of 0.54 ml of thionyl chloride in 10 ml Chim. Acta 50, 1327 (1967), a solution of 7.4 g (20.3 of dioxan is added. The mixture is stirred for 2 hours at mmole) of 66-(N-nitroso)-phenoxyacetamidopenicil room temperature, the poly-Hinig base is filtered off 30 lanic acid methyl ester (crude product according to and the filtrate is concentrated by evaporation in vacuo. U.S. Pat. No. 3,880,837) in 100 ml of benzene is stirred The residue is purified by chromatography over silica for 3 hours at 50' in a nitrogen atmosphere. The solvent gel with toluene/ethyl acetate (1:1) and yields the 2 is evaporated off-in vacuo and the residue is chromato (3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl)-2- graphed over silica gel with toluene/ethyl acetate (9:1). chloroacetic acid p-nitrobenzyl ester in crude form. 35 The resulting oily product is recrystallised from diethyl (b) 812 mg of triphenylphosphine and 3 g of poly ether/hexane and yields the title compound having a Hinig base are added to a solution of 833 mg of 2 melting point of 71; ap=114-1 (CHCl3); IR spec (3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl)-2- trum (in methylene chloride); characteristic absorption chloroacetic acid p-nitrobenzyl ester in 50 ml of dioxan bands at 3.4, 5.6, 5.7, 6.25, 6.69, 7.17, 8.26, 8.55, 9.05 and and the mixture is stirred overnight at 50". The poly 9.18. Hinig base is removed by filtration and the filtrate is concentrated by evaporation in vacuo. The residue is EXAMPLE 40: 6a-phenoxyacetoxypenicillanic acid chromatographed over silica gel with toluene/ethyl methyl ester 1-oxide acetate (9:1, 4:1 and 1:1) and yields the title comcound. 1.1 g (1 equivalent) of 50% m-chloroperbenzoic acid IR spectrum (in methylene chloride): characteristic are added in portions at 0 to a solution of 1.16 g (3.18 absorption bands at 3.40, 5.67, 5.85, 6.15, 6.55, 6.97, 7.42, mmole) of 6a-phenoxyacetoxypenicillanic acid methyl 8.0 and 9.03. ester in 30 ml of absolute methylene chloride. After addition is complete, the reaction mixture is stirred for EXAMPLE 37 30 minutes at 0, then diluted with methylene chloride, (5R,6S)-2-methyl-6-methoxy-2-penen-3-carboxylic 50 washed in succession with aqueous sodium bicarbonate acid p-nitrobenzyl ester solution, water and sodium chloride solution, and dried over sodium sulphate. After evaporating off the solvent A catalytic amount of hydroquinone is added to a the residue is chromatographed over silica gel with solution of 244 mg of 2-((3S,4R)-4-acetylthio-3- toluene/ethyl acetate (4:1). The title compound is ob methoxy-2-oxoazetidin-1-yl)-2-triphenylphos 55 tained in the form of a foam; phoranylideneacetic acid p-nitrobenzyl ester in 100 ml TLC: Rf=0.24 (toluene/ethyl acetate 1:1), IR spec of ahsolute toluene and the mixture is stirred for 32 trum (in methylene chloride); characteristic absorption hours at 90 under nitrogen. The toluene is evaporated bands at 3.33, 3.41, 5.57, 5.72, 6.27, 6.72, 7.0, 8.25, 8.6, off in vacuo and the residue is chromatographed over 9.21 and 9.46. silica gel with toluene/ethyl acetate (19:1). The title compound is obtained in the form of a solid white sub EXAMPLE 41: stance. 2-(3S,4R)-4-(benzthiazol-2-yldithio)-3-phenox IR spectrum (in methylene chloride): characteristic yacetoxy-2-oxoazetidin-1-yl)-3-methylenebutyric acid absorption bands at 3.40, 5.55, 6.30, 6.55, 7.03, 7.42, 7.60, methyl ester 8.20, 8.42, 8.60, 8.90, 9.20, 9.60 and 11.7; NMR spec 65 A solution of 1.01 (2.65 mmole) of 6a-phenox trum (CDCl3/100 Mc, in ppm): 8.22, 2H, d, J =8 Hz; yacetoxypenicillanic acid methyl ester 1-oxide is dis 7.64, 2H, d, J =8 Hz; 5.53, 1H, d, J =2 Hz; 5.35, 2H, AB; solved in 30 ml of toluene, 445 mg (2.65 mmole) of 4.91, 1H, d, J =2 Hz; 3.57, 3H, s; 2.37, 3H, s. 2-mercaptobenzthiazole are added and the mixture is 4,952,690 59 60 refluxed for 60 minutes in a nitrogen atmosphere, The sodium chloride solution, dried over sodium sulphate solvent is distilled off in vacuo and the residue is chro and concentrated by evaporation in vacuo. matographed over silica gel. By eluting with toluene IR spectrum of the resulting oily title compound (in /ethyl acetate (19:1) the title compound is obtained in methylene chloride): characteristic bands at 3.38, 5.48, the form of a faintish brown oil. 5.63, 5.70, 5.83, 6.27, 6.70, 7.00, 7.40, 8.07, 8.25, 8.63 and IR spectrum (in methylene chloride); characteristic 8.95 . The resulting product can be used in the next bands at 3.45, 5.62, 5.75, 6.27, 6.71, 6.89, 7.05, 7.30, 7.54, step without further purification. 7.68, 8.15, 8.55, 9.15, 9.35 and 9.95u; TLC: Rf=0.63 (toluene/ethyl acetate 1:1). EXAMPLE 45: EXAMPLE 42: 10 (3S,4R)-4-acetylthio-3-phenoxyacetoxy-2-oxoazetidine 2(3S,4R)-4-(benzthiazol-2-yldithio)-3-phenoxyacetoxy A solution of 129 mg (0.34 mmole) of (3S,4R)-2-(4- 2-oxoazetidin-1-yl-3-methylcrotonic acid methyl ester acetylthio-3-phenoxyacetoxy-2-oxoazetidin-1-yl)-2- 0.4 ml of triethylamine is added to a solution of 1.28 oxoacetic acid methyl ester (crude product) in 10 ml of g (2.41 mmole) of 2-(3S,4R)-4-(benzthiazol-2-yldithio)- 1% aqueous methanol is stirred for 4 hours at room 3-phenoxyacetoxy-2-oxoazetidin-1-yl-3- 15 temperature. The reaction mixture is diluted with 50 ml methylenebutyric acid methyl ester in 30 ml of methy of methylene chioride, washed in succession with water lene chloride and the mixture is stirred at room temper and saturated sodium chloride solution, dried over so ature for 30 minutes. The reaction mixture is diluted dium sulphate and concentrated by evaporation in with 50 ml of methylene chloride, washed in succession 20 vacuo. The residue is chromatographed over silica gel with 2N hydrochloric acid, water and sodium chloride with toluene/ethyl acetate (9:1) and yields the title com solution, dried over sodium sulphate and freed from pound. solvent in vacuo. The residue is purified by chromatog IR spectrum (in methylene chloride); characteristic raphy over silica gel with toluene/ethyl acetate (19:1) bands at 2.95, 3.45, 5.55, 5.60, 5.88, 6.25, 6.68, 8.33 and and yields the title compound in the form of a faint yellow oil. 25 8.8582; TLC: R=0.36 (toluene/ethyl acetate 1:1). IR spectrum (in methylene chloride); characteristic EXAMPLE 46: absorption bands at 3.46, 5.69, 5.82, 5.90, 6.28, 6.73, 6.90, 2-((3S,4R)-4-acetylthio-3-phenoxyacetoxy-2-oxoazeti 7.06, 7.28, 7.38, 7.75, 8.20, 8.60, 9.27 and 9.96; TLC: dinelyl-2-hydroxyacetic acid p-nitrobenzyl ester Rf=0.61 (toluene/ethyl acetate 1:1). 30 760 mg of 2-ethoxy-2-hydroxyacetic acid p-nitroben EXAMPLE 43: zyl ester and 4 g of molecular sieve A4 are added to a 2-C3S,4R)-4-acetylthio-3-phenoxyacetoxy-2-oxoazeti solution of 283 mg of (3S,4R)-4-acetylthio-3-methoxy-2- din-1-yl-3-methylcrotonic acid methyl ester oxoazetidine in a mixture of 8 ml of toluene and 2 ml of dimethylformamide, and the mixture is stirred over A solution of 687 mg (1.29 mmole) of 2-((3S,4R)-4- 35 (benzthiazol-2-yldithio)-3-phenoxyacetoxy-2Oxoazeti night at room temperature. The molecular sieves are din-1-yl-3-methylcrotonic acid methyl ester in 14 ml of filtered off from the mixture and the filtrate is concen dimethylformamide is added to a solution, cooled to trated by evaporation in vacuo. The residue is chro -20', of 76 mg (2 mmole) of sodium borohydride in 10 matographed over silica gel, and the title compound, ml of dimethylformanide and the mixture is stirred at contaminated with some glyoxylate, is obtained by elut the same temperature for 10 minutes, 7 ml of freshly ing with toluene/ethyl acetate (9:1 and 4:1). distilled acetyl bromide are added to the reaction mix EXAMPLE 47: ture, which is further stirred at O' for 40 minutes. After 2-((3S,4R)-4-acetylthio-3-phenoxyacetoxy adding 400 ml of benzene, the reaction mixture is -2-oxoazetidin-1-yl)-2-triphenylphosphoranylidenea washed in succession with aqueous sodium bicarbonate 45 solution, water and sodium chloride solution, dried over cetic acid p-nitrobenzyl ester sodium sulphate and concentrated by evaporation in (a) A suspension of 2 g of poly-Hinig base in 8 ml of vacuo. After chromatography over silica gel with dioxan is stirred at room temperature for 30 minutes, a toluene/ethyl acetate (19:1) the residue yields the title solution of 962 mg of 2- (3S,4R)-4-acetylthio-3-phenox compound in the form of an oil, which is further puri yacetoxy-2-oxoazetidin-1-yl-2-hydroxyacetic acid p fied on silica gel plates with toluene/ethyl acetate (4:1). nitrobenzyl ester in 10 ml of dioxan is added, then a The title compound is obtained in oily form. solution of 0.38 ml of thionyl chloride in 8ml of dioxan IR spectrum (in methylene chloride): characteristic is added slowly. The mixture is stirred for 2 hours at absorption bands at 3.45, 5.63, 5.83, 6.27, 6.70, 7.00, 7.25, room temperature, the poly-Hinig base is filtered off 7.35, 8.15, 8.58, 8.93 and 9.20 u; TLC: R=0.54 55 and the filtrate is concentrated by evaporation in vacuo. (toluene/ethyl acetate 1:1). The residue is purified by chromatography over silica gel with toluene/ethyl acetate (1:1) and yields the 2 EXAMPLE 44: (3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl)-2- 2-(3S,4R)-4-acetylthio-3-phenoxyacetoxy-2-oxoazeti chloroacetic acid p-nitrobenzyl ester in crude form. din-1-yl)-2-oxoacetic acid methyl ester (b) 786 mg of triphenylphosphine and 3 g of poly 4 equivalents of ozone are conveyed through a solu Hinig base are added to a solution of 960 mg of 2 tion, cooled to -20', of 170 mg (0.42 mmole) of 2 (3S,4R)-4-acetylthio-3-phenoxyacetoxy-2-oxoazetidin (3S,4R)-4-acetylthio-3-phenoxyacetoxy-2- 1-yl)-2-chloroacetic acid p-nitrobenzyl ester in 40 ml of oxoazetidin1-yl)-3-methylcrotonic acid methyl ester in dioxan and the mixture is stirred overnight at 50' under 5 ml of ethyl acetate. The reaction mixture is diluted 65 nitrogen. The poly-Hinig base is removed by filtration with 5 ml of ethyl acetate, and shaken vigorously with and the filtrate is concentrated by evaporation in vacuo. a 10% aqueous sodium bisulphite solution. The organic The residue is chromatographed over silica gel with phase is separated off, washed with water and saturated toluene/ethyl acetate (9:1, 4:1 and 1:1) and yields the 4,952,690 61 62 title compound. IR spectrum (in methylene chloride): chloroethyl ester i-oxide in 40 ml of absolute toluene, characteristic absorption bands at 5.7, 5.9, 6.17, 6.55 and and the mixture is refluxed for 105 minutes under nitro 7.45 p. gen. The solvent is distilled off in vacuo and yields the title compound in the form of a yellowish oil. EXAMPLE 48: IR spectrum (in methylene chloride); characteristic (5R,6S)-2-methyl-6-phenoxyacetoxy-2-penem-3-car absorption bands at 3.39, 5.60, 5.65, 6.85, 8.20, 8.62, 8.97, boxylic acid p-nitrobenzyl ester 9.85 and 9.95. A catalytic amount of hydroquinone is added to a The resulting product can be used in the next step solution of 285 mg of 2-(3S,4R)-4-acetylthio-3-phenox without further purification. yacetoxy-2-oxoazetidin-1-yl)-2-triphenylphos 10 phoranylideneacetic acid p-nitrobenzyl ester in 100 ml EXAMPLE 52: of absolute toluene and the mixture is stirred under 2-(3S,4R)-4-(benzthiazol-2-yldithio)-3-methoxy-2- nitrogen for 35 hours at 90'. The toluene is evaporated oxoazetidin-1-yl)-3-methylcrotonic acid off in vacuo and the residue is chromatographed over 2,2,2-trichloroethyl ester 15 silica gel with toluene/ethyl acetate (19:1). The title 0.78 ml of triethylamine is added to a solution of 4.17 compound is obtained in the form of an oil. g of 2- (3S,4R)-4-benzthiazol-2-yldithio)-3-methoxy-2- IR spectrum (in methylene chloride): characteristic oxoazetidin-1-yl-3-methylenebutyric acid 2,2,2-tri absorption bands at 5.55, 6.30, 6.55 and 7.42 u. chloroethyl ester in 75 ml of absolute methylene chlo EXAMPLE 49 20 ride at 0' and the mixture is stirred at this temperature (SR,6S)-2-methyl-6-phenoxvacetoxy-2-penen-3-car for 15 minutes. boxylic acid The reaction mixture is washed in succession with 4N phosphoric acid, saturated aqueous sodium bicarbonate 75 mg of 10% palladium/carbon catalyst are added solution and sodium chloride solution, and dried over to a solution of 45 mg of (5R,6S)-2-methyl-6-phenox 25 sodium sulphate. The solvent is evaporated off and the yacetoxy-2-penen-3-carboxylic acid p-nitrobenzyl ester residue is purified by chromatography over silica gel in a mixture of 2 ml of ethyl acetate and 2 ml of 2M with toluene and toluene/ethyl acetate (19:1). The title sodium bicarbonate solution, and the mixture is hydro genated under atmospheric pressure for 1.5 hours at compound is obtained in the form of an oil. IR spectrum room temperature. The hydrogenated mixture is fil (in methylene chloride); characteristic absorption bands tered through diatomaceous earth and the filter residue 30 at 3.39, 5.62, 5.76, 6.85, 7.04, 7.25, 6.85, 901, 9.48, 9.85 is washed with 1 ml of 2Maqueous sodium bicarbonate and 9.95. solution and methyl acetate. The aqueous phase is sepa EXAMPLE 53: rated off from the filtrate, acidified with 0.1M aqueous 2-(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl)- citric acid and extracted several times with methylene chloride. The combined methylene chloride extracts are 35 3-methylcrotonic acid 2,2,2-trichloroethyl ester dried over sodium sulphate and concentrated by evapo A solution of 3.26 g of 2- (3S,4R)-4-(benzthiazol-2- ration in vacuo. yldithiol-3-methoxy-2-oxoazetidin-1-yl)-3-methyl-cro IR spectrum (in ethanol) of the resulting crude title tonic acid 2,2,2-trichloroethyl ester in 36.3 ml of acetic compound: characteristic absorption bands at 5.6; UV anhydride and 12.4 ml of acetic acid is cooled to -15 spectrum (in ethanol): Anax=305 nm. and 1.7 g of triphenylphosphine are added. After stir ring under nitrogen at the same temperature for 75 EXAMPLE 50: minutes, 24.8 ml of pyridine are added to the mixture. 6a-methoxypencillanic acid 2,2,2-trichloroethyl ester After stirring for a further 3 hours at 0, the reaction 1-oxide 45 mixture is concentrated by evaporation under reduced A solution of 2 g of 6a-methoxypenicillanic acid pressure and the resulting residue is purified by chroma 2,2,2-trichloroethyl ester (produced according to P. J. tography over silica gel with toluene and toluene/ethyl Giddins, D. I. Johns, E.J. Thomas: T. L. 11,995, 1978) acetate (19:1). IR spectrum (in methylene chloride): in 100 ml of methylene chloride and 0.3 ml of acetone is characteristic absorption bands at 3.40, 5.63, 5.77, 5.80, cooled to -15 C, 1 ml of 40% peracetic acid is added 50 6.13, 7.25, 7.35, 8.26, 9.0, 9.52 and 11.90 p. over the course of 5 minutes, and the mixture is stirred for 15 minutes at the same temperature. Subsequently 15 EXAMPLE 54: ml of a 0.1N sodium thiosulphate solution are added to 2-((3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl)- the reaction mixture. The organic solution is separated 2-oxoacetic acid 2,2,2-trichloroethyl ester off and washed twice with ice water. After drying over 55 3 equivalents of ozone are conveyed through a solu sodium sulphate the solvent is evaporated off in vacuo tion, cooled to -30, of 8.4 g of 2-4R)-4-acetylthio-3- and the residue is recrystallised from ether/petroleum methoxy-2-oxoazetidin-1-yl)-3-methylcrotonic acid ether. The resulting compound has the following physi 2,2,2-trichloroethyl ester in 765 ml of methyl acetate. co-chemical properties: Mp. = 127-128". IR spectrum After treating with ozone, the reaction mixture is left to (in methylene chloride): characteristic absorption bands stand at the same temperature for 15 minutes and then at 3.41, 5.58, 5.65, 8.33, 8.47, 8.70 and 9.48. the excess ozone is removed by a nitrogen current. The EXAMPLE 51: reaction mixture is washed at 0 with a 10% aqueous sodium bisulphite solution and then with sodium chlo 2-((3S,4R)-4-(benzthiazol-2-yldithio)-3-methoxy-2- ride solution. After separating off, the combined aque oxoazetidin-1-yl-3-methylenebutyric acid ous phases are extracted a further 4 times with methyl 2,2,2-trichloroethyl ester acetate. The combined methyl ester solutions are dried 1.39 g of 2-mercaptobenzthiazol are added to a solu over sodium sulphate and concentrated by evaporation tion of 3 g of 6a-methoxypenicillanic acid 2,2,2-tri in vacuo. 4,952,690 63 64 IR spectrum of the resulting oily title compound (in IR spectrum (in methylene chloride); characteristic methylene chloride); characteristic absorption bands at absorption bands at 3.41, 5.59, 5.65, 5.88, 6.21, 6.56, 7.41, 3.39, 5.48, 5.63, 6.09, 6.94, 7.25, 7.38, 7.46, 8.23, 8.93, 8.23, 8.55, 9.05, 10.5 and 11.76. 9.90 and 11.83. EXAMPLE 58: EXAMPLESS: 2-((3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl (3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidine 2-trichenylphosphoranylideneacetic acid p-nitrobenzyl (a) A solution of 1.52 g of 2-(3S,4R)-4-acetylthio-3- ester methoxy-2-oxoazetidin-1-yl)-2-oxoacetic acid 2,2,2-tri 0.84 g of triphenylphosphine is added to a solution of chloroethyl ester (crude product) in 290 ml of metha 10 0.63 g of 2-((3S,4R)-4-acetylthio-3-methoxy-2-oxoazeti nol, 40 ml of methyl acetate and 5.9 ml of water is re din-1-yl-2-chloroacetic acid p-nitrobenzyl ester in 1.8 fluxed for 20 minutes under nitrogen. The solvent is ml of dry tetrahydrofuran, and the mixture is stirred evaporated off in vacuo. After chromatography over overnight at room temperature under nitrogen. The silica gel with toluene/ethyl acetate (3:1) the residue 15 mixture is diluted with methylene chloride and washed yields the title compound. with a cold, saturated, aqueous sodium bicarbonate IR spectrum (in methylene chloride); characteristic solution. Additional washing with water, drying over absorption bands at 2.95, 3.40, 5.60, 5.88, 7.37, 7.52, 8.25, sodium sulphate and concentrating by evaporation in 8.70, 8.85, 10.5 and 12.12 u. vacuo yield the crude title compound which is purified The same compound may also be obtained as follows: 20 by chromatography over silica gel with toluene/ethyl (b) 1.5 equivalents of an aqueous sodium thioacetate acetate (19:1 to 3:1). solution are added to a solution of 40 mg of (3S,4S)-4- IR spectrum (in methylene chloride); characteristic acetoxy-3-methoxy-2-oxoazetidine (for manufacture see absorption bands at 3.40, 5.67, 5.90, 6.20, 6.58, 7.46 and below) in 1.5 ml of phosphate buffer of a pH of 7 and 0.1 9.05 p. ml of dioxan, and the mixture is stirred for 30 minutes at 25 room temperature. The reaction mixture is extracted EXAMPLE 59: with methylene chloride and the separated organic (5R,6S)-2-methyl-6-methoxy-2-penem-3-carboxylic solution is then dried over sodium sulphate. The solvent acid p-nitrobenzyl ester is evaporated offin vacuo and the residue is purified by A catalytic amount of 3,5-di-tert.butyl-4-hydroxytol chromatography over silica gel with toluene/ethyl ace 30 uene is added to a solution of 74 ng of 2-(3S-4R)-4- tate (3:1). The IR spectrum of the resulting title com acetylthio-3-methoxy-2-oxoazetidin-1-yl-2-tri-phenyl pound (in methylene chloride) is identical to that of the phosphoranylideneacetic acid p-nitrobenzyl ester in 30 product obtained according to a). ml of absolute toluene and the mixture is refluxed under EXAMPLE S6: nitrogen for 3 hours. The toluene is evaporated off in 35 vacuo and the residue is chromatographed over silica 2-(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl)- gel with toluene/ethyl acetate (19:1). The title com 2-hydroxyacetic acid p-nitrobenzyl ester pound is obtained in the solid state. 1.15 g of 2-ethoxy-2-hydroxyacetic acid p-nitroben IR spectrum (in methylene chloride); characteristic zyl ester and 4 g of molecular sieves A4are added to a absorption bands at 3.41, 5.60, 5.85, 6.63, 6.58, 7.41, 7.60, solution of 350 mg of (3S,4R)-4-acetylthio-3-methoxy-2- 8.23, 9.26 and 11.76 A. oxoazetidine in a mixture of 24 ml of absolute toluene and 6 ml of absolute dimethylformamide and the mix EXAMPLE 60: ture is stirred overnight at room temperature under 3-ethyl-4-(2-acetylaminoethylthiothiocarbonylthio)-2- nitrogen. The molecular sieves are filtered off and the 45 oxoazetidine (racemic cis-trans compound) filtrate is concentrated by evaporation in vacuo. The (a) A solution of 0.78 g (5 mmole) of 4-acetoxy-3- residue is chromatographed over silica gel, and the title ethyl-azetidin-2-one (racemic mixture of cis- and trans compound is obtained by eluting with toluene and isomer in a ratio of 6:4) in 2 ml of dioxan is added drop toluene/ethyl acetate (19:1). wise under a nitrogen atmosphere to a solution of 1.175 IR spectrum (in methylene chloride); characteristic 50 g of potassium (2-acetylaminoethyl)trithiocarbonate in absorption bands at 2.86, 3.39, 5.60, 5.68, 5.88, 6.21, 6.56, 20 ml of pre-cooled phosphate buffer of a pH of 7 and 7.41, 8.26, 9.01 and 11.76. the mixture is stirred for 60 minutes. The reaction mix EXAMPLE 57: ture is centrifuged, the supernatant clear solution is 2-((3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl)- decanted off and the oily residue is taken up in methy 55 lene chloride. The organic phase is dried over sodium 2-chloroacetic acid p-nitrobenzyl ester sulphate and concentrated by evaporation in vacuo. A solution of 0.6 g of 2-((3S,4R)-4-acetylthio-3- The residue is triturated once with diethyl ether and is methoxy-2-oxoazetidin-1-yl)-2-hydroxyacetic acid p further processed in this form. nitrobenzyl ester in 7 ml of dry tetrahydrofuran is TLC: R=0.16 (ethyl acetate); IR spectrum cooled to -15' and 0.19 ml of thionyl chloride is added. (CH2Cl2): absorption bands at 2.92, 2.97, 5.63, 5.97, 0.37 ml of triethylamine in 0.4 ml of dry tetrahydrofu 6.62, 9.35 and 12.34. ran is then added dropwise at the same temperature. The two starting materials may be produced as foll The reaction mixture is stirred for 1 hour at 0, diluted lows: with cold methylene chloride and washed with an ice (b) 42.7 g (26.3 ml, 0.302 mole) of N-chlorosulphonyl cold 2N HCl solution. After extracting several times by 65 isocyanate are added dropwise at -10 over the course shaking with water, the methylene chloride solution is of 30 minutes to a stirred solution of 34.5 g (0.302 mole) dried over sodium sulphate and concentrated by evapo ofbut-1-enyl acetate in 35 ml of dry methylene chloride. ration. After a further 4 hours of stirring at 0, the reaction 4,952,690 65 66 mixture is diluted with 50 ml of pre-cooled methylene reaction mixture is stirred for 20 minutes at 0, 150 ml of chloride and added dropwise to a hydrolysing mixture methylene chloride are added and washing is carried of 32 ml of water, 144 g of ice, 113 g of sodium bicar out with ice-cold 1N hydrochloric acid. The organic bonate and 38.2 g of anhydrous sodium sulphite. During phase is dried with sodium sulphate and concentrated the hydrolysis the temperature is maintained at 0' by by evaporation in vacuo. The resulting crude 2-3-ethyl external cooling. When the organic phase no longer has 4-(2-acetylaminoethylthiothiocarbonylthio)-2-oxoazeti an acidic reaction, the reaction mixture is diluted with din-1-yl-2-chloroacetic acid p-nitrobenzyl ester is dis 100 ml of diethyl ether and filtered through celite. The solved in 3 ml of dry tetrahydrofuran, 6 g of triphenyl organic phase is separated off, the aqueous phase is phosphine are added and the mixture is stirred for 24 extracted three times with 400 ml of diethyl ether, the O hours at room temperature. The reaction mixture is organic phases are combined, dried and concentrated diluted with 200 ml of methylene chloride, washed with by evaporation in vacuo. The residue is chromato saturated aqueous sodium bicarbonate solution, dried graphed over silica gel with toluene/ethyl acetate (2:1) over sodium sulphate and concentrated by evaporation and yields a racemic mixture of cis- and trans-4-acetoxy in vacuo. After chromatography over silica gel with 3-ethylazetidin-2-one in a ratio of 6:4 in oily form. IR 15 spectrum (CH2Cl2): absorption bands at 2.94, 5.60, 5.75, ethyl acetate, the residue yields the title compound. 7.35, 8.06 and 8.85. TLC: Rf-0.19 (ethyl acetate); IR spectrum (c) A solution of 1.708 g (14.35 mmole) of 2 (CH2Cl2): absorption bands at 2.93, 5.70, 5.97, 6.17, acetylaminoethyl mercaptain in 2 ml of absolute ethanol 6.58, 6.99, 7.00, 8.07, 8.33 and 9.39 p. is added dropwise over the course of 0.5 hours, while EXAMPLE 63: stirring and cooling to 10-15, to a solution of 0.80 g 20 (14.35 mmole) of potassium hydroxide in 5 ml of abso 2-(2-acetylaminoethylthio)-6-ethyl-2-penem-3-carboxy lute ethanol. After a further half hour, a solution of 1.09 lic acid p-nitrobenzyl ester (racemic cis- and g (14.35 mmole) of carbon disulphide in 3 ml of absolute trans-compound) ethanol is added, the temperature being maintained at 25 A catalytic amount of hydroquinone is added to a 10-15. The reaction mixture is further stirred for 3 solution of 1.75 g (2.34 mmole) of 2-3-ethyl-4-(2- hours at room temperature and cooled in an ice bath for acetylaminoethylthiothiocarbonylthio)-2-oxoazetidin 20 minutes. The yellow crystalline precipitate is filtered 1-yl)-2-tri-phenyl-phosphoranylideneacetic acid p off, washed once with absolute ethanol and yields potas nitrobenzyl ester (racemic cis-trans compound) in 1500 sium (2-acetylaminoethyl)-trithiocarbonate having a 30 ml of dry o-xylene and the mixture is refluxed for 7 melting point of 171-174. hours while stirring under nitrogen. The solvent is IR spectrum (KBr): absorption bands at 2.95, evaporated off in vacuo and the residue is chromato 6.18,6.50, 7.00, 7.32, 7.43, 7.79, 8.33, 9.09 and 11.83 p. graphed over silica gel with ethyl acetate. A mixture of EXAMPLE 61: the cis- and trans-title compound is obtained. 2-3-ethyl-4-(2-acetylaminoethylthiothiocarbonylthio)- 35 The cis- and the trans-title compound may be ob tained by a combination of preparative thin layer chro 2-oxoazetidin-1-yl)-2-hydroxyacetic acid p-nitrobenzyl matography (silica gel with methyl isobutyl ketone) and ester (racemic cis-trans compound) column chromatography (silica gel with ethyl acetate). 4.20 g (16.5 mmole) of 2-ethoxy-2-hydroxyacetic acid cis-compound: Melting point 141-142 (after crystal 8-nitrobenzyl ester are added at room temperature to a lisation from methylene chloride/diethyl ether); TLC: solution of 3.30 g (11 mmole) of 3-ethyl-4-(2- R0.62 (methyl isobutyl ketone); IR spectrum (CH2Cl2): acetylaminoethylthiothiocarbonylthio-2-oxoazetidine absorption bands at 2.93, 5.62, 5.98, 6.60, 7.46, 7.57, 8.44 (racemic cis-trans compound) in 120 ml of toluene and and 9.09 p. 32 ml of dimethylformamide. After adding freshly dried trans-compound: Melting point 132-133 (after crys molecular sieves the mixture is stirred under nitrogen for 3 hours at room temperature. The molecular sieves tallisation from methylene chloride/diethyl ether); are filtered off, washed with 20 ml of toluene and the TLC: R-0.56 (methyl isobutyl ketone); IR spectrum filtrate and washing liquid are together concentrated by (CH2Cl2): absorption bands at 2.92, 5.62, 5.96, 6.58, evaporation in vacuo. The residue is dried in a high 7.44, 7.58, 8.40 and 9.01 . vacuum and then triturated with diethyl ether to re 50 EXAMPLE 64: move unreacted 2-ethoxy-2-hydroxyacetic acid p-nitro benzyl ester. The title compound with the following 2-(2-acetylaminoethylthio)-6-ethyl-2-penen-3-carboxy physico-chemical properties is obtained: lic acid (racemic cis- and trans-compound) TLC: R?=0.16 (ethyl acetate); IR spectrum (a) 4 ml of 0.2N aqueous sodium bicarbonate solution (CH2C12): absorption bands at 2.86, 2.92, 3.03, 5.65, 55 and 200 mg of 10% palladium/carbon catalyst are 5.71, 5.97, 6.58, 7.41 and 8.37 p. added to a solution of 100 mg (0.22 mmole) of 2-(2 acetylaminoethylthio)-6-ethyl-2-penem-3-carboxylic EXAMPLE 62: acid p-nitrobenzyl ester (racemic cis-compound in 6 ml 2-3-ethyl-4-(2-acetylaminoethylthiothiocarbonylthio)- of absolute ethyl acetate and the mixture is stirred at 2-oxoazetidin-1-yl-2-triphenylphosphoranylideneacetic normal pressure for 60 minutes under hydrogen. The acid p-nitrobenzyl ester (racemic cis-trans compound) catalyst is filtered off from the hydrogenated mixture A solution of 5.52 g (11 mole) of 2-3-ethyl-4-(2- over diatomaceous earth. The aqueous phase is sepa acetylaminoethylthiothiocarbon-ylthio)-2-oxoazetidin rated off, washed with diethyl ether, acidified with 5% 1-yl)-2-hydroxyacetic acid p-nitrobenzyl ester (racemic aqueous citric acid solution and exhaustively extracted cis-trans compound) in 30 ml of absolute tetrahydrofu 65 with methylene chloride. The combined methylene ran is cooled to -15, while stirring 1.02 ml (14 mmole) chloride phases are dried over sodium sulphate, filtered, of thionyl chloride are added and subsequently 1.95 ml concentrated by evaporation in vacuo and dried in a (14 mmole) of triethylamine are slowly added. The high vacuum. The resulting cis-title compound has the 4,952,690 67 68 following physico-chemical properties: melting point ylformamide. After adding approximately 15 g of 153-154" (methylene chloride/diethyl ether; IR spec freshly dried molecular sieves, the mixture is stirred at trum (KBr): absorption bands at 3.08, 3.22, 3.39, 3.42, room temperature for 3 hours under nitrogen. The no 3.50, 3.77, 4.08, 5.67, 6.06, 6.21, 6.35, 6.75, 7.04, 7.69, lecular sieves are filtered off and washed with dimethyl 7.93, 8,27,901, 9.62 and 14.38 p. formanide/toluene (1:4). The filtrate is concentrated by b) In the safe manner the trans-title compound is evaporation in vacuo, dried in a high vacuum and the obtained from 100 mg of 2-(2-acetylaminoethylthio)- residue is triturated with diethyl ether to remove unre ethyl-2-penen-3-carboxylic acid p-nitrobenzyl ester acted 2-ethoxy-2-hydroxyacetic acid -p-nitrobenzyl (racemic trans-compound). ester. The crude title compound has the following IR spectrum (KBr): absorption bands at 3.01, 3.39, 10 physico-chemical properties: 3.44, 5.68, 6.10, 6.85, 7.75, 8.16, 8.47 and 8.93. TLC: Rs 0.1 (toluene/ethyl acetate 1:1); IR spec EXAMPLE 65: trum (CH2Cl2): absorption bands at 2.83, 2.90, 5.67, 3-ethyl-4-(4-p-nitrobenzyloxycarbonylaminobutyrylthi 5.73, 5.80, 5.99, 6.58, 7.52, 8.26 and 9.52. o)-2-oxoazetidine (racemic cis-trans compound in a 15 EXAMPLE 67: ratio of 1:4) 2-3-ethyl-4-(4-p-nitrobenzyloxycarbonylaminobutyryl A solution, prepared in the cold, of 7.95 g (26.7 thio)-2-oxoazetidin-1-yl)-2-triphenylphos mnole) of 4-p-nitrobenzyloxycarbonylaminothi phoranylideneacetic acid p-nitrobenzyl ester (racemic obutyric acid in 26.7 ml of 1N sodium hydroxide solu cis-trans compound) tion is added dropwise to a pre-cooled solution of 3.24 20 g (20 mmole) of 3-ethyl-4-acetoxyazetidin-2-one (race (a) 3.06 ml (42 mmole) of thionyl chloride and 5.85 ml mic cis-trans compound in a ratio of 6:4) in 50 ml of (42 mmole) of triethylamine are added dropwise, in dioxan and the mixture is stirred for 2 hours at room succession, at -15' to a mixture of 10.40 g (17.2 mmole) temperature. The reaction mixture is exhaustively ex of 2-3-ethyl-4-(4-p-nitrobenzyloxycar tracted with methylene chloride. The combined organic 25 bonylaminobutyrylthio)-2-oxoazetidin-1-yl)-2-hydrox phases are dried over sodium sulphate and concentrated yacetic acid p-nitrobenzyl ester in 40 ml of absolute by evaporation in vacuo. The residue is chromato dioxan. The reaction mixture is stirred for 20 minutes at graphed over silica gel with toluene/ethyl acetate (9:1, O' under nitrogen, diluted with 200 ml of methylene 4:1 and 1:1) and yields the title compound with the chloride and washed with cooled 1N hydrochloric acid. following physico-chemical properties. The organic phase is dried and concentrated by evapo TLC: Rf-0.10 (toluene/ethyl acetate 1:1); ration in vacuo. IR spectrum (CH2Cl2): absorption bands at 2.81, 2.92, (b) The resulting crude 2-3-ethyl-4-(4-p-nitroben 5.66, 5.81, 5.94, 6.58, 7.52 and 8.20 p. zyloxycarbonylaminobutyrylthio)-2-oxoazetidin- 1-yl)- The thiocarboxylic acid used as starting material is 2-chloroacetic acid p-nitrobenzyl ester is dissolved in a obtained as follows: 35 minimum amount of tetrahydrofuran, 9 g of triphenyl (a) A solution of 25.87 g (0.12 mmole) of p-nitroben phosphine are added and the mixture is stirred over zyl chloroformate in 100 ml of dry dioxan is added night at room temperature under nitrogen. The reaction dropwise over the course of 20 minutes to a solution of mixture is diluted with 250 ml of methylene chloride, 10.30 g (0.1 mmole) of 4-aminobutyric acid in 300 ml of washed with saturated aqueous sodium bicarbonate 1N sodium hydroxide solution in an ice bath. The reac 40 solution, dried and concentrated by evaporation in tion mixture is stirred at room temperature for 3 hours, vacuo. The residue is chromatographed over silica gel washed with ethyl acetate and acidified with 2N hydro with toluene/ethyl acetate (1:1) and yields the title com chloric acid. The precipitated 4-p-nitrobenzyloxycar pound with the following physico-chemical properties: bonylaminobutyric acid is filtered off and recrystallised TLC: Rf=0.05 (toluene/ethyl acetate 1:1); IR spec from ethyl acetate; melting point 145-146. 45 (b) In succession, 2.2 g (20 mmole) of triethylamine trum (CH2Cl2): absorption bands at 2.90, 5.73, 5.80, and a solution of 1.4 ml (10 mmole) of isobutyl chloro 5.94, 6.58, 7.52, 8.20 and 9.35. formate in 20 ml of dry methylene chloride are added EXAMPLE 68: dropwise to a solution, cooled to -10", of 2.82 g (10 6-ethyl-2-(3-p-nitrobenzyloxycarbonylaninopropyl)-2- mnole) of 4-p-nitrobenzyloxycarbonylaminobutyric 50 acid in 50 ml of dry methylene chloride. The reaction penen-3-carboxylic acid p-nitrobenzyl ester (racemic mixture is stirred for one hour and then a strong current cis-trans compound) of hydrogen sulphide is conveyed through for 2 hours. A catalytic amount of hydroquinone is added to a After acidifying with 2N sulphuric acid, the organic solution of 5.40 g (6.36 mmole) of 2-3-ethyl-4-(4-p- phase is separated off, dried and concentrated by evapo 55 nitrobenzyloxycarbonylaminobutyrylthio)-2-oxoazeti ration in vacuo. The resulting 4-p-nitrobenzyloxycar din-1-yl-2-triph-enylph-os-phoranylideneacetic acid bonylaminothiobutyric acid can be further processed -p-nitrobenzyl ester (racemic cis-trans compound) in without further purification. 1500 ml of dry toluene and the mixture is stirred under EXAMPLE 66: nitrogen for 20 hours at 100'. The solvent is evaporated off in vacuo and the residue is chromatographed over 2-3-ethyl-4-(4-p-nitrobenzyloxycarbonylaminobutyryl silica gel with toluene/ethyl acetate (4:1). A mixture of thio)-2-oxoazetidin-1-yl)-2-hydroxyacetic acid the cis- and trans-title compound is obtained in the ratio p-nitrobenzyl ester (racemic cis-trans compound) of 1:10 with the following physico-chemical properties: At room temperature 6.50 g (16.45mmole) of 3-ethyl TLC Rf=0.22 (toluene/ethyl acetate 1:1); IR spec 4-(4-p-nitrobenzyloxycarbonylaminobutyrylthio)-2- 65 trun (CH2Cl2): absorption bands at 2.90, 5.62, 5.81, oxoazetidine (racemic cis-trans compound) and 8.41 g 5.85, 6.58, 7.52, 7.87 and 8.20. By repeated chroma of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester tography the cis- and the trans-compound can be ob are dissolved in 160 ml of toluene and 40 ml of dimeth tained in pure form. 4,952,690 69 70 EXAMPLE 69: EXAMPLE 72 6-ethyl-2-(3-aminopropyl)-2-penem-3-carboxylic acid 2-(3S,4S)- and (racemic cis-trans compound) (3S,4R)-4-acetoxy-3-methoxy-2-oxoazetidin-1-yl)-2- 5 2 g of disodium biphosphate and 4 g of 10% palladi oxoacetic acid (3,13,13-trichloroethyl ester um/carbon catalyst are added to a solution of 2 g (3.5 3 equivalents of ozone are conveyed through a solu nmole) of 6-ethyl-2-(3-p-nitrobenzyloxycar tion, cooled to -30', of 0.91 g of 2-((3S,4S)- and bonylaminopropyl)-2-penem-3-carboxylic acid p-nitro (3S,4R)-4-acetoxy-3-methoxy-2-oxoazetidin-1-yl-3- benzyl ester (racemic cis-trans compound) in 600 ml of O methylcrotonic acid g,A},3-trichloroethyl ester in 130 dioxan, 330 ml of ethanol and 600 ml of water, and the ml of methyl acetate. After the ozone treatment, the mixture is stirred at normal pressure for one hour under mixture is left to stand for 15 minutes at the same tem hydrogen. The catalyst is filtered off from the hydroge perature and subsequently the excess ozone is removed nated mixture over diatomaceous earth. The filtrate is 5 by a nitrogen current. The reaction mixture is washed at washed 3 times with 1500 ml of ethyl acetate and lyo 0' with a 10% aqueous sodium sulphite solution and philised. The lyophilisate is chromatographed twice then with sodium chloride solution. The combined over silylated silica gel (thin layer plates ANTEC aqueous solutions are reextracted a further three times GEL, UP-C12) with water/acetonitrile (9:1) and yields with methyl acetate. The combined organic extracts are the title compound (cis:trans approximately 1:10) with dried over sodium sulphate and concentrated by evapo the following physico-chemical properties: TLC (AN ration in vacuo. TEC-GEL, UP-C12) R-0.55 (water/acetonitrile 9:1); IR spectrum (in methylene chloride): characteristic IR spectrum (KBr): absorption bands at 2.94, 3.39, 5.68, absorption bands at 3.41, 5.46, 5.68, 5.81, 7.27, 7.43, 8.23, 6.41, 7.33, 7.81, 8.93, 12.82 and 14.28. Using the pure cis- or trans-starting material, the pure 25 8.40, 9.52 and 9.90. cis- and trans-title compounds can be obtained. EXAMPLE 73 EXAMPLE 70: (3S,4S)- and (3S,4R)-4-acetoxy-3-methoxy -2-oxoazetidine 2-((3S,4S)- and (3S,4R)-4-acetoxy-3-methoxy-2-oxoazetidin-1-yl-3- 30 A solution of 120 mg of 2- (3S,4S)- and (3S,4R)-4- methylenebutyric acid (3, 3, g-trichloroethyl ester acetoxy-3-methoxy-2-oxoazetidin-1-yl-2-oxoacetic acid 0.114 ml of glacial acetic acid and 0.35 ml of trimethyl f3.f3,3-trichloroethyl ester in 25 ml of methanol, 3.5 ml phosphite are added to 200 mg of (6S)-6-methox of methyl acetate and 0.5 ml of water is refluxed for 20 ypenicillanic acid £3,43,3-trichloroethyl ester 1-oxide in 35 minutes. The solvent is evaporated offin vacuo and the 13 ml of absolute benzene and the mixture is refluxed for residue yields, after chromatography over silica gel 7 hours. The solvent is evaporated offin vacuo and the with toluene/ethyl acetate (9:1) the pure (3S,4R)-4- residue is purified by chromatography over silica gel acetoxy-3-methoxy-2-oxoazetidine; with toluene/ethyl acetate (19:1 and 9:1). IR spectrum (in methylene chloride): characteristic The title compounds can thus be separated. IR spec absorption bands at 2.96, 3.42, 5.57, 5.73, 7.30, 8.23, 8.70, trum (in methylene chloride); characteristic absorption 8.85, 9.62, 10.0 and 10.20, and on further elution the bands for (3S,4R)isomer (trans-compound) 3.42, 5.62, pure (3S,4S)-4-acetoxy-3-methoxy -2-oxoazetidine; IR 5.68, 7.25, 7.35, 8,26,9.01, 10.93 and 11.83.; (3S4S)-iso spectrum (in methylene chloride); characteristic absorp mer (cis-compound): 3.42, 5.61, 5.7, 7.25, 7.35, 8.21, 9.61 tion bands at 2.94, 3.41, 5.56, 5.73, 7.35, 7.49, 8.20 and and 10.93. 9.52. The ratio of cis to trans-compound is approximately EXAMPLE 74 1:1. (3S,4R)-4-(2-p-nitrobenzyloxycarbonylaminoethylthio EXAMPLE 71 50 thiocarbonylthio)-3-methoxy-2-oxoazetidine 2-(3S,4S)- and A solution of 422 mg of potassium 2-p-nitrobenzylox (3S,4R)-4-acetoxy-3-methoxy-2-oxoazetidin-1-yl-2- ycarbonylaminoethyl trithiocarbonate in 1 ml of water methylcrotonic acid (3,43,43-trichloroethyl ester. is added dropwise at room temperature under, a nitro A solution of 0.93 g of 2- (3S,4S)- and (3S,4R)-4- 55 gen atmosphere to a solution of 159 mg (1 mmole) of acetoxy-3-methoxy-2-oxoazetidin-1-yl)-3- (3S,4S)-4-acetoxy-3-methoxy-2-oxoazetidine in 3 ml of methylenebutyric acid (3,3,43-trichloroethyl ester in 60 phosphate buffer of a pH of 7 and 0.2 ml of dioxan, and ml of absolute methylene chloride is cooled to 0 and the mixture is stirred at the same temperature for 30 stirred for 10 minutes with 0.33 ml of triethylamine. The minutes. The reaction mixture is exhaustively extracted reaction mixture is then washed in succession with 4N with methylene chloride. The combined organic phases phosphoric acid, saturated aqueous sodium bicarbonate are dried over sodium sulphate and concentrated by solution and water and dried over sodium sulphate. The evaporation in vacuo. The residue is chromatographed solvent is evaporated off in vacuo and the residue is over silica gel and yields the title compound with the purified by chromatography over silica gel. 65 following IR spectrum (in methylene chloride): characteristic IR spectrum (in methylene chloride); characteristic absorption bands at: 3.41, 5.60, 5.73, 6.13, 7.19, 7.33, absorption bands at 2.95, 5.62, 5.78, 6.21, 6.56, 7.41, 8.26 8.26, 9.09, 9.57, 10.64, 10.87 and 12.19. and 9.25. 4,952,690 71 72 ing up, the title compound with the following IR spec EXAMPLE 75 trum (KBr) is obtained: Absorption bands at 2.8-4.16, 2-(3S,4R)-4-(2-p nitrobenzyloxycarbonylaminoethylthiothiocarbonylthi 5.68, 6.41 and 8.26. o)-3-methoxy-2-oxoazetidin-1-yl)-2-hydroxyacetic acid 5 EXAMPLE 79 p-nitrobenzyl ester (3S,4R)-4-(4-p-nitrobenzyloxycarbonylaminobutyryl Analogously to Example 23, 646 mg (1.5 minole) of thio)-3-methoxy-2-oxoazetidine (3S,4R)-4-(2-p-nitrobenzyloxycarbonylaminoethylthio thiocarbonylthio)-3-methoxy-2-oxoazetidine in 22 ml of Analogously to Example 55b), an aqueous solution of absolute toluene and 5.5 ml of absolute dimethylform O 480 mg of 4-p-nitrobenzyloxycarbonylaminothiobutyric amide are reacted with 848 mg of 2-ethoxy-2-hydroxya acid sodium salt is added to 159 mg of (3S,4S)-4- cetic acid p-nitrobenzyl ester in the presence of freshly acetoxy-3-methoxy-2-oxoazetidine in 6 ml of a phos dried molecular sieves. After working up and chroma phate buffer of a pH of 7 and 0.4 ml of dioxan After tography over silica gel the title compound is obtained. working up and chromatography over silica gel, the IR spectrum (in methylene chloride); characteristic 15 title compound with the following IR spectrum absorption bands at 5.62, 5.7, 5.78, 6.56, 7.41 and 8.26. (CH2Cl2) is obtained: characteristic absorption bands at 2.95, 5.6, 5.78, 5.87, 6.56, 7.41 and 8.26. EXAMPLE 76 2-((3S,4R)-4-(2-p-nitrobenzyloxycarbonylaminoethyl EXAMPLE 80 thiothiocarbonylthio)-3-methoxy-2-oxoazetidin-1-yl)-2- 20 2-(3S,4R)-4-(4 triphenylphosphoranylideneacetic acid p-nitrobenzyl p-nitrobenzyloxycarbonylaminobutyrylthio)-3- este methoxy-2-oxoazetidin-1-yl)-2-hydroxyacetic acid Analogously to Example 24, 0.12 ml of thionyl chlo p-nitrobenzyl ester ride and 0.23 ml of triethylamine in 0.23 ml of absolute Analogously to Example 23, 400 mg of (3S,4R)-(4-p- tetrahydrofuran are added to a solution of 640 mg of 25 nitrobenzyloxycarbonylaminobutyrylthio)-3-methoxy 2-((3S,4R)-4-(2-p-nitrobenzyloxycarbonylaminoethyl 2-oxoazetidine in 15 ml of absolute toluene and 3.7 ml of thiothiocarbonylthio)-3-methoxy-2-oxoazetidin-1-yl)-2- absolute dimethylformamide are reacted with 565 mg of hydroxyacetic acid p-nitrobenzyl ester in 4.5 ml of abso 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester in lute tetrahydrofuran. After reacting and working up, 30 the presence of freshly dried molecular sieves. After 0.54 g of triphenylphosphine is added to the crude 2 working up and chromatography over silica gel, the (3S,4R)-4-(2-p-nitrobenzyloxycarbonylaninoethylthio title compound with the following IR spectrum thiocarbonylthio)-3-methoxy-2-oxoazetidin-1-yl)-2- (CH2Cl2) is obtained: characteristic absorption bands at chloroacetic acid p-nitrobenzyl ester, obtained as inter 5.6, 5.7, 5.78, 5.87, 6.56, 7.41 and 8.26. mediate, in 1.15 ml of absolute tetrahydrofuran. After 35 working up and chromatography over silica gel, the EXAMPLE 81 title compound is obtained. 2-(3S,4R)-4-(4-p-nitrobenzyloxycar IR spectrum (in methylene chloride): characteristic bonylaminobutyrylthio)-3-methoxy-2-oxoazetidin-1- absorption bands at 3.4, 5.7, 5.78, 6.15, 6.55, 7.45 and yl)-2-triphenylphosphoranylideneacetic acid 8.26. p-nitrobenzyl ester EXAMPLE 77 Analogously to Example 24, 0.12 ml of thionyl chlo (6S,5R)-2-(2-p-nitrobenzyloxycarbonylaminoethylthi ride and then 0.23 ml of triethylamine in 0.23 ml of o)-6-methoxy-2-penem-3-carboxylic acid p-nitrobenzyl absolute tetrahydrofuran are added to a solution of 606 ester 45 ng of 2-(3S,4R)-4-p-nitrobenzyloxycar Analogously to Example 25, a solution of 500 mg of bonylaminobutyrylthio)-3-methoxy-2-oxoazetidin-1- 2-(3S,4R)-4-(2-p-nitrobenzyloxycarbonylaminoethyl yl)-2-hydroxyacetic acid p-nitrobenzyl ester in 4.5 ml of thiothiocarbonylthio)-3-methoxy-2-oxoazetidin-1-yl-2- absolute tetrahydrofuran. After reacting and working triphenylphosphoranylideneacetic acid p-nitrobenzyl up, 0.54 g of triphenylphosphine is added to the result ester in 165 ml of absolute o-xylene is stirred under 50 ing crude 2-(3S,4R)-4-(4-p-nitrobenzyloxycar reflux. bonylaminobutyrylthio)-3-methoxy-2-oxoazetidin-1- After working up and chromatography over silica gel yl)-2-chloroacetic acid p-nitrobenzyl ester in 1.15 ml of with toluene/ethyl acetate (19:1 to 9:1) the title con absolute tetrahydrofuran. Working up and chromatog pound is obtained. raphy over silica gel produce the title compound with IR spectrum (CH2Cl2): absorption bands at 5.57, 5.78, 55 the following IR spectrum (CH2Cl2): characteristic 5.9, 6.55, 7.45 and 8.26. absorption bands at 5.7, 5.78, 5.9, 6.15, 6.55, 7.45 and EXAMPLE 78 8.26. (6S,5R)-2-(2-aminoethylthio)-6-methoxy-2-penem-3- EXAMPLE 82 carboxylic acid 60 (6S,5R)-2-(3-p-nitrobenzyloxycarbonylaminopropyl)-6- Analogously to Example 69, a solution of 295 mg of (6S,5R)-2-(2-p-nitrobenzyloxycarbonylaminoethylthi methoxy-2-penem-3-carboxylic acid p-nitrobenzyl ester o)-6-methoxy-2-penem-3-carboxylic acid p-nitrobenzyl Analogously to Example 68, a solution of 400 mg of ester in 85 ml of dioxan, 47 ml of ethanol and 85 ml of 2- (3S,4R)-4-(4-p-nitrobenzyloxycarbonylaminobuty water is treated with 286 mg of disodium hydrogen 65 rylthio-3-methoxy-2-oxoazetidin-1-yl)-2-triphenylphos phosphate and 570 mg of a 10% palladium-on-carbon phoranylideneacetic acid p-nitrobenzyl ester in 160 ml catalyst, and the mixture is stirred in a hydrogen atmo of absolute toluene is stirred under reflux. After work sphere under normal pressure. After reacting and work ing up and chromatography over silica gel with 4,952,690 73 74 toluene/ethyl acetate (19:1 to 9:1) the title compound is for 30 minutes. The solvent is evaporated off and the obtained. residue is chromatographed over silica gel. The title IR spectrum (CH2Cl2): characteristic absorption compound has the following IR spectrum (CH2Cl2): bands at 5.57, 5.78, 5.85, 6.55, 7.45 and 8.26. Characteristic absorption bands at 2.94, 5.56, 8.26 and EXAMPLE 83 9.09. (6S,5R)-2-(3-aminopropyl-6-methoxy-2-penem-3-car EXAMPLE 87 boxylic acid. (3S,4R)-4-(4-p-nitrobenzyloxycarbonylaminobutyryl thio)-3-methoxy-2-oxoazetidine (6S,5R)-2-(3-p-nitrobenzyloxycarbonylaminopropyl)-6-0Analogously to Example 69, a solution of 572 ml of methoxy-2-penem-3-carboxylic acid p-nitrobenzyl ester A solution of 350 mg of 4-p-nitrobenzyloxycar in 170 m of dioxan, 94 ml of ethanol and 170 ml of water bonylaminothiobutyric acid sodium salt in 4 ml of water is treated with 571 mg of disodium hydrogen phosphate is added dropwise to a solution of 135 mg of (3S,4R)-4- and 1.14 g of a 10% palladium-on-carbon catalyst and is chloro-3-methoxy-2-oxoazetidine in 6 ml of a phosphate stirred in a hydrogen atmosphere under normal pres buffer of a pH of 7 and 0.4 ml of dioxan in the presence Se. of 150 mg of sodium iodide. After reacting and working up, the title compound After stirring for 30 minutes at room temperature the with the following IR spectrum (KBr) is obtained: Ab mixture is exhaustively extracted with methylene chlo ride. After removing and drying the organic phase over sorption bands at 2.75-4.15, 5.67, 6.42 and 8.25u. sodium sulphate, the solvent is evaporated offin vacuo EXAMPLE 84 and the residue is chromatographed over silica gel. The 2-((3S,4S)- and title compound has the following IR spectrum (C2Cl2): (3S,4R)-4-chloro-3-methoxy-2-oxoazetidin-1-yl)-3- Absorption bands at 2.95, 5.6, 5.78, 5.87, 6.56, 7.41 and methylcrotonic acid 3,3,3-trichloroethyl ester 8.26. 25 3.25 ml of a 1.1M chlorine solution in CC4 are added EXAMPLE 88 dropwise at -80' to 612 mg of (6S)-6-methoxypenicil lanic acid 3,A,A-trichloroethyl ester in 9 ml of absolute Using corresponding starting materials and by way of methylene chloride. corresponding intermediates, the following compounds After stirring for 2 hours at -80, the reaction mix are obtained analogously to the aforegoing Examples: ture is warmed up to room temperature in the course of 30 6-ethyl-2-(2-aminoethylthio)-2-penem-3-carboxylic one hour. The solvent is evaporated off in vacuo and acid, the residue is chromatographed over silica gel 10 % 6-hydroxymethyl-2-penen-3-carboxylic acid, water. The title compounds have the following IR spec 6-hydroxymethyl-2-methyl-2-penen-3-carboxylic acid, trum (in CH2Cl2): characteristic absorption bands at 6-hydroxymethyl-2-(3-aminopropyl)-2-penem-3-car 3.41, 5.60, 5.76, 6.15, 7.22, 7.35, 8.33, 9.09, 9.52 and 35 boxylic acid, 12.20. In the resulting mixture the ratio of (3S,4S)- 6-hydroxymethyl-2-(3-acetylaminopropyl)-2-penem-3- compound to (3S,4R)-compound is 1:10. carboxylic acid, 6-hydroxymethyl-2-ethylthio-2-penem-3-carboxylic EXAMPLE 85 acid, 6-hydroxymethyl-2-(2-aminoethylthio)-2-penem-3-car (3S,4R)-4-chloro-3-methoxy-2-oxoazetidin-1-yl)-2- boxylic acid, oxoacetic acid A.A.A-trichloroethyl ester 6-hydroxymethyl-2-(2-acetylaminoethylthio-2-penem 3 equivalents of ozone are conveyed through a solu 3-carboxylic acid, tion, cooled to -35 C., of 210 mg of 2-((3S,4S)- and 45 6-(1-hydroxyethyl)-2-penem-3-carboxylic acid, (3S,4R)-4-chloro-3-methoxy-2-oxoazetidin-1-yl)-3- 6-(1-hydroxyethyl)-2-methyl-2-penem-3-carboxylic methylcrotonic acid S.A.f3-trichloroethyl ester in 30 ml acid, of methyl acetate. After the ozone treatment, the mix 6-(1-hydroxyethyl)-2-(3-aminopropyl)-2-penem-3-car ture is left to stand for 15 minutes at the same tempera boxylic acid, ture and then the excess ozone is removed by a current so 6-(1-hydroxyethyl)-2-(3-acetylaminopropyl)-2-penem of nitrogen. The reaction mixture is washed at 0 with a 3-carboxylic acid, 10% aqueous sodium bisulphite solution and then with 6-(1-hydroxyethyl)-2-ethylthio-2-penen-3-carboxylic sodium chloride solution. The combined aqueous solu acid, tions are re-extracted a further 3 times with methyl 6-(1-hydroxyethyl)-2-(2-aminoethylthio)-2-penem-3- acetate. The organic extracts are dried over sodium iss carboxylic acid, sulphate and concentrated by evaporation in vacuo. 6-(1-hydroxyethyl)-2-(2-acetylaminoethylthio)-2- The crude title compound has the following IR spec penem-3-carboxylic acid, trum (in CH2Cl2): characteristic absorption bands at 6-methoxy-2-penem-3-carboxylic acid, 3.41, 5.46, 5.65, 5.80, 7.46, 8.23, 8.47, 8.89, 9.57, 9.95 and 6-methoxy-2-(3-acetylaminopropyl)-2-penem-3-car 11.90. boxylic acid, 6-methoxy-2-ethylthio-2-penem-3-carboxylic acid, EXAMPLE 86 6-methoxy-2-(2-acetylaminoethylthio)-2-penem-3-car (3S,4S)- and boxylic acid, (3S,4R)-4-chloro-3-methoxy-2-oxoazetidine 6-methoxy-2-(1,3,4-thiadiazol-2-ylthio)-2-penem3-car A solution of 339 mg of 2-((3S,4S)- and (3S,4R)-4- 65 boxylic acid, chloro-3-methoxy-2-oxoazetidin-1-yl)-2-oxoacetic acid 6-(2 hydroxyprop-2-yl)-2-penem-3-carboxylic acid, f,3,43-trichloroethyl ester and 197 mg of 2,4-dinitro 6-(2-hydroxyprop-2-yl)-2-methyl-2-penem-3-carboxylic phenylhydrazine in 9 ml of tetrahydrofuran are refluxed acid, 4,952,690 75 76 6-(2-hydroxyprop-2-yl)-2-(3-aminopropyl)-2-penem-3- alkylthio, chloro, bromo, fluoro, or by carboxyl; carboxylic acid, and 6-(2-hydroxyprop-2-yl)-2-(3-acetylaminopropyl)-2- Z' is oxygen, sulfur, methoxycarbonylmethylidene or penen-3-carboxylic acid, 1-menthyloxycarbonylmethylidene; and 6-(2-hydroxyprop-2-yl)-2-ethylthio-2-penem-3carboxy- 5 the functional groups in the radicals designated Ra and lic acid, R1 are either in protected or unprotected form. 6-(2-hydroxyprop-2-yl)-2-(2-aminoethylthio-2-penem- 2. A compound of the formula 3-carboxylic acid, 6-(2-hydroxyprop-2-yl)-2-(2-acetylaminoethylthio-2- a Z penen-3-carboxylic acid, O H- SN both in racemic and in optically active form, and their Yr, salts. o? > -o EXAMPLE 89 Os R2A Dry ampoules orphials, containing 0.5g of 6-ethyl-2- (3-aminopropyl)-2-penen -3-carboxylic acid as active wherein substance, are produced as follows: Composition (for 1 Rais (1R)-1-hydroxyethyl; ampoule or phial): R2A together with the carbonyl to which it is at tached is a protected carboxyl group; a als 20 R1 iss SR, ins which R is C1-7 alkyl, phenyl, phenylalkyl composition (for 1 ampoule or phial): having 7-13 carbon atoms, or E. having vibetance Si. up to 10 carbon atoms and up to 4 ring hetero Ug atoms selected from nitrogen, oxygen, and sulphur, 25 with the proviso that two oxygen atoms or two Asterile aqueous solution of the active substance and sulfur atoms or one oxygen aton and one sulfur the mannitol is subjected to freeze-drying under aseptic atom are not adjacent to each other, each R being conditions in 5 ml ampoules or 5 ml phials and the am- unsubstituted or substituted by amino, mono C1-7 poules or phials are sealed and examined. alkylamino, di-C1-7alkylamino, hydroxy, C1-7 alk EXAMPLE 90 30 oxy, mercapto, C1-7 alkylthio, nitro, chloro, bromo, fluoro, cyano or carboxyl; and Dry ampoules orphials, containing 0.25g of 6-ethyl- Z' is oxygen, sulfur, methoxycarbonylmethylidene or 2-(3-aminopropyl)-2-penen-3-carboxylic acid as active 1-menthyloxycarbonylmethylidene; and substance, are produced as follows: the functional groups in the radicals designated Ra and is R1 are either in protected or unprotected form. Composition (for lampoule or phial): 3. The compound of the formula active substance 0.25 g mannitol 0.025 g Z (XII) R. H. I E ES-C-R1 Asterile aqueous solution of the active substance and 40 H the mannitol is subjected to freeze-drying under aseptic e-N conditions in 5 ml ampoules or 5 ml phials and the am- O o poules or phials are sealed and examined. TYRA What is claimed is: 45 1. A compound of the formula wherein Ra is (1R)-1-hydroxyethyl; R. H Z R1 is methylthio, ethylthio, aminoethylthio, 3-amino H--- s- propylthio, 4-aminobutylthio, 5-aminopentylthio, yr SO methyl, 2-furyl, 2-thienyl, 2-pyridyl, or (1-methyl o? Y- O tetrazol-5-yl)thio; and o- R2A together with the carbonyl to which it is at R2A tached is a protected carboxyl group, and Z' is oxygen or sulphur. wherein 55 4. A compound of the formula Ra is (1R)-1-hydroxyethyl; R2A together with the carbonyl to which it is at- Z (XII) tached is a protected carboxyl group; R. H R1 is -R, in which R is C1-7 alkyl, phenyl, phenylal- -Sl kyl having 7-13 carbon atoms, or heterocyclyl or 60 heterocyclylalkyl having up to 10 carbon atoms e-N O and up to 4 ring hetero atoms selected from nitro- o gen, oxygen, and sulphur, with the proviso that RA two oxygen atoms or two sulfur atoms or one oxy gen atom and one sulfur atom are not adjacent to 65 wherein Ra is hydroxymethyl or (1R)-1-hydroxyethyl; each other, each R being unsubstituted or substi- R2A together with the carbonyl to which it is attached tuted by amino, mono C1-7 alkylamino, di-C1-7 al- is a protected carboxyl group; kylamino, hydroxy, C1-7 alkoxy, mercapto, C1-7 R is 4,952,690 77 - 78 (a), lower alkyl, hydroxy-lower alkyl, lower al- 9. The compound of claim 4 wherein said R1 amino koxy-lower alkyl, lower alkanoyloxy-lower al- lower alkyl-thio is amino methylthio or amino-C3-C7 kyl, lower alkylthio-lower alkyl, amino-lower alkylthio. -ami 10. The compound of claim 2 wherein said R1 amino Exity amino-lower alkyl, or car 5 lower alkyl-thio is amino methylthio or amino-C3-C7 (b) pheny which is unsubstituted or substituted by "E. compound of claim 4 wherein lower alkyl, lower alkoxy, hydroxy, halogen, R2A is 2-halo lower alkoxy, 2-lower alkylsulfonyl nitro, or by amino, lower alkoxy, tert-lower alkoxy, diphenylme (c) furyl, thienyl, or pyridyl, or O thoxy, 4-dimethoxydiphenyl methoxy, lower al (d) lower alkenylthio or lower alkylthio which is kenyloxy, lower alkoxyphenyl-lower alkoxy, ni unsubstituted or substituted by lower alkoxy, trobenzyloxy, furfuryloxy, acetonyloxy, phena lower alkanoyloxy, lower alkoxycarbonyl, Car- cryloxy, 2,4-dioxo-3-pentoxy, 1-methoxycarbonyl bamoyl, cyano, nitro, amino, lower alkyl amino, 2-oxopropoxy, 1-ethoxycarbonyl-2oxopropoxy, di-lower alkyl amino, lower alkanoyl amino; or 5 2-cyanoethoxy, 2-cyano-2-phenylethoxy, 2-tri loweralkylsilylethoxy, 2-tri-phenylsilylethoxy, 2 di-lower alkanoyl amino; and tetrahydrofuryloxy, 2-tetrahydropyranyloxy, 2,3- Z' is oxygen, sulfur, or a methoxycarbonylmethyli- dihydro-2-pyranyloxy, nitrophenoxy, polyhalo dene or 1-menthyloxycarbonylmethylidene; and phenoxy, or lower alkoxy. the functional groups in the radicals designated Ra and 20 12. The compound of claim 2 wherein R1 are either in protected or unprotected form. R2A is 2-halo lower alkoxy, 2-lower alkylsulfonyl 5. The compound of claim 4 wherein Ra is hydroxy- lower alkoxy, tert.-lower alkoxy, diphenylme methyl and R1 is ethylthio. thoxy, 4,4'-dimethoxyldiphenyl methoxy, lower 6. The compound of claim 4 wherein Ra is (1R)-1- alkenyloxy, lower alkoxyphenyl-lower alkoxy, hydroxyethyl and R1 is 3-aminopropyl. 25 nitrobenzyloxy, furfuryloxy, acetonyloxy, 7. The compound of claim 4 wherein Ra is (1R)-1- phenacyloxy, 2,4-dioxo-3-pentoxy, 1-methoxycar hydroxyethyl and R1 is ethylthio. bonyl-2-oxopropoxy, 1-ethoxy-carbonyl-2-oxo 8. The compound of claim 4 wherein Ra is (1R)-1- 2-tri-loweralkylsilylethoxy,propoxy, 2-cyanoethoxy, 2-cyano-2-phenylethoxy, 2-tri-phenylsilyle hydroxyethyl and R1 is 30 thoxy, 2-tetrahydrofuryloxy, 2-tetrahy ethylthio, methylthio, aminomethylthio, 3-aminopro- dropyranyloxy, 2,3-dihydro-2-pyranyloxy, nitro pylthio, 4-aminobutylthio, methyl, 2-furyl, 2-thie- phenoxy, polyhalophenoxy, or lower alkoxy. nyl, or 2-pyridyl. it is a

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