United States Patent (19) 11 4,260,746 Taylor et al. 45) Apr. 7, 1981

54 CHEMICAL INTERMEDIATES USEFUL TO (56) References Cited PREPARE CEPHALOSPORINS U.S. PATENT DOCUMENTS 75) Inventors: Andrew W. Taylor, Dorking; George 3,843,641 10/1974 Christensen et al...... 544/21 Burton, Sutton; John P. Clayton, 3,860,585 1/1975 Carroll et al...... 260/306.7 C Horsham, all of England 3,960,845 9/1977 Yanagisawa et al.... r 544/21 4,014,873 3/1977 Christensen et al...... 544/21 73 Assignee: 4,051,299 9/1977 Shimizu et al...... 544/21 Beecham Group Limited, England 4,051,320 9/1977 Yanagisawa et al...... 544/21 21 Appl. No.: 85,039 4,058,661 1 1/1977 Cama et al...... 544/21 4,086,423 4/1978 Firestone et al...... 544/21 (22 Filed: Oct. 15, 1979 FOREIGN PATENT DOCUMENTS Related U.S. Application Data 2534946 3/1976 Fed. Rep. of Germany. 62 Division of Ser. No. 810,330, Jun. 27, 1977, Pat. No. Primary Examiner-Nicholas S. Rizzo 4,202,973. Attorney Agent, or Firm-Jacobs & Jacobs 30 Foreign Application Priority Data 57 ABSTRACT 7a-Methoxy-73-acylamino cephalosporins are prepared Jun. 26, 1976 GB United Kingdom ...... 26684/76 from 7(3-acylamino cephalosporins through formation 51) Int. Cl...... C07D 501/20; C07D 501/36; of a ketenimine by the action of an acid halide, forma CO7D 501/04 tion of an addition reaction adduct of this ketenimine, 52 U.S.C...... 544/021; 544/22; treatment of the adduct with a methoxide to form a 544/24; 544/25; 544/27; 544/28; 544/30; 7a-methoxy ketenimine and hydrolysis of the latter 424/246 ketenimine. 58 Field of Search ...... 544/28, 21, 27, 22, 544/29, 30, 15 Claims, No Drawings 4,260,746

CHEMICAL INTERMEDIATES USEFUL TO (I) PREPARE CEPHALOSPORNS

CROSS-REFERENCE This is a division of Ser. No. 810,330 filed June 27, 1977, now U.S. Pat. No. 4,202,973. DETALED DESCRIPTION 10 This invention relates to a class of intermediates use wherein R represents a furyl, thienyl, cycloalkyl, cy ful for the preparation of antibacterially active cephalo cloalkenyl, or phenyl group, or a phenyl group substi sporin derivatives, in particular 7a-methoxy cephalo tuted by from 1 to 3 hydroxy, halogen, nitro, C1-6alkyl, sporin having a carboxylic acid function at the 2-posi C1-C6alkoxy, amino or carboxy groups; tion in the side chain. The invention also relates to a 15 R represents an ester-forming radical; process for the preparation of the novel intermediates R2 represents an in vivo hydrolysable ester radical or and to a process for their conversion to the cephalospo a carboxyl-blocking group; A represents , pyridyl, acetoxy, car British Pat. No. 1,463,468 discloses a process for the bamoyloxy or a heterocyclicthio group; preparation of 7-alkoxy cephalosporins which com 20 n is zero or 1 and the dotted line represents a double prises reacting a cephalosporin having a hydroxy or bond at either the 2- or 3-positions. halo group on the 2-position of the side chain with a The group A may advantageously be a group of for halogenating agent to form a 2,3-dihaloinine and subse mula: quently reacting this with an alkali metal alkoxide to 25 -S- Het; give a 7-alkoxyketeninine which is hydrated to give the required product. One disadvantage of this process is wherein "Het' is a five or six-membered heterocyclic that the hydroxy- or halo-cephalosporin starting mate ring containing from 1 to 4 atoms selected from N, O, rial must be prepared by acylation of 7-amino cephalo and S unsubstituted or substituted with one or two sporanic acid with the corresponding side chain. The 30 groups selected from C1-6alkyl, C1-C6alkenyl, C1-C- process does not provide a method for the introduction 6alkoxy, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, car of a 7c-alkoxy substituent directly into a 7-acylamino bamoyl, carbamoylmethyl, trifluoromethyl, hydroxy, cephalosporin. and halogen. Furthermore, in the above process the 2,3-dihaloi 35 Examples of the group “Het' include unsubstituted mine intermediate must be isolated in order to remove and substituted diazolyl, triazolyl, tetrazolyl, thiazolyl, excess halogenating agent (such as phosphorus penta thiadiazolyl, thiatriazolyl, oxazolyl, and oxadiazolyl groups. Suitable groups "Het' include unsubstituted chloride) therefrom prior to treatment with the alkali and substituted 1,2,3-triazolyl; 1,2,4-triazolyl; 1,2,3,4- metal alkoxide. However, in the case of cephalosporin tetrazolyl; oxazolyl; thiazolyl; 1,3,4-oxadiazolyl; 1,3,4- derivatives having a carboxylic acid function at the thiadiazolyl, or 1,2,4-thiadiazolyl. 2-position, the dihaloimine is thermally unstable and the Preferably, A is 2-methyl-1,3,4-thiadiazol-5-ylthio; process is therefore unsuitable for that class of cephalo 1-methyl-(1H)-1,2,3,4-tetrazol-5-ylthio; 2-methyl-1,3,4- sporins. oxadiazol-5-ylthio; or (1H)-1,3,4-triazol-5-ylthio. West German Offenlegungsschrift No. 2,534,946 dis Preferably, n is zero and the dotted line in formula (I) closes a related process for the preparation of 7-alkoxy 45 represents a double bond in the 3-position. cephalosporins via a ketenimine intermediate. The Suitable groups R include 2- and 3-furyl, 2- and 3 ketenimine is prepared by reacting a 7-acylamino ceph thienyl, cyclopropy, cyclobutyl, cyclopentyl, cyclo alosporin with a halogenating agent and treating the hexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cy resulting imino halide with a base to give a ketenimine. 50 clohexa-1,4-dienyl, phenyl, 4-hydroxyphenyl, 3-chloro Although the scope of the disclosure covers the case of 4-hydroxyphenyl, 3,4-dihydroxyphenyl. cephalosporins having alkoxycarbonyl groups at the Most suitably R is 2- or 3-thienyl, phenyl or 4 2-position of the side chain, there is no specific example hydroxyphenyl; preferably, phenyl. described therein of a cephalosporin bearing a 2-car In vivo hydrolysable pharmaceutically acceptable boxylic acid or ester group on the side chain. 55 ester forming radicals for the group R2 are those which, when attached at that position on a cephalosporin nu We have now found that for a small group of cepha cleus, hydrolyse readily in the human body to produce losporins derivatives bearing a carboxylic acid or ester. the parent acid. It is well established that simple alkyl substituent at the 2-position on the side chain, a keteni and aryl esters of cephalosporins fail to meet this re mine intermediate can be produced directly from the 60 quirement as they are resistant to hydrolysis by human 7-acylaminocephalosporin without the intermediate tissues. Examples of suitable in vivo hydrolysable ester isolation of an imino-halide and without the need for a radicals for the group R2 include acyloxyalkyl groups separate treatment with a base. This group of keteni such as acetoxymethyl, pivaloyloxymethyl, a-acetox mine intermediate therefore, have advantages over the yethyl, a-acetoxybenzyl and a-pivaloyloxyethyl broad class of intermediates disclosed in Offenlegungss 65 groups; alkoxycarbonyloxyalkyl groups, such as ethox chrift No. 2,534,946. ycarbonyloxymethyl and a-ethoxycarbonyloxyethyl; Accordingly, the present invention provides a keteni and lactone, thiolactone and dithiolactone groups, i.e. mine of formula (I): ester groups of formula: 4,260,746 3 4. with the Lewis acid may be facilitated by addition of a nucleophile such as anisole); -CO. O. -H-7 reduction with agents such as zincMacetic acid, zinc/- X" - CEY' , zincMlower alcohol, zincMpyridine, 5 palladised-charcoal and hydrogen, and sodium and wherein X" and Y are of sulphur and Z' is an liquid ; group or a 1,2-phenylene group optionally attack by nucleophiles, such as those containing a substituted by lower-alkoxy, halogen or nitro. nucleophilic oxygen or sulphur atom for example Preferred ester groups are the phthalide and 5,6- alcohols, mercaptans and ; oxidative meth dimethoxyphthalide esters. 10 ods, for example, those which involve the use of Suitable carboxyl-blocking derivatives for the group and ; and irradiation. R2 in formula (I), include salts, ester, and anhydride The group R may be any ester-forming radical as derivatives of the carboxylic acid. The derivative hydrolysis to the free acid at that position is not essen should be one which may readily be cleaved at a later tial for the activity of the eventually produced cephalo stage of the reaction. Suitable salts include tertiary 15 sporin derivative. The group R may therefore be any of amine salts, such as those with tri-loweralkylamines, the radicals described above as being in vivo hydrolysa N-ethyl-piperidine, 2,6-lutidine, pyridine, N-methylpyr ble when present at the 4-position of the cephalosporin rolidine, dimethylpiparazine. A preferred salt is with nucleus; or it be any of the above-mentioned carboxyl triethylamine. blocking groups. Suitable carboxyl-blocked groups of formula CO2R2 20 In addition the group R may be an alkyl, cycloalkyl, include the following: alkenyl, alkynyl, aryl, or heterocyclic group any of (i) -COOCRRdR wherein at least one of Rc, Rd which may be substituted. Suitable such groups include: and Re is an electron-donor e.g. p-methoxyphenyl, (a) alkyl especially C1-6 alkyl such as methyl, ethyl, n 2,4,6-trimethylphenyl, 9-anthryl, methoxy, acetoxy, and iso-propyl, n-, sec-, iso- and tert-butyl, and methoxymethyl, benzyl or fur-2-yl. The remaining Rc, 25 pentyl; Rd and Regroups may be hydrogen or organic substitut (b) substituted C1-6 alkyl wherein the substituent is at ing groups. Suitable ester groups of this type include least one of chloro, bromo, fluoro, nitro, carbo p-methoxybenzyloxy-carbonyl, 2,4,6-trimethylben (C1-6 alkoxy), C1-6 alkanoyl, C1-6 alkoxy, cyano, zyloxy carbonyl, bis(p-methoxyphenyl)methoxycarbo C1-6 alkylmercapto, (C1-6 alkylsulfinyl, C-6 alkyl nyl, 3,5-di-t-butyl-4-hydroxybenzyloxycarbonyl, me- 30 sulphonyl, 1-indanyl, 2-indanyl, furyl, pyridyl, 4 thoxymethoxycarbonyl and benzyloxycarbonyl. imidazolyl, phthalimido, azetidino, aziridino, pyr (ii) -COOCRRRe wherein at least one of Re, Rd rolidino, piperidino, morpholino, thiomorpholino, and Re is an election-attracting group e.g. benzoyl, p N-(C1-6 alkyl)piperazino, pyrrolo, imidazolo, 2 nitrophenyl, 4-pyridyl, trichloromethyl, tri imidazolino, 2,5-dimethylpyrrolidino, 1,4,5,6-tet bromomethyl, iodomethyl, cyanomethyl, ethoxycar. 35 rahydropyrimidino, 4-methylpiperidino, 2,6-dime bonylmethyl, arylsulphonylmethyl, 2-dimethylsul thylpiperidino, alkylamino, dialkylamino, al phoniumethyl, o-nitrophenyl or cyano. The remaining kanoylamino, N-alkylanilino, of substituted N Rc, Rd and Regroups may be hydrogen or organic sub alkylanilino wherein the substituent is chloro, stituting groups. Suitable esters of this type include bromo, C1-6 alkyl or C1-6 alkoxy; benzoylmethoxycarbonyl, p-nitrobenzyloxycarbonyl, 40 (c) cycloalkyl and (C1-6 alkyl) substituted cycloalkyl 4-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycar having from 3 to 7 carbon atoms in the cycloalkyl bonyl and 2,2,2-tribromoethoxycarbonyl. moiety; (iii) -COOCRRdRe wherein at least two of Re, Rd (d) alkenyl having up to 8 carbon atoms; and Re are hydrocarbons such as alkyl e.g. methyl or (e) alkynyl having up to 8 carbon atoms; ethyl, aryl, e.g. phenyl and the remaining Rc, Rd and Re 45 (f) phenyl and substituted phenyl wherein the substit group, if there is one, is hydrogen. Suitable esters of this uent is at least one of chloro, bromo, fluoro, C1-6 type include t-butyloxycarbonyl, t-amyloxycarbonyl, alkoxy, C1-6 alkanoyl, carbo-(C1-6)alkoxy, nitro, or diphenylmethoxycarbonyl and triphenylmethoxycarbo di(C1-6)alkyl amino; nyl. (g) benzyl or substituted benzyl wherein the substitu (iv) -COOCR? wherein Rris adamantyl, 2-benzylox- 50 ent is chloro, bromo, fluoro, C1-6 alkyl, C1-6 alkoxy, yphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl-tet C1-6alkanoyl carbo(C1-6)alkoxy, nitro, or di(C1 rahydropyran-2-yl, pentachlorophenyl; 6)alkyamino; (v) Sillyloxycarbonyl groups obtained by reaction of a (h) heterocyclic groups such as: furyl, quinolyl, meth silylating agent as described above with the carboxylic yl-substituted quinolyl, phenazinyl, 1,3-benzodiox acid group; 55 olyl, 3-(2-methyl-y-pyronyl), 3-(y-pyronyl) or me (vi) COOP.R.Rb, wherein Ra is an alkyl, haloalkyl, thylpyridyl; aryl, aralkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy or (i) other hydrocarbyl groups such as: ac-indanyl and dialkylamino group, Rb is the same as Ra or is halogen substituted derivatives thereof wherein the substit or Ra and R, together form a ring. uent is methyl, chloro or bromo; ac-tetrahy The carboxyl group may be regenerated from any of 60 dronaphthyl and substituted derivatives thereof the above esters by usual methods for example, acid wherein the substituent is methyl, chloro or bromo; -and base-catalysed hydrolysis, or by enzymical benzohydryl, trityl, cholesteryl, or bicy ly-catalysed hydrolysis. Alternative methods of cleav clo4.4.0decyl. age include: Preferred groups for R1 include C1-6 alkyl, benzyl, reaction with Lewis acids, such as trifluoroacetic 65 phthalidyl, indanyl, phenyl, mono-, di-, and tri acid, formic acid, hydrochloric acid in acetic acid, (C1-C6)-alkyl substituted phenyl such as o-, m or p zinc bromide in and aqueous solutions or methylphenyl, ethylphenyl, n- or iso-propylphenyl, n-, suspensions of mercuric compounds. (The reaction sec-, iso- or t-butylphenyl. 4,260,746 5 6 The intermediate of formula (I) may be prepared by ions for example those from lower alkyla reacting a 7-acylaminocephalosporin of formula (II): mines such as 2-hydroxyethylamine, bis-(2-hydroxye thyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkyla (O) (II) mines such as bicyclohexylamine, or from procaine, dibenzylamine, N,N-dibenzylethylenediamine, 1 ephenamine, N-ethylpiperidine, N-benzyl-g-phene H S thylamine, dehydroabietylamine, N,N'-bis-dehy R Sh CO . ir droabietylethylenediamine, or bases of the pyridine COR N type such as pyridine, collidine or quinoline, or other O amines which have been used to form salts with benzyl penicillin. The double bond addition reagent is a difunctional wherein R, R1, R2, n and A are as defined with respect moiety where each of the groups can be displaced by to formula (I) above; with an acid halide. nucleophiles. Suitably, the reaction with acid halide is carried out 5 in the presence of an acid binding agent such as tertary Suitable double bond addition reagents for the above amine, e.g. pyridine, triethylamine or N,N-dimethylani process include diatomic halogen or a con line. pound of formula Br.N3. If this double bond addition Examples of suitable acid halides are phosphorus reagent is designated X-Y, the adduct formed has the pentachloride, phosgene, phosphorus pentabromide, formula (IV): phosphorus oxychloride, oxalyl chloride and p-toluene sulphonic acid chloride. Phosphorus pentachloride and (Q), (IV) phosphorus oxychloride are preferred. The reaction may be conducted under cooling, preferably at temper S atures from --5 to -30° C. (preferably about 0° C.) 25 when phosphorus pentachloride is employed. The amount of the tertiary amine is preferably 3-5 mois per mole of phosphorus pentachloride. It is also preferable to use the phosphorus halide in an amount in excess of that of the starting material. 30 The value of the keteninine compounds of formula Suitably, both X and Y are halogen, preferably bro (I) derives from their use in the preparation of 7 mine, as the reaction proceeds more smoothly. methoxy cephalosporins. The reaction is suitably carried out in an inert solvent, Thus, in a further aspect, the present invention pro such as tetrahydrofuran or a halogenated hydrocarbon vides a process for preparing a compound of formula 35 e.g. chloroform at low temperatures preferably -20°C. to -70° C., e.g. at about -50' C. (III): The compound of formula (IV) is then reacted with an alkalimetal methoxide of formula CH3O.M. Suitably O9H3 s (III) the alkali metal M may be sodium or potassium, but is R. sh CO . r preferably lithium. The reaction is generally carried out COR3 e- N in an alcoholic solvent, preferably , optionally o21 a NCHA in the presence of another inert solvent, such as tetrahy COR drofuran. The reaction is suitably carried out at low temperature, preferably in the range of -40' to -85, wherein R and A are as defined above with respect to 45 preferably about -75. The reagent CH3O.M. may be formula (I); formed in situ by the use of methanol together with a R represents hydrogen, a pharmaceutically accept base such as butyl lithium, lithium diisopropylamide, able salt-forming ion or ester-forming radical; and lithium or sodium hydride or preferably butyl lithium. R represents hydrogen, a pharmaceutically accept The thus produced 7-a-methoxy ketenimine of for able salt-forming ion or an in vivo hydrolysable ester 50 mula (V): forming radical; which process comprises: (a) reacting a ketenimine of formula (I) with a double (V) bond addition reagent; (b) reacting the resulting product with a compound of formula CH3OM, wherein M is an alkali metal or 55 thallium; (c) hydrolysing the resulting product; (d) removing any carboxyl-blocking groups; (e) optionally salifying or esterifying any free carbox ylic acid group; 60 (f) converting a A2 isomer into the desired A isomer; is then hydrolysed. and Preferably, this hydrolysis is carried out at a pH in (g) reducing a sulphoxide compound (n = 1) to form the range of 1-5, preferably pH 2-4, at ambient temper the desired sulphide compound (n = 0). ature. Suitable salt-forming ions for the groups R3 and R' 65 The ketenimine compounds of formula (I) are also include metal ions e.g. aluminium, alkali metal ions such useful intermediates for the preparation of other 7-sub as sodium or potassium, alkaline earth metal ions such as stituted cephalosporins. calcium or magnesium, and ammonium or substituted Thus a compound of formula (VI): 4,260,746 7 8 EXAMPLE 2 (O)M (VI) Preparation of benzhydryl SCH3 7a-methoxy-76-(2-p-methylphenoxycarbonyl-2'-thien R-CH-CO-NH- 5 3-yl)ketenimino-3-acetoxymethylceph-3-em-carboxy late CO2R o? la CH2A The ketenimine from example 1 (0.29 g, 0.42 mmole) COR2 in tetrahydrofuran (T.H.F.) (10 ml) at -75 C. was - 10 solutionSaid withstirred bye for 30 (0.23 minutes. ml, 0.42 Lithium Alle) methoxide al s wherein , R1, R2 and A defined with respect to (0.042 g, 1.10 mmol) in methanol (0.77ml) was added at formula ( O) may be prepared by: -75. After 20 minutes acetic acid (0.5 ml) was added (a) reacting EGEinnine of file 3. ity and cooling discontinued. Ethyl acetate was added and SES". M.E. y 15 the organic layer washed with sodium bicarbonate and E. Wi. p; p p brine, dried and evaporated to give the crude title com o pound (0.21 g). Purification by chromatography on silica (petrol/ethyl acetate) gave 38% overall yield, (O) (VII) vmax (CHC13) 2010, 1790, 1730, 1500 cm-l. 8 (CDC13) ^ 20 1.87 (3H,s, -OCOCH3), 2.20 (3H,s, ArCH3), 2.13 - SCH3 s (2H,m, C2 ), 2.57 (3H,s, --OCH3), 4.6-5.0 R-=C=N (3H,m, -CH2OCO- and C6-proton), 6.8-7.7 (18H, CO2R W complex, benzhydryl, aromatic and thienyl protons). o1 e1 CH2A 2 25 EXAMPLE 3 CO2R Preparation of 2'-epimers of benzhydryl and: 7a-methoxy-7E8-(2'-p-methylphenoxycarbonyl-2'-thien (b) hydrolysing the compound of formula (VII) to 3-yl)acetamido-3-acetoxymethylceph-3-em-4-carboxy produce a 7-methylthiocephalosporin, of formula late (VI). The ketenimine from Example 2 (0.14g, 0.19 mmol) A suitable readily displaceable group Z is the group was dissolved in T.H.F. (10 ml) containing water (1 ml) -SO2CH3, and the reaction of compound (I) with com- and sufficient H3PO4 to lower the pH to 2.5. After pound MeS-Z is generally carried out at low tempera- standing for three days at room temperature, ethyl ace ture, suitably in the range +5' to -30°C., preferably, 35 tate was added. The organic layer was washed with about 0° C. water, dried and evaporated to give the title compound The thiomethyl cephalosporins of formula (VI) are (0.13 g). Purification by chromatography on silica (pe themselves useful intermediates for the preparation of trol/ethyl acetate) gave 80% yield, umax (CHCl3) 3350, other 7-substituted cephalosporins, including the me- 1780, 1725, 1690 cm-1. 8 (CDCl3) 1.93 thoxy-substituted compounds (III), by methods known 40 (3H,s-OCOCH3), 2.25 (3H,s, ArCH3), 3.20 (2H,m, C2 in the art, for example by treatment with mercuric chlo- methylene), 3.35, 3.38 (3H,2s, -OCH3), 4.6-5.0 (4H, ride and methanol. complex, -CH2OCO-, -CHCONH- and C6-pro The following examples illustrate the preparation of tons), 6.9-7.7 (19H, complex benzhydryl, aromatic,thie ketenimine intermediates of this invention and its use in nyl, and -NH-protons). preparing antibacterially active cephalosporins. 45 EXAMPLE 4 EXAMPLE 1 Preparation of p-bromophenacyl Preparation of benzhydryl 7g-(2'-p-methylphenoxycarbonyl-2'-thien-3- 7(3-(2-p-methylphenoxycarbonyl-2'-thien-3- yl)ketenimino-3-acetoxymethylceph-3-em-4-carboxy yl)ketenimino-3-acetoxymethylceph-3-em-4-carboxy- 50 late late p-bromophenacyl 7.6-(2-p-methylphenoxycarbonyl Benzhydryl 7.6-(2-p-methylphenoxycarbonyl-2'-thi- 2'-thien-3-yl)-acetamido-3-acetoxymethylceph-3-em-4- en-3-yl)-acetamido-3-acetoxymethylceph-3-em-4-car- carboxylate. (5.0 g, 6.7 mmol) in chloroform (100 ml) at boxylate (2.2 g., 3.0 mmol) in chloroform (10 ml) was 5s OC., was treated with pyridine (5.83 ml). Phosphorus treated with pyridine (2.61 ml) added at 0° C. Phospho- pentachloride (4.56 g, 22 mmol) in chloroform (60 ml) rus pentachloride (2.04 g., 10 mmol) in chloroform (40 was added slowly (one hour) with vigorous stirring, at ml) was added slowly with stirring at 0°C. After three O C. After a further three hours at 0° C., the solution hours at 0° C., the solution was filtered. The solids were was concentrated, diluted with ethyl acetate and washed with ethyl acetate, and the combined organic 60 washed successively with water and sodium bicarbon layers washed successively with water and sodium bi- ate solution. The organic layer was dried and evapo carbonate solution, dried (Na2SO4) and evaporated to rated to give almost pure title compound (4.33 g, 89%), give almost pure title compound (1.79g) umax (CHCl3) umax (CHCI3) 2030, 1790, 1735, 1710 cm - i. 8 (CDCl3) 2020, 1790, 1720 cm-1. 8 (CDCl3) 1.98 2.09 (3H,s-OCOCH3), 2.33 (3H,s, ArCH3), 3.59 (3H,s,-OCOCH3), 2.32 (3H,s, ArCH3), 3.40 (2H,m, C2 65 (2H,s,C2methylene), 5.20 (3H, complex, -CH2OCO methylene), 4.91 (3H, complex, -CH2OCO- and C6 and C6-proton), 5.57 (2H,s, -CO2CH2-), 5.84 (1H,d,J proton), 5.77 (1H,d,J 4 Hz, C7-proton), 6.9-7.6 (18H, 5 Hz, C7-proton), 7.0–8.1 (11H, m, aromatic and thienyl complex, benzhydryl, aryl and thienyl protons). protons). 4,260,746 9 10 EXAMPLE 5 EXAMPLE 8 Preparation of p-bromophenacyl Preparation of 2'-epimers pf 7a-methoxy-7(3-(2-p-methylphenoxycarbonyl-2'-thien 7a-methoxy-7(3-(2'carboxy-2'-thien-3-yl)acetamido-3- 3-yl)keteninino-3-acetoxymethyl-ceph-3-en-4-car 5 (1-methyl-1H-tetrazol-5-ylthio)methylceph-3-em-4-car boxylate boxylic acid The ketenimine from Example 4 (4.33 g., 5.96 mmol) The acetoxy cephalosporin from Example 7 (0.31 g, in THF (120 ml) at -50 C., was treated with bromine 0.55 mmol) in water (25 ml): (10 ml) at 70 C. 10 was treated with 5-mercapto-1-methyl-1H-tetrazole (0.326 ml, 5.95 mmol). After 10 minutes the solution was (0.06 g., 0.5 mmol). The pH of the solution was raised to cooled to -70' C. Lithium methoxide (0.84g, 22 mmol) 5.0 by addition of solution and main in methanol (15 ml) was added dropwise at -70° C. and tained at pH 5.0 throughout the reaction by further stirred a further 20 minutes. Acetic acid (3 ml) was additions. The solution was stirred at 70° C. for fourteen added and cooling discontinued. Ethyl acetate was 15 hours, cooled and acidified to pH 1.5. The aqueous added and the organic layer washed with sodium bicar layer was extracted with ethyl acetate. The organic bonate and brine, dried and evaporated to give the title layer was washed with brine, dried and evaporated to compound (3.84 g) vmax (CHCl3). 2030, 1790, 1730, give the crude title compound (0.18 g). 6 (CDCl3) 3.45 1710 cm-1. 6 (CDCl3). 2.07 (3H,s-OCOCH3), 2.33 3.53 (3H,2s,-OCH3), 3.6-3.8 (2H,m, C2methylene), (3H,s,ArCH3), 3.45 (2H,m, C2methylene), 3.75 (3H,s, 20 4.00 (3,s, N-CH3), 4.4–4.6 (2H,m, -CH2S-), -OCH3), 5.15 (3H, complex, -CH2OCO- and C6 5.1-5.3 (2H, complex CHCONH and C6-proton), proton), 5.55 (2H,s, -CO2CH2-), 6.9-8.0 (11H,m, 6.7-7.8 (4H, complex, thienyl, and -NH- protons). aromatic and thienyl protons). The disodiuin salt was precipitated from acetone with 2 Nethylhexoate in methyl isobutyl ketone (0.34 ml.). EXAMPLE 6 25 What we claim is: Preparation of 2'-epimers of p-bromophenacyl 1. The process which comprises reacting a 7 7a-methoxy-7B-(2-p-methylphenoxycarbonyl-2'-thien acylaminocephalosporin of the formula: 3-yl)acetamido-3-acetoxyceph-3-em-4-carboxylate The ketenimine from Example 5 (3.84g, 5.07 mmol) 30 (O) was dissolved in THF (20 ml) containing water (2 ml) and sufficient H3PO4 to lower the pH to 2.5. After standing for three days at room temperature, ethyl ace tate was added. The organic layer was washed with 35 rolCOOR1 N S water, dried and evaporated to give a quantative recov a ery of the title compound, vmax (CHCl3) 3330, 3270, 1780, 1740, 1710 cm-l. 6 (CDCl3). 2.09 (3H,s, -O- COCH3), 2.32 (3H,s,ArCH3), 3.46, 3.50 wherein (3H,2s,-OCH3), 3.60 (2H,m, C2methylene), 5.12 (4H, R is furyl, thienyl, cycloalkyl of 3 to 7 carbon atoms complex, -CH2OCO-, -CHCONH- and C6-pro cycloalkenyl of 3 to 7 carbon atoms, phenyl or ton), 5.50 (2H,s, -CO2CH2-), 7.0-8.0 (12H, complex, phenyl substituted with from 1 to 3 members se aromatic, thienyl, and -NH- protons). lected from the group consisting of hydroxy, halo, nitro, alkyl of 1 to 6 carbon atoms, amino and car EXAMPLE 7 45 boxy; R1 is alkyl of 1 to 6 carbon atoms, benzyl, phthalidyl, Preparation of 2'-epimers of indanyl, phenyl, or phenyl substituted with from 1 7a-methoxy-7(3-(2-p-methylphenoxycarbonyl-2'-thien to 3 alkyl groups of 1 to 6 carbon atoms; 3-yl)acetamido-3-acetoxymethylceph-3-em-4-carboxy R2 is hydrogen an in vivo hydrolysable ester group lic acid 50 selected from the group consisting of acyloxyalkyl, The p-bromophenacyl ester from Example 6 (3.21 g., alkoxycarboniloxyalkyl, lactone, thiolactone and 4.14 mmol) in dimethylformamide (85 ml): acetic acid dithiolactone or a chemically hydrolysable car (21 ml) was stirred with zinc dust (7 g) for one hour at boxy blocking group; room temperature. The solution was filtered, and solids 55 A is hydrogen, pyridyl, acetoxy, carbamoyloxy, or washed with ethyl acetate. The organic layer was S-Het wherein Het is diazolyl, triazolyl, tetrazolyl, washed with water and evaporated. The residue was thiazolyl, thiadiazolyl, thiatriazolyl, oxazolyl or dissolved in sodium bicarbonate solution and washed oxadiazolyl, unsubstituted or substituted with one with ethyl acetate. The aqueous layer was acidified to or two members selected from the group consisting 60 of alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 pH 1.5 and extracted with ethyl acetate. The organic carbon atoms, alkoxy of 1 to 6 carbon atoms, alk layer was washed with brine, dried and evaporated to oxyalkyl, carboxyalkyl, carbamoyl, carbamoyl give the title compound (1.10 g, 47%), vmax (CHCl3) methyl, trifluoromethyl, hydroxy and halo; 3260, 1780, 1760, 1710 cm-1. 8 (CDCl3). 2.05 n is zero or 1; and (3H,s,--OCOCH3), 2.33 (3H,s, ArCH3), 3.2-3.7 (5H, 65 the dotted line represents a double bond at either the complex, C2methylene and -OCH3), 4.9-5.4 (4H, con 2- or 3- position, plex, -CH2OCO-, CHCONH and C6-proton), 6.9-8.0 with an acid halide, thereby forming a ketenimine of the (2H, complex,aromatic, thienyl, and -NH- protons). formula: 4,260,746 11 12 R is furyl, thienyl, cycloalkyl of 3 to 7 carbon atoms cycloalkenyl of 3 to 7 carbon atoms phenyl or phenyl substituted with from 1 to 3 members se lected from the group consisting of hydroxy, halo 5 gen, nitro, alkyl of 1 to 6 carbon atoms, amino and carboxy; R is alkyl of 1 to 6 carbon atoms, benzyl, phthalidyl, indanyl, phenyl, or phenyl substituted with from 1 to 3 alkyl groups of 1 to 6 carbon atoms; 10 R2 is hydrogen an in vivo hydrolysable ester group wherein R, R, R2, A and n and the dotted line are as selected from the group consisting of acyloxyalkyl, herein defined. alkoxycarboniloxyalkyl, lactone, thiolactone and 2. The process which comprises treating a ketenimine dithiolactone or a chemically hydrolysable car of the formula boxy blocking group; 15 A is hydrogen, pyridyl, acetoxy, carbamoyloxy, or S-Het wherein Het is diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, oxazolyl or

oxadiazolyl, unsubstituted or substituted with one or two members selected from the group consisting 20 of alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alk oxyalkyl, carboxyalkyl, carbamoyl, carbamoyl methyl, trifluoromethyl, hydroxy and halo; n is zero or 1; and 25 the dotted line represents a double bond at either the wherein 2- or 3-position, and R is furyl, thienyl, cycloalkyl of 3 to 7 carbon atoms X and Y are the radicals of a double bond addition cycloalkenyl of 3 to 7 carbon atoms phenyl or reagent, phenyl substituted with from 1 to 3 members se with a methoxide of the formula CH3OHM where M is lected from the group consisting of hydroxy, halo 30 an alkali metal or thallium, thereby forming a 7-methox gen, nitro, alkyl of 1 to 6 carbon atoms, amino and yketenimine of the formula: carboxy; R1 is alkyl of 1 to 6 carbon atoms, benzyl, phthalidyl, indanyl, phenyl, or phenyl substituted with from 1 (O) to 3 alkyl groups of 1 to 6 carbon atoms; R2 is hydrogen an in vivo hydrolysable ester group 35 QCH3 selected from the group consisting of acyloxyalkyl, alkoxycarboniloxyalkyl, lactone, thiolactone and * COOR -e-N e dithiolactone or a chemically hydrolysable car O CH2A boxy blocking group; 40 COOR2 A is hydrogen, pyridyl, acetoxy, carbamoyloxy, or S-Het wherein Het is diazolyl, triazolyl, tetrazolyl, wherein R, R, R2, A, n and the dotted line are as herein thiazolyl, thiadiazolyl, thiatriazolyl, oxazolyl or defined. oxadiazolyl, unsubstituted or substituted with one 4. The process which comprises hydrolysing a 7 or two members selected from the group consisting 45 methoxyketenimine of the formula: of alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alk oxyalkyl, carboxyalkyl, carbamoyl, carbamoyl methyl, trifluoromethyl, hydroxy and halo; n is zero or 1; and 50 the dotted line represents a double bond at either the 2- or 3- position, with a double bond addition agent and treating the resultant adduct with a methoxide of the formula CH3OM where M is an alkali metal or thallium. 55 3. The process which comprises treating a compound wherein of the formula R is furyl, thienyl, cycloalkyl of 3 to 7 carbon atoms cycloalkenyl of 3 to 7 carbon atoms phenyl or phenyl substituted with from 1 to 3 members se

60 lected from the group consisting of hydroxy, halo gen, nitro, alkyl of 1 to 6 carbon atoms, amino and carboxy; R is alkyl of 1 to 6 carbon atoms, benzyl, phthalidyl, indanyl, phenyl, or phenyl substituted with from 1 65 to 3 alkyl groups of 1 to 6 carbon atoms; R2 is hydrogen, an in vivo hydrolysable ester group selected from the group consisting of acyloxyalkyl, wherein alkoxycarboniloxyalkyl, lactone, thiolactone and 4,260,746 13 14 dithiolactone or a chemically hydrolysable car boxy blocking group; A is hydrogen, pyridyl, acetoxy, carbamoyloxy, or S-Het wherein Het is diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, oxazolyl or 5 oxadiazolyl, unsubstituted or substituted with one or two members selected from the group consisting of alkyl of 1 to 6 carbon atoms, alkenyl of 1 to 6 COR2 carbon atoms, alkoxy of 1 to 6 carbon atoms, alk 10 oxyalkyl, carboxyalkyl, carbamoyl, carbamoyl wherein A and R are as herein defined, methyl, trifluoromethyl, hydroxy and halo; R is benzyl, phthalyl, indanyl, phenyl or phenyl n is zero or 1; and substituted with from 1 to 3 alkyl groups of 1 to 6 carbon atoms; the dotted line represents a double bond at either the is R2 is hydrogen an in vivo hydrolysable ester group 2- or 3-position, selected from the group consisting of acyloxyalkyl, thereby forming a compound of the formula: alkoxycarboniloxyalkyl, lactone, thiolactone and dithiolactone or a chemically hydrolysable car (O) boxy blocking group; M 20 n is zero or l; and 9CH3 the dotted line represents a double bond at either the 2- or 3-position to form the corresponding 7-acylaminocephalosporin COOR O -- N Y e CH2A 25 and thereafter removing any carboxyl-blocking groups, "LaCOOR2 converting any A2 isomer present to the A3 isomer and reducing any sulphoxide compound where n=1 to the corresponding sulphide where n=0. wherein R, R, R2, A, n and the dotted line are as herein 6. In the process for the preparation of a compound of defined. 3 the formula: 5. In the process for the preparation of a compound of O the formula: (O), QCH3 OCH3 S

*-i-COOR3 N 35 * COOR3Ilir N o1 21 CH2A o? COOR COOR 40 in which wherein R is 2-thienyl, 3-thienyl, phenyl or hydroxyphenyl; R is furyl, thienyl, cycloalkyl of 3 to 7 carbon atoms R3 is hydrogen or a pharmaceutically acceptable cycloalkenyl of 3 to 7 carbon atoms phenyl or cation; phenyl substituted with from 1 to 3 members se R is hydrogen, a pharmaceutically acceptable cation lected from the group consisting of hydroxy, halo 45 or an in vivo hydrolysable ester forming group; gen, nitro, alkyl of 1 to 6 carbon atoms, amino and and carboxy; A is acetoxy or 1-methyl-(1H)-tetrazol-5-ylthio, R is hydrogen, a pharmaceutically acceptable salt the steps which comprise reacting a 7-acylaminoceph forming ion, benzyl, phthalidyl, indanyl, phenyl, or 50 alosporin of the formula: phenyl substituted with from 1 to 3 alkyl groups of 1 to 6 carbon atoms; (O) R is hydrogen, a pharmaceutically acceptable salt H

forming ion or an in vivo hydrolysable ester-form ing radical; and 55 A is hydrogen, pyridyl, acetoxy, carbamoyloxy, or COORto 2 N S S-Het wherein Het is diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, oxazolyl or oxadiazolyl, unsubstituted or substituted with one 60 or two members selected from the group consisting wherein of alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 R and A are as defined above; carbon atoms, alkoxy of 1 to 6 carbon atoms, alk R is alkyl of 1 to 6 carbon atoms, benzyl, phthalidyl, oxyalkyl, carboxyalkyl, carbamoyl, carbamoyl indanyl, phenyl or phenyl substituted with from 1 65 to 3 alkyl groups of 1 to 6 carbon atoms; methyl, trifluoromethyl, hydroxy and halo; R2 is an in vivo hydrolysable ester forming radical or the step which comprises hydrolysing a 7a-methoxy a carboxy-blocking group; ketenimine of the formula n is zero or 1; and 4,260,746 15 16 the dotted line represents a double bond at either the X and Y are the radicals of the double bond addition 2- or the 3-position, reagent, and with an acid halide selected from the group consisting treating said addition product with a compound of the of phosphorus pentachloride, phosgene, phosphorus formula CH3OM where M is an alkali metal or thallium, pentabromide, phosphorus oxychloride, oxalyl chloride 5 thereby forming a 7-methoxyketenimine of the formula: or p-toluenesulphonic acid chloride to form the corre sponding ketenimine, treating said ketenimine with a halogen to form a dihalo adduct, treating said adduct in situ with an alkali metal methoxide to form a 7-methox yketeninine, hydrolyzing said 7-methoxyketenimine to O gCH, RS yield a compound of the formula: firCOOR (O) 4 N N. 15 COOR2 QCH3 wherein R, R1, R2, A, n and the dotted line are as therein defined. routiCOOR 2 N 13. The process according to claim 1 including the step of hydrolyzing said 7-methoxyketenimine, thereby forming a 7a-methoxy-7(3-acylamino compound of the formula: wherein R, R1, R2, A, n and the dotted line are as herein defined. (Q), 7. A process according to claim 1 wherein the acid 25 halide is phosphorus pentachloride, phosgene, phospho OCH3 rus pentabromide, phosphorus oxychloride, oxalyl chlo ride or p-toluenesulphonic acid chloride. *-i-COOR a N 8. A process according to claim 1 in which said reac O a tion is carried out in the presence of a tertiary amine. 9. A process according to claim 5 wherein the hydro COOR2 lysis is carried out at a pH of from 2 to 4. 10. A process according to claim 3 wherein each of X wherein R, R, R2, A, n and the dotted line are as and Y is halogen. therein defined. 35 14. The process according to claim 2 wherein said 11. A process according to claim 2 wherein the dou adduct is treated with said methoxide without isolation ble bond addition reagent is a halogen. of said adduct. 12. The process according to claim 1 including the 15. The process according to claim 3 including the step of treating said ketenimine with a double bond step of hydrolyzing said 7-methoxyketenimine, thereby addition reagent of the formulas X-Y to form an adduct 40 forming a 7a-methoxy-7(3-acylamino compound of the product of the formula: formula:

(O) (O)

S 45 QCH3 h

*-i-COOR a N O a 50 COOR2 wherein wherein R, R, R2, A, n and the dotted line are as R, R, R2, A, n and the dotted line are as herein de therein defined. fined; and 55

60

65