3,461,164 United States Patent Office Patented Aug. 12, 1969 2 3,461,64 propyl-(1), 1-phenoxypropyl-(2), o-, m- or p-hydroxy HYDROXY-2AMNO-1-PHENYLALKANES benzyl, o-, m- or p-methoxybenzyl, o-, m- or p-ethoxy AND THE SALTS THEREOF benzyl, 3,4-dihydroxybenzyl, 3,4-dimethoxybenzyi, 3,4,5- Karl Schulte and Wolfgang Fruhstorfer, Darmstadt, Hein trihydroxybenzyl, 3,4,5-trimethoxybenzyl or 3.4-methyl rich Muller, Pfungstadt, Hans Friebel, Darmstadt-Eber endioxybenzyl. stadt, Hans Joachim Enenkel, Darmstadt, and Josef Particularly preferred compounds are: Gilissen, Escholbrucken, Germany, assignors to E. Merck Aktiengesellschaft, Darmstadt, Germany N-1-(3'-tert, butyl-4'-hydroxy-5'-methyl-phenyl)- No Drawing. Filed Apr. 27, 1964, Ser. No. 364,355 1-hydroxy-butyl-2-N-isopropylamine Claims priority, application Germany, Apr. 25, 1963, N-(1-(3'-tert.butyl-4'-hydroxy-5'-methyl-phenyl)- M 56,597; May 25, 1963, M 56,960 O 1-hydroxy-propyl-2)-N-methylamine Int, C. CO7 91/18 N-1-(3'-tert.butyl-4'-hydroxy-5'-methyl-phenyl)- U.S. C. 260-570.6 22 Claims 1-hydroxy-propyl-2-N-ethylamine N-(1-(3'-tert.butyl-4-hydroxy-5'-methyl-phenyl)- This invention relates to substituted 1-hydroxy-2-amino 1-hydroxy-propyl-2-N-isopropylamine 1-phenyl-alkanes. 5 N-1-(3'-tert.butyl-4'-hydroxy-5'-methyl-phenyl)- It is a principal object of this invention to provide novel 1-hydroxy-propyl-2-N-(4-phenyl-butyl-2)-amine and unobvious chemical compounds. N-E1-(3'-tert.butyl-4'-hydroxy-5'-methyl-phenyl)- Another object is to provide processes for the produc 1-hydroxy-propyl-2-N-(1-phenoxy-propyl-2)-amine tion of these compounds. N-2-(3'-tert.butyl-4'-hydroxy-5'-methyl-phenyl)- A further object is to provide novel pharmaceutical 2-hydroxy-ethyl-N-methylamine compositions, and still another object is to provide novel N-(2-(3'-tert.butyl-4'-hydroxy-5'-methyl-phenyl)- processes for effecting therapeutic activities in mammals. 2-hydroxy-ethyl-N-isopropylamine Upon further study of the specification and claims other N-(2-(3'-tert.butyl-4'-hydroxy-5'-methyl-phenyl)- objects and advantages of the present invention will be 2-hydroxy-ethyl-N-(4-phenyl-butyl-2)-amine come apparent. 25 N-2-(3'-tert.butyl-4'-hydroxy-5'-methyl-phenyl)- To attain the objects of this invention, there are pro 2-hydroxy-ethyl)-N-(1-phenoxy-propyl-2)-amine vided the following compounds and acid-addition salts N-(1-(4'-tert, butyl-3'-hydroxy-phenyl)-1-hydroxy thereof, said compounds having the formula I propyl-2-N-methylamine OH N-1-(4'-tert.butyl-3'-hydroxy-phenyl)-1-hydroxy Rs 30 propyl-2-N-isopropylamine -CHOH-CHR-NHR N-(2-(4'-tert.butyl-3'-hydroxy-2,6'-dimethyl R. mile phenyl)-2-hydroxy-ethyl-N-methylamine R N-1-(4'-tert.butyl-3'-hydroxy-2,6'-dimethyl phenyl)-1-hydroxy-propyl-2)-N-methylamine wherein N-(2-(4'-tert.butyl-3'-hydroxy-2,6'-dimethyl R represents hydrogen or alkyl of 1-4 carbon atoms, phenyl)-2-hydroxy-ethyl)-N-isopropylamine R2 represents any of hydrogen, alkyl of 1-6 carbon atoms, N-(1-(4'-tert.butyl-3'-hydroxy-2,6'-dimethyl hydroxyalkyl of 2-3 carbon atoms, phenoxyalkyl of phenyl)-1-hydroxy-propyl-2)-N-isopropylamine 40 2-(3'-tert, butyl-4'-hydroxy-5'-methyl-phenyl)- 7-1 carbon atoms, or a radical of the formula 2-hydroxy-ethylamine Rg 1-(3'-tert, butyl-4'-hydroxy-5'-methyl-phenyl)- XY-R- 1-hydroxy-2-aminopropane. With respect to the tertiary alkyl group Rs it should be noted that generally the tertiary carbon atom is the t / R11 carbon atom which is joined to the nucleus. According to this invention the compounds of Formula wherein I can be produced by any one of the following processes: Ra represents alkyl of 1 to 5 carbon atoms, (a) A reducing agent is reacted with a compound of Rg, R10 and R1 are each any of hydrogen, hydroxy, Formula II methoxy, ethoxy, or two of R9, R10 and R11 forming methylene dioxy, R5 represents a tertiary alkyl of 4-6 carbon atoms; and OH --|-- R6 and R are each any of hydrogen, methyl or ethyl. 5 5 The compounds of Formula I which are especially therapeutically efficacious are those in which the phenyl R6X -- --Y group is substituted by a hydroxyl group and at least 2 R alkyl groups of which one is tertiary. Preferably, for that purpose are ethanolamine derivations which have one of 60 wherein the following groups-3'-tert.butyl-4'-hydroxy-5'-methyl phenyl,4'-tert.butyl-3-hydroxy-phenyl and 4'-tert.butyl-3'- R5, R6, and R have the previously indicated meanings, hydroxy-2,6'-dimethyl-phenyl. and wherein The group R1 is preferably hydrogen, methyl, ethyl, X is =O or H, OH and n-propyl, isopropyl, n-butyl, sec. butyl, isobutyl or tert. Y is -CHR1-NHR2 or a group that can be converted butyl. The group R2 in the end-product, besides hydrogen, into the latter by reaction, and where is preferably any of methyl, ethyl, n-propyl, isopropyl, R1 and R2 have the meanings already stated and also n-butyl, sec.butyl, isobutyl, tert.butyl, n-amyl, isoamyl, where instead of the hydrogen atoms there can be hy neopentyl, n-hexyl, isohexyl, benzyl, 1-phenylethyl, 2 drogenolytically removable groups; but where when X phenylethyl, 3-phenylpropyl-(1), 4-phenylbutyl-(1), 4 70 is H, OH, Y can be -CHRNHR- simultaneously phenylbutyl-(2), 2-hydroxyethyl, 3-hydroxypropyl, phen only when at least one hydrogenolytically removable oxymethyl, 1-phenoxyethyl, 2-phenoxyethyl, 1-phenoxy group is present. 3,461, 164 3 . . . . . 4 Groups which can be converted by reduction into the o-benzylamino-3-benzyloxy-4-tert-butyl-2,6- group CHR-NHR2 are for example the following: dimethyl-, -CR=NOH (which may be esterified, preferably with o-(N-benzyl-N-methylamino)-3-tert, butyl-4- an alkane-carboxylic acid with up to 4 carbon atoms, e.g. hydroxy-5-methyl-acetophenone, acetic acid), -CHR1-N3, CN, -CHR1-NO2, -, -CHR1-NH-NH2 -, (where one or both of the H-atoms of the terminal N -isobutyrophenone, atom can be optionally substituted by lower alkyl or aryl - and -isovalerophenone, groups, preferably by methyl, ethyl or phenyl), ox-(N-benzyl-N-ethylamino)-3-tert, butyl-4-hydroxy-5- -CRFN-NH2 methyl-acetophenone, (also optionally substituted by a lower alkyl or aryl group, O propiophenone, Preferably by a methyl, ethyl or phenyl group), -butyrophenone, -CO-NH2, -CR-N-R, -CHR1-NH-R'-OH, -isobutyrophenone, -CHR-NH-acyl. -valerophenone and -isovalerophenone, In the above groups R and R2 have the meanings pre 5 o-(N-benzyl-N-methylamino)-4-tert.butyl-3-hydroxy viously given and R is an alkylidene, aralkylidene, hy acetophenone, droxy-alkylidene or phenoxy-alkylidene group. -propiophenone and -butyrophenone, R" can thus e.g. be methylene, ethylidene, propylidene, o-(N-benzyl-N-isopropylamino)-4-tert.butyl-3-hydroxy isopropylidene, butylidene-1, butylidene-2, 2-phenylethyli acetophenone, dene, 4-phenyl-butylidene-2, 1-phenoxypropylidene-2. 20 -propiophenone and -butyrophenone, Suitable hydrogenolytically removable groups are e.g. ce-(N-benzyl-N-methylamino)-4-tert.butyl-3-benzyloxy N-benzal-, O- or N-benzyl-, substituted O- or N-benzyl and acetophenone, carbobenzoxy-groups, also nitroso-, amino- or arylsulfonyl -propiophenone and -butyrophenone, groups attached to amino groups, and/or halogen atoms 0-methylamino-3-tert.butyl-4-hydroxy-5-methyl preferably aromatic nuclei. 25 acetophenone, Suitable starting substances for process (a) are pref -propiophenone, erably the following- - -butyrophenone, -isobutyrophenone, o-benzylamino-3-tert.butyl-4-hydroxy-5-methyl -valerophenone and -isovalerophenone, acetophenone, 30 a-ethylamino-3-tert-butyl-4-hydroxy-5-methyl-aceto -propiophenone, phenone, -butyrophenone, -propiophenone, -isobutyrophenone, -butyrophenone, -valerophenone and -isovalerophenone, -isobutyrophenone, ox-benzylamino-4-tert, butyl-3-hydroxy 35 -Valerophenone and -isovalerophenone, acetophenone, o-isopropylamino-3-tert-butyl-4-hydroxy-5-methyl-aceto c-benzylamino-4-tert, butyl-3-benzyloxy-acetophenone, phenone, a-azido-3-tert.butyl-4-hydroxy-5-methyl-acetophenone, -propiophenone, -propiophenone, -butyrophenone, -butyrophenone, 40 -isobutyrophenone, -isobutyrophenone, -Valerophenone and -isovalerophenone, -valerophenone and -isovalerophenone, o-propylamino-3-tert-butyl-4-hydroxy-5-methyl-aceto ox-azido-4-tert, butyl-3-hydroxy-acetophenone and phenone, -propiophenone, -propiophenone, cy-azido-4-tert.butyl-3-benzyloxy-acetophenone and -butyrophenone, -propiophenone, -isobutyrophenone, c-isonitroso-3-tert.butyl-4-hydroxy-5-methyl -valerophenone and -isovalerophenone, acetopenone, O-isobutylamino-3-tert, butyl-4-hydroxy-5-methyl-aceto -propiophenone and butyrophenone, phenone, 2-benzylamino-1-(3'-tert.butyl-4'-hydroxy-5'-methyl propiophenone, phenyl)-butanol-(1), -butyrophenone, 4-tert, butyl-3-hydroxy-benzaldehyde cyanhydrin, -isobutyrophenone, % ox-benzylamino-4-tert.butyl-3-hydroxy-2,6-dimethyl -valerophenone and isovalerophenone, acetophenone and C-Sec. butylamino-3-tert-butyl-4-hydroxy-5-methyl-aceto -propiophenone, 55 phenone, cx-benzylamino-4-tertamyl-3-hydroxy-2,6- -propiophenone, dimethyl-acetophenone and -butyrophenone, propiophenone, -isobutyrophenone, ox-benzylamino-4-(3'-methylpentyl-3)-3-hydroxy -Valerophenone and -isovalerophenone, 2,6-dimethylacetophenone and 60 C-tert-butylamino-3-tert.butyl-4-hydroxy-5-methyl-aceto -propiophenone, phenone, cy-benzylamino-4-tert.butyl-3-hydroxy-2,6- -propiophenone, dimethylbutyrophenone, -butyrophenone, D-amino-4-tert.butyl-3-hydroxy-2,6-dimethyl -isobutyrophenone, propiophenone, 65 -Valerophenone and -isovalerophenone, o-amino-4-tert.amyl-3-hydroxy-2,6- 0-butylamino-3-tert.butyl-4-hydroxy-5-methyl-aceto dimethylpropiophenone, phenone, 2-benzylamino-1-(4'-tert.butyl-3'-hydroxy-2,6- -propiophenone, dimethyl-phenyl)-butanol-(1). -butyrophenone, o-azido-4-tert.butyl-3-hydroxy-2,6- 70 -isobutyrophenone, dimethylacetophenone, -Valerophenone and -isovalerophenone, -propiophenone and -butyrophenone, O-(4-phenylbutyl-2-amino)-3-tert, butyl-4-hydroxy-5- c-azido-4-tertamyl-3-hydroxy-2,6-dimethyl methyl-acetophenone, propiophenone, 75 -propiophenone, 3,461,164 5 6 -butyrophenone, product to split off the hydrogenolytically removable -isobutyrophenone, grOllp. -valerophenone and -isovalerophenone, If oximes (isonitrosoketones) are used as the starting cy-(1-phenoxy-propyl-2-amino)-3-tert.butyl-4-hydroxy-5- materials, a can be performed advantage methylacetophenone, ously with Raney-nickel in dilute alkaline lye, or with propiophenone, noble metals in acid solution. Azides are advantageously -butyrophenone, hydrogenated with noble metal catalysts in strongly acid -isobutyrophenone, alcoholic solution until the calculated amount of hydro -valerophenone and isovalerophenone, gen has been taken up, while nitriles are hydrogenated c-methylamino-4-tert.butyl-3-hydroxy-2,6-dimethyl-aceto above pH 7 with Raney-nickel, but with noble metal phenone, O catalysts in the acid range. -propiophenone and -butyrophenone, It is generally possible to use nascent hydrogen for -cy (N-benzyl-N-methyl-amino)-4-tert.butyl-3-hydroxy reduction purposes. This can be produced e.g. with zinc 2,6-dimethyl-acetophenone, and acid or alkaline lye, or wtih iron and hydrochloric -propiophenone and butyrophenone, 5 or acetic acid. Sodium or some other alkali metal can o-ethylamino-4-tert.butyl-3-hydroxy-2,6-dimethyl-aceto also be advantageously used with ethanol, isopropanol or phenone, butanol. It is also possible to use an aluminum nickel -propiophenone and -butyrophenone, alloy in aqueous alkaline solution, with the possible addi cy-(N-benzyl-N-ethylamino)-4-tert.butyl-3-hydroxy-2,6- tion of . Sodium or aluminum amalgam in aque dimethyl-acetophenone, 20 ous alcoholic or aqueous solution is also suitable. With -propiophenone and -butyrophenone, these reactions the work is preferably done in the presence c-isopropylamino-4-tert.butyl-3-hydroxy-2,6-dimethyl of a such as , ethanol, glacial acetic acid, acetophenone, benzene, or water. -propiophenone and -butyrophenone, The reaction can also be performed in a heterogeneous cy-(N-benzyl-N-isopropylamino)-4-tert, butyl-3-hydroxy 25 phase with reaction temperatures ranging from room tem 2,6-dimethyl-acetophenone, perature to the boiling point of the solvent. It is gen -propiophenone and -butyrophenone, erally not necessary to work under pressure. The reaction N-2-3'-benzyloxy-4'-tert, butyl-2',6'-dimethyl-phenyl)-2- is advantageously brought to an end by boiling the reac hydroxy-ethyl)-N-methyl- and N-isopropylamine, tion mixture under reflux. N-1-(3'-benzyloxy-4-tert.butyl-2,6-dimethyl-phenyl)-1- 30 A reducing agent that is especially suitable for the hydroxy-propyl-2-N-methyl- and N-isopropylamine, reduction of a nitro compound or an azide is hydrogen 1-(4'-tert, butyl-3'-hydroxy-2,6'-dimethyl-phenyl)-1-hy sulfide which can be used in an acid, neutral or alkaline droxy-2-isopropylidene-amino)-ethane, - and medium. The hydrogen sulfide is generally not used as . such, but rather as alkali or ammonium sulfide or poly 35 sulfide. A compound of Formula II can e.g. be converted into The starting compounds of Formula II can also be a compound of Formula I by treatment with catalytically converted by electrochemical methods into amines of activated hydrogen. The usual catalysts such as the noble Formula I. For that purpose an aqueous acid reaction metal catalysts, -chromium-oxide, as well as nickel solution is used, which may contain an additional solvent and cobalt, are suitable for this purpose. The noble metal 40 such as glacial acetic acid or alcohol. The cathodic re catalysts can be incorporated in the carrier, e.g. catalysts duction can be performed with the use of a lead, copper, such as palladium on charcoal, oxidation catalysts, or nickel or carbon electrode. finely divided metal catalysts. Nickel and cobalt are ad As reducing agents, use can also be made of complex vantageously used as Raney metals, nickel being also used metal hydrides such as lithium-tetrahydrogen-aluminate, on kieselguhr or pumice as a carrier. sodium-tetrahydrogen-borate, or aluminum-tetrahydro Depending on the composition of the starting material, gen-borate. As starting materials for these reduction the hydrogenation is performed under normal conditions methods, oxo-compounds of Formula II (X=O), acyl or under increased pressure and/or elevated temperature. ated amines, nitro-compounds or azides, nitriles, oximes It is also advantageous to perform the reaction in the or imines are especially suitable. The reaction is per presence of a solvent such as methanol, ethanol, isopro 50 formed under the usual conditions, and preferably in the panol, tert, butanol, ethyl acetate, dioxane, tetrahydro presence of an inert solvent, e.g. ether, tetrahydrofuran, furan, water, an aqueous inorganic acid or an alkaline methanol, and on occasions also in the presence of water. lye. For the specific choice of the solvent the composition The reaction is advantageously terminated by heating the of the starting material should, of course, be taken into reaction mixture to the boiling temperature of the solvent. consideration. The metal complexes that are formed can be decomposed The reaction can, in principle, be performed in either 55 in the usual manner, e.g. with aqueous ammonium chlo an acid, a neutral or a basic medium. For those com ride solution. pounds of Formula II which have a C=N double bond, For the reduction of a nitro-compound or a corre a neutral or basic medium is preferred. If a compound Sponding azide, preferred reducing agents are alkali of Formula II with a basic atom is to be hy dithionates or alkaline suspensions of iron (II) hydroxide, drogenated, either the free or a salt of it can be used. 60 Hydrazine or hydrazine hydrate can also be used ad For example, the hydrochloride can be hydrogenated in Vantageously as a reducing agent in some cases. water under normal conditions. If e.g. a compound of the All the usual reduction methods are theoretically ap general Formula II with X as FO and Y as -CHRNR plicable, the selection being based only on the starting benzyl is used as the starting material, the hydrogenation material that is used, such methods being described in for producing the desired ethanolamine can be performed Houben Weyl, "Methoden der organischen Chemie, 4th in one operation with palladium on charcoal. It is also edition, Verlag Georg Thieme, Stuttgart, 1957, vol. 11/1, possible, however, to first split off only the hydrogenoly Stickstoffverbindungen II, pages 341 to 731. tically removable group (here the benzyl group) e.g. in (b) It is also possible to convert a compound of the presence of the palladium catalyst, and then after 70 Formula III separation from the catalyst but without isolation of the OH amino-, reduce the keto-group of the latter to a R5 secondary alcohol. On the other hand, it is also possible >- I- HR to first reduce the keto-group e.g. with lithium tetrahy R6 R3 R4 drogen aluminate and then without isolating the reduction 75 R 3,461,164 7 8 wherein A special case is the hydrolytic splitting of phthalinido R1, R, R and R have the previously indicated meaning, compounds such as are obtained by the method of Ga R3 is a hydroxyl group, and briel (see loc. cit. pages 80-95). R4 is chlorine or bromine or As starting materials for process (c), any one of the R3 and R4 together represent an oxygen atom. 5 following compounds can be used by treatment with an amine of the formula Ra-NH2 2-amino-1-(3-tert.butyl-4'-acetoxy-5'-methyl-phenyl)- wherein R has the meaning previously given, or with a 1-hydroxy-ethane, compound that produces such an amine, into a compound 2-amino-1-(3'-tert.butyl-4'-propionyloxy-5'-methyl of Formula I. phenyl)-1-hydroxy-propane, Preferred starting compounds for process (b) are 2 O 2-amino-1-(4'-tert.butyl-3'-benzyloxy-phenyl)-1- chloro- or 2-bromo-1-(3'-tert.butyl-4'-hydroxy-5'-methyl hydroxy-ethane and -propane, phenyl)-1-hydroxyethane, 2-chloro- or 2-bromo-1-(3'- 2-amino-1-(3'-acetoxy-4'-tert, butyl-2',6'-dimethyl tert.butyl - 4 - hydroxy-5'-methyl-phenyl)-1-hydroxypro phenyl)-1-hydroxy-ethane, pane, 2-chloro- or 2-bromo-1-(4'-tert.butyl-3'-hydroxy 2-acetylamino-1-(3'-acetoxy-4'-tert.butyl-2-',6'- phenyl)-1-hydroxy-ethane, 2-chloro- or 2-bromo-1-(4- 5 dimethyl-phenyl)-1-hydroxy-ethane, tert.butyl-3'-hydroxy-phenyl)-1-hydroxypropane. 2-acetylamino-1-(4'-tert.butyl-3'-hydroxy-2',6'- As ammonia-producing substances, consideration dimethyl-phenyl)-1-hydroxy-ethane, should be given e.g. to hexamethylene-tetramine, am 2-methylamino-, 2-ethylamino- and 2-isopropylamino-1- monium carbonate, ammonium bicarbonate or ammo 20 (3'-tert.butyl-4'-acetoxy-5'-methyl-phenyl)-1-hydroxy nium . The reaction acn be performed in the ethane, presence or in the absence of a solvent. Use can be made 2-methylamino-, 2-ethylamino and 2-isopropylamino-1- e.g. of lower aliphatic such as methanol, ethanol (3-tert.butyl-4'-propionyloxy-5'-methyl-phenyl)-1- or isopropanol, or lower aliphatic such as hydroxy-propane, or butanone, or of benzene, toluene, acetonitrile or mix 25 2-methylamino-1-(3'-acetoxy-4'-tert, butyl-2',6'- tures thereof as . The work can be done at differ dimethyl-phenyl)-1-hydroxy-ethane and -propane, ent temperatures depending on the starting substance 2-ethylamino and 2-isopropylamino-1-(3'-acetoxy-4- that is used, ranging preferably from room temperature tert.butyl-2'-dimethyl-phenyl)-1-hydroxy-ethane. to the boiling point of the solvent that is used. The reac In accordance with process (c), the starting compound tion can also be performed in an excess of the primary 30 is subjected to an initial hydrolysis whereby the hydroxyl amine which would then function as a solvent. For a more and/or amino groups are set free. The hydrolysis can be rapid reaction, the work can be performed under pres performed in an acid or alkaline medium. The work is sure and/or at higher temperatures, the ammonia or the done preferably in an aqueous or alcoholic medium at primary amine, in such cases, being preferably in excess. the boiling temperature of the solvent. If ether groups This method is especially advantageous if epoxides (For have to be hydrolyzed, then the conditions must be more mula III, R and R together representing an oxygen drastic. In any case, the work is preferably done in e.g. atom) are used as starting compounds. The reaction con concentrated aqueous hydrohalide solution and at ele ditions can be chosen as described in Houben Weyl, loc. vated temperature. For splitting ether groups, use can also cit, pages 314-326. If R is a halogen, the methods de be made of sodium amide in liquid ammonia. An acyl scribed in Houben Weyl, loc. cit, pages 24-108 can be ated amino group of an amine of Formula I can be set used. free by alcoholysis by treatment of such a compound It is also possible to perform the reduction described with a lower aliphatic alcohol in the presence of hydro under (a) simultaneously with the amination under (b). gen chloride, or by aminolysis by treatment of the start For example, suitably substituted phenyl-glyoxals or ing material in an autoclave with ammonia or an amine, phenyl-alkyl-diketones can be hydrogenated in the pres 45 e.g. methyl- or ethylamine. The amine or ammonia that ence of ammonia or a primary amine with the preferred is used serves also as a solvent and must therefore be use of platinum, palladium or Raney-nickel as a catalyst, present in great excess. Reaction temperatures up to 250 whereby the desired amino-alcohols are produced. The C. are used. For splitting acyl amines, the methods de work is done under the usual conditions (see e.g. loc. cit. scribed in Houben Weyl, loc. cit, pages 926-936 and pages 646-648). 50 939-948 can be used. (c) Compounds of Formula I can also be produced by By process (c) it is also possible to hydrolytically split starting with a compound having the same general struc suitably substituted phenyl imines. ture as Formula I and whose phenyl group or whose side (d) Compounds of Formula I can also be obtained chain contains one or two functionally altered hydroxal by introducing into a compound of Formula IV groups and/or whose amino group is present in a func 55 tionably altered form, or which instead of the group -CHOH-CHNHR2 contains the group O R5 -CH-CH 60 and liberating the hydroxyl and/or amino group or groups Rg by hydrolysis, alcoholysis or aminolysis, or by splitting R open the imino ring by hydrolysis. The functionally altered hydroxyl groups can be e.g. wherein R1, R5, R6 and R have the previously indicatcd acyloxy- or other ester-groups such as chloride, meanings. or alkoxy-groups. The functionally altered amino groups The group R2 is introduced by means of a known can e.g. be acylated or can be present as -, aryl alkylation process, which must be done under conditions sulfonamino- or nitrosamino-groups. The isocyanate de where a simultaneous etherification of the phenolic and/ rivatives are obtained by the known decomposition reac or alcoholic hydroxyl group or groups would be avoided. tions of the corresponding carboxylic acids. Information For example, the compounds of the general Formula about such decomposition processes will be found in the IV can be converted in the usual manner into compounds publications of Hofmann, Curtius, Lossen and Schmidt. substaituted at the nitrogen atom with alkyl-, aralkyl- or The reaction conditions for the production of compounds phenoxy-alkyl esters of inorganic acids such as e.g. hy of Formula I are not different from those described in drohalide acids, sulfuric acid, phosphoric acid or organic the literature. Sulfonic acids such as e.g. p-toluene sulfonic acid, or with 3,461,164. 9. O ethylene or . The compounds of Formula Additionally, by administering certain compounds of IV can also be condensed with aldehydes or ketones to this invention, there is effectively achieved a preventive form aldehyde ammonias or Schiff bases, these being activity against circulation failure, thereby reducing the then hydrogenated as under (a) or are treated with an danger of collapse. alkylating agent and then hydrolyzed. The alkylation of A further effect of some compounds of this invention the amino group can e.g. be accomplished by condensa is a prolonged bronchospasmolytic action. tion with benzaldehyde to a Schiff base and treatment of A still further effect of certain compounds of this in the condensation product with alkyl halides as e.g. methyl vention is that they are suitable for local treatment of chloride, methyl bromide, methyl iodide, ethyl bromide eXcess blood-containing skin and sections of mucuous or isopropyl bromide. Here the quaternary salt is first O membranes, or for use as vasoconstrictors, with or with formed, which in the subsequent reaction e.g. by treat out the addition of local anaesthetic and other medicinal ment with acids such as hydrochloric acid is converted agentS. into the secondary amine. The new compounds under Lastly, it has been observed that many of the com Formula I can also be obtained by reacting an amine of pounds of this invention stimulate the central nervous Formula IV with an aldehyde in the presence of formic System e.g. they show anorectic, analeptic, and central acid. It is also possible, with good results, to react an Sympathicomimetic effects. amine of Formula IV with an alcohol in the presence of The Sympathicominetic effects of the new compounds lithium-tetrahydrogen aluminate as under (a). were observed by administering appropriate doses to The methods described in Houben Weyl, vol. 1 1/1 for anesthesized rats and dogs. The tests were conducted the alkylation of primary amines can generally be used, 20 according to the usual methods and evaluated according provided one or more of the hydroxyl groups already to standard procedures. present in the molecule are not etherized. In comparison with known substances, and especially Finally an amine of Formula I that may be formed by in comparison with other circulatory- and bronchial the process of this invention can be converted into a Spasmolytically active substances with analogous action, physiologically compatible acid addition salt by treatment 25 the new compounds are characterized by higher stability, with acids. Suitable acids for this purpose are inorganic oral effectiveness, absence of tachyphylaxis, prolonged or organic, e.g. aliphatic, alicyclic, araliphatic, aromatic activity and excellent therapeutic index. or heterocyclic mono- or polybasic acids. It is advan The new compounds can be employed in admixture tageous to use the following acids-mineral acids such as with the usual pharmaceutical carriers. Consideration hydrochloric, hydrobromic, sulfuric, nitric or ortho 30 should be given to those organic and inorganic carrier phosphoric acid, or organic acids such as acetic acid, Substances which are suitable for parenteral, enteral or , 1-ascorbic acid, succinic acid, citric acid, topical application and which do not enter into reaction gluconic acid, lactic acid, methane-sulfonic acid, 6-hy With the new compounds, as for example water, vegetable droxyethane-Sulfonic acid, maleic acid, fumaric acid, tar oils, polyethylene glycol, gelatin, lactose, starch, magne taric acid, malic acid, , salicylic acid, naphth sium Stearate, talc, vaseline, , etc. For paren alene disulfonic acid, pivalic acid, ethane-disulfonic acid, teral application Solutions are especially suitable, prefer p-toluene-sulfonic acid. Preferred salts are the hydrochlo ably oily or watery solutions, as well as emulsions or im rides, hydrobromides, sulfates, maleates, fumarates, plants. For enteral application, tablets and dragees can citrates and tartrates. also be used, while for topical application use can be Conversely, it is also possible by means of a base to 40 made of Salves or cremes, which may be sterilized if liberate the amine from an acid addition salt of a second necessary, or mixed with ancillary substances such as ary amine of Formula I. preservatives, stabilizers, wetting agents, salts for influenc It is to be noted that the compounds of this invention ing the osmotic pressure, or buffer substances. have one asymmetric carbon atom, or two if R is an The new compounds are preferably incorporated in alkyl group. By their synthesis they are produced as unit dosages of 0.01 to 100 mg., and effective amounts racemic mixtures which can be separated into their opti are administered. Preferred pharmaceutical preparations cally active components by known methods of treatment are tablets, coated tablets, drops and injection solutions. with optically active acids, e.g. tartaric, camphor sulfonic, mandelic, malic, or lactic acid. Such a separation can EXAMPLES FOR PHARMACEUTICAL generally be accomplished by the methods described in 50 PREPARATIONS Houben Weyl, loc. cit vol. 4/2, pages 513-519. Com I.--Tablets pounds with R1 = alkyl exist in two racemic forms erythro- and threo-forms). According to their method of Each tablet contains: production, the one or the other of these forms will pre Mg. dominate. In many cases only the more abundant of the 55 N-1-(3'-tert.butyl-4'-hydroxy-5'-methyl-phenyl)-1- two forms will be separated. In other cases where both hydroxypropyl-2 -N-methylamine hydrochloride - 1 forms are obtained, their separation can be accomplished Lactose ------2 in the usual manner e.g., by distillation, crystallization Potato starch ------of the free bases or of suitable sal's, chromatography, or Talic ------0.5 combinations of these methods. It is also possible to first 60 Magnesium Stearate ------0.02 separate a starting compound of Formula II which has only one asymmetric carbon atom, e.g. an amino ketone, II.-Injection solution into its active components, and then to reduce one or Each ampoule contains 1 mg. of N-1-(3'-tert.butyl both of these to produce optically active final products of 4 - hydroxy - 5'-methyl-phenyl)-1-hydroxypropyl-2-N- Formula I. 65 ethylamine hydrochloride in 5 ml. of distilled, pyrogen The new compounds of this invention have very valua free water. ble pharmacological properties. Upon administration to mammals, there is, in general, effected a Sympathicomi III-Drops metic activity which makes them useful as drugs to in 70 5 g. N-1-(3'-tert.butyl-4'-hydroxy-5'-methyl-phenyl)- crease the blood pressure. 1-hydroxybutyl-2 - N-isopropylamine hydrochloride are In addition, a circulation-stabilizing activity is obtained dissolved in 5 1. of distilled water. The solution is sta by administering certain compounds of this inventon. bilized by addition of a preserving agent and filled into Some of these compounds yield prolonged activities in uni appropriate bottles. The average dosage to be admin formly increasing blood pressure. istered is 20 drops (about 1 mg. of the active ingredient). 3,461,164 11 12 IV. Tablets N-ethyl-N-benzylamine or N-benzyl-N-3-hydroxy-ethyl Each tablet contains: amine in benzene: Mg. o-(N-benzyl-N-methyl-amino)-3-tert.butyl-4-hydroxy-5- 2 - (4'-tert.butyl-3'-hydroxy-2',6'-dimethyl-phenyl)-2- methyl-acetophenone, hydrochloride, M.P. 228 C. hydroxy-ethylamine hydrochloride ------1.5 5 o-(N-benzyl-N-methyl-amino)-3-tert.butyl-4-hydroxy-5- Lactose ------3 methyl-propiophenone, M.P. 133-135° C. Corn starch ------5 o-(N-benzyl-N-methyl-amino)-3-tert.butyl-4-hydroxy-5- Talc ------0.3 methyl-butyrophenone, M.P. 110-112 C. Without further elaboration, it is believed that one ox-(N-benzyl-N-ethyl-amino)-3-tert.butyl-4-hydroxy-5- skilled in the art can, using the preceding description, O methyl-propiophenone, hydrochloride, M.P. 178° C. utilize the present invention to its fullest extent. The fol o-(N-benzyl-N-3-hydroxyethylamino)-3-tert.butyl-4-hy lowing preferred specific embodiments are, therefore, to droxy-5-methyl-propiophenone, M.P. 113-114° C. be construed as merely illustrative, and not limitative The ox-(N-benzyl-N-methyl-amino)-3-benzyl - oxy - 4 of the remainder of the specification in any way whatso 5 tert.butyl-acetophenone which is used in Example 3 can ever, be produced as follows: EXAMPLE 1. p-Tert.butyl-acetophenone is nitrated at -2.5 C, with 137 g. ox-(N-benzyl-N-methylamino)-3-tert.butyl-4-hy a mixture of concentrated sulfuric acid and concentrated droxy-5-methyl-propionophenone are dissolved in 3 liters nitric acid (d. = 1.42) to produce 4 - tert.butyl-3-nitro methanol and are hydrogenated in the presence of 25 g. 20 acetophenone, B.P. 136-140° C. at 0.05 mm., which can of a 5% palladium charcoal catalyst until the calculated be hydrogenated in methanol solution in the presence of amount of hydrogen has been taken up. After having a palladium-charcoal catalyst to produce 3-amino-4- been freed from the catalyst the solution is evaporated tert.butyl-acetophenone, M.P. 73° C. (hydrochloride down and the residue recrystallised from 700 ml. ethyl M.P. 183-185 C.). This is then diazotized and boiled acetate. The yield is 78-82 g. (78-82% of the theoreti 25 to produce 4-tert.butyl-3-hydroxy-acetophenone of M.P. cal) N - 1-(3'-tert.butyl-4'-hydroxy-5'-methylphenyl)-1- 127 C. from which 3-benzyloxy-4-tert, butyl-acetophe hydroxy-propyl-2-N-methylamine. M.P. 170-171° C. none, M.P. 62-64 C. is produced, the latter being bro minated to c. - bromo-3-benzyloxy-4-tert.butyl-acetophe Maleate, M.P., 182-183° C. none, M.P. 85 C. By reacting it with N-benzyl-N-meth Fumarate, M.P. 205-206° C. 30 yl-amine it is converted into O-(N-benzyl-N-methyl In an analogous manner the compounds in the follow amino) - 3 - benzloxy - 4-tert.butyl-acetophenone, whose ing table are obtained. hydrochloride melts at 190-192 C.

M.P. of the hydro chloride, Colhould o C. Starting material Example: 2------N-1-(3'-tert.lbutyl-4- 84 a-(N-benzyl-N-methyl hydroxy-5'-methyl anillo)-3-tert.butyl-4- phenyl)-1-hydroxybutyl hydroxy-5-methyl-butyro 2-N-methyl-amine. phenone. 8------N-2-(4-tert-butyl-3- 2 2.n 8 a-(N-benzyl-N-mothy)- hydroxyplienyl)-2- allino)-3-benzyloxy-4- hydroxy-ethyl-N- tert.butyl-acetophenole. Innethyl-amine. 4------N-2-(3'-tert.butyl-4- 64-5 a-(N-benzyl-N-methyl hydroxy-5'-methyl amino)-3-tert.butyl-4- phenyl)-2-hydroxy-ethyl hydroxy-5-methyl-aceto N-methyl-amine. phenone. 5------N-1-(3'-tort.butyl-4- 2OS-20 a-(N-benzyl-N-ethyl hydroxy-5'-methyl amino)-3-tort.butyl-4- phenyl)-1-hydroxy hydroxy-5-methyl propyl-2--N-ethyl-anic. propiophenone. 6.------N-1-(3'-tert.butyl-4- 118 -(N-benzyl-N-3-hydroxy hydroxy-5' methyl ethylamino)-3-tert.butyl phenyl)-1-hydroxy 4-hydroxy-5-methyl propyl-2-N-(3-hydroxy propiophenone. ethyl)-amine.

The substances which have been designated as starting EXAMPLE 7 materials can be subjected to hydrogenation while they are in the form of salts, e.g. hydrochloride, whereupon 25.5 g. O - isopropylamino - 3 - tert.butyl-4-hydroxy-5- the corresponding salts or hydrochlorides will be ob methyl-butyro-phenone-hydrochloride, M.P. 221-223° C., are dissolved in 700 ml. methanol and hydrogenated un tained directly after the usual working up. der 6 atm. at 60° C. in the presence of 10 g. palladium The starting materials used in Examples 1, 2, 4, 5 and charcoal catalyst (5%) until the calculated amount of 6 can be produced as follows: 2-methyl - 6 - tert.butyl hydrogen has been taken up. The solution after being phenyl is reacted with the corresponding acid chloride freed from the catalyst is evaporated down and the resi or acid anhydride in the presence of AlCl3, and the due crystallized from 250 ml. absolute ethanol, yielding ester then saponified to produce the 3-tert.butyl 70 24.2 g. =92.5% theoretical. For hastening the crystalli 4-hydroxy-5-methyl-acetophenone, -propionophenone and Zation, ether is added until the solution becomes turbid. -butyrophenone, which are converted into the substituted The yield is 21.2 g (83% of the theoretical) N-1-(3'- o-bromo-ketones by the usual bromination in tert.butyl-4'-hydroxy-5'-methyl - phenyl) - 1 - hydroxy or benzene. From these the desired amino-ketones are butyl-21 - N-isopropyl-amine-hydrochloride, M.P. 205 obtained by reaction with N-methyl-N-benzylamine or 75 207 C. 3,461,164. 13 4. In an analogous manner the compounds in the follow tert.butyl-4-hydroxy-5-methyl-propionophenone are dis ing table are obtained: solved in 300 ml. methanol and hydrogenated in the pres

M.P. of M.P. of the hydro- the hydro chloride, chloride, Compound ° C. Starting material o C. Example: 8------N-1-(3'-tert.butyl-4- 230 a-n-butylamino-3-tert. 150 hydroxy-5'-methyl- butyl-4-hydroxy-5- phenyl)-1-hydroxy- methyl-propiophenone. propyl-2-N-n-butyl alie. 9------N-I-(3'-tert.butyl-4- 209-211 a-Isopropylamino-3-tert. 238 hydroxy-5'-methyl- butyl-4-hydroxy-5- phenyl)-1-hydroxy- methyl-propiophellone. propyl-2-N-isopropyl 8. 10------N-2-(3'-tert.butyl-4- 184-85 a-N-(4-phenyl-butyl-2)- 212-214 hydroxy-5'-methyl- anino-3'-tert.butyl-4- phenyl)-2-hydroxy-ethyl- hydroxy-5'-methyl N-(4-phenyl-butyl-2)- acetophenone. 3]hile. ll.------N-1-(3'-tert.butyl-4- 198-200 a-N-(4-phenyl-butyl-2)- 216-218 hydroxy-5'-methyl- amino-3'-tert.butyl-4'- phenyl)-1-hydroxy- hydroxy-4-methyl propyl-2-N-(4-phenyl- propiophenone. butyl-2)-amine. 12------N-2-(4-tert.butyl-3- 137-139 a-sorpopylamino-3-ben- 236-238 hydroxy-phenyl)-2- zyloxy-4-tert.butyl hydroxy-ethyl-N-Iso- acetophenone. propyl-amine. 13------N-2-(4-tert...butyl-3- 217-219 a-N-(4-phenyl-butyl-2)- 187-190 hydroxy-phenyl)-2- amino-3'-benzyloxy-4- hydroxy-ethyl-N-(4- ter.butyl-acetophenone. phenyl-butyl-2) amine. 14------N-2-(3'-tert.butyl-4- 181-182 a-sopropylamino-3-tert. 219-22 hydroxy-5'-methyl- butyl-4-hydroxy-5- phenyl)-2-hydroxy-ethyl- Inlethyl-acetophenome. N-isopropyl-amine.

The amino-ketones which are used as starting mate ence of 7 g. palladium-charcoal catalyst (5%) until 0.04 rials in Examples 7 to 14 can be obtained from the cort 35 mol hydrogen has been taken up. The solution is freed responding bromo-ketones by the method described from the catalyst and is then evaporated down under re. above. duced pressure. The residue is recrystallized from ethyl acetate and consists of ox-N-methylamino-3-tert.butyl-4- EXAMPLE 15 hydroxy-5-methyl-propiophenone. M.P. 137-139° C. 5.8 g. cy-isopropylamino-3-tert.butyl-4-hydroxy-5-meth 40 5.0 g. of this amino-ketone are dissolved in 150 ml. yl-butyrophenone are dissolved in 60 ml. methanol and dry ether and added drop-by-drop to 1.5 g. lithium tetra are hydrogenated to completion under 80 atm. at 40 hydrogen aluminate under 20 ml. dry ether. The mixture 50° C. in the presence of 3 g. Raney-nickel moistened is then heated one hour under reflux, cooled to room tem with methanol. The solution is then filtered and the Sol perature, and reacted with water and ammonia. The vent distilled off. The N-1-(3'-tert.butyl-4'-hydroxy-5'- 45 ether phase is separated, the aqueous phase extracted sev methyl - phenyl) - 1-hydroxybutyl-2-N-isopropyl-amine eral times with ether, and the combined extracts dried thus obtained is converted into the hydrochloride in the over sodium sulfate. After evaportion of the solvent and usual manner, which after recrystallization from absolute recrystallization from ethyl acetate the product is N-1- ethanol with a little added ether, melts at 210 C. (4.1 (3' - tert.butyl - 4'-hydroxy-5'-methyl-phenyl)-1-hydroxy g.=62% of the theoretical). 50 propyl-2)-N-methyl-amine. M.P. 169-171° C. EXAMPLE 16 EXAMPLE 19 3.0 g. a-n-butylamino-3-tert.butyl-4-hydroxy-5-methyl 4.4 g. 1-(3'-tert.butyl-4'-propionyloxy-5'-methyl-phen propionophenone are treated with hydrogen as in Exam yl)-1-hydroxy-2-methyl-amino-propane-hydrochloride are ple 15 and are then worked up in a similar manner. The 55 dissolved in a mixture of 45 ml. glacial acetic acid, 24 yield is 2.2 g. (67% theoretical) N-1-(3'-tert.butyl-4- ml. concentrated hydrochloric acid and 14 m. water and hydroxy - 5' - methyl-phenyl)-1-hydroxy-propyl-2)-N-n- the mixture heated 20 hours under reflux. The solution butyl-amine-hydrochloride. M.P. 228° C. with decom is evaporated down under reduced pressure, extracted position. with ether, and dilute NaOH added until the pH reaches 60 about 7.5. The precipitate is taken up in ethyl acetate, EXAMPLE 17 the solution dried over sodium sulfate, and after evapo A solution of 5.3 g. a-benzylamino-3-tert.butyl-4-hy ration of the solvent the N-(1-(3'-tert.butyl-4-hydroxy droxy-5-methyl-butyrophenone in 1000 ml. dry ether is 5' - methyl - phenyl) - 1-hydroxy propyl-2-N-methyl added with stirring and cooling to 4.8 g. lithium tetra amine thus obtained is recrystallized from ethyl acetate. hydrogenaluminate under 100 ml, ether. The mixture is 65 M.P. 169-171. C. then heated one hour under reflux, cooled to room tem The starting material consisting of 1-(3'-tert.butyl-4- perature, and then after being treated with moist ether is propionyloxy - 5' - methyl-phenyl)-1-hydroxy-2-methyl reacted with 300 ml. 12% hydrochloric acid. After work amino-propane-hydrochloride can be obtained as follows: ing it up in the usual manner the yield is 4.3 g. (81% 3 - tert-butyl - 4 - propionyloxy-5-methyl-propionophe theoretical) N - 1 - (3'-tert.butyl-4'-hydroxy-5'-methyl O none (M.P. 90° C.) is converted into ox-bromo-3-tert. phenyl) - 1-hydroxy-butyl-2-N-benzylamine. M.P. 173 butyl-4-propionyloxy-5-methyl-propionophenone by the 175° C. used bromination with bromine in chloroform. After re acting it with N-benzyl-N-methylamine the product is - EXAMPLE 18 (N-benzyl - N - methylamino)-3-tert.butyl-4-propionyl 13.6 g. (0.04 mole) o-(N-benzyl-N-methyl-amino)-3- 75 oxy - 5 - methyl-propionophenone, whose hydrochloride 3,461,164 5 16 melts at 195-197° C. It is hydrogenated in the presence of produced in the usual manner is recrystallized from eth a palladium charcoal catalyst to produce the desired 1 anol. As in the previous example, some of the starting (3 - tert, butyl - 4'-propionyloxy-5'-methyl-phenyl)-1-hy material is regained during the first crystallization, but droxy - 2 - methyl-amino-propane, whose hydrochloride during the second crystallization the desired end product melts at 228-230 C. is obtained. M.P. 202-203 C. Its IR spectrum no longer has any keto-bands. EXAMPLE 20 The starting material is obtained by reaction of ox 3.53 g. c-(N-benzyl-N-methylamino)-3-tertamyl-4-hy bromo-4-tert-butyl-3-hydroxy - 2,6 - dimethyl-acetophe droxy-5-methyl-propionophenone are dissolved in 100 ml. none with ethyl-benzylamine and hydrogenolytic de ethanol and hydrogenated in the presence of 0.5 g. pal 0 benzylation of the product. The hydrochloride melts at ladium charcoal (5%) under 6 atm. until the calculated 220-222 C. with previous sintering and discoloration. amount of hydrogen has been taken up. The solution after being freed from the catalyst is evaporated down under EXAMPLE 23 reduced pressure and the residue recrystallized from ethyl By an analogous reaction ox-isopropyl-amino-4-tert-bu acetate. The product is N-(1-(3'-tertamyl-4'-hydroxy-5'- tyl-3-hydroxy-2,6-dimethyl-ethyl-acetophenone is reduced methyl - phenyl) - 1 - hydroxy-propyl-2I-Nimethylamine with lithium-tetrahydrogen aluminate to produce N-2- which melts at 159-161 C. (4'-tert-butyl-3'-hydroxy-2,6'-dimethyl-phenyl) - 2 - hy By analogy to the above described a-(N-benzyl-N- droxy-ethyl)-N-isopropyl-amine. The crude hydrochlo methyl - amino)-3-tert.butyl-4-hydroxy-5-methyl-propio Tide which is produced in the usual manner is recrystal nophenone, the starting material can be produced from 20 lized from ethanol/ether. M.P. 203. 2-tert, amyl-6-methylphenol by reaction of p-bromo-O- The starting material is obtained by reaction of ox cresol with tert, or amylene in the presence bromo-4-tert.butyl-3-hydroxy - 2,6 - dimethyl-acetophe of concentrated sulfuric acid, followed by reductive re none with isopropyl-benzylamine and hydrogenolytic de moval of the bromine by a palladium-magnesium-oxide benzylation of the product. catalyst. The cy-(N-benzyl-N-methylamino)-3-tertamyl-4- 25 hydroxy-5-methyl-propionophenone melts at 106-108 C. EXAMPLE 24 EXAMPLE 21 5.5 g. 1-(4-tert.-butyl-3'-hydroxy-2,6'-dimethylphen yl)-1-hydroxy-propyl-2-amine and 1.3 g. acetone are 4.5 g. c. - methylamino - 4-tert.butyl-3-hydroxy-2,6-di boiled in 75 ml. toluene 2 hours under reflux. 1.3 g. ace methyl-acetophenone are dissolved in 50 ml. tetrahydro 30 tone are then added and the mixture boiled another 3 furan and without any external cooling are added drop hours. A little water collects in the water separator. The wise with stirring to a suspension of 0.85g. lithium tetra toluene is distilled off under vacuum and the residue is hydrogen aluminate in 50 ml. tetrahydrofuran. The re hydrogenated with 1 g, platinum oxide in 150 ml. meth action mixture is boiled 6 hours under reflux, then cooled, anol under normal pressure and room temperature. The mixed with moist tetrahydrofuran, poured upon ice water, catalyst is filtered off, the solution concentrated and the and acidified with a 16% solution of sulfuric acid. Nell residue converted into the hydrochloride with ether and tral products are removed by extraction with ether. The hydrochloric acid. After recrystallization from alcohol/ acid aqueous phase is mixed with 10 g. tartaric acid and ether the yield is 3.5 g. N-1-(4'-tert.butyl-3'-hydroxy-2, the mixture stirred into a large excess of ice cold con 6 - dimethyl-phenyl)-1-hydroxy-propyl-2-N-isopropyl centrated soda lye. The base is extracted with ether and 40 converted into the hydrochloride by hydrochloric acid amine hydrochloride. M.P. 227-229 with decomposi and ether. By recrystallizing the hydrochoride from tion. ethanol, a small amount of the starting material is ob The starting material is produced by reaction of 3 tained as the first crystalline product. After concentra benzyloxy-4-tert.butyl-2,6' - dimethylbenzaldehyde with tion of the mother liquor, the N-(2-(4'-tert.butyl-3'-hy ethyl magnesium bromide, oxidation by chromic acid to droxy - 2,6'-dimethyl-phenyl)-2-hydroxy-ethyl)-N-meth the ketone, hydrogenolytic debenzylation, bromination yl-amine-hydrochloride is obtained which after recrystal and reaction with benzylamine to substituted ox-benzyl lization from ethanol melts at 220-222 C. with decom aminopropiophenone, another hydrogenolytic debenzyla position. Its IR spectrum no longer exhibits any keto tion, followed by hydrogenation with a Raney nickel cata bands. lyst. The hydrochloride melts at 233-235° C. with de The above mentioned starting material can be produced 50 composition. in the following manner: 4-tert, butyl-3-hydroxy-2,6-di methylbenzyl chloride has its phenolic hydroxyl group EXAMPLE 25 acetylated, saponified and benzylated to convert this com 3.47 c - benzylamino-3-tert.butyl-4-hydroxy-5-methyl pound into 3 - benzyloxy-4-tert.butyl-2,6-dimethyl-benz 55 acetophenone-hydrochloride are dissolved in 100 ml. yl-alcohol. This can be oxidized by means of tert, butyl methanol and hydrogenated to completion under normal chromate to the corresponding substituted benzaldehyde conditions in the presence of 2 g. palladium charcoal cata which is then converted into the 3-benzyloxy-4-tert, butyl lyst (5%). The solution is freed from the catalyst and 2,6-dimethyl-acetophenone by reaction with methyl-mag is evaporated down under reduced pressure. The residue nesium iodide and subsequent oxidation. By hydrogen 60 is dissolved in a small amount of absolute alcohol and re olytic debenzylation with subsequent bromination, the cz crystallized from ether, producing 2.0 g. 2-(3'-tert.butyl bromo - 4 - tert.butyl-3-hydroxy-2,6-dimethyl-acetophe 4'-hydroxy-5'-methyl-phenyl) - 2 - hydroxy-ethylamine none is obtained which is then reacted with benzyl-meth hydrochloride. M.P. 195 C. ylamine. By hydrogenolytic debenzylation the cy-methyl The co - benzylamino-3-tert.butyl-4-hydroxy-5-methyl amino - 4-tert.butyl-3-hydroxy-2,6-dimethyl-acetophenone 65 acetophenone-hydrochloride which was used as the start is obtained. M.P. 144-146 C. Its hydrochloride after ing material can be obtained in the following manner: sintering and discoloration melts at 256° C. with decom 2-methyl-6-tert.butyl-phenol is converted into 3-tert.bu position. tyl-4-hydroxy-5-methyl-acetophenone. (M.P. 123-125 EXAMPLE 22 C.) by treatment with AlCl3, acetylchloride or acetic an O hydride and subsequent saponification of the phenol ester By an analogous reaction o-ethyl-amino-4-tert, butyl-3- (B.P. 125-130° C. at 0.05 mm.). The product is then hydroxy-2,6-dimethyl-acetophenone is reduced with lithi converted into co-bromo-3-tert.butyl-4-hydroxy-5-methyl um-tetrahydrogen-aluminate to produce the N-(2-(4- acetophenone. (M.P. 95-97. C.) by the usual bromina tert-butyl-3'-hydroxy - 2,6'-dimethyl-phenyl)-2-hydroxy tion with bromine in chloroform or benzene. The mate ethyl)-N-ethylamine. The crude hydrochloride which is 75 rial is then reacted with benzylamine in benzene to ob 3,461,164. 17 8 tain the desired w-benzylamino-3-tert.butyl-4-hydroxy-5- The starting material consisting of a-isonitroso-3- methyl-acetophenone which is converted in the usual man tert.butyl-4-hydroxy - 5 - methyl-propionophenone can be ner into the hydrochloride which melts at 240 C. produced as follows: A solution of 39 g. 3-tert.butyl-4-hydroxy-5-methyl EXAMPLE 26 propionophenone in 500 ml. ether is heated to boiling 3.6 g. a-benzylamino-3-tert.butyl-4-hydroxy-5-methyl 5 while a current of dry HCl and methyl nitrite is passed propionophenone-hydrochloride are dissolved in 50 ml. into it, the latter being obtained from a solution of 14.5 absolute alcohol and hydrogenated at 60° C. under 6 g. 95% sodium nitrite in 9 ml. methanol and 8.5 ml. atm. until the calculated amount of hydrogen is taken up. water with the addition of half concentrated sulfuric acid. The mixture is filtered to remove the catalyst and the 10 After being cooled to room temperature the mixture is filtrate evaporated down. The residue is recrystallized extracted six times with 25 ml. of a 10% soda lye solu from absolute alcohol, producing 1.9 g, 1-(3'-tert.butyl tion. The alkaline extracts are poured upon 50 g. ice 4'-hydroxy-5'-methyl-phenyl)-1-hydroxy - 2 - amino-pro and 35 ml. concentrated hydrochloric acid and the pre pane-hydrochloride. M.P. 210° C. cipitated reaction product taken up with ether. The ether The starting material consisting of co-benzylamino-3- 5 solution is dried over sodium sulfate and the solvent tert.butyl-4-hydroxy-5-methyl-propionophenone - hydro evaporated. The yield is 37 g. of the crude product, chloride can be produced from 3-tert-butyl-4-propionyl which is recrystallized from 100 ml. ethyl acetate and oxy-5-methyl-propionophenone, M.P. 90 C. by analogy 50 ml. petroleum ether (B.P. 50-70° C.) to produce 19 to Example 1. It melts at 208-210° C. g. of the pure o-isonitroso-3-tert.butyl-4-hydroxy-5-meth EXAMPLE 27 yl-propionophenone. M.P. 163-165 C. oz-Amino-4-tert.butyl-3-hydroxy-2,6-dimethyl-acetophe EXAMPLE 30 none-hydrochloride is hydrogenated to completion in 55 498 g. cy-isonitroso - 3 - tert.butyl-4-hydroxy-5-methyl ml. methanol with 10 g. Raney nickel at about 65° C and propionophenone are dissolved in 200 ml. 2 N-Soda lye under 100 atm. The catalyst is filtered off with suction, 25 and after the addition of 4 g. water moistened Raney the methanol distilled off, and the residue recrystallized nickel and 130 ml. water are hydrogenated under 6 atm. from alcohol and ether. The yield is 4.5 g. 2-(4'-tert.bu at room temperature to completion. The solution after tyl-3'-hydroxy-2,6'-dimethyl-phenyl)-2-hydroxy - ethyl being freed from the catalyst is concentrated to about amine-hydrochloride. M.P. 217-218 C. 80 ml., is brought to a pH of about 7.5 with 2 N-hydro The above-mentioned starting material is obtained from 30 chloric acid, and extracted with ether to take up the base. 4-tert.butyl-3-hydroxy - 2,6 - dimethyl-acetophenone by After being dried with solvent is evaporated, leaving bromination in chloroform, reaction of the bromo-ketone 3.0 g. crude 1-(3' - tert.butyl - 4 - hydroxy-5'-methyl with benzylamine, conversion into the hydrochloride, phenyl)-1-hydroxy-2-amino-propane which is converted and removal of the benzyl group by hydrogenation with by the usual method into its hydrochloride, melting at palladium charcoal in methanol. After recrystallization 35 210° C. from the product melts at 228-229 C. EXAMPLE 31 EXAMPLE 28 8.2 g. w-azido-(3-tert.butyl-4-hydroxy-5-methyl)-aceto 3.76 g. a-benzylamino-4-tert.butyl-3-hydroxy-2,6-di phenone are dissolved in 200 ml. methanol and hydro methyl-propionophenone-hydrochloride are hydrogenated 40 genated under 6 atm. at 60° C. in the presence of 5 g. with 3 g. 5% palladium charcoal in 200 ml. methanol palladium charcoal catalyst (5%) and 5 ml. concentrated under 6 atm. and at about 60° C. The mixture is then hydrochloric acid (d.-1.19) with continuous analysis filtered and the filtrate after being concentrated is further and flushing until completion. After separation of the hydrogenated under 100 atm. and at 100° C. with 5 g. Icatalyst, the solution is concentrated under reduced pres Raney nickel. During the first hydrogenation stage the 45 sure and the resultant viscous liquid dissolved in 20 ml. benzyl group is removed while during the second stage absolute alcohol and mixed with ether until the turbidity the keto group is reduced. After filtration and concentra point is reached. The yield is 4.8 g. 2-(3'-tert.butyl-4- tion the acidified solution is extracted with ether and after hydroxy - 5' - methyl-phenyl)-2-hydroxy-ethylamine-hy being made alkaline is again extracted to remove the neu drochloride, M.P. 195-197 C. tral and basic products. The latter are converted into 50 If the hydrogenation is stopped after 1, mol hydrogen their hydrochlorides and are then recrystallized from has been taken up, the intermediate product consisting ethyl acetate. The yield is 1.2 g. 1-(4'-tert-butyl-3'-hy of co-amino - 3 - tert.butyl-4-hydroxy-5-methyl-aceto droxy-2,6'-dimethyl-phenyl)-1-hydroxy - 2 - amino-pro phenone-hydrochloride is obtained. M.P. 255-256° C. pane-hydrochloride, melting at 232-233 C. with decom The starting material consisting of a-azido-(3-tert.butyl position. 55 4-hydroxy-5-methyl)-acetophenone can be obtained as The starting material is obtained from 4-tert.butyl-3- follows: hydroxy-2,6-dimethyl-propionophenone by bromination A solution of 30 g. w-bromo-3-tert.butyl-4-hydroxy and reaction with benzylamine. After recrystallization 5 methyl-acetophenone (M.P. 95-97° C.) in 90 ml. ab from alcohol and ether, it melts at 187-188 C. Solute alcohol is reacted with a solution of 6.6 g. sodium 60 azide in 30 ml, water and kept over night at room tem perature. The azide which has crystallized out is filtered EXAMPLE 29 off with suction and recrystallized from ethyl acetate 10 g. a-isonitroso - 3 - tert.butyl-4-hydroxy-5-methyl and petroleum ether. M.P. 107-109 C. propionophenone are dissolved in 150 ml. dry ether and By analogy, the ox-azido-3-tert.butyl-4-hydroxy-5-meth with vigorous stirring are added dropwise to a suspen yl-propiophenone, M.P. 69-72 C. can be obtained. sion of 3.9 g. lithium aluminum hydride in 100 ml. dry 65 ether. The mixture is then heated 2 hours under reflux, EXAMPLE 32 cooled to room temperature, and mixed first with moist 5.05 g. co-azido-3-benzyloxy-4-tert.butyl-acetophenone ether and then with water. The ether is separated and are hydrogenated and worked up as in Example 7, pro the aqueous phase again extracted with the same solvent. 70 ducing 2-(4'-tert-butyl - 3'-hydroxy-phenyl)-2-hydroxy The combined ether extracts are dried over sodium sul fate and concentrated. The base thus obtained is con ether).stylinehydrochloride. M.P. 210-212° C. (alcohol/ verted in the usual manner into the 1-(3'-tert.butyl-4'- The Starting material can be produced as follows-p- hydroxy-5'-methyl-phenyl) - 1 - hydroxy - 2 - amino-pro tert.butyl-acetophenone is nitrated at -25° C. with a pane-hydrochloride. M.P. 210° C. - 5 mixture of concentrated Sulfuric acid and concentrated 3,461,164 19 20 nitric acid (d.1=1.42), producing 4-tert-butyl-3-nitro acid addition salt thereof, said compound being of the acetophenone (B.P. 136-140° C. at 0.05 mm. Hg). When formula it is dissolved in the presence of a palladium charcoal catalyst, it can be hydrogenated to 3-amino-4-tert-butyl OH acetophenone. The latter can then be diazotized and R5 boiled to produce 4-tert.butyl-3-hydroxy-acetophenone --CEOH-CIR-NHR2 (M.P. 127° C.) from which the 3-benzyloxy-4-tert.butyl R acetophenone can be obtained which can then be bromin 7 ated to produce w-bromo-3-benzyloxy - 4 - tert.butyl acetophenone, M.P. 85 C., and then reacted with sodium wherein azide to produce w-azido-3-benzyloxy-4-tert.butyl-accto 10 R is selected from the group consisting of hydrogen and alkyl of 1-4 carbon atoms; phenone. M.P. 87° C. R is selected from the group consisting of hydrogen, EXAMPLE 33 alkyl of 1-6 carbon atoms, hydroxyalkyl of 2-3 car 30.1 g. 1 - (3'-tert.butyl-4'-hydroxy-5'-methylphenyl)- 1 bon atoms, phenoxyalkyl of 7-11 carbon atoms, and 2-bromo-propane-1-ol and 50 g. methylamine are stirred a radical of the formula for 8 hours in a bomb tube at room temperature and Sub sequently for 10 hours at 110° C. The reaction mixture is cooled, the excess of methylamine is evaporated and the residue is treated with dilute HCl (10%) until a 20 slight acidic reaction. The undissolved is filtered off, the filtrate extracted with ether and the aqueous layer R11 is made alkaline by addition of NaOH and extracted with ethylacetate. After drying and evaporating the sol wherein vent, the crude N-1-(3'-tert.butyl-4-hydroxy-5'-methyl Rs represents alkyl of 1-5 carbon atoms; phenyl)-1-hydroxy-propyl-2)-N-methylamine is recrys R9, Rio and R11 are each selected from the group con tallized from ethylacetate. M.P. 168-171 C. sisting of hydrogen, hydroxy, methoxy, ethoxy, and The starting material may be prepared in the follow two of R9, R10 and R11 forming methylene dioxy; ing way: R5 represents tertiary alkyl of 4-6 carbon atoms; and 3-tert.butyl-4-hydroxy - 5 - methyl-propiophenone is 30 R6 and R are each selected from the group consisting hydrogenated catalytically in the presence of palladium of hydrogen, methyl and ethyl, and with the provi charcoal to form (3-tert.butyl-4-hydroxy-5-methylphen sion that when both R6 and R are hydrogen, the yl)-ethyl-carbinol which is dehydrated with oxalic acid phenolic hydroxy group is in other than the 4'-posi to prepare 1-(3'-tert.butyl - 4 - hydroxy - 5' - methyl tion. phenyl)--1. 1-(3 - tert.butyl - 4 - hydroxy - 5'- 35 2. A member as defined by claim 1 with the further methylphenyl)-2-bromo-propane-1-ol is obtained by add provision that when both R6 and R are hydrogen, the ing hypobromide to the double bond. phenolic hydroxy group is in the 3'-position. In analogy, the following compounds may be obtained 3. A member as defined by claim 1 with the provi when using the corresponding amines: sion that at least one of R6 and R is other than hydro 40 gen. N-1-(3'-tert.butyl-4'-hydroxy-5'-methylphenyl)-1-hy 4. A member as defined by claim 1 wherein the phenol droxy-propyl-2-N-isopropyl amine ic hydroxy group is in the 4'-position, R5 is 3'-tert, butyl, N-1-(3'-tert.butyl-4'-hydroxy-5'-methylphenyl)-1-hy and one of the R6 and R represents 5'-methyl. ' droxy-propyl-2-N-2'-phenylethyl)-amine. 5. N-1-(3'-tert.butyl - 4 - hydroxy-5'-methyl-phenyl)- EXAMPLE 34 45 1-hydroxy-butyl-2-N-isopropylamine. 6. N-1-(3'-tert.butyl-4'-hydroxy-5'- methyl-phenyl)- 44.2 g. cz-(3-tert.butyl-4-hydroxy-5-methylphenyl)pro 1-hydroxy-propyl-2-N-methylamine. pylenoxide are dissolved in 500 ml. of a 15% alcoholic 7. N-1-(3'-tert.butyl - 4 - hydroxy-5'-methyl-phenyl)- methylamine solution and stirred for 8 hours in a bomb 1-hydroxy-propyl-2-N-ethylamine. tube at 120-130° C. Upon cooling, the excess of methyl 50 8. N-1-(3'-tert, butyl-4-hydroxy - 5' - methyl-phenyl)- amine and of the solvent is evaporated. The residue is 1-hydroxy-propyl-2)-N-isopropylamine. acidified with HCl and extracted with ether. The aqueous 9.N-1-(3'-tertibutyl - 4 - hydroxy-5'-methyl-phenyl)- layer is made alkaline with NaOH and extracted with 1-hydroxy-propyl-2)-N-(4-phenyl-butyl-2)-amine. ethylacetate. The mixture obtained by drying and evapo 10. N-1-(3'-tert.butyl-4-hydroxy - 5'-methyl-phenyl)- rating the solvent is recrystallized from ethylacetate. N-1- 55 1-hydroxy-propyl-2-N-(1-phenoxy-propyl-2)-amine. (3'-tert.butyl-4-hydroxy - 5 - methylphenyl)-1-hydroxy 11. N-2-(3'-tert.butyl - 4'-hydroxy-5'-methyl-phenyl)- propyl-2-N-methylamine has an M.P. of 168-170° C. 2-hydroxy-ethyl-N-methylamine. The starting material may be prepared from 1-(3'-tert 12. N-(2-(3'-tert.butyl-4'-hydroxy - 5'-methyl-phenyl)- butyl-4'-hydroxy-5'-methylphenyl)-2-bromo-propane-1- 2-hydroxy-ethyl)-N-isopropylamine. ol by treatment with NaOH. 60 13. N-(2-(3'-tert.butyl - 4'-hydroxy-5'-methyl-phenyl)- 2-hydroxy-ethyl-N-(4-phenyl-butyl-2)-amine. EXAMPLE 35 14. N-2-(3'-tert.butyl-4-hydroxy - 5'-methyl-phenyl)- 8.5 g. 1-(3'-tert.butyl-4'-propionyloxy - 5 - methyl 2-hydroxy-ethyl-N-(1-phenoxy-propyl-2)-amine. phenyl)-1-hydroxy-2-methylamino-propane and 0.5 g. so 15. N-(1-(4-tert.butyl-3'-hydroxy - phenyl)-1-hydroxy dium ethylate are dissolved in 100 ml. ethanol and the 65 propyl-2-N-methylamine. solution is refluxed for 48 hours. The mixture is evapo 16. N-(1-(4'-tert.butyl-3'-hydroxy-phenyl)-1-hydroxy rated to dryness, the residue is treated with 80 ml. water propyl-2-N-isopropylamine. and extracted with ethyl acetate. The solution is dried over 17. N-2-(4'-tert.butyl-3' - hydroxy - 2,6'-dimethyl sodium sulfate and the obtained base is recrystallized phenyl)-2-hydroxy-ethyl-N-methylamine. from ethyl acetate. N-1-(3'-tert.butyl-4-hydroxy-5'- 70 18. N-1-(4-tert.butyl - 3 - hydroxy - 2,6'-dimethyl methylphenyl)-1-hydroxypropyl-2-N-methylamine has an phenyl)-1-hydroxy-propyl-2-N-methylamine. M.P. of 168-170° C. 19. N-(2-(4-tert.butyl-3’ - hydroxy - 2,6'-dimethyl What is claimed is: phenyl)-2-hydroxy-ethyl)-N-isopropylamine. 1. A member selected from the group consisting of a 20. N-1-(4 - tert.butyl - 3 - hydroxy-2,6'-dimethyl-, compound and a physiologically compatible, non-toxic 75 phenyl)-1-hydroxy-propyl-2)-N-isopropylamine. 3,461,164. 21 22 21. 2-(3'-tert.butyl - 4 - hydroxy-5'-methyl-phenyl)-2- OTHER REFERENCES hydroxy-ethylamine. Steinberg et al.: Journal Organic Chemistry, vol. 13, pp. 22. 1-(3'-tert.butyl-4'-hydroxy - 5 - methyl-phenyl)-1- 413-20 (1948). hydroxy-2-aminopropane. Moed et al.: Rec. Trav. Chim, vol. 71, pp. 933-44 References Cited 5 (1952). UNITED STATES PATENTS ROBERT V. HINES, Primary Examiner 3,202,711 8/1965 Fruhstorfer et al. --- 260-570.6 U.S. C. X.R. 2,538,792 1/1951 Moersch ------260-570.6 3,184,510 W1965 Levy ------260-570.6 10 260-144, 239, 326, 343, 348, 349, 453, 465, 471, 482, 3,072,530 1/1963 Hoffman ------167-65 483, 488, 501, 556, 559,561, 562, 566,567,569,570,580, 3,098,010 7/1963 Everett ------167-65 592, 600, 613, 618, 622,623,624, 625,626,668; 424-330