Patent GB-1161858-A (GB)
Title: Novel Phenylalanine Derivatives and a process for the Manufacture thereof.
IPC: A61K31/195
Filed: 1967-11-30
Abstract: 1,161,858. Phenylalanine derivatives. F. HOFFMANN-LA ROCHE & CO. A.G. 30 Nov., 1967 [1 Dec., 1966], No. 54476/67. Heading C2C. Novel compounds (including optical isomers thereof and salts of said compounds and optical isomers) of the general formula wherein R<SP>1</SP> signifies a hydroxy, alkoxy, amino or substituted-amino group are obtained by hydrogenating a 3,5-dibenzyloxy-4-methoxybenzene which is substituted at the 1-position by an alanyl group or a residue which is convertible into an alanyl group (includes residues containing, for example, acid, ester, nitrile, alkanoyl, amino, carbamic, acylamino, thioacylamino, hydroxyimino and/or phenylhydrazono groups or an appropriate heterocyclic containing residue), converting said residue into the alanyl group or into an ester or amide thereof if desired, converting any product obtained into a salt if desired and/or resolving any product into its optical isomers if desired. Methyl 3,5 - dibenzyloxy - 4 - methoxy - benzoate (obtained by the interaction of benzyl chloride and methyl 3,5-dihydroxy-4-methoxybenzoate which benzoate is obtained by treating methyl 3,4,5-dihydroxy-benzoate with dimethyl sulphate) reacts with lithium aluminium hydride to give 3,5-dibenzyloxy-4-methoxy-benzyl alcohol which is converted to the corresponding benzyl chloride utilizing thionyl chloride, or is sulphonated with methanesulphonyl or toluenesulphonyl chloride to afford the respective sulphonate, or is converted to the corresponding benzaldehyde utilizing manganese dioxide. DL(3,5 - Dibenzylozy - 4 - methoxy - phenyl) - N-acetyl-alanine is prepared by refluxing (3,5 - dibenzyloxy - 4 - methoxy - benzyl) - acetylamino-malonic acid diethyl ester (obtained by the interaction of 3,5-dibenzyloxy-4-methoxy-benzyl chloride and acetylamino-malonic acid diethyl ester) with sodium hydroxide followed by acidification. (3,5 - Dihydroxy - 4 - Methoxy - benzyl) - acetyl-amino-malonic acid diethyl ester is obtained by hydrogenating the corresponding 3,5-dibenzyloxy compd. 5-(3,5 - Dibenzyloxy - 4 - methoxy - benzylidene)-rhodamine, obtained by the interaction of 3,5-dibenzyloxy-4-methoxy-benzaldehyde and rhodanine, is converted to 2-thio-3-(3,5-dibenzyloxy - 4 - methoxy - phenyl) - propionic acid in the presence of sodium hydroxide; the acid yields 2-hydroxyimino-3-(3,5-dibenzyloxy-4- methoxy-phenyl)-propionic acid (the 2-phenylhydrazono compound is also described) in the presence of hydroxylamine hydrochloride and the 2-hydroxyimino compound affords DL(3,5- dibenzyloxy - 4 - methoxy - phenyl) - alanine by reduction with sodium amalgam [this alanine derivative is also prepared by deacetylating DL - (3,5-dibenzyloxy-4-methoxyphenyl) - N - acetyl - alanine and the sodium salt thereof is also described], thereafter DL - (3,5 - dibenzyloxy - 4 - methoxy - phenyl) - N-benzyloxycarboxyl-alanine utilizing benzyloxy-carbonyl chloride and subsequently DL- (3,5 - dibenzyloxy - 4 - methoxy - phenyl) - N - benzyloxycarbonyl-alanine amide utilizing N- hydroxy-succinimide and N,N<SP>1</SP>-dicyclohexylcarbodiimide. 2 - Phenyl - 4 - (3,5 - dibenzyloxy - 4 - methoxybenzylidene)-5-oxo-oxazole, obtained by the interaction of 3,5-dibenzyloxy-4-methoxy-benzaldehyde and hippuric acid in the presence of anhydrous sodium acetate and acetic anhydride, is converted to DL-(3,5-dibenzyloxy-4-methoxyphenyl)-N-benzoyl alanine by treatment with sodium amalgam in the presence of aqueous ethanol followed by acidification. Pharmaceutical preparations showing hypotensive properties contain as active ingredient the above novel compounds and administration is enterally, parenterally or percutaneously.