Patent GB-1251142-A (GB)
IPC: C07D233/96
Filed: 1969-01-30
Abstract: 1,251,142. 3,5 - Dihydroxy - 4 - methoxyphenylalanine derivatives. F. HOFFMANN-LA ROCHE & CO. A.G. 30 Jan., 1969 [9 Feb., 1968], No. 5179/69. Heading C2C. Phenylalanine derivatives of formula and salts thereof, wherein R 1  is OH, alkoxy or amino optionally substituted by alkyl or hydroxyalkyl-groups or by a divalent alkylene chain optionally interrupted by a hetero atom are prepared by hydrolysis, optionally in two stages, of a compound of Formula II wherein X is a carboxylic or sulphonio -acyl group or a group of formula R a OC(B 3 )(B 4 )- in which R 2  is alkyl or phenylalkyl and R 3  is H, alkyl or phenylalkyl or R 2  and R3 together represent an alkylene group, R 4  is H or alkyl, Y is alkyl and Z is H or acyl and decarboxylation of this hydrolysis product (optionally in the same acid hydrolysis), and if necessary hydrolysis of any remaining X groups and optionally followed by esterifying or amidating the free carboxyl group and/or salt formation and/or isomerizing a D-isomer and/or resolution of a racemate and isolating the L-isomer. Intermediates of Formula II above are prepared for example according to one of the following reaction sequences: benzoyl chloride is reacted with 3,5-dihydroxy-4-methoxybenzoic acid to give 3,5-bis-(benzoyloxy)-4-methoxybenzoic acid which is reduced to the benzyl alcohol and converted to the benzyl chloride which is reacted with formamidomalonic acid dimethyl ester to give 3,5 - bis - (benzoyloxy) - 4 - methoxy - benzylformamidomalcmic acid dimethyl ester; benzene sulphochloride is reacted with gallic acid methyl ester to give 3,4,5-tris-(phenylsulphonyloxy)- benzoic acid methyl ester which on partial hydrolysis with ammonia and H 2 SO 4  yields 3,5-bis- (phenylsulphonyloxy} - 4 - hydroxybensoic acid methyl ester which is methylated to give the 4-methoxy compound and hydrolysed to give 3,5 - bis - (phenylsulphonyloxy) - 4 - methoxybenzoic acid which is converted to the acid chloride, reduced to the benzyl alcohol and converted to the benzyl chloride which is reacted with formamidomalonic acid dimethyl ester to give 3,5 - his - (phenyLsuLphonyloxy)- 4 - methoxy - benzyl - formamido - malonic acid dimethyl ester; by replacing the benzene sulphonyl chloride by mesyl chloride in the last reaction and isolating all the corresponding intermediates, 3,5 - bis - (mesyloxy) - 4 - methoxybenzyl - formamido-malonic acid dimethyl ester is obtained; by replacing benzoyl chloride by chloromethylmethyl ether and the acid by the methyl ester in the first preparation above and isolating the corresponding intermediates, 3,5-bis-(methoxymethoxy) - 4 - methoxybenzyl - formamidomalonic acid dimethyl ester is obtained; 3,5-dihydroxy-4- methoxybenzoic acid methyl ester is reacted with dihydropyran and p-toluene sulphonate to give 3,5 - bis - (tetrahydropyranyloxy)- 4- - methoxyhenzoic acid methyl ester which is reduced to the benzyl alcohol and reacted with p-toluene sulphonyl chloride to give 3,5-bis-(tetrahydropyranyloxy) - 4 - methozybenzyl - p - toluene sulphonate which is reacted with formamidomalonic acid dimethyl ester to give 3,5-bis- (tetrahydropyranyloxy)- 4 - methoxybenzyl - formamidomalonic acid dimethyl ester. 3,5 - Dihydroxy - 4 - methoxybenzoic acid methyl ester is obtained by treatment of gallic acid methyl ester with phosphorus oxychloride and methyl sulphate to methylate the 4-hydroxy group. Resolution of compounds of Formula I above is exemplified by treating DL-3,5-dihydroxy-4- methoxy-phenyl-analine with an acetylating agent in the presence of a weak base to give DL- 3,5 - dihydroxy - 4 - methoxy - phenyl - N - acetylalanine which is converted into its brucine salt which is resolved and treated with cold barium hydroxide solution and L-3,5-dihydroxy-4- methoxy-phenylalanine isolated compounds of Formula I above may be used to prepare pharmaceutical compositions claimed in Specification 1,161,858.