Patent GB-1212290-A (GB)
Title: Preparation of phenylalanine and phenylserine derivatives
Inventor: PINES SEEMON HAYDEN
IPC: C07D263/34
Filed: 1968-09-16
Abstract: 1,212,290. Phenylalanine and phenylserine derivatives; organometallic compounds. MERCK & CO. Inc. 16 Sept., 1968 [21 Sept., 1967], No. 43877/68. Headings C2C and C2J. Phenylalanine and phenylserine derivatives of the formula wherein each of R<SP>6</SP>, R<SP>7</SP> and R<SP>8</SP> is H, C 1-3  alkyl, OH, or Cl (provided m is other than -MgCP), R<SP>5</SP> is C 1-3  alkyl and X is H or OH are prepared by condensing a compound of the formula in which each of R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> is H, F, Cl, C 1-3  alkyl, C 1-3  alkoxy or aryl C 1-3  alkoxy, and m is Li, H, MgX<SP>0</SP>, where X‹ is halogen or the corresponding di-(substituted-phenyl) cadmium with a compound of the formula in which R<SP>4</SP> is C 1-3  alkyl or phenyl, R<SP>5</SP> is C 1-3  alkyl and R<SP>9</SP> is C 1-3  alkyl or phenyl C 1-3  alkyl, by heating in the presence of a Lewis acid when M is H or in ether or tetrahydrofuran at -80‹ C. to + 20‹ C. when M is other than H to produce a keto-ester of the formula and reducing the keto-ester with simultaneous or subsequent replacement of R<SP>9</SP> and COR<SP>4</SP> by hydrogen atoms and cleavage of any alkoxy or phenyl alkoxy groups on the benzene ring. Starting compounds or intermediates of which the preparation is described are: 3,4-dibenzyloxybromobenzene, α - benzyloxycarbonyl - N - acetylalanine, benzyl ester; DL and L-α- carboxy - N - acetylalanine, benzyl ester; dipotassium -acetamido - methylmalonate; DL- and L - 4 - benzyloxycarbonyl - 2,4 - dimethyloxazol - 5 - one; benzyl DL- and L - 2 - acetamido - 2 - (3,4 - dibenzyloxy - benzoyl) - propionate; DL - erythro- and threo-, and L- erythro- and threo - N - acetyl - 3 - (3,4 - dibenzyloxy - phenyl) - 2 - methylserine, benzyl ester; 4 - ethoxycarbonyl - 2,4 - dimethyloxazol- 5 - one; ethyl 2 - acetamido - 2 - benzoylpropionate; DL - erythro- and threo - N - acetyl-2- methyl 3 - phenylserine, ethyl ester; L - α - carboxy - N - acetylalanine, ethyl ester; L - 4 - ethoxycarbonyl - 2,4 - dimethyloxazol - 5 - one; L - ethyl 2 - acetamido - 2 - benzoyl - propionate; L - erythro- and threo - N - acetyl - 2 - methyl- 3 - phenylserine, ethyl ester; L - ethyl 2- acetamido - 2 - (3,4 - dimethoxybenzoyl) propionate; erythro- and threo - L - N - acetyl - 3 - (3,4 - dimethoxy - phenyl) - 2 - methylserine, ethyl ester; ethyl L-2-acetamido - 2 - (3,4 - dibenzyloxybenzoyl) propionate; L - N - acetyl- 2 - methyl - 3 - (3,4 - dihydroxyphenyl) alanine, ethyl ester; DL- and L-α-carboxy-#-methyl-N- acetylalanine, ethyl ester; L-4-ethoxycarbonyl- 2 - methyl - 4 - ethyloxazol - 5 - one; L - ethyl 2 - acetamido - 2 - (3,4 - dimethoxy - 5 - methylbenzoyl.) butyrate; L-N-acetyl-2-ethyl-3-(3,4- dimethoxy - 5 - methylphenyl) alanine, ethyl ester; benzyl L - 2 - acetamido - 2 - (4 - fluorobenzoyl) propionate; DL- and L - α - carboxy- N - benzoylalanine, ethyl ester; L - 4 - ethoxy carbonyl - 2 - phenyl - 4 - methyloxazol - 5 - one; ethyl L - 2 - benzoylamino - 2 - (3 - chlorobenzoyl) propionate; L-N-benzoyl-2-methyl-3- (3-chlorophenyl) alanine, ethyl ester; benzyl L - 2 - acetamido - 2 - (3,4 - diethyl - benzoyl) propionate; and the acid addition salts of D( + ) - α - phenylethylamine with L - α - carboxy - N - acetylalanine, benzyl ester and ethyl ester; L - α - carboxy - N - benzoylalanine, ethyl ester-and L - α - carboxy - # - methyl - N - acetylalanine, ethyl ester. 3,4 - Dibenzyloxyphenylmagnesium bromide is prepared by refluxing 3,4-dibenzyloxybromobenzene in tetrahydrofuran with magnesium turnings. Diphenylcadmium is obtained by refluxing a solution of phenylmagnesium bromide with anhydrous cadmium chloride. 3,4 - Dimethoxyphenylithium is prepared by treating at -70‹ C. a solution of 3,4-dimethoxybromobenzene in tetrahydrofuran with a solution of n-butyllithium in ether. 3-Chlorophenylmagnesium bromide and 3,4-diethylphenylmagnesium bromide are also specified. Reference has been directed by the Comptroller to Specification 1,023,204.