Patent GB-1220591-A (GB)
Title: Beta-phenylalanine derivatives
Inventor: CROOIJ PIERRE
IPC: C07C45/67
Filed: 1967-05-26
Abstract: 1,220,591. #-Phenylalanine derivatives. RECHERCHE ET INDUSTRIE THERAPEUTIQUES R.I.T. 2 May, 1968 [26 May, 1967], No. 24754/67. Heading C2C. Novel DL-, D- and L-#-phenylalanine derivatives of the general formula wherein R 1  and R 2  are each a methyl or ethyl group or one of R 1  and R 2  is a hydrogen atom or a C 2-30  acyl group and the other is a methyl or ethyl group; R 3  is a hydrogen atom, a pharmaceutically acceptable non-toxic alkali metal, ammonium, a pharmaceutically acceptable non-toxic protonated amine with which the rest of the molecule forms an acid addition salt, or a C 1-30  alkyl or C 2-30  alkenyl radical; X is a chlorine, bromine, iodine or fluorine atom; and Z is a hydrogen atom or a C 2-30  carboxylic acyl radical; and non-toxic acid addition salts thereof are prepared (a) when R 3  and Z are each a hydrogen atom, by hydrolysis and decarboxylation of a 2-benzyl-2- amino-malonic acid ester derivative of the general formula wherein Alk<SP>1</SP> is a C 1-4  alkyl radical and Y is a formyl, acetyl, benzoyl, phthaloyl or benzyloxycarbonyl radical, the reaction being conducted in a solvent under the influence of heat in an acid medium and in the presence of a reducing agent; or (b) when R 3  and Z are each a hydrogen atom, by reduction of a phenyl-pyruvic acid derivative of the general formula wherein M is as R 3  above with the exception of an alkyl or alkenyl radical, under mild conditions in the presence of ammonium hydroxide solution, followed optionally by conversion of the product to a non-toxic acid addition salt thereof or resolution of the racemic product into its D- and L-enantiomers. The L(-)ephedrine salt of (-)3-methoxy-4- hydroxy - 5 - bromo - N - acetyl - phenylalanine is prepared by adding DL-3-methoxy-4-hydroxy-5-bronio-N-acetyl-phenylalanine to an ethanolic solution of L(-)ephedrine diluted with acetone. 2 - Benzyl - 2 - aminomalonic acid ester derivatives of the second general formula above wherein R 1  is a methyl or ethyl group and R 2  is a hydrogen atom are prepared by halogenation of 3-(methoxy or ethoxy)-4-hydroxybenzaldehyde, reduction of the resulting 3-(methoxy or ethoxy) - 4 - hydroxy - 5 - halobenzaldehyde with sodium borohydride, reaction of the 3-(methoxy or ethoxy) - 4 - hydroxy - 5 - halobenzyl alcohol so obtained with a hydrogen halide and reaction of the resulting 3-(methoxy or ethoxy)-4- hydroxy-5-halobenzyl halide with an alkali metal salt of a 2-aminomalonic acid ester derivative of the general formula wherein M<SP>+</SP> is an alkali metal ion. Phenylpyruvic acid derivatives of the third general formula above are prepared by reaction of a 3-(methoxy or ethoxy)-4-hydroxy-5-halobenzaldehyde with N-acetylglycine in the presence of excess acetic anhydride and sodium acetate, mild alkaline hydrolysis of the resulting azlactone of the general formula and acid or alkaline hydrolysis of the resulting 2 - acetamido - 3 - [3<SP>1</SP>- methoxy or ethoxy)- 4<SP>1</SP> - hydroxy - 5<SP>1</SP>- halo] - phenylpropenoic acid. 5 - Bromo - isovanallin is prepared by treatment of 5-bromovanallin with anhydrous aluminium chloride in pyridine, while heating, and reaction of the resulting 5-bromo-protocatechualdehyde with methyl iodide and sodium bicarbonate in acetone. Acetamido - 3,4 - dihydroxy - 5 - chlorobenzylmalonic acid diethyl ester is prepared by treatment of diethyl acetamido-(3-methoxy-4-hydroxy - 5 - chlorobenzyl) - malonate with aluminium chloride in pyridine. Pharmaceutical compositions having hypotensive activity comprise, as active ingredient, a DL-, D- or L-#-phenylalanine derivative of the first general formula above or a non-toxic acid addition salt thereof, together with a pharmaceutically acceptable diluent or carrier, and may be administered orally, intramuscularly, intravenously or subcutaneously.