Patent ES-354058-A1 (ES)
Title: Beta-phenylalanine derivatives
IPC: C07C45/67
Filed: 1968-05-18
Abstract: 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 Alk1 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+ 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 - [31- methoxy or ethoxy)- 41 - hydroxy - 51- 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.