Process for the preparation of lower alkyl esters of N-L-- aspartyl- L-phenylalanine and of new intermediates for their preparation

摘要

The invention relates to a selective process for the preparation of N- L--aspartyl-L-phenylalanine-1-lower alkyl ester which comprises:PPA. reacting an L-aspartic acid 4- arylmethyl ester with aPP(i) 1,3-diketone; orP P(ii) acylacetic ester;PP in the presence of a base to form the salt ofPP(i') L-N-(1-alkyl-2-acyl-vinyl)- aspartic acid 4- arylmethyl ester; orPP(ii') L-N-(1-alkyl- 2-alkoxycarbonyl- vinyl)-aspartic acid 4-arylmethyl ester,P P and then either:PP(1) reacting salt (i') or (ii') with an organic or inorganic acid halide having the formula X-A, wherein X represents a halogen and A has the meaning indicated hereinafter, or with an acid anhydride to form ##STR1## wherein R represents an alkyl radical with 1 to 6 carbon atoms;PPR' represents an alkyl or alkoxy radical with 1 to 6 carbon atoms;PPAr represents the phenyl, nitrophenyl, halogenphenyl or alkylphenyl radical; andP PA represents an acyl with 2 to 12 carbon atoms, alkoxycarbonyl with 2 to 12 carbon atoms, or a phosphoric acid, phosphorous acid, sulfuric acid, sulfurous acid or sulfonic acid radical; PP and reacting ester (I) with an L-phenylalanine lower alkyl ester; or PP(2) reacting a salt of (i') or (ii') with a phosphorazo-L- phenyl lower alkyl ester; to formPP (i") N-L--N'-(1- alkyl-2-acyl-vinyl)-aspartyl-L-phenylalanine-1- lower alkyl-4-arylmethyl ester; orPP(ii") N-L--N'-(1- alkyl-2-alkoxycarbonyl) aspartyl-L-phenylalanine-1-lower alkyl-4- arylmethyl ester;P PB. reacting (i") or (ii") with a strong acid to split off the respective N-(1-alkyl-2-acyl-vinyl) or N-(1- alkyl-2-alkoxycarbonyl-vinyl) protective group and produce:P P(iii) N-L--aspartyl- L-phenylalanine-1-lower alkyl-4- (arylmethyl)ester; andPPC. subjecting ester (iii) to catalytic hydrogenation to selectively split off the 4-(arylmethyl)-ester group and leave the N-L--aspartyl-L- phenylalanine-1-lower alkyl ester product.PPNovel intermediates for the synthesis are also disclosed.