Process for producing .alpha.-L-aspartyl-L-phenylalanine methyl ester

A process for producing .alpha.-L-aspartyl-L-phenylalanine methyl ester, comprising the steps of:

• (a) dissolving L-phenylalanine methyl ester in a water-immiscible solvent selected form the group consisting of toluene, benzene, carbon tetrachloride, chloroform, methylene chloride, and ethyl acetate,
• (b) coupling L-phenylalanine methyl ester with N-formyl-L-aspartic anhydride in a said water immiscible solvent,
• (c) evaporating the coupling mixture to produce a crystal mixture,
• (d) adding concentrated hydrochloric acid and water to said crystal mixture for deformylating the N-formyl-L-aspartyl-L-phenylalanine methyl ester,
• (e) cooling and filtering the resulting mixture to produce a first crystal and a first filtrate,
• (f) concentrating said first filtrate to produce a concentrated first filtrate wherein .alpha.-L-aspartyl-L-phenylalanine is 20-40% by volume,
• (g) adding concentrated hydrochloric acid and methanol to said concentrated first filtrate to esterify .alpha.-L-aspartyl-L-phenylalanine and to produce .alpha.-L-aspartyl-L-phenylalanine methyl ester crystal as a second crystal product,
• (h) combining said first .alpha.-L-aspartyl-L-phenylalanine methyl ester crystal product and said second .alpha.-L-aspartyl-L-phenylalanine methyl ester crystal product, and
• (i) neutralizing with a base and filtering to produce .alpha.-L-aspartyl-L-phenylalanine methyl ester.

A process for producing .alpha.-L-aspartyl-L-phenylalanine methyl ester, comprising the steps of:

• (a) esterifying L-phenylalanine with methanol in the presence of a strong acid,
• (b) continuously removing the water produced during the esterification reaction to produce the L-phenylalanine methyl ester strong acid salt,
• (c) neutralizing said L-phenylalanine methyl ester strong acid salt with a base dissolved in methanol, which is substantially free of water, to produce a mixture,
• (d) filtering said mixture and evaporating the methanol to produce a concentrate,
• (e) adding a water-immiscible solvent to dissolve said concentrate and form a solution of L-phenylalanine methyl ester,
• (f) adding said solution to N-formyl-L-aspartic acid anhydride and coupling said L-phenylalanine methyl ester with said N-formyl-L-aspartic anhydride,
• (g) evaporating the coupling mixture to produce a crystal mixture,
• (h) adding concentrated hydrochloric acid and water to said crystal mixture for deformylating the N-formyl-L-aspartyl-L-phenylalanine methyl ester,
• (i) cooling and filtering the resulting mixture to produce a first crystal and a first filtrate,
• (j) concentrating said first filtrate to produce concentrated first filtrate wherein .alpha.-L-aspartyl-L-phenylalanine is 20-40% by volume,
• (k) adding concentrated hydrochloric acid and methanol to said concentrated first filtrate to esterify .alpha.-L-aspartyl-L-phenylalanine therein to obtain a second .alpha.-L-aspartyl-L-phenylalanine methyl ester crystal product,
• (l) combining said first .alpha.-L-aspartyl-L-phenylalanine methyl ester crystal product and said second .alpha.-L-aspartyl-L-phenylalanine methyl ester crystal product, and
• (m) neutralizing with a base and filtering to produce .alpha.-L-aspartyl-L-phenylalanine methyl ester.