Synthesis of N-(N-(3,3-dimethylbutyl)-L-α-aspartyl)L-phenylalanine1-methyl ester by reductive alkylation and crystallization/ isolation in aqueous methanol

A process of synthesizing N-[-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester comprising the steps of:

• (a) preparing a mixture of L-α-aspartyl-L-phenylalanine 1-methyl ester and a catalyst in a solvent consisting of an amount of water and methanol at a ratio of 5:95 to 60:40;
• (b) adding 3,3-dimethylbutyraldehyde gradually to the mixture wherein the ratio of L-α-aspartyl-L-phenylalanine 1-methyl ester to 3,3-dimethylbutyraldehyde is from 1:0.95 to about 1:1;
• (c) reacting the L-α-aspartyl-L-phenylalanine 1-methyl ester and the 3,3-dimethylbutyraldehyde in the presence of the catalyst and in the presence of hydrogen at about 5 psi to about 100 psi and at a temperature of about 20° C. to about 60° C. and for a time of about 1 hour to about 24 hours;
• (d) removing the catalyst;
• (e) adding water to the mixture, wherein the ratio of water to methanol is from 85:15 to 65:35;
• (f) holding the mixture for a time of 0.5 to 24 hours at between 20° C. to 50° C.;
• (g) crystallizing N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester, wherein said crystallization is accomplished by cooling the mixture to a temperature of from about 0° C. to 25° C. over a period of 0.5 to 2 hours;
• and
• (h) isolating the crystallized N-[N-(3,3dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester.