Aspartame Production by Thermolysin

The principles of the thermolysin process were introduced by Oyama et al. (9) in 1987. At first, L-PheOMe from racemic PheOMe is coupled with Z-Asp stereo and regio selectively by thermolysin. The reaction product, Z-APM, forms an insoluble addition compound with one molecule of remaining D-PheOMe immediately and precipitates. When the reaction is completed, the Z-APM-D-PheOMe addition compound is collected as a solid product, and ther-molysin is recovered from the solution. D-PheOMe is separated from Z-APM as its hydrochloride by acid washing (with hydrochloric acid, for example). The Z-group is removed from the Z-APM by hydrogenolysis. Finally, APM is obtained by crystallization and drying. D-PheOMe is recycled after racemization by alkaline treatment and rees-terification in methanol. The process is summarized in Figure 2.

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