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US 5,476,961 AGranted
One-pot process for the preparation of .alpha.-L-aspartyl-L-phenylalanine methyl ester hydrochloride
AssigneeThe NutraSweet Company
InventorsJohn B. Hill, Yefim Gelman, Hugh L. Dryden, Jr., Robert Erickson, Kuang Hsu, Mark R. Johnson
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Abstract
A one-pot process for the preparation of .alpha.-L-aspartyl-L-phenylalanine methyl ester hydrochloride is disclosed (.alpha.-APM(HCl)). .alpha.-APM(HCl) is an intermediate in the preparation of aspartame.
Claims18
A one-pot method of preparing .alpha.-APM hydrochloride which comprises:
- (a) formylating L-Aspartic acid in a first reaction mixture of formic acid, acetic anhydride and a secondary alcohol to yield N-formyl-L-aspartic anhydride;
- (b) coupling said N-formyl-L-aspartic anhydride in situ with L-phenylalanine in the presence of an alkyl ester, a hindered alcohol or mixture thereof in an amount of at least about 1-2 moles per mole of L-phenylalanine and in the presence of an amount of acetic acid and under agitation conditions sufficient to produce a reaction mixture having a viscosity under 15,000 centipoise and at an effective temperature to yield .alpha.,.beta.-N-formyl-L-aspartyl-L-phenylalanine isomers;
- (c) deformylating said isomers by adding an effective amount of hydrochloric acid;
- (d) removing residual acetic acid and formic acid from the reaction mixture;
- (e) esterifying the deformylated isomers by adding an effective amount of methanol, water and HCl to the reaction mixture to yield .alpha.- and .beta.-APM-hydrochloride wherein the .alpha.-APM-hydrochloride precipitates;
- and
- (f) isolating the .alpha.-APM hydrochloride.
4 more elements
A one-pot process of preparing .alpha.-APM hydrochloride which comprises:
- (a) formylating L-aspartic acid in a first reaction mixture of formic acid, acetic anhydride and isopropyl alcohol to yield N-formyl aspartic anhydride;
- (b) coupling said aspattic anhydride in situ with L-phenylalanine in the presence of (i) acetic acid in an amount of at least about 1.2 moles per mole of L-phenylalanine and (ii) a suitable amount of an alkyl ester, a hindered alcohol or mixture thereof, at a temperature of from about 5.degree. C. to about 40.degree. C. and under agitation conditions sufficient to produce a reaction mixture having a viscosity under 15,000 centipoise and to yield .alpha.,.beta.-N-formyl-L-aspartyl-L-phenylalanine isomers;
- (c) deformylating said isomers by adding effective amounts of HCl and methanol;
- (d) vacuum distilling excess acetic acid, formic acid, methyl acetate and methyl formate from the reaction mixture;
- (e) esterifying the deformylated isomers by adding effective amounts of methanol and HCl to the reaction mixture to yield .alpha.,.beta.-APM-hydrochloride wherein the .alpha.-APM-hydrochloride precipitates;
- and
- (f) isolating the .alpha.-APM/hydrochloride.
4 more elements
Dependencies are inferred from the claim text.