Synthesis of N- [N-(3,3-dimethylbutyl)-L-alpha-aspartyl] -L-phenylalantine 1-methyl ester using oxazolidinone derivatives

• US 20020013490A1
• Filed: 05/18/2001
• Published: 01/31/2002
• Est. Priority Date: 05/19/2000
• Status: Active Grant

• Current Assignee: Nutrasweet Company (NutraSweet Property Holdings, Inc.)
• Original Assignee: Nutrasweet Company (NutraSweet Property Holdings, Inc.)
• Inventors: Prakash, Indra
• Granted Patent: US 6,852,875 B2
• Time in Patent Office: Days
• US Class Current: 560/40
• CPC Class Codes: C07K 5/06113 Asp- or Asn-amino acid

Abstract

N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester is produced using novel oxazolidinone derivatives.

Claims

1. A process of synthesizing N-[N-(3,3-dimethylbutyl)-L-α

-aspartyl]-L-phenylalanine 1-methyl ester comprising the steps of;

(a) reacting an admixture of N-(3,3-dimethylbutyl)-L-aspartic acid and a carbonyl compound or an activated carbonyl compound in a first solvent for a time and at a temperature sufficient to produce an oxazolidinone derivative; and

(b) reacting an admixture of the oxazolidinone derivative and L-phenylalanine or L-phenylalanine methyl ester in a second solvent for a time and at a temperature sufficient to produce N-[N-(3,3-dimethylbutyl)-L-α

-aspartyl]-L-phenylalanine 1-methyl ester.

2. The process according to claim 1, wherein the carbonyl compound is selected from the group consisting of hexafluoroacetone, trichloroacetaldehyde, tribromoacetaldehyde, hexachloroacetone, formaldehyde, paraformaldehyde, benzaldehyde, substituted benzaldehydes and combinations thereof.

3. The process according to claim 1, wherein the activated carbonyl compound is selected from the group consisting of dimethyl or diethyl acetals of hexafluoroacetone, trichloroacetaldehyde, tribromoacetaldehyde, hexachloroacetone, formaldehyde, benzaldehyde, substituted benzaldehydes and combinations thereof.

4. The process according to claim 1, wherein the first solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, t-butyl methyl ether, ethyl acetate, dioxane, toluene, butyl acetate, methyl acetate, dichloromethane, dimethylformamide, dimethylsulfoxide and combinations thereof.

5. The process according to claim 1, wherein the ratio of N-(3,3-dimethylbutyl)-L-aspartic acid to the carbonyl compound is from about 1:

1 to about 1;

4.

6. The process according to claim 1, wherein the temperature sufficient to produce the oxazolidinone derivative is from about 20°

C. to about 150°

C.

7. The process according to claim 6, wherein the temperature sufficient to produce the oxazolidinone derivative is from about 22°

C. to about 70°

C.

8. The process according to claim 1, wherein the time sufficient to produce the oxazolidinone derivative is from about 1 hour to about 48 hours.

9. The process according to claim 8, wherein the time sufficient to produce the oxazolidinone derivative is from about 12 hours to about 24 hours.

10. The process according to claim 1, wherein the admixture of N-(3,3-dimethylbutyl)-L-aspartic acid and a carbonyl compound or an activated carbonyl compound further comprises a catalyst.

11. The process according to claim 10, wherein the catalyst is p-toluenesulfonate.

12. The process according to claim 1, wherein the admixture of N-(3,3-dimethylbutyl)-L-aspartic acid and a carbonyl compound or an activated carbonyl further comprises an acid.

13. The process according to claim 12, wherein the acid is selected from the group consisting of formic acid, acetic acid, p-toluene sulfonic acid, methane sulfonic acid and combinations thereof.

14. The process according to claim 1, wherein the second solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, t-butyl methyl ether, ethyl acetate, dioxane, toluene, butyl acetate, methyl acetate, dichloromethane, dimethylformamide, dimethylsulfoxide and combinations thereof.

15. The process according to claim 1, wherein the first solvent and the second solvent are the same.

16. The process according to claim 1, wherein the ratio of L-phenylalanine or L-phenylalanine methyl ester to the oxazolidinone derivative is from about 1:

1 to about 1;

2.

17. The process according to claim 1, wherein the temperature sufficient to produce N-[N-(3,3-dimethylbutyl)-L-α

-aspartyl]-L-phenylalanine 1-methyl ester is from about 0°

C. to about 50°

C.

18. The process according to claim 17, wherein the temperature sufficient to produce N-[N-(3,3-dimethylbutyl)-L-α

-aspartyl]-L-phenylalanine 1-methyl ester is from about 22°

C. to about 40°

C.

19. The process according to claim 1, wherein the time sufficient to produce N-[N-(3,3-dimethylbutyl)-L-α

-aspartyl]-L-phenylalanine 1-methyl ester is from about 1 hour to about 48 hours.

20. The process according to claim 19, wherein the time sufficient to produce N-[N-(3,3-dimethylbutyl)-L-α

-aspartyl]-L-phenylalanine 1-methyl ester is from about 12 hours to about 24 hours.