Synthesis of N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester using oxazolidinone derivatives
Synthesis of N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester by treating N-(3,3-dimethylbutyl)-L-aspartic acid with ketones to give oxazolidinone derivatives, which are condensed with L-phenylalanine methyl ester.
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 (i) N-(3,3-dimethylbutyl)-L-aspartic acid and (ii) a ketone or an acetal of a ketone in a first solvent for a time and at a temperature sufficient to produce an oxazolidinone derivative having the formula
wherein R 1 is R 2 ; R 2 is Ph or CX 3 ; and X is H, Cl, Br or F; 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,
wherein the first solvent and the second solvent are different.
2. The process according to claim 1 , wherein the ketone is selected from the group consisting of hexafluoroacetone, hexachloroacetone, and combinations thereof.
3. The process according to claim 1 , wherein the acetal of a ketone is selected from the group consisting of dimethyl acetal of hexafluoroacetone, diethyl acetal of hexafluoroacetone, dimethyl acetal of hexachloroacetone, diethyl acetal of hexachloroacetone, 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 ketone or the acetal of a ketone 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 the ketone or the acetal of a ketone further comprises a p-toluenesulfonic acid catalyst.
11. The process according to claim 1 , wherein the admixture of N-(3,3-dimethylbutyl)-L-aspartic acid and the ketone or the acetal of a ketone further comprises an acid.
12. The process according to claim 11 , wherein the acid is selected from the group consisting of formic acid, acetic acid, p-toluenesulfonic acid, methane sulfonic acid and combinations thereof.
13. 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.
14. 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.
15. 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.
16. The process according to claim 15 , 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.
17. 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.
18. The process according to claim 17 , 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.