Process for the preparation of polyamino acids
View Patent ↗Among the various aspects of the present invention is an improved process for the preparation of polyamino acids generally, and more specifically, polyglutamic acid and polyaspartic acid. Another aspect is a process for the large scale (i.e. >1 kg) preparation of polyamino acids; particularly polyglutamic and polyaspartic acid.
1. A process for the preparation of a polyamino acid, the process comprising (i) forming a reaction mixture comprising a N-carboxyanhydride compound and a metal alkoxide initiator, (ii) polymerizing the N-carboxyanhydride compound to form a polymer having a mass-average molecular weight of at least 10,000 and a repeat unit, the repeat unit comprising an alkyl ester moiety having the formula —C(O)OR 1 and (iii) hydrolyzing the alkyl ester moiety of the repeat unit in the presence of a base to form a polyamino acid, wherein
the N-carboxyanhydride corresponds to Formula 1
the polymer repeat unit corresponds to Formula 2
the polyamino acid comprises a repeat unit corresponding to Formula 3
R 1 is alkyl;
m is 1 or 2;
n is an integer; and
X is hydrogen or a metal; and
wherein the polyamino acid has less than about 0.5 mole % of repeat units containing the moiety R 1 when analyzed by NMR.
2. The process of claim 1 wherein the polyamino acid has less than about 0.2 mole % of repeat units containing the moiety R 1 when analyzed by NMR.
3. The process of claim 1 wherein the polyamino acid has an absence of repeat units containing the moiety R 1 when analyzed by NMR.
4. The process of claim 1 wherein the metal alkoxide initiator is sodium methoxide, sodium ethoxide, sodium propoxide, potassium methoxide, potassium ethoxide, potassium propoxide, or mixtures thereof.
5. The process of claim 1 wherein the metal alkoxide initiator is sodium methoxide, sodium ethoxide, sodium propoxide or mixtures thereof.
6. The process of claim 1 wherein the metal alkoxide initiator is sodium methoxide.
7. The process of claim 1 wherein the reaction solution has a N-carboxyanhydride to metal alkoxide initiator molar ratio of about 15:1 to about 25:1.
8. The process of claim 1 wherein the reaction solution has a N-carboxyanhydride to metal alkoxide initiator molar ratio of about 15:1 to about 20:1.
9. The process of claim 1 wherein the reaction solution has a N-carboxyanhydride to metal alkoxide initiator molar ratio of about 15:1.
10. The process of claim 1 wherein the reaction mixture comprising N-carboxyanhydride and metal alkoxide initiator is placed in a solvent selected from the group consisting of dioxane, chloroform, dichloromethane, acetonitrile, and combinations thereof.
11. The process of claim 10 wherein the solvent is dioxane.
12. The process of claim 1 wherein polymerizing the N-carboxyanhydride compound takes place at a temperature of from about 20° C. to about 30° C.
13. The process of claim 1 wherein polymerizing the N-carboxyanhydride compound takes place at a temperature of from about 25° C. to about 30° C.
14. The process of claim 1 wherein polymerizing the N-carboxyanhydride compound takes place at a temperature of about 25° C.
15. The process of claim 1 wherein polymerizing the N-carboxyanhydride compound takes about 12 to about 30 hours.
16. The process of claim 1 wherein polymerizing the N-carboxyanhydride compound takes about 18 to about 24 hours.
17. The process of claim 1 wherein the polymer has a mass-average molecular weight of about 11,000 to about 23,000.
18. The process of claim 1 wherein the polymer has a mass-average molecular weight of about 50,000 to about 100,000.
19. The process of claim 1 wherein the polymer has a mass-average molecular weight of at least about 100,000.
20. The process of claim 1 wherein m is 2.
21. The process of claim 1 wherein R 1 is ethyl.
22. The process of claim 1 wherein m is 2 and R 1 is ethyl.
23. The process of claim 1 wherein the base is sodium hydroxide, potassium hydroxide, rubidium hydroxide, or mixtures thereof.
24. The process of claim 1 wherein the base is sodium hydroxide.
25. The process of claim 1 wherein hydrolyzing the alkyl ester moiety takes place in an alcoholic solvent.
26. The process of claim 25 wherein the alcoholic solvent is methanol, ethanol, propanol or mixtures thereof.
27. The process of claim 25 wherein the alcoholic solvent is ethanol.
28. The process of claim 1 wherein hydrolyzing the alkyl ester moiety takes about 5 to about 7 hours.
29. The process of claim 1 wherein hydrolyzing the alkyl ester moiety takes about 6 hours.
30. The process of claim 1 wherein R 1 is ethyl, m is 2, X is sodium, the base is sodium hydroxide and the polymer has a mass-average molecular weight of about 11,000 to about 23,000.
31. The process of claim 1 wherein R 1 is ethyl, m is 2, X is sodium, the base is sodium hydroxide and the polymer has a mass-average molecular weight of about 50,000 to about 100,000.
32. The process of claim 1 wherein R 1 is ethyl, m is 2, X is sodium, the base is sodium hydroxide and the polymer has a mass-average molecular weight of at least about 100,000.