Purification of substituted diaminopyrazine dicarboxylic acids

Patent metadata

Field	Value
Publication number	US-12428382-B2
Application number	US-202217697281-A
Country	US
Kind code	B2
Filing date	Mar 17, 2022
Priority date	Mar 31, 2021
Publication date	Sep 30, 2025
Grant date	Sep 30, 2025

Abstract

The present invention provides methods for the purification of the compound of Formula (I) from the precipitated reaction product comprising the compound of Formula (I), impurities, and/or residual or entrained solvents.

First claim

What is claimed is:

1. A method for purifying a compound of Formula (I) or salt thereof from a precipitated reaction product comprising the compound of Formula (I), impurities, and/or residual or entrained solvents,

the method comprising
(a) contacting the precipitated reaction product comprising the compound of Formula (I), impurities, and/or residual or entrained solvents with a first solvent forming a first reaction mixture;
(b) performing at least one distillation of the first reaction mixture under vacuum maintaining a temperature below 40° C. forming a second reaction mixture;
(c) cooling the second reaction mixture to a temperature of about 0° C.; and
(d) isolating the compound of Formula (I) from the second reaction mixture;

wherein “AA ester” is an ester amino acid comprising an ester portion and an amino acid portion, and
wherein the ester portion of the AA ester includes a C 1 -C 10 unsubstituted alkyl or a C 1 -C 10 substituted alkyl.

2. The method of claim 1 , wherein the amino acid portion of the AA ester or salt thereof of the compound of Formula (I) is a natural amino acid, an unnatural amino acid, or a synthetic amino acid.

3. The method of claim 2 , wherein the amino acid portion of the AA ester or salt thereof of the compound of Formula (I) has an (R) configuration, a(S) configuration, or a mixture thereof.

4. The method of claim 2 , wherein the amino acid portion of the AA ester or salt thereof of the compound of Formula (I) is (R)-serine.

5. The method of claim 2 , wherein the ester portion of the AA ester or salt thereof of the compound of Formula (I) is methyl, ethyl, tert-butyl, or benzyl.

6. The method of claim 2 , wherein the ester portion of the AA ester or salt thereof of the compound of Formula (I) is benzyl.

7. The method of claim 1 , wherein the ester portion of the AA ester or salt thereof of the compound of Formula (I) is a C 1 -C 8 unsubstituted alkyl or a C 1 -C 8 substituted alkyl.

8. The method of claim 1 , wherein the at least one distillation in step (b) comprises at least two distillations.

9. The method of claim 8 , wherein a second solvent is added between distillations.

10. The method of claim 9 , wherein the second solvent may be the same as or different from the first solvent used in step (a).

11. The method of claim 1 , wherein the first reaction mixture is distilled to a volume of less than 50% as compared to the initial volume of the first reaction mixture.

12. The method of claim 11 , wherein the first reaction mixture is distilled to a volume less than 25% as compared to the initial volume of the first reaction mixture.

13. The method of claim 1 , wherein the first solvent is selected from the group consisting of toluene, ethyl acetate, propyl acetate, acetone, methyl iso-butyl ketone, 2-butanone, methanol, ethanol, iso-propanol, iso-butanol, water, and mixtures thereof.

14. The method of claim 13 , wherein the first solvent is selected from the group consisting of ethyl acetate, isopropanol, water, and mixtures thereof.

15. The method of claim 1 , wherein the first solvent and the compound of Formula (I) are present at a volume (mL) to weight ratio (g) from about 2:1 to about 25:1.

16. The method of claim 15 wherein the first solvent and the compound of Formula (I) are present at a volume (mL) to weight ratio (g) from about 15:1 to about 20:1.

17. The method of claim 15 , wherein the first solvent and the compound of Formula (I) are present at a volume (mL) to weight ratio (g) from 4:1 to about 6:1.

18. The method of claim 1 , wherein the temperature is maintained in step (b) at less than 20° C.

19. The method of claim 1 , wherein the vacuum is less than 50 inches of Hg.

20. The method of claim 19 , wherein the vacuum is less than 28 inches of Hg.

21. The method of claim 1 , wherein the compound of Formula (I) has a yield greater than 60%.

22. The method of claim 1 , wherein the compound of Formula (I) has a yield greater than 70%.

23. The method of claim 1 , wherein the compound of Formula (I) has a purity greater than 95%.

24. The method of claim 1 , wherein the compound of Formula (I) has a purity greater than 97%.

25. A method for purifying a compound of Formula (I) or salt thereof from a precipitated reaction product comprising the compound of Formula (I), impurities, and/or residual or entrained solvents,

the method comprising:
(a) contacting the precipitated reaction product comprising the compound of Formula (I), impurities, and/or residual or entrained solvents with a first solvent comprising a mixture of ethyl acetate, iso-propanol, and water, thereby forming a first reaction mixture wherein the first solvent and the compound of Formula (I) are present at a volume (mL) to weight (g) ratio from about 2:1 to about 25:1;
(b1) performing a first distillation of the first reaction mixture under vacuum maintaining a temperature below 40° C. forming a second reaction mixture, wherein the vacuum is less than 50 inches of Hg and the volume of the first reaction mixture after distillation is less than 50% as compared to the initial volume of the first reaction mixture;
(b2) adding a second solvent to the distilled first reaction mixture to form a second reaction mixture, the second solvent comprising isopropanol, wherein the second solvent and the compound of Formula (I) are present at a volume (mL) to weight (g) ratio from about 2:1 to about 25:1;
(b3) performing a second distillation of the second reaction mixture under vacuum maintaining a temperature below 20° C. forming a third reaction mixture, wherein the vacuum is less than 50 inches of Hg and the volume of the first reaction mixture after distillation is less than 50% as compared to the initial volume of the first reaction mixture;

(c) cooling the third reaction mixture to a temperature of about 0° C.; and
(d) isolating the compound of Formula (I) from the third reaction mixture;

wherein “AA ester” is an ester amino acid comprising an ester portion and an amino acid portion, and
wherein the AA ester is

26. The method of claim 25 , wherein the compound of Formula (I) has a yield greater than 60%.

27. The method of claim 25 , wherein the compound of Formula (I) has a purity greater than 95%.

28. A method for purifying a compound of Formula (I) or salt thereof from a precipitated reaction product comprising the compound of Formula (I), impurities, and/or residual or entrained solvents,

the method comprising:
(a) contacting the precipitated reaction product comprising the compound of Formula (I), impurities, and/or residual or entrained solvents with a first solvent comprising a mixture of ethyl acetate, iso-propanol, and water, thereby forming a first reaction mixture wherein the first solvent and the compound of Formula (I) are present at a volume (mL) to weight (g) ratio from about 15:1 to about 20:1;
(b1) performing a first distillation of the first reaction mixture under

Assignees

• Medibeacon Inc

Inventors

• Rogers Thomas
• Adams David
• Hua Xiaogang

Classifications

• C07D241/28 Primary

  in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms · CPC title

• C07D241/32 Primary

  (Amino-pyrazinoyl) guanidines · CPC title