Preparation of substituted diaminopyrazine dicarboxylic acids

Patent metadata

Field	Value
Publication number	US-12319660-B2
Application number	US-202217697275-A
Country	US
Kind code	B2
Filing date	Mar 17, 2022
Priority date	Mar 31, 2021
Publication date	Jun 3, 2025
Grant date	Jun 3, 2025

Abstract

The present invention provides improved methods for preparing a compound comprising Formula (I).

First claim

What is claimed is:

1. A method for preparing a compound of Formula (I):

the method comprising contacting 3,6-diamino-2,5-pyrazinedicarboxylic acid, an ester amino acid (“AA ester”) or a salt thereof, a polar aprotic solvent, a tertiary amine, ethyl-2-cyano-2-(hydroxyimino)acetate, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) hydrochloride under suitable reaction conditions to form the compound of Formula (I);
wherein the ester portion of the AA ester is an C 1 -C 10 unsubstituted alkyl or a C 1 -C 10 substituted alkyl.

2. The method of claim 1 , wherein 3,6-diamino-2,5-pyrazinedicarboxylic acid, the AA ester or salt thereof, the polar aprotic solvent, the tertiary amine, ethyl-2-cyano-2-(hydroxyimino)acetate, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) hydrochloride are added in any sequential order, in any combination, or added all at once.

3. The method of claim 1 , wherein the method comprises:
(a) contacting 3,6-diamino-2,5-pyrazinedicarboxylic acid with the AA ester or salt thereof in a polar aprotic solvent in a vessel to form a suspension;
(b) contacting the suspension from step (a) with the tertiary amine;
(c) contacting the suspension from step (b) with ethyl-2-cyano-2-(hydroxyimino)acetate;
(d) contacting the suspension from step (c) with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) hydrochloride to form the compound of Formula (I).

4. The method of claim 1 , wherein the amino acid portion of the AA ester or salt thereof is a natural amino acid, an unnatural amino acid, or a synthetic amino acid.

5. The method of claim 1 , wherein the amino acid portion of the AA ester or salt thereof is a (R) configuration, a(S) configuration, or a racemic mixture.

6. The method of claim 1 , wherein the amino acid of the AA ester or salt thereof is (R)-serine.

7. The method of claim 1 , wherein the ester portion of the AA ester is a C 1 -C 8 unsubstituted alkyl or a C 1 -C 8 substituted alkyl.

8. The method of claim 1 , wherein the ester portion of the AA ester or salt thereof is methyl, ethyl, tert-butyl, or benzyl.

9. The method of claim 1 , wherein the ester of the AA ester or salt thereof is (R)-serine benzyl ester or (R)-serine benzyl ester HCl.

10. The method of claim 1 , wherein the tertiary amine is selected from the group consisting of trimethylamine, triethylamine, diisopropylethylamine, tripropylamine, tributylamine, 4-methylmorpholine, 4-ethylmorpholine, N-methylpyrrolidine, and N-methylpiperidine.

11. The method of claim 1 , wherein the AA ester and 3,6-diamino-2,5-pyrazinedicarboxylic acid are presented at mole ratio from about 2.01:1.0 to about 2.20:1.0.

12. The method of claim 1 , wherein EDC HCl and 3,6-diamino-2,5-pyrazinedicarboxylic acid are presented at a mole ratio from about 2.20:1.0 to about 2.50:1.0.

13. The method of claim 1 , wherein the ethyl-2-cyano-2-(hydroxyimino)acetate and 3,6-diamino-2,5-pyrazinedicarboxylic acid are presented at a mole ratio from about 2.20:1.0 to about 2.50:1.0.

14. The method of claim 1 , wherein the tertiary amine and 3,6-diamino-2,5-pyrazinedicarboxylic acid are presented at a mole ratio from about 2.10:1.0 to about 3.0:1.0.

15. The method of claim 1 , wherein the polar aprotic solvent is N,N-dimethylformamide, N—N-dimethylacetamide, or dimethylsulfoxide.

16. The method of claim 1 , wherein the polar aprotic solvent and 3,6-diamino-2,5-pyrazinedicarboxylic acid are presented at a volume (mL) to weight (gram) ratio from 10.0:1.0 to about 100.0:1.0.

17. The method of claim 1 , wherein the contacting of each step occurs at a temperature ranging from about-10° C. to about 30° C.

18. The method of claim 1 , wherein the contacting of each step of the method is conducted under helium, nitrogen, argon, or a combination thereof.

19. The method of claim 1 , wherein the compound of Formula (I) has a percent yield of at least 70%.

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

21. The method of claim 1 , wherein the polar aprotic solvent is N,N-dimethylformamide; (R)-serine benzyl ester HCl and 3,6-diamino-2,5-pyrazinedicarboxylic acid are presented at a mole ratio from about 2.01:1.0 to about 2.20:1.0; EDC HCl and 3,6-diamino-2,5-pyrazinedicarboxylic acid are presented at a mole ratio ranging from about 2.20:1.0 to about 2.50:1.0; ethyl-2-cyano-2-(hydroxyimino)acetate and 3,6-diamino-2,5-pyrazinedicarboxylic acid are presented at a mole ratio ranging from about 2.20:1.0 to about 2.50:1.0; diisopropylethylamine and 3,6-diamino-2,5-pyrazinedicarboxylic acid are presented at a mole ratio ranging from about 2.10:1.0 to about 2.30:1.0; N, N-dimethylformamide and 3,6-diamino-2,5-pyrazinedicarboxylic acid are presented at a volume (mL) to weight (gram) ratio from 10.0:1.0 to about 100.0:1.0; and the contacting of each step occurs at a temperature from about −10° C. to about 30° C.

22. The method of claim 21 , wherein the compound of Formula (I) has a percent yield of at least 70%.

23. The method of claim 21 , wherein the compound of Formula (I) has a purity greater than about 95%.

24. The method of claim 1 , wherein the polar aprotic solvent is N,N-dimethylformamide; (R)-serine benzyl ester HCl and 3,6-diamino-2,5-pyrazinedicarboxylic acid are presented at a mole ratio of about 2.10:1.0; EDC HCl and 3,6-diamino-2,5-pyrazinedicarboxylic acid are presented at a mole ratio of about 2.30:1.0; ethyl-2-cyano-2-(hydroxyimino)acetate and 3,6-diamino-2,5-pyrazinedicarboxylic acid are presented at a mole ratio of about 2.36:1.0; diisopropylethylamine and 3,6-diamino-2,5-pyrazinedicarboxylic acid are presented at a mole ratio of about 2.20:1.0; N,N-dimethylformamide and 3,6-diamino-2,5-pyrazinedicarboxylic acid are presented at a volume (mL) to weight (gram) ratio of is about 20.0:1.0; and contacting of each step of the method occurs at the temperature from about 0° C. to about 20° C.

25. The method of claim 24 , wherein the compound of Formula (I) has a percent yield of at least 80%.

26. The method of claim 24 , wherein the compound of Formula (I) has a purity greater than about 98%.

Assignees

• Medibeacon Inc

Inventors

• Rogers Thomas
• Adams David
• Hua Xiaogang

Classifications

• C07D241/26 Primary

  with nitrogen atoms directly attached to ring carbon atoms · CPC title