CN-115427419-B - Preparation of P2X3 antagonists

Abstract

Described herein are two methods of preparing the P2X3 antagonist methyl (5) -2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazo [1, 2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate in a stepwise manner and chemical intermediates used in the synthesis method.

Inventors

• N. Jorette
• JEREMY GREEN
• David R. Cronensell
• Karini Villeneuve

Assignees

• 葛兰素史密斯克莱知识产权(第3号)有限公司
• 贝卢斯医疗咳嗽病公司

Dates

Publication Date

20260421

Application Date

20210212

Priority Date

20210212

Claims (20)

1. 1. A process for the preparation of (S) -methyl 2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (compound 1): (Compound 1), Comprising the steps of: the compound of (2) is contacted with an amide coupling agent and methylamine or a methylamine salt.
2. 2. The method of claim 1, wherein the amide coupling agent is carbonyldiimidazole.
3. 3. The method of claim 1, wherein the amide coupling agent is propane phosphonic anhydride (T 3 P).
4. 4. A method according to any one of claims 1-3, wherein the having the structure: By a method comprising reacting a compound having the structure: Is prepared by contacting the compound with 2-amino-4-methylpyridine, and optionally with sodium borohydride.
5. 5. The method of claim 4, wherein the having the structure: By a method comprising reacting a compound having the structure: is prepared by a method of contacting a compound with a brominating agent.
6. 6. The method of claim 5, wherein the brominating agent is N-bromosuccinimide in the presence of an acid.
7. 7. The method of claim 5, wherein the having the structure: By a method comprising reacting a compound having the structure: Is prepared by a method of contacting the compound with methyl chloroformate and alkali.
8. 8. The method of claim 6, wherein the having the structure: By a method comprising reacting a compound having the structure: Is prepared by a method of contacting the compound with methyl chloroformate and alkali.
9. 9. The process of claim 7, wherein the base is sodium bicarbonate.
10. 10. The process of claim 8, wherein the base is sodium bicarbonate.
11. 11. The method of any one of claims 7-10, wherein the having the structure: By a method comprising reacting a compound having the structure: is prepared by a method of contacting a compound of (a) with hydrogen chloride in the presence of a solvent.
12. 12. The method of claim 11, wherein the solvent is ethyl acetate.
13. 13. The method of claim 11, wherein the having the structure: By a method comprising reacting a compound having the structure: is prepared by a method of contacting a compound with a hydrogenation catalyst and hydrogen.
14. 14. The method of claim 12, wherein the having the structure: By a method comprising reacting a compound having the structure: is prepared by a method of contacting a compound with a hydrogenation catalyst and hydrogen.
15. 15. The process of claim 13, wherein the hydrogenation catalyst is palladium on carbon, palladium hydroxide, rhodium on carbon, rhodium on alumina, platinum oxide, or platinum on carbon.
16. 16. The process of claim 14, wherein the hydrogenation catalyst is palladium on carbon, palladium hydroxide, rhodium on carbon, rhodium on alumina, platinum oxide, or platinum on carbon.
17. 17. The process of claim 15, wherein the hydrogenation catalyst is palladium on carbon.
18. 18. The process of claim 16, wherein the hydrogenation catalyst is palladium on carbon.
19. 19. The method of any one of claims 13-18, wherein the having the structure: By a method comprising reacting a compound having the structure: The compounds of (a) and (b) have the structure: is prepared by a method of contacting the compound with a base.
20. 20. The method of claim 19, wherein the base is a mixture of potassium bicarbonate and potassium carbonate.

Description

Preparation of P2X3 antagonists Cross reference The present application claims the benefit of U.S. provisional application Ser. No. 62/977,004 filed on day 14 and U.S. provisional application Ser. No. 63/144,902 filed on day 2 and 2021, both of which are incorporated herein by reference in their entireties. Background P2X purinergic receptors are a family of ion channels activated by extracellular Adenosine Triphosphate (ATP). Purine receptors are involved in a variety of biological functions. The P2X3 receptor subunit is a member of this family. It was originally cloned from the dorsal root ganglion of rat. Chen et al Nature, vol 377, pp 428-431 (1995). The nucleotide and amino acid sequences of rat and human P2X3 are currently known. Lewis, et al, nature, vol 377, pp 432-435 (1995), and Garcia-Guzman, et al, brain Res.mol.brain Res, vol 47, pp 59-66 (1997). Disclosure of Invention Described herein are methods for the synthesis of a P2X3 antagonist, wherein the P2X3 antagonist is (S) -2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylic acid methyl ester (compound 1) or a pharmaceutically acceptable salt thereof. One aspect is a process for preparing (S) -2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylic acid methyl ester (compound 1): Comprising the steps of: the compound of (2) is contacted with an amide coupling agent and methylamine or a salt thereof. In some embodiments, the amide coupling agent is carbonyl diimidazole. In some embodiments, the amide coupling agent is propane phosphonic acid anhydride (T3P). In some embodiments of the process for preparing (S) -methyl 2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (compound 1) has the structure: By a method comprising reacting a compound having the structure: is prepared by a method of contacting a compound of 2-amino-4-methylpyridine and optionally sodium borohydride in the presence of a solvent. In some embodiments of the process for preparing (S) -methyl 2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (compound 1) has the structure: By a method comprising reacting a compound having the structure: Is prepared by a method of contacting a compound with a brominating agent. In some embodiments, the brominating agent is N-bromosuccinimide in the presence of an acid. In some embodiments of the process for preparing (S) -methyl 2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (compound 1) has the structure: By a method comprising reacting a compound having the structure: Is prepared by a method of contacting the compound with methyl chloroformate and alkali. In some embodiments, the base is sodium bicarbonate. In some embodiments of the process for preparing (S) -methyl 2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (compound 1) has the structure: By a method comprising reacting a compound having the structure: Is prepared by a method of contacting a compound of (a) with hydrogen chloride in the presence of a solvent. In some embodiments, the solvent is ethyl acetate. In some embodiments of the process for preparing (S) -methyl 2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (compound 1) has the structure: By a method comprising reacting a compound having the structure: Is prepared by a method of contacting a compound with a hydrogenation catalyst and hydrogen. In some embodiments, the hydrogenation catalyst is palladium on carbon, palladium hydroxide, rhodium on carbon, rhodium on alumina, platinum oxide, or platinum on carbon. In some embodiments, the hydrogenation catalyst is palladium on carbon. In some embodiments of the process for preparing (S) -methyl 2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (compound 1) has the structure: By a method comprising reacting a compound having the structure: The compounds of (a) and (b) have the structure: is prepared by a method of contacting the compound with a base. In some embodiments, the base is a mixture of potassium bicarbonate and potassium carbonate. In some embodiments of the process for preparing (S) -methyl 2- ((2- (2, 6-difluoro-4- (methylcarbamoyl) phenyl) -7-methylimidazo [1,2-a ] pyridin-3-yl) methyl) morpholine-4-carboxylate (compound 1) has the structure: By a method comprising reacting a compound having the structure: Is prepared by a method of contacting a compound of (2, 6-tetramethylpiperidine 1-oxyl or propane phosphonic anhydride (T3P). Another aspect is a process for preparing (S) -methyl 2