Preparative process

Patent metadata

Field	Value
Publication number	US-11542245-B2
Application number	US-201916980210-A
Country	US
Kind code	B2
Filing date	Mar 8, 2019
Priority date	Mar 15, 2018
Publication date	Jan 3, 2023
Grant date	Jan 3, 2023

Abstract

The present invention relates to a process for preparing 4-{[(2S)-2-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}butanoyl]amino}-2-fluorobenzamide (I) or 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2-fluorobenzamide (II) from 2,5-dimethoxypyridine (III), 1-(2-bromo-4-chlorophenyl)-4-chloro-1H-1,2,3-triazole (X-Cl) or 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (X-CF3), 4-amino-2-fluorbenzamide (XIII) and (2R)-2-aminobutanoic acid (XVII).

First claim

The invention claimed is:

1. A process for preparing 4-{[(2S)-2-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}butanoyl]amino}-2-fluorobenzamide (formula I) or 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}-amino)-2-fluorobenzamide (formula II), comprising:
reacting 4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-methoxypyridin-2(1H)-one (XVI-C1) or 4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-5-methoxypyridin-2(1H)-one (XVI-CF 3 ) with 4-{[(2R)-2-bromobutanoyl]amino}-2-fluorobenzamide (XIX) in the presence of a base in a solvent and the compound of formula (I) or (II) is subsequently isolated.

2. The process according to claim 1 , wherein the process is carried out using N,N,N,N-tetramethylguanidine as base.

3. The process according to claim 1 , wherein the process is carried out using a mixture of a protic and a polar non-protic solvent.

4. The process according to claim 1 , wherein the process is carried out at a temperature of from 15 to 25° C.

5. The process according to claim 1 , wherein the compound of formula (I) or (II) is subsequently isolated in enantiomerically pure form by heating the compound of formula (I) or (II) with ee-values of 85% ee to 93% ee to reflux in an organic solvent and subsequent filtration following evaporation of the organic solvent.

6. The process according to claim 1 , wherein 4-{[(2R)-2-bromobutanoyl]amino}-2-fluorobenzamide (XIX) is obtained by reaction of (2R)-2-bromobutanoic acid (XVIII) with 4-amino-2-fluorobenzamide (XIII).

7. The process according to claim 1 , wherein 4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-5-methoxypyridin-2(1H)-one (XVI-CF 3 ) is obtained, said process comprising reacting 4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-2,5-dimethoxypyridine (XV-CF 3 ) with lithium chloride and p-toluenesulfonic acid in a solvent.

8. The process according to claim 7 , wherein 4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-2,5-dimethoxypyridine (XV-CF 3 ) is obtained, said process comprising reacting (2,5-dimethoxypyridin-4-yl)boronic acid (IV) with 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (X-CF 3 ) in the presence of a Pd-catalyst system with a base in a solvent.

9. The process according to claim 8 , wherein the process is carried out using Pd(Amphos) 2 Cl 2 as the Pd-catalyst system.

10. The process according to claim 7 , wherein the process is carried out using an alcohol as solvent.

11. 4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-2,5-dimethoxy-pyridine having the formula

12. 4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-5-methoxy-pyridin-2(1H)-one having the formula

13. 4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-2,5-dimethoxy-pyridine having the formula

14. 4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-methoxypyridin-2(1H)-one having the formula

15. 4-{[(2R)-2-Bromobutanoyl]amino}-2-fluorobenzamide having the formula

16. 4-({(2S)-2-[4-{-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}-amino)-2-fluorobenzamide acetone having the formula

17. A process for preparing 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}-amino)-2-fluorobenzamide (II), wherein 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}-amino)-2-fluorobenzamide acetone (IIc) is isolated and converted to 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}-amino)-2-fluorobenzamide (II).

Assignees

• Bayer Ag
• Bayer Pharma AG

Inventors

• Egger Julian
• Goetz Daniel
• Sowa Michal

Classifications

• C07D401/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title

• C07C237/30

  having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title