Process for making quinolone compounds
View Patent ↗The present invention relates to the field of synthesizing anti-infective compounds. More particularly, the invention relates to synthesizing a family of quinolone compounds useful as anti-infective agents. The invention includes a process for preparing a quinolone compound wherein less than about 0.40% of dimeric impurity of the quinolone is produced.
1. A process for preparing a quinolone compound comprising the step of reacting a des-chloro quinolone compound or a pharmaceutically acceptable salt or ester thereof with a chlorinating agent and an acid, wherein the molar ratio of the acid to des-chloro quinolone is from about 0.007 0.008 to about 0.02 0.012, and wherein less than about 0.40% 0.35% of dimeric impurity on an area percent basis of the quinolone is produced, wherein the quinolone compound is 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof and the des-chloro quinolone compound is 1-(6-amino-3,5-difluoropyridin-2-yl)-6-fluoro-7-(3-hydroxy-azetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof, and wherein the dimeric impurity is 1-amino-3-(azetidin-3-yloxy)-propan-2-ol-bis(N,N′-quinolone carboxylic acid), or a pharmaceutically acceptable salt or ester thereof.
2. A process according to claim 1 wherein the quinolone compound is 1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof and the des-chloro quinolone compound is 1-(6-amino-3,5-difluoropyridin-2-yl)-6-fluoro-7-(3-hydroxy-azetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof.
3. A process according to claim 2 wherein the dimeric impurity is 1-Amino-3-(azetidin-3-yloxy)-propan-2-ol-bis (N,N′-quinolone carboxylic acid), or a pharmaceutically acceptable salt or ester thereof.
4. A process according to claim 1 wherein the chlorinating agent is N-chlorosuccinimide.
5. A process according to claim 1 wherein the acid is selected from the group consisting of sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, trifluoroacetic acid, triflic acid, methanesulfonic acid, p-toluene-sulfonic acid, or perchloric acid, and mixtures thereof.
6. A process according to claim 1 wherein the acid is sulfuric acid.
7. A process according to claim 1 where the reaction is run at a temperature from about 0° C. to about 30° C.
8. A process according to claim 1 wherein the molar ratio of N-chlorosuccinimide the chlorinating agent to des-chloro quinolone is greater than about 1.
9. A process according to claim 1 using an acetate ester as a solvent.
10. A process according to claim 9 wherein said acetate ester is selected from the group consisting of methyl acetate, ethyl acetate, and mixtures thereof.
11. A process according to claim 9 wherein said acetate ester is methyl acetate.
12. A process according to claim 1 comprising the further step of reacting the quinolone compound with a base.
13. A process according to claim 12 wherein the base is a hydroxide base.
14. A process according to claim 13 wherein the hydroxide base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, and mixtures thereof.
15. A process according to claim 14 wherein the hydroxide base is potassium hydroxide.
16. A process according to claim 12 using a mixture of isopropanol and water as a solvent.
17. A process according to claim 1 wherein said process is a commercial scale process.
18. A composition comprising the quinolone compound 1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt or ester thereof having less than about 0.40% 0.35% of the compound 1-Amino-3-(azetidin-3-yloxy)-propan-2-ol-bis(N,N′-quinolone 1-amino-3-(azetidin-3-yloxy)-propan-2-ol-bis(N,N′-quinolone carboxylic acid), or a pharmaceutically acceptable salt or ester thereof on an area percent basis of the quinolone.
19. A composition according to claim 18 wherein said composition is a commercial scale composition.
20. The process of claim 1 or 2 , wherein the molar ratio of chlorinating agent to des-chloro quinolone is from about 1.05 to about 1.2.
21. The process of claim 1 or 2 , wherein the molar ratio of chlorinating agent to des-chloro quinolone is from about 1.04 to about 1.07.
22. The process of claim 1 or 2 , wherein the molar ratio of acid to des-chloro quinolone is from about 0.008 to about 0.012.