Claims for Patent: RE46617

Summary for Patent: RE46617

Title:	Process for making quinolone compounds
Abstract:	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.
Inventor(s):	Hanselmann; Roger (Branford, CT), Reeve; Maxwell M. (Guilford, CT), Johnson; Graham (Madison, CT)
Assignee:	MELINTA THERAPEUTICS, INC. (New Haven, CT)
Application Number:	14/743,365
Patent Claims:	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.]. .Iadd.0.008 .Iaddend.to about .[.0.02.]. .Iadd.0.012.Iaddend., and wherein less than about .[.0.40%.]. .Iadd.0.35% .Iaddend.of dimeric impurity on an area percent basis of the quinolone is produced.Iadd., wherein the quinolone compound is 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetid- in-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.Iaddend.. .[.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-hydroxyazetid- in-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.degree. C. to about 30.degree. C. 8. A process according to claim 1 wherein the molar ratio of .[.N-chlorosuccinimide.]. .Iadd.the chlorinating agent .Iaddend.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-hydroxyaze- tidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic.]. .Iadd.1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxy- azetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic .Iaddend.acid or .Iadd.a pharmaceutically acceptable .Iaddend.salt or ester thereof having less than about .[.0.40%.]. .Iadd.0.35% .Iaddend.of the compound .[.1-Amino-3-(azetidin-3-yloxy)-propan-2-ol-bis(N,N'-quinolone.]. .Iadd.1-amino-3-(azetidin-3-yloxy)-propan-2-ol-bis(N,N'-quinolone .Iaddend.carboxylic acid), or a pharmaceutically acceptable salt or ester thereof .Iadd.on an area percent basis of the quinolone.Iaddend.. 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..].