Patent EA-002340-B1 (EA)
Title: Process for preparing trovafloxacin acid salts
Inventor: NORRIS TIMOTHY
IPC: C07D209/52
Filed: 1999-09-01
Abstract: 1. A process for preparing a trovafloxacin acid salt having the formula (IV):   wherein ZH is a mineral acid, comprising the step of contacting a compound of formula (I):   wherein R is a C1-C6 alkyl group; and wherein the benzylidene ring of the compound of formula (I) is optionally substituted with one or more fluoro, chloro, bromo, iodo, C1-C6 alkyl or C1-C6 alkoxyl groups, with a composition comprising the mineral acid ZH and water. 2. The process of Claim 1, wherein R is ethyl. 3. The process of Claim 1, wherein the mineral acid is selected from the group consisting of methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, nitric acid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, tartaric acid, citric acid, acetic acid, and maleic acid. 4. The process of Claim 1, wherein the process is performed in the presence of an inert organic solvent. 5. A process for preparing a trovafloxacin acid salt having the formula (IV):   wherein ZH is a mineral acid, comprising the steps of: (a) contacting, in the presence of a tertiary amine base, a compound of formula (V):   wherein R is a C1-C6 alkyl group, with a compound of formula (II):   wherein the benzylidene ring of the compound of formula (II) is optionally substituted with one or more fluoro, chloro, bromo, iodo, C1-C6 alkyl or C1-C6 alkoxyl groups, to afford a compound of formula (I):   (b) contacting the compound of formula (I) with a composition comprising the mineral acid ZH and water. 6. The process of Claim 5, wherein R is ethyl. 7. The process of Claim 5, wherein the mineral acid is selected from the group consisting of methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, nitric acid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, tartaric acid, citric acid, acetic acid, and maleic acid. 8. The process of Claim 5, wherein the tertiary amine base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, dimethylisopropylamine, methyldibutylamine, triphenylamine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, 2,4,6-collidine and N,N,N',N'-tetramethyl-1,8-naphthalenediamine. 9. The process of Claim 6, wherein step (a) of the process is performed in the presence of an inert organic solvent. 10. The process of Claim 6, wherein step (b) of the process is performed in the presence of a water soluble organic solvent. 11. A process for preparing a trovafloxacin acid salt having the formula (IV):   wherein ZH is a mineral acid, comprising the steps of: (a) contacting, under substantially anhydrous conditions, a compound of formula (I):   wherein R is a C1-C6 alkyl group; and the benzylidene ring of the compound of formula (I) is optionally substituted with one or more fluoro, chloro, bromo, iodo, C1-C6 alkyl or C1-C6 alkoxyl groups, with mineral acid to afford a compound of formula (III):   and (b) contacting the compound of formula (III) with a composition comprising the mineral acid ZH and water. 12. The process of Claim 11, wherein R is ethyl. 13. The process of Claim 11, wherein the mineral acid is selected from the group consisting of methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, nitric acid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, tartaric acid, citric acid, acetic acid, and maleic acid. 14. The process of Claim 11, wherein step (a) of the process is performed in the presence of an inert organic solvent. 15. The process of Claim 11, wherein step (b) of the process is performed in the presence of a water soluble organic solvent. 16. A compound of formula (I):   wherein R is a C1-C6 alkyl group; and the benzylidene ring of the compound of formula (I) is optionally substituted with one or more fluoro, chloro, bromo, iodo, C1-C6 alkyl or C1-C6 alkoxyl groups. 17. The compound of Claim 16, wherein R is ethyl. 18. The compound of Claim 16, wherein the compound is ethylic ether (1α,5α,6α)-7-(6-benzylidenylamino-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3 carboxylic acid. 19. A compound of formula (II):   wherein the benzylidene ring of the compound of formula (II) is optionally substituted with one or more fluoro, chloro, bromo, iodo, C1-C6 alkyl or C1-C6 alkoxyl groups. 20. The compound of Claim 19, wherein the compound is (1α,5α,6α)-6-benzylidenylamino-3-azabicyclo[3.1.0]hexane. 21. A compound of formula (III):   wherein R is a C1-C6 alkyl group, and ZH is a mineral acid.