Rapid preparation of 8-alkoxy-quinolone-carboxylic acid derivative antibacterial agent, e.g. gatifloxacin, in high purity

摘要

Preparation of 7-(cyclic amino)-6-fluoro-1,4-dihydro-8-alkoxy-4-oxo-3-quinoline-carboxylic acid derivatives (I) involves reacting 8-halo analogs (II) with an alkali metal tertiary alkoxide in an ether solvent in presence of an alkanol or benzyl alcohol. Preparation of quinolone 3-carboxylic acid derivatives of formula (I) involves reacting an 8-halo compound of formula (II) with an alkali metal tertiary butylate or tertiary amylate of formula MO-C(Me)2Q (III), in presence of a 1-3C alkanol or benzyl alcohol (i.e. R2OH), in a 4-6C aliphatic or cycloaliphatic ether solvent. NR'R = optionally substituted mono- or bicyclic heterocycle, in which both rings optionally contain further N, O or S heteroatoms; R1 = 1-3C alkyl, CH2CH2F, phenyl (optionally substituted by 1-3 halo) or cyclopropyl; R2 = 1-3C alkyl (preferably Me) or benzyl; R3 = H, halo, NH2 or Me; Hal = Cl or preferably F; M = Na or preferably K; Q = Me or Et. The process is especially applied to the preparation of 1-cyclopropyl-7-(S,S)-2,8-diazabicyclo(4.3.0)non-8-yl)-6-fluoro-1,4-di hydro-8-methoxy-4-oxo-3-quinoline-carboxylic acid of formula (Ia). Independent claims are included for: (1) the preparation of (Ia) monohydrochloride, involving treating the reaction mixture obtained in the preparation of (Ia) by the above method with dilute hydrochloric acid (or adding the reaction mixture to dilute HCl) and isolating the precipitated hydrochloride by filtration; (2) the purification of (Ia) hydrochloride (obtained e.g. by method (i)) by recrystallization from water (optionally mixed with a 1-3C alkanol, specifically ethanol); and (3) the preparation of (Ia) hydrochloride monohydrate by drying the product obtained in method (ii) at 40-60 deg C and 80-120 mbar (preferably 50 deg C and 100 mbar).