Moxifloxacin hydrochloride compounds and intermediates and methods for making same

Synthesis of Moxifloxacin Tosylate of Formula (IV, R=p-MePhenyl or Tolyl)

Synthesis Scheme

[0070]

[0071]50.0 g of 1-Cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinic acid of formula (V) (1.0 mol. equiv.), 15.80 g of Mg(OH)2 (1.6 mol. equiv.) and 300 mL of Acetonitrile were introduced into a 4-neck flask provided with a mechanical stirrer, thermometer, cooler and thermostat. Heating was carried out at 78° C. for one hour under slow stirring with the aim of forming the Moxifloxacin complex with Magnesium. A solution formed by 34.20 g of (4aS,7aS)-Octahydro-1H-pyrrole[3,4-b]pyridine of formula (VI) and 150 mL of Acetonitrile was dosed in 1 hour. The reaction mixture was left at reflux for another 4 hours. Upon completing the reaction (conversion exceeding 90%) the mixture was cooled at 50° C. and the ACN was distilled under vacuum up to obtaining a soft pasty residue. Such residue was cooled at 0° C. and a cold solution at 0° C. made up of 150 mL of Acetone and 300 mL of Dich

[0077]Purification of Moxifloxacin Tosylate of Formula (IV, R=p-MePhenyl or Tolyl)

[0078]72.5 g of Moxifloxacin Tosylate obtained in Example 1 were dispersed in a solution of 1276 ml of isopropanol and 142 ml of water. The suspension was heated at 80° C. for one hour, then slowly cooled for one night up to 35° C. The suspension remained at 35° C. for 2 hours, then filtering was carried out a paper filter and washing with 142 ml of isopropanol. The solid was dried in an oven at 50° C. for at least 8 hours.

[0079]68.2 g equivalent to a 94% molar yield of purified Moxifloxacin Tosylate as a dirty white solid were obtained. The obtained Moxifloxacin Tosylate had an HPLC purity equivalent to 99.30% (A %) with a formula (VII) impurity content equivalent to 0.27%.

Synthesis of Moxifloxacin Hydrochloride Starting from Moxifloxacin Tosylate of Formula (IV, R=p-Mephenyl)

Synthesis Scheme

[0080]

[0081]68.2 g of purified moxifloxacin tosylate of example 2 (1.0 mol. Equiv.) (HPLC purity equivalent to 99.30% and impurity of formula (VII) equivalent to 0.27%), 409.2 mL of saturated NaHCO3 solution, 136.4 mL of purified water, 409.2 mL of dichloromethane and 68.2 mL of isopropanol were introduced into a 4-neck flask provided with a mechanical stirrer, thermometer, cooler and thermostat. Heating was carried out at 30-35° C. and stirring was carried out for one hour up to complete dissolution. Then the phases were separated and the aqueous phase was extracted using 136.4 mL of Dichloromethane. The organic phases were collected and dried. The obtained solid was recovered with 954.8 mL of Ethanol and 136.4 mL of purified water. Heating was carried out at reflux up to complete dissolution, then it was brought to 60° C. and a solution of 12.3 mL of concentrated h