WO2008059521A2 - Nouveau procédé pour la préparation de chlorhydrate de moxifloxacine et nouveau polymorphe de moxifloxacine - Google Patents

Nouveau procédé pour la préparation de chlorhydrate de moxifloxacine et nouveau polymorphe de moxifloxacine Download PDF

Info

Publication number
WO2008059521A2
WO2008059521A2 PCT/IN2007/000448 IN2007000448W WO2008059521A2 WO 2008059521 A2 WO2008059521 A2 WO 2008059521A2 IN 2007000448 W IN2007000448 W IN 2007000448W WO 2008059521 A2 WO2008059521 A2 WO 2008059521A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
moxifloxacin
reaction mixture
moxifloxacin hydrochloride
Prior art date
Application number
PCT/IN2007/000448
Other languages
English (en)
Other versions
WO2008059521A3 (fr
Inventor
Manne Satyanarayana Reddy
Chakilam Nagaraju
Srinivasan Thirumalai Rajan
Achampeta Kodanda Ramprasad
Revu Satyanarayana
Original Assignee
Msn Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Msn Laboratories Limited filed Critical Msn Laboratories Limited
Priority claimed from IN1345CH2007 external-priority patent/IN2007CH01345A/en
Publication of WO2008059521A2 publication Critical patent/WO2008059521A2/fr
Publication of WO2008059521A3 publication Critical patent/WO2008059521A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel process for the preparation of moxifloxacin hydrochloride through novel intermediate compound of general formula-2.
  • Moxifloxacin hydrochloride is chemically known as l-cyclopropyl-6-fluoro-l,4-dihydro- 8-methoxy-7-[(4aS 5 7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4-oxo-3-quinoline carboxylic acid hydrochloride compound represented by formula-1.
  • the present invention also relates to novel quinoline carboxamide intermediate compounds of general formula-2 and process for their preparation, which are useful as intermediates in the preparation of important antibacterial compound moxifloxacin hydrochloride compound of formula-1.
  • the present invention also relates to a novel process for the preparation of anhydrous form of moxifloxacin hydrochloride, also a novel crystalline form of moxifloxacin.
  • Moxifloxacin hydrochloride is a synthetic broad-spectrum antibacterial agent.
  • the active moiety, moxifloxacin has been shown to be clinically active against most strains of microorganisms such as aerobic gram-positive microorganisms including staphylococcus aureus, streptococcus pneumonia (penicillin-susceptible strains) and streptococcus pyogenes, aerobic gram-negative microorganisms including haemophilus influenza hemophilus parainfluenzae, klebisiella pneumonia.
  • Moxifloxacin is commercially available under the brand name of AVELOX® marketed by Bayer pharms.
  • Moxifloxacin and its pharmacologically acceptable salts are disclosed in European patents EP 350733, EP 550903 and EP 657,448.
  • the disclosed process for the preparation of moxifloxacin hydrochloride comprises of condensing l-cyclopropyl-6,7- difluoro-8-methoxy-4-oxo-l,4-dihydro-3-quinoline carboxylic acid or its esters with (S,S)2,8-diazobicyclo[4.3.0]nonane, in presence of a base at high temperature followed by conversion into hydrochloride salt .
  • This process not only produces desired moxifloxacin hydrochloride but also its positional isomer namely l-cyclopropyl-7-fluoro- 1,4- dihydro -8- methoxy -6- (4aS,7aS)- octahydro- 6H -pyrrolo [3,4-b] pyridine-6-yl] -4- oxo-quinolinecarboxylic acid as a major impurity which is difficult to separate.
  • the purification of moxifloaxcin to remove this isomer results in lower yields thereby increasing the product cost.
  • the International publication WO 2005/012285 discloses an improved process for the preparation of moxifloxacin hydrochloride incorporated herein by reference.
  • the disclosed process involves the preparation of moxifloxacin hydrochloride from the ethyl 1 -cyclopropyl-6,7-difluoro-8-methoxy-4-oxo- 1 ,4-dihydro-3-quinolme carboxylate through a novel intermediate (4aS-cis)-l-cyclopropyl-7-(2,8-diazabicyclo[4.3.0]non-8- yl)-6-fluoro-8-methoxy-4-oxo- 1 ,4-dihydro-3 -quinolinecarboxylicacid-0 3 ,0 4 )bis(acyloxy -0)-borate.
  • US patent application 6897315 discloses a process for the preparation of 8-methoxy-3-quinoline carboxylic acid especially moxifloxacin incorporated herein by reference. The disclosed process involves the preparation of moxifloxacin from 8-halo moxifloxacin derivative using methanol and potassium tertiary butoxide.
  • US patent 5639886 discloses one-pot process for the preparation of 3-quinoline carboxylic acid derivatives including moxifloxacin.
  • WO 2004 091619 claims anhydrous crystalline form-Ill of moxifloxacin hydrochloride and WO 2004/039804 claims amorphous form of moxifloxacin hydrochloride.
  • US Pat.No.5, 849,752 discloses specific crystalline forms of anhydrous moxifloxacin mono hydrochloride and monohydrated moxifloxacin mono hydrochloride.
  • Anhydrous moxifloxacin mono hydrochloride disclosed in US Pat. No.5, 849,752 has been designated as "Form-I” and the hydrated form as "Form-II" in US Pat. No.7,230,006. It also discloses a novel crystalline Form-Ill of anhydrous moxifloxacin mono hydrochloride.
  • US patent US 5,480,879 discloses the melting range of moxifloxacin in example part as 203-208°C and does not speaks about polymorphism of moxifloxacin. Experiment executed as per the procedure given in example Zl 9 of US 5,480,879 and resulted in acetonitrile solvated form of moxifloxacin with low purity and the obtained solvated form can not used for formulations. Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
  • a single molecule may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, x-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum.
  • One crystalline form may give rise to thermal behaviors different from that of another crystalline form.
  • Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermo gravimetric analysis (“TGA”), and differential scanning calorimetry (“DSC”), which have been used to distinguish polymorphic forms.
  • polymorphs are distinct solids sharing the same molecular formula yet having distinct advantageous physical properties compared to other crystalline forms of the same compound or complex.
  • One of the important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient. For example, where absorption through the gastrointestinal stomach or intestine to dissolve slowly so that it does not accumulate in a deleterious environment. Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities.
  • the present invention provides novel crystalline polymorphic form of moxifloxacin, which is of high purity free flow solid and it can be directly used for the formulation as an active pharmaceutical ingredient
  • Moxifloxacin hydrochloride is an important broad spectrum antibacterial drug which can be used to treat various types of infections, it would be beneficial to have an efficient, high yielding and cost effective process for the preparation of moxifloxacin hydrochloride.
  • the present invention provides a novel process for the preparation of moxifloxacin hydrochloride compound of formula- 1 through a novel amide intermediate compound.
  • the first aspect of the present invention provides a novel process for the preparation of moxifloxacin hydrochloride compound of formula- 1 which comprises of the following steps: a) reacting * the quinoline carboxamide compound of general formula-2 with nonane compound of general formula-3 in presence of a suitable base in a suitable organic solvent to obtain the condensed amide compound of general formula-4, b) reacting the condensed amide compound of general formula-4 with a suitable alkali or alkaline metal hydroxides, alkali metal carbonates in suitable polar solvent to obtain moxifloxacin compound of formula-5, c) reacting the moxifloxacin compound of formula-5 with hydrochloric acid in a suitable aqueous alcoholic solvent to obtain moxifloxacin hydrochloride compound of formula- 1.
  • the second aspect of the present invention provides a novel process for the preparation of moxifloxacin hydrochloride compound of formula- 1 through quinoline nitrile intermediate compound of formula-6., which comprises of the following steps: a) reacting the nitrile compound of formula-6 with nonane compound of general formula-3 in presence of a suitable base in a suitable organic solvent to obtain the condensed compound of general formula-7, b) reacting the condensed compound of general formula-7 with a suitable alkali or alkaline metal carbonates, hydrogen carbonates or hydroxides in suitable polar solvent to obtain moxifloxacin compound of formula-5, c) reacting the moxifloxacin compound of formula-5 with hydrochloric acid in a suitable aqueous alcoholic solvent to obtain moxifloxacin hydrochloride compound of formula- 1.
  • the third aspect of the present invention provides a novel process for the preparation of quinoline nitrile intermediate compound of formula-6, which comprises of the following steps: a) reacting the 2,4,5-trifluoro-3-methoxy benzoic acid of formula-8 with thionyl chloride followed by reaction with 2-cyano ethyl acetate to obtain compound of formula-9, b) decarboxylation of the compound of formula-9 with a suitable aqueous acid or alkali or alkaline base in a suitable solvent to obtain compound of formula- 10, c) reacting * the compound of formula- 10 with triethylorthoformate in presence of acetic anhydride followed by treating with cyclopropyl amine in presence of an alkali or alkaline base to obtain nitrile compound of formula-6.
  • the fourth aspect of the present invention provides a novel process for the preparation of beta keto amide intermediate compound of formula- 13, which comprises of the following steps: a) reacting the 2,4,5 -trifluoro-3-methoxy benzoic acid of formula-8 with thionyl chloride followed by reaction with diethyl melonate to obtain compound of formula-11, b) decarboxylation of the compound of formula-11 with a suitable aqueous acid or alkali or alkaline base in a suitable solvent to obtain compound of formula- 12, c) reacting the compound of formula- 12 with an amine compound to obtain beta keto amide compound of general formula-13,
  • the fifth aspect of the present invention provides moxifloxacin hydrochloride monohydrate with particles having oval shape and porous texture as illustrated in photographs of microscopic moxifloxacin hydrochloride monohydrate in figure-4. These particles are more suitable for the preparation of various medicament forms. It also provides a process for its preparation.
  • the sixth aspect of the present invention provides a novel process for the preparation of anhydrous form of moxifloxacin hydrochloride compound of formula- 1, which comprises of the following steps: a) suspending moxifloxacin hydrochloride in a suitable alcohol solvent and heating the solution, b) optionally adding chloro solvent and stirring the reaction mixture for complete dissolution, c) cooling the reaction mixture, d) stirring the reaction mixture at low temperature for some time, e) separating the precipitated solid by filtration under inert atmosphere and washing with methanol, f) drying tne solid till the moisture content reaches below 0.5%.
  • the seventh aspect of the present invention provides novel crystalline form of moxifloxacin, herein defined as Form-I and process for preparing it, which comprises of the following steps: a) suspending the moxifloxacin HCl or/and its hydrates in a suitable polar solvent, b) adjusting the pH of the reaction mixture to basic, c) extracting with suitable water immiscible solvent, d) distilling off the solvent under reduced pressure, e) cooling the reaction mixture temperature to low temperature, f) adding a suitable keto solvent, g) isolating the product by filtration and optionally washing it with water, h) drying the material to get the crystalline Form-I of moxifloxacin.
  • Moxifloxacin hydrochloride used in step a) of the above process can be prepared by conventional methods known in the art.
  • Figure-1 Illustrates the powder X-ray diffraction pattern of crystalline Form-I of moxifloxacin.
  • Figure-2 Illustrates the IR spectrum of crystalline Form-I of moxifloxacin.
  • Figure-3 Illustrates the DSC of crystalline Form-I of moxifloxacin.
  • Figure-4 Illustrates the photographs of microscopic moxifloxacin hydrochloride monohydrate.
  • Moxifloxacin hydrochloride compound of formula- 1 is chemically known as l-cyclopropyl-6-fluoro-l,4-dihydro-8-methoxy- 7-[(4aS,7aS) - octahydro - 6H- pyrrolo[3,4-b] pyridin-6-yl]-4-oxo-3-quinoline carboxylic acid hydrochloride.
  • the first aspect of the present invention provides a novel process for the preparation of moxifloxacin hydrochloride compound of formula- 1, which comprises of the following steps: a) reacting the quinoline carboxamide compound of general formula-2
  • R and Ri are hydrogen or selected from Ci to C 5 linear or branched chain alkyl group, with nonane compound of general formula-3
  • a suitable aqueous alcoholic solvent like methanol, ethanol and isopropanol preferably aqueous methanol
  • the first aspect of the present invention is represented by the following scheme- 1 SCHEME-I:
  • R and R 1 are hydrogens or selected from C 1 to C 5 linear or branched chain alkyl group, wherein R 2 is Hydrogen , trityl, silyl group like TMS (trimethyl silyl) / TBDMS (tertiary butyl dimethyl silyl) or -COOR 3 wherein R 3 is phenyl or ethy or butyl analogs.
  • the second aspect of the present invention provides a novel process for the preparation of moxifloxacin hydrochloride compound of formula- 1, which comprises of the following steps: a) reacting the nitrile compound of formula-6 with nonane compound of general formula-3 in presence of a suitable base in a suitable organic solvent to obtain the condensed compound of general formula-7, b) reacting the condensed compound of general formula-7 with a suitable alkali or alkaline metal carbonates, hydrogen carbonates, hydroxides like sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, preferably sodium hydroxide in a suitable solvent like ethylene glycol and/or polar solvent like water or mixtures thereof to obtain moxifloxacin compound of formula-5, c) reacting the moxifloxacin compound of formula-5 with hydrochloric acid in a suitable aqueous alcoholic solvent to obtain moxifloxacin hydrochloride compound of formula- 1.
  • the second aspect of the present invention is represented by the following scheme-2 S
  • N-protected compound of general formula-4 and formula-7 can be deprotected by the conventional methods.
  • the third aspect of the present invention provides a novel process for the preparation of quinoline nitrile intermediate compound of formula-6, which comprises of the following steps: a) reacting the 2,4,5-trifluoro-3-methoxy benzoic acid of formula-8 with thionyl chloride followed by reaction with 2-cyano ethyl acetate to obtain compound of formula-9, b) decarboxylation of the compound of formula-9 with a suitable aqueous acid or alkali or alkaline base in a suitable solvent to obtain compound of formula- 10, c) reacting the compound of formula- 10 with triethylorthoformate in presence of acetic anhydride followed by treating with cyclopropyl amine in presence of an alkali or alkaline base to obtain nitrile compound of formula-6.
  • the third aspect of the present invention is represented by the following scheme-3 SCHEME-3:
  • the fourth aspect of the present invention provides a novel process for the preparation of beta keto amide intermediate compound of formula-13, which comprises of the following steps: a) reacting the 2,4,5-trifluoro-3-methoxy benzoic acid of formula-8 with thionyl chloride followed by reaction with diethylmalonate to obtain compound of formula- 11, b) decarboxylation of the compound of formula- 11 with a suitable aqueous acid or alkali or alkaline base in a suitable solvent to obtain compound of formula- 12, c) reacting the compound of formula- 12 with an amine compound to obtain beta keto amide compound of general formula-13.
  • Formula- 13 Formula- 12 wherein R and R 1 are hydrogens or selected from C 1 to C 5 linear or branched chain alkyl group,
  • the quinoline carboxamide compound of formula-2 can be prepared by the following conventional methods as illustrated in scheme-5: SCHEME-5:
  • R and R 1 are hydrogens or selected from C 1 to C 5 linear or branched chain alkyl group
  • US Patent No. 5,849,752 disclosed moxifloxacin hydrochloride monohydrate with crystals in the form of needles and prisms.
  • the crystals in the form of prisms are more suitable for preparation of pharmaceutical formulations, when compared to crystals in the form of needles.
  • the fifth aspect of the present invention provides moxifloxacin hydrochloride monohydrate with particles having oval shape and porous texture as illustrated in photographs of microscopic moxifloxacin hydrochloride monohydrate in figure-4. These particles are also imparted with excellent trickling and free flowing properties, hence suitable for the preparation of various medicament forms or pharmaceutical formulations.
  • the present invention also provides a process for the preparation moxifloxacin hydrochloride monohydrate with particles having oval shape, which comprises of the following steps: a) suspending moxifloxacin hydrochloride in a solution of aqueous alcohol, b) heating the above reaction mixture to higher temperature, c) filtering the reaction mixture in hot condition and cooling the filtrate, d) adjusting the pH of the filtrate to make it acidic by addition of hydrochloric acid, e) further cooling the reaction mixture to lower temperatures to obtain a solid, f) dissolving or dispersing or slurrying or washing the solid obtained with with a mixture of water and water miscible solvent containing above 30% of water ,or with water alone to obtain moxifloxacin hydrochloride monohydrate having oval shaped particles.
  • the water miscible solvent is selected from a group of solvents such as alcohols like methanol, ethanol or ketones like acetone or niltriles like acetonitrile etc., and the like.
  • Moxifloxacin hydrochloride used in step a) may be moxifloxacin hydrochloride Form-Y obtained in the present invention and also disclosed in our earlier patent WO 2007 / 010555 A2 or any other monohydrate or anhydrous crystalline forms of moxifloxacin hydrocloride disclosed in the prior art.
  • the sixth aspect of the present invention provides a novel process for the preparation of anhydrous crystalline Form-I of moxifloxacin hydrochloride of formula- 1 which comprises of the following steps: a) suspending moxifloxacin hydrochloride in a suitable alcohol solvent like methanol and heating the solution to 45-5O 0 C, b) optionally adding chloro solvent like methylene chloride and stirring the reaction mixture at 50°C for 15-50 minutes for complete dissolution, optionally concentrating the solvent partially, c) cooling the reaction mixture to 0-30 0 C, preferably 0-15 0 C, more preferably 0-5 0 C, d) stirring the reaction mixture at 0-5 0 C for 1-2 hours, preferably 60-90 minutes, e) separating the precipitated solid by filtration under inert atmosphere and washing with methanol, f) drying the solid at 100°-150°C, preferably at 110-120 0 C till the moisture content reaches below 0.5%.
  • Form-Y obtained in the present invention and also disclosed in our earlier patent WO 2007/10555 or any anhydrous crystalline forms of moxifloxacin hydrocloride other than form-I disclosed in prior art, like Form-Ill of anhydrous moxifloxacin mono hydrochloride disclosed in US 7,230,006.
  • the seventh aspect of the present invention provides a novel crystalline Form-I of moxifloxacin, which is characterized by its PXRD pattern as illustrated in Figure- 1, IR spectrum as illustrated in Figure-2, and DSC as illustrated in Figure-3.
  • Moxifloxacin Form-I in accordance with the present invention is characterized by X-ray powder diffraction peaks at about 9.7, 10.2, 11.7, 18.4 and 23.3 ⁇ 0.2 degrees two- theta.
  • Moxifloxacin Form-I in accordance with the present invention is characterized by Infrared spectrum peaks at about 3329.4, 1728.4, 1621.0, 1437.1, 1341.9, 881.9 and 804.9cm "1 .
  • Moxifloxacin Form-I in accordance with the present invention is characterized by endotherm at about 211 0 C by differential scanning calorimetry ("DSC").
  • the present invention also provides a method of preparing crystalline Form-I of moxifloxacin comprising of the following steps: a) suspending the moxifloxacin hydrochloride and/or its hydrates in a suitable polar solvent like water, b) adjusting the pH of the reaction mixture to basic with aqueous sodium hydroxide or aqueous ammonia solution at 10-40 0 C, preferably at 20-30 0 C and most preferably at 25-30 0 C, c) extracting the reaction mixture with suitable chloro and/or ester solvents like methylene chloride, chloroform or ethyl acetate preferably methylene chloride, d) concentrating the mass by distillation of the solvent completely preferably under reduced pressure at below 60°C, e) cooling the reaction mixture to 5-35°C, preferably at 25-35
  • Crystalline moxifloxacin as provided by the present invention can in turn be prepared from salts of moxifloxacin such as moxifloxacin hydrochloride or any other suitable salt or directly from the reactions which are schematically represented in scheme-6: SCHEME-6:
  • the process for packaging and storage used herein increased the stability of the anhydrous moxifloxacin hydrochloride and increased its shelf life.
  • a process for packaging and storage of anhydrous moxifloxacin hydrochloride comprises of the following steps: a) placing moxifloxacin hydrochloride in a clear low-density polyethylene bag under nitrogen atmosphere and tying with a thread, b) placing the primary container containing moxifloxacin hydrochloride inside a second low-density black colored polyethylene bag and sealing it, c) placing the second polyethylene bag inside a triple laminated bag along with silica gel bag and then sealing it, or e) optionally vacuum sealing the second polythene bag in step b) and the triple laminated bag in step d) after flushing them with nitrogen , d) placing the sealed triple laminated bag inside a closed high density polyethylene
  • Formula-4e Formula-4f Quinoline carboxamide compound of formula-2 is a novel compound which is used in the preparation of moxifloxacin hydrochloride compound of formula- 1 of the present invention.
  • a Malvern laser diffraction instrument was used to characterize the particle size distribution of crystalline anhydrous moxifloxacin hydrochloride. Instrument: The Malvern Mastersizer S, Ver. 2.15
  • Morphology Method of analysis. Samples were mounted on aluminium stubs using double adhesive tape, coated with gold using HUS-5GB vacuum evaporation and observed in Hitachi S-3000 N SEM, at an acceleration Voltage of 10KV.
  • Example-1 Preparation of (S,S)-2-benzyl-8-trityI-2,8-diazabicyclo (4.3.0) nonane:
  • Moxifloxacin can be prepared from 4b (3grams), by a method which is analogous to the method illustrated in Example-8 Yield: 0.85 grams; M.R: 203-205°C
  • Moxifloxacin can be prepared from 4c (3 grams), by a method which is analogous to the method illustrated in Example-8 Yield: 1.0 grams; M.R: 203-205°C
  • Moxifloxacin can be prepared from 4a (10 grams), by a method which is analogous to the method illustrated in Example-8 Yield: 7.5 grams; M.R: 203-205 0 C
  • the condensed compound of formula-4e (14.5 grams) was dissolved in ethyl acetate 100ml.
  • Aqueous hydrochloric acid (5 ml in 20 ml of water) was added to the above reaction mixture.
  • the reaction mixture was stirred at 25-30°C for 30-45 min. 20ml of water was added to the reaction mixture.
  • the two layers were separated.
  • the aqueous layer was washed twice with ethyl acetate.
  • the pH of the aqueous layer was adjusted to 10.8 using sodium hydroxide solution.
  • the reaction mixture was extracted with methylene chloride. The solvent distilled off to get a residue.
  • Moxifloxacin hydrochloride (Form- Y, 10 grams) suspended in 50 ml of methanol and the reaction mixture was heated to 45-50 0 C. 18 ml of dichloromethane was added slowly to the reaction mixture. The reaction mixture was stirred at 45-50°C for 15-20 minutes. The solvent was distilled off partially. The reaction mixture was cooled slowly to around 0-5°C and stirred for 1-1.5 hours. The precipitated solid was filtered under nitrogen atmosphere and washed with 5 ml of methanol. The solid obtained was dried at 110-120 0 C till the moisture content reached below 0.5%. Yield: 7.5 grams. Bulk density: 0.30g/m; Tapped density: 0.60g/ml
  • Moxifloxacin hydrochloride (Form- Y, 20 grams) suspended in 190 ml of methanol and the reaction mixture was heated to reflux. The reaction mixture was stirred for complete dissolution. The reaction mixture was allowed to cool to 25-35°C, further cooled to 15-20°C and stirred for 60 minutes. Filtered the precipitated solid under nitrogen atmosphere and washed solid with 5 ml of methanol. The solid obtained was dried at 110-120°C till the moisture content reached below 0.5%. Yield: 16.5 grams. Bulk density: 0.28 g/m; Tapped density: 0.49 g/ml
  • Moxifloxacin hydrochloride 120 grams was suspended in 600 ml of water. The pH of the reaction mixture was adjusted to 7.9 with aqueous sodium hydroxide solution.
  • reaction mixture was stirred for 10 minutes at 25-30 0 C.
  • the reaction mixture was extracted with methylene chloride. The solvent completely was distilled off under reduced pressure at below 6O 0 C. 100 ml of acetone was added and the reaction mixture was stirred for 30 minutes at 25-30°C. The solid obtained was filtered and washed with acetone and dried at 60°C.
  • Moxifloxacin hydrochloride 120 grams was suspended in 600 ml of water. The pH of the reaction mixture was adjusted to 7.9 with aqueous sodium hydroxide solution.
  • the reaction mixture was stirred for 10 minutes at 25-30 0 C.
  • the reaction mixture was extracted with methylene chloride.
  • the solvent completely was distilled off under reduced pressure at below 60°C.
  • 100 ml of acetone was added and the reaction mixture was stirred for 30 minutes at 25-30°C.
  • the solid obtained was filtered and washed with acetone.
  • the obtained wet solid taken in 1200 ml of cyclohexane.
  • the reaction mixture was heated to reflux and partially distilled off the solvent to remove the traces of acetone.
  • the reaction mixture was extracted with methylene chloride. The solvent was distilled off completely under reduced pressure. Acetone (300 ml) was added to the obtained residue. The reaction mixture was stirred for 30 minutes at 25-30 0 C. The obtained solid was filtered, washed with acetone and dried at 60 0 C. The obtained solid was recrystallized by using acetone as a solvent. Yield: 100 grams. Water content: 2.2% Chloride content: 130 ppm.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention porte sur un nouveau procédé de préparation d'un composé de chlorhydrate de moxifloxacine représenté par la formule 1 par l'intermédiaire de nouveaux composés intermédiaires de quinoléine carboxamide représentés par la formule générale 2. La présente invention concerne le procédé de préparation de nouveaux composés intermédiaires de quinoléine carboxamide représentés par la formule générale 2. La présente invention concerne également un nouveau procédé pour la préparation d'une forme anhydre de chlorhydrate de moxifloxacine et une nouvelle forme cristalline de la moxifloxacine.
PCT/IN2007/000448 2006-11-14 2007-09-27 Nouveau procédé pour la préparation de chlorhydrate de moxifloxacine et nouveau polymorphe de moxifloxacine WO2008059521A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN2111/CHE/2006 2006-11-14
IN2111CH2006 2006-11-14
IN1345/CHE/2007 2007-06-25
IN1345CH2007 IN2007CH01345A (fr) 2004-10-01 2007-09-27

Publications (2)

Publication Number Publication Date
WO2008059521A2 true WO2008059521A2 (fr) 2008-05-22
WO2008059521A3 WO2008059521A3 (fr) 2008-08-28

Family

ID=39402100

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2007/000448 WO2008059521A2 (fr) 2006-11-14 2007-09-27 Nouveau procédé pour la préparation de chlorhydrate de moxifloxacine et nouveau polymorphe de moxifloxacine

Country Status (1)

Country Link
WO (1) WO2008059521A2 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2154137A1 (fr) 2008-08-04 2010-02-17 Chemo Ibérica, S.A. Formule cristalline à base de moxifloxacine
CN102030751A (zh) * 2010-12-01 2011-04-27 上虞京新药业有限公司 一种盐酸莫西沙星的结晶工艺
US20110212990A1 (en) * 2008-11-06 2011-09-01 Hetero Research Foundation Novel polymorph of moxifloxacin hydrochloride
KR101435244B1 (ko) * 2011-04-12 2014-08-29 씨제이헬스케어 주식회사 목시플록사신 수성 제형 및 이의 제조방법
WO2015093669A1 (fr) * 2013-12-20 2015-06-25 씨제이헬스케어 주식회사 Formulation aqueuse de moxifloxacine et sa méthode de préparation
CN104507938B (zh) * 2013-05-13 2017-02-15 娜塔莉亚·米克拉维娜·德卡奇 1‑环丙基‑7‑(s,s‑2,8‑重氮‑二环[4.3.0]壬烷‑8‑基)‑6‑氟‑8‑甲氧‑1,4‑二氢‑4‑氧‑3‑喹啉羧酸的制备方法
US20220323448A1 (en) * 2017-05-04 2022-10-13 Ocular Science, Inc. Compositions and methods for treating eyes and methods of preparation

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0443498A1 (fr) * 1990-02-19 1991-08-28 Kyorin Pharmaceutical Co., Ltd. Dérivés d'isoindoline
EP0550903A1 (fr) * 1992-01-10 1993-07-14 Bayer Ag Dérivés d'acides carboxyliques de quinolone- et de naphthyridone comme agents antibactériens
US6323213B1 (en) * 1996-02-23 2001-11-27 Bayer Aktiengesellschaft Possibly substituted 8-cyano-1-cyclopropyl-7-(2,8-diazabicyclo-[4.3.0]-nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolin carboxylic acids and their derivatives
WO2005012285A1 (fr) * 2003-08-05 2005-02-10 Matrix Laboratories Ltd Procede ameliore permettant de preparer un hydrochlorure de moxifloxacine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0443498A1 (fr) * 1990-02-19 1991-08-28 Kyorin Pharmaceutical Co., Ltd. Dérivés d'isoindoline
EP0550903A1 (fr) * 1992-01-10 1993-07-14 Bayer Ag Dérivés d'acides carboxyliques de quinolone- et de naphthyridone comme agents antibactériens
US6323213B1 (en) * 1996-02-23 2001-11-27 Bayer Aktiengesellschaft Possibly substituted 8-cyano-1-cyclopropyl-7-(2,8-diazabicyclo-[4.3.0]-nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolin carboxylic acids and their derivatives
WO2005012285A1 (fr) * 2003-08-05 2005-02-10 Matrix Laboratories Ltd Procede ameliore permettant de preparer un hydrochlorure de moxifloxacine

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2154137A1 (fr) 2008-08-04 2010-02-17 Chemo Ibérica, S.A. Formule cristalline à base de moxifloxacine
US20110212990A1 (en) * 2008-11-06 2011-09-01 Hetero Research Foundation Novel polymorph of moxifloxacin hydrochloride
CN102030751A (zh) * 2010-12-01 2011-04-27 上虞京新药业有限公司 一种盐酸莫西沙星的结晶工艺
CN102030751B (zh) * 2010-12-01 2012-11-21 上虞京新药业有限公司 一种盐酸莫西沙星的结晶工艺
KR101435244B1 (ko) * 2011-04-12 2014-08-29 씨제이헬스케어 주식회사 목시플록사신 수성 제형 및 이의 제조방법
CN104507938B (zh) * 2013-05-13 2017-02-15 娜塔莉亚·米克拉维娜·德卡奇 1‑环丙基‑7‑(s,s‑2,8‑重氮‑二环[4.3.0]壬烷‑8‑基)‑6‑氟‑8‑甲氧‑1,4‑二氢‑4‑氧‑3‑喹啉羧酸的制备方法
WO2015093669A1 (fr) * 2013-12-20 2015-06-25 씨제이헬스케어 주식회사 Formulation aqueuse de moxifloxacine et sa méthode de préparation
US20220323448A1 (en) * 2017-05-04 2022-10-13 Ocular Science, Inc. Compositions and methods for treating eyes and methods of preparation

Also Published As

Publication number Publication date
WO2008059521A3 (fr) 2008-08-28

Similar Documents

Publication Publication Date Title
WO2008059521A2 (fr) Nouveau procédé pour la préparation de chlorhydrate de moxifloxacine et nouveau polymorphe de moxifloxacine
AU2007320997B2 (en) Process for the synthesis of moxifloxacin hydrochloride
US9718779B2 (en) Intermediate and polymorphs of 1-(4-methoxypheny1)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetra hydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide and process thereof
WO2007010555A2 (fr) Nouvelles formes cristallines d'hydrochlorure de moxifloxacine et procede de preparation associe
WO2007100387A2 (fr) Procédé de préparation de tadalafil
WO2013186792A2 (fr) Procédé de préparation de 2-éthoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)biphényl-4-yl]méthyl}-lh-benzimidazole-7-carboxylate de (5-méthyl-2-oxo-l,3-dioxol-4-yl)méthyle et de ses sels
US20160113912A1 (en) An improved process for the preparation of apixaban and intermediates thereof
US7781427B2 (en) Process for preparing quinoline compounds and products obtained therefrom
US20040242556A1 (en) Novel crystalline form of cefdinir
WO2006134491A2 (fr) Nouvelle forme cristalline d'hydrochlorure de moxifloxacine et procede de preparation de cette derniere
WO2023131978A1 (fr) Procédé amélioré pour la préparation d'upadacitinib
WO2016135747A2 (fr) Processus de préparation d'un composé amorphe (1s)-1,5-anhvdro-1-[3- [[5- (4 fluorophényl)-2-thiényl]methvl]-4-méthylphényl]-d-glucitol et de ses formes polymorphes
WO2010004578A2 (fr) Nouveaux procédés améliorés de préparation de la palipéridone
WO2010052726A1 (fr) Polymorphe inédit de l'hydrochlorure de moxifloxacine
CA2890961A1 (fr) Nouveaux polymorphes de l'azilsartan medoxomil
WO2017025981A1 (fr) Procédé de préparation de méthyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridine-3-yl]-5-pyrimidinyle(méthyl)carbamate et de ses polymorphes
US20210188778A1 (en) Novel polymorphs of 4-[3-chloro-4-(n'-cyclopropyl ureido)phenoxy]-7-methoxyquinoline-6-carboxamide, its salts and process for the preparation thereof
EP2083010A1 (fr) Formes polymorphes d'hydrochlorure de moxifloxacine et leurs procédés de préparation
WO2010089643A1 (fr) Procédé amélioré de préparation de la palipéridone
US20120259116A1 (en) Novel Process for the Preparation of Paliperidone
EP2161269A1 (fr) Procédé de préparation de gémifloxacine amorphe
JPH0637489B2 (ja) キノロンカルボン酸誘導体およびその製造方法
WO2022215083A1 (fr) Formes à l'état solide de (s)-quinuclidin-3-yl (2-(2-(4-fluorophényl)thiazol-4-yl)propan-2-yl) carbamate ou de sels et procédé de préparation associé
WO2016193997A2 (fr) Procédé de préparation d'acide 6-(3-chloro-2-fluorobenzyl)-1-[(2s)-1-hydroxy-3-méthylbutan-2-yl]-7-méthoxy-4-oxo-1,4-dihydroquinoline-3-carboxylique et des sels acceptables sur le plan pharmaceutique de celui-ci
WO2020065668A1 (fr) Forme cristalline de l'ozénoxacine et procédés de préparation associés

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07827588

Country of ref document: EP

Kind code of ref document: A2

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07827588

Country of ref document: EP

Kind code of ref document: A2

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)