WO2020065668A1 - Crystalline form of ozenoxacin and processes for preparation thereof - Google Patents
Crystalline form of ozenoxacin and processes for preparation thereof Download PDFInfo
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- WO2020065668A1 WO2020065668A1 PCT/IN2019/050697 IN2019050697W WO2020065668A1 WO 2020065668 A1 WO2020065668 A1 WO 2020065668A1 IN 2019050697 W IN2019050697 W IN 2019050697W WO 2020065668 A1 WO2020065668 A1 WO 2020065668A1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- the present invention relates to a crystalline form of l-cyclopropyl-8-methyl-7-(5- methyl-6-(methylamino)pyridin-3-yl)-4-oxo- 1 ,4-dihydroquinoline-3-carboxylic acid compound of formula- 1, which is represented by the following structural formula:
- the present invention also relates to process for the preparation crystalline form of the compound of formula- 1 and processes for the preparation of compound of formula- 1.
- l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3-carboxylic acid is known as Ozenoxacin. It is a novel fluorine-free quinolone antibacterial agent, developed by Ferrer Internation SA under the brand name of XEPITMas 1 % topical cream for the treatment of impetigo due to Staphylococcus aureus or Strepto coccus pyogenes. The drug is approved in USA in December 2017 and September 2015 in Japan.
- the patent US8507684B2 discloses various acid addition salts of l-cyclopropyl-8- methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3 -carboxylic acid, such as citrate salt, hemifumarate salt, maleate salt, L-tartarate salt, mesylate salt, hydrochloride salt, potassium salt and sodium salt and their processes.
- 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 polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA”, or differential scanning calorimetry - “DSC”), X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum.
- TGA thermogravimetric analysis -
- DSC differential scanning calorimetry -
- Discovering new salts and new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms.
- New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional salts and solid state forms of ozenoxacin.
- the present invention provides a crystalline form of l-cyclopropyl-8-methyl-7-(5- methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3 -carboxylic acid of formula- 1 and processes for their preparation.
- the first aspect of the present invention is to provide a crystalline form of 1- cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l,4-dihydroquinoline -3-carboxylic acid of formula- 1, herein after designated as crystalline form-M.
- the second aspect of the present invention is to provide a process for the preparation of crystalline form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)- 4-oxo- 1 ,4-dihydro quinoline-3-carboxylic acid.
- the third aspect of the present invention is to provide process for the preparation of 1 - cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l,4-dihydroquinoline -3-carboxylic acid compound of formula-l.
- Figure 1 Illustrates the PXRD pattern of Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5- methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3 -carboxylic acid of formula-l obtained according to example- 16
- Figure 2 Illustrates the PXRD pattern of Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5- methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3 -carboxylic acid of formula-l obtained according to example- 12.
- Figure 3 Illustrates IR spectrum of Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5- methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3 -carboxylic acid of formula-l obtained according to example- 12.
- Figure 4 Illustrates the DSC thermogram of Crystalline Form-M of l-cyclopropyl-8-methyl- 7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3 -carboxylic acid of formula-l obtained according to example- 12.
- suitable solvent refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like;“ether solvents” such as dimethoxymethane, tetrahydrofuran, l,3-dioxane, l,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, l,2-dimethoxy ethane and the like;“ester solvents” such as methyl acetate,
- suitable base refers to inorganic or organic base.
- Inorganic base refers to“alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like;“alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like;“alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diiso
- the term“acid” used in the present invention refers to inorganic acids selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc; organic acids such as acetic acid, maleic acid, malic acid, tartaric acid, oxalic acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid etc.; Lewis acids and like.
- the first aspect of the present invention provides Crystalline Form-M of l-cyclo propyl-8-methyl-7-(5-methyl- 6-(methylamino) pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3- carboxylic acid of formula- 1.
- the crystalline form-M of the present invention is characterized by its powder X-Ray diffraction pattern having peaks at about 7.28, 9.33, 11.27, 13.97, 15.52, 16.8, 19.19, 22.59, 23.84, 24.94, 26 and 28.29 ⁇ 0.2° 2Q.
- the Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino) pyri din-3 -yl)-4-oxo-l, 4-dihydro quinoline-3-carboxylic acid of formula-l is further characterized by its powder X-Ray diffraction pattern substantially in accordance with figure- 1.
- the Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino) pyri din-3 -yl)-4-oxo-l, 4-dihydro quinoline-3-carboxylic acid of formula-l is further characterized by its IR spectrum substantially in accordance with figure-3.
- Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino) pyri din-3 -yl)-4-oxo-l, 4-dihydro quinoline-3-carboxylic acid of formula-l is further characterized by its DSC thermogram substantially in accordance with figure-4.
- the second aspect of the present invention is to provide a process for the preparation of the Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3- yl)-4-oxo-l, 4-dihydro quinoline-3 -carboxylic acid of formula-l, comprising of:
- step-a) adding a suitable acid to the solution of step-a) and stirring at suitable temperature, isolating the compound
- step-b) adjusting the p H of the solution obtained in step-b) with a suitable base
- step-c) filtering the solid obtained in step-c) provides the crystalline form-M of l-cyclopropyl-8- methyl-7-(5-methyl-6-(methylamino)pyri din-3 -yl)-4-oxo-l,4-dihydroquinoline-3-carboxy licacid compound of formula-l .
- the suitable solvent is selected from polar protic, polar aprotic, alcohol, ether, ketone, water and mixture thereof.
- suitable acid is citricacid, tataricacid, methane sulphonic acid, para toluenesulfonicacid, maleicacid, fumaricacid, camphorsulfonic acid, hydrobromicacid, aceticacid, trifluoroaceticacid;
- suitable temperature is 0°C to l00°C, preferably 20-85°C;
- the suitable base is potassium hydroxide, sodium hydroxide, lithium hydroxide, bariumhydroxide, aq. ammonia, triethylamine, diisopropylamine, diiso propyl ethylamine ; in Step-c) suitable p H range is 5.0 to 7.0;
- the other preferred embodiment of the present invention is to provide a process for the preparation of the Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methyl amino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3-carboxylic acid of formula-l, comprising of:
- step-c) a) stirring the compound of formula-l in isopropanol and water, b) adding methane sulphonic acid to the solution of step-a)and stirring at 40-45°C, c) adjusting the p H of the solution obtained in step-b) with aq. sodium hydroxide solution, d) filtering the solid obtained in step-c) provides the crystalline form-M of l-cyclopropyl-8- methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3 -carboxylic acid compound of formula- 1.
- the other embodiment of the present invention is to provide a process for the preparation of the Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methyl amino) pyri din-3 -yl)-4-oxo-l, 4-dihydro quinoline-3-carboxylic acid of formula-l, comprising of:
- step-b) stirring the compound obtained in step-a) in base solution at suitable temperature, c) isolating the compound obtained in step-b), purifying in suitable solvent,
- step-e) optionally purifying the compound obtained in step-e) in suitable solvent to provide the crystalline form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4- oxo-l, 4-dihydro quinoline-3 -carboxylic acid compound of formula-l .
- the suitable solvent is selected from polar aprotic, alcohol, ether, ketone, water and mixture thereof.
- suitable base solvent is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide in alcoholic solution, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide; preferebly: alcoholic base, potassium hydroxide in ethanol; suitable temperature is 0°C to lOO°C, preferably 20-85°C;
- the suitable solvent is alcohol, ketone, ester;
- suitable solvent is water, alcohol ketone and mixture thereof;
- suitable base is selected from potassium hydroxide, sodium hydroxide;
- suitable acid is selected from hydrochloric acid; citric acid, acetic acid; preferably hydrochloric acid; p H range is 11-12 & 4-6; step-f) suitable solvent is selected from alcohol, ester, ketone, DMF, acetonitrile, polar a
- the other embodiment of the present invention is to provide a process for the preparation of the Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methyl amino) pyri din-3 -yl)-4-oxo-l, 4-dihydro quinoline-3-carboxylic acid of formula-l, comprising of:
- step-b) stirring the compound obtained in step-a) in ethanolic KOH, stirring at 25-35°C, c) isolating the compound obtained in step-b) and purifying in ethanol,
- step-d) adjusting the p of the solution obtained in step-d) with potassium hydroxide and hydrochloric acid at suitable temperature and isolating the compound
- step-e fjpurifying the compound obtained in step-e) in water to provide the crystalline form-M of 1 - cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline -3 -carboxylic acid compound of formula- 1.
- the third aspect of the present invention is to provide processes for the preparation of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline -3- carboxylic acid compound of formula- 1, comprising of ;
- step-a) reacting the compound obtained in step-a) using a suitable reagent to get the compound of formula- 1,
- step-b) suspending the compound obtained in step-b) in an organic solvent
- step-e) stirring the compound obtained in step-c) in base solution at suitable temperature, e) isolating the compound obtained in step-d) purifying in suitable solvent and isolating, f) suspending the compound obtained in step-e) in suitable solvent,
- step-g or b) optionally purifying the compound obtained in step-g or b) in suitable solvent to provide the crystalline form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)- 4-oxo- 1, 4-dihydro quinoline-3 -carboxylic acid compound of formula- 1.
- step-a) catalyst is selected from tetrakis(triphenylphosphine)palladium(0), palladium (II) acetate, tris(dibenzylideneacetone)dipalladium(0), Pd(dppf)Cl 2.
- Another aspect of the present invention is to provide process for the preparation of 1- cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l,4-dihydroquinoline -3- carboxylic acid compound of formula- 1, comprising of ;
- step-a) reacting the compound obtained in step-a) with hydrochloric acid to get the compound of formula- 1,
- step-e) stirring the compound obtained in step-c) in ethanolic KOH, at 25-35°C, e) isolating the compound obtained in step-d) and purifying in ethanol, isolating, f) suspending the compound obtained in step-e) in water,
- step-f) adjusting the p H of the solution obtained in step-f) with potassium hydroxide, hydrochloric acid at suitable temperature and isolating the compound of ofrmula-l,
- step-g) purifying the compound obtained in step-g) in water to provide the crystalline form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l,4-di hydro quinoline-3-carboxylic acid compound of formula-l .
- the obtained compound is reduced with sodium borohydride in tetrahydrofuran to get N-(5-bromo-3-methyl-2-pyridinyl)-N- methylamine, in situ the obtained compound reacting with benzoyl chloride in presence of tri ethylamine to get N-(5-bromo-3-methylpyridin-2-yl)-N-methylbenzamide.
- the obtained compound is reacted with triisopropyl borate in presence n-butyl lithium in tetrahydrofuran to get the 5-methyl-6(N-methylbenzamido)pyridin-3-ylboronic acid.
- the obtained compound is reacted with dimethylformamide dimethylacetal (DMF-DMA) to obtain ethyl-2-(2,4-dichloro -3-methylbenzoyl)-3-(dimethylamino)acrylate.
- the obtained compound is reacted with cyclo propylamine in toluene to get ethyl-3-(cyclopropyl)-2-(2,4-dichloro-3-methyl benzoyl) acrylate.
- the obtained compound is cyclized with potassium carbonate in DMSO to get ethyl- 7-chloro-l-cyclopropyl-8-methyl-4-oxo-l,4-dihydroquinoline-3-carboxylate.
- the particle size of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3- yl)-4-oxo-l, 4-dihydro quinoline-3 -carboxylic acid compound of formula- 1 produced by the present invention can be reduced by micronization or milling to get the desired particle size to achieve desired solubility profile.
- Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
- Particle size of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4- oxo-l, 4-dihydroquinoline-3-carboxylicacid produced according to the present process is D90 ⁇ 100 microns, Preferably D90 ⁇ 50 microns, more preferably D90 ⁇ 20 microns.
- the precipitated compound was filtered, washed with water (100 ml).
- the wet compound was charged in RBF with n-heptane (400 ml), heated to 60-70°C and for 1 hr.
- the reaction mixture was cooled to 0-10°C and stirred for 1 hr, the obtained solid was filtered and washed with n- heptane (100 ml) to get the title compound.
- the reaction mixture was cooled to 25-35°C, charged with cyclo propylamine (30.6gm) stirred for 4 hr.
- the precipitated compound was filtered, washed with toluene (100 ml).
- the obtained compound was charged with water (500 ml), stirred for 2 hr.
- the obtained solid was filtered and washed with water (100 ml), dried to get the title compound.
- a round bottom flask was charged with compound of formula-6a (100 gr), DMSO (300 ml) and potassium carbonate (80 gr), heated to 95-105°C and stirred for 4 hr.
- the reaction mixture was cooled to 25-30°C, diluted with hydrochloric acid (100 ml) and water (800 ml) stirred for 1.5 hr.
- the precipitated solid was filtered and washed with water (100 ml).
- the wet compound was stirred in isopropanol (200 ml) for 1 hr, filtered the obtained solid and washed with isopropanol (100 ml) dried to get the title compound.
- the obtained compound was charged in RBF with ethyl acetate (250 ml), heated to 75-85°C stirred for 2 hr and cooled the solution to 25-35° stirred for 2 hr.
- the obtained solid was filtered and washed with ethyl acetate (50 ml). The same purification process was repeated to get pure title compound.
- the obtained compound was charged in RBF with dil. hydrochloric acid (750 ml), washed with dichloromethane (3x150 ml) and separated both layers.
- the aqueous layer was taken, heated to 90-l00°C stirred for 6 hr.
- the reaction mixture was cooled to 25-35°C, washed with dichloromethane (5x150 ml) and separated the both layers.
- the aqueous layer was diluted with ethanol (375 ml) and the solution p was adjusted to 11.3 with sodium hydroxide solution (300 gr in 600 ml), stirred for 6 hr at 25-35°C.
- the reaction mass p H was adjusted to 5.2 with dil.HCl and stirred for 45 min.
- the obtained solid was filtered and washed with water (100 ml).
- the obtained wet compound was again slurred in water (750 ml) and stirred for 45 min, filtered the obtained solid and dried to get the
- the obtained compound was charged in RBF with water (550 ml), methanesufonicacid (116.3 gr) and washed with dichloromethane (3x150 ml), separated the both layers.
- the aqueous layer was heated to 90-100°C stirred for 6 hr.
- the reaction mixture was cooled to 25-35°C, washed with dichloromethane (5x150 ml) and separated the both layers.
- the aqueous layer was diluted with ethanol (375 ml) and the solution p was adjusted to 11.8 with sodium hydroxide solution (300 gr in 600 ml), stirred for 6 hr at 25-35°C.
- the reaction mass p H was adjusted to 5.3 with dil. hydrochloric acid and stirred for 45 min.
- the obtained solid was filtered and washed with water (100 ml).
- the obtained compound was charged with water (750 ml) and stirred for 45 min, filtered the obtained solid and dried to get the
- the obtained compound was charged in RBF with water (900 ml) adjusted the p H to 11.6 with potassium hydroxide solution (10 ml) and stirred for 2 hr.
- the reaction mass was filtered through hyflow bed to remove solid particles and washed with water (900 ml).
- the filtrate layer p H was adjusted to 5.2 with hydrochloric acid (15 ml) stirred for 1 hr. Filtered the obtained compound and washed with water (100 ml) to get wet compound.
- the obtained wet compound was charged in RBF with water (1 lit), heated to 70- 80°C and stirred for 1 hr.
- the reaction mixture was cooled to 50-60°C stirred for 45 min and filtered the obtained compound and washed with water (100 ml).
- the same purification process was repeated with water and dried the obtained compound to get the tilted compound. Yield: 32 gr.
- the PXRD of the obtained compound is depicted in figure-2
- Example-18 Preparation of crystalline form-M of compound of formula-1.
- the obtained compound was charged in RBF with water (450 ml) adjusted the p H to 11.4 with potassium hydroxide solution (5 ml) and stirred for 2 hr.
- the reaction mass was filtered through hyflow bed to remove solid particles and washed with water (450 ml).
- the filtrate layer p H was adjusted to 5.3 with hydrochloric acid (8 ml) stirred for 1 hr. Filtered the obtained compound and washed with water (50 ml) to get wet compound.
- the obtained compound was suspended in DMF (250 ml) stirred for 4-5 hr.
- the reaction mixture was cooled to 25-35°C stirred for 30 min.
- the obtained solid was filtered and washed with DMF to get the title compound.
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Abstract
The present invention relates to a crystalline form of 1-cyclopropyl-8-methyl-7- (5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid the compound of formula-1, which is represented by the following structural formula-1. The present invention also relates to the process for preparation of crystalline form of compound of formula-1 and process for the preparation of the compound of formula-1.
Description
Crystalline form of Ozenoxacin and processes for preparation thereof.
Related Applications:
This application claims the benefit of Indian provisional patent application number 201841036343 filed on 26 September 2018, the disclosure of which is hereby incorporated by reference as if written herein in its entirety.
Field of the Invention:
The present invention relates to a crystalline form of l-cyclopropyl-8-methyl-7-(5- methyl-6-(methylamino)pyridin-3-yl)-4-oxo- 1 ,4-dihydroquinoline-3-carboxylic acid compound of formula- 1, which is represented by the following structural formula:
Formula- 1
The present invention also relates to process for the preparation crystalline form of the compound of formula- 1 and processes for the preparation of compound of formula- 1.
Background of the Invention: l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3-carboxylic acid is known as Ozenoxacin. It is a novel fluorine-free quinolone antibacterial agent, developed by Ferrer Internation SA under the brand name of XEPI™as 1 % topical cream for the treatment of impetigo due to Staphylococcus aureus or Strepto coccus pyogenes. The drug is approved in USA in December 2017 and September 2015 in Japan.
The patent US6335447B1 first described l-cyclopropyl-8-methyl-7-(5-methyl-6- (methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3-carboxylic acid as compound and disclosed various processes for the preparation of ozenoxacin. The said patent herein after referred to as US’447. The US’447 reported ozenoxacin melting point equal to or higher than 250°C.
The patent US8507684B2 discloses various acid addition salts of l-cyclopropyl-8- methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3 -carboxylic acid, such as citrate salt, hemifumarate salt, maleate salt, L-tartarate salt, mesylate salt, hydrochloride salt, potassium salt and sodium salt and their processes.
There are various processes reported for the preparation of ozenoxacin, but not disclosed any polymorphs or crystalline forms of ozenoxacin in the prior art.
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 polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
Discovering new salts and new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional salts and solid state forms of ozenoxacin.
The present invention provides a crystalline form of l-cyclopropyl-8-methyl-7-(5- methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3 -carboxylic acid of formula- 1 and processes for their preparation.
Brief Description:
The first aspect of the present invention is to provide a crystalline form of 1- cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l,4-dihydroquinoline -3-carboxylic acid of formula- 1, herein after designated as crystalline form-M.
The second aspect of the present invention is to provide a process for the preparation of crystalline form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)- 4-oxo- 1 ,4-dihydro quinoline-3-carboxylic acid.
The third aspect of the present invention is to provide process for the preparation of 1 - cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l,4-dihydroquinoline -3-carboxylic acid compound of formula-l.
Brief description of the drawings:
Figure 1 : Illustrates the PXRD pattern of Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5- methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3 -carboxylic acid of formula-l obtained according to example- 16
Figure 2: Illustrates the PXRD pattern of Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5- methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3 -carboxylic acid of formula-l obtained according to example- 12.
Figure 3: Illustrates IR spectrum of Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5- methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3 -carboxylic acid of formula-l obtained according to example- 12.
Figure 4: Illustrates the DSC thermogram of Crystalline Form-M of l-cyclopropyl-8-methyl- 7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3 -carboxylic acid of formula-l obtained according to example- 12.
Detailed Description:
As used herein the term“suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like;“ether solvents” such as dimethoxymethane, tetrahydrofuran, l,3-dioxane, l,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, l,2-dimethoxy ethane and the like;“ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N- methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbontetrachloride and the like; “ketone solvents” such as
acetone, methyl ethyl ketone, methyl isobutyl ketone and the like;“nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like;“alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2- fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
As used herein the present invention the term“suitable base” refers to inorganic or organic base. Inorganic base refers to“alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like;“alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like;“alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylamino pyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide; organo silicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or mixtures thereof
The term“acid” used in the present invention refers to inorganic acids selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc; organic acids such as acetic acid, maleic acid, malic acid, tartaric acid, oxalic acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid etc.; Lewis acids and like.
The first aspect of the present invention provides Crystalline Form-M of l-cyclo propyl-8-methyl-7-(5-methyl- 6-(methylamino) pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3- carboxylic acid of formula- 1. The crystalline form-M of the present invention is characterized by its powder X-Ray diffraction pattern having peaks at about 7.28, 9.33, 11.27, 13.97, 15.52, 16.8, 19.19, 22.59, 23.84, 24.94, 26 and 28.29 ± 0.2° 2Q.
The Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino) pyri din-3 -yl)-4-oxo-l, 4-dihydro quinoline-3-carboxylic acid of formula-l is further characterized by its powder X-Ray diffraction pattern substantially in accordance with figure- 1. The Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino) pyri din-3 -yl)-4-oxo-l, 4-dihydro quinoline-3-carboxylic acid of formula-l is further characterized by its IR spectrum substantially in accordance with figure-3.
The Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino) pyri din-3 -yl)-4-oxo-l, 4-dihydro quinoline-3-carboxylic acid of formula-l is further characterized by its DSC thermogram substantially in accordance with figure-4.
The second aspect of the present invention is to provide a process for the preparation of the Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3- yl)-4-oxo-l, 4-dihydro quinoline-3 -carboxylic acid of formula-l, comprising of:
a) Stirring the compound of formula-l in a suitable solvent,
b) adding a suitable acid to the solution of step-a) and stirring at suitable temperature, isolating the compound,
c) adjusting the pH of the solution obtained in step-b) with a suitable base,
d) filtering the solid obtained in step-c) provides the crystalline form-M of l-cyclopropyl-8- methyl-7-(5-methyl-6-(methylamino)pyri din-3 -yl)-4-oxo-l,4-dihydroquinoline-3-carboxy licacid compound of formula-l .
Wherein in step-a) the suitable solvent is selected from polar protic, polar aprotic, alcohol, ether, ketone, water and mixture thereof. Step-b) suitable acid is citricacid, tataricacid, methane sulphonic acid, para toluenesulfonicacid, maleicacid, fumaricacid, camphorsulfonic acid, hydrobromicacid, aceticacid, trifluoroaceticacid; suitable temperature is 0°C to l00°C, preferably 20-85°C; in step c) the suitable base is potassium hydroxide, sodium hydroxide, lithium hydroxide, bariumhydroxide, aq. ammonia, triethylamine, diisopropylamine, diiso propyl ethylamine ; in Step-c) suitable pH range is 5.0 to 7.0;
The other preferred embodiment of the present invention is to provide a process for the preparation of the Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methyl amino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3-carboxylic acid of formula-l, comprising of:
a) stirring the compound of formula-l in isopropanol and water,
b) adding methane sulphonic acid to the solution of step-a)and stirring at 40-45°C, c) adjusting the pH of the solution obtained in step-b) with aq. sodium hydroxide solution, d) filtering the solid obtained in step-c) provides the crystalline form-M of l-cyclopropyl-8- methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3 -carboxylic acid compound of formula- 1.
The other embodiment of the present invention is to provide a process for the preparation of the Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methyl amino) pyri din-3 -yl)-4-oxo-l, 4-dihydro quinoline-3-carboxylic acid of formula-l, comprising of:
a) suspending the compound of formula-l in an organic solvent,
b) stirring the compound obtained in step-a) in base solution at suitable temperature, c) isolating the compound obtained in step-b), purifying in suitable solvent,
d) suspending the compound obtained in step-c) in suitable solvent,
e) adjusting the p of the solution obtained in step-d) with suitable base, acid at suitable temperature isolating the compound,
f) optionally purifying the compound obtained in step-e) in suitable solvent to provide the crystalline form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4- oxo-l, 4-dihydro quinoline-3 -carboxylic acid compound of formula-l .
Wherein in step-a) the suitable solvent is selected from polar aprotic, alcohol, ether, ketone, water and mixture thereof. Step-b) suitable base, solvent is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide in alcoholic solution, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide; preferebly: alcoholic base, potassium hydroxide in ethanol; suitable temperature is 0°C to lOO°C, preferably 20-85°C; in step c) the suitable solvent is alcohol, ketone, ester; step-d) suitable solvent is water, alcohol ketone and mixture thereof; step-e) suitable base is selected from potassium hydroxide, sodium hydroxide; suitable acid is selected from hydrochloric acid; citric acid, acetic acid; preferably hydrochloric acid; pH range is 11-12 & 4-6; step-f) suitable solvent is selected from alcohol, ester, ketone, DMF, acetonitrile, polar aprotic solvents, water and mixture thereof;
The other embodiment of the present invention is to provide a process for the preparation of the Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methyl amino) pyri din-3 -yl)-4-oxo-l, 4-dihydro quinoline-3-carboxylic acid of formula-l, comprising
of:
a) suspending the compound of formula- 1 in tetrahydrofuran,
b) stirring the compound obtained in step-a) in ethanolic KOH, stirring at 25-35°C, c) isolating the compound obtained in step-b) and purifying in ethanol,
d) suspending the compound obtained in step-c) in water,
e) adjusting the p of the solution obtained in step-d) with potassium hydroxide and hydrochloric acid at suitable temperature and isolating the compound,
fjpurifying the compound obtained in step-e) in water to provide the crystalline form-M of 1 - cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline -3 -carboxylic acid compound of formula- 1.
The third aspect of the present invention is to provide processes for the preparation of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline -3- carboxylic acid compound of formula- 1, comprising of ;
Formula- 1 a) reacting the compound of formula-7
Formula-7
with compound of formula- 8
Formula- 8
in presence of a palladium catalyst, base in a suitable solvent to produce compound of
formula-9
Formula-9
b) reacting the compound obtained in step-a) using a suitable reagent to get the compound of formula- 1,
c) suspending the compound obtained in step-b) in an organic solvent,
d) stirring the compound obtained in step-c) in base solution at suitable temperature, e) isolating the compound obtained in step-d) purifying in suitable solvent and isolating, f) suspending the compound obtained in step-e) in suitable solvent,
g) adjusting the p of the solution obtained in step-f) with suitable base, acid at suitable temperature and isolating the compound of formula- 1,
h) optionally purifying the compound obtained in step-g or b) in suitable solvent to provide the crystalline form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)- 4-oxo- 1, 4-dihydro quinoline-3 -carboxylic acid compound of formula- 1.
Wherein the step-a) catalyst is selected from tetrakis(triphenylphosphine)palladium(0), palladium (II) acetate, tris(dibenzylideneacetone)dipalladium(0), Pd(dppf)Cl2. Dichlorobis(tri cyclohexylphosphine)palladium(II); preferably Dichlorobis (tricyclohexyl phosphine) palladium (II); ligand is selected from xantphos, X-phos, BINAP, bis(diphenyl phosphino) ferrocene, triphenylphosphine; Sphos, bis(diphenylphosphino)methane; base is selected from inorganic base, organic base; solvent is selected form toluene, benzene, dioxane, acetonitrile, tetrahydrofuran, dimethylformamide, ester, water, alcohol and mixture thereof; step-b) suitable reagent is selected from Con.Hydrochloric acid, methane sulphonic acid, sulphuric acid, hydrobromic acid; preferably Con.Hydrochloric acid, methane sulphonic acid; suitable solvent is alcohol, ketone, ester, acetonitrile, ether, water and mixture thereof; step-c) the suitable solvent is selected from polar aprotic, alcohol, ether, ketone, water and mixture thereof; in step-d) suitable base, solvent is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide in an alcoholic solution, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide; preferebly: potassium hydroxide in ethanol; suitable
temperature is 0°C to l00°C, preferably 20-85°C; in step e) the suitable solvent is alcohol, ketone, ester; in step-f) suitable solvent is water, alcohol acetone and mixture thereof; in step- g) suitable base is selected from potassium hydroxide, sodium hydroxide; suitable acid is selected hydrochloric acid; citric acid, acetic acid; preferably hydrochloric acid; pH range is 11-12 & 4-6; step-h) suitable solvent is selected from alcohol, ester, ketone, ester, polar aprotic, nitrile, polar protic, water and mixture thereof;
Other aspect of the present invention is to provide process for the preparation of 1- cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l,4-dihydroquinoline -3- carboxylic acid compound of formula- 1, comprising of ;
a) reacting the compound of formula-7a
Formula-7a
with compound of formula-8a
Formula- 8a
in presence of bis(tricyclohexylphosphine palladium dichloride), sodium bicarbonate in toluene, water to produce compound of formula-9a
Formula-9a
b) reacting the compound obtained in step-a) with hydrochloric acid to get the compound of formula- 1,
c) suspending the compound obtained in step-b) in tetrahydrofuran,
d) stirring the compound obtained in step-c) in ethanolic KOH, at 25-35°C,
e) isolating the compound obtained in step-d) and purifying in ethanol, isolating, f) suspending the compound obtained in step-e) in water,
g) adjusting the pH of the solution obtained in step-f) with potassium hydroxide, hydrochloric acid at suitable temperature and isolating the compound of ofrmula-l,
h) purifying the compound obtained in step-g) in water to provide the crystalline form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l,4-di hydro quinoline-3-carboxylic acid compound of formula-l .
The process for preparation of 5-methyl-6(N-methylbenzamido)pyridin-3-ylboronic acid compound of formula-8a is known in the art. 2-amino-5-bromo-3-methylpyridine is reacted with formaline solution in presence of sodium hydroxide in methanol to get N-(5- bromo-3-methyl-2-pyridyl)-N-(methoxymethyl)amine. The obtained compound is reduced with sodium borohydride in tetrahydrofuran to get N-(5-bromo-3-methyl-2-pyridinyl)-N- methylamine, in situ the obtained compound reacting with benzoyl chloride in presence of tri ethylamine to get N-(5-bromo-3-methylpyridin-2-yl)-N-methylbenzamide. The obtained compound is reacted with triisopropyl borate in presence n-butyl lithium in tetrahydrofuran to get the 5-methyl-6(N-methylbenzamido)pyridin-3-ylboronic acid.
The process for preparation of ethyl-7-chloro-l-cyclopropyl-8-methyl-4-oxo-l,4- dihydroquinoline-3-carboxylate compound of formula-7a is known in the art. Reacting 2,4- dichloro-3-methylbenzoic acid with ethyl-3-(N,N-dimethylamino)acrylate in presence thionyl chloride in toluene, in situ the obtained compound reacting with cyclopropyl amine in toluene to get ethyl-3 -(cyclopropyl) -2-(2,4-dichloro-3-methylbenzoyl) acrylate. The obtained compound is reacted with potassium carbonate in DMSO to get the ethyl-7-chloro-l-cyclo propyl-8-methyl-4-oxo-l,4-dihydroquinoline-3-carboxylate.
The other process for preparation of ethyl-7-chloro-l-cyclopropyl-8-methyl-4-oxo-l,4- dihydroquinoline-3-carboxylate compound of formula-7a is by reacting 2, 4-dichloro-3 -methyl benzonitrile with potassium ethylmalonate in presence of zinc chloride in 1 ,2 dichloroethane to obtain ethyl 3-(2,4-dichloro-3-methylphenyl)-3-oxopropanoate. The obtained compound is reacted with dimethylformamide dimethylacetal (DMF-DMA) to obtain ethyl-2-(2,4-dichloro -3-methylbenzoyl)-3-(dimethylamino)acrylate. The obtained compound is reacted with cyclo propylamine in toluene to get ethyl-3-(cyclopropyl)-2-(2,4-dichloro-3-methyl benzoyl)
acrylate. The obtained compound is cyclized with potassium carbonate in DMSO to get ethyl- 7-chloro-l-cyclopropyl-8-methyl-4-oxo-l,4-dihydroquinoline-3-carboxylate.
Schematic representation of the process for the preparation of oxenoxacin :
Scheme- 1
Wherein X is Cl, Br; Protecting group (PG): Boc, Acetyl, trifluoroacetyl, F-moc, benzoyl, benzyl, t-butyloxycarbonyl;
Scheme-2:
(Ozenoxacin)
The particle size of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3- yl)-4-oxo-l, 4-dihydro quinoline-3 -carboxylic acid compound of formula- 1 produced by the present invention can be reduced by micronization or milling to get the desired particle size to achieve desired solubility profile. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product. Particle size of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4- oxo-l, 4-dihydroquinoline-3-carboxylicacid produced according to the present process is D90
<100 microns, Preferably D90 <50 microns, more preferably D90 <20 microns.
PXRD analysis of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)- 4-oxo- l,4-dihydroquinoline-3-carboxylicacid was carried out using BRUKER D8 ADVANCED/ AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min. IR spectra were recorded on a Perkin-Elmer FT-IR spectrometer.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example- 1: Preparation of N-(5-bromo-3-methyl-2-pyridyl)-N-(methoxymethyl)amine
A round bottom flask was charged with 40 % formaldehyde solution (60 ml), methanol (300 ml) and sodium hydroxide (21.4 gr) and stirred for 30-45 min at 25-35°C. 2-amino-5-bromo- 3-methylpyridine (100 gr) was charged to the above solution and stirred for 4-5 hr. The reaction mixture was quenched with water (600 ml) stirred for 2 hr. The obtained solid was filtered, again suspended in water (600 ml) and stirred for 30 min. The obtained solid was filtered and washed with water (100 ml) and dried to get the title compound.
Yield: 115.5 gr
Example-2: Preparation of N-(5-bromo-3-methylpyridin-2-yl)-N-methylbenzamide
A round bottom flask was charged with N-(5-bromo-3-methyl-2-pyridyl)-N-(methoxy methyl) amine (100 gr), tetrahydrofuran (250 ml) and stirred for 10 min. The reaction mixture cooled 25-35°C, charged sodium borohydride (4.9 gr) and stirred for 1 hr. After completion of the reaction, the reaction mixture was charged with triethylamine (87 gr) and benzoyl chloride (91. gr) was added slowly and refluxed for 5 hr. The reaction mixture was cooled to 25-30°C, quenched with water (750 ml) and further cooled to 0-l0°C and stirred for 2 hr. The precipitated compound was filtered, washed with water (100 ml). The wet compound was charged in RBF with n-heptane (400 ml), heated to 60-70°C and for 1 hr. The reaction mixture was cooled to 0-10°C and stirred for 1 hr, the obtained solid was filtered and washed with n- heptane (100 ml) to get the title compound.
Yield: 132 gr
Example-3: Preparation of compound of formula-8a
A round bottom flask was charged with N-(5-bromo-3-methylpyridin-2-yl)-N-methyl benzamide (150 gr), tetrahydrofuran (1500 ml) and triisopropyl borate (111 gr) stirred for 10 min under nitrogen atmosphere. The reaction mixture was cooled to -70°C to -75°C, charged n-Butyl lithium solution (255 ml, 2.5 M) cautiously for 2hr, and stirred at same temperature for 2 hr. The reaction mixture was quenched with water (1.5 lit) slowly at below -20°C, gradually raised the temperature to 25-35°C and stirred for 1 hr. The both layers were separated; the aqueous layer was washed with ethyl acetate (3x300 ml). The aqueous layer p was adjusted to 4.25 with hydrochloric acid (90 ml), the precipitated compound was filtered and washed with water (150 ml) and dried to get the title compound.
Yield: 95 gr
Example-4: Preparation of compound of formula-6a
A round bottom flask was charged with thionylchloride (348 gr), 2,4-dichloro-3-methyl benzoic acid (100 gr) and N, N-dimethyl formamide (2 ml) and heated to relux and stirred for 4 hr. The reaction mixture was distilled off, co-distilled with toluene (100 ml). The reaction mixture was charged with toluene (500 ml), triethylamine (98.5 gr) and ethyl-3-(N, N-dimethyl amino)acrylate (95.05 gr) heated to l00-H5°C stirred for 3 hr. The reaction mixture was cooled to 25-35°C, charged with cyclo propylamine (30.6gm) stirred for 4 hr. The precipitated compound was filtered, washed with toluene (100 ml). The obtained compound was charged with water (500 ml), stirred for 2 hr. The obtained solid was filtered and washed with water (100 ml), dried to get the title compound.
Yield: 116.90 gr
Example-5: Preparation of compound of formula-7a
A round bottom flask was charged with compound of formula-6a (100 gr), DMSO (300 ml) and potassium carbonate (80 gr), heated to 95-105°C and stirred for 4 hr. The reaction mixture was cooled to 25-30°C, diluted with hydrochloric acid (100 ml) and water (800 ml) stirred for 1.5 hr. The precipitated solid was filtered and washed with water (100 ml). The wet compound was stirred in isopropanol (200 ml) for 1 hr, filtered the obtained solid and washed with isopropanol (100 ml) dried to get the title compound.
Yield: 88 gr.
Example-6: Preparation of compound of formula-7a
A round bottom flask was charged with compound of formula-6a (100 gr), DMSO (300 ml) and potassium carbonate (120.9 gr), heated to 80-90°C and stirred for 4 hr. The reaction mixture was cooled to 25-30°C, diluted with water (800 ml) stirred for 1.5 hr. The precipitated solid was filtered and washed with water (100 ml), dried to get the title compound.
Yield: 88 gr
Example-7: Preparation of compound of formula-9a
A round bottom flask was charged with compound of formula-7a (50 gr), toluene (150 ml), compound of formula-8a (66 gr), sodium bicarbonate (33 gr) and water (100 ml) stirred for 1 hr under nitrogen atmosphere. Bis(triphenylphosphine)palladium dichloride (0.6 gr) was added to the above reaction mixture at 25-35°C, stirred for 12 hr at 80-90°C. The reaction mixture was cooled to 25-35°C charged with water (250 ml), further cooled to 0-10°C and stirred for 4 hr. The obtained compound was filtered and washed with water (100 ml) to get the wet compound. The obtained compound was charged in RBF with ethyl acetate (250 ml), heated to 75-85°C stirred for 2 hr and cooled the solution to 25-35° stirred for 2 hr. The obtained solid was filtered and washed with ethyl acetate (50 ml). The same purification process was repeated to get pure title compound.
Yield: 55 gr.
Example-8: Preparation of compound of formula- 1
A round bottom flask was charged with compound of formula-9a (50 gr), hydrochloric acid (500 ml) and heated to 90-l00°C stirred for 6 hr. The reaction mixture was cooled to 25-35°C, washed with dichloromethane (5x100 ml) and separated both layers. The aqueous layer was diluted with ethanol (250 ml) and the solution p was adjusted to 11.2 with sodium hydroxide solution (180 gr in 350 ml), stirred for 4 hr at 25-35°C. The obtained solution pH was adjusted to 5.25 with dil.HCl and stirred for 45 min. The obtained solid was filtered and washed with water (50 ml). The obtained compound was suspended with water (500 ml) and stirred for 45 min, filtered the obtained solid and dried to get the title compound.
Yield: 35.9 gr.
Purity by HPLC: NLT 96 %
Example-9: Preparation of compound of formula- 1
A round bottom flask was charged with compound of formula-9a (50 gr), methane sulfonic acid (77.5 gr) and heated to 90-l00°C stirred for 6 hr. The reaction mixture was cooled to 25- 35°C, washed with dichloromethane (5x100 ml) and separated both layers. The aqueous layer was diluted with ethanol (250 ml) and the solution pH was adjusted to 11.5 with sodium hydroxide solution (180 gr in 350 ml), stirred for 4 hr at 25-35°C. The obtained solution reaction mass p was adjusted to 5.25 with dil. hydrochloric acid and stirred for 45 min. The obtained solid was filtered and washed with water (50 ml). The obtained compound was charged with water (500 ml) and stirred for 45 min, filtered the obtained solid and dried to get the title compound.
Yield: 35 gr.
Example-10: Preparation of compound of formula-1
A round bottom flask was charged with compound of formula-7a (50 gr), toluene (150 ml), compound of formula-8a (66 gr), sodium bicarbonate (33 gr) and water (100 ml) stirred for 1 hr under nitrogen atmosphere. Bis(triphenylphosphine)palladiumdi chloride (0.3 gr) was added to the above reaction mixture at 25-35°C, stirred for 12 hr at 80-90°C. The reaction mixture was cooled to 25-35°C quenched with water (250 ml), further cooled to 0-l0°C and stirred for 4 hr. The obtained compound was filtered and washed with water (100 ml) to get the wet compound of formula-9a. The obtained compound was charged in RBF with dil. hydrochloric acid (750 ml), washed with dichloromethane (3x150 ml) and separated both layers. The aqueous layer was taken, heated to 90-l00°C stirred for 6 hr. The reaction mixture was cooled to 25-35°C, washed with dichloromethane (5x150 ml) and separated the both layers. The aqueous layer was diluted with ethanol (375 ml) and the solution p was adjusted to 11.3 with sodium hydroxide solution (300 gr in 600 ml), stirred for 6 hr at 25-35°C. The reaction mass pH was adjusted to 5.2 with dil.HCl and stirred for 45 min. The obtained solid was filtered and washed with water (100 ml). The obtained wet compound was again slurred in water (750 ml) and stirred for 45 min, filtered the obtained solid and dried to get the title compound.
Yield: 37 gr.
Example-11: Preparation of compound of formula-1
A round bottom flask was charged with compound of formula-7a (50 gr), toluene (150 ml), compound of formula-8a (66 gr), sodium bicarbonate (33 gr) and water (100 ml) stirred for 1
hr under nitrogen atmosphere. Bis(triphenylphosphine)palladium dichloride (0.3 gr) was added to the above reaction mixture at 25-35°C, stirred for 12 hr at 80-90°C. The reaction mixture was cooled to 25-35°C charged with water (250 ml), further cooled to 0-10°C and stirred for 4 hr. The obtained compound was filtered and washed with water (100 ml) to get the wet compound. The obtained compound was charged in RBF with water (550 ml), methanesufonicacid (116.3 gr) and washed with dichloromethane (3x150 ml), separated the both layers. The aqueous layer was heated to 90-100°C stirred for 6 hr. The reaction mixture was cooled to 25-35°C, washed with dichloromethane (5x150 ml) and separated the both layers. The aqueous layer was diluted with ethanol (375 ml) and the solution p was adjusted to 11.8 with sodium hydroxide solution (300 gr in 600 ml), stirred for 6 hr at 25-35°C. The reaction mass pH was adjusted to 5.3 with dil. hydrochloric acid and stirred for 45 min. The obtained solid was filtered and washed with water (100 ml). The obtained compound was charged with water (750 ml) and stirred for 45 min, filtered the obtained solid and dried to get the title compound.
Yield: 55 gr.
Example-12: Preparation of crystalline form-M of compound of formula-1
A round bottom flask was charged with compound of formula- 1 (50 gr), tetrahydrofuran (250 ml), and solution of KOH in ethanol (7.7 gr in 250 ml) and stirred for 2 hr at 25-35°C. Filtered the obtained compound and washed with ethanol (50 ml). The obtained potassium salt of compound of formula was charged in RBF with ethanol (375 ml), heated to 40-50°C and stirred for 30 min. The reaction mixture was cooled to 25-35°C stirred for 2 hr and filtered the obtained solid, washed with ethanol (50 ml). The same purification process was repeated twice in ethanol and filtered. The obtained compound was charged in RBF with water (900 ml) adjusted the pH to 11.6 with potassium hydroxide solution (10 ml) and stirred for 2 hr. The reaction mass was filtered through hyflow bed to remove solid particles and washed with water (900 ml). The filtrate layer pH was adjusted to 5.2 with hydrochloric acid (15 ml) stirred for 1 hr. Filtered the obtained compound and washed with water (100 ml) to get wet compound. The obtained wet compound was charged in RBF with water (1 lit), heated to 70- 80°C and stirred for 1 hr. The reaction mixture was cooled to 50-60°C stirred for 45 min and filtered the obtained compound and washed with water (100 ml). The same purification process was repeated with water and dried the obtained compound to get the tilted compound.
Yield: 32 gr. The PXRD of the obtained compound is depicted in figure-2
Purity by HPLC: 99.78%
PSD: D(90) =14 microns; D(50) = 6 microns; D(l0)= 2 microns;
Example-13: Purification of compound of formula-1
A round bottom flask was charged with compound of formula- 1 (10 gr), dimethyl formamide (100 ml) and stirred for 4 hr at H0-l20°C. The reaction mixture was cooled to 25-35°C and stirred for 30 min. The precipitated solid was filtered and washed with DMF (25 ml) to get the title compound- 1.
Yield: 6.0 gm.
Example-14: Purification of compound of formula-1
A round bottom flask was charged with compound of formula- 1 (10 gr), N-methylpyrrolidone (100 ml) and stirred for 4 hr at 70-80°C. The reaction mixture was cooled to 25-35°C stirred for 30 min. The precipitated solid was filtered and washed with NMP (50 ml) to get the title compound.
Yield: 5.4 gm.
Example-15: Purification of compound of formula-1
A round bottom flask was charged with compound of formula- 1 (10 gr), DMSO (100 ml) and stirred for 4 hr at 70-80°C. The reaction mixture was cooled to 25-35°C stirred for 30 min. The precipitated solid was filtered and washed with DMSO (50 ml) to get the title compound. Yield: 6. 4 gm.
Example-16: Preparation of crystalline form-M of compound of formula-1
A round bottom flask was charged with the compound of formula- 1 (12 gm), water (12 ml) and isopropanol (60 ml). The obtained suspension was stirred at 40-45°C for 30 min. methanesulphonicacid (6.5 gm) was added to the above suspension and stirred at same temperature for 30 min. The obtained solution was filtered through hyflow bed and washed with isopropanol (12 ml). The obtained solution was cooled to 25-30°C and stirred for 2 hrs, filtered the resulting solid. The obtained solid was charged in water (12 ml) and pH of the solution was adjusted to 5.7 with 10 % sodium hydroxide solution (6 ml) and stirred for 30 min. The obtained solid was filtered and washed with water (25 ml) dried to get the title compound. The PXRD of the obtained compound is depicted in figure- 1.
Yield: 5.5 gm;
Example-17: Preparation of crystalline form-M of compound of formula-1
A round bottom flask was charged with the compound of formula- 1 (12 gm), water (10 gm) and isopropanol (50 ml). The obtained suspension was stirred at 40-45°C for 30 min. Hydrobromic acid (6.5 ml) was added to the above solution and stirred at same temperature for 30 min. The obtained solution was filtered through hyflow bed and washed with isopropanol (12 ml). The obtained filtrate was cooled to 25-30°C and stirred for 2 hrs, filtered the resulting solid. The obtained solid was charged in water (12 ml) and p of the solution was adjusted to 5.6 with 10 % sodium hydroxide solution (6 ml) and stirred for 30 min. The obtained solid was filtered and washed with water (20 ml) dried to get the title compound. Yield: 6.2 gm;
Example-18: Preparation of crystalline form-M of compound of formula-1.
A round bottom flask was charged with compound of formula-l (25 gr), tetrahydrofuran (125 ml), and solution of KOH in ethanol (4.2 gr in 125 ml) and stirred for 2 hr at 25-35°C. Filtered the obtained compound and washed with ethanol (25 ml). The obtained potassium salt compound was charged in RBF with ethanol (190 ml), heated to 40-50°C and stirred for 30 min. The reaction mixture was cooled to 25-35°C stirred for 2 hr and filtered the obtained solid, washed with ethanol (25 ml). The same purification process was repeated twice in ethanol and filtered. The obtained compound was charged in RBF with water (450 ml) adjusted the pH to 11.4 with potassium hydroxide solution (5 ml) and stirred for 2 hr. The reaction mass was filtered through hyflow bed to remove solid particles and washed with water (450 ml). The filtrate layer pH was adjusted to 5.3 with hydrochloric acid (8 ml) stirred for 1 hr. Filtered the obtained compound and washed with water (50 ml) to get wet compound. The obtained compound was suspended in DMF (250 ml) stirred for 4-5 hr. The reaction mixture was cooled to 25-35°C stirred for 30 min. The obtained solid was filtered and washed with DMF to get the title compound.
Yield: 17.5 gr; The PXRD is matching with figure-2.
Claims
1. Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino) pyridin-3-yl)-4-oxo-l,4-dihydro quinoline -3-carboxylic acid of formula- 1.
is characterized by its powder X-Ray diffraction pattern having peaks at about 7.28, 13.97, 15.52 ± 0.2° 2Q.
2. The crystalline Form-M of compound of formula- 1 according to claim 1, the powder X-Ray diffraction pattern having peaks at about 9.33, 11.27, 16.8, 19.19, 22.59, 23.84, 24.94, 26 and 28.29 ± 0.2° 2Q.
3. The crystalline Form-M of compound of formula- 1 according to claim 1 further characterized by its PXRD pattern as depicted in figure- 1, 3.
4. The crystalline Form-M of compound of formula- 1 according to claim 1 further characterized by its IR as depicted in figure-3.
5. The crystalline Form-M of compound of formula- 1 according to claim 1 further characterized by its DSC thermogram as depicted in figure-4.
6. A process for the preparation of the Crystalline Form-M of l-cyclo propyl -8- methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro
quinoline-3-carboxylic acid of formula- 1, comprising of:
a) Stirring the compound of formula- 1 in a suitable solvent,
b) adding a suitable acid to the solution obtained in step-a) and stirring at suitable temperature,
c) adjusting the p of the solution obtained in step-b) with a suitable base, isolating the compound,
d) filtering the obtained solid in step-c) provides the crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l,4-dih ydroquinoline-3-carboxylic acid compound of formula- 1.
7. Process for the preparation of the crystalline Form-M according to claim 6 wherein in step-a) the suitable solvent is selected from polar protic, polar aprotic, alcohol, ether, ketone, water and mixture thereof. Step-b) suitable acid is selected form organic acid, inorganic acid; suitable temperature is 0°C to l00°C, preferably 20-85°C; in step c) the suitable base is organic base, inorganic base; in Step-c) suitable p range is
between 5.0 to 7.0;
8. A process for the preparation of the crystalline Form-M of 1 -cyclopropyl -8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3- carboxylic acid of formula- 1, comprising of:
a) stirring the compound of formula- 1 in isopropanol and water,
b) adding methane sulphonic acid to the solution obtained in step-a) stirring at 40-45°C, isolating the compound,
c) adjusting the p of the solution obtained in step-b) with aq. sodium hydroxide solution,
d) filtering the obtained solid in step-c) provides the crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l,4- dihydroquinoline-3-carboxylic acid compound of formula- 1.
9. A process for the preparation of the crystalline Form-M of l-cyclopropyl -8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l, 4-dihydro
quinoline-3-carboxylic acid of formula- 1, comprising of:
a) suspending the compound of formula- 1 in an organic solvent,
b) stirring the compound obtained in step-a) in base solution at suitable temperature,
c) isolating the compound obtained in step-b) purifying in a suitable solvent, d) suspending the compound obtained in step-c) in a suitable solvent, e) adjusting the p of the solution obtained in step-d) with a suitable base and acid at a suitable temperature isolating the compound,
f) optionally purifying the compound obtained in step-e) in suitable solvent to provide the crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methyl amino)pyridin-3-yl)-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula- 1.
10. Process for preparation of the crystalline Form-M according to claim 9 wherein the suitable solvent is selected from polar protic, polar aprotic, alcohol, ether, ketone, ester, nitrile, water and mixture thereof; step-b) suitable base is alcoholic base; preferably: potassium hydroxide in ethanol; suitable temperature is 0°C to l00°C, preferably 20-85°C; step-e) suitable base is selected from inorganic base; suitable acid is selected hydrochloric acid; p range is 11-12 and 4-6;
11. A preparation of the crystalline Form-M of l-cyclopropyl -8-methyl-7- (5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo- 1,4- dihydro quinoline-3-carboxylic
acid of formula- 1, comprising of:
a) suspending the compound of formula- 1 in tetrahydrofuran,
b) stirring the compound obtained in step-a) in ethanolic KOH, stirring at 25-35°C,
c) isolating the compound obtained in step-b) and purified in ethanol, d) suspending the compound obtained in step-c) in water,
e) adjusting the p of the solution obtained in step-d) with potassium hydroxide, hydrochloric acid at suitable temperature and isolating the compound, f) purifying the compound obtained in step-e) in water to provides the crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methyl amino) pyridin -3-yl)-4-oxo-l,4-di hydro quinoline-3-carboxylic acid compound of formula- 1.
12. A preparation of the crystalline Form-M of l-cyclopropyl-8-methyl-7 -(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l,4-dihydroquinoline-3-carboxylic acid of formula- 1, comprising of:
a) Suspending compound of formula- 1 in a suitable solvent, suitable temperature,
b) stirring the solution obtained in step-b) at a suitable temperature,
c) filtering the compound obtained in step-a) isolating the Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl)-4-oxo-l,4- dihydroquinoline-3-carboxylic acid of formula- 1.
13. Process for preparation of crystalline Form-M according to 12 wherein the suitable solvent is selected from polar protic, polar aprotic, alcohol, ether, ketone, ester, water and mixture thereof; suitable temperature 25-l20°C.
14. A process for the preparation of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methyl amino)pyridin-3-yl)-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula- 1.
Formula- 1
comprising of ;
a) reacting the compound of formula-7
Formula-7
with compound of formula-8
Formula- 8
in presence of palladium catalyst, base in suitable solvent to produce compound of formula-9
Formula-9
b) reacting the compound obtained in step-a) using suitable reagent to get the compound of formula- 1,
c) suspending the compound of formula- 1 in an organic solvent,
d) stirring the compound obtained in step-c) in base solution at suitable temperature,
e) isolating the compound obtained in step-d) purifying in a suitable solvent, f) suspending the compound obtained in step-e) in a suitable solvent,
g) adjusting the p of the solution obtained in step-f) with a suitable base, acid at a suitable temperature and isolating the compound of formula- 1
h) optionally purifying the compound obtained in step-g or b) in suitable solvent to provide the crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6 -(methyl amino)pyridin-3-yl)-4-oxo-l, 4-dihydro quinoline-3-carboxylic acid compound of formula- 1.
15. Process for preparation of compound of formula- 1 according to claim 14 wherein
the suitable solvent is selected form toluene, benzene, polar aprotic solvent, polar protic, ether, nitrile, ester, water, alcohol and mixture thereof; palladium catalyst; base is selected from inorganic base, organic base; step-b) suitable reagent is organic acid, inorganic acid; preferably Con.HCl, methane sulphonic acid; step-d) suitable base is alcoholic base; preferably: potassium hydroxide in ethanol; suitable temperature is 0°C to l00°C, preferably 20-85°C; step-g) suitable base is selected from inorganic base; suitable acid is selected hydrochloric acid; p range is 11-12 and 4-6;
16. A process for the preparation of l-cyclopropyl-8-methyl-7-(5-methyl -6-(methyl amino) pyridin-3-yl)-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula- 1, comprising of;
a) reacting the compound of formula-7a
Formula-7a
with compound of formula-8a
Formula-8a
in presence of bis(tricyclohexylphosphine palladiumdichloride), sodium bicarbonate in toluene, water to produce compound of formula-9a
Formula-9a
b) reacting the compound obtained in step-a) with hydrochloric acid, to get the compound of formula- 1,
c) suspending the compound obtained in step-b) in tetrahydrofuran,
d) stirring the compound obtained in step-c) in ethanolic KOH, stirring at 25-35°C,
e) isolating the compound obtained in step-d) and purifying in ethanol, f) suspending the compound obtained in step-e) in water,
g) adjusting the p of the solution obtained in step-f) with potassium hydroxide, hydrochloric acid at suitable temperature and isolated,
h) purifying the compound obtained in step-g) in water to provides the crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino) pyridin-3-yl)-4-oxo-l,4-dihydroquinoline-3-carboxylic acid compound of formula- 1.
17. The l-cyclopropyl-8-methyl-7-(5-methyl-6-(methylamino)pyridin-3-yl) -4-oxo-l,4 -dihydro quinoline-3-carboxylic acid compound of formula- 1 obtained according to any of preceding claims having purity > 95%, preferably > 99% by HPLC; more preferably > 99.5 %.
18. Crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6- (methylamino)pyridin-3-yl)-4-oxo-l,4-di hydroquinoline-3-carboxylic acid of formula- 1 obtained according to any preceding claims having particle size of D(0.9) < 14 microns, D(50)<6 microns, D(l0)<2 microns.
19. Use of crystalline Form-M of l-cyclopropyl-8-methyl-7-(5-methyl-6-(methyl amino)pyridin-3-yl)-4-oxo-l,4-di hydroquinoline-3-carboxylic acid compound of formula- 1 obtained according to any of preceding claims in the preparation of pharmaceutical composition.
20. A pharmaceutical composition comprising l-cyclopropyl -8-methyl-7-(5-methyl -6-(methylamino)pyridin-3-yl)-4-oxo-l,4-dihydroquinoline-3-carboxylicacid of formula- 1 obtained according to any of preceding claims and a pharmaceutically acceptable carrier.
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| IN201841036343 | 2018-09-26 | ||
| IN201841036343 | 2018-09-26 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6335447B1 (en) * | 1998-04-06 | 2002-01-01 | Toyama Chemical Co., Ltd. | Quinolonecarboxylic acid derivatives or salts thereof |
| US8507684B2 (en) * | 2010-04-06 | 2013-08-13 | Ferrer Internacional S.A. | 1-cyclopropyl-8-methyl-7-[5-methyl-6-(methylamino)-3-pyridinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid salts |
-
2019
- 2019-09-24 WO PCT/IN2019/050697 patent/WO2020065668A1/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6335447B1 (en) * | 1998-04-06 | 2002-01-01 | Toyama Chemical Co., Ltd. | Quinolonecarboxylic acid derivatives or salts thereof |
| US8507684B2 (en) * | 2010-04-06 | 2013-08-13 | Ferrer Internacional S.A. | 1-cyclopropyl-8-methyl-7-[5-methyl-6-(methylamino)-3-pyridinyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid salts |
Non-Patent Citations (1)
| Title |
|---|
| CAIRA M R: "CRYSTALLINE POLYMORPHISM OF ORGANIC COMPOUNDS", TOPICS IN CURRENT CHEMISTRY, vol. 198, 1 January 1998 (1998-01-01), BERLIN, DE, pages 163 - 208, XP001156954 * |
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