Process for the preparation of 4-[-(amino)-3-fluorophenoxy]-n-methylpyridine-2-carboxamide and its polymorphs thereof
AssigneeMsn Laboratories Private Limited
InventorsSrinivasan THIRUMALAI RAJAN, Sajja ESWARAIAH, Gutta MADHUSUDHAN
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Abstract
The present invention relates to a process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluophenoxy]-N-methylpyridine-2-carboxamide compound of formula-I, its amorphous form and its crystalline polymorph-I which is represented by the following structural formula: (I)
Claims26
A process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1 substantially free of genotoxic impurity such as 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4, comprising of:
- a) Reacting 4-chloro-N-methylpicolinamide compound of formula-2
- with 4-amino-3-fluorophenol compound of formula-3
- in presence of a suitable base in a suitable solvent in presence or absence of a suitable catalyst provides 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4,
- b) adding first lot of compound of formula-4 to the first lot of 1-chloro-4-cyanato-2-(trifluoro methyl) benzene compound of formula-5
- in dichloromethane,
- c) stirring the reaction mixture at a suitable temperature,
- d) adding second lot of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4 to the reaction mixture,
- e) stirring the reaction mixture at a suitable temperature and filtering the precipitated solid,
- f) dissolving the compound obtained in step-(e) in dimethylsulfoxide,
- g) adding second lot of 1-chloro-4-cyanato-2-(trifluoromethyl)benzene compound of formula-5 to the reaction mixture and stirring the reaction mixture at a suitable temperature,
- h) adding methanol to the reaction mixture,
- i) cooling and stirring the reaction mixture,
- j) filtering the precipitated solid and drying to get DMSO solvate of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-1,
- k) dissolving DMSO solvate obtained in step-(j) in dimethylsulfoxide,
- l) adding methanol to the reaction mixture and filtering the reaction mixture,
- m) stirring the reaction mixture at −15 to −25° C.,
- n) filtering the precipitated solid and drying the compound to get compound of formula-1,
- o) optionally, slurrying the solid obtained in step-(n) with methanol to provide compound of formula-1 substantially free of genotoxic impurity such as 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4.
A process for the preparation of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methyl pyridine-2-carboxamide compound of formula-1 substantially free of genotoxic impurity such as 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4, comprising of:
- a) Reacting 4-chloro-N-methylpicolinamide compound of formula-2 with 4-amino-3-fluorophenol compound of formula-3 in presence of a suitable base in a suitable solvent in presence or absence of a suitable catalyst provides 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4,
- b) adding first lot of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4 to first lot of 1-chloro-4-cyanato-2-(trifluoromethyl)benzene compound of formula-5 in dichloromethane,
- c) stirring the reaction mixture at 0-5° C.,
- d) adding second lot of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4 to the reaction mixture,
- e) stirring the reaction mixture at 0-5° C. and filtering the precipitated solid,
- f) dissolving the compound obtained in step-(e) in dimethylsulfoxide,
- g) adding second lot of 1-chloro-4-cyanato-2-(trifluoromethyl)benzene compound of formula-5 to the reaction mixture and stirring the reaction mixture at 19° C.-23° C.,
- h) adding methanol to the reaction mixture,
- i) cooling and stirring the reaction mixture,
- j) filtering the precipitated solid and drying to get DMSO solvate of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-1,
- k) dissolving DMSO solvate obtained in step-(j) in dimethylsulfoxide,
- l) adding methanol to the reaction mixture and filtering the reaction mixture,
- m) stirring the reaction mixture at −15 to −25° C.,
- n) filtering the solid and drying the compound to get compound of formula-1,
- o) slurrying the solid obtained in step-(n) with methanol provides compound of formula-1 substantially free of genotoxic impurity such as 4-(4-amino-3-fluoro phenoxy)-N-methylpicolinamide compound of formula-4.
DMSO solvate of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methyl pyridine-2-carboxamide compound of formula-1.
Crystalline form-M of DMSO solvate of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methyl pyridine-2-carboxamide compound of formula-1 is characterized by:
- a) its powder X-ray diffraction pattern having peaks at 7.3, 9.2, 11.0, 13.5, 14.6, 14.9, 16.5, 17.0, 17.3, 18.1, 19.0, 19.5, 19.9, 21.6, 23.8, 24.6, 24.9, 25.1, 26.1 and 27.5±0.2 degrees of 2-theta;
- and
- b) its powder X-ray diffraction pattern as illustrated in FIG. 1.
A process for the preparation of DMSO solvate of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1, comprising of:
- a) Adding first lot of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4 with 1-chloro-4-cyanato-2-(trifluoromethyl)benzene compound of formula-5 in a suitable solvent,
- b) stirring the reaction mixture at a suitable temperature,
- c) adding another lot of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4 to the reaction mixture,
- d) stirring the reaction mixture at a suitable temperature,
- e) filtering the solid obtained in step-(d),
- f) dissolving the compound obtained in step-(e) in dimethylsulfoxide,
- g) adding a suitable solvent to the reaction mixture,
- h) cooling and stirring the reaction mixture,
- i) filtering the solid and drying to get DMSO solvate of compound of formula-1.
The process for the preparation of DMSO solvate of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1, comprising of:
- a) Adding first lot of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4 with 1-chloro-4-cyanato-2-(trifluoromethyl)benzene compound of formula-5 in dichloromethane,
- b) stirring the reaction mixture at 0-5° C.,
- c) adding another lot of 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4 to the reaction mixture,
- d) stirring the reaction mixture at 0-5° C.,
- e) filtering the solid obtained in step-(d),
- f) dissolving the compound obtained in step-(e) in dimethylsulfoxide,
- g) adding methanol to the reaction mixture,
- h) cooling and stirring the reaction mixture,
- i) filtering the solid and drying to get DMSO solvate of compound of formula-1.
A process for the preparation of crystalline polymorph-I of 4-[4-({[4-chloro-3-(trifluoro methyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1, comprising of:
- a) Dissolving DMSO solvate of compound of formula-1 in a suitable solvent,
- b) adding anti-solvent to the reaction mixture,
- c) cooling and stirring the reaction mixture at a suitable temperature,
- d) filtering the solid and drying the compound to get crystalline polymorph-I of compound of formula-1,
- e) optionally, slurrying the solid obtained in step-(d) with a suitable solvent to provide crystalline polymorph-I of compound of formula-1.
A process for the preparation of crystalline polymorph-I of 4-[4-({[4-chloro-3-(trifluoro methyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1, comprising of:
- a) Dissolving DMSO solvate of compound of formula-1 in dimethylsulfoxide,
- b) adding methanol to the reaction mixture,
- c) cooling and stirring the reaction mixture at −15 to −25° C.,
- d) filtering the solid and drying the compound to get crystalline polymorph-I of compound of formula-1,
- e) optionally, slurrying the solid obtained in step-(d) with methanol to provide crystalline polymorph-I of compound of formula-1.
The process according to any of the preceding claims, the 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1 substantially free of impurities such as 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4 (amine impurity), chloro impurity compound of formula-2, 4-amino-3-fluorophenol impurity compound of formula-3, trifluoro impurity, methyl ester impurity and dimer impurity.
An amorphous 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide, characterized by
- a) its powder X-ray diffraction pattern as illustrated in FIG. 2.
A process for the preparation of amorphous 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide, comprising of:
- a) Dissolving 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide in a suitable solvent,
- b) stirring the reaction mixture,
- c) filtering the reaction mixture,
- d) distilling off the solvent from the filtrate obtained in step-(c) to get amorphous 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide.
A process for the preparation of amorphous 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide premix, comprising of:
- a) Dissolving 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide in a suitable solvent,
- b) stirring the reaction mixture,
- c) filtering the reaction mixture,
- d) adding a suitable premixing agent to the filtrate obtained in step-(c),
- e) distilling off the solvent from the filtrate obtained in step-(d) to get amorphous 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide.
A process for the preparation of amorphous 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide, comprising the following steps of:
- a) Dissolving 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide in tetrahydrofuran,
- b) stirring the reaction mixture,
- c) filtering the reaction mixture and washing with tetrahydrofuran,
- d) distilling off the solvent from the filtrate obtained in step-(c) to get amorphous 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide.
A process for the preparation of amorphous 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide, comprising the following steps of:
- a) Dissolving 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluoro phenoxy]-N-methylpyridine-2-carboxamide in a mixture of tetrahydrofuran and methanol,
- b) stirring the reaction mixture,
- c) filtering the reaction mixture,
- d) distilling off the solvent from the filtrate obtained in step-(c) to get amorphous 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide.
A process for the preparation of amorphous 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide premix, comprising the following steps of:
- a) Dissolving 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide in methyl ethyl ketone,
- b) stirring the reaction mixture,
- c) filtering the reaction mixture,
- d) adding micro crystalline cellulose (MCC) to the filtrate obtained in step-(c),
- e) distilling off the solvent from the filtrate obtained in step-(d) to get amorphous 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide premix.
Amorphous 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide.
Use of crystalline Form-M of DMSO solvate of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1 in the preparation of crystalline polymorph-I of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1.
Use of amorphous and crystalline polymorph-I of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1 obtained according to the preceding claims in the pharmaceutical composition as a medicament.
Particle size distribution of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1 having D(0.9)≦100 μm and D(4,3)≦100 μm.
Particle size distribution of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1 having D(0.9)≦50 and D(4,3)≦50 μm.
The process according to any of the preceding claims, the 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1 having <10 ppm of 4-(4-amino-3-fluorophenoxy)-N-methyl picolinamide compound of formula-4 (amine impurity) and substantially free of 4-amino-3-fluorophenol impurity compound of formula-3, trifluoro impurity, methyl ester impurity and dimer impurity.
The process according to any of the preceding claims, the 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1 having <10 ppm of chloro impurity compound of formula-2.
4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1 obtained according to any of the preceding claims having 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4≦20 ppm.
4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1 obtained according to any of the preceding claims having 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide compound of formula-4≦10 ppm.
4-[4-({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide compound of formula-1 obtained according to any of the preceding claims having purity greater than 99.5% by HPLC, preferably greater than 99.8% by HPLC.
Dependencies are inferred from the claim text.