WO2015029063A2 - Novel polymorph of (z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethyl phenyl)-amide and process for the preparation thereof - Google Patents
Novel polymorph of (z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethyl phenyl)-amide and process for the preparation thereof Download PDFInfo
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- WO2015029063A2 WO2015029063A2 PCT/IN2014/000547 IN2014000547W WO2015029063A2 WO 2015029063 A2 WO2015029063 A2 WO 2015029063A2 IN 2014000547 W IN2014000547 W IN 2014000547W WO 2015029063 A2 WO2015029063 A2 WO 2015029063A2
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/23—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same unsaturated acyclic carbon skeleton
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- the present invention provides a novel crystalline form of (Z)-2-cyano-3-hydroxy- but-2-enoic acid-(4-trifluoromethylphenyl)-amide represented by the following structural formula- 1 and process for its preparation.
- Teriflunomide is (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4- trifluoromethylphenyl)-amide, which is used as Immunosupressant. It acts as tyrosine kinase inhibitor. It is used in the treatment of rheumatoid arthritis, autoimmune disease and multiple sclerosis.
- Teriflunomide was first disclosed in US5679709. US5494911, US5990141 discloses various processes for preparing Teriflunomide. These patents do not disclose any polymorphic forms of teriflunomide or its process. 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, thermogravimetric analysis ('TGA'), and differential scanning calorimetry ('DSC) which have been used to distinguish polymorphic forms.
- 'TGA' thermogravimetric analysis
- 'DSC differential scanning calorimetry
- 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 most 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 tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's 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 solubility.
- Pharmaceutical compounds having different crystalline forms or polymorphs have different dissolution property. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
- the present inventors have developed a novel polymorph of Teriflunomide and process for the preparation of said polymorph.
- the first aspect of the present invention is to provide novel crystalline form-M of (Z)-
- the second aspect of the present invention is to provide a process for the preparation of crystalline form-M of (Z)-2-cyano-3-hydroxy-but-2-enoicacid-(4-trifluoromethylphenyl)- amide.
- the third aspect of the present invention is to provide a process for the preparation of (Z)-2-cyano-3 -hydroxy-but-2-enoicacid j -(4-trifluoromethylphenyl)-amide compound of formula- 1, comprising of the following steps:
- Figure 1 Illustrates the PXRD pattern of crystalline form-M of (Z)-2-cyano-3-hydroxy-but- 2-enoic acid-(4-trifluoromethylphenyl)-amide.
- Figure 2 Illustrates the DSC thermogram of crystalline form-M of (Z)-2-cyano-3-hydroxy- but-2-enoic acid-(4-trifluoromethylphenyl)-amide.
- Figure 3 Illustrates the PXRD pattern of crystalline form of (Z)-2-cyano-3-hydroxy-but-2- enoic acid-(4-trifluoromethylphenyl)-amide obtained according to reference example- 1.
- Figure 4 Illustrates the DSC thermogram of crystalline form of (Z)-2-cyano-3-hydroxy-but- 2-enoic acid-(4-trifluoromethylphenyl)-amide obtained according ⁇ *) reference example- 1.
- Figure 5 Illustrates the PXRD pattern of micronized crystalline form of (Z)-2-cyano-3- hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide.
- suitable solvent refers to "hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; "ether solvents” such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane 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, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents” such as dichloromethane, dichloro
- chlorinating agent is selected from pivaloyl chloride, thionyl chloride, sulfuryl chloride, phosphorus oxychloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and the like.
- suitable base refers to inorganic bases selected from “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate lithium bicarbonate, cesium 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; ammonia; and organic bases like methylamine, eth
- the first aspect of the present invention provides novel crystalline form-M of (Z)-2- cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide, which is characterized by:
- the second aspect of the present invention provides a process for the preparation of crystalline form-M of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)- amide compound of formula- 1, comprising of:
- the suitable solvent is selected from ester solvents, ether solvents, polar aprotic solvents, ketone solvents, chloro solvents or mixtures thereof,
- the suitable anti-solvent is selected from alcohol solvents or polar solvents such as water.
- the suitable temperature used is ranging from 25°C-30°C to the reflux temperature of the solvent used.
- the preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4- trifluoromethylphenyl)-amide compound of formula- 1, comprising of;
- the present inventors have produced the compound by in-toto repetition of the process disclosed in US5494911 and characterized the PXRD pattern of the obtained (Z)-2- cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide compound of formula- 1.
- the obtained PXRD pattern is shown in figure-3.
- the third aspect of the present invention provides a process for the preparation of (Z)- 2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide compound of formula- 1 , comprising of the following steps:
- the suitable chlorinating agent is selected from pivaloyl chloride, thionyl chloride, sulfuryl chloride, phosphorus oxychloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride;
- the suitable solvent is selected from chloro solvents, alcohol solvents, ester solvents, nitrile solvents, polar aprotic solvents, hydrocarbon solvents, ether solvents, ketone solvents, polar solvents such as water or mixtures thereof;
- the suitable base is selected from organic or inorganic base, preferably inorganic base and suitable acid is aqueous hydrochloric acid.
- the crystalline form-M of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoro methylphenyl)-amide compound of formula- 1 obtained from the process of the present invention is stable at room temperature.
- Apparatus A liquid chromatographic system equipped with variable wavelength UV- detector; Column: Cosmicsil APT CI 8, 100 x 4.6 mm, 3 ⁇ (or) equivalent; Flow rate: 1.5 ml/min; Wavelength: 210 nm; Column Temperature: 25°C; Injection volume: 20 ⁇ ; Run time: 40 min; Diluent: Mobile phase; Needle wash: Tetrahydrofuran; Elution: Isocratic; Mobile phase: 5 ml of triethyl amine into a 650 ml of water. Adjusted the pH to 3.4 with dil. Orthophosphoric acid and filter this solution through 0.22 ⁇ nylon membrane filter paper and sonicate to degas it. (Z)-2-cyano-3-hydroxy-but-2-enoicacid-(4-trifluoromethyl phenyl)-amide compound of formula- 1:
- Apparatus A liquid chromatographic system equipped with variable wavelength UV- detector; Column: Kromasil 100 C18, 250 x 4.6 mm, 5 ⁇ (or) equivalent; Flow rate: 1.0 ml/min; Wavelength: 250 nm; Column Temperature: 35°C; Injection volume: 5 ⁇ ; Run time: 37 min; Diluent: 0.01 M dipotassium hydrogen orthophosphate in 1000 ml of water; Elution: Gradient; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile : Buffer (70:30 v/v); Buffer: 1 ml of ortho phosphoric acid into a 1000 ml of water and 3.0 grams of 1 -octane sulfonic acid sodium salt anhydrous. Adjust pH to 6.0 with potassium hydroxide solution and filtered through 0.22 ⁇ Nylon membrane filter paper and sonicate to degas it.
- DSC Differential scanning calorimetric
- the (Z)-2-cyano-3 -hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
- 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.
- Acetonitrile (50 ml) was added to the obtained compound at 25-30°C and slowly added to a mixture of acetonitrile (300 ml) and 4-(trifluoromethyl)aniline (64.45 gms) at 25-30°C and stirred the reaction mixture for 5 hours at the same temperature. Filtered the reaction mixture and distilled off the solvent completely from the filtrate. Methanol (225 ml), followed by activated carbon (2.5 gms) were added to the obtained compound at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with methanol. Water (250 ml) was slowly added to the obtained filtrate at 25-30°C and stirred the reaction mixture for 2 hours. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 39.8 gms; Melting point: 165-168°C. Purity by HPLC: 99.63%.
Abstract
The present invention relates to novel crystalline form of (z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide represented by the following structural formula-1 and process for its preparation
Description
Novel polymorph of (Z)-2-cvano-3-hvdroxy-but-2-enoic acid-(4-trifluoromethyl phenyl)- amide and process for the preparation thereof
Related Application:
This application claims the benefit of priority of our Indian patent application number 3883/CHE/2013 filed on 30th Aug. 2013 which is incorporated herein by reference.
Field of the Invention:
The present invention provides a novel crystalline form of (Z)-2-cyano-3-hydroxy- but-2-enoic acid-(4-trifluoromethylphenyl)-amide represented by the following structural formula- 1 and process for its preparation.
Formula- 1
Background of the Invention:
The chemical name of Teriflunomide is (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4- trifluoromethylphenyl)-amide, which is used as Immunosupressant. It acts as tyrosine kinase inhibitor. It is used in the treatment of rheumatoid arthritis, autoimmune disease and multiple sclerosis.
Teriflunomide was first disclosed in US5679709. US5494911, US5990141 discloses various processes for preparing Teriflunomide. These patents do not disclose any polymorphic forms of teriflunomide or its process. 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, thermogravimetric analysis ('TGA'), and differential scanning calorimetry ('DSC) which have been used to distinguish polymorphic forms.
The difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk
solid. Accordingly, 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 most 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 tract is slow, it is often desirable for a drug that is unstable to conditions in the patient's 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 solubility. Pharmaceutical compounds having different crystalline forms or polymorphs have different dissolution property. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
The discovery of new crystalline or polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic.
Hence, there is a significant need in the art to develop novel polymorphs of Teriflunomide which are stable and also improves the performance characteristics of a pharmaceutical product.
The present inventors have developed a novel polymorph of Teriflunomide and process for the preparation of said polymorph.
Brief description of the invention: The first aspect of the present invention is to provide novel crystalline form-M of (Z)-
2-cyano-3 -hydroxy-but-2-enoicacid-(4-trifluoromethylphenyl)-amide.
The second aspect of the present invention is to provide a process for the preparation of crystalline form-M of (Z)-2-cyano-3-hydroxy-but-2-enoicacid-(4-trifluoromethylphenyl)- amide.
The third aspect of the present invention is to provide a process for the preparation of (Z)-2-cyano-3 -hydroxy-but-2-enoicacidj-(4-trifluoromethylphenyl)-amide compound of formula- 1, comprising of the following steps:
a) Reacting 5-methylisoxazole-4-carboxylic acid compound of formula-5 with a suitable chlorinating agent in a suitable solvent to provide 5-methylisoxazole-4-carbonyl chloride compound of formula-4,
b) reacting the compound of formula-4 in-situ with 4-(trifluoromethyl)aniline compound of formula-3 in a suitable solvent to provide N-(4'-trifluoromethylphenyl)-5- methylisoxazole-4-carboxamide compound of formula-2,
c) reacting the compound of formula-2 with a suitable base in a suitable solvent followed by treating it with a suitable acid to provide (Z)-2-cyano-3-hydroxy-but-2- enoic acid-(4-trifluoromethylphenyl)-amide compound of formula- 1,
d) optionally, purifying the compound of formula- 1 from a suitable solvent to provide pure (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide compound of formula- 1.
Brief description of Drawings:
Figure 1: Illustrates the PXRD pattern of crystalline form-M of (Z)-2-cyano-3-hydroxy-but- 2-enoic acid-(4-trifluoromethylphenyl)-amide.
Figure 2: Illustrates the DSC thermogram of crystalline form-M of (Z)-2-cyano-3-hydroxy- but-2-enoic acid-(4-trifluoromethylphenyl)-amide.
Figure 3: Illustrates the PXRD pattern of crystalline form of (Z)-2-cyano-3-hydroxy-but-2- enoic acid-(4-trifluoromethylphenyl)-amide obtained according to reference example- 1.
Figure 4: Illustrates the DSC thermogram of crystalline form of (Z)-2-cyano-3-hydroxy-but- 2-enoic acid-(4-trifluoromethylphenyl)-amide obtained according^*) reference example- 1.
Figure 5: Illustrates the PXRD pattern of micronized crystalline form of (Z)-2-cyano-3- hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide.
Detailed Description of Invention:
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane 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, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride 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 and the like; "polar solvents" such as water or mixtures thereof.
As used herein the term "chlorinating agent" is selected from pivaloyl chloride, thionyl chloride, sulfuryl chloride, phosphorus oxychloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and the like.
The term "suitable base" used in the present invention refers to inorganic bases selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate lithium bicarbonate, cesium 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; ammonia; and organic bases like methylamine, ethylamine, dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP) or mixtures thereof.
The first aspect of the present invention provides novel crystalline form-M of (Z)-2- cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide, which is characterized by:
a) Its powder X-ray diffractogram having peaks at 7.7, 8.3, 10.0, 12.6, 15.6, 15.9, 16.7,
19.3, 20.1, 23.1, 24.7, 25.2, 25.6, 26.8, 28.1, 30.7, 31.6, 32.1, 32.9, 34.6, 36.5, 38.7, 39.3, 40.7, 42.7, 45.4, 46.9 and 48.2 ± 0.2 degrees of two-theta as illustrated in figure- i;
b) its DSC thermogram showing an endotherm at 230.83°C and another endotherm at 245.07°C as illustrated in figure-2.
The second aspect of the present invention provides a process for the preparation of crystalline form-M of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)- amide compound of formula- 1, comprising of:
a) Suspending the compound of formula- 1 in a suitable solvent,
b) heating the reaction mixture to a suitable temperature,
c) filtering the reaction mixture,
d) adding a suitable anti-solvent to the filtrate obtained in step-(c),
e) cooling the reaction mixture to a suitable temperature,
f stirring the reaction mixture,
g) filtering the precipitated solid and drying to get the crystalline form-M of (Z)-2- cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide compound of formula- 1.
Wherein,
in step-a) the suitable solvent is selected from ester solvents, ether solvents, polar aprotic solvents, ketone solvents, chloro solvents or mixtures thereof,
in step-d) the suitable anti-solvent is selected from alcohol solvents or polar solvents such as water.
in step-b) the suitable temperature used is ranging from 25°C-30°C to the reflux temperature of the solvent used.
The preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4- trifluoromethylphenyl)-amide compound of formula- 1, comprising of;
a) Suspending the compound of formula- 1 in dimethyl formamide,
b) heating the reaction mixture to 55-60°C,
c) filtering the reaction mixture,
d) adding methanol to the filtrate obtained in step-(c),
e) cooling the reaction mixture to 10-15 °C,
f) stirring the reaction mixture,
g) filtering the precipitated solid and drying to get the crystalline form-M of (Z)-2- cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide compound of formula- 1.
Teriflunomide as a crystalline solid is first reported in US5494911. The said patent disclosed the crystals of teriflunomide having melting point 205°C to 206°C which is isolated/crystallized from methanol but does not disclose the PXRD pattern of the obtained compound. The present inventors have produced the compound by in-toto repetition of the process disclosed in US5494911 and characterized the PXRD pattern of the obtained (Z)-2- cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide compound of formula- 1. The obtained PXRD pattern is shown in figure-3.
The third aspect of the present invention provides a process for the preparation of (Z)- 2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide compound of formula- 1 , comprising of the following steps:
a) Reacting 5-methylisoxazole-4-carboxylic acid compound of formula-5 with a suitable chlorinating agent in a suitable solvent provides 5-methylisoxazole-4-carbonyl chloride compound of formula-4,
b) reacting the compound of formula-4 in-situ with 4-(trifluoromethyl)aniline compound of formula-3 in a suitable solvent provides N-(4'-trifluoromethylphenyl)-5- methylisoxazole-4-carboxamide compound of formula-2,
c) reacting the compound of formula-2 with a suitable base in a suitable solvent followed by treating it with a suitable acid provides (Z)-2-cyano-3-hydroxy-but-2- enoic acid-(4-trifluoromethyl phenyl)-amide compound of formula- 1 ,
d) optionally, purifying the compound of formula- 1 from a suitable solvent to provide pure (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethyl phenyl)-amide compound of formula- 1.
Wherein,
in step-a) the suitable chlorinating agent is selected from pivaloyl chloride, thionyl chloride, sulfuryl chloride, phosphorus oxychloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride;
in step-a), b), c) & d) the suitable solvent is selected from chloro solvents, alcohol solvents, ester solvents, nitrile solvents, polar aprotic solvents, hydrocarbon solvents, ether solvents, ketone solvents, polar solvents such as water or mixtures thereof; in step-c) the suitable base is selected from organic or inorganic base, preferably inorganic base and suitable acid is aqueous hydrochloric acid.
The preferred embodiment of the present invention provides a process for the preparation of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide compound of formula- 1 , which comprising of the following steps:
a) Reacting 5-methylisoxazole-4-carboxylic acid compound of formula-5 with thionyl chloride in a mixture of dimethyl formamide and dichloromethane provides 5- methylisoxazole-4-carbonyl chloride compound of formula-4,
b) reacting the compound of formula-4 in-situ with 4-(trifluoromethyl) aniline compound of formula-3 in acetonitrile provides N-(4'-trifluoromethylphenyl)-5- methylisoxazole-4-carboxamide compound of formula-2,
c) reacting the compound of formula-2 with sodium hydroxide in methanol followed by treating it with aqueous hydrochloric acid provides (Z)-2-cyano-3-hydroxy-but-2- enoic acid-(4-trifluoromethyl phenyl)-amide compound of formula- 1,
d) optionally, purifying the compound of formula- 1 from a mixture of methanol and dimethylformamide provides pure (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4- trifluoromethyl phenyl)-amide compound of formula- 1.
The crystalline form-M of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoro methylphenyl)-amide compound of formula- 1 obtained from the process of the present invention is stable at room temperature.
The said crystalline form-M of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoro methylphenyl)-amide compound of formula- 1 is useful in the preparation of pharmaceutical composition.
HPLC method of analysis:
N-(4'-trifluoromethylphenyI)-5-methylisoxazole-4-carboxamide of formula-2:
Apparatus: A liquid chromatographic system equipped with variable wavelength UV- detector; Column: Cosmicsil APT CI 8, 100 x 4.6 mm, 3 μιη (or) equivalent; Flow rate: 1.5 ml/min; Wavelength: 210 nm; Column Temperature: 25°C; Injection volume: 20 μί; Run time: 40 min; Diluent: Mobile phase; Needle wash: Tetrahydrofuran; Elution: Isocratic; Mobile phase: 5 ml of triethyl amine into a 650 ml of water. Adjusted the pH to 3.4 with dil. Orthophosphoric acid and filter this solution through 0.22 μπι nylon membrane filter paper and sonicate to degas it.
(Z)-2-cyano-3-hydroxy-but-2-enoicacid-(4-trifluoromethyl phenyl)-amide compound of formula- 1:
Apparatus: A liquid chromatographic system equipped with variable wavelength UV- detector; Column: Kromasil 100 C18, 250 x 4.6 mm, 5 μηι (or) equivalent; Flow rate: 1.0 ml/min; Wavelength: 250 nm; Column Temperature: 35°C; Injection volume: 5 μί; Run time: 37 min; Diluent: 0.01 M dipotassium hydrogen orthophosphate in 1000 ml of water; Elution: Gradient; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile : Buffer (70:30 v/v); Buffer: 1 ml of ortho phosphoric acid into a 1000 ml of water and 3.0 grams of 1 -octane sulfonic acid sodium salt anhydrous. Adjust pH to 6.0 with potassium hydroxide solution and filtered through 0.22μηι Nylon membrane filter paper and sonicate to degas it.
P-XRD method of Analysis
PXRD analysis of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethyl phenyl)-amide compound of formula- 1 produced by the present invention was carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.
Differential scanning calorimetric (DSC) analysis was performed with Q10 V9.6 Build 290 calorimeter. Samples of about 2 to 3 milligrams held in a closed pan were analyzed at a heating rate of 10°C per minute.
The (Z)-2-cyano-3 -hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. 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.
The present invention is schematically represented as follows. Scheme-A
Pure Teriflunomide Crude Teriflunomide
Formula- 1 Formula- 1
The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation of the scope of the invention.
Examples
Example- 1: Preparation of N-(4'-trifluoromethylphenyl)-5-methylisoxazole-4- carboxamide (Formula-2)
Methylene chloride (125 ml) and dimethyl formamide (2.87 gms) were added to 5- methylisoxazole-4-carboxylic acid (25 gms) at 25-30°C. Heated the reaction mixture to 35- 40°C and thionyl chloride (47.59 gms) was slowly added and stirred for 4 hours at the same temperature. After completion of the reaction, distilled off the solvent completely from the reaction mixture. To the obtained compound, dichloromethane was added at 25-30°C. Distilled off the solvent completely from the reaction mixture. Acetonitrile (50 ml) was added to the obtained compound at 25-30°C and slowly added to a mixture of acetonitrile (300 ml) and 4-(trifluoromethyl)aniline (64.45 gms) at 25-30°C and stirred the reaction mixture for 5 hours at the same temperature. Filtered the reaction mixture and distilled off the solvent completely from the filtrate. Methanol (225 ml), followed by activated carbon (2.5 gms) were added to the obtained compound at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with methanol. Water (250 ml) was slowly added to the obtained filtrate at 25-30°C and stirred the reaction
mixture for 2 hours. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 39.8 gms; Melting point: 165-168°C. Purity by HPLC: 99.63%.
Example-2: Preparation of N-(4'-trifluoromethylphenyl)-5-methylisoxazoIe-4- carboxamide (FormuIa-2)
Methylene chloride (15 Its) and dimethyl formamide (40 ml) were added to 5- methylisoxazole-4-carboxylic acid (3 kgs) at 25-30°C. Thionyl chloride (5.70 kgs) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 4 hours at the same temperature. After completion of the reaction, distilled off the solvent completely from the reaction mixture. Cooled the reaction mixture to 25-30°C and dichloromethane was added at the same temperature. Distilled off the solvent completely from the reaction mixture. Cooled the reaction mixture to 25-30°C and dissolved the obtained compound in acetonitrile (6.0 Its) at the same temperature. Slowly added to a mixture of acetonitrile (36 Its) and 4-(trifluoromethyl)aniline (7.70 kgs) at 25-30°C and stirred the reaction mixture for 5 hours at the same temperature. After completion of the reaction, filtered the reaction mixture and distilled off the solvent completely from the filtrate. Methanol (27 Its), followed by activated carbon (30 gms) was added to obtained compound at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with methanol. Water (30 Its) was slowly added to the obtained filtrate at 25-30°C and stirred the reaction mixture for 2 hours. Filtered the precipitated solid, washed with water. To the obtained wet compound, toluene (9 Its) was added at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Filtered the solid, washed with toluene and dried to get the title compound. Yield: 4.7 kg.
Example-3: Preparation of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethyl phenyl)-amide (Formula-l)
Methanol (150 ml) was added to N-(4'-trifluoromethylphenyl)-5-methylisoxazole-4- carboxamide (50 gms) at 25-30°C. Cooled the reaction mixture to 0-5°C and aqueous sodium hydroxide solution was slowly added to the reaction mixture at the same temperature. Stirred the reaction mixture for 2 hours at 0-5°C. Water was added to the reaction mixture. Adjust the pH of the reaction mixture to 7.5 by using dilute hydrochloric acid at 25-30°C. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 46.0 gms;
Example-4: Preparation of crystalline form-M of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethyl phenyl)-amide (Formula-1)
Dimethylformamide (300 ml) was added to (Z)-2-cyano-3-hydroxy-but-2-enoic acid- (4-trifluoromethylphenyl)-amide (50 gms) at 25-30°C. Heated the reaction mixture to 55- 60°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture and washed with dimethyl formamide. To the obtained filtrate, methanol (350 ml) was added at 25-30°C. Cooled the reaction mixture to 10-15°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with chilled methanol and dried to get the title compound. Yield: 41 gms;
Melting point: 228-231°C; Water content: 0.06% w/w; Phenyl isoxazole impurity: 0.004%; Purity by HPLC: 99.97%.
Particle size distribution before micronisation: D10: 6.71 μιτι; D50: 34.4 μπι; D90: 109.8 μηι; Particle size distribution after micronisation: DIO: 1.35 μητ, D50: 4.52 μητ, D90: 10.26 μιη.
The P-XRD of the obtained compound is shown in figure- 1.
The DSC thermogram of the obtained compound is shown in figure-2.
Reference Example- 1: Preparation of (Z)-2-cyano-3-hydroxy-but-2-enoicacid-(4- trifluoromethylphenyl)-amide according to US5494911 (Formula-1)
Methanol (74 ml) was added to N-(4'-trifluoromethylphenyl)-5-methylisoxazole-4- carboxamide (20 gms) at 25-30°C. Cooled the reaction mixture to 0-5°C and aqueous sodium hydroxide solution {prepared by dissolving sodium hydroxide (3.26 gms) in water (74 ml)} was slowly added to the reaction mixture at the same temperature. Stirred the reaction mixture for 1 hour at 0-5°C. After completion of the reaction, 20% aqueous hydrochloric acid solution was added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 8.7 gms.
The P-XRD pattern of the obtained compound is shown in figure-3.
The DSC thermogram of the obtained compound is shown in figure-4.
Claims
We Claim:
1. Crystalline form-M of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoro methyl phenyl)-amide is characterized by its DSC thermogram having an endotherm at 230.83°C and another endotherm at 245.07°C.
2. Crystalline form-M of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethyl phenyl)-amide, which is characterized by its powder X-ray diffractogram having peaks at 7.7, 12.6, 15.6, 19.3, 20.1, 24.7, 28.1, 31.6, 34.6 and 40.7 ± 0.2 degrees of two-theta.
3. Crystalline form-M of 5-(Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethyl phenyl)-amide of claim-2 is further characterized by its X-ray powder diffractogram having peaks at 8.3, 10.0, 15.9, 16.7, 23.1, 25.2, 25.6, 26.8, 30.7, 32.1, 32.9, 36.5, 38.7, 39.3, 42.7, 45.4, 46.9 and 48.2 ± 0.2 degrees of two-theta as illustrated in figure- 1.
4. A process for the preparation of crystalline form-M of (Z)-2-cyano-3-hydroxy-but-2- enoic acid-(4-trifluoromethylphenyl)-amide compound of formula- 1, comprising of: a) Suspending the compound of formula- 1 in a suitable solvent,
b) heating the reaction mixture to a suitable temperature,
c) filtering the reaction mixture,
d) adding a suitable anti-solvent to the filtrate obtained in step-(c),
e) cooling the reaction mixture to a suitable temperature,
f) stirring the reaction mixture,
g) filtering the precipitated solid and drying to get the crystalline form-M of (Z)-2- cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide compound of formula- 1.
5. The process according to claim-4, wherein,
in step-a) the suitable solvent is selected from ester solvents, ether solvents, polar
aprotic solvents, ketone solvents, chloro solvents or mixtures thereof;
in step-d) the suitable anti-solvent is alcohol solvents or polar solvents such as water; in step-b) the suitable temperature is ranging from 25°C-30°C to the reflux temperature of the solvent used.
A process for the preparation of crystalline form-M of (Z)-2-cyano-3-hydroxy-but-2- enoic acid-(4-trifluoromethylphenyl)-amide compound of formula- 1, comprising of; a) Suspending the compound of formula- 1 in dimethyl formamide,
b) heating the reaction mixture to 55-60°C,
c) filtering the reaction mixture,
d) adding methanol to the filtrate obtained in step-(c),
e) cooling the reaction mixture to 10-15 °C,
f) stirring the reaction mixture,
g) filtering the precipitated solid and drying to get the crystalline form-M of (Z)-2- cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide compound of formula- 1.
A process for the preparation of crystalline form-M of (Z)-2-cyano-3-hydroxy-but-2- enoic acid-(4-trifluoro methylphenyl)-amide compound of formula- 1, comprising of the following steps:
a) Reacting 5-methylisoxazole-4-carboxylic acid compound of formula-5
Formula-5
with thionyl chloride in a mixture of dimethyl formamide and methylene provides 5-methylisoxazole-4-carbonyl chloride compound of formula-4,
b) reacting the compound of formula-4 in-situ with 4-(trifluoromethyl)aniline
compound of formula-3 in acetonitrile provides N-(4'-trifluoromethylphenyl)-5- methylisoxazole-4-carboxamide compound of formula-2,
Formula-2
c) reacting the compound of formula-2 with sodium hydroxide in methanol followed
by treating with aqueous hydrochloric acid provides (Z)-2-cyano-3 -hydro xy-but-2- enoic acid-(4-trifluoromethyl phenyl)-amide compound of formula-1,
Formula- 1
d) optionally, purifying the compound of formula-1 from a mixture of methanol and dimethylformamide provides crystalline form-M of (Z)-2-cyano-3 -hydro xy-but-2- enoic acid-(4-trifluoromethyl phenyl)-amide compound of formula-1.
8. Use of crystalline form-M of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoro methylphenyl)-amide in the preparation of pharmaceutical composition.
9. (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide compound of formula-1 having particle size distribution of D90 less than 200 μηι.
10. (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide compound of formula-1 having particle size distribution of D90 less than 100 μηι.
11. (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide compound of formula-1 having particle size distribution of D¾> less than 50 μπι, preferably less than 25 μηι, more preferably less than 15 μηι.
12. (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide compound of formula-1 obtained by the process according to claims 4-7 having purity greater than
99.9 % by HPLC.
Dated this day of August 2014.
ut or zed ignatory
(Srinivasan Thirumalai Raj an)
MSN Laboratories Private Limited
**********
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| WO2016203410A1 (en) * | 2015-06-17 | 2016-12-22 | Biocon Limited | A novel process for the preparation of teriflunomide |
| EP4023215A1 (en) | 2020-12-30 | 2022-07-06 | Sanovel Ilac Sanayi ve Ticaret A.S. | A film coated tablet comprising teriflunomide |
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| JP2995086B2 (en) * | 1990-05-18 | 1999-12-27 | ヘキスト・アクチエンゲゼルシヤフト | Preparation containing isoxazole-4-carboxamides and hydroxyalkylidene cyanoacetamides |
| US20120171490A1 (en) * | 2009-07-09 | 2012-07-05 | Alembic Pharmaceuticals Limited | Novel polymorphic form of teriflunomide salts |
| WO2012110911A1 (en) * | 2011-02-18 | 2012-08-23 | Alembic Pharmaceuticals Limited | Novel polymorphic form of teriflunomide |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2016203410A1 (en) * | 2015-06-17 | 2016-12-22 | Biocon Limited | A novel process for the preparation of teriflunomide |
| EP3310755A4 (en) * | 2015-06-17 | 2019-02-27 | Biocon Limited | A novel process for the preparation of teriflunomide |
| US10526279B2 (en) | 2015-06-17 | 2020-01-07 | Biocon Limited | Process for the preparation of teriflunomide |
| RU2722316C2 (en) * | 2015-06-17 | 2020-05-29 | Биокон Лимитед | New method of producing teriflunomide |
| AU2016280243B2 (en) * | 2015-06-17 | 2020-12-03 | Biocon Limited | A novel process for the preparation of teriflunomide |
| EP4023215A1 (en) | 2020-12-30 | 2022-07-06 | Sanovel Ilac Sanayi ve Ticaret A.S. | A film coated tablet comprising teriflunomide |
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