WO2015128882A2 - Crystalline forms of n-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide and process for the preparation thereof - Google Patents
Crystalline forms of n-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide and process for the preparation thereof Download PDFInfo
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- WO2015128882A2 WO2015128882A2 PCT/IN2015/000112 IN2015000112W WO2015128882A2 WO 2015128882 A2 WO2015128882 A2 WO 2015128882A2 IN 2015000112 W IN2015000112 W IN 2015000112W WO 2015128882 A2 WO2015128882 A2 WO 2015128882A2
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- ILNJBIQQAIIMEY-UHFFFAOYSA-N OC(C1=CNc2ccccc2C1=O)=O Chemical compound OC(C1=CNc2ccccc2C1=O)=O ILNJBIQQAIIMEY-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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- the present invention relates to crystalline forms of N-(2,4-di-tert-butyl-5- hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 , which is represented by the following structural formula:
- the present invention also provides a process for the preparation of crystalline forms of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula- 1.
- Background of the invention :
- N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula- 1 commonly known as "Ivacaftor” has been demonstrated to restore the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, the defective cell membrane protein responsible for the progression of CF. Defects in the CFTR protein can affect the transport of chloride and other ions across cells, and lead to the accumulation of thick, sticky miicus in the lungs of patients with CF. This mucus can foster chronic infection and inflammation, and can result in irreversible lung damage.
- CFTR cystic fibrosis transmembrane conductance regulator
- Potentiator compounds such as compound of formula- 1 can increase the probability that the CFTR channel is open, which could result in an increase in chloride transport across the cell surface in some patients.
- formula- 1 has restored the function of defective CFTR channels.
- Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
- a single molecule like Ivacaftor, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, x-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum.
- One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, 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.
- US 8410274 B2 describes crystalline forms (form-A & form-B) and amorphous form of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide.
- US8471029 B2 describes crystalline forrn ⁇ Tof N-(2,4-di-tert-butyl-5- hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3-carboxamide.
- US8623894 B2 and US20130281487 Al describes the crystalline solvate (or) hydrate forms of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide.
- the present inventors have developed novel crystalline ' forms of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide which have advantageous properties over the prior art polymorphs.
- the first aspect of the present invention is to provide a crystalline form of yV-(2,4- di-tert-butyl-5-hydroxy phenyl)- l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 (hereinafter 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 N-(2,4-di-tert-butyl-5-hydroxy phenyl)- 1 ,4-dihydro- 4-oxoquinoline-3-carboxamide compound of formula- 1.
- the third aspect of the present invention is to provide a crystalline form of N-(2,4- di-tert-butyl-5-hydroxy phenyl)- l ,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 (hereinafter designated as crystalline form-S).
- the fourth aspect of the present invention is to provide a process for the preparation of crystalline form-S of N-(2,4-di-tert-butyl-5-hydroxy phenyl)- 1 ,4-dihydro- 4-oxoquinoline-3-carboxamide compound of formula- 1.
- the fifth aspect of the present invention is to provide a crystalline form of JV-(2,4- di-tert-butyl-5-hydroxy phenyl)- l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 (hereinafter designated as crystalline form-N).
- the sixth aspect of the present invention is to provide a process for the preparation of crystalline form-N of 7V-(2,4-di-tert-butyl-5-hydroxy phenyl)- 1 ,4-dihydro- 4-oxoquinoline-3-carboxamide compound of formula- 1.
- the seventh aspect of the present invention is to provide an improved process for the preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)- l ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula- 1.
- the eighth aspect of the present invention is to provide a process for the preparation of crystalline form-B of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro- 4-oxoquinoline-3-carboxamide compound of formula-1.
- Figure-1 Illustrates the powder X-Ray diffraction pattern of crystalline form of N-(2,4- di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 according to example- 1.
- Figure-2 Illustrates the powder X-Ray diffraction pattern of crystalline form-M of N- (2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1.
- Figure-3 Illustrates the powder X-Ray diffraction pattern of crystalline form-S of N- (2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oXoquinoline-3-carboxamide compound of formula-1.
- Figure-4 Illustrates the powder X-Ray diffraction pattern of crystalline form-N of N- (2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1.
- Figure-5 Illustrates the DSC thermogram of crystalline form of N-(2,4-di-tert-butyl-5- hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 according to example- 1.
- Figure-6 Illustrates the DSC thermogram of crystalline form-M of N-(2,4-di-tert-butyl- 5-hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1.
- Figure-7 Illustrates the DSC thermogram of crystalline form-S of N-(2,4-di-tert-butyl-5- hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1.
- suitable solvent used in the present invention is selected from, but not limited to "ester solvents” such as ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate and the like; "ether solvents” such as tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane and the like; “hydrocarbon solvents” such as toluene, hexane, heptane, pet ether, xylene, cyclohexane and the like; “polar aprotic solvents” such as dimethyl acetamide, dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like;
- suitable base refers, but not limited to "inorganic bases” selected from alkali and alkaline earth metal hydroxides, alkoxides, carbonates and bicarbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium tert- butoxide, lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali meta amides such as sodium amide ⁇ potassium amide, lithium amide and the like, ammonia; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpho
- the first aspect of the present invention provides a crystalline form of N-(2,4-di- tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 (hereinafter designated as crystalline form-M), which is characterized by; i. its PXRD pattern substantially in accordance with figure-2,
- the second aspect of the present invention provides a process for the preparation of crystalline . form-M of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4- oxoquinoline-3-carboxamide compound of formula-1 , comprising the following steps of: a) Dissolving N-(2,4-di-tert-butyl-5-hydroxyphenyl)- 1 ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula-1 in a suitable solvent at a suitable temperature,
- step a) filtering the precipitated solid and drying to get crystalline form-M of compound of formula-1.
- step a) the starting material "N-(2,4-di-tert-butyl-5-hydroxyphenyl)- l,4-dihydro-4-oxoquinoline-3-carboxamide" can be prepared by the process of the present invention (or) process known in the art (or) process disclosed in US7495103 B2.
- the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, polar aprotic solvents, ether solvents, alcoholic solvents, polar solvents and/or mixtures thereof.
- the suitable temperature is 0°C to reflux temperature of a solvent used.
- the preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro- 4-oxoquinoline-3-carboxamide compound of formula-1 , comprising the following steps of:
- the preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of N-(2,4-di-tert-butyl-5 -hydro xyphenyl)-! , 4-dihydro- 4-oxoquinoline-3-carboxamide compound of formula-1 , comprising the following steps of:
- the preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro- 4-oxoquinoline-3-carboxamide compound of formula-1 , comprising the following steps of:
- the third aspect of the present invention provides a crystalline form of N-(2,4-di- tert-butyl-5 -hydro xyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula-1 (hereinafter designated as crystalline form-S), which is characterized by:
- the fourth aspect of the present invention provides a process for the preparation of crystalline form-S of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4- oxoquinoline-3-carboxamide compound of formula-1 , comprising the following steps of: a) Dissolving N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula- 1 in a suitable solvent at a suitable temperature,
- the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, polar aprotic solvents, ether solvents, alcoholic solvents, polar solvents and/or mixtures thereof.
- the suitable temperature is 0°C to reflux temperature of a solvent used.
- the preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro- 4-oxoquinoline-3-carboxamide compound of formula- 1 , comprising the following steps of:
- the fifth aspect of the present invention provides crystalline form of N-(2,4-di- tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 (hereinafter designated as crystalline form-N), which is characterized by;
- the sixth aspect of the present invention provides a process for the preparation of crystalline form-N of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-
- the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, polar aprotic solvents, ether solvents, alcoholic solvents, polar solvents and/or mixtures thereof.
- the suitable temperature is 0°C to reflux temperature of a solvent used.
- the preferred embodiment of the present invention provides a process for the preparation of crystalline form-N of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-
- the seventh aspect of the present invention is to provide an improved process for the preparation of iV-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula- 1, comprising of reacting 4-oxo-l ,4- dihydroquinoline-3-carboxylic acid
- the suitable base is selected from organic base or inorganic base; and a suitable solvent is selected from polar aprotic solvents and alcohol solvents.
- the amount of l -(3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl) used in the above reaction is in the range of 1 -3 molar equivalents, preferably 1-2 molar equivalents with respect to 1 molar equivalent of 4-oxo-l ,4-dihydroquinoline- 3-carboxylic acid.
- the amount of hydroxybenzotriazole (HOBt) used in the above reaction is in the range of 1-3 molar equivalents, preferably 1-2 molar equivalents with respect to 1 molar equivalent of 4-oxo-l,4-dihydroquinoline-3-carboxylic acid.
- the above reaction can also be carried out using N,N'-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) to get the compound of formula- 1.
- DCC N,N'-dicyclohexylcarbodiimide
- DMAP 4-dimethylaminopyridine
- the preferred embodiment of the present invention provides an improved process for the preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline- 3-carboxamide compound of formula- 1 , comprising of reacting 4-oxo-l ,4- dihydroquinoline-3-carboxylic acid with 5-Amino-2,4-di-tert-butylphenol in presence of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HC1), hydroxybenzotriazole (HOBt) and sodium bicarbonate in N,N-dimethylformamide provides N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-l ,4-dihydroquinoline-3- carboxamide compound of formula- 1, followed by purifying the obtained compound from ethanol provides pure compound of formula- 1.
- EDC.HC1
- the another preferred embodiment of the present invention provides an improved process for the preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4- oxoquinoline-3-carboxamide compound of formula-1 , comprising of reacting 4-oxo-l ,4- dihydroquinoline-3-carboxylic acid with 5-Amino-2,4-di-tert-butylphenol in presence of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HC1), hydroxybenzotriazole (HOBt) and triethylamine in ⁇ , ⁇ -dimethylformamide provides N- (2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide compound of formula-1, followed by purifying the obtained compound from methanol provides pure compound of formula-1.
- the 4-oxo-l ,4-dihydroquinoline-3-carboxylic acid and 5-amino-2,4-di-tert- butylphenol used in the present invention can be obtained by the process known in the art (or) process disclosed in US7495103 B2.
- the prior reported process involves reacting 4-oxo-l ,4-dihydroquinoline-3- carboxylic acid with 5-Amino-2,4-di-tert-butylphenol by the usage of HATU which is expensive and uneconomical thereby increases the cost of production.
- the present inventors have used EDC.HCl and HOBt for the above reaction which are less expensive and compatible for large scale production thereby decreasing the cost of production.
- the eighth aspect of the present invention is to provide a process for the preparation of crystalline form-B of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro- 4-oxoquinoline-3-carboxamide compound of formula-1 , comprising of:
- step-c) & step-g) the suitable second & third solvent is water.
- the preferred embodiment of the present invention provides a process for the preparation of crystalline form-B of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro- 4-oxoquinoline-3-carboxamide compound of formula-1 , comprising of:
- the crystalline form-N of N-(2,4-di-tert-butyl-5 -hydro xyphenyl)-l ,4-dihydro-4- oxoquinoline-3-carboxamide compound of formula-1 of the present invention having water content about 2.0 to 2.5 % w/w.
- the crystalline form-M, S & N of compound of formula-1 of the present invention can be utilized for the preparation of pure compound of formula-1 as well in the preparation of pharmaceutical composition.
- a liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: Symmetry shield RP 18,250 x 4.6 mm, 5 ⁇ (or) equivalent; Flow rate: 1.5 ml/min; Wavelength: 225 nm; Column Temperature: 25°C;
- Injection volume 10 ⁇ ,; Run time: 45 minutes; Diluent: Acetonitrile: water (98:0.2 v/v);
- Needle wash Acetonitrile: water (90: 10 v/v); Elution: Gradient; Mobile phase-A: Buffer
- DSC Differential scanning calorimetric
- the water content of crystalline form-N of Ivacaftor compound of formula- 1 obtained by the production method of the present invention was measured by the Karl Fischer method which is well known to those skilled in the art.
- the compound produced by the present invention can be further micronized or milled by the conventional methods 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.
- Triethyl amine (32.3 ml) was added to a mixture of 4-oxo-l ,4-dihydroquinoline- 3-carboxylic acid (25 gm), N,N-dimethylformamide (197 ml), 2-(l H)-(7- Azabenzotriazole-l-yl)-l ,l ,3,3-tetramethyl uronium hexafluorophosphate (HATU) (60.3 gm), 5-amino-2,4-di-tert-butylphenol (35.2 gm) at 25-30° C and stirred for 12 hrs at 25- 30° C. Distilled off solvent from the reaction mixture under reduced pressure.
- Example-3 Preparation of crystalline form-M of N-(2,4-di-tert-butyl-5-hydroxy phenyl)-l,4-dihydro-4-oxoquinoIine-3-carboxamide (Formula-1)
- Example-4 Preparation of crystalline form-M of N-(2,4-di-tert-butyl-5-hydroxy phenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide (Formula-1)
- Example-6 Preparation of crystalline form-S of N-(2,4-di-tert-butyl-5-hydroxy phenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide (Formula-1)
- Methylisobutylketone content 70,000 ppm.
- Example-7 Preparation of crystalline form-N of N-(2,4-di-tert-butyl-5-hydroxy phenyI)-l,4-dihydro-4-oxoquinoline-3-carboxamide (Formula-1)
- Example-9 Preparation of crystalline form-B of N-(2,4-di-tert-butyl-5- hydroxyphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide
- N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-l ,4-dihydroquinoline-3- carboxamide (20 gm) was added to 2-butanone (100 ml) at 30-35°C. The reaction mixture was heated to 75-80°C. Water (10 ml) was added to the reaction mixture at 75- 80°C and stirred for 30 minutes at the same temperature. Carbon was added to the reaction mixture at 75-80°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through high flow bed and washed with 2-butanone. Distilled off the solvent from the filtrate completely under reduced pressure and co-distilled with water. Water was added to the obtained compound and stirred for 30 minutes at 65-70°C. The obtained solid was filtered at 65-70°C, washed with water and dried to get the title compound.
- the PXRD pattern of the obtained compound is matching with crystalline form-B of compound of formula- 1 disclosed in US 8410274B2.
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Abstract
The present invention relates to crystalline forms of N-(2,4-di-tert-butyl-5- hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 and also process for the preparation of said compound of formula- 1 which is represented by the following structural formula:
Description
Crystalline forms of N-(2,4-di-tert-butvI-5-hvdroxyphenyl)-l,4-dihvclro-4- oxoquinoIine-3-carboxamide and process for the preparation thereof
Related Applications:
This application claims the benefit of priority of our Indian patent application number 1006/CHE/2014 filed on 27th Feb. 2014 which is incorporated herein by reference.
Field of the invention:
The present invention relates to crystalline forms of N-(2,4-di-tert-butyl-5- hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 , which is represented by the following structural formula:
Formula- 1
The present invention also provides a process for the preparation of crystalline forms of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula- 1. Background of the invention:
N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula- 1 , commonly known as "Ivacaftor" has been demonstrated to restore the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, the defective cell membrane protein responsible for the progression of CF. Defects in the CFTR protein can affect the transport of chloride and other ions across cells, and lead to the accumulation of thick, sticky miicus in the lungs of
patients with CF. This mucus can foster chronic infection and inflammation, and can result in irreversible lung damage.
Potentiator compounds such as compound of formula- 1 can increase the probability that the CFTR channel is open, which could result in an increase in chloride transport across the cell surface in some patients. In laboratory experiments, using cells from patients with CF where CFTR proteins are present on the cell surface, formula- 1 has restored the function of defective CFTR channels.
N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula- 1 and its process was disclosed in US7495103(B2).
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule, like Ivacaftor, may give rise to a variety of crystalline forms having distinct crystal structures and physical properties like melting point, x-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, 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.
Different crystalline forms or polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubilities.
The discovery of new 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. Therefore, there is a need for additional crystalline forms of Ivacaftor.
US 8410274 B2 describes crystalline forms (form-A & form-B) and amorphous form of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide. US8471029 B2 describes crystalline forrn^Tof N-(2,4-di-tert-butyl-5- hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3-carboxamide.
US8623894 B2 and US20130281487 Al describes the crystalline solvate (or) hydrate forms of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide. In view of the foregoing, the present inventors have developed novel crystalline' forms of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide which have advantageous properties over the prior art polymorphs.
Brief description of the invention:
The first aspect of the present invention is to provide a crystalline form of yV-(2,4- di-tert-butyl-5-hydroxy phenyl)- l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 (hereinafter 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 N-(2,4-di-tert-butyl-5-hydroxy phenyl)- 1 ,4-dihydro- 4-oxoquinoline-3-carboxamide compound of formula- 1.
The third aspect of the present invention is to provide a crystalline form of N-(2,4- di-tert-butyl-5-hydroxy phenyl)- l ,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 (hereinafter designated as crystalline form-S).
The fourth aspect of the present invention is to provide a process for the preparation of crystalline form-S of N-(2,4-di-tert-butyl-5-hydroxy phenyl)- 1 ,4-dihydro- 4-oxoquinoline-3-carboxamide compound of formula- 1. The fifth aspect of the present invention is to provide a crystalline form of JV-(2,4- di-tert-butyl-5-hydroxy phenyl)- l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 (hereinafter designated as crystalline form-N).
The sixth aspect of the present invention is to provide a process for the preparation of crystalline form-N of 7V-(2,4-di-tert-butyl-5-hydroxy phenyl)- 1 ,4-dihydro- 4-oxoquinoline-3-carboxamide compound of formula- 1.
The seventh aspect of the present invention is to provide an improved process for the preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)- l ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula- 1.
The eighth aspect of the present invention is to provide a process for the preparation of crystalline form-B of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro- 4-oxoquinoline-3-carboxamide compound of formula-1.
Brief description of the drawings:
Figure-1: Illustrates the powder X-Ray diffraction pattern of crystalline form of N-(2,4- di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 according to example- 1.
Figure-2: Illustrates the powder X-Ray diffraction pattern of crystalline form-M of N- (2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1.
Figure-3: Illustrates the powder X-Ray diffraction pattern of crystalline form-S of N- (2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oXoquinoline-3-carboxamide compound of formula-1.
Figure-4: Illustrates the powder X-Ray diffraction pattern of crystalline form-N of N- (2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1.
Figure-5: Illustrates the DSC thermogram of crystalline form of N-(2,4-di-tert-butyl-5- hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 according to example- 1.
Figure-6: Illustrates the DSC thermogram of crystalline form-M of N-(2,4-di-tert-butyl- 5-hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1.
Figure-7: Illustrates the DSC thermogram of crystalline form-S of N-(2,4-di-tert-butyl-5- hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1.
Detailed description of the invention:
The term "suitable solvent" used in the present invention is selected from, but not limited to "ester solvents" such as ethyl acetate, methyl acetate, isopropyl acetate, n-butyl acetate and the like; "ether solvents" such as tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane and the like; "hydrocarbon solvents" such as toluene, hexane, heptane, pet ether, xylene, cyclohexane and the like; "polar aprotic solvents" such as dimethyl acetamide, dimethylsulfoxide, dimethylformamide, N-methyl-2-pyrrolidone and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol and the like; "chloro solvents" such as dichloromethane, chloroform, dichloroethane, carbon tetrachloride and the like; "nitrile solvents" such as acetonitrile, butyronitrile, isobutyronitrile and the like; "protic solvent" such as acetic acid; "polar solvent" such as water or mixtures thereof.
The term "suitable base" used herein the present invention refers, but not limited to "inorganic bases" selected from alkali and alkaline earth metal hydroxides, alkoxides, carbonates and bicarbonates such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium tert- butoxide, lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate,
sodium bicarbonate, potassium bicarbonate and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali meta amides such as sodium amide^ potassium amide, lithium amide and the like, ammonia; and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and/or mixtures thereof.
The first aspect of the present invention provides a crystalline form of N-(2,4-di- tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 (hereinafter designated as crystalline form-M), which is characterized by; i. its PXRD pattern substantially in accordance with figure-2,
ii. its powder X-Ray diffractogram having peaks at 7.28, 10.76, 13.05, 13.87, 14.03, 20.39, 20.95 and 21.82±0.2 degrees of two-theta, and'
iii. its DSC thermogram substantially in accordance with figure-6.
The second aspect of the present invention provides a process for the preparation of crystalline . form-M of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4- oxoquinoline-3-carboxamide compound of formula-1 , comprising the following steps of: a) Dissolving N-(2,4-di-tert-butyl-5-hydroxyphenyl)- 1 ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula-1 in a suitable solvent at a suitable temperature,
b) adding methanol to the reaction mixture,
c) stirring the reaction mixture,
d) optionally, treating the reaction mixture with carbon,
e) cooling the reaction mixture,
f) filtering the precipitated solid and drying to get crystalline form-M of compound of formula-1.
Wherein in step a), the starting material "N-(2,4-di-tert-butyl-5-hydroxyphenyl)- l,4-dihydro-4-oxoquinoline-3-carboxamide" can be prepared by the process of the present invention (or) process known in the art (or) process disclosed in US7495103 B2.
Wherein in step a), the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, polar aprotic solvents, ether solvents, alcoholic solvents, polar solvents and/or mixtures thereof.
in step a), the suitable temperature is 0°C to reflux temperature of a solvent used.
The preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro- 4-oxoquinoline-3-carboxamide compound of formula-1 , comprising the following steps of:
a) Dissolving N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula-1 in Ν,Ν-dimethyl formamide at reflux temperature,
b) adding methanol to the reaction mixture,
c) stirring the reaction mixture,
d) treating the reaction mixture with carbon,
e) cooling the reaction mixture to 0°C to 5°C,
f) filtering the precipitated solid and drying to get crystalline form-M of compound of formula-1.
The preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of N-(2,4-di-tert-butyl-5 -hydro xyphenyl)-! , 4-dihydro- 4-oxoquinoline-3-carboxamide compound of formula-1 , comprising the following steps of:
a) Dissolving N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula-1 in dichloromethane at reflux temperature, b) adding methanol to the reaction mixture,
c) stirring the reaction mixture,
d) treating the reaction mixture with carbon,
e) cooling the reaction mixture to 0PC to 5°C,
f) filtering the precipitated solid and drying to get crystalline form-M of compound of formula-1.
The preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro- 4-oxoquinoline-3-carboxamide compound of formula-1 , comprising the following steps of:
a) Dissolving N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula-1 to ethylacetate at reflux temperature, b) adding methanol to the reaction mixture,
c) stirring the reaction mixture,
d) treating the reaction mixture with carbon,
e) cooling the reaction mixture to 0°C to 5°C,
f) filtering the precipitated solid and drying to get crystalline form-M of compound of formula-1.
The third aspect of the present invention provides a crystalline form of N-(2,4-di- tert-butyl-5 -hydro xyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula-1 (hereinafter designated as crystalline form-S), which is characterized by:
i. its PXRD pattern substantially in accordance with figure-3,
ii. its powder X-Ray diffractogram having peaks at 4.40, 5.07, 8.86, 1 1 .81 and 15.47 ±0.2 degrees of two-theta, and
iii. its DSC thermogram substantially in accordance with figure-7.
The fourth aspect of the present invention provides a process for the preparation of crystalline form-S of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4- oxoquinoline-3-carboxamide compound of formula-1 , comprising the following steps of:
a) Dissolving N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula- 1 in a suitable solvent at a suitable temperature,
b) stirring the reaction mixture,
c) optionally, treating the reaction mixture with carbon,
d) cooling the reaction mixture,
e) filtering the precipitated solid and drying to get crystalline form-S of compound of formula- 1.
Wherein in step a) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, polar aprotic solvents, ether solvents, alcoholic solvents, polar solvents and/or mixtures thereof.
in step a), the suitable temperature is 0°C to reflux temperature of a solvent used.
The preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro- 4-oxoquinoline-3-carboxamide compound of formula- 1 , comprising the following steps of:
a) Dissolving N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula- 1 in methylisobutylketone at reflux temperature,
b) stirring the reaction mixture,
c) treating the reaction mixture with carbon,
d) cooling the reaction mixture to 0° C to 5° C,
e) filtering the precipitated solid and drying to get crystalline form-S of compound of formula- 1.
The fifth aspect of the present invention provides crystalline form of N-(2,4-di- tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 (hereinafter designated as crystalline form-N), which is characterized by;
i. its PXRD pattern substantially in accordance with figure-4;
ii. its powder X-Ray diffractogram having peaks at 3.61 , 7.22, 7.85, 9.78, 14.30, 14.75, 16.59, 18.27, 18.79, 20.46, 21.68 and 23.8 ±0.2 degrees of two-theta.
The sixth aspect of the present invention provides a process for the preparation of crystalline form-N of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-
3- carboxamide compound of formula-1, comprising the following steps of:
a) Dissolving N-(2,4-di-tert-butyl-5-hydroxyphenyl)- 1 ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula-1 in a suitable solvent at a suitable temperature,
b) adding water to the reaction mixture,
c) optionally, treating the reaction mixture with carbon,
d) cooling the reaction mixture,
e) stirring the reaction mixture at the same temperature,
f) filtering the solid and drying to get crystalline form-N of compound of formula-1.
Wherein in step a) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, polar aprotic solvents, ether solvents, alcoholic solvents, polar solvents and/or mixtures thereof.
In step a), the suitable temperature is 0°C to reflux temperature of a solvent used. The preferred embodiment of the present invention provides a process for the preparation of crystalline form-N of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-
4- oxoquinoline-3-carboxamide compound of formula-1 , comprising the following steps of:
a) Dissolving N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula-1 in Ν,Ν-dimethylformamide at reflux temperature,
b) adding water to the reaction mixture,
c) treating the reaction mixture with carbon,
d) cooling the reaction mixture to 0° C to 5° C,
e) stirring the reaction mixture for 1 hour at the same temperature,
f) filtering the precipitated solid and drying to get crystalline form-N of qompound of formula- 1.
The seventh aspect of the present invention is to provide an improved process for the preparation of iV-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula- 1, comprising of reacting 4-oxo-l ,4- dihydroquinoline-3-carboxylic acid
with 5-Amino-2,4-di-tert-butylphenol
in presence of l-(3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl), hydroxybenzotriazole (HOBt) and a suitable base in a suitable solvent provides N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-l ,4-dihydroquinoline-3- carboxamide compound of formula- 1 , followed by purifying the obtained compound from a suitable solvent provides pure compound of formula- 1.
Wherein, the suitable base is selected from organic base or inorganic base; and a suitable solvent is selected from polar aprotic solvents and alcohol solvents.
The amount of l -(3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl) used in the above reaction is in the range of 1 -3 molar equivalents, preferably 1-2 molar equivalents with respect to 1 molar equivalent of 4-oxo-l ,4-dihydroquinoline- 3-carboxylic acid.
The amount of hydroxybenzotriazole (HOBt) used in the above reaction is in the range of 1-3 molar equivalents, preferably 1-2 molar equivalents with respect to 1 molar
equivalent of 4-oxo-l,4-dihydroquinoline-3-carboxylic acid.
The above reaction can also be carried out using N,N'-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) to get the compound of formula- 1.
The preferred embodiment of the present invention provides an improved process for the preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline- 3-carboxamide compound of formula- 1 , comprising of reacting 4-oxo-l ,4- dihydroquinoline-3-carboxylic acid with 5-Amino-2,4-di-tert-butylphenol in presence of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HC1), hydroxybenzotriazole (HOBt) and sodium bicarbonate in N,N-dimethylformamide provides N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-l ,4-dihydroquinoline-3- carboxamide compound of formula- 1, followed by purifying the obtained compound from ethanol provides pure compound of formula- 1.
The another preferred embodiment of the present invention provides an improved process for the preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4- oxoquinoline-3-carboxamide compound of formula-1 , comprising of reacting 4-oxo-l ,4- dihydroquinoline-3-carboxylic acid with 5-Amino-2,4-di-tert-butylphenol in presence of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HC1), hydroxybenzotriazole (HOBt) and triethylamine in Ν,Ν-dimethylformamide provides N- (2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide compound of formula-1, followed by purifying the obtained compound from methanol provides pure compound of formula-1.
The 4-oxo-l ,4-dihydroquinoline-3-carboxylic acid and 5-amino-2,4-di-tert- butylphenol used in the present invention can be obtained by the process known in the art (or) process disclosed in US7495103 B2.
The prior reported process involves reacting 4-oxo-l ,4-dihydroquinoline-3- carboxylic acid with 5-Amino-2,4-di-tert-butylphenol by the usage of HATU which is expensive and uneconomical thereby increases the cost of production. The present
inventors have used EDC.HCl and HOBt for the above reaction which are less expensive and compatible for large scale production thereby decreasing the cost of production.
The eighth aspect of the present invention is to provide a process for the preparation of crystalline form-B of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro- 4-oxoquinoline-3-carboxamide compound of formula-1 , comprising of:
a) Adding a suitable solvent to N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4- oxoquinoline-3-carboxamide compound of formula-1 ,
b) heating the reaction mixture,
c) adding a second solvent to the reaction mixture,
d) stirring the reaction mixture,
e) treating the reaction mixture with carbon,
f) distilling off the solvent completely from the reaction mixture,
g) adding third solvent to the obtained compound,
h) stirring the reaction mixture at a suitable temperature,
i) filtering the reaction mixture,
j) drying the, solid to get crystalline form-B of compound of formula-1.
wherein, in step-c) & step-g) the suitable second & third solvent is water.
The preferred embodiment of the present invention provides a process for the preparation of crystalline form-B of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro- 4-oxoquinoline-3-carboxamide compound of formula-1 , comprising of:
a) Adding 2-butanone to N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4- oxoquinoline-3-carboxamide compound of formula-1,
b) heating the reaction mixture at 70°C to 80°C,
c) adding water to the reaction mixture,
d) stirring the reaction mixture,
e) treating the reaction mixture with carbon,
f) distilling off the solvent completely from the reaction mixture,
g) adding water to the obtained compound,
h) stirring the reaction mixture at 60°C to 70°C,
i) filtering the reaction mixture,
j) drying the solid to get crystalline form-B of compound of formula-1. The crystalline form-M of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4- oxoquinoline-3-carboxamide compound of formula-1 of the present invention having methanol content about 50,000 to 70,000 ppm. Similarly, the crystalline form-S compound of formula-1 having methyl isobutyl ketone content about 65,000 to 75,000 ppm.
The crystalline form-N of N-(2,4-di-tert-butyl-5 -hydro xyphenyl)-l ,4-dihydro-4- oxoquinoline-3-carboxamide compound of formula-1 of the present invention having water content about 2.0 to 2.5 % w/w. The crystalline form-M, S & N of compound of formula-1 of the present invention can be utilized for the preparation of pure compound of formula-1 as well in the preparation of pharmaceutical composition.
HPLC Method of Analysis:
N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula-1 :
Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: Symmetry shield RP 18,250 x 4.6 mm, 5 μιτι (or) equivalent; Flow rate: 1.5 ml/min; Wavelength: 225 nm; Column Temperature: 25°C;
Injection volume: 10 μί,; Run time: 45 minutes; Diluent: Acetonitrile: water (98:0.2 v/v);
Needle wash: Acetonitrile: water (90: 10 v/v); Elution: Gradient; Mobile phase-A: Buffer
(100%); Mobile phase-B: Acetonitrile: Water: Methanol (80: 10: 10) v/v; Buffer: 1.6 grams of potassium hydrogen orthophosphate in about 2 gm of 1 -Octane sulfonic acid sodium salt anhydrous into 1000 ml of milli-Q-water, then filter this solution through
0.22μηι nylon membrane filter paper and sonicate to degas it.
PXRD analysis of crystalline forms of Ivacaftor was carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A0 and continuous scan speed of 0.03°/min.
Differential scanning calorimetric (DSC) analysis was performed on a Q10 V9.6 Build 290 calorimeter with open aluminium pans, heating the samples from 40 to 250° C in a dry nitrogen atmosphere at a rate of 5°C/min.
The water content of crystalline form-N of Ivacaftor compound of formula- 1 obtained by the production method of the present invention was measured by the Karl Fischer method which is well known to those skilled in the art.
The compound produced by the present invention can be further micronized or milled by the conventional methods 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 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-(2,4-di-tert-butyI-5-hydroxyphenyl)-l,4-dihydro-4-oxo quinoline-3-carboxamide (formula-1)
A mixture of 4-oxo-l,4-dihydroquinoline-3-carboxylic acid (5 gm), N,N- dimethylformamide (50 ml), 1-Hydroxybenzotriazole (HOBT) (3.40 gm), l-Ethyl-3-(3- dimethyllaminopropyl)carbodiimide hydrochloride (EDC.HC1) (5.57 gm), 5-amino-2,4- di-tert-butylphenol (7.36 gm) and triethylamine (6 ml) was stirred for 52 hrs at 25-35° C. Distilled off the solvent completely under reduced pressure. Methanol (75 ml) was added to the obtained compound at 25-35° C and stirred for 45 min at the same temperature.
The reaction mixture was cooled to 0° C to 5° C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the ■ title compound.
Yield: 5 gm; Purity by HPLC: 99.5%.
The PXRD and DSC of the obtained compound are illustrated in figure- 1 and figure-5 respectively.
Example-2: Preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oxo quinoline-3-carboxamide (formula-1)
Triethyl amine (32.3 ml) was added to a mixture of 4-oxo-l ,4-dihydroquinoline- 3-carboxylic acid (25 gm), N,N-dimethylformamide (197 ml), 2-(l H)-(7- Azabenzotriazole-l-yl)-l ,l ,3,3-tetramethyl uronium hexafluorophosphate (HATU) (60.3 gm), 5-amino-2,4-di-tert-butylphenol (35.2 gm) at 25-30° C and stirred for 12 hrs at 25- 30° C. Distilled off solvent from the reaction mixture under reduced pressure. Methanol (375 ml) was added to the obtained compound at 25-35° C and stirred for 45 min at the same temperature. The reaction mixture was cooled to 0° C to 5° C and stirred for 60 min at the same temperature. Filtered the solid, washed with methanol and dried to get the title compound. Yield: 50 gm; Purity by HPLC: 99.48%.
Example-3: Preparation of crystalline form-M of N-(2,4-di-tert-butyl-5-hydroxy phenyl)-l,4-dihydro-4-oxoquinoIine-3-carboxamide (Formula-1)
Dissolving N-(2,4-di-tert-butyl-5-hydroxyphenyl)- 1 ,4-dihydro-4-oxoquinoline-3- carboxamide (5 gm) in N,N-dimethyl formamide (50 ml) at reflux temperature. Methanol (30 ml) was slowly added to the reaction mixture at reflux temperature and the reaction mixture was stirred for 30 min at the same temperature. Carbon (0.5 gm) was added to the reaction mixture and stirred for 30 min at reflux temperature. Filtered the reaction mixture through high flow bed and washed with methanol. Cooled the filtrate at 25-30° C and stirred for 30 min. The reaction mixture was cooled to 0° C to 5° C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound. Yield: 3.8 gm. Purity by HPLC: 99.89%.
Methanol content: 70,000 ppm;
The PXRD and DSC of the obtained compound are illustrated in figure-2 and figure-6 respectively.
Example-4: Preparation of crystalline form-M of N-(2,4-di-tert-butyl-5-hydroxy phenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide (Formula-1)
Dissolving N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide (5 gm) in dichloromethane (100 ml) at reflux temperature. Methanol (50 ml) was slowly added to the reaction mixture at reflux temperature and the reaction mixture was stirred for 30 min at the same temperature. Carbon (0.5 gm) was added to the reaction mixture and stirred for 30 min at reflux temperature. Filtered the reaction mixture through high flow bed and washed with methanol. Cooled the filtrate to 0° C to 5° C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound.
Yield: 4 gm; Purity by HPLC: 99.90%;
Methanol content: 63,000 ppm;
ExanipIe-5: Preparation of crystalline form-M of N-(2,4-di-tert-butyI-5-hydrox phenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide (Formula-1)
Dissolving N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquiholine-3- carboxamide (5 gm) in ethylacetate (250 ml) at reflux temperature. Methanol (120 ml) was slowly added to the reaction mixture at reflux temperature and the reaction mixture was stirred for 30 min at the same temperature. Carbon (0.5 gm) was added to the reaction mixture and stirred for 30 min at reflux temperature. Filtered the reaction mixture through high flow bed and washed with methanol. Cooled the filtrate to 0° C to 5° C and stirred for 60 min at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound.
Yield: 3.6 gm; Purity by HPLC: 99.91%;
Methanol content: 69,000 ppm;
Example-6: Preparation of crystalline form-S of N-(2,4-di-tert-butyl-5-hydroxy phenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide (Formula-1)
Dissolving N-(2,4-di-tert-butyl-5-hydroxyphenyl)- 1 ,4-dihydro-4-oxoquinoline-3- carboxamide (5 gm) in methylisobutylketone (70 ml) at reflux temperature and stirred for
30 min. Carbon was added to the reaction mixture at reflux temperature and stirred for 30 min at the same temperature. Filtered the reaction mixture and washed with methylisobutylketone. The obtained filtrate was cooled to 25° C to 30° C and stirred for 30 min at the same temperature. The reaction mixture was cooled to 0° C to 5° C and stirred for 60 min. Filtered the precipitated solid, washed with MIBK and dried to get the title compound. Yield: 3.4 gm. Purity by HPLC: 99.88%;
Methylisobutylketone content: 70,000 ppm.
The PXRD and DSC of the obtained compound are illustrated in figure-3 and figure-7 respectively.
Example-7: Preparation of crystalline form-N of N-(2,4-di-tert-butyl-5-hydroxy phenyI)-l,4-dihydro-4-oxoquinoline-3-carboxamide (Formula-1)
Dissolving N-(2,4-di-tert-butyl-5-hydroxyphenyl)- 1 ,4-dihydro-4-oxoquinoline-3- carboxamide (5 gm) in Ν,Ν-dimethyl formamide (20 ml) at reflux temperature. Water (60 ml) was slowly added to the reaction mixture at reflux temperature and the reaction mixture was stirred for 30 min at the same temperature. Carbon (0.5 gm) was added to the reaction mixture and stirred for 30 min at reflux temperature. Filtered the reaction mixture through high flow bed and washed with water. Cooled the filtrate to 0° C to 5° C and stirred for 60 min at the same temperature. Filtered the solid, washed with methanol and dried to get the title compound.
Yield: 3.6 gm; Water content: 2.5%.
The PXRD of the obtained compound is illustrated in figure-4.
Example-8: Preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oxo quinoIine-3-carboxamide (formula-1)
A mixture of 4-oxo-l,4-dihydroquinoline-3-carboxylic acid (25 gm), N,N- dimethylformamide (125 ml) and l-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC.HC1) (50.8 gm) was stirred for 10 minutes at 25-30°C. 1- Hydroxybenzotriazole (HOBT) (17.87 gm) was added to the reaction mixture at 25-30°C and stirred for 45 minutes. 5-amino-2,4-di-tert-butylphenol (35 gm) and sodium bicarbonate (27 gm) was added to the reaction mixture at 25-30°C and stirred for 22
hours at the same temperature. Quenched the reaction mixture into water at 25-30°C and stirred for 1 hour. Filtered the precipitated solid and washed with water. Water was added to the above wet compound at 25-30°C and stirred for 2 hours at the same temperature. Filtered the solids washed with water and dried. Recrystallized the obtained compound from ethanol to get the title compound.
Yield: 46 gm; Purity by HPLC: 99.88%.
Example-9: Preparation of crystalline form-B of N-(2,4-di-tert-butyl-5- hydroxyphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide
N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-l ,4-dihydroquinoline-3- carboxamide (20 gm) was added to 2-butanone (100 ml) at 30-35°C. The reaction mixture was heated to 75-80°C. Water (10 ml) was added to the reaction mixture at 75- 80°C and stirred for 30 minutes at the same temperature. Carbon was added to the reaction mixture at 75-80°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through high flow bed and washed with 2-butanone. Distilled off the solvent from the filtrate completely under reduced pressure and co-distilled with water. Water was added to the obtained compound and stirred for 30 minutes at 65-70°C. The obtained solid was filtered at 65-70°C, washed with water and dried to get the title compound.
Yield: 15 gm: MR: 291.3 TC (DSC); Purity by HPLC: 99.90%.
Particle size distribution: D (0.1): 5.47 μηι; D(0.5): 15.26 μπι; D(0.9): 61.25 μηι; D[4,3] : 26.35.
The PXRD pattern of the obtained compound is matching with crystalline form-B of compound of formula- 1 disclosed in US 8410274B2.
Claims
We Claim:
1. A process for the preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4- oxoquinoline-3 -carboxamide compound of formula-1 , comprising of reacting 4-oxo- l ,4-dihydroquinoline-3-carboxylic acid
with 5-Amino-2,4-di-tert-butylphenol
in presence of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl), hydroxybenzotriazole (HOBt) and a suitable base in a suitable solvent provides N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-l ,4-dihydroquinoline-3- carboxamide compound of formula-1 , optionally purifying the obtained compound from a suitable solvent provides pure compound of formula-1. 2. The process according to claim- 1, wherein, the suitable base is selected from organic base or inorganic base; and the suitable solvent is selected from polar aprotic solvents, ether solvents, ketone solvents, ester solvents, hydrocarbon solvents and alcohol solvents. 3. A process for the preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4- oxoquinoline-3-carboxamide compound of formula-1 , comprising of reacting 4-oxo- l ,4-dihydroquinoline-3-carboxylic acid with 5-Amino-2,4-di-tert-butylphenol in presence of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl), hydroxybenzotriazole (HOBt) and sodium bicarbonate in N,N- dimethylformamide provides N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-l ,4- dihydroquinoline-3-carboxamide compound of formula-1.
A process for the preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4- oxoquinoline-3-carboxamide compound of formula- 1 , comprising of reacting 4-oxo- l,4-dihydroquinoline-3-carboxylic acid with 5-Amino-2,4-di-tert-butylphenol in presence of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl), hydroxybenzotriazole (HOBt) and triethylamine in N,N-dimethyl formamide provides N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-l ,4-dihydro quinoline-3-carboxamide compound of formula- 1.
A process for the preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4- oxoquinoline-3-carboxamide compound of formula- 1 , comprising of reacting 4-oxo- l,4-dihydroquinoline-3-carboxylic acid with 5-Amino-2,4-di-tert-butylphenol in presence of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl), hydroxybenzotriazole (HOBt) and sodium bicarbonate in N,N- dimethylformamide provides N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-l ,4- dihydroquinoiine-3-carboxamide compound of formula- 1 , wherein the amount of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl) used in the range of 1-3 molar equivalents, preferably 1 -2 molar equivalents and the amount of hydroxybenzotriazole (HOBt) used in the range of 1-3 molar equivalents, preferably 1-2 molar equivalents with respect to 1 molar equivalent of 4-oxo-l ,4- dihydroquinoline-3-carboxylic acid.
The process according to any of the preceding claims, wherein the amount of l-(3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC.HCl) used in the range of 1-3 molar equivalents, preferably 1 -2 molar equivalents and the amount of hydroxybenzotriazole (HOBt) used in the range of 1-3 molar equivalents, preferably 1-2 molar equivalents with respect to 1 molar equivalent of 4-oxo-l ,4- dihydroquinoline-3-carboxylic acid.
A process for the preparation of crystalline form-B of N-(2,4-di-tert-butyl-5- hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 , comprising of:
a) Adding a suitable solvent to N-(2,4-di-tert-butyl-5-hydroxyphenyl)- 1 ,4-dihydro-4- oxoquinoline-3-carboxamide compound of formula- 1,
b) heating the reaction mixture,
c) adding a second solvent to the reaction mixture,
d) stirring the reaction mixture,
e) optionallyj treating the reaction mixture with carbon,
f) distilling off the solvent completely from the reaction mixture,
g) adding third solvent to the obtained compound,
h) stirring the reaction mixture at a suitable temperature,
i) filtering the reaction mixture,
j) drying the solid to get crystalline form-B of compound of formula- 1.
8. The process according to claim-7, wherein in step-c) & step-g) the suitable second & third solvent is water.
9. A process for the preparation of crystalline form-B of jV-(2,4-di-tert-butyl-5- hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula-1 , comprising of:
a) Adding 2-butanone to N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4- oxoquinoline-3-carboxamide compound of formula-1 ,
b) heating the reaction mixture at 70°C to 80°C,
c) adding water to the reaction mixture,
d) stirring the reaction mixture,
e) treating the reaction mixture with carbon,
f) distilling off the solvent completely from the reaction mixture,
g) adding water to the obtained compound,
h) stirring the reaction mixture at 60°C to 70°C,
i) filtering the reaction,
j) drying the solid to get crystalline form-B of compound of formula-1.
10. A crystalline form-M of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4- oxoquinoline-3-carboxamide compound of formula-1 , which is characterized by:
i) its PXRD pattern substantially in accordance with figure-2,
ii) its powder X-ray diffractogram having peaks at 7.28, 10.76, 13.05, 13.87, 14.03, 20.39, and 32.7±0.2 degrees of two-theta, and
iii) its DSC thermogram substantially in accordance with figure-6,
1 1. A crystalline form-S of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4- oxoquinoline-3-carboxamide compound of formula- 1, which is characterized by; i. its PXRD pattern substantially in accordance with figure- 3,
ii. its powder X-Ray diffractogram having peaks at 4.40, 5.07, 8.86, 1 1.81 and 15.47 ±0.2 degrees of two-theta, and
iii. its DSC thermogram substantially in accordance with figure-7.
12. N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3-carboxamide hemihydrate.
13. N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3-carboxamide hemihydrate according to claim-12 is a crystalline solid (crystalline form-N).
14. The crystalline form-N according to claim- 13, is characterized by:
i) its PXRD pattern substantially in accordance with figure-4,
ii) its powder X-Ray diffractogram having peaks at 3.61 , 7.22, 7.85, 9.78, 14.30, 14.75, 16.59, 18.27, 18.79, 20.46, 21.68 and 23.8 ±0.2 degrees of two-theta.
15. A process for the preparation of crystalline form-M of N-(2,4-di-tert-butyl-5- hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1, comprising of:
a) Dissolving N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula- 1 in a suitable solvent at a suitable temperature,
b) adding methanol to the reaction mixture,
c) stirring the reaction mixture,
d) optionally, treating the reaction mixture with carbon,
e) cooling the reaction mixture,
f) filtering the precipitated solid and drying to get crystalline form-M of compound of formula- 1. 16. The process according to claim-15, wherein in step a), the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, polar aprotic solvents, ether solvents, alcoholic solvents, polar solvents and/or mixtures thereof.
17. A process for the preparation of crystalline form-M of N-(2,4-di-tert-butyl-5- hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula-1 , comprising of:
a) Dissolving N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula-1 in Ν,Ν-dimethyl formamide at reflux temperature,
b) adding methanol to the reaction mixture,
c) stirring the reaction mixture,
d) treating the reaction mixture with carbon,
e) cooling the reaction mixture to 0°C to 5°C,
f) filtering the precipitated solid and drying to get crystalline form-M of compound of formula-1.
18. A process for the preparation of crystalline form-M of N-(2,4-di-tert-butyl-5- hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula-1 , comprising of:
a) Dissolving N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula-1 in dichloromethane at reflux temperature, b) adding methanol to the reaction mixture,
c) stirring the reaction mixture,
d) treating the reaction mixture with carbon,
e) cooling the reaction mixture to 0°C to 5°C,
f) filtering the precipitated solid and drying to get crystalline form-M of compound of formula-1.
19. A process for the preparation of crystalline form-M of N-(2,4-di-tert-butyl-5- hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 , comprising of:
a) Dissolving N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula- 1 in ethylacetate at reflux temperature, b) adding methanol to the reaction mixture,
c) stirring the reaction mixture,
d) treating the reaction mixture with carbon,
e) cooling the reaction mixture to 0°C to 5°C,
f) filtering the precipitated solid and drying to get crystalline form-M of compound of formula- 1.
A process for the preparation of crystalline form-S of N-(2,4-di-tert-butyl-5- hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3 -carboxamide compound of formula- 1 , comprising of:
a) Dissolving N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula- 1 in methylisobutylketone at reflux temperature,
b) stirring the reaction mixture,
c) treating the reaction mixture with carbon,
d) cooling the reaction mixture to 0° C to 5° C,
e) filtering the precipitated solid and drying to get crystalline form-S of compound of formula- 1. 21. A process for the preparation of crystalline form-N of N-(2,4-di-tert-butyl-5- hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3 -carboxamide compound of formula- 1 , comprising the following steps of:
a) Dissolving N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3- carboxamide compound of formula- 1 in Ν,Ν-dimethylformamide at reflux temperature,
b) adding water to the reaction mixture,
c) treating the reaction mixture with carbon,
d) cooling the reaction mixture to 0° C to 5° C,
e) stirring the reaction mixture for 1 hour at the same temperature,
f) filtering the precipitated solid and drying to get crystalline form-N of compound of formula- 1.
22. Particle size distribution of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4- oxoquinoline-3-carboxamide compound of formula- 1 having D(0.9) less than 200 μιη, preferably less than 150 μηι, more preferably less than 100 μπι. 23. N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l ,4-dihydro-4-oxoquinoline-3-carboxamide compound of formula- 1 obtained according to any of the preceding claims having purity more than 99% by HPLC, preferably more than 99.9% purity by HPLC.
24. Use of crystalline Form-M or Form-S or Form-N of N-(2,4-di-tert-butyl-5- hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide according to the preceding claims for the preparation of crystalline form-B of compound of formula- 1.
25. Use of crystalline Form-M or Form-S or Form-N of N-(2,4-di-tert-butyl-5- hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide according to the preceding claims for the preparation of pharmaceutical composition.
Dated this day ^ ' ζ of February 2015.
(Srinivasan Thirumalai Rajan) MSN Laboratories Private Limited.
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| US20160096807A1 (en) * | 2014-10-07 | 2016-04-07 | Vertex Pharmaceuticals Incorporated | Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator |
| WO2017037672A1 (en) | 2015-09-02 | 2017-03-09 | Laurus Labs Private Limited | Processes for the preparation of ivacaftor |
| US9670163B2 (en) | 2005-12-28 | 2017-06-06 | Vertex Pharmaceuticals Incorporated | Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
| CN114380746A (en) * | 2020-10-22 | 2022-04-22 | 台湾神隆股份有限公司 | Novel crystalline form of ivacaiton and preparation method thereof |
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| ME02799B (en) * | 2004-06-24 | 2018-01-20 | Vertex Pharma | Modulators of transporters of the ATP binding cassette |
| CA2635581C (en) * | 2005-12-28 | 2017-02-28 | Vertex Pharmaceuticals Incorporated | Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
| NZ600865A (en) * | 2007-09-14 | 2014-01-31 | Vertex Pharma | Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
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| US9670163B2 (en) | 2005-12-28 | 2017-06-06 | Vertex Pharmaceuticals Incorporated | Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
| US20160096807A1 (en) * | 2014-10-07 | 2016-04-07 | Vertex Pharmaceuticals Incorporated | Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator |
| US9701639B2 (en) | 2014-10-07 | 2017-07-11 | Vertex Pharmaceuticals Incorporated | Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator |
| WO2017037672A1 (en) | 2015-09-02 | 2017-03-09 | Laurus Labs Private Limited | Processes for the preparation of ivacaftor |
| US10815202B2 (en) | 2015-09-02 | 2020-10-27 | Laurus Labs Limited | Process for the preparation of ivacaftor |
| US11414386B2 (en) | 2015-09-02 | 2022-08-16 | Laurus Labs Limited | Process for the preparation of ivacaftor and its intermediates |
| CN114380746A (en) * | 2020-10-22 | 2022-04-22 | 台湾神隆股份有限公司 | Novel crystalline form of ivacaiton and preparation method thereof |
| WO2022086434A1 (en) | 2020-10-22 | 2022-04-28 | Scinopharm Taiwan, Ltd. | A novel crystalline form of ivacaftor and a process for preparing the same |
| US11384054B2 (en) | 2020-10-22 | 2022-07-12 | Scinopharm Taiwan, Ltd. | Crystalline form of ivacaftor and a process for preparing the same |
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