DESC:The following specification particularly describes the invention and the manner in
which it is to be performed:

IMPROVED PROCESS FOR PREPARATION OF IVACAFTOR
INTRODUCTION
Aspects of the present application relate to an improved process for preparation of Ivacaftor.
The drug compound having the adopted name Ivacaftor, has a chemical name 4N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4oxoquinoline-3-carboxamide, and is represented by structure of formula I.

I
Ivacaftor is a is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis (CF) who have one of the following mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R.
U.S. Patent No. 7,495,103 and U.S. Patent No. 8, 476, 442 discloses process for preparation of ivacaftor and intermediates thereof.
The reported processes suffer from disadvantages including tedious workup procedures and multiple purifications using column chromatography.
There remains a need to provide a simple, economic, industrially viable processes for preparation of Ivacaftor.
SUMMARY
In the first embodiment, the present application provides a process for preparation of ivacaftor of formula I, said process comprising reacting a compound of formula VII with a compound of formula VIII in a solvent comprising an ester solvent.

In the second embodiment, the present application provides a process for preparation of ivacaftor of formula I, said process comprising reacting a compound of formula VII with a compound of formula VIII in a solvent comprising ethyl acetate.

In the third embodiment, the present application provides an improved process for preparation of ivacaftor of formula I, said process comprising:

(a) reducing nitro compound of formula Va to provide amino compound of formula VI,

(b) converting compound of formula VI to compound of formula VII, and

(c) optionally purifying the compound of formula VII obtained in step (b) in a solvent comprising aliphatic or alicyclic hydrocarbons, and
(d) reacting compound of formula VII with a compound of formula VIII in a solvent comprising an ester solvent to provide ivacaftor.

In the fourth embodiment, the present application provides an improved process for preparation of ivacaftor of formula I, said process comprising:

(a) reducing nitro compound of formula Va to provide amino compound of formula VI,

(b) converting compound of formula VI to compound of formula VII, and

(c) purifying the compound of formula VII obtained in step (b) in a solvent comprising cyclohexane, and
(d) reacting compound of formula VII with a compound of formula VIII in a solvent comprising ethyl acetate to provide ivacaftor.

DETAILED DESCRIPTION
In the first embodiment, the present application provides a process for preparation of ivacaftor of formula I, said process comprising reacting a compound of formula VII with a compound of formula VIII in a solvent comprising an ester solvent.

Suitable coupling agents that may be used during the reaction of compound of formula VII with a compound of formula VIII include, propylphosphonic anhydride (T3P), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM), N-hydroxybenzotriazole (HOBT), 4,5-dicyanoimidazole, dicyclohexylcarbodiimide (DCC), dicyclopentylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HCl), 1,1’-carbonyldiimidazole, cyclohexylisopropylcarbodiimide (CIC), bis[[4-(2,2-dimethyl-1,3-dioxolyl)]methyl] carbodiimide, N,N’-bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (BOP-Cl), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa?uorophosphate (HBTU) or via mixed anhydride formation and the like or the any two or more reagents combination thereof or any other suitable reagents known in the art.
Suitable bases that may be used during the reaction of compound of formula VII with a compound of formula VIII include, triethylamine, tributylamine, N-methylmorpholine, N, N-diisopropylethylamine, N-methylpyrrolidine, N-methylpiperidine, pyridine, 4-(N, N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and the like or any other suitable reagents known in the art.
Suitable ester solvents that may be used in the present invention include C3-C12 esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate and the like.
Ivacaftor obtained from the above embodiment may be further purified using suitable purification methods include, recrystallization, slurring in a suitable solvent, acid-base treatment, column chromatography, treating with adsorbent materials such as silica gel, aluminium oxide, synthetic resin, and the like; or any other suitable techniques.
Suitable solvents that may be used for purification of ivacaftor of formula I include, alcohols, ketones, esters, ethers, unsubstituted or substituted aliphatic or alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents, water; and any mixtures of two or more thereof.
The product thus obtained may be recovered as solid using conventional methods including decantation, centrifugation, gravity filtration, suction filtration, or other techniques known in the art. The resulting compound may be in the form of a crystalline compound, a solvate, an amorphous compound, or a mixture thereof. The solid may be optionally further dried. Drying may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 180°C, less than about 120°C, less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere, such as nitrogen, argon, neon, or helium. The drying may be carried out for desired time periods to achieve the desired quality of the product, such as, for example, about 1 to about 15 hours, or longer.
In the second embodiment, the present application provides a process for preparation of ivacaftor of formula I, said process comprising reacting a compound of formula VII with a compound of formula VIII in a solvent comprising ethyl acetate.

In the third embodiment, the present application provides an improved process for preparation of ivacaftor of formula I, said process comprising:

(a) reducing nitro compound of formula Va to provide amino compound of formula VI,

(b) converting compound of formula VI to compound of formula VII, and

(c) optionally purifying the compound of formula VII obtained in step (b) in a solvent comprising aliphatic or alicyclic hydrocarbons, and
(d) reacting compound of formula VII with a compound of formula VIII in a solvent comprising an ester solvent to provide ivacaftor.

Step (a) involves reducing nitro compound of formula Va to provide amino compound of formula VI.

Suitable reducing agents that may be used in step (a) include, palladium-on-carbon, platinum(IV) oxide, Raney nickel, Sodium hydrosulfite, Sodium sulfide, Tin(II) chloride, Titanium(III) chloride, Zinc, sodium borohydride, lithium aluminium hydride, diisobutylaluminium hydride and the like or any other suitable reagents that are known in the art.
Suitable solvents that may be used in step (a) include alcohols, ethers, halogenated hydrocarbons or any mixtures of two or more thereof.
The reaction mixture obtained from step (a) may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the removal of solids. The product of step (a) may be isolated directly from the reaction mixture itself after the reaction is complete in step (a), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally, the resulting product may be directly used for step (b) with or without isolation or it may be further purified to improve the purity of the product.
Step (b) involves converting compound of formula VI to compound of formula VII, and
Suitable bases that may be used in step (b) include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide; carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, alkoxides such as sodium methoxide, potassium methoxide and the like or any other suitable bases known in the art.
Suitable solvents that may be used in step (b) include water, alcohols, ethers, halogenated hydrocarbons, polar aprotic solvents or any mixtures of two or more thereof.
The reaction mixture obtained from step (b) may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other suitable techniques for the removal of solids. The product of step (b) may be isolated directly from the reaction mixture itself after the reaction is complete in step (b), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like. Optionally, an obtained crude product may be directly used for step (c) with or without isolation or it may be further purified, if isolated, to improve the purity of the product.
Step (c) involves optionally purifying the compound of formula VII obtained in step (b) in a solvent comprising aliphatic or alicyclic hydrocarbons.
Suitable purification methods that may be used in step (c) include, recrystallization, slurring in a suitable solvent, acid-base treatment, column chromatography, treating with adsorbent materials such as silica gel, aluminium oxide, synthetic resin, and the like; or any other suitable techniques.
Suitable aliphatic or alicyclic hydrocarbons solvents that may be used in step (c) include, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers or any mixtures of two or more thereof.
Step (d) involves reacting compound of formula VII with a compound of formula VIII in a solvent comprising an ester solvent to provide ivacaftor.

Suitable coupling agents that may be used in step (d) include, propylphosphonic anhydride (T3P), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM), N-hydroxybenzotriazole (HOBT), 4,5-dicyanoimidazole, dicyclohexylcarbodiimide (DCC), dicyclopentylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HCl), 1,1’-carbonyldiimidazole, cyclohexylisopropylcarbodiimide (CIC), bis[[4-(2,2-dimethyl-1,3-dioxolyl)]methyl] carbodiimide, N,N’-bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (BOP-Cl), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa?uorophosphate (HBTU) or via mixed anhydride formation and the like or the any two or more reagents combination thereof or any other suitable reagents known in the art.
Suitable bases that may be used in step (d) include, triethylamine, tributylamine, N-methylmorpholine, N, N-diisopropylethylamine, N-methylpyrrolidine, N-methylpiperidine, pyridine, 4-(N, N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and the like or any other suitable reagents known in the art.
Suitable ester solvents that may be used in step (d) include C3-C12 esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate and the like.
Ivacaftor obtained from the above embodiment may be further purified using suitable purification methods include, recrystallization, slurring in a suitable solvent, acid-base treatment, column chromatography, treating with adsorbent materials such as silica gel, aluminium oxide, synthetic resin, and the like; or any other suitable techniques.
Suitable solvents that may be used for purification of ivacaftor of formula I include, alcohols, ketones, esters, ethers, unsubstituted or substituted aliphatic or alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents, water; and any mixtures of two or more thereof.
The product thus obtained may be recovered as solid using conventional methods including decantation, centrifugation, gravity filtration, suction filtration, or other techniques known in the art. The resulting compound may be in the form of a crystalline compound, a solvate, an amorphous compound, or a mixture thereof. The solid may be optionally further dried. Drying may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 180°C, less than about 120°C, less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere, such as nitrogen, argon, neon, or helium. The drying may be carried out for desired time periods to achieve the desired quality of the product, such as, for example, about 1 to about 15 hours, or longer.
In the fourth embodiment, the present application provides an improved process for preparation of ivacaftor of formula I, said process comprising:

(a) reducing nitro compound of formula Va to provide amino compound of formula VI,

(b) converting compound of formula VI to compound of formula VII, and

(c) purifying the compound of formula VII obtained in step (b) in a solvent comprising cyclohexane, and
(d) reacting compound of formula VII with a compound of formula VIII in a solvent comprising ethyl acetate to provide ivacaftor.

DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise. In general, the number of carbon atoms present in a given group or compound is designated “Cx-Cy”, where x and y are the lower and upper limits, respectively. For example, a group designated as “C1-C6” contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions or the like.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol and the like.
An “aliphatic hydrocarbon” is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called “aromatic.” Examples of “C5-C8 aliphatic or aromatic hydrocarbons” include n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, and the like.
An “aromatic hydrocarbon solvent” refers to a liquid, unsaturated, cyclic, hydrocarbon containing one or more rings which has delocalized conjugated p system. Examples of an aromatic hydrocarbon solvent include benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-C12 aromatic hydrocarbons and the like.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6 esters” include ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate and the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two other carbon atoms. “C2-C6 ethers” include diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole and the like.
A “halogenated hydrocarbon” is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride and the like.
A “polar aprotic solvents” include N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, sulfolane, N-methylpyrrolidone, ethyl acetate, tetrahydrofuran, acetonitrile and the like;
An “alicyclic hydrocarbons” is an organic compound containing both aliphatic and cyclic carbon atoms. They contain one or more all-carbon rings which may be either saturated or unsaturated, but do not have aromatic character. Alicyclic hydrocarbons include cyclohexane, methylcyclohexane, cycloheptane and the like.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present application. While particular aspects of the present application have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this application.

EXAMPLES
EXAMPLE 1: Preparation of 5-amino-2,4-di-tert-butylphenol. 2-bromo-4,6-di-tert-butyl-3-nitrophenyl methyl carbonate (300 g) Sodium bicarbonate (71.4 g), 10% Pd/C (45 g;15% loading) and methanol (4.5 L) were charged into autoclave vessel at 30 °C. Reaction mass was flushed with nitrogen two times and with hydrogen times. Hydrogen gas (7kg/cm2) was applied at 30 °C and stirred at 45 °C for 5 hours. Hydrogen gas was released, reaction mass filtered, washed with methanol (900 mL) and filtrate concentrated until solvent collection reaches to 1.5 L (5.0 volumes). Sodium hydroxide (46.4 g) was added to the reaction mass at 5 °C and stirred at 11 °C for 1 hour. Water (1.8 L) was slowly added to the reaction mass at 15 °C and the resultant reaction mass pH was adjusted to 5-6 using 50% hydrochloric acid. Reaction mass was stirred at 28 °C for 30 minutes, separated solid was filtered, washed with water (900 mL) & cyclohexane (600 mL) and wet compound dried at 50 °C under reduced pressure to afford title compound (143.7 g).
EXAMPLE 2: Preparation of Ivacaftor
2-(1H-benzotriazol-1-yl)-1, 1, 3, 3-tetramethyluronium hexa?uorophosphate (72.2 g) was added to the reaction mass containing 4-oxo-1, 4-dihydroquinoline-3-carboxylic acid (30 g) and ethyl acetate (600 mL) at 26 °C. Triethylamine (32.1 g) was slowly added to the reaction mass at 26 °C, heated to 45 °C and stirred at 45 °C for 1 hour. 5-amino-2,4-di-tert-butylphenol (42.1 g) was added at 45 °C and the resultant reaction mass was stirred at 45 °C for 7 hours. 10% hydrochloric acid solution (150 mL) was slowly added to the reaction mass and stirred for 10 minutes. Layers were separated, organic layer washed with water (180 mL), 10% sodium bicarbonate solution (150 mL) and the resultant organic layer concentrated in vacuo. Methanol (300 mL) was added to the crude at 27 °C, heated to 60 °C and stirred at 60 °C for 30 minutes. Separated solid was filtered at 30 °C, washed with methanol (90 mL) and dried at 51 °C to afford title compound (47.1 g).
,CLAIMS:WE CLAIM:

1. A process for preparation of ivacaftor of formula I, said process comprising reacting a compound of formula VII with a compound of formula VIII in a solvent comprising an ester solvent.

2. The process according to claim 1, wherein an ester solvent is ethyl acetate.

3. An improved process for preparation of ivacaftor of formula I, said process comprising:

(a) reducing nitro compound of formula Va to provide amino compound of formula VI,

(b) converting compound of formula VI to compound of formula VII, and

(c) optionally purifying the compound of formula VII obtained in step (b) in a solvent comprising aliphatic or alicyclic hydrocarbons, and
(d) reacting compound of formula VII with a compound of formula VIII in a solvent comprising an ester solvent to provide ivacaftor.

4. The process according to claim 3, wherein the aliphatic or alicyclic hydrocarbons solvent is cyclohexane

5. The process according to claim 3, wherein the ester solvent is cyclohexane