DESC:Field of the Invention
The present invention relates to a process for the preparation of ivacaftor. The present invention also relates to the process for the preparation of intermediates of ivacaftor, which are further used for the preparation of ivacaftor.
Background of the Invention
Ivacaftor is a drug used to treat cystic fibrosis in people with certain mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (primarily the G551D mutation), who account for 4–5% cases of cystic fibrosis. It is also included in a combination drug, lumacaftor/ivacaftor (trade name Orkambi), which is used to treat people with cystic fibrosis who have the F508del mutation in CFTR. More recently, a new combination of Tezacaftor / Ivacaftor (trade name Symdeco) has been approved by USFDA.
Ivacaftor was approved by FDA and is marketed by Vertex pharma under the brand name KALYDECO®.

Ivacaftor is chemically known as N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, having molecular weight 392.49 and formula C24H28N2O3. Ivacaftor has the following structural Formula 1:

Formula 1

Ivacaftor was first referred in US7495103. However, ivacaftor process was not specifically disclosed. The '103 patent disclosed that heating a mixture of aniline of Formula 2 and diethyl 2-(ethoxymethylene)malonate of Formula 3 at 140-150°C to afford 2-phenylamino methylene-malonic acid diethyl ester of Formula 4, which further treated with polyphosphoric acid and phosphoryl chloride to form ethyl 1,4-dihydro-4-oxoquinoline-3-carboxylate of Formula 5. Further hydrolyzed to form 1,4-dihydro-4-oxoquinoline-3-carboxylic acid of Formula 6, then on condensation with 2,4-di-tert-butyl-5-aminophenol of Formula 7 in presence of a coupling reagent such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide-hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIEA) in dimethylformamide and purifying the obtained compound by HPLC. The process disclosed in the '103 patent as per below mentioned Scheme 1:

This process for the preparation of ivacaftor disclosed heating at very high temperature (140-150°C), which is not feasible for commercial scale production. Moreover, the process involves the use of high quantity of polyphosphoric acid and phosphoryl chloride, which generates huge quantity of effluent and large amount of impurities, which are difficult to remove or require successive purifications to get the pure compound. Therefore, yield obtained of ivacaftor is low. In-addition of this, large quantity of base will be required to neutralize the high quantity of acidic effluent generated.

US8476442B2 discloses a process for the preparation of ivacaftor by heating a mixture of aniline of Formula 2 and diethyl 2-(ethoxymethylene)malonate of Formula 3 at 100-110°C to afford 2-phenylamino methylene-malonic acid diethyl ester of Formula 4, which further treated in presence of phenyl ether at 228-232°C to form ethyl 1,4-dihydro-4-oxoquinoline-3-carboxylate of Formula 5. Subsequently, the compound of Formula 5 is hydrolyzed to form 1,4-dihydro-4-oxoquinoline-3-carboxylic acid of Formula 6, which on further reaction with 5-amino-2,4-di-tert-butylphenyl methyl carbonate of Formula 8 in the presence of propane phosphonic anhydride and pyridine using 2-methyltetrahydrofuran gives hydroxy protected ivacaftor of Formula 9. Finally, the compound of Formula 9 is deprotected using NaOMe/MeOH in presence of 2-methyltetrahydrofuran to obtain ivacaftor as per below mentioned scheme 2:

This process for the preparation of ivacaftor is cumbersome, which involves many numbers of steps and costlier reagent like propane phosphonic anhydride, NaOMe and pyridine. The strong unpleasant odor of pyridine is not conducive to industrial application. Further, it causes the health hazards to the plant chemists / workers. The unavoidable inhalation of pyridine causes dizziness, headache, insomnia, ataxia, nervousness, loss of appetite, gastrointestinal dysfunction, and in turn, liver and kidney damage can occur. It can also cause dermatitis. Also, use of ethereal solvent such as 2-methyltetrahydrofuran is not preferred on commercial scale due to the cost and safety of the same. This process involves heating at higher temperature 100-110°C and 228-232°C, due to which intermediate compounds 4 and 5 respectively are formed with large amount of impurities.
Increased number of steps / unit operations, in turn increases the cost of chemicals, utilities, occupancy of the plant, requirement of manpower and hence the cost of the production.
IN4022/MUM/2015 discloses a process for the preparation of compound of Formula 6 by coupling diethyl 2-(ethoxymethylene)malonate of Formula 3 with aniline of Formula 2 in the presence of isopropyl alcohol to obtain compound of Formula 4. Further treating with polyphosphoric acid in the presence of sulfolane at 102± 3°C. Then hydrolyse with sodium hydroxide to obtain compound of Formula 6. This process involves the use of additional solvent isopropyl alcohol and higher temperature 102± 3°C. In addition, the solvent used sulfolane is costlier and more toxic as compare to other solvents. Therefore, process is relatively less economical, hence, not suitable for commercial production.
Therefore, the prior art processes are relatively costly, unsafe and hence, not suitable for commercial production.
Many other patent publications have also been disclosed so far, which describe the process for the preparation of ivacaftor. Still there is a need to develop a simple, cost effective, high yielding and easy to implement process for the preparation of ivacaftor and intermediates thereof, on industrial scale.
Object of the invention
The principal object of the present invention is to provide a process for the preparation of ivacaftor, which alleviates one or more of the drawbacks of prior art processes.
One object of the present invention is to provide an improved, efficient, safe and convenient process for preparation of ivacaftor.
Another object of the present invention is to provide a process for preparation of ivacaftor intermediate i.e 1,4-dihydro-4-oxoquinoline-3-carboxylic acid of Formula 6 and its use in preparation of ivacaftor.
Further, another object of the present invention is to provide a process for the preparation of crystalline ivacaftor.ethanol solvate and its conversion to pure ivacaftor.
Another object of the present invention is to provide Ivacaftor having High Performance Liquid chromatographic (HPLC) purity of at least 99.9%.

Summary of the invention
In accordance with principal embodiment, the present invention provides a process for the preparation of ivacaftor, comprising the steps of:
(a) coupling of compound of Formula 2

with compound of Formula 3

to provide compound of Formula 4;

(b) cyclizing the compound of Formula 4 using a suitable cyclizing agent, in the presence or absence of solvent, to provide compound of Formula 5;

(c) hydrolyzing compound of Formula 5 using suitable base in the presence of suitable solvent to provide compound of Formula 6;

(d) coupling of compound of Formula 6 with compound of Formula 7

using suitable base and reagent in the presence of suitable solvent to form ivacaftor; and
e) optionally, purifying by suitable method.
In accordance with another embodiment, the present invention provides a process for the preparation of ivacaftor, comprising the steps of:
(a) coupling of compound of Formula 2

with compound of Formula 3

to provide compound of Formula 4;

(b) cyclizing the compound of Formula 4 using phosphorous oxychloride and polyphosphoric acid to provide compound of Formula 5;

(c) hydrolyzing compound of Formula 5 using sodium hydroxide in the presence of water as solvent to provide compound of Formula 6;

(d) coupling of compound of Formula 6 with compound of Formula 7

using triethyl amine and HBTU in the presence of N,N- dimethylformamide to form ivacaftor; and
e) optionally, purifying by suitable method.
In accordance with another embodiment, the present invention provides a process for the preparation of ivacaftor intermediate of Formula 6 and its use in preparation of ivacaftor, comprising the steps of:
(a) coupling of compound of Formula 2

with compound of Formula 3

to provide compound of Formula 4 at a temperature of 55-65°C;

(b) cyclizing the compound of Formula 4 using phosphorous oxychloride and polyphosphoric acid to provide compound of Formula 5;

(c) hydrolyzing compound of Formula 5 using sodium hydroxide in the presence of water as solvent to provide compound of Formula 6; and

d) finally, converting to ivacaftor.
In accordance with another embodiment, the present invention provides a process for the preparation of crystalline ivacaftor.ethanol solvate and further conversion to pure ivacaftor.
Detail description of the drawings:
Fig.1: Illustrates the X-ray powder diffraction (XRPD) pattern of ivacaftor ethanol solvate.
Fig.2: Illustrates the X-ray powder diffraction (XRPD) pattern of ivacaftor.

Detail description of the invention
The present invention provides an efficient and industrially advantageous process for the preparation of ivacaftor and intermediate thereof.
In accordance with one embodiment, the present invention provides a process for the preparation of ivacaftor comprising the first step a) involves coupling aniline of Formula 2 with diethyl 2-(ethoxymethylene)malonate of Formula 3 in the presence or absence of the solvent to afford 2-phenylamino methylene-malonic acid diethyl ester of Formula 4. Generally, reaction may be carried out at a temperature of 40 to 80°C for few minutes to few hours or until completion of reaction. Preferably, reaction is conducted at a temperature of 50 to 70°C, more preferably reaction is conducted at 55 to 65°C and it takes 6 to 8 hours for completion of the reaction.
After completion of reaction, compound of Formula 4 with or without isolation may be taken for next step.
Second, step b) involves cyclizing the compound of Formula 4 using a suitable cyclizing agent, in the presence or absence of solvent, to provide compound of Formula 5. Generally, reaction may be carried out at a temperature of room temperature to 80°C for few minutes to few hours or until completion of reaction. Preferably, reaction is conducted at a temperature of 50 to 70°C, more preferably, reaction is conducted at a temperature of 55 to 65°C for 12 to 15 hours.
Suitable reagent used for cyclization in step b) includes but not limited to phosphorous oxychloride/polyphosphoric acid, polyphosphoric acid/pyridine, Eaton’s reagent (phosphorus pentoxide in methanesulfonic acid) or the like and mixture thereof. Preferably, reagent used are phosphorous oxychloride/ polyphosphoric acid.
Third, step c) involves hydrolyzing compound of Formula 5 in the presence of suitable reagent to form compound of Formula 6. Generally, hydrolysis may be carried out at room temperature to reflux temperature for few minutes to few hours, preferably at a temperature of 20 to 90°C, more preferably reaction is conducted at a temperature of 70 to 80°C for 5 to 6 hours.
The base used for hydrolysis in step c) may be selected from inorganic or organic base, wherein inorganic base is selected from alkali or alkaline earth metal hydroxides, carbonates, bicarbonates such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate, cesium bicarbonate, sodium with liquid ammonia, sodamide or the like and mixture thereof. Organic base is selected from diisopropylethylamine, triethylamine, tributylamine and pyridine or the like and mixture thereof. Preferably, base used is sodium hydroxide.
Fourth, step d) involves coupling of compound of Formula 6 with compound of Formula 7 using suitable reagent and base in the presence of suitable solvent to form ivacaftor. Generally, coupling may be carried out at room temperature to reflux temperature for few minutes to few hours, preferably at a temperature of 25 to 75°C, more preferably reaction is conducted at a temperature of 45 to 50°C for 4 to 6 hours.
The suitable reagent used in step d) is selected from group comprising of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide-hexa fluorophosphate (HATU), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate(HBTU),N,N’-Dicyclohexylcarbodimide(DCC),1-(3-dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride(EDC.HCl), propanephosphonic acid anhydride (PPAA, T3P), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), 1,1'-Carbonyldiimidazole (CDI), N-hydroxysuccinimide (HOSu),(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), isobutyl chloroformate(IBCF), O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU) or the like and mixture thereof. Preferably, reagent used is HBTU.
The suitable solvent used in step d) is selected from group comprising of water, sulfoxides, alcohols, halogenated hydrocarbons, ethers, esters, amides, hydrocarbons such as dimethyl sulfoxide (DMSO), methanol, ethanol, n-propanol, isopropanol, n-butanol, dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene, diethyl ether, methyl tert-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, dioxane, methyl acetate, ethyl acetate, butyl acetate, isopropyl acetate, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylformamide, N-methylpyrrolidone, pentane, hexane, heptane, octane, cyclohexane, cyclopentane, toluene, xylene or the like and mixture thereof, preferably, solvent used is N,N-dimethylformamide (DMF).
The base used during condensation in step d) may be selected from inorganic or organic base, wherein inorganic base is selected from alkali or alkaline earth metal hydrides, hydroxides, carbonates, bicarbonates, sodium with liquid ammonia, sodamide or like and mixture thereof; organic bases may be selected from diisopropylethylamine, triethylamine, tributylamine, N-methylmorpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and pyridine or the like and mixture thereof, preferably, base used is triethyl amine.
The reaction completion is monitored by suitable techniques such as thin layer chromatography (TLC), high performance liquid chromatography (HPLC), ultra-performance liquid chromatography (UPLC), gas chromatography (GC) and the like thereof.
In accordance with another embodiment, the present invention provides a process for the preparation of ivacaftor, comprising the steps of:
(a) coupling of compound of Formula 2 with of Formula 3 at a temperature of 55 to 60 °C to provide compound of Formula 4;
(b) cyclizing the compound of Formula 4 using phosphorous oxychloride and polyphosphoric acid to provide compound of Formula 5;
(c) hydrolyzing compound of Formula 5 using sodium hydroxide in the presence of water as solvent to provide compound of Formula 6;
(d) coupling of compound of Formula 6 with compound of Formula 7 using triethylamine and HBTU in the presence of N,N-dimethylformamide to form ivacaftor; and
(e) optionally, purifying by suitable method.
The purification of ivacaftor can be conducted by using suitable reagents, solvents and any suitable method known in the art.
In accordance with another embodiment, the present invention provides a process for the preparation of crystalline ivacaftor.ethanol solvate comprising adding ethanol to ivacaftor obtained by reacting compound of Formula 6 with compound of Formula 7 using triethyl amine and HBTU, which further isolated using ethyl acetate and distilled out the solvent. To the reaction mass containing ivacaftor, solvent ethanol is added and heated to reflux temperature. Preferably, the mixture is heated to a temperature of about 70 to 85 °C followed by cooling the solution to obtain crystalline ivacaftor.ethanol solvate.

The next step involves conversion of crystalline ivacaftor.ethanol solvate to pure ivacaftor by heating the mixture of crystalline ivacaftor.ethanol solvate and 10% aq. ethyl acetate at 70 to 80 °C. The reaction mass is stirred at the same temperature to get the clear solution, optionally treated with activated carbon. Further solvent is distilled untill volume remains 5 to 8 V and stirred at reflux temperature for 4 to 5 hours. The reaction mass is cooled to 0 to 5 °C, stirred, filtered to get pure ivacaftor.

In accordance with yet another embodiment, the present invention provides a process for the preparation of ivacaftor intermediate of Formula 6 and its use in preparation of ivacaftor, comprising the steps of:
(a) coupling of compound of Formula 2 with of Formula 3 to provide compound of Formula 4 at a temperature of 50-60°C;
(b) cyclizing the compound of Formula 4 using phosphorous oxychloride and polyphosphoric acid to provide compound of Formula 5;
(c) hydrolyzing compound of Formula 5 using sodium hydroxide in the presence of water as solvent to provide compound of Formula 6; and
(d) finally, converting to ivacaftor.
Accordingly, ivacaftor obtained according to the instant invention possess the relative particle size distribution, wherein the 10th volume percentile particle size D (0.1) is less than about 10 µm, the 50th volume percentile particle size D(0.5) is less than about 25 µm, the 90th volume percentile particle size D(0.9) is less than about 100 µm, or any combination thereof.
In general, the particle size measurement is determined by Malvern light scattering, laser light scattering technique etc. In particular, the particle size measurement is measured using a Malvern particle size analyzer.
Chromatographic conditions for the analysis of ivacaftor compound of Formula I are as follows: Column: Kromasil-C8, (250x4.6) mm 5 µm; Column Temperature: 25oC; Auto Sample Temperature: 25oC; Rinsing solution/ needle wash solution: water: acetonitrile (25: 75); Flow rate: 1.0 mL per minute; injection volume: 10 µL; Detection wavelength: 225 nm; Run time: 50 minutes.
In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of ivacaftor according to the process of the present invention and one or more pharmaceutically acceptable carriers, excipients or diluents.
In yet another aspect there is provided a use of a pharmaceutical composition that includes a therapeutically effective amount of ivacaftor according to the process of the present invention and one or more pharmaceutically acceptable carriers, excipients or diluents to treat conditions in a subject in need thereof.
Major advantages realized in the present invention are that the process involves preparation of the compounds of Formula 4 and 5 at low temperature 55 to 60°C and use of less mole equivalent of polyphosphoric acid and phosphoryl chloride, so less amount of impurities and acidic effluent are formed. Therefore, the intermediates formed in the present invention are highly pure, which do not require additional purifications. Moreover, the present invention does not involve the use of costlier/ hazardous reagents, solvents and additional number of steps disclosed in US8476442B2. In addition, of this, the present invention does not involve use of the additional solvent such as isopropyl alcohol, costlier and toxic solvent such as sulfolane. Therefore, the present invention is relatively safe, simple, involves less number of steps, highly economical, giving high yield throughout and environment friendly, and can be easily and conveniently scaled-up for the industrial large scale production than the processes already known from the prior art.
Although the following examples illustrate the present invention in more detail but the examples are not intended in any way to limit the scope of the present invention. It will thus be readily apparent to the one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modifications and variation of the concepts herein disclosed may be resorted to by those skilled in the art and that such modifications and variations are considered to be falling within the scope of the invention.

Example 1: Preparation of diethyl 2-((phenylamino)methylene)malonate
A mixture of aniline (100 g) and diethyl 2-(ethoxymethylene)malonate (239 g) was heated at 55 to 60°C for 6 to 8 hours. The progress of the reaction was monitored by HPLC/TLC. After the completion of reaction, by-product ethanol was distilled off and residue was degassed to obtain the title compound. (Yield: 283 g, 100 %, HPLC purity: 97.17 %)

Example 2: Preparation of ethyl 1,4-dihydro-4-oxoquinoline-3-carboxylate
The mixture of diethyl 2-((phenylamino)methylene)malonate (283 g) and phosphoryl chloride (436 g) was heated at 55 to 65°C and polyphosphoric acid (150g) was added slowly. The reaction mixture stirred at same temperature for 10 to 12 hours. The progress of the reaction was monitored by HPLC. After the completion of reaction, cooled to 25 to 30oC, the reaction mass was added to the cooled mixture of water (1000ml) and methanol (400ml) at 10 to 20°C. The pH of reaction mass was adjusted between 1.5 to 3.5 using 30% aq. NaOH solution at 10 to 15°C. The reaction mass was stirred at 20 to 30oC for 1 to 2 hour, filtered, washed with water (100ml) and suck dried. To the wet solid, water (1000ml) was added and pH was adjusted between 5.0 to 7.0 using 30% aq. NaOH solution, stirred for 1 to 2 hour, filtered, washed with water (100ml), suck dried to obtained the title compound as wet solid. (Yield: about 500 g wet solid, HPLC purity: 91.84%)

Example 3: Preparation of 1,4-Dihydro-4-oxoquinoline-3-carboxylic acid
The mixture of ethyl 1, 4-dihydro-4-oxoquinoline-3-carboxylate (about 500 g wet solid) and aq. NaOH solution (86g in water 1000ml) stirred at 70 to 75oC for 5 to 6 hour. The progress of the reaction was monitored by HPLC. After the completion of reaction, reaction mass was cooled to 20 to 30oC, water (1000ml) was added and the pH was adjusted to 1.0 to 3.0 using conc. HCl solution (205ml). The reaction mixture stirred for 1 to 2 hour, filtered, washed with water (100ml) and suck dried. The wet solid obtained was suspended in methanol (1500ml), heated to reflux, stirred for 1 to 2 hour, cooled to 25 to 30oC, filtered, washed with methanol (100ml) and dried under vacuum to yield the title compound. (Yield: 152g, 75% with respect to aniline; HPLC purity: 99.9%)

Example 4: Preparation of 1,4-Dihydro-4-oxoquinoline-3-carboxylic acid
The mixture of ethyl 1,4-dihydro-4-oxoquinoline-3-carboxylate (about 500g wet solid) and aq. NaOH solution (86g in water 1000ml) stirred at 70 to 75oC for 5 to 6 hours. The progress of the reaction was monitored by HPLC. After the completion of reaction, reaction mass was cooled to 20 to 30oC, water (1000ml) was added and the pH was adjusted to 1.0 to 3.0 using conc. HCl solution (205ml). The reaction mixture stirred for 1 to 2 hours, filtered, washed with water (100ml) and suck dried. The wet solid obtained was suspended in methanol (1500ml), heated to reflux, stirred for 1 to 2 hours, cooled to 25 to 30oC, filtered, washed with methanol (100ml) and suck dried. Further, obtained wet solid was suspended in methanol (1200ml), heated to reflux, stirred for 1 to 2 hours, cooled to 25 to 30oC, filtered, washed with methanol (100ml) and dried under vacuum to obtained the title compound. (Yield: 142g, 70% with respect to aniline; HPLC purity: 99.97%)

Example 5: Preparation of ivacaftor ethanol solvate
To the mixture of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid (100g) in DMF (300ml) was added triethylamine (117g) slowly in 30 to 60 minutes. The reaction mixture became homogeneous and 2,4-di-tert-butyl-5-aminophenol (117g) was added. The mixture stirred for 30 minutes and added HBTU (220 g) in three to four lots at 25 to 30oC in 45 to 60 minutes. The reaction mixture stirred at 45 to 50oC for 2 to 3 hours. The progress of the reaction was monitored by HPLC. After the completion of reaction, reaction mass was cooled to 25 to 30oC and ethyl acetate (1800ml), water (500ml) added. The resulting layers were separated. The organic layer washed with 10% aqueous hydrochloric acid, further washed with 10% aqueous sodium bicarbonate solution followed by washing with water. The organic layer was distilled up to the volume of about 200ml and ethanol (400ml) was added. The reaction mass was heated to reflux, stirred for 1 hour and further cooled to 0 to 5oC and stirred for 2 hours. The resulting material was filtered, washed with ethanol (200ml) and dried under vacuum to obtain the title compound as solid (Yield: 210g, 91% & Purity: 99.91%)

Example 6: Preparation of pure ivacaftor
The mixture of ethanol solvate of ivacaftor (100g) and 10% aq. ethyl acetate (1900 ml) was heated at reflux to obtain the clear solution. Then, carbon (10g) was added to reaction mixture and stirred for 30 minutes at the same reflux temperature. Filtered the reaction mixture through hyflo bed and washed with 10% aq. ethyl acetate (100ml). The resulting layers were separated and organic layer was distilled up to the volume of about 500 to 800ml. The reaction mass was refluxed for 4 to 5 hours and then stirred at 25 to 30oC for 3 to 4 hours. The suspension was further cooled to 0 to 5oC and stirred for 2 hours. Filtered, washed with ethyl acetate (100ml) and dried under vacuum to obtained pure ivacaftor as solid. (Yield 74g, 83%; HPLC purity: 99.99%; Particle size: d(0.1) 5.5 µm, d(0.5) 14.3 µm, d(0.9) 66.8 µm)

Dated this the 25th day of Jun. 2019

Dr. Dinesh Kumar
Jubilant Generics Limited
D-12, Sec-59, Noida, 201 301, Uttar Pradesh, India
/digitally signed/

,CLAIMS:We claim:
1. A process for the preparation of ivacaftor, of Formula 1, comprising the steps of:

Formula 1

a) coupling of compound of Formula 2

with compound of Formula 3

to provide compound of Formula 4;

b) cyclizing the compound of Formula 4 using a suitable cyclizing agent, in the presence or absence of solvent, to provide compound of Formula 5;

c) hydrolyzing compound of Formula 5 using suitable base in the presence of a suitable solvent to provide compound of Formula 6;

d) coupling of compound of Formula 6 with compound of Formula 7

using a suitable base, a reagent in the presence of the suitable solvent to form ivacaftor; and
e) optionally, purifying by suitable method
wherein HPLC purity of ivacaftor thus obtained in at least 99.9%.
2. The process as claimed in claim 1, wherein cyclizing agent is selected from phosphorous oxychloride/polyphosphoric acid, polyphosphoric acid/pyridine, Eaton’s reagent (phosphorus pentoxide in methanesulfonic acid) and mixture thereof.
3. The process as claimed in claim 1, wherein base is selected from inorganic or organic base, wherein inorganic base is selected from group comprising of alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, sodium with liquid ammonia, sodamide and mixture thereof; organic base is selected from group comprising of diisopropylethylamine, triethylamine, tributylamine and pyridine and mixture thereof.
4. The process as claimed in claim 1, wherein solvent is selected from group comprising of water, sulfoxides, alcohols, halogenated hydrocarbons, ethers, esters, amides, hydrocarbons and mixture thereof.
5. The process as claimed in claim 1, wherein in step d) reagent is selected from 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide-hexafluoro phosphate(HATU), N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uraniumhexa-fluoro phosphate (HBTU), N,N’-Dicyclohexylcarbodimide (DCC), 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride(EDC.HCl), propanephosphonic acid anhydride (PPAA, T3P), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline(EEDQ), 1,1'-Carbonyl-diimidazole(CDI), N-hydroxy succinimide(HOSu), (benzotriazol-1-yloxy)tris- (dimethylamino)phosphonium hexafluorophosphate (BOP), isobutyl chloroformate(IBCF), O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate(HCTU) and mixture thereof.
6. The process as claimed in claim 1, for the preparation of ivacaftor comprising the steps of:
a) coupling of compound of Formula 2 with of Formula 3 at a temperature of 40 to 80 °C to provide compound of Formula 4;
b) cyclizing the compound of Formula 4 using phosphorous oxychloride, polyphosphoric acid to provide compound of Formula 5;
c) hydrolyzing compound of Formula 5 using sodium hydroxide in the presence of water as solvent to provide compound of Formula 6;
d) coupling of compound of Formula 6 with compound of Formula 7 using trimethylamine, HBTU in the presence of N,N-dimethylformamide as solvent to form ivacaftor; and
e) optionally, purifying by suitable method.
7. The process as claimed in claim 1, for the preparation of ivacaftor intermediate of Formula 6 and its use in preparation of ivacaftor, comprising the steps of:
a) coupling of compound of Formula 2

with compound of Formula 3 at a temperature of 40-80°C

to provide compound of Formula 4;

b) cyclizing the compound of Formula 4 using phosphorous oxychloride, polyphosphoric acid to provide compound of Formula 5;

c) hydrolyzing compound of Formula 5 using sodium hydroxide in the presence of water as a solvent to provide compound of Formula 6; and

d) finally, converting to ivacaftor.
8. The process as claimed in claim 1, for the preparation of ivacaftor ethanol solvate, further conversion to pure ivacaftor comprising the steps of:
a) adding ethanol into ivacaftor,
b) heating to reflux, stirring,
c) isolating ivacaftor ethanol solvate,
d) adding aq. ethyl acetate solution into ivacaftor ethanol solvate,
e) heating, stirring to obtain clear solution,
f) optionally, treating with activated carbon, and
g) isolating pure ivacaftor.
9. Ivacaftor having High Performance Liquid chromatographic (HPLC) purity of at least 99.9%.
10. Ivacaftor having 90th volume percentile particle size D(0.9) is less than 100 µm.

Dated this the 25th day of Jun. 2019

Dr. Dinesh Kumar
Jubilant Generics Limited
D-12, Sec-59, Noida, 201 301, Uttar Pradesh, India
/digitally signed/