DESC:AN IMPROVED PROCESS FOR THE PREPARATION OF IVACAFTOR
RELATED APPLICATION
This application claims the benefit of priority of Indian patent application number 4022/MUM/2015 filed on 19th October 2015, which is incorporated herein by reference.
FIELD OF INVENTION
The present invention provides an improved process for the preparation of Ivacaftor of Formula-I.

Formula-I
BACKGROUND OF THE INVENTION
Ivacaftor which is chemically known as N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4oxoquinoline-3-carboxamide, and is represented structurally by a compound of Formula-I.

Formula-I
Ivacaftor is marketed under the name KALYDECO (US) is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis in patients age 6 years and older who have one of the following G55ID mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R.
United States Patent No. 7495103 discloses Ivacaftor, a process for its preparation and its intermediates, and patents numbered US 8754224, US 8410274, and US 8471029 discloses amorphous, solid dispersion and Polymorph Forms of Ivacaftor.
There is always for a novel preparation process of drugs with inexpensive, feasible reagents, solvents and intermediates and the process that can afford desired products with good yields and to prepare a substantially pure Form thereof.
SUMMARY OF THE INVENTION
The present invention provides a novel process of preparation of Ivacaftor of Formula-I

Formula-I
comprising the steps of ;
a) Condensation of aniline of Formula-VII with Diethyl(ethoxymethylene)propanedioate of Formula-VI to give Diethyl[(phenylamino)methylidene]propanedioate of Formula-V optionally, in presence of a suitable solvent;

Formula-VII Formula-VI Formula-V
b) cyclization of Diethyl[(phenylamino)methylidene]propanedioate of Formula-V to give ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate of Formula-IV in presence of polyphosphoric acid and suitable solvent;

Formula-IV
c) addition of suitable alcohol in the reaction mixture of step b without isolation of compound of formula IV;
d) addition of reaction solution of step c in the aqueous base to obtain 4-oxo-1,4-dihydroquinoline-3-carboxylic acid of Formula-III;

Formula-III
e) coupling of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid of Formula-III to 5-amino-2,4-di-tert-butylphenol of Formula-II in presence of a coupling agent and a suitable solvent to afford crude ivacaftor of Formula-I;

Formula-II
f) purification of crude ivacaftor of formula-I in suitable solvent to obtain pure ivacaftor.
The present invention relates to solvates of Ivacaftor selected from Ivacaftor benzyl alcohol solvate, ethanol solvate, iso-butanol solvate and n-pentanol solvate.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1 is an illustration of a powder X-ray diffraction (PXRD) pattern of the Ivacaftor Ethanol solvate
Fig 2 is an illustration of a powder X-ray diffraction (PXRD) pattern of the Ivacaftor benzyl alcohol solvate
Fig 3 is an illustration of a powder X-ray diffraction (PXRD) pattern of the Ivacaftor n-pentanol solvate
Fig 4 is an illustration of a powder X-ray diffraction (PXRD) pattern of the Ivacaftor isobutyl alcohol solvate
Fig 5 is an illustration of a powder X-ray diffraction (PXRD) pattern of the Ivacaftor Amorphous Form
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides a process of preparation of Ivacaftor of Formula-I

Formula-I
comprising the steps of;
a) Condensation of aniline of Formula-VII with Diethyl(ethoxymethylene)propanedioate of Formula-VI to give Diethyl[(phenylamino)methylidene]propanedioate of Formula-V optionally, in presence of a suitable solvent;

Formula-VII Formula-VI Formula-V
b) cyclization of Diethyl[(phenylamino)methylidene]propanedioate of Formula-V to give ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate of Formula-IV in presence of polyphosphoric acid and suitable solvent;

Formula-IV
c) addition of suitable alcohol in the reaction mixture of step b without isolation of compound of formula IV;
d) addition of reaction solution of step c in the aqueous base to obtain 4-oxo-1,4-dihydroquinoline-3-carboxylic acid of Formula-III;

Formula-III
e) coupling of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid of Formula-III to 5-amino-2,4-di-tert-butylphenol of Formula-II in presence of a coupling agent and a suitable solvent to afford crude ivacaftor of Formula-I;

Formula-II
f) purification of crude ivacaftor of formula-I in suitable solvent to obtain pure ivacaftor.
In one embodiment, the suitable solvent in step a) is selected from alcohol such as methanol, ethanol, propanol, isopropyl alcohol, water or mixtures thereof, preferably isopropyl alcohol and water.
In one embodiment, the suitable solvent in step b) is sulfolane.
In one embodiment, the suitable alcohol in step c) is selected from methanol, ethanol, propanol, isopropyl alcohol, preferably methanol.
In one embodiment, the aqueous base in step d) can be sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.
In one embodiment, the step b), c) and d) are performed by following the procedure as below:
Diethyl[(phenylamino)methylidene]propanedioate of Formula-V, PPA and sulfolane are charged in to the reaction flask, and reaction is carried out using suitable conditions and then a suitable solvent such as alcohol is charged. In another flask base solution was prepared by mixing water and base. Reaction mass containing carboxylate is added in to the prepared base solution. pH was adjusted using acid such as ortho-phosphoric acid.
In one embodiment, in step e), the said coupling agent is selected from HATU, (0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), BOP (Benzotriazol- 1 -yloxy)tris(dimethylamino)phosphonium hexafluorophosphate), HBTU 0-Benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro- phosphate and PFP-TFA pentafluorophenyltrifluoroacetate, DIC (?,?'- Diisopropylcarbodiimide), EDC l-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide, TBTU O- (Benzotriazol- l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, DCC (?,?'- dicyclohexylcarbodiimide), PyBOP (benzotriazol- 1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, EDC/HOSu (N-hydroxysuccinimide), DCC/HOBT, DCC/HOSu, Isobutyl chloroformate and l-methyl-2-chloropyridinium iodide, propane phosphonic anhydride.
In one embodiment, in step e) the suitable solvent is selected from DMF, CH2Cl2, and THF.
In one embodiment, in step e) is carried out using DCC (Dicyclohexylcarbodiimide) as a coupling agent and DMF as a solvent to afford crude ivacaftor of Formula-I.
In one embodiment, in step f) the suitable solvent is isopropyl acetate to obtain pure ivacaftor.
In one embodiment, the present invention provides Ivacaftor solvates such as Ivacaftor ethanol, isobutanol, benzyl alcohol and n-pentanol.
In one embodiment, ivacaftor solvate is crystalline ivacaftor benzyl alcohol solvate characterized by X-ray Diffraction (XRD) spectrum having peak at 4.3, 5.3, 6.3, 7.5, 11.0 and 19.2 in degrees of two-theta in accordance with figure 2.
In one embodiment, ivacaftor solvate is crystalline ivacaftor pentanol solvate characterized by X-ray Diffraction (XRD) spectrum having peak at 4.7 and 5.1 in degrees of two-theta in accordance with figure 3.
In one embodiment, ivacaftor solvate is crystalline ivacaftor isobutyl alcohol solvate characterized by X-ray Diffraction (XRD) spectrum having peak at 6.4, 13.1, 19.7, 22.0 and 23.2 in degrees of two-theta in accordance with figure 4.
In one embodiment, process for preparation of ivacaftor solvate comprises:
(a) providing a solution of Ivacaftor in a suitable solvent
(b) removing the solvent
(c) isolating crystalline ivacaftor solvate
In one embodiment, in step a) of above process the suitable solvent is benzyl alcohol, pentanol, isobutanol to obtain corresponding ivacaftor solvate.
In one embodiment, preparation of amorphous Ivacaftor comprises drying such as spray drying Ivacaftor solvate obtained according to present invention.
In one embodiment, the present invention provides a process for the preparation of compound of Formula-I as represented schematically in scheme I as shown below.

Scheme-I
The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art.
Example 1: Preparation of 2-Phenylaminomethylene-malonic acid diethyl ester
Charge Diethyl(ethoxymethylene)propanediote (100g) in to a vessel containing isopropyl alcohol (150 ml). Allowed to cool the reaction mass at 12±3 °C and then charge Aniline (45.2g) in to the reaction mass and stir for 6 hrs at 28± 3°C and was cooled to 12± 2°C. Water was added to reaction mass, stirred then filtered. Wet cake was washed with chilled water and dried in ATD for 20-24 hrs at 25 ±5°C to obtain title compound.
Example 2: Preparation of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Reaction flask-1 was charged with sulfolane (200 ml), polyphosphoric acid (PPA) (400 g) and 2-Phenylaminomethylene-malonic acid diethyl ester (100 g). The reaction mixture was heated to 102± 3°C and stirred at the same temperature for 2 hours ± 10 min and then allowed to cool to 35± 5°C. Methanol (400 mL) was added to the reaction mass below 50°C. Meanwhile water (2300 ml) and sodium hydroxide (472 g) were charged at 25±5°C to the reaction flask-2 and stirred for 30± 5 minutes. Then reaction mass from flask-1 was added to above sodium hydroxide solution below 50°C. The reaction mass was heated to 88±3°C and stirred at the same temperature for 2 hours ± 10 min, then cooled to 50± 5°C. Then pH of reaction mass was adjusted between 3.5 to 4.5 by ortho phosphoric acid (440 mL) below 55°C. Then reaction mass was allowed to stirred, filtered, washed with hot (45±5°C) water and suck dried. Obtained wet solid was charged with water, heated, stirred, filtered, washed with water and dried to obtain 4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
Example 3: Preparation of N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
Reaction flask was charged with N, N-Dimethylformamide (200 mL), 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 g), N, N’-Dicyclohexylcarbodiimide (185 g) and 5-amino-2, 4-di-tert-butyl phenol (129 g) at 27±3°C. The reaction mixture was stirred at 27±3°C for 10 minutes and then heated to 95±3°C, after completion of reaction, reaction mass was cooled. Ethyl acetate was added to the above reaction mass, stirred and solid was filtered (keep aside its filtrate) and suck dried. Water was added to obtained ethyl acetate filtrate, the reaction mixture was heated and stirred. Reaction mass was allowed to settled and upper organic layer was separated. Obtained organic layer was distilled under vacuum at 65±3°C and residue was degassed under vacuum for 2 hours at 65±3°C. To the above reaction mass denatured ethanol with 1% Acetone (1000 mL) was charged at 65±3°C and heated to 79±3°C (reflux to be maintained) then stirred for 3 hrs±10 minutes at same temperature. Reaction mass was allowed cool to 62±3°C and stirred at same temperature for 60±10 minutes. Then reaction mass was filtered and obtained solid was washed with denatured ethanol with 1% Acetone. Obtained wet cake was treated with water and ethyl acetate and reaction mass was stirred and allowed to settle. Separated organic layer was filtered distilled off under vacuum below 50°C and residue was degassed under vacuum below 50°C (utility temperature). Ethyl acetate was charged in above obtained reaction mass, reflux and stirred. The reaction mass was cooled and stirred, filtered and obtained solid was washed with ethyl acetate then suck dried. Obtained wet cake was dried for 9 hours ±10 minutes in VTD at 52±3°C under vacuum to get N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide.
Example 4: Preparation of Pure Ivacaftor
Reaction vessel was charged with N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (100 g) and isopropyl acetate (1000 mL) at 27±3°C and stirred for 15-30 min at 25± 5°C. The reaction mixture was heated to 60±3°C and stirred for 3 hrs±10 minutes at 60°C, then cooled to 27±3°C. Obtained reaction mass was stirred for 12 hrs ±30 minutes at 27±3°C then filtered to get solid which was washed with isopropyl acetate and suck dried. Obtained wet cake was dried for 12 hours ±10 minutes in VTD at 27±3°C under vacuum to obtain pure ivacaftor.
Example 5: Preparation of Ivacaftor ethanol solvate
Reaction vessel was charged with 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 g), DCC (185.5 g), DMF (300 ml) and 5-amino-2,4-di-tert-butylphenol (128.7 g) and stirred for 10 min at 27± 3°C, reaction mixture was heated to 92± 3°C and cooled to 27± 3°C. Water was added to the reaction mass and the product was extracted with ethyl acetate. 10 % Brine solution was charged and the organic layer was concentrated and solvent was distilled off and the residue was degassed at 65± 3°C. Ethanol was charged and stirred for 5-10 mins 65 ± 3°C and ethanol is distilled out at 65± 3°C. Ethanol (1000 ml) was charged and heated to reflux at 80-83 °C and stirred for 3 hrs and cooled, filtered and washed with ethanol and dried and washed with cyclohexane and dried. X-ray Diffraction (XRD) spectrum as shown figure 1.
Example 6: Preparation of Ivacaftor ethanol solvate
Reaction vessel was charged with 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 g), DCC (185.5 g), DMF (300 ml) and 5-amino-2,4-di-tert-butylphenol (128.7 g) and stirred for 10 min at 27± 3°C, reaction mixture was heated to 92± 3°C and cooled to 27± 3°C. Water was added to the reaction mass and the product was extracted with ethyl acetate. 10 % Brine solution was charged and the organic layer was concentrated and solvent was distilled and the residue was degassed at 65± 3°C. Ethanol (300 ml) was charged and stirred for 5-10 mins 65 ± 3°C and ethanol is distilled out at 65± 3°C under vacuum. Isobutanol (1100 ml) was charged and heated to reflux at 100-105 °C and stirred for 3 hrs and then cooled, filtered and washed with isobutanol and suck dried to obtain wet cake. Ethanol (1000 ml) was charged in to a reaction vessel with above wet cake at 27± 3°C, heated to 80-85 °C and stirred and cooled to 62 ± 3°C and then stirred and filtered and dried to obtain wet cake. To the obtained wet cake ethanol (500 ml) was charged, heated to 80-85° C, cooled, stirred, filtered and washed with ethanol and dried to obtain wet cake. Dry the obtained wet cake for 9 hrs in VTD at 62± 3°C under vacuum and if required mill the material after 9 hrs of drying. X-ray Diffraction (XRD) spectrum as shown figure 1.
Example 7: Preparation of Ivacaftor isobutanol solvate
Reaction vessel was charged with 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 g), DCC (185.5 g), DMF (300 ml) and 5-amino-2,4-di-tert-butylphenol (128.7 g) and stirred for 10 min at 27± 3°C, reaction mixture was heated to 92± 3°C and cooled to 27± 3°C. Water was added to the reaction mass and the product was extracted with ethyl acetate. 10 % Brine solution was charged and the organic layer was concentrated and solvent was distilled off and the residue was degassed at 65± 3°C. Isobutanol was charged and stirred for 5-10 mins 65 ± 3°C and Isobutanol was distilled out. Isobutanol was charged and heated to reflux and stirred for 3 hrs and cooled, filtered and washed with Isobutanol and dried and washed with cyclohexane and dried. X-ray Diffraction (XRD) spectrum as shown figure 4.
Example 8: Preparation of Ivacaftor benzyl alcohol solvate
Reaction vessel was charged with 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 g), DCC (185.5 g), DMF (300 ml) and 5-amino-2,4-di-tert-butylphenol (128.7 g) and stirred for 10 min at 27± 3°C, reaction mixture was heated to 92± 3°C and cooled to 27± 3°C. Water was added to the reaction mass and the product was extracted with ethyl acetate. 10 % Brine solution was charged and the organic layer was concentrated and solvent was distilled off and the residue was degassed at 65± 3°C. Benzyl alcohol was charged and stirred for 5-10 mins 65 ± 3°C and benzyl alcohol is distilled out. Benzyl alcohol was charged and heated to reflux and stirred for 3 hrs and cooled, filtered and washed with benzyl alcohol and dried and washed with cyclohexane and dried. X-ray Diffraction (XRD) spectrum as shown figure 2.
Example 9: Preparation of Ivacaftor n-pentanol solvate
Reaction vessel was charged with 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 g), DCC (185.5 g), DMF (300 ml) and 5-amino-2,4-di-tert-butylphenol (128.7 g) and stirred for 10 min at 27± 3°C, reaction mixture was heated to 92± 3°C and cooled to 27± 3°C. Water was added to the reaction mass and the product was extracted with ethyl acetate. 10 % Brine solution was charged and the organic layer was concentrated and solvent was distilled off and the residue was degassed at 65± 3°C. n-pentanol was charged and stirred for 5-10 mins 65 ± 3°C and n-pentanol is distilled out. n-pentanol was charged and heated to reflux and stirred for 3 hrs and cooled, filtered and washed with n-pentanol and dried and washed with cyclohexane and dried. X-ray Diffraction (XRD) spectrum as shown figure 3.
Example 10: Preparation of Amorphous Ivacaftor
Ivacaftor solvate obtained according to above examples was charged with acetone (1600.0 mL) and DM Water (200 mL) Stirred for 15-30 minutes at 25±5°C to get clear solution and filtered the solution through cartridge and wash with mixture of acetone (100 mL) and DM water (12.5 mL) at 25±5°C. Spray dried and dried in VTD/RVD at 65±5°C for 24 hours ±10 minutes.
Example 11: Preparation of Amorphous Ivacaftor
Ivacaftor solvate obtained according to above examples was charged with MEK and water and spray dried to obtain amorphous material.
Example 12: Preparation of Amorphous Ivacaftor
Ivacaftor solvate obtained according to above examples was charged with 2-methyl tetrahydrofuran and spray dried to obtain amorphous material.
,CLAIMS:1. A process for preparing N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide compound of formula (I)

Formula I
Comprising:
a) Condensation of aniline of Formula-VII with Diethyl(ethoxymethylene)propanedioate of Formula-VI to give Diethyl[(phenylamino)methylidene]propanedioate of Formula-V optionally, in presence of a suitable solvent;

Formula-VII Formula-VI Formula-V
b) cyclization of Diethyl[(phenylamino)methylidene]propanedioate of Formula-V to give ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate of Formula-IV in presence of polyphosphoric acid and suitable solvent;

Formula-IV
c) addition of suitable alcohol in the reaction mixture of step b without isolation of compound of formula IV;
d) addition of reaction solution of step c in the aqueous base to obtain corresponding acid, 4-oxo-1,4-dihydroquinoline-3-carboxylic acid of Formula-III;

Formula-III
e) coupling of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid of Formula-III to 5-amino-2,4-di-tert-butylphenol of Formula-II in presence of a coupling agent and a suitable solvent to afford crude ivacaftor of Formula-I;

Formula-II
f) purification of crude ivacaftor of formula-I in suitable solvent to obtain pure ivacaftor.
2. The process of claim 1, wherein the suitable solvent in step a) is selected from alcohol such as methanol, ethanol, propanol, isopropyl alcohol, water or mixtures thereof, preferably isopropyl alcohol and water.
3. The process of claim 1, wherein the suitable solvent in step b) is sulfolane.
4. The process of claim 1, wherein the suitable alcohol in step c) is selected from alcohol such as methanol, ethanol, propanol, isopropyl alcohol, preferably methanol.
5. A process of claim 1 wherein, in step d) aqueous base is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.
6. A process of claim 1 wherein, in step e) the said coupling agent is selected from HATU, (0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate), BOP (Benzotriazol- 1 -yloxy)tris(dimethylamino)phosphonium hexafluorophosphate), HBTU 0-Benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro- phosphate and PFP-TFA pentafluorophenyltrifluoroacetate, DIC (?,?'- Diisopropylcarbodiimide), EDC l-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide, TBTU O- (Benzotriazol- l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, DCC (?,?'- dicyclohexylcarbodiimide), PyBOP (benzotriazol- 1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, EDC/HOSu (N-hydroxysuccinimide), DCC/HOBT, DCC/HOSu, Isobutyl chloroformate and l-methyl-2-chloropyridinium iodide, propane phosphonic anhydride, preferably DCC (Dicyclohexylcarbodiimide).
7. A process of claim 1 wherein, in step e) suitable solvent is selected from DMF, DCM, and THF, preferably DMF.
8. Crystalline ivacaftor benzyl alcohol solvate characterized by X-ray Diffraction (XRD) spectrum having peak at 4.3, 5.3, 6.3, 7.5, 11.0 and 19.2 in degrees of two-theta in accordance with figure 2.
9. Crystalline ivacaftor pentanol solvate characterized by X-ray Diffraction (XRD) spectrum having peak at 4.7 and 5.1 in degrees of two-theta in accordance with figure 3.
10. Crystalline ivacaftor isobutyl alcohol solvate characterized by X-ray Diffraction (XRD) spectrum having peak at 6.4, 13.1, 19.7, 22.0 and 23.2 in degrees of two-theta in accordance with figure 4.