Process for the preparation of Ivacaftor and its intermediates

1. A process for the preparation of ivacaftor of Formula I,

comprising:

a) coupling a protected quinoline carboxylic acid compound of Formula IV or an ester thereof

wherein “R” represents a cleavable group, with 5-amino-2,4-di-(tert-butyl) phenol of Formula III

in the presence of a coupling reagent and optionally in the presence of a base to obtain a protected ivacaftor compound of Formula II

and

b) deprotecting the resulting protected ivacaftor compound of Formula II.

2. The process according to claim 1 , wherein the coupling agent is one of HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluoro phosphate) and HBTU (O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate).

3. The process according to claim 1 , wherein the base used in the step a) is one of an organic base and an inorganic base,

wherein the organic base is one of methyl amine, ethyl amine, dimethylamine, diethylamine, triethylamine, tripropylamine, triisopropylamine, triisobutylamine N,N-diisopropylethylamine, N,N-dimethylaniline, tributylamine, N,N-dimethyl aminopyridine and mixtures thereof; and

wherein the inorganic base is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, ammonia and mixtures thereof.

4. The process according to claim 1 , wherein the base is N,N-diisopropylethylamine.

5. The process according to claim 1 , wherein the step a) further comprises the presence of an organic solvent selected from the group consisting of alcohols, ethers, esters, nitriles, amides, and mixtures thereof,

wherein the alcohols is one of methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol and t-butanol,

wherein the ethers is one of dimethyl ether, diethyl ether, methyl ethyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran and 1,4-dioxane,

wherein the esters is one of ethyl acetate, isopropyl acetate and isobutyl acetate,

wherein the nitriles is one of acetonitrile and propionitrile, and

wherein the amide is one of dimethyl formamide, dimethyl acetamide and N-methyl pyrrolidinone.

6. The process according to claim 5 , wherein the solvent is dimethyl formamide.

7. The process according to claim 1 , wherein the deprotection of formula II is carried out by treating it with a deprotecting agent.

8. The process according to claim 7 , wherein the deprotecting agent is selected from one of palladium, raney nickel, hydrazine, hydrochloric acid, hydrobromic acid, trifluoro acetic acid, and mixtures thereof.

9. A process for the preparation of ivacaftor of Formula I, comprising:

i) condensing 2-fluorobenzoic acid or a reactive derivative thereof of Formula IX

with an acrylate compound of Formula VIII

wherein “P” represents H or C 1-4 alkyl, to obtain a compound of Formula VII

wherein “P” is defined as above,

ii) reacting the compound of Formula VII with an amine of formula R—NH2, wherein “R” represents one of an aralkyl and alkyl group, optionally substituted with one or more of a compound selected from the group consisting of halo, nitro, cyano, amino, hydroxyl, alkyl, halo alkyl and alkoxy, to obtain a compound of Formula VI

wherein “R” and “P” are defined as above;

iii) cyclizing the compound of Formula VI in the presence of a base to obtain a compound of Formula V

wherein “R” and “P” are defined as above;

iv) hydrolyzing the compound of formula V with a base to obtain a protected quinoline carboxylic acid compound of Formula IV,

and

wherein “R” is defined as above;

v) converting the protected quinoline carboxylic acid compound of Formula IV into the ivacaftor of Formula I.

10. The process according to claim 9 , wherein the step i) is conducted in the presence of a base selected from methyl amine, ethyl amine, dimethylamine, diethylamine, triethylamine N,N-diisopropyl ethyl amine, N,N-dimethylaniline and N,N-dimethyl aminopyridine.

11. The process according to claim 9 , wherein in the step ii) the amine of formula, R—NH 2 used is one of benzylamine, 4-methoxy benzylamine, 4-trifluoromethyl benzylamine, 4-chloro benzyl amine, ethylamine, isopropylamine, n-butylamine, tert-butylamine, pentylamine, 2-aminopentane, 3-aminopentane, hexylamine, 2-aminohexane, 3-aminohexane, heptylamine, 2-aminoheptane, 3-aminoheptane, 4-aminoheptane, octylamine, 2-amino octane, 3-aminooctane, 4-aminooctane, 2-amino-1-ethanol, 2-amino-2-methyl-1-propanol and 3-amino-1-butanol.

12. The process according to claim 9 , wherein in the step iii) the base used for cyclization is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, and ammonia.

13. The process according to claim 9 , wherein the cyclization of step iii) is carried out at a temperature of about 35° C. to 110° C.

14. The process according to claim 13 , wherein the temperature is about 85° C. to 90° C.

15. The process according to claim 9 , wherein the base in the step iv) is one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate and ammonia.

16. An intermediate compound of Formula VI,

wherein “P” represents H or C 1-4 alkyl and “R” represents a cleavable group selected from aralkyl, alkyl group, optionally substituted with one or more groups selected from halo, nitro, cyano, amino, hydroxyl, alkyl, halo alkyl or alkoxy.

17. An intermediate compound of Formula VIA

18. An intermediate compound of Formula II,

wherein “R” represents a cleavable group selected from aralkyl, alkyl group, optionally substituted with one or more groups selected from halo, nitro, cyano, amino, hydroxyl, alkyl, halo alkyl or alkoxy.

19. An intermediate compound of Formula IIA

20. A process for preparation of ivacaftor of Formula I, comprising:

a) condensing 2-fluorobenzoylchloride with ethyl-3-N,N-dimethyl amino acrylate in presence of triethylamine in toluene to obtain ethyl-3-(dimethylamino)-2-(2-fluorobenzoyl)-2-propenoate,

b) reacting the ethyl-3-(dimethylamino)-2-(2-fluorobenzoyl)-2-propenoate with benzylamine in toluene to obtain ethyl-3-(benzylamino)-2-(2-fluorobenzoyl)-2-propenoate,

c) cyclizing the ethyl-3-(benzylamino)-2-(2-fluorobenzoyl)-2-propenoate in presence of potassium carbonate in dimethylformamide to obtain ethyl-1-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxylate,

d) hydrolyzing the ethyl-1-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxylate with aqueous sodium hydroxide to obtain 1-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxyli acid,

e) coupling the 1-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid with 5-amino-2,4-di-(tert-butyl)phenol in presence of HA TU and diisopropylethylamine in dimethylformamide to obtain N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide; and

f) deprotecting the N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1-benzyl-4-oxo-1,4-dihydro quinoline-3-carboxamide by treating it with palladium hydroxide and ammonium formate in dimethylformamide to obtain ivacaftor.

21. A process for the preparation of a pharmaceutical composition comprising ivacaftor of Formula I or a pharmaceutically acceptable salt thereof, comprising:

a) coupling a protected quinoline carboxylic acid compound of Formula IV or an ester thereof

wherein R is a cleavable group, with 5-amino-2,4-di-(tert-butyl) phenol of Formula III

in the presence of a coupling reagent and optionally in the presence of a base to obtain a protected ivacaftor compound of Formula II

and

b) deprotecting the resulting protected ivacaftor compound of Formula II; and

c) combining the ivacaftor of Formula I with at least one pharmaceutically acceptable excipient.

22. A process for the preparation of a pharmaceutical composition comprising ivacaftor of Formula I or a pharmaceutically acceptable salt thereof, comprising:

i) condensing 2-fluorobenzoic acid or a reactive derivative thereof of Formula IX

with an acrylate compound of Formula VIII

wherein “P” represents H or C 1-4 alkyl, to obtain a compound of Formula VII

wherein “P” is defined as above,

ii) reacting the compound of Formula VII with an amine of formula R—NH2, wherein “R” represents one of an aralkyl and alkyl group, optionally substituted with one or more of a compound selected from the group consisting of halo, nitro, cyano, amino, hydroxyl, alkyl, halo alkyl and alkoxy, to obtain a compound of Formula VI

wherein “R” and “P” are defined as above;

iii) cyclizing the compound of Formula VI in the presence of a base to obtain a compound of Formula V

wherein “R” and “P” are defined as above;

iv) hydrolyzing the compound of formula V with a base to obtain a protected quinoline carboxylic acid compound of Formula IV,

and

wherein “R” is defined as above;

v) converting the protected quinoline carboxylic acid compound of Formula IV into the ivacaftor of Formula I; and

vi) combining the ivacaftor of Formula I with at least one pharmaceutically acceptable excipient.

23. A process for the preparation of a pharmaceutical composition comprising ivacaftor of Formula I or a pharmaceutically acceptable salt thereof, comprising:

a) condensing 2-fluorobenzoylchloride with ethyl-3-N,N-dimethyl amino acrylate in presence of triethylamine in toluene to obtain ethyl-3-(dimethylamino)-2-(2-fluorobenzoyl)-2-propenoate,

b) reacting the ethyl-3-(dimethylamino)-2-(2-fluorobenzoyl)-2-propenoate with benzylamine in toluene to obtain ethyl-3-(benzylamino)-2-(2-fluorobenzoyl)-2-propenoate,

c) cyclizing the ethyl-3-(benzylamino)-2-(2-fluorobenzoyl)-2-propenoate in presence of potassium carbonate in dimethylformamide to obtain ethyl-1-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxylate,

d) hydrolyzing the ethyl-1-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxylate with aqueous sodium hydroxide to obtain 1-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxyli acid,

e) coupling the 1-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid with 5-amino-2,4-di-(tert-butyl)phenol in presence of HA TU and diisopropylethylamine in dimethylformamide to obtain N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide;

f) deprotecting the N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1-benzyl-4-oxo-1,4-dihydro quinoline-3-carboxamide by treating it with palladium hydroxide and ammonium formate in dimethylformamide to obtain ivacaftor; and

g) combining the ivacaftor of Formula I with at least one pharmaceutically acceptable excipient.