Process for the preparation of ivacaftor and solvates thereof

1. A solvate of N-(2,4-di-tert-butyl-5-hydroxyphenyl-1, 4-dihydro-4-oxoquiniline-3-carboxamide, a compound of formula I,

wherein the solvate is selected from a crystalline N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1, 4-dihydro-4-oxoquiniline-3-carboxamide.n-butanol solvate characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 3.4 and 14.2±0.2 degrees 2 theta or a crystalline N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1, 4-dihydro-4-oxoquiniline-3-carboxamide.methanol solvate characterized by X-ray Diffraction (XRD) spectrum having peak reflections at about 7.28, 13.84, 14.03, 19.78, 20.27 and 20.92±0.2 degrees 2 theta.

2. A process for the preparation of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1, 4-dihydro-4-oxoquiniline-3-carboxamide, a compound of formula I,

in amorphous form, the process comprising:

(a) dissolving the crystalline N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1, 4-dihydro-4-oxoquiniline-3-carboxamide.n-butanol solvate or the crystalline N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1, 4-dihydro-4-oxoquiniline-3-carboxamide.methanol solvate according to claim 1 , in a solvent to form a solution; and

(b) removing the solvent from the solution obtained in (a).

3. The process of claim 2 wherein the solvent is selected from the group consisting of water, methyl ethyl ketone, n-butanol and mixtures thereof.

4. The process of claim 2 , wherein in step (b) the solvent is removed by spray drying, fluid bed drying, lyophilization, flash drying, spin flash drying, or thin-film drying.

5. The process of claim 2 , wherein a compound of formula XII or XIII is less than 0.1% w/w of amorphous N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1, 4-dihydro-4-oxoquiniline-3-carboxamide as measured by high performance liquid chromatography.

6. The process of claim 2 , wherein N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1, 4-dihydro-4-oxoquiniline-3-carboxamide in amorphous form is free from the listed genotoxic impurities, compounds of formula XI, II, VIII, XIV, VII, XV and XVI

7. The process of claim 2 wherein the crystalline N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1, 4-dihydro-4-oxoquiniline-3-carboxamide.n-butanol solvate is prepared by a process comprising:

a) converting N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1, 4-dihydro-4-oxoquiniline-3-carboxamide to the crystalline N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1, 4-dihydro-4-oxoquiniline-3-carboxamide.methanol solvate; and

b) converting the crystalline N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1, 4-dihydro-4-oxoquiniline-3-carboxamide.methanol solvate to the crystalline N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1, 4-dihydro-4-oxoquiniline-3-carboxamide.n-butanol solvate.

8. The process of claim 7 , wherein N-(2,4-di-tert-butyl-5-hydroxyphenyl-1, 4-dihydro-4-oxoquiniline-3-carboxamide is prepared by a process comprising:

a) converting a compound of formula IX to a compound of formula X

in the presence of Eaton's reagent;

b) hydrolysing the compound of formula X to obtain the compound of formula XI; and

c) reacting the compound of formula XI with a compound of formula II to obtain N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1, 4-dihydro-4-oxoquiniline-3-carboxamide.

9. The process of claim 2 wherein the crystalline N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1, 4-dihydro-4-oxoquiniline-3-carboxamide.n-butanol solvate is prepared by a process comprising:

a) treating N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1, 4-dihydro-4-oxoquiniline-3-carboxamide or a solvate thereof with a n-butanol;

b) optionally, heating the above mixture of step (a);

c) cooling the above mixture of step (b); and

d) isolating the crystalline N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1, 4-dihydro-4-oxoquiniline-3-carboxamide.n-butanol solvate.

10. The process of claim 2 wherein the crystalline N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1, 4-dihydro-4-oxoquiniline-3-carboxamide methanol solvate is prepared by a process comprising:

a) treating N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1, 4-dihydro-4-oxoquiniline-3-carboxamide with methanol to obtain a mixture;

b) optionally, heating the above mixture of step (a);

c) cooling the above mixture of step (b); and

d) isolating crystalline N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1, 4-dihydro-4-oxoquiniline-3-carboxamide.methanol solvate.

11. The process of claim 2 , comprising:

a) dissolving crystalline N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1, 4-dihydro-4-oxoquiniline-3-carboxamide.methanol solvate in n-butanol to form a solution; and

b) removing the solvent from the solution by a process comprising:

i) filtering the solvent to obtain N-(2,4-di-tert-butyl-5-hydroxyphenyl-1, 4-dihydro-4-oxoquiniline-3-carboxamide.n-butanol solvate; and

ii) drying the N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1, 4-dihydro-4-oxoquiniline-3-carboxamide.n-butanol solvate to obtain amorphous N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1, 4-dihydro-4-oxoquiniline-3-carboxamide.

12. The process of claim 11 , wherein in step (b) (ii) drying is carried out at a temperature of 70 to 75° C. for a time period of 20 to 24 hours.