Process for the preparation of tofacitinib and intermediates thereof

1. A process for the preparation of a compound of Formula V-II

wherein, R 1 is trityl; R is hydrogen or tosyl; and X is a halogen; wherein the process comprises:

(a) reacting a compound of Formula IV wherein R 1 is trityl;

with a compound of Formula III-I wherein X is a halogen and R is tosyl,

to form a compound of Formula V-II wherein R 1 and X have the aforestated meanings; and

(b) optionally, deprotecting the compound of Formula V-II so obtained to form a compound of Formula V-II wherein at least one of R or R 1 is hydrogen and X is a halogen.

2. The process according to claim 1 , for the preparation of the compound of Formula V-II and salts thereof, wherein each of R and R 1 is hydrogen and X is a halogen; and salts thereof,

wherein the deprotecting step (b) comprises

(a)

(i) converting the compound of Formula V-II, wherein R 1 is trityl; R is tosyl; and X is a halogen, into a compound of Formula V-II wherein R 1 is trityl; R is hydrogen and X is a halogen; followed by

(ii) converting the compound of Formula V-II so obtained into a compound of Formula V-II wherein each of R and R 1 is hydrogen; and X is a halogen; or

(b)

(i) converting the compound of Formula V-II, wherein R 1 is trityl; R is tosyl; and X is a halogen, into a compound of Formula V-II wherein R 1 is hydrogen; R is tosyl and X is a halogen, followed by

(ii) converting the compound of Formula V-II so obtained into a compound of Formula V-II wherein each of R and R 1 is hydrogen; and X is a halogen or

(c) converting compound of Formula V-II, wherein R 1 is trityl; R is tosyl; and X is a halogen, directly into a compound of Formula V-II wherein each of R and R 1 is hydrogen and X is a halogen, in a single step.

3. The process according to claim 2 wherein deprotection in step (b)(a)(i) is performed using a base and deprotection in step (b)(a)(ii) is performed using an acid or by hydrogenation.

4. The process according to claim 2 wherein deprotection in step (b)(b)(i) is performed using an acid and deprotection in step (b)(b)(ii) is performed using a base.

5. The process according to claim 2 wherein deprotection in step (b)(c) is performed using an acid or base or by hydrogenation.

6. The process according to claim 2 further comprising dehalogenation of the compound of Formula V-II, wherein each of R and R 1 is hydrogen and X is a halogen, to form a compound of Formula XII followed by conversion of the compound of Formula XII into tofacitinib

7. The process according to claim 1 , wherein the-compound of Formula IV in which R 1 is trityl

is prepared by the process comprising:

(a) converting a compound of Formula XIV to a compound of Formula XV-I wherein R 1 is trityl, and R 3 is a C 1 to C 5 straight or branched chain alkyl;

(b) converting the compound of Formula XV-I so obtained to a compound of Formula XVI-I wherein R 1 is trityl; followed by

(c) resolution of the compound of Formula XVI-I so obtained.

8. The process according to claim 7 wherein R 3 is methyl.

9. The process of claim 6 , further comprising the steps of:

treating tofacitinib with citric acid in a suitable solvent to obtain tofacitinib monocitrate; and

recrystallizing tofacitinib monocitrate from a mixture of acetonitrile and water.

10. The process according to claim 1 , wherein in step b, the compound of Formula V-II, in which R 1 is trityl; R is tosyl; and X is a halogen, is deprotected with a base to obtain a compound of Formula V-II, wherein R 1 is trityl; R is hydrogen and X is a halogen.

11. The process according to claim 1 , wherein in step b, the compound of Formula V-II, in which R 1 is trityl; R is tosyl; and X is a halogen, is deprotected with an acid to obtain a compound of Formula V-II, wherein R 1 is hydrogen; R is tosyl, and X is a halogen.

12. The process according to claim 7 , wherein the compound of Formula IV

wherein R 1 is trityl, is thereafter converted to tofacitinib or salts thereof.

13. The process of claim 1 , wherein the compound of Formula V-II, wherein R 1 is hydrogen or trityl and R is hydrogen or tosyl, represented by a compound of Formula V,

is thereafter converted to tofacitinib or salts thereof.

14. A process for the preparation of a compound of Formula V-II

wherein, R 1 is hydrogen or trityl; R is hydrogen or tosyl; and X is a halogen; wherein the process comprises:

(a) reacting a compound of Formula IV wherein R 1 is trityl;

with a compound of Formula III-I wherein X is a halogen and R is tosyl,

to form a compound of Formula V-II wherein R 1 and X have the aforestated meanings; and

(b) deprotecting the compound of Formula V-II so obtained to form a compound of Formula V-II wherein at least one of R or R 1 is hydrogen and X is a halogen.

15. The process according to claim 14 , further comprising dehalogenation of the compound of Formula V-II, wherein each of R and R 1 is hydrogen and X is a halogen, to form a compound of Formula XII followed by conversion of the compound of Formula XII into tofacitinib

16. The process of claim 15 , further comprising the steps of:

treating tofacitinib with citric acid in a suitable solvent to obtain tofacitinib monocitrate; and

recrystallizing tofacitinib monocitrate from a mixture of acetonitrile and water.

17. The process according to claim 14 , wherein in step (b), the compound of Formula V-II, in which R 1 is trityl; R is tosyl; and X is a halogen, is deprotected with a base to obtain a compound of Formula V-II, wherein R 1 is trityl; R is hydrogen and X is a halogen.

18. The process according to claim 17 , further comprising converting the compound of Formula V-II, in which R 1 is trityl; R is hydrogen and X is a halogen, into tofacitinib.

19. The process according to claim 14 , wherein in step (b), the compound of Formula V-II, in which R 1 is trityl; R is tosyl; and X is a halogen, is deprotected with an acid to obtain a compound of Formula V-II, wherein R 1 is hydrogen; R is tosyl, and X is a halogen.

20. The process according to claim 19 , further comprising converting the compound of Formula V-II, in which R 1 is hydrogen; R is tosyl, and X is a halogen, into tofacitinib.