Improved process for the preparation of upadacitinib

A process for preparation of 8-((3R,4S)-4-ethylpyrrolidin-3-yl)-3H-imidazo[1,2-a] pyrrolo[2,3-e]pyrazine compound of formula-2, comprising treating (3S,4R)-benzyl 3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidine-1-carboxylate of formula-3a with barium hydroxide octa hydrate in a mixture of isopropanol and water to provide 8-((3R,4S)-4-ethylpyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine compound of formula-2.

A process for preparation of compound of formula-2, comprising reacting the compound of general formula-3(i) with base to provide compound of formula-2.

A process for the preparation of compound of formula-2, comprising, reacting (3S,4R)-benzyl 3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidine-1-carboxylate of formula-3a(i) with barium hydroxide octa hydrate in a mixture of isopropanol and water to provide 8-((3R,4S)-4-ethylpyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine compound of formula-2.

Crystalline form of 8-((3R,4S)-4-ethylpyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e] pyrazine.

Crystalline form of 8-((3R,4S)-4-ethylpyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e] pyrazine compound of formula-2, is characterized by its powder X-Ray diffractogram as illustrated in FIG. 1.

8-((3R,4S)-4-ethylpyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine having purity of at least about 98.80% as measured by HPLC.

Dibenzoyl-L-tartaric acid salt of Upadacitinib.

A process for the preparation of crystalline Form-I of dibenzoyl-L-tartaric acid salt of Upadacitinib, comprising:

• a) treating the compound of formula-1 with dibenzoyl-L-tartaric acid in isopropanol, water and isopropyl acetate,
• b) heating the mixture obtained in step-a) to a temperature ranging from 25° C. to 60° C.,
• c) isolating crystalline Form-I of dibenzoyl-L-tartaric acid salt of Upadacitinib.

A process for the preparation of crystalline Form-II of dibenzoyl-L-tartaric acid salt of Upadacitinib, comprising:

• a) treating the compound of formula-1 with dibenzoyl-L-tartaric acid in acetonitrile and water,
• b) heating the mixture obtained in step-a) to a temperature ranging from 25° C. to 65° C.,
• c) isolating crystalline Form-II of dibenzoyl-L-tartaric acid salt of Upadacitinib.

4-Nitrobenzoic acid salt of Upadacitinib.

A process for the preparation of crystalline form of 4-nitrobenzoic acid salt of Upadacitinib, comprising:

• a) treating the compound of formula-1 with 4-nitrobenzoic acid in acetonitrile to provide 4-nitrobenzoic acid salt of Upadacitinib,
• b) isolating crystalline form of 4-nitrobenzoic acid salt of Upadacitinib.

Crystalline form-M of Upadacitinib tartrate is characterized by its powder X-Ray diffractogram as illustrated in FIG. 5.

A process for the preparation of crystalline Form-M of Upadacitinib tartrate, which comprises:

• a) providing a solution of Upadacitinib of formula-1,
• b) providing a solution of tartaric acid,
• c) adding the solution obtained in step-a) to the solution obtained in step-b) to provide crystalline Form-M of Upadacitinib tartrate.

Upadacitinib obtained according to the any of preceding claims is having purity of at least about 95%;

• preferably of at least about 97%;
• more preferably of at least about 98%;
• most preferably of at least about 99.9% as measured by HPLC.

Upadacitinib obtained according to the any of preceding claims is having chiral purity of at least about 95%;

• preferably of at least about 97%;
• more preferably of at least about 98%;
• most preferably of at least about 99.9% as measured by HPLC.

Amorphous form of Upadacitinib obtained according to the preceding claims is having purity of greater than about 99.80% as measured by HPLC.

Upadacitinib obtained according to the preceding claims is having particle size distribution D90<250 μm.

Upadacitinib obtained according to the preceding claims is useful for the preparation of pharmaceutical composition.

A pharmaceutical composition comprising Upadacitinib according to the preceding claims and one or more pharmaceutically acceptable excipients.