DESC:“IMPROVED PROCESSES FOR THE PREPARATION OF UPADACITINIB”

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Upadacitinib with high yield and purity.

BACKGROUND OF THE INVENTION

Upadacitinib (ABT-494), which was approved in US under the brand name of RINVOQ® for the treatment of rheumatoid arthritis, Crohn's disease, ulcerative colitis, atopic dermatitis, psoriatic arthritis, axial SpA Giant Cell Arteritis and Takayasu Arteritis. Upadacitinib, is represented by structural Formula (I).

Upadacitinib was first disclosed in US RE47221 (US 8,426,411).

WO 2017/066775 A1 discloses a process for the preparation of Upadacitinib (I), which comprises compound of formula (XI) is condensed with compound of formula (III) in presence of LiOtBu (lithium tert-butoxide)/DMA (N, N-dimethylacetamide) to obtain compound of formula (XII). Compound of formula (XII) is treated with TFAA (trifluoroacetic anhydride) in presence of pyridine/NaOH to obtain compound of formula (XIII). Compound of formula (XIII) is treated with HCl to obtain compound of formula (XIV). The compound of formula (XIV) is reacted with 2,2,2-trifluoroethylamine in presence of CDI to obtain Upadacitinib (I).

The above process is schematically shown as below:

Scheme 1

In the above prior art process disubstituted trifluoroethylamine impurity is formed, removal of this impurity is very difficult and required multiple purification techniques. Hence, above prior-art process is not suitable for commercially in industrial scalable, provide the compound of formula (I) with very low overall yield, low purity, high cost and not environmentally-friendly.

Therefore, it is necessary to design a safer and more environmentally-friendly synthetic route. So, our inventors have developed an improved process for the preparation of Upadacitinib with a low-cost, environmentally-friendly, and efficient synthesis method with high purity and good yield.

OBJECT OF THE INVENTION

The present invention relates to an improved process for the preparation of Upadacitinib (I) with high yield and purity.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of Upadacitinib with high yield and purity.

One embodiment of the present invention provides an improved process for the preparation of Upadacitinib (I), comprising the steps of:

a) reacting compound of formula (II) with compound of formula (III) in presence of base to obtain the in-situ compound of formula (IV),

b) cyclizing in-situ compound of formula (IV) with an acid anhydride or acid to obtain the compound of formula (V),

c) optionally, isolating compound of formula (V) from suitable solvents,
d) treating compound of formula (V) with acid to obtain the in-situ compound of formula (VI),

e) coupling in-situ compound of formula (VI) with 2,2,2-trifluoroethyl amine in presence of coupling agent to obtain compound of formula (VII),

f) optionally, isolating compound of formula (VII) from mixture of suitable solvents,
g) treating compound of formula (VII) with base to obtain compound of formula (I), and

h) recrystallizing compound of formula (I) from suitable solvents.

In yet another embodiment of the invention provides a process for preparation of pure crystalline form of Upadacitinib having purity of greater than 99.8%, comprising the steps of:

a. crude Upadacitinib is dissolved in an ester solvent,
b. heating the reaction mixture at suitable temperature,
c. cooling the reaction mixture, and
d. isolating the pure crystalline of Upadacitinib.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of Upadacitinib (I) with high yield and purity.

The present invention provides an improved process for the preparation of Upadacitinib (I), comprising the steps of:

a) reacting compound of formula (II) with compound of formula (III) in presence of base to obtain the in-situ compound of formula (IV),

b) cyclizing in-situ compound of formula (IV) with an acid anhydride or acid to obtain the compound of formula (V),

c) optionally, isolating compound of formula (V) from suitable solvents,
d) treating compound of formula (V) with acid to obtain the in-situ compound of formula (VI),

e) coupling in-situ compound of formula (VI) with 2,2,2-trifluoroethyl amine in presence of coupling agent to obtain compound of formula (VII),

f) optionally, isolating compound of formula (VII) from mixture of suitable solvents,
g) treating compound of formula (VII) with base to obtain compound of formula (I), and

h) recrystallizing compound of formula (I) from suitable solvents.

In an embodiment of the present invention, reacting compound of formula (II) with compound of formula (III) in presence of base or aqueous base and the reaction is carried out at -5 to 10°C for 18-24 hours or the reaction is carried out at -20 to -5°C for 1-4 hours to obtain the in-situ compound of formula (IV). Cyclizing in-situ compound of formula (IV) with acid anhydride or acid, the reaction is carried out at 60 to 85°C for 5-9 hours to obtain the compound of formula (V) and optionally, isolating compound of formula (V) from suitable solvents.

In an embodiment of the present invention, treating compound of formula (V) with acid, the reaction is carried out at 70 to 90ºC for 5 to 9 hours, followed by pH adjustment with base (8.0 to 10) to obtain the in-situ compound of formula (VI). Coupling in-situ compound of formula (VI) with 2,2,2-trifluoroethyl amine in presence of suitable coupling agent, the reaction is carried out at 20 to 30ºC for 2 to 6 hours to obtain compound of formula (VII) and optionally, compound of formula (VII) is isolating from mixture of suitable solvents, compound of formula (VII) is specifically isolating from mixture of methyl tert-butyl ether and n-heptane, stirred for 90 min at 25-30°C, filtered the solid and washed with n-heptane to obtain compound of formula (VII).
In an embodiment of the present invention, treating compound of formula (VII) with base to obtain compound of formula (I), the reaction is carried out at 45 to 65ºC for 2 to 6 hours, optionally pH adjustment with base (10 to 12) and compound of formula (I) is recrystallization from suitable solvents, compound of formula (I) is specifically recrystallization from ethyl acetate, heated to 70-75°C for one hour and then cooled to 25-30°C. Filtered the solid at 25-30°C and washed the solid with ethyl acetate and dried to obtain the Upadacitinib (I).

According to an embodiment of the present invention, wherein Upadacitinib (I) is isolating as a pure hydrate crystalline form or pure anhydrous crystalline form or amorphous form.

According to an embodiment of the present invention, wherein Upadacitinib (I) is isolating as a pure hydrate crystalline form is hemihydrate Form C (free base).

According to an embodiment of the present invention provides Upadacitinib (I) having HPLC purity = 99.8%.

According to an embodiment of the present invention, the reaction is carried out by using base selected from triethylamine, tert-butylamine, pyridine, diazabicycloundecane (DBU); sodium methoxide, potassium methoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium hydride, lithium hydroxide, lithium tert-butoxide, Sodium tert-butoxide, potassium tert-butoxide, Caesium hydroxide, potassium carbonate or potassium hydrogen carbonate. According to a more preferred embodiment the base is lithium hydroxide, sodium chloride, sodium hydroxide and triethylamine or mixtures thereof or other suitable bases.

According to an embodiment of the present invention. wherein the suitable solvent is selected alcohols such as methanol, ethanol, propanol, butanol, n-propyl alcohol, isopropyl alcohol, and t-butyl alcohol; nitriles such as acetonitrile and propionitrile; ether solvent such as tetrahydrofuran, diisopropylether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; and aromatic hydrocarbons such as toluene, heptane and xylene; esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone; halogenated hydrocarbons such as chloroform, dichloromethane; water; cyclohexane and or mixtures thereof.

According to an embodiment of the present invention, wherein the suitable acid anhydrides include trifluoroacetic anhydride, pentafluoropropionic anhydride, heptafluorobutyric anhydride and or mixtures thereof.

According to an embodiment of the present invention, wherein the suitable acid selected used in the present invention can be selected from but not limited to "inorganic acids" such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, perchloric acid, carbonic acid; and "organic acids" such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, capric acid, oxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid, succinic acid, citric acid, uric acid, tartaric acid, benzoic acid, 4-hydroxybenzoic acid, salicylic acid, oleic acid, octanoic acid, stearic acid, mandelic acid, adepic acid, pivalic acid, camphorsulfonic acid, substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and or mixtures thereof.

According to an embodiment of the present invention, wherein the “suitable coupling agent" used in the present invention can be selected from but not limited to ?, ?'-dicyclohexylcarbodiimide (DCC), ?,?'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl), ?,?'-carbonyl diimidazole (CDI), l-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU), 2-(1H-benzotriazol-l-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and the like.

Abbreviation for the terms used in this invention as follows:
Boc - tert-butyloxycarbonyl
Ts - p-Toluenesulfonyl
Cbz - benzyloxycarbonyl

In another embodiment of the invention provides a process for preparation of pure crystalline form of Upadacitinib having purity of greater than 99.8%, comprising the steps of:

a. Crude Upadacitinib is dissolved in an ester solvent,
b. heating the reaction mixture at suitable temperature,
c. cooling the reaction mixture, and
d. isolating the pure crystalline of Upadacitinib.

According to embodiment of the invention provides a process for preparation of pure crystalline form of Upadacitinib having purity of greater than 99.8%, comprising the steps of:

a. Crude Upadacitinib is dissolved in an ethyl acetate,
b. heating the reaction mixture at 65 to 78ºC,
c. cooling the reaction mixture at 25 to 30ºC, and
d. isolating the pure crystalline of Upadacitinib.

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES
Example-1:
Preparation of (3R,4S)-Benzyl-3-(2-((tert-butoxycarbonyl)(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)-4-ethylpyrrolidine-1-carboxylate (IV):
A solution of tert-butyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl-carbamate (50 g), lithium hydroxide monohydride (8.1 g) in N,N-Dimethylacetamide (225 ml) at -5 to 0°C were added to a solution of (3R,4S)-3-(2-bromoacetyl)-4-ethyl-1-pyrrolidinecarboxylic acid phenyl methyl ester (54.7 g) in N,N-Dimethylacetamide (225 ml) and stirred for 20-22 hours at -5 to 0°C. After confirmation of completion of the reaction, reaction mass was quenched with purified water (1250 ml) at 0-5°C and filtered the precipitated solid at 25-30°C and maintained for 2 hrs, then dried to obtain (3R,4S)-Benzyl-3-(2-((tert-butoxycarbonyl) (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino) acetyl)-4-ethylpyrrolidine-1-carboxylate (IV) (85 g).
Yield: 100% (85 g)
Purity: 91.77% by HPLC

Example-2:
Preparation of (3R,4S)-Benzyl-3-(2-((tert-butoxycarbonyl)(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)-4-ethylpyrrolidine-1-carboxylate (IV):
A solution of tert-butyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (200 g), lithium tert. butoxide (49.4 g) in N, N-Dimethylacetamide (800 ml) at -5 to 0°C were added to a solution of (3R,4S)-3-(2-bromoacetyl)-4-ethyl-1-pyrrolidinecarboxylic acid phenyl methyl ester (218 g) in N,N-Dimethylacetamide (800 ml) at -15°C to-10°C and stirred for 3 hours at same temperature. After confirmation of completion of the reaction, reaction mass was quenched with acetic acid (15.4 g) at -5°C to 0°C and added toluene (1000 ml), followed by added purified water (1000 ml). Separated the toluene layer and washed with aqueous sodium chloride solution (1200 ml), then concentrated the toluene layer to obtain (3R,4S)-Benzyl 3-(2-((tert-butoxycarbonyl) (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)-4-ethylpyrrolidine-1-carboxylate (IV) as a syrup mass (380 g).
Yield: 111.76% (380 g)
Purity: HPLC:90.94%.

Example-3:
Preparation of (3S,4R)-Benzyl-3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl) pyrrolidine-1-carboxylate (V):
Trifluoroacetic anhydride (161.9 g) was added to a solution of (3R,4S)-Benzyl 3-(2-((tert-butoxycarbonyl) (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)-4-ethylpyrrolidine-1-carboxylate (255 g) in acetonitrile (2550 ml) and heated to 70-75°C for 6-8 hours. After confirmation of completion of the reaction, reaction mass was concentrated under vacuum and added dichloromethane (1530 ml), followed by added purified water (1275 ml). The reaction mixture was neutralized with aqueous sodium bicarbonate solution (2550 ml) and stirred for 20-30 min at 25-30°C. Dichloromethane layer was separated and washed with purified water (1275 ml), then concentrated the dichloromethane layer. The resultant product was added to methanol (765 ml) and stirred for 1-2 hours. The obtained solid was filtered and dried to obtain (3S,4R)-Benzyl 3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl) pyrrolidine-1-carboxylate (V) (142 g).
Yield: 67.91% (142 g)
Purity: HPLC: 96.98%.

Example-4:
Preparation of (3S,4R)-Benzyl-3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl) pyrrolidine-1-carboxylate (V):
To a stirred solution of tert-butyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (200 g), lithium tert-butoxide (41.2g) in N, N-Dimethylacetamide (800 ml) at -5 to 0°C was added a solution of (3R,4S)-3-(2-bromoacetyl)-4-ethyl-1-pyrrolidinecarboxylic acid phenyl methyl ester (182.4 g) in N, N-Dimethylacetamide (800 ml) at -15°C to-10°C and stirred for 2-3 hours at the same temperature. After confirmation of completion of the reaction, reaction mass was quenched with acetic acid (15.5 g) at -5°C to 0°C and added toluene (1000 ml), followed by added purified water (2000 ml). Separated the toluene layer and washed with aqueous sodium chloride solution (2x600 ml), then concentrated the toluene layer to obtain (3R,4S)-Benzyl 3-(2-((tert-butoxycarbonyl) (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)-4-ethyl pyrrolidine-1-carboxylate (IV) as a syrup mass and diluted with acetonitrile (2720 ml). To the above acetonitrile solution contained (3R,4S)-Benzyl 3-(2-((tert-butoxycarbonyl) (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)-4-ethylpyrrolidine-1-carboxylate (IV) was added Trifluoroacetic anhydride (216.2 g) and heated to 70-75°C for 6-8 hours. After confirmation of completion of the reaction, reaction mass was concentrated under vacuum and dissolved the concentrated mas in dichloromethane (1700 ml) then adjusted the pH of the solution to 7.0-8.0 with aqueous sodium bicarbonate solution (3400 ml). Dichloromethane layer was separated and extracted the aqueous layer with dichloromethane (680 ml) and washed combined dichloromethane layer with purified water (1700 ml), then concentrated the dichloromethane layer. Methanol (1020 ml) was added to the concentrated mass and stirred for 1-2 hours. The obtained solid was filtered, washed with methanol (340 ml) and dried to obtain (3S,4R)-Benzyl 3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidine-1-carboxylate (V).
Yield: 70.94% (198.5 g)
Purity: HPLC: 96.9%.

Example-5:
Preparation of 8-((3R,4S)-4-Ethylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e] pyrazine (VI):
Concentrated hydrochloric acid (420 ml) was added to a solution of (3S,4R)-benzyl 3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidine-1-carboxylate (140 g) in isopropyl alcohol (420 ml) and heated to 75-80°C for 6-8 hours. After confirmation of completion of the reaction, reaction mass cooled to 25-30°C, followed by added purified water (1400 ml) and stirred for 10-20 min. The reaction mass was washed with dichloromethane (1400 ml). Dichloromethane (1400 ml) was added to the aqueous layer and adjusted the pH to 9.0-9.5 with triethylamine (650 ml) at 10-15°C and stirred at 25-30°C for 20-30 min. Separated the dichloromethane layer and washed with purified water (700 ml) and concentrated the organic layer under reduced pressure. The obtained mass was added to methyl tert-butyl ether (700 ml), stirred for 90 min and filtered the solid to obtain 8-((3R,4S)-4-Ethylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e] pyrazine (VI) (97.5 g).
Yield: 92.85% (97.5 g)
Purity: HPLC: 98.89%.

Example-6:
Preparation of (3S,4R)-3-Ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (VII):
2,2,2-trifluoroethanamine (30.8 g) was added to a solution of 1,1'-Carbonyldiimidazole (47.1 g) in tetrahydrofuran (510 ml) at 0-5°C and maintained for 2 hours at same temperature. The reaction mixture solution was added to a solution of 8-((3R,4S)-4-Ethylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e] pyrazine (85 g) in dichloromethane (850 ml) at 0-5°C and stirred for 3-5 hours at 25-30°C. After confirmation of completion of the reaction, 1N hydrochloric solution (850 ml) was added to the reaction mass, stirred at 25-30°C for 20-30 min. Separated the dichloromethane layer and washed with purified water (850 ml) and concentrated the organic layer under reduced pressure. Mixture of methyl tert-butyl ether (425 ml) and n-heptane (850 ml) was added to the concentrated mass and stirred for 90 min at 25-30°C. The obtain solid was filtered and washed with n-heptane (85 ml) to give (3S,4R)-3-Ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl) pyrrolidine-1-carboxamide (VII) (106 g).
Yield: 95.92% (106 g)
Purity: HPLC:99.29%.

Example-7:
Preparation of (3S,4R)-3-Ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (VII):
Concentrated hydrochloric acid (370 ml) was added to a solution of (3S,4R)-benzyl 3-ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidine-1-carboxylate (185 g) in isopropyl alcohol (370 ml) and heated to 75-80°C for 6-8 hours. After confirmation of completion of the reaction, reaction mass cooled to 25-30°C, added purified water (1480 ml) and stirred for 10-20 min. The reaction mass was washed with dichloromethane (2x740 ml). Dichloromethane (920 ml) was added to the aqueous layer and adjusted the pH to 9.0-10.0 with triethylamine (555 ml) at 10-15°C and stirred at 25-30°C for 20-30 min. Separated the dichloromethane layer, washed with purified water (925 ml) and concentrated the organic layer under reduced pressure and dissolved in dichloromethane (1110 ml) to give a solution of 8-((3R,4S)-4-Ethylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e] pyrazine (VI). 2,2,2-trifluoroethanamine (50.6 g) was added to a solution of 1,1'-Carbonyldiimidazole (77.3 g) in tetrahydrofuran (674 ml) at 0-5°C and maintained for 2 hours at same temperature. The reaction mixture solution was added to the above dichloromethane solution of 8-((3R,4S)-4-Ethylpyrrolidin-3-yl)-3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e] pyrazine (VI) at 0-5°C and stirred for 2-3 hours at 25-30°C. After confirmation of completion of the reaction, 1N hydrochloric solution (1387.5 ml) was added to the reaction mass and stirred at 25-30°C for 20-30 min. Separated the dichloromethane layer and washed with purified water (694 ml) and concentrated the organic layer under reduced pressure. Mixture of methyl tert-butyl ether (417 ml) and n-heptane (832.5 ml) was added to the concentrated mass and stirred for 90 min at 25-30°C. The obtain solid was filtered and washed with n-heptane (139 ml) to give (3S,4R)-3-Ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl) pyrrolidine-1-carboxamide (VII).
Yield: 96.52% (175 g)
Purity: HPLC:99%.

Example-8:
Preparation of amorphous form of (3S,4R)-3-Ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e] pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Upadacitinib):
Aqueous sodium hydroxide solution (2.7 g in 27 ml of water) was added to a solution of (3S,4R)-3-Ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (18 g) in tetrahydrofuran (180 ml) at 25-30°C and heated to 50-55°C for 4-6 hours. After confirmation of completion of the reaction and it was allow to cooled at 25-30°C, added saturated sodium chloride solution (180 ml) and followed by ethyl acetate (180 ml), stirred for 20-30 min at 25-30°C. Separated the dichloromethane layer, added 2.5 % aqueous hydrochloric acid at 25-30°C and then stirred for 30-45 min. Separated the aqueous layer, removed the traces of ethyl acetate at 40°C under vacuum and adjusted the pH to 11-12 with 10% aqueous sodium hydroxide solution at 0-5°C, stirred for 2 hours at same temperature. Filtered the solid at 0-5°C, washed with purified water to obtain amorphous form of (3S,4R)-3-Ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoro ethyl)pyrrolidine-1-carboxamide (9.9 g).
Yield: 77.34% (9.9 g)
Purity: 98.18%.

Example-9:
Preparation of amorphous form of (3S,4R)-3-Ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e] pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (Upadacitinib):

Aqueous sodium hydroxide solution (2.3 g in 30 ml of water) was added to a stirred solution of (3S,4R)-3-Ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide (20 g) in tetrahydrofuran (100 ml) at 25-30°C and heated to 50-55°C for 6-8 hours. After confirmation of completion of the reaction and its was allow to cooled at 25-30°C, added purified water (100 ml), followed by ethyl acetate (100 ml) and stirred for 20-30 min at 25-30°C. Separated the ethyl acetate layer, washed with aqueous sodium chloride solution (60 ml), treated with activated carbon (2 g) and concentrated the ethyl acetate layer under vacuum. ethyl acetate (100 ml) was added to concentrated mass and heated to 70-75°C for 1 hour, then cooled to 25-30°C. Filtered the solid at 25-30°C and washed the solid with ethyl acetate (20 ml). Ethyl acetate (50 ml) was added to the obtained wet solid, stirred for 10-20 min at 25-30°C and was added 2.5 % aqueous hydrochloric acid (100 ml), then stirred for 2-3 hours. Separated the aqueous layer and removed the traces of ethyl acetate at 40°C under vacuum and adjusted the pH to 11-12 with 10% aqueous sodium hydroxide solution at 0-5°C and stirred for 2 hours at same temperature. Filtered the solid at 0-5°C, washed the solid with purified water (20 ml) and dried under vacuum to obtain amorphous form of (3S,4R)-3-Ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoro ethyl)pyrrolidine-1-carboxamide (7 g).
Yield: 50% (7 g)
Purity: 99.76%.

Example-10:
Preparation of crystalline form of (3S,4R)-3-Ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e] pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide hydrate (2:1) (Upadacitinib):
Aqueous sodium hydroxide solution (12.8 g in 127.5 ml of water) was added to a solution of (3S,4R)-3-Ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoro ethyl)pyrrolidine-1-carboxamide (85 g) in tetrahydrofuran (425 ml) at 25-30°C and heated to 50-55°C for 3-5 hours. After confirmation of completion of the reaction and it was allow to cooled at 25-30°C and added purified water (425 ml), followed by ethyl acetate (425 ml), then stirred for 20-30 min at 25-30°C. Separated the ethyl acetate layer, washed with aqueous sodium chloride solution (425 ml) and treated with activated carbon (8.5 g) and concentrated the ethyl acetate layer under vacuum. ethyl acetate (255 ml) was added to concentrated mass, and heated to 70-75°C for 1 hour, then cooled to 25-30°C. Filtered the solid at 25-30°C and washed the solid with ethyl acetate (85 ml) and dried to give crystalline form of (3S,4R)-3-Ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl) pyrrolidine-1-carboxamide hydrate (2:1).
Yield: 80% (48.5 g)
Purity: 99.89%.

Example-11:
Preparation of crystalline form of (3S,4R)-3-Ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e] pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide hydrate (2:1) (Upadacitinib):
Aqueous sodium hydroxide solution (24 g in 240 ml of water) was added to a solution of (3S,4R)-3-Ethyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoro ethyl)pyrrolidine-1-carboxamide (160 g) in tetrahydrofuran (800 ml) at 25-30°C and heated to 50-55°C for 5-7 hours. After confirmation of completion of the reaction and it was allowed to 25-30°C and added purified water (800 ml), followed by ethyl acetate (800 ml), then stirred for 20-30 min at 25-30°C. Separated the ethyl acetate layer and extracted the aqueous layer with ethyl acetate (480 ml). Adjusted the combined ethyl acetate layer pH to 0.5-1.0 with 1N hydrochloric acid (1600 ml), stirred for 20-30 min and separated the aqueous layer. To the aqueous layer, ethyl acetate (800 ml) was added and adjusted the pH to 10.0-11.0 with aqueous sodium hydroxide solution (800 ml) and stirred for 10-20 min. Separated the ethyl acetate layer and extracted the aqueous layer with ethyl acetate (480 ml) then washed with aqueous sodium chloride solution (480 ml) and treated with activated carbon (16 g) and concentrated the ethyl acetate layer under vacuum. ethyl acetate (480 ml) was added to the concentrated mass, and heated to 70-75°C for 30-45 min, then cooled to 25-30°C. Filtered the solid at 25-30°C and washed the solid with ethyl acetate (120 ml) and dried to give crystalline form of (3S,4R)-3-Ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl) pyrrolidine-1-carboxamide hydrate (2:1).
Yield: 71.18% (82 g)
Purity: 99.87%.
,CLAIMS:We Claim:
1. An improved process for the preparation of Upadacitinib (I), comprising the steps of:

a) reacting compound of formula (II) with compound of formula (III) in presence of base to obtain the in-situ compound of formula (IV),

b) cyclizing in-situ compound of formula (IV) with an acid anhydride or acid to obtain the compound of formula (V),

c) optionally, isolating compound of formula (V) from suitable solvents,
d) treating compound of formula (V) with acid to obtain the in-situ compound of formula (VI),

e) coupling in-situ compound of formula (VI) with 2,2,2-trifluoroethyl amine in presence of coupling agent to obtain compound of formula (VII),

f) optionally, isolating compound of formula (VII) from mixture of suitable solvents,
g) treating compound of formula (VII) with base to obtain compound of formula (I), and

h) recrystallizing compound of formula (I) from suitable solvents.

2. The process as claimed in claim 1, wherein the base is selected from triethylamine, tert-butylamine, pyridine, diazabicycloundecane (DBU); sodium methoxide, potassium methoxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium hydride, lithium hydroxide, lithium tert-butoxide, Sodium tert-butoxide, potassium tert-butoxide, Caesium hydroxide, potassium carbonate or potassium hydrogen carbonate. According to a more preferred embodiment the base is lithium hydroxide, sodium chloride, sodium hydroxide and triethylamine or mixtures thereof or other suitable bases.

3. The process as claimed in claim 1, wherein the acid anhydride is selected from trifluoroacetic anhydride, pentafluoropropionic anhydride, heptafluorobutyric anhydride and or mixtures thereof.

4. The process as claimed in claim 1, wherein the acid is selected from "inorganic acids" such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, perchloric acid, carbonic acid; and "organic acids" such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, capric acid, oxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid, succinic acid, citric acid, uric acid, tartaric acid, benzoic acid, 4-hydroxybenzoic acid, salicylic acid, oleic acid, octanoic acid, stearic acid, mandelic acid, adepic acid, pivalic acid, camphorsulfonic acid, substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and or mixtures thereof.

5. The process as claimed in claim 1, wherein the suitable solvent is selected alcohols such as methanol, ethanol, propanol, butanol, n-propyl alcohol, isopropyl alcohol, and t-butyl alcohol; nitriles such as acetonitrile and propionitrile; ether solvent such as tetrahydrofuran, diisopropylether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; and aromatic hydrocarbons such as toluene, heptane and xylene; esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone; halogenated hydrocarbons such as chloroform, dichloromethane; water; cyclohexane and or mixtures thereof.

6. The process as claimed in claim 1, wherein the coupling agent is selected from ?, ?'-dicyclohexylcarbodiimide (DCC), ?, ?'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide.HCl (EDC.HCl), ?,?'-carbonyl diimidazole (CDI), l-[bis(dimethylamino) methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide-hexafluoro phosphate (HATU), 2-(1H-benzotriazol-l-yl)-1,1,3,3-tetramethyluroniumhexafluoro phosphate (HBTU) and or mixtures thereof.

7. A process for preparation of pure crystalline form of Upadacitinib having purity of greater than 99.8%, comprising the steps of:
a. crude Upadacitinib is dissolved in an ester solvent,
b. heating the reaction mixture at suitable temperature,
c. cooling the reaction mixture, and
d. isolating the pure crystalline of Upadacitinib.

8. The process as claimed in claim 7, wherein the ester solvent is selected from ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate and or mixtures thereof.

9. The process as claimed in claim 7, wherein the pure crystalline form of Upadacitinib is hemihydrate Form C.