DESC:Field of the Invention:
The present application relates to an improved process for abrocitinib and intermediates thereof, is represented by the following structural formula-I.

Formula-I

Background of the Invention:
Abrocitinib, is a Janus kinase (JAK) inhibitor indicated for the treatment of adults with refractory, moderate-to-severe atopic dermatitis whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies is inadvisable, is approved in USA with the brand name CIBINQO® developed by Pfizer pharmaceutical in the form of tablet. The chemical name of Abrocitinib is N-((1s,3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide.

The US patent US9035074B2 first reported Abrocitinib and pharmaceutically acceptable salts. The US’074 disclosed various processes for intermediates of abrocitinib. The said patent reported purification of abrocitinib by column chromatography on silica gel eluting with a mixture of dichloromethane and methanol.
The US patent US10815240B2 reported various salts, co-crystals for abrocitinib and purification of abrocitinib and processes thereof. Also reported an alternative process for abrocitinib using novel intermediates and processes thereof.
The PCT application publication WO2020261041A1 reported various purification processes for abrocitinib and amorphous solid dispersion for abrocitinib.
Based on drawbacks in the prior art process and certain limitations, there is a need for providing an improved process for the preparation of abrocitinib, which involves simple experimental procedures, well suited to industrial production, which avoids the use of column chromatography purification, and which affords highly pure abrocitinib.
The present invention provides an improved process for preparation of abrocitinib and intermediates thereof and free from other impurities or isomers and nitroso amine impurities. The present invention involves cost effective key starting material, reagents and solvents, and suitable industrial production.
Brief Description:
The first aspect of the present invention is to provide an improved process for N-((1s,3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide compound of formula-I
The second aspect of the present invention is to provide a process for N-((1s,3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide compound of formula-I
The third aspect of the present invention is to provide benzyl ((1s,3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)carbamate a compound of formula-4.

Brief description of the drawings:
Figure 1: Illustrates the PXRD pattern of crystalline Form of N-((1s,3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide compound of formula-I obtained from example-11.
Figure 2: Illustrates the IR of crystalline Form of N-((1s,3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide compound of formula-I obtained from example-11.

Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbontetra chloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
As used herein the present invention the term “suitable base” refers to inorganic or organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases such as like dimethylamine, diethylamine, diisopropyl amine, diisopropyl ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine (DMAP), N-methyl morpholine (NMM), or mixtures thereof.
The term “reducing” agent used in the present invention refers suitable reducing reagents are selected from Lithium aluminum hydride, sodium borohydride, BF3 etherate solution, Pd/C, Raney-nickel;
The first aspect of the present invention is to provide an improved process for N-((1s, 3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide compound of formula-I,
Comprising of:
a) reacting compound of formula-1 with suitable reagent, solvent to provide compound of formula-2.

b) reducing the compound of formula-2 with suitable reagent, solvent to provide compound of formula-3,

c) reacting the compound of formula-3 with compound of formula-A to provide compound of formula-4,

d) deprotecting the compound of formula-4 with suitable reagent, solvent to provide the compound of formula-5, optionally isolating as suitable acid addition salts (such hydrochloride acid, hydrobromic acid),

e) reacting the compound of formula-5 with Propane sulfonyl chloride in presence of suitable reagent, solvent to provide the compound of formula-I,
f) optionally purifying the compound obtained is step-e) by using suitable solvents to provide the pure compound of formula-I.
Wherein in step-a), b), c), d), e), and f) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, polar aprotic solvents, polar protic solvents, ester solvent, nitrile solvent, ketone solvent, alcohol solvent, water or any mixture thereof; the suitable temperature is 0-100°C.
Wherein in step-a) suitable reagent is selected from diphenyl phosphoroazide, trimethylsilyl azide, tributyl tin azide, p-toluene sulfonyl azide, 4-acetamidobenzenesulfonyl azide, Sodium azide, lithium azide, benzyl alcohol, p-methyl benzyl alcohol, p-methoxy benzyl alcohol, p-cyano benzyl alcohol, organic base, inorganic base
Wherein in step-b) suitable reagents is selected from monomethyl amine solution in methanol, monomethyl amine (g) in organic solvents, monomethyl amine HCl, sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium cyano acetoxy borohydride, lithium aluminum hydrate and mixture thereof.
Wherein in step-c) suitable reagent is selected from inorganic base, organic base, preferable solvents are DMF, DMA, IPA, dioxane, NMP and water mixture thereof.
Wherein in step-d) suitable reagents are selected from inorganic base such as KOH, NaOH, LiOH, preferable salts are HCl, HBr .
Wherein in step-e) suitable reagents are selected from organic bases.
The preferred embodiment of the present invention is to provide an improved process for N-((1s, 3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide compound of formula-I,
Comprising of:
a) reacting compound of formula-1 with diphenylphosphoroazide, benzyl alcohol in presence of triethylamine to provide compound of formula-2.

b) reducing the compound of formula-2 with monomethylamine in presence sodium borohydride in methanol to provide compound of formula-3a,

c)reacting the compound of formula-3a with compound of formula-A in presence of potassium carbonate in water to provide compound of formula-4,

d)deprotecting the compound of formula-4 with sodium hydroxide in ethanol, water to provide the compound of formula-5a,

e)reacting the compound of formula-5a with 1-Propane sulfonyl chloride in presence of triethylamine in dimethyl formamide and further purified in isopropanol, water to provide the compound of formula-I,
f) purifying the compound obtained is step-e) in mixture of ethanol, water at 80-90° C to provide the pure crystalline form of compound of formula-I.
The second aspect of the present invention is a process for N-((1s, 3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide compound of formula-I,
Comprising of:
a) reacting the compound of formula-3 with compound of formula-B to provide compound of formula-6,

b) reacting the compound of formula-6 with suitable reagent, solvent to provide the compound of formula-5, optionally isolating as suitable acid additional salts (such hydrochloride acid, hydrobromic acid),

c) reacting the compound of formula-5 with Propane sulfonyl chloride in presence of suitable reagent, solvent to provide the compound of formula-I,
d)optionally purifying the compound obtained is step-c) by using suitable solvents to provide the pure compound of formula-I.
Wherein in step-a), b), c) and d) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, polar aprotic solvents, polar protic solvents, ester solvent, nitrile solvent, ketone solvent, alcohol solvent, water or any mixture thereof; the suitable temperature is 0-100°C. Wherein in step-a) suitable reagent is selected from inorganic base, organic base, preferable solvents are DMF, DMA, DMSO, IPA, alcohol, 1,4-dioxane, NMP and water mixture thereof. Wherein in step-b) suitable reagent is selected from inorganic base such as KOH, NaOH, LiOH and mixture thereof, preferable salts are HCl, HBr. Wherein in step-c) suitable reagent is selected from organic bases.
The third aspect of the present invention is to provide benzyl ((1s,3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)carbamate a compound of formula-4.

[4]
The process of the present invention can be represented schematically as follows:
Scheme-1:

The other aspect of the present invention is to provide a process for N-((1s,3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide compound of formula-I as mentioned in scheme-2
Scheme-2:

The other aspect of the present invention is to provide a purification process for N-((1s,3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide compound of formula-I
Comprising of
a)Stirring compound of formula-I in a suitable solvents at suitable temperature,
b)adding anti solvent and stirring at suitable temperature,
c)isolating and drying to get the pure compound of formula-I.
Wherein in step-a to c) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, polar aprotic solvents, polar protic solvents, ester solvent, nitrile solvent, ketone solvents, alcohol solvent, water or any mixture thereof; the suitable temperature is 0-100°C.
The other aspect of the present invention compound of formula-I is having particle size distribution of D90 <300 µm, D50 <150 µm. D10 <75 µm.
The compound of formula-I produced by the process of the present invention has purity of at least about 95%; preferably of at least about 97%; more preferably of at least 20 about 98%; most preferably of at least about 99% as measured by HPLC.
The other isomer of compound of formula-I is having preferably < 0.5 %, more preferably < 0.15 %; and other related impurities are preferably < 0.5 %, more preferably < 0.15 % in compound of formula-I of the present invention.
The isopropyl sulfonyl impurity and disulfonyl impurity in compound of formula-I is preferably < 0.5 %, more preferably < 0.15 %.
The isopropyl sulfonyl impurity, with the chemical name N-((1s,3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-2-sulfonamide.
The disulfonyl impurity, with the chemical name N-(3-(methyl(7-(propylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide.
N-((1s,3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide compound of formula-I produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills, milling or micronization may be performed before drying, or after the completion of drying of the product.
PXRD analysis of N-((1s,3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino) cyclobutyl) propane-1-sulfonamide compound of formula-I was carried out using BRUKER D8 ADVANCED/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min. IR spectra were recorded on a Perkin-Elmer FTIR spectrometer.
N-((1s,3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide compound of formula-I used in the present invention is synthesized by the prior known processes.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of compound of formula-2 (benzyl (3-oxocyclobutyl) carbamate)
A round bottom flask was charged with 3-oxocyclobutane carboxylic acid (1.0 eq), tetrahydrofuran (500 ml) and toluene (500 ml), added triethyl amine (102.0 g) at 25-30° C. Cooled the reaction mixture to 0-5°C, slowly add diphenyl phosphorazide (254.70 g), stirred for 2 hr at same temperature and slowly heated to 60°C, and maintained for 2 hr. Charged benzyl alcohol (104.0 g) slowly and stirred at 100-110°C for 12 hr . Cooled the reaction mixture to 25°C, added water (1000 ml) and separated the layers. The organic layer was washed with 1N HCl (500 ml) solution, followed by saturated bicarbonate solution. The combined organic layer was washed with brine solution, dried with sodium sulfate and distilled-off the solvent under vacuum to get the title compound.
Yield: 170.0 g.
Example-2: Preparation of compound of formula-3 (benzyl ((1s,3s)-3-(methylamino) cyclobutyl) carbamate)
A round bottom flask was charged with methanol (500 ml), compound-2 (170 g) and 40% mono methyl amine solution (690.0 g) and stirred for 15 min. at 25-35°C. Cooled the reaction mixture to 0-5°C and added acetic acid and maintained for 2 hr at 25-35°C. Further cooled to 0-5°C and gradually added sodium borohydride (32.74 g) and maintained reaction at same temperature for 3 hr. The reaction mixture was charged with purified water (2000 ml) and MDC (500 ml) and separated into both layers. The organic layer was charged with water (500 ml) and adjusted the pH to 1-2 with Con HCl solution and separated organic layer and aqueous layer. The aqueous layer was washed with MDC (500 ml), the aqueous layer is taken into RBF and charge MDC (500 ml) and adjusted the reaction pH to 9-10 with NaOH solution. The reaction mixture was separated into an aqueous layer and organic layer, the aqueous layer was extracted with MDC. The combined organic layer washed with purified water and with brine solution. The organic layer was distilled off under vacuum to get the residue compound. The obtained residue was charged with IPA and cooled to 0-5°C, charged with IPA-HCl, the precipitated solid was stirred at 25-35° C for 12 hr and filtered the solid and washed with IPA and dried to obtain the title compound.
Yield: 85.0 g
Example-3: Preparation of compound of formula-4 (benzyl ((1s,3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)carbamate)
A round bottom flask was charged with water (700 ml), potassium carbonate (93.97 g), compound-3 (65.58 g), 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (35.0 g) and heated reaction mixture to 90-95°C and maintained for 4 hr at same temperature. Cooled the reaction mixture to room temperature, maintained the reaction mass for 2 hr at 25-35°C and filtered the reaction mixture and washed with water and dried to get the title compound.
Yield: 74.0 g
Example-4: Preparation of compound of formula-5b (1s, 3s)-N1-methyl-N1-(7H-pyrrolo [2,3-d] pyrimidin-4-yl) cyclobutane-1,3-diamine hydrobromide)
A round bottom flask was charged with ethyl acetate (30.0 ml), compound-4 (10 g), added acetic acid (30 ml) and HBr in acetic acid (30 ml) and maintained at 55-65°C for 8 hr. Filtered the reaction mixture and washed with ethyl acetate and MTBE, the wet solid was charged with ethyl acetate and stirred for 3 hr and filtered the solid compound and washed with ethyl acetate and dried to get the title compound. Yield: 10 g
Example-5: Preparation of Abrocitinib.
A round bottom flask was charged with DMF (240 ml), triethylamine (22.2 ml), and compound-5b (12 g) and cooled the reaction mixture to 5-10°C, added 1-propane sulfonyl chloride (6.72 g) and maintained at 25-35°C for 8 hr. The reaction mass was charged with water and MDC and stirred and separated the two layers. The aqueous layer was extracted with MDC and the combined organic layer and washed with water and brine solution. Distilled-off the organic layer under vacuum to obtain the residue compound. The obtained residue was charged with MTBE (60 ml) and stirred for 45 min and filtered the obtain solid and washed with MTBE and dried to obtain title compound. Yield: 7.15 g
Example-6: Preparation of compound of formula-3 (benzyl ((1s,3s)-3-(methylamino) cyclobutyl) carbamate)
A round bottom flask was charged with 3-oxocyclobutane carboxylic acid (100 g), tetrahydrofuran (500 ml), toluene (500 ml), and triethyl amine (102.0 g) at 25-30° C. Cool the reaction mixture to 0-5°C, slowly added diphenyl phosphorazide (254.70 g) at same temperature, and heated to 60-70°C, and stirred for 2 hr at same temperature. Benzyl alcohol (104.0 g) was added to the reaction mixture and stirred at 75-85°C for 12 hr. Cooled the reaction mixture to 25°C, added purified water (1000 ml), separated both layers. The organic layer was washed with 1N HCl solution, followed by sodium bicarbonate solution. The organic layer was washed with brine solution, dried with sodium sulfate and distilled off the solvent to get compound-2 as residue.
A round bottom flask was charged with methanol (500 ml), residue compound-2 and 40% mono methyl amine solution (690.0 g) and stirred for 15 min. Cooled the reaction mixture to 0-5°C and added acetic acid (0.4 Vol) and maintained for 2 hr at same temperature, stirred at room temperature for 2 hr. Further, cooled the reaction mixture to 0-5°C and gradually charged sodium borohydride (32.74 g) and stirred the reaction at same temperature for 3 hr . Charged purified water (2000 ml) and MDC (500 ml) and separated into two layers. The organic layer was charged with water and adjusted the pH to 1.5 with Con HCl solution and separated both layers. The aqueous layer was washed with MDC and adjusted the pH to 9.5 with 10% NaOH solution. Both layers were separated, the aqueous layer was extracted with MDC, and the combined organic layer was washed with purified water and with 10% sodium chloride solution. The organic layer was distilled-off under vacuum to get the residue compound. The obtained residue was charged with IPA (350 ml) and cooled to 0-5°C and added IPA-HCl (150 ml) and stirred for 12 hr, the precipitated solid was filtered and washed with IPA to obtain the title compound.
Yield: 85 g
Example-7: Preparation of compound of formula-4 (benzyl ((1s,3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)carbamate)
A round bottom flask was charged with water (700 ml), potassium carbonate (93.97 g), compound-3 (65.58 g) and followed by 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (35.0 g) and heated reaction mixture to 90-95°C and stirred for 4 hr at same temperature. Cooled the reaction mixture to 25-35°C and stirred for 1 hr, the precipitated solid was stirred for 2 hr at same temperature and filtered and washed with water and dried to get the title compound.
Yield: 74 g.
Example-8: Preparation of compound of formula-5a ((1s, 3s)-N1-methyl-N1-(7H-pyrrolo [2,3-d] pyrimidin-4-yl) cyclobutane-1,3-diamine dihydrochloride)
A round bottom flask was charged with ethanol (80 ml), water (20 ml), compound-4 (10 g), and sodium hydroxide (10 M) and heated the reaction mass 95-105°C and stirred for 12 hr. Cooled the reaction mass to room temperature, followed by addition of water and 10% methanol-DCM and stirred for 15 min and separated the layers. The aqueous layer was extracted with 10 % methanol and DCM. The organic layer was washed with brine solution and separated the organic layer and distilled-off the solvent under vacuum to get the crude compound. The crude compound is charged with isopropanol, cooled to 0-5°C and gradually charged with IPA-HCl and stirred for 1 hr. Filtered the precipitated solid and washed with isopropanol and dried to get the title compound.
Yield: 7.5 g; Purity by HPLC: >98.5%.
Example-9: Process for the preparation of Abrocitinib.
A round bottom flask was charged with dimethylformamide (120 ml), triethylamine (22.2 ml), and compound-5a (12 g) and stirred for 15 min. Cooled the reaction mixture to 0-5°C and added 1-propane sulfonyl chloride (6.72g) and maintained for 2 hr at 25-35 °C. The reaction mass was charged with water and stirred for 10 min, the precipitated solid was further stirred for 2h at room temperature. Filtered the obtain solid and washed with water and dried to get the title compound.
Yield: 10 g; Purity by HPLC: >98%
Example-10: Process for purification of Abrocitinib:
A round bottom flask was charged with abrocitinib (10 g), methanol (350 ml) and heated to 60-70°C and maintained until the clear solution is obtained. The reaction mixture was charged with activated carbon and maintained for 20 min, filtered the reaction mass through hyflow bed and washed with preheated methanol. The filtrate solution was distilled-off under vacuum and further, the solid compound was charged with methanol (1.5V) and toluene (1.5V) heated to 90-100°C and maintained for 45 min and 3 hr at 25-35°C. Filtered the obtain solid and washed with methanol and toluene, the wet compound was charged with ethyl acetate and heated to 70-80°C and maintained for 45 min. Cooled the reaction mass and maintained for 3 hr, filtered the solid and washed with ethyl acetate, dried to get the title compound. The obtained compound PXRD is similar to figure 1.
Yield: 9.0 g; Purity by HPLC: >99.5%.
Example-11: Process for purification of Abrocitinib:
A round bottom flask was charged with abrocitinib (10 g), ethanol (6.70 V) and water (3.35 V) heating to reflux until all solids dissolved. The reaction mixture gradually cooled to 25-35°C, the obtained solid was stirred for 1 hr and filtered, washed with ethanol and dried to get the title compound. The obtained compound PXRD is depicted in figure 1.
Yield: 9.25 g
Example-12: Preparation of compound of formula-3a (benzyl ((1s,3s)-3-(methylamino) cyclobutyl) carbamate) hydrochloride.
A round bottom flask was charged with 3-oxocyclobutane carboxylic acid (50 g), tetrahydrofuran (750 ml), toluene (750 ml), and triethyl amine (50.8 g) at 25-30° C and stirred for 30 min. Cool the reaction mixture to 0-5°C, slowly added diphenyl phosphorazide (127.8 g) at same temperature, and stirred for 2 hr at same temperature. Benzyl alcohol (52.12 g) was added to the reaction mixture and stirred at 60-70°C for 12 hr. Cooled the reaction mixture to 25°C, added purified water, toluene and separated both layers. The aqueous layer was extracted with toluene and the combined organic layer was washed with aq., sodium bicarbonate solution and water, dried with sodium sulfate and distilled-off the solvent to get residue compound.
A round bottom flask was charged with the above obtained residue compound, methanol (125 ml), and charged 40% mono methyl amine solution (690.0 g) and stirred for 15 min. Cooled the reaction mixture to 0-5°C and added acetic acid (20 mL) and maintained for 2 hr at same temperature. Further, the reaction mixture gradually charged with sodium borohydride (9.94 g) and stirred at same temperature for 3 hr. The reaction mixture was charged with water and MDC and separated into two layers. The organic layer was charged with water and adjusted the pH to 1.5 with Con. HCl solution and separated both layers. The aqueous layer was washed with MDC and adjusted the pH of aqueous layer to 11.5 with 10% NaOH solution. Both layers were separated, the aqueous layer was extracted with MDC, and the combined organic layer was washed with purified water and with 10% sodium chloride solution. The organic layer was distilled-off under vacuum to get the residue compound. The obtained residue was charged with ethyl acetate and cooled to 0-5°C and added ethyl acetate-HCl and stirred for 4 hr. Filtered the solid and washed with ethyl acetate to obtain the title compound. Further the obtained compound was charged with methanol and heated to 55-65°C and charged with methyl tert-butyl ether and stirred for 3 hr. Filtered the solid compound and washed with a mixture of methanol and MTBE and dried to get the title compound.
Yield: 115 g
Example-13: Preparation of compound of formula-5a ((1s, 3s)-N1-methyl-N1-(7H-pyrrolo [2,3-d] pyrimidin-4-yl) cyclobutane-1,3-diamine hydrochloride)
A round bottom flask was charged with water (1000 ml), potassium carbonate (134.79 g), compound-3a (92.36 g), 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (50.0 g) and heated reaction mixture to 90-95°C and maintained for 2.5 hr at same temperature. Cooled the reaction mixture to room temperature, maintained the reaction mass for 2 hr at 25-35°C and filtered the reaction mixture and washed with water and dried to get the title compound.
A round bottom flask was charged with the above compound, ethanol (900.0 ml), water (200 g), and sodium hydroxide (132 g) were heated to 90-100°C and stirred for 14 h. The reaction mixture was cooled and distilled off the solvent completely to get the residue compound. Further, the obtained compound was charged with water, dichloromethane, methanol and separated both layers. The aq. layer was extracted with dichloromethane and methanol with (9:1) and the combined organic layer was distilled off completely to obtain the residue compound.
Further, the obtained compound was charged with ethyl acetate and ethyl acetate-HCl and stirred for 2 hr at 20-30°C and filtered the solid compound. The obtained compound was charged with methanol and heated to 55-65°C and charged with methyl tert-butyl ether and stirred for 2 hr. Filtered the solid compound and washed with ethyl acetate and methyl tert-butyl ether, and dried to get the title compound.
Yield: 78 g
Example-14: process for the preparation of Abrocitinib.
A round bottom flask was charged with dimethyl formamide (800 ml), and compound-5a (100 g) were stirred for 1 hr at 25-35°C. Cooled the reaction mixture to 0-5°C and added 1-propane sulfonyl chloride (56.3g), triethylamine (122 g) and maintained for 2 hr at same temperature. The reaction mass was quencehd with water and stirred for 15 min, charged with aq. sodium bicarbonate and stirred for 3 hr. Filtered the solid compound and washed with water. The obtained compound was charged with isopropanol, water at 20-30 °C, and heated to 65-75°C and stirred for 1 hr at the same temperature for 4 hr. Filtered the solid compound and washed with water and dried to get the title compound.
Yield: 113.64 g;
Example-15: Purification process for Abrocitinib:
A round bottom flask was charged with abrocitinib (100 g), ethanol (800 ml) and water (400 ml) were heating to 80-90°C and stirred for 30 min at same temperature. The reaction mixture was charged with activated carbon and stirred for 15 min. Filtered through hy-flow and washed with preheated mixture of ethanol and water. Cooled the filtrate to 20-30°C and stirred for 3 hr at same temperature, filtered the solid compound and dried to get the title compound.
The obtained compound PXRD is similar to figure 1.
Yield: 92.5 g
,CLAIMS:We claim:
1. A Compound of the structural formula-IV

[IV]
Wherein PG: benzyl, substituted benzyl, t-butyl, methyl, ethyl, isopropyl, butyl, trityl
2. A Compound of the structural formula-4

[4]
3. An improved process for preparation of compound of formula-I
Comprising of,
a) reacting compound of formula-1 with suitable reagent, solvent to provide compound of formula-2.

b) reducing the compound of formula-2 with suitable reagent, solvent to provide compound of formula-3,

c) reacting the compound of formula-3 with compound of formula-A to provide compound of formula-4,

d) deprotecting the compound of formula-4 with suitable reagent, solvent to provide the compound of formula-5, optionally isolating as suitable acid addition salts (such hydrochloride acid, hydrobromic acid),

e) reacting the compound of formula-5 with propane sulfonyl chloride in presence of suitable reagent, solvent to provide the compound of formula-I,
f) optionally purifying the compound obtained is step-e) by using suitable solvents to provide the pure compound of formula-I.
4. A process for preparation of compound of formula I as per the claim 3, wherein in step-a), b), c), d), e), and f) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ether solvents, polar aprotic solvents, polar protic solvents, ester solvent, nitrile solvent, ketone solvent, alcohol solvent, water or any mixture thereof; the suitable temperature is 0-130°C;
5. A process for preparation of compound of formula I as per the claim 3, wherein in step-a) suitable reagent is selected from diphenyl phosphoroazide, trimethylsilyl azide, tributyl tin azide, p-toluene sulfonyl azide, 4-acetamidobenzenesulfonyl azide, Sodium azide, lithium azide, benzyl alcohol, p-methyl benzyl alcohol, p-methoxy benzyl alcohol, p-cyano benzyl alcohol, organic base, inorganic base; wherein in step-b) suitable reagents is selected from monomethyl amine solution in methanol or water, monomethyl amine (g) in organic solvents, monomethyl amine HCl, sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium cyano acetoxy borohydride, lithium aluminum hydrate and mixture thereof. wherein in step-c) suitable reagent is selected from inorganic base, organic base, preferable solvents are DMF, DMA, IPA, dioxane, NMP and water mixture thereof. wherein in step-d) suitable reagents are selected from inorganic base such as KOH, NaOH, LiOH, preferable salts are HCl, HBr. wherein in step-e) suitable reagents are selected from organic bases.
6. An improved process for N-((1s, 3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino) cyclobutyl)propane-1-sulfonamide compound of formula-I,
Comprising of:
a) reacting compound of formula-1 with diphenylphosphoroazide, benzyl alcohol in presence of triethylamine in toluene to provide compound of formula-2,

b) reacting the compound of formula-2 with monomethylamine in presence sodium borohydride in methanol to provide compound of formula-3a,

c) reacting the compound of formula-3a with compound of formula-A in presence of potassium carbonate in water to provide compound of formula-4,

d) deprotecting the compound of formula-4 with sodium hydroxide in ethanol, water to provide the compound of formula-5a,

e) reacting the compound of formula-5a with 1-propane sulfonyl chloride in presence of triethylamine in dimethyl formamide and further purifying in isopropanol, water to provide the compound of formula-I,
f) purifying the compound obtained is step-e) in a mixture of ethanol, water at 80-90° C to provide the pure crystalline form of compound of formula-I.
7. A process for the preparation of compound of formula-4
Comprising of:
a) reacting compound of formula-1 with diphenylphosphoroazide, benzyl alcohol in presence of triethylamine in toluene to provide compound of formula-2,

b) reacting the compound of formula-2 with monomethylamine in presence sodium borohydride in methanol to provide compound of formula-3a,

c)reacting the compound of formula-3a with compound of formula-A in presence of potassium carbonate in water to provide compound of formula-4,

8. A crystalline form of the compound of formula I, obtained according to the preceding claims, having the PXRD pattern shown in Figure 1.
9. A crystalline form of the compound of formula I, obtained according to the preceding claims having particle size distribution of D90 <300 pm, D50 <150 µm, D10 <75 µm.
10. A compound of formula I having less than 0.15% of isopropyl sulfonyl impurity and disulfonyl impurity.