DESC:FIELD OF THE INVENTION

Present invention provides novel compound of Formula II or pharmaceutically acceptable salts thereof, which act as intermediates for the preparation of Abrocitinib and pharmaceutically acceptable salts thereof.

Formula II

Present invention further provides process for the preparation novel compounds of Formula II or pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION

Abrocitinib is an effective Janus Kinase Inhibitor used for treatment of atonic dermatitis (eczema).

Abrocitinib is known from U.S. Patents 9,035,074 and which further discloses process for the preparation of Abrocitinib by treating compound of Formula A with aryl sulphonyl protecting group such as tosyl group, followed by reaction with compound of Formula C to give compound of Formula D. The said compound of Formula D is then converted to Abrocitinib by following protection and de-protection methods. The major drawback of said disclosed process is use of tosyl protecting agents which requires higher amounts of strong base for deprotection at elevated temperatures, i.e. 4.0 equivalents or more of strong base is required for removal of tosyl groups and the de-protection reaction is carried out at a temperature of 60oC and above. This causes formation of various unwanted side impurities which are removed by using tedious purification processes, such as column chromatography to get pure Abrocitinib.

In view of the above, there is a need to develop a novel process for the preparation of Abrocitinib and its pharmaceutically acceptable salts, that requires minimal steps and provides highly pure Abrocitinib and its salts. Hence, present invention is focussed toward the development of the process for the preparation of Abrocitinib by using novel intermediates and which not only provides pure Abrocitinib in high yields but is reproducible and easy to handle during large scale production.

OBJECTIVE OF THE INVENTION

The Main object of the present invention is to provides compounds of Formula II or pharmaceutically acceptable salts thereof, wherein said compounds of Formula II can be used as intermediates in the preparation of Abrocitinib of Formula I and/or its pharmaceutically acceptable salts.

Another object of the present invention is to provide novel compounds of Formula II or pharmaceutically acceptable salts thereof, for the preparation of Abrocitinib or pharmaceutically acceptable salts thereof, wherein said Abrocitinib or salts thereof are isolated with high yields and purity.

Another object of the present invention is to provides a process for the preparation of compounds of Formula II by involving commercially viable process which results in improved yield and purity.

Another object of the present invention is to provides a process for the preparation of compounds of Formula II and purification thereof.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides process for the preparation of Abrocitinib or pharmaceutically acceptable salt thereof, by using novel intermediates of Formula II or pharmaceutically acceptable salt thereof,

Formula II.

Another aspect of the present invention provides a compound of Formula II,

Formula II
wherein R1 is selected from –COOR3, -CH2-O-(CH2)nSi(CH3)3, -COR4, -CH2C6H5, -OSO2R5; and R2 is selected from –NHR6, -CONH2,
wherein,
R6 is hydrogen, -COOR3, -SO2(CH2)mCH3,
R3 is C1-C4 straight or branched chain alkyl, -CH2C6H5,
R4 is substituted or unsubstituted aryl, C1-C3 straight or branched chain alkyl,
R5 is C1-C4 straight or branched chain alkyl or –C6H5-CH3
Q1 is H or Me
n is an integer of 2-4, and
m is an integer of 1-3.

Another aspect of the present invention provides novel compound of Formula II, wherein said compound is represented by formulae:
, , ,

, , , and

wherein R1 is as defined above.

Another aspect of the present invention provides a process for the preparation of Abrocitinib of Formula I or pharmaceutically acceptable salts thereof, comprising the steps of:
a) condensing compound of Formula IX with compound of Formula X to give compound of Formula II,
,
wherein,
X is halogen,
R1 selected from –COOR3, -CH2-O-(CH2)nSi(CH3)3, -COR4, -CH2C6H5, -OSO2R5; and R2 is selected from –NHR6, -CONH2,
wherein,
R6 is hydrogen, -COOR3, -SO2(CH2)mCH3,
R3 is C1-C4 straight or branched chain alkyl, -CH2C6H5,
R4 is substituted or unsubstituted aryl, C1-C3 straight or branched chain alkyl,
R5 is C1-C4 straight or branched chain alkyl or –C6H5-CH3,
Q1 is H or Me
n is an integer of 2-4,
m is an integer of 1-3, and
b) converting compound of Formula II to Abrocitinib of Formula I or its pharmaceutically acceptable salts thereof.

Another aspect of the present invention provides process for the preparation of Abrocitinib or pharmaceutically acceptable salt thereof, by using compound of Formula II, wherein said compound of Formula II is represented by Formula V and said process comprising the steps of:
a) de-protecting compound of Formula V to give Abrocitinib of Formula I,
, and
b) optionally converting compound of Formula I to its pharmaceutically acceptable salts.

Another aspect of the present invention provides compound of Formula IX, wherein said compound is represented as compounds of Formulae IXa and IXb,
.

Another aspect of the present invention provides compound of Formula II wherein said compound is isolated as crystalline solid.

Another aspect of the present invention provides compound of Formula II wherein said compound is isolated as amorphous solid.

Another aspect of the present invention relates to novel crystalline form of Abrocitinib and its preparation.

DETAILED DESCRIPTION OF THE INVENTION

There are few processes known for the preparation of Abrocitinib, however known processes suffer from drawbacks such use of large amount of de-protecting agents or tedious purification process such as column chromatography to isolate pure Abrocitinib. Present invention has dealt with aforesaid drawbacks by developing a novel process for the preparation of Abrocitinib by using novel intermediates of Formula II or pharmaceutically acceptable salt thereof,

Formula II.

Accordingly, in main embodiment, the present invention provides a compound of Formula II,

Formula II
wherein R1 is selected from –COOR3, -CH2-O-(CH2)nSi(CH3)3, -COR4, -CH2C6H5, -OSO2R5; and R2 is selected from –NHR6, -CONH2,
wherein,
R6 is hydrogen, -COOR3, -SO2(CH2)mCH3,
R3 is C1-C4 straight or branched chain alkyl, -CH2C6H5,
R4 is substituted or unsubstituted aryl, C1-C3 straight or branched chain alkyl,
R5 is C1-C4 straight or branched chain alkyl or –C6H5-CH3,
Q1 is H or Me
n is an integer of 2-4, and
m is an integer of 1-3.

In another embodiment, the present invention provides novel compound of Formula II, wherein said compound is represented by formulae:
, , ,

, , , and
,
wherein R1 is as defined above.

In another embodiment, the present invention provides a process for the preparation of Abrocitinib of Formula I or pharmaceutically acceptable salts thereof, comprising the steps of:
a) condensing compound of Formula IX with compound of Formula X to give compound of Formula II,
,
wherein,
X is halogen,
R1 selected from –COOR3, -CH2-O-(CH2)nSi(CH3)3, -COR4, -CH2C6H5, -OSO2R5; and R2 is selected from –NHR6, -CONH2,
R6 is hydrogen, -COOR3, -SO2(CH2)mCH3,
R3 is C1-C4 straight or branched chain alkyl, -CH2C6H5,
R4 is substituted or unsubstituted aryl, C1-C3 straight or branched chain alkyl,
R5 is C1-C4 straight or branched chain alkyl or –C6H5-CH3,
n is an integer of 2-4,
m is an integer of 1-3, and
b) converting compound of Formula II to Abrocitinib of Formula I or its pharmaceutically acceptable salts thereof.

In another embodiment, the present invention provides compound of Formula IX, wherein said compound is represented as compounds of Formulae IXa and IXb,
.

In another embodiment, the preparation of compound of Formula II is performed by condensing compound of Formula IX with compound of Formula X in presence of suitable solvent selected from, but not limited to, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone, acetone, methyl ethyl ketone, dichloromethane, chloroform, acetonitrile, ethylacetate, propyl acetate, benzene, toluene, cyclohexane, acetone, methyl ethyl ketone, methyl tert butyl ether, tetrahydrofuran, methanol, ethanol, diisopropyl alcohol and water or mixture thereof. The said condensation reaction may be carried out in presence of suitable base selected from triethylamine, diisopropylethylamine, dimethyl amino pyridine, potassium carbonate, sodium carbonate, and the like. The reaction is typically run at about 23° C. to about 150° C., preferably about 50° C to 100oC.

In another embodiment, the present invention provides process for the preparation of Abrocitinib or pharmaceutically acceptable salt thereof, by using compound of Formula II represented as compound of III, comprising the steps of:
a) preparing compound of Formula III,

wherein,
R1 is selected from –COOR3, -CH2-O-(CH2)nSi(CH3)3, -COR4, -CH2C6H5, -OSO2R5;
wherein,
R3 is C1-C4 straight or branched chain alkyl, -CH2C6H5,
R4 is substituted or unsubstituted aryl, C1-C3 straight or branched chain alkyl,
R5 is C1-C4 straight or branched chain alkyl or –C6H5-CH3,
n is an integer of 2-4;
by reacting compound of Formula IX with compound of Formula Xa, wherein X is halogen and R1 is as defined above,
;
or,
a1) reacting compound of Formula XI with compound of Formula XII to give compound of Formula XIV, wherein R1 is as defined above,
,
a2) resoluting compound of Formula XIV to give compound of Formula XXI,

wherein compounds of Formula XIV and XXI are optionally isolated, and
a3) converting compound of XXI to compound of Formula III,
,
b) de-protecting compound of Formula III to give compound of Formula IV,
,
c) sulfonating compound of Formula IV to give compound of Formula V,
, and
d) converting compound of Formula V to Abrocitinib or pharmaceutically acceptable salts thereof.

Another embodiment of the present invention provides a process for the preparation of Abrocitinib or pharmaceutically acceptable salt thereof, by using compound of Formula II, wherein said compound of Formula II is represented by Formula V and said process comprising the steps of:
a) de-protecting compound of Formula V to give Abrocitinib of Formula I,
, and
b) optionally converting compound of Formula I to its pharmaceutically acceptable salts.
In another embodiment, the present invention provides process for the preparation of Abrocitinib or pharmaceutically acceptable salt thereof, by using compound of Formula II represented as compound of III, comprising the steps of:
a) preparing compound of Formula III,

wherein,
R1 is selected from –BOC , benzoyl, tosyl or Actyl.
wherein,
R3 is C1-C4 straight or branched chain alkyl, -CH2C6H5,
R4 is substituted or unsubstituted aryl, C1-C3 straight or branched chain alkyl,
R5 is C1-C4 straight or branched chain alkyl or –C6H5-CH3 or –C6H5-CH3,
n is an integer of 2-4;
by reacting compound of Formula IX with compound of Formula Xa, wherein X is halogen and R1 is as defined above,
;
or,
a1) reacting compound of Formula XI with compound of Formula XII to give compound of Formula XIV, wherein R1 is as defined above,
,
a2) resoluting compound of Formula XIV to give compound of Formula XXI,

wherein compounds of Formula XIV and XXI are optionally isolated, and
a3) converting compound of XXI to compound of Formula III,
,
b) de-protecting compound of Formula III to give compound of Formula IV,
,
c) sulfonating compound of Formula IV to give compound of Formula V,
, and
d) converting compound of Formula V to Abrocitinib or pharmaceutically acceptable salts thereof.

In another embodiment, the de-protection of compound of Formula V, may be carried out in presence of alkaline earth metal carbonate or hydroxides such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and the like, in an organic solvent selected from, but not limited to, acetone, methyl ethyl ketone, dichloromethane, chloroform, acetonitrile, ethylacetate, propyl acetate, toluene, cyclohexane, cyclohexene, methanol, ethanol, water and the like. In another embodiment, the de-protection of compound of Formula V, may be carried out by hydrogenolysis using hydrogen transfer reagent such as cyclohexene or tetrahydrofuran in the presence of a hydrogenation catalyst (metal catalyst) such as Raney nickel, palladium hydroxide or Pd/C using a solvent such as methanol, acetic acid, ethanol and the like. The de-protection may optionally be carried out in presence of de-protecting agent selected from a solution of hydrogen bromide in acetic acid, aqueous or alcoholic hydrochloric acid and the like.

In another embodiment, resolution of compound of Formula XIV is done by treating the compound of Formula XIV with anhydrous hydrochloride in dioxane using methylene dichloride as solvent to give crude compound which was further recrystallized using mixture of solvent selected from alcohol such as ethanol, propanol, isopropanol, t-butanol; hydrocarbon such as cyclohexane, toluene, heptane; ethers such as tetrahydrofuran, methyl t-butyl ether; esters such as ethyl acetate, propyl acetate; nitriles such as acetonitrile, propionitrile, ketones such as acetone, methyl ethyl ketone; polar solvents such as dimethyl acetamide, N-methylpyrrolidone, water halogenated solvents such as dichloromethane.

In another embodiment, the present invention provides novel compound of Formula XIV, pharmaceutically acceptable salts and isomers thereof,

wherein,
R1 is selected from –COOR3, -CH2-O-(CH2)nSi(CH3)3, -COR4, -CH2C6H5, -OSO2R5;
wherein,
R3 is C1-C4 straight or branched chain alkyl, -CH2C6H5,
R4 is substituted or unsubstituted aryl, C1-C3 straight or branched chain alkyl,
R5 is C1-C4 straight or branched chain alkyl or –C6H5-CH3,
n is an integer of 2-4.

In another embodiment, compound of Formula XI is prepared by hydrogenating compound of Formula XV in presence of suitable hydrogenating agent, followed by protecting with suitable protecting groups, wherein compound of Formula XVI is optionally not isolated,

wherein R1 is as defined above.

In another embodiment, the suitable hydrogenating agent is selected from concentrated solution of ammonia in alcohol, saturated solution of aqueous ammonium hydroxide and the like. The amination reaction can be carried out at a temperature ranging between room temperature to the reflux temperature of the reaction solvent.

In another embodiment, the present invention provides process for the preparation of Abrocitinib of Formula I or pharmaceutically acceptable salt thereof,

Formula I
by using novel compound of Formula II represented as compound of Formula VII, comprising the steps of:
a) condensing compound of Formula IX with compound of Formula Xb to give compound of Formula VII, wherein X and R1 are as defined above,
,
b) de-protecting compound of Formula VII to give compound of Formula IV,
,
c) sulfonating compound of Formula IV to give compound of Formula V,
, and
d) converting compound of Formula V to Abrocitinib of Formula I or its pharmaceutically acceptable salts.

In another embodiment, the present invention provides process for the preparation of Abrocitinib of Formula I or pharmaceutically acceptable salt thereof,

Formula I
by using novel compound of Formula II represented as compound of Formula VII, comprising the steps of:
a) condensing compound of Formula IX with compound of Formula Xb to give compound of Formula VII, wherein X is as defined above and R1 is selected from tert-butoxy carbonyl,benzyl,acetyl,tosyl,
,
b) de-protecting compound of Formula VII to give compound of Formula IV,
,
c) sulfonating compound of Formula IV to give compound of Formula V,
, and
d) converting compound of Formula V to Abrocitinib of Formula I or its pharmaceutically acceptable salts.

In another embodiment, sulfonation reaction according to present invention is carried out by reacting 1-propane sulfonyl chloride with compound of Formula IV or VI in presence of suitable solvent.

In another embodiment, solvent used for the sulfonation reaction is selected from, but not limited to, alcohol such as ethanol, propanol, isopropanol, t-butanol; hydrocarbon such as cyclohexane, toluene, heptane; ethers such as tetrahydrofuran, methyl t-butyl ether; esters such as ethyl acetate, propyl acetate; nitriles such as acetonitrile, propionitrile, ketones such as acetone, methyl ethyl ketone; polar solvents such as dimethyl acetamide, N-methylpyrrolidone, water halogenated solvents such as dichloromethane. Most preferred solvent is dichloromethane.

In another embodiment, the compound of Formula X is prepared by reacting compound of Formula XVII with methyl amine in presence of suitable solvent,
.

In another embodiment, the present invention provides process for the preparation of Abrocitinib of Formula I or pharmaceutically acceptable salt thereof,

Formula I
by using compound of Formula II represented as compound of VI, comprising the steps of:
a) aminating compound of Formula XVIII with methyl amine without isolating imine intermediate to give compound of Formula XIX,
,
b) amidating compound of Formula XIX to give compound of Formula XX, wherein said compound of Formula XX is optionally not isolated,
,
c) condensing compound of Formula XX with compound of Formula IX to give compound of Formula VI,
, and
d) converting compound of Formula VI to Abrocitinib of Formula I or pharmaceutically acceptable salt thereof.

In another embodiment, amination of compound of Formula XVIII is done by reaction of compound of Formula XVIII with methyl amine in presence of suitable solvent and catalytic amount of an acid to form an imine and reduction of formed imine with suitable reducing agent followed by resolution of intermediate compound using an acid and to give compound of Formula XIX.

In another embodiment, acid used as catalyst in amination reaction is selected from hydrochloric acid, sulphuric acid or acetic acid. Preferred acid is hydrochloric acid.

In another embodiment, reducing agent used for the reduction of intermediate imine is sodium borohydride.

In another embodiment, reaction of methyl amine and to form intermediate imine and reduction of formed imine is done in a temperature range from 0oC to -70oC.

In another embodiment, amidation of compound of Formula XIX is done by reaction of compound of Formula XIX with ammonia solution under pressure condition by heating to a temperature 70-80oC.

In another embodiment, the process of preparing Abrocitinib or its pharmaceutically acceptable salt may be carried out in presence of suitable solvent selected from, but not limited to, alcohol such as ethanol, propanol, isopropanol, t-butanol; hydrocarbon such as cyclohexane, toluene, heptane; ethers such as tetrahydrofuran, methyl t-butyl ether; esters such as ethyl acetate, propyl acetate; nitriles such as acetonitrile, propionitrile, ketones such as acetone, methyl ethyl ketone; polar solvents such as dimethyl acetamide, N-methylpyrrolidone, water halogenated solvents such as dichloromethane, carbon tetrachloride, chloroform, dichloromethane and mixture thereof.

In another embodiment, the process of preparing Abrocitinib or its pharmaceutically acceptable salt is carried out at temperature ranging from 0oC to reflux temperature of the solvent.

In another embodiment, the process of preparing Abrocitinib or its pharmaceutically acceptable salt may involve isolation and/or purification of intermediate, or may be carried out in one pot without isolation of intermediates.

Another embodiment of the present invention provides compound of Formula II wherein said compound is isolated as crystalline solid.

Another embodiment of the present invention provides compound of Formula II wherein said compound is isolated as amorphous solid.

Another embodiment of the present invention relates to novel crystalline form of Abrocitinib and its preparation involving crystallization of obtained Abrocintib.

Another embodiment of the present invention relates to novel crystalline form of Abrocitinib and its preparation involving crystallization of obtained abrocintib using solvent selected from but not limited to methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, ethyl acetate, n-butyl acetate or heptane, hexane or cyclohexane, acetonitrile, dichloromethane, water or mixture thereof. Preferred solvents are methanol, ethanol, isopropanol, n-butyl acetate or mixture thereof.

Another embodiment of the present invention relates to amorphous Abrocitinib and its preparation involving suitable techniques like but not limited to spray drying, freeze drying, solvent-antisolvent techniques.

Another embodiment of the present invention relates to amorphous Abrocitinib solid dispersion and its preparation involving suitable excipient or solid dispersion agent.

In another embodiment, Abrocitinib as prepared by the process of the present invention is characterized by particle size distribution wherein, d90 is 0.1µm to 500µm.

In further embodiment, the present invention further provides a composition comprising Abrocitinib of Formula I obtained by the process of the present invention along with at least one pharmaceutically acceptable excipients thereof.

In further embodiment, the present invention provides a solid comprising Abrocitinib with purity more than 99% and preferably more than 99.5%.

Examples
Example 1:
a) synthesis of tert-butyl 4-(((1s,3s)-3-(((benzyloxy)carbonyl) amino) cyclobutyl) (methyl) amino)-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate (Formula III, where R1= BOC)
4-chloro-7H-pyrrolo [2,3-d] pyrimidine (200.0 g) and Dichloromethane(1000 ml) was taken in round bottom flask added triethyl amine (150.0 g) and cooled to 0-5ºC. Slowly added di-tert-butyldicarbonate (426.0 g) into above reaction mass and stirred for 3-4 hour at room temperature. Water was added and material was extracted with dichloromethane. Organic layer was washed with water and concentrated the organic layer to get crude tert-butyl 4-chloro-7H-pyrrolo [2,3-d]pyrimidine-7-carboxylate .
crude tert-butyl 4-chloro-7H-pyrrolo [2,3-d] pyrimidine-7-carboxylate (300.0 g) and benzyl [cis-3-(methylamino) cyclobutyl] carbamate (Formula Xa) (306.0g) and potassium carbonate (150.0 g) was taken in round bottom flask in water (1500 ml) and the resulting mass was stirred at 90°C to 100° for 14-15 hours and obtained mass was filtered and recrystallized using Ethanol and filtered. Wet solid was dried to get tert-butyl 4-(((1s,3s)-3-(((benzyloxy)carbonyl) amino) cyclobutyl) (methyl)amino)-7H-pyrrolo[2,3-d] pyrimidine-7-carboxylate (yield 509.0 g, purity 95%).

b) Synthesis of tert-butyl 4-(((1s,3s)-3-aminocyclobutyl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate (Formula IV , R1=BOC)
Product of step a) (509.0 g and ethanol (2500 ml) was taken in autoclave. Palladium in carbon 10% (50.0 g) was added and hydrogen pressure 5-6 kg was applied and stirred the mass at 70°C to 80°C for 14-15 hours. Cooled and filtered the mass and concentrate under vacuum to get desired product (please mentioned process of concentration, product. yield =339.0 g, purity= 90.0%.
c) synthesis of tert-butyl 4-(methyl((1s,3s)-3-(propylsulfonamido)cyclobutyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylate (Formula V, R1=BOC)
Product obtained in step b) (339.0g) was taken in dichloromethane (DCM) (1500 ml) in a round bottom flask. Pyridine (200.0 g) and 1-propane sulfonyl chloride (182.0 g) was added and stirred the reaction mass at 40-70° for 4-5 hours. HCl solution (100.0 ml) was added and extracted the material with dichloromethane and washed with water and added aq. NaCl solution. Organic layer was distilled to get the product. (yield=430.0g, purity=85%).
d) Synthesis of Abrocitinib
Product obtained in step c) (430.0 g) and dichloromethane (DCM) (2000 ml) was added in round bottom flask. Concentrated hydrochloric acid (350.0 g) was added dropwise and stirred for 5-6 hours and reaction mass was quenched with aqueous sodium bicarbonate to basic pH (>9) Material was extracted with dichloromethane and washed with water and aq. NaCl solution. Organic layer was concentrate under the vacuum to get crude compound which was further crystallised in methanol 800ml followed by crystallization in acetonitrile (600 ml) to get pure abrocitinib. yield=263.0 g, HPLC purity=99.0%.

Example 2:
a) Synthesis of tert-butyl 3-oxocyclobutane-1-carboxylate:
3-oxocyclobutanecarboxylic acid (200.0 g) and tertiary butanol (250.0 ml) was taken in a round bottom flask and to this was added catalytic amount of sulphuric acid (25.0 g) and heated to reflux for 15 hr. and obtained reaction mass was concentrated under vacuum. Charge water 300 ml and extract material with dichloromethane. Organic layer was washed with water and concentrated to get crude material. yield=253.0 g, purity=95.0%.

b) Synthesis of tert-butyl (1s,3s)-3-(methylamino)cyclobutane-1-carboxylate
Product obtained in step a) (253.0 g) and Methyl amine solution in THF (550.0 ml) was taken in round bottom flask to this was added acetic acid (15.0 g) and THF (1000 ml) and reaction mass was stirred at 0-5ºC for, 14-15 hours. Temperature was maintained at room temperature and stirred the reaction mass for 10-12 hours and cooled to -60 to -70ºC.To the cooled reaction mass sodium borohydride (113.0 g) was added and stirred at room temperature for 5-6 hours. Water (100.0 ml) and aq. HCl (350.0 ml) solution was added to separate the layer. Aqueous layer was washed twice with DCM (1500 ml) basified and extracted using dichloromethane 200 ml and washed with water 350 ml and aqueous NaCl solution 350. Obtained organic layer was distilled to get crude product. yield=234.0 g, purity=91.0%.

Crude product (234 g) was dissolved in DCM (800 ml) and add anhydrous 4M HCl in dioxane (350 ml) and stirred at room temperature for 10-12 hours. Solid was filtered and recrystallized in mixture of methanol and methyl tertiary butyl ether (2:8). Solid material was dried to get pure product as cis isomer. Yield 115 g and purity=98%).
c) synthesis of 1-((1s,3s)-3-(methylamino) cyclobutyl) ethan-1-one
Product obtained in step b) (115 g) and ammonia solution in ethanol (500 ml) was taken in autoclave and reaction mass was heated 70°C to 80°C for 25-30 hours. Reaction mass was concentrated on Rota vapour under vacuum to get desired product. (yield=80.0 g and purity=95%).
d) Synthesis of Intermediate 7-benzyl-4-chloro-7H-pyrrolo [2, 3-d] pyrimidine
4-chloro-7H-pyrrolo [2,3-d] pyrimidine (200 g), THF (500 ml) and K2CO3 (200 g) was taken in round bottom flask. Benzyl bromide (210 g) was added slowly into above reaction mass and stirred for 3-4 hour at room temperature and heated to 60-70ºC for 14-15 hours. Water (400 ml) was added and extracted the material with dichloromethane (400 ml X 2), washed with water and concentrated the organic layer to get crude material (yield=320g, purity=85%).). Triturated the material with n-heptane to get pure material. yield=310 g, purity= 97%.
e) Synthesis of (1s,3s)-3-((7-benzyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino)cyclobutane-1-carboxamide
Product obtained in step c) (80g), water (400 ml) and 7-benzyl-4-chloro-7H-pyrrolo [2, 3-d] pyrimidine (152.0 g) was taken in round bottom flask and to this was added potassium carbonate (120 g) and the reaction mass was stirred at 90°C to 100°C for 14-15 hours and filtered the mass. Obtained solid was recrystallized Ethanol (350 ml) filtered and dried to get the desired product. (yield=189g, purity=95%).
f) synthesis of (1s,3s)-N1-(7-benzyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N1 methylcyclobutane-1,3-diamine
Product obtained in step e) (189 g) and water (500 ml) was taken in round bottom flask and to it was added sodium hydroxide (100 g). Bromine (170 g) was added dropwise to reaction mass and heated the reaction mass to 60-80º C for 14-15 hours. Water (400 ml) was added and material was extracted with dichloromethane (400ml X 2). Organic layer was washed with water and concentrated to get the crude compound. (yield=138g, purity=92%).
g) synthesis of N-((1s,3s)-3-((7-benzyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl) (methyl)amino) cyclobutyl) propane-1-sulfonamide
Product obtained in step f) (138 g), dichloromethane (350 ml) and pyridine (350 ml) was taken in round bottom flask and stirred for 4-5 hours .1-propane sulfonyl chloride (98 g) was added and stirred reaction mass at 40-70°C for 10-12 hours. Aqueous hydrochloride solution (400 ml) was added and material was extracted using dichloromethane (400 ml X 2and washed with water and aqueous NaCl solution. Organic layer was distilled out to get the desired product. yield=157g, purity= 95%.
h) synthesis of Abrocitinib
Product obtained in step g) (157 g) and ethanol (400 ml) was taken in autoclave and 10% palladium in carbon (25gm) was added and hydrogen pressure 5-6kg was applied. Stirred the reaction mass under pressure at 70°C to 80°C for 14-15 hours. Reaction mass was cooled, filtered and concentrated the organic layer under vacuum to get crude material (yield 90.0g, purity=94.0%). Crude product was further recrystallized in methanol (300 ml) followed by in acetone (250 ml) to get pure abrocitinib. (yield=85.0 g, HPLC purity=99.0).
Example 3:
a) Synthesis of benzyl (3-oxocyclobutyl)carbamate
3-oxocyclobutanecarboxylic acid (200g) and toluene (600 ml) was taken in round bottom flask and to this was added diisopropylethylamine (270 g) and diphenyl Phosphorazidate (DPPA) (500g) and heated to 60-80ºC for 10-12 hours. Benzyl alcohol (284 g) was added and heating was done overnight (15-16 hours). Water (250 ml) was added and extracted the material with dichloromethane (500 ml). Organic layer was washed with water (300 ml) and concentrated the organic layer to get crude material. (yield=365 g, purity= 95%).
b) synthesis of 1-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethan-1-one
4-chloro-7H-pyrrolo [2, 3-d] pyrimidine (300 g), THF (600 ml) and K2CO3 (300g) was taken in round bottom flask to this was slowly added acetyl chloride (250g) and Stirred the reaction mass for 3-4 hours at room temperature and increases the temperature to 60-70ºC and heated for 2-3 hours. Water (400 ml) was added and extracted the material with dichloromethane (800 ml). Organic layer was washed with water (300 ml) and concentrated to get crude material. (Yield 340g, purity = 98%)
c) synthesis of benzyl (3-((7-acetyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl) amino) cyclobutyl) carbamate
Product obtained in step a) (365 g) and b) (293g), was taken in ethanol (600ml) in round bottom flask. Catalytic amount of acetic acid (25g) was added and stirred for 10-12 hours and cooled to 0-5ºC. Sodium cyanoborohydride (209g) was added and stirred for 3-4 hour at room temperature timing. Water (500 ml) was charged and concentrated the reaction mass. Extracted the desired material with dichloromethane (700 ml). Organic layer was washed with water 300 ml and concentrated to get the crude material. (yield= 570 g, purity =95%).
d) synthesis of benzyl ((1s,3s)-3-((7-acetyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)carbamate
Product obtained in step c) (570g) and DCM (2500 ml) was taken in round bottom flask and added anhydrous HCl solution in dioxane (1500 ml) and stirred the reaction mass at room temperature for 10-12 hours. Solid material was filtered and recrystallized in mixture of methanol and methyl tertiary butyl ether (ratio 2:8). Solid material was dried to get pure product. (yield=228g and HPLC purity=98%).
e) synthesis of benzyl ((1s,3s)-3-((7-acetyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl) amino)cyclobutyl)(methyl)carbamate
Compound obtained in step d) (228g) and DCM (600 g) was taken in round bottom flask and triethylamine (151 g), methyl iodide (102.0g) was added dropwise. Stirred the reaction mask for 2-3 hours. Water (400 ml) was added and extracted the material with dichloromethane (800 ml). Organic layer was concentrated to get crude material. (yield, 212g, purity=95%).
f) synthesis of 1-(4-(((1s,3s)-3-aminocyclobutyl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethan-1-one
Compound obtained in step e) (212 g) and ethanol (600 ml) was taken in autoclave. 10% Palladium in carbon (21 g) was added under pressure and stirred the reaction mass at 70°C to 80°C for 14-15 hours and cooled the reaction mass and filtered. Concentrated the filtrate to get crude material. (yield=132 g, purity=92%).
g) synthesis of N-((1s,3s)-3-((7-acetyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl) (methyl)amino) cyclobutyl) propane-1-sulfonamide
Compound obtained in strep f) (132 g) and dichloromethane (DCM) (500 ml) was taken in round bottom flask added pyridine (100 g) and stirred timing. 1-propane sulfonyl chloride (87.0 g) was added to the reaction mass and stirred the mass at 40-70°C for 10-12 hours. Aq. HCl solution (250 ml) was added and material was extracted using dichloromethane (600 ml) and wash with water (300 ml) and Aq. NaCl solution. Organic layer was distilled out to get product. (yield=167 g, purity 92%).
h) synthesis of Abrocitinib
Product obtained in step g) (167g) and methanol (1000 ml) was taken in round bottom flask and sodium hydroxide (80 g) was added and heated at 50- for 10-12 hours. Solvent was distilled out and material was extracted using dichloromethane (500 ml) and wash with water (400 ml) and saturated Aq. solution of NaCl (300 ml). Organic layer was extracted under vacuum to get crude material which was further crystallised in ethanol (400 ml) followed by IPA (500 ml) to get pure abrocitinib. (yield 118g, HPLC purity=99.0%).
Example 4:
a) Synthesis of tert-butyl (3-oxocyclobutyl)carbamate
3-oxocyclobutanecarboxylic acid (200 g), Toluene (1200 ml) was taken in round bottom flask added diisopropylethylamine (270g) and Diphenyl Phosphorazidate (DPPA) (500g) and heated the reaction mixture at 60-80ºC for 10-12 hours. Tertiary butanol (290 g) was added and heated overnight period of time. Water (400 ml) was added and extracted the material with dichloromethane (800 ml). Washed the organic layer with water (400 ml) and concentrated to get crude material. (yield=309, purity=97%).
b) synthesis of tert-butyl [cis-3-(methylamino)cyclobutyl] carbamate
Product obtained in step a) (309g), methyl amine solution in THF (700 ml), acetic acid (30 g) and THF (700 ml) was taken in round bottom flask and stirred the reaction mass at 0-5ºC for 10-12 hours. Cooled the reaction mass to -60 to -70ºC and add sodium borohydride (127g) was added slowly over a period of 2-3 hours. Water (100 ml) and aq. HCl solution (100 ml) was added. Aqueous layer was washed twice with DCM (600 ml) and basify aqueous layer with saturated sodium bicarbonate solution (350 ml). Material was extracted using dichloromethane (1000ml) and wash with water (400 ml) and Aq. NaCl solution (300ml). Distil out organic layer to get crude. (yield= 190g, purity=90%).
c) synthesis of Intermediate 7-benzyl-4-chloro-7H-pyrrolo [2, 3-d] pyrimidine
4-chloro-7H-pyrrolo [2,3-d] pyrimidine (200 g), THF (500 ml) and K2CO3(360 g) was taken in round bottom flask. Benzyl bromide (190g) was added slowly into above reaction mass and stirred for 3-4 hour at room temperature and heated to 60-70ºC for 10-12 hours. Water (400 ml) was added and extracted the material with dichloromethane ((600 ml), washed with water and concentrated the organic layer to get crude material (yield=310g, purity=85%). Crude was triturated using n-heptane (200 ml) to get pure material. (yield= 301 g, purity=98%).
d) Synthesis of tert-butyl ((1s,3s)-3-((7-benzyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl) (methyl)amino) cyclobutyl) carbamate
Product obtained in step b) (133 g), water (500 ml), and product obtained in step c) (161 g) was added in round bottom flask. Potassium carbonate (120 g) was added and stirred the reaction mass at 90°C to 100°C for 10-12 hours and filtered the mass and recrystallize the solid in ethanol (600 ml). Wet solid was dried to get desired product. (yield=243g, purity= 97%).
e) synthesis of (1s,3s)-N1-(7-benzyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl)-N1-methylcyclobutane-1,3-diamine
Product obtained in Step d) (243 g), dichloromethane (DCM) (800 ml) was taken in round bottom flask and concentrated hydrochloric acid (250 ml) was added dropwise and stirred for 5-6 hours. Reaction mass was quenched with aqueous Sodium bicarbonate (350 ml) to basic pH (>9 pH) and extracted the material with dichloromethane (1000 ml) and washed with water and aq. NaCl solution (400 ml). Organic layer was concentrated under vacuum to get Crude material. (Yield (165), purity=92%).
f) synthesis of N-((1s,3s)-3-((7-benzyl-7H-pyrrolo[2,3-d] pyrimidin-4-yl) (methyl)amino) cyclobutyl) propane-1-sulfonamide
Product obtained in Step e) (165 g), dichloromethane (DCM) (600 ml) and pyridine (150 g) was taken in round bottom flask and starred for 30 minutes. 1-propane sulfonyl chloride (92 g) was added and stirred the reaction mass 40-70°C for 5-6 hours. Aqueous HCl solution (300 ml) was added and extract the material with dichloromethane and wash with water (400 mL) and Aq. NaCl solution (300 ml). Organic layer was distilled out to get product. (yield= 199.0, purity=92%).
g) Synthesis of Abrocitinib
Product obtained in step f) (199 g) and ethanol (800 ml) was taken in autoclave. Added 10% palladium in carbon [50% wet] (20 g). Under pressure condition reaction mass was stirred at 70°C to 80°C for 15-18 hours. Cooled the reaction mass and filter. Organic layer was concentrated under vacuum to get crude material which was further crystallised in methanol (400 ml) followed by IPA (400 ml) to get pure Abrocitinib. (yield=124 g, purity=99%).
Example 5:
a) Synthesis of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine
4-chloro-7H-pyrrolo [2, 3-d] pyrimidine (200 g) and THF (600 ml) was taken in round bottom flask and K2CO3 (200 g) was added. To the above mass was slowly add 2-(Trimethylsilyl) ethoxymethyl chloride (260 g) and stirred the reaction mass for 3-4 hour at room temperature. Water (400 ml) was material was extracted using dichloromethane (800 ml). Organic layer was washed with water and concentrated to get crude material. Yield=351, purity=95%.
b) synthesis of tert-butyl ((1s,3s)-3-(methyl(7-((2-(trimethylsilyl) ethoxy) methyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl) amino) cyclobutyl) carbamate
Product obtained in step a) (351 g), water (1500 ml) and tert-butyl [cis-3-(methylamino) cyclobutyl] carbamate (273 g) was taken in round bottom flask. Added potassium carbonate (250 g) and stirred the reaction mass at 90°C to 100°C for 18 hours. Obtained reaction mass was filtered and recrystallized the solid in methanol (800 ml) and filter. Wet solid was dried to get desired product. (yield=590g, purity=95%).
c) synthesis of (1s,3s)-N1-methyl-N1-(7-((2-(trimethylsilyl) ethoxy) methyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl) cyclobutane-1,3-diamine
Product obtained in step b) (590g) and ethanol (2200 ml) was taken in autoclave. 10% Palladium in carbon (60 g) was added and stirred the reaction mass under pressure at 70°C to 80°C for 22 hours. Reaction mass was cooled filtered and concentrated under vacuum to get the desired product. (yield =383 g and purity=91%).
d) synthesis of N-((1s,3s)-3-(methyl(7-((2-(trimethylsilyl) ethoxy) methyl)-7H-pyrrolo[2,3-d] pyrimidin-4-yl) amino) cyclobutyl) propane-1-sulfonamide
Product obtained in step c) (383 g), dichloromethane (800 ml) and pyridine (250 g) was taken in round bottom flask and stirred for 30 minutes. 1-propane sulfonyl chloride (188 g) was added and stirred the reaction mass at 40-70°C for 8 hours. Aqueous HCl solution (350 ml) was added and extracted the material with dichloromethane (800 ml) and washed with water and Aq. NaCl solution (350 ml). Organic layer was distilled to get the desired product. (yield=449 and purity=89%).
e) synthesis of Abrocitinib
Product obtained in step d), (449 g) dichloromethane (DCM) (2500 ml) was taken in round bottom flask to this was added trifluoro acetic acid (225 g) and stirred for 10-12 hours at 25-30 ºC. Layer was separated and aqueous layer was basified with Aq. sodium carbonate solution (800 ml). Extracted the desired product with dichloromethane (1500 ml). Organic layer was washed with water and concentrated to get crude material which was further Crystallised in methanol (1200 ml) to get pure Abrocitinib. (Yield=240 g, Purity =99%.).
,CLAIMS:WE CLAIM:
1. A compound of Formula II,

Formula II
wherein R1 is selected from –COOR3, -CH2-O-(CH2)nSi(CH3)3, -COR4, -CH2C6H5, -OSO2R5; and R2 is selected from –NHR6, -CONH2,
wherein,
R6 is hydrogen, -COOR3, -SO2(CH2)mCH3,
R3 is C1-C4 straight or branched chain alkyl, -CH2C6H5,
R4 is substituted or unsubstituted aryl, C1-C3 straight or branched chain alkyl,
R5 is C1-C4 straight or branched chain alkyl or –C6H5-CH3,
Q1 is H or Me,
n is an integer of 2-4, and
m is an integer of 1-3.

2. A process for the preparation of Abrocitinib or pharmaceutically acceptable salts, wherein said process comprises the steps of:
a) condensing compound of Formula IX with compound of Formula X to give compound of Formula II,
,
wherein,
X is halogen,
R1 selected from –COOR3, -CH2-O-(CH2)nSi(CH3)3, -COR4, -CH2C6H5, -OSO2R5; and R2 is selected from –NHR6, -CONH2,
R6 is hydrogen, -COOR3, -SO2(CH2)mCH3,
R3 is C1-C4 straight or branched chain alkyl, -CH2C6H5,
R4 is substituted or unsubstituted aryl, C1-C3 straight or branched chain alkyl,
R5 is C1-C4 straight or branched chain alkyl or –C6H5-CH3,
Q1 is H or Me,
n is an integer of 2-4,
m is an integer of 1-3, and

b) converting compound of Formula II to Abrocitinib of Formula I or its pharmaceutically acceptable salts thereof.

3. The process as claimed in claim 2, wherein R1 is selected from acetyl, benzyl or tertiary butoxy carbonyl group.

4. A process for the preparation of Abrocitinib or pharmaceutically acceptable salts, wherein said process comprises the steps of:
a) preparing compound of Formula III,

wherein,
R1 is selected from –BOC , benzoyl, tosyl or Actyl.
wherein,
R3 is C1-C4 straight or branched chain alkyl, -CH2C6H5,
R4 is substituted or unsubstituted aryl, C1-C3 straight or branched chain alkyl,
R5 is C1-C4 straight or branched chain alkyl or –C6H5-CH3 or –C6H5-CH3,
n is an integer of 2-4;
by reacting compound of Formula IX with compound of Formula Xa, wherein X is halogen and R1 is as defined above,
;
or,
a1) reacting compound of Formula XI with compound of Formula XII to give compound of Formula XIV, wherein R1 is as defined above,
,
a2) resoluting compound of Formula XIV to give compound of Formula XXI,

wherein compounds of Formula XIV and XXI are optionally isolated, and
a3) converting compound of XXI to compound of Formula III,
,
b) de-protecting compound of Formula III to give compound of Formula IV,
,
c) sulfonating compound of Formula IV to give compound of Formula V,
, and
d) converting compound of Formula V to Abrocitinib or pharmaceutically acceptable salts thereof.

5. A process for the preparation of Abrocitinib of Formula I or pharmaceutically acceptable salts, wherein said process comprises the steps of:
a) condensing compound of Formula IX with compound of Formula Xb to give compound of Formula VII, wherein X and R1 are as defined above,
,
b) de-protecting compound of Formula VII to give compound of Formula IV,
,
c) sulfonating compound of Formula IV to give compound of Formula V,
, and
d) converting compound of Formula V to Abrocitinib of Formula I or its pharmaceutically acceptable salts.

6. The process as claimed in claim 3 or 4, further comprises de-protecting compound of Formula V to give Abrocitinib of Formula I,
, and
optionally converting compound of Formula I to its pharmaceutically acceptable salts.

7. The process as claimed in claim 4, wherein said de-protection is carried out in presence of acid, base or using metal catalyst.

8. The process as claimed in claim 5, wherein acid used for deprotection is HCl or H2SO4 and base used for deprotection is sodium hydroxide or sodium bicarbonate and metal catalyst used is palladium over carbon or raney nickel.

9. A process for the preparation of Abrocitinib of Formula I or pharmaceutically acceptable salts, wherein said process comprises the steps of:
a) aminating compound of Formula XVIII with methyl amine without isolating imine intermediate to give compound of Formula XIX,
,
b) amidating compound of Formula XIX to give compound of Formula XX, wherein said compound of Formula XX is optionally not isolated,
,
c) condensing compound of Formula XX with compound of Formula IX to give compound of Formula VI,
, and
d) converting compound of Formula VI to Abrocitinib of Formula I or pharmaceutically acceptable salt thereof.

10. The process as claimed in claim 8, wherein said process comprising steps of:
a) converting compound of Formula VI to compound of Formula IV;
,
b) reacting compound of Formula IV with 1-propane sulfonyl chloride
to give compound of Formula V;
, and
b) optionally converting compound of Formula I to its pharmaceutically acceptable salts.