DESC:FIELD OF THE INVENTION
Present invention provides novel process for the preparation of Abrocitinib compound of Formula I or its pharmaceutically acceptable salts thereof.

Present invention further provides novel compound of Formula II or its salt and process of their preparation, which act as intermediates for the preparation of Abrocitinib and pharmaceutically acceptable salts thereof.
.
BACKGROUND OF THE INVENTION
Abrocitinib is an effective Janus Kinase Inhibitor used for treatment of atonic dermatitis (eczema). Abrocitinib is chemically known as N-((1s,3s)-3-(methyl(7H-pyrrolo[2,3-d] pyrimidin-4-yl) amino) cyclobutyl) propane-1-sulfonamide and represented by structural Formula I,
.
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 also reproducible and easy to handle during large scale production.

OBJECTIVE OF THE INVENTION
Main objective of the present invention provides process for the preparation of Abrocitinib or pharmaceutically acceptable salt thereof.

Another objective of the present invention is to provides compound of Formula II or its salts thereof.

Another objective of the present invention is to provides a process for the preparation of compound of Formula II or its salt by involving commercially viable process.

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

SUMMARY OF THE INVENTION
Main aspect of the present invention provides process for the preparation of abrocitinib or pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a compound of Formula II or its salt,
.
Another aspect of the present invention is to provide process for preparing abrocitinib or pharmaceutically acceptable salt by using novel intermediates of Formula II or its salt thereof.

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) reacting compound of Formula II or its salt with 4-halo-7-H-pyrolo[2,3-d] pyrimidine of Formula III to give abrocitinib of Formula I,
, , ,
wherein X = Leaving group; and
b) optionally purifying the compound of Formula, I and optionally converting to its pharmaceutically acceptable salts.

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) reacting compound of Formula VI with propane-1-sulfonyl halide to give compound of Formula IIa,
, , ,
wherein X= Cl, Br, I;
b) reacting compound of Formula IIa with methyl amine in presence of reducing agent to give compound of Formula II,
, ,
c) reacting compound of Formula II with 4-halo-7-H-pyrolo[2,3-d] pyrimidine of Formula III to give abrocitinib of Formula I,
, , ,
wherein X = leaving group; and
d) optionally purifying the compound of Formula, I and optionally converting to its pharmaceutically acceptable salts.

Another aspect of the present invention provides a process for the preparation of novel compound of Formula II or its salt comprising the steps of:
a) converting 3-oxocyclobutane carboxylic acid of Formula VII to compound of Formula IV or V,
, , ,
wherein Pg = protecting group; Z1 and Z2 is selected from H, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl or Z1 and Z2 together form a 5 to 6-member cyclic ring;
b) deprotecting compound of Formula IV or V to give compound of Formula VI,
, , ;
c) reacting compound of Formula VI with propane-1-sulfonyl halide to give compound of Formula IIa ,
, , ,
wherein X= Cl, Br, I; and
d) reacting compound of Formula IIa with methyl amine in presence of reducing agent to give compound of Formula II,
.

DETAILED DESCRIPTION OF THE INVENTION

“Pharmaceutically acceptable salts” or “salt” as used in the context of the present invention refers to pharmaceutically acceptable bases such as metal salts including alkali metal or alkaline earth metal salts for example sodium, potassium, magnesium, calcium, barium or zinc salts, ammonium salts; organic amines such as benethamine, benzathine, diethanolamine, dicyclohexyl amine, tromethamine, ethanolamine, 4-(2-hydroxyethyl)morpholine, 1-(2-hydroxyethyl)pyrrolidine, N-methyl glucamine, piperazine, triethanol amine, organic or inorganic acid addition salt such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid , maleic acid, fumaric acid, citric acid, succinic acid, oxalic acid, tartaric acid, methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, (+)-camphor-10-sulfonic acid and and the like.

The term “protecting group” as used in the context of the present invention refers to nitrogen protecting group selected from methoxyethoxymethyl, ethoxymethyl, methoxypropyl, 3-methylbutanoyl, 2-tetrahydropyranyl (THP), substituted benzyl, Bn, PMB, DMB, TMB, Cbz, unsubstituted benzyl, Boc and Fmoc. Preferred protecting group is Benzyl (Bn) and Boc (tert-butoxycarbonyl).

Processes disclosed in prior art for the preparation of abrocitinib, 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,
.
Main embodiment of the present invention provides process for the preparation of abrocitinib or pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a process for preparing abrocitinib or pharmaceutically acceptable salt by using novel intermediates of Formula II or its salt thereof.

In another embodiment, the present invention provides a compound of Formula II,
.
In another embodiment, the present invention provides novel compounds of Formula V and IIa,
, ,
wherein Pg = protecting group; Z1 and Z2 is selected from H, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl or Z1 and Z2 together form a 5 to 6-member cyclic ring;

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) reacting compound of Formula II with 4-halo-7-H-pyrolo[2,3-d] pyrimidine of Formula III to give abrocitinib of Formula I,
, , ,
wherein X = leaving group; and
b) optionally purifying the compound of Formula, I and optionally converting to its pharmaceutically acceptable salts.

In another embodiment reaction of compound of Formula II with compound of Formula III takes place in presence of solvent and base.

In another embodiment solvent used for the preparation of abrocitinib and intermediates thereof is selected from but not limited to alcohol such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol; halogenated solvent such as dichloromethane, chloroform, carbon tetrachloride, chlorobenzene; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole; ketones such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; esters solvents such as ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate; hydrocarbon such as toluene, xylene, hexane, n-heptane, n-pentane, anisole, ethyl benzene, cyclohexane and the like; nitriles such as acetonitrile, propionitrile, butanenitrile; water; dimethylformamide; dimethyl sulfoxide; dimethyl acetamide; and mixtures thereof.

In another embodiment, the base used in the preparation of abrocitinib and intermediates thereof is selected, but not limited to, the group comprising of organic and inorganic bases such as sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, magnesium carbonate, pyridine, triethyl amine, dimethyl amino pyridine, aniline, N,N-dimethyl aniline, diisopropyl ethyl amine, diisopropyl amine, diethyl amine, dimethyl amine or mixture thereof .

In another embodiment, the present invention provides a process for the preparation of novel compound of Formula II or its salt comprising the steps of:
a) converting 3-oxocyclobutane carboxylic acid of Formula VII to compound of Formula IV or V,
, , ,
wherein Pg = protecting group; Z1 and Z2 is selected from H, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl or Z1 and Z2 together form a 5 to 6-member cyclic ring;
b) deprotecting compound of Formula IV or V to give compound of Formula VI,
, , ;
c) reacting compound of Formula VI with propane-1-sulfonyl halide to give compound of Formula IIa,
, , ,
wherein X= Cl, Br, I; and
d) reacting compound of Formula IIa with methyl amine in presence of reducing agent to give compound of Formula II,
.

In another embodiment, deprotection of compound of Formula IV and V is carried out in acidic medium using suitable acid selected from hydrochloric acid, hydrobromic, sulphuric acid, phosphoric acid, trifluoroacetic acid, using suitable solvent selected from but not limited to methanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol)1-butanol, 2-butanol, t-butyl alcohol, dichloromethane, chloroform, diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxan, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, toluene, hexane, n-heptane, n-pentane, cyclohexane, acetonitrile, propionitrile, butanenitrile; water; dimethylformamide; dimethyl sulfoxide; dimethyl acetamide; and mixtures thereof. In preferred embodiment acid used in hydrochloric acid.

In another embodiment, the de-protection of compound of Formula IV and V, may be carried out by hydrogenolysis using hydrogen transfer reagent such as cyclohexene or tetrahydrofuran in the presence of a hydrogenation catalyst such as 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 preferred embodiment deprotecting agent are aqueous or alcoholic hydrochloric acid and Pd/C in methanol or ethanol.

In another embodiment, reaction of compound of Formula VI with propane-1-sulfonyl halide is carried out in basic medium using suitable base selected but not limited to the group comprising of, organic and inorganic bases such as sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide, pyridine, triethyl amine, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, magnesium carbonate, dimethyl amino pyridine, aniline, N,N-dimethyl aniline, diisopropyl ethyl amine, diisopropyl amine, diethyl amine, dimethyl amine or mixture thereof. In preferred embodiment base used are pyridine, diisopropyl ethyl amine or diisopropyl amine.

In another embodiment, process of preparing abrocitinib or its intermediate according to present invention may carried out at a temperature range of 0oC to boiling point of the solvent used in reaction.

In another embodiment, the present invention provides a process of purification of abrocitinib of Formula I or its pharmaceutically acceptable salts thereof, wherein said process comprising the steps of:
a) dissolving abrocitinib of Formula I or its pharmaceutically acceptable salts thereof in a suitable solvent;
b) optionally heating the reaction mixture upto reflux temperature of solvent; and
c) isolating pure abrocitinib or its pharmaceutically acceptable salts thereof.

In one another embodiment, the present invention provides a process of purification for abrocitinib of Formula I, wherein said process comprising the steps of:
a) dissolving pharmaceutically acceptable salts of abrocitinib in a suitable solvent;
b) neutralizing or desalting the pharmaceutically acceptable salts of abrocitinib to give abrocitinib free base; and
c) isolating the pure abrocitinib free base.
In one another embodiment, the present invention provides a process of purification for abrocitinib of Formula I, wherein said process comprising the steps of:
a) dissolving pharmaceutically acceptable salts of abrocitinib in a suitable solvent;
b) neutralizing or desalting the pharmaceutically acceptable salts of abrocitinib to give abrocitinib free base;
c) optionally converting the abrocitinib free base to its pharmaceutically acceptable salt;
d) providing a solution of abrocitinib free base of step b) or its salt of step c) in a suitable solvent (s); and
e) removing the solvent from the solution obtained in step d) to get pure abrocitinib free base or its pharmaceutically acceptable salt.

In another embodiment, suitable solvent used for the purification of abrocitinib or compound of Formula II is selected from, but not limited to, the group comprising of alcohols, hydrocarbons, halogenated solvents, esters, ethers, ketones, sulfoxides, formamide, amides, nitriles, pyrrolidines, carbonates, water and the like. Specifically, the suitable solvent as used in the present invention is selected from, but not limited to, tetrahydrofuran, toluene, o/m/p-xylene, 1,4-dioxane, dichloromethane, carbon tetrachloride, dichloroethane, dichlorobenzene, chlorobenzene, methanol, ethanol, isopropyl alcohol, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, 2-methyl tetrahydrofuran, butyl acetate, isobutyl acetate, t-butyl acetate, propyl acetate, propylene acetate, butanol, t-butanol, methyl t-butyl ketone, dimethyl sulfoxide, N-methyl pyrrolidine, dimethyl acetamide, dimethyl formamide, N-methyl acetamide, acetamide, acetone, methyl isobutyl ketone, acetonitrile, propionitrile, methyl ethyl ether, methyl tert-butyl ether, dimethyl ether, diethyl ether, cyclohexane, n-heptane, water and mixture thereof.

In another embodiment the present invention provides the process of purification of compound of Formula II or its salt, wherein said process comprising the steps of:
a) dissolving compound of Formula II or its salt in a suitable solvent;
b) optionally heating the reaction mixture upto reflux temperature of solvent; and
c) isolating pure compound of Formula II or its salt.

In another embodiment the present invention provides the process of purification of compound of Formula II or its salt, wherein said process comprising the steps of:
a) dissolving compound of Formula II or its salt in a suitable solvent;
b) adding another solvent to the solution of step a);
c) optionally heating the reaction mixture upto reflux temperature of solvent; and
d) isolating pure compound of Formula II or its salt.

In another embodiment leaving group of Formula III is selected from but not limited to halogen, mesylate and tosylate.

In preferred embodiment leaving group of Formula III is halogen, most preferably chlorine.

In another embodiment, reducing agent used for the reduction of compound of Formula IIa is selected from but not limited to Lithium borohydride (LiBH4), sodium borohydride (NaBH4), sodium cyano borohydride, sodium triacetoxyborohydride, palladium/carbon (Pd/C), raney nickel. In preferred embodiment reducing agent used are sodium borohydride or Lithium borohydride.

In another embodiment, present invention provides a process for preparing compound of Formula V.

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

In preferred embodiment, reduction of compound of Formula IIa is carried out at very low temperature condition of – 80 to -10oC.

In another embodiment, the present invention provides an amorphous solid dispersion of abrocitinib thereof, with atleast one pharmaceutically acceptable carrier or polymer.

In the present invention, the solid dispersion technology is used for dispersing abrocitinib monomolecularly in a solid state into an inert carrier. The technology specifically includes a solvent process, a fusion process, and a mixed-grinding process.

The solvent process either comprises dissolving abrocitinib or its pharmaceutically acceptable salt and a water-soluble polymer, i.e. the carrier, in an organic solvent capable of dissolving both and removing the solvent by evaporation or comprises dissolving the abrocitinib or its pharmaceutically acceptable salt in an organic solvent, dispersing the solution in the carrier and removing the solvent by evaporation to provide the desired solid dispersion.

The fusion process either comprises heating abrocitinib or its pharmaceutically acceptable salt and the water-soluble polymer together by utilizing the phenomenon of melting point depression, cooling the melt to solidify and pulverizing the resulting solid to provide the desired solid dispersion, or comprises dissolving the abrocitinib or its pharmaceutically acceptable salt in a comparatively low-melting water-soluble polymer under heating, cooling the resulting solution to solidify and pulverizing the solid to provide the desired solid dispersion.

The mixed-grinding technology, in which the abrocitinib or its pharmaceutically acceptable salt and the water-soluble polymer are mix-ground or roll-mixed without heating. It is considered that here various factors arising from mechanical manipulation, such as lattice defect or lattice modulation, increases in specific surface area and surface energy and so on, enhances the activity of the solid phase to encourage transition of abrocitinib or its pharmaceutically acceptable salt to an amorphous state and, hence, dispersion of abrocitinib or its pharmaceutically acceptable salt in this amorphous state into the carrier.

Accordingly, in an embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of abrocitinib or its pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of abrocitinib or pharmaceutically acceptable salt thereof in a suitable solvent;
b) adding atleast one pharmaceutically acceptable carrier or polymer to the solution obtained in step a); and
c) isolating to get amorphous solid dispersion of abrocitinib or its pharmaceutically acceptable salt thereof.

In another embodiment, the abrocitinib or its pharmaceutically acceptable salt and the pharmaceutically acceptable carriers may be dissolved either in the same solvent or they may be dissolved in different solvents and then combined to form a mixture.

In embodiments, the solid dispersion described herein comprises amorphous or crystalline abrocitinib or its pharmaceutically acceptable, and the carrier present in weight ratios ranging from about 1:99 to about 99:1. Preferably, the ratio is about 50:50. In some embodiments, the solid dispersion described herein comprises one or more pharmaceutically acceptable carrier or polymer.

The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, as long as a clear solution of abrocitinib or its pharmaceutically acceptable salt is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflo) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflo.

In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of abrocitinib or its pharmaceutically acceptable salt thereof, comprising the steps of:
a) heating abrocitinib or its pharmaceutically acceptable salt thereof in presence of atleast one pharmaceutically acceptable carrier or polymer to get a solution;
b) cooling the solution; and
c) isolating to get amorphous solid dispersion of abrocitinib or its pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of abrocitinib or its pharmaceutically acceptable salt thereof, wherein said abrocitinib or its pharmaceutically acceptable salt is mixed with pharmaceutically acceptable water-soluble polymer at ambient temperature.

In preferred embodiment, the present invention provides a simple process which comprises mixing a abrocitinib or its pharmaceutically acceptable salt and a water-soluble polymer together under no more than the usual agitation force with heating within the temperature region not melting them, making the water insoluble abrocitinib or its pharmaceutically acceptable salt as amorphous in nature to thereby yield a solid dispersion insuring very high solubility and bioavailability which have never been achieved by any dry process heretofore known.

In another embodiment, the suitable solvent used for preparing solid dispersion of abrocitinib or its pharmaceutically acceptable salt thereof, is selected from, but not limited to, the group comprising of alcohol such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, polyethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol and the like; halogenated solvent such as dichloromethane, chlorobenzene, tetrachloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform and the like; ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, methyl t-butyl ketone and the like; ester solvent such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, propenyl acetate, t-butyl acetate, isobutyl acetate, n-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate and the like; hydrocarbon solvent such as toluene, xylene, heptane, cyvlohexane and the like, ether such as tetrahydrofuran, methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole and the like; nitrile such as acetonitrile, propionitrile, butanenitrile and the like; water; and mixture thereof.

In another embodiment, abrocitinib or its pharmaceutically acceptable salt thereof as used for preparing amorphous solid dispersion, can be either crystalline, amorphous or mixture in nature.

In preferred embodiment, the solid dispersion is a substance obtained by dispersing abrocitinib or its pharmaceutically acceptable salt into a carrier in a mono-molecular state. In this dispersion, the abrocitinib or its pharmaceutically acceptable salt remains in a completely amorphous state. Generally, the amorphous form is in a higher energetic state compared to the crystalline form and is therefore expected to have a higher absorptivity.

In another embodiment, the present application provides a pharmaceutical composition comprising a stable solid dispersion of abrocitinib or its pharmaceutically acceptable salt together with atleast one pharmaceutically acceptable excipient.

The pharmaceutical composition of the present invention may be formulated in accordance with conventional methods, and may be prepared in the form of oral formulations such as tablets, pills, powders, capsules, syrups, emulsions, micro emulsions, and others, or formulation for parenteral injection, e.g., intramuscular, intravenous, or subcutaneous administration. The pharmaceutical composition of the present invention may comprise the inventive solid dispersion, and any possible carrier and excipient.

In an embodiment, the present application provides a stable solid dispersion of abrocitinib or its pharmaceutically acceptable salt thereof, with less than 5% of crystallinity, preferably with less than 1% crystallinity and more preferably with less than 0.5% crystallinity as per X-ray diffraction analysis.

In one another embodiment, the present invention provides a premix of abrocitinib or its pharmaceutically acceptable salt with atleast one pharmaceutical acceptable polymer and/or excipient.

In one another embodiment, the present invention provides a process for the preparation of a premix of abrocitinib or its pharmaceutically acceptable, comprising the steps of:
a) adding abrocitinib or its pharmaceutically acceptable salt to atleast one pharmaceutically acceptable polymer to get a solid mass;
b) optionally adding solvent to get a solution; and
c) isolating the premix of abrocitinib or its pharmaceutically acceptable salt either by removal of solvent from solution of step b) or by isolating the solid mass of step a).

In another embodiment, the present application provides a pharmaceutical composition comprising a premix of abrocitinib or its pharmaceutically acceptable salt thereof, together with atleast one pharmaceutically acceptable excipient.

In preferred embodiment, the suitable solvent used for preparing premix of abrocitinib or its pharmaceutically acceptable salt thereof, may be selected from, but not limited to, the group comprising of alcohols such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole; ketones such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; esters solvents such as ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate; hydrocarbon such as toluene, xylene, hexane, n-heptane, n-pentane, anisole, ethyl benzene and the like; nitriles such as acetonitrile, propionitrile, butanenitrile; water; and mixtures thereof.

In one more embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of abrocitinib free base comprising the steps of:
a) providing a solution of amorphous form of free base in a suitable solvent;
b) adding atleast one pharmaceutically acceptable carrier or polymer; and
c) removing the solvent and isolating to get amorphous solid dispersion of abrocitinib free base.

In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of abrocitinib or its pharmaceutically acceptable salt comprising the steps of:
a) providing a solution of amorphous form of abrocitinib or its pharmaceutically acceptable salt in a suitable solvent;
b) adding atleast one pharmaceutically acceptable carrier or polymer; and
c) removing the solvent and isolating to get amorphous solid dispersion of abrocitinib or its pharmaceutically acceptable salt.

In another embodiment, a solution of abrocitinib or its pharmaceutically acceptable salt thereof used to prepare amorphous solid dispersion/ premix/ amorphous form of abrocitinib or its pharmaceutically acceptable salt, may be prepared by dissolving abrocitinib or its pharmaceutically acceptable salt thereof in a suitable solvent or by taking the reaction mixture containing abrocitinib or its pharmaceutically acceptable salt thereof directly.

In an embodiment, a solution of abrocitinib or its pharmaceutically acceptable salt thereof in a suitable solvent can be prepared at any suitable temperature, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.

In an embodiment, a solution of abrocitinib or its pharmaceutically acceptable salt thereof in a suitable solvent may be filtered to make it clear, free of unwanted particles. In an embodiment, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove coloured components, etc., before filtration.

In preferred embodiments, removal of solvent at any stage of preparation of amorphous form/ solid dispersion/ premix of abrocitinib or its pharmaceutically acceptable salt salt may include, but not limited to, solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, flash evaporation, rotational dying, agitated nutsche filter drying, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD), lyophilization, and the like. In preferred embodiment, the solvent may be removed under reduced pressures and at a temperature of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C, or any other suitable temperatures.

In another embodiment, stable amorphous form of abrocitinib or its pharmaceutically acceptable salt thereof may be combined with excipient either by physical blending of both the solid components or by suspending both the components in a suitable solvent and conditions, such that both the components remain unaffected. Blending may be carried out using techniques known in art such as rotatory cone dryer, fluidized bed dryer or the like optionally under reduced pressure / vacuum or inert atmosphere such nitrogen at suitable temperature and sufficient time to obtain uniform composition of amorphous form of abrocitinib or its pharmaceutically acceptable salt thereof and atleast one pharmaceutically acceptable excipient.

In another embodiment, stable amorphous form of abrocitinib or its pharmaceutically acceptable salt thereof may be combined with the excipient by evaporating the suspension or solution of stable amorphous form of abrocitinib or its pharmaceutically acceptable salt thereof and atleast one pharmaceutically acceptable excipient.

In another embodiment, pharmaceutically acceptable carrier used for preparing solid dispersion may include, but not limited to, an inorganic oxide such as SiO2, TiO2, ZnO2, ZnO, Al2O3 and zeolite; a water insoluble polymer is selected from the group consisting of cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene glycol, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolat, and cross-linked styrene divinyl benzene or any other excipient at any aspect of present application. In an embodiment, atleast one pharmaceutically acceptable excipient may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxy methyl ethyl cellulose and the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other excipient at any aspect of present application. The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation. Solid dispersions of the present application also include the solid dispersions obtained by combining abrocitinib or its pharmaceutically acceptable salt thereof with a suitable non-polymeric excipient by employing techniques known in the art or procedures described or exemplified in any aspect of the instant application.

Stable amorphous form or stable solid dispersion or premix of abrocitinib or its pharmaceutically acceptable salt, may be dried in suitable drying equipment such as vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In another embodiment, the present invention provides the abrocitinib of Formula I that is characterized by particle size distribution wherein, d90 is 0.1µm to 200µm, preferably d90 is 2.0 µm to 150µm. Preferably, the particle size distribution d90 is not more than 1.0mm.

In another embodiment, the present invention provides the abrocitinib of Formula I substantially free from (1s,3s)-N-hydroxy-3-(methyl(7H-pyrrolo[2,3-d] pyrimidin-4-yl) amino) cyclobutane-1-carboxam of Formula A,
.

In another embodiment, the present invention provides substantially pure abrocitinib of Formula I characterized by the chemical purity of 90.0% and above, preferably 95% and above, more preferably 98% and above and most preferably 99% and above by HPLC.

In another embodiment, the present invention provides substantially pure abrocitinib of Formula I characterized by the purity of 99.0% and above, preferably 99.5% and above, and most preferably 99.9% and above by HPLC.

In another embodiment, the present invention further provides abrocitinib, or a pharmaceutically acceptable salt thereof, having an optical purity of =96%, preferably =98%, more preferably >99%, even more preferably =99.9%. For the purposes of the present invention, the term "optical purity" is defined as the percentage of a given enantiomer in an enantiomeric mixture when measured by chiral HPLC.

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.

EXAMPLES
EXAMPLE-1: Synthesis of tert-butyl (3-oxocyclobutyl) carbamate
In a round bottom flask 3-oxocyclobutanecarboxylic acid (50g) was charged dichloromethane (250 ml) add to it thionyl chloride (104.3 g) at 0-20oC and stirred the reaction mass for 2-3 hrs and distilled out the solvent. Dichloromethane (250 ml) was added to remaining mass and slowly added aqueous solution of sodium azide and stirred the reaction mass at 0-20oC for 3-4 hrs and extracted the material with dichloromethane and washed the water and sodium chloride solution. Organic solvent was distilled off to reduce the volume to 1/4th and to this was added tert-butanol (150 ml) and heat the reaction mass from 50-90oC. After completion of reaction solvent was distilled off and obtained crude was purified by column chromatography. Purity 98% by HPLC, Yield – 35 g.
EXAMPLE-2: Synthesis of benzyl (3-oxocyclobutyl) carbamate
In a round bottom flask was added 3-oxocyclobutanecarboxylic acid (50g) in dichloromethane (300 ml), and to it was added thionyl chloride (115g) and the mixture was stirred at 0-20oC and distilled to remove the solvent. Aqueous sodium azide solution sodium azide (85 g) in water (400 ml) was added slowly and stirred the reaction mass at 0-20oC for 2-3 hrs and after completion, reaction mass was extracted using dichloromethane and washed with water and sodium chloride solution. Organic layer was distilled to reduce the volume to 1/4th and benzyl alcohol (150 ml), was added and the reaction mass was heated at 50-90oC and distilled the solvent to get the crude. Crude was purified by using column chromatography. Purity 98% by HPLC, Yield – 42 g.

EXAMPLE-3: Synthesis of tert-butyl (5,8-dioxaspiro [3.4] octan-2-yl) carbamate
In a round bottom flask product obtained in example 2, (30g) was taken in toluene (300 ml) and ethylene glycol (50g), and p-Toluene sulfonic acid (6g), was added. Mixture was stirred for 12 h, at 80-120°C. After the completion of reaction solvent was distilled out and water was added. Material was extracted using toluene and washed with water. Remaining organic layer was distilled out to get the product. Purity 95% by HPLC, Yield – 32 g.

EXAMPLE-4: Synthesis of 3-aminocyclobutan-1-one
Product obtained in example 1, (30g) was taken in dichloromethane (300 ml) added (10 g), of anhydrous HCl. Stirred the reaction mass at 40-50 oC for 12 hrs and solvent was distilled off to get the product. Purity: 95% by HPLC; Yield – 11g.
Alternate Process: 1
Product obtained in example 3(30 g) was added in tetrahydrofuron (150 ml) and anhydrous hydrochloric acid (13g) at 40-50oC.After completion of reaction solvent was distilled off to get the product. Purity: 95% by HPLC; Yield – 13 g.
Alternate Process: 2
Product obtained in example 2, (30g) was taken in round bottom flask in ethanol (210 ml) and to this was added Pd/C under hydrogen pressure at temperature 20-80oC for 2-3 hrs. Filtered the mass and solvent was distilled to get the product. Purity: 92% by HPLC; Yield – 14 g.
EXAMPLE-5: Synthesis of N-(3-oxocyclobutyl) propane-1-sulfonamide
3-aminocyclobutan-1-one (20 g) was taken in dichloromethane (250 ml) and added pyridine (120 ml) and 1-propane sulfonyl chloride (32 g) and stirred the reaction mass at, 15oC for 1 hr. Aqueous hydrochloric acid was added and the material was extracted using dichloromethane and ethyl acetate solution and wash with water and aqueous NaCl solution. Organic solvent was distilled out to get the product. Purity: 95% by HPLC; Yield – 15g.

EXAMPLE-6: Synthesis of N-((1s,3s)-3-(methylamino)cyclobutyl)propane-1-sulfonamide
Compound obtained in step 3 (10 g), was taken in tetrahydrofuran (100 ml) in a round bottom flask and to this was added acetic acid (15g), methyl amine (300 ml) stirred the reaction mass and cooled to -75oC to -60oC and added sodium borohydride (0.6 g) and stirred the reaction mass at -10oC for (2.5 hrs) added water (10 ml) and aqueous hydrochloric acid solution (5ml) and layer was separated. Aqueous layer was washed twice with ethyl acetate (50ml) each and basified with 10% aq. NaOH solution and extracted with dichloromethane (70ml) and organic layer was washed with water and aqueous sodium chloride solution. Organic layer was distilled off to get the crude compound. Crude product was dissolved in dichloromethane (10 ml) and aqueous hydrochloride (5 ml) and stirred the mass for 2 hrs. Solid was filtered and dried. Purity: 97% by HPLC; Yield – 6 g.

EXAMPLE-7: Synthesis of Abrocitinib
Compound prepared in example 6, (5g) and 4-Chloro-7-H-pyrrolo[2,3-d] pyrimidine (4g), potassium carbonate (17g) was taken in round bottom flask with water (50 ml). Stirred the reaction mass at 80-100°C for 12 hrs and filtered the reaction mass and obtained solid was recrystallized using ethanol. Product obtained was dried. Purity: 99.5% by HPLC; Yield – 4 g, 99.5%ee.

Example-8: Preparation of stable amorphous solid dispersion of Abrocitinib with PVP K-90
A mixture of Abrocitinib free base (0.4g) and PVP K-90 (0.6g) was dissolved in ethanol (25mL) at 25°C and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 50°C to obtain title compound.

Example-10: Preparation of solid dispersion of Abrocitinib with more than one pharmaceutically acceptable carrier
To a mixture of hydroxypropylmethylcellulose (1g), low-substituted hydroxypropylcellulose (2.5g) and lactose (4.2g) is added a solution of abrocitinib (1.2g) in absolute ethanol and after stirring, the ethanol is evaporated in vacuo to provide a solid dispersion.

Example-11: Preparation of a pre-mix of amorphous Abrocitinib with 10 w/w
microcrystalline cellulose
Abrocitinib (5g) was dissolved in dimethyl sulfoxide (12.5 ml) at 25°C - 30°C. The solution was filtered to remove undissolved particulate and washed with dimethyl sulfoxide (2.5ml). The clear solution of abrocitinib was added into water (150ml) maintained at 25°C-30°C for 30 minutes. The reaction mass was further stirred for 30 minutes. Microcrystalline cellulose (0.556 g, Grade: AVICEL PH 101) was then added into the reaction mass and which was then stirred for 1 hr. The solid obtained was filtered out, washed with water (20 ml), and dried at 30°C under vacuum for 16 hours. It was then further dried at 40°C under vacuum for 24 hours.
,CLAIMS:WE CLAIM:

1. A process for the preparation of abrocitinib of Formula I or pharmaceutically acceptable salts thereof, comprising treating compound of Formula II or its salt with 4-halo-7-H-Pyrolo[2,3-d]pyrimidine of Formula III to give abrocitinib of Formula I or pharmaceutically acceptable salts thereof,
, , ,
wherein X = Cl, Br, I.

2. The process as claimed in claim 1, wherein the preparation of compound of Formula II, comprising the steps of:
a) reacting compound of Formula VI with propane-1-sulfonyl halide to give compound of Formula IIa
, , ; and
wherein X= Cl, Br, I; and
b) reacting compound of Formula IIa with methylamine in presence of reducing agent to give compound of Formula II,
, .

3. The process as claimed in claim 2, wherein the preparation of compound of Formula VI, comprising the steps of:
a) converting 3-oxocyclobutane carboxylic acid of Formula VII to compound of Formula IV or V,
, , ,
wherein Pg = protecting group; Z1 and Z2 is selected from H, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl or Z1 and Z2 together form a 5 to 6-member cyclic ring; and
b) deprotecting compound of Formula IV or V to give compound of Formula VI,
, , .

4. The process as claimed in claim 2 wherein, the reducing agent used is selected from lithium borohydride (LiBH4), sodium borohydride (NaBH4), sodium cyano borohydride, sodium triacetoxyborohydride, palladium/carbon (Pd/C) or raney nickel.

5. A compound of Formula II, V or IIa,
, , ,
wherein Pg = protecting group; Z1 and Z2 is selected from H, substituted or unsubstituted C1-4 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted hetroaryl, substituted or unsubstituted hetrocyclyl or Z1 and Z2 together form a 5 to 6-member cyclic ring.

6. The compound as claimed in claim 5, wherein the compound of Formula II, V or IIa used in the preparation of abrocitinib of Formula I or pharmaceutically acceptable salts thereof.

7. The process as claimed in claim 1, wherein, abrocitinib of Formula I or pharmaceutically acceptable salts prepared has particle size d90 not more than 20 microns.

8. The process as claimed in claim 1, wherein, abrocitinib of Formula I or pharmaceutically acceptable salts prepared is free from (1s,3s)-N-hydroxy-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutane-1-carboxam of Formula A,
.
9. The process as claimed in claim 1, wherein, abrocitinib of Formula I or pharmaceutically acceptable salts prepared has purity 99% and above by HPLC.

10. The process as claimed in claim 1, wherein, abrocitinib of Formula I or pharmaceutically acceptable salts prepared has optical purity of 99.5%.

Dated this 09th day of Sept, 2024
For Mankind Pharma Ltd.

Dr. Anil Kumar

Chief Scientific Officer