DESC:The following specification particularly describes the invention and the manner in which it is to be performed.
PROCESS FOR THE PREPARATION OF DEUCRAVACITINIB
FIELD OF THE INVENTION
The present application relates to synthetic process of Deucravacitinib and process for the preparation of crystalline Deucravacitinib.
BACKGROUND OF THE INVENTION
Deucravacitinib has the chemical name 6-(cyclopropanecarbonylamido)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl)anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide and the following chemical structure:

Deucravacitinib is a selective tyrosine kinase 2 (TYK2) inhibitor which is investigated and developed for the treatment of psoriasis.
Deucravacitinib is described in International Publication No. WO2014074661A1. In this publication, Deucravacitinib is prepared by a process which includes reacting a triazole-aniline compound (which will be described herein below as Compound IV) with a methyl deuterium carboxamide-pyridazine compound, i.e., the methyl deuterium is introduced at an early step of the process.
J. Med. Chem. 2019, 62, 8953-8972 describes a similar process for Deucravacitinib. International Publication Nos. WO2018183649A1 and WO2018183656A1 describe a synthetic process for Deucravacitinib that uses a different rearrangement of steps, in which an ethyl-ester pyridazine compound is first hydrolysed to an acid or a salt compound, which is then reacted with the triazole-aniline compound. In this process, the methyl deuterium is introduced into the molecule at a later stage, by reaction of a later intermediate with deuterated methylamine.
Deucravacitinib process is described in International Publication No. WO2023102085A1. In this publication, Deucravacitinib is prepared by a process which includes the reaction of ethyl 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-t riazol-3-yl)phenyl)amino)pyridazine-3-carboxylate with methan-d3-amine hydrochloride may be carried out using lithium bis(trimethylsilyl)amide (LiHMDS) in THF.
The prior art process for the preparation of Deucravacitinib involves highly toxic, extremely hygroscopic reagents and difficult to store those reagents. The present disclosure provides a simple and cost-efficient process for preparation of a Deucravacitinib.
SUMMARY OF THE INVENTION
Aspect of the present application provides a process for the preparation of Deucravacitinib, comprising:

a) reacting a compound of Formula (II) with POCl3 in presence base and solvent to produce a compound of Formula (III);

b) reacting a compound of Formula (III) with a compound of Formula (IV) in presence of base and solvent to produce a compound of Formula (V);

c) reacting a compound of Formula (V) with Methan-d3-amine or its hydrochloride in presence of base and solvent to produce a compound of Formula (VI);

d) reacting a compound of Formula (VI) with a compound of Formula (VII) in presence of catalyst, ligand and base to produce Deucravacitinib;

In another aspect, the present application provides process for the preparation of crystalline Deucravacitinib, comprising the steps:
a) providing a solution of Deucravacitinib in a solvent;
b) optionally seeding with crystalline Deucravacitinib;
c) removing the solvent to obtain crystalline Deucravacitinib.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline Deucravacitinib prepared by the method of Example No 5.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, "comprising" means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.
Terms such as "about," "generally," "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute, but does not read on the prior art. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
Aspect of the present application provides a process for the preparation of Deucravacitinib, comprising:

a) reacting a compound of Formula (II) with POCl3 in presence base and solvent to produce a compound of Formula (III);

b) reacting a compound of Formula (III) with a compound of Formula (IV) in presence of base and solvent to produce a compound of Formula (V);

c) reacting a compound of Formula (V) with Methan-d3-amine or its hydrochloride in presence of base and solvent to produce a compound of Formula (VI);

d) reacting a compound of Formula (VI) with a compound of Formula (VII) in presence of catalyst, ligand and base to produce Deucravacitinib;

In one embodiment, the above reactions may be carried out in the presence of suitable solvent include, but are not limited to aromatic hydrocarbon solvents, such as toluene, xylene, chlorobenzene, tetralin or the like; ether solvents, such as, for example, diethyl ether, Isopropyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1, 4-dioxane or the like; ketone solvents, such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, methylbutyl ketone, C3-C6 ketones or the like; halogenated hydrocarbons such as dichloromdmaethane, 1,2-dichloroethane, 1,1-dichloroethene, 1,2-dichloroethene, 1,1,1-trichloroethane, 1,1,2-trichloroethene, chloroform or the like; aliphatic hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane or the like; nitrile solvent, such as acetonitrile, propionitrile, C2-C6 nitriles or the like; ester solvents, such as ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate. alcoholic solvents such as methanol, ethanol, 1-propanol, isopropyl alcohol, n-butanol, 2-butanol, tert-butyl alcohol, 1-pentanol; acetic acid, carbon tetrachloride, benzene, cumene, cyclohexane, methylcyclohexane, dimethylacetamide, N,N- dimethylformamide, dimethyl sulfoxide(DMSO), ethyleneglycol, formamide, formic acid, 3-methyl-1-butanol, 2-methyl-1-propanol, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane or the like; water or mixtures thereof.
In another embodiment, the above reaction may be carried out in the presence of suitable base include, but are not limited to sodium ethoxide (NaOEt), potassium tert-butoxide (KOtBu), lithium methoxide (LiOMe), magnesium ethoxide (Mg(OEt)2), aluminum isopropoxide (Al(OiPr)3), titanium isopropoxide (Ti(OiPr)4), zirconium tert-butoxide (Zr(OtBu)4), hafnium tert-butoxide (Hf(OtBu)4), vanadium(V) ethoxide (VO(OEt)3), niobium(V) ethoxide (Nb(OEt)5), sodium methoxide (NaOMe), sodium tert-butoxide (NaOtBu), potassium carbonate (K2CO3), sodium carbonate (Na2CO3), calcium carbonate (CaCO3), Cesium carbonate (Cs2CO3), magnesium carbonate (MgCO3), Iron(II) carbonate (FeCO3), Manganese carbonate (MnCO3), barium carbonate (BaCO3), lead(II) carbonate (PbCO3), lithium hydroxide (LiOH), sodium hydroxide(NaOH), potassium hydroxide(KOH), rubidium hydroxide(RbOH), magnesium hydroxide Mg(OH)2, barium hydroxide Ba(OH)2, calcium hydroxide Ca(OH)2, strontium hydroxide Sr(OH)2, copper hydroxide (Cu(OH)2), ferric hydroxide (Fe(OH)3), zinc hydroxide (Zn(OH)2), triethylamine, methylamine, ammonium hydroxide, alanine, N, N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), N-methylmorpholine (NMM) or mixture thereof.
In another embodiment, suitable catalyst used in step d) include, but are not limited to Pd2(dba)3, Pd(dppf), Pd(dppf).DCM, PdCl2 Pd(PPh3)4 and Pd(OAc)2
In another embodiment, suitable ligand used in step d) include, but are not limited to Xantphos, S-Phos or X-Phos, Ruphos, Brettphos, tBuBrettphos, tBuxphos, Amphos, Josiphos, Davephos, tBuDavephos, Johnphos, CyJohnphos, AdJohnphos, Mephos, tBuPhPhos, tBuMePhos, PhDavephos, TrixiePhos, PhXPhos, Xphos-So3Na, sSphos, Me4tBuXPhos, Jakiephos, Cphos, Rockphos, AdBrettphos, TMM-tBuXphos, tBuBrettCy3Phos, PhCPhos, TMM-PhXPhos, TMM-Xphos, HGPhos, EtCPhos, (tBu)PhCPhos, CyPhCPhos, Cphos-Jakiephos hybrid, RuPhos-Jakiephos hybrid, Alphos, Vphos, TMM-tBuCy3phos, Ephos, AdCyBrettPhos and Gphos.
The temperature at which the above steps may be carried out in between about -20 °C and about 200°C, preferably at about 0°C and about 150°C, most preferably at about 0°C and about 100°C, based on the solvent or mixture of solvent used in particular step.
The removal of solvent at any stage of the process of the present application may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation or sublimation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying (Lyophilization), agitated thin film drying and the like.
The compounds at any stage of the process of the present application may be isolated using conventional techniques known in the art. For example, useful techniques include but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, combining with an anti-solvent, adding seed crystals, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, or the like. The isolation may be optionally carried out at atmospheric pressure or under reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor.
The resulting solid may be optionally further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100 °C, less than about 60 °C, less than about 40 °C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, about 1 to about 15 hours, or longer.
Specific aspect of the present application provides a process for the preparation of Deucravacitinib, comprising:

a) reacting a compound of Formula (II) with POCl3 in presence base and solvent to produce a compound of Formula (III);

b) reacting a compound of Formula (III) with a compound of Formula (IV) in presence of base and solvent to produce a compound of Formula (V);

c) reacting a compound of Formula (V) with Methan-d3-amine or its hydrochloride in presence of base and solvent to produce a compound of Formula (VI);

d) reacting a compound of Formula (VI) with a compound of Formula (VII) in presence of catalyst, ligand and base to produce Deucravacitinib;

In another aspect, the present application provides process for the preparation of crystalline Deucravacitinib, comprising the steps:
a) providing a solution of Deucravacitinib in a solvent;
b) optionally seeding with crystalline Deucravacitinib;
c) removing the solvent to obtain crystalline Deucravacitinib.
In another embodiment, the above steps may be carried out in the presence of suitable solvent include, but are not limited to aromatic hydrocarbon solvents, such as toluene, xylene, chlorobenzene, tetralin or the like; ether solvents, such as, for example, diethyl ether, Isopropyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1, 4-dioxane or the like; ketone solvents, such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, methylbutyl ketone, C3-C6 ketones or the like; halogenated hydrocarbons such as dichloromdmaethane, 1,2-dichloroethane, 1,1-dichloroethene, 1,2-dichloroethene, 1,1,1-trichloroethane, 1,1,2-trichloroethene, chloroform or the like; aliphatic hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane or the like; nitrile solvent, such as acetonitrile, propionitrile, C2-C6 nitriles or the like; ester solvents, such as ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate. alcoholic solvents such as methanol, ethanol, 1-propanol, isopropyl alcohol, n-butanol, 2-butanol, tert-butyl alcohol, 1-pentanol; acetic acid, carbon tetrachloride, benzene, cumene, cyclohexane, methylcyclohexane, dimethylacetamide, N,N- dimethylformamide, dimethyl sulfoxide(DMSO), ethyleneglycol, formamide, formic acid, 3-methyl-1-butanol, 2-methyl-1-propanol, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane or the like; water or mixtures thereof.
The temperature at which the above steps may be carried out in between about -20 °C and about 200°C, preferably at about 0°C and about 150°C, most preferably at about 0°C and about 100°C, based on the solvent or mixture of solvent used in particular step.
The compounds at any stage of the process of the present application may be isolated using conventional techniques known in the art. For example, useful techniques include but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, combining with an anti-solvent, adding seed crystals, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, or the like. The isolation may be optionally carried out at atmospheric pressure or under reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor.
The resulting solid may be optionally further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100 °C, less than about 60 °C, less than about 40 °C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, about 1 to about 15 hours, or longer.
Figure 1 is an illustrative X-ray powder diffraction pattern of crystalline Deucravacitinib prepared by the method of Example No 5.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.

Examples
Example 1: Preparation of ethyl 4,6-dichloropyridazine-3-carboxylate.
Ethyl 4,6-dihydroxypyridazine-3-carboxylate (1 g), Toluene (0.26 mL) and sulfolane(3.4 g) were charged into an RBF at room temperature and stirred for 5 minutes. POCl3(1.645 mL) was added to the reaction mass at room temperature and stirred for 5 minutes. The rection mass was cooled to 0oC and Triethylamine (1.24 mL) was added to the reaction mass and stirred for 10 minutes. The reaction mass was heated to 60oC and stirred for 2 hrs. After completion of reaction as indicated by TLC, the reaction mass was cooled to 5oC and added to water (10 mL). The reaction mass was stirred for 1 hr at the same temperature. MIBK (15 mL) was added to the reaction mass. The layers were separated and MIBK layer was washed with water (10 mL). The MIBK layer was evaporated to dryness to afford the titled intermediate compound (83.33% yield).

Example 1A: Preparation of 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.
Ethyl 4,6-dihydroxypyridazine-3-carboxylate (100 g), Toluene (600 mL) and POCl3(197 mL) were charged into reactor under nitrogen atmosphere. Triethylamine (106 mL) was added to the reaction mass at 45oC and stirred for 15 minutes. The rection mass was heated to 63oC and stirred for 2hrs. The reaction mass was heated to 60oC and stirred for 2 hrs. After completion of the reaction as indicated by TLC, the reaction mass was cooled to 25oC and added to water (1000 mL). The reaction mass was stirred for 1 hr at 15oC. Sodium bicarbonate solution was added to the reaction mass. The layers were separated and toluene layer was washed with water. Sodium chloride solution was added to the reaction mass. The layers were separated and toluene layer was evaporated to afford the residue mass. 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (144.2 g), t-Butanol (300mL) and triethylamine (102.2 mL) were added to the residue mass at 25oC. The reaction mass was heated to 77.5oC and stirred for 42 hrs. The reaction mass was evaporated till 1 volume t-Butanol left inside the reactor. Dimethylsulfoxide (400 mL), methan-d3-amine hydrochloride(38.3 g) and potassium t-butaoxide (152 g) were charged into the reactor at 25oC and stirred for 3 hrs. The reaction mass was added to water (2000 mL) at 30oC and stirred for 1 hr. The resultant suspension was filtered, and the filtered cake was washed with water (500 mL). The obtained solid was dried under reduced pressure to afford 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxa mide. The resultant compound, hydrochloride solution (400 mL HCl in 3600 mL water) and dichloromethane (500 mL) were charged into the reactor at 30oC and stirred for 45 minutes. The layers were separated and aqueous layer and 20%NaOH solution were charged into the reactor at 30oC and stirred for 45 minutes. The resultant suspension was filtered, and the filtered cake was washed with water (3500 mL). The obtained solid was dried under reduced pressure at a temperature of about 44°C for 20 hrs to afford the titled compound (80% yield)

Example 2: Preparation of ethyl 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-t riazol-3-yl)phenyl)amino)pyridazine-3-carboxylate.
Ethyl 4,6-dichloropyridazine-3-carboxylate (5 g), 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (4.16 g) and triethylamine (6.31mL) were charged into a RBF at room temperature. The reaction mass was heated to 87oC and stirred for 8 hrs. TEA (3.15 mL) and Ethyl acetate (10 mL) were added to the reaction mass at room temperature. The rection mass was heated to 88oC and stirred for 3 hrs. Ethyl acetate (50 mL) was added to the reaction mass and cooled to room temperature. The resultant suspension was filtered, and the filtered cake was washed with MTBE (25 mL) and water (50 mL). The obtained solid was dried under reduced pressure at a temperature of about 60°C to afford the titled compound (80.68% yield)

Example 3: Preparation of 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide.
Ethanol (10 mL), ethyl 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate (1 g), methan-d3-amine hydrochloride (0.218 g) and potassium carbonate (0.711 g) were charged into a RBF at room temperature. The reaction mass was heated to 68oC and stirred for 12 hrs. After completion of reaction as indicated by TLC, the reaction mass was cooled to room temperature. MTBE (20 mL) was added to the reaction mass and stirred for 30 minutes. The resultant suspension was filtered, and the filtered cake was washed with MTBE (5 mL). The solid was dried under reduced pressure at room temperature. The obtained solid and water (10 mL) were charged into a RBF and stirred for 30 minutes at room temperature. The suspension was filtered, and the filtered cake was washed with water (5 mL). The obtained solid was dried under reduced pressure at a temperature of about 44°C for 6 hrs to afford the titled compound (84.62% yield)

Example 4: Preparation of Deucravacitinib.
1,4-dioxane (9 mL), 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (300 mg), cyclopropanecarboxamide (203 mg), Cs2CO3 (519 mg), Pd2(dba)3 (109 mg) and Xantphous (115 mg) were charged in to a RBF at room temperature under N2 atmosphere. The reaction mass was heated to 140oC and stirred for 5-6 hrs. The reaction mass cooled to room temperature. Water (10 mL) and ethyl acetae (10 mL) were added to the reaction mass and stirred for 10 minutes at room temperature. The layers were separated and the aqueous layer was extracted with ethyl acetae (10 mL). The combined
ethyl acetae layer was evaporated completely at 50oC. Acetone (5 mL) was added to the obtained reaction mass and stirred for 30 min at 50oC . The reaction mass was cooled to room temperature and stirred for 30 minutes. The resultant suspension was filtered, and the filtered cake was washed with acetone (5 mL). The obtained solid was dried under reduced pressure at a temperature of about 50°C to afford the titled compound (14.75% yield)

Example 5: Preparation of crystalline form of Deucravacitinib.
Deucravacitinib (10 g), methanol (15 volume) and toluene (20 volume) were charged into RBF. The reaction mass was heated to 70oC and stirred for 1hr and 30 minutes. The reaction mass cooled to 45oC. The reaction mass was seeded with crystalline deucravacitinib and stirred for 5hrs at the same temperature. The reaction mass was cooled to 12oC and stirred for 1 hr and 30 minutes. The resultant suspension was filtered, and the filtered cake was washed with methanol (2 volume). The obtained solid was dried under reduced pressure at a temperature of about 47°C to afford the titled compound (Dry weight:4.72 g)

Example 6: Preparation of Deucravacitinib.
1,4-dioxane (10 volume), 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (700g), cyclopropanecarboxamide (474g), Cs2CO3 (1211 g), Pd2(dba)3 (170 g) and Xantphous (215 g) were charged in to a RBF at room temperature under N2 atmosphere. The reaction mass was heated to 100oC and stirred for 7 hrs. The reaction mass cooled to 30oC. The reaction mass was filtered through hyflow and was washed with 1,4-dioxane (2 volume). The reaction mass contain dioxane (350g) was evaporated at 45oC under reduced pressure. Dichloromethane (5 volume) and 2N HCl (10 volume) were added to the reaction mass at 15oC and stirred for 15 minutes. The layers were separated and the dichloromethane layer was extracted with 2NHCl (5 volume). The combined aqueous layer was washed with dichloromethane (5 volume). The obtained aqueous layer, 15% methanol in dichloromethane and aqueous ammonia (3 volume) were charged into a reactor at 15oC and stirred for 20 minutes. The layers were separated and aqueous layer was extracted with 30% methanol in dichloromethane (20 volume). The layers were separated and combined organic layer was washed with water (5 volume). The organic layer was evaporated at 45oC to afford the titled compound.

Example 7: Preparation of Deucravacitinib.
Deucrvacitinib crude (5 g), dichloromethane (5 volume) and 2N HCl (10 volume) were charged into RBF and stirred for 10 minutes. The layers were separated and the dichloromethane layer was extracted with 2NHCl (5 volume). The combined aqueous layer was washed with dichloromethane (5 volume). The obtained aqueous layer, 30% methanol in dichloromethane (30 volume) and aqueous ammonia (3 volume) were charged into a reactor at 8oC and stirred for 20 minutes. The layers were separated and aqueous layer was extracted with 30% methanol in dichloromethane (10 volume). The layers were separated and combined organic layer was washed with water (5 volume). The organic layer was evaporated at 45oC to afford the titled compound. The obtained soild (8 g), methanol (15 volume) and toluene (20 volume) were charged into RBF. The reaction mass was heated to 65oC and stirred for 1 hr. The reaction mass was cooled to 48oC. The reaction mass was seeded with crystalline deucravacitinib and stirred for 22hrs at 27°C. The resultant suspension was filtered, and the filtered cake was washed with methanol (2 volume). The obtained solid was dried under reduced pressure at a temperature of about 47°C to afford the titled compound (Dry weight:4.46 g)
,CLAIMS:We claim
1. A process for the preparation of Deucravacitinib, comprising:

a) reacting a compound of Formula (II) with POCl3 in presence base and solvent to produce a compound of Formula (III);

b) reacting a compound of Formula (III) with a compound of Formula (IV) in presence of base and solvent to produce a compound of Formula (V);

c) reacting a compound of Formula (V) with Methan-d3-amine or its hydrochloride in presence of base and solvent to produce a compound of Formula (VI);

d) reacting a compound of Formula (VI) with a compound of Formula (VII) in presence of catalyst, ligand and base to produce Deucravacitinib;

2. The process of claim 1, wherein the base is selected from sodium ethoxide (NaOEt), potassium tert-butoxide (KOtBu), lithium methoxide (LiOMe), magnesium ethoxide (Mg(OEt)2), aluminum isopropoxide (Al(OiPr)3), titanium isopropoxide (Ti(OiPr)4), zirconium tert-butoxide (Zr(OtBu)4), hafnium tert-butoxide (Hf(OtBu)4), vanadium(V) ethoxide (VO(OEt)3), niobium(V) ethoxide (Nb(OEt)5), sodium methoxide (NaOMe), sodium tert-butoxide (NaOtBu), potassium carbonate (K2CO3), sodium carbonate (Na2CO3), calcium carbonate (CaCO3), Cesium carbonate (Cs2CO3), magnesium carbonate (MgCO3), Iron(II) carbonate (FeCO3), Manganese carbonate (MnCO3), barium carbonate (BaCO3), lead(II) carbonate (PbCO3), lithium hydroxide (LiOH), sodium hydroxide(NaOH), potassium hydroxide(KOH), rubidium hydroxide(RbOH), magnesium hydroxide Mg(OH)2, barium hydroxide Ba(OH)2, calcium hydroxide Ca(OH)2, strontium hydroxide Sr(OH)2, copper hydroxide (Cu(OH)2), ferric hydroxide (Fe(OH)3), zinc hydroxide (Zn(OH)2), triethylamine, methylamine, ammonium hydroxide, alanine, N, N-diisopropylethylamine (DIPEA), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), N-methylmorpholine (NMM) or mixture thereof.
3. The process of claim 1, wherein the catalyst is selected from Pd2(dba)3, Pd(dppf), Pd(dppf).DCM, PdCl2 Pd(PPh3)4 and Pd(OAc)2.
4. The process of claim 1, wherein the ligand is selected from Xantphos, S-Phos or X-Phos, Ruphos, Brettphos, tBuBrettphos, tBuxphos, Amphos, Josiphos, Davephos, tBuDavephos, Johnphos, CyJohnphos, AdJohnphos, Mephos, tBuPhPhos, tBuMePhos, PhDavephos, TrixiePhos, PhXPhos, Xphos-So3Na, sSphos, Me4tBuXPhos, Jakiephos, Cphos, Rockphos, AdBrettphos, TMM-tBuXphos, tBuBrettCy3Phos, PhCPhos, TMM-PhXPhos, TMM-Xphos, HGPhos, EtCPhos, (tBu)PhCPhos, CyPhCPhos, Cphos-Jakiephos hybrid, RuPhos-Jakiephos hybrid, Alphos, Vphos, TMM-tBuCy3phos, Ephos, AdCyBrettPhos and Gphos.
5. A process for the preparation of crystalline Deucravacitinib, comprising the steps:
a) providing a solution of Deucravacitinib in a solvent;
b) optionally seeding with crystalline Deucravacitinib;
c) removing the solvent to obtain crystalline Deucravacitinib.
6. The process of claim 1 and claim 6, wherein the solvent is selected from toluene, xylene, chlorobenzene, tetralin diethyl ether, Isopropyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1, 4-dioxane, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, methylbutyl ketone, dichloromdmaethane, 1,2-dichloroethane, 1,1-dichloroethene, 1,2-dichloroethene, 1,1,1-trichloroethane, 1,1,2-trichloroethene, chloroform, n-pentane, n-hexane, n-heptane, acetonitrile, propionitrile, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, methanol, ethanol, 1-propanol, isopropyl alcohol, n-butanol, 2-butanol, tert-butyl alcohol, 1-pentanol; acetic acid, carbon tetrachloride, benzene, cumene, cyclohexane, methylcyclohexane, dimethylacetamide, N,N- dimethylformamide, dimethyl sulfoxide(DMSO), ethyleneglycol, formamide, formic acid, 3-methyl-1-butanol, 2-methyl-1-propanol, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, isooctane, water or mixtures thereof.

Signature: __________ ___________ Dr. B.Dinesh kumar,
Intellectual Property Management,
Dr. Reddy’s Laboratories Limited.