DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Deucravacitinib of Formula-(I) having structure depicted below.

(I)
BACKGROUND OF THE INVENTION
Tyrosine kinase 2 (TYK2) is an intracellular signal transduction kinase that can mediate interleukin-23 (IL-23), interleukin-12 (IL-12) and type I interferon (IFN) These cytokines are involved in inflammation and immune response.

Deucravacitinib is the first and only new type of oral selective TYK2 inhibitor, clinically used to treat autoimmune and autoinflammatory diseases (such as psoriasis, psoriatic arthritis, lupus and inflammatory bowel disease, Crowe Grace, etc.). The results of a phase III clinical study of the drug announced in November 2020 showed that Deucravacitinib has shown positive clinical effects in the treatment of moderate to severe plaque psoriasis. In addition, Deucravacitinib also shows good therapeutic effects in the treatment of systemic lupus erythematosus and Crohn's disease.

The chemical name of Deucravacitinib is 6-[(cyclopropylcarbonyl)amino]-4-[[2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]-amino]-N-(methyl-d3), the structural formula is shown below, and is hereinafter referred to as "compound of Formula-(I)":

Formula-(I)

US RE 47929 discloses a process for the preparation of Deucravacitinib of Formula-(I) as illustrated in the scheme-I below. First, a compound of Formula-(VI) is reacted with compound of Formula-(VII) in the presence of lithium bis(trimethylsilyl )amide ( LiHMDS) in THF to obtain compound of Formula-(VIII). Compound of Formula-(VIII) is further reacted with cyclopropane carboxamide in the presence of catalyst Pd2(dba), Xantphos and cesium carbonate as a base in dioxane to obtain crude Deucravacitinib of Formula-(I), which is further purified by column chromatography.

Scheme-I:

The process disclosed in US RE 47929 suffers from the following disadvantages outlined below:
1. On higher scale production, column chromatographic purification techniques are time consuming and not viable as it requires huge quantity of organic solvents. The output quantity would be very low and is unviable on commercial scale.
2. Highly expensive catalyst like Pd2(dba) impacts overall cost of the product.
US 10899745 discloses a process for the preparation of Deucravacitinib of Formula-(I) as illustrated in the scheme-II below. First, a compound of Formula-(II) is reacted with POCl3 in the presence of triethylamine in toluene to obtain compound of Formula-(III). Thereafter, compound of Formula-(III) is reacted with LiBr in the presence of DIPEA in acetonitrile and water to obtain compound of Formula-(IVa), which is further reacted with compound of Formula-(VII) in the presence of Zn(AcO)2 in 2-propanol and water to obtain compound of Formula-(IX). Later, the compound of Formula-(IX) is reacted with cyclopropane carboxamide in the presence of catalyst Pd(Ac)2, Josiphos SL- 009-01 in the presence of DBU/ K2CO3 in toluene and acetonitrile to obtain compound of Formula-(X). Further, the compound of Formula-(X) is reacted with methyl-d3-amine hydrochloride in the presence of EDC HCl and HOBt in NMP/ ACN/ NMI solvents to obtain Deucravacitinib of Formula-(I).

Scheme-II:

The process disclosed in US 10899745 suffers from the following disadvantage outlined below:
1. Highly expensive Ligand like Josiphos SL- 009-01 impacts overall cost of the product.

WO2018183656A1 discloses Deucravacitinib crystal form A and its process for the preparation. WO2021129467A1 discloses two crystalline forms of Deucravacitinib (CSI and CSII) and process for the preparation of crystalline Form of CSI.

WO2021143498A1 discloses crystalline Form of Deucravacitinib (CSIII) and process for the preparation of crystalline Form of CSIII. WO2021055652A1 discloses Deucravacitinib dosage form comprising amorphous Deucravacitinib dispersed in a polymer matrix.

OBJECTIVE OF THE INVENTION

Keeping in view of the above disadvantages associated with the prior art processes disclosed in the literature for the preparation of Deucravacitinib of Formula-(I), the inventors of the present invention have developed a simple, economical and commercially viable process for production of Deucravacitinib of Formula-(I) by circumventing the above-mentioned disadvantages.

Accordingly, the main objective of the present invention is to provide an improved process for the preparation of Deucravacitinib of Formula-(I), which comprises simple, safe, economical and commercially viable process which surpasses the above-mentioned disadvantages.

SUMMARY OF THE INVENTION

One aspect of the present invention is to provide an improved process for the preparation of Deucravacitinib of Formula-(I),

Formula-(I)
comprising the steps of:
(i) reacting a compound of Formula-(II)

Formula-(II)

with a chlorinating agent in presence of a base in a suitable solvent to obtain compound of Formula-(III);

Formula-(III)

(ii) hydrolyzing the compound of Formula-(III) in-situ with a base to obtain compound of Formula-(IV);

Formula-(IV)

(iii) reacting the compound of Formula-(IV) with a chlorinating agent in presence of a catalyst in a suitable solvent to obtain compound of Formula-(V);

Formula-(V)

(iv) reacting the compound of Formula-(V) in-situ with methy-d3-amine hydrochloride in presence of a base in a suitable solvent to obtain compound of Formula-(VI)

Formula-(VI)

(v) condensing the compound of Formula-(VI) with a compound of Formula-(VII)

Formula-(VII)
in presence of a base in a suitable solvent to obtain compound of Formula-(VIII)

Formula-(VIII)
(vi) condensing the compound of Formula-(VIII) with cyclopropane carboxamide in presence of a catalyst and a base in a suitable solvent to obtain Deucravacitinib of Formula-(I).

Another aspect of the present invention provides a process for the preparation of crystalline Form-A of Deucravacitinib of Formula-(I), comprising the steps of:
a) treating crude Deucravacitinib with acid-base in a suitable solvent;
b) dissolving the product obtained in step-a) in a solvent;
c) adding an anti-solvent to the solution obtained in step-b);
d) seeding the reaction mixture with crystalline Form-A of Deucravacitinib of Formula-(I);
e) isolating crystalline Form-A of Deucravacitinib of Formula-(I).

Brief description of the drawings
FIG. 1 shows a representative X-ray powder diffraction (XRPD) pattern of
crystalline Form-A of Deucravacitinib of Formula-(I).
FIG. 2 shows a representative differential scanning calorimetry (DSC) thermogram
of crystalline Form-A of Deucravacitinib of Formula-(I).

Detailed Description of the Invention
The present invention provides a simple and cost-effective process for the preparation of Deucravacitinib of Formula-(I), comprising the steps of:
(i) reacting a compound of Formula-(II) with a chlorinating agent in presence of a base in a suitable solvent to obtain compound of Formula-(III);
(ii) hydrolyzing the compound of Formula-(III) in-situ with a base to obtain compound of Formula-(IV);
(iii) reacting the compound of Formula-(IV) with a chlorinating agent in presence of a catalyst in a suitable solvent to obtain compound of Formula-(V);
(iv) reacting the compound of Formula-(V) in-situ with methy-d3-amine hydrochloride in presence of a base in a suitable solvent to obtain compound of Formula-(VI);
(v) condensing the compound of Formula-(VI) with a compound of Formula-(VII) in presence of a base in a suitable solvent to obtain compound of Formula-(VIII);
(vi) condensing the compound of Formula-(VIII) with cyclopropane carboxamide in presence of a catalyst and a base in a suitable solvent to obtain Deucravacitinib of Formula-(I).

In step-(i) of the present invention, wherein the chlorinating agent is selected from POCl3, PCl5, thionyl chloride etc.,
In step-(i) of the present invention, wherein the base used is selected from triethylamine, diisopropylethylamine etc.,

In step-(i) of the present invention, wherein the suitable solvent used is selected from acetonitrile, toluene, sulfolane etc.,

In step-(i) of the present invention, wherein the temperature at which reaction carried out is 60°C to 85°C preferably 75-80°C.

In step-(i) of the present invention, the compound of Formula-(III) is purified by under vacuum or the compound of formula (III) can be used in the next reaction directly without further isolation.

In step-(ii) of the present invention, wherein the base is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, etc.,
In step-(ii) of the present invention, wherein the temperature at which reaction carried out at 0°C to 25°C preferably 5-10°C.

In step-(ii) of the present invention, the compound of Formula-(IV) is purified by acid-base treatment or formula-IV used in next step without purification.

In step-(ii) of the present invention, wherein the acid used in purification step of compound Formula-(IV) is selected from HCl, acetic acid, etc.,

In step-(ii) of the present invention, wherein the base used in purification step of compound Formula-(IV) is selected from NaOH, KOH, Na2CO3, etc.,

In step-(iii) of the present invention, wherein the chlorinating agent is selected from oxalyl chloride, thionyl chloride, etc.,

In step-(iii) of the present invention, wherein the catalyst is selected from DMF, etc.,

In step-(iii) of the present invention, the solvent is selected from dichloromethane, chloroform , toluene, etc.,

In step-(iii) of the present invention, the temperature at which reaction carried out at 0°C to 35°C preferably 25-30°C.

In step-(iii) of the present invention, the obtained compound of Formula-(V) can be used in the next reaction directly without isolation.

In step-(iv) of the present invention, wherein the base is selected from diisopropylethylamine (DIPEA), triethylamine etc.,

In step-(iv) of the present invention, the solvent is selected from dichloromethane, chloroform, toluene, etc.,

In step-(iv) of the present invention, wherein the temperature at which reaction carried out at 0°C to 25°C preferably 0-5°C.

In step-(iv) of the present invention, wherein the compound of Formula-(VI) is purified from organic solvent selected from ethyl acetate, toluene, acetone, acetonitrile, methyl tert-butylether, etc.,

In step-(v) of the present invention, wherein the base is selected from Lithium bis(trimethylsilyl)amide (LiHMDS), Sodium bis(trimethylsilyl)amide (NaHMDS), Potassium bis(trimethylsilyl)amide (KHMDS), etc.,
In step-(v) of the present invention, wherein the solvent is selected from THF, toluene , etc.,

In step-(v) of the present invention, wherein the temperature at which reaction carried out at 5°C to 30°C preferably 20-35°C.

In step-(v) of the present invention, the compound of Formula-(VIII) is purified by acid-base treatment by solvent selected from methanol, ethanol, isopropylalcohol, ethyl acetate, toluene, acetonitrile, acetone etc.,

In step-(v) of the present invention, wherein the acid used in acid-base treatment step is selected from HCl, acetic acid etc.,

In step-(v) of the present invention, wherein the base used in acid-base treatment step is selected from sodium hydroxide, potassium hydroxide, sodium carbonate , ammonia solution etc.,

In step-(v) of the present invention, wherein the compound of Formula-(VIII) is purified from organic solvent selected from alcohol solvent such as methanol, ethanol, propanol, isopropanol, butanol or mixture thereof.

In step-(vi) of the present invention, wherein the catalyst is selected from [1,1`-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)Pd(dppf)Cl2, Tris(dibenzylidene acetone) dipalladium Pd2(dba)3, palladium (II) acetate, Xantphos etc.,
In step-(vi) of the present invention, wherein the base is selected from potassium phosphate, potassium carbonate, Cesium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate etc.,

In step-(vi) of the present invention, wherein the solvent is selected from dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, etc.,

In step-(vi) of the present invention, wherein the temperature at which reaction carried out is 80°C to 140°C preferably 120°C-125°C.

In step-(vi) of the present invention, wherein Deucravacitinib of Formula-(I) can be isolated as crude compound.

Another aspect of the present invention provides a process for the preparation of crystalline Form-A of Deucravacitinib of Formula-(I), comprising the steps of:
a) treating crude Deucravacitinib with acid-base in a suitable solvent;
b) dissolving the product obtained in step-a) in a solvent;
c) adding an anti-solvent to the solution obtained in step-b);
d) seeding the reaction mixture with Crystalline form-A of Deucravacitinib of Formula-(I);
e) isolating crystalline Form-A of Deucravacitinib of Formula-(I).

In step-(a) of the present invention, the crude Deucravacitinib is purified by acid-base treatment step in a suitable solvent selected from acetonitrile, water, N,N-dimethylformamide, tetrahydrofuran, acetone, methanol, ethyl acetate, isopropyl alcohol, acetonitrile or mixture thereof.

In step-(a) of the present invention, the acid used in acid-base treatment step is selected from HCl, acetic acid etc.,

In step-(a) of the present invention, wherein the base used in acid-base treatment step is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, ammonia solution etc.,

In step-(a) of the present invention, wherein the temperature at which reaction carried out at 80°C to 140°C preferably 120°C-125°C.
In step-(b) of the present invention, wherein the solvent is selected from, DMSO and THF or mixture thereof.

In step-(b) of the present invention, wherein the temperature at which reaction carried out at 5°C to 40°C preferably 25-30°C.

In step-(c) of the present invention, wherein the anti-solvent is selected from alcohols such as methanol, ethanol, propanol, isopropanol, butanol, Iso-butanol or mixture thereof.
In step-(c) of the present invention, wherein the temperature at which reaction carried out at 5°C to 70°C preferably 60-65°C.

In step-(d) of the present invention, wherein the temperature at which reaction carried out at 0°C to 85°C preferably 60-75°C.

Advantages of the present invention:
1. The process of the present invention successfully avoids column chromatography for isolation of pure intermediates.
2. The process of the present invention successfully avoids flash and preparative HPLC which are expensive on commercial scale.
3. The process of the present invention successfully avoids usage of large volumes of organic solvent by avoiding chromatographic techniques.

Another aspect of the present invention is to provide crystalline Form-A of Deucravacitinib of Formula-1, which is characterized by:
i) Its powder X-ray diffractogram having peaks at about 10.0, 12.3, 15.7, 18.8, 19.2, 20.3, 21.6, 25.2, and 31.4± 0.2 degrees 2-theta.
ii) Its powdered X-ray diffraction pattern as shown in Figure-1.
iii) Its DSC thermogram as shown in Figure-2

Scheme-III: The process of present invention for the preparation of Deucravacitinib of Formula-(I), is shown below:

The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention
Examples:
Example-1: Preparation of 4,6-dichloropyridazine-3-carboxylic acid monohydrate of Formula (IV)
Charged 750 ml of acetonitrile and 150 g of Ethyl 4,6-dihydroxypyridazine-3-carboxylate of Formula-(II) into a 5.0L 4 necked RB flask equipped with a mechanical stirrer, thermometer socket, and condenser under stirring. The reaction mass was stirred for 5-10 min at 30 ± 5oC. Phosphorus oxychloride (POCl3) (325 g, 2.6 meq) was added to the reaction mass at 30 ± 5oC and cooled to 2.5 ±2.5 oC. Further, Triethylamine (149 g, 1.80 meq) was added to the reaction mass at 7.5 ±7.5 oC for 30-60 min and raised the reaction mass temperature to 80±2.5 oC in 60-90 min. The reaction mass was stirred at 80±2.5oC for 240-270 min. Thereafter, reaction mass was cooled to 2.5 ±2.5 oC and 300 ml of DM water was added to the reaction mass at 7.5 ±7.5 oC in 30-60 min. Further, Potassium phosphate buffer solution [dissolved 112.5 g of Dipotassium hydrogen orthophosphate and 22.5 g of potassium hydroxide in 1125 ml of DM water] was added to the reaction mass at 15 ±15 oC for 30-60 min and raised the mass temperature to 30 ± 5 oC and stirred for 20-30 min at 30 ± 5 oC. Ethyl 4,6-dichloropyridazine-3-carboxylate of Formula-(III) was extracted with 2x750 ml of methyl tert-butylether and washed the organic layer with Potassium phosphate buffer solution [dissolved 112.5 g of Dipotassium hydrogen orthophosphate and 22.5 g of potassium hydroxide in 1125 ml of DM water] at 30 ± 5 oC. Finally organic layer was washed with 600 ml of DM water at 30 ± 5 oC and cooled the organic layer containing Ethyl 4,6-dichloropyridazine-3-carboxylate of Formula-(III) to 7.5 ± 2.5oC. To the organic layer, 900 ml of ~3% of dilute sodium hydroxide solution [dissolved 34.2 g of sodium hydroxide in 900 ml of DM water] was added at 7.5 ±2.5 oC in 20-30 min and stirred the reaction mass at 7.5 ± 2.5oC for 75-90 min till obtain the Ethyl 4,6-dichloropyridazine-3-carboxylate content is below 0.1% by HPLC. The reaction mass was allowed to settled for 15-20 min , separated the lower aqueous layer at 7.5±2.5oC and adjusted the reaction mass pH to below 1.5 by using dil HCl solution [diluted 90 ml of conc HCl with 90 ml of DM water] at 7.5 ±2.5oC and stirred the mass for 60-90 min at 7.5 ±2.5 oC. The resulting product was filtered and washed with 150 ml of DM water. The wet compound was dried in hot air tray drier at 37.5 ±2.5oC till water content was below 10.0% w/w to get 150 g of 4,6-Dichloropyridazine-3-carboxylic acid monohydrate of Formula- (IV) (Yield: 87.2%) with 99.5% purity by HPLC.

Example-2: Preparation of 4,6-dichloro-N-(methyl-d3)-3-pyridazine carboxamide of Formula (VI).
Charged 2800 ml of methylene chloride and 140.0 g of 4,6-Dichloropyridazine-3-carboxylic acid monohydrate of Formula- (IV) into a 5.0 L 4 necked RB flask equipped with a mechanical stirrer, thermometer socket and condenser under stirring. The reaction mass was stirred for 5-10 min at 30 ± 5oC. Dimethylformamide (11.2 g; 0.23 meq) was added to the reaction mass at 30 ± 5 oC and cooled the reaction mass to 2.5 ±2.5 oC. Oxalyl chloride (186 g ; 2.2 meq) was added to the reaction mass, maintaining the mass temperature at 2.5 ± 2.5 oC in 30-60 min and further stirred for 10-15 min. Thereafter, the reaction mass temperature was raised to 27.5 ±2.5 oC and stirred for 60-90 min. The reaction mass was cooled to 2.5 ±2.5oC. Methyl-D3-amine HCl was added (50.7 g ;1.08 meq) to the reaction mass at 2.5 ±2.5oC and stirred for 20-30 min at 2.5 ±2.5 oC. N,N-Diisopropylethylamine (258 g ;3.0 meq) was added to the reaction mass, maintaining the mass temperature at 2.5 ± 2.5 oC in 30 -60 min and stirred for 120-150 min at 2.5 ±2.5oC. Further, 840 ml of DM water was added to the reaction mass at 2.5 ±2.5 oC for 30-45 min and stirred the reaction mass for 10-15 min at 2.5 ±2.5 oC. The reaction mass was allowed to settle for 10-15 min at 2.5 ±2.5 oC. The lower organic layer was separated and washed with 2x1400 ml of 5% sodium bicarbonate solution at 2.5 ±2. 5 oC. Finally organic layer was washed with 1400 ml of saturated sodium chloride solution. Organic layer was evaporated and crude mass was stripped with 2x280 ml of ethyl acetate. Further, 420 ml of Ethyl acetate was added to crude mass at 30 ±5°C. The temperature of the reaction mass was raised to 57.5 ±2.5 °C and stirred the reaction mass for 30-40 min at 57.5 ±2.5 °C. The reaction mass was cooled to 27.5 ±2.5 °C and stirred for 45-60 min. Further, the mass was cooled to 2.5 ±2.5°C and stirred for 45-60 min. The resulting product was filtered and washed with 90 ml of chilled ethyl acetate. The wet product was dried under vacuum at 37.5 ±2.5°C to get 90 g of 4,6-Dichloro-N-(methyl-d3)-3-pyridazinecarboxamide of Formula (VI) (Yield: 64.8%) with 99.5% purity by HPLC.
Example-3: 6-Chloro-4-[[2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) phenyl]amino]-N-(methyl-d3)-3-pyridazinecarboxamide of Formula-(VIII).
Charged 1062.5ml of Tetrahydrofuran and 85.0 g of 4,6-Dichloro-N-(methyl-d3)-3-pyridazinecarboxamide of Formula-(VI) into a 5.0 L 4 necked RB flask equipped with a mechanical stirrer, thermometer socket, condenser under nitrogen atmosphere. The reaction mass was stirred for 5-10 min at 30 ± 5oC. 2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)benzenamine (MMTA) of Formula- (VII) (83.0 g ; 1.0 meq) was added to the reaction mass at 30 ± 5oC and cooled the reaction mass to 22.5 ±2.5 oC. Lithium(bis) trimethylsilylamide (748.0 g; 3.0 meq) 25.0 w/w solution in THF was added to the reaction mass, maintaining the mass temperature at 22.5 ± 2.5 oC in 45-75 min and stirred the reaction mass for 120-150 min at 22.5 ± 2.5 oC till 4,6-Dichloro-N-(methyl-d3)-3-pyridazinecarboxamide content showed below 1.0% by HPLC. Dil HCl solution [diluted 108.8 g of conc. HCl with 935 ml of DM water] was added to the reaction mass at 22.5 ±2.5 oC and stirred the reaction mass for 20-30 min at 22.5 ±2.5oC. Tetrahydrofuran was distilled off from the reaction mass under reduced pressure (NLT 600 mm/Hg) and mass temperature not crossing 30oC. Further, 4250 ml of DM water was charged to reaction mass at 27.5 ±2.5oC and stirred the reaction mass for 60-75 min. The crude product was filtered and washed with 510 ml of DM water. The wet crude product was dried under vacuum (NLT 600 mm/Hg) at 52.5 ±2.5 °C. Crude product dry weight:110 g. Crude product was dissolved in 920 ml of aqueous HCl solution [260 ml of conc. HCl was diluted with 660 ml of DM water] and treated with 11 g of carbon activated at 30 ±5oC. The carbon was filtered off and clear filterate was collected in a 5.0 L 4 necked RB flask equipped with a mechanical stirrer, thermometer socket and condenser. The reaction mass was cooled to 17.5 ±2.5°C. The mass pH was adjusted to 11.5 with ~30% dilute sodium hydroxide solution at 22.5 ±7.5°C and stirred the reaction mass for 60-75 min at 27.5 ±2.5°C. The product was filtered and washed with 550 ml of DM water. Wet product was leached with 1320 ml of DM water and dried under vacuum (NLT 600 mm/Hg) at 52.5 ±2.5°C. Product dry weight ~ 100 g. Further, product was leached with 700 ml of methanol at 57.5 ± 2.5°C for 30-45 min, cooled the mass to 30 ± 5 °C and stirred for 30-45 min. Further, reaction mass was cooled to 2.5 ± 2.5°C and stirred for 60-75 min. The product was filtered and washed with 130 ml of chilled methanol. The obtained wet product was dried under vacuum (NLT 600 mm/Hg) at 52.5 ±2.5°C to get 101 g of 6-Chloro-4-[[2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)-phenyl]amino]-N-(methyl-d3)-3-pyridazinecarboxamide of Formula-(VIII) (Yield : 66%) with 99.3% purity by HPLC.

Example-4: Preparation of Deucravacitinib of Formula-(I).
Charged 1950 ml of 1,4-dioxane and 75.0 g of 6-Chloro-4-[[2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]amino]-N-(methyl-d3)-3-pyridazine carboxamide of Formula-(VIII) into a 5.0 L autoclave equipped mechanical stirrer, thermometer socket. Evacuated the autoclave twice with vacuum. Cyclopropanecarboxamide (33.9 g; 2.0 meq), potassium carbonate (55.0 g ; 2.0 meq) and Xantphos (17.28 g ; 0.15 meq) were added to the reaction mass at 30 ± 5oC. The reaction mass was purged with nitrogen for 15-20 min at 30 ± 5oC. Thereafter, 7.35 g of [1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium [Pd(dppf)Cl2] was added to the reaction mass at 30 ± 5oC and purged the reaction mass with nitrogen for 15-20 min at 30 ± 5oC. Sealed the autoclave. The temperature of the reaction mass was raised to 122.5 ±2.5oC and stirred the reaction mass temperature at122.5 ±2.5oC for 300-330 min obtain 6-Chloro-4-[[2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]amino]-N-(methyl-d3)-3-pyridazinecarboxamide below 0.2%. The reaction mass was cooled to 30 ±5oC, filtered the reaction mass on hyflo bed and washed with 375 ml of 1,4-dioxane. The filtrate was collected into a flask. 1,4-dioxane was distilled off from the reaction mass under vacuum (NLT 700 mm/Hg) mass temperature not crossing 60oC. The reaction mass was cooled to 30± 5oC. Further, 150 ml of DM water was added to reaction mass and stirred the reaction mass for 15-20 min at 30 ±5oC. To the reaction mass, 400 ml of acetonitrile was added at 30 ±5oC. The reaction mass temperature was raised to 62.5 ± 2.5°C and stirred for 30-45 min. Cooled the reaction mass to 27.5 ± 2.5°C and stirred for 30-45 min. Further the reaction mass was cooled to 7.5 ± 2.5°C and stirred for 60-75 min at 7.5 ± 2.5°C. The crude Deucravacitinib was filtered and washed with chilled (7.5 ± 2.5°C) aqueous acetonitrile [diluted 270 ml of DM water with 135 ml of acetonitrile] at 7.5 ±2.5°C. The wet cake was washed with 375 ml of acetonitrile. Wet weight of crude Deucravacitinib of Formula-(I) is ~105g.

Example-5: Preparation of Crystalline Form-A of Deucravacitinib of Formula-(I).
Crude Deucravacitinib of Formula-(I) 105 g was dissolved in 825 ml of DM water and 187.5 ml of conc HCl . The reaction mass was filtered on hyflo bed and washed the hyflo bed with dil HCl solution [diluted 142.5 ml of DM water with 45 ml of conc HCl]. The clear filtrate was collected into a 3.0 L 4 neck RB flask equipped mechanical stirrer, thermometer socket and addition flask. Further, 450 ml of dimethylformamide and 225 ml of tetrahydrofuran were added to reaction mass at 27.5 ±2.5oC. The reaction mass pH was adjusted to between 11.0 and 13.0 with 20% dilute sodium hydroxide solution at 27.5 ±2.5oC and stirred the reaction mass for 60-75 min at 27.5 ±2.5oC. The precipitated product was filtered and washed with 600 ml of DM water. Wet product was leached with 150 ml of DM water and 400 ml of acetonitrile mixture at 62.5 ± 2.5°C for 30-45 min and cooled the reaction mass to 27.5 ± 2.5°C for 45-60 min. Further, the reaction mass was cooled to 7.5 ± 2.5°C and stirred the mass for 45-60 min. The crude product was filtered and washed with 150 ml of acetonitrile, the wet Deucravacitinib crude product was dried under vacuum at 62.5 ±2.5 °C to constant weight. Yield: 65 g.

Charged 195 ml of Dimethyl sulfoxide and 65 g of Deucravacitinib into a 500 ml 4 neck RB flask equipped with a mechanical stirrer, thermometer socket and condenser. The reaction mass was raised to 82.5 ± 2.5°C and stirred for 30-40 min at 82.5 ± 2.5 °C. Remains as hazy mass was observed. Filtered the hazy mass on hyflo bed and washed with 65 ml of Dimethyl sulfoxide. The clear filtrate was collected into a pre heated of 2.0 L4 neck RB flask equipped with a mechanical stirrer, thermometer socket and condenser. The pre heated to 45-50 oC reaction mass was raised to 72.5 ± 2.5°C. Further, 260 ml of methanol was added at maintaining the reaction mass temperature 72.5 ± 2.5°C for 30-60 min and stirred the reaction mass for 5-10 min at 72.5 ± 2.5°C. Slightly hazy mass was observed. Deucravacitinib (0.65 g) was added to reaction mass at 72.5 ± 2.5 °C and stirred the reaction mass for 60-75 min at 72.5 ± 2.5°C. Remains as suspension mass. Added 1430 ml of methanol maintaining the mass temperature 67.5 ± 7.5°C for 30-60 min and stirred the reaction mass for 30-45 min at 67.5 ± 7.5°C. The reaction mass was cooled to 27.5 ± 2.5°C and stirred for 60-75 min at 27.5 ± 2.5°C. Further, the reaction mass was cooled to 2.5 ± 2.5°C and stirred for 60-75 min at 2.5 ± 2.5°C. The resulting product was filtered and washed with 195 ml of chilled methanol at 2.5 ±2.5°C. Wet product was leached with 2x 825 ml of DM water at 30 ± 5°C and dried under vacuum (NLT 700 mm/Hg) at 62.5 ±2.5°C till water content was not more than 0.40% w/w to get 59.1g of Crystalline Form-A of Deucravacitinib of Formual-(I) (Yield:69.8%) with 99.9% purity by HPLC.
,CLAIMS:We Claim:
1. A process for the preparation of Deucravacitinib of Formula-(I),

Formula-(I)

comprising the steps of:
(i) reacting a compound of Formula-(II)

Formula-(II)
with a chlorinating agent in presence of a base in a suitable solvent to obtain compound of Formula-(III);

Formula-(III)

(ii) hydrolyzing the compound of Formula-(III) in-situ with a base to obtain compound of Formula-(IV);

Formula-(IV)
(iii) reacting the compound of Formula-(IV) with a chlorinating agent in presence of catalyst in a suitable solvent to obtain compound of Formula-(V);

Formula-(V)

(iv) reacting the compound of Formula-(V) in-situ with methy-d3-amine hydrochloride in presence of a base in a suitable solvent to obtain compound of Formula-(VI);

Formula-(VI)

(v) condensing the compound of Formula-(VI) with a compound of Formula-(VII)

Formula-(VII)

in presence of a base in a suitable solvent to obtain compound of Formula-(VIII)

Formula-(VIII)

(vi) condensing the compound of Formula-(VIII) with cyclopropane carboxamide in presence of a catalyst and a base in a suitable solvent to obtain Deucravacitinib of Formula-(I).

2. The process as claimed in claim 1, wherein,
In step-(i) and (iii) of the present invention, the chlorinating agent used is selected
from POCl3, PCl5, thionyl chloride and oxalyl chloride.
In step-(i), (ii), (iv), (v) and (vi) of the present invention, wherein the base used is
selected from organic base or inorganic base. The organic base is selected from triethylamine, diisopropylethylamine, tertiary butylamine, 1,8-diazabicyclo (5.4.0)undec-7-ene (DBU), Lithium bis(trimethylsilyl)amide (LiHMDS), Sodium bis(trimethylsilyl)amide (NaHMDS), Potassium bis(trimethylsilyl) amide (KHMDS) or any other equivalent organic base. The inorganic base is selected from alkali and alkaline metal hydroxide and acetates or carbonates such as sodium hydroxide, potassium hydroxide, sodium acetate, sodium bicarbonate, sodium carbonate, potassium acetate, potassium bicarbonate, potassium carbonate, cesium carbonate, or any other equivalent base.
In step-(iii) and (vi) of the present invention, wherein the catalyst used is selected
from DMF, [1,1`-Bis(diphenylphosphino)ferrocene]dichloro palladium(II) Pd(dppf)Cl2, Tris(dibenzylidene acetone) dipalladium Pd2(dba)3, palladium (II) acetate, Xantphos.
In step- (i), (iii), (iv), (v) and (vi) of the present invention, the suitable solvent used
is selected from acetonitrile, toluene, sulfolane, dichloromethane, chloroform, toluene, ethyl acetate, acetone, methanol, ethanol, isopropanol, methyl tert-butyl ether, water or mixture thereof

3. A process for the preparation of Deucravacitinib of Formula-(I),

Formula-(I)
comprising the steps of:
(i) reacting a compound of Formula-(II)

Formula-(II)

with POCl3 in presence of triethylamine in acetonitrile to obtain compound of Formula-(III);

Formula-(III)
(ii) hydrolyzing the compound of Formula-(III) in-situ with NaOH to obtain compound of Formula-(IV);

Formula-(IV)
(iii) reacting the compound of Formula-(IV) with oxalyl chloride in presence of DMF as catalyst in dichloromethane to obtain compound of Formula-(V);

Formula-(V)

(iv) reacting the compound of Formula-(V) in-situ with methy-d3-amine hydrochloride in presence of diisopropylethylamine amine in dichloromethane to obtain compound of Formula-(VI);

Formula-(VI)
(v) condensing the compound of Formula-(VI) with a compound of Formula-(VII)

Formula-(VII)
in presence of Lithium bis(trimethylsilyl)amide (LiHMDS) in tetrahydrofuran to obtain compound of Formula-(VIII)

Formula-(VIII)
(vi) condensing the compound of Formula-(VIII) with cyclopropane carboxamide in presence of [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), Xantphos and potassium carbonate in 1,4-dioxan to obtain Deucravacitinib of Formula-(I).

4. A process for the preparation of crystalline Form-A of Deucravacitinib of Formula-(I), comprising the steps of:
a) treating crude Deucravacitinib with acid-base in a suitable solvent;
b) dissolving the product obtained in step-a) in a solvent;
c) adding an anti-solvent to the solution obtained in step-b);
d) seeding the reaction mixture with crystalline Form-A of Deucravacitinib of Formula-(I);
e) isolating crystalline Form-A of Deucravacitinib of Formula-(I).

5. The process as claimed in claim 4, wherein,
In step-(a) of the present invention, wherein the acid used in acid-base treatment
step is selected from HCl and acetic acid.
In step-(a) of the present invention, wherein the base used in acid-base treatment
step is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, ammonia solution.
In step-(a) of the present invention, wherein the suitable solvent is selected from
acetonitrile, water, N,N-dimethylformamide, tetrahydrofuran, acetone, methanol, ethyl acetate, isopropyl alcohol, acetonitrile or mixture thereof.

6. The process as claimed in claim 4, wherein, the solvent used in step-(b) is selected from DMSO and THF or mixture thereof.

7. The process as claimed in claim 4, wherein, the anti-solvent used in step-(c) is selected from methanol, ethanol, propanol, isopropanol, butanol, Iso-butanol or mixture thereof.

8. The intermediate compound of Formula-(IV)

Formula-(IV)