DESC:FIELD OF THE INVENTION
The present invention relates to a process for the preparation of deucravacitinib, or a pharmaceutically acceptable salt, or a solvate thereof. Further, the present invention relates to a novel intermediate compound and process for preparation thereof. More particularly, the present invention relates to use of the novel intermediate compound for the preparation of deucravacitinib, or a pharmaceutically acceptable salt, or a solvate thereof.

BACKGROUND OF THE INVENTION
Deucravacitinib (BMS-986165) is a selective tyrosine kinase 2 (TYK2) inhibitor approved by USFDA and marketed in the United States under the brand name SOTYKTU®. Deucravacitinib is structurally represented as a compound of Formula I as shown below:
.
International (PCT) Publication No. WO 2014/074661 A1 (WO ‘661) discloses deucravacitinib and process for preparation thereof.

International (PCT) Publication No. WO 2018/183649 A1 (WO ‘649) discloses a process for the preparation deucravacitinib.

International (PCT) Publication No. WO 2018/183656 A1 (WO ‘656) discloses process for the preparation deucravacitinib and a crystalline form thereof.

The journal article: Org. Process Res. Dev. 2022, 26, 4, 1202–1222 also discloses process for the preparation of deucravacitinib.

Still there is need to develop an alternative process that is economically viable and industrially scalable for preparing deucravacitinib.

SUMMARY OF THE INVENTION
In one general aspect, the present invention provides a process for the preparation of deucravacitinib of Formula I,

or a pharmaceutically acceptable salt, or a solvate thereof, the process comprising:
(a) reacting a compound of Formula VII or a hydrate thereof,

wherein X1 and X2 are independently halogen or sulfonate,
with a compound of Formula VI, or a salt thereof,

in the presence of a zinc salt, to obtain a compound of Formula IV,

wherein X2 is halogen or sulfonate;
(b) reacting the compound of Formula IV with a compound of Formula V,

to obtain a compound of Formula III; and

(c) reacting the compound of Formula III with a compound of Formula II, or a salt thereof,

to obtain deucravacitinib of Formula I, or a pharmaceutically acceptable salt, or a solvate thereof.

In another general aspect, the present invention provides a process for the preparation of a compound of Formula VII or a hydrate thereof,

wherein X1 and X2 are independently halogen or sulfonate, the process comprising:
reacting a compound of Formula VIII,

wherein R1 is C1-6 alkyl or aryl, and X1 and X2 are independently halogen or sulfonate; with barium salt in one or more solvents.

In another general aspect, the present invention provides a process for the preparation of deucravacitinib of Formula I,

or a pharmaceutically acceptable salt, or solvate thereof, the process comprising:
(a) reacting a compound of Formula VIIa or a hydrate thereof,

with a compound of Formula VI, or a salt thereof

in the presence of a zinc salt, to obtain a compound of Formula IVa;

(b) reacting the compound of Formula IVa with a compound of Formula V,

to obtain a compound of Formula III; and

(c) reacting the compound of Formula III with a compound of Formula II, or a salt thereof,

to obtain deucravacitinib of Formula I, or a pharmaceutically acceptable salt, or a solvate thereof.

In another general aspect, the present invention provides a compound of Formula VIIa or a hydrate thereof,

as an intermediate in the preparation of deucravacitinib.

The process of the present invention is a better alternative process that is economically viable and industrially scalable for preparing deucravacitinib or pharmaceutically acceptable salt thereof. Also, the present invention provides novel intermediate compound, which gives advantage by providing a product with better quality for final drug substance in terms of purity and yield.

DETAILED DESCRIPTION OF THE INVENTION
The invention can further be understood in light of the description of the embodiments provided herein after. It is to be understood that the description, in no way, is intended to limit the scope of the invention to the expressly specified embodiments only. The equivalents and variants thereof or trivial modifications thereof which are apparently obvious to those skilled in the art, are also intended to be included within the scope of the present invention.

Detailed description of routine and conventional unit operations, which are easily understood by the skilled artisan, are not included herein. Such routine unit operations are to be construed as ordinarily understood and as routinely practiced by the person skilled in the field of the invention, unless otherwise specifically described.

The following definitions are used in connection with present application, unless it is indicated otherwise.

In general, the term ‘reacting’ is used in their ordinary meaning as they are used in the field of the invention, unless defined specifically otherwise.

The terms ‘isolating’, ‘obtaining’ and ‘purifying’ are generally interchangeable, and include but not specifically limited to decantation, precipitation, extraction, filtration, evaporation, lyophilisation, spray drying, crystallization, recrystallization or chromatographic operations.

The term ‘optionally’ is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

The term ‘pharmaceutically acceptable’ means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and includes that which is acceptable for veterinary use and/or human pharmaceutical use.

The pharmaceutical acceptable salts of deucravacitinib of Formula I includes acid addition salts such as those formed from hydrochloric acid, hydrobromic acid, methanesulfonic acid, benzenesulfonic acid, sulfuric acid and the like.

The term ‘alkyl’ as used herein, unless otherwise specifically described, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, one or more of which may be substituted with hetero atom(s) independently selected from nitrogen, oxygen, and sulfur. The non-limiting examples of alkyl group includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, etc.

The numerical in phrases like “C1- 6alkyl”, refers that there are 1 to 6 carbon atoms in the alky chain.

The term ‘sulfonate’ as used herein, refers to a group having a structure represented by a formula -O-SO2R, wherein R is C1-6 alkyl, C3-10 cycloalkyl, aryl, or heteroaryl and wherein R is optionally further substituted with one or more groups selected from halogen, C1-6 alkyl, -NO2 and C3-10 cycloalkyl. The non-limiting examples of sulfonate group includes but not limited to mesylate, triflate, ethanesulfonate, tosylate, besylate, closilate, camphorsulfonate and nosylate.

The term ‘aryl’ as used herein, unless otherwise specifically described, refers to a substituted or unsubstituted aromatic cyclic hydrocarbon ring containing 6 to 15 carbon atoms. The non-limiting examples of aryl group includes phenyl, naphthyl, etc.

The term ‘halogen’ denotes fluorine, chlorine, bromine or iodine.

The product(s) obtained may further be purified to obtain them in purer form. The product(s) obtained may further be dried additionally to achieve desired level of moisture and/or residual solvents.

The product(s) obtained may further be converted to any other physical forms thereof which includes but not specifically limited to polymorph(s), salt(s), solvate(s), hydrate(s), co-crystal(s) or solid dispersion(s); and crystalline or amorphous forms thereof.

The product(s) obtained may further be subjected to physical processing which includes, but not limited to, pressing, crushing, triturating, milling or grinding to adjust the particle size of the product(s) to desired levels.

Thus, in one general aspect, the present invention provides a process for the preparation of deucravacitinib of Formula I,

or a pharmaceutically acceptable salt, or a solvate thereof, the process comprising:
(a) reacting a compound of Formula VII or a hydrate thereof,

wherein X1 and X2 are independently halogen or sulfonate,
with a compound of Formula VI, or a salt thereof

in the presence of a zinc salt, to obtain a compound of Formula IV,

wherein X2 is halogen or sulfonate;
(b) reacting the compound of Formula IV with a compound of Formula V,

to obtain a compound of Formula III; and

(c) reacting the compound of Formula III with a compound of Formula II, or a salt thereof,

to obtain deucravacitinib of Formula I, or a pharmaceutically acceptable salt, or a solvate thereof.

In general, the zinc salt used at step (a) is selected from zinc acetate, zinc bromide, zinc chloride, zinc nitrate, zinc sulfate, or hydrate thereof; or mixtures thereof. In particular, the zinc salt is zinc acetate. More particularly, the zinc salt is zinc acetate dihydrate.

In general, the step (a) is carried out in one or more solvents selected from water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, tert-butanol, acetonitrile, acetone, tetrahydrofuran, dimethylformamide, dimethylsulfoxide or mixtures thereof. In particular, the solvent is a mixture of 2-propanol and water. More particularly, the solvent is a mixture of tetrahydrofuran and water.

In one embodiment, each one of X1 and X2 in the compound of Formula VII is halogen. Particularly, each one of X1 and X2 is -Cl.

In another embodiment, X2 in the compound of Formula IV is halogen. Particularly, X2 in the compound of Formula IV is -Cl.

In general, the reaction of compound of Formula VII, or hydrate thereof with the compound of Formula VI or a salt thereof, can be carried out at a temperature ranging from room temperature to reflux temperature of the solvent used. Particularly, the reaction may be carried out at a temperature ranging from 40 °C to the reflux temperature of the solvent used. More particularly, the reaction may be carried out at a temperature ranging from 60 °C to 80 °C. The reaction may be carried out for a time sufficient for the completion of reaction. After completion of the reaction, the reaction mixture may be cooled and the compound of Formula IV may be isolated from the reaction mixture by any of the processes under common knowledge of a person skilled in the art like filtration or extraction.

In general, the step (b) is carried out in the presence of a suitable transition metal catalyst and optionally a ligand. The suitable transition metal catalyst for the purpose is a palladium catalyst selected from PdCl2, Pd(OAc)2, Pd(PPh3)4, PdCl2(CH3CN)2, PdCl2(PPh3)2, Pd2(dba)3, Pd(dba)2, [(Allyl)PdCl]2, Pd(dppf)Cl2 and [PdCl(crotyl)]2. The suitable palladium catalyst can also be selected from preform catalyst such as Josiphos SL-J009-1 Pd G3 or Josiphos SL-J009-2 Pd G3.

In general, a suitable ligand for the step (b) may be selected from Josiphos SL-J009-1, Josiphos SL-J009-2, Joshiphos SL-J002-1, Josiphos SL-J002-2, Josiphos SL-J003 and Josiphos SL-J004, XPhos, DPEphos, Xantphos, 1,1'-bis(diphenylphosphino)ferrocene (DPPF), DCyPF, BINAP, triphenylphosphine, tributylphosphine or derivatives thereof.

In general, the step (b) may be carried out in the presence of one or more bases and one or more suitable solvents.

In general, the one or more bases for the step (b) may be selected from potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium phosphate, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 1,1,3,3-tetramethylguanidine (TMG), 1,4-diazabicyclo[2.2.2]octane (DABCO), diisopropylethylamine (DIPEA), triethylamine, pyridine or mixtures thereof. Particularly, the base is potassium carbonate. More particularly, the base is a combination of potassium carbonate and DBU.

In general, the step (b) is carried out in the presence of one or more solvents selected from toluene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, xylene, N-methyl-2-pyrrolidone (NMP), N,N-dimethylformamide (DMF), dimethylacetamide (DMAc), or mixtures thereof. Particularly, the solvent is 1,4-dioxane. More particularly, the solvent is a mixture of toluene and acetonitrile.

In general, the reaction of compound of Formula III with the compound of Formula II or a salt thereof as per step (c) may be carried out in the presence of a coupling agent optionally in presence of a base. The coupling agent for the purpose is selected from 1,1'-carbonyldiimidazole (CDI), N,N’-dicyclohexylcarbodiimide (DCC), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) and hydroxybenzotriazole (HOBt), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), isobutyl chloroformate, ethyl chloroformate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP), N,N’-diisopropylcarbodiimide (DIC) and HOBt, propylphosphonic anhydride, or mixtures thereof. In particular, the coupling agent is 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) and hydroxybenzotriazole (HOBt).

In general, the reaction of compound of Formula III with the compound of Formula II or a salt thereof as per step (c) may be carried out in the presence of one or more solvents selected from acetonitrile, N-methyl-2-pyrrolidone (NMP), dichloromethane, chloroform, carbon tetrachloride, N,N-dimethylformamide (DMF), dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), tetrahydrofuran, ethyl acetate, 1,4-dioxane, 2-methyltetrahydrofuran, isopropyl acetate, or mixtures thereof. In particular, the solvent is a mixture of acetonitrile and N-methyl-2-pyrrolidone.

In general, the reaction of compound of Formula III with the compound of Formula II or a salt thereof as per step (c) may be carried out optionally in the presence of one or more bases. The one or more bases for the purpose may be selected from N-methylimidazole, N-methylpyrrolidine, triethylamine, diisopropylethylamine (DIPEA), 4-dimethylaminopyridine, N-methylmorpholine, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), pyridine or mixtures thereof. In particular the base is N-methylimidazole.

In another general aspect, the present invention provides a process for the preparation of deucravacitinib of Formula I,

or a pharmaceutically acceptable salt, or a solvate thereof, the process comprising:
(a) reacting a compound of Formula VII, or a hydrate thereof,

wherein X1 and X2 are independently halogen or sulfonate,
with a compound of Formula VI, or a salt thereof

in the presence of a zinc salt, to obtain a compound of Formula IV,

wherein X2 is halogen or sulfonate; and
(b) converting the compound of Formula IV to deucravacitinib of Formula I, or a pharmaceutically acceptable salt, or a solvate thereof.

In general, the reaction of compound of Formula VII or hydrate thereof with the compound of Formula VI or salt thereof can be carried out by following the processes as described supra.

In general, the compound of Formula IV can be converted to deucravacitinib of Formula I by following the processes as described supra. Alternatively, the compound of Formula IV can be converted to deucravacitinib of Formula I by following the analogous processes described in International (PCT) Publication No. WO 2018/183649 A1.

In another general aspect, the present invention provides a process for the preparation of a compound of Formula VII, or a hydrate thereof,

wherein X1 and X2 are independently halogen or sulfonate, the process comprising:
reacting a compound of Formula VIII,

wherein R1 is C1-6 alkyl or aryl, and X1 and X2 are independently halogen or sulfonate, with barium salt in one or more solvents.

In general, the barium salt for the reaction can be selected from one or more of barium chloride, barium bromide, barium acetate, barium hydroxide, barium sulfate or hydrates thereof. Particularly, the barium salt is barium chloride dihydrate.

In general, the reaction of the compound of Formula VIII with barium salt is carried out in one or more solvents optionally in the presence of one or more bases. The one or more solvents for the purpose are selected from water, acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane, 2-propanol, DMF, DMAc, NMP, or mixtures thereof. In particular, the solvent is a mixture of acetonitrile and water.

In general, the reaction of the compound of Formula VIII with barium salt is carried out optionally in the presence of one or more bases selected from triethylamine, diisopropylethylamine (DIPEA), 1,8-diazabicyclo(5.4.0)undec-7-ene, pyridine, 2,6-leutidine, N-methyl pyrrolidine, N-methyl piperidine, N-methyl morpholine, N,N-diethyl aniline, 4-dimethylaminopyridine (DMAP), or mixtures thereof. Particularly, the base is DIPEA.

In another embodiment, X1 and X2 in the compound of Formula VII or compound of Formula VIII are independently halogen. Particularly, X1 and X2 both are -Cl.

In another embodiment, R1 in the compound of Formula VIII is C1-6alkyl. Particularly, R1 in the compound of Formula VIII is methyl or ethyl.

In another embodiment, R1 in the compound of Formula VIII is methyl or ethyl, and X1 and X2 both are -Cl.

In general, the reaction of compound of Formula VIII with barium salt, can be carried out at a temperature ranging from 0 °C to 50 °C. Particularly, the reaction may be carried out at a temperature ranging from 20 °C to 40 °C. The reaction may be carried out for a time sufficient for the completion of reaction. After completion of the reaction, the compound of Formula VII or hydrate thereof may be isolated from the reaction mixture by any of the processes under common knowledge of a person skilled in the art like filtration or extraction.

The obtained compound of Formula VII or a hydrate thereof, was found to be highly pure i.e. purity of about 99% or more, by area percentage of HPLC. Particularly, the obtained compound of Formula VII or a hydrate thereof was having the purity of about 99.5% or more, or about 99.9 % or more by area percentage of HPLC.
In another general aspect, the present invention provides a process for the preparation of deucravacitinib of Formula I,

or a pharmaceutically acceptable salt, or a solvate thereof, the process comprising:
(a) reacting a compound of Formula VIIa, or a hydrate thereof,

with a compound of Formula VI, or a salt thereof,

in the presence of a zinc salt, to obtain a compound of Formula IVa,

(b) reacting the compound of Formula IVa with a compound of Formula V,

to obtain a compound of Formula III; and

(c) reacting the compound of Formula III with a compound of Formula II, or a salt thereof,

to obtain deucravacitinib of Formula I, or a pharmaceutically acceptable salt, or a solvate thereof.

In general, the reaction of compound of Formula VIIa or a hydrate thereof with the compound of Formula VI, or a salt thereof can be carried out in a manner as described supra for the reaction of compound of Formula VII with the compound of Formula VI, or a salt thereof.

Similarly, the reaction of the compound of Formula IVa with a compound of Formula V or a salt thereof, can be carried out in a manner as described supra for the reaction of compound of Formula IV with the compound of Formula V or a salt thereof.

In another general aspect, the present invention provides a compound of Formula VIIa or a hydrate thereof,
.
In another general aspect, the present invention provides a compound of Formula VIIa or a hydrate thereof, as an intermediate for the synthesis of deucravacitinib of Formula I.

In another general aspect, the present invention provides use of the compound of Formula VIIa or a hydrate thereof for the preparation of deucravacitinib of Formula I.

In one embodiment, the compound of Formula VIIa of the present invention is present in the form of a monohydrate.

In another embodiment, the present invention provides a compound of Formula VIIa or a hydrate thereof, with a purity of about 99 % or more, by area percentage of HPLC, for example about 99.5 % or more, about 99.9% or more, by area percentage of HPLC.

The product(s) obtained by the process of the present invention may further be purified to obtain them in purer forms. The product(s) obtained may further be dried additionally to achieve the desired level of moisture and/or residual solvents.

The product(s) obtained may further be converted to any other physical forms thereof which include but not limited to salt(s), solvate(s), hydrate(s), co-crystal(s) and solid dispersion(s) in either crystalline or amorphous forms.

The complete process for the preparation of deucravacitinib of the present invention can be depicted by the Scheme below:

The present invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modification and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in various publications.
Examples
Example 1: Preparation of Barium(II) 4,6-dichloropyridazine-3-carboxylate

To a solution of water (25 mL) and acetonitrile (30 mL) at 25°C to 35°C were charged barium chloride dihydrate (8.84 g, 36.23 mmol) followed by methyl 4,6-dichloropyridazine-3-carboxylate (5 g, 24 mmol). N,N-di-isopropylethylamine (12.48 ml, 72.46 mmol) was added and the reaction mixture was stirred at 25°C to 35°C. After completion of reaction, the solid was filtered and washed with acetonitrile (20 mL). The solid was dried at 45°C to 55°C to obtain barium(II) 4,6-dichloropyridazine-3-carboxylate in quantitative yield as monohydrate. 1H NMR (DMSO-d6, 400MHz): d 8.22 (s, 1H); 13C NMR (DMSO-d6, 100MHz): d 166.75, 159.48, 154.17, 135.94, 129.45.
Example 2: Preparation of zinc(II) 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate

A solution of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (4.5 g, 22 mmol) in isopropyl alcohol (4.5 mL) and water (31.5 mL) was added barium(II) 4,6-dichloropyridazine-3-carboxylate (6.25 g, 25 mmol) followed by zinc acetate dihydrate ( 4.83 g, 22 mmol) at 25°C to 35°C. The reaction mixture was heated at 65°C to 75°C and stirred at this temperature till the completion of reaction. After completion of reaction, water (31.5 mL) was charged and the reaction mixture was cooled to 25°C to 35°C. The solid was filtered and washed with water (54 mL) and THF (54 mL). The solid was dried at 60°C to 70°C to obtain zinc(II) 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate (7 g, 81%).
Example 3: Preparation of zinc (II) 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate

To a 100 mL pressure round bottom flask was charged acetonitrile (15 mL), toluene (27.5 mL), zinc(II) 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate (5 g, 12.75 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.9 mL, 12.74 mmol), cyclopropane carboxamide (2.71 g, 31.85 mmol) and potassium carbonate (6.33 gm, 45.86 mmol) at 25°C to 35°C. In another flask catalyst solution was prepared by dissolving palladium acetate (0.06 g) and josiphos (SL-J009) (0.25 g) in mixture of acetonitrile (5 mL) and toluene (10 mL) under nitrogen atmosphere. The resultant solution was degassed thoroughly and transferred into main reaction mixture. The main reaction mixture was degassed and the pressure flask was sealed. The reaction mixture was heated to 65°C to 75°C and the progress of reaction mixture was monitored by TLC. After completion of reaction, the reaction mixture was cooled to 20°C to 30°C and 1:1 mixture of acetic acid:water (25 mL) was added slowly. Acetic acid (52.5 mL) and n-heptane (35 mL) was charged into reaction mixture and stirred for 15 min. Aqueous layer was separated and diluted with water (30 ml). The reaction mixture was cooled to 15°C to 20°C and stirred for 2-3 hour. The solid was filtered and washed with 1:1 mixture of acetonitrile:water (50 mL) followed by acetonitrile (30 mL). The product was dried at 60°C to 70°C to obtain zinc(II) 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate (4.6 g, 82.6%).
Example 4: Preparation of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide

N-methyl imidazole (0.5 gm, 6.12 mmol) was charged into a solution of acetonitrile (4.5 mL), N-methyl pyrrolidone (11.25 ml). Deuterated methylamine (0.86 g, 12.24 mmol) and zinc(II) (4.5 g, 10.2 mmol) were added into reaction mixture at temperature 15°C to 20°C. The reaction mixture was heated to 40 °C to 50 °C and charged 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.HCl (2.73 g, 14.28 mmol) followed by 1-hydroxybenzotriazole (0.78 g, 5.10 mmol). The resultant reaction mixture was heated at 65 °C to 70 °C and stirred for 1 hour. Water (94.5 mL) and acetonitrile (13.5 mL) were charged into reaction mixture. The reaction mixture was cooled at -10 °C to 0 °C and stirred for 1 hour. The solid was filtered and washed with 1:2 acetonitrile:water mixture (13.5 mL), followed by acetonitrile (13.5 mL). The product was dried at 60 °C to 70 °C to obtain deucravacitinib (3.3 g, 76%).
Example 5: Preparation of barium(II) 4,6-dichloropyridazine-3-carboxylate monohydrate

To a solution of water (1300 mL) and barium chloride (306.8 g, 1255.98 mmol) at 20 °C to 35 °C were charged acetonitrile (1560ml) followed by methyl 4,6-dichloropyridazine-3-carboxylate (260 g, 1255.98 mmol). N,N-Di-isopropyl ethylamine (437.56 mL, 2511.96 mmol) was added and the reaction mixture was stirred at 20 °C to 35 °C for 5 hours. After completion of reaction, the reaction mixture was cooled at 0 °C to 10 °C. The solid was filtered and washed with acetonitrile (780 mL). The solid was dried at 50 °C to 60 °C to obtain barium(II) 4,6-dichloropyridazine-3-carboxylate monohydrate (299.5 g, 88.6%). HPLC purity: 99.95%. 1H NMR (DMSO-d6, 400MHz): d 8.22 (s, 1H); 13C NMR (DMSO-d6, 100MHz): d 166.75, 159.48, 154.17, 135.94, 129.45.

Example 6: Preparation of zinc(II) 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate

To a solution of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (160 g, 783.4 mmol) in tetrahydrofuran (320 mL) and water (960 mL) was added barium(II) 4,6-dichloropyridazine-3-carboxylate (261.95 g, 485.72 mmol) followed by zinc acetate (219.51 g, 783.43 mmol) at 25°C to 35°C. The reaction mixture was heated at 62 °C to 70 °C and stirred at this temperature till the completion of reaction. After completion of reaction, added DMF (320 mL) and stirred for 30 min. and then water (800 mL) were charged and the reaction mixture was cooled to 25 °C to 35 °C and stirred for 1 hour. The solid was filtered and washed with water (2 x 800 mL) and THF (2 x 800 mL). The solid was dried at 65 °C to 75 °C to obtain zinc(II) 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate (292.1 g, 95.0%). HPLC Purity: 99.15%.
Example 7: Preparation of zinc(II) 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate

To a 5L autoclave reactor, acetonitrile (750 mL), toluene (1250 mL), zinc(II) 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate (250 g, 318.5 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (96.98 g, 318.52 mmol), cyclopropane carboxamide (135.55 g, 1592.60 mmol) and potassium carbonate (308.15 g, 2229.64 mmol) were charged at 25 °C to 35 °C. The reaction mixture was degassed using nitrogen for 15 min to 30 minutes. In another flask with stringent exclusion of air, catalyst solution was prepared by dissolving palladium acetate (2.15 g, 9.56 mmol) and josiphos (SL-J009) (10.60 g, 19.11 mmol) in a mixture of acetonitrile (250 mL) and toluene (550 mL). The resultant solution was thoroughly degassed by purging nitrogen and transferred into main reaction mixture. The flask was rinsed with toluene (200 mL) and transferred into main reaction mixture. The main reaction mixture was degassed and the reactor was sealed. The reaction mixture was heated to 75 °C to 85 °C and stirred for 22 hours. After completion of reaction, the reaction mixture was cooled to 20 °C to 30 °C and a 1:1 mixture of acetic acid: water (1250 mL) was slowly added to it. Acetic acid (2500 mL) and n-heptane (1750 mL) were charged into the reaction mixture and stirred for 15 min. The aqueous layer was separated and diluted with water (1000 mL). Seed material (2.5 g) was added into reaction mixture and stirred for 1 hour. Additional water (500 mL) was added and the resultant slurry was stirred for 8-10 hours at 25 °C to 35 °C. The solid was filtered and washed with 1:1 mixture of acetonitrile: water (2500 mL) followed by washing with acetonitrile (2500 mL). The product was dried at 65 °C to 75 °C to obtain zinc(II) 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate (254.3 g, 90.8%). HPLC Purity: 98.21%.
Example 8: Preparation of deucravacitinib
N-methyl imidazole (220 g, 299.26 mmol) was charged into a solution of acetonitrile (220 mL), N-methyl pyrrolidone (550 mL). Deuterated methyl amine hydrochloride (42.22 g, 598.52 mmol) and zinc(II) 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate (220 g, 249.38 mmol) were added into reaction mixture at temperature 20 °C to 30 °C. The resultant slurry was heated to 60 °C to 70 °C. Hydroxybenzotriazole monohydrate (38.19 g, 249.38 mmol) was charged followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.HCl (133.85 g, 698.273.49 mmol) and flushed with acetonitrile (220 mL) The resultant reaction mass was stirred for 1 hour. After completion of reaction, water (220 mL) and acetonitrile (1320 mL) were charged into the reaction mixture. The reaction mixture was cooled at -5 °C to 5 °C and stirred for 4 hours. The solid was filtered and washed with 1:2 acetonitrile: water mixture (990 mL), followed by washing with acetonitrile (660 mL). The wet cake was unloaded. The wet cake and DMSO (880 mL) were charged in 1 L reactor, the reaction mass was heated at 65 °C to 75 °C and stirred it for 30 min. Ethanol (506 mL) was added into the reaction mass and seeded with deucravacitinib (1.6 g) at 65 °C to 75 °C. The reaction mass was stirred for 30 min at 65 °C to 75 °C. Then ethanol (1034mL) was further added at 55 °C to 75 °C. The reaction mass was cooled up to -5 °C to 5 °C and stirred for 4 hours. The solid was filtered and washed with ethanol (1320 mL). The product was dried at 60 °C to 70 °C to obtain deucravacitinib (143.5g, 67.94%).
HPLC Purity: 99.61%.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

,CLAIMS:We Claim:
1. A process for the preparation of deucravacitinib of Formula I,

or a pharmaceutically acceptable salt, or a solvate thereof, the process comprising:
(a) reacting a compound of Formula VII or a hydrate thereof,

wherein X1 and X2 are independently halogen or sulfonate,
with a compound of Formula VI, or a salt thereof,

in the presence of a zinc salt, to obtain a compound of Formula IV,

wherein X2 is halogen or sulfonate;
(b) reacting the compound of Formula IV with a compound of Formula V,

to obtain a compound of Formula III; and

(c) reacting the compound of Formula III with a compound of Formula II, or a salt thereof,

to obtain deucravacitinib of Formula I, or a pharmaceutically acceptable salt, or a solvate thereof.

2. The process as claimed in claim 1, wherein the step (a) is carried out in a solvent selected from water, methanol, ethanol, n-propanol, 2-propanol, n-butanol, tert-butanol, acetonitrile, acetone, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, or mixtures thereof.
3. The process as claimed in claim 1, wherein the zinc salt used at step (a) is selected from zinc acetate, zinc bromide, zinc chloride, zinc nitrate, zinc sulfate, or hydrates thereof, or mixtures thereof.
4. The process as claimed in claim 1, wherein the step (b) is carried out in the presence of a transition metal catalyst, base, and optionally a ligand in a solvent;
wherein the transition metal catalyst is a palladium catalyst selected from PdCl2, Pd(OAc)2, Pd(PPh3)4, PdCl2(CH3CN)2, PdCl2(PPh3)2, Pd2(dba)3, Pd(dba)2, [(Allyl)PdCl]2, and [PdCl(crotyl)]2; and
the ligand is a phosphine ligand selected from Josiphos SL-J009-1, Josiphos SL-J009-2, Joshiphos SL-J002-1, Josiphos SL-J002-2, Josiphos SL-J003 and Josiphos SL-J004, XPhos, DPEphos, Xantphos, 1,1'-bis(diphenylphosphino)ferrocene (DPPF), DCyPF, BINAP, triphenylphosphine, tributylphosphine, or derivatives thereof;
the base is selected from potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium phosphate, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 1,1,3,3-tetramethylguanidine (TMG), or mixtures thereof; and
the solvent is selected from toluene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, xylene, or mixtures thereof.
5. The process as claimed in claim 1, wherein the step (c) is carried out in the presence of a coupling agent, optionally base in a solvent;
wherein the coupling agent is selected from 1,1'-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI) and hydroxybenzotriazole (HOBt), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), isobutyl chloroformate, ethyl chloroformate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), or mixtures thereof;
the base is selected from N-methylimidazole, N-methylpyrrolidine, triethylamine, diisopropylethylamine (DIPEA), 4-dimethylaminopyridine, N-methylmorpholine, 1,8-diazabicyclo(5.4.0)undec-7-ene, or mixtures thereof; and
the solvent is selected from acetonitrile, N-methyl-2-pyrrolidone, dichloromethane, chloroform, carbon tetrachloride, N,N-dimethylformamide (DMF), dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, or mixtures thereof.
6. The process as claimed in clam 1, wherein X1 and X2 in the compound of Formula VII are independently -Cl, and X2 in the compound of Formula IV is -Cl.
7. A process for the preparation of a compound of Formula VII, or a hydrate thereof,

wherein X1 and X2 are independently halogen or sulfonate, the process comprising:
reacting a compound of Formula VIII,

wherein R1 is C1-6 alkyl or aryl, and X1 and X2 are independently halogen or sulfonate, with barium salt in a solvent.
8. The process as claimed in claim 7, wherein the barium salt is selected from barium chloride, barium bromide, barium acetate, barium hydroxide, barium sulfate, or hydrates thereof.
9. The process as claimed in claim 7, wherein the solvent is selected from water, acetonitrile, acetone, tetrahydrofuran, 1,4-dioxane, 2-propanol, N,N-dimethylformamide (DMF), dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), or mixtures thereof.
10. The process as claimed in claim 7, wherein the reaction is carried out optionally in the presence of a base selected from triethylamine, diisopropylethylamine (DIPEA), 1,8-diazabicyclo(5.4.0)undec-7-ene, pyridine, 2,6-leutidine, N-methyl pyrrolidine, N-methyl piperidine, N-methyl morpholine, N,N-diethyl aniline, 4-dimethylaminopyridine (DMAP), or mixtures thereof.
11. The process as claimed in claim 7, wherein the X1 and X2 in the compound of Formula VII are independently -Cl, and X1 and X2 in the compound of Formula VIII are independently -Cl, and R1 is methyl or ethyl.
12. A compound of Formula VIIa, or a hydrate thereof
.
13. The compound of Formula VIIa as claimed in claim 12, is in the form of a monohydrate.
14. A process for the preparation of deucravacitinib of Formula I,

or a pharmaceutically acceptable salt, or a solvate thereof, the process comprising:
(a) reacting a compound of Formula VII, or a hydrate thereof,

wherein X1 and X2 are independently halogen or sulfonate,
with a compound of Formula VI, or a salt thereof

in the presence of a zinc salt, to obtain a compound of Formula IV,

wherein X2 is halogen or sulfonate; and
(b) converting the compound of Formula IV to deucravacitinib of Formula I, or a pharmaceutically acceptable salt, or a solvate thereof.

Dated this 10th day of October 2023.

(HARIHARAN SUBRAMANIAM)
IN/PA-93
Of SUBRAMANIAM & ASSOCIATES
ATTORNEYS FOR THE APPLICANTS