DESC:The following specification particularly describes the invention and the manner in which it is to be performed.
PROCESS FOR THE PREPARATION OF INTERMEDIATE OF DEUCRAVACITINIB
FIELD OF THE INVENTION
The present application relates to process for the preparation of intermediate of deucravacitinib. The present application also relates to the process for the preparation of 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 present disclosure provides a simple and cost-efficient process for preparation of intermediate of deucravacitinib using metal alkoxide.

SUMMARY OF THE INVENTION
In an aspect, the present application provides a process for the preparation of a compound of Formula (II) comprising: reacting a compound of Formula (I) with Methan-d3-amine or its hydrochloride in presence of metal alkoxide to produce a compound of Formula (II).

In another aspect, the present application provides a process for the preparation of deucravacitinib using Formula II obtained from the above mentioned process.

DETAILED DESCRIPTION OF THE INVENTION
In an aspect, the present application provides a process for the preparation of a compound of Formula (II) comprising: reacting a compound of Formula (I) with Methan-d3-amine or its hydrochloride in presence of metal alkoxide to produce a compound of Formula (II).

The above reaction may be carried out in the presence of suitable metal alkoxide such as potassium tert-butoxide (KOtBu), sodium tert-butoxide (NaOtBu), sodium ethoxide (NaOEt), sodium methoxide (NaOMe), lithium methoxide (LiOMe), magnesium ethoxide (Mg(OEt)2), aluminum isopropoxide (Al(OiPr)3), aluminum sec-butoxide, titanium isopropoxide (Ti(OiPr)4), zirconium tert-butoxide (Zr(OtBu)4), hafnium tert-butoxide (Hf(OtBu)4), vanadium(V) ethoxide (VO(OEt)3) (or) niobium(V) ethoxide (Nb(OEt)5).
The above reaction may be carried out in the presence of suitable organic solvents such as dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), N, N-dimethyl acetamide (DMAc), tetrahydrofuran (THF), tertiary butanol, isopropyl alcohol, ethyl acetate, ethyl formate, methyl acetate, propyl acetate, isopropyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1,4-dioxane, methanol, ethanol, n-butanol, 1-propanol, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, toluene, xylene, chlorobenzene, tetralin, dichloromethane, chloroform, n-pentane, n-hexane, n-heptane or water or mixtures thereof.
The temperature at which the above reaction 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 reaction.
The removal of solvent 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: filtration, centrifugation, decantation, 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 or any other technique for the recovery of solids under pressure or under reduced pressure.
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.
In another aspect, the present application provides a process for the preparation of deucravacitinib using Formula II obtained from the above mentioned process.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following example, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.

Example 1: 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.
DMSO (30 mL), ethyl 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate (10 g), methan-d3-amine hydrochloride (2.358 g) and potassium tert-butoxide (5.77 g) were charged into a RBF at room temperature. The reaction mass was stirred for 5 minutes. Water (150 mL) was added to the reaction mass. The reaction mass was stirred for 30 minutes. The resultant suspension was filtered, and the filtered cake was washed with water. The obtained solid was dried under reduced pressure at a temperature of about 40°C for 5 hrs to afford the titled compound (91.12% yield)

Dated 25th day of Apr 2024 ¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬ Signature____________________
Dr. B. Dinesh Kumar
Dr. Reddy’s Laboratories Ltd
,CLAIMS:WE CLAIM:
1. A process for the preparation of compound of Formula (II), an intermediate of deucravacitinib comprising:
a) reacting a compound of Formula (I) with Methan-d3-amine or its salt in presence of metal alkoxide and suitable organic solvents to produce a compound of Formula (II).

2. The process as claimed in claim 1, wherein Methan-d3-amine salt in step a) is selected from hydrochloride, sulphate, phosphate, nitrate, citrate and acetate.
3. The process as claimed in claim 1, wherein metal alkoxide in step a) is selected from potassium tert-butoxide (KOtBu), sodium tert-butoxide (NaOtBu), sodium ethoxide (NaOEt), sodium methoxide (NaOMe), lithium methoxide (LiOMe), magnesium ethoxide (Mg(OEt)2), aluminum isopropoxide (Al(OiPr)3), aluminum sec-butoxide, titanium isopropoxide (Ti(OiPr)4), zirconium tert-butoxide (Zr(OtBu)4), hafnium tert-butoxide (Hf(OtBu)4), vanadium(V) ethoxide (VO(OEt)3) (or) niobium(V) ethoxide (Nb(OEt)5) or mixture thereof.
4. The process as claimed in claim 1, wherein organic solvents in step a) selected from dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), N, N-dimethyl acetamide (DMAc), tetrahydrofuran (THF), tertiary butanol, isopropyl alcohol, ethyl acetate, ethyl formate, methyl acetate, propyl acetate, isopropyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1,4-dioxane, methanol, ethanol, n-butanol, 1-propanol, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, toluene, xylene, chlorobenzene, tetralin, dichloromethane, chloroform, n-pentane, n-hexane, n-heptane or water or mixtures thereof.
5. A process for the preparation of deucravacitinib, comprising:
a) reacting a compound of Formula (I) with Methan-d3-amine or its salt in presence of metal alkoxide and suitable organic solvents to produce a compound of Formula (II).
b) converting compound of Formula (II) to deucravacitinib.