DESC:FIELD OF THE INVENTION
Present invention relates to an improved process for the preparation of Deucravacitinib as well as novel intermediates used in the process thereof.
BACKGROUND OF THE INVENTION
Deucravacitinib i.e. 6-(Cyclopropanecarbonylamido)-4-[2-methoxy-3-(1-methyl-1,2,4-triazol-3-yl) anilino]-N-(trideuteriomethyl)pyridazine-3-carboxamide, also known as SOTYKTU®, has following chemical structure:

SOTYKTU® is developed by Bristol Myers Squibb and approved by USFDA as tyrosine kinase-2 (TYK2) inhibitor indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
Deucravacitinib (or its salts) and/or the (pseudo)polymorphic forms thereof, along with their preparation methods are disclosed in multiple patent/non-patent references, for instance, not limited to USRE47929, WO2018183649A1, WO2018183656A1, WO2021129467A1, WO2021143498A1, WO2023102085A1, WO2021055652A1, WO2024017150A1, IN202221058490, WO2024236491A1, IN202321042975, IN202321042976, IN202341048682, Journal of Medicinal Chemistry (2019), 62(20), 8973-8995 and Org. Process Res. Dev. 2022, 26, 1202-1222.
The prior art processes pose multiple challenges in terms of stability of intermediates, use of expensive and corrosive reagents, low overall yield/purity and difficult handling & industrial non-scalability due to harsh reaction conditions.
Thus, there remains a need to provide commercially viable and advantageous processes for preparation of pure Deucravacitinib so as to tackle the challenges posed by earlier known processes.
The present invention addresses the challenges of prior art and provides a simple and efficient process which is economical and easy to handle in terms of safety and industrial level production. Active Pharmaceutical Ingredient (API) prepared by the present process is obtained in high yield and purity wherein unnecessary multiple purification steps are avoided.
SUMMARY OF THE INVENTION
The present invention provides an advantageous process for preparation of highly pure Deucravacitinib or intermediates thereof.
In a first aspect of the present application, a process for the preparation of Deucravacitinib is provided, wherein the said process comprises:
a) reacting a compound of formula II

wherein R4 & R5 are halogens, and x is selected from 0-4;
with a ‘first compound’ which is either selected from CD3NH2, compound of Formula I and compound of Formula IV

; and
b) reacting the compound obtained from step a) in any order with a ‘second compound’ and a ‘third compound’, which are independently selected from CD3NH2, compound of Formula I and compound of Formula IV; provided that the ‘first compound’, the ‘second compound’ and the ‘third compound ‘are different.
In a second aspect of the present application, a process for the preparation of compound of formula II is provided wherein; the said process comprises, reacting compound of formula VI

wherein R4 & R5 are halogens; and R3 is OX2 wherein X2 is selected from H or C1-C6 alkyl; with a Calcium source which is selected from calcium chloride (CaCl2), calcium bromide (CaBr2), calcium nitrate (Ca(NO3)2), calcium citrate, calcium malate, calcium carbonate, calcium formate, calcium oxide or calcium acetate (Ca(OAc)2) or any calcium source known in the literature, in a solvent, optionally in the presence of base.
In a third aspect, the present invention provides a compound of formula II,

wherein x can be selected from 0, 1, 2, 3, 4 and R4 & R5 are halogens.
Also, further aspect of the present invention provides highly pure Deucravacitinib with purity of more than 99 %.
DETAILED DESCRIPTION OF THE INVENTION
The process of the present invention overcomes the drawbacks of prior art by providing a synthetic method wherein the Deucravacitinib API is obtained using a novel intermediate in high yield and purity of more than 99 % (w/w), using mild reaction conditions. The process of the present invention is economical and industrially viable.
First embodiment of the present application provides a process for the preparation of Deucravacitinib which comprises:
a) reacting a compound of formula II

wherein R4 & R5 are halogens and x is selected from 0-4;
with a ‘first compound’ which is either selected from CD3NH2, compound of Formula I and compound of Formula IV

; and

b) reacting the compound obtained from step a) in any order with a ‘second compound’ and a ‘third compound’, which are independently selected from CD3NH2, compound of Formula I and compound of Formula IV; provided that the ‘first compound’, the ‘second compound’ and the ‘third compound ‘are different.
In further embodiment, compound of formula II is reacted sequentially with compound of Formula I, CD3NH2 and compound of Formula IV, to obtain Deucravacitinib.
In another embodiment, compound of formula II is reacted sequentially with compound of Formula I, compound of Formula IV and CD3NH2, to obtain Deucravacitinib.
In yet another embodiment, compound of formula II is reacted sequentially with compound of Formula IV, CD3NH2 and compound of Formula I, to obtain Deucravacitinib.
In yet one another embodiment, compound of formula II is reacted sequentially with CD3NH2, compound of Formula I and compound of Formula IV, to obtain Deucravacitinib.
In a preferred embodiment of the present application, a compound of formula IIa

wherein x is selected from 0-4;
a) compound of formula IIa is reacted with CD3NH2 or its salt, optionally in the presence of a reagent, to afford a compound of formula III or a salt or a hydrate thereof;

b) reacting the compound of formula III or a salt or a hydrate thereof, with the compound of formula I or a salt/hydrate thereof,

to afford compound of formula IIIa; and

c) reacting the compound of formula IIIa with a compound of formula IV or a salt or a hydrate thereof,

optionally in the presence of a suitable transition metal salt selected from zinc acetate, zinc chloride and/or zinc bromide, a catalyst and/or additives.
The reagent used in step a) is selected from POCl3, (COCl)2 and SOCl2.
Furthermore, the catalyst and/or additive used in step c) is selected from Pd2(dba)3, Pd2(dba)3.CHCl3, Pd(OAc)2, Xantphos, 1,1'-Bis(diphenylphosphino)ferrocene, 1,1- Bis(dicyclohexylphosphino)-ferrocene, N-acetyl cysteine, Josiphos SL-009-01 and/or 1,4- Bis(diphenylphosphino)butane.
In general, step a), b) and/or c) as mentioned above may be carried out optionally in the presence of an acid which is selected from acetic acid and/or hydrochloric acid and a base which is selected from cesium carbonate, N, N-diisopropylethylamine (DIPEA), triethylamine, ammonia and/or pyridine. Isolation/purification of the end product of these steps may also be done in the presence of the mentioned acid and/or base.
In a preferred embodiment, step a) takes place in the presence of an acid, wherein the compound of formula IIa first gets converted into its acid derivative.
Solvent used in above mentioned step a), b) and/or c) is selected from water, acetonitrile, 1-methyl-2-pyrrolidinone, acetic acid, ether solvents (For eg: tetrahydrofuran, 1,4-dioxane, diethyl ether, methyl tertiary butyl ether), chlorinated solvents (For eg: dichloromethane, chloroform) dimethylformamide, dimethyl sulfoxide, ester solvents (For eg: ethyl acetate), toluene, alcoholic solvents (For eg: methanol, ethanol, isopropanol) or mixture thereof.
Second embodiment of the present application provides the process for the preparation of compound of formula II:

which comprises, reacting compound of formula VI

wherein R4 & R5 are halogens (F, Cl, Br, I); and R3 is OX2 wherein X2 is selected from H or C1-C6 alkyl;
with a Calcium source which is selected from calcium chloride (CaCl2), calcium bromide (CaBr2), calcium nitrate (Ca(NO3)2), calcium citrate, calcium malate, calcium carbonate, calcium formate, calcium oxide or calcium acetate (Ca(OAc)2) or any calcium source known in the literature, in a solvent which is selected from water, dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, dichloromethane, methyl tertiary butyl ether, 1,4-dioxane, alcoholic solvents (For eg: methanol, ethanol, isopropanol), toluene or mixture thereof, optionally in the presence of base.
In general, the base used herein is selected from K2CO3, KOH, NaOH, N,N-diisopropylethylamine (DIPEA), triethylamine and/or pyridine.
Third embodiment of the present application provides a compound of formula II which is one of the intermediates used for the preparation of Deucravacitinib.

wherein x is selected from 0, 1, 2, 3, 4; and R4 & R5 are halogens (F, Cl, Br, I).
Preferably, the compound of formula II is represented by the compound of formula IIa and is as mentioned below.

According to the present invention process, Deucravacitinib obtained, is of high purity of about more than 99 % w/w, with the impurities of formula X, XI, XII being present in an amount of less than 0.15 % w/w.

Further alternative embodiments for the preparation of Deucravacitinib, it’s intermediates and/or it’s KSMs (Key starting materials) are described henceforth:
A process to prepare compound of formula VI’, that can be Deucravacitinib, comprising, reacting compound of formula VI with CD3NH2 or its salt;

wherein,
R4’ & R5’ are independently selected from the group comprising of halogens, sulfonates, NH2, OH, H, CN, amide, NHX1; wherein X1 is selected from -CO- C1-C6 alkyl, CO- C3-C8 cycloalkyl, C6-C8 aryl which are optionally substituted at one or more than one position by OH, alkoxy, 1-methyl-1,2,4-triazolyl, CONH2 or CN;
R3’ is independently selected from the group comprising of halogens and OX2’; wherein X2’ is selected from H, alkali metal cation, transition metal cation, C1-C6 alkyl or C6-C8 aryl.
In general, the reaction for preparation of compound of formula VI’ takes place in the presence of base, solvent and reagent.
The solvent used herein is selected from the group comprising of water, dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, dichloromethane, methyl tertiary butyl ether, 1,4-dioxane, alcoholic solvents (For eg: methanol, ethanol, isopropanol), toluene or mixtures thereof.
The reagent used herein is selected from the group comprising of ZnCl2, MnCl2, LiCl, LiBr, LiI, KCl, MgCl2, sodium trimethylsilanolate, potassium trimethylsilanolate, lithium trimethylsilanolate or mixture thereof
The above reaction is carried out optionally in the presence of a base; wherein the base is selected from the group comprising such as K2CO3, KOH, NaOH, N,N-diisopropylethylamine (DIPEA), triethylamine and/or pyridine and the like.
Further, when R3’= OX2’, wherein X2’ is C1-C6 alkyl or C6-C8 aryl, then the compound of formula VI first converted either into its acid derivative or metal salt followed by activating the same with activating agents which reacted with CD3NH2 or its salt to provide compound of formula VI’ using above mentioned reaction conditions.
The acid derivative or itsmetal cation of compound of formula VI can be optionally isolated or directly taken in-situ for preparation of compound of formula VI’.
The activating agent used in the above reaction is selected from the group comprising of POCl3, PBr5, PBr3, POBr3, (COCl)2, SOCl2 and/or PCl5 or the like.
The reagents for conversion into metal salt is selected from the group comprising ZnCl2, MnCl2, KCl, MgCl2, sodium trimethylsilanolate, potassium trimethylsilanolate and the like and combinations thereof.
Further, if the compound of Formula VI’ does not represent Deucravacitinib, i.e., when R4’ is other than C6-C8 aryl optionally substituted in two position by alkoxy and 1-methyl-1,2,4-triazolyl and R5 is other than NHX1 wherein X1 is -CO-C3-C8 cycloalkyl; then by chemical transformations, it can be transformed to Deucravacitinib, by the process of the present invention or the chemistry known in literature.
A process for preparing a compound of formula III’, comprising: reacting compound of formula I’ with the compound of formula II’;

wherein,
R1 is independently selected from the group comprising of 1-methyl-1,2,4-triazol-, -CONH2 or -CN; and
R2 is independently selected from group comprising of -NHX1, -OX1, sulphonic ester or sulfonamide; wherein X1 is selected from the group comprising optionally deuterated C1-C6
alkyl, hydrogen, metal cation or the like.
The process of preparing compound of formula III’ as per above reaction is carried out in presence of water, one or more organic solvents such as polar aprotic solvents (e.g. tetrahydrofuran, dimethylformamide, dimethyl sulfoxide), 1,4-dioxane, C1-C6 alcohols (for e.g. methanol, ethanol, IPA) or combinations thereof.
The process of preparing compound of formula III’ by reaction of compound of formula I’ with compound of formula II’ is optionally carried out in presence of an acid such as acetic acid, hydrochloric acid or the like or a base such as trimethylamine, DIPEA or an additive selected from group comprising of LiHMDS, trimethylolpropane, zinc acetate, LiCl, NaCl, KCl or MgCl2 at a suitable temperature.
The present disclosure or invention also provides the reaction of a compound of formula III’ with a compound of formula IV to provide a compound of formula V.

wherein, R1, R2 are as defined earlier.
The process of preparing compound of formula V as per above reaction is carried out in presence transition metal salts such as zinc acetate, zinc chloride or zinc bromide, with or without bases such as cesium carbonate and optionally a catalyst and/or additives, wherein the catalyst is selected from palladium catalyst not limited to Pd2(dba)3, Pd2(dba)3.CHCl3, Pd(OAc)2 and additive is selected from xantphos, 1,1'-Bis(diphenylphosphino)ferrocene, 1,1-Bis(dicyclohexylphosphino)-ferrocene, N-acetyl cysteine, josiphos SL-009-01 and/or 1,4- Bis(diphenylphosphino)butane or metal alkylcarboxylate.
The process of preparing compound of formula V and its isolation as per above reaction is carried out in a solvent selected from a group comprising of water, 1-methyl-2-pyrrolidinone, acetic acid, ether solvents such as 1,4- dioxane, chlorinated solvents such as MDC, ester solvents such as ethyl acetate, aromatic hydrocarbon such as toluene, alcoholic solvents (For example: methanol, ethanol and isopropanol) or a combination thereof.
The process of preparing compound(s) of formula V by reaction of compound of formula III’ with compound of formula IV as per above reaction can optionally be carried out in absence of an alkali metal base, at a suitable temperature.
Further, if the compound of Formula V does not represent Deucravacitinib; then by chemical transformations at any stage(s) as mentioned above, it can be transformed to Deucravacitinib, by the process of the present invention or the chemistry known in literature.
The present disclosure or invention further provides a process of preparing the compound of formula IX comprising, reacting compound of formula VII and VIII in the presence of catalyst as mentioned below or by any literature known in the prior art.

wherein,
R6 is independently selected from CONH2 or CN; and
R7 is independently selected from NO2, halogens and NH2.
The catalyst used herein is selected from transition metal catalyst which is selected from the group comprising of Cu(I), Cu(II), Zn(II) and the like.
The above reaction can be carried out in presence of one or more bases and one or more suitable solvents, wherein the base is selected from the group comprising of potassium carbonate, sodium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, LiHMDS, NaHMDS, KHMDS, N-butyllithium, LDA, triethylamine, diisopropylethylamine, DABCO or DBU and the like or combinations thereof; and the one or more reaction and/or isolation solvent is selected from the group comprising of water, DMF, DMSO, N, N-dimethylacetamide, ethyl acetate, N-methylpyrrolidone, acetonitrile, THF, 2-methyltetrahydrofuran, 1,4-dioxane or toluene, C1-C6 alcohols for e.g. methanol, ethanol, IPA or combinations thereof.
In general, all the intermediates are isolated or kept in-situ and taken in the next step directly and starting material/KSM used may be solid/isolated material or they may be used in-situ (in solution) from the reaction wherein they have been synthesized.
Starting materials for the present invention is obtained from any process known in prior art or the general modifications of the same as known to a medicinal chemist. All the reactants/reagents/solvents used in this process are added as a single batch or in lot-wise manner.
As per the present invention, Deucravacitinib is isolated as a solid material from the suspension and/or solution by filtration or by decantation or by any suitable method known in prior art. The solid form of Deucravacitinib is dried under ambient conditions or under vacuum.
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. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
EXAMPLES
Example-1a: Preparation of Calcium (II) 4,6-dichloropyridazine-3-carboxylate

Calcium chloride was taken in acetonitrile and water at room temperature (RT) and the reaction temperature was cooled to 5-15 °C. Ethyl 4,6-dichloropyridazine-3 carboxylate in acetonitrile was then added dropwise to the reaction mass at 5-15 °C followed by the addition of DIPEA. The reaction temperature was raised to 15-20 °C then the reaction was continued until the complete conversion was observed. Reaction mass was filtered under vacuum, to obtain the title compound as a brown solid.
NMR:
1H NMR (500 MHz, DMSO-d6) & 8.23 (s, 1H).
13C NMR (100 MHz, DMSO-d6) & 164.44, 161.53, 152.28, 134.37, 128.16. LC-MS m/z: 192.19 [M+H] +.
Example-1a’: Preparation of 4,6-dichloropyridazine-3-carboxylic acid

Calcium chloride was taken in acetonitrile and water at RT and stirred. Ethyl 4,6-dichloropyridazine-3 carboxylate in acetonitrile was then added dropwise to the reaction mass at 5-15 °C followed by the addition of DIPEA. The reaction temperature was raised to 25-30 °C then the reaction was continued until the complete conversion was observed and adjusted the pH using HCl. Reaction mass was filtered under vacuum, to obtain the title compound as a solid.
Example -1b: Preparation of 4,6-Dichloro-N-(methyl-d3)-3-pyridazinecarboxamide

4,6-dichloropyridazine-3-carboxylic acid and DCM was taken in RBF and cooled. Oxalyl chloride was added to the reaction mass at RT and added DMF. The reaction temperature was raised to reflux then continued at reflux until the complete conversion was observed. Reaction mass was evaporated under vacuum, followed by dilution with MDC. DIPEA was added followed by methyl(d3) amine. HCl addition to the reaction mass and the reaction was continued till the reaction complies. Reaction was then quenched with water followed by layer separation. Organic layer was evaporated followed by purification to get 4,6-dichloro-N-(methyl-d3)-3-pyridazinecarboxamide as a solid.
Example -1b’: Preparation of 4,6-Dichloro-N-(methyl-d3)-3-pyridazine carboxamide

Calcium (II) 4,6-dichloropyridazine-3-carboxylate monohydrate and toluene was taken in RBF equipped with dean’s stark distillation and the toluene was evaporated up to 1.0 vol. Oxalyl chloride was charged to the reaction mass at RT and the reaction temperature was raised to reflux then continued at reflux until the complete conversion was observed. Reaction mass was evaporated under vacuum, followed by dilution with MDC. DIPEA was added followed by methyl(d3) amine. HCl to the reaction mass and continued the reaction till the reaction complies. Reaction was then quenched with followed by layer separation. Organic layer was evaporated followed by purification to get 4,6-Dichloro-N-(methyl-d3)-3-pyridazinecarboxamide as a brown solid.
Example-1c: Preparation of 4-(2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) phenylamino)-6-chloro-N-methyl-d3 pyridazine-3-carboxamide

Option 1: 4,6-Dichloro-N-(methyl-d3)-3-pyridazinecarboxamide was taken in IPA at RT. Subsequently 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline was charged to the reaction mass at RT followed by which IPA.HCl was added to the reaction mixture. The reaction temperature was raised to 70-80 °C and maintained until the complete conversion was observed. Reaction mixture was gradually cooled to RT and then stirred for some time. Reaction mass was filtered under vacuum to obtain the title compound as a solid.
Option 2: 2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (1.0 eq.) was taken in water at RT and lithium chloride was charged to the reaction mass; subsequently 4,6-Dichloro-N-(methyl-d3)- 3-pyridazinecarboxamide (1.0 eq.) was charged to the reaction mass at RT followed by which IPA was added to the reaction mixture. The reaction temperature was raised to 60-70 °C. Reaction mixture was gradually cooled to RT and then stirred for 1 hour. Reaction mass was filtered under vacuum to obtain the title compound (with 85% yield) as an off-white solid.
Option 3: 2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (1.0 eq.) was taken in water at RT. Subsequently 4,6-Dichloro-N-(methyl-d3)-3-pyridazinecarboxamide (1.0 eq.) was charged to the reaction mass at RT followed by which IPA was added to the reaction mixture. The reaction temperature was raised to 60-70 °C and maintained until the complete conversion was observed. Reaction mixture was gradually cooled to RT and then stirred for 1 hour. Reaction mass was filtered under vacuum to obtain the title compound (with 84% yield) as an off-white solid.
Option 4: 2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (1.0 eq.) was taken in water at RT and subsequently 4,6-Dichloro-N-(methyl-d3)-3-pyridazinecarboxamide (1.0 eq.) was charged to the reaction mass at RT. The reaction temperature was raised to 60-70 °C. Reaction mixture was gradually cooled to RT and then stirred for 1 hour. Reaction mass was filtered under vacuum to obtain the title compound (with 86% yield) as an off-white solid.
Option 5: 2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (1.0 eq.) was taken in IPA at RT and subsequently 4,6-Dichloro-N-(methyl-d3)-3-pyridazinecarboxamide (1.0 eq.) was charged to the reaction mass at RT. The reaction temperature was raised to 60-70 °C. Reaction mixture was gradually cooled to RT and added TEA and then stirred. Reaction mass was filtered and washed and dried under vacuum to obtain the title compound (with 60-70% yield) as an off-white solid.
Example-1d: Preparation of Deucravacitinib

Option 1: 4-(2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-6-chloro-N-methyl-d3 pyridazine-3-carboxamide was taken in 1,4-Dioxane at RT. Cyclopropanecarboxamide and cesium carbonate were charged to the reaction, followed by Xantphos and Pd2(dba)3. The reaction temperature was raised to 90-100 °C. Reaction mixture was filtered and solvent evaporated completely under vacuum. Residue was dissolved with MDC. Ethyl acetate was added to the residue and heated to the 65 °C and stirred for 30 minutes. Solid slurry was gradually cooled to RT and stirred to obtain Deucravacitinib as an off-white solid having purity 99.7 %.
Option 2: 4-(2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-6-chloro-N-methyl-d3 pyridazine-3-carboxamide (1.0 eq.) was taken in 1,4-Dioxane at RT followed by which cyclopropanecarboxamide and Zn(OAc)2 were charged to the reaction. To the reaction mass was added Xantphos and Pd2(dba)3. The reaction temperature was raised to 90-100 °C. Reaction mass was filtered through hyflow bed and filtrate was evaporated completely under vacuum to obtain Deucravacitinib (with 75% yield) as an off- white solid having purity 99.8 %.
Option 3: 4-(2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenylamino)-6-chloro-N-methyl-d3 pyridazine-3-carboxamide was taken in 1,4-Dioxane at RT. Cyclopropanecarboxamide and cesium carbonate were charged to the reaction, followed by 1,1-Bis(dicyclohexylphosphino)-ferrocene and Pd2(dba)3. The reaction temperature was raised to 90-100 °C. Reaction mixture was filtered and solvent evaporated completely under vacuum. Residue was dissolved with MDC. Ethyl acetate was added to the residue and heated to the 65 °C and stirred for 30 min. Solid slurry was gradually cooled to RT and stirred to obtain Deucravacitinib as an off-white solid having purity 99.9 %.
PXRD and DSC pattern of the crystalline material as obtained in this example were also recorded.
Example-2a: Preparation of Calcium (II) 6-chloro-4-((2-methoxy-3-(1-methyl- 1H- 1,2,4-triazol-3-yl) phenyl) amino) pyridazine-3-carboxylate

2-Methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline was taken in IPA at RT. Subsequently Calcium (II) 4,6-dichloropyridazine-3-carboxylate was charged to the reaction mass at RT. The reaction temperature was raised to 60-70 °C and continued until the complete conversion was observed. Reaction mixture was gradually cooled and stirred. Reaction mass was filtered under vacuum to obtain the title compound as an off-white solid.
NMR:
1H NMR (500 MHz, DMSO-d6) & 14.12 (bs, 1H), 10.22 (s, 1H), 8.56 (s, 1H), 7.77-7.75 (dd, 1H), 7.61-7.58 (dd, 1H), 7.30 (t, 1H), 7.15 (s, 1H), 3.97 (s, 3H), 3.67 (s, 3H).
13C NMR (100 MHz, DMSO-d6) & 167.6, 158.71, 156.54, 145.60, 145.17, 136.90, 131.33, 127.47, 126.25, 124.64, 124.47, 108.26, 61.16, 36.03. LC-MS m/z: 360.86 [M+H] +.
Example-2b: Preparation of Calcium (II) 6-(cyclopropanecarboxamido)-4-((2- methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) phenyl) amino) pyridazine-3- carboxylate

Calcium (II) 6-chloro-4-((2-methoxy-3-(1-methyl-1H- 1,2,4-triazol-3-yl) phenyl) amino) pyridazine-3-carboxylate was taken in 1,4-dioxane at RT followed by charging of cyclopropanecarboxamide and Zn(OAc)2 to the reaction. The reaction mass was degassed, followed by the charging of Xantphos and Pd2(dba)3 to the reaction mass. The reaction temperature was raised to 90-100 °C and then continued until the complete conversion. The reaction mass was charged with acetic acid and filtered through celite and filtrate was evaporated completely under vacuum to obtain the title compound as an off-white solid.
Example-2c: Preparation of Deucravacitinib

N-methyl imidazole was charged into a solution of acetonitrile and N-methyl pyrrolidone. Deuterated methylamine and 6- (cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) phenyl) amino) pyridazine-3- carboxylic acid were added into reaction mixture at RT. The reaction temperature was raised to 40 °C to 50 °C and charged 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide. HCl followed by 1- hydroxybenzotriazole to the reaction. The reaction mixture was heated at 65 °C to 70 °C and stirred for 1 hour. Water and acetonitrile were charged into reaction mixture. The reaction mixture was cooled at and stirred. The solid was filtered and washed with acetonitrile. The product was dried at to obtain Deucravacitinib.
PXRD and DSC pattern of the crystalline material as obtained in this example were also recorded.
Further below are few more examples to prepare Deucravacitinib as well its intermediate(s) and KSM(s):
Example-A: Preparation of 4,6-Dichloro-N-(methyl-d3)-3- pyridazinecarboxamide

Lithium bromide was taken in acetonitrile at RT and the reaction temperature was cooled to -20 to -30 °C. Ethyl 4,6-dichloropyridazine-3-carboxylate in acetonitrile was added dropwise to the reaction mass followed by DIPEA. Then the reaction was continued until the complete conversion was observed. Reaction mass was quenched with water and extracted with ethyl acetate, followed by which organic layer was evaporated to obtain the title compound as a brown solid.
Example-B: Preparation of 4,6-Dichloro-N-(methyl-d3)-3-pyridazinecarboxamide

Lithium 4,6-dichloropyridazine-3-carboxylate was taken in oxalyl chloride at RT and the reaction temperature was raised to reflux then continued the reaction at reflux until the complete conversion was observed. Reaction mass was evaporated under vacuum, followed by dilution with MDC. DIPEA was added followed by the addition of methyl(d3) amine. HCl and the reaction was continued till the reaction complies. Reaction was quenched with water and mass temperature was increased to RT followed by layer separation. Organic layer was evaporated followed by purification to get title compound as a brown solid.
Example-C: Preparation of Potassium (I) 4,6-dichloropyridazine-3-carboxylate

Potassium trimethylsilanolate was taken in acetonitrile at RT and the reaction temperature was cooled to 5-15 °C. Ethyl 4,6-dichloropyridazine-3-carboxylate in acetonitrile was added dropwise to the reaction mass at 5-15 °C. The reaction temperature was raised to 15-20 °C then continued until the complete conversion was observed. Reaction mass was filtered under vacuum, to obtain the title compound as an off-white solid.
NMR:
1H NMR (500 MHz, DMSO-d6) & 8.23 (s, 1H).
13C NMR (100 MHz, DMSO-d6) & 164.44, 161.53, 152.28, 134.37, 128.16. LC-MS m/z: 192.19 [M+H] +.
Example-D: Preparation of Potassium (I) 4,6-dichloropyridazine-3-carboxylate

Potassium trimethylsilanolate was taken in acetonitrile at RT and the reaction temperature was cooled to 5-15 °C. Ethyl 4,6-dichloropyridazine-3-carboxylate in acetonitrile was added dropwise to the reaction mass. The reaction temperature was raised then continued until the complete conversion was observed. IPA. HCl was added to the reaction mass to make the reaction mass pH to 5-6 and the reaction mass was evaporated under vacuum to obtain the title compound as an off-white solid.
Example -E: Preparation of 3-(3-bromo-2-methoxyphenyl)-1-methyl-1H-1,2,4-triazole.

To a solution of 2-methoxy-3-bromobenzonitrile and N-Methyl-N-formyl hydrazine in DMSO, cesium carbonate followed by copper(I) bromide was added. Mass was stirred for about 12 hours at 100°C. Reaction mass was cooled to RT and celite filtered. Charged water and extracted with ethyl acetate. Organic layer was concentrated and dried to afford the title compound as a brown solid.
Example -F: Preparation of 4,6-Dichloro-N-(methyl-d3)-3-pyridazinecarboxamide

Potassium (I) 4,6-dichloropyridazine-3-carboxylate was taken in oxalyl chloride at RT and the reaction temperature was raised to reflux then continued the reaction at reflux until the complete conversion was observed. Reaction mass was evaporated under vacuum, followed by dilution with MDC. DIPEA was added followed by methyl(d3) amine. HCl to the reaction mass and continued the reaction till the reaction complies. Reaction was quenched with water followed by layer separation. Organic layer was evaporated followed by purification to get 4,6-Dichloro-N-(methyl-d3)-3-pyridazinecarboxamide as a brown solid.
Example-G: Preparation of Deucravacitinib

Lithium bromide was taken in acetonitrile at RT and the reaction temperature was cooled to 15 to 20 °C. Ethyl 4-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) phenylamino)-6-(cyclopropanecarboxamido) pyridazine-3-carboxylate and subsequently methyl(d3) amine. HCl was charged to the reaction mass at 15 to 20 °C followed by the addition of DIPEA. The reaction was continued until the complete conversion was observed. Reaction mass was quenched with water and solid was isolated by the filtration to get the title compound Deucravacitinib as a pale yellow solid. ,CLAIMS:1. A process for preparation of Deucravacitinib

comprising the steps of:
a) reacting a compound of formula II

wherein R4 & R5 are independently selected from F, Cl, Br and I; and x is selected from 0-4;
with a ‘first compound’ which is either selected from CD3NH2, compound of Formula I and compound of Formula IV; and
,

b) reacting the compound obtained from step a) in any order with a ‘second compound’ and a ‘third compound’, which are independently selected from CD3NH2, compound of Formula I and compound of Formula IV; provided that the ‘first compound’, the ‘second compound’ and the ‘third compound ‘are different.

2. The process for preparation of Deucravacitinib as claimed in claim 1, comprising the steps of:
a) reacting compound of formula IIa

wherein x is selected from 0-4;
with CD3NH2 or its salt, optionally in the presence of a reagent, to afford a compound of formula III or a salt or a hydrate thereof;

b) reacting the compound of formula III or a salt or a hydrate thereof, with the compound of formula I or a salt/hydrate thereof,

to afford compound of formula IIIa; and

c) reacting the compound of formula IIIa with a compound of formula IV or a salt or a hydrate thereof,

optionally in the presence of a transition metal salt, wherein the transition metal salt is selected from zinc acetate, zinc chloride and/or zinc bromide, a catalyst and/or additives.
3. The process as claimed in claim 2, wherein in step a), the reagent is selected from POCl3, (COCl)2 and SOCl2.

4. The process as claimed in claim 2, wherein step a), b) and/or c) is optionally carried out in the presence of an acid wherein the acid is selected from acetic acid or hydrochloric acid; and/or a base wherein the base is selected from cesium carbonate, N, N-diisopropylethylamine (DIPEA), triethylamine, ammonia and pyridine; and/or a solvent wherein the solvent is selected from water, acetonitrile, 1-methyl-2-pyrrolidinone, acetic acid, ether solvents, 1,4-dioxane, methyl tertiary butyl ether, chlorinated solvents, dichloromethane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, ester solvents, ethyl acetate, toluene, alcoholic solvents, methanol, ethanol, isopropanol or mixture thereof.

5. The process as claimed in claim 2, wherein in step c) the catalyst and/or additive is selected from Pd2(dba)3, Pd2(dba)3.CHCl3, Pd(OAc)2, Xantphos, 1,1'-Bis(diphenylphosphino)ferrocene, 1,1- Bis(dicyclohexylphosphino)-ferrocene, N-acetyl cysteine, Josiphos SL-009-01 and/or 1,4- Bis(diphenylphosphino)butane.

6. A process for preparation of compound of formula II as defined in claim 1,

comprising reacting a compound of formula VI,
wherein R4 & R5 are as defined in claim 1;
R3 is OX2 wherein X2 is selected from H or C1-C6 alkyl;
with a Calcium source which is selected from calcium chloride (CaCl2), calcium bromide (CaBr2), calcium nitrate (Ca(NO3)2), calcium citrate, calcium malate, calcium carbonate, calcium formate, calcium oxide or calcium acetate (Ca(OAc)2) or its hydrate in a solvent, optionally in the presence of base.

7. The process as claimed in claim 6, wherein the solvent is selected from water, dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, dichloromethane, methyl tertiary butyl ether, 1,4-dioxane, alcoholic solvents, methanol, ethanol, isopropanol, toluene or mixture thereof.

8. The process as claimed in claim 6, wherein the base is selected from K2CO3, KOH, NaOH, N, N-diisopropylethylamine (DIPEA), triethylamine and/or pyridine.

9. A compound of formula II:


wherein R4 & R5 are independently selected from F, Cl, Br and I, preferably R4 & R5 both being Cl; and x is selected from 0-4.

10. The process as claimed in any of the preceding claims, wherein the Deucravacitinib is having chemical purity of above 99 % as measured by HPLC, and has less than 0.15% w/w of one or more of the following compounds:
.