DESC:FIELD OF THE INVENTION
The present invention relates to high purity deucravacitinib, compositions and process for the preparation thereof. In particular, the present invention relates to compositions comprising deucravacitinib having a purity of about 99% or more by weight, and one or more impurities of compounds of Formulae A, B, C, D, E, F, G or H, as described herein, wherein each of the compounds of Formulae A, B, C, D, E, F, G, or H is present in the composition in an amount less than about 0.15 % by weight, when measured by high-performance liquid chromatography (HPLC), relative to deucravacitinib.

BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.

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 a 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.

Identification of impurities is a critical analytical activity in the drug development process whose goal is to fully elucidate the chemical structures of unknown impurities present in either drug substances or drug products above a particular threshold. In a pharmaceutical product, an impurity is first and foremost a quality issue, since it could potentially compromise the efficacy of the drug product. Secondly, impurities also cause safety concerns. Therefore, the objective is to know the plausible impurities for allowing assessment of their toxicological implications, which is an important knowledge for improving the synthetic chemical pathway and optimizing the formulation.

In view of the above, it is therefore desirable to provide a composition comprising deucravacitinib having higher purity and substantially free from one or more impurities, which could plausibly affect the safety and efficacy of the drug product as stated above and method of its preparation thereof.

SUMMARY OF THE INVENTION
In one general aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight, and one or more compounds of Formulae A, B, C, D, E, F, G, or H, wherein each of the compounds of Formulae A, B, C, D, E, F, G, or H is present in the composition in an amount less than about 0.15 % by weight percentage of high-performance liquid chromatography (HPLC), relative to deucravacitinib,
, , ,
, , , , .
In another general aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight, and one or more compounds of Formulae A, B, C, D, E, F, G, or H, wherein each of the compounds of Formulae A, B, C, D, E, F, G, or H is present in the composition in an amount in the range of about 0.001% to about 0.15 % by weight percentage of HPLC, relative to deucravacitinib,
, , ,
, , , , .

In another general aspect, the present invention provides a compound selected from the group consisting of:
, , ,
, , , and .

In another general aspect, the present invention provides the impurities selected from from the group consisting of compound of Formula A, compound of Formula B, compound of Formula C, compound of Formula D, compound of Formula E, compound of Formula F, compound of Formula G, or compound of Formula H as a "reference marker" and/or "reference standard" in methods for determining the identity and/or the amount of said impurities in a sample of deucravacitinib.
In another general aspect, the present invention provides a pharmaceutical composition comprising deucravacitinib and one or more compounds of Formulae A, B, C, D, E, F, G, or H together with one or more pharmaceutically acceptable excipients, diluents and carriers.

In another general aspect, the present invention provides a process for the preparation of deucravacitinib substantially free of the compounds of Formulae A, B, C, D, E, F, G, and H, the process comprising:
(a) heating a mixture of deucravacitinib and dimethyl sulfoxide to a temperature of about 50 °C to about 80 °C to obtain a solution;
(b) adding ethanol to the obtained solution to obtain a reaction mixture; and
(c) cooling.

BRIEF DESCRIPTION OF DRAWING
Figure 1. X-ray powder diffraction pattern of crystalline form of compound of Formula IVa as prepared in example 2.

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.

Optionally, the solution, prior to any solid formation, can be filtered to remove any undissolved solids, solid impurities prior to removal of the solvent. Any filtration
system and filtration techniques known in the art can be used.

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

All ranges recited herein include the endpoints, including those that recite a range “between” two values. Terms such as “about”, “generally”, “substantially,” and the like are to be construed as modifying a term or value such that it is not an absolute. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

The term “substantially free” herein means impurity content within the permissible ICH limits suitable for pharmaceutical preparations. In particular, the impurity content for each of the impurities of compound of Formulae A, B, C, D, E, F, G, and H by weight percentage of HPLC is about 0.15% or less, particularly, about 0.10% or less, more particularly about 0.05% or less, or more particularly not in detectable amount by HPLC method of analysis.

As used herein, the phrase “not in detectable amount” abbreviated as ND, refers to the level of impurity in the product, which is below the level of detection limit of the HPLC method.

In general, the terms “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 “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 term “composition” as used herein means a physical mixture of two or more components.

The term “pharmaceutical composition” as used herein means a drug product comprising the active ingredient(s) & pharmaceutically acceptable excipient(s), as well as any product, which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients including an active ingredient.

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 composition comprising: deucravacitinib having a purity of about 99% or more by weight, and one or more compounds of Formulae A, B, C, D, E, F, G, or H, wherein each of the compounds of Formulae A, B, C, D, E, F, G, or H is present in the composition in an amount less than about 0.15 % by weight percentage of HPLC, relative to deucravacitinib.

In another embodiment, the deucravacitinib in the composition is having a purity about 99.5% or more by weight.

In another embodiment, each of the compounds of Formulae A, B, C, D, E, F, G, or H present in the composition is in an amount less than about 0.1 % by weight percentage of HPLC, relative to deucravacitinib.
In another embodiment, each of the compounds of Formulae A, B, C, D, E, F, G, or H present in the composition is in an amount less than about 0.05 % by weight percentage of HPLC, relative to deucravacitinib.

In another embodiment, each of the compounds of Formulae A, B, C, D, E, F, G, or H present in the composition is in an amount less than about 0.01 % by weight percentage of HPLC, relative to deucravacitinib.

In another embodiment, each of the compounds of Formulae A, B, C, D, E, F, G, or H present in the composition is not in detectable amount by weight percentage of HPLC.

In another embodiment, each of the compounds of Formulae A, B, C, D, E, F, G, or H present in the composition is in an amount in the range of about 0.001% to about 0.15 % by weight percentage of HPLC, relative to deucravacitinib.

In another embodiment, each of the compounds of Formulae A, B, C, D, E, F, G, or H present in the composition is in an amount in the range of about 0.01% to about 0.15 % by weight percentage of HPLC, relative to deucravacitinib.

In another aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight, and a compound of Formula A, wherein the compound of Formula A is present in the composition in an amount less than about 0.15 % by weight percentage of HPLC, relative to deucravacitinib.

In another aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight, and a compound of Formula B, wherein the compound of Formula B is present in the composition in an amount less than about 0.15 % by weight percentage of HPLC, relative to deucravacitinib.

In another aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight, and a compound of Formula C, wherein the compound of Formula C is present in the composition in an amount less than about 0.15 % by weight percentage of HPLC, relative to deucravacitinib.

In another aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight, and a compound of Formula D, wherein the compound of Formula D is present in the composition in an amount less than about 0.15 % by weight percentage of HPLC, relative to deucravacitinib.

In another aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight, and a compound of Formula E, wherein the compound of Formula E is present in the composition in an amount less than about 0.15% by weight percentage of HPLC, relative to deucravacitinib.

In another aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight, and a compound of Formula F, wherein the compound of Formula F is present in the composition in an amount less than about 0.15 % by weight percentage of HPLC, relative to deucravacitinib.

In another aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight, and a compound of Formula G, wherein the compound of Formula G is present in the composition in an amount less than about 0.15 % by weight percentage of HPLC, relative to deucravacitinib.

In another aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight, and a compound of Formula H, wherein the compound of Formula H is present in the composition in an amount less than about 0.15 % by weight percentage of HPLC, relative to deucravacitinib.

In another general aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight, and one or more compounds of Formulae A, B, C, D, E, F, G, or H, wherein each of the compounds of Formulae A, B, C, D, E, F, G, or H is present in the composition in an amount in the range of about 0.001% to about 0.15% by weight percentage of HPLC, relative to deucravacitinib.

In another embodiment, the deucravacitinib in the composition is having a purity about 99.5% or more, by weight percentage of HPLC.

In another aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight, and one or more compounds of Formulae A, B, C, D, E, F, G, or H, wherein each of the compounds of Formulae A, B, C, D, E, F, G, or H is present in the composition in an amount in the range of about 0.002% to about 0.15% by weight percentage of HPLC, relative to deucravacitinib.

In another aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight, and one or more compounds of Formulae A, B, C, D, E, F, G, or H, wherein each of the compounds of Formulae A, B, C, D, E, F, G, or H is present in the composition in an amount in the range of about 0.003% to about 0.15% by weight percentage of HPLC, relative to deucravacitinib.

In another embodiment, each of the compounds of Formulae A, B, C, D, E, F, G, or H present in the composition, is in an amount in the range of about 0.005% to about 0.15%, or about 0.01% to about 0.15%, or about 0.01% to about 0.1%, or about 0.01% to about 0.05%, or about 0.05% to about 0.1%, by weight percentage of HPLC, relative to deucravacitinib.

In another embodiment, each of the compounds of Formulae B, C, E, or H is present in an amount in the range of about 0.001% to about 0.15 % by weight percentage of HPLC, relative to deucravacitinib.

In another embodiment, the present invention provides a compound selected from compound of Formula B, compound of Formula C, compound of Formula E, or compound of Formula H.

In another aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight, and a compound of Formula A, wherein the compound of Formula A is present in the composition in an amount in the range of about 0.001% to about 0.15% by weight percentage of HPLC, relative to deucravacitinib.

In another aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight, and a compound of Formula B, wherein the compound of Formula B is present in the composition in an amount in the range of about 0.001% to about 0.15% by weight percentage of HPLC, relative to deucravacitinib.

In another aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight, and a compound of Formula C, wherein the compound of Formula C is present in the composition in an amount in the range of about 0.001% to about 0.15% by weight percentage of HPLC, relative to deucravacitinib.

In another aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight, and a compound of Formula D, wherein the compound of Formula D is present in the composition in an amount in the range of about 0.001% to about 0.15% by weight percentage of HPLC, relative to deucravacitinib.

In another aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight, and a compound of Formula E, wherein the compound of Formula E is present in the composition in an amount in the range of about 0.001% to about 0.15% by weight percentage of HPLC, relative to deucravacitinib.

In another aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight, and a compound of Formula F, wherein the compound of Formula F is present in the composition in an amount in the range of about 0.001% to about 0.15% by weight percentage of HPLC, relative to deucravacitinib.

In another aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight, and a compound of Formula G, wherein the compound of Formula G is present in the composition in an amount in the range of about 0.001% to about 0.15% by weight percentage of HPLC, relative to deucravacitinib.

In another aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight, and a compound of Formula H, wherein the compound of Formula H is present in the composition in an amount in the range of about 0.001% to about 0.15% by weight percentage of HPLC, relative to deucravacitinib.

In another general aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight percentage of HPLC and one or more of the following:
(i) less than about 0.15% compound of Formula A as an impurity; or
(ii) less than about 0.15% compound of Formula B as an impurity; or
(iii) less than about 0.15% compound of Formula C as an impurity; or
(iv) less than about 0.15% compound of Formula D as an impurity; or
(v) less than about 0.15% compound of Formula E as an impurity; or
(vi) less than about 0.15% compound of Formula F as an impurity; or
(vii) less than about 0.15% compound of Formula G as an impurity; or
(viii) less than about 0.15% compound of Formula H as an impurity; by weight percentage of HPLC relative to deucravacitinib.

In another general aspect, the present invention provides a composition comprising: deucravacitinib having a purity of about 99% or more by weight percentage of HPLC and one or more of the following:
(i) about 0.001% to 0.15% compound of Formula A as an impurity; or
(ii) about 0.001% to 0.15% compound of Formula B as an impurity; or
(iii) about 0.001% to 0.15% compound of Formula C as an impurity; or
(iv) about 0.001% to 0.15% compound of Formula D as an impurity; or
(v) about 0.001% to 0.15% compound of Formula E as an impurity; or
(vi) about 0.001% to 0.15% compound of Formula F as an impurity; or
(vii) about 0.001% to 0.15% compound of Formula G as an impurity;
(viii) about 0.001% to 0.15% compound of Formula H as an impurity; by weight percentage of HPLC relative to deucravacitinib.

In another general aspect, the present invention provides a pharmaceutical composition comprising deucravacitinib and one or more compounds of Formulae A, B, C, D, E, F, G, or H together with one or more pharmaceutically acceptable excipients, diluents and carriers.

In general, the pharmaceutical compositions comprising deucravacitinib of the invention may be prepared by using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants.

In another general aspect, the present invention provides a pharmaceutical composition comprising deucravacitinib having a purity of about 99% or more by weight, and one or more compounds of Formulae A, B, C, D, E, F, G, or H together with one or more pharmaceutically acceptable excipients, diluents and carriers, wherein each of the compounds of Formulae A, B, C, D, E, F, G, or H is present in the pharmaceutical composition in an amount less than about 0.15 % by weight percentage of HPLC, relative to deucravacitinib.

In another general aspect, the present invention provides a pharmaceutical composition comprising deucravacitinib having a purity of about 99% or more by weight, and one or more compounds of Formulae A, B, C, D, E, F, G, or H together with one or more pharmaceutically acceptable excipients, diluents and carriers, wherein each of the compounds of Formulae A, B, C, D, E, F, G, or H is present in the pharmaceutical composition in an amount in the range of 0.001 % to 0.15 % by weight percentage of HPLC, relative to deucravacitinib.

In another general aspect, the composition or pharmaceutical composition comprising deucravacitinib described herein are useful for the treatment of psoriasis in a patient.

In another general aspect, the present invention provides a process for the preparation of deucravacitinib substantially free of the compounds of Formulae A, B, C, D, E, F, G, and H, the process comprising:
(a) heating a mixture of deucravacitinib and dimethyl sulfoxide to a temperature of about 50 °C to about 80 °C to obtain a solution;
(b) adding ethanol to the obtained solution to obtain a reaction mixture; and
(c) cooling.

In general, step (a) of the above process is carried out by heating the mixture of deucravacitinib and dimethylsulfoxide to a temperature of about 50 °C to about 80 °C, or more particularly, to a temperature of about 65 °C to about 75 °C. The reaction mixture then can be stirred at this temperature for a time sufficient to obtain the solution of deucravacitinib in dimethylsulfoxide. Optionally, after stirring the reaction mixture, it can be filtered to obtain the solution of deucravacitinib in dimethylsulfoxide.

In an embodiment, the process as described above, further comprises optional seeding with the deucravacitinib during the addition of ethanol in step (b).

In general, dimethylsulfoxide at step (a), is used in an amount which is 4 to 6 times the quantity of deucravacitinib in volumes.

In general, ethanol is added to the solution of deucravacitinib at a temperature of about 50 °C to about 80 °C, particularly, at a temperature of about 65 °C to about 75 °C.
In general, ethanol at step (b), is used in an amount which is 7 to 10 times the quantity of deucravacitinib in volumes.
In general, the cooling at step (c) comprises cooling the reaction mixture obtained at step (b) to a temperature of about 25 °C to 35 °C with stirring, and optionally, further cooling to a temperature of about -10 °C to about 5 °C with stirring.

The deucravacitinib thus obtained can be isolated by the methods known to person skilled in the art such as filtration, decantation, centrifugation, etc.

In general, the deucravacitinib used at step (a) of the above process, is prepared by a process comprising:
(a) reacting a compound of Formula VIIa or hydrate thereof,

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

in 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 the deucravacitinib.

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) of the above process is carried out in presence of 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. Particularly, the solvent is a mixture of 2-propanol and water. More particularly, the solvent is a mixture of tetrahydrofuran and water.

In general, the reaction of compound of Formula VIIa 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 IVa 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 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 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 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 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 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 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 crystalline form of a compound of Formula IVa,

characterized by x-ray powder diffraction (XRPD) pattern having at least four peaks expressed in 2? selected from 10.2°, 10.9°, 11.8°, 12.1°, 14.6°, 18.5°, 23.4°, 24.4°, and 26.7°± 0.2°.
In another embodiment, the present invention provides a crystalline form of a compound of Formula IVa, characterized by x-ray powder diffraction (XRPD) pattern having at least six peaks expressed in 2? selected from 10.2°, 10.9°, 11.8°, 12.1°, 14.6°, 18.5°, 23.4°, 24.4°, and 26.7°± 0.2°.

In another embodiment, the present invention provides a crystalline form of a compound of Formula IVa, characterized by x-ray powder diffraction (XRPD) pattern having peaks expressed in 2? at 10.2°, 10.9°, 11.8°, 12.1°, 14.6°, 18.5°, 23.4°, 24.4°, and 26.7°± 0.2°.

In another general aspect, the present invention provides a process for the preparation of a crystalline form of a compound of Formula IVa,

characterized by x-ray powder diffraction (XRPD) pattern having at least four peaks expressed in 2? selected from 10.2°, 10.9°, 11.8°, 12.1°, 14.6°, 18.5°, 23.4°, 24.4°, and 26.7°± 0.2°, the process comprising:
(a) reacting a compound of Formula VIIa or hydrate thereof,

with a compound of Formula VI, or a salt thereof

in presence of a zinc salt, in a solvent mixture of tetrahydrofuran and water, at a temperature of 40 °C to reflux temperature of solvent, to obtain a reaction mixture; and
(b) cooling the reaction mixture to obtain the crystalline form of a compound of Formula IVa.

In general, the cooling at step (b) comprises cooling the reaction mixture obtained at step (a) to a temperature of about 25 °C to 35 °C with stirring and optionally further cooling to a temperature of about -10 °C to about 5 °C with stirring.

The crystalline form of compound of Formula IVa, may be isolated by the methods known to skilled artisan such as filtration, centrifugation, etc.

The present invention is further illustrated by the following examples 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:
HPLC method of analysis:
Method A:
Chromatographic conditions:
Equipment : HPLC equipped with UV/PDA detector
Column : C8 (250 x 4.6) mm, 5µm
Flow rate : 1.0 mL/minute
Column oven temp. : 40°C
Wavelength : 210 nm
Injection volume : 20 µL
Buffer solution-A: Mixture of 10 mM monobasic potassium phosphate and 0.1 % v/v of Triethyl amine solution adjusted pH 2.5 + 0.05 with orthophosphoric acid
Buffer solution-B: Mixture of 10 mM monobasic potassium phosphate and 0.1 % v/v of Triethyl amine solution adjusted pH 6 + 0.05 with orthophosphoric acid
Mobile phase-A: Mixture of Buffer-A and Acetonitrile in the ratio of 95:05 % v/v.
Mobile phase-B: Mixture of Acetonitrile and Buffer-B in the ratio of 70:30 % v/v
Diluent: Mixture of Acetonitrile, water and Trifluoracetic acid in the ratio of 50:50:0.5 %v/v/v.
Sample conc: 500 µg/mL of Deucravacitinib

Gradient Program:
Time (min) % Mobile Phase-B
0 0
10 0
50 65
60 65
61 70
70 0

Impurity/compound Relative retention time (RRT)
Impurity-D 0.88
Impurity-F 0.90
Impurity-C 0.98
Deucravacitinib 1.00
Impurity-A 1.14
Impurity-E 1.19
Impurity-B 1.28

Method B:
Chromatographic conditions:
Equipment : HPLC equipped with UV/PDA detector
Column : Two columns in series C8 (250 x 4.6) mm, 5µm and C8 (150 x 4.6) mm, 3.5µm
Flow rate : 1.0 mL/minute
Column oven temp. : 35°C
Wavelength : 230 nm
Injection volume : 15 µL

Dilute Potassium Hydroxide solution: 1.0 g potassium hydroxide dissolved in 100 mL of water and mixed.
Buffer: About 1.36 g of potassium dihydrogen phosphate was transferred in 1000 mL of water and sonicated to dissolve, pH of the solution was adjusted to 5.0 ± 0.05 with dilute Potassium Hydroxide solution, then it was filtered through 0.45 µm PVDF filter.
Mobile phase-A: Mixture of Water, Acetonitrile and Orthophosphoric acid in the ratio of 95:5:0.1 % v/v/v.
Mobile phase-B: Mixture of Acetonitrile and Buffer in the ratio of 50:50 % v/v
Diluent: Mixture of Water, Acetonitrile and Trifluoro acetic acid in the ratio of 50:50:0.5 %v/v/v.
Sample conc: 500 µg/mL of Deucravacitinib

Gradient Program:
Time (min) % Mobile Phase-A % Mobile Phase-B
0 85 15
30 32 68
50 20 80
60 20 80
62 85 15
80 85 15

Impurity/compound Relative retention time (RRT)
Impurity-D 0.83
Impurity-F 0.81
Impurity-C 1.08
Deucravacitinib 1.00
Impurity-A 1.28
Impurity-E 1.45
Impurity-B 1.75
Impurity-G 0.74
Impurity-H 0.49

Example 1: Preparation of barium(II) 4,6-dichloropyridazine-3-carboxylate monohydrate :

To a solution of water (250 mL) and barium chloride (59 g, 241.53 mmol) at 20 °C to 35 °C were charged acetonitrile (300 ml) followed by methyl 4,6-dichloropyridazine-3-carboxylate (50 g, 241.53 mmol). N,N-Di-isopropyl ethylamine (84.15 mL, 483.06 mmol) was added and the reaction mixture was stirred at 20 °C to 35 °C for 5 hours. After completion of reaction, the solid was filtered and washed with acetonitrile (150 mL). The solid was dried at 50 °C to 60 °C to obtain barium(II) 4,6-dichloropyridazine-3-carboxylatemonohydrate in quantitative yield. (59.10 g, 90.7%) 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:

To a solution of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline (33 g, 100.18mmol) in tetrahydrofuran (66 mL) and water (132 mL) was added barium(II) 4,6-dichloropyridazine-3-carboxylate (54.03 g, 200.36 mmol) followed by zinc acetate (35.47 g, 161.58 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, DMF (66 mL) and water (165 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 165 mL) and THF (2 x 165 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 ( 60.02 g, 95.0%).
X-ray powder diffraction pattern is as set forth in Figure 1.

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 2L autoclave reactor, acetonitrile (300mL), toluene (500 mL), zinc(II) 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate (100 g, 254.82 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (38.79 mL, 254.82 mmol), cyclopropane carboxamide (54.22 g, 637.04 mmol) and potassium carbonate (123.25 g, 891.86 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 (0.858 g, 3.82 mmol) and josiphos (SL-J009) (4.239 g, 7.64 mmol) in a mixture of acetonitrile (100 mL) and toluene (300 mL). The resultant solution was thoroughly degassed by purging nitrogen and transferred into main reaction mixture. The flask was rinsed with toluene (100 mL) and transferred into main reaction mixture. The main reaction mixture was degassed and the reactor was sealed. The reaction mixture was heated to 65 °C to 75 °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 (500 mL) was slowly added to it. Acetic acid (1100 mL) and n-Heptane (700 mL) were charged into the reaction mixture and stirred for 15 min. The aqueous layer was separated and diluted with water (400 mL). Seed material (1 g) was added into reaction mixture and stirred for 1 hour. Additional water (200 mL) was added and the resultant slurry was stirred for 4-5 hours at 25 °C to 35 °C. The solid was filtered and washed with 1:1 mixture of acetonitrile: water (1000 mL) followed by washing with acetonitrile (600 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 (103.6 g, 92.5%).
Example 4: 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 (900 mL), toluene (1500 mL), zinc(II) 6-chloro-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate (300 g, 0.382 mol), 1,8-diazabicyclo[5.4.0]undec-7-ene (116.38 g, 0.764 mol), cyclopropane carboxamide (162.66 g, 1.911 mol) and potassium carbonate (369.78 g, 2.675 mol) were charged under nitrogen atmosphere 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 (1.297 g, 5.7 mmol) and josiphos (SL-J009) (6.36 g, 11.0 mmol) in a mixture of acetonitrile (300 mL) and toluene (600 mL). The resultant solution was thoroughly degassed by purging nitrogen and transferred into main reaction mixture under nitrogen atmosphere. The flask was rinsed with toluene (300 mL) and transferred into main reaction mixture. The main reaction mixture was degassed and the reactor was sealed. The reaction mixture was heated to 65 °C to 75 °C and stirred for 22 hours. After completion of reaction, the reaction mixture was cooled to 10 °C to 25 °C and a 1:1 mixture of acetic acid: water (1500 mL) was slowly added to it. Acetic acid (3300 mL) and n-Heptane (700 mL) were charged into the reaction mixture and stirred for 15 min. The aqueous layer was separated and diluted with water (1200 mL). Seed material (3 g) was added into reaction mixture and stirred for 2 hours. Additional water (600 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 (3000 mL) followed by washing with acetonitrile (1800 mL). The product was dried at 55 °C to 65 °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 (314 g, 93.4 %).

Example 5: Preparation of Deucravacitinib
N-methyl imidazole (122.84 g, 1.496 mol) was charged into a solution of acetonitrile (2.2 L), N-methyl pyrrolidone (2.75 L). Deuterated methyl amine hydrochloride (211.09 g, 2.992 mol) and zinc(II) 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate (1.1 kg, 2.49 mol) 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 (190.95 g, 1.246 mol) was charged followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.HCl (669.28 g, 3.49 mol) and flushed with acetonitrile (1.1 L) The resultant reaction mass was stirred for 1 hour. After completion of reaction, water (1.1 L) and acetonitrile (6.6 L) were charged into the reaction mixture. The reaction mixture was cooled at -10 °C to 0 °C and stirred for 4 hours. The solid was filtered and washed with 1:2 acetonitrile: water mixture (3.3 L), followed by washing with acetonitrile (3.3 L). The wet cake was unloaded. The wet cake and DMSO (4.4 L) were charged in 10 L reactor, the reaction mass was heated at 65 °C to 75 °C and stirred it for 30 min. 2.53 L Ethanol was charged into the reaction mass and seeded with deucravacitinib (8.8 g) at 65 °C to 75 °C. The reaction mass was stirred for 30 min at 65 °C to 75 °C. Then ethanol (5.17 L) was further charged at 55 °C to 75 °C. The reaction mass was cooled up to -10 °C to 0 °C and stirred for 4 hours. The solid was filtered and washed with ethanol (5.06 L). The product was dried at 60 °C to 70 °C to obtain deucravacitinib (0. 726 kg, 68.7%).
HPLC Purity: 99.54% (Method A)
Content of Compound of Formula A: 0.09 % by weight,
Content of Compound of Formula B: 0.01 % by weight,
Content of Compound of Formula C: Not detected,
Content of Compound of Formula D: Not detected,
Content of Compound of Formula E: 0.08 % by weight,
Content of Compound of Formula F: 0.01 % by weight.

Example 6. Preparation of Deucravacitinib
N-methyl imidazole (128.43 g, 1.564 mol) was charged into a solution of acetonitrile (1.15 L), N-methyl pyrrolidone (2.875 L). Deuterated methyl amine hydrochloride (220.69 g, 3.129 mol) and zinc(II) 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate (1.15 kg, 1.304 mol) were added into reaction mixture at temperature 25 °C to 35 °C. The resultant slurry was heated to 60 °C to 70 °C. Hydroxybenzotriazole monohydrate (199.63 g, 1.304 mol) was charged followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.HCl (699.71 g, 3.650 mol) and flushed with acetonitrile (1.15 L). The resultant reaction mass was stirred for 1 hour. After completion of reaction, water (1.15 L) and acetonitrile (6.9 L) 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 (3.45 L), followed by washing with acetonitrile (3.45 L). The wet cake was unloaded. The wet cake and DMSO (4.6 L) were charged in 10 L reactor, the reaction mass was heated at 65 °C to 75 °C and stirred it for 30 min. 2.645 L Ethanol was charged into the reaction mass and seeded with deucravacitinib (9.2 g) at 65 °C to 75 °C. The reaction mass was stirred for 30 min at 65 °C to 75 °C. Then ethanol (5.405 L) was further charged 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 (6.9 L). The product was dried at 60 °C to 70 °C to obtain the crystalline form of deucravacitinib (0. 810 kg, 73.36 %).
HPLC Purity: 99.54% (Method B)
Content of Compound of Formula A: 0.06 % by weight,
Content of Compound of Formula B: 0.02 % by weight,
Content of Compound of Formula C: Not detected,
Content of Compound of Formula D: Not detected,
Content of Compound of Formula E: 0.02 % by weight,
Content of Compound of Formula F: 0.01 % by weight,
Content of Compound of Formula G: 0.01 % by weight,
Content of Compound of Formula H: 0.02% by weight.

Example 7. Preparation of crystalline Deucravacitinib
Deucravacitinib (2.5 g) and DMSO (12.5 mL) were charged in 3N-RBF, the reaction mass was heated at 65°C to 75 °C and stirred it for 30 min. Ethanol (7.5 mL) was charged into the reaction mass at 65 °C to 75 °C and the reaction mass was stirred for 30 min at 65 °C to 75 °C. Ethanol (15 ml) was charged at 55 °C to 75 °C. The reaction mass was cooled up to -10 °C to 0 °C and stirred for 4 hours. The solid was filtered and washed with ethanol (2 X 5 mL). The product was dried at 60 °C to 70 °C to obtain the crystalline form of deucravacitinib (2.20 g, 88 %).

Example 8. The tablet composition of the highly pure deucravacitinib substantially free of impurities of compounds of Formulae A, B, C, D, E, F, G, and H.
Sr. No. Name of ingredient Quantity
(%w/w)
1 Deucravacitinib 3
2 Hypromellose acetate succinate 17
2 Microcrystalline cellulose 49.75
3 Croscarmellose sodium 4
4 Lactose anhydrous 22
5 Magnesium stearate 0.25
6 Silicon dioxide 1
8 Opadry pink (Film coating) 3

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 compound selected from the group consisting of:
, , ,
, , , , and .

2. The compound as claimed in claim 1, wherein the compound is
, ,
, or .

3. A composition comprising deucravacitinib having a purity of about 99% or more by weight, and one or more compounds of Formulae A, B, C, D, E, F, G, or H, wherein each of the compounds of Formulae A, B, C, D, E, F, G, or H is present in the composition in an amount less than about 0.15 % by weight percentage of high-performance liquid chromatography (HPLC), relative to deucravacitinib,
, , ,
, , , , .
4. The composition as claimed in claim 3, wherein the deucravacitinib is having a purity of about 99.5% or more by weight percentage of HPLC.

5. The composition as claimed in claim 3, wherein the each of the compounds of Formulae A, B, C, D, E, F, G, or H is present in the composition in an amount in the range of about 0.001% to about 0.15 % by weight percentage of HPLC relative to Deucravacitinib.

6. The composition as claimed in claim 3, wherein the each of the compounds of Formulae A, B, C, D, E, F, G, or H is present in the composition in an amount in the range of about 0.01% to about 0.15 % by weight percentage of HPLC relative to deucravacitinib.

7. The composition as claimed in claim 3, wherein the each of the compounds of
Formulae A, B, C, D, E, F, G, or H is present in the composition in a detectable amount by weight percentage of HPLC relative to deucravacitinib.

8. The composition as claimed in claim 3, wherein the each of the compounds of Formulae B, C, E, or H is present in an amount in the range of about 0.001% to about 0.15 % by weight percentage of HPLC relative to deucravacitinib.

9. A pharmaceutical composition comprising deucravacitinib and one or more compounds of Formulae A, B, C, D, E, F, G, or H together with one or more pharmaceutically acceptable excipients, diluents and carriers,
, , ,
, , ,

, .
10. The pharmaceutical composition as claimed in claim 9, wherein the each of the compounds of Formulae A, B, C, D, E, F, G, or H is present in the composition in an amount in the range of about 0.001% to about 0.15 % by weight percentage of HPLC relative to deucravacitinib.

11. A process for the preparation of deucravacitinib substantially free of the compounds of Formulae A, B, C, D, E, F, G, and H,
, , ,
, ,
, , .
the process comprising:
(a) heating a mixture of deucravacitinib and dimethyl sulfoxide to a temperature of about 50°C to about 80°C to obtain a solution;
(b) adding ethanol to the obtained solution to obtain a reaction mixture; and
(c) cooling.

Dated this 25th day of June 2024.

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