DESC:The following specification describes particularly the invention and in the manner in which it is to be performed:

PROCESS FOR PREPARTION OF RITLECITINIB

FIELD OF THE INVENTION
The present application relates to a process for preparation of Ritlecitinib or its pharmaceutically acceptable salt thereof. The present application also relates to a novel intermediate of Ritlecitinib and its application in the preparation of Ritlecitinib or its pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION
Ritlecitinib tosylate (I) is a dual inhibitor of the TEC family of tyrosine-protein kinases and of Janus kinase 3 (JAK3) being developed by Pfizer for the treatment of Alopecia Areata, Rheumatoid Arthritis, Ulcerative Colitis, Crohn's Disease, Vitiligo. Till date Ritlecitinib tosylate is only approved in US (June 2023). As per US label, it is indicated for the treatment of severe alopecia areata in adults and adolescents 12 years and older. Ritlecitinib tosylate is chemically known as 1-{(2S,5R)-2-Methyl-5-[(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}prop-2-en-1-one 4-methylbenzene-1-sulfonic acid.

WO2015083028A (herein after referred as WO’028) first discloses Ritlecitinib along with the process for preparation thereof. WO2020084435A1 (herein after referred as WO’435) discloses a process for preparation Ritlecitinib and its tosylate salt. Apart from the above various synthetic routes have been reported in the literature viz. KR102228668B1 (herein after referred as KR’ 668), CN113121539A (herein after referred as CN’ 539), CN112430235 A (herein after referred as CN’ 235), J. Med. Chem. 2017, 60, 1971–1993 and Org. Process Res. Dev. 2019, 23, 1872-1880. However, all of the above literature routes involves the use of acrylic acid or acid derivative or 3-chloropropionyl chloride for the final amide formation, which suffers from drawbacks such as incomplete conversion of starting material, lower reaction yield and formation of dimer impurity. Further, it requires stringent reaction conditions like low temperature to control or limit the formation of dimer impurity. Hence it is important to find an alternate process to improve purity and ease of manufacturing.
The inventors of the present application have developed a process for preparation of Ritlecitinib or pharmaceutically acceptable salt thereof, which overcomes the above drawbacks and provides certain advantages including;
1. Lower catalyst loading and lower hydrogen pressure for hydrogenation step
2. No stringent temperature or time control required for amidation step
3. Control of dimer impurity (less than or equal to 1%)
4. High yield and purity
5. Easy of manufacturing

SUMMARY OF THE INVENTION
First aspect of the present application relates to a process for preparation of Ritlecitinib (II) or pharmaceutically acceptable salt thereof, comprising
(i) reacting compound of formula (V) or salt or hydrate or solvate thereof with compound of formula (IV) to obtain compound of formula (III)
;
(ii) converting compound of formula (III) to compound of formula (II) or pharmaceutically acceptable salt thereof
;
wherein R is a linear, cyclic, branched alkyl or hetero alkyl; an aryl or hetero aryl or an aryl alkyl, optionally one or more carbon atoms in aryl or hetero aryl or an aryl alkyl are substituted with one or more groups selected from lower alkyl, lower alkoxy, amino, halo, cyano, nitro, azido, and hydroxyl; X is a halogen, hydroxyl, -OR, -OCOR; .

Second aspect of the present application relates to a process for preparation of compound of formula (V) or salt or hydrate or solvate thereof comprising converting compound of formula (VI) to compound of formula (V) or salt or hydrate or solvate thereof in presence of a suitable reagent.

P is an amino protecting group.

Third aspect of the present application relates to a process for preparation of Ritlecitinib (II) or pharmaceutically acceptable salt thereof, comprising
(i) reacting compound of formula (VIII) or its salt with compound of formula (VII) to obtain compound of formula (VI)
;
(ii) converting compound of formula (VI) to compound of formula (V) or salt or hydrate or solvate thereof
;
(iii) reacting compound of formula (V) or salt or hydrate or solvate thereof with compound of formula (IV) to obtain compound of formula (III)
;
(iv) converting compound of formula (III) to compound of formula (II) or pharmaceutically acceptable salt thereof

wherein R is a linear, cyclic, branched alkyl or hetero alkyl; an aryl or hetero aryl or an aryl alkyl, optionally one or more carbon atoms in aryl or hetero aryl or an aryl alkyl are substituted with one or more groups selected from lower alkyl, lower alkoxy, amino, halo, cyano, nitro, azido, and hydroxyl; X is a halogen, hydroxyl, -OR, -OCOR; .

Fourth aspect of the present application relates to the compound of formula (III) or its salt thereof.

wherein R is a linear, cyclic, branched alkyl or hetero alkyl; an aryl or hetero aryl or an aryl alkyl, optionally one or more carbon atoms in aryl or hetero aryl or an aryl alkyl are substituted with one or more groups selected from lower alkyl, lower alkoxy, amino, halo, cyano, nitro, azido, and hydroxyl;

Fifth aspect of the present application relates to a process for preparation of Ritlecitinib or its pharmaceutically acceptable salt thereof comprising converting compound of formula (III) to Ritlecitinib or its pharmaceutically acceptable salt thereof.

Sixth aspect of the present application relates to a process for preparation of Ritlecitinib or its pharmaceutically acceptable salt thereof comprising reacting compound of formula (V) with compound of formula (IV) to obtain Ritlecitinib or its pharmaceutically acceptable salt thereof.

Seventh aspect of the present application relates to a process for preparation of Ritlecitinib tosylate (I) comprising converting Ritlecitinib (II) prepared by any of the above aspects to Ritlecitinib tosylate (I).

DETAILED DESCRITPION
First aspect of the present application relates to a process for preparation of Ritlecitinib (II) or pharmaceutically acceptable salt thereof, comprising
(i) reacting compound of formula (V) or salt or hydrate or solvate thereof with compound of formula (IV) to obtain compound of formula (III)
;
(ii) converting compound of formula (III) to compound of formula (II) or pharmaceutically acceptable salt thereof
;
wherein R is a linear, cyclic, branched alkyl or hetero alkyl; an aryl or hetero aryl or an aryl alkyl, optionally one or more carbon atoms in aryl or hetero aryl or an aryl alkyl are substituted with one or more groups selected from lower alkyl, lower alkoxy, amino, halo, cyano, nitro, azido, and hydroxyl; X is a halogen, hydroxyl, -OR, -OCOR; .

In embodiments of step i) compound of formula (III) is obtained by reacting compound of formula (V) with compound of formula (IV) in presence of a suitable reagent in a suitable solvent.
Suitable solvent may include but not limited to ethers such as 1,4-dioxane, tetrahydrofuran and the like; ester solvents such as ethyl acetate, propyl acetate and the like; ketone solvents such as acetone, methyl ethyl ketone, butanone and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like. nitrile solvent such as acetonitrile, propionitrile, water and mixture thereof. Preferably, the solvent may be a mixture of ether and water. More preferably, solvent is a mixture of tetrahydrofuran and water. Suitable reagent may include but not limited to metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal carbonates and bicarbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate and the like; potassium phosphates such as potassium phosphates tribasic (K3PO4), potassium phosphate dibasic (K2HPO4), potassium phosphate monobasic (KH2PO4); sodium phosphates such as sodium phosphate mono basic, sodium phosphate dibasic, sodium phosphate tribasic; organic base includes but not limited to triethylamine (TEA), diisopropylethylamine (DIPEA), pyridine, 4-dimethylaminopyridine (DMAP), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo(4.3.0)non-5-ene (DBN), N-methylmorpholine, N-methylpyrrolidine and the like. Preferably the suitable reagent is potassium phosphates tribasic(K3PO4). The reaction may be carried out at a temperature of about 5 °C to about boiling point of the solvent.
Further, in embodiments of step i) compound of formula (IV) can be an acid or its derivative or any of its activated form thereof.
In embodiments of step ii) conversion of compound of formula (III) to compound of formula (II) is carried out in presence of a suitable base in a suitable solvent.
Suitable solvent may include but not limited to ethers such as 1,4-dioxane, tetrahydrofuran and the like; alcohol solvents such as methanol, ethanol, isopropanol and the like; ester solvents such as ethyl acetate, propyl acetate and the like; ketone solvents such as acetone, methyl ethyl ketone, butanone and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like; nitrile solvent such as acetonitrile, propionitrile, water and mixture thereof. Preferably, the solvent is a nitrile solvent. More preferably, solvent is acetonitrile. Suitable base may be organic or inorganic base. Inorganic base includes but not limited to metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal carbonates and bicarbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate and the like; metal alkoxides base such as sodium methoxide, sodium t-butoxide and the like; phosphate base such as potassium phosphates and sodium phosphates; silanote bases such as potassium trimethylsilanolate; organometallic base, such as lithium diisopropylamide, butyl lithium, lithium bis(trimethylsilyl)amide, lithium tetramethylpiperidide (LTMP) and the like; metal hydrides such as sodium hydride, potassium hydride and the like. Organic base includes but not limited to triethylamine (TEA), diisopropylethylamine (DIPEA), pyridine, 4-dimethylaminopyridine (DMAP), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo(4.3.0)non-5-ene (DBN), N-methylmorpholine, N-methylpyrrolidine and the like. Preferably the suitable base is metal hydroxide. More preferably the suitable base is sodium hydroxide. The reaction may be carried out at a temperature of about 10 °C to about boiling point of the solvent.
Specific aspect of the present application relates to a process for preparation of Ritlecitinib (II) or pharmaceutically acceptable salt thereof, comprising
(i) reacting compound of formula (V) or salt or hydrate or solvate thereof with compound of formula (IVa) to obtain compound of formula (IIIa)
;
(ii) converting compound of formula (IIIa) to compound of formula (II) or pharmaceutically acceptable salt thereof
;

In an embodiment of present application, the conversion of compound of formula (V) to compound of formula (II) is carried with or without isolation of compound of formula (III) and/or (IIIa).

Second aspect of the present application relates to a process for preparation of compound of formula (V) or salt or hydrate or solvate thereof comprising converting compound of formula (VI) to compound of formula (V) or salt or hydrate or solvate thereof in presence of a suitable reagent.

P is an amino protecting group.
In an embodiment compound of formula (VI) is converted to compound of formula (V) in presence of suitable hydrogenating agent in a suitable solvent.
Suitable solvent may include but not limited to ethers such as 1,4-dioxane, tetrahydrofuran and the like; alcohol solvents such as methanol, ethanol, isopropanol and the like; ester solvents such as ethyl acetate, propyl acetate and the like; ketone solvents such as acetone, methyl ethyl ketone, butanone and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like. nitrile solvent such as acetonitrile, propionitrile mixture thereof. Preferably, the solvent is a mixture of ether and alcohol solvent. More preferably, solvent is a mixture of tetrahydrofuran and methanol. Suitable hydrogenating agent includes hydrogen source and a catalyst. Hydrogen source may be hydrogen gas or ammonium format. Catalyst may include but not limited to Pd(OH)2/C, Pd/C, Pd(OAc)2/C, Pd/Alumina, Raney Ni, Iron, and the like. Specifically, the suitable hydrogenating agent is Pd/C and H2 gas. In an embodiment conversion of compound of formula (VI) to compound of formula (V) is carried out in presence of suitable acid. Suitable acid may include but not limited acetic acid, adipic acid, aspartic acid, p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, citric acid, hydrochloric acid, hydrobromic acid, lactic acid, malonic acid, methanesulfonic acid, oxalic acid, succinic acid, tartaric acid, trifluoroacetic acid and the like. Preferably acid is Hydrochloric acid. The reaction may be carried out at a temperature of about 20 °C to about boiling point of the solvent.
In an embodiment, the amount of catalyst used for hydrogenation is less than 10% w/w. Specifically, less than or equal to 5% w/w.
Amino protecting group is defined as any amino protecting group as known in Greene et al., Protecting groups in organic chemistry, Third Edition, 1999. Examples include benzyloxycarbonyl (Cbz) and tert-Butyloxycarbonyl (Boc), acetyl, benzyl, p-methoxy benzyl, trityl and the like.

Specific aspect of the present application relates to a process for preparation of compound of formula (V) or salt or hydrate or solvate thereof comprising converting compound of formula (VIa) to compound of formula (V) or salt or hydrate or solvate thereof in presence of a suitable reagent
.
In an embodiment of present application, the conversion of compound of formula (V) may be isolated as free base or in form of its salt or hydrate or solvate thereof. Specifically isolated as hydrochloride or hydrate.

Third aspect of the present application relates to a process for preparation of Ritlecitinib (II) or pharmaceutically acceptable salt thereof, comprising
(i) reacting compound of formula (VIII) or its salt with compound of formula (VII) to obtain compound of formula (VI)
;
(ii) converting compound of formula (VI) to compound of formula (V) or salt or hydrate or solvate thereof
;
(iii) reacting compound of formula (V) or salt or hydrate or solvate thereof with compound of formula (VI) to obtain compound of formula (III)
;
(iv) converting compound of formula (III) to compound of formula (II) or pharmaceutically acceptable salt thereof

wherein R is a linear, cyclic, branched alkyl or hetero alkyl; an aryl or hetero aryl or an aryl alkyl, optionally one or more carbon atoms in aryl or hetero aryl or an aryl alkyl are substituted with one or more groups selected from lower alkyl, lower alkoxy, amino, halo, cyano, nitro, azido, and hydroxyl; X is a halogen, hydroxyl, -OR, -OCOR; .

In embodiments of step i) compound of formula (VI) obtained by reacting compound of formula (VIII) with compound of formula (VII) in presence of a suitable reagent in a suitable solvent.
Suitable solvent may include but not limited to ethers such as 1,4-dioxane, tetrahydrofuran and the like; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol and the like; ester solvents such as ethyl acetate, propyl acetate and the like; ketone solvents such as acetone, methyl ethyl ketone, butanone and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like. nitrile solvent such as acetonitrile, propionitrile mixture thereof. preferably, the solvent is an alcohol solvent. More preferably, solvent is n-butanol. Suitable reagent may be an organic or inorganic base. Inorganic base include but not limited to metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal alkoxides base such as sodium methoxide, sodium t-butoxide and the like; metal carbonates and bicarbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate and the like; metal alkoxides base such as sodium methoxide, sodium t-butoxide and the like; phosphate base such as potassium phosphates and sodium phosphates; organometallic base, such as lithium diisopropylamide, butyl lithium, lithium bis(trimethylsilyl)amide, lithium tetramethylpiperidide (LTMP) and the like; metal hydrides such as sodium hydride, potassium hydride and the like. Organic base includes but not limited to triethylamine (TEA), diisopropylethylamine (DIPEA), pyridine, 4-dimethylaminopyridine (DMAP), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo(4.3.0)non-5-ene (DBN), N-methylmorpholine, N-methylpyrrolidine and the like. Preferably the suitable reagent is diisopropylethylamine (DIPEA). The reaction of step c) may be carried out at a temperature of about 20 °C to about boiling point of the solvent.
In an embodiments of step ii) compound of formula (VI) is converted to compound of formula (V) in presence of suitable hydrogenating agent in a suitable solvent.
Suitable solvent may include but not limited to ethers such as 1,4-dioxane, tetrahydrofuran and the like; alcohol solvents such as methanol, ethanol, isopropanol and the like; ester solvents such as ethyl acetate, propyl acetate and the like; ketone solvents such as acetone, methyl ethyl ketone, butanone and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like. nitrile solvent such as acetonitrile, propionitrile mixture thereof. Preferably, the solvent is a mixture of ether and alcohol solvent. More preferably, solvent is a mixture of tetrahydrofuran and methanol. Suitable hydrogenating agent includes hydrogen source and a catalyst. Hydrogen source may be hydrogen gas or ammonium format. Catalyst may include but not limited to Pd(OH)2/C, Pd/C, Pd(OAc)2/C, Pd/Alumina, Raney Ni, Iron, and the like. Specifically, the suitable hydrogenating agent is Pd/C and H2 gas. In an embodiment conversion of compound of formula (VI) to compound of formula (V) is carried out in presence of suitable acid. Suitable acid may include but not limited acetic acid, adipic acid, aspartic acid, p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, citric acid, hydrochloric acid, hydrobromic acid, lactic acid, malonic acid, methanesulfonic acid, oxalic acid, succinic acid, tartaric acid, trifluoroacetic acid and the like. Preferably acid is Hydrochloric acid. The reaction may be carried out at a temperature of about 20 °C to about boiling point of the solvent.
In an embodiment of step ii), the amount of catalyst used for hydrogenation is less than 10% w/w. Specifically, less than or equal to 5% w/w.
In embodiments of step iii) compound of formula (III) obtained by reacting compound of formula (V) with compound of formula (IV) in presence of a suitable reagent in a suitable solvent.
Suitable solvent may include but not limited to ethers such as 1,4-dioxane, tetrahydrofuran and the like; ester solvents such as ethyl acetate, propyl acetate and the like; ketone solvents such as acetone, methyl ethyl ketone, butanone and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like. nitrile solvent such as acetonitrile, propionitrile, water and mixture thereof. preferably, the solvent may be a mixture of ether and water. More preferably, solvent is a mixture of tetrahydrofuran and water. Suitable reagent may include but not limited to metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal carbonates and bicarbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate and the like; potassium phosphates such as potassium phosphates tribasic (K3PO4), potassium phosphate dibasic (K2HPO4), potassium phosphate monobasic (KH2PO4); sodium phosphates such as sodium phosphate mono basic, sodium phosphate dibasic, sodium phosphate tribasic; organic base includes but not limited to triethylamine (TEA), diisopropylethylamine (DIPEA), pyridine, 4-dimethylaminopyridine (DMAP), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo(4.3.0)non-5-ene (DBN), N-methylmorpholine, N-methylpyrrolidine and the like. Preferably the suitable reagent is potassium phosphates tribasic(K3PO4). The reaction may be carried out at a temperature of about 5 °C to about boiling point of the solvent.
In embodiments of step iv) conversion of compound of formula (III) to compound of formula (II) is carried out in presence of a suitable base in a suitable solvent.
Suitable solvent may include but not limited to ethers such as 1,4-dioxane, tetrahydrofuran and the like; alcohol solvents such as methanol, ethanol, isopropanol and the like; ester solvents such as ethyl acetate, propyl acetate and the like; ketone solvents such as acetone, methyl ethyl ketone, butanone and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like; nitrile solvent such as acetonitrile, propionitrile, water and mixture thereof. Preferably, the solvent is a nitrile solvent. More preferably, solvent is acetonitrile. Suitable base may be organic or inorganic base. Inorganic base includes but not limited to metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal carbonates and bicarbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate and the like; metal alkoxides base such as sodium methoxide, sodium t-butoxide and the like; phosphate base such as potassium phosphates and sodium phosphates; silanote bases such as potassium trimethylsilanolate; organometallic base, such as lithium diisopropylamide, butyl lithium, lithium bis(trimethylsilyl)amide, lithium tetramethylpiperidide (LTMP) and the like; metal hydrides such as sodium hydride, potassium hydride and the like. Organic base includes but not limited to triethylamine (TEA), diisopropylethylamine (DIPEA), pyridine, 4-dimethylaminopyridine (DMAP), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo(4.3.0)non-5-ene (DBN), N-methylmorpholine, N-methylpyrrolidine and the like. Preferably the suitable base is metal hydroxide. More preferably the suitable base is sodium hydroxide. The reaction may be carried out at a temperature of about 10 °C to about boiling point of the solvent.

Specific aspect of the present application relates to a process for preparation of Ritlecitinib (II) or pharmaceutically acceptable salt thereof, comprising
(i) reacting compound of formula (VIIIa) or its salt with compound of formula (VII) to obtain compound of formula (VI)
;
(ii) converting compound of formula (VIa) to compound of formula (V) or salt or hydrate or solvate thereof
;
(iii) reacting compound of formula (V) or salt or hydrate or solvate thereof with compound of formula (VIa) to obtain compound of formula (IIIa)
;
(iv) converting compound of formula (IIIa) to compound of formula (II) or pharmaceutically acceptable salt thereof
.

Fourth aspect of the present application relates to the compound of formula (III) or its salt thereof.
;
wherein R is a linear, cyclic, branched alkyl or hetero alkyl; an aryl or hetero aryl or an aryl alkyl, optionally one or more carbon atoms in aryl or hetero aryl or an aryl alkyl are substituted with one or more groups selected from lower alkyl, lower alkoxy, amino, halo, cyano, nitro, azido, and hydroxyl; Preferably, methyl, ethyl, trifluoromethyl, phenyl, toulyl, benzyl and the like.

Specific aspect of the present application relates to the compound of formula (IIIa)

Fifth aspect of the present application relates to a process for preparation of Ritlecitinib or its pharmaceutically acceptable salt thereof comprising converting compound of formula (III) and/or (IIIa) to Ritlecitinib or its pharmaceutically acceptable salt thereof.

Sixth aspect of the present application relates to a process for preparation of Ritlecitinib or its pharmaceutically acceptable salt thereof comprising reacting compound of formula (V) with compound of formula (IV) and/or (IVa) to obtain Ritlecitinib or its pharmaceutically acceptable salt thereof.

Seventh aspect of the present application relates to a process for preparation of Ritlecitinib tosylate (I) comprising converting Ritlecitinib (II) prepared by any of the above aspects to Ritlecitinib tosylate (I).

In further embodiments, the compounds of the present invention may be purified by any method known in the art such as chromatographic purification, crystallization, acid-base salt formation and the like using suitable solvents. Suitable solvent include but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; alcohol solvent but not limited to methanol, ethanol, isopropanol and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; polar aprotic solvents such as DMF, DMSO, DMAc; water; and mixtures thereof.
In further embodiments, pharmaceutically acceptable salts of the compounds of the invention include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, ascorbate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts. Preferably tartrate, tosylate and mesylate. Pharmaceutically acceptable salts of compounds of the invention, may be prepared, respectively, by one or more of three methods: (i) by reacting the compound with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of the invention, or by ring- opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one salt of the compound of the invention, to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column. All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt may vary from completely ionized to almost non-ionized.

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. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

DEFINITIONS
The following definitions are used in connection with the present invention unless the context indicates otherwise.
The term “Halogen” is defined as non-metallic elements found in group VII of the periodic table and is selected from fluorine, bromine, chlorine and iodine.
The term “Hydroxy” is defined as the group –OH.
The term “Alkyl” is defined as straight or branched hydrocarbon radical, or combinations thereof, having 1-12 carbon atoms. Examples may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like.
The term “Hetero Alkyl group” is defined as a straight or branched chain hydrocarbon radical, or combinations thereof, consisting of 1-12 carbon atoms and at least one heteroatom, wherein heteroatoms can be selected from the group consisting of B, O, N and S.
The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
“Aryl group” is defined as monocyclic, bicyclic, and tricyclic ring systems having a total of six to twelve ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “heteroaryl” refers to monocyclic, bicyclic, and tricyclic ring systems having a total of six to twelve ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members.
“Aryl-alkyl group” is defined as an aryl group, as previously defined, attached to the principal carbon chain through an alkyl group, as previously defined. “Substitution” on an “Aryl-alkyl group” is defined by a substitution over the aryl group. Examples may be benzyl, 4-methoxy-benzyl and the like.
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example, "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, “comprising” means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range “between” two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
Amino protecting group is defined as any amino protecting group as known in Greene et al., Protecting groups in organic chemistry, Third Edition, 1999. Examples include benzyloxycarbonyl (Cbz) and tert-Butyloxycarbonyl (Boc), acetyl, benzyl, p-methoxy benzyl, trityl and the like.
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-1: Preparation of benzyl (2S,5R)-5-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidine-1-carboxylate (VIa):

To a mixture of benzyl (2S,5R)-5-amino-2-methylpiperidine-1-carboxylate hydrochloride (VIIIa) (40g) and 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (VII) (22.7g) in 1-butanol (400 mL) was added N,N’-diisopropylethylamine (DIPEA, 122.3 mL) at room temperature. The reaction mixture was heated to 115-120 °C and stirred at the same temperature for 36 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure at 45-50 °C. The obtained residue was mixed with water (280 mL) and extracted with ethyl acetate (3 X 200 mL). The combined ethyl acetate extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure at 45-50 °C. The obtained residue was dissolved in a mixture of ethyl acetate (34 mL) and methanol (107 mL) at room temperature. Water (107 mL) was added to the above solution in drop wise manner at room temperature. The suspension thus obtained was stirred at room temperature for 16 h and then filtered under suction. The obtained solid was washed with water-methanol (1:1, 50 mL) and then dried in oven at 50 °C for 4 hours to obtain the title compound (40.1 g) (HPLC purity: 96.89%).

Example-2: Preparation of N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (V):

To a solution of benzyl (2S,5R)-5-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidine-1-carboxylate (VIa) (20 g) in tetrahydrofuran (150 mL) and methanol (500 mL) was added 10% Pd-C (5 g, 25% w/w) at room temperature. The reaction mixture was degassed with nitrogen and hydrogen. The reaction mixture was subjected to hydrogen pressure (5-6 bar) and heated at 50-55 °C for 24 h. The reaction mixture was then filtered through Celite bed and washed with methanol (100 mL). The combined filtrates were concentrated under reduced pressure at 40-45 °C to obtain the hydrochloride salt of compound of formula (V). The obtained solid was dissolved in a mixture of methanol (50 mL) and water (100 mL) and cooled to 20 °C. Aqueous solution of sodium hydroxide (28 mL, 2N) was added to the above reaction mixture which was then heated to 50-55 °C and stirred at the same temperature for 2 h. The reaction mixture was then cooled to room temperature and stirred for 16 h at the same temperature. The resulting solid was filtered and washed with water (40 mL) and dried in oven at 45-50 °C for 6 hours to obtain the title compound. (9.2 g, HPLC purity: 99.24%).

Example-3: Preparation of N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride (V-HCl salt):

To a solution of benzyl (2S,5R)-5-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidine-1-carboxylate (VIa) (2g), tetrahydrofuran (15 mL) and methanol (50 mL) was added 10% Pd/C (100 mg, 5% w/w) and conc. HCl (1 mL) under nitrogen atmosphere. The reaction mixture was degassed with nitrogen and hydrogen. The reaction mixture was subjected to hydrogen pressure (balloon) and heated at 50-55 °C for 24 h. The reaction mixture was then filtered through Celite bed and washed with methanol (100 mL). The combined filtrates were concentrated under reduced pressure at 30-35 °C to obtain the hydrochloride salt of compound of formula (V) (1.2 g, HPLC purity 99.28%).

Example 4: Preparation of 3-(phenylsulfonyl)propanoyl chloride (IVa):
Thionyl chloride (15 mL) was added slowly to 3-(phenylsulfonyl)propanoic acid (3 g) at 25-30 °C under nitrogen atmosphere. The reaction mixture was heated to 75-80 °C and stirred for 16 hours at the same temperature. The reaction mixture was then concentrated under reduced pressure at 35-40 °C. The resulting solid was mixed with toluene (30 mL) and concentrated under reduced pressure at 35-40 °C to obtain the title compound (3.15 g), which was taken forward to the next step without further purification.

Example-5: Preparation of Ritlecitinib (II):

To a solution of N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (V) (1 g) in tetrahydrofuran (10 mL) and water (5 mL) was added potassium phosphate tribasic (2.128 g) in portion-wise manner. The reaction mixture was cooled to 5-10 °C and treated with 3-(phenylsulfonyl)propanoyl chloride (1.21 g) at the same temperature. The reaction mixture was warmed to room temperature and stirred at the same temperature for 2 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (3X10 mL). The combined ethyl acetate extracts were dried over sodium sulphate and concentrated under reduced pressure at 25-30 °C. The resulting solid was dissolved in acetonitrile (10 mL) and cooled to 20-25 °C. To the above reaction mixture was added aqueous sodium hydroxide solution (6 mL, 2N) and stirred at 20-25 °C for 10 min. The reaction mixture was then heated to room temperature and stirred for 5 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 X 10 mL). The extracts were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure at 25-30 °C. The obtained crude product was purified by silica gel chromatography using DCM-MeOH as an eluent to obtain the title compound (0.7 g, HPLC purity 99.82%).
Characteristic data for compound of formula (IIIa): 1H NMR (400 MHz, DMSO-d6): d 11.53 (s, 0.6H), 11.48 (s, 0.4H), 8.09 (s, 0.6H), 8.07 (s, 0.4H), 7.99 – 7.88 (m, 2H), 7.82 – 7.71 (m, 1H), 7.71 – 7.58 (m, 2H), 7.31 (d, J = 6.9 Hz, 0.6H), 7.19 (d, J = 8.1 Hz, 0.4H), 7.13 – 7.08 (m, 0.6H), 7.08 – 7.02 (m, 0.4H), 6.60 – 6.54 (m, 0.6H), 6.54 – 6.47 (m, 0.4H), 4.72 – 4.57 (m, 0.6H), 4.50 – 4.36 (m, 0.4H), 4.19 – 4.06 (m, 0.4H), 4.05 – 3.80 (m, 1.6H), 3.78 – 3.64 (m, 0.6H), 3.63 – 3.47 (m, 1.4H), 2.98 – 2.75 (m, 1.6H), 2.74 – 2.53 (m, 1.4H), 1.90 – 1.46 (m, 4H), 1.19 (d, J = 6.8 Hz, 1.2H), 1.08 (d, J = 7.0 Hz, 1.8H). Mass (m/z): 428 [M+H]+

Example-6: Preparation of Ritlecitinib (II):

To a solution of N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (V) as hydrochloride salt (0.5 g) in tetrahydrofuran (5 mL) and water (2.5 mL) was added potassium phosphate tribasic (1.387 g) in portion-wise manner. The reaction mixture was cooled to 5-10 °C and treated with 3-(phenylsulfonyl)propanoyl chloride (0.565 g) at the same temperature. The reaction mixture was warmed to room temperature and stirred at the same temperature for 1.5 hours. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (3 X 5 mL). The combined ethyl acetate extracts were dried over sodium sulphate and concentrated under reduced pressure at 25-30 °C. The resulting solid was dissolved in acetonitrile (5 mL) and cooled to 20-25 °C. To the above reaction mixture was added aqueous sodium hydroxide solution (2.8 mL, 2N) and stirred at 20-25 °C for 10 min. The reaction mixture was then heated to room temperature and stirred for 5 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 X 5 mL). The extracts were combined, dried over anhydrous sodium sulphate and concentrated under reduced pressure at 25-30 °C. The obtained crude product was purified by silica gel chromatography using DCM-MeOH as an eluent to obtain the title compound (0.27 g, HPLC purity 96.08%).

Dated: 11th Day of February 2025.
Signature: _________________
Dr. B. Dinesh Kumar.
Intellectual Property Management,
Dr. Reddy’s Laboratories Limited.
,CLAIMS:We Claim:
1. A process for preparation of Ritlecitinib (II) or pharmaceutically acceptable salt thereof, comprising
(i) reacting compound of formula (V) or salt or hydrate or solvate thereof with compound of formula (IV) to obtain compound of formula (III)
;
(ii) converting compound of formula (III) to compound of formula (II) or pharmaceutically acceptable salt thereof
;
wherein R is a linear, cyclic, branched alkyl or hetero alkyl; an aryl or hetero aryl or an aryl alkyl, optionally one or more carbon atoms in aryl or hetero aryl or an aryl alkyl are substituted with one or more groups selected from lower alkyl, lower alkoxy, amino, halo, cyano, nitro, azido, and hydroxyl; X is a halogen, hydroxyl, -OR, -OCOR; .

2. The process as claimed in claim 1, wherein step (i) is carried out in presence of a suitable reagent selected form group comprising lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium phosphates tribasic (K3PO4), potassium phosphate dibasic (K2HPO4), potassium phosphate monobasic (KH2PO4), sodium phosphate mono basic, sodium phosphate dibasic, sodium phosphate tribasic; triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-Diazabicyclo[5.4.0]undec-7-ene, 1,5-Diazabicyclo(4.3.0)non-5-ene, N-methylmorpholine, N-methylpyrrolidine.

3. The process as claimed in claim 1) wherein step (ii) is carried out in presence of a suitable base selected from a group comprising lithium hydroxide, sodium hydroxide and potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, sodium methoxide, sodium t-butoxide, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 1,8-Diazabicyclo[5.4.0]undec-7-ene.

4. A process for preparation of Ritlecitinib (II) or pharmaceutically acceptable salt thereof, comprising
(i) reacting compound of formula (VIII) or its salt with compound of formula (VII) to obtain compound of formula (VI)
;
(ii) converting compound of formula (VI) to compound of formula (V) or salt or hydrate or solvate thereof
;
(iii) reacting compound of formula (V) or salt or hydrate or solvate thereof with compound of formula (IV) to obtain compound of formula (III)
;
(iv) converting compound of formula (III) to compound of formula (II) or pharmaceutically acceptable salt thereof

wherein R is a linear, cyclic, branched alkyl or hetero alkyl; an aryl or hetero aryl or an aryl alkyl, optionally one or more carbon atoms in aryl or hetero aryl or an aryl alkyl are substituted with one or more groups selected from lower alkyl, lower alkoxy, amino, halo, cyano, nitro, azido, and hydroxyl; X is a halogen, hydroxyl, -OR, -OCOR; .

5. A process for preparation of Ritlecitinib or pharmaceutically acceptable salt thereof, comprising
(i) reacting compound of formula (V) or salt or hydrate or solvate thereof with compound of formula (IVa) to obtain compound of formula (IIIa) in presence of a suitable reagent
;
(ii) converting compound of formula (IIIa) to compound of formula (II) or its tosylate, in presence of a suitable reagent
.

6. The process as claimed in claim 5) wherein, suitable reagents of step (i) and (ii) are potassium phosphate tribasic and sodium hydroxide respectively.

7. Compound of formula (III) or its salt thereof.

wherein R is a linear, cyclic, branched alkyl or hetero alkyl; an aryl or hetero aryl or an aryl alkyl, optionally one or more carbon atoms in aryl or hetero aryl or an aryl alkyl are substituted with one or more groups selected from lower alkyl, lower alkoxy, amino, halo, cyano, nitro, azido, and hydroxyl.

8. A process for preparation of Ritlecitinib or its pharmaceutically acceptable salt thereof comprising converting compound of formula (III) to Ritlecitinib or its pharmaceutically acceptable salt thereof.