Process for the preparation of ritlecitinib and intermediates thereof

Abstract

The present invention provides processes for the preparation of ritlecitinib or a pharmaceutically acceptable salt thereof substantially free of a dimer compound (the dimer impurity). The invention also relates to a process for the preparation of an amorphous form of ritlecitinib tosylate.

Description

RITLE-2026PROCESS FOR THE PREPARATION OF RITLECITINIB AND INTERMEDIATES THEREOFPRIORITY

[0001] This application claims the benefit of Indian Provisional Application 202521024883 filed on March 19, 2025, entitled “PROCESS FOR THE PREPARATION OF RITLECITINIB AND INTERMEDIATES THEREOF”, the contents of which are incorporated herein by reference.BACKGROUND OF THE INVENTIONTechnical Field

[0002] The present invention relates to processes for the preparation of ritlecitinib or a pharmaceutically acceptable salt thereof substantially free of a dimer compound (the dimer impurity). The present invention also relates to a process for the preparation of an amorphous form of ritlecitinib tosylate.Description of the Related Art

[0003] The chemical name of ritlecitinib is l-{(2S,5R)-2-methyl-5-[(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-l-yl}prop-2-en-l-one, which is represented by the compound of formula I (the “compound I”).

[0004] Ritlecitinib and its pharmaceutically acceptable salts are described in U.S. Patent No. 9,617,258 (the “US’258 Patent”).

[0005] Ritlecitinib tosylate, represented by the compound of formula la (“the compound la”), is described in U.S. Patent No. 12,116,368 (the “US’368 Patent”).la

[0006] Ritlecitinib tosylate is a kinase inhibitor indicated for the treatment of severe alopecia areata. Ritlecitinib tosylate is marketed in the US as LITFULO® in capsule dosage form for oral administration.

[0007] Various processes for the preparation of ritlecitinib and its tosylate salt are reported in the art.

[0008] The US’258 patent describes a process for the preparation of ritlecitinib (the compound I) wherein rac-N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine HC1 (hydrochloride salt of the compound II) is reacted with acryloyl chloride in tetrahydrofuran, and in the presence of sodium bicarbonate to obtain racemic ritlecitinib, which is purified by chiral SFC (Supercritical fluid chromatography) to obtain ritlecitinib (the compound I).

[0009] The US’368 patent describes a process for the preparation of ritlecitinib (the compound I) and ritlecitinib tosylate (the compound la) wherein N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrate (hydrate of the compound II) is reacted with 3 -chloropropionyl chloride in water, tetrahydrofuran, and in the presence of tripotassium phosphate to obtain ritlecitinib (the compound I). Ritlecitinib is further treated with p-toluenesulfonic acid in methyl ethyl ketone to obtain ritlecitinib tosylate (the compound la).

[0010] A non-patent literature reference namely Org. Process Res. Dev. 2019, 23, 9, 1872-1880 describes that there are certain disadvantages associated with the processes for the preparation of ritlecitinib or a pharmaceutically acceptable salt thereof described in the afore mentioned US patent. Among other things, the non-patent literature indicates that the processes reported in the said US patent result in the formation of undesired byproducts or impurities, for instance it is reported that these processes result in the formation of the unwanted dimer compound (as described hereinafter) in undesired quantity along with the final product, ritlecitinib or its tosylate salt. The impurities thatare formed are required to be removed by column chromatography, which ultimately affects the yield of the final product.

[0011] It is a known fact that providing drug substances having high purity in good yield is considered a critical aspect in pharmaceutical industry, particularly for ensuring the safety, efficacy and consistency of the pharmaceutical composition containing the drug substance. The present invention provides processes for the preparation of ritlecitinib and pharmaceutically acceptable salts thereof having higher purity.SUMMARY OF THE INVENTION

[0012] The present invention provides a process for the preparation of ritlecitinib represented by a compound of formula I (the “compound I”) or a pharmaceutically acceptable salt thereof,the process comprising the steps of:(a) reacting a compound of formula II (the “compound II”) or a hydrate or a salt thereof,IIwith a compound of formula III (the “compound III”),IIIwherein Y is an activating group; and X is -S(O)2R; wherein R is selected from (Ci- Cs)alkyl optionally substituted with aryl or (C3-Cs)cycloalkyl, or aryl optionally substituted with one or more groups selected from (Ci-C5)alkyl, (Ci-C5)alkoxy,bromine, chlorine, fluorine, iodine or nitro; to obtain a compound of formula IV (the “compound IV”)IVwherein X is as defined above;(b) reacting the compound IV with a base to obtain the compound I, and(c) optionally converting the compound I to its pharmaceutically acceptable salt.

[0013] In the compound of formula III, the activating group Y is selected from hydroxy, chlorine, bromine, fluorine, iodine, -OR1or -O(CO)R2, wherein R1and R2are (Ci-C5)alkyl.

[0014] The present invention also provides an intermediate compound represented by the compound of formula IV (the “compound IV”)--- AW HIVwherein X is -S(O)2R, and wherein R is selected from (Ci-Cs)alkyl optionally substituted with aryl or (C3-Cs)cycloalkyl, or aryl optionally substituted with one or more groups selected from (Ci-C5)alkyl, (Ci-C5)alkoxy, bromine, chlorine, fluorine, iodine or nitro.

[0015] The present invention also relates to the compound of formula IV (the compound IV) for use in the preparation of ritlecitinib, the compound I or a pharmaceutically acceptable salt thereof.

[0016] The present invention also provides a further process for the preparation of ritlecitinib represented by a compound of formula I (the “compound I”) or a pharmaceutically acceptable salt thereof,Icomprising reacting a compound of formula II (the “compound II”) or a hydrate or a salt thereof,IIwith acryloyl chloride in the presence of a buffer solution to obtain the compound I, and optionally converting it to its pharmaceutically acceptable salt.

[0017] The processes for the preparation of ritlecitinib (the “compound I”) of the present invention provides the compound I or a pharmaceutically acceptable salt thereof, which is substantially free of a dimer compound, represented by the compound of Formula A (the “compound A” or the dimer impurity).A

[0018] The present invention also provides a process for the preparation of an amorphous form of ritlecitinib tosylate represented by the compound of formula la (the compound la)lawherein the process comprises the steps of:(i) providing a reaction mixture of ritlecitinib tosylate in a mixture of solvents comprising of an alcohol solvent and a chlorinated solvent; and(ii) removing the solvents from the reaction mixture obtained in the step (i) to obtain the amorphous form of the compound la.

[0019] These and other aspects of the present invention will be apparent from the following description.BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 illustrates characteristic XRPD (X-Ray Powder Diffraction) pattern of an amorphous form of ritlecitinib tosylate as obtained in example 9.DETAILED DESCRIPTION OF THE INVENTION

[0021] In an aspect, the present invention relates to a process for the preparation of ritlecitinib represented by a compound of formula I (the “compound I”) or a pharmaceutically acceptable salt thereof,O JkC X.,, Js*Ithe process comprising the steps of:(a) reacting a compound of formula II (the “compound II”) or a hydrate or a salt thereof,with a compound of formula III (the “compound III”),IIIwherein Y is an activating group; and X is -S(O)2R; and wherein R is selected from (Ci-Cs)alkyl optionally substituted with aryl or (Cs-Csjcycloalkyl, or aryl optionally substituted with one or more groups selected from (Ci-C5)alkyl, (Ci-C5)alkoxy, bromine, chlorine, fluorine, iodine or nitro, to obtain a compound of formula IV (the “compound IV”)IVwherein X is as defined above;(b) reacting the compound IV with a base to obtain the compound I, and(c) optionally converting the compound I to its pharmaceutically acceptable salt.

[0022] In the compound of formula III, the activating group Y is selected from hydroxy, chlorine, bromine, fluorine, iodine, -OR1or -O(CO)R2, wherein R1and R2are (Ci-C5)alkyl.

[0023] The term “pharmaceutically acceptable salts” as used herein includes, but not limited to salts selected from tosylate, phosphate, malonate, maleate, tartrate, and glutamate salts of ritlecitinib.

[0024] In the context of the present invention, the term "optionally" when used in reference to a process step e.g. conversion of a compound to its pharmaceutically acceptable salt thereof, as applicable, it is intended to mean that the subject compound may be converted to pharmaceutically acceptable salt, or alternatively, the subject compound may not be converted to its salt or pharmaceutically acceptable salt. Both alternatives are intended to be within the scope of the present invention.

[0025] As used herein, the term “about” refers to any value which lies within the range defined by a number up to 10% of the value.

[0026] As used herein, the term “(Ci-C5)alkyl” includes groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, or n-pentyl; wherein the (C1-C5) alkyl group is optionally substituted with aryl or (C3-C5)cycloalkyl.

[0027] As used herein, the term “(C3-C5)cycloalkyl” includes groups such as cyclopropyl, cyclobutyl, or cyclopentyl.

[0028] As used herein, the term “(Ci-C5)alkoxy” includes groups such as methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, or n-pentyloxy.

[0029] As used herein, the term “aryl” includes groups such as phenyl, tolyl, xylyl, or naphthyl.

[0030] In the process of the present invention, the compound of formula II (the “compound II”) or a hydrate or a salt thereof used in the step (a) of the afore mentioned process, can be prepared according to the process reported in the US ’368 Patent, or the non-patent literature reference namely Org. Process Res. Dev. 2019, 23, 9, 1872-1880.

[0031] In the process of the present invention, the salt of the compound of formula II (the “compound II”) that can be used in the step (a) of the process of the present invention is selected from the hydrochloride salt, the hydrobromide salt or the hydrofluoride salt of the compound of formula II.

[0032] In an embodiment, in the process of the present invention, Y is an activating group selected from hydroxy, chlorine, bromine, fluorine, iodine, -OR1and -O(CO)R2, wherein R1and R2are (Ci-C5)alkyl.

[0033] In an embodiment, in the process of the present invention, the step (a) is carried out in a solvent selected from a nitrile solvent or an ether.

[0034] In an embodiment, in the process of the present invention, the step (a) is carried out in nitrile solvent selected from the group consisting of acetonitrile, propionitrile, and butyronitrile.

[0035] In another embodiment, in the process of the present invention, the step (a) is carried out in ether selected from the group consisting of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane.

[0036] In an embodiment, in the process of the present invention, the step (a) is carried out in the presence of a base selected from an organic base, an inorganic base, or a mixture thereof.

[0037] In an embodiment, in the process of the present invention, the step (a) is carried out in the presence of an organic base selected from triethylamine, diisopropylethylamine, trimethylamine, tributylamine, or triphenylamine.

[0038] In another embodiment, in the process of the present invention, the step (a) is carried out in the presence of an inorganic base selected from potassium carbonate, sodium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, or a mixture thereof.

[0039] In an embodiment, in the process of the present invention, the step (a) is carried out in the presence of a mixture of an organic base and an inorganic base; wherein the organic base and the inorganic base are as described above.

[0040] In an embodiment, in the process of the present invention, the reaction of the compound II or a hydrate or a salt thereof with the compound III in the step (a) is carried out at a temperature ranging from about 5°C to about 40°C.

[0041] In an aspect, the present invention relates to a compound of formula IV (the compound IV),IVwherein X is -S(O)2R, and wherein R is selected from (Ci-Cs)alkyl optionally substituted with aryl or (C3-Cs)cycloalkyl, or aryl optionally substituted with one or more groups selected from (Ci-C5)alkyl, (Ci-C5)alkoxy, bromine, chlorine, fluorine, iodine or nitro.

[0042] In another embodiment, the present invention relates to a compound of formula IV, wherein X is -S(O)2R, and wherein R is (Ci-C5)alkyl optionally substituted with aryl or (C3-C5)cycloalkyl.

[0043] In another embodiment, the present invention relates to a compound of formula IV, wherein X is -S(O)2R, and wherein R is (Ci-Cs)alkyl.

[0044] In an embodiment, in the process for the present invention, the step (b) involving reaction of the compound IV with a base is carried out in a solvent selected from the solvents as described above in respect of the step (a).

[0045] In an embodiment, in the process for the present invention, the base used in the step (b) is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, potassium carbonate, sodium carbonate, and lithium carbonate.

[0046] In an embodiment, in the step (b) of the process of the present invention, the reaction of the compound IV with the base is carried out at a temperature ranging from about 0°C to about 40°C.

[0047] In an embodiment, in the process of the present invention, in the step (c) of the process of the present invention, the compound I obtained in the step (b) can be converted to a pharmaceutically acceptable salt thereof.

[0048] In an embodiment, in the step (c) of the process of the present invention, the pharmaceutically acceptable salt of ritlecitinib is obtained by treating the compound I (ritlecitinib) with a suitable acid selected from p-toluenesulfonic acid, phosphoric acid, malonic acid, maleic acid, tartaric acid, or L-glutamic acid.

[0049] In an embodiment, in the step (c) of the process of the present invention involving conversion of the compound I to its pharmaceutically acceptable salt, the compound I is treated with an acid in the presence of a solvent selected from water, ketone, alcohol, ester, nitrile, chlorinated solvent; wherein the ketone is selected from acetone, methyl isobutyl ketone, methyl ethyl ketone, cyclohexanone; the alcohol is selected from methanol, ethanol, propanol, isopropanol, butanol; the ester is selected from ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate; the nitrile is selected from acetonitrile, propionitrile, butyronitrile; and the chlorinated solvent is selected from dichloromethane, dichloroethane, chloroform, or a mixture thereof.

[0050] In an embodiment, in the step (c) of the process of the present invention, the compound I is converted to its tosylate salt, ritlecitinib tosylate (the compound la) by treating the compound I with p-toluenesulfonic acid.

[0051] In yet another aspect, the present invention provides a further process for the preparation of ritlecitinib represented by a compound of formula I (the “compound I”) or a pharmaceutically acceptable salt thereof,¥Icomprising reacting a compound of formula II (the “compound II”) or a hydrate or a salt thereof,HIIwith acryloyl chloride in the presence of a buffer solution to obtain the compound I, and optionally converting the compound I to a pharmaceutically acceptable salt thereof.

[0052] In an embodiment, in the process of the present invention, the buffer solution has pH in the range of 7.5 to 8.5.

[0053] In an embodiment, the buffer solution is composed of reagents such that the pH of the buffer ranges from 7.5 to 8.5.

[0054] In the process of the present invention, the buffer solution having pH in the range of 7.5 to 8.5 is composed of reagents selected from, but not limited to, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydroxide, potassium hydroxide, sodiumcarbonate, potassium carbonate, lithium hydroxide, ammonium hydroxide, cesium hydroxide and calcium hydroxide.

[0055] In an embodiment, in the process of the present invention, the buffer solution is composed of reagents selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydroxide and potassium hydroxide.

[0056] The inventors of the present invention have found through their diligent efforts that when the reaction of the compound II or its salt or its hydrate with acryloyl chloride is carried out in the presence of a buffer solution having pH between 7.5 and 8.5, it surprisingly results in the formation of the desired compound, ritlecitinib (the compound I) substantially free of the dimer impurity (compound A). Particularly, the inventors observed that use of the buffer solution having pH less than 7.5 results in an incomplete reaction, that is less than 50% of the compound II or its salt or its hydrate is converted to ritlecitinib. Also, the present inventors found that use of buffer solution having pH greater than 8.5 results in the formation of the undesired dimer impurity, the compound A in higher content.

[0057] In an embodiment, the process of the present invention involving reaction of the compound II or its hydrate or its salt with acryloyl chloride is carried out in a solvent selected from tetrahydrofuran (THF), acetone, methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, pentanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,4- dioxane, acetonitrile or sulfolane.

[0058] In an embodiment, the process of the present invention involving reaction of the compound II or its salt or its hydrate with acryloyl chloride is carried out at a temperature ranging from 0°C to 10°C.

[0059] In an embodiment, the obtained compound I as per the above process is converted to a pharmaceutically acceptable salt thereof.

[0060] In one embodiment, in the process of the present invention involving reaction of the compound II or its salt or its hydrate with acryloyl chloride; the resulting ritlecitinib, the compound I is converted to its pharmaceutically acceptable salt by treating it with a suitable acid as described above in respect of the step (c).

[0061] In one aspect, the processes for the preparation of ritlecitinib (the “compound I”) of the present invention provides compound I, which is substantially free of a dimer impurity, the compound A.

[0062] The term “substantially free” as used herein, unless otherwise defined, refers to ritlecitinib (the “compound I”), or its tosylate salt (the “compound la”) that contains the dimer impurity, the compound A, in a range from about 0.01 % to about 0.5 % w / w, as measured by HPLC (High-performance liquid chromatography).A

[0063] It is known in the art that impurities associated with therapeutic active pharmaceutical ingredients should be limited to a level as recommended by ICH guidelines and the removal of such impurities involve complex process. The present inventors have found processes that result in the formation of substantially pure ritlecitinib having lower content of dimer impurity, the compound A as described herein.

[0064] In an aspect, the present invention relates to a process for the preparation of an amorphous form of ritlecitinib tosylate represented by the compound of formula la (the compound la)Glawherein the process comprises the steps of:(i) providing a reaction mixture of ritlecitinib tosylate in a mixture of solvents comprising of an alcohol solvent and a chlorinated solvent; and(ii) removing the solvents from the reaction mixture obtained in the step (i) to obtain the amorphous form of the compound la.

[0065] In an embodiment, in the process for the preparation of the amorphous form of ritlecitinib tosylate of the present invention, the ritlecitinib tosylate used in the step (i) is obtained by the process for the preparation of ritlecitinib described above, wherein the process involves the reaction of the compound II or its salt or its hydrate with acryloyl chloride.

[0066] In an embodiment, in the process for the preparation of the amorphous form of ritlecitinib tosylate of the present invention, the ritlecitinib tosylate used in the step (i) can be obtained by any process for the preparation of ritlecitinib tosylate known in the art, for instance the process reported in the US Patent No. 12, 116,368.

[0067] In an embodiment, in the step (i) of the process for the preparation of an amorphous form of ritlecitinib tosylate of the present invention, wherein the alcohol solvent used in the solvent mixture is selected from methanol, ethanol, n-propanol, isopropanol, or n-butanol.

[0068] In an embodiment, in the step (i) of the process for the preparation of an amorphous form of ritlecitinib tosylate of the present invention, wherein the chlorinated solvent used in the solvent mixture is selected from dichloromethane, dichloroethane, or chloroform.

[0069] In an embodiment, in the step (i) of the process for the preparation of an amorphous form of ritlecitinib tosylate, the solvent mixture comprises of methanol and dichloromethane .

[0070] In an embodiment, in the step (i) of the process for the preparation of an amorphous form of ritlecitinib tosylate of the present invention, the reaction mixture of the step (i) is stirred at a temperature ranging from about 10°C to about 40°C for a period from about 10 minutes to about 5 hours.

[0071] In an embodiment, in the step (ii) of the process for the preparation of an amorphous form of ritlecitinib tosylate of the present invention, the solvent is removed using a suitable method selected from solvent evaporation, distillation, lyophilization, spray drying, agitated thin fdm drying (ATFD), fdtration, air tray drying, vacuum tray drying or cooling the solution.

[0072] In an embodiment, in the step (ii) of the process for the preparation of an amorphous form of ritlecitinib tosylate of the present invention, the solvent is removed by spray drying.

[0073] The amorphous form of ritlecitinib tosylate as described herein, is characterized by the X-ray powder diffraction pattern as substantially illustrated in Figure 1.

[0074] In an aspect, the present invention relates to a pharmaceutical composition comprising an amorphous form of ritlecitinib tosylate prepared by a process of the present invention, and at least one pharmaceutically acceptable excipient selected from a diluent, a disintegrant, a binder, a lubricant, a glidant, a surfactant or a mixture thereof

[0075] In an embodiment, the present invention provides pharmaceutical composition comprising ritlecitinib, the compound I or a pharmaceutically acceptable salt thereof obtained by the process described herein, having a D90 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns, and most preferably less than about 10 microns.

[0076] In an embodiment, the present invention provides pharmaceutical compositions comprising ritlecitinib, the compound I or a pharmaceutically acceptable salt thereof obtained by the processes described herein, having a D50 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns, and most preferably less than about 10 microns.

[0077] The compound I having the specified particle size can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state ritlecitinib or a pharmaceutically acceptable salt thereof into any of the foregoing desired particle size range.

[0078] The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. 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.Examples:General Methods:HPLC method:High performance liquid chromatography (HPLC) was performed with the conditions described below for detecting chemical purity:Apparatus: A High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and integrator software.Column: YMC Triart C18, 150 X 4.6mm, 5pPart no: TA12S05-1546WTMake: YMCColumn temperature: 30°CSample cooler Temperature: 10°CBuffer: 0.01M Ammonium Bicarbonate in 1000 ml of water and adjust pH 9.0 with Dil. Ammonia solutionMobile Phase A: Buffer: Methanol (1000:20, v / v)Mobile Phase B: Acetonitrile: Methanol (700:300, v / v)Time (min) % Mobile Phase A % Mobile Phase B0.01 85 153 85 1530 60 4040 20 8050 20 8051 85 1558 85 15Diluent: Water: Methanol (20:80, v / v)Flow Rate: LO mL / minuteDetection: UV 275 nmInjection Volume: 5pLRuntime: 58.0 MinutesRinsing solution: Methanol: water (80:20, v / v)Needle wash: Methanol: water (80:20, v / v)Seal wash: Methanol: Water (10:90, v / v)X-Ray Powder Diffraction (XRPD) (Instrumental settings):Incident Beam Optics:PreFIX Module : Programmable Divergence Slit with FAAS (Offset 0.0000°) Filter : NickelSeller Slit : Seller 0.02 radMask : 10mmDivergence Slit : PDSAutomatic, 10mm Irradiated length, Offset 0.00mmAnti-scatter Slit : Slit Fixed 1 / 2°Beam Knife : *Beam Knife for linear DetectorsDiffracted Beam Optics:PreFIX Module : *PIXcel-lD (Offset 0.0000°)Seller Slit : Seller 0.02 radAnti-scatter Slit : Programmable Anti-scatter SlitAutomatic, 10mm Observed length, Offset 0.00mmDetector : *PIXcel-lDScanning Mode, Active length (2Theta) = 3.3482°Measurement Parameters:Scan axis : GonioScan mode : ContinuousStart angle (°) : 2.0End angle (°) : 50.0Step size (°) : 0.013Time per step (s) : 1000* Parameters may change based on the make and model of the instrument.Sample Preparation:Take adequate amount of the sample so as to fill the sample holder using Back-loading technique. Then load the sample holder between the X-ray optics-path and scan using the above-described parameters. Integrate the obtained powder X-ray diffraction profiles using High Score software.Example 1 : l-((2S,5R)-5-((7H-pyrrolo [2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-l-yl)-prop-3-methylsulfonyl-l-one (the compound IV)In a round botom flask, N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]-pyrimidin-4-amine monohydrate (1.08 g) and acetonitrile (10 ml) were added to obtain a reaction mass. Triethylamine (1.31 g) was added to the reaction mass under stirring at a temperature in the range of 20°C to 30°C. A solution of 3-(Methyl sulphonyl) propionic chloride (1.12 g) in acetonitrile (5 ml) was slowly added to the reaction mass and the reaction mass was stirred for about 2 hours at a temperature in the range of 20°C to 30°C. After the completion of the reaction, acetonitrile was distilled and degassed to obtain a residue. The residue was dissolved in dichloromethane (10 ml). Water (10 ml) was added to the reaction mass under stirring and organic layer was separated. Dichloromethane was distilled and degassed to obtain the compound IV.Yield: 1.34 g (85%)Purity: 98.29% (as determined by HPLC).JH-NMR (DMSO-d6): 5(ppm) 11.51 (brs, 2H), 8.11 (d, 2H), 7.35 (d, 1H), 7.24 (d, 1H),7.O9 (m, 2H), 6.55 (m, 2H), 4.77 (m, 1H), 4.54 (m, 1H), 4.24 (m, 1H), 4.05 (m, 3H), 3.05 (m, 7H), 2.75 (m, 2H), 1.79 (m, 4H), 1.67 (m, 3H), 1.25 (d, 3H), 1.14 (d, 3H);HRMS [M+H]+: 366.30Example 2: Ritlecitinib (the compound I)In a round botom flask, l-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-l-yl)-prop-3 -methylsulfonyl- 1 -one (1.34 g) and THF (15 ml) were added to obtain a reaction mass. The reaction mass was stirred at a temperature in the range of 20°C to 30°C for a period of 15 minutes. The reaction mass was cooled to a temperature in the range of 0°C to 5 °C. A solution of sodium hydroxide (0.5 g) in water (2 ml) was added to the reaction mass and the reaction mass was stirred for about 30 minutes at a temperature in the range of 0°C to 5°C. The temperature of the reaction mass was raised in the range of 20°C to 30°C. The reaction mass was stirred at a temperature in the range of 20°C to 30°C for a period of 10 to 15 hours. After the completion of the reaction, purified water (10 ml) and isopropyl acetate (10 ml) were added to the reaction mass. The organic layer was separated, and organic layer was distilled out to obtain ritlecitinib.Yield: 0.99 g (95%)Purity: 98.5% (as determined by HPLC).Dimer impurity (the compound A): 0.02% (as determined by HPLC)Example 3: Ritlecitinib (the compound I)In a round bottom flask, buffer solution having pH 8.0 was prepared by using a solution potassium dihydrogen phosphate (81.87 g) in water (400 ml) and 10% sodium hydroxide aqueous solution (180 ml). N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]-pyrimidin-4-amine monohydrate (10 g) and tetrahydrofuran (200 ml) were added to the buffer solution to obtain a reaction mass. The reaction mass was cooled to a temperature in the range of 0°C to 5°C. A solution of acryloyl chloride (7.26 g) in tetrahydrofuran (10 ml) was cooled to a temperature in the range of 0°C to 10°C, and was slowly added to the reaction mass under stirring at a temperature in the range of 0°C to 5 °C. The reaction mass was stirred for about 1 to 2 hours at a temperature in the range of 0°C to 5°C. After the completion of the reaction, the reaction mass was warmed to a temperature in the range of 12°C to 15 °C. Sodium chloride (7.8 g) and isopropyl acetate (100 ml) were added to the reaction mass. The organic layer was separated, the aqueous layer was extracted twice with isopropyl acetate (100 ml). The combined organic layer was distilled out to obtain ritlecitinib.Yield: 9.7 g (85%)Purity: 99.3% (as determined by HPLC).Dimer impurity (the compound A): 0.02% (as determined by HPLC)Example 4: Ritlecitinib tosyate (the compound la)In a round bottom flask, ritlecitinib (2 g) and methyl ethyl ketone (10 ml) were added to obtain a reaction mass. The reaction mass was stirred at a temperature in the range of 20°C to 30°C for a period of 15 minutes. The reaction mass was cooled to a temperature in the range of 0°C to 5°C. A solution of p-toluenesulfonic acid (1.35 g) in methyl ethyl ketone (10 ml) was slowly added to the reaction mixture at a temperature in the range of 0°C to 5°C and the reaction mass was stirred for about 120 minutes at a temperature in the range of 0°C to 5 °C. The product was filtered and washed with methyl ethyl ketone (4 ml) . The wet cake was dried at a temperature in the range of 30°C to 40°C in vacuum tray dryer to obtain ritlecitinib tosylate.Yield: 2.72 g (85%)Purity: 99.8% (as determined by HPLC).Dimer impurity (the compound A): 0.02% (as determined by HPLC)Example 5: Ritlecitinib tosylate (the compound la)In a round bottom flask, ritlecitinib (2 g) and ethanol (8 ml) were added to obtain a reaction mass. The reaction mass was stirred at a temperature in the range of 20°C to 30°C for a period of 15 minutes. The reaction mass was cooled to a temperature in the range of 0°C to 5°C. A solution of p-toluene sulfonic acid (1.35 g) in ethanol (2 ml) was slowly added to the reaction mixture at a temperature in the range of 0°C to 5 °C and the reaction mass was stirred for about 120 minutes at a temperature in the range of 0°C to 5 °C. The product was filtered and washed with ethanol (2 ml) . The wet cake was dried at a temperature in the range of 30°C to 40°C in vacuum tray dryer to obtain ritlecitinib tosylate.Yield: 2.56 g (80%)Purity: 99.85% (as determined by HPLC).Dimer impurity (the compound A): 0.02% (as determined by HPLC)Example 6: Ritlecitinib tosylate (the compound la)In a round bottom flask, ritlecitinib (2 g) and isopropanol (20 ml) were added to obtain a reaction mass. The reaction mass was stirred at a temperature in the range of 20°C to 30°C for a period of 15 minutes. The reaction mass was cooled to a temperature in the range of 0°C to 5°C. A solution of p-toluene sulfonic acid (1.35 g) in isopropanol (10 ml) was slowly added to the reaction mixture at a temperature in the range of 0°C to 5 °C and the reaction mass was stirred for about 120 minutes at a temperature in the range of 0°C to 5 °C. The product was filtered and washed with isopropanol (2 ml) . The wet cake was dried at a temperature in the range of 30°C to 40°C in vacuum tray dryer to obtain ritlecitinib tosylate.Yield: 2.72 g (85%)Purity: 99.7% (as determined by HPLC).Dimer impurity (the compound A): 0.02% (as determined by HPLC)Example 7: Ritlecitinib tosylate (the compound la)In a round bottom flask, ritlecitinib (2 g) and methanol (2 ml) were added to obtain a reaction mass. The reaction mass was stirred at a temperature in the range of 20°C to 30°C for a period of 15 minutes. The reaction mass was cooled to a temperature in the range of 0°C to 5°C. A solution of p-toluene sulfonic acid (1.35 g) in acetonitrile (15 ml) was slowly added to the reaction mixture at a temperature in the range of 0°C to 5 °C and the reaction mass was stirred for about 120 minutes at a temperature in the range of 0°C to 5 °C. The product was filtered and washed with acetonitrile (2 ml) . The wet cake was dried at a temperature in the range of 30°C to 40°C in vacuum tray dryer to obtain ritlecitinib tosylate.Yield: 2.50 g (79%)Purity: 99.55% (as determined by HPLC).Dimer impurity (the compound A): 0.02% (as determined by HPLC)Example 8: Ritlecitinib tosylate (the compound la)In a round bottom flask, buffer solution having pH 8.0 was prepared by using a solution potassium dihydrogen phosphate (81.87 g) in water (400 ml) and 10% sodium hydroxide aqueous solution (180 ml). N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]-pyrimidin-4-amine monohydrate (10 g) and tetrahydrofuran (200 ml) were added to the buffer solution to obtain a reaction mass. The reaction mass was cooled to a temperature in the range of 0°C to 5°C. A solution of acryloyl chloride (7.26 g) in tetrahydrofuran (10 ml) was cooled to a temperature in the range of 0°C to 10°C, and was slowly added to the reaction mass under stirring at a temperature in the range of 0°C to 5 °C. The reaction mass was stirred 1 hour at a temperature in the range of 0°C to 5°C. After the completion of the reaction, the reaction mass was warmed to a temperature in the range of 12°C to 15 °C. Sodium chloride (7.8 g) and isopropyl acetate (100 ml) were added to the reaction mass. The organic layer was separated, the aqueous layer was extracted twice with isopropyl acetate (100 ml). The combined organic layer was cooled to a temperature in the range of 0°C to 5°C. A solution of -toluene sulfonic acid (1.35 g) in ethanol (10ml) or isopropyl alcohol (20ml) or methanol (10 ml) was slowly added to the combined organic layer at a temperature in the range of 0°C to 5 °C to obtain a reaction mass. The reaction mass was stirred for 120 minutes at a temperature in the range of 0°C to 5°C. The product was filtered and washed with isopropyl acetate (20 ml) . The wet cake was driedat a temperature in the range of 30°C to 40°C in vacuum tray dryer to obtain ritlecitinib tosylate.Yield: 15.6 g (85%)Purity: 99.8% (as determined by HPLC).Dimer impurity (the compound A): 0.02% (as determined by HPLC)Example 9: Amoprphous form of Ritlecitinib tosylate (the compound la)In a round bottom flask, ritlecitinib tosylate (10 g), methanol (25 ml) and dichloromethane (25 ml) were added to obtain a reaction mass. The reaction mass was stirred at a temperature in the range of 20°C to 30°C for a period of 15 minutes to get a clear solution. The reaction mass water filter through a hyflo bed and the hyflo bed was washed with a mixture of methanol (5 ml) and dichloromethane (5 ml) to obtain the filtrate. The filtrate was spray dried to obtain the amorphous form of ritlecitinib tosylate.Yield: 9 g (90 %)Purity: 99.9% (as determined by HPLC).Dimer impurity (the compound A): 0.02% (as determined by HPLC)XRPD: Fig. 1

Claims

CLAIMS1. A process for the preparation of ritlecitinib represented by a compound of formula I (the “compound I”) or a pharmaceutically acceptable salt thereof,comprising reacting a compound of formula II (the “compound II”) or a hydrate or a salt thereof,IIwith acryloyl chloride in the presence of a buffer solution to obtain the compound I, and optionally converting the compound I to its pharmaceutically acceptable salt.

2. The process as claimed in the claim 1, wherein the buffer solution has pH in the range of 7.5 to 8.5.

3. The process as claimed in the claim 1 or the claim 2, wherein the buffer solution is composed of reagents selected from potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium hydroxide, ammonium hydroxide, cesium hydroxide and calcium hydroxide.

4. The process as claimed in the claim 1, wherein the reaction of the compound II or its hydrate or its salt with acryloyl chloride is carried out in a solvent selected from tetrahydrofuran (THF), acetone, methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butyl alcohol, pentanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,4- dioxane, acetonitrile or sulfolane.

5. The process as claimed in the claim 1 , wherein the compound I or its pharmaceutically acceptable salt is free of a dimer compound, represented by the compound of Formula A (the “compound A” or the dimer impurity)6. The process as claimed in the claim 1, wherein ritlecitinib, the compound I is converted to ritlecitinib tosylate (the compound la) by treating the compound I with p-toluenesulfonic acid.

7. A process for the preparation of an amorphous form of ritlecitinib tosylate represented by the compound of formula la (the compound la)lawherein the process comprises the steps of:(i) providing a reaction mixture of ritlecitinib tosylate in a mixture of solvents comprising of an alcohol solvent and a chlorinated solvent; and(ii) removing the solvents from the reaction mixture obtained in the step (i) to obtain the amorphous form of the compound la.

8. The process as claimed in the claim 7, wherein ritlecitinib tosylate used in the step (i) is obtained by the process claimed in any one of the claims 1 to 6.

9. The process as claimed in the claim 7, wherein in the step (i), the alcohol solvent used in the solvent mixture is selected from methanol, ethanol, n-propanol, isopropanol, or n-butanol.

10. The process as claimed in the claim 7, wherein in the step (i), the chlorinated solvent used in the solvent mixture is selected from dichloromethane, dichloroethane, or chloroform.

1. The process as claimed in the claim 7, wherein in the step (ii) the solvent is removed using a method selected from solvent evaporation, distillation, lyophilization, spray drying, agitated thin fdm drying (ATFD), fdtration, air tray drying, vacuum tray drying or cooling the solution.

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