Novel process for the preparation of (r)-3-(4-(7h-pyrrolo[2,3d]pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropanenitrile or a salt thereofnovel process for the preparation of (r)-3-(4-(7h-pyrrolo[2,3d]pyrimidin-4-yl)-1h-pyrazol-1-yl)-3-cyclopentylpropanenitrile or a salt thereof

Abstract

Title of the Invention: Novel process for the preparation of (R)-3-(4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile or a salt thereof The present invention relates to a novel process for the preparation of (R)-3-(4-(7H- pyrrolo[2,3­d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile or a salt thereof, which is referred to as Ruxolitinib and represented by the following structural formulae, Formula-1

Description

[0001] Novel process for the preparation of (R)-3-(4-(7H-pyrrolor2,3-dlpyrimidin-4-yl)-lH- pyrazol-l-yl)-3-cvclopentylpropanenitrile or a salt thereof

[0002] Related Application:

[0003] This application claims the benefit of priority of our Indian patent application number 202441067641 filed on 06 September 2024, which is incorporated herein by reference.

[0004] Field of the Invention:

[0005] The present invention relates to a novel process for the preparation of (R)-3-(4-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile or a salt thereof, which is referred to as Ruxolitinib and represented by the following structural formulae,

[0006] Background of the Invention:

[0007] (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropane nitrile phosphate is commonly known as Ruxolitinib phosphate, which is a selective inhibitor of Janus Associated Kinase 1 (JAK1) and JAK2 which mediates the signalling of a number of cytokines and growth factors that are important for haematopoiesis and immune function.

[0008] Ruxolitinib phosphate is approved under the brand name Jakafi in the USFDA and Jakavi in Europe for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, postpolycythemia vera myelofibrosis and postessential thrombocythemia myelofibrosis.

[0009] (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropane nitrile or a pharmaceutically acceptable salt is disclosed in US7598257 B2. Brief description of the Invention:

[0010] The present invention relates to a novel process for the preparation of Ruxolitinib of formula- 1 or a salt thereof.

[0011] Detailed description of the Invention:

[0012] As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n- butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyro nitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, 1, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol, monoethyl ether, cyclohexanol, benzyl alcohol or glycerol and the like; “polar solvents” such as water or mixtures thereof.

[0013] The “suitable base” as used in the present invention is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; ammonia; and organic bases such as “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; triethyl amine, methyl amine, ethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithiumdiisopropylamide (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine, diisopropylethylamine, N- methylmorpholine, N-ethylmorpholine, piperidine, dimethylamino pyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1-methyl imidazole, 1,2,4-triazole, 1,4- diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.

[0014] The “amino protecting group” as used in the present invention is selected from benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), p-methoxybenzylethers (PMB), methyloxycarbonyl, acetoxy carbonyl, propoxycarbonyl, tert-butyloxycarbonyl (Boc), acetyl, propanoyl, iso-butyryl, tert-butyryl, t-butylacetyl, pivaloyl, benzoyl, trimethylsilyl, ter- butyldimethylsilyl, methanesulphonyl, ptolylsulphonyl, 2-nitrophenylsulfenyl; urethane; nitroso, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(4-trifluoromethyl phenylsufony)ethoxycarbonyl, 1-adamantyloxycarbonyl, 2-adamantyloxycarbonyl, 2,4- dimethylpent-3-yloxycarbonyl, benzyl, vinyl, cyclohexyloxycarbonyl, l,l-dimethyl-2,2,2- trichloroethoxy carbonyl, 2-chloroethyl, 2-phenysulfonylethyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, N,N-dimethylhydrazinyl, methoxymethyl, tert-butoxymethyl, benxyloxymethyl, 2-tetrahydropyranyl, allyl, 2-(trimethylsilyl)ethoxymethyl, N-pivaloyloxy methyl, l-(ethoxy)ethyl, triphenylmethyl, diphenylmethyl, hydroxylmethyl and diethoxymethyl .

[0015] As used herein the term “deprotection” can be carried out in presence of a suitable “deprotection agent” which is selected from but not limited to acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, formic acid, lithium tetrafluoroborate, boron trifluoride-diethyl etherate; acetyl chloride, Lewis acid such as aluminum trichloride, boron trichloride, titanium tetrachloride, zinc chloride, ferric chloride, trialkyl aluminum, trialkoxy boron, substituted / unsubstituted alkyl / aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, pyridinium p-toluene sulfonic acid, trifluromethane sulfonic acid optionally in combination with alcohols and "hydrogen fluoride (HF) sources" such as ammonium fluoride, tetrabutyl ammonium fluoride, pyridine-HF, Et3N-3HF etc; metal catalysts in presence of hydrogen source and the like;

[0016] As used herein the term “salt” can be a chiral salt or an achiral salt. In the present invention, a chiral acid used to form the chiral salt may be selected from the following acids or an enantiomeric excess form thereof: mandelic acid, 2 -chloromandelic acid, camphoric acid, lactic acid, malic acid, 3- bromocamphor-8-sulfonic acid, 3 -bromocamphor- 10-sulfonic acid, 10-camphorsulfonic acid, 2-amino-7,7-dimethylbicyclo[2,2,l]heptan-l-methylene sulfonic acid, 2-acrylamide-7,7-dimethylbicyclo[2,2,l]heptan-l -methylene sulfonic acid, or tartaric acid and acyl derivatives thereof, preferably lactic acid, malic acid, camphoric acid, 10-camphorsulfonic acid, tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, di-p- toluoyl tartaric acid, di-p-anisoyl tartaric acid, di- p-chlorobenzoyl tartaric acid, di-p- bromobenzoyl tartaric acid, di-p-fluorobenzoyl tartaric acid, di-p-nitrobenzoyl tartaric acid, di-p-aminobenzoyl tartaric acid or di- p-cyanobenzoyl tartaric acid and the like; preferably tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid or di-p-toluoyl tartaric acid. In the present invention, a chiral acid used to form the chiral salt may be selected from D-tartaric acid, D-diacetyl tartaric acid, D-dibenzoyl tartaric acid, D- di-p-toluoyl tartaric acid, D-di-p- anisoyl tartaric acid, D-di-p-chlorobenzoyl tartaric acid, D-di-p-bromobenzoyl tartaric acid, D-di-p-fluorobenzoyl tartaric acid, D-di- p-nitrobenzoyl tartaric acid, D-di-p-aminobenzoyl tartaric acid, D-di-p- cyanobenzoyl tartaric acid and the like; preferably D-tartaric acid, D- dibenzoyl tartaric acid or D-di-p-toluoyl tartaric acid; more preferably D-tartaric acid. In the present invention, the achiral salt is selected from hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate and p-toluene sulfonate, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methane sulphonate, or p-toluene sulphonate and the like;

[0017] The term “enantiopure” as used herein in the present invention means that a compound has an enantiomeric excess of at least 80%, preferably at least 90%, more preferably at least 95%, even more preferably at least 99%.

[0018] The term “enantiopure” as used herein in the present invention means that an enantiomer is present with a purity of at least 99% enantiomeric excess, preferably in a purity of 99.5-100% enantiomeric excess.

[0019] In the first embodiment, the present invention provides a process for the preparation of Ruxolitinib of formula- 1 or a salt thereof, comprising one or more reaction steps of the following synthetic scheme. z— CN

[0020] - / .Chiral salt > HN-NH2

[0021] Formula 9 Formula 8

[0022] Formula 7

[0023] Ruxolitinib wherein Pi and P2 is selected from H or a suitable amino protecting group.

[0024] In the process of the first embodiment, the Vilsmeier reagent is prepared by a process comprising reacting dimethylformamide with a suitable chlorinating agent, wherein, the suitable chlorinating agent is selected from oxalyl chloride, phosphorus oxychloride, triphosgene, thionyl chloride, sulfuryl chloride, and phosphorus pentachloride.

[0025] In the first aspect of the first embodiment, the present invention provides a process for the preparation of Ruxolitinib of formula- 1 or a salt thereof, comprising one or more reaction steps of the following synthetic scheme. / — CN

[0026] — / .Chiral salt > HN-NH2

[0027] Formula 9 Formula 8

[0028] Formula 7

[0029] Formula 1 Formula 2

[0030] Ruxolitinib

[0031] In the second aspect of the first embodiment, the present invention provides a process for the preparation of Ruxolitinib of formula- 1 or a salt thereof, which comprises: a) converting compound of formula 7 to compound of formula 6; and Formula 7 wherein P2 is selected from H or a suitable amino protecting group. b) converting compound of formula 6 to Ruxolitinib or a salt thereof.

[0032] In the another aspect of the first embodiment, the present invention provides a process for the preparation of Ruxolitinib of formula- 1 or a salt thereof, which comprises: a) converting compound of formula 7a to compound of formula 6a; and Boc Boc

[0033] Formula 7 a Formula 6a b) converting compound of formula 6a to Ruxolitinib or a salt thereof.

[0034] In the third aspect of the first embodiment, the present invention provides a process for the preparation of Ruxolitinib of formula- 1 or a salt thereof, which comprises: a) reacting compound of formula 4 with compound of formula 6 to provide compound of formula 3 ; and

[0035] Formula 3 wherein Pi and P2 is selected from H or a suitable amino protecting group b) converting compound of formula 3 to Ruxolitinib or a salt thereof.

[0036] In the another aspect of the first embodiment, the present invention provides a process for the preparation of Ruxolitinib of formula- 1 or a salt thereof, which comprises: a) reacting compound of formula 4a with compound of formula 6a to provide compound of formula 2; and b) converting compound of formula 2 to Ruxolitinib or a salt thereof.

[0037] In the fourth aspect of the first embodiment, the present invention provides a process for the preparation of Ruxolitinib of formula- 1 or a salt thereof, which comprises converting compound of formula 6 or 7 to Ruxolitinib or a salt thereof.

[0038] In the fifth aspect of the first embodiment, the present invention provides a process for the preparation of Ruxolitinib of formula- 1 or a salt thereof, comprising one or more reaction steps of the following synthetic scheme. 2

[0039] Formula 9 Formula 8 Boe

[0040] Formula 7a

[0041] Formula 5a Formula 4a Formula 6a

[0042] Formula 1 Formula 2 Ruxolitinib

[0043] In the second embodiment, the present invention provides novel intermediate compounds represented by the following structural formulae. Boc Boc

[0044] Formula 6?2Formula 7 aantl Formula 6a wherein P2 is selected from H or a suitable amino protecting group.

[0045] In the third embodiment, the present invention provides novel intermediate compound represented by the following structural formula.

[0046] Formula 7 wherein P2 is selected from a suitable amino protecting group.

[0047] The above mentioned novel intermediate compounds are useful in the preparation of Ruxolitinib of formula- 1 or a salt.

[0048] In the fourth embodiment, the present invention provides a process for preparing a salt of Ruxolitinib comprising treating Ruxolitinib with phosphoric acid, hydrochloric acid, or fumaric acid in a suitable solvent to provide the corresponding salt of Ruxolitinib.

[0049] In the process of the fourth embodiment, the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

[0050] Ruxolitinib phosphate obtained according to the present invention is having Acid impurity and Amide impurity and Other isomer impurity, less than about 0.05% as measured by HPLC.

[0051]

[0052] In the fifth embodiment, Ruxolitinib or a salt thereof obtained according to the present invention has a particle size distribution of D90 less than about 150 pm, preferably less than about 100 pm, more preferably less than about 50 pm.

[0053] In the first aspect of the fifth embodiment, Ruxolitinib phosphate obtained according to the present invention has a particle size distribution of D90 less than about 150 pm, preferably less than about 100 pm, more preferably less than about 50 pm.

[0054] In the second aspect of the fifth embodiment, Ruxolitinib hydrochloride obtained according to the present invention has a particle size distribution of D90 less than about 150 pm, preferably less than about 100 pm, more preferably less than about 50 pm.

[0055] In the sixth embodiment, the present invention provides Ruxolitinib or a salt thereof having a chiral purity of about 99.90% ee; preferably of about 99.95% ee; more preferably of about 99.98% ee; most preferably of about 99.99% ee as measured by chiral HPLC method.

[0056] In the first aspect of the sixth embodiment, the present invention provides Ruxolitinib hydrochloride having a chiral purity of about 99.90% ee; preferably of about 99.95% ee; more preferably of about 99.99% ee as measured by chiral HPLC method.

[0057] In the second aspect of the sixth embodiment, the present invention provides Ruxolitinib phosphate having a chiral purity of about 99.90% ee; preferably of about 99.95% ee; more preferably of about 99.99% ee as measured by chiral HPLC method. In the seventh embodiment of the present invention a process for the purification of compound of formula 2, which comprises: a) Suspending or dissolving compound of formula 2 in a solvent, b) optionally treating the mixture obtained in step-a) with carbon, c) isolating the compound of formula 2.

[0058] In the process of the seventh embodiment wherein the solvent used in step-a) is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar- aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

[0059] In an embodiment the compound of formula 2 obtained according to the present invention having a purity of about 99.90% as measured by HPLC.

[0060] In an embodiment, Ruxolitinib or a salt thereof obtained according to the present invention is enantiopure.

[0061] Ruxolitinib or a salt thereof obtained according to the present invention is having a purity of about 97% by HPLC or purity of about 99.0% by HPLC or purity of about 99.5% or purity of about 99.97% by HPLC.

[0062] Ruxolitinib hydrochloride obtained according to the present invention is having a purity of about 97% by HPLC or purity of about 99.0% by HPLC or purity of about 99.5% or purity of about 99.97% by HPLC.

[0063] The compound of formula 9 used in the present invention are synthesized from any of the known prior art processes.

[0064] Ruxolitinib or a salt thereof obtained according to the present invention is purified by suspending or dissolving Ruxolitinib in a suitable solvent selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof to provide pure Ruxolitinib or a salt thereof.

[0065] Ruxolitinib or a salt thereof produced according to the present invention can be further micronized or milled in conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball milling, roller milling and hammer milling, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.

[0066] The present invention also encompasses pharmaceutical compositions comprising Ruxolitinib or a salt thereof.

[0067] As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

[0068] The process described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

[0069] Examples:

[0070] Example-1: Preparation of compound of Formula-5a

[0071] N-methylpyrrolidine (600.0 ml) was added to 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (200 gm) at 25-30°C and stirred for 10 minutes. Tris(acetylacetonato)iron(III) (27.59 gm) was added to the mixture at 25-30°C and stirred for 10 minutes. Cooled the mixture to 20-25°C. Methyl magnesium chloride (1519.39 ml) was slowly added to the mixture at 20-25°C. Raised the temperature of the mixture to 25-30°C and stirred for 2 hours. Cooled the mixture to 5- 10°C. Aqueous hydrochloric acid solution was slowly added to the mixture at 5-10°C and stirred for 30 minutes. Raised the temperature of the mixture to 25-30°C. Dichloromethane (2000 ml) was added to the mixture at 25-30°C and stirred for 15 minutes. Filtered the mixture through hyflow bed and washed with water. Layers were separated. Dichloromethane (2000 ml) was added to aqueous layer at 25-30°C and stirred for 10 minutes. Layers were separated. Dichloromethane (1000 ml) was added to aqueous layer at 25-30°C and stirred for 10 minutes. Layers were separated. Sodium carbonate solution was added to aqueous layer at 25-30°C and stirred for 10 minutes. Ethyl acetate was added to aqueous layer at 25-30°C and stirred for 10 minutes. Layers were separated and aqueous layer extracted with ethyl acetate. Combined the total organic layers and washed with aqueous sodium chloride solution. Layers were separated and organic layer washed with water. Layers were separated. Distilled off the solvent completely from the organic layer at below 50°C under vacuum and co-distilled with ethyl acetate. Ethyl acetate (300 ml) was added to the obtained compound at 25-30°C. Cooled the mixture to 0-5°C and stirred for 90 minutes. Filtered the solid, washed with ethyl acetate and dried to get the title compound. Yield: 116 gm.

[0072] Example-2: Preparation of compound of Formula -6a.

[0073] Hydrazine hydrate (142.77 gm) was slowly added to the pre-cooled 3-cyclopentyl acrylonitrile (200 gm) at 0-5°C. Raised the temperature of the mixture to 20-25°C and stirred for 48 hours. Aqueous sodium chloride solution was added to the mixture at 20-25°C and stirred for 15 minutes. Dichloromethane (400 ml) was added to the mixture at 20-25°C and stirred for 15 minutes. Layers were separated. Dichloromethane (200 ml) was added to aqueous layer at 20-25°C and stirred for 15 minutes. Layers were separated. Combined the total organic layers. Water (200 ml) was added to organic layer at 20-25°C and stirred for 15 minutes. Layers were separated. Distilled off the solvent completely from the organic layer at below 25°C under vacuum. A mixture of acetonitrile (100 ml) and water (100 ml) was added to the obtained compound at 25-30°C. A solution containing water (700 ml), acetonitrile (700.0 ml) and L-(+)-tartaric acid (272.41 gm) was slowly added to the mixture at 20-25°C and stirred for 2 hours. Cooled the mixture to 0-5°C and stirred for 4 hours. Filtered the solid, washed with a mixture of acetonitrile and water, and dried. Acetonitrile (900 ml) and water (100 ml) was added to the obtained compound at 20-25°C and stirred for 9 hours. Filtered the solid, washed with a mixture of acetonitrile and water, and dried.

[0074] A mixture of methanol (2000 ml) and water (1400 ml) was added to the obtained compound at 25-30°C and stirred for 30 minutes. Cooled the mixture to 0-5°C. Aqueous sodium hydroxide solution (sodium hydroxide (26.40 gm) and water (900.0 ml)) was slowly added to mixture at 0-5°C and stirred for 30 minutes. Di-tert-butyl dicarbonate (100.39 gm) was slowly added to the mixture at 0-5°C. Raised the temperature of the mixture to 25-30°C and stirred for 3 hours. Dichloromethane (2000 ml) was added to the mixture at 25-30°C and stirred for 15 minutes. Layers were separated. Dichloromethane (400 ml) was added to aqueous layer at 25-30°C and stirred for 15 minutes. Layers were separated. Combined the total organic layers. Aqueous sodium chloride solution was added to the organic layer and stirred for 15 minutes. Layers were separated. Distilled off the solvent completely from the organic layer at below 30°C under vacuum.

[0075] Dimethyl sulfoxide (1000 ml) was added to the obtained compound at 25-30°C and stirred for 10 minutes. Aqueous lithium hydroxide solution (lithium hydroxide (59.19 gm) and water (600.0 ml)) was added to the mixture at 25-30°C and stirred for 10 minutes. Aqueous hydrogen peroxide solution (hydrogen peroxide (200 ml) and water (600 ml)) was slowly added to mixture at 25-30°C and stirred for 90 minutes. Water was slowly added to the mixture at 25-30°C and stirred for 1 hour. Filtered the solid, washed with water and dried to get the title compound. Yield: 70.0 gm.

[0076] Example-3: Preparation of compound of Formula-2

[0077] Oxalyl chloride (428.97 gm) was slowly added to pre-cooled acetonitrile at 0-5°C and stirred for 15 minutes. Dimethylformamide (1427.2 gm) was slowly added to mixture at 0- 5°C. Raised the temperature of the mixture to 25-30°C and stirred for 40 minutes. Compound of formula-5a (200 gm) was added to the mixture at 25-30°C and stirred for 15 minutes. Heated the mixture to 85-90°C and stirred for 2 hours. Cooled the mixture to 25-30°C. Acetone (2000 ml) was slowly added to the mixture at 25-30°C and stirred for 5 hours. Filtered the solid, washed with acetone and dried.

[0078] To the obtained compound was added to n-butanol (1080 ml) at 25-30°C and stirred for 15 minutes. Compound of formula-6a (244.8 gm) was added to the mixture at 25-30°C. Heated the mixture to 45-50°C and stirred for 5 hours. Cooled the mixture to 25-30°C and stirred for 2 hours. Filtered the solid and washed with acetone.

[0079] To the obtained compound was added to acetone (720 ml) at 25-30°C and stirred for 90 minutes. Filtered the solid, washed with acetone and dried to get the title compound. Yield: 236 gm.

[0080] Example-4: Preparation of Ruxolitinib

[0081] Dichloromethane (1000 ml) and dimethylformamide (50.0 ml) were added to the compound of formula-2 (50.0 gm) at 25-30°C. Cooled the mixture to 0-5°C. Phosphorus oxychloride (96.90 gm) was slowly added to mixture at 0-5°C. Raised the temperature of the mixture to 25-30°C and stirred for 3 hours. Cooled the mixture to 0-5°C. Ammonia (350 ml) was slowly added to mixture at 0-5°C. Water (500 ml) was added to mixture at 0-5°C and stirred for 10 minutes. Layers were separated and aqueous layer extracted with dichloromethane. Combined the total organic layers and washed with hydrose solution, aqueous sodium chloride solution and water. Distilled off the solvent completely from the organic layer at below 40°C under vacuum and co-distilled with isopropyl alcohol.

[0082] Yield: 41.0 gm.

[0083] Example-5: Preparation of Ruxolitinib phosphate

[0084] Dichloromethane (400.0 ml) and dimethylformamide (20.0 ml) were added to the compound of formula-2 (20.0 gm) at 25-30°C. Cooled the mixture to 0-5°C. Phosphorus oxychloride (38.76 gm) was slowly added to mixture at 0-5°C. Raised the temperature of the mixture to 25-30°C and stirred for 4 hours. Cooled the mixture to 0-5°C. Ammonia (140.0 ml) was slowly added to mixture at 0-5°C. Water (200.0 ml) was added to mixture at 0-5°C and stirred for 10 minutes. Layers were separated and aqueous layer extracted with dichloromethane. Combined the total organic layers. Hydrose solution was added to organic layer at 25-30°C. Layers were separated and organic layer washed with sodium chloride solution and water. Distilled off the solvent completely from the organic layer at below 40°C under vacuum and co-distilled with isopropyl alcohol. To the obtained compound was dissolved in isopropyl alcohol (80 ml) at 25-30°C. Carbon was added to mixture at 25-30°C. Heated the mixture to 50-55°C and stirred for 90 minutes. Cooled the mixture to 25-30°C. Filtered the mixture through hyflow bed and washed with isopropyl alcohol. Heated the filtrate to 50-55°C. Phosphoric acid (6.64 gm) and isopropyl alcohol (10 ml) were slowly added to filtrate at 50-55°C and stirred for 2 hours. Cooled the mixture to 25-30°C and stirred for 15 minutes. Filtered the solid, washed with isopropyl alcohol and dried to get the title compound. Yield: 15.0 gm. Chiral Purity: 99.95%., Other Isomer: 0.05% Particle size distribution [PSD]: D90: 49.59 pm; D50: 17.80 pm; D10: 5.28 pm.

[0085] Example-6: Preparation of Ruxolitinib hydrochloride.

[0086] Dichloromethane (400 ml) was added to the compound of formula-2 (20 gm) at 25- 30°C. Dimethylformamide (20 ml) was added to mixture at 25-30°C and stirred for 15 minutes. Cooled the mixture to 0-5°C. Phosphorus oxychloride (38.76 gm) was slowly added to mixture at 0-5°C and stirred for 10 minutes. Raised the temperature of the mixture to 25- 30°C and stirred for 3 hours. Cooled the mixture to 0-5°C. Ammonia (120 ml) was slowly added to mixture at 0-5°C. Water (200 ml) was added to mixture at 0-5°C and stirred for 10 minutes. Filtered the mixture through hyflow bed and washed with dichloromethane. Layers were separated and aqueous layer extracted with dichloromethane. Combined the total organic layers. Hydrose solution was added to organic layer at 25-30°C. Layers were separated and organic layer washed with sodium chloride solution and water. Distilled off the solvent completely from the organic layer at below 40°C under vacuum and co-distilled with isopropyl alcohol. To the obtained compound was added to isopropyl alcohol (80 ml) at 25- 30°C. Carbon was added to mixture at 25-30°C. Heated the mixture to 50-55°C and stirred for 90 minutes. Cooled the mixture to 25-30°C. Filtered the mixture through hyflow bed and washed with isopropyl alcohol. Ethyl acetate-HCl (2.09 gm) was slowly added to filtrate at 25-30°C and stirred for 7 hours. Filtered the solid and washed with isopropyl alcohol. Isopropyl alcohol (160 ml) and methanol (20 ml) were added to the obtained compound at 25- 30°C. Raised the temperature of the mixture to 80-85°C and stirred for 15 minutes. Carbon was added to mixture at 80-85°C and stirred for 1 hour. Filtered the mixture through hyflow bed followed by micron filter paper and washed with isopropyl alcohol. Cooled the filtrate to 25-30°C and stirred for 3 hours. Filtered the solid and washed with isopropyl alcohol. Ethyl acetate (10.0 ml) and methanol (10.0 ml) were added to obtained compound at 25-30°C. raised the temperature of the mixture to 60-65°C and stirred for 1 hour. Cooled the mixture to 25-30°C and stirred for 2 hours. Filtered the solid, washed with ethyl acetate and dried to get the title compound. Yield: 14.7 gm.

[0087] Purity by HPLC: 99.97%; Chiral Purity: 99.99%, Other Isomer: 0.01%.

[0088] Chloride content: 10.67%.

[0089] Particle size distribution [PSD]: D90: 33.51 pm; D50: 12.46 pm; D10: 3.46 pm.

Claims

We Claim:

1. A process for the preparation of Ruxolitinib of formula- 1 or a salt thereof, which comprises: a) reacting compound of formula 4 with compound 6 to provide compound of formula 3; andFormula 3 wherein Pi and P2 is selected from H or a suitable amino protecting group, b) converting compound of formula 3 to Ruxolitinib or a salt thereof.

2. A process for the preparation of Ruxolitinib of formula- 1 or a salt thereof, which comprises: a) reacting compound of formula 4a with compound 6a to provide compound of formula 2; andb) converting compound of formula 2 to Ruxolitinib or a salt thereof.

3. A process for the preparation of Ruxolitinib of formula- 1 or a salt thereof, which comprises:a) converting compound of formula 7 to compound of formula 6; andFormula 7 Formula 6 wherein P2 is selected from H or a suitable amino protecting group. b) converting compound of formula 6 to Ruxolitinib or a salt thereof.

4. A process for the preparation of Ruxolitinib of formula- 1 or a salt thereof, which comprises: a) converting compound of formula 7a to compound of formula 6a; andBoc BocFormula 7a Formula 6a b) converting compound of formula 6a to Ruxolitinib or a salt thereof.

5. The process as claimed in claims 1 and 3, wherein amino protecting group is selected from benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), p- methoxybenzylethers (PMB), methyloxycarbonyl, acetoxy carbonyl, propoxycarbonyl, tert-butyloxycarbonyl (Boc), acetyl, propanoyl, iso-butyryl, tert-butyryl, t-butylacetyl, pivaloyl, benzoyl, trimethylsilyl, ter-butyldimethylsilyl, methanesulphonyl, ptolylsulphonyl, 2-nitrophenylsulfenyl; urethane; nitroso, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(4-trifluoromethyl phenylsufony)ethoxycarbonyl, 1- adamantyloxycarbonyl, 2-adamantyloxycarbonyl, 2,4-dimethylpent-3-yloxycarbonyl, benzyl, vinyl, cyclohexyloxycarbonyl, 1 , 1 -dimethyl-2,2,2-trichloroethoxy carbonyl, 2- chloroethyl, 2-phenysulfonylethyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4- pyridylmethyl, N,N-dimethylhydrazinyl, methoxymethyl, tert-butoxymethyl, benxyloxymethyl, 2-tetrahydropyranyl, allyl, 2-(trimethylsilyl)ethoxymethyl, N- pivaloyloxy methyl, l-(ethoxy)ethyl, triphenylmethyl, diphenylmethyl, hydroxylmethyl and diethoxymethyl.

6. A compounds of formulae 6, 6a and 7a.and wherein P2 is selected from H or amino protecting group as defined above.

7. A compound of formula 7.Formula 7 wherein P2 is selected from amino protecting group as defined above.

8. A process using one or more compounds of formulae 6, 6a, 7 or 7a for preparing Ruxolitinib or a salt thereof.

9. A process for the purification of compound of formula 2, which comprises: a) Suspending or dissolving compound of formula 2 in a solvent, b) optionally treating the mixture obtained in step-a) with carbon, c) isolating the compound of formula 2.

10. The process as claimed in claim 9 wherein, the solvent used in step-a) is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

11. Compound of formula 2 having a purity of about 99.90% as measured by HPLC.

12. Ruxolitinib phosphate having a particle size distribution of D90 less than 150 pm, preferably less than 100 pm, more preferably less than 50 pm.

13. Ruxolitinib hydrochloride having a particle size distribution of D90 less than 150 pm, preferably less than 100 pm, more preferably less than 50 pm.

14. Ruxolitinib phosphate having a chiral purity of about 99.95% as measured by HPLC.

15. Ruxolitinib hydrochloride having a purity of about 99.97% and chiral purity of about 99.99% as measured by HPLC.

16. A pharmaceutical composition comprising Ruxolitinib or a salt thereof according to any of the preceding claims and one or more pharmaceutically acceptable excipients.

17. The use of Ruxolitinib or a salt thereof according to any of preceding claims for the preparation of a medicament for treating patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, postpolycythemia vera myelofibrosis and postessential thrombocythemia myelofibrosis.

Images