Improved method for preparing rucotinib and novel crystal form thereof

Abstract

The present invention relates to an improved process for the preparation of rucotinib or salts thereof and intermediates thereof. The present invention also relates to a novel crystalline form G of rucotinib, a process for its preparation, its use in the preparation of rucotinib salts, pharmaceutical compositions comprising the same and a process for its use. The present invention also relates to an improved process for the preparation of the crystal variant 3 of rucotinib hydrochloride.

Description

[0001] priority

[0002] This application claims the benefit of Indian Provisional Application No. 202341059245, filed on September 4, 2023, entitled “IMPROVED PROCESS FOR THEPREPARATION OF RUXOLITINIB”; Indian Provisional Application No. 202441009264, filed on February 12, 2024, entitled “NOVEL CRYSTALLINE FORM OF RUXOLITINIB”; and Indian Provisional Application No. 202441017545, filed on March 12, 2024, entitled “NOVEL CRYSTALLINE FORM OF RUXOLITINIB AND PROCESS FOR THEPREPARATION THEREOF”, the contents of which are incorporated herein by reference. Invention Field

[0003] This invention relates to an improved method for preparing ruxolitinib or its salts and intermediates. The invention also relates to a new crystal form G of ruxolitinib, a method for its preparation, its use in the preparation of ruxolitinib salts, pharmaceutical compositions comprising ruxolitinib, and methods for its use. The invention further relates to an improved method for preparing crystal variant 3 of ruxolitinib hydrochloride. Background of the Invention

[0004] Ruxolitinib is a selective JAK1 / JAK2 tyrosine kinase inhibitor developed by Incyte and Novartis. It was the first drug approved by the FDA in November 2011 for the treatment of myelofibrosis (brand name: Jakafi), and its indication is intermediate- or high-risk myelofibrosis, including primary myelofibrosis, secondary polycythemia myelofibrosis, and post-essential thrombocythemia myelofibrosis.

[0005] Ruxolitinib is chemically known as (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile and has the following structural formula I:

[0006]

[0007] US Patent 7598257 discloses ruxolitinib and its pharmaceutically acceptable salts. The patent also discloses methods for preparing ruxolitinib, involving the separation of intermediates using HPLC and the purification of the final product using column chromatography, methods that are laborious and time-consuming, and suffer from low yields and low purity.

[0008] US Patent 8410265 discloses a method for preparing ruxolitinib, involving the chemical resolution of D-(+)-dibenzoyl tartaric acid, asymmetric hydrogenation under a chiral metal catalyst, and an asymmetric synthetic route of ruxolitinib catalyzed by a chiral small molecule. The method involves chemical resolution and repeated recrystallization with low yields; the starting materials for asymmetric hydrogenation are difficult to prepare, and the chiral catalyst is also difficult to prepare; the chiral small molecule catalyst is a non-commercial product, costly to prepare, and exhibits low stereoselectivity.

[0009] The existing techniques described above involve a chiral resolution reaction in the final stage, which leads to yield loss, chromatographic purification methods, and the use of expensive chiral and harmful reagents. The use of complex chiral agents increases production costs. Chromatographic purification methods are unsuitable for industrial production.

[0010] There remains a need in the art for improved methods for preparing ruxolitinib or its salts that are economical, easily scalable, and commercially viable. Therefore, the main objective of this invention is to provide an improved method for preparing ruxolitinib or its salts that avoids the disadvantages of the prior art.

[0011] Polymorphism is the phenomenon of a single compound existing in different crystal forms, and it is a characteristic of some compounds and complexes. Therefore, polymorphs are unique solids sharing the same molecular formula, but each polymorph can possess unique physical properties. Consequently, a single compound can produce multiple polymorphic forms, each with different and unique physical properties, such as different solubility profiles, different melting temperatures, and / or different X-ray diffraction peaks. Since the solubility of each polymorph can vary, determining the existence of drug polymorphs is important for providing drugs with predictable solubility profiles. It is desirable to investigate all solid forms of drugs, including all polymorphs and solvates, and to determine the stability, solubility, and flow properties of each polymorph.

[0012] Ruxolitinib is one of the key drugs approved in the United States and Europe as an oral medication for the treatment of myelofibrosis, polycythemia vera, acute graft-versus-host disease, and chronic graft-versus-host disease. Ruxolitinib has also been approved as a topical cream for the treatment of atopic dermatitis and vitiligo. Developing new polymorphic forms of pharmaceutically useful compounds offers new opportunities for improving the performance characteristics of drugs such as ruxolitinib.

[0013] WO2017008772A1 describes the preparation of crystalline variant 3 of ruxolitinib hydrochloride. However, existing methods do not prepare crystalline variant 3 of ruxolitinib hydrochloride in a single reaction step, i.e., the reaction step of ruxolitinib with hydrochloric acid. They involve multiple steps, including first separating crystalline variant 1, converting crystalline variant 1 into crystalline variant 2, and then converting crystalline variant 2 into crystalline variant 3. Obviously, these existing methods are very laborious and commercially unfeasible.

[0014] There is still a need to develop new polymorphs of ruxolitinib and improved methods for their preparation. The inventors of this invention have developed new polymorphs of ruxolitinib and methods for their preparation.

[0015] Purpose of the invention

[0016] The purpose of this invention is to overcome the shortcomings of the prior art.

[0017] The object of this invention is to provide an improved method for preparing ruxolitinib or its salts, which is economical, easily scalable, and commercially viable.

[0018] Another object of the present invention is to provide an improved method for preparing intermediate compounds of ruxolitinib.

[0019] Another object of the present invention is to provide a new crystal form of ruxolitinib, a method for its preparation, its use in the preparation of ruxolitinib salts, pharmaceutical compositions comprising it, and its use in treating JAK-related diseases or disorders in individuals.

[0020] Another object of the present invention is to provide an improved method for preparing ruxolitinib hydrochloride crystal variant 3. Invention Overview

[0022] According to one aspect of the invention, an improved method for preparing ruxolitinib or its salts is provided, which is economical, easily scalable, and commercially viable.

[0023] According to another aspect of the present invention, an improved method for preparing intermediates of ruxolitinib is provided.

[0024] According to another aspect of the invention, an improved method is provided for preparing an intermediate compound of formula 3 in the presence of a reagent prepared in situ from trifluoromethanesulfonic anhydride and DMF and a suitable solvent, and the use of intermediate formula 3 in the preparation of ruxolitinib or its salts is provided.

[0025]

[0026] According to another aspect of the invention, a new crystal form G of ruxolitinib is provided, a method for its preparation, its use in the preparation of ruxolitinib salts, a pharmaceutical composition comprising the form, and its use for treating JAK-related diseases or disorders in an individual.

[0027] According to another aspect of the invention, a new crystal form G of ruxolitinib is provided, characterized in that its PXRD pattern has one or more peaks at about 10.1, 13.6, 17.5 and 22.8 ± 0.2° 2θ.

[0028] According to another aspect of the present invention, a new crystal form G of ruxolitinib is provided, characterized in that the DSC thermal analysis chart has an exothermic peak at about 138-146°C.

[0029] According to another aspect of the present invention, a method for preparing a new crystal form G is provided.

[0030] According to another aspect of the invention, the use of ruxolitinib crystal form G in the preparation of ruxolitinib salts is provided.

[0031] According to another aspect of the present invention, an improved method for preparing crystalline ruxolitinib hydrochloride is provided.

[0032] According to another aspect of the invention, a pharmaceutical composition is provided comprising a novel crystal form G of ruxolitinib and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0033] According to another aspect of the invention, a new crystal form G of ruxolitinib is provided for use in the treatment of JAK-related diseases or disorders.

[0034] According to another aspect of the present invention, an improved method for preparing ruxolitinib hydrochloride crystal variant 3 is provided. Brief description of the attached diagram

[0035] Figure 1 X-ray powder diffraction (XRPD) pattern of ruxolitinib crystal form G.

[0036] Figure 2 Differential scanning calorimetry (DSC) thermal analysis of ruxolitinib crystal form G.

[0037] Figure 3 Thermogravimetric analysis (TGA) of ruxolitinib crystal form G.

[0038] Figure 4 X-ray powder diffraction (XRPD) pattern of crystal variant 3 of ruxolitinib hydrochloride.

[0039] Detailed description

[0040] The following description and accompanying drawings are provided to aid in a full understanding of exemplary embodiments of the present invention. They include various specific details to aid understanding, but these details should be considered exemplary only.

[0041] Therefore, those skilled in the art will recognize that various changes and modifications can be made to the embodiments described herein without departing from the scope of the invention. Furthermore, for clarity and brevity, descriptions of well-known functions and structures have been omitted.

[0042] The terms and words used in the following description and claims are not limited to their literal meaning, but are used only by the inventors to make the understanding of the invention clear and consistent. Therefore, it will be apparent to those skilled in the art that the following description of exemplary embodiments of the invention is for illustrative purposes only and is not intended to limit the scope of the invention as defined by the appended claims and their equivalents.

[0043] It should be understood that the singular forms “a”, “an”, and “the” include plural referents unless the context clearly indicates otherwise.

[0044] Features described and / or illustrated in one embodiment may be used in the same or similar manner in one or more other embodiments, and / or combined with or substituted for features of other embodiments.

[0045] It should be emphasized that when the term "comprising / including" is used in this specification, it is intended to specify the presence of the described feature, step, or component, but does not exclude the presence or addition of one or more other features, steps, components, or groups thereof.

[0046] Unless otherwise stated, the term "base" as used in this invention is selected from inorganic bases, such as "alkali metal hydroxides," such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; "alkali metal carbonates," such as sodium carbonate, potassium carbonate, lithium carbonate, etc.; "alkali metal bicarbonates," such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, etc.; "alkali metal hydrides," such as sodium hydride, potassium hydride, lithium hydride, etc.; "alkali metal alkoxides," such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, etc.; ammonia; and organic bases, such as triethylamine, methylamine, ethylamine, 1,8-diazabicyclo[5.4.0] Undecane-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithium diisopropylamino(LDA), n-butyllithium, tribenzylamine, isopropylamine, diisopropylamine (DIPA), diisopropylethylamine (DIPEA), N-methylmorpholine (NMM), N-ethylmorpholine, piperidine, dimethylaminopyridine (DMAP), morpholine, pyridine, 2,6-rutidine, 2,4,6-coridine, imidazole, 1-methylimidazolium, 1,2,4-triazole, 1,4-diazabicyclo[2.2.2]octane (DABCO), etc., or mixtures thereof.

[0047] In this invention, the term "solvent / suitable solvent" is selected from water, alcohol, ether, amide, ester, nitrile, sulfoxide, ketone, hydrocarbon, and halogenated solvent; wherein alcohol is selected from methanol, ethanol, isopropanol (IPA), n-butanol, isobutanol, etc.; ester is selected from ethyl acetate, isopropyl acetate (IPAc), etc.; ketone is selected from acetone, methyl isobutyl ketone, methyl ethyl ketone, etc.; ether is selected from methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran ether, 2-methyltetrahydrofuran, cyclopentylmethyl ether, dioxane, etc.; halogenated solvent is selected from dichloromethane, chloroform, chlorobenzene, bromobenzene, etc.; hydrocarbon is selected from heptane, hexane, cyclohexane, cycloheptane, toluene, xylene, cyclohexane, etc.; nitrile is selected from acetonitrile (ACN), propionitrile, etc.; amide is selected from N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), etc.; sulfoxide is, for example, dimethyl sulfoxide; sulfone; or mixtures thereof.

[0048] Suitable "amino protecting group P" can be selected from, but is not limited to, benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), 2-(trimethyl-silyl)ethoxycarbonyl (Teoc), 2-(4-trifluoromethylbenzenesulfonyl)ethoxycarbonyl (Tsc), tert-butoxycarbonyl (Boc), 1-adamantaneoxycarbonyl (Adoc), 2-adamantane-carbonyl (2-Adoc), 2,4-dimethylpent-3-yloxycarbonyl (Doc), cyclohexyloxycarbonyl (Hoc), 1,1-dimethyl-2,2,2-trichloroethoxycarbonyl (TcB). (oc), vinyl, 2-chloroethyl, 2-benzenesulfonylethyl, p-nitrobenzenesulfonyl, p-toluenesulfonyl, benzyl, methanesulfonyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, N',N'-dimethylhydrazine, methoxymethyl, tert-butoxymethyl (Bum), benzyloxymethyl (Bom), 2-tetrahydropyranyl (THP), tris(C1-4 alkyl)silyl, 1,1-diethoxymethyl, 2-(trimethylsilyl)ethoxymethyl (SEM), N-neopentyloxymethyl (POM), etc.

[0049] In one embodiment of the present invention, an improved method for preparing ruxolitinib or a salt thereof is provided, comprising:

[0050] a) Make the compound of formula 2:

[0051]

[0052] Wherein, "P" represents an amino protecting group;

[0053] The compound of formula 3 is reacted with a reagent prepared in situ from trifluoromethanesulfonic anhydride and DMF in the presence of a suitable solvent to provide the compound.

[0054]

[0055] b) Contact the compound of formula 3 with the compound of formula 4 or its salt.

[0056]

[0057] To provide compounds of formula 5;

[0058]

[0059] c) Optionally, the acid intermediate of formula 5 is purified by reaction with dicyclohexylamine (DCHA) in a suitable solvent to provide a dicyclohexylamine salt of the acid intermediate of formula 5a, and

[0060]

[0061] By reacting it with a base to further convert it into its free base, a pure acid intermediate of formula 5 can be provided;

[0062] d) React the compound of formula 5 with carbonyl diimidazole (CDI) in a suitable solvent, followed by reaction with ammonia to provide the compound of formula 6;

[0063]

[0064] e) Treating the compound of formula 6 with trifluoroacetic anhydride in the presence of a base and a suitable solvent to provide ruxolitinib; and

[0065]

[0066] f) Optionally convert ruxolitinib to its salt.

[0067] The starting compounds of formulas 2 and 4 can be prepared by methods known in the prior art or by methods described in this invention.

[0068] Step a) of the method involves reacting the compound of Formula 2 (wherein “P” represents an amino protecting group as defined above; preferably benzyloxycarbonyl, tert-butyloxycarbonyl or N-neopentyloxymethyl; more preferably benzyloxycarbonyl) with a reagent prepared in situ from trifluoromethanesulfonic anhydride and DMF in the presence of a suitable solvent and under suitable reaction conditions to provide the compound of Formula 3.

[0069] The suitable solvents used in the above methods are as defined above, and are preferably selected from nitrile solvents such as acetonitrile, propionitrile, etc.; most preferably acetonitrile.

[0070] The reaction is carried out at a suitable temperature of about 0°C to about 50°C for a sufficient period of time; preferably at about 5°C to about 35°C for about 10 to 16 hours.

[0071] In this application, the use of amino-protecting groups is important because it has the following advantages: chemical purity, high yield without any side reactions, stability under various reaction conditions, improved solubility and reduced polarity, and easier structural analysis.

[0072] In previously known methods, the salt of the protected compound of formula 3 is prepared by using oxalyl chloride, and the reaction is carried out at a higher temperature, which in turn makes the salt of the compound of formula 3 unstable, and this leads to the cleavage of the protecting group and the subsequent formation of an N-formyl compound as an impurity.

[0073] However, the inventors of this invention were surprised to discover that when a reagent prepared in situ from trifluoromethanesulfonic anhydride and DMF is used in the preparation of the compound of Formula 3, the reaction can be carried out at a lower temperature, which helps to avoid deprotection and also helps to eliminate the formation of N-formyl impurities, which are among the possible impurities when the amine is not protected with a protecting group.

[0074] Step b) of the method involves the reaction of the compound of Formula 3 with the compound of Formula 4 or a salt thereof, which can be carried out in the presence of a suitable deprotecting agent and under suitable reaction conditions to provide the compound of Formula 5.

[0075] The deprotecting agent used under acidic conditions is selected from trifluoroacetic acid, trifluoroacetic anhydride, lithium tetrafluoroborate, boron trifluoride-diethyl ether compound, aqueous HCl solution, and aqueous H2SO4 solution, etc.; preferably, aqueous HCl solution or aqueous H2SO4 solution.

[0076] The deprotecting agent used under alkaline conditions is selected from aqueous or alcoholic solutions of alkali metal hydroxides or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, barium hydroxide, calcium hydroxide, beryllium hydroxide, strontium hydroxide, radium hydroxide, etc.; preferably, an aqueous solution of sodium hydroxide or a methanol solution of sodium hydroxide.

[0077] The reaction is carried out at a suitable temperature of about 40°C to about 90°C for a sufficient period of time; preferably at about 50°C to about 80°C for about 20 to 24 hours.

[0078] Step c) of the method involves purifying the acid intermediate of formula 5 by reacting it with dicyclohexylamine in a suitable solvent to provide a dicyclohexylamine salt of the acid intermediate of formula 5a, and then further converting it to its free base by reacting it with a base under suitable reaction conditions, followed by adjusting the pH using an aqueous acid to provide a pure acid intermediate of formula 5.

[0079] In the above method, the alkali used is selected from alkali metal hydroxides or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, barium hydroxide, calcium hydroxide, beryllium hydroxide, strontium hydroxide, radium hydroxide, etc.; sodium hydroxide is preferred; and the suitable solvent used is selected from ketone solvents such as acetone, methyl isobutyl ketone, methyl ethyl ketone, etc.; acetone is preferred.

[0080] The reaction is carried out at a suitable temperature of about 15°C to about 60°C for a sufficient period of time; preferably at about 25°C to about 55°C for about 1 to 4 hours.

[0081] Step d) of the method involves the reaction of the compound of formula 5 with carbonyl diimidazole in a suitable solvent, followed by a reaction with ammonia under suitable reaction conditions to provide the compound of formula 6.

[0082] The suitable solvents used in the above method are as defined above, but are also selected from amides such as dimethylformamide, dimethylacetamide, etc.; preferably dimethylacetamide or dimethylformamide.

[0083] The reaction is carried out at a suitable temperature of about 0°C to about 60°C for a sufficient period of time; preferably at about 0°C to about 30°C for about 1 to 4 hours.

[0084] Step e) of the method involves the reaction of the compound of formula 6 with trifluoroacetic anhydride in the presence of a base and a suitable solvent, under suitable reaction conditions, to provide ruxolitinib.

[0085] In another embodiment, the molar ratio of trifluoroacetic anhydride to the compound of formula 6 is about 1.1 to 5 molar equivalents; preferably 2 to 4 molar equivalents.

[0086] The bases and suitable solvents used in the methods described above are as defined above, but are also selected from organic bases such as triethylamine, methylamine, ethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, diisopropylaminolithium, n-butyllithium, tribenzylamine, isopropylamine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethylaminopyridine The solvent used is selected from esters such as ethyl acetate, isopropyl acetate, etc., or halogenated solvents such as dichloromethane, chloroform, chlorobenzene, bromobenzene, etc.; preferably N-methylmorpholine; and the suitable solvent used is selected from esters such as ethyl acetate, isopropyl acetate, etc., or halogenated solvents such as dichloromethane, chloroform, chlorobenzene, bromobenzene, etc.; preferably ethyl acetate, isopropyl acetate or dichloromethane.

[0087] The reaction is carried out at a suitable temperature of about 0°C to about 60°C for a sufficient period of time; preferably at about 10°C to about 30°C for about 1 to 4 hours.

[0088] In previously known methods, ruxolitinib was prepared from compounds of formula 6 using phosphorous oxychloride / N-methyl-2-pyrrolidone (NMP) or oxalyl chloride, and the inventors discovered that the reported reaction conditions yielded crude ruxolitinib with a low purity of approximately 85%, which improved to approximately 95% after column chromatography. Based on LC-MS, the main impurities (6-7%) were presumed to be NMP adducts. Furthermore, chromatography is not suitable for large-scale production.

[0089] However, the inventors of this invention were surprised to discover that when trifluoroacetic anhydride is used in the preparation of ruxolitinib from the compounds of Formula 6, the reaction conditions are mild, the operation is friendly and industrially applicable, and high purity of over 99% can be obtained directly without further purification steps or column chromatography.

[0090] Therefore, the inventors of this invention have avoided laborious purification techniques such as column chromatography and provided a simple, cost-effective and industrially feasible improved method.

[0091] In one embodiment, the following table shows a comparison between the prior art method and the present invention in terms of conversion rate (conversion of the amide compound of formula 6 to ruxolitinib) and purity of ruxolitinib:

[0092]

[0093] Step f) of the method involves converting ruxolitinib into its salt, which can be carried out by treating ruxolitinib with an acidic component, such as phosphoric acid, in a suitable solvent under suitable reaction conditions to provide ruxolitinib phosphate.

[0094] Suitable solvents used in the above method are as defined above, but are also selected from alcohols such as methanol, ethanol, isopropanol, n-butanol, isobutanol, etc.; isopropanol is preferred.

[0095] The reaction is carried out at a suitable temperature of about 20°C to about 60°C for a sufficient period of time; preferably at about 20°C to about 30°C for about 1 to 2 hours.

[0096] The intermediate compounds of formula 3, formula 5 or formula 5a obtained in this invention can be optionally isolated.

[0097] In another embodiment of the invention, an improved method for preparing the intermediate compound of formula 3 is provided, comprising:

[0098] Compounds of Formula 2:

[0099]

[0100] Wherein, "P" represents an amino protecting group;

[0101] The compound of formula 3 is reacted with a reagent prepared in situ from trifluoromethanesulfonic anhydride and DMF in the presence of a suitable solvent to provide the compound.

[0102]

[0103] In this invention, the suitable solvent used in the above method is as defined above, but is also selected from nitrile solvents such as acetonitrile, propionitrile, etc.; preferably acetonitrile.

[0104] The reaction is carried out at a suitable temperature of about 0°C to about 50°C for a sufficient period of time; preferably at about 5°C to about 35°C for about 10 to 16 hours.

[0105] In another embodiment, the intermediate compound of formula 3 obtained according to the above embodiment is further converted into ruxolitinib or a salt thereof.

[0106] In another embodiment of the invention, an improved method for preparing ruxolitinib or a salt thereof is provided, comprising:

[0107] a) Make the compound of formula 5:

[0108]

[0109] The compound is reacted with carbonyl diimidazole (CDI) in a suitable solvent, followed by reaction with ammonia to provide the compound of formula 6.

[0110]

[0111] b) Reacting the compound of formula 6 with trifluoroacetic anhydride in the presence of a base and a suitable solvent to provide ruxolitinib; and

[0112]

[0113] c) Optionally convert ruxolitinib to its salt.

[0114] Step a) of the method involves the reaction of the compound of formula 5 with carbonyl diimidazole in a suitable solvent, followed by a reaction with ammonia under suitable reaction conditions to provide the compound of formula 6. Suitable solvents used in the method described above are as defined above, but are also selected from amides such as dimethylformamide, dimethylacetamide, etc.; preferably dimethylacetamide or dimethylformamide.

[0115] The reaction is carried out at a suitable temperature of about 0°C to about 60°C for a sufficient period of time; preferably at about 0°C to about 30°C for about 1 to 4 hours.

[0116] Step b) of the method involves the reaction of the compound of Formula 6 with trifluoroacetic anhydride in the presence of a base and a suitable solvent, under suitable reaction conditions, to provide ruxolitinib.

[0117] In another embodiment, the molar ratio of trifluoroacetic anhydride to the compound of formula 6 is about 1.1 to 5 molar equivalents; preferably 2 to 4 molar equivalents.

[0118] In addition to the base and suitable solvent used in the methods described above, the base may also be selected from organic bases such as triethylamine, methylamine, ethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, diisopropylaminolithium, n-butyllithium, tribenzylamine, isopropylamine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethyl... Aminopyridine, morpholine, pyridine, 2,6-rutidine, 2,4,6-carbidol, imidazole, 1-methylimidazolium, 1,2,4-triazole, 1,4-diazabicyclo[2.2.2]octane, etc.; preferably N-methylmorpholine; and suitable solvents are selected from esters such as ethyl acetate, isopropyl acetate, etc., or halogenated solvents such as dichloromethane, chloroform, chlorobenzene, bromobenzene, etc.; preferably ethyl acetate, isopropyl acetate or dichloromethane.

[0119] The reaction is carried out at a suitable temperature of about 0°C to about 60°C for a sufficient period of time; preferably at about 10°C to about 30°C for about 1 to 4 hours.

[0120] Step c) of the method involves converting ruxolitinib into its salt, which can be carried out by treating ruxolitinib with an acidic component, such as phosphoric acid, in a suitable solvent under suitable reaction conditions to provide ruxolitinib phosphate.

[0121] Suitable solvents used in the above method are as defined above, but are also selected from alcohols such as methanol, ethanol, isopropanol, n-butanol, isobutanol, etc.; isopropanol is preferred.

[0122] The reaction is carried out at a suitable temperature of about 20°C to about 60°C for a sufficient period of time; preferably at about 20°C to about 30°C for about 1 to 2 hours.

[0123] In another embodiment of the invention, an improved method for preparing ruxolitinib or a salt thereof is provided, comprising:

[0124] a) Make the compound of formula 6:

[0125]

[0126] Reaction with trifluoroacetic anhydride in the presence of a base and a suitable solvent to provide ruxolitinib; and

[0127]

[0128] b) Optionally convert ruxolitinib to its salt.

[0129] Step a) of the method involves the reaction of the compound of Formula 6 with trifluoroacetic anhydride in the presence of a base and a suitable solvent, under suitable reaction conditions, to provide ruxolitinib.

[0130] In another embodiment, the molar ratio of trifluoroacetic anhydride to the compound of formula 6 is about 1.1 to 5 molar equivalents; preferably 2 to 4 molar equivalents.

[0131] In this invention, the base and suitable solvent used in step a) above are as defined above, but are also selected from organic bases such as triethylamine, methylamine, ethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, diisopropylaminolithium, n-butyllithium, tribenzylamine, isopropylamine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, di... Methylaminopyridine, morpholine, pyridine, 2,6-rutidine, 2,4,6-coridine, imidazole, 1-methylimidazolium, 1,2,4-triazole, 1,4-diazabicyclo[2.2.2]octane, etc.; preferably N-methylmorpholine; and the suitable solvent used is selected from esters such as ethyl acetate, isopropyl acetate, etc., or halogenated solvents such as dichloromethane, chloroform, chlorobenzene, bromobenzene, etc.; preferably ethyl acetate, isopropyl acetate or dichloromethane.

[0132] The reaction is carried out at a suitable temperature of about 0°C to about 60°C for a sufficient period of time; preferably at about 10°C to about 30°C for about 1 to 4 hours.

[0133] Step b) of the method involves converting ruxolitinib into its salt, which can be carried out by treating ruxolitinib with an acidic component, such as phosphoric acid, in a suitable solvent under suitable reaction conditions to provide ruxolitinib phosphate.

[0134] In this invention, the suitable solvent used in step b) above is as defined above, but is also selected from alcohols such as methanol, ethanol, isopropanol, n-butanol, isobutanol, etc.; isopropanol is preferred.

[0135] The reaction is carried out at a suitable temperature of about 20°C to about 60°C for a sufficient period of time; preferably at about 20°C to about 30°C for about 1 to 2 hours.

[0136] ruxolitinib crystal form G

[0137] In another embodiment of the invention, a new crystal form G of ruxolitinib is provided.

[0138] In another embodiment of the invention, a novel crystal form G of ruxolitinib is provided, characterized by having one or more peaks in its PXRD pattern at approximately 10.1, 13.6, 17.5, and 22.8 ± 0.2° 2θ.

[0139] In another embodiment of the invention, a novel crystal form G of ruxolitinib is provided, further characterized in that its PXRD pattern has one or more peaks at approximately 6.5, 9.3, 10.1, 11.1, 12.0, 13.6, 14.41, 17.5, 22.8 ± 0.2° 2θ.

[0140] The new crystal form G of ruxolitinib exhibits the following diffraction peaks in its PXRD pattern, as shown in Table 1 below:

[0141] Table 1

[0142] In another embodiment of the invention, a new crystal form G of ruxolitinib is provided, characterized by an exothermic peak at approximately 138-146 °C in the DSC thermal analysis diagram.

[0143] Further characteristics of ruxolitinib crystal form G are shown in the XRPD pattern, DSC thermal analysis pattern, and TGA, as follows: Figure 1 , Figure 2 and Figure 3 As depicted in the text.

[0144] The novel polymorphic form of ruxolitinib G of the present invention has advantageous properties selected from at least one of the following: chemical purity, fluidity, solubility, morphology or crystal habit, and stability—for example, storage stability.

[0145] In another embodiment of the invention, a method for preparing a new crystal form G of ruxolitinib is provided, comprising:

[0146] a) Dissolve ruxolitinib in a suitable solvent at a suitable temperature; and

[0147] b) Separation of ruxolitinib crystal form G.

[0148] In step a) of the above method, ruxolitinib is dissolved in a suitable solvent at a suitable temperature of about 15°C to the boiling point of the solvent used; preferably at about 30°C to about 160°C; wherein the suitable solvent is as defined above, but is also selected from aprotic solvents such as ethers, amides, esters, nitriles, sulfoxides, ketones, halogenated solvents, etc.; preferably esters such as ethyl acetate, isopropyl acetate, etc., or halogenated solvents such as dichloromethane, chloroform, chlorobenzene, bromobenzene, etc.; more preferably ethyl acetate, isopropyl acetate, or dichloromethane; and in step b) the crystal form G of ruxolitinib can be separated by any conventional technique known in the art, such as filtration, evaporation or decantation of the solution, followed by drying.

[0149] In another embodiment of the invention, a method for preparing a new crystal form G of ruxolitinib is provided, comprising:

[0150] a) Dissolve ruxolitinib in a suitable solvent at a suitable temperature;

[0151] b) Optionally treated with activated carbon;

[0152] c) Add a suitable antisolvent to the solution from step b) at a suitable temperature; and

[0153] d) Separation of ruxolitinib crystal form G.

[0154] In step a) of the above method, ruxolitinib is dissolved in a suitable solvent at a suitable temperature of 15°C to the reflux temperature of the solvent used; preferably at about 30°C to about 160°C; wherein the suitable solvent is as defined above, but is also selected from aprotic solvents such as ethers, amides, esters, nitriles, sulfoxides, ketones, and halogenated hydrocarbons; preferably esters such as ethyl acetate, isopropyl acetate, etc., or halogenated solvents such as dichloromethane, chloroform, chlorobenzene, bromobenzene, etc.; more preferably ethyl acetate, isopropyl acetate, or dichloromethane; then optionally treated with activated carbon in step b). In step c), the suitable antisolvent is added to the solution from step b) at a suitable temperature of about 20°C to about 60°C for a sufficient period of time until complete crystallization; preferably at about 25°C to 55°C; wherein the suitable antisolvent is selected from, but not limited to, hydrocarbon solvents such as heptane, hexane, cyclohexane, cycloheptane, toluene, xylene, cyclohexane, etc., or ethers such as methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentylmethyl ether, dioxane, etc.; preferably hexane, heptane, or methyl tert-butyl ether; and finally in step d), the crystal form G of ruxolitinib can be separated by any conventional technique known in the art, such as filtration, evaporation, or decantation of the solution, followed by drying.

[0155] In another embodiment of the invention, a novel crystal form G of ruxolitinib is provided, which is prepared by a method involving single solvent crystallization and / or solvent and antisolvent crystallization.

[0156] In another embodiment of the invention, a method for preparing ruxolitinib crystal form G is provided, comprising reacting a ruxolitinib acid addition salt with a base in a suitable solvent under suitable reaction conditions to provide ruxolitinib crystal form G.

[0157] In the above method, the ruxolitinic acid addition salt is selected from phosphoric acid, maleic acid, sulfuric acid, benzenesulfonic acid, oxalic acid, hydrobromic acid, hydrochloric acid, citric acid, fumaric acid, tartaric acid, p-toluenesulfonic acid, benzoic acid, benzenesulfonic acid, ethanesulfonic acid, 2-naphthalenesulfonic acid, 4-chlorobenzenesulfonic acid, etc.; preferably phosphoric acid or hydrochloric acid.

[0158] In some embodiments, the base used is selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, etc.; preferably potassium carbonate; and the suitable solvent is selected from esters such as ethyl acetate, isopropyl acetate, etc., or halogenated solvents such as dichloromethane, chloroform, chlorobenzene, bromobenzene, etc.; preferably ethyl acetate, isopropyl acetate, or dichloromethane.

[0159] In some embodiments, the base used is in an amount of about 1 to about 10 molar equivalents relative to the ruxolitinic acid addition salt. In some embodiments, the base used is in an amount of about 1 to about 5 molar equivalents relative to the ruxolitinic acid addition salt. In some embodiments, the base used is in an amount of about 1 to about 3 molar equivalents relative to the ruxolitinic acid addition salt.

[0160] In some implementations, the reaction of the ruxolitinic acid addition salt with a base involves using an amount of base sufficient to achieve a pH greater than 7.

[0161] In other embodiments, the ruxolitinic acid addition salt is dissolved in a suitable solvent at a suitable temperature of about 15°C to the reflux temperature of the solvent used; in some embodiments, the crystal form G of ruxolitinib can be separated by any conventional technique known in the art, such as filtration, evaporation or decanting of the solution, followed by drying.

[0162] In another embodiment of the invention, a method for preparing ruxolitinib crystal form G is provided, comprising reacting ruxolitinib phosphate with a base in a solvent component.

[0163] In some embodiments, the base used is selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, etc.; preferably potassium carbonate; and the suitable solvent is selected from esters such as ethyl acetate, isopropyl acetate, etc., or halogenated solvents such as dichloromethane, chloroform, chlorobenzene, bromobenzene, etc.; preferably ethyl acetate, isopropyl acetate, or dichloromethane.

[0164] In some embodiments, the base used is in an amount of about 1 to about 10 molar equivalents relative to ruxolitinib phosphate. In some embodiments, the base used is in an amount of about 1 to about 5 molar equivalents relative to ruxolitinib phosphate. In some embodiments, the base used is in an amount of about 1 to about 3 molar equivalents relative to ruxolitinib phosphate.

[0165] In some implementations, the reaction of ruxolitinib phosphate with a base involves using an amount of base sufficient to achieve a pH greater than 7.

[0166] In other embodiments, ruxolitinib phosphate is dissolved in a suitable solvent at a suitable temperature of about 15°C to the boiling point of the solvent used; in some embodiments, the crystal form G of ruxolitinib can be separated by any conventional technique known in the art, such as filtration, evaporation or decanting of the solution, followed by drying.

[0167] In another embodiment of the invention, a method for preparing ruxolitinic acid addition salt is provided, comprising:

[0168] The crystalline ruxolitinib form G is reacted with the acid component in a suitable solvent under suitable reaction conditions to provide an addition salt of ruxolitinib acid.

[0169] In the above method, crystalline ruxolitinib form G is reacted with an acid component selected from the following in a suitable solvent and under suitable reaction conditions: phosphoric acid, maleic acid, sulfuric acid, benzenesulfonic acid, oxalic acid, hydrobromic acid, hydrochloric acid, citric acid, fumaric acid, tartaric acid, p-toluenesulfonic acid, benzoic acid, benzenesulfonic acid, ethanesulfonic acid, 2-naphthalenesulfonic acid, 4-chlorobenzenesulfonic acid, etc.; preferably phosphoric acid or hydrochloric acid; to provide an addition salt of ruxolitinib acid.

[0170] In this invention, suitable solvents used in the methods described above are as defined above, but are also selected from alcohols, esters, nitriles, sulfoxides, ketones, hydrocarbons and halogenated solvents; preferably alcohols such as methanol, ethanol, isopropanol, n-butanol, isobutanol, etc., or esters such as ethyl acetate, isopropyl acetate, etc.; more preferably methanol, ethanol, isopropanol, ethyl acetate or isopropyl acetate.

[0171] The reaction is carried out at a suitable temperature of about 0°C to about 60°C for a sufficient period of time; preferably at about 25°C to about 55°C for about 1 to 4 hours.

[0172] The crystal form G of ruxolitinib of the present invention can be administered as part of a pharmaceutical composition for the treatment of JAK-related diseases or disorders.

[0173] Therefore, in another aspect, pharmaceutical compositions are provided comprising crystal form G of ruxolitinib of the present invention, one or more pharmaceutically acceptable carriers, diluents or excipients, and optionally other therapeutic ingredients.

[0174] Pharmaceutical compositions comprising ruxolitinib crystal form G of the present invention can be administered orally, topically, parenterally, by inhalation or spray, rectal or by injection.

[0175] Method for preparing crystal variant 3 of ruxolitinib hydrochloride

[0176] Another embodiment of the present invention provides an improved method for preparing ruxolitinib hydrochloride crystal variant 3, comprising:

[0177] Ruxolitinib was reacted with hydrochloric acid in a mixture of ethyl acetate and ethanol solvent systems under suitable reaction conditions to provide crystalline variant 3 of ruxolitinib hydrochloride.

[0178] As used in this article, the term “crystal variant” for ruxolitinib is synonymous with the commonly used expression for “polymorphic form” or “crystal form” of ruxolitinib.

[0179] As described in the background section, WO2017008772A1 describes the preparation of crystalline variant 3 of ruxolitinib hydrochloride. However, existing methods do not prepare crystalline variant 3 of ruxolitinib hydrochloride in a single-step reaction, i.e., the reaction step of ruxolitinib with hydrochloric acid. They involve multiple steps, including first separating crystalline variant 1, converting crystalline variant 1 into crystalline variant 2, and then converting crystalline variant 2 into crystalline variant 3. It is obvious that these existing methods are very laborious and commercially unfeasible.

[0180] The inventors have surprisingly developed a simple and single-step method for preparing crystalline variant 3 of ruxolitinib hydrochloride by using a specific solvent mixture and solvent system volume ratio.

[0181] Therefore, in one embodiment, the volume ratio of ethanol to ethyl acetate is about 1:1 to 1:10.

[0182] In another embodiment, the reaction of ruxolitinib with hydrochloric acid is carried out at a suitable temperature of about 0°C to about 50°C for a sufficient period of time; preferably at about 20°C to about 40°C for about 2 to 6 hours.

[0183] In another embodiment, the crystal variant 3 of ruxolitinib hydrochloride is separated by conventional methods known in the art, such as by cooling or adding an antisolvent.

[0184] In another embodiment, the crystal variant 3 of ruxolitinib hydrochloride is separated by adding an antisolvent such as ethyl acetate.

[0185] Figure 4 The X-ray powder diffraction (XRPD) pattern of crystal variant 3 of ruxolitinib hydrochloride is shown.

[0186] In the foregoing sections, embodiments have been described by way of example to illustrate the method of the present invention. However, these examples are not intended to limit the scope of the invention in any way. Variations of the examples that will be obvious to those skilled in the art are all within the scope of the present invention. Example

[0187] The methodological details of the invention are provided in the embodiments given below. These embodiments are provided for illustrative purposes only and should not be construed as limiting the scope of the invention.

[0188] Example 1: Preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionate dicyclohexylamine:

[0189]

[0190] At room temperature (RT), acetonitrile (150 ml) and DMF (184.5 ml) were added to a round-bottom flask (RBF). Trifluoromethanesulfonic anhydride (237.5 ml) was added to the reactants, and the reactants were maintained at RT for 2 to 3 hours. At a temperature below 10°C, 4-methyl-7H-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid benzyl ester (50 g) was added to the reactants, and the reactants were maintained at a temperature below 20°C until completion. At a temperature below 20°C, water (100 ml) was added to the reactants, and the pH of the reactants was adjusted to 2.5-3.5 with an aqueous solution of NaOH (10 V). At a temperature below 20°C, (R)-5-cyclopentylpyrazolidine-3-one D-tartrate (68.32 g) was added to the reactants, and the reactants were stirred at 50-70°C until completion.

[0191] The reactants were cooled to below 30°C, and the pH was adjusted to 3.0-5.0 with an aqueous NaOH solution. The compound was extracted with DCM, and the DCM layer was washed with a brine solution. The solvent was completely removed by distillation under vacuum below 40°C, and an aqueous HCl solution was added. The reactants were stirred at 50-70°C until the reaction was complete. The pH was adjusted to 10.0-12.0 with an aqueous sodium hydroxide solution at RT, and the reactants were stirred at 40-60°C until the reaction was complete. The reactants were cooled to RT, washed with ethyl acetate, and the compound was extracted with ethyl acetate containing methanol at a pH of 3.5-6.0. The organic layer was washed with an aqueous NaCl solution, and the solvent was removed by distillation under reduced pressure to obtain the crude compound. The crude compound was dissolved in acetone and treated with activated carbon, followed by the addition of DCHA (33.91 g) at 40-50°C. The resulting material was kept under reflux, cooled to RT, and filtered. The material was then purified with acetone to obtain the DCHA salt of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionic acid. Yield: 40-45 g.

[0192] Example 2: Preparation of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionamide:

[0193]

[0194] 100 g of the DCHA salt of (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionic acid was dissolved in water, and the pH was adjusted to >11 using an aqueous NaOH solution. The mixture was washed and the pH was adjusted to 3.5 to 5.5, followed by extraction with a mixture of acetonitrile and ethyl acetate. The combined organic layers were washed with brine, and the solvent was removed by distillation. The crude product was dissolved in DMF (2.5V). CDI (1.0 eq-4.0 eq) was added to the mixture at below 15°C under a nitrogen atmosphere, and the mixture was stirred at the same temperature. After the reaction was complete, an ammonia solution was added at below 15°C and the mixture was stirred for 1 to 2 hours. An aqueous sodium chloride solution was added to the reaction mixture, the mixture was stirred, and then filtered. The substance was purified using an aqueous IPA solution to obtain (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionamide. Yield: 25-45 g.

[0195] Example 3: Preparation and purification of ruxolitinib:

[0196]

[0197] Under RT and nitrogen atmosphere, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionamide (20 g) and DCM (5 V) were added to RBF. 4-Methylmorpholine (4.0 eq) was added and the mixture was stirred for 10 to 15 min.

[0198] Cool the reactants to below 20°C, add trifluoroacetic anhydride (2-3 mg / eq) and stir until the reaction is complete. After the reaction is complete, wash the reactants with NaHCO3 solution, water, and brine. Remove the organic layer by vacuum distillation and separate from ethyl acetate / n-heptane to obtain ruxolitinib (crystal form G). Yield: 12-18 g.

[0199] Example 4: Preparation of Ruxolitinib Phosphate:

[0200]

[0201] At 20–30 °C, 100 g of ruxolitinib and 30 V of IPA obtained above were added to an RBF. The mixture was heated to 50–60 °C and maintained at the same temperature for 30–50 min. The reaction mixture was filtered on a hyflo bed and washed with IPA. A solution of orthophosphoric acid (1.0 eq.) was added to the reaction mixture at 50–60 °C, and the mixture was stirred at 50–60 °C for 1–2 h. The mixture was cooled to 25–30 °C and stirred at 25–30 °C for 1–2 h. The resulting solid was filtered, washed with IPA, and the wet compound was dried under vacuum at 50–60 °C to obtain ruxolitinib phosphate.

[0202] Yield: 95g.

[0203] Example 5: Preparation of ruxolitinib hydrochloride:

[0204]

[0205] Ruxolitinib (20 g) and ethyl acetate (20 V) were added to an RBF container and stirred at 20–40 °C for 20–30 min. The mixture was then heated to 40–60 °C and stirred for 10–40 min. Ethanol (2 V) was added to the mixture at below 50 °C, followed by ethyl acetate containing HCl (1.0–2.0 V) at below 50 °C. The mixture was stirred until a heterogeneous mixture was formed. Ethyl acetate (40 V) was added to the mixture at below 40 °C and stirred for 2–4 h. The mixture was then cooled to below 10 °C and stirred for 2–4 h. The resulting solid was filtered, washed with ethyl acetate, and dried under vacuum to give ruxolitinib hydrochloride crystal variant 3. Yield: 13–16 g.

[0206] Example 6: Preparation of ruxolitinib hydrochloride:

[0207]

[0208] Ruxolitinib (20 g) and ethyl acetate (20 V) were added to an RBF container and stirred at 20–40 °C for 20–30 min. The mixture was then heated to 40–60 °C and stirred for 10–40 min. Ethanol (3 V) was added to the mixture at below 50 °C, followed by ethyl acetate (2.0–3.0 V) containing HCl at below 50 °C. The mixture was stirred until a heterogeneous mixture was formed. Ethyl acetate (20 V) was added to the mixture at below 40 °C and stirred for 2–4 h. The mixture was then cooled to below 10 °C and stirred for 2–4 h. The resulting solid was filtered, washed with ethyl acetate, and dried under vacuum to give ruxolitinib hydrochloride crystal variant 3. Yield: 18–20 g.

[0209] Example 7: Preparation of ruxolitinib hydrochloride:

[0210]

[0211] Ruxolitinib (20 g) and ethyl acetate (20 V) were added to an RBF container and stirred at 20–40 °C for 20–30 min. The mixture was then heated to 40–60 °C and stirred for 10–40 min. Ethanol (3–4 V) was added to the mixture at below 50 °C, followed by ethyl acetate containing HCl (2.0–3.0 V) at below 50 °C. The mixture was stirred until a heterogeneous mixture was formed. Ethyl acetate (35–45 V) was added to the mixture at below 40 °C and stirred for 2–4 h. The mixture was then cooled to below 10 °C and stirred for 2–4 h. The resulting solid was filtered, washed with ethyl acetate, and dried under vacuum to obtain ruxolitinib hydrochloride crystal variant 3. Yield: 16–18 g.

[0212] Example 8: Preparation and purification of ruxolitinib:

[0213]

[0214] Under RT and nitrogen atmosphere, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionamide (20 g) and ethyl acetate (8 V) were added to RBF, followed by the addition of 4-methylmorpholine (NMM, 5.0 eq.) and stirring for 10-15 min. The reaction mixture was cooled to 10-15 °C and trifluoroacetic anhydride (TFAA, 2-3 m eq.) was slowly added below 20 °C under nitrogen atmosphere. The reaction mixture was stirred for 1-2 h at 15-20 °C under nitrogen atmosphere. The reaction mixture was quenched with NaHCO3 aqueous solution (10 V) and stirred for 15-20 min. The layers were separated, and the aqueous layer was extracted with ethyl acetate (10 V). The combined organic layers were washed with aqueous NaHCO3 solution (10V), DM-water (2 x 10V), and saturated NaCl solution (6V) at RT. The organic layers were concentrated at 50°C under vacuum to obtain ruxolitinib (crude product). Yield: ~19g (crude product).

[0215] At RT, crude ruxolitinib (19 g) and ethyl acetate (3 V) were added to an RBF. The reactants were heated to 45-50 °C and stirred at the same temperature for 30-45 min. The reactants were then cooled to 0-5 °C and stirred at the same temperature for 1-2 h. The resulting solid was filtered and washed with pre-cooled ethyl acetate (1 V). The wet material was dried under vacuum to obtain ruxolitinib crystal form G. Yield: 13 to 16 g; Purity: >99%.

[0216] Example 9: Preparation and purification of ruxolitinib:

[0217]

[0218] Under RT and nitrogen atmosphere, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionamide (20 g) and isopropyl acetate (8 V) were added to RBF, followed by the addition of 4-methylmorpholine (NMM, 5.0 eq.) and stirring for 10-15 min. The reaction mixture was cooled to 10-15 °C, and trifluoroacetic anhydride (TFAA, 2-3 m. eq.) was slowly added below 20 °C under nitrogen atmosphere. The reaction mixture was stirred for 1-2 h at 15-20 °C under nitrogen atmosphere. The reaction mixture was quenched with NaHCO3 aqueous solution (10 V) and stirred for 15-20 min. The layers were separated, and the aqueous layer was extracted with isopropyl acetate (10 V). Under RT, the combined organic layers were washed with an aqueous solution of NaHCO3 (10V), DM-water (2 x 10V), and a saturated aqueous solution of NaCl (6V). The organic layers were treated with activated carbon, filtered, and the solvent was removed from the filtrate by distillation below 50°C and under reduced pressure until 4.0 ± 0.5V remained in the RBF. n-Heptane (3.0V) was added to the reactants at 50 ± 5°C, and then cooled to 25–30°C. The reactants were stirred at 25–30°C for 1–2 hours, filtered, and washed with a mixture of isopropyl acetate:n-heptane (2V, 1:1 ratio). The resulting wet material was dried under vacuum to obtain ruxolitinib crystal form G. Yield: 13–16 g; Purity: >99%.

[0219] Example 10: Preparation and purification of ruxolitinib:

[0220]

[0221] Under RT and nitrogen atmosphere, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionamide (20 g) and dichloromethane (8 V) were added to RBF, followed by the addition of 4-methylmorpholine (NMM, 5.0 eq.) and stirring for 10-15 min. The reaction mixture was cooled to 10-15 °C and trifluoroacetic anhydride (TFAA, 2-3 m. eq.) was slowly added below 20 °C under nitrogen atmosphere. The reaction mixture was stirred for 1-2 h at 15-20 °C under nitrogen atmosphere. The reaction mixture was quenched with NaHCO3 aqueous solution (10 V) and stirred for 15-20 min. The layers were separated, and the aqueous layer was extracted with dichloromethane (10 V). Under RT, the combined organic layers were washed with an aqueous solution of NaHCO3 (10V), DM-water (2 x 10V), and a saturated aqueous solution of NaCl (6V). The organic layers were treated with activated carbon, filtered, and the solvent was removed from the filtrate by distillation below 50°C and under reduced pressure until 4.0 ± 0.5V remained in the RBF. n-Heptane (3.0V) was added to the reactants at 50 ± 5°C, and then cooled to 25–30°C. The reactants were stirred at 25–30°C for 1–2 hours, filtered, and washed with a mixture of dichloromethane:n-heptane (2V, 1:1 ratio). The resulting wet material was dried under vacuum to obtain ruxolitinib crystal form G. Yield: 13–16 g; Purity: >99%.

[0222] Example 11: Preparation and purification of ruxolitinib:

[0223]

[0224] Under RT and nitrogen atmosphere, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionamide (20 g) and ethyl acetate (8 V) were added to RBF, followed by the addition of 4-methylmorpholine (NMM, 5.0 eq.) and stirring for 10-15 min. The reaction mixture was cooled to 10-15 °C, and trifluoroacetic anhydride (TFAA, 2-3 m. eq.) was slowly added below 20 °C under nitrogen atmosphere. The reaction mixture was stirred for 1-2 h at 15-20 °C under nitrogen atmosphere. The reaction mixture was quenched with NaHCO3 aqueous solution (10 V) and stirred for 15-20 min. The layers were separated, and the aqueous layer was extracted with ethyl acetate (10 V). Under RT, the combined organic layers were washed with an aqueous NaHCO3 solution (10V), DM-water (2 x 10V), and a saturated NaCl aqueous solution (6V). The organic layers were treated with activated carbon, filtered, and the solvent was removed from the filtrate by distillation below 50°C and under reduced pressure until 4.0 ± 0.5V remained in the RBF. n-Heptane (3.0V) was added to the reactants at 50 ± 5°C, and then cooled to 25–30°C. The mixture was stirred at 25–30°C for 1–2 hours, filtered, and washed with a mixture of ethyl acetate:n-heptane (2V, 1:1 ratio). The resulting wet material was dried under vacuum to give ruxolitinib crystal form G. Yield: 13–16 g; Purity: >99%.

[0225] Example 12: Preparation and purification of ruxolitinib:

[0226]

[0227] Under RT and nitrogen atmosphere, (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionamide (20 g) and ethyl acetate (8 V) were added to RBF, followed by the addition of 4-methylmorpholine (NMM, 5.0 eq.) and stirring for 10-15 min. The reaction mixture was cooled to 10-15 °C, and trifluoroacetic anhydride (TFAA, 2-3 m. eq.) was slowly added below 20 °C under nitrogen atmosphere. The reaction mixture was stirred for 1-2 h at 15-20 °C under nitrogen atmosphere. The reaction mixture was quenched with NaHCO3 aqueous solution (10 V) and stirred for 15-20 min. The layers were separated, and the aqueous layer was extracted with ethyl acetate (10 V). Under RT, the combined organic layers were washed with an aqueous solution of NaHCO3 (10V), DM-water (2 x 10V), and a saturated aqueous solution of NaCl (6V). The organic layers were treated with activated carbon, filtered, and the solvent was removed from the filtrate by distillation below 50°C and under reduced pressure until 4.0 ± 0.5V remained in the RBF. MTBE (3.0V) was added to the reactants at 50 ± 5°C, and then cooled to 25–30°C. The reactants were stirred at 25–30°C for 1–2 hours, filtered, and washed with a mixture of ethyl acetate:MTBE (2V, 1:1 ratio). The resulting wet material was dried under vacuum to obtain ruxolitinib crystal form G. Yield: 13–16 g; Purity: >99%.

[0228] Example 13: Preparation and purification of ruxolitinib:

[0229] Cool the slurry (10 vol.) of DCM containing ruxolitinib phosphate to 10–15 °C. Add water (3 vol.) to the material at 10–15 °C and adjust the pH to 9–10 using an aqueous K₂CO₃ solution at 10–15 °C. Stir the reaction mixture at 10–15 °C for 20–30 min, then stop stirring and separate the layers. Extract the aqueous layer with DCM (5–10 vol.). Wash the combined organic layers with water (10 vol.) and brine (5–10 vol.). Dry the organic layers with anhydrous sodium sulfate and filter. Concentrate the filtrate under vacuum until ~2 vol remains in the RBF. Add isopropyl acetate (5 vol.) to the RBF and distill off the solvent under vacuum until ~2 vol remains in the RBF. The material was heated to 50-55°C and n-heptane (6 Vol.) was added at 45-55°C, followed by stirring at 50-55°C for 45 min to 1 h. The material was cooled to RT and stirred for 1 to 2 h, filtered, and washed with chilled (0-5°C) isopropanol (1 Vol.). The wet material was dried at 45-50°C under vacuum to obtain ruxolitinib crystal form G. Purity: >99% purity.

[0230] Example 14: Preparation and purification of ruxolitinib:

[0231] Cool the slurry (10-20 vol.) of isopropyl acetate containing ruxolitinib phosphate to 10-15°C. Add water (3 vol.) to the material at 10-15°C and adjust the pH to 9-10 using an aqueous K₂CO₃ solution at 10-15°C. Stir the reaction mixture at 10-15°C for 20-30 min, then stop stirring and separate the layers. Extract the aqueous layer with isopropyl acetate (10-20 vol.). Wash the combined organic layers with water (10 vol.) and brine (5-10 vol.). Dry the organic layers with anhydrous sodium sulfate and filter. Concentrate the filtrate under vacuum until ~2 vol remains in the RBF. Add isopropyl acetate (5 vol.) to the RBF and distill off the solvent under vacuum until ~2 vol remains in the RBF. The material was heated to 50-55°C and n-heptane (6 Vol.) was added at 45-55°C, followed by stirring at 50-55°C for 45 min to 1 h. The material was cooled to RT and stirred for 1 to 2 h, filtered, and washed with chilled (0-5°C) isopropanol (1 V). The wet material was dried at 45-50°C under vacuum to obtain ruxolitinib crystal form G.

[0232] Purity: >99%.

[0233] Example 15: Preparation and purification of ruxolitinib:

[0234] Cool the slurry of ethyl acetate containing ruxolitinib phosphate (10-20 vol.) to 10-15 °C. Add water (3 vol.) to the mixture at 10-15 °C and adjust the pH to 9-10 using an aqueous K₂CO₃ solution at 10-15 °C. Stir the reaction mixture at 10-15 °C for 20-30 min, then stop stirring and separate the layers. Extract the aqueous layer with ethyl acetate (10-20 vol.). Wash the combined organic layers with water (10 vol.) and brine (5-10 vol.). Dry the organic layers with anhydrous sodium sulfate and filter. Concentrate the filtrate under vacuum until ~2 vol remains in the RBF. Add ethyl acetate (5 vol.) to the RBF and distill off the solvent under vacuum until ~2 vol remains in the RBF. The material was heated to 50-55°C and n-heptane (6 Vol.) was added at 45-55°C, followed by stirring at 50-55°C for 45 min to 1 h. The material was cooled to RT and stirred for 1 to 2 h, filtered, and washed with chilled (0-5°C) isopropanol (1 V). The wet material was dried at 45-50°C under vacuum to obtain ruxolitinib crystal form G. Purity: >99% purity.

[0235] It will be understood that the present invention can be modified, altered, and adapted by those skilled in the art. Such modifications, alterations, and adaptations are intended to fall within the scope of the present invention.

Claims

1. An improved method for preparing ruxolitinib or its salts, comprising: a) Make the compound of formula 2: Wherein, "P" represents an amino protecting group; The compound of formula 3 is reacted with a reagent prepared in situ from trifluoromethanesulfonic anhydride and DMF in the presence of a suitable solvent to provide the compound. b) Contact the compound of formula 3 with the compound of formula 4 or its salt. To provide compounds of formula 5; c) Optionally, the acid intermediate of formula 5 is purified by reaction with dicyclohexylamine (DCHA) in a suitable solvent to provide a dicyclohexylamine salt of the acid intermediate of formula 5a, and By reacting it with a base to further convert it into its free base, a pure acid intermediate of formula 5 can be provided; d) React the compound of formula 5 with carbonyl diimidazole (CDI) in a suitable solvent, followed by reaction with ammonia to provide the compound of formula 6; e) Treating the compound of formula 6 with trifluoroacetic anhydride in the presence of a base and a suitable solvent to provide ruxolitinib; and f) Optionally convert ruxolitinib to its salt.

2. The method claimed in claim 1, wherein the base is selected from an aqueous or alcoholic solution of an alkali metal hydroxide, an alkaline earth metal hydroxide, or an organic base; and the suitable solvent is selected from nitriles, ketones, amides, esters, or halogenated solvents.

3. An improved method for preparing the intermediate compound of formula 3, comprising: Compounds of Formula 2: Wherein, "P" represents an amino protecting group; The compound of formula 3 is reacted with a reagent prepared in situ from trifluoromethanesulfonic anhydride and DMF in the presence of a suitable solvent to provide the compound. 。 4. The method claimed in claim 3, wherein the intermediate compound of formula 3 is further converted into ruxolitinib or a salt thereof.

5. An improved method for preparing ruxolitinib or its salts, comprising: a) Make the compound of formula 5: The compound is reacted with carbonyl diimidazole (CDI) in a suitable solvent, followed by reaction with ammonia to provide the compound of formula 6. b) Reacting the compound of formula 6 with trifluoroacetic anhydride in the presence of a base and a suitable solvent to provide ruxolitinib; and c) Optionally convert ruxolitinib to its salt.

6. An improved method for preparing ruxolitinib or its salts, comprising: a) Make the compound of formula 6: Reaction with trifluoroacetic anhydride in the presence of a base and a suitable solvent to provide ruxolitinib; and b) Optionally convert ruxolitinib to its salt.

7. The new crystalline form G of ruxolitinib, characterized by... Its PXRD plot has one or more peaks at approximately 10.1, 13.6, 17.5, and 22.8 ± 0.2° 2θ.

8. The novel crystalline form G of ruxolitinib as claimed in claim 7, further characterized in that its PXRD pattern has one or more peaks at approximately 6.5, 9.3, 10.1, 11.1, 12.0, 13.6, 14.41, 17.5, 22.8 ± 0.2° 2θ.

9. The novel crystalline form G of ruxolitinib as claimed in claim 7, further characterized in that the DSC thermal analysis chart has an exothermic peak at approximately 138-146 °C.

10. A method for preparing a new crystal form G of ruxolitinib, comprising: a) Dissolve ruxolitinib in a suitable solvent at a suitable temperature; as well as b) Separation of ruxolitinib crystal form G.

11. The method claimed in claim 10, wherein the suitable solvent comprises at least one aprotic solvent.

12. A method for preparing a new crystal form G of ruxolitinib, comprising: a) Dissolve ruxolitinib in a suitable solvent at a suitable temperature; b) Optionally treated with activated carbon; c) Add a suitable antisolvent to step b) at a suitable temperature; and d) Separation of ruxolitinib crystal form G.

13. The method claimed in claim 12, wherein the suitable solvent comprises at least one aprotic solvent and the suitable antisolvent is selected from hydrocarbons and ethers.

14. A method for preparing a new crystal form G of ruxolitinib, comprising reacting a ruxolitinib acid addition salt with a base in a solvent component.

15. A method for preparing ruxolitinic acid addition salt, comprising: The crystalline form G of ruxolitinib is reacted with an acid in a suitable solvent to prepare the ruxolitinib acid addition salt.

16. An improved method for preparing crystalline variant 3 of ruxolitinib hydrochloride, comprising: Ruxolitinib was reacted with hydrochloric acid in a mixture of ethyl acetate and ethanol solvents to prepare crystalline ruxolitinib hydrochloride.

17. The method claimed in claim 16, wherein the volume ratio of ethanol to ethyl acetate is about 1:1 to 1:

10.

18. The method claimed in claim 16, wherein the reaction is carried out at a suitable temperature of about 0°C to about 50°C.

Images