A preparation method of ruxolitinib and its intermediates

Abstract

The present invention provides a method for preparing ruxolitinib and its intermediates. The method has high synthesis efficiency, simple process, low synthesis cost, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemical synthesis, and in particular to a method for preparing ruxolitinib and its intermediates. Background Art

[0002] Ruxolitinib is a selective Janus kinase (JAK) tyrosine kinase inhibitor initially developed for the treatment of myeloproliferative disorders such as myelofibrosis. JAK protein tyrosine kinase is a non-receptor protein tyrosinase that is closely associated with cell growth and proliferation and plays a major role in the signal transduction of hematopoietic cytokines and growth factors. Ruxolitinib phosphate tablets are the first JAK-STAT targeted inhibitor approved internationally for the treatment of myelofibrosis (MF).

[0003] WO2022 / 040180 provides a method for preparing ruxolitinib, which uses (R)-3-cyclopentyl-3-hydrazinopropionitrile-L-tartrate (3a) to react with compound 2a to obtain ruxolitinib. However, the preparation process of compound 2a is complicated. The preparation of compound 2a from compound 1a requires the use of hazardous reagents such as (COCl)2, ((CCl3O)2CO, and POCl3, which is not suitable for large-scale industrial production. The synthesis route is as follows:

[0004]

[0005] Alexander M. Haydl et al. disclosed a method for preparing ruxolitinib via the intermediate (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile (Angew Chem. Int. Ed. 2015, 54, 7149-7153). This intermediate is obtained by adding cyclopentyl allene to 4-bromopyrazole in the presence of rhodium and a chiral ligand noble metal catalyst. This method is difficult to purify, the noble metal Rh catalyst is expensive, and the raw materials are difficult to obtain, making it unsuitable for scale-up production. The synthetic route is as follows:

[0006]

[0007] Patent CN104496904A discloses a method for preparing the intermediate (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile. The first step of this route requires the use of hazardous substances such as sodium hydride and potassium hydride. In the second step, reductase-catalyzed reduction is performed to obtain the S-configuration intermediate. In the third step, a Mitsunobu reaction is performed to obtain the R-configuration product. Azo compounds have the risk of explosion under heating or other hazardous conditions, resulting in low synthesis efficiency and unsuitable for industrial production. The synthesis route is shown below:

[0008]

[0009] Patent CN107674026A discloses a method for preparing an intermediate (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile. This route uses chiral borane R-CBS. The preparation process is complex and requires the use of hazardous substances such as sodium hydride and lithium hydride. The synthetic route is as follows:

[0010]

[0011] Lin, Q. et al. disclosed a method for preparing ruxolitinib using the intermediate (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile (Compound 30) (Organic Letters, 11(9), 1999-2002.). The chiral inducing reagent has a large molecular weight and high preparation cost. The asymmetric Michael addition method has low selectivity. In addition, iodine is used in the preparation, which poses certain risks and is not suitable for large-scale production.

[0012] Summary of the Invention

[0013] The present invention aims to provide a method for preparing ruxolitinib and its intermediates, which has higher synthesis efficiency, simple process, low synthesis cost, and is suitable for large-scale industrial production.

[0014] In a first aspect, the present invention provides a method for preparing (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile, comprising:

[0015] Step 1): Compound 3 and / or its salt reacts with compound 4 to obtain compound 5

[0016]

[0017] Step 2): Compound 5 reacts with a brominating agent to obtain (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile (Compound 6)

[0018]

[0019] In a second aspect, the present invention provides a method for preparing ruxolitinib, comprising:

[0020] Step 1): Compound 3 and / or its salt reacts with compound 4 to obtain compound 5

[0021]

[0022] Step 2): Compound 5 reacts with a brominating agent to obtain compound 6

[0023]

[0024] Step 3): Compound 6 reacts with boric acid or boric acid ester to obtain compound 7

[0025]

[0026] Step 4): Compound 7 reacts with compound 8 to obtain Ruxolitinib

[0027]

[0028] Wherein, -BR1R2 is -B(OH)2 or a borate group;

[0029] X is chlorine, bromine or iodine; preferably, X is chlorine.

[0030] In a preferred embodiment, in step 1), the salt of compound 3 is not particularly limited and includes inorganic acid salts and organic acid salts;

[0031] The inorganic acid salt is selected from the group consisting of sulfate, phosphate, nitrate, and hydrochloride;

[0032] The organic acid salt is selected from the group consisting of formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, ethylenesulfonic acid, formic acid, fumaric acid, furoic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, lysine, arginine, aspartic acid, cinnamic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, and trifluoromethanesulfonic acid.

[0033] In a preferred embodiment, in step 1), the salt of compound 3 is L-tartrate, and the L-tartrate is not particularly limited, including anhydrous L-tartrate and hydrated L-tartrate; the water content of the hydrated L-tartrate is not particularly limited, including but not limited to: monohydrate, dihydrate, trihydrate.

[0034] In a preferred embodiment, the L-tartrate of compound 3 is (Compound 3-1).

[0035] In a preferred embodiment, the brominating agent in step 2) is N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide, phenyltrimethylammonium tribromide, liquid bromine, or N-bromoacetamide.

[0036] In a preferred embodiment, the brominating agent in step 2) is N-bromosuccinimide.

[0037] In a preferred embodiment, the borate in step 3) is selected from the group consisting of: bipyrocatechol borate, bipyrocatechol borate, bi(3,3-dimethyl-2,4-pentanediol) borate, trimethyl borate, triethyl borate, tributyl borate, triisopropyl borate, bipyrocatechol borate, or a combination thereof;

[0038] The -BR1R2 is selected from: -B(OH)2, pinacol borate, catechol borate, (3,3-dimethyl-2,4-pentanediol) borate, dimethyl borate, diethyl borate, dibutyl borate, diisopropyl borate, neopentyl glycol borate;

[0039] Preferably, the borate ester is pinacol diborate;

[0040] Preferably, the -BR1R2 is a pinacol borate ester group.

[0041] In a preferred embodiment, the salt of compound 3 is The method comprises

[0042] Step 1): Compound 3-1 reacts with compound 4 to obtain compound 5;

[0043] Step 2): reacting the compound 5 with N-bromosuccinimide to obtain compound 6;

[0044] Step 3): Compound 6 is reacted with diboronic acid pinacol ester to obtain compound 7-1;

[0045] Step 4): The compound 7-1 reacts with the compound 8-1 to obtain the ruxolitinib

[0046]

[0047] In a preferred embodiment, the salt of compound 3 is (Compound 3-1), the method further comprises: reacting compound 1 with hydrazine hydrate to obtain compound 2, adding L-tartaric acid, and splitting to obtain the salt of compound 3

[0048]

[0049] Preferably, seed crystals of the compound 3-1 are added during the separation.

[0050] In a preferred embodiment, the step 1) is carried out under acidic conditions.

[0051] In a preferred embodiment, the step 2) is carried out in an inert solvent.

[0052] Preferably, the inert solvent is an alcohol solvent; preferably, the alcohol solvent is C1-C 10 Alcohol solvent; more preferably methanol.

[0053] In a preferred embodiment, in step 1), concentrated hydrochloric acid is slowly added in an ice bath, and after the addition is complete, the reaction is carried out at room temperature.

[0054] In a preferred embodiment, in step 1), the equivalent ratio of compound 3:compound 4:concentrated hydrochloric acid is 1:1:3.

[0055] In a preferred embodiment, the method for preparing ruxolitinib has one or more of the following features c) to g):

[0056] c) reacting in the presence of a palladium catalyst in step 3);

[0057] d) reacting in DMSO in step 3);

[0058] e) reacting in a mixed solution of 1,4-dioxane and water in step 4);

[0059] f) reacting in step 4) under alkaline conditions;

[0060] g) Step 3) and / or step 4) are carried out in an inert gas atmosphere.

[0061] In a preferred embodiment, the inert gas is selected from: nitrogen, helium, neon, and argon; more preferably, the inert gas is nitrogen.

[0062] In a preferred embodiment, the palladium catalyst is selected from: tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), palladium acetate, palladium chloride, dichlorobis(triphenylphosphine)palladium (PdCl2(PPh3)2), palladium trifluoroacetate, triphenylphosphine palladium acetate, [1,1`-bis(diphenylphosphino)ferrocene]dichloropalladium (PdCl2(dppf)), bis(tri-o-phenylmethylphosphine)palladium dichloride, 1,2-bis(diphenylphosphino)ethanepalladium dichloride, or a combination thereof.

[0063] In a preferred embodiment, the palladium catalyst is [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.

[0064] Each step of the reaction of the present invention is preferably carried out in an inert solvent, and the inert solvent includes but is not limited to: toluene, benzene, water, methanol, ethanol, isopropanol, ethylene glycol, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof.

[0065] In a third aspect of the present invention, an intermediate is provided, wherein the intermediate is (R)-3-cyclopentyl-3-(1H-pyrazol-1-yl)-propionitrile

[0066]

[0067] In a fourth aspect, the present invention provides a method according to the first aspect of the present invention or an intermediate according to the third aspect of the present invention for preparing ruxolitinib.

[0068] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention.

[0069] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The resulting group definitions and compound structures shall fall within the scope of the description of this specification.

[0070] Unless otherwise defined, all technical and scientific terms herein have the same meanings as commonly understood by persons skilled in the art to which the claimed subject matter belongs. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated by reference in their entirety. If multiple definitions of a term are used herein, the definitions in this section shall prevail.

[0071] It should be understood that the above brief description and the detailed description below are exemplary and are only used for explanation, and do not impose any restrictions on the subject matter of the present invention. In this application, unless otherwise specifically stated, the use of the singular also includes the plural. It must be noted that unless otherwise clearly stated in the text, the singular forms used in this specification and claims include the plural forms of the things referred to. It should also be noted that unless otherwise stated, the use of "or" and "or" means "and / or". In addition, the use of the term "including" and other forms, such as "comprising", "including" and "containing" are not restrictive.

[0072] Definitions of standard chemical terms can be found in the references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4 THE ED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy and pharmacological methods, are used. Unless specifically defined, the terms used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceuticals and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and in the treatment of patients. For example, the manufacturer's instructions for use of the kit can be utilized, or reactions and purification can be carried out in accordance with methods well known in the art or the description of the present invention. The above techniques and methods can generally be implemented according to conventional methods well known in the art, based on the descriptions in the multiple summary and more specific literature cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0073] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result from writing the formula from right to left. For example, CHO is equivalent to OCH. As used herein, As used herein, "R1", "R2" and "R 1 " have the same meaning and can be replaced with each other. For other symbols such as R2, similar definitions have the same meaning.

[0074] The section headings used herein are for organizational purposes only and should not be construed as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0075] In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings indicated below unless otherwise specifically stated.

[0076] As used herein, the term "halogen" by itself or as part of another substituent refers to fluorine, chlorine, bromine, or iodine.

[0077] Compounds provided herein include intermediates that can be used to prepare compounds provided herein, which contain reactive functional groups (such as, but not limited to, carboxyl, hydroxyl, and amino moieties), and also include protected derivatives thereof."Protected derivatives" are compounds in which one or more reactive sites are blocked by one or more protecting groups (also referred to as blocking groups). Suitable carboxyl moiety protecting groups include benzyl, tert-butyl, etc., and isotopes, etc. Suitable amino and amido protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl, benzyloxycarbonyl, etc. Suitable hydroxyl protecting groups include benzyl, etc. Other suitable blocking groups are well known to those of ordinary skill in the art.

[0078] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0079] Depending on the choice of starting materials and methods, the compounds of the present invention may exist in one of the possible isomers or in a mixture thereof, for example as pure optical isomers, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes D and L or (+) and (–) are used to designate the signs for the rotation of plane-polarized light caused by the compound, where (–) or L indicates that the compound is levorotatory. Compounds prefixed with (+) or D are dextrorotatory.

[0080] When bonds to chiral carbon atoms in formulae of the present invention are depicted as straight lines, it is understood that both the (R) and (S) configurations of the chiral carbon atoms and the enantiomerically pure compounds and mixtures thereof are encompassed within the scope of the formula. The diagrammatic representation of racemates or enantiomerically pure compounds herein is adapted from Maehr, J. Chem. Ed. 1985, 62: 114-120. Wedge-shaped bonds and dashed bonds are used to represent the absolute configuration of a stereocenter.

[0081] The reaction temperature and reaction time for each step can be appropriately selected based on the solvent, starting materials, reagents, and other factors. After the completion of each step, the target compound can be isolated and purified from the reaction system using conventional methods, such as filtration, extraction, recrystallization, washing, and silica gel column chromatography. The target compound can also be directly used in the next step without isolation or purification, provided this does not affect the next step.

[0082] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0083] The reagents and raw materials used in the present invention are commercially available.

[0084] The positive progress of the present invention is that the present application provides a preparation method of ruxolitinib and its intermediate (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile, the method has higher synthesis efficiency, the resolution ee value can reach more than 99%, and can well solve the problem of isomer purification; the synthesis steps are concise, the process is simple, there are no hazardous processes, no hazardous materials are used, the material cost is low, the yield is high, and no special equipment is required, which is easy to industrialize. DETAILED DESCRIPTION

[0085] The present invention will be further described below in conjunction with specific examples. It should be understood that the following description is only the most preferred embodiment of the present invention and should not be considered as limiting the scope of protection of the present invention. Based on a full understanding of the present invention, the experimental methods in the following examples that do not specify specific conditions are generally carried out under conventional conditions or under conditions recommended by the manufacturer. Those skilled in the art may make non-essential changes to the technical solutions of the present invention, and such changes should be considered as included in the scope of protection of the present invention.

[0086] Example 1

[0087] Step 1:

[0088]

[0089] To a 100mL three-necked flask, add 20.00g of 3-cyclopentyl propionitrile, replace 3 times under nitrogen atmosphere, and place under ice bath and stir. Slowly add 21.68g of hydrazine hydrate (2.1eq) (80% w / w) dropwise, controlling the temperature below 10°C. After completion of the addition, remove the ice bath and stir the reaction at room temperature. After about 43h, TLC detection shows that the raw material reaction is complete. Add 40mL of dichloromethane and 20mL of saturated brine, stir for 10min, separate the liquid, and extract the aqueous phase twice with 20mL of dichloromethane. Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain 3-cyclopentyl-3-hydrazine propionitrile (23.60g).

[0090] Take 22.00 g of 3-cyclopentyl-3-hydrazinopropionitrile and add it to 55 mL of V (乙腈) / V (水)=1 / 1 solvent, stirring until molten. Weigh 23.71g L-tartaric acid, add to a 250mL three-necked flask, add 77mL water and 77mL acetonitrile, stir and dissolve clearly, nitrogen replace 3 times, and stir at room temperature. The acetonitrile and aqueous solution of 3-cyclopentyl-3-hydrazine propionitrile is slowly added dropwise to a 250mL three-necked flask, stirred, and after adding 1 / 2 volume, the solution gradually becomes turbid and solid is subsequently precipitated. Continue to dropwise addition, and stir at room temperature overnight. Filter, rinse with 95% acetonitrile aqueous solution, and dry to obtain (R)-3-cyclopentyl-3-hydrazine propionitrile-L-tartrate dihydrate (19.20g, yield 34.3%).

[0091] 1 H NMR (400MHz, DMSO-d6) δ4.09(s,2H),2.83–2.60(m,3H),1.88–1.63(m,3H),1.52(ddd,J=23.9,12.5,7.4Hz,4H),1.30–1.13(m,2H).

[0092] LC-MS, M / Z(ESI):154.1[M+H] +

[0093] Step 2:

[0094]

[0095] To a 100 mL three-necked flask, 5.00 g of (R)-3-cyclopentyl-3-hydrazinopropionitrile-L-tartrate dihydrate, 40 mL of ethanol, and 2.42 g of 1,1,3,3-tetramethoxypropane (1.0 eq) were added. About 4 mL of concentrated hydrochloric acid (3.0 eq) was slowly added under ice-cooling. The solution gradually became clear and was stirred at room temperature overnight. TLC confirmed the complete reaction. The mixture was then concentrated to dryness and separated by column chromatography to yield (R)-3-cyclopentyl-3-(1H-pyrazol-1-yl)-propionitrile (2.37 g, 85.1% yield).

[0096] 1 H NMR (400MHz, CDCl3) δ7.49(d,J=1.7Hz,1H),7.44(d,J=2.3Hz,1H),6.19(t,J=2.1Hz,1H),4.15–4.07(m,1H),2.98(dd,J=1 6.9,8.7Hz,1H),2.80(dd,J=16.9,4.0Hz,1H),2.50–2.37(m,1H),1.87–1.79(m,1H),1.65–1.35(m,5H),1.24–1.14(m,2H).

[0097] LC-MS, M / Z(ESI):190.1[M+H] +

[0098] Step 3:

[0099]

[0100] To a 50 mL three-necked flask was added 2.00 g of (R)-3-cyclopentyl-3-(1H-pyrazol-1-yl)-propionitrile, 16 mL of methanol was added and stirred to dissolve, followed by the addition of 2.26 g of N-bromosuccinimide (1.2 eq), and the mixture was stirred at room temperature overnight. After TLC analysis, the reaction was complete, and the mixture was extracted with 30 mL of ethyl acetate and 30 mL of water. The aqueous phase was further extracted with 30 mL of ethyl acetate, and the combined organic phases were directly concentrated to dryness. 20 mL of n-heptane was added for crystallization, and the mixture was filtered to obtain (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile (2.68 g, 94.6% yield).

[0101] 1 H NMR (400MHz, CDCl3) δ7.50 (d, J=6.7Hz, 2H), 4.10 (ddd, J=8.7, 7.7, 3.9Hz, 1H), 3.00 (dd, J=17.0, 8.6Hz, 1H) ,2.83(dd,J=17.0,3.9Hz,1H),2.53–2.36(m,1H),1.92–1.84(m,1H),1.68–1.45(m,5H),1.28-1.12(m,2H).

[0102] LC-MS, M / Z(ESI):268.0[M+H] +

[0103] Step 4:

[0104]

[0105] To a 100 mL three-necked flask, add 1.00 g of (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile, 1.24 g of potassium acetate (3.4 eq), and 0.99 g of pinacol diboron (1.05 eq). Add 20 mL of DMSO and stir to dissolve. After nitrogen purge three times, add 0.14 g of PdCl2(dppf) (0.05 eq) and react overnight at 90°C. TLC analysis indicates complete reaction. Add 100 mL of ethyl acetate to the flask, stir for 10 minutes, and filter to collect the filtrate. 50 mL of water was added to the filtrate, and the extract was separated. The organic phase was washed twice with 50 mL of water, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and separated by column chromatography to obtain 0.98 g of an oily liquid, which was slurried with 5 mL of n-heptane to obtain (R)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propionitrile (0.82 g, yield 70.4%).

[0106] 1 H NMR(400MHz, DMSO-d6)δ8.05(s,1H),7.63(s,1H),4.40(td,J=9.5,4.5Hz,1H),3.09(qd,J=17.1,6.9Hz,2H), 2.36–2.23(m,1H),1.80–1.69(m,1H),1.63–1.31(m,5H),1.24(s,12H),1.19–1.11(m,1H),1.11–0.98(m,1H).

[0107] LC-MS, M / Z(ESI):316.2[M+H] +

[0108] Step 5:

[0109]

[0110] To a 100 mL three-necked flask, add 0.10 g of (R)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propionitrile, 54 mg of 4-chloropyrrolopyrimidine (1.1 eq), and 124 mg of potassium carbonate (3.0 eq). Then, add 4 mL of 1,4-dioxane and 2 mL of water. After purging with nitrogen three times, add 11 mg of PdCl2(PPh3)2 (0.05 eq), and incubate in a 100°C oil bath for 24 h. TLC analysis indicated complete reaction. Add 20 mL of ethyl acetate and 20 mL of water to the flask, extract, and separate. The aqueous phase is extracted twice with 20 mL of ethyl acetate. The combined organic phases are then dried over anhydrous sodium sulfate. The residue was filtered and concentrated to dryness, and the sample was separated by Prep-TLC to obtain ruxolitinib (80 mg, yield 82.5%).

[0111] 1 H NMR (400MHz, CDCl3) δ11.65(s,1H),8.85(s,1H),8.34(d,J=9.2Hz,2H),7.41(d,J=3.1Hz,1H),6.76(d,J=2.7Hz,1H),4.27(td,J=9.7,3.9Hz,1H), 3.13(dd,J=17.0,8.6Hz,1H),2.95(dd,J=17.0,3.9Hz,1H),2.56(dt,J=1 6.8,8.5Hz,1H),1.99–1.89(m,1H),1.77–1.44(m,5H),1.34–1.24(m,2H).

[0112] LC-MS, M / Z(ESI):307.2[M+H] +

[0113] Example 2

[0114] The (R)-3-cyclopentyl-3-hydrazinopropionitrile-L-tartrate dihydrate in step 2 of Example 1 was replaced with (R)-3-cyclopentyl-3-hydrazinopropionitrile. After a similar reaction as in step 2, (R)-3-cyclopentyl-3-(1H-pyrazol-1-yl)-propionitrile was obtained (yield 71.5%).

[0115]

[0116] Example 3

[0117] The (R)-3-cyclopentyl-3-hydrazinopropionitrile-L-tartrate dihydrate in step 2 of Example 1 was replaced with (R)-3-cyclopentyl-3-hydrazinopropionitrile-L-tartrate. After a similar reaction as in step 2, (R)-3-cyclopentyl-3-(1H-pyrazol-1-yl)-propionitrile was obtained (yield 81.5%).

[0118]

[0119] The compounds of the present invention can be prepared by the synthetic methods described below, wherein the substituents of the general formula have the meanings given above. These methods are intended to illustrate the present invention but not to limit the scope of its subject matter and the compounds claimed for these examples.

Claims

1. A method for preparing (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile, characterized in that: Comprising step 1): compound 3 and / or a salt of compound 3 reacts with compound 4 under acidic conditions to obtain compound 5 Step 2): The compound 5 reacts with a brominating agent to obtain the (R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile 2. A method for preparing ruxolitinib, characterized in that: include Step 1): Compound 3 and / or its salt reacts with compound 4 to obtain compound 5 Step 2): Compound 5 reacts with a brominating agent to obtain compound 6 Step 3): Compound 6 reacts with boric acid or boric acid ester to obtain compound 7 Step 4): Compound 7 reacts with compound 8 to obtain Ruxolitinib Wherein, -BR1R2 is -B(OH)2 or a borate group; X is chlorine, bromine or iodine.

3. The method according to claim 2, wherein X is chlorine.

4. The method according to claim 1 or 2, wherein: In step 1), the salt of compound 3 includes inorganic acid salts and organic acid salts; The inorganic acid salt is selected from the group consisting of sulfate, phosphate, nitrate, and hydrochloride; The organic acid salt is selected from the group consisting of formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, ethylenesulfonic acid, formic acid, fumaric acid, furoic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, lysine, arginine, aspartic acid, cinnamic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, and trifluoromethanesulfonic acid.

5. The method according to claim 1 or 2, wherein: In step 1), the salt of compound 3 is L-tartrate of compound 3.

6. The method according to claim 5, wherein The L-tartrate of compound 3 is 7. The method according to claim 1 or 2, wherein: The brominating agent is N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide, phenyltrimethylammonium tribromide, liquid bromine, and N-bromoacetamide.

8. The method according to claim 1 or 2, wherein: The brominating agent is N-bromosuccinimide.

9. The method according to claim 2, wherein The borate ester in step 3 is selected from the group consisting of: bipyrocatechol borate, bipyrocatechol borate, bi(3,3-dimethyl-2,4-pentanediol) borate, trimethyl borate, triethyl borate, tributyl borate, triisopropyl borate, bipyrocatechol borate, or a combination thereof; The -BR1R2 is selected from: -B(OH)2, pinacol borate, catechol borate, (3,3-dimethyl-2,4-pentanediol) borate, dimethyl borate, diethyl borate, dibutyl borate, diisopropyl borate, and neopentyl glycol borate.

10. The method according to claim 9, wherein The borate ester is pinacol diborate.

11. The method according to claim 9, wherein The -BR1R2 is a pinacol borate ester group.

12. The method according to claim 2, wherein The salt of compound 3 is The method comprises Step 1): Compound 3-1 reacts with compound 4 to obtain compound 5; Step 2): reacting the compound 5 with N-bromosuccinimide to obtain compound 6; Step 3): Compound 6 is reacted with diboronic acid pinacol ester to obtain compound 7-1; Step 4): The compound 7-1 reacts with the compound 8-1 to obtain the ruxolitinib 13. The method according to claim 1 or 2, wherein: The salt of compound 3 is The method further comprises: reacting compound 1 with hydrazine hydrate to obtain compound 2, adding L-tartaric acid, and splitting to obtain the salt of compound 3.

14. The method according to claim 13, wherein During the separation, seed crystals of the compound 3-1 were added.

15. The method according to claim 1 or 2, wherein: The step 2) is carried out in an inert solvent.

16. The method according to claim 15, wherein The inert solvent is an alcohol solvent.

17. The method according to claim 16, wherein The alcohol solvent is C1-C 10 Alcohol solvents.

18. The method according to claim 16, wherein The alcohol solvent is methanol.

19. The method according to claim 1 or 2, wherein: In the step 1), concentrated hydrochloric acid was slowly added under ice bath conditions, and after the addition was complete, the mixture was reacted at room temperature.

20. The method according to claim 1 or 2, wherein In the step 1), the equivalent ratio of compound 3:compound 4:concentrated hydrochloric acid is 1:1:

3.

21. The method according to claim 2, wherein Having one or more of the following characteristics c) to g): c) reacting in the presence of a palladium catalyst in step 3); d) reacting in DMSO in step 3); e) reacting in a mixed solution of 1,4-dioxane and water in step 4); f) reacting in step 4) under alkaline conditions; g) Step 3) and / or step 4) are carried out in an inert gas atmosphere.

22. The method according to claim 21, wherein The inert gas is selected from the group consisting of nitrogen, helium, neon and argon.

23. The method according to claim 21, wherein The inert gas is nitrogen.

24. The method of claim 21, wherein: The palladium catalyst is selected from the group consisting of tris(dibenzylideneacetone)dipalladium, tetrakis(triphenylphosphine)palladium, palladium acetate, palladium chloride, dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate, triphenylphosphine palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, bis(tri-o-phenylmethylphosphine)palladium dichloride, 1,2-bis(diphenylphosphino)ethanepalladium dichloride, or a combination thereof.

25. The method of claim 21, wherein The palladium catalyst is [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.

26. An intermediate, which is (R)-3-cyclopentyl-3-(1H-pyrazol-1-yl)-propionitrile 27. Use of the intermediate as claimed in claim 26 in the preparation of ruxolitinib.

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