A method for preparing roscovitine

Abstract

The application belongs to the technical field of drug synthesis, and particularly relates to a preparation method of roscovitine, which comprises six preparation steps: S1, preparation of an intermediate I; S2, preparation of an intermediate II; S3, preparation of an intermediate III; S4, preparation of an intermediate IV; S5, preparation of an intermediate V; and S6, preparation of roscovitine. The preparation method of roscovitine has the remarkable advantages of mild reaction condition, good stereoselectivity, simple operation, low cost, environmental friendliness, high yield, high purity and the like, and provides strong support for industrialized production and wide application of roscovitine.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of drug synthesis, and particularly relates to a preparation method of ruxolitinib. BACKGROUND

[0002] Ruxolitinib, also known as ruxolitinib, ruxolitinib, research code INCB018424, chemical name (R)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-cyclopentylpropionitrile, CAS:941685-37-6, its structural formula is as follows:

[0003] .

[0004] Ruxolitinib is developed by Incyte Corporation and Novartis Corporation, which is an orally administered selective Janus kinase (JAK) inhibitor, approved by the US FDA in November 2011, and the trade name is Jakafi, which is used for the treatment of myelofibrosis with medium or high risk. Myelofibrosis (MF) is a rare myeloproliferative tumor, which is a disease caused by the occupation of too much fibrous tissue in the body marrow, leading to the migration of hematopoietic cells from the bone marrow to the liver and spleen and other organs, resulting in serious impact on bone marrow hematopoietic function and even failure, and its characteristic performance is splenomegaly, anemia, leukopenia and thrombocytopenia, and different degrees of osteosclerosis; the disease has poor prognosis, and the median survival time after diagnosis is 5 years, and nearly 20% of patients evolve into acute leukemia. Ruxolitinib can target and inhibit kinases JAK1 and JAK2, block JAK signal transduction and transcription, regulate the signal transduction of multiple cytokines and growth factors that play an important role in cell growth, growth and hematopoiesis, and thus achieve the effect of treating myelofibrosis. Ruxolitinib is the first drug for treating myelofibrosis in the world, which has been granted rare disease drug qualification by FDA and EU, and has been approved for marketing in 18 countries, and its indications include primary myelofibrosis, primary thrombocytosis myelofibrosis, true red cell hyperplasia myelofibrosis, true red cell hyperplasia, graft versus host disease (GVHD) and dozens of other diseases, which greatly changes the treatment status of myeloproliferative neoplasms.

[0005] In the preparation of ruxolitinib, the key technical difficulty lies in the construction of chiral center. The reported ruxolitinib synthesis processes in the prior art mainly include the following three methods:

[0006] Method 1: Asymmetric Michael addition induced by diaryl prolinol silyl ether

[0007] As reported by Qiyan Lin et al. of Incyte Corporation in the literature Org. Lett. 2009, 11(9), 1999-2002: cyclopentylacrolein 20 was used as raw material, and asymmetric Michael addition reaction was carried out with intermediate 6 or 4-bromopyrazole under the induction of chiral diarylprolinol silyl ether to construct chiral center, and then a series of transformations were carried out to obtain the target product Ruxolitinib, and the synthetic route is as follows:

[0008] ;

[0009] This method has problems of large molecular weight of chiral induction reagent, harsh preparation conditions and high preparation cost, and the selectivity of asymmetric Michael addition is not high, which is not suitable for large-scale production.

[0010] Method 2: Asymmetric reduction of double bond

[0011] As reported in the patent application CN105669676-Preparation of JAK inhibitor and related intermediate compounds: intermediate 10 was added with alkyne compound 11 to obtain intermediate 12, and chiral intermediate 13 was obtained by rhodium asymmetric catalytic hydrogenation, and the target product Ruxolitinib was obtained after hydrolysis, and the synthetic route is as follows:

[0012] ;

[0013] As reported in the patent application WO2020163653: intermediate 16 was reacted with alkenyl sulfonate compound 17 to obtain intermediate 18, and then the double bond was reduced by rhodium asymmetric catalytic hydrogenation, and the target product Ruxolitinib was obtained by ring closure under acidic conditions, and the synthetic route is as follows:

[0014] ;

[0015] The above method needs to use rhodium catalytic asymmetric hydrogenation to construct chiral center, and the amount of rhodium catalyst and chiral ligand is large, the price is expensive, the cost is high, and the reaction needs to be carried out under pressurized conditions, the risk of industrial production is high, in addition, alkyne compound 11 and alkenyl sulfonate compound 17 as important structural fragments need to be converted by multi-step reaction, which further increases the cost of reaction.

[0016] Method 3: Chiral resolution

[0017] As reported in CN102348693A-Method for preparing JAK inhibitor and related intermediate compounds, CN113292569A-Preparation method of JAK inhibitor, CN114044777A-Preparation method of ruxolitinib phosphate, and WO202304224 and other patents, chiral reagents such as dibenzoyl-D-tartaric acid (DBTA) and D-camphorsulfonic acid are used for chemical resolution of key intermediates, and the synthetic route is as follows:

[0018] ;

[0019] This method has the problems of low ee value of the split product, the need for multiple splitting or refining, low splitting yield, high cost, etc., and the other enantiomer becomes a byproduct, causing great waste of resources, which does not conform to the green and environmentally friendly production concept, and the actual application value is low.

[0020] In summary, the existing technology reports that the synthesis method of ruxolitinib has the problems of harsh reaction conditions, poor stereoselectivity, low operation safety, and high preparation cost. Therefore, a new technical solution is needed to solve the above technical problems. SUMMARY

[0021] The purpose of the present application is to provide a preparation method of ruxolitinib to solve the problems of harsh reaction conditions, poor stereoselectivity, low operation safety, and high preparation cost in the existing synthesis method of ruxolitinib.

[0022] To achieve the above purpose, the present application provides the following technical solution: a preparation method of ruxolitinib, comprising the following specific steps:

[0023] S1, preparation of intermediate I: taking 3-cyclopentyl propenoic acid as the starting material, dissolving it in a reaction solvent and condensing with a chiral auxiliary in the presence of an activating reagent to obtain intermediate I,

[0024] wherein the molar ratio of 3-cyclopentyl acrylic acid to the activating agent is 1:1.05-1:1.2, the activating agent is selected from one of N,N'-diisopropyl carbodiimide, N,N'-dicyclohexyl carbodiimide, EDCI, HATU, HBTU, T3P condensing agent or one of pivaloyl chloride, isobutyl chloroformate, sulfurous chloride, oxalyl chloride, and when the activating agent is one of pivaloyl chloride, isobutyl chloroformate, sulfurous chloride, oxalyl chloride, an acid binding agent needs to be added, the acid binding agent is selected from one of triethylamine, N-methyl morpholine, DIPEA, DBU, pyridine, NaH, n-butyllithium, at this time the molar ratio of 3-cyclopentyl acrylic acid to the acid binding agent is 1:1.05-1:2, the molar ratio of 3-cyclopentyl acrylic acid to the chiral auxiliary agent is 1:1-1:1.2, the chiral auxiliary agent is levorotatory camphor sulfone lactam, (R)-4-benzyl oxazolidine, (R)-4-phenyl oxazolidine, (R)-4-isopropyl oxazolidine or (R)-4-isobutyl oxazolidine, the reaction solvent is one or several of dichloromethane, tetrahydrofuran, ethylene glycol dimethyl ether, toluene, and the reaction temperature is -78-80℃;

[0025] The reaction equation is as follows:

[0026] ;

[0027] S2, preparation of intermediate II: the intermediate I obtained in S1 is subjected to asymmetric Michael addition reaction with intermediate M in a reaction solvent in the presence of a base to obtain chiral intermediate II;

[0028] wherein the molar ratio of intermediate I to intermediate M is 1:1-1:1.2; the molar ratio of intermediate I to the base is 1:1.2-1:1.5, wherein the base is selected from one of inorganic bases such as potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide or one of organic bases such as DBU, triethylamine, DIPEA, 2-methyl pyridine, 4-dimethylamino pyridine; the reaction solvent is one or several of acetonitrile, N,N-dimethyl formamide, N,N-dimethyl acetamide, N-methyl pyrrolidone, dimethyl sulfoxide, and the reaction temperature is 40-80℃;

[0029] The reaction equation is as follows:

[0030] ;

[0031] S3, preparation of intermediate III: the intermediate II obtained in S2 is subjected to hydrolysis to remove the chiral auxiliary group in a reaction solvent in the presence of a base to obtain intermediate III;

[0032] The molar ratio of the intermediate II to the base is 1:1.5-1:4, wherein the base is one of lithium hydroxide, lithium hydroxide-hydrogen peroxide, sodium hydroxide and potassium hydroxide, the reaction solvent is one or more of tetrahydrofuran, water, methanol, ethanol and acetonitrile, when the reaction solvent is a mixture of tetrahydrofuran and water, the volume ratio of tetrahydrofuran to water is 2:1-4:1, and the reaction temperature is -10-25℃;

[0033] The reaction equation is as follows:

[0034] ;

[0035] S4, preparation of the intermediate IV: the intermediate III obtained in S3 is dissolved in a reaction solvent, and condensed with an amination reagent to obtain an amide intermediate IV;

[0036] The molar ratio of the intermediate III to the amination reagent is 1:1.5-1:6, wherein the amination reagent is one or more of liquid ammonia, ammonia water, ammonia gas and ammonium chloride; the reaction solvent is one or more of tetrahydrofuran, dichloromethane, toluene, dioxane and acetonitrile, and the reaction temperature is 0-30℃;

[0037] The reaction equation is as follows:

[0038] ;

[0039] S4, preparation of the intermediate IV: the intermediate III obtained in S3 is dissolved in a reaction solvent, and condensed with an amination reagent to obtain an amide intermediate IV;

[0040] The molar ratio of the intermediate III to the amination reagent is 1:1.5-1:6, wherein the amination reagent is one or more of liquid ammonia, ammonia water, ammonia gas and ammonium chloride; the reaction solvent is one or more of tetrahydrofuran, dichloromethane, toluene, dioxane and acetonitrile, and the reaction temperature is 0-30℃;

[0041] The reaction equation is as follows:

[0042] ;

[0043] S6, preparation of the lucotinib: the intermediate V obtained in S5 is dissolved in a reaction solvent and mixed with a deprotection reagent to perform a de-SEM protection group reaction, and the lucotinib is obtained;

[0044] The molar ratio of the intermediate V to the deprotection reagent is 1:2-1:10, wherein the deprotection reagent is one of boron trifluoride-ethyl ether complex, lithium tetrafluoroborate, hydrochloric acid, phosphoric acid and trifluoroacetic acid; the reaction solvent is one or more of dichloromethane, acetonitrile, methanol, acetone and water, and the reaction temperature is 25-80℃;

[0045] The reaction equation is as follows:

[0046] .

[0047] The overall synthesis route of Luspaterin obtained according to the above specific preparation steps is as follows:

[0048] ;

[0049] wherein R1 is a corresponding chiral auxiliary group formed after chiral auxiliary and carboxylic acid are dehydrated and condensed; SEM is (trimethylsilyl)ethoxymethyl, which is a protecting group on the pyrrole nitrogen.

[0050] Compared with the prior art, the present application has the following beneficial effects:

[0051] The present application uses more economical and easily available raw materials and reagents, effectively avoids the problem of high preparation cost caused by the use of expensive rare metal catalysts and complex chiral ligands, and induces asymmetric Michael addition to construct a chiral center by introducing a chiral auxiliary agent. Compared with the synthesis method of the prior art, the chiral purity of Luspaterin is significantly improved, the difficulty and cost of subsequent separation and purification are reduced, high stereoselectivity is maintained, a six-step synthesis process of condensation-asymmetric Michael addition-hydrolysis-condensation-conversion-SEM protecting group removal is used to prepare Luspaterin, the reaction conditions of Luspaterin are more mild, extreme temperature or high pressure environment is not required, the operation difficulty and safety risk are effectively reduced, harmful solvents and by-products are effectively reduced, the resource utilization rate is improved, the production concept of green environmental protection is met, and the practical application value of Luspaterin is ensured.

[0052] The present application effectively promotes the reaction by selecting appropriate base and solvent in asymmetric Michael addition, maintains high stereoselectivity, thereby ensuring the purity of the target product Luspaterin, avoids harsh reaction environment by using conventional reaction solvents and temperature conditions, improves the safety and controllability of operation, effectively improves the production efficiency, and is suitable for industrial production.

[0053] The present application effectively improves the yield of each step by fine reaction control and optimization, effectively reduces the generation of by-products, improves the purity and quality of the final product, and effectively reduces the use of harmful solvents and reagents, effectively avoids resource waste and environmental pollution caused by multiple splitting, meets the concept of green chemistry, and ensures the practical application value of Luspaterin.

[0054] The Luspaterin preparation method of the present application is not only suitable for laboratory scale research, but also has good industrialization amplification potential, can meet the demand of large-scale production of Luspaterin, and provides more choices and hope for patients with diseases such as myelofibrosis. Attached Figure Description

[0055] Figure 1 The 1H NMR spectrum of ruxolitinib;

[0056] Figure 2 The carbon NMR spectrum of ruxolitinib;

[0057] Figure 3 Mass spectrometry of ruxolitinib;

[0058] Figure 4 The related material spectrum of ruxolitinib;

[0059] Figure 5 The chiral purity spectrum of ruxolitinib. Detailed Implementation

[0060] The following examples are used to further illustrate the content of the present invention and do not limit the application of the present invention.

[0061] Example 1: Preparation of Intermediate I

[0062] 42 g of 3-cyclopentylacrylic acid (0.3 mol, 1.0 eq) was dissolved in 500 mL of dichloromethane. 64.6 g of L-camphor sulfonamide (0.3 mol, 1.0 eq) and 11 g of 4-dimethylaminopyridine (0.09 mol, 0.3 eq) were added. The reaction mixture was cooled to 0 °C, and 74.3 g of N,N'-dicyclohexylcarbodiimide (0.36 mol, 1.2 eq) was added. After the addition was complete, the mixture was heated to 25–30 °C and stirred for 17 h. After the reaction was complete, the mixture was filtered, the filtrate was washed with water, dried over anhydrous sodium sulfate, filtered again, and concentrated to obtain 92.1 g of a white solid (intermediate I), with a yield of 91%.

[0063] Example 2: Preparation of Intermediate I

[0064] 30 g of 3-cyclopentylacrylic acid (0.21 mol, 1.0 eq), 50.7 g of L-camphor sulfonamide (0.24 mol, 1.1 eq), and 59.5 mL of triethylamine (0.43 mol, 2.0 eq) were dissolved in 250 mL of toluene. The mixture was cooled to 10–15 °C, and 27.6 mL of pentanoyl chloride (0.22 mol, 1.05 eq) was added dropwise, keeping the temperature below 20 °C. After the addition was complete, the temperature was raised to 75–80 °C, and the mixture was stirred for 6 h. The reaction solution was then cooled to room temperature, washed successively with 2N HCl solution and 5% sodium carbonate solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 64.5 g of a white solid (intermediate I), with a yield of 89%.

[0065] Example 3: Preparation of Intermediate I

[0066] To a solution of 3-cyclopentylacrylic acid (10 g, 71.3 mmol, 1.0 eq) and triethylamine (10.9 mL, 78.5 mmol, 1.1 eq) in tetrahydrofuran (50 mL) was added pivaloyl chloride (9.7 mL, 78.5 mmol, 1.1 eq) slowly at -78 °C under nitrogen atmosphere, stirred for 5 min and then raised to 0 °C for 1 h and then cooled to -78 °C again; in another flask, to a solution of levorotatory camphorsultam (15.4 g, 71.3 mmol, 1.0 eq) in tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M in hexane, 30 mL, 74.9 mmol, 1.05 eq) slowly at -78 °C, stirred for 30 min and then poured into the above reaction mixture, stirred for 15 min and then raised to 0 °C for 1 h. After the reaction was completed, water was added to quench the reaction and the aqueous phase was extracted with ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated to give white solid (i.e. Intermediate I) 21.7 g in 90% yield.

[0067] Example 4: Preparation of Intermediate I

[0068] To a solution of levorotatory camphorsultam (15.4 g, 71.3 mmol, 1.0 eq) in 30 mL of ethylene glycol dimethyl ether was added NaH (sodium hydride) (30% wt, 6.3 g, 78.5 mmol, 1.1 eq) in ethylene glycol dimethyl ether (30 mL) slowly at room temperature and stirred for 1 h. In another flask, to a solution of 3-cyclopentylacrylic acid (10 g, 71.3 mmol, 1.0 eq) in ethylene glycol dimethyl ether (50 mL) was added isobutyl chloroformate (10.2 mL, 78.5 mmol, 1.1 eq) and N-methylmorpholine (8.7 mL, 78.5 mmol, 1.1 eq) at -15 °C and stirred for 15 min. The reaction mixture was added to the above reaction mixture and stirred for 1 h at room temperature. After the reaction was completed, water was added to quench the reaction and the aqueous phase was extracted with ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated to give white solid (i.e. Intermediate I) 22.2 g in 92% yield.

[0069] The reaction equation of Examples 1-4 is as follows:

[0070] .

[0071] Example 5: Preparation of Intermediate II

[0072] To 20 g of intermediate I (59.3 mmol, 1.0 eq) and 25.1 g of cesium carbonate (77.0 mmol, 1.3 eq) was added 100 mL of N,N-dimethylformamide, and then a solution of intermediate M (18.7 g, 59.3 mmol, 1.0 eq) in N,N-dimethylformamide (20 mL) was added dropwise. After the addition was completed, the reaction was stirred at 40-50°C for 4 h. After the reaction was completed, the reaction solution was poured into water, and a solid was precipitated. The solid was filtered, and the filter cake was slurried with water. The filter cake was filtered, and 80 mL of isopropyl acetate was added to the filter cake. After the mixture was heated to reflux and maintained at reflux for 30 min, it was slowly cooled to room temperature, stirred for 2 h, filtered, and the filter cake was dried under vacuum to obtain a white solid (i.e., intermediate II) 32.9 g, which had a yield of 85% and a de value of 99%.

[0073] Example 6: Preparation of intermediate II

[0074] To 20 g of intermediate I (59.3 mmol, 1.0 eq) and 25.1 g of cesium carbonate (77.0 mmol, 1.3 eq) was added 100 mL of N,N-dimethylformamide, and then a solution of intermediate M (18.7 g, 59.3 mmol, 1.0 eq) in N,N-dimethylformamide (20 mL) was added dropwise. After the addition was completed, the reaction was stirred at 40-50°C for 4 h. After the reaction was completed, the reaction solution was poured into water, and a solid was precipitated. The solid was filtered, and the filter cake was slurried with water. The filter cake was filtered, and 80 mL of isopropyl acetate was added to the filter cake. After the mixture was heated to reflux and maintained at reflux for 30 min, it was slowly cooled to room temperature, stirred for 2 h, filtered, and the filter cake was dried under vacuum to obtain a white solid (i.e., intermediate II) 32.9 g, which had a yield of 85% and a de value of 99%.

[0075] Example 7: Preparation of intermediate II

[0076] To 20 g of intermediate I (59.3 mmol, 1.0 eq) and 25.1 g of cesium carbonate (77.0 mmol, 1.3 eq) was added 100 mL of N,N-dimethylformamide, and then a solution of intermediate M (18.7 g, 59.3 mmol, 1.0 eq) in N,N-dimethylformamide (20 mL) was added dropwise. After the addition was completed, the reaction was stirred at 40-50°C for 4 h. After the reaction was completed, the reaction solution was poured into water, and a solid was precipitated. The solid was filtered, and the filter cake was slurried with water. The filter cake was filtered, and 80 mL of isopropyl acetate was added to the filter cake. After the mixture was heated to reflux and maintained at reflux for 30 min, it was slowly cooled to room temperature, stirred for 2 h, filtered, and the filter cake was dried under vacuum to obtain a white solid (i.e., intermediate II) 32.9 g, which had a yield of 85% and a de value of 99%.

[0077] The reaction equations of Examples 5-7 are as follows:

[0078] .

[0079] Example 8: Preparation of Intermediate III

[0080] The 40 g of Intermediate II (61.3 mmol, 1.0 eq) was dissolved in 240 mL of tetrahydrofuran, cooled to 0-5 °C, and 12.5 mL of 30% H2O2 aqueous solution (122.6 mmol, 2.0 eq) was added dropwise. After stirring for 5 min, 61.3 mL of LiOH aqueous solution (2N, 122.6 mmol, 2.0 eq) was slowly added dropwise. After the addition was completed, the reaction was stirred at 0-5 °C for 2 h. After the reaction was completed, saturated sodium sulfite solution was added dropwise to quench the reaction. Then, saturated sodium carbonate solution was added dropwise to adjust the pH to 8-9. The aqueous phase was washed with dichloromethane. Then, 2N HCl solution was added dropwise to adjust the pH to 3-4. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 26.5 g of white solid (i.e., Intermediate III) with a yield of 95% and an ee value of 99%.

[0081] Example 9: Preparation of Intermediate III

[0082] The 60 g of Intermediate II (91.9 mmol, 1.0 eq) was dissolved in 360 mL of tetrahydrofuran, cooled to 0-5 °C, and 37.5 mL of 30% H2O2 aqueous solution (367.6 mmol, 4.0 eq) was added dropwise. After stirring for 5 min, 184 mL of LiOH aqueous solution (2N, 368 mmol, 4.0 eq) was slowly added dropwise. After the addition was completed, the reaction was stirred at 0-5 °C for 0.5 h. After the reaction was completed, saturated sodium sulfite solution was added dropwise to quench the reaction. Then, saturated sodium carbonate solution was added dropwise to adjust the pH to 8-9. The aqueous phase was washed with dichloromethane. Then, 2N HCl solution was added dropwise to adjust the pH to 3-4. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 38.1 g of white solid (i.e., Intermediate III) with a yield of 91% and an ee value of 97%.

[0083] Example 10: Preparation of Intermediate III

[0084] To 20 g of intermediate II (30.6 mmol, 1.0 eq) dissolved in 70 mL of tetrahydrofuran, cool to 0-5 °C, dropwise add 4.7 mL of 30% aqueous H2O2 solution (45.9 mmol, 1.5 eq), after stirring for 5 min, slowly dropwise add 23 mL of aqueous LiOH solution (2N, 46 mmol, 1.5 eq), after addition, raise to 25-30 °C and stir for 4 h, after the reaction is complete, dropwise add saturated sodium sulfite solution to quench the reaction, then dropwise add saturated sodium carbonate solution to adjust the pH to 8-9, wash the aqueous phase with dichloromethane, then dropwise add 2N HCl solution to adjust the pH to 3-4, extract the aqueous phase with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 12.8 g of white solid (i.e., intermediate III) with a yield of 92% and an ee value of 98%.

[0085] The reaction equation of Examples 8-10 is as follows:

[0086] .

[0087] Example 11: Preparation of intermediate IV

[0088] To 45.5 g of intermediate III (0.1 mol, 1.0 eq) dissolved in 220 mL of tetrahydrofuran, add 0.5 mL of DMF (N,N-dimethylformamide), cool to 0-5 °C, dropwise add 14.5 mL of thionyl chloride (0.2 mol, 2.0 eq), control the temperature of the reaction liquid to not exceed 5 °C, after addition, raise to 25-30 °C and stir for 2 h, then concentrate under reduced pressure, dissolve the residue in 200 mL of tetrahydrofuran, and dropwise add to 45 mL of 25% aqueous ammonia solution (0.6 mol, 6.0 eq) at 0-5 °C, stir for 1 h, after the reaction is complete, dilute with water, then extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 44.5 g of the product (i.e., intermediate IV) with a yield of 98%.

[0089] Example 12: Preparation of intermediate IV

[0090] Dissolve 9.1 g of intermediate III (20.0 mmol, 1.0 eq) in 30 mL of dichloromethane, under nitrogen protection, add 4.06 g of CDI (N,N'-carbonyldiimidazole) (25.0 mmol, 1.25 eq), and stir the reaction mixture at 25-30 °C for 1 h. Cool the reaction mixture to 0-5 °C, add 6 mL of 25% aqueous ammonia solution (80 mmol, 4.0 eq), and allow the reaction mixture to naturally warm to room temperature. Stir the reaction mixture for 10-12 h. After the reaction is completed, separate the layers, extract the aqueous phase with dichloromethane, dry the combined organic phases over anhydrous sodium sulfate, filter, and concentrate to obtain 8.6 g of the product (i.e., intermediate IV) in a yield of 95%.

[0091] Example 13: Preparation of intermediate IV

[0092] Dissolve 22.8 g of intermediate III (50.0 mmol, 1.0 eq) in tetrahydrofuran, and cool to 0-5 °C. Add 6.7 mL of ethyl chloroacetate (70.0 mmol, 1.4 eq) and 21 mL of triethylamine (150.0 mmol, 3.0 eq) dropwise. After the addition is completed, stir the reaction mixture at 0-5 °C for 30 min, add 75 mL of 1.0 M aqueous ammonium chloride solution (75.0 mmol, 1.5 eq), and stir the reaction mixture at 0-5 °C for 30 min. After the reaction is completed, quench with water, extract the aqueous phase with ethyl acetate, dry the combined organic phases over anhydrous sodium sulfate, filter, and concentrate to obtain 20.5 g of the product (i.e., intermediate IV) in a yield of 90%.

[0093] The reaction equations of Examples 11-13 are as follows:

[0094] .

[0095] Example 14: Preparation of intermediate V

[0096] Dissolve 20 g of intermediate IV (44.0 mmol, 1.0 eq) in 200 mL of dichloromethane, and cool to 0-5 °C. Slowly add 16.4 mL of phosphorus oxychloride (176 mmol, 4.0 eq), and allow the reaction mixture to warm to 25-30 °C. Stir the reaction mixture for 4 h. After the reaction is completed, quench with water, separate the organic phase, extract the aqueous phase with ethyl acetate, dry the combined organic phases over anhydrous sodium sulfate, filter, and concentrate to obtain 17.7 g of the product (i.e., intermediate V) in a yield of 92%.

[0097] Example 15: Preparation of intermediate V

[0098] Dissolve 45.5 g of intermediate IV (0.1 mol, 1.0 eq) in 300 mL of tetrahydrofuran, add 27.8 mL of triethylamine (0.2 mol, 2.0 eq), cool to 0-5 °C, and dropwise add 27.8 mL of triflic anhydride (0.2 mol, 2.0 eq). After the addition is complete, raise the reaction liquid to 40-50 °C, and stir for 10 h. Quench the reaction by adding saturated sodium carbonate solution, extract the aqueous phase with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 38.9 g of the product (i.e., intermediate V) at a yield of 89%.

[0099] Example 16: Preparation of intermediate V

[0100] Dissolve 19.5 g of intermediate IV (43.0 mmol, 1.0 eq) in 300 mL of tetrahydrofuran, and add 18.5 g of phosphorus pentoxide (130.0 mmol, 3.0 eq) under nitrogen protection. After the addition is complete, raise the temperature to 60-70 °C, and stir for 2 h. After the reaction is complete, quench the reaction by adding saturated sodium carbonate solution, extract the aqueous phase with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 17.8 g of the product (i.e., intermediate V) at a yield of 95%.

[0101] The reaction equations of Examples 14-16 are as follows:

[0102] .

[0103] Example 17: Preparation of luspaterin

[0104] Dissolve 30 g of intermediate V (68.7 mmol, 1.0 eq) in 150 mL of acetonitrile, and dropwise add 19.5 g of boron trifluoride-ether complex (137.4 mmol, 2.0 eq). After the addition is complete, heat the reaction liquid to 60-70 °C, and stir for 5-6 h. After the reaction is complete, cool the reaction liquid to room temperature, add 15 mL of 20% ammonia water solution, stir at room temperature for 4-5 h, remove acetonitrile by concentration under reduced pressure, extract the aqueous phase with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate to dryness to obtain an oil. Dissolve the oil in 150 mL of isopropyl acetate, heat to reflux, dropwise add 4.6 mL of 85% phosphoric acid (68.7 mmol, 1.0 eq), and gradually turn turbid. After the addition is complete, maintain the temperature for 30 min, slowly cool to room temperature, continue to stir for 1 h, filter, and dry under vacuum to obtain 19.4 g of a white solid (i.e., luspaterin) at a yield of 92%, an HPLC purity of ≥99%, and an ee value of ≥99%.

[0105] Example 18: Preparation of luspaterin

[0106] To 15 g of intermediate V (34.3 mmol, 1.0 eq) dissolved in 60 mL of dichloromethane, 21 mL of trifluoroacetic acid (275 mmol, 8.0 eq) was added dropwise, and the reaction was stirred at 25-30 °C for 7 h. After the reaction was completed, the pH was adjusted to 9-10 by adding a saturated sodium hydroxide solution dropwise, and the mixture was stirred at room temperature for 0.5 h. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain an oil. The oil was dissolved in 150 mL of isopropyl acetate, heated to reflux, and 2.3 mL of 85% phosphoric acid (34.3 mmol, 1.0 eq) was added dropwise. The mixture gradually became turbid, and after 30 min of incubation, it was slowly cooled to room temperature and stirred for an additional 1 h. The mixture was filtered and dried under vacuum to obtain 7.9 g of a white solid (i.e., lucitanib) in a yield of 75%, with a purity of ≥99% by HPLC and an ee value of ≥99%.

[0107] Example 19: Preparation of lucitanib

[0108] To 20 g of intermediate V (45.8 mmol 1.0 eq) dissolved in 375 mL of acetonitrile and 35 mL of water, 43 g of lithium tetrafluoroborate (458 mmol, 10.0 eq) was added, and the mixture was heated to 70-80 °C and stirred for 8-10 h. After the reaction was completed, the mixture was cooled to room temperature, and the pH was adjusted to 9-10 by adding a 20% aqueous ammonia solution. The mixture was stirred at room temperature for 4-6 h, filtered, and concentrated under reduced pressure to remove the acetonitrile. The residue was diluted with water, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain an oil. The oil was dissolved in 130 mL of isopropyl acetate, heated to reflux, and 3 mL of 85% phosphoric acid (45.8 mmol, 1.0 eq) was added dropwise. The mixture gradually became turbid, and after 30 min of incubation, it was slowly cooled to room temperature and stirred for an additional 1 h. The mixture was filtered and dried under vacuum to obtain 11.2 g of a white solid (i.e., lucitanib) in a yield of 80%, with a purity of ≥99% by HPLC and an ee value of ≥99%.

[0109] The reaction equations of Examples 17-18 are as follows:

[0110] ;

[0111] The nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum, mass spectrum, related substance spectrum, and chiral purity spectrum of the lucitanib prepared above are shown in Figure 1 , Figure 2 , Figure 3 , Figure 4 and Figure 5 , respectively, and the nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum, and mass spectrum data are as follows:

[0112] 1H NMR (DMSO-d6, 500 MHz) δ 12.14 (br. s, 1H), 8.81 (s, 1H), 8.71 (s,1H), 8.39 (s, 1H), 7.61 (dd, 1H, J=1.4, 3.4 Hz), 7.00 (dd, 1H, J=1.5, 3.4Hz), 4.55 (td, 1H, J=9.7, 4.0 Hz), 3.29 (dd, 1H, J=17.2, 9.8 Hz), 3.20 (dd,1H, J=17.2, 4.0 Hz), 2.44 (m, 1H), 1.86-1.80 (m, 1H), 1.68-1.18 (m, 7H). 13CNMR (DMSO-d6, 125 MHz) δ 152.09, 150.87, 149.86, 139.22, 130.99, 126.72,120.48, 118.13, 112.80, 99.76, 62.49, 44.29, 29.06, 29.03, 24.91, 24.29,22.49. MS m / z: 307.2[M+H]+.

Claims

1. A process for the preparation of Ruxolitinib, characterized in that, The specific steps include the following: S1, preparation of intermediate I: 3-cyclopentyl acrylic acid as a starting material is dissolved in a reaction solvent and condensed with a chiral auxiliary in the presence of an activating agent to obtain intermediate I, wherein the molar ratio of 3-cyclopentyl acrylic acid to the chiral auxiliary is 1:1-1:1.2, and the chiral auxiliary is levorotatory camphorsultam, (R)-4-benzyl oxazolidine, (R)-4-phenyl oxazolidine, (R)-4-isopropyl oxazolidine or (R)-4-isobutyl oxazolidine; S2, preparation of intermediate II: intermediate I obtained in S1 is subjected to asymmetric Michael addition with intermediate M in a reaction solvent in the presence of a base to obtain chiral intermediate II; S3, preparation of intermediate III: intermediate II obtained in S2 is subjected to hydrolysis in a reaction solvent in the presence of a base to remove the chiral auxiliary to obtain intermediate III; S4, preparation of intermediate IV: intermediate III obtained in S3 is subjected to amide condensation with an aminating agent to obtain amide intermediate IV, wherein the molar ratio of intermediate III to the aminating agent is 1:1.5-1:6, the aminating agent is one or more of liquid ammonia, aqueous ammonia, ammonia gas and ammonium chloride, and the reaction solvent for the amide condensation is one or more of tetrahydrofuran, dichloromethane, toluene, dioxane and acetonitrile; S5, preparation of intermediate V: intermediate IV obtained in S4 is dissolved in a reaction solvent, and the amide is converted into a cyano group under the action of a dehydrating agent to obtain intermediate V; S6, preparation of luspaterin: intermediate V obtained in S5 is dissolved in a reaction solvent and mixed with a deprotecting agent to perform a de-SEM protecting group reaction to obtain luspaterin. The synthetic route is as follows: ， wherein R1 is a corresponding chiral auxiliary formed by dehydration condensation of a chiral auxiliary and a carboxylic acid; and SEM is a (trimethylsilyl)ethoxymethyl group, which is a protecting group on the pyrrole nitrogen.

2. The process for the preparation of Ruxolitinib according to claim 1, characterized in that, In S1, the molar ratio of 3-cyclopentyl acrylic acid to the activating agent is 1:1.05-1:1.2, wherein the activating agent is selected from one of N,N'-diisopropyl carbodiimide, N,N'-dicyclohexyl carbodiimide, EDCI, HATU, HBTU and T3P, or one of pivaloyl chloride, isobutyl chloroformate, sulfurous chloride and oxalyl chloride, and when the activating agent is one of pivaloyl chloride, isobutyl chloroformate, sulfurous chloride and oxalyl chloride, a deacidifying agent needs to be added, and the deacidifying agent is selected from one of triethylamine, N-methyl morpholine, DIPEA, DBU, pyridine, NaH and n-butyllithium, and in this case, the molar ratio of 3-cyclopentyl acrylic acid to the deacidifying agent is 1:1.05-1:

2.

3. The process for the preparation of Ruxolitinib according to claim 1, characterized in that, In S1, the reaction solvent is one or more of dichloromethane, tetrahydrofuran, ethylene glycol dimethyl ether and toluene, and the reaction temperature is -78-80°C.

4. The process for the preparation of lucotinib according to claim 1, characterized in that, In S2, the molar ratio of intermediate I to intermediate M is 1:1-1:1.2; the molar ratio of intermediate I to base is 1:1.2-1:1.5, wherein the base is selected from one of inorganic bases of potassium carbonate, cesium carbonate, potassium phosphate, sodium hydroxide or one of organic bases of DBU, triethylamine, DIPEA, 2-methylpyridine, 4-dimethylaminopyridine; the reaction solvent is one or more of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and the reaction temperature is 40-80℃.

5. The process for the preparation of lucotinib as claimed in claim 1 wherein, In S3, the molar ratio of intermediate II to base is 1:1.5-1:4, wherein the base is one of lithium hydroxide, lithium hydroxide-hydrogen peroxide, sodium hydroxide, potassium hydroxide.

6. The process for the preparation of lucotinib according to claim 1, characterized in that, In S3, the reaction solvent is one or more of tetrahydrofuran, water, methanol, ethanol, acetonitrile, when the reaction solvent is a mixture of tetrahydrofuran and water, the volume ratio of tetrahydrofuran to water is 2:1-4:1, and the reaction temperature is -10-25℃.

7. The process for the preparation of lucotinib as claimed in claim 1 wherein, In S4, the reaction temperature is 0-30℃.

8. The process for the preparation of lucotinib as claimed in claim 1 wherein, In S5, the molar ratio of intermediate IV to dehydrating agent is 1:2-1:4, wherein the dehydrating agent is one of trifluoroacetic anhydride, triflic anhydride, phosphorus oxychloride, phosphorus pentoxide, thionyl chloride, diethylaminodifluorosulfonium tetrafluoroborate, tricyanochloride; the reaction solvent is one or more of dichloromethane, tetrahydrofuran, dioxane, methyltetrahydrofuran, and the reaction temperature is 25-70℃.

9. The process for the preparation of lucotinib according to claim 1, characterized in that, In S6, the molar ratio of intermediate V to deprotection reagent is 1:2-1:10, wherein the deprotection reagent is one of boron trifluoride-ether complex, lithium tetrafluoroborate, hydrochloric acid, phosphoric acid, trifluoroacetic acid; the reaction solvent is one or more of dichloromethane, acetonitrile, methanol, acetone, water, and the reaction temperature is 25-80℃.

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