Synthesis method of key intermediate of Selpatinib

Abstract

The invention discloses a synthesis method of a key intermediate of Selpatinib. The synthesis method comprises the following steps: step (1), taking 4-cyanopyrazole as a raw material, and carrying out N-alkylation on the 4-cyanopyrazole and chloroacetone ethylene glycol or epoxypropane; (2) purifying the coupling product obtained in the step (1), carrying out 5-site lithiation, and reacting with 6-fluoronicotinoyl chloride; (3) deprotecting a product obtained after the reaction in the step (2) under an acidic condition; (4) carrying out self ring closing on the product obtained in the step (3) under the action of high-steric-hindrance alkali; and (5) reacting the product obtained in the step (4) with an epoxy compound to generate the key Selpatinib intermediate. According to the synthesis method, the synthesis steps are greatly shortened, the operation is simple, the reaction condition is mild, few byproducts are produced, the cost is low, the product yield is high, and a coupling reaction catalyzed by noble metal is avoided.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and in particular relates to a method for synthesizing a key intermediate of selpatinib. Background Art

[0002] Selpercatinib (LOXO-292) is a highly selective and effective oral investigational drug developed by Eli Lilly and Company for the treatment of cancer patients with abnormal RET kinase mutations. 29 H 31 N7O3) as follows:

[0003]

[0004] The drug specifically targets the RET gene. Genomic alterations in the RET kinase include fusions and point mutations, which lead to overactive RET signaling and uncontrolled cancer cell growth.

[0005] The currently approved indications for LOXO-292 are:

[0006] 1. Patients with metastatic RET fusion-positive non-small cell lung cancer who require systemic treatment and have progressed after platinum chemotherapy and anti-PD-1 or anti-PD-L1 treatment;

[0007] 2. Patients with RET-mutant medullary thyroid cancer (MTC) who require systemic therapy, have progressed after previous treatment, and have no acceptable alternative treatment options;

[0008] 3. Advanced RET fusion-positive thyroid cancer requiring systemic therapy that has progressed after prior therapy and has no acceptable alternative treatment options.

[0009] The currently disclosed synthesis method of Serpatinib is first disclosed in Array BioPharma's patent WO2018071447A1: First, the pyridine raw material 26 is N-aminized using O-(formylsulfonyl)hydroxylamine in dichloromethane, and the yield is 83% after crystallization in ether. Product 27 reacts with ethyl propiolate and triethylamine in DMF to obtain a 4:1 mixture of regional isomer products 28a (required) and 28b (unnecessary), which is separated by precipitation by adding the reaction mixture to ice water, with a yield of 84%. Ester hydrolysis and decarboxylation of the 28a / 28b mixture are carried out with 48% HBr aqueous solution at 80°C. The precipitated solid is filtered and mixed with MTBE to obtain product 29 with a regional isomer ratio of 98:2. Additional material is extracted from the mother liquor by flash chromatography, with a total yield of 63%. The introduction of the nitrile group is completed in three steps. First, product 29 was formylated with POCl3 in DMF to give product 30 in 86% yield. Subsequently, hydroxylamine was used to generate oxime (yield 100%) and dehydrated with acetic anhydride at 140°C to give product 31 in 81% yield, which was separated from the reaction mixture by crystallization. Product 31 was deprotected with aluminum chloride in dichloroethane at 76°C to give product 32, and the reaction mixture was added to an aqueous sodium sulfate solution, followed by tetrahydrofuran, to precipitate and separate product 32 in 98% yield. The phenolic hydroxyl group of product 32 was ring-opened with 2,2-dimethylchloroethane (33) in potassium carbonate and DMF at 85°C to give product 34, which was precipitated and separated in 84% yield after adding water to the reaction mixture. Under the catalysis of Pd(PPh3)4, borate ester 35 was cross-coupled with aqueous sodium carbonate solution in 1,4-dioxane with a yield of 95%. It was separated as a crude solid by water precipitation to obtain product 36. Product 36 and 6-(tert-butyloxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane under the action of base under nucleophilic substitution reaction to prepare product 38. Product 38 was removed from the Boc protecting group under the action of hydrochloric acid to obtain product 39. Finally, product 39 and 6-methoxy-3-pyridinecarboxaldehyde shown in formula 40 underwent reductive amination reaction to obtain serpatinib.

[0010]

[0011] The product 36 is a key intermediate in the synthesis method of selpatinib. In the above synthesis route, the key intermediate needs to be obtained through 8 steps with a yield of 24%.

[0012] The second-generation route was jointly developed by Loxo Oncology and Array BioPharma. It also requires 7-9 steps to obtain the above-mentioned key intermediates, and two steps require precious metal-catalyzed coupling reactions. They are as follows:

[0013]

[0014] The synthesis method of the key intermediates described above has many steps, a relatively complex route, and a low yield. Therefore, it is necessary to develop other better synthesis methods to produce the key intermediates of selpatinib. Summary of the invention

[0015] In order to solve the above technical problems, the purpose of the present invention is to provide a method for synthesizing a key intermediate of selpatinib, which has few reaction steps, simple operation, low production cost, high production efficiency, high yield, high product purity, and is suitable for large-scale production.

[0016] In order to achieve the above technical objectives and the above technical effects, the present invention is implemented through the following technical solutions:

[0017] A method for synthesizing a key intermediate of selpatinib, comprising the following steps:

[0018] Step (1), using 4-cyanopyrazole as a raw material and carrying out N-alkylation with chloroacetone glycol acetal or propylene oxide;

[0019] Step (2), purifying the coupling product obtained in step (1), performing 5-position lithiation, and then reacting with 6-fluoronicotinoyl chloride;

[0020] Step (3), deprotecting the product after the reaction in step (2) under acidic conditions;

[0021] Step (4), the product obtained in step (3) is self-cyclized under the action of a large steric hindered base;

[0022] Step (5), reacting the product obtained in step (4) with an epoxy compound to produce the key intermediate of selpatinib shown in formula A;

[0023]

[0024] Furthermore, a method for synthesizing a key intermediate of serpatinib comprises the following steps:

[0025] Step (1), using 4-cyanopyrazole shown in Formula 1 as a raw material and carrying out N-alkylation with chloroacetone glycol acetal shown in Formula 2 to obtain a coupling product shown in Formula 3;

[0026] Step (2), the coupling product of Formula 3 is purified and then lithiation is performed at the 5-position, and then reacted with 6-fluoronicotinoyl chloride of Formula 4 to obtain the product of Formula 5;

[0027] Step (3), the product shown in Formula 5 is deprotected under acidic conditions to obtain the product shown in Formula 6;

[0028] Step (4), the product shown in Formula 6 is self-ring-closed under the action of a large steric hindered base to obtain a product shown in Formula 7;

[0029] Step (5), the product shown in Formula 7 and the epoxy compound shown in Formula 8 react to produce the key intermediate of selpatinib shown in Formula A;

[0030] The synthetic route is as follows:

[0031]

[0032] Furthermore, in the above synthetic route, the preparation process of the coupling product shown in Formula 3 is:

[0033] 4-Cyanopyrazole is used as a raw material and dissolved in a solvent with chloroacetone glycol acetal, a base is added, a catalyst is added to replace nitrogen, and then the mixture is heated to a certain temperature, and stirring is continued until the reaction is completed. The mixture is cooled and concentrated, water and an extraction solvent are added, and the liquids are separated. The organic layer is concentrated to near dryness to obtain a crude product; the crude product is purified by column chromatography to obtain a coupling product 1-〔2-methyl-2-(2,5-dioxolane)methyl〕4-cyanopyrazole shown in formula 3.

[0034] Furthermore, in the preparation process of the coupling product shown in Formula 3, the molar ratio of 4-cyanopyrazole to chloroacetone glycol acetal is 1: (1.2-1.8), the molar ratio of the base to 4-cyanopyrazole is (1-3): 1, the molar ratio of the catalyst to 4-cyanopyrazole is (0.05-0.25): 1, the reaction temperature is 80-110°C, and the reaction time is 16-24h. Among them, the base is at least one of sodium carbonate, potassium carbonate, and sodium bicarbonate. The catalyst is at least one of tetrabutylammonium bromide, tetrabutylammonium iodide, sodium bromide, potassium bromide, potassium iodide, sodium iodide, etc. The volume mass ratio of the solvent to 4-cyanopyrazole is (12-16) ml: 1g. The extraction solvent is at least one of ethyl acetate, tetrahydrofuran and 2-methyltetrahydrofuran; the volume mass ratio of the extraction solvent to 4-cyanopyrazole is (10-30) ml:1 g.

[0035] Furthermore, the preparation process of the product shown in Formula 5 is:

[0036] The coupling product 1-〔2-methyl-2-(2,5-dioxolane)methyl〕4-cyanopyrazole shown in formula 3 is dissolved in an anhydrous solvent to replace nitrogen, cooled to a certain temperature (below -50°C), organic lithium compound is added dropwise, and the reaction is kept warm for 0.5-1h, 6-fluoronicotinoyl chloride is added dropwise, and the reaction is kept warm for a period of time. After the reaction is completed, water is added and stirred, extracted with an organic solvent, and refined by beating with a refined solvent to obtain the product 5-[(6-fluoropyridin-3-yl)carbonyl]-1-[(2-methyl-1,3-dioxolane-2-yl)methyl]pyrazole-4-carbonitrile shown in formula 5.

[0037] Furthermore, in the preparation process of the product shown in Formula 5, the molar ratio of the organic lithium compound to the coupling product shown in Formula 3 is (1.05-1.2):1, and the molar ratio of the 6-fluoronicotinoyl chloride to the coupling product shown in Formula 3 is (1.05-1.2):1. The organic lithium compound is n-hexyl lithium or phenyl lithium. The reaction solvent is one or more of diisopropyl ether, dioxane, THF, 2-MeTHF, etc.; the volume mass ratio of the reaction solvent to the coupling product shown in Formula 3 is (5-8) ml: 1g; the extraction solvent is one or more of toluene, dichloromethane, and ethyl acetate; the volume mass ratio of the extraction solvent to the coupling product shown in Formula 3 is (5-9) ml: 1g; the refining solvent is one or more of methyl tert-butyl ether, isopropyl ether and or cyclopentyl methyl ether, etc.

[0038] Furthermore, the specific preparation process of step (3) is as follows: dissolving the product obtained after the reaction of step (2) in a solvent, adding dilute acid and stirring the reaction for a period of time; after the reaction is completed, extracting the solvent, concentrating the organic phase to dryness or replacing the solvent to obtain the deprotected product; the reaction temperature is 10-30°C, and the reaction time is 8-20h; in the preparation process, the reaction solvent is one or more of methanol, ethanol, isopropanol, tetrahydrofuran, etc.; the volume mass ratio of the reaction solvent to the product obtained after the reaction of step (2) is (1-5) ml: 1g; the molar ratio of the product obtained after the reaction of step (2) to the acid is 1: (2-6); the dilute acid is one or more of 2M hydrochloric acid aqueous solution, 1M sulfuric acid, 50% trifluoroacetic acid, and 10% methanesulfonic acid.

[0039] The specific process of step (4) and step (5) is as follows: the product obtained in step (3) is placed in a solvent, nitrogen is replaced, the system is cooled to -55 to -50°C, a large steric hindrance base is added and the temperature is kept for reaction for 1-2 hours, 2,2-dimethyloxirane is added dropwise, the temperature is gradually restored after stirring for 30 minutes, and the reaction is continued for 3-16 hours, the system is quenched with dilute acid, the liquid is separated, extraction is performed, the organic phase is concentrated to dryness, and 4-(6-fluoropyridin-3-yl)-6-[(2-hydroxy-2-methylpropyl)oxy]pyrazolo[1,5-a]pyridine-3-carbonitrile is obtained by crystallization. The extraction solvent is one or more of ethyl acetate, dichloromethane, isopropyl acetate, etc.; the volume mass ratio of the extraction solvent to the product obtained in step (3) is (18-30) ml:1 g.

[0040] Furthermore, the bulky hindered base is at least one of LDA, LiHMDS and LiTM.

[0041] Furthermore, the molar ratio of the product obtained in step (3) to the bulky hindered base is 1:(1.05-1.5).

[0042] Furthermore, the molar ratio of the epoxy compound used in step (5) to the product obtained in step (3) is (1.1-1.3):1.

[0043] The beneficial effects of the present invention are:

[0044] The present invention provides a novel synthesis method of a key intermediate of serpatinib, which greatly shortens the synthesis steps, is simple to operate, has mild reaction conditions, produces fewer by-products, is low in cost, has a higher product yield, and avoids noble metal-catalyzed coupling reactions. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 This is the NMR spectrum of the key intermediate of selpatinib prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0046] The technical solutions in the present invention will be described clearly and completely below in conjunction with specific embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0047] The present invention provides a method for synthesizing a key intermediate of serpatinib, comprising the following steps:

[0048] Step (1), using 4-cyanopyrazole as a raw material and carrying out N-alkylation with chloroacetone glycol acetal or propylene oxide;

[0049] Step (2), purifying the coupling product obtained in step (1), performing 5-position lithiation, and then reacting with 6-fluoronicotinoyl chloride;

[0050] Step (3), deprotecting the product after the reaction in step (2) under acidic conditions;

[0051] Step (4), the product obtained in step (3) is self-cyclized under the action of a large steric hindered base;

[0052] Step (5), reacting the product obtained in step (4) with an epoxy compound to produce the key intermediate of selpatinib shown in formula A;

[0053]

[0054] The synthesis method using 4-cyanopyrazole and chloroacetone glycol acetal as starting materials specifically comprises the following steps:

[0055] Step (1), using 4-cyanopyrazole shown in Formula 1 as a raw material and carrying out N-alkylation with chloroacetone glycol acetal shown in Formula 2 to obtain a coupling product shown in Formula 3;

[0056] Step (2), the coupling product of Formula 3 is purified and then lithiation is performed at the 5-position, and then reacted with 6-fluoronicotinoyl chloride of Formula 4 to obtain the product of Formula 5;

[0057] Step (3), the product shown in Formula 5 is deprotected under acidic conditions to obtain the product shown in Formula 6;

[0058] Step (4), the product shown in Formula 6 is self-ring-closed under the action of a large steric hindered base to obtain a product shown in Formula 7;

[0059] Step (5), the product shown in Formula 7 and the epoxy compound shown in Formula 8 react to produce the key intermediate of selpatinib shown in Formula A;

[0060] The synthetic route is as follows:

[0061]

[0062] In step (1), the specific preparation process of the coupling product shown in formula 3 is:

[0063] 4-Cyanopyrazole is used as a raw material and dissolved in a solvent with chloroacetone glycol acetal, a base is added, a catalyst is added to replace nitrogen, and then the mixture is heated to 80-90°C, and stirring is continued until the reaction is completed. The mixture is cooled and concentrated, water and an extraction solvent are added, and the liquids are separated. The organic layer is concentrated to near dryness to obtain a crude product; the crude product is purified by column chromatography to obtain a coupling product 1-〔2-methyl-2-(2,5-dioxolane)methyl〕4-cyanopyrazole shown in formula 3.

[0064] In the preparation process of the coupling product shown in Formula 3, the molar ratio of 4-cyanopyrazole to chloroacetone glycol acetal is 1:(1.2-1.8), the molar ratio of the base to 4-cyanopyrazole is (1-3):1, the molar ratio of the catalyst to 4-cyanopyrazole is (0.05-0.25):1, the reaction temperature is 80-110°C, and the reaction time is 16-24h.

[0065] In step (2), the preparation process of the product shown in formula 5 is:

[0066] The coupling product 1-〔2-methyl-2-(2,5-dioxolane)methyl〕4-cyanopyrazole shown in formula 3 is dissolved in an anhydrous solvent to replace nitrogen, cooled to -55 to -50°C, organic lithium compound is added dropwise, and the reaction is kept warm for 0.5-1h, 6-fluoronicotinoyl chloride is added dropwise, and the reaction is kept warm for a period of time. After the reaction is completed, water is added and stirred, and the product is extracted with an organic solvent. After purification, the product 5-[(6-fluoropyridin-3-yl)carbonyl]-1-[(2-methyl-1,3-dioxolane-2-yl)methyl]pyrazole-4-carbonitrile shown in formula 5 is obtained.

[0067] In the preparation process of the product shown in Formula 5, the molar ratio of the organic lithium compound to the coupling product shown in Formula 3 is (1.05-1.2):1, and the molar ratio of 6-fluoronicotinoyl chloride to the coupling product shown in Formula 3 is (1.05-1.2):1.

[0068] In step (3), the molar ratio of the product obtained after the reaction in step (2) to the acid is 1:(2-6).

[0069] In step (4), the bulky hindered base is at least one of LDA, LiHMDS, and LiTM.

[0070] In the reaction of step (4), the molar ratio of the product obtained in step (3) to the bulky hindered base is 1:(1.05-1.5).

[0071] The molar ratio of the epoxy compound used in step (5) to the product obtained in step (3) is (1.1-1.3):1.

[0072] The synthesis method of the present invention is further described below by means of specific examples.

[0073] Example 1

[0074] Chloroacetone glycol acetal (44.0 g, 322.3 mmol, 1.5 eq.) and 4-cyano-pyrazole (20.0 g, 214.8 mmol, 1.0 eq.) were dissolved in dioxane (300 ml), K2CO3 (74.2 g, 537.1 mmol, 2.5 eq.) and tetrabutylammonium bromide (3.5 g, 10.7 mmol, 0.05 eq.) were added to replace the nitrogen atmosphere and heated to 100°C. ℃, after continuous stirring for 16 hours, the liquid phase was controlled, the reaction was completed, and the mixture was concentrated to remove dioxane. After cooling, water (200 ml) and ethyl acetate (200 ml) were added, and the liquids were separated. The organic layer was concentrated to near dryness to obtain a crude product; the crude product was subjected to column chromatography, with an EA:PE volume ratio of 1:1 to 2:1, to obtain 34.5 g of pure 1-〔2-methyl-2-(2,5-dioxolane)methyl〕4-cyanopyrazole, with a liquid phase purity of 97.4% and a yield of 83%.

[0075] 1-〔2-methyl-2-(2,5-dioxolane)methyl〕4-cyanopyrazole (25.0 g, 129.4 mmol, 1.0 eq.) was dissolved in anhydrous tetrahydrofuran (195 ml) and replaced with nitrogen. The mixture was cooled to -55 to -50°C. A 1M phenyllithium ether solution (142.3 ml, 142.3 mmol, 1.1 eq.) was added dropwise while maintaining the temperature at -50°C. The mixture was kept warm for 0.5-1 h. 6-fluoronicotinoyl chloride (21.7 g, 136.0 m mol, 1.05eq.), keep warm for reaction for 2-3h. After the reaction is completed, add water (100ml) into the system and stir, extract with dichloromethane (195ml), concentrate the organic phase, beat with methyl tert-butyl ether (100ml) at 20℃ for 3h, collect the solid by suction filtration, and dry to obtain 5-[(6-fluoropyridin-3-yl)carbonyl]-1-[(2-methyl-1,3-dioxolan-2-yl)methyl]pyrazole-4-carbonitrile, 27.4g, purity 98.7%, yield 67%.

[0076] 5-[(6-fluoropyridin-3-yl)carbonyl]-1-[(2-methyl-1,3-dioxolan-2-yl)methyl]pyrazole-4-carbonitrile (25g, 79.0mmol, 1eq.) was dissolved in ethanol (100ml), and 2M dilute hydrochloric acid (79ml, 2eq.) was added at 20-25°C, and stirred for 16h. After the reaction was completed, ethyl acetate (100ml*3) was used for extraction, and the organic phases were combined and concentrated to obtain 5-[(6-fluoropyridin-3-yl)carbonyl]-1-(2-oxyylidenepropyl)pyrazole-4-carbonitrile (20.0g) with a purity of 97.8% and a yield of 93%.

[0077] 5-[(6-Fluoropyridin-3-yl)carbonyl]-1-(2-oxyylidenepropyl)pyrazole-4-carbonitrile (20.0 g, 73.5 mmol, 1.0 eq.) was placed in tetrahydrofuran (105 ml), and the nitrogen was replaced. The system was cooled to -55 to -50 ° C, and LiHMDS (1.0 M, 88.2 ml, 88.2 mmol, 1.2 eq.) was added and kept warm for 1-2 hours. When the residual raw material was less than 1A%, 2,2-dimethyloxirane (6.4 g, 88.2 mmol, 1.2 eq.) was added dropwise at -55 to -50 degrees to complete the reaction. Stirring After reacting for 30 minutes, the mixture was gradually warmed up and stirred for 15 hours. The system was quenched with dilute hydrochloric acid (1M, 110 mL). The liquids were separated and extracted with ethyl acetate (160 ml*3). The organic phase was concentrated to near dryness (35 ml slurry) and cooled for crystallization. 4-(6-fluoropyridin-3-yl)-6-[(2-hydroxy-2-methylpropyl)oxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (17.3 g) was obtained with a purity of 97.8% and a yield of 72%.

[0078] The total yield of the synthesis method in Example 1 is 37%.

[0079] The NMR spectrum of the key intermediate of Serpatinib prepared in Example 1 is as follows: Figure 1 As shown, the data is as follows:

[0080] 1 H NMR (400MHz, CDCl3): δ8.93 (d, 1H, J = 2.7Hz), 8.65 (d, 1H, J = 2.7Hz), 8.18 (dd, 1H, J1 = 7.2Hz, J2 = 2.7H z), 7.96 (s, 1H), 7.36 (d, 1H, J = 2.7Hz), 7.32 (dd, 1HJ1 = 7.2Hz, J2 = 2.7Hz), 4.51 (s, 2H), 1.14 (s, 6H).

[0081] Example 2

[0082] Chloroacetone glycol acetal (25.1 g, 183.7 mmol, 1.5 eq.) and 4-cyano-pyrazole (11.4 g, 122.5 mmol, 1.0 eq.) were dissolved in dimethylformamide (171 ml), and K2CO3 (42.3 g, 306.2 mmol, 2.5 eq.) and NaBr (1.89 g, 18.37 mmol, 0.1 eq.) were added to replace the nitrogen atmosphere and then heated. To 100 ° C, after continuous stirring for 16 hours, the liquid phase was controlled, and the remaining 4-cyano-pyrazole was less than 2%, which indicated the end of the reaction. The mixture was cooled, and water (280 ml) and ethyl acetate (350 ml) were added. The liquids were separated, and the organic layer was washed with water and concentrated to near dryness to obtain a crude product. The crude product was subjected to column chromatography to obtain 14.9 g of pure 1-〔2-methyl-2-(2,5-dioxolane)methyl〕4-cyanopyrazole with a liquid phase purity of 97.8A% and a yield of 63%.

[0083] 1-〔2-methyl-2-(2,5-dioxolane)methyl〕4-cyanopyrazole (22.6 g, 117.0 mmol, 1.0 eq.) was dissolved in anhydrous tetrahydrofuran (135 ml) and replaced with nitrogen. The mixture was cooled to -55 to -50°C. A 1M phenyllithium ether solution (126.3 ml, 126.3 mmol, 1.08 eq.) was added dropwise while maintaining the temperature at -50°C. The mixture was reacted for 0.5-1 h. 6-fluoronicotinoyl chloride (19.6 g, 122.8 mmol, 1.05eq.), keep warm for 2-3h, after the reaction is completed, add water (95ml) into the system and stir, extract with dichloromethane (185ml), concentrate the organic phase, slurry with methyl tert-butyl ether (100ml) at 20℃ for 3h, collect the solid by suction filtration, and dry to obtain 5-[(6-fluoropyridin-3-yl)carbonyl]-1-[(2-methyl-1,3-dioxolan-2-yl)methyl]pyrazole-4-carbonitrile, 23.7g, purity 98.2%, yield 64%.

[0084] 5-[(6-fluoropyridin-3-yl)carbonyl]-1-[(2-methyl-1,3-dioxolane-2-yl)methyl]pyrazole-4-carbonitrile (23.6 g, 74.6 mmol, 1 eq.) was dissolved in ethanol (95 ml), and 2M dilute hydrochloric acid (74.6 ml, 2 eq.) was added at 20-25°C, and stirred for 16 hours. After the reaction was completed, saturated NaHCO3 (95 mL) was added, and ethyl acetate (95 ml*3) was used for extraction. The organic phases were combined and concentrated to obtain 5-[(6-fluoropyridin-3-yl)carbonyl]-1-(2-oxyylidenepropyl)pyrazole-4-carbonitrile (19.1 g) with a purity of 97.7% and a yield of 94%.

[0085] 5-[(6-Fluoropyridin-3-yl)carbonyl]-1-(2-oxyylidenepropyl)pyrazole-4-carbonitrile (19.0 g, 69.9 mmol, 1.0 eq.) was placed in tetrahydrofuran (100 ml), and the nitrogen was replaced. The system was cooled to -55 to -50 degrees, and LDA (2.0 M, 41.9 ml, 83.8 mmol, 1.2 eq.) was added and the reaction was kept warm for 1-2 hours. When the residual raw material was less than 1A%, 2,2-dimethyloxirane (6.5 g) was added dropwise at -55 to -50 degrees. , 90.7mmol, 1.3eq.) was completed, the reaction was stirred for 30 minutes and then gradually warmed up and stirred for 15h. The system was quenched with dilute hydrochloric acid (1M, 110mL), separated, and extracted with ethyl acetate (150ml*3). The organic phase was concentrated to near dryness (30-35ml slurry) and cooled for crystallization. 4-(6-fluoropyridin-3-yl)-6-[(2-hydroxy-2-methylpropyl)oxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (15.9g) was obtained with a purity of 97.9% and a yield of 70%.

[0086] Example 3

[0087] Chloroacetone glycol acetal (36.8 g, 269.4 mmol, 1.5 eq.) and 4-cyano-pyrazole (16.7 g, 179.6 mmol, 1.0 eq.) were dissolved in dioxane (250 ml), and K2CO3 (62.0 g, 449.2 mmol, 2.5 eq.) and KI (4.5 g, 26.9 mmol, 0.1 eq.) were added. After replacing nitrogen, the mixture was heated to 100°C and stirred for 16 hours. The liquid phase was controlled to show that the remaining 4-cyano-pyrazole was less than 2%, indicating that the reaction was completed. The mixture was cooled, and water (280 ml) and ethyl acetate (350 ml) were added. The mixture was separated, and the organic layer was washed with water and concentrated to near dryness to obtain a crude product. The crude product was subjected to column chromatography to obtain 25.7 g of pure 1-〔2-methyl-2-(2,5-dioxolane)methyl〕4-cyanopyrazole with a liquid phase purity of 98.1A% and a yield of 75%.

[0088] 1-〔2-methyl-2-(2,5-dioxolane)methyl〕4-cyanopyrazole (13.7 g, 70.9 mmol, 1.0 eq.) was dissolved in anhydrous tetrahydrofuran (85 ml) and the nitrogen atmosphere was replaced. The mixture was cooled to -65 to -60°C and kept below -60°C. A 2M n-hexyllithium n-hexane solution (35.5 ml, 78.0 mmol, 1.1 eq.) was added dropwise. The mixture was kept warm for 0.5-1 h. 6-fluoronicotinoyl chloride (11.9 g, 74.5 mmol, 1.05 eq.) was added dropwise. The mixture was kept warm for 2-3 h. After the reaction is completed, water (60 ml) is added into the system with stirring, and the mixture is extracted with dichloromethane (120 ml). The organic phase is concentrated, methyl tert-butyl ether (60 ml) is added to slurry at 20°C for 3 h, and the solid is collected by filtration and dried to obtain 5-[(6-fluoropyridin-3-yl)carbonyl]-1-[(2-methyl-1,3-dioxolan-2-yl)methyl]pyrazole-4-carbonitrile, 13.7 g, purity 98.4%, yield 58%.

[0089] 5-[(6-fluoropyridin-3-yl)carbonyl]-1-[(2-methyl-1,3-dioxolane-2-yl)methyl]pyrazole-4-carbonitrile (13.6 g, 43.0 mmol, 1 eq.) was dissolved in ethanol (55 ml), and 2M dilute hydrochloric acid (43.0 ml, 2 eq.) was added at 20-25°C, and stirred for 16 hours. After the reaction was completed, saturated NaHCO3 (55 mL) was added, and ethyl acetate (55 ml*3) was used for extraction. The organic phases were combined and concentrated to obtain 5-[(6-fluoropyridin-3-yl)carbonyl]-1-(2-oxyylidenepropyl)pyrazole-4-carbonitrile (11.0 g) with a purity of 97.9% and a yield of 93%.

[0090] 5-[(6-Fluoropyridin-3-yl)carbonyl]-1-(2-oxyylidenepropyl)pyrazole-4-carbonitrile (11.0 g, 40.4 mmol, 1.0 eq.) was placed in tetrahydrofuran (55 ml), and the nitrogen was replaced. The system was cooled to -55 to -50 ° C, and LDA (2.0 M, 24.3 ml, 48.5 mmol, 1.2 eq.) was added and kept warm for 1-2 h. When the residual raw material was less than 1A%, 2,2-dimethyloxirane (3.5 g, 48.5mmol, 1.2eq.) was completed, the reaction was stirred for 30 minutes and then gradually warmed up and stirred for 15h. The system was quenched with dilute hydrochloric acid (1M, 60mL), separated, and extracted with ethyl acetate (75ml*3). The organic phase was concentrated to near dryness (15-20ml slurry) and cooled for crystallization. 4-(6-fluoropyridin-3-yl)-6-[(2-hydroxy-2-methylpropyl)oxy]pyrazolo[1,5-a]pyridine-3-carbonitrile (8.8g) was obtained with a purity of 96.9% and a yield of 67%.

[0091] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the present invention can be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the embodiments should be considered exemplary and non-restrictive in all respects, and the scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims be included in the present invention.

[0092] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. A method for synthesizing a key intermediate of serpatinib, characterized in that: The steps include: Step (1), using 4-cyanopyrazole as a raw material and carrying out N-alkylation with chloroacetone glycol acetal or propylene oxide; Step (2), purifying the coupling product obtained in step (1), performing 5-position lithiation, and then reacting with 6-fluoronicotinoyl chloride; Step (3), deprotecting the product after the reaction in step (2) under acidic conditions; Step (4), the product obtained in step (3) is self-cyclized under the action of a large steric hindered base; Step (5), reacting the product obtained in step (4) with an epoxy compound to produce the key intermediate of selpatinib shown in formula A; 2. The method for synthesizing a key intermediate of serpatinib according to claim 1, characterized in that: The steps include: Step (1), using 4-cyanopyrazole shown in Formula 1 as a raw material and carrying out N-alkylation with chloroacetone glycol acetal shown in Formula 2 to obtain a coupling product shown in Formula 3; Step (2), the coupling product of Formula 3 is purified and then lithiation is performed at the 5-position, and then reacted with 6-fluoronicotinoyl chloride of Formula 4 to obtain the product of Formula 5; Step (3), the product shown in Formula 5 is deprotected under acidic conditions to obtain the product shown in Formula 6; Step (4), the product shown in Formula 6 is self-ring-closed under the action of a large steric hindered base to obtain a product shown in Formula 7; Step (5), the product shown in Formula 7 and the epoxy compound shown in Formula 8 react to produce the key intermediate of selpatinib shown in Formula A; The synthetic route is as follows:

3. The method for synthesizing a key intermediate of selpatinib according to claim 2, characterized in that: The preparation process of the coupling product shown in Formula 3 is: 4-Cyanopyrazole is used as a raw material and dissolved in a solvent with chloroacetone glycol acetal, a base is added, a catalyst is added to replace nitrogen, and then the mixture is heated to a certain temperature, and stirring is continued until the reaction is completed. The mixture is cooled and concentrated, water and an extraction solvent are added, and the liquids are separated. The organic layer is concentrated to near dryness to obtain a crude product; the crude product is purified by column chromatography to obtain a coupling product 1-〔2-methyl-2-(2,5-dioxolane)methyl〕4-cyanopyrazole shown in formula 3.

4. The method for synthesizing a key intermediate of selpatinib according to claim 3, characterized in that: In the preparation process of the coupling product shown in Formula 3, the molar ratio of 4-cyanopyrazole to chloroacetone glycol acetal is 1:(1.2-1.8), the molar ratio of the base to 4-cyanopyrazole is (1-3):1, the molar ratio of the catalyst to 4-cyanopyrazole is (0.05-0.25):1, the reaction temperature is 80-110°C, and the reaction time is 16-24h.

5. The method for synthesizing a key intermediate of selpatinib according to claim 2, characterized in that: The preparation process of the product shown in Formula 5 is: The coupling product 1-〔2-methyl-2-(2,5-dioxolane)methyl〕4-cyanopyrazole shown in formula 3 is dissolved in an anhydrous solvent to replace nitrogen, cooled to a certain temperature, organic lithium compound is added dropwise, and the reaction is kept warm for 0.5-1h, 6-fluoronicotinoyl chloride is added dropwise, and the reaction is kept warm for a period of time. After the reaction is completed, water is added and stirred, extracted with an organic solvent, and purified to obtain the product 5-[(6-fluoropyridin-3-yl)carbonyl]-1-[(2-methyl-1,3-dioxolane-2-yl)methyl]pyrazole-4-carbonitrile shown in formula 5.

6. The method for synthesizing a key intermediate of selpatinib according to claim 5, characterized in that: In the preparation process of the product shown in Formula 5, the molar ratio of the organic lithium compound to the coupling product shown in Formula 3 is (1.05-1.2): the molar ratio of 1,6-fluoronicotinoyl chloride to the coupling product shown in Formula 3 is (1.05-1.2):

1.

7. A method for synthesizing a key intermediate of selpatinib according to claim 1 or 2, characterized in that: The molar ratio of the product obtained after the reaction in step (2) to the acid is 1:(2-6).

8. A method for synthesizing a key intermediate of selpatinib according to claim 1 or 2, characterized in that: The bulky hindered base is at least one of LDA, LiHMDS and LiTM.

9. A method for synthesizing a key intermediate of selpatinib according to claim 1 or 2, characterized in that: The molar ratio of the product obtained in step (3) to the bulky hindered base is 1:(1.05-1.5).

10. A method for synthesizing a key intermediate of serpatinib according to claim 1 or 2, characterized in that: The molar ratio of the epoxy compound used in step (5) to the product obtained in step (3) is (1.1-1.3):1.

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