A preparation method of darolamide key intermediate (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile

Abstract

The invention discloses a preparation method of a key intermediate of darolamide (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile, and belongs to the technical field of pharmaceutical chemical industry. The invention uses 3-bromopyrazole as a starting material, and replaces it with (S)-2-((tert-butyloxycarbonyl)amino)propyl methanesulfonate to obtain (S)-(1-(3-bromo-1H-pyrazol-1-yl)propyl-2-yl)carbamate tert-butyl ester, and then couples it with 2-chloro-4-cyanophenyl borate to obtain (S)-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl-2-yl)carbamate tert-butyl ester, and finally hydrolyzes it to obtain (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile. The method has few synthetic steps, simple operation, high safety, high yield and the like, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical industry, and specifically relates to a method for preparing a key intermediate of darolamide, (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile. Background Art

[0002] Prostate cancer (PC) is one of the most common malignant tumors of the male urogenital system and the second leading cause of death in men. In recent years, the incidence of PC in China has also shown an increasing trend. After treatment, some patients have elevated prostate-specific antigens, and tumor cells still frequently metastasize, which is called metastatic castration-resistant prostate (mCRPC).

[0003] Androgen receptor (AR) is a steroid hormone receptor with a ligand binding region, a DNA binding region, and multiple phosphorylation sites. After binding to the ligand androgen in vivo, it forms an AR dimer, which is then phosphorylated and transferred from the cytoplasm to the nucleus, mediating the transcription and activation of various pathways in the nucleus. Under normal circumstances, AR regulates the dynamic balance between proliferation and apoptosis of prostate epithelial cells, but this dynamic balance is broken in PC tissue, promoting the proliferation and survival of tumor cells, which is the main cause of PC. AR antagonists can inhibit AR from entering the cell nucleus to treat PC. Given that AR plays an important role in the occurrence and development of PC, the design and development of antagonists targeting AR has become a research hotspot for the treatment of PC.

[0004] Darolutamide, also known as darolutamide, darolutamide or dolamid, codenamed ODM-201 or BAY-1841788, is a new generation of non-steroidal AR antagonists, which is structurally different from enzalutamide and apalutamide. Darolutamide is a mixture of two diastereoisomers. There is a chiral center in its molecular structure. There is a pair of optical isomers (S, R)-Darolutamide and (S, S)-Darolutamide, which have similar pharmacological activities. In 2019, the FDA approved darolutamide for marketing, and the trade name of the film-coated tablets was Nubeqa; in 2020, darolutamide was launched in the European Union and Japan; in 2021, my country approved its use for the treatment of non-metastatic castration-resistant prostate cancer with a high risk of metastasis.

[0005] At present, many patents or literatures have reported the preparation methods of darolamide, among which the key intermediate (S)-4-(1-(2-aminopropyl)-1H-pyridin-3-yl)-2-chlorobenzonitrile is involved in almost all preparation methods, and its structural formula is shown in Formula I:

[0006]

[0007] The preparation methods that have been disclosed so far are reported in WO2016162604A, CN111116477B, CN111087324, and CN110590668.

[0008] However, these methods all have defects to varying degrees. The method reported in WO2016162604A has long steps, harsh reaction conditions, and involves anhydrous and oxygen-free reactions; the method reported in CN111116477B has unstable and difficult-to-obtain starting materials, and highly toxic and irritating reaction reagents; the method reported in CN110590668 has expensive starting materials and long steps; the method reported in CN111087324 has difficult-to-obtain starting materials, harsh reaction conditions, and is not suitable for industrial production.

[0009] Based on this, the current synthesis process of the key intermediate of darolamide, (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile, needs to be improved, and the present invention is specially proposed. Summary of the invention

[0010] The technical problem solved by the present invention is to provide a preparation method of (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile, a key intermediate of darolamide.

[0011] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0012] A method for preparing a key intermediate of darolamide, (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile, comprising the following steps:

[0013] 1) Using 3-bromopyrazole as a starting material, reacting with (S)-2-((tert-butyloxycarbonyl)amino)propyl methanesulfonate in the presence of an acid-binding agent at room temperature, followed by post-treatment to obtain a compound of formula 3, (S)-(1-(3-bromo-1H-pyrazol-1-yl)propan-2-yl)carbamic acid tert-butyl ester;

[0014] 2) using the compound of formula 3 obtained in step 1) as a raw material, reacting with 2-chloro-4-cyanophenyl borate in the presence of a catalyst, heating and then post-treating to obtain a compound of formula 5, (S)-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)carbamic acid tert-butyl ester;

[0015] 3) The compound of formula 5 obtained in step 2) is used as a raw material and hydrolyzed under acidic conditions to obtain a compound of formula I (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile.

[0016] The reaction formula is as follows:

[0017]

[0018] The acid binding agent in step 1) is selected from at least one of potassium carbonate, cesium carbonate, DBU and DIEA.

[0019] The step 1) is carried out in an organic solvent, and the organic solvent used is selected from at least one of N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, N-methylpyrrolidone, dichloromethane and acetone.

[0020] In the step 1), the molar amount of (S)-2-((tert-butyloxycarbonyl)amino)propyl methanesulfonate is 100% to 300%; and the molar amount of the acid binding agent is 100% to 300%.

[0021] The catalyst in step 2) is selected from at least one of bistriphenylphosphine palladium dichloride, tetrakistriphenylphosphine palladium, palladium chloride, and palladium acetate; the base in the reaction is selected from at least one of potassium carbonate, cesium carbonate, potassium phosphate, and sodium acetate.

[0022] The step 2) is carried out in an organic solvent, and the organic solvent used is selected from at least one of toluene, dioxane, tetrahydrofuran, acetonitrile, purified water, or a mixture of two thereof.

[0023] The molar amount of 2-chloro-4-cyanophenyl borate in step 2) is 100% to 150%; the molar amount of the catalyst is 10% to 20%; the molar amount of the base is 150% to 200%; and the reaction temperature is 90 to 100°C.

[0024] The molar amount of the acid in step 3) is 1000% to 1500%.

[0025] The step 3) is carried out in an organic solvent, and the organic solvent used is at least one selected from dichloromethane, ethyl acetate, methanol, and ethanol.

[0026] The reaction temperature of step 3) is 0-40°C; the reaction time is 4-24 h.

[0027] Compared with the prior art, the present invention has the following advantages:

[0028] The invention has the advantages of simple operation, short steps, high yield, good purity, etc. Compared with the prior art, the industrial operability of the reaction is greatly improved. DETAILED DESCRIPTION

[0029] The present invention is further illustrated below in conjunction with specific examples. The examples are implemented based on the technical solutions of the present invention. It should be understood that these examples are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0030] Synthesis of (S)-tert-butyl (1-(3-bromo-1H-pyrazol-1-yl)propan-2-yl)carbamate (Compound 3)

[0031] The reaction formula is:

[0032]

[0033] Example 1

[0034] After adding 68.04 mmol of compound 1 and 102.06 mmol of compound 2 to the reaction flask, 50 mL of N,N-dimethylformamide was added to dissolve. Under stirring at room temperature, 136.08 mmol of potassium carbonate was added and stirred at room temperature for 8 h. After the reaction was completed, the reaction solution was poured into 300 mL of water and stirred. A large amount of solid precipitated and was filtered after 30 min. The filter cake was slurried with 100 mL of n-hexane to obtain 18.83 g of compound 3, with a molar yield of 90.98% and a purity of ≥95%.

[0035] 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 7.86 (d, J = 2.36 Hz, 1H), 6.95 (d,J = 2.36 Hz, 1H), 6.89 (d, J = 8.44 Hz, 1H), 4.14 (d, J = 6.52 Hz, 2H), 3.95-3.88 (m, 1H), 1.32 (s, 9H), 1.02 (d, J = 6.80 Hz, 3H).

[0036] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 149.61, 137.84, 129.11, 118.23, 81.23, 67.12, 48.55, 27.67, 19.49.

[0037] ESI-MS (m / z): 304.1 [M+H] + .

[0038] Example 2

[0039] After adding 68.04 mmol of compound 1 and 102.06 mmol of compound 2 to the reaction flask, 50 mL of N,N-dimethylformamide was added to dissolve. Under stirring at room temperature, 204.12 mmol of DBU was added and stirred at room temperature for 12 h. After the reaction was completed, the reaction solution was poured into 300 mL of water and stirred. A large amount of solid precipitated and was filtered after 30 min. The filter cake was slurried with 100 mL of n-hexane to obtain 17.53 g of compound 3, with a molar yield of 84.70% and a purity of ≥92%.

[0040] Example 3

[0041] After adding 68.04 mmol of compound 1 and 102.06 mmol of compound 2 to the reaction bottle, 50 mL of N,N-dimethylformamide was added to dissolve. Under stirring at room temperature, 204.12 mmol of DIEA was added and stirred at room temperature for 8 h. After the reaction was completed, the reaction solution was poured into 300 mL of water and stirred. A large amount of solid precipitated and was filtered after 30 min. The filter cake was slurried with 100 mL of n-hexane to obtain 19.23 g of compound 3, with a molar yield of 92.91% and a purity of ≥95%.

[0042] Example 4

[0043] After adding 68.04 mmol of compound 1 and 204.12 mmol of compound 2 to the reaction flask, 50 mL of N,N-dimethylformamide was added to dissolve. Under stirring at room temperature, 136.08 mmol of potassium carbonate was added and stirred at room temperature for 8 h. After the reaction was completed, the reaction solution was poured into 300 mL of water and stirred. A large amount of solid precipitated and was filtered after 30 min. The filter cake was slurried with 100 mL of n-hexane to obtain 17.88 g of compound 3, with a molar yield of 86.39% and a purity of ≥95%.

[0044] Example 5

[0045] After adding 68.04 mmol of compound 1 and 102.06 mmol of compound 2 to the reaction flask, 50 mL of N,N-dimethylformamide was added to dissolve. Under stirring at room temperature, 204.12 mmol of potassium carbonate was added and stirred at room temperature for 8 h. After the reaction was completed, the reaction solution was poured into 300 mL of water and stirred. A large amount of solid precipitated and was filtered after 30 min. The filter cake was slurried with 100 mL of n-hexane to obtain 19.55 g of compound 3, with a molar yield of 94.46% and a purity of ≥95%.

[0046] Synthesis of tert-butyl (S)-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)carbamate (Compound 5)

[0047] The reaction formula is:

[0048]

[0049] Example 6

[0050] 49.31 mmol of compound 3 (Example 1) and 59.17 mmol of compound 4 were added to the reaction flask, dissolved with 120 mL of dioxane and 30 mL of water, and stirred at room temperature. After adding 73.97 mmol of potassium carbonate and 4.93 mmol of bistriphenylphosphine palladium dichloride, the temperature was raised to 90 °C and stirred under nitrogen protection. After the reaction was completed, 80 mL of dioxane was evaporated under reduced pressure, and the reaction solution was poured into 300 mL of water. A large amount of solid precipitated, which was filtered by suction. After the filter cake was slurried with 100 mL of petroleum ether, 14.77 g of compound 5 was obtained, with a molar yield of 83.01% and a purity of ≥90%.

[0051] 1 H NMR (300 MHz, DMSO-d6) δ (ppm): 8.10 (d, J = 1.48 Hz, 1H), 7.99-7.92 (m, 2H), 7.78 (d, J = 2.32 Hz, 1H), 6.95 (d, J = 2.36 Hz, 1H), 6.89 (d,J = 8.36 Hz, 1H), 4.13 (d, J = 6.52 Hz, 2H), 3.95-3.88 (m, 1H), 1.32 (s, 9H),1.03 (d, J = 6.68 Hz, 3H).

[0052] 13 C NMR (101 MHz, DMSO-d6) δ (ppm): 155.30, 147.64, 140.19, 136.32,135.46, 133.45, 126.05, 124.52, 116.68, 110.33, 104.70, 78.18, 68.29, 56.64,28.64, 18.46.

[0053] ESI-MS (m / z): 361.1 [M+H] + .

[0054] Example 7

[0055] 49.31 mmol of compound 3 (Example 2) and 59.17 mmol of compound 4 were added to the reaction flask, dissolved with 120 mL of dioxane and 30 mL of water, and stirred at room temperature. After adding 73.97 mmol of potassium carbonate and 4.93 mmol of tetrakistriphenylphosphine palladium, the temperature was raised to 100 °C and stirred under nitrogen protection. After the reaction was completed, 80 mL of dioxane was evaporated under reduced pressure, and the reaction solution was poured into 300 mL of water. A large amount of solid precipitated, which was filtered by suction. After the filter cake was slurried with 100 mL of petroleum ether, 15.13 g of compound 5 was obtained, with a molar yield of 85.03% and a purity of ≥90%.

[0056] Example 8

[0057] 49.31 mmol of compound 3 (Example 3) and 59.17 mmol of compound 4 were added to the reaction flask, dissolved with 120 mL of dioxane and 30 mL of water, and stirred at room temperature. After adding 73.97 mmol of potassium carbonate and 4.93 mmol of palladium acetate, the temperature was raised to 90 °C and stirred under nitrogen protection. After the reaction was completed, 80 mL of dioxane was evaporated under reduced pressure, and the reaction solution was poured into 300 mL of water. A large amount of solid precipitated, which was filtered by suction. After the filter cake was slurried with 100 mL of petroleum ether, 13.55 g of compound 5 was obtained, with a molar yield of 76.15% and a purity of ≥90%.

[0058] Example 9

[0059] 49.31 mmol of compound 3 (Example 4) and 59.17 mmol of compound 4 were added to the reaction flask, dissolved with 120 mL of dioxane and 30 mL of water, and stirred at room temperature. After adding 73.97 mmol of potassium phosphate and 4.93 mmol of bistriphenylphosphine palladium dichloride, the temperature was raised to 90 °C and stirred under nitrogen protection. After the reaction was completed, 80 mL of dioxane was evaporated under reduced pressure, and the reaction solution was poured into 300 mL of water. A large amount of solid precipitated, which was filtered by suction. After the filter cake was slurried with 100 mL of petroleum ether, 11.78 g of compound 5 was obtained, with a molar yield of 66.20% and a purity of ≥90%.

[0060] Example 10

[0061] 49.31 mmol of compound 3 (Example 5) and 59.17 mmol of compound 4 were added to the reaction flask, dissolved with 120 mL of dioxane and 30 mL of water, and stirred at room temperature. After adding 73.97 mmol of sodium acetate and 4.93 mmol of bistriphenylphosphine palladium dichloride, the temperature was raised to 100 °C and stirred under nitrogen protection. After the reaction was completed, 80 mL of dioxane was evaporated under reduced pressure, and the reaction solution was poured into 300 mL of water. A large amount of solid precipitated, which was filtered by suction. After the filter cake was slurried with 100 mL of petroleum ether, 13.41 g of compound 5 was obtained, with a molar yield of 75.36% and a purity of ≥90%.

[0062] Embodiment 11

[0063] 49.31 mmol of compound 3 (Example 1) and 59.17 mmol of compound 4 were added to the reaction flask, dissolved with 150 mL of toluene and stirred at room temperature. After adding 73.97 mmol of potassium carbonate and 4.93 mmol of bistriphenylphosphine palladium dichloride, the temperature was raised to 90 °C and stirred under nitrogen protection. After the reaction was completed, 80 mL of dioxane was evaporated under reduced pressure, and the reaction solution was poured into 300 mL of water. A large amount of solid precipitated, which was filtered by suction. After the filter cake was slurried with 100 mL of petroleum ether, 10.05 g of compound 5 was obtained, with a molar yield of 56.48% and a purity of ≥90%.

[0064] Example 12

[0065] 49.31 mmol of compound 3 (Example 1) and 59.17 mmol of compound 4 were added to the reaction flask, dissolved with 120 mL of tetrahydrofuran and 30 mL of water, and stirred at room temperature. After adding 73.97 mmol of potassium carbonate and 4.93 mmol of bistriphenylphosphine palladium dichloride, the temperature was raised to 90 °C and stirred under nitrogen protection. After the reaction was completed, 80 mL of dioxane was evaporated under reduced pressure, and the reaction solution was poured into 300 mL of water. A large amount of solid precipitated, which was filtered, and the filter cake was slurried with 100 mL of petroleum ether to obtain 9.83 g of compound 5, with a molar yield of 55.24% and a purity of ≥90%.

[0066] Example 13

[0067] 49.31 mmol of compound 3 (Example 1) and 73.97 mmol of compound 4 were added to the reaction flask, dissolved with 120 mL of dioxane and 30 mL of water, and stirred at room temperature. After adding 73.97 mmol of potassium carbonate and 4.93 mmol of bistriphenylphosphine palladium dichloride, the temperature was raised to 90 °C and stirred under nitrogen protection. After the reaction was completed, 80 mL of dioxane was evaporated under reduced pressure, and the reaction solution was poured into 300 mL of water. A large amount of solid precipitated, which was filtered, and the filter cake was slurried with 100 mL of petroleum ether to obtain 15.11 g of compound 5, with a molar yield of 84.92% and a purity of ≥90%.

[0068] Embodiment 14

[0069] 49.31 mmol of compound 3 (Example 1) and 59.17 mmol of compound 4 were added to the reaction flask, dissolved with 120 mL of dioxane and 30 mL of water, and stirred at room temperature. After adding 98.62 mmol of potassium carbonate and 4.93 mmol of bistriphenylphosphine palladium dichloride, the temperature was raised to 90 °C and stirred under nitrogen protection. After the reaction was completed, 80 mL of dioxane was evaporated under reduced pressure, and the reaction solution was poured into 300 mL of water. A large amount of solid precipitated, which was filtered by suction. After the filter cake was slurried with 100 mL of petroleum ether, 14.38 g of compound 5 was obtained, with a molar yield of 80.82% and a purity of ≥90%.

[0070] Synthesis of (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (Compound I)

[0071] The reaction formula is:

[0072]

[0073] Embodiment 15

[0074] Add 38.80 mmol of compound 5 (Example 6) and 140 mL of dichloromethane to the reaction flask, stir at room temperature to dissolve. Slowly drop 84 mL of concentrated hydrochloric acid (37%) and control the internal temperature to 25-35 °C. After the addition is complete, stir at room temperature for 6 h. After the reaction is completed, stop stirring, let stand and separate the liquids, collect the aqueous phase, continue to extract the organic phase with water (100 mL×3), and combine the aqueous phases. After the aqueous phase is washed with dichloromethane (100 mL×3), adjust the pH>11 with 50% sodium hydroxide. After adjustment, stir at room temperature for 4 h, and a large amount of solid precipitates. Filter by suction, wash the filter cake with water (100 mL×3) and dry it in vacuo at 60 °C to obtain 9.58 g of white solid compound I, with a molar yield of 94.70% and HPLC purity>99.7%.

[0075] 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.10 (d, J = 1.48 Hz, 1H), 7.98-7.93 (m, 2H), 7.86 (d, J = 2.36 Hz, 1H), 6.97 (d, J = 2.36 Hz, 1H), 4.09-4.00(m, 2H), 3.32-3.24 (m, 1H), 2.69-2.51 (m, 2H), 1.00 (d, J = 6.44 Hz, 3H).

[0076] 13 C NMR (101 MHz, DMSO-d6) δ (ppm):147.61, 140.13, 136.33, 135.38,133.53, 126.02, 124.45, 116.67, 110.31, 104.55, 60.18, 47.66, 21.25.

[0077] ESI-MS (m / z): 262.1 [M+H] + .

[0078] Example 16

[0079] Add 27.71 mmol of compound 5 (Example 7) and 100 mL of dichloromethane to the reaction flask, stir at room temperature to dissolve. Slowly drop 60 mL of concentrated hydrochloric acid (37%) and control the internal temperature to 25-35 °C. After the addition is complete, stir at room temperature for 6 h. After the reaction is completed, stop stirring, let stand and separate the liquids, collect the aqueous phase, continue to extract the organic phase with water (100 mL×3), and combine the aqueous phases. After the aqueous phase is washed with dichloromethane (100 mL×3), adjust the pH>11 with 50% sodium hydroxide. After adjustment, stir at room temperature for 4 h, and a large amount of solid precipitates. Filter by suction, wash the filter cake with water (100 mL×3) and dry it in vacuo at 60 °C to obtain 7.02 g of white solid compound I, with a molar yield of 97.06% and HPLC purity>99.7%.

[0080] Embodiment 17

[0081] Add 2.77 mmol of compound 5 (Example 7) and 10 mL of dichloromethane to the reaction flask, stir at room temperature to dissolve. Slowly drop 6 mL of concentrated hydrochloric acid (37%) and control the internal temperature to <40 °C. After the addition is complete, stir at room temperature for 6 h. After the reaction is completed, stop stirring, let stand and separate the liquids, collect the aqueous phase, continue to extract the organic phase with water (10 mL×3), and combine the aqueous phases. After the aqueous phase is washed with dichloromethane (10 mL×3), adjust the pH>11 with 50% sodium hydroxide. After adjustment, stir at room temperature for 4 h, and a large amount of solid precipitates. Filter by suction, wash the filter cake with water (10 mL×3) and dry it in vacuo at 60 °C to obtain 0.70 g of white solid compound I, with a molar yield of 96.88% and HPLC purity>99.7%.

[0082] Embodiment 18

[0083] Add 27.71 mmol of compound 5 (Example 9) and 100 mL of dichloromethane to the reaction flask, stir at room temperature to dissolve. Slowly drop 80 mL of concentrated hydrochloric acid (37%) and control the internal temperature to 25-35 °C. After the addition is complete, stir at room temperature for 4 h. After the reaction is completed, stop stirring, let stand and separate the liquids, collect the aqueous phase, continue to extract the organic phase with water (100 mL×3), and combine the aqueous phases. After the aqueous phase is washed with dichloromethane (100 mL×3), adjust the pH>11 with 50% sodium hydroxide. After adjustment, stir at room temperature for 4 h, and a large amount of solid precipitates. Filter by suction, wash the filter cake with water (100 mL×3) and dry it in vacuo at 60 °C to obtain 6.99 g of white solid compound I, with a molar yield of 96.74% and HPLC purity>99.7%.

[0084] Embodiment 19

[0085] Add 27.71 mmol of compound 5 (Example 10) and 100 mL of ethyl acetate to the reaction flask, stir at room temperature to dissolve. Slowly drop 600 mL of concentrated hydrochloric acid (37%) and control the internal temperature to 25-35 °C. After the addition is complete, stir at room temperature for 6 h. After the reaction is completed, stop stirring, let stand for separation, collect the aqueous phase, continue to extract the organic phase with water (100 mL×3), and combine the aqueous phases. After the aqueous phase is washed with dichloromethane (100 mL×3), adjust the pH>11 with 50% sodium hydroxide. After adjustment, stir at room temperature for 4 h, and a large amount of solid precipitates. Filter by suction, wash the filter cake with water (100 mL×3) and dry it in vacuo at 60 °C to obtain 6.57 g of white solid compound I, with a molar yield of 90.93% and HPLC purity>99.7%.

[0086] Embodiment 20

[0087] Add 27.71 mmol of compound 5 (Example 11) and 100 mL of dichloromethane to the reaction flask, stir at room temperature to dissolve. Slowly drop 60 mL of concentrated hydrochloric acid (37%) and control the internal temperature to 40-50 °C. After the addition is complete, stir at room temperature for 4 h. After the reaction is completed, stop stirring, let stand for separation, collect the aqueous phase, continue to extract the organic phase with water (100 mL×3), and combine the aqueous phases. After the aqueous phase is washed with dichloromethane (100 mL×3), adjust the pH>11 with 50% sodium hydroxide. After adjustment, stir at room temperature for 4 h, and a large amount of solid precipitates. Filter by suction, wash the filter cake with water (100 mL×3) and dry it in vacuo at 60 °C to obtain 6.73 g of white solid compound I, with a molar yield of 93.14% and HPLC purity>99.7%.

[0088] Embodiment 21

[0089] Add 27.71 mmol of compound 5 (Example 12) and 100 mL of dichloromethane to the reaction flask, stir at room temperature to dissolve. Slowly drop 600 mL of concentrated hydrochloric acid (37%) and control the internal temperature to 40-50 °C. After the addition is complete, stir at room temperature for 24 h. After the reaction is completed, stop stirring, let stand for separation, collect the aqueous phase, continue to extract the organic phase with water (100 mL×3), and combine the aqueous phases. After washing the aqueous phase with dichloromethane (100 mL×3), adjust the pH>11 with 50% sodium hydroxide. After adjustment, stir at room temperature for 4 h, and a large amount of solid precipitates. Filter by suction, wash the filter cake with water (100 mL×3) and dry it in vacuo at 60 °C to obtain 7.03 g of white solid compound I, with a molar yield of 97.29% and HPLC purity>99.7%.

[0090] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing a key intermediate of darolamide, (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile, characterized in that: The following steps are involved: 1) Compound 1 is used as a starting material, reacted with compound 2 in the presence of an acid-binding agent at room temperature, and then post-treated to obtain compound 3; 2) Compound 3 obtained in step 1) is used as a raw material, reacted with compound 4 in the presence of a catalyst, and then subjected to post-treatment to obtain compound 5; 3) Compound 5 obtained in step 2) is used as a raw material and hydrolyzed under acidic conditions to obtain compound I; The reaction formula is as follows: 。 2. The method for preparing the key intermediate of darolamide (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile according to claim 1, characterized in that: The acid binding agent in step 1) is selected from at least one of potassium carbonate, cesium carbonate, DBU and DIEA.

3. The method for preparing the key intermediate of darolamide (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile according to claim 1, characterized in that: The step 1) is carried out in an organic solvent, and the organic solvent used is selected from at least one of N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, N-methylpyrrolidone, dichloromethane and acetone.

4. The method for preparing the key intermediate of darolamide (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile according to claim 1, characterized in that: In the step 1), the molar amount of compound 2 is 100% to 300%; the molar amount of the acid binding agent is 100% to 300%.

5. The method for preparing the key intermediate of darolamide (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile according to claim 1, characterized in that: The catalyst in step 2) is selected from at least one of bistriphenylphosphine palladium dichloride, tetrakistriphenylphosphine palladium, palladium chloride, and palladium acetate; the base in the reaction is selected from at least one of potassium carbonate, cesium carbonate, potassium phosphate, and sodium acetate.

6. The method for preparing the key intermediate of darolamide (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile according to claim 1, characterized in that: The step 2) is carried out in an organic solvent, and the organic solvent used is selected from at least one of toluene, dioxane, tetrahydrofuran, acetonitrile, purified water, or a mixture of two thereof.

7. The method for preparing the key intermediate of darolamide (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile according to claim 1, characterized in that: The molar amount of compound 4 in step 2) is 100% to 150%; the molar amount of the catalyst is 10% to 20%; the molar amount of the base is 150% to 200%; and the reaction temperature is 90 to 100°C.

8. The method for preparing the key intermediate of darolamide (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile according to claim 1, characterized in that: The molar amount of the acid in step 3) is 1000% to 1500%.

9. The method for preparing the key intermediate of darolamide (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile according to claim 1, characterized in that: The step 3) is carried out in an organic solvent, and the organic solvent used is at least one selected from dichloromethane, ethyl acetate, methanol, and ethanol.

10. The method for preparing the key intermediate of darolamide (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile according to claim 1, characterized in that: The reaction temperature of step 3) is 0-40°C; the reaction time is 4-24 h.

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