Novel method for preparing zalvizepam intermediate

Abstract

The invention discloses a novel method for preparing a zavigepam intermediate, the intermediate is 3-(piperidine-4-yl)-1, 2-dihydroquinoline-2-one hydrochloride, and the preparation method of the intermediate comprises the following steps: taking a piperidine-4-acetic acid derivative and aniline as initial raw materials, and sequentially carrying out condensation reaction, cyclization reaction and hydrolysis reaction to obtain the 3-(piperidine-4-yl)-1, 2-dihydroquinoline-2-one hydrochloride. The invention further discloses a preparation method of the 2, 2-dihydroquinoline-2-ketone hydrochloride. The preparation method provided by the invention has the advantages of short steps, cheap and easily available raw materials, low cost, avoidance of cryogenic reaction, low requirements on equipment, high product yield and purity, and suitableness for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical intermediate synthesis, and specifically relates to a new method for preparing a zavirigopam intermediate. Background Art

[0002] Migraine is the most common chronic neurovascular disease in the world, characterized by recurrent attacks of moderate to severe unilateral or throbbing headaches, often accompanied by symptoms such as nausea and sensitivity to light or sound.

[0003] Zavigipan is a novel calcium gene-related peptide (CGRP) receptor antagonist used to treat migraine. Zavigipan ((R)-N-(3-(7-methyl-1H indazol-5-yl)-1-(4-(1-methylpiperidin-4-yl) piperazin-1-yl)-1-oxopropan-2-yl)-4-(2-oxo-1,2-dihydroquinolin-3-yl) piperidine-1-carboxamide) is a third-generation high-affinity, highly selective small molecule CGRP receptor antagonist used for the acute treatment of adult migraine with or without aura. This product is also a CGRP receptor antagonist nasal spray for the acute treatment of adult migraine, and its molecular formula is shown below:

[0004]

[0005] 3-(Piperidin-4-yl)-1,2-dihydroquinolin-2-one hydrochloride is an important intermediate for the synthesis of zavirigepam, and its structural formula is as follows:

[0006]

[0007] At present, there are two main synthetic routes for the Zavigipan intermediate:

[0008] In 2022, Biohaven (US20220401439) reported a synthetic route for the intermediate of zavigipan: using N-Boc-4-piperidone as the starting material, 3-(piperidin-4-yl)-1,2-dihydroquinolin-2-one hydrochloride was obtained through coupling, hydrogenation, condensation, cyclization, and deprotection. This synthetic route has a long process, requires deep cooling reaction, and has high requirements for production equipment.

[0009]

[0010] In 2005, Merck & Co. (WO 2005000807) reported the synthesis of benzodiazepine CGRP receptor antagonists, which involved the synthesis of this intermediate. This synthesis route also involves deep cold reaction, high requirements for production equipment, expensive raw materials, and high production costs.

[0011]

[0012] In view of the problems existing in the above synthesis methods, such as expensive raw materials, long synthesis steps, high requirements for production equipment, and high production costs, the present invention patent has developed a preparation method for an important intermediate of Zavigipan with easily available raw materials, simple process, and economic and environmental protection. Summary of the invention

[0013] In view of the problems existing in the prior art, the purpose of the present invention is to provide a new preparation method of 3-(piperidin-4-yl)-1,2-dihydroquinolin-2-one hydrochloride (I), an important intermediate of zavidipam. The preparation method has short steps, cheap and easily available raw materials, low cost, avoids deep cold reaction, has low requirements on equipment, has high product yield and purity, and is suitable for industrial production.

[0014] To achieve the above object, the technical solution of the present invention is as follows:

[0015] A new method for preparing a zavigipan intermediate, wherein the intermediate is 3-(piperidin-4-yl)-1,2-dihydroquinolin-2-one hydrochloride, and its structural formula is shown in formula (I). Piperidin-4-acetic acid derivative (II) and aniline (III) are used as starting materials, and 3-(piperidin-4-yl)-1,2-dihydroquinolin-2-one hydrochloride (I) is prepared by sequentially undergoing condensation reaction, cyclization reaction, and hydrolysis reaction. The new method for preparing the intermediate comprises the following steps:

[0016] 1) Adding the compounds represented by formula (II) and formula (III) into solvent A, causing condensation reaction under the action of condensation reagent, auxiliary condensation reagent and base, and after the reaction, washing with dilute hydrochloric acid, washing with water, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, concentrating and purifying to obtain the compound represented by formula (IV);

[0017] 2) then adding the compound of formula (IV) obtained in step 1) to the prepared Vilsmeier reagent to carry out a cyclization reaction, after the reaction is completed, the phosphorus oxychloride is removed by concentration, dichloromethane is added, the solid is removed by filtration, the pH value is adjusted with a base, the liquid is separated, concentrated, and purified to obtain the compound of formula (V);

[0018] 3) adding concentrated hydrochloric acid to the compound represented by formula (V) obtained in step 2) to carry out a hydrolysis reaction, concentrating to remove the hydrochloric acid after the reaction, filtering and purifying to obtain the compound represented by formula (I);

[0019] The reaction process is as follows:

[0020]

[0021] In the formula (I), R is tert-butyloxycarbonyl (Boc) or benzyloxycarbonyl (Cbz).

[0022] Furthermore, the solvent A in step 1) is one of dichloromethane, ethyl acetate, N,N-dimethylformamide, tetrahydrofuran, acetonitrile and toluene; the condensation reagent is N,N'-dicyclohexylcarbodiimide (DCC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI); the auxiliary condensation reagent is 1-hydroxybenzotriazole (HOBT) or N-hydroxysuccinimide (NHS); the base is triethylamine or sodium carbonate; and the temperature of the condensation reaction is 10 to 60°C.

[0023] Furthermore, in step 1), when solvent A is N,N-dimethylformamide, tetrahydrofuran or acetonitrile, an auxiliary solvent is added, and the auxiliary solvent is dichloromethane or ethyl acetate.

[0024] Furthermore, in step 1), the molar ratio of the compound represented by formula (II) to the compound represented by formula (III), the condensation reagent and the base is 1:1-1.5:1-1.8:1-2.4.

[0025] Furthermore, in step 2), Vilsmeier reagent is prepared by reacting phosphorus oxychloride with N,N-dimethylformamide.

[0026] Furthermore, the temperature of the cyclization reaction in step 2) is 55-100°C.

[0027] Furthermore, in step 2), the molar ratio of the compound represented by formula (IV) to N,N-dimethylformamide and phosphorus oxychloride is 1:2-6:5-15.

[0028] Furthermore, in step 2) and step 3), the concentration of concentrated hydrochloric acid is 4-8 mol / L, and the hydrolysis reaction temperature is 60-100°C.

[0029] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0030] 1) The present invention uses piperidine-4-acetic acid derivatives and aniline as starting materials, and sequentially undergoes condensation reaction, cyclization reaction, and hydrolysis reaction to prepare 3-(piperidin-4-yl)-1,2-dihydroquinolin-2-one hydrochloride. The preparation method of the present invention has short steps, cheap and readily available raw materials, low cost, avoids deep cooling reaction, has low requirements on equipment, has high product yield and purity, and is suitable for industrial production;

[0031] 2) The present invention has simple process, simple operation, mild reaction conditions, cheap and readily available raw materials, low production cost, avoids deep cold reaction, has low requirements on production equipment, avoids the use of highly active lithium reagents, and has high operation safety. DETAILED DESCRIPTION

[0032] The present invention will be further described below in conjunction with embodiments, but the scope of protection of the present invention is not limited to the described scope.

[0033]

[0034] Example 1 Preparation of tert-butyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-a)

[0035] In a 50mL three-necked flask with magnetic stirring and a thermometer, 1-Boc-4-piperidineacetic acid (2.43g, 10mmol) of formula (II-a), condensing agent EDCI (2.30g, 12mmol), auxiliary condensing agent HOBT (0.68g, 5mmol), base triethylamine (1.21g, 12mmol) and solvent A dichloromethane 30mL were added and stirred for 30min. Aniline (1.12g, 12mmol) of formula (III) was added and kept warm at 10°C. The reaction was monitored by TLC until completion. The product was washed with appropriate amounts of 0.5mol / L hydrochloric acid solution, water and saturated sodium chloride solution in sequence, and then dried over anhydrous sodium sulfate (3g). After concentration, the product was recrystallized from ethyl acetate to obtain tert-butyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-a) with a yield of 84.2% and a purity of 99.7%.

[0036] LC-MS (m / z): 319.6 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ9.86(s,1H),7.61–7.55(m,2H),7.30–7.24(m,2H),7.02(m,1H),3.91(d,J=13.0H z, 2H), 2.71 (s, 2H), 2.23 (d, J = 7.1Hz, 2H), 1.92 (m, 1H), 1.64 (d, J = 12.8Hz, 2H), 1.39 (s, 9H), 1.06 (m, 2H).

[0037] Example 2 Preparation of tert-butyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-a)

[0038] In a 50mL three-necked flask with magnetic stirring and a thermometer, 1-Boc-4-piperidineacetic acid (2.43g, 10mmol) of formula (II-a), condensing agent EDCI (2.30g, 12mmol), auxiliary condensing agent HOBT (0.68g, 5mmol), base triethylamine (1.21g, 12mmol) and solvent A ethyl acetate 30mL were added and stirred for 30min. Aniline (0.93g, 10mmol) of formula (III) was added and kept warm at 20°C. The reaction was monitored by TLC until completion. The product was washed with appropriate amounts of 0.5mol / L hydrochloric acid solution, water and saturated sodium chloride solution in sequence, and then dried over anhydrous sodium sulfate (3g). After concentration, the product was recrystallized from ethyl acetate to obtain tert-butyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-a) with a yield of 86.4% and a purity of 99.7%.

[0039] Example 3 Preparation of tert-butyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-a)

[0040] In a 50 mL three-necked flask with magnetic stirring and a thermometer, 1-Boc-4-piperidineacetic acid (2.43 g, 10 mmol) of formula (II-a), condensing agent EDCI (2.30 g, 12 mmol), auxiliary condensing agent HOBT (0.68 g, 5 mmol), base triethylamine (1.21 g, 12 mmol) and solvent AN, 30 mL of N-dimethylformamide were added, stirred for 30 min, aniline (0.75 g, 8 mmol) of formula (III) was added, and the mixture was kept warm at 30 °C. TLC was performed. After monitoring the completion of the reaction, the reaction solution was concentrated and 30 mL of dichloromethane was added. The original solvent was miscible with water. The concentrated product became a viscous oil. After adding dichloromethane to dissolve, it was convenient to carry out the subsequent extraction process. It was washed with appropriate amounts of 0.5 mol / L hydrochloric acid solution, water, and saturated sodium chloride solution in sequence, and then dried over anhydrous sodium sulfate (3 g). After concentration, it was recrystallized from ethyl acetate to obtain tert-butyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-a) with a yield of 72.6% and a purity of 99.6%.

[0041] Example 4 Preparation of tert-butyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-a)

[0042] In a 50 mL three-necked flask with a magnetic stirrer and a thermometer, 1-Boc-4-piperidineacetic acid (2.43 g, 10 mmol) of formula (II-a), EDCI (2.88 g, 15 mmol), HOBT (1.35 g, 10 mmol), triethylamine (1.21 g, 12 mmol) and 30 mL of tetrahydrofuran were added, and the mixture was stirred for 30 min. Aniline (0.93 g, 10 mmol) of formula (III) was added, and the mixture was kept warm at 30° C. The reaction was monitored by TLC until completion. After the reaction solution was concentrated, 30 mL of dichloromethane was added, and the mixture was washed with appropriate amounts of 0.5 mol / L hydrochloric acid solution, water, and saturated sodium chloride solution in sequence, and then dried over anhydrous sodium sulfate (3 g). After concentration, the mixture was recrystallized from ethyl acetate to obtain tert-butyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-a) with a yield of 78.4% and a purity of 99.6%.

[0043] Example 5 Preparation of tert-butyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-a)

[0044] In a 50 mL three-necked flask with a magnetic stirrer and a thermometer, 1-Boc-4-piperidineacetic acid (2.43 g, 10 mmol) of formula (II-a), EDCI (1.92 g, 10 mmol), HOBT (1.35 g, 10 mmol), triethylamine (1.21 g, 12 mmol) and 30 mL of acetonitrile were added and stirred for 30 min. Aniline (1.12 g, 12 mmol) of formula (III) was added and kept warm at 30°C. The reaction was monitored by TLC until completion. After concentrating the reaction solution, 30 mL of dichloromethane was added, and the solution was washed with appropriate amounts of 0.5 mol / L hydrochloric acid solution, water, and saturated sodium chloride solution in sequence, and then dried over anhydrous sodium sulfate (3 g). After concentrating, the solution was recrystallized from ethyl acetate to obtain tert-butyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-a) with a yield of 82.1% and a purity of 99.6%.

[0045] Example 6 Preparation of 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylic acid benzyl ester (IV-b)

[0046] In a 50mL three-necked flask with a magnetic stirrer and a thermometer, 1-Cbz-4-piperidineacetic acid (2.77g, 10mmol) of formula (II-b), EDCI (2.30g, 12mmol), HOBT (0.68g, 5mmol), triethylamine (1.21g, 12mmol) and 30mL of toluene were added, and the mixture was stirred for 30min. Aniline (1.21g, 13mmol) of formula (III) was added, and the mixture was kept warm at 50°C. The reaction was monitored by TLC until completion. The mixture was washed with appropriate amounts of 0.5mol / L hydrochloric acid solution, water, and saturated sodium chloride solution, and then dried over anhydrous sodium sulfate (3g). After concentration, the mixture was recrystallized from ethyl acetate to obtain benzyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-b) with a yield of 83.3% and a purity of 99.7%.

[0047] LC-MS (m / z): 353.6 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ9.88(s,1H),7.67–7.49(m,2H),7.43–7.20(m,6H),7.09–6.94(m,1H),5.06( s,2H),3.99(m,2H),2.82(s,2H),2.24(d,J=7.1Hz,2H),1.96(m,1H),1.72–1.62(m,2H),1.10(m,2H).

[0048] Example 7 Preparation of tert-butyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-a)

[0049] In a 50mL three-necked flask with magnetic stirring and a thermometer, 1-Boc-4-piperidineacetic acid (2.43g, 10mmol) of formula (II-a), EDCI (2.30g, 12mmol), HOBT (1.35g, 10mmol), triethylamine (1.01g, 10mmol) and 30mL of dichloromethane were added and stirred for 30min. Aniline (1.12g, 12mmol) of formula (III) was added and kept warm at 30°C. The reaction was monitored by TLC until completion. The mixture was washed with appropriate amounts of 0.5mol / L hydrochloric acid solution, water and saturated sodium chloride solution in sequence, and then dried over anhydrous sodium sulfate (3g). After concentration, the mixture was recrystallized from ethyl acetate to obtain tert-butyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-a) with a yield of 91.1% and a purity of 99.6%.

[0050] Example 8 Preparation of 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylic acid benzyl ester (IV-b)

[0051] In a 50 mL three-necked flask with a magnetic stirrer and a thermometer, 1-Cbz-4-piperidineacetic acid (2.77 g, 10 mmol) of formula (II-b), EDCI (2.30 g, 12 mmol), HOBT (1.35 g, 10 mmol), triethylamine (1.01 g, 10 mmol) and 30 mL of dichloromethane were added and stirred for 30 min. Aniline (1.12 g, 12 mmol) of formula (III) was added and kept warm at 30°C. The reaction was monitored by TLC until completion. The mixture was washed with appropriate amounts of 0.5 mol / L hydrochloric acid solution, water and saturated sodium chloride solution in sequence, and then dried over anhydrous sodium sulfate (3 g). After concentration, the mixture was recrystallized from ethyl acetate to obtain benzyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-b) with a yield of 91.3% and a purity of 99.8%.

[0052] Example 9 Preparation of tert-butyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-a)

[0053] In a 50 mL three-necked flask equipped with a magnetic stirrer and a thermometer, 1-Boc-4-piperidineacetic acid (2.43 g, 10 mmol) of formula (II-a), NHS N-hydroxysuccinimide (1.15 g, 10 mmol) and 30 mL of dichloromethane, solvent A, were added dropwise with condensing agent DCC (2.33 g, 12 mmol), stirred at 10°C, and the substrate was completely consumed as monitored by TLC. The solid was removed by filtration, and the reaction solution was reserved for use. In another 100 mL three-necked flask with a magnetic stirrer and a thermometer, sodium carbonate (2.54 g, 24 mmol), 30 mL of water and aniline (III) (1.12 g, 12 mmol) were added dropwise, and the reaction solution was then added dropwise. The mixture was stirred at 10°C, and the reaction was completed as monitored by TLC. The mixture was washed with appropriate amounts of 0.5 mol / L hydrochloric acid solution, water and saturated sodium chloride solution in sequence, and then dried over anhydrous sodium sulfate (3 g). After concentration, the mixture was recrystallized from ethyl acetate to obtain tert-butyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-a) with a yield of 84.6% and a purity of 99.6%.

[0054] Example 10 Preparation of tert-butyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-a)

[0055] In a 50mL three-necked flask with a magnetic stirrer and a thermometer, 1-Boc-4-piperidineacetic acid (2.43 g, 10 mmol) of formula (II-a), NHS (1.15 g, 10 mmol) and 30 mL of toluene were added, and DCC (2.53 g, 13 mmol) was added dropwise. The mixture was stirred at 60°C and the substrate was completely consumed after monitoring by TLC. The solid was filtered out and the reaction solution was reserved for later use. Sodium carbonate (2.54 g, 13 mmol) was added to another 100mL three-necked flask with a magnetic stirrer and a thermometer. , 24mmol), 30mL of water and aniline of formula (III) (0.93g, 10mmol), then dropwise add the above reaction solution, stir at 60°C, monitor the completion of the reaction by TLC, wash with appropriate amounts of 0.5mol / L hydrochloric acid solution, water, and saturated sodium chloride solution in sequence, and then dry over anhydrous sodium sulfate (3g), concentrate and recrystallize from ethyl acetate to obtain tert-butyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-a), with a yield of 83.7% and a purity of 99.7%.

[0056] Example 11 Preparation of 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylic acid benzyl ester (IV-b)

[0057] In a 50mL three-necked flask with a magnetic stirrer and a thermometer, add 1-Cbz-4-piperidineacetic acid (2.77 g, 10 mmol) of formula (II-b), NHS (1.15 g, 10 mmol) and 30 mL of ethyl acetate, add DCC (1.94 g, 10 mmol) dropwise, stir at 30°C, monitor the complete consumption of the substrate by TLC, filter out the solid, and keep the reaction solution for later use; take another 100mL three-necked flask with a magnetic stirrer and a thermometer, add sodium carbonate (2.54 g, 24mmol), 30mL of water and aniline of formula (III) (1.12g, 12mmol), then dropwise add the above reaction solution, stir at 30°C, monitor the completion of the reaction by TLC, wash with appropriate amounts of 0.5mol / L hydrochloric acid solution, water, and saturated sodium chloride solution in sequence, and then dry over anhydrous sodium sulfate (3g), concentrate, and recrystallize from ethyl acetate to obtain 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylic acid benzyl ester (IV-b) with a yield of 86.6% and a purity of 99.7%.

[0058] Example 12 Preparation of 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylic acid benzyl ester (IV-b)

[0059] In a 50mL three-necked flask with a magnetic stirrer and a thermometer, 1-Cbz-4-piperidineacetic acid (2.77 g, 10 mmol) of formula (II-b), NHS (1.15 g, 10 mmol) and 30 mL of ethyl acetate were added, and DCC (2.33 g, 12 mmol) was added dropwise. The mixture was stirred at 40°C and the substrate was completely consumed after monitoring by TLC. The solid was removed by filtration and the reaction solution was kept for later use. In another 100mL three-necked flask with a magnetic stirrer and a thermometer, sodium carbonate (1.27 g, 12 mmol), 30 mL of water and aniline (III) (0.93 g, 10 mmol) were added dropwise, and the reaction solution was then added dropwise. The mixture was stirred at 40°C and the reaction was completed after monitoring by TLC. The residue was washed with appropriate amount of 0.5 mol / L hydrochloric acid solution, water and saturated sodium chloride solution in sequence, and then dried over anhydrous sodium sulfate (3 g). After concentration, it was recrystallized from ethyl acetate to obtain 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylic acid benzyl ester (IV-b) with a yield of 85.1% and a purity of 99.6%.

[0060] Example 13 Preparation of tert-butyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-a)

[0061] In a 50mL three-necked flask with a magnetic stirrer and a thermometer, add 1-Boc-4-piperidineacetic acid (2.43 g, 10 mmol) of formula (II-a), NHS (1.15 g, 10 mmol) and 30 mL of dichloromethane, add DCC (2.33 g, 12 mmol) dropwise, stir at 30°C, monitor the complete consumption of the substrate by TLC, filter out the solid, and keep the reaction solution for later use; take another 100mL three-necked flask with a magnetic stirrer and a thermometer, add sodium carbonate (2.54 g, 24mmol), 30mL of water and aniline of formula (III) (1.12g, 12mmol), then dropwise add the above reaction solution, stir at 30°C, monitor the completion of the reaction by TLC, wash with appropriate amounts of 0.5mol / L hydrochloric acid solution, water, and saturated sodium chloride solution in sequence, and then dry over anhydrous sodium sulfate (3g). After concentration, recrystallize from ethyl acetate to obtain tert-butyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-a) with a yield of 90.2% and a purity of 99.6%.

[0062] Example 14 Preparation of 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylic acid benzyl ester (IV-b)

[0063] In a 50mL three-necked flask with a magnetic stirrer and a thermometer, add 1-Cbz-4-piperidineacetic acid (2.77 g, 10 mmol) of formula (II-b), NHS (1.15 g, 10 mmol) and 30 mL of dichloromethane, add DCC (2.33 g, 12 mmol) dropwise, stir at 30°C, monitor the complete consumption of the substrate by TLC, filter out the solid, and keep the reaction solution for later use; in another 100mL three-necked flask with a magnetic stirrer and a thermometer, add sodium carbonate (2.54 g, 24mmol), 30mL of water and aniline of formula (III) (1.12g, 12mmol), then dropwise add the above reaction solution, stir at 30°C, monitor the completion of the reaction by TLC, wash with appropriate amounts of 0.5mol / L hydrochloric acid solution, water, and saturated sodium chloride solution in sequence, and then dry over anhydrous sodium sulfate (3g). After concentration, recrystallize from ethyl acetate to obtain 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylic acid benzyl ester (IV-b) with a yield of 92.2% and a purity of 99.8%.

[0064]

[0065] Example 15 Preparation of 4-(2-chloroquinolin-3-yl)piperidine-1-carboxaldehyde (V)

[0066] N,N-dimethylformamide (2.19 g, 30 mmol) was added to a 50 mL three-necked flask with a magnetic stirrer and a thermometer, and the mixture was cooled to 0°C. Phosphorus oxychloride (10.73 g, 70 mmol) was added dropwise under stirring. The mixture was stirred for 30 min, tert-butyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-a) (3.18 g, 10 mmol) was added, the temperature was slowly increased, and the mixture was kept at 75°C for 16 h. The reaction was completed by monitoring by TLC. The phosphorus oxychloride was removed by concentration, dichloromethane was added, the solid was removed by filtration, the pH was adjusted to 10 with 10% NaOH solution, the mixture was separated, concentrated, and purified by column chromatography to obtain 4-(2-chloroquinoline-3-yl)piperidine-1-carboxaldehyde (V) with a yield of 60.5% and a purity of 99.8%.

[0067] LC-MS(m / z):275.4[M+H]+; 1H NMR (400MHz, DMSO-d6) δ8.41(s,1H),8.07(s,1H),8.00(dd,J=8.2,1.4Hz,1H),7.93(dd,J=8.4,1.1Hz,1H),7.78(m,1H), 7.65(m,1H),4.43-4.34(m,1H),3.91-3.82(m,1H),3.32-3.20(m,2H),2.78(m,1H),2.04-1.92(m,2H),1.71-1.49(m,2H).

[0068] Example 16 Preparation of 4-(2-chloroquinolin-3-yl)piperidine-1-carboxaldehyde (V)

[0069] N,N-dimethylformamide (2.92 g, 40 mmol) was added to a 50 mL three-necked flask with a magnetic stirrer and a thermometer, and the mixture was cooled to 0°C. Phosphorus oxychloride (15.33 g, 100 mmol) was added dropwise under stirring. The mixture was stirred for 30 min, tert-butyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-a) (3.18 g, 10 mmol) was added, the temperature was slowly increased, and the mixture was kept at 85°C for 16 h. The reaction was completed by monitoring by TLC. The phosphorus oxychloride was removed by concentration, dichloromethane was added, the solid was removed by filtration, the pH was adjusted to 10 with 10% NaOH solution, the mixture was separated, concentrated, and purified by column chromatography to obtain 4-(2-chloroquinoline-3-yl)piperidine-1-carboxaldehyde (V) with a yield of 62.0% and a purity of 99.8%.

[0070] Example 17 Preparation of 4-(2-chloroquinolin-3-yl)piperidine-1-carboxaldehyde (V)

[0071] N,N-dimethylformamide (1.46 g, 20 mmol) was added to a 50 mL three-necked flask with a magnetic stirrer and a thermometer, and the mixture was cooled to 0°C. Phosphorus oxychloride (12.27 g, 80 mmol) was added dropwise under stirring. The mixture was stirred for 30 min, tert-butyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-a) (3.18 g, 10 mmol) was added, the temperature was slowly increased, and the mixture was kept at 85°C for 16 h. The reaction was completed after monitoring by TLC. The phosphorus oxychloride was removed by concentration, dichloromethane was added, the solid was removed by filtration, the pH was adjusted to 10 with 10% NaOH solution, the mixture was separated, concentrated, and purified by column chromatography to obtain 4-(2-chloroquinoline-3-yl)piperidine-1-carboxaldehyde (V) with a yield of 46.6% and a purity of 99.8%.

[0072] Example 18 Preparation of 4-(2-chloroquinolin-3-yl)piperidine-1-carboxaldehyde (V)

[0073] N,N-dimethylformamide (2.19 g, 30 mmol) was added to a 50 mL three-necked flask with a magnetic stirrer and a thermometer, and the mixture was cooled to 0°C. Phosphorus oxychloride (10.73 g, 70 mmol) was added dropwise under stirring. The mixture was stirred for 30 min, tert-butyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-a) (3.18 g, 10 mmol) was added, the temperature was slowly increased, and the mixture was kept at 65°C for 16 h. The reaction was completed by monitoring by TLC. The phosphorus oxychloride was removed by concentration, dichloromethane was added, the solid was removed by filtration, the pH was adjusted to 10 with 10% NaOH solution, the mixture was separated, concentrated, and purified by column chromatography to obtain 4-(2-chloroquinoline-3-yl)piperidine-1-carboxaldehyde (V) with a yield of 33.4% and a purity of 99.8%.

[0074] Example 19 Preparation of 4-(2-chloroquinolin-3-yl)piperidine-1-carboxaldehyde (V)

[0075] N,N-dimethylformamide (2.92 g, 40 mmol) was added to a 50 mL three-necked flask with a magnetic stirrer and a thermometer, and the mixture was cooled to 0°C. Phosphorus oxychloride (10.73 g, 70 mmol) was added dropwise under stirring. The mixture was stirred for 30 min, and 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylic acid benzyl ester (IV-b) (3.52 g, 10 mmol) was added. The temperature was slowly raised and kept at 95°C for 16 h. The reaction was completed by monitoring by TLC. The phosphorus oxychloride was removed by concentration, and dichloromethane was added. The solid was removed by filtration. The pH value was adjusted to 10 with 10% NaOH solution. The mixture was separated, concentrated, and purified by column chromatography to obtain 4-(2-chloroquinoline-3-yl)piperidine-1-carboxaldehyde (V) with a yield of 62.3% and a purity of 99.7%.

[0076] Example 20 Preparation of 4-(2-chloroquinolin-3-yl)piperidine-1-carboxaldehyde (V)

[0077] Add N,N-dimethylformamide (2.92 g, 40 mmol) to a 50 mL three-necked flask with a magnetic stirrer and a thermometer, cool to 0°C, add phosphorus oxychloride (15.33 g, 100 mmol) dropwise under stirring, stir for 30 min, add 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylic acid benzyl ester (IV-b) (3.52 g, 10 mmol), slowly heat up, keep at 75°C for 16 h, and monitor the reaction by TLC. Concentrate to remove phosphorus oxychloride, add dichloromethane, filter to remove solids, adjust pH to 10 with 10% NaOH solution, separate, concentrate, and purify by column chromatography to obtain 4-(2-chloroquinoline-3-yl)piperidine-1-carboxaldehyde (V), with a yield of 60.4% and a purity of 99.8%.

[0078]

[0079] Example 21 Preparation of 3-(piperidin-4-yl)-1,2-dihydroquinolin-2-one hydrochloride (I)

[0080] In a 50mL three-necked flask with magnetic stirring and a thermometer, add 4-(2-chloroquinoline-3-yl)piperidine-1-carboxaldehyde (V) (2.75g, 10mmol) and 30mL of 8mol / L hydrochloric acid, and keep at 80℃ for 8h. After the reaction is completed, the reaction solution is concentrated and recrystallized from 5% water-isopropanol to obtain 3-(piperidin-4-yl)-1,2-dihydroquinoline-2-one hydrochloride (I), with a yield of 67.2% and a purity of 99.6%.

[0081] LC-MS (m / z): 229.4 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ11.86(s,1H),9.10(s,1H),8.99(d,J=11.3Hz,1H),7.72–7.65(m,2H),7.4 5(m,1H),7.33–7.28(m,1H),7.16(m,1H),3.07–2.94(m,3H),2.00(d,J=13.4Hz,2H),1.83(m,2H).

[0082] Example 22 Preparation of 3-(piperidin-4-yl)-1,2-dihydroquinolin-2-one hydrochloride (I)

[0083] In a 50mL three-necked flask with magnetic stirring and a thermometer, 4-(2-chloroquinoline-3-yl)piperidine-1-carboxaldehyde (V) (2.75 g, 10 mmol) and 30 mL of 6 mol / L hydrochloric acid were added and kept at 70°C for 8 h. After the reaction was completed, the reaction solution was concentrated and recrystallized from 5% water-isopropanol to obtain 3-(piperidin-4-yl)-1,2-dihydroquinoline-2-one hydrochloride (I) with a yield of 53.8% and a purity of 99.6%.

[0084] Example 23 Preparation of 3-(piperidin-4-yl)-1,2-dihydroquinolin-2-one hydrochloride (I)

[0085] In a 50mL three-necked flask with magnetic stirring and a thermometer, add 4-(2-chloroquinoline-3-yl)piperidine-1-carboxaldehyde (V) (2.75g, 10mmol) and 30mL of 6mol / L hydrochloric acid, and reflux at 100°C for 8h. After the reaction is completed, the reaction solution is concentrated and recrystallized from 5% water-isopropanol to obtain 3-(piperidin-4-yl)-1,2-dihydroquinoline-2-one hydrochloride (I), with a yield of 88.3% and a purity of 99.6%.

[0086] Example 24 Preparation of 3-(piperidin-4-yl)-1,2-dihydroquinolin-2-one hydrochloride (I)

[0087] In a 50mL three-necked flask with magnetic stirring and a thermometer, add 4-(2-chloroquinoline-3-yl)piperidine-1-carboxaldehyde (V) (2.75g, 10mmol) and 30mL of 4mol / L hydrochloric acid, and reflux at 100°C for 8h. After the reaction is completed, the reaction solution is concentrated and recrystallized from 5% water-isopropanol to obtain 3-(piperidin-4-yl)-1,2-dihydroquinoline-2-one hydrochloride (I), with a yield of 81.6% and a purity of 99.6%.

Claims

1. A novel method for preparing a zavigipan intermediate, wherein the intermediate is 3-(piperidin-4-yl)-1,2-dihydroquinolin-2-one hydrochloride, and its structural formula is shown in formula (I). Piperidin-4-acetic acid derivative (II) and aniline (III) are used as starting materials, and 3-(piperidin-4-yl)-1,2-dihydroquinolin-2-one hydrochloride (I) is prepared by condensation reaction, cyclization reaction, and hydrolysis reaction in sequence, wherein: The novel method for preparing the intermediate comprises the following steps: 1) Adding the compounds represented by formula (II) and formula (III) into solvent A, causing condensation reaction under the action of condensation reagent, auxiliary condensation reagent and base, and after the reaction, washing with dilute hydrochloric acid, washing with water, washing with saturated sodium chloride solution, drying with anhydrous sodium sulfate, concentrating and purifying to obtain the compound represented by formula (IV); 2) then adding the compound of formula (IV) obtained in step 1) to the prepared Vilsmeier reagent to carry out a cyclization reaction, after the reaction is completed, the phosphorus oxychloride is removed by concentration, dichloromethane is added, the solid is removed by filtration, the pH value is adjusted with a base, the liquid is separated, concentrated, and purified to obtain the compound of formula (V); 3) adding concentrated hydrochloric acid to the compound represented by formula (V) obtained in step 2) to carry out a hydrolysis reaction, concentrating to remove the hydrochloric acid after the reaction, filtering and purifying to obtain the compound represented by formula (I); The reaction process is as follows: In the formula (I), R is tert-butyloxycarbonyl or benzyloxycarbonyl.

2. A novel method for preparing a zavigipan intermediate according to claim 1, characterized in that The solvent A in step 1) is one of dichloromethane, ethyl acetate, N,N-dimethylformamide, tetrahydrofuran, acetonitrile and toluene; the condensation reagent is N,N'-dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; the auxiliary condensation reagent is 1-hydroxybenzotriazole or N-hydroxysuccinimide; the base is triethylamine or sodium carbonate; and the condensation reaction temperature is 10 to 60°C.

3. A novel method for preparing a zavigipan intermediate according to claim 2, characterized in that In step 1), when solvent A is N,N-dimethylformamide, tetrahydrofuran or acetonitrile, an auxiliary solvent is added, and the auxiliary solvent is dichloromethane or ethyl acetate.

4. A novel method for preparing a zavigipan intermediate according to claim 1, characterized in that In step 1), the molar ratio of the compound represented by formula (II) to the compound represented by formula (III), the condensation reagent and the base is 1:1-1.5:1-1.8:1-2.

4.

5. A novel method for preparing a zavigipan intermediate according to claim 1, characterized in that Step 2) Vilsmeier reagent is prepared by reacting phosphorus oxychloride with N,N-dimethylformamide.

6. A novel method for preparing a zavigipan intermediate according to claim 1, characterized in that The temperature of the cyclization reaction in step 2) is 55-100°C.

7. A novel method for preparing a zavigipan intermediate according to claim 1, characterized in that In step 2), the molar ratio of the compound represented by formula (IV) to N,N-dimethylformamide and phosphorus oxychloride is 1:2-6:5-15.

8. A novel method for preparing a zavigipan intermediate according to claim 1, characterized in that In step 2) and step 3), the concentration of concentrated hydrochloric acid is 4-8 mol / L, and the hydrolysis reaction temperature is 60-100°C.

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