A novel process for the preparation of a zavegepant intermediate

Abstract

The application discloses a novel method for preparing a zavegepant intermediate, i.e. 3-(piperidin-4-yl)-1,2-dihydroquinolin-2-one hydrochloride, which comprises the following steps: taking a piperidin-4-acetic acid derivative and aniline as starting materials, and sequentially performing condensation reaction, cyclization reaction and hydrolysis reaction to obtain 3-(piperidin-4-yl)-1,2-dihydroquinolin-2-one hydrochloride. The preparation method is simple in steps, low in cost, low in requirement for equipment, high in product yield and purity, and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical intermediate synthesis, and particularly 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] Zavril is a novel calcium gene-related peptide (CGRP) receptor antagonist used to treat migraine. Zavril ((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 migraine in adults with or without aura. This product is also a CGRP receptor antagonist nasal spray for the acute treatment of migraine in adults. Its molecular formula is shown below:

[0004]

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

[0006]

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

[0008] In 2022, Biohaven (US20220401439) reported a synthetic route for a zavidipam intermediate: starting with N-Boc-4-piperidone, 3-(piperidin-4-yl)-1,2-dihydroquinolin-2-one hydrochloride is obtained through coupling, hydrogenation, condensation, cyclization, and deprotection. This synthetic route is long, requires deep cooling, and places high demands on production equipment.

[0009]

[0010] In 2005, Merck & Co. (WO 2005000807) reported the synthesis of a benzodiazoline CGRP receptor antagonist, which involved the synthesis of this intermediate. This synthetic route also involved a cryogenic reaction, requiring high production equipment, and the raw materials were expensive, resulting in high production costs.

[0011]

[0012] In response to 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 has developed a preparation method for an important intermediate of zavidizopam with readily 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 for 3-(piperidin-4-yl)-1,2-dihydroquinolin-2-one hydrochloride (I), an important intermediate of zavidipam. The preparation method has short steps, uses cheap and readily available raw materials, has low cost, avoids deep cooling reaction, has low equipment requirements, and has high product yield and purity, making it 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 through condensation reaction, cyclization reaction, and hydrolysis reaction in sequence. The new method for preparing the intermediate comprises the following steps:

[0016] 1) adding the compounds represented by formula (II) and formula (III) to solvent A, and causing a condensation reaction under the action of a condensation reagent, an auxiliary condensation reagent, and a base. After the reaction is completed, washing with dilute hydrochloric acid, washing with water, washing with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, concentrating, and purifying to obtain a 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 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 of formula (V) obtained in step 2) for hydrolysis, concentrating to remove the hydrochloric acid after the reaction, filtering, and purifying to obtain the compound of formula (I);

[0019] The reaction process is as follows:

[0020]

[0021] In 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 condensation reaction temperature is 10 to 60°C.

[0023] Furthermore, when the solvent A in step 1) 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 a piperidine-4-acetic acid derivative and aniline as starting materials, and sequentially undergoes a condensation reaction, a cyclization reaction, and a hydrolysis reaction to prepare 3-(piperidin-4-yl)-1,2-dihydroquinolin-2-one hydrochloride. The preparation method of the present invention has simple steps, readily available and inexpensive raw materials, low cost, avoids deep cooling reaction, has low equipment requirements, and has high product yield and purity, making it 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 operational safety. DETAILED DESCRIPTION

[0032] The present invention will be further described below with reference to the 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 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), a condensing agent EDCI (2.30 g, 12 mmol), an auxiliary condensing agent HOBT (0.68 g, 5 mmol), a base triethylamine (1.21 g, 12 mmol) and 30 mL of dichloromethane (solvent A) were added and stirred for 30 min. Aniline (1.12 g, 12 mmol) of formula (III) was added and kept warm at 10°C. The reaction was monitored by TLC until completion. The product was washed with an appropriate amount of 0.5 mol / L hydrochloric acid solution, water, and saturated sodium chloride solution, 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) in 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 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), 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 A ethyl acetate 30 mL were added and stirred for 30 min. Aniline (0.93 g, 10 mmol) of formula (III) was added and kept warm at 20°C. The reaction was monitored by TLC. The product was washed with appropriate amounts of 0.5 mol / L hydrochloric acid solution, water, and saturated sodium chloride solution, 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) in 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 equipped with a magnetic stirrer 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, N-dimethylformamide 30 mL were added and stirred for 30 min. Aniline (0.75 g, 8 mmol) of formula (III) was added and kept warm at 30 ° C. TLC 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, and the concentrated product became a viscous oil. After adding dichloromethane to dissolve it, it was convenient to carry out the subsequent extraction process. It was washed with an appropriate amount of 0.5 mol / L hydrochloric acid solution, water, and saturated sodium chloride solution, 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 stirred for 30 min. Aniline (0.93 g, 10 mmol) of formula (III) was added and kept at 30° C. The reaction was monitored by TLC until completion. The reaction solution was concentrated and 30 mL of dichloromethane was added. The solution was washed with appropriate amounts of 0.5 mol / L hydrochloric acid solution, water, and saturated sodium chloride solution, 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) in 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. The reaction solution was concentrated and 30 mL of dichloromethane was added. The solution was washed with appropriate amounts of 0.5 mol / L hydrochloric acid solution, water, and saturated sodium chloride solution, 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) in a yield of 82.1% and a purity of 99.6%.

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

[0046] 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 (0.68 g, 5 mmol), triethylamine (1.21 g, 12 mmol) and 30 mL of toluene were added and stirred for 30 min. Aniline (1.21 g, 13 mmol) of formula (III) was added and kept at 50°C. The reaction was monitored by TLC. The mixture was washed with appropriate amounts of 0.5 mol / L hydrochloric acid solution, water, and saturated sodium chloride solution, and then dried over anhydrous sodium sulfate (3 g). After concentration, it was recrystallized from ethyl acetate to obtain benzyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-b) in 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 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 (2.30 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 an appropriate amount of 0.5 mol / L hydrochloric acid solution, water, and saturated sodium chloride solution, 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) in a yield of 91.1% and a purity of 99.6%.

[0050] Example 8 Preparation of benzyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (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 at 30° C. The reaction was monitored by TLC. The mixture was washed with appropriate amounts of 0.5 mol / L hydrochloric acid solution, water, and saturated sodium chloride solution, and then dried over anhydrous sodium sulfate (3 g). After concentration, it was recrystallized from ethyl acetate to obtain benzyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-b) in 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-piperidinylacetic acid (2.43 g, 10 mmol) of formula (II-a) and 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) and stirred at 10°C. The substrate was completely consumed as monitored by TLC. The solid was removed by filtration and the reaction solution was retained for later use. In another 100 mL three-necked flask equipped with a magnetic stirrer and a thermometer, sodium carbonate (2.54 g, 24 mmol), 30 mL of water and aniline of formula (III) (1.12 g, 12 mmol) were added dropwise, and the reaction solution was then added dropwise. The mixture was stirred at 10°C. 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, 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) in 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 50 mL three-necked flask with a magnetic stirrer and a thermometer, 1-Boc-4-piperidinylacetic 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. The substrate was completely consumed by monitoring by TLC. The solid was filtered out and the reaction solution was reserved for use. Sodium carbonate (2.54 g, 13 mmol) was added to another 100 mL three-necked flask with a magnetic stirrer and a thermometer. , 24mmol), 30mL of water and aniline of formula (III) (0.93g, 10mmol), then the above reaction solution was added dropwise, stirred at 60°C, and the reaction was monitored by TLC to complete. The product was washed with an appropriate amount of 0.5mol / L hydrochloric acid solution, water, and saturated sodium chloride solution, and then dried over anhydrous sodium sulfate (3g). 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 83.7% and a purity of 99.7%.

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

[0057] In a 50 mL three-necked flask equipped with a magnetic stirrer and a thermometer, 1-Cbz-4-piperidinylacetic 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 (1.94 g, 10 mmol) was added dropwise. The mixture was stirred at 30°C and the substrate was completely consumed by monitoring by TLC. The solid was filtered out and the reaction solution was reserved for later use. In another 100 mL three-necked flask equipped with a magnetic stirrer and a thermometer, sodium carbonate (2.54 g, 24 mmol), 30 mL of water and aniline of formula (III) (1.12 g, 12 mmol), then the above reaction solution was added dropwise, stirred at 30°C, and the reaction was monitored by TLC. The product was washed with appropriate amounts of 0.5 mol / L hydrochloric acid solution, water, and saturated sodium chloride solution, and then dried over anhydrous sodium sulfate (3 g). After concentration, it was recrystallized from ethyl acetate to obtain benzyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-b) with a yield of 86.6% and a purity of 99.7%.

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

[0059] 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), 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 retained for later use. In another 100 mL 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, and the above 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 amounts of 0.5 mol / L hydrochloric acid solution, water, and saturated sodium chloride solution, dried over anhydrous sodium sulfate (3 g), concentrated, and recrystallized from ethyl acetate to obtain benzyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (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 50 mL three-necked flask with a magnetic stirrer and a thermometer, 1-Boc-4-piperidinylacetic acid (2.43 g, 10 mmol) of formula (II-a), NHS (1.15 g, 10 mmol) and 30 mL of dichloromethane were added, and DCC (2.33 g, 12 mmol) was added dropwise. The mixture was stirred at 30°C and the substrate was completely consumed by monitoring by TLC. The solid was removed by filtration and the reaction solution was reserved for later 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 of formula (III) (1.12 g, 12 mmol), then the above reaction solution was added dropwise, stirred at 30°C, and the reaction was monitored by TLC. The product was washed with appropriate amounts of 0.5 mol / L hydrochloric acid solution, water, and saturated sodium chloride solution, 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 90.2% and a purity of 99.6%.

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

[0063] In a 50 mL three-necked flask equipped with a magnetic stirrer and a thermometer, 1-Cbz-4-piperidinylacetic acid (2.77 g, 10 mmol) of formula (II-b), NHS (1.15 g, 10 mmol) and 30 mL of dichloromethane were added, and DCC (2.33 g, 12 mmol) was added dropwise. The mixture was stirred at 30°C and the substrate was completely consumed by monitoring by TLC. The solid was filtered out and the reaction solution was reserved for later use. In another 100 mL three-necked flask equipped with a magnetic stirrer and a thermometer, sodium carbonate (2.54 g, 24 mmol), 30 mL of water and aniline of formula (III) (1.12 g, 12 mmol), then the above reaction solution was added dropwise, stirred at 30°C, and the reaction was monitored by TLC. The product was washed with appropriate amounts of 0.5 mol / L hydrochloric acid solution, water, and saturated sodium chloride solution, and then dried over anhydrous sodium sulfate (3 g). After concentration, it was recrystallized from ethyl acetate to obtain benzyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (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 magnetic stirring and a thermometer. The mixture was cooled to 0°C and phosphorus oxychloride (10.73 g, 70 mmol) was added dropwise with stirring. The mixture was stirred for 30 min and 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 kept at 75°C for 16 h. The reaction was monitored by TLC to complete. The phosphorus oxychloride was removed by concentration, dichloromethane was added, and 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-chloroquinolin-3-yl)piperidine-1-carboxaldehyde (V) in 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 magnetic stirring and a thermometer. The mixture was cooled to 0°C and phosphorus oxychloride (15.33 g, 100 mmol) was added dropwise with stirring. The mixture was stirred for 30 min and 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 kept at 85°C for 16 h. The reaction was monitored by TLC to determine completion. The phosphorus oxychloride was removed by concentration and dichloromethane was added. The solid was removed by filtration and the pH was adjusted to 10 with 10% NaOH solution. The mixture was separated, concentrated, and purified by column chromatography to obtain 4-(2-chloroquinolin-3-yl)piperidine-1-carboxaldehyde (V) in 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 magnetic stirring and a thermometer. The mixture was cooled to 0°C and phosphorus oxychloride (12.27 g, 80 mmol) was added dropwise with stirring. The mixture was stirred for 30 min and 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 kept at 85°C for 16 h. The reaction was monitored by TLC to complete. The phosphorus oxychloride was removed by concentration and dichloromethane was added. The solid was removed by filtration and the pH was adjusted to 10 with 10% NaOH solution. The mixture was separated, concentrated, and purified by column chromatography to obtain 4-(2-chloroquinolin-3-yl)piperidine-1-carboxaldehyde (V) in 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 magnetic stirring and a thermometer. The mixture was cooled to 0°C and phosphorus oxychloride (10.73 g, 70 mmol) was added dropwise with stirring. The mixture was stirred for 30 min and 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 kept at 65°C for 16 h. The reaction was monitored by TLC to determine completion. The phosphorus oxychloride was removed by concentration and dichloromethane was added. The solid was removed by filtration and the pH was adjusted to 10 with 10% NaOH solution. The mixture was separated, concentrated, and purified by column chromatography to obtain 4-(2-chloroquinolin-3-yl)piperidine-1-carboxaldehyde (V) in 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 magnetic stirring and a thermometer. The mixture was cooled to 0°C and phosphorus oxychloride (10.73 g, 70 mmol) was added dropwise with 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 increased and kept at 95°C for 16 h. The reaction was monitored by TLC to complete. The phosphorus oxychloride was removed by concentration and dichloromethane was added. The solid was removed by filtration and the pH was adjusted to 10 with 10% NaOH solution. The mixture was separated, concentrated, and purified by column chromatography to obtain 4-(2-chloroquinolin-3-yl)piperidine-1-carboxaldehyde (V) in 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] To a 50 mL three-necked flask equipped with a magnetic stirrer and a thermometer, add N,N-dimethylformamide (2.92 g, 40 mmol). Cool to 0°C and add phosphorus oxychloride (15.33 g, 100 mmol) dropwise with stirring. Stir for 30 minutes, then add benzyl 4-(2-oxo-2-(phenylamino)ethyl)piperidine-1-carboxylate (IV-b) (3.52 g, 10 mmol). Slowly increase the temperature and maintain at 75°C for 16 hours. The reaction is monitored by TLC for completion. Concentrate to remove the phosphorus oxychloride, add dichloromethane, filter to remove the solid, adjust the pH to 10 with 10% NaOH solution, separate the layers, concentrate, and purify by column chromatography to obtain 4-(2-chloroquinolin-3-yl)piperidine-1-carboxaldehyde (V) in 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 equipped with a magnetic stirrer and a thermometer, add 4-(2-chloroquinolin-3-yl)piperidine-1-carboxaldehyde (V) (2.75g, 10mmol) and 30mL of 8mol / L hydrochloric acid. The mixture is incubated at 80°C for 8h. After the reaction is complete, the reaction solution is concentrated and recrystallized from 5% water-isopropanol to obtain 3-(piperidin-4-yl)-1,2-dihydroquinolin-2-one hydrochloride (I) in 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] 4-(2-chloroquinolin-3-yl)piperidine-1-carboxaldehyde (V) (2.75 g, 10 mmol) and 30 mL of 6 mol / L hydrochloric acid were added to a 50 mL three-necked flask equipped with a magnetic stirrer and a thermometer. The mixture was 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-dihydroquinolin-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 50 mL three-necked flask equipped with a magnetic stirrer and a thermometer, 4-(2-chloroquinolin-3-yl)piperidine-1-carboxaldehyde (V) (2.75 g, 10 mmol) and 30 mL of 6 mol / L hydrochloric acid were added and refluxed at 100°C for 8 h. After the reaction, the reaction solution was concentrated and recrystallized from 5% water-isopropanol to obtain 3-(piperidin-4-yl)-1,2-dihydroquinolin-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 50 mL three-necked flask equipped with a magnetic stirrer and a thermometer, 4-(2-chloroquinolin-3-yl)piperidine-1-carboxaldehyde (V) (2.75 g, 10 mmol) and 30 mL of 4 mol / L hydrochloric acid were added and refluxed at 100°C for 8 h. After the reaction, the reaction solution was concentrated and recrystallized from 5% water-isopropanol to obtain 3-(piperidin-4-yl)-1,2-dihydroquinolin-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, whose structural formula is shown in formula (I), and a piperidine-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, characterized in that The novel method for preparing the intermediate comprises the following steps: 1) adding the compounds represented by formula (II) and formula (III) to solvent A, and causing a condensation reaction under the action of a condensation reagent, an auxiliary condensation reagent, and a base. After the reaction is completed, washing with dilute hydrochloric acid, washing with water, washing with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, concentrating, and purifying to obtain a 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 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 of formula (V) obtained in step 2) for hydrolysis, concentrating to remove the hydrochloric acid after the reaction, filtering, and purifying to obtain the compound of formula (I); The reaction process is as follows: In 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 10-60°C.

3. A novel method for preparing a zavirigopam 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 The concentration of concentrated hydrochloric acid in step 2) and step 3) is 4-8 mol / L, and the hydrolysis reaction temperature is 60-100°C.

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