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Synthesis method and application of 1-methylhexahydroazepine-4-one hydrochloride

A technology for the synthesis of methylhexahydronitrogen and its synthesis method, which is applied in the field of synthesis of azelastine hydrochloride pharmaceutical intermediates, can solve the problems of cumbersome operation of the overall reaction route, unfavorable industrial production, and long production cycle of the process, and achieve green environmental protection industrialization, The effect of low cost and short synthetic route

Pending Publication Date: 2022-05-17
SICHUAN GOODDOCTOR PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] (2) The process of concentrated water in the hydrolysis process requires extremely high equipment;
[0014] (3) The reaction steps are long, resulting in a long production cycle of the whole process;
[0015] (4) The yield of the whole process route is extremely low;
[0016] (5) The cumbersome operation of the overall reaction route is not conducive to industrial production

Method used

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  • Synthesis method and application of 1-methylhexahydroazepine-4-one hydrochloride
  • Synthesis method and application of 1-methylhexahydroazepine-4-one hydrochloride
  • Synthesis method and application of 1-methylhexahydroazepine-4-one hydrochloride

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Experimental program
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Effect test

Embodiment 1

[0033] Embodiment 1: the preparation of 1-methyl-4-(nitromethyl) piperidin-4-ol

[0034] Nitromethane (66 mL, 1.22 mol) and MeONa (2.21 g, 0.041 mol) were added to a solution of compound 1-methylpiperidin-4-one (100 mL, 0.81 mol) in EtOH (100 mL). After 30 min, additional ethanol (150 mL) was added to facilitate stirring. The reaction mixture was stirred at room temperature for 48 h, then filtered. The separated solid was washed with MTBE to give the product 1-methyl-4-(nitromethyl)piperidin-4-ol (114 g, yield 80.4%).

[0035] H-NMR (d-DMSO, 400MHz): δ5.01(s, 1H), 4.47(s, 2H), 2.41-2.40 (m, 2H), 2.21-2.15(m, 2H), 2.12(s, 3H) ), 1.64-1.53 ​​(m, 4H).

Embodiment 2

[0036] Embodiment 2: Preparation of 4-(aminomethyl)-1-methylpiperidin-4-ol

[0037] A mixture of 1-methyl-4-(nitromethyl)piperidin-4-ol (6 g, 35 mmol) and Raney nickel 600 mg in methanol 250 ml was stirred at room temperature under hydrogen atmosphere for 20 h. The mixture was filtered through celite and evaporated under reduced pressure. The residue was obtained without further purification as 4-(aminomethyl)-1-methylpiperidin-4-ol (4 g, 74%).

Embodiment 3

[0038] Embodiment 3: the preparation of N-methylhexahydroazepin-4-one hydrochloride

[0039] Dissolve 5g (34.67mmol) of 4-(aminomethyl)-1-methylpiperidin-4-ol in 50ml of glacial acetic acid, cool down to 0°C, slowly add sodium nitrite (2.46g, 35.71mmol) in water (25ml) solution, keep warm at 0°C, stir and react overnight, the reaction is complete, add 250ml DCM and adjust the pH of the reaction solution to 7-8 with sodium bicarbonate, separate the DCM layer, wash the water layer twice with 50ml DCM, combine the organic layer and concentrate , add 20ml of isopropanol to dissolve the oil, adjust the pH value to <6 with 3ml of hydrogen chloride isopropanol solution, cool down and crystallize to obtain N-methylhexahydroazepin-4-one hydrochloride, dry under reduced pressure and vacuum , to obtain a solid (4.96 g, 87.0%).

[0040] H-NMR (d-DMSO, 400MHz): δ11.69(s, 1H), 3.56-3.48(m, 2H), 3.46-3.43(m, 2H), 3.44(M, 2H), 2.79(s, 3H ), 2.69-2.50 (m, 2H), 2.07-1.99 (m, 2H).

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Abstract

The invention belongs to the technical field of synthesis of azelastine hydrochloride drug intermediates, and provides a synthesis method of 1-methylhexahydroazepine-4-one hydrochloride and application of the 1-methylhexahydroazepine-4-one hydrochloride in preparation of azelastine hydrochloride. The synthesis method comprises the following steps: (1) preparing 1-methyl-4-(nitromethyl) piperidine-4-alcohol; (2) preparation of 4-(aminomethyl)-1-methylpiperidine-4-alcohol; and (3) preparation of the 1-methylhexahydroazepine-4-one hydrochloride. The synthesis method adopts easily available 1-methylpiperidine-4-ketone as a reaction raw material, and has the advantages of short synthesis route, mild reaction conditions, safety, feasibility, high yield, low cost, greenness, environmental protection and easy realization of industrialization.

Description

technical field [0001] The invention belongs to the synthetic technical field of azelastine hydrochloride pharmaceutical intermediates, in particular, relates to a synthetic method of 1-methylhexahydroazepin-4-one hydrochloride and its preparation of azelastine hydrochloride on the application. Background technique [0002] Azelastine hydrochloride (Azelastine) is a derivative of phthalazinone, chemical name: (4-(4-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepine-4- Base)-1-(2H)-phthalazine hydrochloride, CAS NO: 79307-93-0, the structural formula is: [0003] [0004] This product is medicinal as its hydrochloride. Azelastine hydrochloride was developed by Asta-Werke AG of Germany and Eisai of Japan. It was launched in Germany and Japan in 1986 and has received extensive attention since it was launched. At present, the product is produced in China, the United States, Germany, Britain, Japan and France, and has been included in the pharmacopoeia of many countries and the...

Claims

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Application Information

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IPC IPC(8): C07D223/08C07D211/44
CPCC07D223/08C07D211/44Y02P20/55
Inventor 耿福能胥树波褚旭
Owner SICHUAN GOODDOCTOR PHARMA GRP
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