Method for synthesizing N-methylhexahydroazepin-4-one hydrochloride, azelastine hydrochloride intermediate

A technique for the synthesis of methylhexahydrogen, applied in the direction of organic chemistry, can solve the problems of high market price of ethyl ester, unfavorable industrial production, low yield of cyclization, etc., and achieve small amount of waste water, easy treatment, and process operation easy effect

Inactive Publication Date: 2010-07-21
山东众诚生物医药股份有限公司
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  • Abstract
  • Description
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Problems solved by technology

This technique is because 4-[(3-ethoxy-3-propyl) methyl amino] ethyl ester market price is high, and purchase is difficult, and cyclization yield is not high, uses acid hydrolysis and evaporates water distillation process to equipment The requirements are extremely high, and the yield of the product obtained after a long time is extremely low, which is not conducive to industrial production, and the operation is cumbersome

Method used

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  • Method for synthesizing N-methylhexahydroazepin-4-one hydrochloride, azelastine hydrochloride intermediate
  • Method for synthesizing N-methylhexahydroazepin-4-one hydrochloride, azelastine hydrochloride intermediate
  • Method for synthesizing N-methylhexahydroazepin-4-one hydrochloride, azelastine hydrochloride intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Embodiment 1: synthetic reaction route is as follows:

[0046]

[0047] (1) Add 18g of N-methyl-2-pyrrolidone to 37ml of concentrated hydrochloric acid and stir to reflux for 5 hours. Cool, evaporate the hydrochloric acid to dryness under reduced pressure, add 50ml of cold acetone to the remaining solid, stir, cool, the solid becomes crystallized, freeze to make it completely precipitate, filter, wash twice with 15ml of acetone, drain and dry, Obtained 24.2g, the total yield was 88.2%.

[0048] (2) Add 40ml of thionyl chloride dropwise to 150ml of anhydrous methanol under stirring at -5°C to 0°C in the external bath, keep the internal temperature not exceeding -3°C, and dropwise add in about 3 hours, then add step (1 ) product 20g, the reaction solution was reacted at 25°C for 12 hours, after the methanol was concentrated under reduced pressure, the mother liquor was stirred evenly for the next step.

[0049] (3) 22g of methyl acrylate, 20g of triethylamine and 150ml...

Embodiment 2

[0054] As described in Example 1, the difference is that the extractant in step (5) is chloroform to obtain 7.1 g of N-methylhexahydro-4-one hydrochloride with a yield of 94.3%.

Embodiment 3

[0056] As described in Example 1, the difference is that the extractant in step (5) is dichloroethane to obtain 6.8 g of N-methylhexahydro-4-one hydrochloride with a yield of 90.3%.

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Abstract

The invention relates to a method for synthesizing N-methylhexahydroazepin-4-one hydrochloride. In the method, N-methyl-2-pyrrolidone (NMP) is taken as the raw material. The method is characterized by heating and carrying out reflux on NMP in the presence of hydrochloric acid to prepare 4-methylaminobutyric acid hydrochloride, adding 4-methylaminobutyric acid hydrochloride into methanol and thionyl chloride to carry out mono-esterification reaction to prepare 4-methylaminobutyric acid methyl ester hydrochloride, then adding 4-methylaminobutyric acid methyl ester hydrochloride into the solution of methyl acrylate, triethylamine and methanol to react to prepare diester, carrying out cyclization reaction on the diester and metal organic alcohols such as potassium tert-butoxide to obtain N- methylhexahydroazepin-4-one and finally salifying and crystallizing N- methylhexahydroazepin-4-one to obtain the N-methylhexahydroazepin-4-one hydrochloride. The product has high purity and yield, the process is simple and convenient to operate, a single solvent can be used in the whole reaction process, and N-methylhexahydroazepin-4-one hydrochloride is convenient to recycle, small in wastewater quantity, low in comprehensive cost and suitable for large-scale production.

Description

technical field [0001] The invention relates to a synthesis method of an intermediate compound N-methylhexahydro-4-one hydrochloride, and belongs to the technical field of synthesis of azelastine hydrochloride pharmaceutical intermediates. Background technique [0002] Azelastine hydrochloride (Azelastine hydrochloride) is an oral long-acting antiallergic drug developed by German Asta-Werke A G Company and Japanese Eisai Company, and what is used clinically is hydrochloride. Its chemical name is (4-(4-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepine-4-yl)-1-(2H)-phthalazine hydrochloride, CAS No : 79307-93-0, the structural formula is: [0003] [0004] The product was first launched in Germany and Japan in 1986, due to its phthalazine N 2 With hexahydro-1-methyl-1H-azepine-4-yl in the position, C 4 There is a 4-chlorobenzyl group at the position, thus greatly improving the antihistamine and pharmacokinetic characteristics of the original drug. Compared with other secon...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/08
Inventor 丁伟达李义李勇刘希刚
Owner 山东众诚生物医药股份有限公司
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