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Method for synthesizing Lomerizine Hydrochlortde

A technology of lomerizine hydrochloride and its synthesis method, which is applied in the direction of organic chemistry, etc., and can solve the problems of low industrial production value, low yield of lomerizine hydrochloride synthesis technology, and difficulty in obtaining medicinal crystal forms of lomerizine hydrochloride To achieve the effect of shortening treatment time, reasonable treatment, and relieving pain

Inactive Publication Date: 2005-01-12
NANJING CHANGAO PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The technical problem to be solved in the present invention is that the existing lomerizine hydrochloride synthesis technology yield is low, the industrial production value is not big, and the problem that a single lomerizine hydrochloride pharmaceutical crystal form is difficult to obtain

Method used

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  • Method for synthesizing Lomerizine Hydrochlortde

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Embodiment 1

[0021] Put 1020g of 2,3,4-trimethoxybenzaldehyde and 1500g of bis(4-fluorophenyl)methylpiperazine into the reaction flask, and slowly melt it in an oil bath at 100°C. After the melting is complete, slowly add 260ml of formic acid dropwise, After dripping, continue to stir and react at this temperature for 1 hour, be cooled to room temperature, add 960ml concentrated hydrochloric acid (37%) and 9600ml absolute ethanol and stir and reflux for 1 hour, then add gac 60g, continue to stir and decolorize 0.5 hour. After filtration, the filtrate was slowly cooled and crystallized to obtain 2507.4 g of white crystals, with a yield of 90.02%, mp: 202°C (document mp: 204°C). The crude product of lomerizine hydrochloride can still be obtained after cooling the mother liquor, which can increase the yield.

[0022] Get lomerizine hydrochloride crude product 1950.3g, add acetonitrile-methanol (80%-20%) mixed solution 7000ml, heat under stirring for 1 hour, cool and filter to obtain white crys...

Embodiment 2

[0024] Put 1020g of 2,3,4-trimethoxybenzaldehyde and 3750g of bis(4-fluorophenyl)methylpiperazine into the reaction flask, and slowly melt it in an oil bath at 100°C. After the melting is complete, slowly add 260ml of formic acid dropwise, After dripping, continue to stir and react at this temperature for 3 hours, be cooled to room temperature, add 960ml concentrated hydrochloric acid (37%) and 9600ml absolute ethanol and stir and reflux for 5 hours, then add gac 90g, continue to stir and decolorize 1 hour. After filtration, the filtrate was slowly cooled and crystallized to obtain 2548.6 g of white crystals, with a yield of 91.5%, mp: 202° C. (document mp: 204° C.).

[0025] Take 1950.3 g of lomerizine hydrochloride crude product, add acetonitrile-ethanol (80%-20%) mixed solution 7000 ml, heat with stirring for 1 hour, cool and filter to obtain white crystals, and dry to obtain fine product 1057.7 g. Yield 54.23%, mp: 207.8-208.9°C.

[0026] Acetonitrile-methanol ra...

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Abstract

This invention synthesis process consists of steps: (1) 2,3,4-trimethoxy benzaldehyde and di(4-fluorobenzyl) methyl piperazne, in molar ratio of (1:1) to (1:2.5) are fed in, heating to melt; (2) dropping-in formic acid, in mole ratio of (1:1) to 2,3,4-trimethoxy benzaldehyde, reacting for 1-3 hrs; (3) after cooled, adding concentrate hydrochloride acid-anhydrous alcohole mixed solution reacting for 1-5 hrs, to obtain crude product; (4) recrystallization of said product, by adding acetonitrile-methanol mixed solution or acetonitrile-ethanol mixed solution, refluxing for 1 hr. to obtain the final product. Advantages are: no need of salification, directly to obtain final product, high yield (more than 80%), to obtain pharmaceutical product after recrystallization, commercial (ton-scale) prodn.

Description

technical field [0001] The invention relates to a method for synthesizing lomerizine hydrochloride (1-(2,3,4-trimethoxybenzyl)-4-[bis(4-fluorophenyl)methyl]piperazine dihydrochloride) method. Background technique [0002] Migraine is a common chronic recurrent unilateral headache. my country is an area with a high incidence of migraine. Lomerizine hydrochloride (Lomerizine hydrochloride) is a new type of diphenylpiperazine calcium channel blocker, it can selectively increase the blood flow of cerebral blood vessels with little effect on peripheral blood vessels, and can also inhibit the diffusion inhibition ( Spreadingdepression) and neuritis, protect people and animals from the damage of cerebral ischemia and hypoxia, so developing lomerizine hydrochloride to treat migraine has broad market prospect. In view of the obvious economic and social benefits of lomerizine hydrochloride, many different synthetic methods have been developed. Although there are many methods for s...

Claims

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Application Information

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IPC IPC(8): C07D295/096
Inventor 李强朱月刘彩连唐平曹富陈慧
Owner NANJING CHANGAO PHARMA SCI & TECH CO LTD
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