Preparation method of (E)-4-(methyl imidazolyl) methyl cinnamate

A technology of methyl cinnamate and imidazolyl methyl is applied in the field of preparation of ozagrel intermediates, and can solve the problems of ozagrel cycle and cost impact, cumbersome preparation process of imidazolate salts, complicated raw materials and processes, etc. The effect of production cycle, easy control of reaction and short reaction time

Active Publication Date: 2016-03-23
山东诚汇双达药业有限公司
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  • Abstract
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  • Application Information

AI Technical Summary

Problems solved by technology

For example, a method adopts to prepare imidazolium salt first, and then reacts with methyl p-bromomethyl cinnamate to generate (E)-4-(imidazolylmethyl) methyl cinnamate, but the preparation process of its imidazolium salt is loaded down with trivial details, and the period is long , which affects the cycle and cost of preparing ozagrel
Although another kind adopts imidazole and methyl p-bromomethyl cinnamate to react through N-alkylation to produce (E)-4-(imidazolylmethyl) methyl cinnamate, but its raw materials and process are complicated, and impurities Generally, it is 10-15%. The process of removing impurities is relatively complicated. At the same time, the yield of the operation method is low, and the reaction uses dangerous substances such as sodium metal.

Method used

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  • Preparation method of (E)-4-(methyl imidazolyl) methyl cinnamate
  • Preparation method of (E)-4-(methyl imidazolyl) methyl cinnamate

Examples

Experimental program
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Embodiment １

[0030] Put 245kg of acetonitrile into a 500L reaction kettle, add 35kg of methyl p-bromomethyl cinnamate, 30kg of potassium carbonate, and 10.5kg of imidazole under stirring to obtain a mixed solution; heat up to reflux, and after reflux for 4 hours, distill to remove the solvent acetonitrile Add 210kg of deionized water to stir and crystallize after lowering the temperature, shake off the filter after the crystallization is complete, and dry the wet product at 70°C for 22 hours to obtain 30.7kg of (E)-4-(imidazolylmethyl)methyl cinnamate. The purity is 99.25%, and the yield is 92%.

[0031] The obtained (E)-4-(imidazolylmethyl) methyl cinnamate of this preparation method is detected by high-performance liquid chromatography: using octadecylsilane bonded silica gel as a filler, using methanol-water as a mobile phase, in Detected at a specific wavelength and flow rate, and the liquid chromatogram calculated by the area normalization method is shown in the attached drawing of th...

Embodiment 2

[0033] Put 450kg of acetonitrile into a 1000L reaction kettle, add 70kg of methyl p-bromomethyl cinnamate, 50.6kg of sodium carbonate, and 21kg of imidazole under stirring to obtain a mixed solution; heat up to reflux, reflux for 6 hours, and evaporate the acetonitrile under reduced pressure Add 420kg of deionized water to stir and crystallize after lowering the temperature. After the crystallization is completed, shake off the filter, dry the wet product at 70° C. for 24 hours, and obtain 61 kg of (E)-4-(imidazolylmethyl) methyl cinnamate. The purity is 99.38%, and the yield is 91.5%. The purity detection method is the same as in Example 1.

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Abstract

The invention discloses a preparation method of an ozagrel intermediate (E)-4-(methyl imidazolyl) methyl cinnamate. According to the method, bromomethyl methyl cinnamate, potash or sodium carbonate, imidazole and acetonitrile react. The method has the advantages that a production cycle of the (E)-4-(methyl imidazolyl) methyl cinnamate is greatly shortened, operation is simple, and cost is reduced.

Description

technical field [0001] The invention relates to the technical field of preparation of an ozagrel intermediate, in particular to a preparation method of (E)-4-(imidazolylmethyl)methyl cinnamate. Background technique [0002] Ozagrel is the world's first marketed powerful thromboxane synthetase inhibitor, which was jointly researched by Japan's Ono and Kissei Pharmaceutical Industry Co., Ltd. and first launched in April 1988. Its sodium salt is mainly used clinically in the treatment of cerebral spasm and cerebral ischemia after subarachnoid hemorrhage. (E)-4-(Imidazolylmethyl)methyl cinnamate is a key intermediate of ozagrel, and its production method and the quality of the obtained product seriously affect the quality of ozagrel. For example, a method adopts to prepare imidazolium salt first, and then reacts with methyl p-bromomethyl cinnamate to generate (E)-4-(imidazolylmethyl) methyl cinnamate, but the preparation process of its imidazolium salt is loaded down with trivi...

Claims

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Application Information

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Patent Type & AuthorityApplications(China)
IPC IPC(8): C07D233/56
CPCC07D233/56
Inventor赵忠贵王永广王文新曹晓华刘学文
Owner山东诚汇双达药业有限公司