Preparation process of ozagrel intermediate methyl (E)-4-(imidazolylmethyl) cinnamate

A technology of imidazolyl methyl and methyl cinnamate, which is applied in the field of preparation of ozagrel intermediate-methyl 4-cinnamate, can solve the impact of ozagrel cycle and cost, complicated process of removing impurities, and imidazolium salts. The preparation process is cumbersome and other problems, to achieve the effect of shortening the production cycle, short production cycle and easy purchase

Active Publication Date: 2016-04-13
DEZHOU HANHUA CHEM
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Problems solved by technology

Because the quality of its key intermediate (E)-4-(imidazolylmethyl)methyl cinnamate directly affects the quality of ozagrel in the preparation process, and the preparation methods of the intermediate that have been reported all have deficiencies
For example, using imidazole and methyl p-bromomethyl cinnamate to react through N-alkylation to produce (E)-4-(imidazolylmethyl) methyl cinnamate, the impurities in this method are generally in the range of 10- 15%, the process of removing impurities is relatively complicated, and it is difficult

Method used

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  • Preparation process of ozagrel intermediate methyl (E)-4-(imidazolylmethyl) cinnamate

Examples

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Embodiment 1

[0038] 1. Preparation of Potassium Imidazole:

[0039] Put 63kg of DMF into a 500L reactor, put in 12.7kg of potassium hydroxide and 15.5kg of imidazole, stir at 10-20°C for 1 hour to obtain a mixed solution; react at 15°C for 3 hours; drop to below 0°C to obtain a spare material ;

[0040] 2. Preparation of methyl (E)-4-(imidazolylmethyl)cinnamate:

[0041] Dissolve 50 kg of methyl p-bromomethyl cinnamate in 55 kg of DMF, control the temperature of the methyl p-bromomethyl cinnamate solution below 15°C and add it dropwise, and continue stirring for 4 hours after dropping; add 300 kg of deionized Stir and crystallize with water, and dry at 60-70°C for 23 hours after rejection filtration to obtain 37.3kg of (E)-4-(imidazolylmethyl)cinnamic acid methyl ester. The yield is 78.5%, the purity is 99.24%, and the appearance is off-white flaky solid.

Embodiment 2

[0043] 1, the preparation of potassium imidazole:

[0044] Put 125 kg of DMF into a 1000L reactor, put in 25.4 kg of potassium hydroxide and 31 kg of imidazole, stir at 14°C for 1 hour; add 60 kg of sodium carbonate, and react at 14°C for 5 hours; ℃ below to obtain spare materials.

[0045] 2. Preparation of methyl (E)-4-(imidazolylmethyl)cinnamate:

[0046] Dissolve 100 kg of methyl p-bromomethyl cinnamate in 110 kg of DMF, control the temperature of the methyl p-bromomethyl cinnamate solution below 15°C and drop in, and continue stirring for 5 hours after dropping; add 600 kg of deionized Stir and crystallize with water, shake off and dry at 60-70°C for 24 hours to obtain 75.5kg of (E)-4-(imidazolylmethyl)cinnamic acid methyl ester. The yield is 79.5%, the purity is 99.2%, and the appearance is off-white flaky solid.

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Abstract

The invention discloses a preparation process of an ozagrel intermediate methyl (E)-4-(imidazolylmethyl) cinnamate. The preparation process comprises the following steps: (1) preparing imidazolium salt: putting DMF (dimethyl formamide) in a reaction kettle, putting potassium hydroxide and imidazole, stirring the materials to react, then adding potassium carbonate, stirring the materials for hours and removing water generated by a reaction system, thus obtaining a DMF solution of imidazolium salt; (2) preparing methyl (E)-4-(imidazolylmethyl) cinnamate: dissolving methyl p-bromomethyl cinnamate in DMF and dropwise adding the solution to the DMF solution of imidazolium salt; adding deionized water and stirring the materials for crystallization, thus obtaining methyl (E)-4-(imidazolylmethyl) cinnamate. The preparation process has the beneficial effects that the appearance of obtained methyl (E)-4-(imidazolylmethyl) cinnamate is obviously changed and methyl (E)-4-(imidazolylmethyl) cinnamate becomes an off-white solid, thus being beneficial to improving the quality of ozagrel; the production cycle is substantially shortened and the material cost is reduced.

Description

technical field [0001] The invention relates to the technical field of preparation of ozagrel intermediates, in particular to a preparation process of ozagrel intermediate (E)-4-(imidazolylmethyl)methyl cinnamate. Background technique [0002] Ozagrel is an antithrombotic drug with a powerful thrombosynthetic enzyme inhibitor, mainly used for the treatment of acute thrombotic cerebral infarction and the movement disorder associated with cerebral infarction; it can also be used for the treatment of bronchial asthma and angina pectoris. Because this drug has broad application prospects, in order to reduce the cost of patients, many pharmaceutical companies are also researching this drug in order to achieve the purpose of high product quality and low cost of raw materials. Because the quality of its key intermediate (E)-4-(imidazolylmethyl)methyl cinnamate directly affects the quality of ozagrel in the preparation process, and the reported preparation methods of this intermedia...

Claims

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Application Information

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IPC IPC(8): C07D233/56
CPCC07D233/56
Inventor 王永广赵忠贵于伟强马见英林军
Owner DEZHOU HANHUA CHEM
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