Preparation method of Ozagrel sodium

A technology of sodium ozagrel and sodium hydroxide, which is applied in the field of medicine, can solve the problems that acetone is easy to produce poison, the yield and purity of ethyl ozagrel are affected, and the synthesis reaction time of ethyl imidazole methyl cinnamate is long, and the like, To achieve the effect of improving yield and purity

Inactive Publication Date: 2018-02-16
浙江科瑞医药科技有限公司
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Problems solved by technology

[0005] But, p-bromomethyl cinnamate ethyl and imidazole are the reaction carried out in the acetone solution in the above-mentioned method, and acetone belongs to precursor, and purchase and management all have larger problem; Secondly, p-bromomethyl cinnamate and imidazole In the...

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  • Preparation method of Ozagrel sodium
  • Preparation method of Ozagrel sodium
  • Preparation method of Ozagrel sodium

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Embodiment 1

[0034] A kind of preparation method of ozagrel sodium, concrete steps are as follows:

[0035] (1) Put 20g of ethyl p-methylcinnamate in a three-necked flask, add 0.05g of azoisobutyronitrile, 50ml of acetonitrile, and heat to 65°C; then add 20.6g of N-bromosuccinimide , warming up to 80° C., reflux reaction for 2 hours, sampling, detection (HPLC) purity of ethyl p-bromomethyl cinnamate: 81.01%, stop the reaction to obtain reaction solution I.

[0036] After the reaction, the solvent acetonitrile (60° C.) of the reaction solution I was vacuum distilled to obtain an oily substance (containing solid granular substances, mainly succinimide); 40 ml of ethyl acetate was added to the oily substance, and stirred for 0.5 h Afterwards, filter, filter out the insoluble matter (succinimide), wash the solid with a small amount of ethyl acetate, add 40ml of water to the ethyl acetate, stir for 15min, let stand to separate the layers, separate the water layer and the ethyl acetate layer ; ...

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Abstract

The invention discloses a preparation method of Ozagrel sodium. The method comprises the following steps: performing a bromination reaction on ethyl 4-methylcinnamate and N-bromo-succinimide by takingacetonitrile as a solvent under the triggering of azodiisobutyronitrile, so as to obtain ethyl 4-bromomethylcinnamate; performing a condensation cyclization reaction on the ethyl 4-bromomethylcinnamate and imidazole by taking sodium hydroxide as an acid-binding agent and taking tetrahydrofuran as a solvent, so as to obtain imidazole ethyl 4-methylcinnamate; performing alkali hydrolysis on the imidazole ethyl 4-methylcinnamate, so as to obtain the Ozagrel sodium. According to the preparation method, the condensation cyclization reaction is performed by taking the sodium hydroxide as the acid-binding agent and taking the tetrahydrofuran as the solvent, so that the finally obtained product does not contain toxic components, the yield and the purity of the product can be effectively improved,and the content of genotoxic impurities (the ethyl 4-bromomethylcinnamate and ethyl 4-dibromomethylcinnamate) in the product is zero.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of ozagrel sodium. Background technique [0002] Sodium ozagrel, whose chemical name is trans-3-[4-(1H-imidazole-1-methyl)phenyl]-2-sodium acrylate, was established in 1989 by Japan Ono Pharmaceutical Co., Ltd. The first thromboxane synthase inhibitor to be marketed under the trade name Cataclot; it blocks prostaglandin (PGH 2 ) generates thromboxane (TXA 2 ), promote platelet-derived PGH 2 Turn to endothelial cells, which synthesize PGI 2 , thus improving the TXA 2 PGI 2 abnormal balance. Ozagrel sodium has the effect of inhibiting platelet aggregation and dilating blood vessels. Clinically, Ozagrena is mainly used for the treatment of acute thrombotic cerebral infarction and the movement disorder associated with cerebral infarction. [0003] At present, there are several synthesis routes of ozagrel sodium, the commonly used one is to bromide the p-...

Claims

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Application Information

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IPC IPC(8): C07D233/56
CPCC07D233/56
Inventor 斯卫东程绍红马华仕施蒋伟吴海立
Owner 浙江科瑞医药科技有限公司
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