Preparation method of ozagrel bulk drug

The technology of raw material drug and ethyl radoxylate, which is applied in the field of improved preparation of ozagrel bulk drug, can solve the problems of human health threat, large environmental pollution, low refining yield and the like, so as to avoid toxic reagents and expensive reagents, environmental The effect of low pollution and high yield

Inactive Publication Date: 2011-11-16
辽宁远大诺康医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the preparation process of intermediate 1, carbon tetrachloride is used as a solvent, which is highly toxic and poses a threat to human health. In the preparation process of intermediate

Method used

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  • Preparation method of ozagrel bulk drug
  • Preparation method of ozagrel bulk drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] The preparation process of ethyl p-bromomethyl cinnamate (intermediate 1) described in the present embodiment is as follows:

[0017] (1), 950g (5mol) ethyl p-methyl cinnamate, 979g (5.5mol) N-bromosuccinimide, 47.5g benzoyl peroxide, and 5000ml ethyl acetate were added to a 10000ml four-necked bottle in turn , stirred and heated to reflux for 6 hours to obtain a light yellow turbid liquid, which was cooled and left to stand overnight. Filter out the white crystals, soak and wash the filter cake with a small amount of ethyl acetate, drain, the filtrate is yellow and transparent, add 200g of anhydrous magnesium sulfate to dry for 1 hour, filter to obtain a yellow transparent liquid, concentrate to dryness under reduced pressure to obtain a yellow viscous liquid, add Absolute ethanol, freeze and stand overnight, filter, soak and wash with a small amount of ice-free ethanol, and dry to obtain 1139 g (4.25 mol) of off-white intermediate 1 p-bromomethyl cinnamate ethyl ester...

Embodiment 2

[0021] The preparation process of ozagrel ethyl ester (intermediate 2) described in this embodiment is as follows:

[0022] (1), 1139g (4.25mol) of intermediate 1, 578g (8.5mol) of imidazole, 476g (8.5mol) of potassium hydroxide and 4500ml of anhydrous ether were sequentially added to a 10000ml four-necked flask, stirred and heated, and refluxed for 6 hours to obtain yellow Cloudy liquid, stand overnight. Filter out the slightly brown solid, concentrate the filtrate to dryness under reduced pressure, add n-hexane to crystallize, suction filter, wash with n-hexane, and dry to obtain 512 g (2 mol) of intermediate 2 ozagrel ethyl ester, melting point 88-90°C, yield 47.1% .

[0023] (2), 1139g (4.25mol) of intermediate 1, 578g (8.5mol) of imidazole, 901g (8.5mol) of anhydrous sodium carbonate and 4500ml of anhydrous ether were sequentially added to a 10000ml four-necked flask, stirred and heated, and refluxed for 6h to obtain Yellow cloudy liquid, stand overnight. The slightly ...

Embodiment 3

[0026] The preparation process of the crude ozagrel described in this embodiment is as follows:

[0027] (1) Dissolve 400g (10mol) of sodium hydroxide in 2500ml of water, stir and add 512g (2mol) of intermediate 2 below 40°C, heat up and reflux for 4h, drop to normal temperature, slowly add hydrochloric acid dropwise below 30°C, and control the pH value 4-5. Stand at room temperature for 2-3 hours, filter, wash with a small amount of water, and dry to obtain 341 g (1.5 mol) of yellow crude ozagrel with a yield of 75%.

[0028] (2) Dissolve 560g (10mol) of potassium hydroxide in 2500ml of water, stir and add 512g (2mol) of intermediate 2 below 40°C, heat up and reflux for 4h, drop to normal temperature, slowly add hydrochloric acid dropwise below 30°C, and control the pH value 4-5. Stand at room temperature for 2-3 hours, filter, wash with a small amount of water, and dry to obtain 316 g (1.39 mol) of yellow crude ozagrel, with a yield of 69.5%.

[0029] (3) Dissolve 480g (12m...

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Abstract

The invention discloses a preparation method of an ozagrel bulk drug. The method comprises the following steps of: bromating methyl ethyl cinnamate serving as a starting material with NBS (B-Bromosuccinimide) to obtain ethyl 4-bromomethylcinnamate; undergoing a condensation reaction on the ethyl 4-bromomethylcinnamate and imidazole to generate ozagrel ethyl ester; hydrolyzing under an alkaline condition; performing acid precipitation to obtain crude ozagrel; and refining to obtain an ozagrel bulk drug. Due to the adoption of the method, a method for refining catalysts, solvents and crude products used in each reaction step is improved, the product yield is high, the product quality is good, the use of toxic reagents and expensive reagents is avoided, little environmental pollution is caused, and the production cost is low. The method is suitable for industrial production, and is an improved and environmentally-friendly method for preparing the ozagrel bulk drug.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an improved preparation method of an ozagrel bulk drug. Background technique [0002] With the development of human society and the aging of the population, the death caused by thrombotic diseases has accounted for 52% of the total death toll in the world. The number of patients with thrombotic diseases continues to increase, and the incidence of thrombotic diseases such as myocardial infarction and cerebral thrombosis is on the rise, which seriously threatens people's health. The incidence of thrombosis in my country has always been very high. According to reports, an average of 1.5 million people die from thrombosis every year, accounting for 40% of the national population death rate, and it is the first cause of population death. Therefore, the research and development of new antithrombotic drugs is an important task for contemporary medical workers. [0003] Ozagrel, Engl...

Claims

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Application Information

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IPC IPC(8): C07D233/64
Inventor 薛百忠石权达王宏英薛雁张广财蒙娅赵凯华
Owner 辽宁远大诺康医药有限公司
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