Method for synthesizing and preparing pradaxa formamidine intermediates

A dabigatran etexilate and synthetic method technology, applied in the direction of organic chemistry, etc., can solve the problems that alcoholysis impurities cannot be effectively removed, ammonolysis impurities have no refining effect, and impurities cannot be effectively removed, so as to shorten the time of dangerous operations and save energy. Solvent, reduce the effect of equipment pressure resistance

Inactive Publication Date: 2016-02-03
YANTAI DONGCHENG PHARMA GRP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] 2) High equipment requirements
[0012] 3) Ammonolysis impurities are not easy to control
[0016] Patent WO2010 / 45900 adopts ethyl acetate: ethanol = 2: 1 (volume ratio) to carry out recrystallization operation, and it is verified by experiments that the defects of this method are: 1) it can only remove alcoholysis impurities; 2) the product recovery rate is low, only 65 %; 3) there is no refining effect on the ammonolysis impurities, causing the subsequent step product impurities to exceed the standard; 4) this method wastes a large amount of solvent (requires 30 times the quality of solvent relative to the product);
[0018] The patent WO2012 / 77136 adopts ethyl acetate:ethanol=10:1 (volume ratio) for recrystallization operation. It has been verified by experiments that the defects of this method are: 1) alcoholysis impurities cannot be effectively removed, resulting in excessive impurities in the subsequent steps; 4 ) This method wastes a large amount of solvent (requires 100 times the solvent of quality relative to product);
[0019] Patent WO2012 / 152855 uses solvent systems such as ethanol / water / NaOH, water / acetone, methanol / ethyl acetate, and ethanol to wash, filter, and recrystallize the product. The steps are cumbersome, and it has been verified that it cannot effectively remove impurities.

Method used

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  • Method for synthesizing and preparing pradaxa formamidine intermediates
  • Method for synthesizing and preparing pradaxa formamidine intermediates
  • Method for synthesizing and preparing pradaxa formamidine intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] In a 5L dry three-neck round bottom reaction flask, add 3-(3-(2-(4-cyanoanilino)acetamido)4-(methylamino)-N-(pyridin-2-yl)benzene Add 300 g of formamido)-ethyl propionate, add 2.4 L of absolute ethanol, stir and cool down to -10°C. Pass dry hydrogen chloride gas, control the solution temperature below 35°C, until the hydrogen chloride in the solution reaches saturation. Stop feeding hydrogen chloride gas, and raise the temperature to 35°C. After 3.0 hours, HPLC monitoring showed that the remaining raw materials were about 8.2%, and the temperature was raised to 40° C., and excess hydrogen chloride gas was distilled under reduced pressure.

[0041] Add 2.4L of absolute ethanol to the reaction bottle, continue to cool down to 5°C, and pass ammonia gas under stirring to control the solution temperature at 5-15°C. It was detected that the pH of the reaction solution was 9.5, the feeding of ammonia gas was stopped, and the temperature was raised to 30°C. HPLC monitors, an...

Embodiment 8

[0047] In a 50L dry glass double-layer reactor, add 3-(3-(2-(4-cyanoanilino)acetamido)4-(methylamino)-N-(pyridin-2-yl)benzyl Amino)-ethyl propionate 1kg, add 6L absolute ethanol, stir and cool down to -10°C. Start to feed dry hydrogen chloride gas, and control the temperature of the solution to be lower than 30°C until the hydrogen chloride in the solution reaches saturation. Stop feeding hydrogen chloride gas, and raise the temperature to 30°C. After 3.0 hours, HPLC monitoring showed that the remaining raw materials were about 8.9%, and the temperature was raised to 40° C., and excess hydrogen chloride gas was distilled under reduced pressure.

[0048] Add 6L of absolute ethanol to the reaction bottle, continue to cool down to -5°C, and pass ammonia gas under stirring to control the solution temperature at 25-30°C. It was detected that the pH of the reaction solution was 9.5, the feeding of ammonia gas was stopped, and the temperature was raised to 30°C. HPLC monitors, and...

Embodiment 9

[0051] In a 50L dry glass double-layer reactor, add 3-(3-(2-(4-cyanoanilino)acetamido)4-(methylamino)-N-(pyridin-2-yl)benzyl Amino)-ethyl propionate 3kg, add 18L absolute ethanol, stir and cool down to -10°C. Start to feed dry hydrogen chloride gas, and control the temperature of the solution to be lower than 30°C until the hydrogen chloride in the solution reaches saturation. Stop feeding hydrogen chloride gas, and raise the temperature to 30°C. After 3.0 hours, HPLC monitoring showed that the remaining raw materials were about 8.8%, and the temperature was raised to 40° C., and excess hydrogen chloride gas was distilled under reduced pressure.

[0052] Add 18L of absolute ethanol to the reaction flask, continue to cool down to -5°C, and pass ammonia gas under stirring to control the solution temperature at 25-30°C. It was detected that the pH of the reaction solution was 9.5, the feeding of ammonia gas was stopped, and the temperature was raised to 30°C. HPLC monitors, an...

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Abstract

The invention relates to a method for synthesizing and preparing pradaxa formamidine intermediates. A concrete compound refers to 3-(2-(4-guanyl-phenylamino)methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzo[d]imidazole-5-acylamino) alanine ethyl ester hydrochloride. The compound has the main purpose of preparing anticoagulants of methylsulfonic acid pradaxa formamidine. The method has the advantages that a solvent reducing method is adopted; the consumption of HCl/NH3 gas is reduced; in addition, the HCl solution is subjected to pressure reduction distillation under the relative low temperature condition; the distillation time is shortened; the requirements on the pressure resistance performance and the anti-corrosion performance of equipment are lowered; the impurity content is reduced. The invention also adopts a novel purification method; the solvent loss is reduced; the product purity is improved; the product cost is reduced.

Description

technical field [0001] The present invention relates to a kind of method that is used for synthetically preparing and purifying dabigatran etexilidine amidine intermediate, and specific compound refers to 3-(2-(4-amidino-phenylamino)methyl)-1-methyl- N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-amido) ethyl propionate hydrochloride, the main purpose of the compound is to prepare the anticoagulant drug Dabiga methanesulfonate Group esters. Background technique [0002] Dabigatran etexilate mesylate is a new type of synthetic direct thrombin inhibitor, mainly used for the prevention of DVT after total hip / knee arthroplasty, and to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation . At present, the elderly population over 65 years old in China exceeds 150 million, and according to statistics, the prevalence rate of thrombosis in the population over 65 years old is about 20%. In China, there are more than 1 million new ACS (acute cor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 刘兆贵赵永强曹红光祁静仰振球吕慧忠由守谊
Owner YANTAI DONGCHENG PHARMA GRP
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