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Method for purifying kilogram-grade dabigatran etexilate free alkali

A technology for dabigatran etexilate and a purification method is applied in the field of purifying kilogram-level crude dabigatran etexilate free base, which can solve the problems such as the inability to reduce the content of new impurities, and achieve the effect of reducing the difficulty of removing impurities

Inactive Publication Date: 2016-05-25
YANTAI DONGCHENG PHARMA GRP
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But along with the enlargement of experimental scale (kilogram level), new impurity appeared, and original method can't reduce the content of new impurity (impurity B), in view of this impurity belongs to unknown impurity, its pharmacological and toxicological property also belongs to unknown, therefore New purification methods must be explored to reduce its content

Method used

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  • Method for purifying kilogram-grade dabigatran etexilate free alkali
  • Method for purifying kilogram-grade dabigatran etexilate free alkali
  • Method for purifying kilogram-grade dabigatran etexilate free alkali

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Embodiment 1

[0026] Take by weighing 2752g of amidinated product, according to the patent US98802623.6, YuChen published the preparation method in HETEROCYCLES and Hauel, NorbertH. in Journal of Medicinal Chemistry, through procedures such as washing with water, drying, distillation, ethyl acetate recrystallization, obtain dabigatran etexilate Free alkali crude product 2513g (HPLC sees figure 1 ).

[0027] Dissolve the crude product in 10L of dichloromethane, add 100-200 mesh silica gel (600g) for column chromatography, stir at 25°C for 3h, filter with suction, wash the silica gel layer with 1L of dichloromethane, and distill the combined organic phases under reduced pressure (40°C , -0.09MPa), until no dichloromethane flows out.

[0028] Add 20 L of ethyl acetate and heat to 60°C to dissolve, stir overnight, and crystallize.

[0029] Suction filter, wash the filter cake with 2.0L ethyl acetate, and dry the filter cake in vacuum for 12 hours.

[0030] Weighing, dabigatran etexilate free...

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Abstract

The invention relates to a method for purifying a kilogram-grade dabigatran etexilate free alkali crude product, wherein a compound specifically refers to 3-(2-(4-amidino(hexyloxy carbonyl)-phenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-amido)ethyl propionate, and has the main use for preparing an anti-coagulant drug dabigatran etexilate mesylate. With adopting of a relatively simple purification method, the content of new impurities appearing in a process of kilogram-grade preparation of the dabigatran etexilate free alkali is effectively reduced, so that design and development of new pharmacological and toxicological tests are avoided. The purity of the product is also improved, and the preparation cost is reduced.

Description

technical field [0001] The present invention relates to a kind of method that is used for purifying the crude product of dabigatran etexilate free alkali in kilogram level, and concrete compound refers to 3-(2-(4-amidino (n-hexyloxycarbonyl)-phenylamino) methyl)-1 -Methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-amido)ethyl propionate, the main purpose of the compound is to prepare the anticoagulant drug Darby Methanesulfonate Gatrene etexilate. 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...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 刘兆贵赵永强祁静仰振球吕慧忠由守谊
Owner YANTAI DONGCHENG PHARMA GRP
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