Novel method for producing dabigatran etexilate

Abstract

The invention relates to a novel method for synthesizing dabigatran etexilate. The method comprises the following steps of: 1, performing an esterification reaction by using methylamino-m-nitrobenzoate (D1) as a raw material to obtain an esterification product (D2); 2, reducing the nitryl of the obtained esterification product (D2) into amino to obtain a reducing product (D3); 3, reacting the reducing product (D3) with a compound (D10) to obtain an intermediate (D4); 4, reacting the intermediate (D4) with hydrogen to obtain an intermediate (D5); 5, reacting the intermediate (D5) with chloroformate to obtain an intermediate (D6); 6, removing the R1-O- from the intermediate (D6) to obtain an intermediate (D7); and 7, reacting the intermediate (D7) with a reaction raw material (D8) to obtain the dabigatran etexilate (D9). According to the novel method for synthesizing the dabigatran etexilate, the required raw materials and reagents are cheap and easily available, and the cost is low; reaction at each step is good, the selectivity is high, the synthesis method is simple to operate, and the condition is mild; the total yield can reach 52 percent and the purity is over 99 percent; the method is less in emission of three wastes, environment-friendly and suitable for industrialized mass production; and the dabigatran etexilate has stable quality and accords with the requirement of serving as a medicine intermediate.

Description

technical field [0001] The present invention relates to a kind of production method of compound, relate in particular to a kind of novel production method of dabigatran etexilate. Background technique [0002] Dabigatran etexilate is a new synthetic direct thrombin inhibitor, which is the prodrug of dabigatran, which is a non-peptide thrombin inhibitor. After oral administration and gastrointestinal absorption, it is transformed into dabigatran with direct anticoagulant activity in vivo. Dabigatran binds to the fibrin-specific binding site of thrombin, preventing fibrinogen from being cleaved into fibrin, thereby blocking the final step of the coagulation cascade network and thrombus formation. Dabigatran can dissociate from the fibrin-thrombin complex, Play a reversible anticoagulant effect. [0003] Dabigatran etexilate is the most cutting-edge new generation of oral anticoagulant direct thrombin inhibitors (DTIs), aiming at the urgent clinical needs of prevention and tr...

AI Technical Summary

Problems solved by technology

Above-mentioned these shortcomings, make the method for this synthetic dabigatran etexilate be unsuitable for the enlarged production of industrial grade

The selectivity of the subsequent amidination reaction is also poor, resulting in strongly acidic wastewater

And because n-hexyl chloroformate contains more isomer impurities, as the main raw material of the last step reaction, the final product needs to be refined many times to make a qualified product, and the cost is high

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