Synthesis method of dabigatran etexilate

Abstract

The invention relates to a synthetic method of dabigatran etexilate, which comprises the following steps: adding (Z)-hexyl (amino (4-aminophenyl) methylene) carbamate into a reaction flask filled with a solvent, dropwise adding a sodium hydroxide solution, heating for dissolving, separating liquid, and retaining an organic phase; adding sodium iodide, sodium bicarbonate, tetrabutylammonium bromide and 3-(1-(2-(chloromethyl)-1H-indole-5-yl) vinyl) (phenyl) amino) ethyl propionate into the organic phase, and performing liquid separation, cooling crystallization and centrifugation after the reaction is completed to obtain a dabigatran etexilate crude product; and refining the crude product of dabigatran etexilate to obtain a refined product of dabigatran etexilate. The synthesis route is simple, the cost is low, the amount of three wastes is small, the method is green and environment-friendly, the product purity is high, and the method is more suitable for large-scale industrial production; the molar yield of the obtained product is about 96%, the purity is about 99.8%, which is higher than 99.71% reported in the current literature, and the maximum single impurity is less than 0.1%, so that the requirements on next-step synthesis of the dabigatran etexilate mesylate are met.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical industry, in particular to a synthetic method of dabigatran etexilate. Background technique [0002] Dabigatran etexilate is an important intermediate of oral anticoagulant dabigatran etexilate mesylate, and its structural formula is as follows: [0003] [0004] Dabigatran etexilate mesylate is a new type of oral anticoagulant, which binds to the fibrin-specific binding site of thrombin potently, competitively and reversibly, thereby blocking the synthesis of fibrin and inhibiting the thrombus. form. Dabigatran etexilate is a small-molecule prodrug without any pharmacological activity itself. After oral administration, it is metabolized into the active ingredient in the body, and dabigatran exerts the pharmacological effect of anticoagulant. Dabigatran etexilate can be administered orally, and there is no need to frequently detect blood coagulation function and adjust the dosag...

AI Technical Summary

Problems solved by technology

[0007] This method has the following defects: the used solvent butyl acetate is expensive on the market and is not easy to purchase, so the production cost is high; the method shows high yield, but the product purity is unknown, which is not conducive to large-scale industrial production; Cyclohexane increases the types of solvents used, which is not conducive to the establishment of standards and further increases the cost

And the synthetic method of dabigatran etexilate of other reports, the overwhelming majority all is to adopt direct synthetic method, and synthetic step is loaded down with trivial details complicated, is unfavorable for suitability for industrialized production

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