The industrialized preparation method of Entecavir

Abstract

The invention discloses an industrialized preparation method of entecavir, and belongs to the technical field of organic synthesis. The method comprises the steps of making an Nysted reagent reacted with an intermediate 8, after the reaction is completed, adding quenching liquid and maintaining the pH value of the reaction system to be 7.0-8.5, and after the reaction is completed, obtaining an intermediate 9; making the intermediate 9 reacted with hydrochloric acid, after the reaction is completed, adding an extraction agent and adjusting the pH value to 6.5-7.0, taking an organic phase to beconcentrated to 1 / 15-1 / 10 by volume, and conducting devitrification and solid-liquid separation to obtain an intermediate 10; making the intermediate 10 reacted with boron trichloride in dichloromethane, wherein the mole ratio of the intermediate 10 to boron trichloride is 1:(5-10), and the reaction temperature is minus 30 DEG C to minus 20 DEG C; after the reaction is completed, cooling to minus30 DEG C or below, dropwise adding methyl alcohol, after dropwise adding is completed, drying by distillation and adding methyl alcohol again, conducting pressure reduction concentration, adding an extraction agent which is composed of water and an organic solvent B, taking a water phase, adjusting the pH value to 6.5-7.0, and concentrating and refining to obtain entecavir.

Description

Technical field [0001] The invention relates to the technical field of organic synthesis, in particular to an industrialized preparation method of entecavir. The method adopts a known synthetic route and optimizes the last three steps of the process to adapt to large-scale industrial production. Background technique [0002] Entecavir is a deoxyguanosine compound that can effectively inhibit the replication of hepatitis B virus. It was developed by the Bristol-Myers Squibb company in the United States. It was launched in the United States in April 2005. It is currently a large-scale anti-oxidant in the market. Hepatitis B drugs. In terms of synthesis, the construction of chiral five-membered ring intermediates determines the industrial prospects of the entire synthesis process. For this reason, people have carried out research on the synthesis of intermediates and there are many synthetic methods for entecavir. [0003] For example, Chinese patent ZL91110831.9 and international a...

AI Technical Summary

Problems solved by technology

As the third step disclosed in document 3, not only is the operation complicated, but also affects the yield;

[0018] (3) The reaction process is not well controlled, as in the 3rd step disclosed in document 3, if the speed of adding quenching solution (mixed solution of saturated sodium bicarbonate and chloroform) is too slow, the local reaction solution is acidic and a large amount of by-products will be produced ;

[0019] (4) It is not easy to realize on a large scale, and is only suitable for small-scale production in the laboratory. For example, in the fourth step disclosed in Document 3, after the reaction of intermediate IX with hydrochloric acid, the solvent is usually removed by rotary evaporation to obtain a residue, but the actual situation is that intermediate X It is highly viscous, and it will adhere to the inner wall of the equipment after it is concentrated to a certain extent, and it is very difficult to separate;

[0020] (5) The yield and purity of the crude product are all low, as the total yield of the method disclosed in document 3 is less than 25% (only in the case of 1 decolorization); but the refining process usually requires 2-3 decolorization, 2- Only 4 times of recrystallization can obtain a product with higher purity, and the yield will be lower in order to ensure the purity

[0021] In summary, the existing synthetic methods are not suitable for industrial production

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