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Preparation method of capecitabine intermediate suitable for industrial production

A technology of capecitabine and intermediates, applied in the field of pharmaceutical drug synthesis, can solve the problems of increased industrial production cost, polyisopropanol solvent, and low production efficiency, and achieve stable yield, high product purity, and reduced processing cost effect

Pending Publication Date: 2021-08-31
SCINOPHARM CHANGSHU PHARMA
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Problems solved by technology

[0004] The above-mentioned distillation replacement method needs to be repeatedly distilled, dichloromethane is removed, and isopropanol is added. In the process route of industrial production of capecitabine intermediates, not only the production efficiency is low, but also more isopropanol is consumed. Solvents increase the cost of industrial production

Method used

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  • Preparation method of capecitabine intermediate suitable for industrial production
  • Preparation method of capecitabine intermediate suitable for industrial production
  • Preparation method of capecitabine intermediate suitable for industrial production

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Embodiment

[0028] A kind of preparation method that is applicable to the capecitabine intermediate of industrialized production, comprises following preparation steps:

[0029] The first step, feeding reaction: After adding acetonitrile, 5-fluorocytosine, hexamethyldisilazane, and trifluoromethanesulfonic acid into the reaction kettle, heat up to reflux, and maintain stirring until the solids are completely dissolved and then continue to reflux At least 2 hours, then lower the temperature to 20~35°C, add 1,2,3-triacetoxy-5-deoxy-D-ribose, then slowly add trifluoromethanesulfonic acid into the reaction kettle through the feeding tank, heat to 45-55°C, and stir for at least 24 hours. In this synthesis temperature range, it is because, in the case of exceeding 55°C, large impurities will be produced, which will affect the yield, and in the case of lower than 45°C, it will affect the reaction. Speed, and finally control the internal temperature of the reactor not higher than 35 ℃.

[0030] ...

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Abstract

The invention discloses a preparation method of a capecitabine intermediate suitable for industrial production. The preparation method of the capecitabine intermediate comprises the following steps: carrying out feeding reaction, namely adding acetonitrile, 5-flucytosine, hexamethyldisilazane, trifluoromethanesulfonic acid, 1,2,3-triacetoxy-5-deoxy-D-ribose and trifluoromethanesulfonic acid into a reaction kettle, and performing stirring; carrying out concentrating reaction, namely performing reduced pressure distillation on the solution in the reaction kettle until the volume is 4 times of the reference volume, and adding dichloromethane which is 5-6 times of the reference volume and a sodium bicarbonate solution with the concentration of 8.9 mol / L; carrying out liquid separation and extraction to obtain an aqueous phase and an organic phase; carrying out equal-liquid-level distillation, namely distilling the organic phase until the volume of the liquid is 2.5 times of the volume of the starting material, maintaining the liquid level by continuously replenishing isopropanol in the subsequent distillation process, and replenishing isopropanol to the distillation end-point liquid level after dichloromethane in the system is removed; and then, carrying outcrystallization and filtration drying to obtain the capecitabine intermediate. According to the method, conventional distillation replacement is replaced by equal-liquid-level distillation operation on time; and moreover, the preparation route is further optimized. Thus, the method is suitable for industrial production and popularization of capecitabine intermediates.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical synthesis, in particular to a method for preparing a capecitabine intermediate suitable for industrial production. Background technique [0002] The chemical name of capecitabine is 5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]cytidine, which is an oral nucleoside antineoplastic drug developed by Roche Pharmaceuticals. Intestinal mucosa is rapidly absorbed, and then converted into an inactive intermediate 5'-deoxy-5'flucytidine by carboxylesterase in the liver, and then converted into 5'-deoxycytidine by the action of cytidine deaminase in the liver and tumor tissue -5'fluorouridine, which is finally catalyzed by thymidine phosphorylase into fluorouracil (5-FU) in tumor tissue; it is mainly used clinically for the treatment of metastatic colorectal cancer, breast cancer, colon cancer and gastric cancer and other malignancies Tumor: According to statistics, in 2016, the global capecitabine API ...

Claims

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Application Information

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IPC IPC(8): C07H19/06C07H1/00C07H1/06
CPCC07H19/06C07H1/00C07H1/06
Inventor 倪梦燚王澄霆
Owner SCINOPHARM CHANGSHU PHARMA
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