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Preparation method of capecitabine

A technology of capecitabine and acetyl, which is applied in the field of drug synthesis, can solve problems such as difficult dissolution, lower product yield, and high cost, and achieve the effects of improving yield and purity, increasing product yield, and saving reaction costs

Inactive Publication Date: 2014-02-26
HARBIN PHARMA GRP CO LTD GENERAL PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Among them, in the step of preparing 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N-(n-pentyloxycarbonyl)cytidine, most of them use anhydrous sodium sulfate for dehydration, For example, patent WO2009 / 082844, resulting in a significant decrease in product yield; in the capecitabine crystallization step, most of them use ethyl acetate for crystallization, such as patent CN101812104 (no patent can be retrieved through the patent publication number, please The inventor checked and corrected), but the capecitabine crude product is not easy to dissolve in ethyl acetate, the crystallization state is not good, the yield is low, the cost is high, the purity after refining is almost the same as the crude product purity, and has no practical significance

Method used

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  • Preparation method of capecitabine

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Effect test

Embodiment 12

[0029] Example 12', Preparation of 3'-di-O-acetyl-5'-deoxy-5-fluoro-N-(n-pentyloxycarbonyl)cytidine

[0030] 20g of 2’,3’-di-O-acetyl-5’-deoxy-5-fluorocytidine was dissolved in 50ml of dichloromethane at room temperature, added 4ml of pyridine, and stirred until dissolved. 10 ml of n-pentyl chloroformate was added dropwise at -5°C to -10°C. After the dropwise addition was completed, the reaction was carried out for 2 hours. Wash with 60 ml of water for 15 minutes, twice, and discard the aqueous layer to obtain an organic layer. Concentrate the organic layer under reduced pressure until no distillate flows out, add 80ml of isopropyl ether and 4ml of acetonitrile into the oily substance, dissolve them all at room temperature, slowly cool down to 0°C-5°C, and slowly crystallize to obtain white powder 2',3' -Di-O-acetyl-5'-deoxy-5-fluoro-N-(n-pentyloxycarbonyl)cytidine 17g, mass yield 85%, purity 99.86%.

Embodiment 2

[0031] The preparation of embodiment 2 capecitabine crude product

[0032] Add 10g of 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N-(n-pentyloxycarbonyl)cytidine to 27ml of methanol at room temperature until dissolved, and cool down to -7°C Add 15 ml of 5N sodium hydroxide solution dropwise, and react at -3°C for 0.5 hours after the dropwise addition. After the reaction is completed, add concentrated hydrochloric acid to adjust the pH to 4.5-4.6. After the dropwise addition, add 50ml of dichloromethane to extract for 15 minutes, extract twice, combine the organic layers, add 30ml of water to wash for 15 minutes, add anhydrous sodium sulfate to the organic layer Dry, filter, concentrate under reduced pressure until viscous, slowly add 150ml of toluene dropwise for crystallization for 2 hours, and obtain 8.7g of crude capecitabine. Suction filtration, washing with toluene. The mass yield is 87%, and the purity is 99.86%.

Embodiment 3

[0033] Embodiment 3 capecitabine crude product refining

[0034] 3g of capecitabine crude product was dissolved in 10ml of dichloromethane, dissolved at room temperature until clarified, 50ml of toluene was added dropwise, and after the dropping, crystallized for 2 hours. Suction filtration and washing with toluene yielded 2.79 g of capecitabine product. The mass yield is 93%, and the purity is 99.96%.

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Abstract

The invention discloses a preparation method of capecitabine. The method employs isopropyl ether and acetonitrile to carry out crystallization on an intermediate 2', 3'-bis-O-acetyl-5'-deoxy-5-fluoro-N-(pentyloxycarbonyl)cytidine, coverts an oil-like matter into a solid, improves the yield and purity of the intermediate, and can achieve precise feeding for the next step reaction, thus greatly lowering the reaction cost. Dichloromethane and toluene are employed to perform crystallization and refine capecitabine, thus overcoming the disadvantages of bad state, low yield and the like in the prior art using ethyl acetate / n-hexane to perform crystallization. Also, the method can effectively remove impurities from a crude product, and can make the purity of a capecitabine product reach 99.96%.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of capecitabine. Background technique [0002] Capecitabine (Capecitabine), chemical name: 5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]cytidine, developed by Roche Pharmaceutical Company (Roche), Switzerland, in April 1998 under the trade name Xeloda (Xeloda) was approved for marketing in the United States, and was approved for import by SFDA in 2000. The dosage form for the market is tablets. Capecitabine is an anti-metabolite fluoropyrimidine deoxynucleoside carbamate that can be converted into 5-FU in the body. It can inhibit cell division and interfere with RNA and protein synthesis. It is suitable for paclitaxel and anthracycline antibiotics Further treatment of advanced primary or metastatic breast cancer that is ineffective with chemotherapy regimens, mainly for the treatment of advanced primary or metastatic breast cancer, rectal cancer, colon cancer and g...

Claims

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Application Information

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IPC IPC(8): C07H19/06C07H1/00
Inventor 马杰王喜军石瑛
Owner HARBIN PHARMA GRP CO LTD GENERAL PHARMA FACTORY
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