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

AI Technical Summary

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 CN1018121

Method used

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  • Preparation method of capecitabine

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

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

[0030] 20g of 2',3'-Di-O-acetyl-5'-deoxy-5-fluorocytidine was dissolved in 50ml of dichloromethane at room temperature. 4ml of pyridine was added and stirred until dissolved. 10ml of n-amyl chloroformate was added dropwise at -5°C to -10°C. After the addition is complete, react for 2 hours. Wash with 60 ml of water for 15 minutes, wash twice, discard the water layer to obtain the organic layer. The organic layer was concentrated under reduced pressure until no distillate flowed out. Add 80ml of isopropyl ether and 4ml of acetonitrile to the oil, all dissolved at room temperature, slowly cooled to 0℃~5℃, slowly crystallized to obtain white powder 2', 3' -Di-O-acetyl-5'-deoxy-5-fluoro-N-(n-pentyloxycarbonyl)cytidine 17g, mass yield 85%, purity 99.86%.

Example Embodiment

[0031] Example 2 Preparation of crude capecitabine

[0032] Add 10g of 2',3'-Di-O-acetyl-5'-deoxy-5-fluoro-N-(n-pentyloxycarbonyl)cytidine to 27ml methanol at room temperature to dissolve, and then cool to -7℃ Add 15ml of 5N sodium hydroxide solution dropwise, and after the dropwise addition is completed, react at -3°C for 0.5 hours. After the reaction is complete, add concentrated hydrochloric acid to adjust the pH to 4.5-4.6. After the addition is complete, add 50ml of dichloromethane for 15 minutes, extract twice, combine the organic layers, add 30ml of water and wash for 15 minutes, add anhydrous sodium sulfate to the organic layer After drying, filtering, and concentrating under reduced pressure to viscous, 150ml of toluene was slowly added dropwise to crystallize for 2 hours to obtain 8.7g of crude capecitabine. Filter with suction and wash with toluene. The mass yield is 87%, and the purity is 99.86%.

Example Embodiment

[0033] Example 3 Refining of crude capecitabine

[0034] 3g of the crude capecitabine was dissolved in 10ml of dichloromethane, dissolved at room temperature until clear, 50ml of toluene was added dropwise, after the drop, crystallized for 2 hours. Suction filtration and washing with toluene obtain 2.79 g of capecitabine. 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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