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A kind of preparation method of high-purity capecitabine

A capecitabine, high-purity technology, applied in the field of medicine and chemical industry, can solve the problems of poor impurity removal effect, cumbersome operation, and high cost, and achieve the effect of good removal effect, simple operation, and low cost

Active Publication Date: 2014-10-22
福安药业集团重庆博圣制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The inventors of the present invention surprisingly developed a preparation method of high-purity capecitabine, which overcomes the defects of poor impurity removal effect, cumbersome operation, low yield and high cost in the prior art

Method used

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Experimental program
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Effect test

Embodiment 1

[0034] Add capecitabine precursor-5′-deoxy-2′,3′-di-O-acetyl-N-[(n-pentyloxy)carbonyl]-5-fluorocytidine 16g into a 250ml three-necked flask, Add 100ml of methanol to dissolve, cool down to 0°C, add 27ml of 2N sodium hydroxide solution dropwise, keep the temperature for 3-5 hours, add 2N hydrochloric acid dropwise to adjust the pH to 6-7, evaporate most of the methanol under reduced pressure, and add 40ml of methyl The organic layer was extracted with tert-butyl ether, the aqueous layer was extracted twice with 30ml methyl tert-butyl ether, the organic layers were combined, washed with 50ml of saturated saline, washed with 25ml of water, dried over anhydrous sodium sulfate, filtered, and added dropwise at 25°C Heptane 500ml, precipitated product, filtered, and vacuum dried at 40°C for 6 hours to obtain capecitabine as a white solid, dry weight: 11.6g, yield: 93.2%, HPLC purity: 99.83%. m.p.112.5~113.5℃; 1 H-NMR (400Hz, DMSO-d 6 )δ: 0.90-0.93 (t, J=6.9Hz, 3H, CH 2 CH 3 ), 1....

Embodiment 2

[0036]Add capecitabine precursor-5'-deoxy-2',3'-di-O-acetyl-N-[(n-pentyloxy)carbonyl]-5-fluorocytidine 20g into a 250ml three-necked flask, Add 100ml of methanol to dissolve, cool down to 0°C, add 34ml of 2N sodium hydroxide solution dropwise, keep the temperature for 3 hours, add 2N hydrochloric acid dropwise to adjust the pH to 6-7, evaporate most of the methanol under reduced pressure, add 40ml of dichloromethane to extract The organic layer and the aqueous layer were extracted twice with 25ml of dichloromethane, the organic layers were combined, washed with 60ml of saturated brine, washed with 60ml of water, dried over anhydrous sodium sulfate, filtered, and 290ml of n-hexane was added dropwise at 25°C to precipitate the product, filtered, Vacuum drying at 40°C for 6 hours yielded capecitabine as a white solid, dry weight: 14.5 g, yield: 89.5%, HPLC purity: 99.86%.

Embodiment 3

[0038] Add 50 g of capecitabine precursor—5′-deoxy-2′,3′-di-O-acetyl-N-[(n-pentyloxy)carbonyl]-5-fluorocytidine into a 1L three-necked flask, Dissolve in 500ml of methanol, cool down to -5°C, add 85ml of 2N sodium hydroxide solution dropwise, keep the temperature for 5 hours, add 2N hydrochloric acid dropwise to adjust the pH to 6-7, evaporate most of the methanol under reduced pressure, add 100ml of methyl tert-butyl Extract the organic layer with base ether, extract the aqueous layer twice with 60ml methyl tert-butyl ether, combine the organic layers, wash with 150ml of saturated brine, wash with 100ml of water, dry over anhydrous sodium sulfate, filter, and add 720ml of n-hexane dropwise at 25°C , the product was precipitated, filtered, and vacuum-dried at 40° C. for 6 hours to obtain a white solid, namely capecitabine, with a dry weight of 36.8 g, a yield of 91%, and a HPLC purity of 99.92%.

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Abstract

The invention discloses a preparation method of high-purity capecitabine, which is characterized in that capecitabine precursor-5'-deoxy-2',3'-di-O-acetyl-N-[(normal The sodium hydroxide hydrolyzate of pentyloxy)carbonyl]-5-fluorocytidine is adjusted to pH, concentrated, extracted with organic solvents such as ethers or halogenated hydrocarbons, dried, and directly added to alkane organic solvents without distillation; High purity capecitabine. The present invention designs a brand-new capecitabine refining method, so that the purity of the capecitabine is obviously improved, and the yield is significantly increased. Compared with the previous refining process, it has the advantages of good impurity removal effect, high yield, safe and simple operation, and easy large-scale industrial production.

Description

technical field [0001] The invention relates to pharmaceutical chemical technology, in particular to a preparation method of high-purity capecitabine. Background technique [0002] Capecitabine (Capecitabine) is a new type of anti-tumor drug developed by Roche, Switzerland. It was approved by the FDA in 1998 and listed in the United States. The trade name is XELODA (Xeloda); Further treatment of advanced primary or metastatic breast cancer that is ineffective in regimen treatment; it is also applicable to the treatment of colon cancer and rectal cancer. [0003] Capecitabine was first synthesized by Roche, as reported in European Patent EP602454A1 published in 1994. In this patent, the post-treatment and refining method for preparing the finished product of capecitabine is as follows: the precursor of capecitabine——5′-deoxy-2′, 3′-di-O-acetyl-N-[(normal After hydrolysis of pentyloxy)carbonyl]-5-fluorocytidine, dichloromethane was used as the extraction solvent, evaporated ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/06C07H1/06
Inventor 陈小勇李佩杰冯秀梅付飞徐霞张稳稳
Owner 福安药业集团重庆博圣制药有限公司
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