Novel technology for synthesis of capecitabine

A capecitabine and synthetic process technology, applied in the field of medicinal chemistry, can solve problems such as long route and complicated operation, and achieve the effects of reducing environmental pollution, convenient post-processing, and improving product yield

Inactive Publication Date: 2013-09-11
北京博时安泰科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The raw materials of this method are easy to get and the price is cheap, but the route is long and the operation is slightly complicated

Method used

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  • Novel technology for synthesis of capecitabine
  • Novel technology for synthesis of capecitabine
  • Novel technology for synthesis of capecitabine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Synthesis of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine (3):

[0044] Add 332.1g of trimethylsilyl-protected 5-fluorocytosine (1) into 1200mL of dichloromethane, stir to dissolve, then add 345.9g of 5-deoxy-1,2,3-tri-O-acetyl-D- Ribofuranose (2), stirred for a while, partially dissolved, and added dropwise 322.4g (96.2mmol) trimethylsilyl trifluoromethanesulfonate (TMSOTf) in 300mL DCM solution to the above reaction solution at room temperature, controlled temperature 20~ Between 25°C, after dropping, stir at room temperature for about 15h, TLC monitors that the reaction is complete (developer: DCM:MeOH=15:1), control the temperature at 20°C, add 3900ml saturated sodium bicarbonate solution to the reaction solution, and Stir at low temperature for 1 h, separate the liquids, extract the aqueous phase twice with 1300 mL of dichloromethane, combine the organic phases, wash once with 20% aqueous sodium chloride solution, once with saturated brine, dry over anhydrous sodium...

Embodiment 2

[0046] 2',3'-Di-O-acetyl-5'-deoxy-5-fluoro- N Synthesis of -[(pentyloxy)carbonyl]cytidine (4):

[0047] Dissolve 108 g of intermediate 3 (5'-deoxy-2',3'-di-O-acetyl-5-fluorocytidine) in 900 mL of anhydrous CH at room temperature 2 Cl 2 Add 51.9g of anhydrous pyridine, cool and control the temperature between -5~-10°C, add dropwise a solution of 69.2g of n-pentyl chloroformate dissolved in 100mL of anhydrous DCM to the above reaction solution, dropwise, and react at room temperature 1h, TLC monitoring (developing solvent: DCM; MeOH=15:1) After the reaction of intermediate 3 is complete, add 75mL of methanol, stir for 15min, add 330mL of pure water for extraction, and then extract the aqueous layer twice with 110mL of DCM, combine the organic phase, 20 % sodium chloride aqueous solution was washed once, saturated sodium chloride aqueous solution was washed once, dried over anhydrous sodium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pr...

Embodiment 3

[0049] Synthesis of capecitabine:

[0050] Intermediate 4 (2',3'-di-O-acetyl-5'-deoxy-5-fluoro- N -[(pentyloxy)carbonyl]cytidine) 110g was dissolved in 330mL of methanol, the temperature was controlled between -15~-20°C, and 120mL of methanol solution containing 13.4g of sodium methoxide was added dropwise, and the temperature was controlled to react 15min, TLC monitoring (developing agent: DCM:MeOH=50:1,) the reaction is complete, add 2N hydrochloric acid dropwise to the above reaction solution at low temperature to adjust the pH of the reaction solution to 5~6, evaporate methanol under reduced pressure at 40°C, add Extract with 1000mL DCM, wash the organic phase once with distilled water, wash the organic phase once with 20% aqueous sodium chloride solution, dry over anhydrous sodium sulfate, filter off the desiccant, distill off the solvent under reduced pressure at 40°C to obtain 98.3g of crude product, and wash with 500mL acetic acid Ethyl ester was recrystallized and dr...

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Abstract

The invention relates to a novel technology for synthesis of capecitabine. The technology is characterized in that: 5-fluorocytosine protected by trimethyl silicon is taken as raw material; and the capecitabine is obtained after condensation, esterification and deacetylation. The Reaction sequence is more economically reasonable, the synthetic route is short, the cost is low, the operation is simplified, the yield is high, the synthetic period is short, the quality of intermediates can be controlled, solvents used in reaction are few, pollution to the environment is little, and the technology is suitable for industrial production. Comparing the technology with the prior art for capecitabine production, trimethylsilyl trifluoromethanesulfonate (TMSOTf) which replaces a heavy metal agent stannic chloride is used as a condensing agent for glycosylation (condensation), and a sodium methoxide / methanol system replaces an ammonia gas / methanol system for deacetylation, so that the production yield is increased, and heavy metal residues of the products and the environmental pollution are reduced. The overall yield of the technology of the invention reaches 59%, the purity of the production is high and meets the standards of the United States Pharmacopeia.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a new process for synthesizing antitumor drug capecitabine. Background technique [0002] Capecitabine (capecitabine, such as Figure I ), the chemical name is 5'-deoxy-5-fluoro- N -[(Pentyloxy)carbonyl]cytidine, developed by Swiss Hoffmann-LaRoche Company, was first launched in Switzerland in 1998, and was approved for marketing in my country in October 2000. The product name is Xeloda. Xeloda is the only brand in the domestic capecitabine market, which is mainly monopolized by Hoffman-Roche and Shanghai Roche. This product is a new type of oral flucytosine nucleoside analogue, which has no cytotoxicity itself, and is metabolized into 5-fluorouracil (5-FU) under the action of enzymes in the body, and then exerts anti-tumor effect. It is mainly used clinically for the treatment of advanced breast cancer Carcinoma, colorectal cancer and other solid tumors...

Claims

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Application Information

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IPC IPC(8): C07H19/06C07H1/00
Inventor 颜文革漆新国孟永刚张典鹏刘念
Owner 北京博时安泰科技发展有限公司
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