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Synthesis method of capecitabine intermediate

A technology of capecitabine and synthesis method, which is applied in chemical instruments and methods, preparation of sugar derivatives, sugar derivatives, etc., can solve the problems of high market price of n-amyl chloroformate, increase of production cost, etc., and achieve favorable Industrial production, less by-products, and the effect of avoiding impurities

Inactive Publication Date: 2018-04-20
SHANDONG BOYUAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

And the market price of n-pentyl chloroformate is relatively high, about 130 yuan / kg, which increases the production cost

Method used

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  • Synthesis method of capecitabine intermediate
  • Synthesis method of capecitabine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1. Add 500ml of dichloromethane, 75g of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine, 44.3g of carbonyldiimidazole, and 22g of n-pentanol into a 1000ml reaction flask , and react at a temperature of 20°C for 4 hours, monitor the end point of the reaction by TLC (developer, dichloromethane:methanol=20:1), add 200ml of 10% hydrochloric acid solution to the reaction solution for washing, separate the organic layer, wash with 200ml of purified water, Separate the organic layer, control the temperature of the water bath at 50°C, concentrate the organic layer to dryness under reduced pressure, add 150ml of ethyl acetate and 300ml of n-hexane to the residue and stir for 30 minutes, lower the temperature below 10°C, and start suction filtration to obtain a white solid. Dry at 65°C to obtain 92.5 g of 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N4-(n-pentyloxycarbonyl)cytidine, with a yield of 91.6% and a purity of 99.6% .

Embodiment 2

[0025] Example 2. Add 660ml of dichloromethane, 97.8g of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine, 56.9g of carbonyldiimidazole, and n-amyl alcohol into a 1000ml reaction flask 29.1g, reacted at 20°C for 4 hours, monitored the reaction end point by TLC (developing solvent, dichloromethane:methanol=20:1), added 250ml of 10% hydrochloric acid solution to the reaction solution for washing, separated the organic layer, and washed with 250ml of purified water Wash, separate the organic layer, control the temperature of the water bath at 55°C, concentrate the organic layer to dryness under reduced pressure, add 170ml of ethyl acetate and 340ml of n-hexane to the residue and stir for 30 minutes, lower the temperature below 10°C, and start suction filtration to obtain a white solid , controlled temperature at 70°C, dried to obtain 120.9g of 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N4-n-pentyloxycarbonyl cytidine, yield 91.5%, purity 99.6% .

Embodiment 3

[0026] Example 3. Add 600ml of dichloromethane, 84.8g of 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine, 48.6g of carbonyldiimidazole, and n-amyl alcohol into a 1000ml reaction flask 25.2g, reacted at 20°C for 4 hours, monitored the reaction end point by TLC (developer, dichloromethane:methanol=20:1), added 220ml of 10% hydrochloric acid solution to the reaction solution for washing, separated the organic layer, and washed with 220ml of purified water Wash, separate the organic layer, control the temperature of the water bath at 60°C, concentrate the organic layer to dryness under reduced pressure, add 160ml of ethyl acetate and 320ml of n-hexane to the residue and stir for 30 minutes, lower the temperature below 10°C, and start suction filtration to obtain a white solid , controlled temperature at 65°C, dried to obtain 104.8g of 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N4-n-pentyloxycarbonylcytidine, yield 91.6%, purity 99.7% .

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Abstract

The invention provides a synthesis method of a capecitabine intermediate. The synthesis method comprises the following steps of performing a reaction on 2',3'-di-O-acetyl-5'-deoxy-5-fluorocytidine, carbonyldiimidazole and n-pentanol at a low temperature to produce 2', 3'-di-O-acetyl-5'-deoxy-5-fluoro-N4-(n-pentyloxycarbonyl) cytidine. By the synthesis method, the reaction yield is increased, and the yield is higher than or equal to 91%. By the synthesis method, the step is simple, the operation is convenient, few byproducts are produced, and industrial production is facilitated.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a method for synthesizing a capecitabine intermediate. Background technique [0002] Capecitabine (Capecitabine) is an anti-metabolite fluoropyrimidine deoxynucleoside carbamate drug that can be converted into 5-FU in the body. It is developed by Roche and its trade name is Xeloda. It can inhibit cell division and interfere with RNA and protein synthesis. It is suitable for the further treatment of advanced primary or metastatic breast cancer that is ineffective in paclitaxel and chemotherapy regimens including anthracyclines. It is mainly used for the treatment of advanced primary or metastatic breast cancer, rectal cancer, colon cancer and gastric cancer. Capecitabine is contraindicated in patients with severe side effects of Xeloda or history of allergy to fluorouracil (capecitabine metabolite). [0003] 2',3'-Di-O-acetyl-5'-deoxy-5-fluoro-N4-n-pentyloxycarbonyl cytidine i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/06C07H1/00
Inventor 赵孝杰苏曼
Owner SHANDONG BOYUAN PHARM CO LTD
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