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Preparation method of 2'3'-di-O-acetyl-5'-desoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine

A technology of pentoxycarbonyl and acetyl groups, which is applied in the preparation of sugar derivatives, chemical instruments and methods, sugar derivatives, etc., can solve the problems of difficult removal of pyridine, high residue of pyridine, difficult treatment of waste water, etc., and achieve good product quality, The effect of less environmental hazard and short reaction time

Inactive Publication Date: 2013-03-20
QILU TIANHE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The organic base pyridine is used in the above route. It is difficult to remove pyridine during the post-treatment process. The residue of pyridine is high and the toxicity is very high. In addition, due to the mutual solubility of pyridine in the organic phase and the water phase, the waste water is difficult to treat and causes environmental pollution.

Method used

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  • Preparation method of 2'3'-di-O-acetyl-5'-desoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine
  • Preparation method of 2'3'-di-O-acetyl-5'-desoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine
  • Preparation method of 2'3'-di-O-acetyl-5'-desoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Put 32.9g (0.1mol) of 2'3'-di-O-acetyl-5'-deoxy-5-fluorocytidine, 380ml of dichloromethane, and 63.6g of anhydrous sodium carbonate into a 1000ml three-necked flask. ), 0.24g (2mmol) of 4-dimethylaminopyridine, 5ml (2mmol) of 10% tetra-n-butylammonium hydroxide, 42.5ml (0.3mol) of n-pentyl chloroformate was added dropwise at room temperature, after addition, the temperature was raised to reflux for 5h, Cool down to room temperature, filter the reaction system with suction, add 70ml of purified water to the filtrate, stir, let stand for stratification, discard the water layer, stir the organic phase with 70ml of saturated sodium bicarbonate solution, let stand for stratification, discard the water layer, do not use directly proceed to the next reaction; or continue to add 30g of anhydrous sodium sulfate to the organic phase to dry, filter, concentrate the filtrate to dryness under reduced pressure, and recrystallize with ether to obtain a white solid 2'3'-di-O-acetyl -5'...

Embodiment 2

[0029] Put 32.9g (0.1mol) of 2'3'-di-O-acetyl-5'-deoxy-5-fluorocytidine, 380ml of dichloromethane, and 82.8g of anhydrous potassium carbonate into a 1000ml three-necked flask. ), 0.24g (2mmol) of 4-dimethylaminopyridine, 5ml (2mmol) of 10% tetra-n-butylammonium hydroxide, 42.5ml (0.3mol) of n-pentyl chloroformate was added dropwise at room temperature, after the addition was completed, the temperature was raised to reflux for 9h, Cool down to room temperature, filter the reaction system with suction, add 70ml of purified water to the filtrate, stir, let stand for stratification, discard the water layer, stir the organic phase with 70ml of saturated sodium bicarbonate solution, let stand for stratification, discard the water layer, do not use directly proceed to the next reaction; or continue to add 30g of anhydrous sodium sulfate to the organic phase to dry, filter, concentrate the filtrate to dryness under reduced pressure, and recrystallize with ether to obtain a white solid ...

Embodiment 3

[0031] Put 32.9g (0.1mol) of 2'3'-di-O-acetyl-5'-deoxy-5-fluorocytidine, 380ml of dichloromethane, and 63.6g of anhydrous sodium carbonate into a 1000ml three-necked flask. ), 0.24g (2mmol) of 4-dimethylaminopyridine, 10ml (4mmol) of 10% tetra-n-butylammonium hydroxide, 42.5ml (0.3mol) of n-pentyl chloroformate was added dropwise at room temperature, after the addition was completed, the temperature was raised to reflux for 5h, Cool down to room temperature, filter the reaction system with suction, add 70ml of purified water to the filtrate, stir, let stand for stratification, discard the water layer, stir the organic phase with 70ml of saturated sodium bicarbonate solution, let stand for stratification, discard the water layer, do not use directly proceed to the next reaction; or continue to add 30g of anhydrous sodium sulfate to the organic phase to dry, filter, concentrate the filtrate to dryness under reduced pressure, and recrystallize with ether to obtain a white solid 2'...

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Abstract

The invention relates to a preparation method of 2'3'-di-O-acetyl-5'-desoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine, belonging to the technical field of medicine. The compound is an important intermediate of Capecitabine. The preparation method comprises the following step: by using anhydrous sodium carbonate or anhydrous potassium carbonate as alkali, quaternary ammonium salt as a phase-transfer catalyst and 4-substituted-pyridine as a catalyst, carrying out amidation reaction on 2'3'-di-O-acetyl-5'-desoxy-5-fluorocytidine and amyl chloroformate to obtain the 2'3'-di-O-acetyl-5'-desoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine. The invention adopts the anhydrous sodium carbonate or anhydrous potassium carbonate instead of the high-toxicity organic alkali pyridine, and obtains ideal yield and product purity. The method has the advantages of accessible raw materials, low cost, small environmental hazard, high safety and reliability, short reaction time and good product quality.

Description

technical field [0001] The invention relates to a preparation method of 2'3'-di-O-acetyl-5'-deoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine, an important intermediate of capecitabine, and belongs to the technical field of medicine. Background technique [0002] Capecitabine (trade name Xeloda) was developed by the Swiss Roche Pharmaceutical Company and first launched in the United States in May 1998. It is the only oral fluorouracil drug approved by the FDA so far, and it is also the most biologically active oral fluorouracil. Drugs that can reach or even exceed the curative effect of intravenous administration of other fluorouracil drugs. It is currently on sale in countries such as the United States, Canada, Sweden and China. Capecitabine has an ingenious structural design and a unique activation mechanism, which successfully improves its anti-tumor specificity. [0003] 2'3'-di-O-acetyl-5'-deoxy-5-fluoro-N4-(pentyloxycarbonyl) cytidine is an important intermediate of cape...

Claims

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Application Information

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IPC IPC(8): C07H19/06C07H1/00
Inventor 杜云锋张小勇李保勇樊长莹陈中南
Owner QILU TIANHE PHARMA
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