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Preparation method of 2'-3'-bis-O-acetyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine

A technology of cytidine nucleoside and pentyloxy, applied in the field of medicinal chemistry, can solve the problems of difficult purification of final products, difficult treatment of waste water, high toxicity of pyridine, etc., and achieve the effects of avoiding pyridine residues, reducing production costs, and high product purity

Active Publication Date: 2017-03-08
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the above route, the reaction of the compound of formula IV and n-pentyl chloroformate to obtain the compound of formula V uses pyridine as a condensation agent, and pyridine is more toxic and easily causes solvent residues, which causes greater difficulties in the purification of the final product as a drug; at the same time , Pyridine is miscible in the organic phase and the water phase, and the waste water is not easy to treat, causing environmental pollution

Method used

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  • Preparation method of 2'-3'-bis-O-acetyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine
  • Preparation method of 2'-3'-bis-O-acetyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine
  • Preparation method of 2'-3'-bis-O-acetyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine

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Experimental program
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Effect test

Embodiment 1

[0040] Formula IV compound (100g, 0.30mol), K 3 PO 4(95.5g, 0.45mol), solvent (800mL, isopropanol:dichloromethane=1.0:2.0, volume ratio) were put into the reaction flat bottle, under nitrogen protection, the temperature was lowered to 0-10°C, and chloroformic acid was added dropwise under stirring Amyl ester (54.2g, 0.36mol) solution (200mL, isopropanol:dichloromethane=1.0:2.0, volume ratio), the dropwise addition process controlled the temperature at 0-10°C, and the dropwise was completed within 1h. After dropping, the temperature was naturally raised to 20-25°C for 4 hours, and the raw materials were completely reacted by TLC detection. Add 400mL of purified water to the feed liquid, stir for half an hour and separate the liquids, wash the organic layer once with 400mL hydrochloric acid solution (1mol / L), combine the aqueous layer, extract with 200mL dichloromethane, combine the organic layer, wash once with 400mL saturated salt water, Wash once with 400mL 5% aqueous sodiu...

Embodiment 2

[0042] Put formula IV compound (50g, 0.15mol), pyridine (17.8g, 0.23mol), solvent (400mL, isopropanol:dichloromethane=1.0:2.0, volume ratio) into reaction flat bottle, nitrogen protection, cool down to 0-10°C, add n-amyl chloroformate (27.1g, 0.18mol) solution (100mL, isopropanol:dichloromethane=1.0:2.0, volume ratio) dropwise under stirring, and control the temperature during the dropping process at 0-10°C ℃, 1h drop completed. After dropping, the temperature was naturally raised to 20-25°C for 4 hours, and the raw materials were completely reacted by TLC detection. Add 200mL of purified water to the feed solution, stir for half an hour, then separate the liquids, wash the organic layer once with 200mL hydrochloric acid solution (1mol / L), combine the aqueous layer, extract with 100mL dichloromethane, combine the organic layer, wash once with 200mL saturated saline, Wash once with 200mL 5% aqueous sodium bicarbonate solution, once with 200mL saturated brine, and dry over anhy...

Embodiment 3

[0044] Put the compound of formula IV (50g, 0.15mol), triethylamine (23.3g, 0.23mol), solvent (400mL, isopropanol:dichloromethane=1.0:2.0, volume ratio) into the reaction flat bottle, nitrogen protection, Cool down to 0-10°C, add n-amyl chloroformate (27.1g, 0.18mol) solution (100mL, isopropanol:dichloromethane=1.0:2.0, volume ratio) dropwise under stirring, and control the temperature at 0 -10°C, 1h dripping. After dropping, the temperature was naturally raised to 20-25°C for 4 hours, and the raw materials were completely reacted by TLC detection. Add 200mL of purified water to the feed solution, stir for half an hour, then separate the liquids, wash the organic layer once with 200mL hydrochloric acid solution (1mol / L), combine the aqueous layer, extract with 100mL dichloromethane, combine the organic layer, wash once with 200mL saturated saline, Wash once with 200mL 5% aqueous sodium bicarbonate solution, once with 200mL saturated brine, and dry over anhydrous sodium sulfat...

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Abstract

The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of 2'-3'-bis-O-acetyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine; the method comprises: reacting a compound of formula IV as a raw material with n-amyl chloroformate under the action of K3PO4 to obtain the compound of formula V, 2',3'-bis-O-acetyl-5'-deoxy-5-fluorine-N4-[(pentyloxy)carbonyl]cytidine. The invention also provides application of the method in the preparation of capecitabine. The preparation method has the advantages that reaction yield can be significantly increased, product purity is high, reaction conditions are mild, the use of pyridine is avoided, pyridine residue in the product is avoided, and the method is suitable for industrial production of medicine.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular, the present invention relates to 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N4-[(pentyloxy)carbonyl]cytidine nucleoside Preparation. Background technique [0002] Capecitabine (Capecitabine) is a kind of oral cytotoxic preparation with selective activity on tumor cells developed by Swiss Roche (Roche) Pharmaceutical Company. It is marketed in other countries and is used for the treatment of various malignant tumors. The chemical name of capecitabine is 5'-deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine, and its structure is shown below: [0003] [0004] In the preparation method of capecitabine, Bioorganic & Medicinal Chemistry 8, 2000, 1697-1706 discloses that 2',3'- Di-O-acetyl-5'-deoxy-5-fluorocytidine nucleoside (IV), the compound of formula IV reacts with n-pentyl chloroformate to form an amide bond to obtain 2',3'-di-O-acetyl-5' -Deoxy-5-fluoro-N4-[(pentyloxy)carbo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/067C07H1/00
Inventor 郭猛夏春光张爱明张喜全
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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