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Method for preparing cytosine arabinoside ester by enzyme catalysis

A technology of cytarabine ester and cytarabine, which is applied in the field of biocatalysis and biosynthesis, biomedicine and materials, can solve the problems of few reaction by-products, low substrate utilization rate, low product purity, etc. Fewer products, no need for group protection and deprotection, high conversion rate of substrate

Inactive Publication Date: 2006-12-13
SOUTH CHINA UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The purpose of the present invention is to solve the problems existing in the prior art process, and provide a method for preparing cytarabine by enzymatic catalysis, which has high regioselectivity, a yield of more than 95%, easy control of the product structure, and can obtain arabinoside Cytidine 5'-monoester or 3'-monoester, and the product has high purity and few reaction by-products, thus overcoming the low selectivity of traditional chemical methods leading to low substrate utilization, low product purity, and easy formation of by-products Disadvantages such as esters;

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] will contain 0.5g (2.05×10 -3 mol) Cytarabine, 2.10g (1.84×10 -2 mol) vinyl butyrate, 0.1L 10% (v / v) isopropyl ether-pyridine mixed solvent reaction solution was added in a stoppered Erlenmeyer flask, followed by adding 25,000U lipase derived from Candida antarctica (10,000U / g ), placed in a water bath constant temperature oscillator at 30°C and 150rpm under normal pressure to oscillate, and reacted for 3 hours. After separation and purification by silica gel column chromatography, 0.628g of the product cytarabine 5'-butyrate was obtained, with a yield of 97.5%, and the reaction regioselectivity was 99.9% (the concentration of the product cytarabine 5'-butyrate was high. at 99%).

Embodiment 2

[0021] will contain 0.5g (2.05×10 -3 mol) Cytarabine, 45.9g (2.05×10 -1 mol) vinyl laurate, 0.5L 35% (v / v) the reaction liquid of heptane-dimethylformamide mixed solvent joins in the Erlenmeyer flask with stopper, then adds 100,000U lipase (10,000U) derived from Candida antarctica U / g), placed in a water bath constant temperature oscillator at 40°C and 200rpm under normal pressure to oscillate, after 12 hours of reaction, the reaction mixture was filtered to remove enzymes, concentrated by vacuum evaporation, and the concentrated solution was dried in methanol or ethanol or ethyl acetate Recrystallization or separation and purification through silica gel column chromatography to obtain 0.831 g of the product cytarabine 5'-laurate, with a yield of 96.0%, and a reaction regioselectivity of 99.9% (the product cytarabine 5'-lauric acid The ester concentration is above 99%).

Embodiment 3

[0023] will contain 0.5g (2.05×10 -3 mol) Cytarabine, 313g (8.2×10 -1 mol) methyl tetracosanate, 0.5L 35% (v / v) tetrahydrofuran-pyridine mixed solvent reaction solution was added in a stoppered Erlenmeyer flask, followed by adding 400,000U lipase derived from Candida antarctica (10,000U / g ), placed in a water bath constant temperature oscillator at 60°C and 250rpm under normal pressure to oscillate, and reacted for 8 hours. After separation and purification by silica gel column chromatography, 1.16 g of the product cytarabine 5'-tetradecanoic acid ester was obtained, with a yield of 96.0%; the reaction regioselectivity was 99.9% (the product cytarabine 5'-tetracosine Carbonate concentration is above 99%).

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Abstract

The invention relates to an enzymatic method for preparation of alexan ester, which selects carboxylic acid enolester or acid anhydride as acyl donator and performs acylation reaction using enzymatic alexan to synthesize the alexan ester. The invention has advantages that its reaction condition is mild and environment is friendly, the reaction has high regioselectivity, the reaction process is simple and can be controlled, and the products can be separated easily.

Description

technical field [0001] The invention belongs to the fields of biocatalysis and biosynthesis, biomedicine and materials, and relates to a method for preparing cytarabine by enzymatic catalysis. It is an optional invention of CN200410077504X. Background technique [0002] Cytarabine is a class of unnatural nucleosides, belonging to deoxycytidine analogues, has high anti-leukemia activity, and is one of the most effective chemotherapy drugs clinically used for the treatment of acute myeloid leukemia. Cytarabine ester derivatives are one of the prodrugs of cytarabine, which are obtained by acylation of the hydroxyl group of the glycosyl moiety of cytarabine. Pharmacological test results show that cytarabine carboxylate derivatives are more suitable for the treatment of systemic or local malignant tumors than cytarabine itself, especially for malignant tumors in the reticuloendothelial system and central nervous system, and the curative effect is more sig...

Claims

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Application Information

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IPC IPC(8): C12P19/38
Inventor 宗敏华李晓凤吴虹娄文勇
Owner SOUTH CHINA UNIV OF TECH