Method for synthesizing decitabine

A synthetic method, the technology of decitabine, applied in the field of medicinal chemistry, can solve the problems of not increasing the ratio of β-configuration products of glycosylation reaction, poor selectivity of glycosylation reaction, and low yield of β-isomer, and achieve cost Low, easy to separate, short preparation route

Pending Publication Date: 2022-06-21
LUNAN PHARMA GROUP CORPORATION
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method mainly has the following disadvantages: 1) the selectivity of the glycosylation reaction is poor, and the yield of the β-isomer is low; 2) the resolution process is complicated and the yield is low
[0010] In patent CN201110389414, by controlling the deprotection conditions, the double-protected decitabine and the isomer mixture are prepared through alcoholysis reaction to obtain the single-protected mixture, and the difference in solubility in alcohol is used to separate and then remove the protecting group to obtain high-purity decitabine. Bin, although this method reduces the number of subsequent resolutions, it does not increase the proportion of β-configuration products in the glycosylation reaction, and the deprotection condition is still a strong base, which cannot avoid the formation of ring-opening impurities

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  • Method for synthesizing decitabine
  • Method for synthesizing decitabine
  • Method for synthesizing decitabine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Add 50 g of compound II to the reaction flask, add 750 mL of chloroform and 56 g of pyridine, cool down to 5 °C, add 195 g of tert-butyldiphenylchlorosilane dropwise, keep stirring for 2 h after the drop, add 750 mL of sodium phosphate buffer solution , the liquid is separated, the organic phase is dried with 50 g of anhydrous sodium sulfate, and filtered to obtain the chloroform solution of compound II-1.

[0049]The chloroform solution of compound II-1 was added to the reaction flask, 86.48 g of compound III was added, the temperature was lowered to 10 °C, and 88 g of tin tetrachloride was added dropwise. : ethyl acetate=4:1) detected the basic reaction was completed, the reaction solution was slowly added to 4L saturated sodium bicarbonate solution, the liquid was separated, and the organic phase was evaporated to dryness under reduced pressure to obtain the colorless oily substance of compound IV (α and β different The composition ratio is about 1:4, see for details...

Embodiment 2

[0052] Add 50 g of compound II to the reaction flask, add 500 mL of chloroform and 53 g of pyridine, cool down to 5 °C, add 185 g of tert-butyldiphenylchlorosilane dropwise, keep stirring for 2 h after the drop, add 500 mL of sodium phosphate buffer solution , the liquid is separated, the organic phase is dried with 50 g of anhydrous sodium sulfate, and filtered to obtain the chloroform solution of compound II-1.

[0053] The chloroform solution of compound II-1 was added to the reaction flask, 95.13 g of compound III was added, the temperature was lowered to 10°C, 96.8 g of tin tetrachloride was added dropwise, the dropping was completed, and the reaction was kept under stirring for 6 to 8 hours. Ether: ethyl acetate=4:1) detected that the basic reaction was completed, the reaction solution was slowly added to 4L of saturated sodium bicarbonate solution, separated, and the organic phase was evaporated to dryness under reduced pressure to obtain a colorless oily substance (α an...

Embodiment 3

[0056] Add 50 g of compound II to the reaction flask, add 1 L of chloroform and 66.3 g of pyridine, cool down to 5 °C, add 232 g of tert-butyldiphenylchlorosilane dropwise, keep stirring for 2 h after the drop, add 750 mL of sodium phosphate buffer The liquid was separated, and the organic phase was dried with 50 g of anhydrous sodium sulfate, and filtered to obtain a chloroform solution of compound II-1.

[0057] The chloroform solution of compound II-1 was added to the reaction flask, 86.48 g of compound III was added, the temperature was lowered to 10 °C, and 88 g of tin tetrachloride was added dropwise. : ethyl acetate=4:1) detected the basic reaction was completed, the reaction solution was slowly added to 4L saturated sodium bicarbonate solution, the liquid was separated, and the organic phase was evaporated to dryness under reduced pressure to obtain the colorless oily substance of compound IV (α and β different The composition ratio is about 1:4). 150 mL of acetonitri...

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Abstract

The invention provides a method for synthesizing decitabine. According to the method, the proportion of beta-configuration products of the decitabine glycosylation reaction is increased, and the isomer resolution process is simplified, so that the yield of decitabine is increased. According to the method, a beta-configuration glycosylation product is generated with high selectivity by utilizing a silicon-based protecting group, recrystallization separation of an isomer is realized, finally, the protecting group is removed under a neutral condition, generation of ring-opening impurities is avoided, and the yield is increased.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular to a method for synthesizing decitabine. Background technique [0002] Decitabine chemical name is 4-amino-1-(2-deoxy-β-D-erythro-ribofuranose)-1,3,5-triazine-2(1H)-one, its structure as follows: [0003] [0004] Mainly used for the treatment of myelodysplasia. Developed by American Super Gen Company and launched in 2006. Decitabine has a unique methyltransferase inhibitor effect. It is converted from 2'-deoxycytidine to 5'-deoxycytidine in the body, and is incorporated into DNA under the action of DNA polymerase. Inhibit DNA synthesis and methylation, so as to achieve the purpose of inhibiting the growth of tumor cells. [0005] At present, the synthesis methods of decitabine are mainly divided into three categories. The most commonly used method is the glycosidation reaction of protected 2-deoxy-D-ribose and silylated 5-azacytosine under the catalysis of Lewis ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/12C07H1/06
CPCC07H19/12C07H1/06
Inventor 巩孝顺白文钦刘忠
Owner LUNAN PHARMA GROUP CORPORATION
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