CN-114634540-B - Method for preparing decitabine from alpha isomer

Abstract

The invention provides a method for preparing decitabine by converting alpha isomer, which mainly comprises the steps of reacting decitabine isomer with a silanization reagent to obtain a compound III, adding pyridine-Lewis acid complex after the reaction is finished, and obtaining the decitabine through alkaline washing, deprotection and recrystallization after the high-temperature reaction is finished. The method provided by the invention utilizes the byproduct alpha isomer in the decitabine production process to prepare the decitabine, realizes the recycling of materials, saves energy consumption, and can ensure that the conversion rate of the decitabine isomer reaches more than 75%, and the method has high yield and small loss.

Inventors

• SUN XIULING
• BAI WENQIN

Assignees

• 鲁南制药集团股份有限公司
• 鲁南制药集团股份有限公司

Dates

Publication Date

20260421

Application Date

20201215

Priority Date

20201215

Claims (9)

1. 1. A method for preparing decitabine by conversion of an alpha isomer, comprising the steps of: , The method specifically comprises the following steps: step a, adding a compound II, an acid binding agent and a silanization reagent into an organic solvent A to obtain a compound III, continuously adding a pyridine-Lewis acid complex, and reacting to obtain a compound IV; And b, dissolving the compound IV in absolute methanol, removing a protecting group, and recrystallizing to obtain the high-purity decitabine.
2. 2. The method of claim 1, wherein the silylating agent of step a is selected from one of trimethylchlorosilane, trimethylbromosilane, hexamethyldisilazane.
3. 3. The method of claim 1, wherein the acid-binding agent is selected from the group consisting of imidazole, triethylamine, methylamine, and N, N-diisopropylethylamine.
4. 4. The method of claim 1, wherein the lewis acid in step a is selected from the group consisting of tin tetrachloride, boron trifluoride, aluminum chloride, zinc chloride, and trimethylsilyl triflate.
5. 5. The method of claim 1, wherein the pyridine-lewis acid complex of step a has a molar ratio of pyridine to lewis acid of from 1:0.9 to 1.1.
6. 6. The process of claim 1, wherein the pyridine-lewis acid complex is used in step a in an amount such that the molar ratio of compound II to pyridine-lewis acid complex is from 1:1.1 to 1.3.
7. 7. The preparation method according to claim 1, wherein the organic solvent A in the step a is selected from one or more of dichloromethane, chloroform, ethyl acetate and toluene.
8. 8. The method according to claim 1, wherein the deprotecting agent in step b is a methanol solution of an acidic reagent or a fluorine-containing neutral reagent, wherein the acidic reagent is selected from one of hydrochloric acid, sulfuric acid and formic acid, and the fluorine-containing reagent is selected from one of sodium fluoride, potassium fluoride and tetrabutylammonium fluoride.
9. 9. The method of claim 1, wherein the recrystallization in step b is performed by dissolving the compound IV in a certain amount of methanol, and cooling and crystallizing to obtain high-purity decitabine, wherein the dosage of the compound IV and the methanol is 1:70 in g/mL.

Description

Method for preparing decitabine from alpha isomer Technical Field The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for preparing decitabine by using an alpha isomer. Background Decitabine (decitabine) has the chemical name 4-amino-1- (2-deoxy-beta-D-erythro-ribofuranose) -1,3, 5-triazin-2 (1H) -one, and has the following structure: The synthesis route of decitabine is mostly that protected 2-deoxy-D-ribose is coupled with protected 5-azacytosine and then the protecting group is removed, and then the decitabine is obtained after resolution and refining. When decitabine is prepared by the above route, even if conditions such as a protecting group, a catalyst, a solvent and the like are changed, the formation of an alpha-isomer during glycosylation reaction cannot be avoided due to the oxygen Weng Zheng ion process, but decitabine can be made into a dominant configuration product by some technical means. Chen Jijun, research on the synthesis of the anticancer drug decitabine [ D ], zhejiang university of industry, 2010, summarized the synthesis method of decitabine, studied in detail on the factors influencing the configuration of the glycosylation reaction product and proposed the reaction mechanism, and the result shows that the proportion of beta product can be improved by increasing the volume of the protecting group, but the reaction time is prolonged, and a large amount of isomers are still generated when the reaction temperature is increased. It follows that the glycosylation product of the beta configuration is a kinetic product and its isomer is a thermodynamic product, further illustrating the unavoidable nature of the isomer. The isomer mixed in the product can be separated through recrystallization, the purity of the decitabine obtained through repeated resolution can reach more than 99.9%, but the highest resolution yield can only reach about 80% each time, and when the content of the alpha isomer in the mother solution is too high, the pure decitabine is difficult to obtain. Thus, this approach not only results in waste of decitabine, but also a large number of isomers cannot be reused. Although researchers have explored further extraction methods and mode of configuration conversion of low purity decitabine mixtures to achieve recycling of the alpha configurational isomer. For example, patent CN200910056111 takes decitabine alpha-configuration intermediate as raw material, and converts the decitabine alpha-configuration intermediate into beta-configuration intermediate under the action of Lewis acid, wherein the molar ratio of beta to alpha in the product reaches 3:2, thus initially realizing isomer conversion. However, the method has the problems of complex process, high cost and lower conversion efficiency. Thus, there is an urgent need for a low cost, simple to operate, high conversion process for recovering decitabine isomers. Disclosure of Invention Aiming at the problems existing in the prior art, the invention provides a method for converting decitabine alpha isomer into decitabine, which has the advantages of simple operation, high conversion rate and low cost. The invention provides a method for preparing decitabine by converting alpha isomer, which is mainly technically characterized by comprising the steps of reacting the decitabine alpha isomer, namely a compound II, with a silanization reagent in an organic solvent to obtain a compound III, adding pyridine-Lewis acid complex after the reaction is finished, and obtaining the decitabine through alkali washing, deprotection and recrystallization after the high-temperature reaction is finished. The technical scheme adopted comprises the following steps: and a step a of adding the compound II, an acid binding agent and a silanization reagent into an organic solvent A to obtain a compound III, and continuously adding a pyridine-Lewis acid complex to react to obtain a compound IV. And b, dissolving the compound IV in absolute methanol, removing a protecting group, and recrystallizing to obtain the high-purity decitabine. Preferably, the silylating agent in the step a is selected from one of trimethylchlorosilane, trimethylbromosilane and hexamethyldisilazane, and is preferably trimethylchlorosilane. Preferably, the molar ratio of compound II to silylating agent in step a is from 1:3 to 3.5, preferably 1:3.1. Preferably, the acid-binding agent of step a is selected from the group consisting of imidazole, triethylamine, methylamine, N-Diisopropylethylamine (DIPEA), preferably imidazole. Preferably, the molar ratio of compound II to acid-binding agent in step a is 1:3-3.5, preferably 1:3.1. Preferably, the Lewis acid of the pyridine-Lewis acid complex in the step a is selected from one of tin tetrachloride, boron trifluoride, aluminum chloride, zinc chloride and trimethyl silyl triflate, and is preferably trimethyl silyl triflate. Preferably, the pyridine-lewis acid complex of step