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Method for preparing decitabine

A technology of citabine and methanol, applied in the field of chemical pharmaceuticals, can solve the problems of cumbersome industrial operation, low value of large-scale production, expensive protective agent, etc., and achieve the effect of simple process operation

Active Publication Date: 2012-06-06
苏州科耐尔医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] 1. Isocyanate method (1978, Wiley, New York, N.Y., 443-449): This method uses silver isocyanate, has a long synthetic route, and requires separation of isomers, which has no meaning for industrialization
[0006] 2. 5-azacytosine direct glycosidation: need to use different protective agents, some protective agents are expensive, and this method is a mixture of α, β-anomers, which must be separated by a column to obtain Citabine, little value for scale-up
It is also obtained by fractional crystallization, but the industrial operation is cumbersome and difficult to control
[0007] 3. Azacitidine deoxygenation method (J.A.C.S, 1983, 105(12), 4059-4065): This method requires the use of phenyl thiochloroformate and TTMSS, and the cost is too high

Method used

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  • Method for preparing decitabine
  • Method for preparing decitabine
  • Method for preparing decitabine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1: the preparation of II

[0027] 12.2g I, 17.8g TPDS-Cl 2 Put 100ml of pyridine into a four-necked bottle, start stirring, and react at 25-30°C for 5 hours. After the reaction, concentrate the reactant to dryness, slowly add 100ml of ethyl acetate, stir to dissolve, add 30ml of dilute hydrochloric acid, 30ml of water , 30mlNaHCO 3 Wash the organic layer with anhydrous Na 2 SO 4 Dry, filter after drying, distill to dryness, add 100ml of ethanol to obtain 20.9g of product II after refining.

Embodiment 2

[0028] Embodiment 2: Preparation of III

[0029] Dissolve 14.6g of II and 20.3g of MTPI in 100ml of anhydrous DMF, add 10ml of methanol after stirring, and react at 25-30°C for 30min. After the reaction was completed, the reactant was distilled to dryness, added 100ml of chloroform and stirred to dissolve, washed with 30ml of water three times, and the organic layer was collected and washed with anhydrous Na 2 SO 4 After drying, distill to dryness after drying, and add ethanol to refine to obtain 15.4 g of product III.

Embodiment 3

[0030] Embodiment 3: Preparation of III

[0031] Dissolve 14.6g of II and 16.3g of MTPI in 100ml of anhydrous DMF, add 10ml of methanol after stirring, and react at 20-25°C for 1 hour. After the reaction was completed, the reactant was distilled to dryness, added 100ml of chloroform and stirred to dissolve, washed with 30ml of water three times, and the organic layer was collected and washed with anhydrous Na 2 SO 4 After drying, distill to dryness after drying, and add chloroform-n-hexane to refine to obtain 16.1 g of product III.

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Abstract

The invention provides a method for preparing decitabine, which takes azacitidine as a raw material, the method comprises the following steps: reacting with 1,3-dichloro-1,1,3,3,-tetraisopropyldisiloxane (TPDS-C12) by taking pyridine as a solvent to prepare silane compounds, then reacting with methyl triphenoxyl phosphonium iodide (MTPI) to obtain 2-iodine substituent, reducing by introducing H2 under Pd / C catalysis to obtain the deoxidant, reacting with tetrabutylammonium fluoride (TBAF) and carrying out deprotection to obtain the decitabine. The product purity can reach 99%, the overall yield is 62%, the technology operation is simple and easy for large scale production realization.

Description

[0001] Inventor (Chuhong Wang Hao) technical field [0002] The invention relates to a preparation method of decitabine, which belongs to the technical field of chemical pharmacy. Background technique [0003] Myelodysplastic syndrome (Myelodysplastic syndrome, MDS) is a group of heterogeneous hematopoietic stem cell diseases characterized by abnormal blood cell quality and quantity and high risk of acute leukemia. Due to the abnormal methylation of the genomic DNA of MDS cells, the promoter CpG islands of many important functional genes are highly methylated, and the transcription level is inhibited, resulting in functional inactivation. If there is new methylation in the promoter region of tumor suppressor genes and genes related to the maintenance of genome stability, these genes will be silenced, so that cells may gain a growth advantage and proliferate abnormally, becoming the main factor that promotes tumor formation. Decitabine is a demethylation drug with a unique t...

Claims

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Application Information

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IPC IPC(8): C07H19/12C07H1/00
Inventor 初虹王浩
Owner 苏州科耐尔医药科技有限公司
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