Synthesis of decitabine

A decitabine, coupling reaction technology, applied in the direction of carbohydrate active ingredients, drug combinations, esterification saccharides, etc., can solve the problem of not developing and utilizing tin tetrachloride and so on

Active Publication Date: 2011-10-05
SCINOPHARM TAIWAN LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] There are several reasons why no methods have been developed based on the prior art described in the literature to utilize tin tetrachloride or to use completely non-catalyzed systems

Method used

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  • Synthesis of decitabine
  • Synthesis of decitabine
  • Synthesis of decitabine

Examples

Experimental program
Comparison scheme
Effect test

example 1-3

[0010] Example 1-3, the preparation of 5-two-O-(p-chlorobenzoyl)-decitabine

[0011]

[0012] 1-O-acetyl-3,5-di-O-(p-chlorobenzoyl)-2-deoxy-D-ribofuranose (500 g, 90% HPLC purity, equivalent to 0.99 mol), dichloromethane DCM (5.93 Kg) and silyl 5-azacytosine (254 g, 0.99 mol) were cooled to -45°C to -40°C and TMSOTf (231 g, 1.04 mol) was added and cooled at -40°C to -35°C The solution was stirred for 9h. 33% MeNH in MeOH at -40°C to -35°C 2 (97.6 g, 1.04 mol) was added to the reaction solution which was then diluted with DCM (5.93 Kg). Warm the solution to 20°C to 25°C and add NaHCO at 20°C to 25°C 3 The solution was saturated (8.3Kg) and it was stirred for 30min to 40min. separate the organic phase, Molecular sieve dried and filtered and rinsed with additional DCM (3.7Kg) Molecular sieve. The filtrates were combined and evaporated to dryness. The solid was dried in vacuo at 50°C, then ground to a fine powder and dried again in vacuo at 50°C. 460 g of the title c...

example 2

[0013] Example 2 - crude decitabine

[0014]

[0015] MeOH (1.8 Kg) and 3,5-di-O-(p-chlorobenzoyl)-decitabine (455 g, 63.9% HPLC purity, corresponding to 0.58 mol) were stirred at 20°C to 25°C. 29% MeONa in MeOH (42.8 g, 0.23 mol) was added to the mixture, which was then stirred at 20°C to 25°C for 30 min. The solid was filtered, washed 3 times with n-heptane (120 mL each), and then dried in vacuo at 50° C. to obtain 42.5 g of crude decitabine with a purity of 93.6% indicated by HPLC analysis.

example 3

[0016] Example 3 - Purification of crude decitabine with MeOH

[0017] Crude decitabine (42.5 g) and MeOH (2.85 kg) were stirred and heated to reflux until the mixture was almost completely dissolved. The solution was filtered hot to remove insoluble material. The filtrate was stirred and cooled, and crystals started to form at about 40°C. The resulting slurry was stirred at cloud point for 1 h, then cooled further slowly. The slurry was stirred at 10°C to 25°C for 4-8h, then filtered. The filter cake was washed 3 times with MeOH (40 mL each) and dried in vacuo at 50 °C for 8 h to obtain 27.5 g of pure decitabine with a yield of 64.7%.

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Abstract

The present invention provides a method for producing a protected precursor of Decitabine as well as the Decibatine final product in high yield and purity.

Description

[0001] Related Application Cross Reference [0002] This application claims priority to Provisional Patent Application Serial No. 61 / 102,571, filed October 3, 2008, which is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates to Decitabine (also known as 2'-deoxy-5-azacytidine; 5-aza-2'-deoxycytidine; DAC; 4-amino-1-(2- Synthesis of deoxy-β-D-erythro-pentofuranosyl)-1,3,5-triazin-2(1H)-one) API (Active Pharmaceutical Ingredient) ready for use in injectable form after formulation Treats myelodysplastic syndrome (MDS). In addition, decitabine is being studied in other diseases such as AML, CML, stem cell transplantation, sickle cell anemia and thalassemia. [0004] The present invention is a method of synthesizing decitabine. Specifically, in one embodiment, the present invention relates to a set of reaction conditions useful for the synthesis of a decitabine precursor (p-Cl-Bz-IM4), which has a certain quality in itself t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/04A61K31/70
CPCC07H19/12C07H13/08A61P35/02
Inventor 朱利安·保罗·汉史克张孝恒余剑波胡坤梅丽君
Owner SCINOPHARM TAIWAN LTD
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