Preparation of 2-chloro-9-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-adenine

一种氯腺嘌呤、氯法拉滨的技术，应用在糖衍生物制备、糖衍生物、糖衍生物等方向，能够解决未表明大规模制造氯法拉滨等问题，达到降低负担、提高产率、工艺方法有效的效果

Inactive Publication Date: 2012-01-11
SCINOPHARM KUNSHAN BIOCHEM TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0038] Despite these improvements, the main disadvantage of this method, the anomeric mixture of intermediates requiring column chromatography for separation, remains
Furthermore, the examples in said patent do not show that this procedure is suitable for the large-scale manufacture of clofarabine

Method used

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  • Preparation of 2-chloro-9-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-adenine
  • Preparation of 2-chloro-9-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-adenine
  • Preparation of 2-chloro-9-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-adenine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment Construction

[0107] Embodiments of the inventive method

[0108]

[0109] Preparation of 2',3',5'-tri-O-benzoyl-2-chloroadenosine (CF-IM1)

[0110] Step 1a - Silanization :

[0111] 2-Chloroadenine (CF-SM1(9), 50 g, 294.9 mmol, 1.0 eq.), MeCN (600 mL, 12P w.r.t. CF-SM1(9)) and BSTFA (227.5 g , 883.8mmol, 3.0eq.) into a flask equipped with mechanical stirring and a thermometer. The mixture was stirred and heated at reflux until the mixture became roughly clear (about 1 hour).

[0112] Step 1b - Wilbergen Glycosylation :

[0113] TfOH (8.77g, 58.5mmol, 0.2eq.) and 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (CF-SM2, 142.5g, 282.5 mmol, 0.95eq.) were sequentially added to the mixture prepared in step 1a. Subsequently, the mixture was stirred under reflux for 1 hour. The mixture was cooled to 20-35 °C, diluted with MTBE (500 mL), and washed with saturated NaHCO 3 (750 mL) for 0.5 to 1 hour. Evaporation of organic volatiles in vacuo at 40 to 50°C afforded CF-IM1: 1 H NMR (30...

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Abstract

The invention discloses a novel synthesis method for clofarabine (also called 2-chloro-9-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-adenine), and relates to direct coupling of 1-O-acetyl-2,3,5-tri-O-benzoyl-ribofuranose (also called protected sugar) and bis-siliconized 2-chloroadenine (also called siliconized nucleobase), selective removal of a single benzoyl group, formation of sulphonate (sulfonylation), fluorination and removal of a protective group (scheme 8).

Description

technical field [0001] The present invention encompasses a novel synthesis of clofarabine (also known as 2-chloro-9-(2'-deoxy-2'-fluoro-β-D-arabinofuranosyl)-adenine). Background technique [0002] Clofarabine is an anticancer therapy originally developed by Ilex Oncology Active pharmaceutical ingredient (API; API) in a drug product. It was approved for marketing by the FDA in 2004 for the treatment of children with refractory or relapsed acute lymphoblastic leukemia (lymphoblastic leukemia). Clofarabine is a fluoro-deoxyarabinoside, which is a synthetic analog of adenosine. [0003] Synthesis of Clofarabine [0004] 2-Dechloro-clofarabine. White et al. 1 It has been reported that acid-catalyzed (p-toluenesulfonic acid) 1,3-di-O-acetyl-5-O-benzyl-2-deoxy-2-fluoro-D-arabinofuranoside (2) (from methyl Preparation of 2,3-anhydro-α-D-ribofuranoside (3) 2 ) is fused (coupled) with 2,6-dichloropurine (4) (note that it is a free purine, i.e., it is not silanated or deproto...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/173C07H1/00
CPCC07H19/19C07H19/167Y02P20/55
Inventor 朱利安·保罗·汉史克张孝恒梅丽君陈勇发
Owner SCINOPHARM KUNSHAN BIOCHEM TECH
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