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Synthesis and refinement of nelarabine

A technology of nerabine and a composition, which is applied to the refining treatment of nerabine and the field of preparation of nerabine, can solve the problems of low yield, increased cost, strict equipment requirements and the like

Active Publication Date: 2009-01-21
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Base-6-methoxypurine and uracil arabinoside are raw materials, and the product nelarabine is obtained under the action of purine nucleoside phosphorylase and uridine phosphorylase. In this method, the bacterial species is difficult to obtain and the reaction time is long , stricter requirements on equipment, resulting in increased cost and difficulties in industrial production
Also disclosed in the prior art is another synthetic method, using 2-amino-6-chloropurine as a raw material, through methanol nucleophilic substitution, 2,3,5-tri-oxo-benzyl-1-oxo-p-nitrogen Benzoyl-D-arabinofuranose is chlorinated, and the two are condensed to obtain nelarabine, but the raw material 2,3,5-tri-oxo-benzyl-1-oxo-p-nitrobenzoyl in this scheme -D-arabinofuranose is expensive, and the yield is not high, and its manufacturing cost is relatively high

Method used

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  • Synthesis and refinement of nelarabine
  • Synthesis and refinement of nelarabine
  • Synthesis and refinement of nelarabine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Embodiment 1: Preparation of 6-O-methylguanosine

[0068] Take 248.0 grams of sodium methoxide and add it to 4.6 L of methanol, stir for 15 minutes to obtain a white turbid liquid, add 310 grams of 6-chloroguanosine material to dissolve quickly, and obtain a light yellow solution, and then precipitate a white solid, heat to reflux, and continue the reaction After 2.5 hours, cool to room temperature, carefully add hydrochloric acid solution dropwise under stirring to neutralize to PH=8-9, evaporate the solvent under reduced pressure, add 12L distilled water to the remaining light yellow viscous substance, dissolve it under stirring at 70°C, and then add 12g Activated carbon, hot filtration after 10min, filtrate, natural cooling and crystallization, filtration, to obtain a colorless crystalline solid, vacuum drying to obtain 196.7 g of 6-O-methylguanosine white solid, yield 64.3%, mp: 133-135 °C; TLC (ethyl acetate:methanol=6:1), product Rf=0.4, raw material Rf=0.45.

Embodiment 2

[0069] Embodiment 2: Preparation of 6-O-methylguanosine

[0070] Take 128 grams of sodium methoxide and add it to methanol, stir to obtain a white turbid liquid, add 160 grams of 6-chloroguanosine to dissolve rapidly, and obtain a light yellow solution, and then precipitate a white solid, heat to reflux, continue the reaction, and cool to At room temperature, carefully add hydrochloric acid solution dropwise under stirring to neutralize to PH = 8-9, evaporate the solvent, add distilled water to the remaining light yellow sticky substance, dissolve under stirring at 70°C, then add activated carbon, heat filter, filtrate, and cool naturally Crystallization and filtration gave a colorless crystalline solid, which was dried in vacuo to give 102.6 g of a white solid, ie, 6-O-methylguanosine. Yield 65.0%, mp: 133-135°C; TLC (ethyl acetate:methanol=6:1), product Rf=0.4, raw material Rf=0.45.

Embodiment 3

[0071] Embodiment 3: Preparation of 6-O-methylguanosine

[0072] Take 800 grams of sodium methoxide and add it to methanol, stir to obtain a white turbid liquid, add 1000 grams of 6-chloroguanosine to dissolve rapidly, and obtain a light yellow solution, and then precipitate a white solid, heat to reflux, continue the reaction, and cool to At room temperature, under stirring, carefully add hydrochloric acid solution dropwise to neutralize to PH = 8-9. After removing the solvent, add distilled water to the remaining light yellow viscous substance, dissolve it under stirring at 70°C, then add activated carbon, heat filter, filtrate, and naturally cool and analyze. crystal, filtered to obtain a colorless crystalline solid, and dried in vacuo to obtain 598.8 g of a white solid, namely 6-O-methylguanosine. Yield 60.7%, mp: 133-135°C; TLC (ethyl acetate:methanol=6:1), product Rf=0.4, raw material Rf=0.45.

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Abstract

The invention discloses a method for preparing and refining a nucleotide compound, and particularly a method for preparing and refining Nalarabine. The preparation method has low requirements on facilities, with shorter synthesis process and simplified operation; the yielding rate of the whole production line is high with low production cost, and the method is economically viable and suitable for industrialized production. In addition, the invention also discloses a method for synthesizing an intermediate of Nalarabine.

Description

technical field [0001] The present invention relates to the preparation method and refining treatment of nucleoside compounds, specifically relates to the preparation method of nalarabine, and also includes the refining treatment of nalarabine. Background technique [0002] Nelarabine is the prodrug of deoxyguanosine analogue 9-β-D-arabinofuranosylguanine (ara-G), which has been approved for marketing in 2005 and can be used for the treatment of T-cell acute lymphoblastic leukemia (T -ALL) and T-cell lymphoblastic lymphoma (T-LBL). [0003] Nelarabine has the following structural formula, and its chemical name is 2-amino-9-β-D-arabinofuranosyl-6-methoxy-9H-purine. ZL88103820 discloses the preparation technology of nelarabine, and this process method uses 2-ammonia [0004] [0005] Base-6-methoxypurine and uracil arabinoside are raw materials, and the product nelarabine is obtained under the action of purine nucleoside phosphorylase and uridine phosphorylase. In this me...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/19A61K31/708A61P35/00
Inventor 顾群孙学伟徐春霞
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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