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Method for synthesizing nelarabine

A synthesis method and a technology for chemical synthesis, applied in the field of medicine, can solve the problems of strict equipment requirements, high price, low nerabine yield and the like

Inactive Publication Date: 2007-12-26
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The patent "EP 0294114" discloses the preparation process of nelarabine, but the process method uses 2-amino-6-methoxypurine and uracil arabinoside as raw materials, and uses biochemical methods to obtain the target product nelarabine. The difficulty is that the strains are difficult to obtain, the reaction time is too long, nearly one month, and the equipment requirements are relatively strict. Therefore, the cost of nelarabine prepared by this process is quite expensive, which will bring a huge economic burden to patients; literature The synthesis process of nelarabine is also disclosed. The process uses 2-amino-6-chloropurine as a raw material, undergoes nucleophilic substitution with methanol, and 2,3,5-tri-oxo-benzyl-1-oxo-p-nitrobenzene Formyl-D-arabinofuranose can be obtained by chlorination and condensation of the two. The difficulty of this scheme is that the starting material 2,3,5-tri-oxo-benzyl-1-oxo-p-nitrobenzoyl- D-arabinofuranose is expensive and has limited sources, and the yield of nelarabine is not high. Similarly, obtaining nelarabine is expensive and will bring a huge economic burden to patients; therefore, research has developed an economically feasible synthetic The technology of Nalarabine is the hope of many medical workers

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Experimental program
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Effect test

Embodiment 1

[0073] The preparation method of 6-methoxyguanosine is as follows: take 248.0 grams of sodium methoxide and add it to methanol, stir to obtain a white turbid liquid, add 310 grams of 6-chloroguanosine material to dissolve rapidly to obtain a light yellow solution, and then add Precipitate a white solid, heat to reflux, continue the reaction, cool to room temperature, carefully add hydrochloric acid solution dropwise with stirring to neutralize to pH=8-9, remove the solvent and add distilled water to the remaining pale yellow viscous material, dissolve under stirring at 70°C, Then add activated carbon, hot filter, filtrate, naturally cool and crystallize, filter to obtain colorless crystalline solid, vacuum dry to obtain 196.7 g of white solid, namely 6-methoxyguanosine. mp: 133-135°C; TLC (ethyl acetate:methanol=6:1), product Rf=0.4, starting Rf=0.45.

[0074] The preparation method of 2', 3', 5'-tri-O-acetyl-6-methoxyguanosine is as follows: dissolve 195.0 grams of 6-methoxyg...

Embodiment 2

[0082] Wherein the preparation method of 6-methoxyguanosine is: get 128 grams of sodium methylate and join in the methanol, stir, obtain white turbid liquid, add 160 grams of 6-chloroguanosine materials and dissolve rapidly, obtain light yellow solution, then again Precipitate a white solid, heat to reflux, continue the reaction, cool to room temperature, carefully dropwise add hydrochloric acid solution to neutralize to PH = 8-9 while stirring, add distilled water to the remaining light yellow viscous substance after removing the solvent, dissolve under stirring at 70°C, Activated carbon was then added, hot filtered, and the filtrate was naturally cooled and crystallized, filtered to obtain a colorless crystalline solid, and vacuum-dried to obtain 102.6 g of a white solid, namely 6-methoxyguanosine. mp: 133-135°C; TLC (ethyl acetate:methanol=6:1), product Rf=0.4, starting material Rf=0.45.

[0083] Wherein 2′, 3′, 5′-tri-O-acetyl-6-methoxyguanosine is prepared by dissolving 1...

Embodiment 3

[0091] Wherein the preparation method of 6-methoxyguanosine is: get 800 grams of sodium methylate and join in methanol, stir, obtain white turbid liquid, add 1000 grams of 6-chloroguanosine materials and dissolve rapidly, obtain light yellow solution, then again Precipitate a white solid, heat to reflux, continue the reaction, cool to room temperature, carefully dropwise add hydrochloric acid solution to neutralize to PH = 8-9 while stirring, add distilled water to the remaining light yellow viscous substance after removing the solvent, dissolve under stirring at 70°C, Activated carbon was then added, hot filtered, and the filtrate was naturally cooled and crystallized, filtered to obtain a colorless crystalline solid, and vacuum-dried to obtain 598.8 g of a white solid, namely 6-methoxyguanosine. mp: 133-135°C; TLC (ethyl acetate:methanol=6:1), product Rf=0.4, starting material Rf=0.45.

[0092]Wherein, the preparation method of 2', 3', 5'-tri-O-acetyl-6-methoxyguanosine is a...

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Abstract

This invention discloses a method for synthesizing nelarabine. The method comprises: utilizing 6-chloroguanosine as the raw material, and performing chemical synthesis to convert ribofuranose configuration into arabinofuranosyl configuration and obtain nelarabine. The method has such advantages as abundant raw materials, simple process, easy operation and high yield, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a method for synthesizing nerabine. [0002] The chemical synthesis in this application refers to a synthetic method in organic chemistry, that is, a method for preparing a compound using an organic substance and an organic solvent, and no biological method, such as an enzymatic method, is used in the preparation process. Background technique [0003] T-ALL and T-LBL are two diseases with very fast deterioration, which seriously affect the body's hematopoietic function. The incidence of T-ALL in my country is second only to common acute lymphoblastic leukemia (C-ALL), accounting for the second place in the incidence of acute lymphoblastic leukemia. T-cell acute lymphoblastic leukemia usually develops in older children, adolescents, and young adults and is less common than B-cell acute lymphoblastic leukemia. Approximately 1,600 adults and children in the United States are diag...

Claims

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Application Information

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IPC IPC(8): C07H19/167A61K31/708A61P35/02
Inventor 顾群孙学伟徐春霞
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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