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A kind of synthetic method of aglycoside compound impurity

A synthesis method and compound technology are applied in the synthesis of arabinoside compounds and impurities, and the field of arabinoside compounds can solve problems such as affecting product quality research, obtaining key impurities, poor selectivity, etc., and achieve important economic value and social significance. Friendly, low-cost effects

Active Publication Date: 2022-04-08
CHONGQING HAITENG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the poor selectivity of the deprotection process, the key impurity cannot be obtained by conventional synthesis methods
In the prior art, usually from the by-products produced during the selective removal of the acetyl group at the 2' position, the 2' and 3' hydroxyl deprotection products with high purity are obtained through multiple liquid-mass separations. This method requires Specialized liquid quality equipment consumes a lot of energy and is not easy to obtain, which seriously affects product quality research

Method used

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  • A kind of synthetic method of aglycoside compound impurity
  • A kind of synthetic method of aglycoside compound impurity
  • A kind of synthetic method of aglycoside compound impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] At 10°C, 12 g of 2-amino-6-methoxy-9β-D-(2',3',5'-trioxybenzyl-arabinofuranosyl)purine, containing 50% The dichloromethane solution 180ml of pyridine, stirred and dissolved clear, added 11g phenylhydrazine, 3.0g acetic acid and 19.7g ammonium bicarbonate, stirred and reacted for 18 hours (reaction control: HPLC purity 76.5%, formula III and formula IV compound were respectively 10.3 %, 5.2%). 12 ml of acetone were added and stirring was continued for 2 hours. Concentrate to dryness under reduced pressure, add 240ml of toluene, stir and disperse at room temperature, and filter. The filter cake was added to 100ml of water, stirred and beaten at room temperature for 2 hours, and filtered. The filter cake was recrystallized successively with 1:1 water / ethanol solution, ethanol, and 1:1 water / acetone solution to obtain 5.5 g of the target product with an HPLC purity of 96.6% (2.1% of the compound of formula III, 0.3% of the compound of formula IV) .

[0027] 1 HNMR (DMS...

Embodiment 2

[0029] At 25°C, put 10 g of 2-hydroxy-6-amino-9β-D-(2',3',5'-trioxyacetyl-arabinofuranosyl)purine and 100 ml of pyridine into the reaction flask, stir to dissolve Clear, add 11.5g phenylhydrazine, 2.9g acetic acid and 19.1g ammonium bicarbonate, stir and react for 24 hours (reaction control: HPLC purity 75.9%, formula III and formula IV compound are 11.1%, 4.1% respectively). 20 ml of acetone was added and stirring was continued for 2 hours. Concentrate to dryness under reduced pressure, add 100ml of toluene, stir and disperse at room temperature, and filter. The filter cake was added to 100ml of water, stirred and beaten at room temperature for 2 hours, and filtered. The filter cake was recrystallized sequentially with ethanol and a 1:1 water / ethanol solution to obtain 4.9 g of the target product with an HPLC purity of 95.0% (2.9% for the compound of formula III and 0.8% for the compound of formula IV). 1 H NMR (DMSO-d 6 )δ2.00(s,3H,CH 3 ),2.13(s,3H,CH 3 ),4.3-4.45(m,3H)...

Embodiment 3

[0031] At 20°C, 10 g of 2-hydroxy-6-hydroxy-9β-D-(2',3',5'-trioxybenzyl-arabinofuranosyl)purine, containing 20% ​​pyridine 200ml of DMF solution, stirred to dissolve, added 13.0g phenylhydrazine, 2.0g acetic acid and 13.2g ammonium bicarbonate, stirred and reacted for 24 hours (reaction control: HPLC purity 76.7%, formula III and formula IV compounds were 11.0%, 5.4% respectively %). 10 ml of acetone was added and stirring was continued for 2 hours. Concentrate to dryness under reduced pressure, add 200ml of toluene, stir at room temperature to disperse, and filter. The filter cake was added to 100ml of water, stirred and beaten at room temperature for 2 hours, and filtered. The filter cake was recrystallized successively with 1:1 water / ethanol solution, ethanol, and 1:1 water / acetone solution to obtain 4.2 g of the target product with an HPLC purity of 96.0% (2.3% of the compound of formula III, 0.7% of the compound of formula IV) .1 HNMR (DMSO-d 6 )δ2.01(s,3H,CH 3 ),2.1...

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Abstract

The invention provides a method for synthesizing impurities of arabinoside compounds, which uses 2',3',5'-trihydroxyl-protected arabinoside compounds as raw materials, and undergoes deprotection under the action of phenylhydrazine, acetic acid and ammonium bicarbonate. The reaction condition of the method is mild, the cost is low, and the environment is friendly, and the obtained arabinoside compound impurity can be used for the synthesis and quality research of the arabinoside drug, so as to improve the quality standard of the drug.

Description

technical field [0001] The invention relates to arabinoside compounds, in particular to a method for synthesizing impurities of arabinoside compounds, and belongs to the technical field of drug synthesis. Background technique [0002] Alglucoside compounds have superior physiological and pharmacological activities, and are widely used as anticancer and antiviral drugs clinically (fludarabine, flufarabine, clofarabine, nelarabine, etc. in the following formula). Therefore, the synthesis of this type of compound has received extensive attention from pharmaceutical workers. [0003] [0004] Since the main difference between nucleosides and arabinosides is the configuration of the 2'-hydroxyl group of arabinose, the 2'-hydroxyl of nucleosides is in the α-type, and the 2'-hydroxyl of arabinosides is in the β-type, and nucleosides are cheap and easy to obtain Therefore, in the synthesis of arabinoside drugs, nucleosides are generally used as starting materials, and after a se...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/19C07H1/00
Inventor 蒋世盛陈琳郭真余马永涛姚承良
Owner CHONGQING HAITENG PHARMA