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Preparation method of entecavir intermediate

A technology of entecavir and intermediates, applied in the field of medicinal chemistry, can solve the problems of low product yield and difficult post-processing, and achieve the effects of simple post-processing, overcoming the difficulty of post-processing, and short reaction time

Inactive Publication Date: 2017-05-31
JIAXING MINSHI MASCH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The object of the present invention is to overcome defects such as low yield of existing entecavir intermediates (compound shown in formula I), difficulty in post-processing, and provide a kind of high reaction yield and convenient post-processing of entecavir intermediates that are more suitable for industrialized production Preparation

Method used

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  • Preparation method of entecavir intermediate
  • Preparation method of entecavir intermediate
  • Preparation method of entecavir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] The preparation of the compound shown in formula IV

[0032]

[0033] Add 187.3g (0.5mol) of the compound shown in formula V, 94.9g (1.2mol) of pyridine, 120g (1.1mol) of trimethylchlorosilane and 500ml of anhydrous THF into a 1000ml flask, stir and react at room temperature for 4 hours, monitor To the end of the reaction, add 400ml of saturated ammonium chloride solution, extract with ethyl acetate, wash with saturated brine three times, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and flash column chromatography to obtain 218g of the compound represented by formula E, with a yield of 97.7% .

Embodiment 2

[0035] The preparation of the compound shown in formula III

[0036]

[0037]Add 44.6g (100mmol) of the compound shown in formula IV, 11.3g (120mmol) of 1,2-ethanedithiol and 7.1g (50mmol) of boron trifluoride etherate complex into the reaction vessel, dichloromethane After reacting at room temperature for 2 hours, the reaction was completed. The reaction solution was washed with saturated sodium bicarbonate, extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 51.6 g of the compound represented by formula III with a yield of 98.7%.

Embodiment 3

[0039] The preparation of the compound shown in formula III

[0040] 44.6g (100mmol) of the compound shown in formula IV, 13.2g (140mmol) of 1,2-ethanedithiol and 4.3g (30mmol) of boron trifluoride etherate complex were added to the reaction vessel, dichloromethane After reacting at room temperature for 1 hour, the reaction was completed. The reaction solution was washed with saturated sodium bicarbonate, extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 51.8 g of the compound represented by formula III with a yield of 99.0%.

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Abstract

The invention discloses a preparation method of an entecavir intermediate. The preparation method comprises the following steps of (1) performing reaction on a compound shown as a formula V and trimethylchlorosilane under the existence of pyridine to obtain a compound shown as a formula IV; (2) performing reaction on the compound shown by the formula IV and 1,2-dithioglycol under the existence of boron trifluoride etherates to obtain a compound shown as the formula III; (3) performing reaction on the compound shown by the formula III and (trimethylsilyl) methyl-magnesium-chloride under the catalysis of cuprous chloride; after the reaction is completed, treating the reaction liquid by ammonium chloride to obtain a compound shown by a formula II; (4) performing stirring reaction on the compound shown by the formula II in a sodium alkoxide alcoholic solution to obtain the entecavir intermediate shown by the formula I. The method provided by the invention is used for preparing compounds such as the entecavir intermediate (the compound shown by the formula I and analogues thereof), and has the advantages that the yield is high; the reaction can be easily treated; the method is suitable for industrial enlarged production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a preparation method of an entecavir intermediate. Background technique [0002] Entecavir, whose chemical name is 2-amino-9-[(1s,3s,4s)-4-hydroxy-3-hydroxymethyl-2-methylenepentyl]-1,9-hydro-6-H-purine -6-Keto-hydrate is an effective deoxyguanosine analogue that selectively inhibits the replication of hepatitis B virus. It was developed by Bristol-Myers Squibb for the treatment of hepatitis B. In vitro tests show that entecavir is more effective than other nucleoside analogues. The results of animal models and human clinical studies show that entecavir has a strong effect of inhibiting the replication of hepatitis B virus and reducing the level of serum viral DNA. It is still effective against lamivudine-resistant mutant virus strains, and no obvious adverse reactions and Mitochondrial toxicity. A large number of clinical trials have shown that it has a direct inhibitory effec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/18
CPCC07F7/1804C07F7/1892
Inventor 陈令浩
Owner JIAXING MINSHI MASCH CO LTD