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Method for preparing entecavir

A technology of entecavir and benzyloxy, which is applied in the field of preparation of entecavir, a drug for treating hepatitis B, to achieve the effects of easy separation and purification, simple reaction technical conditions and high yield

Active Publication Date: 2010-06-30
SHANGAI PHARMA GRP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the above-mentioned two kinds of coupling methods, its base all adopts 6-substituted (X is benzyloxy, chlorine, bromine, iodine)-2-aminopurine. linked, resulting in the formation of the 7-position isomer

Method used

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  • Method for preparing entecavir
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  • Method for preparing entecavir

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Preparation of [1S(1α, 2β, 3α, 5β)]-5-(2,6-diaminopurin-9-yl)-3-benzyloxy-2-benzyloxymethylcyclopentanol IV

[0028] 15g of 2,6-diaminopurine, 2g of 60% NaH, and 250ml of dry DMF were mixed, stirred at 85°C for 20 minutes, cooled to room temperature, and added [1S(1α,2α,3β,5α)]-3-Benzyloxy- 15.5 g of 2-benzyloxymethyl-6-oxabicyclo[3,1,0]hexane II and 61.4 g of 18-crown ether were heated under reflux for four hours. After the reaction, the DMF was evaporated under reduced pressure, and the residue was extracted with ethyl acetate, washed with water and saturated sodium chloride solution in turn, dried, concentrated, and the crude product was passed through the column to obtain 17.2 g of condensate IV, with a yield of 74%.

Embodiment 2

[0030] [1S(1α, 2β, 3α, 5β)-5-[2,6-bis(tritylamino)purin-9-yl]-3-benzyloxy-2-benzyloxymethylcyclopentanol Preparation of V

[0031] Mix 12g of condensate IV obtained in the previous step, 21.76g of triphenylchloromethane, 7.9g of triethylamine, and 240ml of dry dichloromethane, and stir overnight at room temperature. After the reaction was completed, saturated sodium bicarbonate solution was added to terminate the reaction. Separate the organic layer, extract the aqueous layer with dichloromethane, combine the organic layers, wash with water and saturated sodium chloride solution successively, dry, evaporate the solvent and recrystallize to obtain 15 g of the double-protected product V with a yield of 60%.

Embodiment 3

[0033] [2R(2α, 3β, 5α)]-5-[2,6-bis(tritylamino)purin-9-yl]-3-benzyloxy-2-benzyloxymethylcyclopentanone VI preparation of

[0034] After mixing 60ml of anhydrous dichloromethane and 4.17g of oxalyl chloride, add dropwise a solution of 5g of dimethyl sulfoxide in 20ml of anhydrous dichloromethane at -70°C, stir for 15 minutes, then add dropwise the solution prepared in Example 2 A solution prepared with 10 g of the obtained double-protected product V and 40 ml of anhydrous dichloromethane. Continue to react at low temperature for two hours. 7.5 g of triethylamine was added dropwise, followed by stirring for another hour. The reaction solution was poured into saturated sodium bicarbonate solution to terminate the reaction. Separate the organic layer, extract the aqueous layer with dichloromethane, combine the organic phases, wash with water until neutral, dry and evaporate the solvent under reduced pressure to obtain 10 g of crude VI.

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Abstract

The invention relates to a method for preparing a medicament for treating hepatitis B, i.e. entecavir I. The method uses [1S(1alpha, 2alpha, 3beta, 5alpha)]-3-benzoyloxy-2-benzyl methoxymethyl-6-oxabicyclo[3.1.0]hexane II and 2,6-diaminopurine III as the raw materials, and prepares the entecavir by carrying out ring-opening condensation, carrying out trityl amino protection, oxidization and methylenenation, then using acetyl to protect 2-amino and 6-amino to carry out diazotization hydrolysis, and finally carrying out de-protection. The invention has high reaction yield, high optical purity of the product and simple and convenient operation, and is suitable for the industrial production.

Description

technical field [0001] The invention relates to medicine preparation, in particular to a preparation method of entecavir, a medicine for treating hepatitis B. Background technique [0002] Entecavir is a deoxyguanosine analogue. Its chemical name is [1S-(1α,3α,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-hydroxymethyl-2-methylenecyclopentyl]- 6H-purin-6-one monohydrate, the structural formula I is as follows: [0003] [0004] In vitro tests show that it has a direct inhibitory effect on reverse transcriptase and hepatitis B virus DNA polymerase in liver cells, can effectively inhibit the replication of hepatitis B virus, has strong anti-hepatitis B virus ability, and has high selectivity. Its anti-hepatitis B virus activity is 8,000 times greater than its cytotoxicity, and it has a very good selective therapeutic index. A large number of clinical applications have proved that entecavir can effectively treat chronic hepatitis B by oral administration of 0.1mg-0.5mg daily. ...

Claims

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Application Information

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IPC IPC(8): C07D473/18
CPCY02P20/55
Inventor 周智善魏宪明许杏祥陈慧新
Owner SHANGAI PHARMA GRP CO LTD
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