Method for preparing entecavir

A technology of entecavir and compounds, applied in the field of chemical synthesis, can solve the problems of large pollution and low yield, and achieve the effect of simple purification, high yield and low environmental pollution

Inactive Publication Date: 2010-07-21
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The purpose of the present invention is to provide a method for the preparation of entecavir with high yield, low environmental pollution and easy purification for solving the shortcomings of low yield and large pollution in the prior art

Method used

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  • Method for preparing entecavir
  • Method for preparing entecavir
  • Method for preparing entecavir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Embodiment 1: preparation compound 1

[0050] Under anhydrous and oxygen-free conditions, NaH (4.023g, 60%, 100mmol) was mixed with anhydrous THF (50ml), cooled to below -10°C by ice-salt bath, and fresh cyclopentadiene (10.02ml , 100mmol), attention should be paid to degassing during the dropwise addition. After the dropwise addition, slowly rise to room temperature, let stand for more than 1h, and take the supernatant for later use.

[0051] Under anhydrous and oxygen-free conditions, the IPC 2 BH [Refer to J.Org.Chem.1982, 47, 5065-5069 for the preparation method] (100mmol) was mixed with anhydrous THF (40ml), cooled to -78°C, and set aside.

[0052] Under anhydrous and oxygen-free conditions, benzyl chloromethyl ether (20.8ml, 150mmol) was mixed with anhydrous THF (80ml), cooled to -78°C through a dry ice acetone bath, and then sodium cyclopentadiene in tetrahydrofuran was added dropwise Solution, keep the inner temperature between -30--40°C during the whole drop...

Embodiment 2

[0055] Embodiment 2: preparation compound 2

[0056] Under anhydrous and oxygen-free conditions, compound 1 (4.813g, 23.56mmol) was dissolved in anhydrous dichloromethane (40ml), and then mixed with vanadyl acetylacetonate (122mg, 0.46mmol) in anhydrous dichloromethane (10ml ) solution mixed. At 0°C, tert-butanol peroxide (5N in DCM, 9.4ml, 47.12mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature.

[0057] The reaction mixture was cooled to 0° C., and a saturated solution of sodium sulfite (30 ml) was added dropwise. After the addition was complete, the mixture was stirred at room temperature until the starch-KI test paper did not change color. Separate the organic phase, extract the aqueous phase twice with water (20ml×2), combine the organic phases, wash with water (30ml), wash with saturated sodium chloride solution (30ml), and dry over anhydrous sodium sulfate. Filtration, concentration, and filtration t...

Embodiment 3

[0059] Embodiment 3: preparation compound 3

[0060] The crude product from the previous step (4.852 g) was dissolved in absolute ethanol (40 ml), and palladium on carbon (500 mg, 10% wt) was added, and hydrogenated at normal pressure overnight. Palladium carbon was removed by filtration, the filtrate was spin-dried, purified by column chromatography, and rinsed with ethyl acetate to obtain a colorless oily liquid (2.731 g, yield 88.5%, 2 steps).

[0061] Product ESI: 131.2 (M+1). 1 H NMR (CDCl 3 , 300MHz, rt): δ=3.93-3.87(m, 1H, H-3), 3.66-3.64(m, 1H, H-5), 3.63-3.64(m, 1H, H-1), 3.45(m , 1H, OCHH), 3.39(m, 1H, OCHH), 2.52(dd, 1H, J=6.5, 5.5Hz, H-2), 2.40-2.15(m, 2H, 20H), 2.09-2.05(m, 2H, H-4). TLC: Rf = 0.3 in ethyl acetate.

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Abstract

The invention belongs to the field of chemical synthesis, and relates to a preparation method of entecavir, in particular to a new preparation method of an intermediate compound related in the entecavir as a hydrate and a synthetic method. The method of the invention overcomes the defects of low yield, large pollution and the like existing in the prior art, and provides the method for preparing the entecavir in a formula (I), which has high yield, little environment pollution and convenient purification.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and relates to a preparation method of entecavir, more specifically, to a preparation method of entecavir monohydrate. Background technique [0002] Entecavir (Entecavir) is an antiviral (HBV) prescription drug, which was first listed in the United States in April 2005 by Bristol-Myers Squibb. Its chemical name is: 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H - Purin-6-ones, having the structure of formula (I): [0003] [0004] Studies have shown that entecavir can selectively inhibit HBV DNA polymerase and prevent all three stages of viral replication. Clinical trials have shown that entecavir has excellent anti-HBV activity, is not prone to clinical drug resistance, and is still effective for patients who have failed treatment with Adefovir and Lamivudine. At present, entecavir is one of the most important drugs in the treatment of hepatitis B...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/18
CPCY02P20/55
Inventor 雷新胜林国强曾裕文
Owner FUDAN UNIV
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