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Preparation method of entecavir

A technology of entecavir and compound, which is applied in the field of preparation of entecavir to achieve the effects of mild reaction conditions, high purity and simple operation

Active Publication Date: 2017-09-15
HUBEI GRAND LIFE SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Containing three asymmetric carbon atoms in the entecavir result brings challenges to chemical synthesis. There are multiple synthetic methods reported at present, most of which are more than ten steps of chemical reactions (WO2004052310A2, WO2013135165A1 and Shen Guobing, Chinese Journal of Pharmaceutical Industry, 2007, 38(10, 749-752)

Method used

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  • Preparation method of entecavir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Preparation of (3aS, 6aR)-5-formaldehyde-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]furan-2-ol

[0037] Succindialdehyde (5.75 g, 66.8 mmol) was stirred in tetrahydrofuran (130 ml) at 25°C, (R)-proline (150 mg, 1.3 mmol) was added at one time, stirred at 25°C for 40h, and then di Benzylamine trifluoroacetate (416 mg, 1.34 mmol). Stirring was continued at 25 °C for 20 h. After the reaction solution was concentrated to 20 ml, 30 ml of methyl tert-butyl ether was added, filtered, and the filtrate was concentrated to obtain (3aR,6aS)-5-formaldehyde-3,3a,6,6a-tetrahydro-2H-cyclopenta [b] The crude product of furan-2-ol was directly used in the next reaction.

Embodiment 2

[0038] Example 2 Preparation of (3aS, 6aR)-5-formaldehyde-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]furan-2-ol (2)

[0039] The crude product obtained above was dissolved in 12 ml of dichloromethane, methanol (340 mg), ion exchange resin 15 (76 mg) and magnesium sulfate (1.6 g) were added at 25 °C, stirred at 25 °C for 20 h, and the reaction solution was filtered Concentration and column chromatography gave 2.10 g of (3aS,6aR)-5-formaldehyde-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]furan-2-ol (2). The two-step total yield is 35%, and the proton magnetic spectrum is consistent with the literature.

Embodiment 3

[0040] Example 3 Preparation of (3aS, 6aR)-2-methoxyl-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]furan

[0041] Mix 180 mg of (3aR,6aS)-2-methoxy-5-formyl-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]furan (1.0 mmol) with tris(triphenyl Phosphine) rhodium chloride (0.8 g, 0.8 mmol) was added to benzonitrile (5 ml) respectively, heated to 130° C., kept for 1.5 hours, added ether after cooling in an ice bath, filtered, the solid was washed with ether, and combined The extract was dried, concentrated, and purified by column chromatography to obtain (3aS,6aR)-2-methoxy-3,3a,6,6a-tetrahydro-2H-cyclopenta[b]furan 129 mg, yield 85%, 1 H NMR (DMSO-d 6 )δ: 1.95 (brs, 2H), 2.41 (m, 2H), 2.58 (m, 1H), 3.24 (m, 1H), 3.27 (s, 3H), 5.10 (m, 1H).

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Abstract

The invention relates to a preparation method of entecavir. The method comprises the steps: by adopting butanedial as a raw material, firstly synthesizing optically pure double-loop olefine aldehyde in the presence of a catalytic amount (R)-proline and dibenzylamine trifluoroacetate, protecting hydroxyl by using methyl, and carrying out decarbonylation by utilizing chlorotris(triphenylphosphine)-rhodium as a catalyst to obtain (3aS, 6aR)-2-methoxyl-3,3a-6,6a-tetrahydro-2H-cyclopentano [b] furan; carrying out Prins reaction in the presence of sulfuric acid to obtain a reduzate of Corey lactone, carrying out deprotection on all hydroxyls by using TBS, selectively removing a 2-bit protecting group and carrying out decarboxylic reaction in the presence of lead acetate to obtain a methylene compound; and finally introducing guanine by adopting a conventional method and carrying out deprotection to obtain the entecavir. By adopting butanedial as an initial raw material, the method has less than ten steps, and is mild in reaction condition, available in raw material and reagent, simple in operation, moderate in yield and suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of organic chemical industry, in particular to a preparation method of entecavir. Background technique [0002] The chemical name of Entecavir is 2-amino-9-[(1S,3S,4S)-4-hydroxy-3-hydroxymethyl-2-methylenecyclopentyl]-1,9-dihydro-6H-purine -6-ketone, developed by Bristol-Myers Squibb Company and launched in 2005, is clinically used in patients with hepatitis B virus (Shen Guobing, China Journal of Pharmaceutical Industry, 2007, 38(10), 749-752). Containing three asymmetric carbon atoms in the result of entecavir brings challenges to chemical synthesis. There are multiple synthetic methods reported at present, and most synthetic routes exceed ten steps of chemical reactions (WO2004052310A2, WO2013135165A1 and Shen Guobing, Chinese Journal of Pharmaceutical Industry, 2007, 38(10), 749-752). Due to the importance of entecavir synthesis, a more economical preparation method will reduce the synthesis cost of th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/18C07D307/935C07B53/00
CPCY02P20/55C07D473/18C07B53/00C07B2200/07C07D307/935
Inventor 孙华君杨尚金朱毅熊先胜谢国范赵涛涛雷大有何本斌郭晨
Owner HUBEI GRAND LIFE SCI & TECH CO LTD
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