Anti-hepatitis B drug entecavir intermediate and synthesis thereof
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A technology for entecavir and anti-hepatitis B, which is applied to the intermediate of entecavir and its synthesis field, and can solve the problems of long synthesis steps, difficulty in product purification, low economic benefits and the like
Inactive Publication Date: 2013-03-06
NANJING UNIV OF TECH
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[0016] At present, the defect that still exists in the synthesis of this type of intermediate (17) is that a large amount of tar is generated in the reaction, which makes product purification difficult and also affects the yield
In order to solve this difficult problem, in 2005, Maotang X.Zhou carried out further group m
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Embodiment 11
[0030] Embodiment 1.1, the synthesis of 1-diphenylcyclotrisilane (3a)
[0031] Under nitrogen protection, magnesium chips (53g, 2.21mol) and anhydrous tetrahydrofuran (1400mL) were added to a 2L dry four-neck flask, heated to reflux, and 1,3-dibromopropane (202g, 1.01mol) was slowly added dropwise, After dropping within 2h, continue to reflux for 2h, remove the oil bath, cool to 0°C, add diphenyldichlorosilane (2) (240g, 0.92mol) dropwise, drop within 2h, reflux for 24h, cool down To 0°C, quench the reaction with saturated ammonium chloride solution, extract with petroleum ether, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and distill under reduced pressure to obtain 1,1-diphenylcyclotrisilane (3a) (148.38g, yield: 70%, bp.=110°C-114°C / 2mmHg).
Embodiment 21
[0032] Embodiment 2.1, the synthesis of 1-diphenylcyclotetrasilane (3b)
[0033] Diphenyldichlorosilane (2) and Grignard reagent BrMg(CH 2 ) 4 MgBr was reacted according to the operation steps of Example 1 to obtain 1,1-diphenylcyclotetrasilane (3b), yield: 79%, bp.=124°C-127°C / 3mmHg, 1 H-NMR (300MHz, CDCl 3 )δ: 7.55-7.52 (m, 4H), 7.36-7.23 (m, 6H), 1.82-1.77 (m, 4H), 1.14-1.09 (m, 4H).
Embodiment 31
[0034] Embodiment 3.1, the synthesis of 1-diphenylcyclopentasilane (3c)
[0035] Diphenyldichlorosilane (2) and Grignard reagent BrMg(CH 2 ) 5 MgBr was reacted according to the operation steps of Example 1 to obtain 1,1-diphenylcyclopentasilane (3c), yield: 81%, bp.=133°C-136°C / 3mmHg.
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Abstract
The invention belongs to the field of drug intermediates and provides a five-membered ring chiral intermediate (1R, 2S, 3S, 5R)-3-(1-phenylcyclo silicon)-6-oxa-bicyclo [3.1.0] hexane-1, 2-dimethyl carbinol for synthesis of entecavir and a synthesis of the five-membered ring chiral intermediate. A chiral five-membered carboatomic ring is obtained by reacting 1-phenyl-1-chlorocyclosilane with alkali metal salt of cyclopentadiene and introducing cyclosilane into a molecule to serve as a construction protecting group and by the aid of a chemical resolution method. Introduction of the cyclosilane enhances molecule rigidity to enable a solid product to be crystallized and purified more easily, and the synthesis method is simpler in reaction operation, cheap in raw materials, available to raw materials and suitable for industrial production.
Description
technical field [0001] The invention belongs to the field of pharmaceutical intermediates, and in particular relates to an entecavir intermediate and a synthesis method thereof. Background technique [0002] Entecavir (Entecavir) is a kind of deoxyguanosine compound that can effectively inhibit the replication of hepatitis B virus. It was developed by the U.S. Bristol-Myers Squibb company and was listed in the U.S. in April 2005. Hepatitis B drugs. In terms of synthesis, the construction of chiral five-membered ring intermediates determines the industrial prospects of the entire synthesis process. Therefore, people have launched research on the synthesis of intermediates. [0003] In 1993, Robert Zahler reported for the first time in the patent US5206244 the method for synthesizing entecavir with compounds of this type 15 as key intermediates. In this method, a chiral five-membered carbocyclic structure (15) is first obtained through asymmetric synthesis, and then combined...
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