Novel synthetic method for entecavir compound

A technology of entecavir and synthetic method, which is applied in the field of new synthesis of entecavir compounds, can solve the problems of expensive process route, high technical requirements of the method, and rare raw materials

Active Publication Date: 2015-11-11
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0019] The purpose of the present invention is to provide a synthetic method of an entecavir compound and its intermediates, to solve the prob...

Method used

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  • Novel synthetic method for entecavir compound
  • Novel synthetic method for entecavir compound
  • Novel synthetic method for entecavir compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] 1) Synthesis of compound 2

[0102]

[0103] (S)-Dimethyl 3-hydroxyadipate (190.2g, 1mol) was dissolved in 2000ml of dichloromethane, and imidazole (81.7g, 1.2mol) and TBSCl (165.8g, 1.1mol) were added successively, and the reaction solution Stir at room temperature for 4 hours. 1500ml of water was added to quench the reaction, the layers were separated, the organic phase was washed twice with 2000ml of water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 2 (289.25g, yield 95%).

[0104] 2) Synthesis of Compound 2

[0105]

[0106] (S)-Dimethyl 3-hydroxyadipate (190.2g, 1mol) was dissolved in 2000ml tetrahydrofuran, and pyridine (103.1g, 1.3mol) and TBSCl (180.9g, 1.2mol) were added successively, and the reaction solution was heated at room temperature Stirring was continued for 3 hours. 1500ml of water was added to quench the reaction, the layers were separated, and the organic phase was washed twice ...

Embodiment 2

[0108] 1) Synthesis of compound 3

[0109]

[0110] Compound 2 (228.35g, 750mmol) was dissolved in 12500ml methanol, 25% sodium methoxide methanol solution (486g, 2250mmol) was added, and heated to reflux for 3 hours. After the reaction was completed, methanol was removed by concentration under reduced pressure. The residue was added to 5000ml of 0.5M hydrochloric acid solution, extracted with 2500ml of dichloromethane, the organic phase was washed twice with 2500ml of water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was subjected to column chromatography (petroleum ether / ethyl acetate=80: 1) Compound 3 (147.1 g, yield 72%) was purified.

[0111] 2) Synthesis of compound 3

[0112]

[0113] Compound 2 (243.6 g, 0.8 mol) was dissolved in 12500 ml of tert-butanol, 25% potassium tert-butoxide (t-BuOK) in tert-butanol (179.5 g, 1.6 mol) was added, and heated to reflux for 2 hours. After the reaction, tert-but...

Embodiment 3

[0115] 1) Synthesis of compound 4

[0116]

[0117] Compound 3 (136.2g, 500mmol) was dissolved in 280ml of toluene, ethylene glycol (93.1g, 1500mmol) and p-toluenesulfonic acid monohydrate (7.6g, 40mmol) were added, heated to reflux to separate water, and reacted for 8 hours. After no moisture is produced, stop heating and cool to room temperature. Add 750ml of saturated sodium bicarbonate solution and stir for 10 minutes, separate the organic phase, wash twice with 1000ml of water, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain compound 4 (145.6g, yield 92%).

[0118] 2) Synthesis of Compound 4

[0119]

[0120] Compound 3 (136.2g, 500mmol) was dissolved in 280ml of dichloromethane, ethylene glycol (62.1g, 1000mmol) and pyridine hydrochloride (5.8g, 50mmol) were added, heated to reflux to separate water, reacted for 9 hours, and waited until no After moisture is generated, stop heating and cool to room temperature. Add 750...

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Abstract

The invention belongs to the field of drug synthesis and relates to an entecavir compound and a synthetic method of an intermediate of the entecavir compound. The novel synthetic method comprises: by taking (S)-3-hydroxyl dimethyl adipate as an initial raw material, preparing an intermediate 9 through hydroxyl TBS protection, Dieckmann condensation reaction, ketone protection to ketal, ester group reduction to hydroxyl, hydroxyl protection, deprotection, ketone to silyl enol ether and Rubottom oxidizing reaction; and preparing entecavir from the intermediate 9 through wittig reaction, Mitsunobu reaction, silicon preventing radical group removal and basic hydrolysis. The novel synthetic method provided by the invention is mild and easily controllable in reaction condition, simple to operate, high in product yield, high in purity and suitable for industrialized mass production.

Description

technical field [0001] The invention belongs to the field of drug synthesis and relates to a new synthesis method of an entecavir compound. Background technique [0002] Entecavir, chemical name: [1-S-(1α, 3α, 4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2 -Methylenecyclopentyl]-6H-purin-6-one, is a deoxyguanosine analogue that is effective and selectively inhibits the replication of hepatitis B virus, and has inhibitory effect on hepatitis B virus (HBV) polymerase , researched and developed by Bristol-Myers Squibb (Bristol-Myers Squibb) company of the United States, listed in the United States in April 2005, and its structural formula is as follows: [0003] [0004] 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 effectiv...

Claims

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Application Information

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IPC IPC(8): C07D473/18C07F7/18
CPCC07D473/18C07F7/1804
Inventor 侯俊凯王文鑫司马芹
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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