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Method for synthesizing Entecavir

A technology of entecavir and synthetic methods, which is applied in the field of drug synthesis, can solve the problems of harsh reaction conditions, high cost of process routes, and rare raw materials, and achieve the effect of cost reduction

Inactive Publication Date: 2016-04-27
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] Based on this, in view of the problems such as the high cost of the process route, the rare raw materials, and the harsh requirements of some reaction conditions in the industrialized production of entecavir, the purpose of the present invention is to overcome the defects of the prior art and provide a synthetic method of entecavir. Low cost, mild reaction conditions, short synthetic route, etc.

Method used

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  • Method for synthesizing Entecavir
  • Method for synthesizing Entecavir
  • Method for synthesizing Entecavir

Examples

Experimental program
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Effect test

Embodiment 1

[0058] A synthetic method for entecavir, comprising the following steps:

[0059] (1) Preparation of compound XV

[0060] Add 1,3-propanediol (1457.6g, 19.15mol), DMF (dimethylformamide) (5L), DCM (dichloromethane) (1L) in a 20L reactor with temperature control and mechanical stirring, and then When the system is lower than 10°C under mechanical stirring, slowly add 60% NaH (281g, 7.024mol) into the kettle for about 2 hours, control the temperature in the reaction kettle not higher than 15°C, and keep the temperature in the kettle below 70min. Stirring was continued at 10°C for 30min.; then TBAI (tetrabutylammonium iodide) (23.6g, 0.064mol) was added, and the addition was completed in 15min; PMBCl (p-methoxybenzyl) (1000g, 6.385 mol), slowly dropwise into the kettle, 4h. The dropwise addition was completed; then the system was raised to room temperature and stirred overnight. TLC showed that the raw material was completely consumed. Then, lower the temperature of the system...

Embodiment 3

[0098] The preparation method of the present embodiment is basically the same as the preparation method in Example 1, the difference is:

[0099] In step (10), the preparation method of compound IX is as follows:

[0100] Under argon protection, add SmI to a 2000ml two-necked bottle 2 (Samarium diiodide) (812ml, 0.1M tetrahydrofuran solution, 81.2mmol) was placed in a low-temperature tank at -40°C and stirred; in another 25ml two-necked bottle with argon protection, the compound (VIII) obtained in the previous step was added ( 7.5g, 20.3mmol), anhydrous tert-butanol (4.5g, 60.8mmol), anhydrous THF (50ml), placed in a low-temperature tank at -40°C and stirred, and after the system remained stable at -40°C, drop it Add it to the reaction system at -40°C above, and drop it in 5 minutes. The reaction was tracked by TLC, and the raw material was consumed within 15 min. Add saturated aqueous ammonium chloride solution to quench the reaction, and add EA to it, let stand to separat...

Embodiment 4

[0102] The preparation method of the present embodiment is basically the same as the preparation method in Example 1, the difference is:

[0103] In step (10), the preparation method of compound IX is as follows:

[0104] Under the protection of argon, metal sodium (1.55g, 67.45mmol) was added to 100ml of liquid ammonia under stirring at -50°C, compound VIII (5.00g, 13.49mmol) was diluted with 50ml of anhydrous THF and added to the reaction system, and stirred 15min.; then place it at room temperature until all the liquid ammonia has evaporated. Add 50ml of saturated ammonium chloride aqueous solution to quench the reaction, add 100ml of EA, wash with saturated brine (3×50ml), anhydrous Na 2 SO 4 Dry, filter, concentrate, separate and purify to obtain 3.08g yellow liquid as compound (IX). Yield: 61.3%.

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Abstract

The invention discloses a method for synthesizing Entecavir and belongs to the technical field of medicine synthesis methods. According to the method, Entecavir is synthesized through taking 1,3-propanediol as a starting raw material, carrying out oxidation so as to form an aldehyde, then, producing an unsaturated ester, and then, carrying out reactions such as reduction, asymmetric epoxidation, ring opening, silane protecting group removing, hydroxyl protection, deprotection, oxidation, ring closing, oxidation, reduction, condensation and deprotection. According to the method, the used raw material is cheap and readily available, and the reaction conditions are mild and are easy in control, so that the industrial production is facilitated.

Description

technical field [0001] The present invention relates to a kind of synthetic method of medicine, particularly relate to a kind of synthetic method of entecavir. Background technique [0002] Entecavir is a guanosine analog used to treat hepatitis B. It was developed by Bristol-Myers Squibb in the United States and was approved by the FDA in March 2005. Entecavir has a strong effect of inhibiting the replication of hepatitis B virus and reducing the level of serum viral DNA, and it is still effective against lamivudine-resistant mutant virus strains, and no obvious adverse reactions and mitochondrial toxicity have been seen. Compared with other similar drugs, entecavir is an effective drug for the treatment of hepatitis B with relatively high safety. [0003] There are many synthetic methods about entecavir at present, such as the following synthetic route disclosed by Bristol-Myers Squibb: [0004] [0005] But there is starting raw material not easy to get in the above...

Claims

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Application Information

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IPC IPC(8): C07D473/18
CPCY02P20/55
Inventor 张健存姚国强叶康志
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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