Method of preparing antivirotic entecavir hydrate

An antiviral drug, the technology of entecavir, applied in the field of compound preparation, can solve the problems of large-scale preparation difficulties, difficult reaction detection, low reaction yield, etc., and achieve simple product purification methods, high selectivity and stereoselectivity, and improved Effect of Reaction Conditions

Inactive Publication Date: 2007-08-08
SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

PCT / US2003 / 039554 (Chinese patent CN1747959A) discloses 7 kinds of methods for preparing anhydrous entecavir free base, but these methods and above-mentioned methods also have low reaction yield, severe isomerization in the reaction process, and the reaction is difficult to detect, large-scale preparation Difficulty and other issues

Method used

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  • Method of preparing antivirotic entecavir hydrate
  • Method of preparing antivirotic entecavir hydrate
  • Method of preparing antivirotic entecavir hydrate

Examples

Experimental program
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Effect test

Embodiment 1

[0039] Example 1 (1S, 2R)-[(4-methylbenzyloxy)methyl]-3-cyclopenten-1-ol 1

[0040] Under anhydrous and oxygen-free conditions, anhydrous tetrahydrofuran (300.0 mL) and sodium hydride (32.2 g, 60%, 805.0 mmol) were mixed, stirred and cooled to below -10 ° C, and cyclopentadiene (80.2 mL, 882.2 mmol). After the dropwise addition was completed, the ice-salt bath was removed and left overnight at room temperature for later use.

[0041] Anhydrous tetrahydrofuran (300.0 mL) and p-methylbenzyl chloride methyl ether (150.8 g, 804.2 mmol) were mixed under anhydrous and oxygen-free conditions, cooled to -78 ° C, and then cyclopentadiene prepared in advance was added dropwise sodium tetrahydrofuran solution. After the dropwise addition was completed, the reaction was carried out at -78°C for 2 hours. stand-by.

[0042]Add anhydrous tetrahydrofuran (600.0mL) and cyclopentadiene sodium and chlorine The reaction mixture of methylbenzyl ether was stirred at -78°C for 2 hours after the...

Embodiment 2

[0043] Example 2. (S, 2R, 3S, 5R)-2-[(4-methylbenzyloxy)-methyl]-6-oxobicyclo[3.1.0]heptan-3-ol 2

[0044] Peroxy tert-butanol (65%, 80.0mL, 540.0mmol) mixed with 1,2-dichloroethane (120.0mL), at 0 ° C, N 2 Added dropwise to a mixture of cycloenol 1 (56.0g, 257.0mmol) and Vo(acac) under protection 2 (0.7g, 2.6mmol) in 1,2-dichloroethane (37.0mL), the dropwise addition was completed, and the temperature was controlled below 25°C for 16 hours. The reaction mixture was cooled to 0°C, and a saturated solution of sodium sulfite (280.0 mL) was added dropwise. After the addition was complete, stirring was continued at room temperature for 2 hours. Separate the organic phase, extract the aqueous phase with dichloromethane twice (200.0mL×2), combine the organic phases, wash with water, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 2 (57.0g) , which can be used in the next reaction without furt...

Embodiment 3

[0045] Example 3. (1S, 2R, 3S, 5R)-3-(benzyloxy)-2-[(4-methylbenzyloxy)-methyl]-6-oxobicyclo[3.1.0 ] Heptane 3

[0046] Epoxy alcohol 2 (50.5g, 215.8mmol) was dissolved in anhydrous tetrahydrofuran (160.0mL) under ice cooling, and added dropwise to a THF suspension containing sodium hydride (12.9g, 60%, 323.7mmol) under N2 protection . After the dropwise addition was completed, benzyl chloride (36.0 mL, 302.7 mmol) was added after the stirring was continued for 2 hours, and the mixture was stirred overnight under cooling in a water bath. The mixture was concentrated under reduced pressure, the residue was added with water (300.0 mL) and ethyl acetate (300.0 mL) and stirred well, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (150.0 mL×2), the organic phase was washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filter and concentrate to obtain 95.0 g of crude product. Column chromatogra...

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PUM

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Abstract

The invention discloses a making technique of entikawei monohydrate as antiviral drug, which comprises the following steps: reacting cyclopentadiene monomer and sodium hydride protected by inert gas to make sodium cyclopentadiene; oxidizing through tert-butyl hydroperoxide; reacting with benzyl halogen under alkaline to obtain compound 3 to react with 6-benzyloxy guanine acted by alkaline to obtain compound 4; reacting with amino protective group to prepare compound 5; oxidizing through DMP tert-butanol oxidizing system to obtain ketone compound 6 to generate methylene compound 7 acted by Zn/TiCl4/CH2Br2; stripping protective product under acid condition to produce compound 8; recrystallizing to obtain the product.

Description

technical field [0001] The present invention relates to a preparation method of a compound, more specifically to a preparation method of antiviral drug Entecavir (Entecavir, BMS-200475) monohydrate. Background technique [0002] Entecavir monohydrate is a carbocyclic nucleoside anti-hepatitis B virus drug developed by Bristol-Myers Squibb [EP481754, the priority date is October 18, 1990; Drugs of the Future1999, 24 (11): 1173-1177], 2005 In March, it was approved by the US FDA for marketing in the US. Entecavir is a selective inhibitor of HBV DNA polymerase and blocks all three stages of HBV replication. Clinical studies have proved that entecavir monohydrate has strong anti-HBV activity, which is significantly better than lamivudine and is still effective for patients who have failed lamivudine treatment. Although the safety and tolerability of entecavir monohydrate is similar to that of lamivudine, it has a much lower chance of clinical drug resistance than lamivudine. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/18
CPCY02P20/55
Inventor 陈义朗韩硕尹建新孙田江蔡伟张玉斌阮刚朱清岭王晓梅
Owner SHANGHAI SUN SAIL PHARMA SCI & TECH CO LTD
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