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Synthesis method for medicine entecavir for treating hepatitis B

A technology of entecavir and medicine, which is applied in the field of synthesizing entecavir, can solve the problems of excessive tar, affecting yield and product purification, etc.

Active Publication Date: 2013-03-06
NANJING UNIV OF TECH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] Comparing the above three synthetic methods, the method shown in Scheme 2 has the advantages of simple operation, good reagent stability, low price, stable yield, little environmental pollution, etc., and has a better industrialization prospect, but at present, the reaction of this method produces less tar Many, affecting the yield and product purification

Method used

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  • Synthesis method for medicine entecavir for treating hepatitis B
  • Synthesis method for medicine entecavir for treating hepatitis B
  • Synthesis method for medicine entecavir for treating hepatitis B

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Example 1. (1S, 2S, 3S, 5S)-5-(2-amino-6-(benzyloxy)-9hydro-purine)-1-hydroxyl-3-(1-phenylcyclotrisilyl) ) Synthesis of cyclopentane-1,2-dimethanol (2a)

[0020] Add O-6-benzylguanine (2.76g, 11.45mmol), lithium hydroxide (0.23g, 9.54mmol), DMF (21mL) in 50mL one-necked flask, stir for 30min, add (1R, 2S, 3S, 5R )-3-(1-phenylcyclotrisilyl)-6-oxabicyclo[3.1.0]hexane-1,2-dimethanol (1a) (2.77g, 9.54mmol), heated to 80°C, React for 24 hours, add 50 mL of water, stir for 10 minutes, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and recrystallize from ethyl acetate / petroleum ether to obtain (1S, 2S , 3S, 5S)-5-(2-amino-6-(benzyloxy)purine)-1-hydroxyl-3-(1-phenylcyclotrisilyl)cyclopentane-1,2-dimethanol ( 2a) (3.39 g, yield: 67%).

Embodiment 2

[0021] Example 2. (1S, 2S, 3S, 5S)-5-(2-amino-6-(benzyloxy)-9hydro-purine)-1-hydroxyl-3-(1-phenylcyclotetrasilyl) ) Synthesis of cyclopentane-1,2-dimethanol (2b)

[0022] (1R, 2S, 3S, 5R)-3-(1-phenylcyclobutasilyl)-6-oxabicyclo[3.1.0]hexane-1,2-dimethanol (1b) under the catalysis of lithium hydroxide, React with 6-benzylguanine according to the operation steps of Example 1 to obtain (1S, 2S, 3S, 5S)-5-(2-amino-6-(benzyloxy)-9 hydrogen-purine)-1- Hydroxy-3-(1-phenylcyclotetrasilyl)cyclopentane-1,2-dimethanol (2b), yield: 66%, mp=54-56°C, 1 HNMR (500MHz, DMSO-d 6 )δ: 7.87(s, 1H), 7.59-7.58(m, 2H), 7.51-7.49(m, 2H), 7.39-7.32(m, 6H), 6.47(s, 2H), 5.48(t, 2H, J=12.55, 14.1), 5.05(t, 1H, J=5.8), 4.97(s, 1H), 4.75(t, 1H, J=4.6), 4.48(t, 1H, J=9.8), 3.58-3.52 (m, 2H), 3.35(m, 1H), 3.24(m, 1H), 2.70(m, 1H), 2.09-2.02(m, 2H), 1.84-1.78(m, 1H), 1.69-1.60(m , 4H), 0.98-0.83 (m, 4H).

Embodiment 3

[0023] Example 3. (1S, 2S, 3S, 5S)-5-(2-amino-6-(benzyloxy)-9hydro-purine)-1-hydroxy-3-(1-phenylcyclopentasilyl) ) Synthesis of cyclopentane-1,2-dimethanol (2c)

[0024] (1R, 2S, 3S, 5R)-3-(1-phenylcyclopentasilyl)-6-oxabicyclo[3.1.0]hexane-1,2-dimethanol (1c) was catalyzed by lithium hydroxide Next, react with 6-benzylguanine according to the operation steps of Example 1 to obtain (1S, 2S, 3S, 5S)-5-(2-amino-6-(benzyloxy)-9 hydrogen-purine)- 1-Hydroxy-3-(1-phenylcyclopentasilyl)cyclopentane-1,2-dimethanol (2c), yield: 69%.

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Abstract

The invention belongs to the field of medicine synthesis, and provides a method for synthesising entecavir by taking (1R,2S,3S,5R)-3-(1-phenyl cyclo-silicon)-6-oxa-bicyclo[3.1.0] hexane-1,2-dimethyl carbinol as a raw material. The synthesis method comprises the following steps of: combining the raw material with purine compounds at first, then building a chiral five-membered exocyclic double bond via deoxidization reaction, and finally removing a protecting group to obtain entecavir. Via the cyclosilane structure of the raw material, the rigidity of molecules is enhanced, so that the product obtained via the method is easier to crystallize and purify; and the tar generated during the reaction is less, and the yield is high. Therefore, the synthesis method is good in industrialization prospect.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a method for synthesizing entecavir. Background technique [0002] Entecavir (Entecavir) is a new hepatitis B drug with significant anti-HBV activity developed by Bristol-Myers Squibb Company of the United States. It was launched in the United States in April 2005. Its chemical name is 2-amino-9-[(1S,3S,4S)-4-hydroxy-3-hydroxymethyl-2-methylenepentyl]-1,9-hydrogen-6-H-purine-6 -ketone. Compared with other anti-HBV drugs, Entecavir has the advantages of small dosage and low incidence of drug resistance after long-term use. More importantly, for patients who develop resistance to other anti-HBV drugs, taking Entecavir is also effective, and in addition, it can also improve the anti-HBV curative effect when used in combination with other anti-HBV drugs. Therefore, entecavir is currently considered as one of the clinical candidate drugs for the treatment of chronic HBV in...

Claims

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Application Information

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IPC IPC(8): C07D473/18
CPCY02P20/55
Inventor 朱红军许毅何广科宋广亮施路任冬寅李焕陈晨
Owner NANJING UNIV OF TECH
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