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9-[2-(phosphonomethoxy)ethyl] adenine bicycloalkoxide and its preparation

A technology of bicyclic alcohol and phosphonyl, applied in the field of bicyclic alcohol ester compound and preparation thereof, can solve the problems such as insufficient antiviral resistance of bicyclic alcohol

Inactive Publication Date: 2007-09-19
山东中科泰斗化学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But bicyclol is far from enough in the application of antiviral

Method used

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  • 9-[2-(phosphonomethoxy)ethyl] adenine bicycloalkoxide and its preparation
  • 9-[2-(phosphonomethoxy)ethyl] adenine bicycloalkoxide and its preparation
  • 9-[2-(phosphonomethoxy)ethyl] adenine bicycloalkoxide and its preparation

Examples

Experimental program
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Effect test

example 1

[0060] Example 1 Preparation of diethyl p-toluenesulfonylmethylphosphonate (intermediate 1)

[0061] Add 74ml of diethyl phosphite, 9ml of triethylamine, 22g of paraformaldehyde and 340ml of toluene into a three-necked flask, control the temperature at 87°C for 2hrs, then raise the temperature and reflux for 5hrs, stop the reaction, cool to 0°C, add 100g of benzenesulfonyl chloride After that, 82 g of triethylamine was added dropwise (the temperature was controlled to be less than 10°C, and the drop was completed in about 3 hours), reacted at room temperature for 24 hours, cooled, filtered, washed with toluene, washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 100 g of intermediate 1.

example 2

[0062] Example 2 Preparation of 9-[2-hydroxyethyl)adenine (intermediate 2)

[0063] Add 4g of sodium hydroxide, 200g of adenine, 160g of ethylene carbonate and 1000ml of DMF into a three-neck flask, raise the temperature to 135°C and react for 8hr-10hr (TLC detects that no adenine stops the reaction, developer: acetone: ethyl acetate: ammonia water =4:3:1), cooled to 50°C, added 1400ml of toluene, freeze crystallized, filtered, washed with cold toluene and absolute ethanol, dried in vacuum (60°C) to obtain 290g of off-white solid.

example 3

[0064] Example 3 Preparation of 9-[2-[diethyloxyphosphorylmethoxy]ethyl]adenine (intermediate 3, referred to as PMEA ethyl ester)

[0065] Add 20g of 9-(2-hydroxyethyl)adenosine and 80ml of DMF into a three-necked flask, raise the temperature to 125°C for 1 hour, and add 19g of sodium tert-butoxide in batches under cooling conditions (the feeding temperature should be less than 20°C). Complete, ice-bath cooling, dropwise the solution (temperature control 0 ℃) of the 80ml DMF of 54g benzenesulfonylmethylphosphonic acid diethyl ester, dropwise, 0 ℃ reaction 5hr (TLC detects that there is no 9-(2-hydroxyethyl base) adenine raw material, developer: ethanol: dichloromethane=1:4), add 67g of glacial acetic acid, react for 1hr at 20°C, concentrate in vacuum to semi-solid, add dichloromethane, filter, the filtrate is concentrated, and dichloromethane Extract with methane, wash with water, dry, concentrate, add 150ml of toluene to the concentrated solution, freeze and crystallize, filt...

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Abstract

An anti-virus active compound 9 -[2 - (phosphine carboxylmethoxy) ethyl] bicyclic alcohol ester is manufactured by: reacting 9 - [ 2- (phosphine carboxylmethoxy) ethyl ] adenosine purine with 4, 4'- dimethyl-5, 6, 5' 6'- bis(methylenedioxy) - 2 - hydroxymethyl - 2' - methoxycarbonyl biphenyl. This bicyclic alcohol ester could exist as its salt and are a kind white solid. Experiment shows that the compounds have the characteristics of high melting point, low hygroscopicity, photo-stability and thermal-stability, obvious anti-virus effect, protect and well care liver. It's a preferred pharmaceutical for anti-hepatitis virus.

Description

Technical field [0001] The present invention relates to the field of medical heterocyclic compounds, more specifically to bicyclic alcohol ester compounds of phosphonomethoxy nucleotide analogues and preparation techniques thereof. Background technique [0002] The following definitions apply throughout the specification and claims. [0003] PMEA=Adefovir (Adefovir), the chemical name is 9-[2-(phosphinecarboxymethoxy)ethyl]adenine; [0004] AD=Adefovir Dipivoxil, the bis-pivaloyloxymethyl ester of Adefovir; [0005] PMEA-DBOL=chemical name: 2-(N 9 -Adenyl)-ethoxymethyl bisbicyclic alcohol phosphate; [0006] "Medicinal salt" = refers to a class of salts formed by some Chinese medicine extracts containing acidic groups and having liver-protecting and liver-protecting medicinal activities and compounds of formula (I); [0007] PMEA-BOL=2-(N 9 - adenyl) ethoxymethyl bicyclol monophosphate; [0008] Bicyclic alcohol = (Bicyclol), the chemical name is 4,4'-dimethoxy-5,6,5'6...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6561A61K31/675A61P31/12A61P1/16
Inventor 王法平李晓翔
Owner 山东中科泰斗化学有限公司
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