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Entecavir derivative and preparation method thereof

A technology of entecavir and valentecavir, applied in the directions of active ingredients of heterocyclic compounds, antiviral agents, organic chemistry, etc., can solve the problems of low bioavailability of D-amino acid esters and cannot be used as acyclovir prodrugs, etc., and achieves improved pharmacopeia performance, Easy deprotection, low effective dose effect

Active Publication Date: 2014-06-18
FUJIAN TIANQUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Table 1 of this publication gives the chemical data and oral bioavailability of 18 amino acid esters, from which it can be seen that the bioavailability of D-amino acid esters is lower than that of acyclovir itself
Thus, since D-amino acid esters have no benefit to acyclovir, they cannot act as prodrugs of acyclovir

Method used

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  • Entecavir derivative and preparation method thereof
  • Entecavir derivative and preparation method thereof
  • Entecavir derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] 1. Preparation of (S)-2-(tert-butoxycarbonyl-amino)-3-methylbutanoic acid-Entecavir

[0053] Take entecavir: 60.9g, add dimethylformamide 1250mL, shake to dissolve.

[0054] Take (S)-2-(tert-butoxycarbonyl-amino)-3-methylbutanoic acid: 104.2g, dicyclohexylcarbodiimide: 69.6g, 4-dimethylaminopyridine: 8.2g, add di Methylformamide 1250mL, stirred for 60min, added the above entecavir solution, stirred and reacted at 100°C for 24h.

[0055] After the reaction is completed, filter with suction, add 650 g of silica gel to the filtrate, and dry it on a water bath at 90°C.

[0056] Take 2900g of silica gel, put it on a column, put the fried silica gel on the column, wash it with methanol-ethyl acetate (10:90), and collect every 12L. TLC monitors the fractions, merges the fractions containing the target product, and evaporates to dryness under reduced pressure to obtain (S)-2-(tert-butoxycarbonyl-amino)-3-methylbutanoic acid-entecavir, i.e. Boc-protected valeric acid Amino ...

Embodiment 2

[0066] 1. Preparation of (S)-2-(tert-butoxycarbonyl-amino)-3-methylbutanoic acid-Entecavir

[0067] Take entecavir: 60.9g, add dimethylformamide 2500mL, shake to dissolve.

[0068] Take (S)-2-(tert-butoxycarbonyl-amino)-3-methylbutanoic acid: 52.1g, dicyclohexylcarbodiimide: 34.8g, 4-dimethylaminopyridine: 4.1g, add di Methylformamide 2500mL, stirred for 30min, added the above entecavir solution, stirred and reacted at 100°C for 1h.

[0069] After the reaction is completed, filter with suction, add 650 g of silica gel to the filtrate, and dry it on a water bath at 90°C.

[0070] Take 2900g of silica gel, put it on a column, put the fried silica gel on the column, wash it with methanol-ethyl acetate (10:90), and collect every 12L. The fractions were monitored by TLC, and the fractions containing the target product were combined and evaporated to dryness under reduced pressure to obtain (S)-2-(tert-butoxycarbonyl-amino)-3-methylbutanoic acid-entecavir.

[0071] , 2-amino-...

Embodiment 3

[0075] 1. Preparation of (S)-2-(tert-butoxycarbonyl-amino)-3-methylbutanoic acid-Entecavir

[0076] Take entecavir: 60.9g, add dimethylformamide 1250mL, shake to dissolve.

[0077] Take (S)-2-(tert-butoxycarbonyl-amino)-3-methylbutanoic acid: 208.4g, dicyclohexylcarbodiimide: 139.2g, 4-dimethylaminopyridine: 16.4g, add di Methylformamide 1250mL, stirred for 60min, added the above entecavir solution, stirred and reacted at 100°C for 72h.

[0078] After the reaction is completed, filter with suction, add 650 g of silica gel to the filtrate, and dry it on a water bath at 90°C.

[0079] Take 2900g of silica gel, put it on a column, put the fried silica gel on the column, wash it with methanol-ethyl acetate (10:90), and collect every 12L. The fractions were monitored by TLC, and the fractions containing the target product were combined and evaporated to dryness under reduced pressure to obtain (S)-2-(tert-butoxycarbonyl-amino)-3-methylbutanoic acid-entecavir.

[0080] , 2-am...

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Abstract

The invention discloses an entecavir derivative and a preparation method thereof. The chemical name of the entecavir derivative is 2-amino-9-[(1S, 3R, 4S)-4-hydroxy-2-methylene cyclopentyl]-1,9-dihydro-6H-purine-6-one-3-methyl hydroxyl-L-valine ester, namely valerian entecavir for short. The preparation method comprises the following steps: reacting 0.5-5 equivalent of (S)-2-(tert-butoxy carbonyl-amino)-3-methylbutyric acid, 0.5-5 equivalent of dicyclohexyl carbodiimide, and 0.01-0.5 equivalent of 4-dimethylamino-pyridine with 0.5-5 equivalent of entecavir in dimethylformamide for 0.5-240 hours; separating and purifying by silica gel column chromatography after reaction, and then deprotecting to obtain a target product. The valerian entecavir prepared by the method has the advantages of being good in water solubility and targeting property, and low in toxicity on other organs, can achieve high liver distribution, and is a stable prodrug of the entecavir.

Description

technical field [0001] The invention relates to an anti-hepatitis B virus drug, especially an amino acid ester of a purine derivative, specifically an ester synthesized from entecavir and L-valine; the invention also relates to a preparation method of the entecavir derivative. Background technique [0002] Entecavir is epoxy hydroxycarbodeoxyguanosine, a deoxyguanosine analogue that can effectively inhibit the replication of hepatitis B virus, and has a strong anti-HBV effect. In vitro tests, entecavir can inhibit the replication of HBV at a very low concentration, while its cytotoxicity is very low, and it has a very good selective therapeutic index. [0003] However, because hepatitis B requires long-term treatment, the incidence of adverse reactions after 62-63 weeks of entecavir 0.5-1.0mg / d treatment is about 85%, and the incidence of serious adverse reactions is 7%. The main adverse reactions are: headache, upper respiratory tract infection, nasal Pharyngitis, epigastr...

Claims

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Application Information

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IPC IPC(8): C07D473/18A61K31/522A61P31/12
CPCC07D473/18
Inventor 邓志明朱靖华邓志清邓志平徐广鑫卢仲森陈维林罗炳华
Owner FUJIAN TIANQUAN PHARMA
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