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Intermediates of Entecavir and synthesis method thereof

A compound and hydroxyl technology, applied in the field of intermediates for the preparation of entecavir, can solve the problems of high cost, unsuitability, complicated separation, complicated process and the like

Active Publication Date: 2012-04-25
LIANYUNGANG RUNZHONG PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] 1. The yield of the ring-opening reaction is low: for example, the yield reported in WO9809964 is about 50%, and the yield reported in JOC1985, 50, 755 is 27%
[0007] 2. It is difficult to separate and purify the ring-opening reaction product, which requires multiple column chromatography. The ring-opening reaction product is a mixture of stereoisomers. Even after repeated purification by silica gel column chromatography, it is still difficult to separate from each other and affects the final product purity
[0008] 3. The amino group on guanine needs to be protected in the follow-up reaction, the protection reaction is difficult, the product is unstable, the separation is complicated, and column chromatography is required. For example, WO9809964 reports that the reaction of protecting the amino group on guanine with MMT is difficult to complete, and the product is difficult to complete in the subsequent reaction. The purification process requires silica gel column chromatography, and it is easy to decompose on the silica gel column
[0010] Therefore, the reaction route of directly using guanine ring-opening is not suitable for industrial production in the process of actual use with complicated process, high yield and low cost.

Method used

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  • Intermediates of Entecavir and synthesis method thereof
  • Intermediates of Entecavir and synthesis method thereof
  • Intermediates of Entecavir and synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1: [1s-(1α, 2β, 3α, 5β)]-5-(phthalimide)-3-(benzyloxy)-2-[(benzyloxy)methyl base] cyclopentanol (intermediate 2') preparation

[0066] In a 5L three-neck flask, add 145g (0.98mol) of phthalimide, 3.77g of LiH and 765ml of anhydrous DMF, and stir for 10min. After heating to 60°C, stir for 15 minutes, at which time the cloudy solution becomes clear. Slowly drop 152g (0.49mol) [1s-(1α, 2α, 3β, 5α)]-3-(benzyloxy)-2-[(benzyloxy)methyl] dissolved in 1.87L of anhydrous DMF -6-Oxabicyclo[3.1.0]hexane (intermediate 1'), stirred at 60°C for 15min. Heated to 125°C, reacted for 2 hours, TLC (B: positive = 1:3) showed that the raw material disappeared, and terminated the reaction with 28ml of glacial acetic acid. Stir for 10 min. Add 2.5 L of saturated brine, extract with ethyl acetate 3×1.2 L, combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, and recover the solvent. The remaining oil was separated on a silica gel column and...

Embodiment 2

[0070] Example 2: [1s-(1α, 2β, 3α, 5β)]-5-[phthalimide]-3-(benzyloxy)-2-[(benzyloxy)methyl Base] the preparation of cyclopentanone (intermediate 3')

[0071] In a 3L three-neck flask, add 203g of Dess-Martin reagent, add 1.4L of anhydrous CH 2 Cl 2 Stir. 137.7g intermediate 2' was dissolved in 890ml anhydrous CH 2 Cl 2 Dissolved and added dropwise to the suspension in the previous step. After 20 min, TLC (B:positive=1:3) showed that the raw material disappeared, and the reaction was stopped. NaHSO 3 Washed three times with saturated aqueous solution, and then washed with NaHCO 3 Washed with saturated aqueous solution for 3 times, and finally washed with saturated brine for 3 times, and the organic layer was dehydrated and dried to obtain 196 g of a yellow oily compound.

Embodiment 3

[0072] Example 3: 1s-(1α, 3α, 4β)-5-phthalimido-2-methylene-4-(benzyloxy)-3-[(benzyloxy)methanol Preparation of Cyclopentane (Intermediate 4')

[0073] In a 5L three-necked flask, add Nysted Reagent (Wt=20%) 1.46L and 800ml anhydrous THF, stir, N 2 Protected and cooled to -78°C. 196g intermediate 3' with appropriate amount of CH 2 Cl 2 Dissolved and added dropwise to the reaction. Take TiCl 4 / CH 2 Cl 2 (1:9) 393ml was slowly added dropwise to the reaction, maintaining the temperature at -60°C to -78°C. After the dropwise addition was completed, the mixture was maintained at -78°C for 15 min. Slowly warm up to room temperature, and continue to stir for 1-3 h. TLC (B: positive = 1:4) showed that the raw materials disappeared, and the reaction solution was purple-black. Pour this reaction solution into 2.3L saturated NaHCO 3 In the middle, stir thoroughly, and white turbidity will appear at this time. Extracted three times with ethyl acetate, back-extracted once with ...

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Abstract

The invention relates to a synthesis method of nucleoside analogs, particularly to a synthesis method of an anti-virus-activity compound Entecavir. The invention also relates to intermediates for preparing Entecavir and a method for preparing the intermediates.

Description

[0001] This application is a divisional application of an invention patent application with an application date of August 24, 2006, an application number of 200610088464.8, and an invention title of "synthetic method of antiviral nucleoside analogues". technical field [0002] The present invention relates to a synthesis method of nucleoside analogues, in particular to a synthesis method of entecavir, a compound with antiviral activity, and also relates to intermediates for preparing entecavir and methods for preparing these intermediates. Background technique [0003] Entecavir (entecavir) is a carbocyclic guanosine analogue, chemical name: [1S-(1α, 3α, 4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3 -Hydroxymethyl-2-methylenecyclopentyl]-6H-purolin-6-one; Molecular formula: C 12 h 15 o 3 N 5 , molecular weight 277.3; the chemical structural formula is as follows: [0004] [0005] Entecavir is an effective anti-hepatitis B virus therapeutic drug. The compound and its monohy...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C217/52C07C213/02C07D473/18
Inventor 袁建栋张喜全刘飞张凯叶新建葛雅
Owner LIANYUNGANG RUNZHONG PHARMA CO LTD
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