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Intermediates of Entecavir and preparation thereof

A technology of compounds and structural formulas, applied in the fields of compounds, organic chemistry, chemical instruments and methods of elements of group 4/14 of the periodic table, can solve problems such as difficult separation and purification of ring-opening reaction products, complex processes, and complicated separations

Active Publication Date: 2012-04-18
CHIA TAI TIANQING PHARMA GRP 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 preparation thereof
  • Intermediates of Entecavir and preparation thereof
  • Intermediates of Entecavir and preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1: [1s-(1α, 2β, 3α, 5β)]-5-(phthalimido)-3-(benzyloxy)-2-[(benzyloxy)methyl Preparation of cyclopentanol (intermediate 2')

[0066] In a 5L three-necked flask, add 145g (0.98mol) phthalimide, 3.77g LiH and 765ml anhydrous DMF, and stir for 10min. After heating to 60°C and stirring for 15 min, the turbid liquid became clear. 152g (0.49mol) [1s-(1α, 2α, 3β, 5α)]-3-(benzyloxy)-2-[(benzyloxy)methyl] dissolved in 1.87L anhydrous DMF was slowly added dropwise. -6-oxabicyclo[3.1.0]hexane (intermediate 1'), stirred at 60°C for 15 min. It was heated to 125°C and reacted for 2h. TLC (B:positive=1:3) showed that the raw materials disappeared, and the reaction was terminated with 28ml of glacial acetic acid. Stir for 10 minutes. 2.5L of saturated brine was added, extracted with ethyl acetate 3×1.2L, the organic phases were combined and washed once with saturated brine, dried over anhydrous sodium sulfate, and the solvent was recovered. The remaining oil was separated o...

Embodiment 2

[0070] Example 2: [1s-(1α, 2β, 3α, 5β)]-5-[phthalimido]-3-(benzyloxy)-2-[(benzyloxy)methyl Preparation of yl]cyclopentanone (intermediate 3')

[0071] In a 3L three-necked flask, add 203g of Dess-Martin reagent, add 1.4L anhydrous CH 2 Cl 2 Stir. 137.7g of intermediate 2' was mixed with 890ml of anhydrous CH 2 Cl 2 Dissolved, added dropwise to the suspension in the previous step, after 20 min, TLC (B: positive = 1:3) showed that the raw materials disappeared, and the reaction was stopped. first with NaHSO 3 Washed with saturated aqueous solution 3 times, then washed with NaHCO 3 Washed with saturated aqueous solution 3 times, and finally washed with saturated brine 3 times, the organic layer was dehydrated and drained 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)methyl Preparation of cyclopentane (intermediate 4')

[0073] In a 5L three-necked flask, add 1.46L of Nysted Reagent (Wt=20%) and 800ml of anhydrous THF, stir, N 2 Protect and cool to -78°C. 196g of intermediate 3' was added to an 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, the mixture was maintained at -78°C for 15 min. The temperature was slowly raised to room temperature, and stirring was continued for 1-3 h. TLC (B:positive=1:4) showed that the raw materials disappeared, and the reaction solution was purple-black. The reaction solution was poured into 2.3L saturated NaHCO 3 , stir well, and white turbidity will appear at this time. Extract with ethyl acetate three times, back-extract once wit...

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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 "synthesis method of antiviral nucleoside analogs". technical field [0002] The present invention relates to a method for synthesizing nucleoside analogs, in particular to a method for synthesizing 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 analog, chemical name: [1S-(1α, 3α, 4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3 -Hydroxymethyl-2-methylenecyclopentyl]-6H-purin-6-one; Molecular formula: C 12 H 15 O 3 N 5 , the molecular weight is 277.3; the chemical structural formula is as follows: [0004] [0005] Entecavir is an effective anti-hepatitis B virus treatment drug. The compound and its m...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/40C07F7/18C07D239/50C07D473/18
Inventor 袁建栋张喜全刘飞张凯叶新建葛雅
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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