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A kind of preparation method of entecavir utilizing boc protecting group

A technology of entecavir and n-butyllithium, which is applied in the field of drug synthesis, can solve the problems of large space structure, high price, and low yield, and achieve the effects of increasing reaction yield, increasing synthesis yield, and increasing overall yield

Active Publication Date: 2020-09-04
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the currently disclosed method, there are generally low yields in the reaction process between the compound of formula I and 6-benzyloxy-2-aminopurine in the above steps, and the subsequent introduction of a relatively large and expensive MMT protecting group on the amino group of the aminopurine

Method used

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  • A kind of preparation method of entecavir utilizing boc protecting group
  • A kind of preparation method of entecavir utilizing boc protecting group
  • A kind of preparation method of entecavir utilizing boc protecting group

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1: the preparation of formula III compound

[0036]

[0037] Into a 3L three-necked flask, add 119g (0.35mol) of the compound of formula II and 1.1L of DMF and stir to dissolve, add 2.22g (0.28mol) of LiH, then raise the temperature to 60°C, stir for 15min, and add 55g (0.18mol) of the compound of formula I 0.55L of DMF solution, then warmed up to 125°C, reacted for 2.5h, TLC detected that the reaction was complete, cooled to room temperature, added 60mL of water, evaporated the solvent to dryness under reduced pressure, dissolved the residue with 1L of ethyl acetate, filtered off the insoluble matter, and the filtrate Wash with saturated brine three times, dry over anhydrous sodium sulfate, recover the solvent under reduced pressure, and separate the crude product on a silica gel column to obtain 97 g. Yield: 83%. 1 H-NMR (CDCl 3 ,500MHz)δ:7.72(s,1H),7.48~7.22(m,15H),5.56(m,2H),4.77(s,1H),4.61(m,1H),4.50(m,4H),4.31 (m,1H), 4.05(m,1H), 3.72~3.59(m,2H), ...

Embodiment 2

[0038] Embodiment 2: the preparation of formula IV compound

[0039]

[0040] In a 2L three-necked flask, add 63.6g (0.15mol) of Dess-Martin reagent, add 0.3L of dry dichloromethane under nitrogen protection, stir evenly, add dropwise 65g (0.1mol) of the compound of formula III and 0.3L of dry dichloromethane Chloromethane, control the reaction temperature at about 20°C, stir and react for 4 hours, HPLC monitors that the reaction is complete, pour it into 1.5L saturated sodium bicarbonate solution with 120g sodium thiosulfate dissolved, stir until clear, separate layers, water layer was extracted twice with dichloromethane, the organic layers were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, spin-dried, and the residual solvent was drained under reduced pressure by an oil pump to obtain 75 g of crude product (purity 76%), which was washed without The purification was directly used in the next reaction.

Embodiment 3

[0041] Embodiment 3: the preparation of formula V compound

[0042]

[0043] Into a 2L three-necked flask, add 230 mL of anhydrous tetrahydrofuran and 322 g (0.7 mol) of Nysted reagent, and stir. Cool to -78°C, add dropwise a mixture of 75g of the compound of formula IV and 230mL of dichloromethane, and then dropwise add a mixture of 19.5g (0.1mol) of titanium tetrachloride and 96mL of dichloromethane. After dropping, the reaction was continued for 30 minutes, and the temperature was raised to about 20°C. After 1 h of reaction, TLC detected that the reaction was complete. Added to 2.2L saturated aqueous sodium bicarbonate solution, stirred for 30min, filtered, the filter cake was washed with dichloromethane, the filtrate was separated, the aqueous layer was extracted twice with 0.3L dichloromethane, the organic layers were combined, washed twice with 0.5L saturated saline Second-rate. Dry over anhydrous sodium sulfate and concentrate under reduced pressure to obtain 64 g...

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Abstract

The invention belongs to the field of drug synthesis, and provides an entecavir preparation method using a Boc protection group, wherein particularly a compound represented by a formula III is prepared in a high yield manner by carrying out a reaction on a compound represented by a formula II and having a Boc group and a compound represented by a formula I, and the total yield of the subsequent oxidation, the methyleneation and the protection group removal is further improved so as to integrally improve the synthesis yield of entecavir, such that the method is suitable for industrial large-scale production. The formulas I, II and III are defined in the specification.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a preparation method of entecavir using a Boc protecting group. Background technique [0002] Entecavir (Entecavir) is an oral antiviral drug developed by Bristol-Myers Squibb (Bristol-Myers Squibb). In February 2006, Entecavir tablets were approved for marketing in China. Its chemical name is [1S-(1α, 3α ,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one. [0003] The preparation method of existing entecavir has multiple, mainly contains a kind of synthetic route disclosed by Bisacchi etc. (Bioorganic & Medicinal Chemistry Letters, Vol.7, No.2, pp.127-132, 1997) and CN1061972A, and process mainly comprises the following steps: [0004] [0005] MMT: 4'-Monomethoxytrityl [0006] In addition, there are domestic application publications CN101805339A and CN102477036A which disclose similar preparation methods. [0007] In the currentl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D473/18
CPCC07D473/18Y02P20/55
Inventor 王善春顾红梅张喜全刘飞刘彦龙周浩胡中元邢磊蔡正贵
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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