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New synthesis process of antiviral drug entecavir

A compound and generative technology, which is applied in the field of new synthesis technology of entecavir, can solve the problems of expensive process route, rare raw materials, and high technical requirements of the method

Active Publication Date: 2010-11-24
聊城高新生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to provide a new synthetic method of the antiviral drug entecavir, and provide a synthetic route that is convenient for domestic industrial production, so as to solve the problems in the prior art that the cost of the process route is high, the raw materials are rare, and the technical requirements of the method are high.

Method used

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  • New synthesis process of antiviral drug entecavir
  • New synthesis process of antiviral drug entecavir
  • New synthesis process of antiviral drug entecavir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116] The preparation of embodiment 1 (1R, 5S)-5-[dimethyl (1-naphthyl) silane]-2-(hydroxymethyl)-2-cyclopentene-1-carboxylic acid methyl ester

[0117] This example is used to prepare (1R, 5S)-5-[dimethyl(1-naphthyl)silane]-2-(hydroxymethyl)-2-cyclopentene-1-carboxylic acid methyl ester, the substance As a raw material for the synthesis of Entecavir. The specific steps are as follows:

[0118] 1) 1-(dimethylchlorosilyl)-naphthalene (X, R 1 = naphthalene)

[0119] Under a nitrogen atmosphere, add magnesium powder (7.2 g, 0.3 mol) dried THF 60 ml and a grain of iodine into a 1000 ml three-necked flask. Add 1-bromonaphthalene (62.1 g, 0.3 mol) THF 180 ml solution dropwise. After triggering at 50° C., control the rate of addition to maintain reflux. After dropping, heat to 60° C. and reflux and stir for 1 hour.

[0120] A solution of dichlorodimethylsilane (51 g, 0.39 mol) in 180 ml of THF was added dropwise, and the mixture was heated under reflux and stirred for 15 ho...

Embodiment 2

[0132] The preparation of embodiment 2 entecavir

[0133] (1R,5S)-5-[Dimethyl(1-naphthyl)silane]-2-[(1-methoxy-1-methylethoxy)methyl] - Preparation of 2-cyclopentene-1-methanol (IIIa)

[0134] Add compound 5 (16 g, 0.05 mol) and 40 ml of toluene to a 500 ml three-necked round bottom flask equipped with a mechanical stirrer and a thermometer under a nitrogen atmosphere. The resulting solution was cooled to about 0°C in an ice-water bath, and 2-methoxypropene (70ml, 0.05mol) was added. 0.4 g of pyridinium p-toluenesulfonate was added at 0°C, and the resulting mixture was stirred at 0°C for 10 minutes. The cooling bath was removed and the reaction mixture was stirred at 120°C for 1.5 hours. After the reaction was complete, the reaction mixture was cooled to -78°C. Lithium aluminum hydride (2.0 g, 0.05 mol) was added. After 30 minutes, the cooling bath was removed, stirred at room temperature for 2 hours, and 20 ml of sodium hydroxide 2N solution was added. After the addi...

Embodiment 3

[0146] The preparation of embodiment 3 entecavir

[0147] [1R-(1α, 2α, 3β, 5α)]-3-[Dimethyl(1-naphthyl)silane]-6-oxabicyclo[3.1.0] Preparation of hexane-1,2-dimethanol (V')

[0148] Under a nitrogen atmosphere, add 20 g of molecular sieves and 100 ml of DCM to a 500 ml three-neck flask equipped with a mechanical stirrer, a temperature probe and a nitrogen inlet. 2.3 g of DIPT and 2.3 ml of titanium isopropoxide were sequentially added to the mixture. The reaction was stirred at 30°C for 20 minutes. Compound (II) (10 g, 0.03 mol) in DCM 40 ml was added. Then add TBHP30ml. Stir at room temperature for 5 hours. Aqueous sodium sulfite solution quenched the reaction. Washed with saturated sodium bicarbonate and saturated brine. The organic layer was concentrated under reduced pressure to obtain a crude oil (10 g, 0.028 mol). Add 10 g of the newly obtained epoxide and 75 ml of isopropanol to a 500 ml three-necked flask equipped with a mechanical stirrer, a temperature pro...

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Abstract

The invention discloses a method for preparing a compound shown as the formula (I), which is characterized by comprising the following steps of: (1) carrying out hydroxyl protection on a compound shown as the formula (II) by using a first hydroxyl protecting group, and then, reacting with hydride to generate a compound shown as the formula (III); (2) carrying out hydroxyl protection on the compound shown as the formula (III) by using a second hydroxyl protecting group, and then, removing the first hydroxyl protecting group to obtain a compound shown as the formula (IV); (3) enabling the compound shown as the formula (IV) to carry out non-corresponding selective epoxidation reaction to generate a compound shown as the formula (V); (4) reacting the compound shown as the formula (V) with thecompound shown as the formula (VI) in a polar aprotic solvent to obtain a compound shown as the formula (VII); and (5) carrying out condensation, desilylation and oxidization on the compound shown asthe formula (VII) to generate the compound shown as the formula (I). In the general formulas of the compounds in each step, R1 is selected from naphthyl or any substituted naphthyl; R2 is selected from alkyl or benzyl of C1-C4; P is selected from hydroxyl protecting groups, such as 2-methoxyl propyl or p-methoxyl benzyl and the like; P' is a hydroxyl protecting group capable of resisting and removing P, such as benzyl; and X is selected from Cl, Br, I or benzyloxyl.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a new synthesis process of entecavir. Background technique [0002] Chronic hepatitis B is a chronic inflammatory necrotic disease of the liver caused by persistent hepatitis B virus (HBV) infection. Fatigue, general malaise, loss of appetite, discomfort or pain in the liver area, abdominal distension, insomnia, low-grade fever, etc. appear clinically. The disease is a common disease that seriously endangers human health. The prevention and treatment of chronic hepatitis B is a global public health problem, which has attracted the attention of countries all over the world. my country is a high incidence area of ​​viral hepatitis, with an average annual incidence rate of 120-140 / 100,000. Among them, hepatitis B (HB) is the most prominent. The infection rate of hepatitis B virus (HBV) in my country is as high as 57.63%, that is, at least 600 million peop...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/18
CPCY02P20/55
Inventor 方洋李晨曦殷飞
Owner 聊城高新生物技术有限公司
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