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Method for synthesizing (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate

A synthesis method and technology of formate, applied in organic chemistry methods, chemical instruments and methods, preparation of organic compounds, etc., can solve difficult production scale-up, low material safety, and octane-2-carboxylate preparation cost Advanced problems, to achieve the effect of relatively mild reaction conditions and novel process routes

Active Publication Date: 2019-04-26
SHENZHEN HUAXIAN PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The present invention provides a new method for improving the disadvantages of (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate, such as high preparation cost, low material safety, and difficult production and scale-up. process route

Method used

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  • Method for synthesizing (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate

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Embodiment 1

[0020] Embodiment 1: The synthetic method of the present embodiment uses methyl glyoxylate as the starting material, and successively carries out Henry reaction, elimination, ring closure, and reduction reaction to obtain the compound; specifically, the following reaction steps are included:

[0021] Step (1) Henry reaction (triethylamine method)

[0022] 10g methyl glyoxylate and 20g nitromethane were added to the single-necked bottle in turn, and 0.7g triethylamine was added dropwise at room temperature. After the dropwise addition was completed, the temperature was raised to react overnight. The nitromethane and triethylamine were removed by concentration under reduced pressure to obtain 13.5 g of methyl 2-hydroxy-3-nitropropionate with a yield of 80%.

[0023] Step (2) elimination (sodium hydroxide method)

[0024] Add 10g methyl 2-hydroxy-3-nitropropionate and 50mL dichloromethane to the single-necked bottle, add 6.7g sodium hydroxide, turn on stirring, drop to 0°C, dro...

Embodiment 2

[0029] Embodiment 2: The synthetic method of this embodiment uses ethyl glyoxylate as the starting material, and successively carries out Henry reaction, elimination, ring closure, and reduction reaction to obtain the compound; specifically, the following reaction steps are included:

[0030] Step (1) Henry reaction (sodium acetate method)

[0031] Add 20 g of nitromethane and 0.8 g of sodium acetate to the single-neck bottle, and slowly add 10 g of ethyl glyoxylate dropwise at 0°C. After the dropwise addition was completed, the reaction was carried out at room temperature for 12 h. Concentrate under reduced pressure to remove nitromethane, dissolve the product in ethyl acetate, wash the organic phase twice with 1N hydrochloric acid, and concentrate under reduced pressure to obtain 13.6 g of ethyl 2-hydroxy-3-nitropropionate with a yield of 85%.

[0032] Step (2) elimination (tert-butyl lithium method)

[0033] Under nitrogen protection, add 10 g of ethyl 2-hydroxy-3-nitropr...

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Abstract

The invention discloses a method for synthesizing (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate, belongs to the field of synthesis of medical intermediates and aims to solve the problems that preparation of (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate has higher cost, low material safety, difficulty in enlarged production and the like. According to the method, glyoxylate is taken as a starting material and subjected to Henry reaction, elimination, ring closure and reduction reaction sequentially, and an intermediate is obtained. Through the adoption of the method for synthesizing (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate, a novel process route is adopted, the yield is higher than 45%, and the method has the characteristics of novel route, relatively mild reaction conditions, low cost and the like.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis of pharmaceutical intermediates, in particular to a new synthesis method of (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate. Background technique [0002] (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate is a class of chiral small molecules with high synthesis difficulty. The chiral fragment appears in a class of influenza virus RNA polymerase inhibitors, the most representative of which is Pimodivir (code VX-787) developed by Vertex Corporation of the United States, which has entered the phase III clinical research stage. Due to the novel targets of such drugs, it is of great significance to solve the drug resistance of influenza virus. [0003] [0004] The current synthetic route of this structural fragment is shown in the following formula. Although the starting materials are relatively cheap, the main drawbacks of this route are (1), the need to use expensive chiral organic...

Claims

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Application Information

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IPC IPC(8): C07C227/16C07C229/50
CPCC07B2200/07C07C201/12C07C227/16C07C2602/22C07C229/50C07C205/51C07C205/50C07C205/55
Inventor 周章涛叶伟平费安杰高明陈科
Owner SHENZHEN HUAXIAN PHARMA TECH CO LTD
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