A 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 novel process route and relatively mild reaction conditions

Active Publication Date: 2021-11-30
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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  • A method for synthesizing (2s, 3s)-3-amino-bicyclo[2.2.2]octane-2-carboxylate
  • A method for synthesizing (2s, 3s)-3-amino-bicyclo[2.2.2]octane-2-carboxylate
  • A 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 is that the structure is methyl glyoxylate as the starting material, followed by 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] 10 g of methyl glyoxylate and 20 g of nitromethane were sequentially added to the single-necked bottle, and 0.7 g of triethylamine was added dropwise at room temperature. After the dropwise addition was completed, the temperature was raised to react overnight. Concentrate under reduced pressure to remove nitromethane and triethylamine 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 of methyl 2-hydroxy-3-nitropropionate and 50mL of dichloromethane into a single-necked bottle, add 6.7g of sodium hydroxide, start stirring, dr...

Embodiment 2

[0029] Embodiment 2: The synthesis method of this embodiment is to use ethyl glyoxylate as the starting material, and then carry out Henry reaction, elimination, ring closure, and reduction reactions in sequence 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 into the single-necked bottle, and slowly add 10 g of ethyl glyoxylate dropwise at 0°C. After the dropwise addition was completed, it was raised to room temperature and reacted for 12h. 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) eliminates (tert-butyllithium method)

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

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Abstract

The invention discloses a method for synthesizing (2S, 3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate, belonging to the field of synthesis of pharmaceutical intermediates. The purpose of the present invention is to improve the disadvantages of (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate, such as high preparation cost, low material safety, and difficulty in production and scale-up. The method of the present invention uses glyoxylate as a starting material, and sequentially carries out Henry reaction, elimination, ring closure and reduction reaction to obtain the intermediate. (2S, 3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate is synthesized by the synthetic method of the present invention, the yield is greater than 45%, and the route is novel and the reaction conditions are novel. Relatively mild, low cost and so on.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis of pharmaceutical intermediates, and specifically relates 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 that are difficult to synthesize. The chiral fragment appears in a class of influenza virus RNA polymerase inhibitors, the most representative of which is Pimodivir (code name 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 this type of drug, 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 material is comparatively cheap, the main defect of this route is (1), need to use expen...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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