Method for preparing (2s, 3s)-3-amino-bicyclo [2.2. 2] octane-2-formate

A technology of formate and octane, which is applied in the field of organic chemical synthesis of pharmaceutical intermediates, can solve the problems of difficult production scale-up, high preparation cost, low material safety, etc., and achieve a short route, low cost, and low equipment requirements. Effect

Active Publication Date: 2020-07-28
RAFFLES PHAMRMATECH CO LTD
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AI Technical Summary

Problems solved by technology

[0017] Aiming at the deficiencies of the existing technology, in order to solve the problems of (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate with high preparation cost, low material safety and difficulty in production scale-up, etc., The present invention provides a method for preparing (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate through two independently designed and innovative intermediates

Method used

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  • Method for preparing (2s, 3s)-3-amino-bicyclo [2.2. 2] octane-2-formate
  • Method for preparing (2s, 3s)-3-amino-bicyclo [2.2. 2] octane-2-formate
  • Method for preparing (2s, 3s)-3-amino-bicyclo [2.2. 2] octane-2-formate

Examples

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Embodiment 1

[0046]

[0047] 1. Synthesis of (S)-3-(1-phenethylamino)-bicyclo[2.2.2]octene-2-carboxylic acid ethyl ester

[0048]Add 1000L toluene to the reactor, 100.0kg 3-carbonyl-bicyclo[2.2.2]octane-2-ethyl carboxylate, 12kg p-toluenesulfonic acid, 80.0kg S-1-phenylethylamine, nitrogen protection Under reflux for 12 hours, the enamine intermediate (S)-3-(1-phenethylamino)-bicyclo[2.2.2]octene-2-carboxylic acid ethyl ester was obtained, which was used in the next reaction.

[0049] 2. Synthesis of (2R,3S)-3-((S)-1-phenethylamino)-bicyclo[2.2.2]octane-2-carboxylic acid ethyl ester

[0050] Precipitate the above-mentioned enamine intermediate (S)-3-(1-phenethylamino)-bicyclo[2.2.2]octene-2-carboxylate ethyl ester solution, then add 1500L tetrahydrofuran, 500L acetic acid, and then cool Then 106.2 kg of sodium triacetoxyborohydride were added. Warm up to room temperature and react for 3 hours. 3N sodium hydroxide solution was added dropwise to adjust to alkalinity, extracted with eth...

Embodiment 2

[0057]

[0058] 1. Synthesis of (S)-3-(1-naphthylethylamino)-bicyclo[2.2.2]octene-2-ethyl carboxylate

[0059] Add 1000L toluene to the reactor, 100.0kg 3-carbonyl-bicyclo[2.2.2]octane-2-ethyl carboxylate, 10.0kg trifluoroacetic acid, 113kg S-1-naphthylethylamine, reflux reaction under nitrogen protection 12 hours. Cool down to room temperature, wash with 300L saturated sodium bicarbonate solution, concentrate the organic layer to 200L, add 500L n-heptane, stir at room temperature for 3 hours, filter, wash with a small amount of n-heptane, and dry in vacuo to obtain 133.6kg (S)-3-(1 -Phenylethylamino)-bicyclo[2.2.2]octene-2-carboxylic acid ethyl ester, white solid, yield 75.3%.

[0060] 2. Synthesis of (2R,3S)-3-((S)-1-naphthylethylamino)-bicyclo[2.2.2]octane-2-carboxylic acid ethyl ester

[0061] Add 300L ethanol to 1000L stainless steel autoclave, 200L ethyl acetate, 100.0kg (S)-3-(1-naphthylethylamino)-bicyclo[2.2.2]octene-2-ethyl carboxylate, 10.0kg 5% platinum carbo...

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Abstract

The invention discloses a method for synthesizing (2S,3S)-3-amino-bicyclo[2.2.2] octane-2-formate and belongs to the field of pharmaceutical intermediate synthesis. The purposes of the invention are to solve the problems of high preparation cost, low material safety and the like of (2S, 3S)-3-amino-bicyclo[2.2.2] octane-2-formate, further improve the productivity and reduce the production cost. According to the method disclosed by the invention, 3-carbonyl-bicyclo[2.2.2] octane-2-formate is used as a starting material, and reductive amination, basic configuration inversion, hydrogenation protection group removal and the like are sequentially carried out, so that the target product is obtained. According to the invention, the (2S, 3S)-3-amino-bicyclo [2.2. 2] octane-2-formate is synthesizedby using the synthesis method, the novel process route is used, the yield is more than 65%, and the method has characteristics of novel route, mild reaction condition, low cost and the like.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis of pharmaceutical intermediates, and specifically relates to the synthesis and industrialization of (2S, 3S)-3-amino-bicyclo[2.2.2]octane-2 using an independently designed and innovative intermediate - A new method of formate. 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. This chiral fragment is widely used in the production of a class of influenza virus RNA polymerase inhibitors, the most representative of which is Pimodesvir developed by Vertex Corporation of the United States, which has entered the phase III clinical research stage. This type of drug has a novel target, which is of milestone significance for solving the drug resistance of influenza virus. [0003] [0004] At present, there are three main routes for the synthesis of (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carbo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/18C07C229/50C07C227/32
CPCC07C227/18C07C227/32C07C227/16C07C227/08C07C229/50C07B2200/07C07C2602/44Y02P20/55
Inventor 周章涛黄志宁陈润林崔锦栋陈科蓝天琪叶伟平费安杰
Owner RAFFLES PHAMRMATECH CO LTD
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