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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 low chiral selectivity, high preparation cost, low production efficiency, etc., and achieves short synthetic route, improved chiral purity, Effects with low equipment requirements

Active Publication Date: 2020-09-04
RAFFLES PHAMRMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] Based on this, in view of the shortcomings of the above methods for preparing (2S, 3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate, it is necessary to address the low chiral selectivity in the preparation process. , low production efficiency and high preparation cost, provide a preparation (2S,3S)-3-amino-bicyclic [2.2 .2] Octane-2-carboxylate method

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

Experimental program
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Effect test

Embodiment 1

[0073] When R are all selected from methyl, the synthetic route is:

[0074]

[0075] The specific synthesis steps are:

[0076] 1. Synthesis of (2R,3S)-3-(S-tert-butylsulfamido)-bicyclo[2.2.2]octane-2-carboxylic acid ethyl ester

[0077] In a 2L reaction flask, add 1L tetrahydrofuran, 93g ethyl 3-carbonyl-bicyclo[2.2.2]octane-2-carboxylate, 232.5g ethyl titanate, 64.9g S-tert-butylsulfinamide, Under nitrogen protection, the temperature was raised and refluxed for 3 hours, the temperature was lowered, the THF was distilled off under reduced pressure, 600 mL of isobutyric acid was added to the residue, the temperature was lowered to between 0 and 10 ° C, the reaction temperature was controlled, and 21.2 g of sodium borohydride was added; Add 20% aqueous sodium hydroxide solution, adjust pH=7~8, extract with ethyl acetate (500mL x 2), the combined organic phases are filtered through silica gel and concentrated under reduced pressure to obtain 127.26g (2R,3S)-3-(S -tert-buty...

Embodiment 2

[0084] When R are all selected from ethyl, the synthetic route is:

[0085]

[0086] 1. Synthesis of (2R,3S)-3-(S-tert-butylsulfamido)-bicyclo[2.2.2]octane-2-carboxylic acid ethyl ester

[0087] In a 2L reaction flask, add 1L tetrahydrofuran, 100g ethyl 3-carbonyl-bicyclo[2.2.2]octane-2-carboxylate, 232.5g ethyl titanate, 64.9g S-tert-butylsulfinamide, Under nitrogen protection, the temperature was raised and refluxed for 3 hours, the temperature was lowered, the THF was distilled off under reduced pressure, 600 mL of isobutyric acid was added to the residue, the temperature was lowered to 0-10 ° C, the reaction temperature was controlled, and 21.2 g of sodium borohydride was added; Add 20% aqueous sodium hydroxide solution, adjust pH=7-8, extract with ethyl acetate (500mL x 2), the combined organic phases are filtered through silica gel, and concentrated under reduced pressure to obtain 143.42g (2R,3S)-3-( S-tert-butylsulfamido)-bicyclo[2.2.2]octane-2-carboxylic acid ethyl ...

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Abstract

The invention discloses a method for preparing (2S,3S)-3-amino-bicyclo [2.2.2]octane-2-formate. The method comprises the following steps: 3-carbonyl-bicyclo [2.2. 2] octane-2-formate is used as a rawmaterial, condensation, reduction, basic configuration inversion and acidic protection group removal are sequentially performed to obtain the (2S, 3S)-3-amino-bicyclo [2.2. 2] octane-2-formate, and Ris an organic substituent group. The synthetic route is short, the reaction conditions are mild, and the total yield is greater than 80%; through a chiral induction mode, an intermediate with high chiral purity can be obtained, and the chiral purity of a target product is improved to 99.5% or above; the used raw materials are easily available bulk raw materials, the equipment requirement is low, and the method is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of organic chemical synthesis of pharmaceutical intermediates, relates to a pharmaceutical intermediate, in particular to a method for preparing (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 small-molecule drug intermediates with two chiral centers, and this chiral fragment is widely used in a Among the new drug research and development of influenza-like RNA polymerase inhibitors, the most representative one is pimotevir developed by Vertex Corporation of the United States, which has entered the phase III clinical research stage. [0003] [0004] At present, there are mainly the following four routes for the synthesis of the structural fragment of (2S,3S)-3-amino-bicyclo[2.2.2]octane-2-carboxylate, three of which use cyclohexane Diene as starting material: [0005] Route 1 is shown in Route 1 of the following p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/04C07C229/50
CPCC07C227/04C07C313/06C07B2200/07C07C2602/44C07C229/50Y02P20/55
Inventor 黄志宁叶伟平周章涛费安杰陈润林崔锦栋蓝天琪
Owner RAFFLES PHAMRMATECH CO LTD
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