Method for synthesizing 5-benzylazaspiro[2,4]heptane

A synthesis method and technology of benzyl nitrogen, which are applied in the practical synthesis field of 5-benzylazaspiro[2,4]heptane, can solve the problem that reaction equipment has high anti-corrosion requirements, cannot be produced on a large scale, and is troublesome in post-processing and other problems, to achieve the effect of low cost, simple route and convenient post-processing

Active Publication Date: 2013-01-09
SUZHOU KANGRUN PHARMA
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  • Abstract
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  • Application Information

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Problems solved by technology

There are the following disadvantages: 1. The synthetic route is long, and 8 steps are required before and after the reaction, resulting in low overall yield, troublesome post-processing, and cannot be produced on a large scale. 2
Reagents such as liquid bromine

Method used

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  • Method for synthesizing 5-benzylazaspiro[2,4]heptane

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[0017] Example

[0018] The first step: the synthesis of 3-benzyloxyethyl N-benzylpyrrolidone

[0019] At 0°C, under nitrogen protection, n-butyllithium (2.4M, 9.3ml) was slowly added dropwise to diisopropylamine (3.2ml) in dry THF (10ml), stirred for half an hour, and then cooled to -78°C. A solution of N-benzylpyrrolidone (3.5g, 20.0mmol) in THF (30ml) was slowly added dropwise, and after stirring at -78°C for 15 minutes, 2-benzyloxyiodoethane (5.3g, 20.2mmol) was added to the reaction liquid, and the mixture was stirred overnight for reaction. The reaction was quenched with saturated ammonium chloride solution. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The organic phase was dried and then spun dry, and the crude product was passed through a column to obtain 3-benzyloxyethyl N-benzylpyrrolidone (4.8 g, 78%).

[0020] The second step: the synthesis of 3-hydroxyethyl N-benzyl pyrrolidone

[0021] A mixture of 3-benzyloxyethyl ...

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Abstract

The invention relates to a method for synthesizing 5-benzylazaspiro[2,4]heptane. The method comprises the following steps of: making N-benzylpyrrolidone (compound 1) react with 2-benzyloxyiodoethane in the presence of lithium diisopropylamide to generate 3-benzyloxyethylN-benzylpyrrolidone; and carrying out hydroxyl protective reaction and reacting with methane sulfonyl chloride to generate methane sulfuryl ester, performing intramolecular nucleophilic substitution in the presence of lithium hexamethyldisilaneamine to generate 4-oxo-5-benzylazaspiro[2,4]heptane, and reducing through lithium aluminum hydride to obtain 5-benzylazaspiro[2,4]heptane. The method has the advantages of concise route, reasonable process, simple and readily-available raw materials, low cost, convenience in post-treatment, high total yield and easiness in amplifying. Due to the adoption of the method, the defects of long synthesizing route, low total yield, high operation complexity, difficulty in post-treatment, difficulty in amplifying and the like existing in the conventional literature process are overcome.

Description

technical field [0001] The invention relates to a practical synthesis method of 5-benzylazaspiro[2,4]heptane. Background technique [0002] 5-benzylazaspiro[2,4]heptane can be debenzylated to obtain 5-azaspiro[2,4]heptane, which is an important intermediate in organic synthesis, and its derivatives Has high biological activity, the latest research shows that these derivatives have anti-CNS disorders in addition to the activity of anti-Grass-positive and Grass-negative bacteria (Arch.Pharm.Chem.Life Sci., 2007,340,530). The destruction of the cognitive system caused by it, such as Alzheimer's disease (EP1961750, WO2011018495). In recent years, by linking 5-azaspiro[2,4]heptane to some specific structures to seek some active screening Drugs have become one of the hotspots in medicinal chemistry. [0003] The synthetic method of 5-benzylazaspiro[2,4]heptane mainly generates benzylamine acetoacetate through the condensation of ethyl acetoacetate and benzylamine, and then forms...

Claims

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Application Information

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IPC IPC(8): C07D209/54
CPCY02P20/55
Inventor 徐卫良左兵徐炜政
Owner SUZHOU KANGRUN PHARMA
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