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Method for synthesizing gamma-aminobutyric acid chiral compound

A technology of chiral compounds and aminobutyric acid, which is applied in the preparation of organic compounds, chemical instruments and methods, and preparation of cyanide reactions, etc., can solve the problems of expensive thiourea catalysts and lower industrial application value, and meet the reaction conditions Gentle, simple operation, high yield effect

Inactive Publication Date: 2015-04-29
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, chiral Ni(II) catalysts and quinine-derived thiourea catalysts are relatively expensive, which reduces the industrial application value of this route

Method used

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  • Method for synthesizing gamma-aminobutyric acid chiral compound
  • Method for synthesizing gamma-aminobutyric acid chiral compound
  • Method for synthesizing gamma-aminobutyric acid chiral compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] A method for synthesizing baclofen, comprising the following steps:

[0031] (1) P-chloronitrostyrene (3.66g, 20.0mmol), dimethyl malonate (7.92g, 60.0mmol), 6'-demethylquinidine (0.62g, 10mol%) and N , N-diisopropylethylamine (0.52g, 20mol%) was dissolved in THF (100mL), stirred at room temperature for 24 hours, concentrated after the reaction was completed, and purified by column chromatography (ethyl acetate / petroleum ether=1 / 10) , to obtain (R)-dimethyl 2-(1-(4-chlorophenyl)-2-nitroethyl)maleate (6.00 g, yield 95%, ee 94%).

[0032] The structural characterization data of the product are as follows:

[0033] 1 H NMR (400MHz, CDCl 3 ): δ7.31(d, J=8.4Hz, 2H), 7.18(d, J=8.4Hz, 2H), 4.91(dd, J=4.8, 12.8Hz, 1H), 4.85(dd, J=8.4, 13.6Hz, 1H), 4.23(dt, J=4.8, 9.2Hz, 1H), 3.83(d, J=9.2Hz, 1H), 3.77(s, 3H), 3.60(s, 3H); 13 C NMR (100MHz, CDCl 3 ): δ167.6, 167.0, 134.6, 134.4, 129.3, 129.2, 77.1, 54.4, 53.0, 52.9, 42.3. Chiral HPLC: Daicel chiralcel OD-H Column, Hexane / 2...

Embodiment 2

[0050] A method for synthesizing baclofen, comprising the following steps:

[0051] (1) p-chloronitrostyrene (3.66g, 20.0mmol), dimethyl malonate (7.92g, 60.0mmol), 9-O-allyl-6'-demethylquinidine ( 0.67g, 10mol%) and N,N-diisopropylethylamine (0.52g, 20mol%) were dissolved in THF (100mL), stirred at room temperature for 24 hours, concentrated after the completion of the reaction, column chromatography (ethyl acetate / Petroleum ether=1 / 10) was purified to obtain (R)-2-(1-(4-chlorobenzene)-2-nitroethyl)) dimethyl maleate (6.13g, yield 97%, ee 97%). The structural characterization data of the product are the same as in Example 1.

[0052] (2) This step is the same as in Example 1.

[0053] (3) This step is the same as in Example 1.

Embodiment 3

[0055] A method for synthesizing baclofen, comprising the following steps:

[0056] (1) P-chloronitrostyrene (3.66g, 20.0mmol), dimethyl malonate (7.92g, 60.0mmol), 9-benzoyl-6'-demethylquinidine (0.82g , 2.0mmol) and 4-dimethylaminopyridine (0.26g, 2.0mmol) were dissolved in THF (100mL), stirred at room temperature for 24 hours, after the reaction was completed and concentrated, column chromatography (ethyl acetate / petroleum ether=1 / 10) Purification to obtain (R)-2-(1-(4-chlorobenzene)-2-nitroethyl) dimethyl maleate (5.87 g, yield 93%, ee 88%). The structural characterization data of the product are the same as in Example 1.

[0057] (2) This step is the same as in Example 1.

[0058] (3) This step is the same as in Example 1.

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Abstract

The invention discloses a method for synthesizing a gamma-aminobutyric acid chiral compound. The method comprises the following steps of: adding nitroolefin and malonate to a solvent in the presence of a catalyst A and an additive; carrying out conjugate addition reaction on nitroolefin and malonate to selectively obtain a compound V; carrying out hydrogenation reduction reaction on the compound V under the action of a catalyst B and hydrogen, decarboxylation and amidation to obtain a compound II; carrying out acidolysis on the compound II to obtain a compound I. According to the method, a gamma-aminobutyric acid chiral drug prepared by taking a low-cost easily-prepared quinidine derivative as a catalyst and alkali as an additive is high in yield and high in enantioselectivity. The method disclosed by the invention is moderate in reaction condition and easy to operate and is a green synthesis process for synthesizing gamma-aminobutyric acid chiral drugs.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a method for synthesizing gamma-aminobutyric acid chiral compounds. Background technique [0002] β-substituted chiral γ-aminobutyric acid and its lactam derivatives have a very wide range of physiological activities, clinically used for sedative hypnosis, antidepressant, skeletal muscle spasm, anti-senile dementia and anti-epilepsy. Among them, representative drugs include baclofen, a skeletal muscle relaxant and antispasmodic drug, pregabalin, an antiepileptic, anxiolytic, and neuralgia drug, fenibut, an anxiolytic and insomnia drug, and rolipram, an antidepressant drug. [0003] For the synthesis of such chiral drugs, the existing main methods are: 1) chiral resolution (WO9638405, WO2009147528; WO2010061403; CN101362696A); 2) synthesis from chiral raw materials (Tetrahedron: Asymmetry 2008, 19, 651; J. Org.Chem.2007,72,7390; CN101585778A); 3) Synthesis using chira...

Claims

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Application Information

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IPC IPC(8): C07C229/34C07C229/08C07C227/22C07D207/267
Inventor 鄢明董雪娇张学景
Owner SUN YAT SEN UNIV
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