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Alpha, beta-diamino acid derivative with optically active alpha-quaternary carbon and preparation method and application thereof

An optically active, diamine acid technology, applied in the α field of α-position quaternary carbon, can solve problems such as low efficiency, poor economy, limited substrate scope, etc., and achieve the effects of simple synthetic route, high yield and low cost

Inactive Publication Date: 2015-09-16
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the substrate amines of the above-mentioned patents are phosphoramidates, and good results have not been obtained for aromatic amines
The substrates of imines are mainly prepared from ketoesters and p-methoxyaniline. The range of substrates is relatively limited, and imines are prepared and separated in advance, so the reaction efficiency is low and the economy is poor.

Method used

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  • Alpha, beta-diamino acid derivative with optically active alpha-quaternary carbon and preparation method and application thereof
  • Alpha, beta-diamino acid derivative with optically active alpha-quaternary carbon and preparation method and application thereof
  • Alpha, beta-diamino acid derivative with optically active alpha-quaternary carbon and preparation method and application thereof

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preparation example Construction

[0039] The preparation method of the present invention is as follows:

[0040] First weigh the amine: aldehyde: chiral phosphoric acid: p-cymene dichloride ruthenium dimer = 1.0: 1.0: 0.05: 0.01 in molar ratio, and add to the pre-dried round bottom flask in sequence Amines, aldehydes, chiral phosphoric acid catalysts, p-cymene dichloride ruthenium dimers and water absorbents Molecular sieve, water absorbent The amount of molecular sieve added is 1-2g / mmol aldehyde, and organic solvent is added to the round bottom flask at room temperature, the amount of organic solvent is 20-30ml / mmol aldehyde; the round bottom flask is stirred at room temperature for 1h, and then put into Stir in a low-temperature reaction bath at 10°C for 1 hour. Then, weigh the diazo:amine=1.1:1.0 by molar ratio, put the diazo and amine into a small bottle, and dissolve it with an organic solvent to dissolve diazoamine The amount of the organic solvent is 20-30ml / mmol aldehyde, stir evenly to obtain the...

Embodiment 1

[0042]

[0043] Weigh 2,5-dimethoxyaniline (15.3mg, 0.1mmol), p-cymene dichloride ruthenium dimer (1.2mg, 0.00lmmol), (S)-3,3'-triphenyl Silicon-substituted BINOL phosphoric acid (4.3mg, 0.005mmmol), p-bromobenzaldehyde (18.5mg, 0.1mmol), Molecular sieves (100mg), add 2ml of redistilled toluene, put them into a small test tube reactor, react at room temperature for 1h, and then put them into a low-temperature reaction bath to cool to -10°C. Weigh phenyldiazoacetate methyl ester (19.4mg, 0.11mmol), 2,5-dimethoxyaniline (15.3mg, 0.1mmol), the two compounds are mixed and dissolved in 2ml of redistilled toluene, and by peristaltic Inject the pump into the reaction system for 1 hour. After the injection, continue to stir at -10°C for 1 hour, then filter, and the filtrate is rotary evaporated at 40°C to remove the solvent, and then pass column chromatography (petroleum ether: ethyl acetate = 1:30~1: 10) Isolate the pure product A of the α,β-diaminic acid derivative with the opti...

Embodiment 2

[0047]

[0048] Weigh 2,5-dimethoxyaniline (15.3mg, 0.1mmol), p-cymene dichloride ruthenium dimer (1.2mg, 0.()()lmmol), (S)-3,3 '-Triphenylsilyl substituted BINOL phosphoric acid (4.3mg, 0.005mmmol), p-chlorobenzaldehyde (14.1mg, 0.1mmol), Molecular sieves (100mg), add 2ml of redistilled toluene, put them into a small test tube reactor, react at room temperature for 1h, and then put them into a low-temperature reaction bath to cool to -10°C. Weigh phenyldiazoacetate methyl ester (19.4mg, 0.11mmol), 2,5-dimethoxyaniline (15.3mg, 0.1mmol), the two compounds are mixed and dissolved in 2ml of redistilled toluene, and by peristaltic Inject the pump into the reaction system for 1 hour. After the injection, continue to stir at -10°C for 1 hour, then filter, and the filtrate is rotary evaporated at 40°C to remove the solvent, and then pass column chromatography (petroleum ether: ethyl acetate = 1:30~1: 10) Isolate the pure product B of the α,β-diaminic acid derivative with the op...

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Abstract

The invention discloses a preparation method of an alpha, beta-diamino acid derivative with optically active alpha-quaternary carbon. The preparation method comprises the following steps: dissolving aromatic aldehyde, arylamine, chiral phosphoric acid, p-cymene ruthenium dichloride dimer and a 4A molecular sieve in an organic solvent, adding an organic solvent of a diazo-compound, reacting at the temperature of minus 10 DEG C- minus 20 DEG C, and carrying out rotary evaporateion to obtain the alpha, beta-diamino acid derivative of alpha-quaternary carbon. Raw materials of the derivative are simple and easily available. The preparation method is simple and safe to operate, has advantages of high atom economy, high yield and high selectivity, and is of great significance for the screening and pharmaceutical preparation technology of a new drug.

Description

technical field [0001] The invention belongs to the technical field of synthetic chemical industry, and specifically relates to an α,β-diamic acid derivative with an α-quaternary carbon and a preparation method and application thereof. Background technique [0002] Optically active α, β-diaminic acid derivatives are a class of important skeleton structures with special medicinal compounds. They are used in anti-lymphoma drug bleomycin, anti-tuberculosis drug capreomycin, purple This kind of skeleton structure is found in structures such as viomycin. [0003] A series of α developed in recent years, the synthetic methods of β-diaminic acid derivatives complement each other and improve (Chem.Rev.2005,105,3167., Org.Biom0l.Chem., 2005,3,1362., J. Am. Chem. Soc., 2008, 130, 2170.). Most of the existing α, β-diaminic acid derivatives are synthesized through the Mannich reaction of glycine esters and imines. [0004] Recently, such structures were synthesized by the Mannich rea...

Claims

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Application Information

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IPC IPC(8): C07C229/36C07C227/32C07D307/54A61P35/00
Inventor 胡文浩郑庆江俊刘顺英马晓初
Owner EAST CHINA NORMAL UNIV
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