Alpha-quaternary carbon contained alpha, beta-diamino acid derivative, synthetic method thereof and application thereof

A synthesis method and technology of diamine acid, applied in the α field of α-position quaternary carbon, can solve the problems of poor substrate universality, large amount of catalyst, harsh reaction conditions, etc.

Inactive Publication Date: 2012-06-20
EAST CHINA NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Most of the existing methods for synthesizing α, β-diaminic acid derivatives are obtained through the Mannich reaction of glycine esters and imines. However, the biggest defect of this type of method is that only cis-configuration α can be selectively obtained, β-Diamino acid derivatives
[0006] The present invention overcomes the disadvantages of poor substrate universality, large amount of catalyst, and harsh reaction conditions in the synthesis method of the prior art, and proposes an optically pure α-position quaternary carbon α, β-diamine derivative and its Synthetic method and application, the synthetic method of the present invention has characteristics such as simple operation, high selectivity, high atom economy

Method used

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  • Alpha-quaternary carbon contained alpha, beta-diamino acid derivative, synthetic method thereof and application thereof
  • Alpha-quaternary carbon contained alpha, beta-diamino acid derivative, synthetic method thereof and application thereof
  • Alpha-quaternary carbon contained alpha, beta-diamino acid derivative, synthetic method thereof and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069]

[0070] Weigh 2-p-methoxyphenylimine ethyl acetate (0.25mmol), rhodium acetate (0.005mmol), chiral phosphoric acid catalyst (Ar=9-phenanthrenyl) (0.005mmol), aminophosphoric acid di(2,6 -xylene) ester (0.3mmol), Molecular sieves (100 mg) were placed in a small test tube reactor, and 6 ml of redestilled toluene was added. Weigh phenyldiazoacetate methyl ester (0.3mmol) and dissolve it in 5ml redistilled toluene, and inject it into the reaction system through a peristaltic pump for 1 hour at room temperature. After the reaction is completed, filter, and the filtrate is rotary evaporated at 40°C to remove the solvent. Then by column chromatography (eluent: petroleum ether: ethyl acetate = 1: 30 ~ 1: 10) to separate the optically active trans α-position quaternary carbon α, β-diamine derivative pure product II -1. Yield 66%, d.r. value 17:1, ee value 95%.

[0071] 1 H NMR (400MHz, CDCl 3 ): 7.38-7.40(m, 2H), 7.20-7.22(m, 3H), 6.89-6.97(m, 6H), 6.75(d, J=9.2Hz, 2H)...

Embodiment 2

[0073]

[0074] Weigh 2-p-methoxyphenylimine ethyl acetate (0.25mmol), rhodium acetate (0.025mmol), the same chiral phosphoric acid catalyst (Ar=9-phenanthrenyl) (0.025mmol) as in Example 1, amino Di(2,6-xylyl)phosphate (0.75mmol), Molecular sieves (100 mg) were placed in a small test tube reactor, and 6 ml of redestilled toluene was added. Weigh methyl p-fluorophenyldiazoacetate (0.75mmol) and dissolve it in 5ml redistilled toluene, and inject it into the reaction system through a peristaltic pump for 1 hour at room temperature. After the reaction is completed, filter and remove the filtrate by rotary evaporation at 40°C Solvent, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 1: 30 ~ 1: 10) to obtain optically active trans α-position quaternary carbon α, β-diamine derivative pure Product II-2. Yield 55%, d.r. value 15:1, ee value 91%.

[0075] 1 H NMR (400MHz, CDCl 3 ): 7.32-7.35(m, 2H), 6.96-6.99(m, 3H), 6.90(s, 3H), 6.84(t, J=...

Embodiment 3

[0077]

[0078] Weigh 2-p-methoxyphenylimine ethyl acetate (0.25mmol), rhodium acetate (0.0125mmol), the same chiral phosphoric acid catalyst as in Example 1 (Ar=3,5-ditrifluorophenyl) ( 0.0125mmmol), bis (2,6-xylyl) phosphoramidate (0.5mmol), Molecular sieves (100 mg) were placed in a small test tube reactor, and 6 ml of redestilled toluene was added. Weigh methyl p-chlorophenyldiazoacetate (0.5mmol) and dissolve it in 5ml redistilled toluene, and inject it into the reaction system through a peristaltic pump for 1 hour at room temperature. After the reaction is completed, filter and remove the filtrate by rotary evaporation at 40°C Solvent, and then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 1: 30 ~ 1: 10) to obtain optically active trans α-position quaternary carbon α, β-diamine derivative pure Product II-3. Yield 55%, d.r. value 23:1, ee value 90%.

[0079] 1 H NMR (400MHz, CDCl 3 ): 7.25-7.28(d, J=9.2Hz, 2H), 8.8(d, J=8.8Hz, 2H), ...

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Abstract

The invention discloses a synthetic method of an alpha-quaternary carbon-contained alpha, beta-diamino acid derivative. The alpha-quaternary carbon-contained alpha, beta-diamino acid derivative is obtained by treating a diazo compound, an imine and a phosphoramidate as raw materials, chiral phosphoric acid and rhodium acetate as catalysts, an organic solvent as a solvent and a molecular sieve as a water absorbent, and carrying out a catalytic reaction. The synthetic method of the invention has the advantages of simple and easily available raw materials, simple and safe operation, high atom economy, high yield and high selectivity. The alpha-quaternary carbon-contained alpha, beta-diamino acid derivative obtained through the method of the invention, which has a diverse compound skeleton, has a very important meaning to a new medicine screening and preparing technology.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis chemistry, and specifically relates to an α,β-diamic acid derivative with an α-position quaternary carbon and a synthesis 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, the synthetic method of β-diaminic acid derivatives developed in recent years complement each other and improve (Chem.Rev.2005,105,3167., Org.Biomol.Chem., 2005,3,1362., J. Am. Chem. Soc., 2008, 130, 2170.). Most of the existing methods for synthesizing α, β-diaminic acid derivatives are obtained through the Mannich reaction of glycine esters and imines. However, the biggest defect of this ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/24A61P35/00A61P19/02
Inventor 胡文浩江俊马晓初钱宇吕峰平邱林周静杨琍苹
Owner EAST CHINA NORMAL UNIV
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