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Alpha-quaternary carbon contained alpha,beta-diamino acid derivatives, and cocatalytic preparation method and application thereof

A diamine acid and derivative technology, applied in the field of pharmaceutical synthesis chemistry, can solve the problems of narrow reaction applicability, ineffective removal, harsh reaction conditions, etc., and achieve the effects of high efficiency and low cost, low synthesis cost, and mild reaction conditions.

Inactive Publication Date: 2014-10-22
EAST CHINA NORMAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But the disadvantage is that in the three-component product constructed by this reaction, the protection of the aryl group on the nitrogen atom cannot be effectively removed and further derivatization
[0004] In summary, most of the existing methods for the synthesis of α, β-diaminic acid derivatives have a narrow substrate reaction applicability, limited to the reaction of some raw materials and substrates, a large amount of catalyst, and harsh or unfavorable reaction conditions. Further Derived Disadvantages

Method used

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  • Alpha-quaternary carbon contained alpha,beta-diamino acid derivatives, and cocatalytic preparation method and application thereof
  • Alpha-quaternary carbon contained alpha,beta-diamino acid derivatives, and cocatalytic preparation method and application thereof
  • Alpha-quaternary carbon contained alpha,beta-diamino acid derivatives, and cocatalytic preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050]

[0051] Weigh N-p-toluenesulfonyl p-bromophenylimine (0.20mmol), rhodium acetate (1.00mg, 0.002mmol), squarylamide IIIA (0.02mmmol), aniline (0.30mmol), put them into a small test tube Reactor, add redistilled 5.6ml dichloromethane at room temperature. Weigh phenyldiazoacetate methyl ester (0.26mmol) and dissolve it in 2.8ml redistilled dichloromethane, and inject it into the reaction system through a peristaltic pump for 1 hour. The solvent was removed by rotary evaporation at 40°C, and the α, β-diamic acid derivatives at the α-position quaternary carbon were separated by column chromatography (eluent: petroleum ether: ethyl acetate = 1:20~1:5) Pure product A. Yield 53%, dr 50::50.

[0052]

[0053] Characterization of A:

[0054] 1 H NMR (400MHz, CDCl 3 )δ7.35-7.26(m, 4H), 7.26-7.13(m, 3H), 7.07(m, 2H), 7.00-6.84(m, 4H), 6.60(m, 1H), 6.44(d, J= 8.5Hz, 2H), 6.20(d, J=7.8Hz, 2H), 5.36(d, J=9.1Hz, 1H), 5.15(d, J=9.2Hz, 1H), 4.83(s, 1H), 3.56 (s, 3H), 2.26(s...

Embodiment 2

[0056]

[0057] Weigh N-p-toluenesulfonyl p-bromophenylimine (0.20mmol), rhodium acetate (1.00mg, 0.002mmol), squarylamide IIIB (0.02mmmol), aniline (0.30mmol), put them into a small test tube Reactor, add redistilled 5.6ml dichloromethane at room temperature. Weigh phenyldiazoacetate methyl ester (0.26mmol) and dissolve it in 2.8ml redistilled dichloromethane, and inject it into the reaction system through a peristaltic pump for 1 hour. The solvent was removed by rotary evaporation at 40°C, and the α, β-diamic acid derivatives at the α-position quaternary carbon were separated by column chromatography (eluent: petroleum ether: ethyl acetate = 1:20~1:5) Pure product A. Yield 52%, dr 50::50.

Embodiment 3

[0059]

[0060] Weigh N-p-toluenesulfonyl p-bromophenylimine (0.20mmol), rhodium acetate (1.00mg, 0.002mmol), squarylamide IIIC (0.02mmmol), aniline (0.30mmol), put them into a small test tube Reactor, add redistilled 5.6ml dichloromethane at room temperature. Weigh phenyldiazoacetate methyl ester (0.26mmol) and dissolve it in 2.8ml redistilled dichloromethane, and inject it into the reaction system through a peristaltic pump for 1 hour. The solvent was removed by rotary evaporation at 40°C, and the α, β-diamic acid derivatives at the α-position quaternary carbon were separated by column chromatography (eluent: petroleum ether: ethyl acetate = 1:20~1:5) Pure product A. Yield 50%, dr is 50::50.

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Abstract

The invention discloses a co-catalyzing preparation method of alpha, betal-diamino acid derivative of alpha-quaternary carbon. The alpha, betal-diamino acid derivative of alpha-quaternary carbon is synthesized by a reaction of three components: aryl acetic acid ester diazonium, arylamine, and sulfamide imine under co-catalysis of rhodium acetate squaric acid amide or metal magnesium salt. The alpha, betal-diamino acid derivative of alpha-quaternary carbon comprises a threo form alpha, betal-diamino acid derivative of alpha-quaternary carbon and an erythro form alpha, betal-diamino acid derivative of alpha-quaternary carbon shown as formula (II). The raw material provided by the invention is low in cost and easily available, and two chiral carbons are constructed at the same time by a one-pot method. The method is short in preparation line, simple to operate, mild in reaction condition, easy to synthesize the catalyst, high in atomic economy, high in yield and free from environmental pollution, and the threo form or / and the erythro form alpha, betal-diamino acid derivative of alpha-quaternary carbon can be conveniently obtained at the same time. A diversified compound framework is provided, and the method has important meaning on new medicine screening and pharmaceutical preparation technology.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis chemistry and relates to an α,β-diaminic acid derivative with an α-quaternary carbon and a preparation method and application thereof. Background technique [0002] α, β-Diamino 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, viomycin ) and other structures have such skeleton structures. The α,β-diaminic acid derivatives at the α-quaternary carbon can be used as synthetic precursors of imidazoline heterocyclic compounds with anticancer and antiarthritic activities (US2009156830A1), and can be used to synthesize a series of new and highly effective anticancer drugs. [0003] Synthesis methods of α,β-diaminic acid derivatives disclosed in recent years, for example, Chem.Rev.2005, 105, 3167., Org.Biomol.Chem., 2005, 3, 1362., J.Am.Chem. Soc., 2008, 130,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C311/19C07C303/40A61K31/216A61K31/63A61P3/10A61P3/04
Inventor 胡文浩邱林郭鑫吕峰平刘顺英杨琍苹吴翔
Owner EAST CHINA NORMAL UNIV
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