Optically active α-amino β-hydroxyamino acid derivatives and preparation method and application thereof

A hydroxyamino acid and optically active technology, which is applied in the field of α-amino-β-hydroxyamino acid derivatives and their preparation, can solve problems such as multi-step operations and complex reaction substrates, improve the utilization rate of raw materials, and simplify the synthesis route , low cost effect

Active Publication Date: 2016-09-14
广东和博制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these synthetic methods of the prior art all have shortcomings such as multi-step operation and complicated reaction substrates.

Method used

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  • Optically active α-amino β-hydroxyamino acid derivatives and preparation method and application thereof
  • Optically active α-amino β-hydroxyamino acid derivatives and preparation method and application thereof
  • Optically active α-amino β-hydroxyamino acid derivatives and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039]Weigh N-p-chlorophenyl glycine ethyl ester (0.20mmol), rhodium acetate (0.002mmol), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.20mmol) and chiral Phosphoric Acid A (0.01 mmol) was put into a small test tube reactor, 2.0 ml of 1,2-dichloroethane was added, stirred at room temperature for 4 hours, and then placed at -10°C. Weigh acetophenone diazonium (0.30mmol) and dissolve it in 1.0ml 1,2-dichloroethane, and inject it into the reaction system through a peristaltic pump for 1 hour. After the injection is completed, continue to stir overnight, and remove it by rotary evaporation at 50°C-60°C. Solvent, to obtain crude product; then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 1:20 ~ 1:5) to obtain pure optically active α-amino-β-hydroxy amino acid derivatives 2A. The yield was 80%, the dr value was 95:5, and the ee was 93%.

[0040] In this example, chiral phosphoric acid A is: Structural formula

[0041] Product 2A is: structural form...

Embodiment 2

[0045] Weigh N-p-chlorophenyl glycine ethyl ester (0.20mmol), rhodium acetate (0.002mmol), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.20mmol) and chiral Phosphoric Acid A (0.01 mmol) was put into a small test tube reactor, 2.0 ml of 1,2-dichloroethane was added, stirred at room temperature for 4 hours, and then placed at -10°C. Weigh p-methylacetophenone diazo (0.30mmol) and dissolve it in 1.0ml 1,2-dichloroethane, and inject it into the reaction system through a peristaltic pump for 1 hour, and continue stirring overnight after the injection is completed, at 50°C-60°C The solvent was removed by rotary evaporation to obtain a crude product; then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 1:20 ~ 1:5) to obtain an optically active α-amino-β-hydroxy amino acid derivative Pure product 2B. The yield was 85%, the dr value was 90:10, and the ee was 92%.

[0046] In this example, chiral phosphoric acid A is: Structural formula

[0047] Product ...

Embodiment 3

[0052] Weigh N-p-chlorophenyl glycine ethyl ester (0.20mmol), rhodium acetate (0.002mmol), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.20mmol) and chiral Phosphoric Acid A (0.01 mmol) was put into a small test tube reactor, 2.0 ml of 1,2-dichloroethane was added, stirred at room temperature for 4 hours, and then placed at -10°C. Weigh p-methoxyacetophenone diazonium (0.30mmol) and dissolve it in 1.0ml 1,2-dichloroethane, and inject it into the reaction system through a peristaltic pump for 1 hour. After the injection is completed, continue to stir overnight. The solvent was removed by rotary evaporation at ℃ to obtain the crude product; then separated by column chromatography (eluent: petroleum ether: ethyl acetate = 1:20 ~ 1:5) to obtain an optically active α-amino-β-hydroxy amino acid Derivative pure 2C. The yield was 74%, the dr value was 85:15, and the ee was 94%.

[0053] In this example, chiral phosphoric acid A is: Structural formula

[0054] Product 2C is: struct...

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Abstract

The present invention relates to an optically active α-amino-β-hydroxy amino acid derivative as shown in formula (I) and its preparation method and application. , 3-dichloro-5, 6-dicyano-1, 4-benzoquinone and water as raw materials, with rhodium acetate and chiral phosphoric acid as catalyst, with organic solvent as solvent, through three components at -10°C reaction to obtain the optically active α-amino-β-hydroxyl amino acid derivative of the present invention. The raw materials of the invention are cheap and easy to obtain, two chiral carbons are constructed simultaneously, the preparation route is short, the operation is safe and simple, the reaction conditions are mild, the atom economy is high, and the selectivity is high, and it is convenient to obtain α-amino-β-hydroxy amino acid derivatives It provides a variety of compound skeletons and is widely used in new drug screening and pharmaceutical fields.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis chemistry, and relates to an optically active α-amino-β-hydroxy amino acid derivative and a preparation method and application thereof. Background technique [0002] Optically active α-amino-β-hydroxy amino acid derivatives are a class of important skeleton structures of special pharmaceutical compounds, as shown below, for example, vancomycin (Angew.Chem., Int.Ed.1999, 38, 2096 ) and sphingofungin series (J.Antibiot.1992, 45, 1692) and so on. [0003] [0004] Most of the synthetic strategies in the prior art are to utilize chemical or enzyme-catalyzed methods to synthesize such compounds, for example, Sharpless dihydroxylation reaction (J.Am.Chem.Soc.1997,119,11734), epoxidation reaction (J .Org.Chem.1996,61,2582), asymmetric Adol reaction (Chem.Soc.Rev.2010,39,1600) and asymmetric hydrogenation imine reaction (J.Am.Chem.Soc.1989,111,9134 )Wait. For example, the four-compo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C229/36
Inventor 胡文浩邱林郭鑫钱宇荆常诚马超群谢叶归刘顺英杨琍苹
Owner 广东和博制药有限公司
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