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Cyclopropane alpha-amino acid derivatives containing continuous quaternary carbon center and synthesis method thereof

A synthesis method and cyclopropane technology are applied in the field of cyclopropane α-amino acid derivatives and synthesis fields containing continuous quaternary carbon centers, which can solve the problems of high cost, narrow substrate application range, high toxicity, etc. The effect of good enantioselectivity and mild reaction conditions

Active Publication Date: 2015-09-16
SOUTH CHINA UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

It should be pointed out that the substrate scope of the above two methods is extremely narrow, and only 1–2 substrates are reported; at the same time, some reaction systems also use expensive and highly toxic transition metal catalysts
However, there is no report on the direct synthesis of cyclopropane α-amino acid derivatives containing continuous quaternary carbon centers using N-p-toluenesulfonyl ketone hydrazone as a raw material.

Method used

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  • Cyclopropane alpha-amino acid derivatives containing continuous quaternary carbon center and synthesis method thereof
  • Cyclopropane alpha-amino acid derivatives containing continuous quaternary carbon center and synthesis method thereof
  • Cyclopropane alpha-amino acid derivatives containing continuous quaternary carbon center and synthesis method thereof

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Experimental program
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Effect test

Embodiment 1

[0029] In a 25ml reaction flask equipped with a reflux condenser, add 0.2mmol of acetophenone p-toluenesulfonylhydrazone, 0.2mmol of cesium carbonate, 0.02mmol of benzyltriethylammonium chloride, 2ml of toluene, at 25°C After stirring and reacting for 1 hour, 0.1 mmol of methyl 2-acetamidoacrylate was added, and the reaction system was stirred and reacted at 90° C. for 12 hours, then heating and stirring were stopped, and cooled to room temperature. The reaction solution was extracted with ethyl acetate, the solvent was removed by rotary evaporation under reduced pressure, and then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 2:1 , the main diastereomer of the product was obtained with a yield of 82%.

Embodiment 2

[0031] In a 25ml reaction flask equipped with a reflux condenser, add 0.2mmol of acetophenone p-toluenesulfonylhydrazone, 0.2mmol of potassium carbonate, 0.02mmol of benzyltriethylammonium chloride, 2ml of toluene, at 25°C After stirring and reacting for 1 hour, 0.1 mmol of methyl 2-acetamidoacrylate was added, and the reaction system was stirred and reacted at 90° C. for 12 hours, then heating and stirring were stopped, and cooled to room temperature. The reaction solution was extracted with ethyl acetate, the solvent was removed by rotary evaporation under reduced pressure, and then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 2:1 , the main diastereoisomer of the product was obtained with a yield of 63%.

Embodiment 3

[0033] In a 25 ml reaction flask equipped with a reflux condenser, add 0.2 mmol of acetophenone-p-toluenesulfonylhydrazone, 0.2 mmol of potassium tert-butoxide, 0.02 mmol of benzyltriethylammonium chloride, and 2 ml of toluene. After stirring and reacting at 25°C for 1 hour, 0.1 mmol of methyl 2-acetamidoacrylate was added, and the reaction system was stirred and reacted at 90°C for 12 hours, then heating and stirring were stopped, and cooled to room temperature. The reaction solution was extracted with ethyl acetate, the solvent was removed by rotary evaporation under reduced pressure, and then separated and purified by column chromatography to obtain the target product. The column chromatography eluent used was a mixed solvent of petroleum ether:ethyl acetate with a volume ratio of 2:1 , the main diastereoisomer of the product was obtained with a yield of 57%.

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Abstract

The invention belongs to the technical field of chemical synthesis of drugs, and discloses cyclopropane alpha-amino acid derivatives containing continuous quaternary carbon center and a synthesis method thereof. The synthesis method comprises the following steps: adding N-p-tolylsulfonylone hydrazone, methyl 2-acetaminoacrylate, an alkali, a phase-transfer catalyst and a solvent into a reactor, and stirring at 70-90 DEG C to react for 12-24 hours; and after the reaction finishes, cooling to room temperature, filtering the reaction solution, distilling under reduced pressure to remove the solvent to obtain a crude product, and purifying by column chromatography to obtain the cyclopropane alpha-amino acid derivatives containing continuous quaternary carbon center. The method avoids using any transition metal catalyst, and uses the nontoxic, cheap and accessible raw materials. The method has the advantages of high reaction adaptability to functional groups, wide substrate adaptability, high product yield and favorable diastereoselectivity, can implement gram-scale production and synthesis, and is beneficial to industrial production. The obtained product has wide application range in synthesis of pesticides, drugs and natural products.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and specifically relates to a cyclopropane alpha-amino acid derivative containing a continuous quaternary carbon center and a synthesis method. Background technique [0002] α-Amino acid is the basic unit of biofunctional macromolecular protein, the basic substance of protein required for animal nutrition, and an important structural unit of many drugs, bioactive molecules and natural products. In order to meet the needs of human production and life for the types and quantities of substances, the synthesis and application of artificially synthesized α-amino acid derivatives has received extensive attention. Since the rigid cyclopropane structural block can effectively improve the physical, chemical properties and biological activities of the molecule, the cyclopropane α-amino acid structural block widely exists in drugs and functionally active molecules, such as NS3-prot...

Claims

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Application Information

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IPC IPC(8): C07C233/06C07C231/12C07D333/24
Inventor 江焕峰竺传乐伍婉卿
Owner SOUTH CHINA UNIV OF TECH
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