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Synthesis method of cyclopropane phosphoramidate compound comprising continuous quaternary carbon center

A technology of cyclopropane phosphoramidate and acetamido enphosphate, applied in the field of synthesis of cyclopropane phosphoramidate compounds containing continuous quaternary carbon centers, achieving high atom economy, wide substrate adaptability, and environmental friendliness

Inactive Publication Date: 2017-05-17
SOUTH CHINA UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Generally, cyclopropane compounds are used to directly construct compounds containing N and P at the same time, which has great limitations in the selection of substrates.
However, there is no report on the direct synthesis of cyclopropane phosphoramidate derivatives containing continuous quaternary carbon centers using N-p-toluenesulfonyl ketone hydrazone as a raw material.

Method used

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  • Synthesis method of cyclopropane phosphoramidate compound comprising continuous quaternary carbon center
  • Synthesis method of cyclopropane phosphoramidate compound comprising continuous quaternary carbon center
  • Synthesis method of cyclopropane phosphoramidate compound comprising continuous quaternary carbon center

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Add 0.2 mmol of acetophenone-p-toluenesulfonylhydrazone, 0.2 mmol of potassium tert-butoxide, 0.02 mmol of benzyltriethylammonium chloride (TEBAC) and 2 ml of toluene into the reaction tube, under inert atmosphere Stir and react at room temperature at 600 rpm under protection for 2 hours, then stop stirring. Add 0.1 mmol of acetaminophenophosphate (Nicolas Lefevre, Jean-Louis Brayer, Benoit Folleas, Sylvain Darses, Organic Letters, 2013, 15, 4274–4276), stir and react at 90 degrees Celsius at 600 rpm for 12 hours, then stop heating And stir, cool to room temperature. Add 4 mL of water, extract 3 times with ethyl acetate, combine the organic phases and use 0.5 g of anhydrous magnesium sulfate to dry, filter, evaporate the solvent under reduced pressure, and then separate and purify by column chromatography to obtain the target product. The eluent was petroleum ether:ethyl acetate mixed solvent with a volume ratio of 10:1, and the yield was 62%.

Embodiment 2

[0035]Add 0.2 mmol of acetophenone p-toluenesulfonylhydrazone, 0.2 mmol of sodium carbonate, 0.02 mmol of TEBAC and 2 ml of toluene into the reaction tube, stir and react at room temperature at 600 rpm for 2 hours under the protection of an inert atmosphere, and stop stirring. Add 0.1 mmol of acetaminophenophosphate (Nicolas Lefevre, Jean-Louis Brayer, Benoit Folleas, Sylvain Darses, Organic Letters, 2013, 15, 4274–4276), stir the reaction at 90 degrees Celsius at 600 rpm for 12 hours, then stop Heat and stir, and cool to room temperature. Add 4 mL of water, extract 3 times with ethyl acetate, combine the organic phases and use 0.5 g of anhydrous magnesium sulfate to dry, filter, evaporate the solvent under reduced pressure, and then separate and purify by column chromatography to obtain the target product. The eluent was petroleum ether:ethyl acetate mixed solvent with a volume ratio of 10:1, and the yield was 72%.

Embodiment 3

[0037] Add 0.2 mmol of acetophenone p-toluenesulfonylhydrazone, 0.2 mmol of cesium carbonate, 0.02 mmol of TEBAC and 2 ml of toluene into the reaction tube, stir and react at room temperature at 600 rpm for 2 hours under the protection of an inert atmosphere, and stop stirring. Add 0.1 mmol of acetaminophenophosphate (Nicolas Lefevre, Jean-Louis Brayer, Benoit Folleas, Sylvain Darses, Organic Letters, 2013, 15, 4274–4276), stir the reaction at 90 degrees Celsius at 600 rpm for 12 hours, then stop Heat and stir, and cool to room temperature. Add 4 mL of water, extract 3 times with ethyl acetate, combine the organic phases and use 0.5 g of anhydrous magnesium sulfate to dry, filter, evaporate the solvent under reduced pressure, and then separate and purify by column chromatography to obtain the target product. The eluent was petroleum ether:ethyl acetate mixed solvent with a volume ratio of 10:1, and the yield was 85%.

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Abstract

The invention belongs to the technical field of medicinal and chemical synthesis, and discloses a synthesis method of a cyclopropane phosphoramidate compound comprising a continuous quaternary carbon center. The synthesis method comprises the following steps of adding an N-tosylhydrazones compound, a phase transfer catalyst, an alkali and an organic solvent into a reactor, stirring at the room temperature for a certain period of time under the protection of inert atmosphere, then adding acetamido phosphate, heating to 60-100 DEG C, stirring to react for 10-24 hours, cooling to the room temperature after the reaction is finished, separating and purifying the product, so as to obtain the cyclopropane phosphoramidate compound comprising the continuous quaternary carbon center. According to the synthesis method, the raw materials are easy to get, the cost is low, the atom economy is high, the operation is safe and simple, no transition metal participates in the reaction, the method is environmentally friendly, is high in adaptability of the functional group and wide in adaptability of the substrate, and has an excellent industrial application prospect.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a synthesis method of cyclopropane phosphoramidate compounds containing continuous quaternary carbon centers. Background technique [0002] Amino acid is the basic unit of biological functional macromolecular protein, the basic substance of protein required for animal nutrition, and an important structural unit of many drugs, bioactive molecules and natural products. As phosphorous analogs of amino acids, phosphoramidates have attracted widespread attention from scientists in terms of antibacterial, anti-plant virus, and regulation of plant growth activities (FTanaka, K Kinoshita, A Ryuji Tanimura, I Fujii, J.Am.Chem.Soc. 1996, 118, 2332-2339). Since the rigid cyclopropane structural building blocks can effectively improve the physical and chemical properties and biological activities of molecules, the cyclopropane phosphoramidate structure ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/40
CPCC07B2200/07C07F9/4018
Inventor 伍婉卿林芝铭竺传乐
Owner SOUTH CHINA UNIV OF TECH
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