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Chemical synthesis method of (1R, 2S)-2-aryl cyclopropylamine derivative

A technology of arylcyclopropylamine and arylcyclopropylmethylamine, which is applied in the field of chemical synthesis of (1R,2S)-2-arylcyclopropylamine derivatives, and can solve the problems of low stereoselectivity and the like

Inactive Publication Date: 2014-05-07
NANTONG UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] In order to overcome the defect of low stereoselectivity of the existing synthesis method, the present invention provides a chemical synthesis method of (1R,2S)-2-arylcyclopropylamine series derivatives with high e.e. value

Method used

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  • Chemical synthesis method of (1R, 2S)-2-aryl cyclopropylamine derivative
  • Chemical synthesis method of (1R, 2S)-2-aryl cyclopropylamine derivative
  • Chemical synthesis method of (1R, 2S)-2-aryl cyclopropylamine derivative

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Embodiment 1

[0019] Synthesis of N-methoxy-N-methyl-3-phenylacrylamide: 50.0 g 3-phenylacrylic acid, 30.0 g triethylamine, 31.0 g N-O-dimethylhydroxylamine hydrochloride, 400 ml dichloro Add methane into a 1L reaction flask, stir mechanically for 30 min, then add 60.0 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride at room temperature overnight, wash the dichloromethane phase with water twice, and use Wash with saturated sodium bicarbonate, ammonium chloride, dilute acid and sodium chloride aqueous solution, dry and concentrate to obtain 52.0 g of light yellow N-methoxy-N-methyl-3-phenylacrylamide liquid with a yield of 80.6%.

[0020] Synthesis of 2-phenyl-cyclopropylcarboxylic acid: Add 10.0 g NaH and 250 ml dimethyl sulfoxide into a three-necked flask under nitrogen protection, and add N-methoxy-N methyl-3-phenylpropene in batches amide 27.4 g, stirred and dissolved for 30 min, then added dropwise 42.0 g trimethylsulfoxide iodide, and reacted at room temperature. After...

Embodiment 2

[0024] Synthesis of N-methoxy-N-methyl-3-(4'-methoxyphenyl)acrylamide: 60.0 g 3-(4'-methoxyphenyl)acrylic acid, 33.5 g triethylamine , 32.7 g of N-O-dimethylhydroxylamine hydrochloride, 400 ml of dichloromethane were added to a 1L reaction flask, mechanically stirred for 30 min, and then 62.0 g of 1-ethyl-3-(3-dimethylaminopropyl) carbodisulfide was added Amine hydrochloride at room temperature overnight, washed with dichloromethane phase twice, washed with saturated sodium bicarbonate, ammonium chloride, dilute acid, sodium chloride aqueous solution, dried and concentrated to obtain yellow N-methoxy-N methyl-3 -(4'-methoxyphenyl)acrylamide liquid 55.3 g, yield 74.3%.

[0025] Synthesis of 2-(4'-methoxyphenyl)-cyclopropanecarboxylic acid: Add 10.0 g NaH and 300 ml dimethyl sulfoxide into a three-necked flask under nitrogen protection, and add N-methoxy-N 31.7 g of methyl-3-(4'-methoxyphenyl)acrylamide was stirred and dissolved for 30 min, then 42.0 g of trimethylsulfoxide iod...

Embodiment 3

[0029] Synthesis of N-methoxy-N-methyl-3-(4'-bromophenyl)acrylamide: 75.0 g 3-(4'-bromophenyl)acrylic acid, 33.0 g triethylamine, 32.7 g N-O -Add dimethylhydroxylamine hydrochloride and 400 ml of dichloromethane into a 1L reaction flask, stir mechanically for 30 min, then add 64.0 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride Overnight at room temperature, the dichloromethane phase was washed twice with water, washed with saturated sodium bicarbonate, ammonium chloride, dilute acid, sodium chloride aqueous solution, dried and concentrated to obtain yellow N-methoxy-N methyl-3-(4' -Bromophenyl) acrylamide liquid 75.4 g, the yield is 84.5%.

[0030]Synthesis of 2-(4'-bromophenyl)-cyclopropanecarboxylic acid: Add 10.0 g NaH and 350 ml dimethyl sulfoxide into a three-necked flask under nitrogen protection, and add N-methoxy-N methyl - 38.7 g of 3-(4'-bromophenyl) acrylamide, stirred and dissolved for 30 min, then added dropwise 42.0 g of trimethylsulfoxide iodi...

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Abstract

The invention relates to a chemical synthesis method of a (1R, 2S)-2-aryl cyclopropylamine derivative. 3-aryl crylic acid serves as a raw material, the raw material and N,O-dimethyl hydroxy amine hydrochloride are subjected reaction to prepare a corresponding amide intermediate, cyclization reaction is conducted, 2- aryl cyclopropylamine is obtained; and finally D-mandelic acid serves as a resolving agent to obtain the (1R, 2S)-2-aryl cyclopropylamine derivative. The method has the advantages of being high in yield and high in e.e. value.

Description

technical field [0001] The invention relates to a chemical synthesis method of (1R,2S)-2-arylcyclopropylamine derivatives. Background technique [0002] (1R,2S)-2-Arylcyclopropylamine derivatives are an important class of chiral pharmaceutical intermediates. Many literatures describe their modification in new anticancer drug molecules. Therefore, the synthesis research of this kind of compounds has important practical significance. [0003] Although (1R,2S)-2-arylcyclopropylamine derivatives have important functions in drug molecules, there are few reports on their synthesis. It has been reported in the literature that (1R,2S)-phenylcyclopropylamine was synthesized by the following route using styrene as a raw material. In general, although this route directly generates a chiral center, its stereoselectivity is not high. [0004] Contents of the invention [0005] In order to overcome the defect of low stereoselectivity of the existing synthesis method, the present i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C211/40C07C209/88C07C213/10C07C217/74
Inventor 朱金丽孙同明朱国华王树清喻红梅高鹏飞项蕊张素梅
Owner NANTONG UNIVERSITY
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