Chemical method used for preparing aromatic cyclopropanecarbonitrile and cyclopropylamine

An aryl and system technology, applied in chemical instruments and methods, nitrile preparation, organic chemistry and other directions, can solve the problems of high cost and low product yield, and achieve the effects of easy handling, high stereoselectivity and high yield

An aryl and system technology, applied in chemical instruments and methods, nitrile preparation, organic chemistry and other directions, can solve the problems of high cost and low product yield, and achieve the effects of easy handling, high stereoselectivity and high yield

CN103664697AActive Publication Date: 2014-03-26BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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  • Chemical method used for preparing aromatic cyclopropanecarbonitrile and cyclopropylamine
  • Chemical method used for preparing aromatic cyclopropanecarbonitrile and cyclopropylamine
  • Chemical method used for preparing aromatic cyclopropanecarbonitrile and cyclopropylamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Preparation method of compound (2S)-2-(3,4-difluorophenyl)oxirane of formula (V-1)

[0065]

[0066] (V-1)

[0067] Combine (1S)-2chloro-1-(3,4-difluorophenyl)-1-ethanol (50g, prepared according to the method disclosed in CN10149544), toluene (128ml), sodium hydroxide (11g) and water (106ml) ) were mixed, the reaction was stirred at 40° C. for 1 hour, the organic solvent was separated, washed with water, and the solvent was evaporated under reduced pressure to obtain 38.16 g of the compound of formula (V-1) (yield: 94%).

[0068] 1 H-NMR: (CDCl 3 ): δ 2.71-2.73 (1H, dd), 3.13-3.15 (1H, m), 3.82-3.83 (1H, m), 7.01-7.27 (4H, m).

Embodiment 2

[0070] Preparation method of compound (1R, 2R)-2-(3,4-difluorophenyl)cyclopropanenitrile of formula (IV-1)

[0071]

[0072] (IV-1).

[0073] NaH (45g, 60%, 1.13mol) and ethylene glycol dimethyl ether (300ml) were combined and stirred. To the resulting suspension was added dropwise a solution of diethyl cyanomethyl phosphate (166.4 g, 0.94 mol) in ethylene glycol dimethyl ether (120 ml) at 0°C. A solution of (2S)-2-(3,4-difluorophenyl)oxirane (38g, 244mmol) in ethylene glycol dimethyl ether (200ml) was slowly added dropwise at 40-60°C. , the reaction was carried out at 60°C, monitored by TLC, and the reaction was completed in about 10 hours. Cooled to room temperature, separated the organic layer, washed with water, concentrated, and precipitated 40.5 g of solid, the yield was 92.8%, the HPLC purity was >98%, and the ee value was greater than 99.9%.

[0074] of the compound 1 H-NMR and 13 C-NMR as figure 1 and figure 2 shown.

Embodiment 3

[0076] Preparation method of compound (1R, 2R)-2-(3,4-difluorophenyl)cyclopropylcarboxylic acid

[0077]

[0078] (1R,2R)-2-(3,4-difluorophenyl)cyclopropanenitrile (20g) prepared in Example 2 and aqueous sodium hydroxide solution (10%, 100ml) were heated and refluxed for about 4 hours to The reaction is complete. Cool to room temperature, concentrate, and extract with ether. It was acidified by dropwise addition of 15% HCl, extracted with ether, and concentrated to obtain 21.0 g of (1R,2R)-2-(3,4-difluorophenyl)cyclopropylcarboxylic acid with a yield of 95%.

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Abstract

The invention relates to a method for preparing trans-aryl cyclopropanecarbonitrile with a structure shown in a formula (IV) in the specification through reaction between aryl substituted ethylene oxide and cyan substituted phosphate and further relates to a method for preparing cyclopropylamine from trans-aryl cyclopropanecarbonitrile. Trans-aryl cyclopropanecarbonitrile and cyclopropylamine are used for preparing drugs, especially ticagrelor.

Description

technical field [0001] The present invention relates to aromatic cyclopropanenitriles, methods for preparing said cyclopropanenitriles, and their application in the preparation of medicines or medicine intermediates. Background technique [0002] Ticagrelor belongs to cyclopentyl triazolopyrimidine compounds, chemical name is (1S, 2S, 3R, 5S)-3-[7-[(1R,2S)-2-(3,4- Difluorophenyl)cyclopropylamino]-5-(thiopropyl)-3H-[1,2,3]triazol[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethyl Oxy)cyclopentane-1,2-diol is a novel, selective small molecule anticoagulant drug developed by AstraZeneca. It is especially suitable for those patients who need to undergo surgery after anticoagulation therapy in advance. The structures of ticagrelor and its analogues are disclosed in WO0034283 and WO9905143, wherein ticagrelor has a chemical structure represented by the following formula: [0003] [0004] Ticagrelor and its analogs are usually prepared by splicing and synthesizing three intermediate fr...

Claims

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Application Information

Patent Timeline
26 Mar 2014
Publication
CN103664697A
IPC
C07C255/50; C07C253/30; C07C61/04; C07C51/08; C07C231/02; C07C233/57; C07C211/40; C07C209/58; C07C209/56; C07D487/04
Inventors
袁建栋; 黄仰青