Preparation method of trans-(1R, 2S)-2-(3, 4-difluoro phenyl) cyclopropylamine

A technology of difluorophenyl and cyclopropylamine, applied in the field of preparation of intermediates, can solve the problems of many synthetic process routes, difficult industrialized production, cumbersome reaction conditions, etc., and achieves wide source of raw materials, easy industrialized production, and reaction conditions. simple effect

Inactive Publication Date: 2012-11-14
江苏富泽药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] 1) There are many steps in the synthetic process route, the operation is cumbersome, and it is not easy for industrial production;
[0019] 2) In the prior art, chiral chlorohydrins (II) are synthesized by chiral prosthetic group method, the reaction conditions are cumbersome and not easy to operate;
[0020] 3) The product yield in the prior art is low, and the purity is difficult to improve

Method used

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  • Preparation method of trans-(1R, 2S)-2-(3, 4-difluoro phenyl) cyclopropylamine
  • Preparation method of trans-(1R, 2S)-2-(3, 4-difluoro phenyl) cyclopropylamine
  • Preparation method of trans-(1R, 2S)-2-(3, 4-difluoro phenyl) cyclopropylamine

Examples

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Embodiment 1

[0051] Example 1 Preparation of trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine

[0052] step 1:( R )-Preparation of chlorophenylethanol (Ⅱ)

[0053] 20 g racemic chlorophenylethanol (I) and 0.6 equivalent of Boc- R - Proline was dissolved in dichloromethane, 15 g EDCI and 2 g DMAP were sequentially added, the mixture was stirred at room temperature for 4-12 h, and detected by TLC. Boc- R -Proline disappeared, quenched the reaction with water, extracted, dried, and passed through HCl (g), TLC detected that the raw materials were completely reacted, concentrated and then column chromatographed to obtain 8 g of solids, with a yield of 40%.

[0054] Step 2: Preparation of epoxy compound (Ⅲ)

[0055] at 0 o C, Chlorohydrin (6.60g, 34.2mmol) was added to THF and 15% aqueous sodium hydroxide solution (1:1) mixture, stirred at room temperature for 1.5 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added, and after extraction...

Embodiment 2

[0062] Example 2 Preparation of trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine

[0063] step 1:( R )-Preparation of chlorophenylethanol (Ⅱ)

[0064] 20 g of racemic chlorophenethyl alcohol and 0.6 equivalent of Boc- R - Proline was dissolved in dichloromethane, 15 g EDCI and 2 g DMAP were sequentially added, the mixture was stirred at room temperature for 4-12 h, and detected by TLC. Boc- R - Proline disappeared, quenched the reaction with water, extracted, dried, and passed through HCl (g), TLC detected that the raw materials were completely reacted, concentrated and then column chromatographed to obtain 7 g of solids, with a yield of 35%.

[0065] Step 2: Preparation of epoxy compound (Ⅲ)

[0066] at 0 o C, Chlorohydrin (6.60g, 34.2mmol) was added to THF and 15% aqueous sodium hydroxide solution (1:1) mixture, stirred at room temperature for 1.5 hours. The reaction was monitored by TLC. After the reaction was completed, ethyl acetate was added, and after extr...

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Abstract

The invention provides a preparation method of trans-(1R, 2S)-2-(3, 4-difluoro phenyl) cyclopropylamine. The preparation method comprises the following steps: enabling racemic chloro phenethyl alcohol (I) and N-protection proline to undergo a reaction under the effects of a condensing agent A1 and a catalyst C1, and obtaining chiral chlorohydrin (II); enabling the chiral chlorohydrin (II) to generate an epoxy compound (III) under the conditions of alkalinity; enabling the epoxy compound (III) and TEPA to react and generate cyclopropyl ethyl formate (IV) under the conditions of alkalinity; removing ester from cyclopropyl ethyl formate (IV) under the conditions of alkalinity, and generating cyclopropanecarboxylic acid (V); and enabling cyclopropanecarboxylic acid (V) and azide to generate a target compound (3) by Curtius rearrangement. The preparation method has the advantages that the steps of a used synthetic process route are few, the operation is simple, and industrial production is achieved easily; a kinetic resolution method is utilized to synthesize chiral chlorohydrin (II) and is simple in reaction conditions and easy to operate; and a TEPA method is utilized synthesize the cyclopropyl ethyl formate, the product yield is high, cis-trans selectivity is good, and the purity is over 99%.

Description

technical field [0001] The present invention relates to a kind of preparation method of the intermediate of anticoagulant drug ticagrelor, specifically [0002] In other words, it relates to a preparation method of trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine. Background technique [0003] Ticagrelor, developed by AstraZeneca, was approved by the FDA on July 20, 2011 to reduce the occurrence of thrombotic events in patients with acute coronary syndrome (ACS). Ticagrelor is a novel, selective anticoagulant and the first reversible binding P2Y12 adenosine diphosphate receptor (ADP) antagonist that can reversibly act on vascular smooth muscle cells (VSMC) The purine 2 receptor subtype P2Y12 on ADP has obvious inhibitory effect on platelet aggregation caused by ADP, and can effectively improve the symptoms of patients with acute coronary heart disease. [0004] The chemical structure of ticagrelor is shown in the following formula: [0005] [0006] In the existi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/40C07C209/56C07C33/46C07C29/74
Inventor 王明文吴鹏程唐虹
Owner 江苏富泽药业有限公司
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