Method for synthesizing trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine

A technology of difluorophenyl and cyclopropylamine, which is applied in the preparation of amino compounds, chemical instruments and methods, preparation of organic compounds, etc., can solve the problem of increasing the difficulty of the reaction process, the difficulty of preparation and the increase in cost, and is not suitable for large-scale industrialization. Production and other problems, to achieve the effect of improving the reaction yield and reducing the difficulty of the reaction

CN102249929AInactive Publication Date: 2011-11-23BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Publication Date
2011-11-23
Estimated Expiration
Not applicable · inactive patent

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Abstract

The invention relates to a method for synthesizing trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine which is an intermediate for preparing an anticoagulation medicine Ticagrelor. The method provided by the invention mainly comprises the following steps of: synthesizing the trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine protected by tertiarybutoxy carbonyl through carrying out a rearrangement reaction of DPPA (Diphenylphosphoryl Azide); then removing the protective group of the trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine protected by the tertiarybutoxy carbonyl and then alkalifying to obtain the product. The whole reaction can be finished through a one-pot boiling synthetic method so that synthesizing steps and synthesizing time are greatly saved, the cost is effectively reduced and the yield is improved; and the method for synthesizing the trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine has the very active meaning in the industrial production.
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Description

technical field

[0001] The invention relates to the field of chemical synthesis, in particular to a synthesis method of an intermediate trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine of an anticoagulant drug ticagrelor. Background technique

[0002] Ticagrelor (a) is a new type of selective small molecule anticoagulant drug developed by AstraZeneca, the chemical name is (1S, 2S, 3R, 5S)-3 -[7-[(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamino]-5-(thiopropyl)-3H-[1,2,3]triazole[4, 5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol has the chemical structure shown in the following formula.

[0003] .

[0004] In the existing synthetic route of industrial production of ticagrelor, trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (formula b) is a necessary intermediate, such as The synthesis process of ticagrelor disclosed in patent documents CN1334816 and CN1432017 (route 1).

[0005] Route 1:

[0006] .

[0007] In view of the importance of the in...

Examples

Embodiment 1

[0029] Example 1 Synthetic method of trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine

[0030] .

[0031] In a 500ml three-necked flask, add 50.0g (252.3mmol) of the formula under nitrogen protection The shown compound [made according to CN1431992A Example 9], 76.4g (277.54mmol) diphenylphosphoryl azide (DPPA), 25.5g (253.3mmol) triethylamine (Et 3 N), 250ml tert-butanol (t-BuOH), stirred and dissolved, heated to 85°C and reacted for 2 hours, TLC (EA:PE=1:10) showed that the raw material disappeared, concentrated under reduced pressure, removed the solvent, and purified by column chromatography to obtain 54.0 g of white solid, 79.5% yield.

[0032] 1 HNMR (CDCl 3 , 400Mhz) δ:7.07~6.90(3H,m),4.84(1H,s),2.65~2.64(1H,m),2.03~1.99(1H,m),1.45(9H,s),1.15~1.10( 2H,m).

[0033] Ms (API-ES): 270 (M+1).

[0034]

[0035] In a 500ml three-necked flask, add 50.0g (185.7mmol) of formula under nitrogen protection The compound shown, 200ml of 2N hydrochloric acid / ethyl ac...