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

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.

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...

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Problems solved by technology

[0012] In the preparation process disclosed by CN1431992A, the temperature and pH change are relatively severe during the entire reaction process, for example, the reaction temperature drops from 100°C to below 0°C, and the pH needs to be adjusted to 12 during alkalization, which will undoubtedly increase the difficulty of the reaction process; and , the second step requires the use of flammable and explosive sodium azide, which will increase the danger of the preparation process

In the preparation process disclosed by CN101495444A, thionyl chloride, ammonia water, sodium hypochlorite and other corrosive or dangerous reagents need to be used, and the two-step reaction process takes 20 to 30 hours. These factors lead to a substantial increase in the difficulty and cost of preparation

It is not difficult to see that the above two preparation processes are not suitable for large-scale industrial production. Therefore, it is necessary to develop a preparation process that can meet the needs of industrialization.

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