Method for preparing ticagrelor midbody (1R,2S)-2-(2,3-difluorophenyl) cyclopropylamine

A technology of difluorophenyl and ticagrelor, which is applied in the field of preparation of ticagrelor intermediate-2-cyclopropylamine, can solve the problems of unfavorable operator health and ecological environment, high cost of synthesis method and yield yield. Low efficiency and other problems, to achieve the effect of large-scale production, simple and convenient post-processing, and mild reaction conditions

Active Publication Date: 2015-02-04
CHENGDU BAIYU PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] The above reports on (1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (compound VIII) have the following problems: the synthesis methods of WO2008018822A1 and EP2589587A1 have the disadvantages of low yield and difficult purification; The synthesis methods of WO201101718 and WO2012001531A2 have high cost and low yield; the synthesis route disclosed in CN103508899A uses sodium cyanide, which is not conducive to the health of operators and the ecological environment; WO2013124280A1 uses a large amount of o-difluorobenzene in the synthesis and aluminum trichloride, which have the disadvantages of high cost and no environmental protection

Method used

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  • Method for preparing ticagrelor midbody (1R,2S)-2-(2,3-difluorophenyl) cyclopropylamine
  • Method for preparing ticagrelor midbody (1R,2S)-2-(2,3-difluorophenyl) cyclopropylamine
  • Method for preparing ticagrelor midbody (1R,2S)-2-(2,3-difluorophenyl) cyclopropylamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Add compound I succinic anhydride (100 g, 1 mol) and ethanol (200 ml) into a reaction flask, reflux at 80-82° C. for 3 hours, and the reaction is complete; concentrate ethanol to obtain compound II (121 g, yield: 83%).

[0040] Add compound II (116.8g, 0.8mol), methylene chloride (300ml) and thionyl chloride (104g, 0.88mol) into the reaction flask, N 2 N, N-dimethylformamide (0.8 g) was added under protection, the temperature was raised at 38° C. under reflux and stirred for 5 hours, the reaction was complete, and the dichloromethane was concentrated to obtain compound III (124 g, yield: 95%).

[0041]Aluminum trichloride (102g, 0.77mol) and dichloromethane (400ml) were added to the reaction flask, the temperature was lowered to 0-5°C under the protection of nitrogen, and compound III (114.8g, 0.7mol) and o-difluorobenzene ( 80g, 0.7mol) mixed solution, the temperature of the whole process is less than 10°C, after dropping, keep stirring for 6 hours, then naturally rise...

Embodiment 2

[0047] Take compound I succinic anhydride (100g, 1mol) and isopropanol (250ml) into the reaction flask, heat and reflux at 82-85°C for 4 hours, and the reaction is complete; concentrate the isopropanol to obtain compound II (107g, yield: 67 %).

[0048] Add compound II (96g, 0.6mol), dichloromethane (200ml) and thionyl chloride (79g, 0.66mol) into the reaction flask, N 2 N,N-dimethylformamide (0.6g) was added under protection, heated to 42°C and refluxed to stir for 7 hours. After the reaction was complete, dichloromethane was concentrated to obtain compound III (102g, yield: 95.5%).

[0049] Aluminum trichloride (74g, 0.55mol) and dichloromethane (250ml) were added into the reaction flask, the temperature was lowered to 0-5°C under the protection of nitrogen, and compound III (89g, 0.5mol) and o-difluorobenzene (57g , 0.5mol) mixed solution, the whole temperature is less than 10°C, after dripping, keep stirring for 6 hours, then naturally rise to 28°C and react for 22 hours;...

Embodiment 3

[0055] Get compound I succinic anhydride (100g, 1mol) and n-butanol (300ml) into the reaction flask, heat and reflux at 119~112°C for 3.4 hours, the reaction is complete; concentrate n-butanol to obtain compound II (59g, yield: 34% ).

[0056] Add compound II (53g, 0.3mol), dichloromethane (200ml) and thionyl chloride (39g, 0.33mol) into the reaction flask, N 2 N, N-dimethylformamide (0.4 g) was added under protection, and the temperature was raised to 42° C. and refluxed and stirred for 6 hours. After the reaction was complete, the dichloromethane was concentrated to obtain compound III (52 g, yield: 91%).

[0057] Aluminum trichloride (30g, 0.22mol) and dichloromethane (100ml) were added to the reaction flask, the temperature was lowered to 0-5°C under the protection of nitrogen, and compound III (38g, 0.2mol) and o-difluorobenzene (23g , 0.2mol) mixed solution, the whole temperature is less than 10°C, after dripping, keep stirring for 6 hours and then naturally rise to 28°...

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Abstract

The invention discloses a method for preparing ticagrelor midbody (1R,2S)-2-(2,3-difluorophenyl) cyclopropylamine, belonging to the technical fields of organic synthesis route design and preparation of raw material medicines and midbodies. The method comprises the following steps: performing alcoholysis on succinic anhydride, thereby obtaining mono-methyl succinate, performing acylating chlorination reaction on mono-methyl succinate, thereby obtaining a compound methyl 4-chloro-4-oxobutyrate, performing Fridel-Crafts reaction on methyl 4-chloro-4-oxobutyrate and o-difluorobenzene, thereby obtaining a compound methyl 4-ketone-4-(3,4-difluorophenyl) butyrate (IV), and further performing asymmetric reduction reaction, cyclization reaction and Hoffman degradation on the compound IV, thereby obtaining the compound (1R,2S)-2-(2,3-difluorophenyl) cyclopropylamine. Initial raw materials used in the method are low in cost and easy to obtain, the reaction condition is gentle, the operation is safe, simple and convenient, the environment pollution is small, and the key ticagrelor midbody prepared by using the method is simple and convenient in after treatment, and is beneficial to on-scale production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, in particular to the preparation of a ticagrelor intermediate (1R,2S)-2-(2,3-difluorophenyl)cyclopropylamine method. Background technique [0002] Ticagrelor (also known as Ticagrelor) is a new type of selective small molecule anticoagulant drug publicly developed by AstraZeneca, and it is also the first reversible conjugated oral P2Y12 adenosine The diphosphate receptor antagonist can obviously inhibit the platelet aggregation caused by ADP, and can effectively improve the symptoms of patients with acute coronary heart disease. The drug was approved by the European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA) in 2010 and 2011, respectively, and was launched in the EU and the US under the trade name Brilinta. Its imported preparation, ticagrelor tablets, has been approved by the China Food and Dru...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/40C07C209/58
Inventor 魏农农陈茂平杨应朗熊武
Owner CHENGDU BAIYU PHARMA CO LTD
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