A kind of preparation method of ticagrelor intermediate

Abstract

The invention discloses a preparation method of a ticagrelor intermediate, comprising the following steps: Step 1: using compound 1 and the compound as raw materials, reacting with ethylene glycol and triethylamine under the protection of nitrogen, the reaction is complete, and the temperature is lowered , add dichloromethane and purified water, separate the layers, wash the organic layer with purified water, dry, and concentrate the organic layer under reduced pressure to obtain the crude product (II); Step 2: pretreat the mixed solvent, lower the temperature under the protection of an inert gas, add The crude product (II) obtained in step 1 is stirred and dissolved, added with activated carbon for decolorization, filtered, an inert solvent is added to the filtrate, cooled and crystallized, and filtered to obtain the intermediate product (II) of ticagrelor, wherein the mixed solvent is an alcoholic solvent / weak alkaline Reagent, the purity of the intermediate product (II) is not less than 99.2%, and the amount of impurity 3 contained therein is not more than 0.05%; the purity of the ticagrelor intermediate obtained in the present invention is not less than 99.2%, and the content of impurity 3 Not to exceed 0.05%.

Description

Technical field [0001] The present invention relates to the field of organic chemistry, and more particularly to a method of preparing a reelstate intermediate. Background technique [0002] Tigero, chemical name: (1s, 2S, 3R, 5S) -3- [7 - [1R, 2S) -2- (3,4-difluorophenyl) cyclopropylamine group] -5- (Prophyrid) -3H- [1, 2, 3] triazole [4,5-D] pyrimidine-3-yl] -5- (2-hydroxyethoxy) cyclopentane-1,2-diol , Molecular Formula: C23H28F2N6O4S, CAS: 274693-27-5; It is a new type of selective small molecule anticoagulant developed by Astrazeneca. In July 2011, the US FDA was approved by the US FDA. In November 2012, the imported drug license issued by the State Food and Drug Administration (SFDA) was officially launched in China. Treatment for non - ST segment raising myocardial infarction and acute coronary syndrome. Its structural formula is as follows: [0003] [0004] Compound 2 - [((3Ar, 4S, 6R, 6AS) -6 - {[5-amino-6-chloro-2- (propyl) pyrimidine-4-yl] amino} -2,2-dimethyl Tetra...

AI Technical Summary

Problems solved by technology

Patent WO2010030224 points out that the above-mentioned impurity 1 is difficult to remove by ethyl acetate-isooctane recrystallization

Chinese patent CN105936637 pointed out that: in the reaction of preparing intermediate II, the process is generally used at present, due to the use of 4,6-dichloro-2-(propylthio)-5-aminopyrimidine (compound 2) to replace 4,6-dichloro -2-(propylthio)-5-nitropyrimidine, which causes the activity of the chlorine atom on the amino-substituted pyrimidine to be greatly reduced, requires higher temperature and longer time to obtain an acceptable conversion rate, and due to the severe reaction conditions, Makes the generation of more impurities inevitable

[0016] The intermediate 2-[((3aR,4S,6R,6aS)-6-{[5-amino-6-chloro-2-(propylthio)pyrimidine- 4-yl]amino}-2,2-dimethyltetrahydro-3aH-cyclopenteno[d][1,3]-dioxan-4-yl)oxy]ethanol) will generate impurity 4. Its structure contains multiple unprotected hydroxyl groups, the polarity becomes larger and the number of active groups increases. This impurity 4 will continue to participate in the reaction in the subsequent synthesis, which further increases the purification burden of ticagrelor products

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