Detection method of ticagrelor starting material

Abstract

The invention relates to the field of chemical substance analysis and detection, in particular to a detection method for ticagrelor starting material. Provided is a detection method for chemicals containing 2-[[(3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopentene-1 , 3-dioxolane-4-yl] oxy]ethanol tartaric acid and / or its enantiomers, the method comprising: (1) utilizing nitro-substituted benzoyl chloride compounds for the chemical The product is subjected to a derivatization reaction so as to obtain a derivative product; (2) using high performance liquid chromatography to detect the derivative product. The detection method provided by the invention is economical and reasonable, simple and easy to operate, can accurately and sensitively detect the starting material of ticagrelor and its impurity content, and has good detection stability and high repeatability.

Description

technical field [0001] The invention relates to the field of chemical substance analysis and detection, in particular to a detection method of ticagrelor starting material. Background technique [0002] Ticagrelor (trade name: BRILINTA) is a selective adenosine diphosphate (ADP) receptor antagonist developed by AstraZeneca AB, which activates P2Y12 receptors, Reversibly blocks ADP-mediated platelet activation and aggregation. [0003] Ticagrelor starting material 2-[[(3aR,4S,6R,6aS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopentene-1,3-dioxolane Alkyl-4-yl]oxy]ethanol tartaric acid is an important starting material for the synthesis of ticagrelor, and its enantiomer impurity 2-[[(3aS,4R,6S,6aR)-6-aminotetrahydro- 2,2-Dimethyl-4H-cyclopentene-1,3-dioxolan-4-yl]oxy]ethanol tartaric acid is commonly present in commercially available ticagrelor starting material products, The structural formulas of the two are as follows: [0004] [0005] Due to enantiomeric impurity 2-[[(3...

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Problems solved by technology

[0005] Due to enantiomeric impurity 2-[[(3aS,4R,6S,6aR)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopentene-1,3-dioxolane Alkyl-4-yl]oxyl]ethanol tartaric acid has a simple molecular structure and small molecular weight, and the molecule itself has no chromophore, has no absorption and / or terminal absorption is very weak under ultraviolet light, and has no response under ordinary chromatographic conditions, so Difficult to detect directly by ordinary liquid chromatography

However, several other detection methods often have different problems, such as 1. The specific optical rotation of the compound tested by the polarimeter is low in cost and fast, but has poor accuracy, poor stability, and poor reproducibility, and is easily affected by external factors. Large deviations, especially when testing for racemate or stereochiral mixtures, accurate and reliable results cannot be obtained, and the content of enantiomers in the starting materials cannot be effectively controlled; 2. Determination by X-ray , this method has high requirements on the purity and crystal form of the compound, otherwise it cannot be tested, the test method is cumbersome and expensive, and is not suitable for batch detection or detection at any time; 3. NMR determination requires the use of expensive deuterated reagents to dissolve the compound , and there are certain requirements for the purity of the compound, and accurate analytical results cannot be obtained for the mixture of stereoisomers; 4. CD spectrum determination is not suitable for the test of the optical purity of stereoisomers

[0006] The Chinese invention patent with the application number 201711423224.3 discloses a liquid chromatography analysis method for the starting material of ticagrelor, but it does not contain tartaric acid, the derivative agent FDAA is expensive, and it does not involve the content of enantiomer impurities , so it is not practical

[0007] It can be seen that the enantiomeric impurity 2-[[(3aS,4R,6S,6aR)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopentene-1,3-dioxa There are obvious deficiencies in the detection of cyclopentan-4-yl]oxy]ethanol tartaric acid

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