A method for detecting enantiomers in avapritinib intermediates

A technology for enantiomers and intermediates, applied in the field of detection of enantiomers in Avapritinib intermediates, to achieve the effect of strong practicability, good detection effect, and simple detection process

Active Publication Date: 2022-04-26
HAINAN MEDICAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] There is no effective ((S)-1-(4-fluorophenyl)-1-[2-(piperazin-1-yl)pyrimidin-5-yl]ethylamine chiral effective control detection method in the prior art , Therefore, in order to continuously improve the safety and effectiveness of Avapritinib, it is urgent to establish a key intermediate (S)-1-(4-fluorophenyl)-1 in Avapritinib that is easy to operate, high in sensitivity and good in reproducibility. Quantitative detection method of enantiomers of -[2-(piperazin-1-yl)pyrimidin-5-yl]ethylamine

Method used

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  • A method for detecting enantiomers in avapritinib intermediates
  • A method for detecting enantiomers in avapritinib intermediates
  • A method for detecting enantiomers in avapritinib intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Select the content of (S)-1-(4-fluorophenyl)-1-[2-(piperazin-1-yl)pyrimidin-5-yl]ethylamine whose batch number is 20210421 for detection, including the following steps:

[0049] S1. Preparation of (S)-1-(4-fluorophenyl)-1-[2-(piperazin-1-yl)pyrimidin-5-yl]ethylamine test solution:

[0050] Weigh 10mg of (S)-1-(4-fluorophenyl)-1-[2-(piperazin-1-yl)pyrimidin-5-yl]ethanamine sample and add 10mL n-hexane-absolute ethanol solution, by It is prepared by mixing n-hexane and absolute ethanol with a volume ratio of 1:1. After mixing evenly, it is prepared to contain (S)-1-(4-fluorophenyl)-1-[2-(piperazine-1 -yl) pyrimidin-5-yl] ethylamine 1.0mg solution, as need testing solution, stand-by.

[0051] S2. Preparation of (R)-1-(4-fluorophenyl)-1-[2-(piperazin-1-yl)pyrimidin-5-yl]ethylamine reference substance stock solution:

[0052] Weigh (R)-1-(4-fluorophenyl)-1-[2-(piperazin-1-yl)pyrimidin-5-yl]ethylamine, accurately weigh 100mg, n-hexane-absolute ethanol solution Dissolve and...

Embodiment 2

[0065] Choose the (S)-1-(4-fluorophenyl)-1-[2-(piperazin-1-yl) pyrimidin-5-yl] ethylamine sample of the same batch as Example 1, to (R )-1-(4-fluorophenyl)-1-[2-(piperazin-1-yl)pyrimidin-5-yl]ethanamine peak purity is detected, the difference between the present embodiment and embodiment 1 is only : different detectors are used in the chromatographic conditions, and other detection conditions are consistent with embodiment 1. In this embodiment, the assay conditions of high performance liquid chromatography include:

[0066] Chromatographic column: CHIRALCEL*OD-H (model: length 250mm, inner diameter 4.6mm, cellulose surface covalently bonded silica gel filler, filler particle size 5μm);

[0067] Detector: DAD detector;

[0068] Detection wavelength: 220nm;

[0069] Column temperature: 30°C;

[0070] Flow rate: 1.0mL / min;

[0071] Mobile phase: Calculated by volume ratio, n-hexane:ethanol:isopropanol=99:0.5:0.5. It can be seen from the test that the peak purity of (S)-1-(...

Embodiment 3

[0073] Select (R)-1-(4-fluorophenyl)-1-[2-(piperazin-1-yl)pyrimidin-5-yl]ethanamine reference substance solution for detection limit and quantification limit detection, signal-to-noise ratio 10:1 is the quantification limit, and the signal-to-noise ratio is 3:1 is the detection limit. The detection conditions of this embodiment are consistent with those of Embodiment 1. In this embodiment, the assay conditions of high performance liquid chromatography include:

[0074] Chromatographic column: CHIRALCEL*OD-H (model: length 250mm, inner diameter 4.6mm, cellulose surface covalently bonded silica gel filler, filler particle size 5μm);

[0075] Detector: UV detector;

[0076] Detection wavelength: 220nm;

[0077] Column temperature: 30°C;

[0078] Flow rate: 1.0mL / min;

[0079] Mobile phase: Calculated by volume ratio, n-hexane:isopropanol:triethylamine=80:20:0.05.

[0080] After testing, it can be seen that the detection limit of (R)-1-(4-fluorophenyl)-1-[2-(piperazin-1-yl)py...

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Abstract

The invention provides a method for detecting the enantiomer of the key intermediate of Avapritinib. The chromatographic conditions adopted are: the chromatographic column is CHIRALCEL*OD‑H 4.6*250mm, the 5um chromatographic column, the column temperature is 30°C, and the detection wavelength 220nm, mobile phase is normal hexane: ethanol: isopropanol=99~102:0.1~1:0.5, flow velocity is 0.8~1.0mL / min; Utilize the method of the present invention to be able to carry out (S)-1-(4 ‑Fluorophenyl)‑1‑[2‑(piperazin‑1‑yl)pyrimidin‑5‑yl]ethylamine enantiomer (R)‑1‑(4‑fluorophenyl)‑1‑[ Quantitative analysis of 2-(piperazine-1-yl)pyrimidin-5-yl]ethylamine, the present invention can effectively separate and detect enantiomers, with symmetrical peak shape, no tailing phenomenon, high resolution, exclusive The performance, quantitative limit and detection limit, linearity, repeatability, accuracy, precision, solution stability, and durability all meet the requirements, and the detection effect is good.

Description

technical field [0001] The invention relates to the technical field of Avapritinib, in particular to a method for detecting enantiomers in Avapritinib intermediates. Background technique [0002] Avapritinib (Ava) is an oral, potent and highly selective tyrosine kinase inhibitor (tyrosinekinase inhibitors, TKI), developed by Blueprint Medicines, on January 9, 2020, the US Food and Drug Administration (FDA) ) is approved for listing. [0003] In the latest study of GIST patients with KIT / PDGFRα mutation, Ava has shown preliminary efficacy including patients with PDGFRα D842V mutation, and may become the first-line treatment drug for this mutation subgroup. The conventional dosage regimen of Ava is to take orally once a day on an empty stomach, 300 mg each time, until the patient’s disease progresses or unacceptable adverse reactions occur. The structural formula is shown in figure 1 . [0004] [0005] Its structural formula see figure 1 . [0006] Ava is a type I TKI...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): G01N30/02G01N30/06G01N30/74
CPCG01N30/02G01N30/06G01N30/74
Inventor 陈年根
Owner HAINAN MEDICAL UNIV
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