Crystalline form of ERK inhibitor and preparation method thereof
A technology of crystal form and chlorophenyl, applied in the field of crystal form of ERK inhibitor and its preparation, can solve the problems of poor fluidity, easy caking, poor product stability, etc.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Publication Date
- 2022-04-12
Smart Images
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Abstract
Description
technical field
[0001] The invention belongs to the technical field of medicine, and relates to a crystal form of an ERK inhibitor and a preparation method thereof. Background technique
[0002] The proliferation, differentiation, metabolism, and apoptosis of normal cells are strictly regulated by cell signal transduction pathways in vivo. Mitogen-activated protein kinase (MAPK) plays an extremely important role in signal transduction pathways, and extracellular signal regulated kinase (ERK) is a member of the MAPK family. Through the RAS-RAF-MEK-ERK step, the exogenous stimulating signal is transmitted to ERK, and the activated ERK is transferred into the nucleus to regulate the activity of transcription factors, thereby regulating biological functions such as cell proliferation, differentiation and apoptosis, or by phosphorylation Cytoskeleton components in the cytoplasm participate in the regulation of cell morphology and the redistribution of the cytoskeleton.
[0003] ...
Examples
Embodiment 1
[0092] Embodiment 1: Formula I compound (S)-2-(1-(3-chlorophenyl)-2-hydroxyethyl)-6-(2-((1-methyl-1H-pyrazole-5- Base)amino)pyrimidin-4-yl)-1,2-dihydro-3H-pyrrolo[1,2-c]imidazol-3-one
[0093]
[0094] The first step: (S)-2-((tert-butyldimethylsilyl)oxy)-1-(3-chlorophenyl)ethylamine 1b
[0095] Dissolve (S)-2-amino-2-(3-chlorophenyl)ethanol 1a (4g, 23.3mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.), imidazole (3.2g, 46.6mmol) in 80mL dichloromethane , tert-butyldimethylsilyl chloride (5.2 g, 35 mmol) was added under ice-cooling, and the reaction was stirred for 14 hours. Add water and extract with dichloromethane (80 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography with eluent system C to obtain the title compound 1b (6.5 g), yield: 97% .
[0096] MS m / z (ESI): 286.1 [M+1].
[0097] ...
Embodiment 2
[0156] Embodiment 2: Preparation of formula I compound A crystal form
[0157] The amorphous compound (527 mg, 1.17 mmol) represented by formula I was added to 50 mL of methyl tert-butyl ether, stirred at room temperature for 72 hours, filtered, the filter cake was collected, and dried in vacuo to obtain the title product (371 mg, yield: 70 %)
[0158] Detected by X-ray powder diffraction, the product is defined as crystal form A, and the XRPD spectrum is as follows: figure 1 . The positions of the characteristic peaks are shown in Table 1 below. The DSC spectrum shows an endothermic peak at 116.28°C. The TGA spectrum shows a weight loss of 5.83% before 150°C.
[0159] DVS detection shows that under normal storage conditions (i.e. 25°C, 60% RH), the sample has a moisture absorption weight gain of about 1.56%; under accelerated test conditions (i.e. 70% RH), the moisture absorption weight gain is about 1.74%; Under (90%RH), the moisture absorption weight gain is about 2.60...
Embodiment 3
[0162] Embodiment 3: Preparation of formula I compound A crystal form
[0163] The amorphous compound (60 mg, 0.13 mmol) represented by formula I was added to 5 mL of cyclopentane, stirred at room temperature for 72 hours, filtered, the filter cake was collected, and dried in vacuo to obtain the title product (58 mg, yield: 96.7%).
[0164] The product was found to be Form A by X-ray powder diffraction detection.