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Crystal form of free base of imidazoisoindole derivatives and preparation method thereof

A crystal form and drug technology, which is applied in the field of crystal form of imidazoisoindole derivatives free base and its preparation, can solve the problems of poor product stability, difficult production scale-up, poor fluidity, etc., and achieve good crystal form stability , stable production process and high chemical stability

Active Publication Date: 2020-09-11
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Generally speaking, amorphous pharmaceutical products have no regular crystal structure and often have other defects, such as poor product stability, difficult filtration, easy agglomeration, poor fluidity, etc. These differences often lead to difficulties in production scale-up
However, the stability of the existing crystal forms needs to be improved

Method used

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  • Crystal form of free base of imidazoisoindole derivatives and preparation method thereof
  • Crystal form of free base of imidazoisoindole derivatives and preparation method thereof
  • Crystal form of free base of imidazoisoindole derivatives and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] 300mg of (S)-2-(4-(4-(4-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)phenyl )-1H-pyrazol-1-yl)ethanol (prepared according to the method in Examples 40 and 41 in patent application WO2016169421) crude product was added to the reaction flask, and then 35 mL of dichloromethane was added, heated to reflux, and the solid was dissolved. Turn off the heat and stir for crystallization. The next day, it was filtered by suction and dried to obtain 238 mg of white solid with a yield of 79.3%. The X-ray diffraction pattern of this crystalline sample is shown in figure 1 , whose DSC spectrum is shown in figure 2 , define this crystal form as II crystal form, and its characteristic peak positions are shown in the table below:

[0070] Table 1. Characteristic peaks of crystal form II

[0071]

[0072]

Embodiment 2

[0074] 300mg of (S)-2-(4-(4-(4-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)phenyl )-1H-pyrazol-1-yl)ethanol crude product was added to the reaction flask, 15 mL of tetrahydrofuran was added, heated to reflux, the solid dissolved, turned off the heating, and stirred for crystallization. The next day, it was suction filtered and dried to obtain 264 mg of white solid with a yield of 88.0%. The crystalline sample was determined to be Form II by XRPD detection.

Embodiment 3

[0076] 300mg of (S)-2-(4-(4-(4-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)phenyl )-1H-pyrazol-1-yl)ethanol crude product was added to the reaction flask, ethylene glycol dimethyl ether 45mL was added, heated to reflux, the solid was dissolved, the heating was turned off, and the mixture was stirred for crystallization. The next day, it was filtered by suction and dried to obtain 185 mg of white solid with a yield of 61.7%. The crystalline sample was determined to be Form II by XRPD detection.

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Abstract

The invention relates to a crystal form of a free alkali of an imidazoisoindole derivative and a preparation method thereof. Specifically, the invention relates to the crystal form II of a compound asshown in a formula (I) which is described in the specification, and the chemical name of the crystal form II is (S)-2-(4-(4-(4-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)phenyl)-1H-pyrazol-1-yl)ethanol. The invention further relates to the preparation method of the crystal form II, the application of the crystal form II to a pharmaceutical composition, and the application of the crystal form II and the composition to the treatment of diseases having pathological features of an IDO-mediated (indoleamine-pyrrole-2,3-dioxygenase-mediated) tryptophan metabolism approach. The preparedcrystal form II of the compound as shown in the formula (I) has good stability and can be better used for clinical treatment.

Description

technical field [0001] The present invention relates to (S)-2-(4-(4-(4-(6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)benzene Base) -1H-pyrazol-1-yl) II crystal form of ethanol and its preparation method, its application in pharmaceutical compositions and the II crystal form, composition in the preparation of treatment with IDO-mediated tryptophan metabolism Use in diseases characterized by pathway pathology. Background technique [0002] Tumor biotherapy is a new treatment for tumor prevention and treatment using modern biotechnology and related products. Because of its safety, effectiveness, and low adverse reactions, it has become the fourth mode of tumor treatment after surgery, radiotherapy, and chemotherapy. It mobilizes The host's natural defense mechanism (such as the inhibition of IDO-mediated tumor immune escape mechanism) or the administration of naturally occurring highly targeted substances to obtain anti-tumor effects. [0003] Indoleamine-pyrrole-2,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/454A61P35/00A61P35/02A61P25/28A61P37/06A61P25/22A61P25/24A61P27/12A61P25/00A61P31/18
CPCA61P25/00A61P25/22A61P25/24A61P25/28A61P27/12A61P31/18A61P35/02A61P37/06C07B2200/13C07D487/04
Inventor 张全良徐红玉高晓晖
Owner JIANGSU HENGRUI MEDICINE CO LTD
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