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Crystal form of macrocyclic compound and preparation method and application thereof

A technology of compounds and macrocycles, which is applied in the field of drug synthesis, can solve problems such as inability of drugs to function, affect clinical efficacy and safety, and differences in stability, and achieve good chemical stability, good physical stability, and good drug stability. Effects of Kinetic Properties

Active Publication Date: 2021-12-07
GUANGZHOU BAIYUNSHAN PHARMA HLDG CO LTD BAIYUNSHAN PHARMA GENERAL FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A drug can have multiple crystal forms. Different crystal forms of the same drug may not only have different stability, but also have different dissolution and absorption in the body, thus affecting clinical efficacy and safety.
At present, there is no research on the macrocyclic compound (6R,16R)-9-fluoro-16-methyl-13-oxa-2,17,21,25-tetraazolane[16.6.2.02 ,6.07,12.022,26]Research on related crystal forms of hexacane-1(25),7,9,11,18(26),19,21,23-octane-19-carbonitrile, the hygroscopicity and stability of amorphous compounds poor performance, the prepared drug can not play a good role

Method used

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  • Crystal form of macrocyclic compound and preparation method and application thereof
  • Crystal form of macrocyclic compound and preparation method and application thereof
  • Crystal form of macrocyclic compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] A method for preparing a crystal form of a macrocyclic compound, comprising the following steps:

[0053] 1 mg of the macrocyclic compound (6R,16R)-9-fluoro-16-methyl-13-oxa-2,17,21,25-tetraazaolane[16.6 .2.0 2 , 6 .0 7 , 12 .0 22 , 26 ] Hexacane-1(25), 7,9,11,18(26), 19,21,23-octane-19-carbonitrile was added into 1.0mL methanol, stirred at room temperature (25±5°C) to dissolve After clearing, slowly add 0.8 mL of water dropwise, after the solid precipitates, continue to stir for a period of time, filter, and dry the filter residue to obtain a crystalline powder.

[0054] The obtained crystalline powder was subjected to X-ray powder diffraction, differential scanning calorimetry and thermogravimetric analysis. After the crystalline samples were characterized, they were named crystal forms. Its PXRD spectrum (X-ray powder diffraction spectrum) see figure 1 , figure 1 It shows that the 2θ values ​​of the samples are 5.69, 9.49, 10.60, 11.54, 14.10, 16.11, 17.09,...

Embodiment 2

[0056] A method for preparing a crystal form of a macrocyclic compound, comprising the following steps:

[0057] 15 mg of (6R,16R)-9-fluoro-16-methyl-13-oxa-2,17,21,25-tetraazolane[16.6.2.0 2 , 6 .0 7 , 12 .0 22 , 26 ] Hexacane-1(25), 7,9,11,18(26), 19,21,23-octane-19-carbonitrile was added to 0.4mL methanol, stirred at room temperature to dissolve, then slowly added the solution In 0.8mL of water, after the solid precipitated, continue to stir for a period of time, filter and dry to obtain light yellow crystalline powder. After comparing the PXRD spectrum and DSC spectrum of the crystalline sample, it was determined to be the same crystal form as in Example 1.

Embodiment 3

[0059] A method for preparing a crystal form of a macrocyclic compound, comprising the following steps:

[0060] 15 mg of (6R,16R)-9-fluoro-16-methyl-13-oxa-2,17,21,25-tetraazolane[16.6.2.0 2, 6 .0 7 , 12 .0 22,26 ] Hexacane-1(25), 7,9,11,18(26), 19,21,23-octane-19-carbonitrile was added into 0.2mL of dichloromethane, stirred at room temperature to dissolve, then slowly drop Add 3.6 mL of n-heptane, after the solid precipitates, continue stirring for a period of time, filter and dry to obtain a crystalline powder. After comparing the PXRD spectrum and DSC spectrum of the crystalline sample, it was determined to be the same crystal form as in Example 1.

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Abstract

The invention belongs to the technical field of medicine synthesis, and discloses a crystal form of a macrocyclic compound and a preparation method and application thereof. The macrocyclic compound is (6R, 16R)-9-fluoro-16-methyl-13-oxa-2, 17, 21, 25-tetraazapentane [16.6.2. 02, 6.07, 12.022, 26] hexacosan-1 (25), 7, 9, 11, 18 (26), 19, 21, 23-octane-19-nitrile, and the X-ray diffraction pattern of the crystal form has characteristic peaks at the positions where the 2 theta values are 9.49 + / -0.2, 10.60 + / -0.2, 11.54 + / -0.2, 14.10 + / -0.2, 17.09 + / -0.2, 19.15 + / -0.2, 20.30 + / -0.2, 22.85 + / -0.2, 23.89 + / -0.2 and 27.74 + / -0.2. The crystal form has no hygroscopicity, and has good stability and pharmacokinetic properties.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to crystal forms of macrocyclic compounds and their preparation methods and applications. Background technique [0002] Tropomyosin-related kinase (Trk kinase for short) is a kind of nerve growth factor receptor, and its family consists of highly homologous TrkA, TrkB and TrkC, encoded by NTRK1, NTRK2 and NTRK3 genes, respectively. Under normal physiological conditions, Trk protein is a high-affinity receptor for nerve growth factor. Trk proteins are expressed in neuronal tissues during organogenesis, and they play key roles in central and peripheral nervous system development. When chromosomal mutations lead to NTRK gene fusion, resulting in high expression of chimeric Trk protein, resulting in dysregulation of Trk kinase downstream signaling pathway, overactivation of this pathway can lead to cancer. [0003] NTRK gene fusions occur in a variety of s...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61P17/10A61P11/06A61P13/08A61P13/12A61P1/00A61P15/00A61P19/02A61P37/06A61P9/00A61P11/00A61P13/10A61P37/08A61P29/00A61P9/10A61P25/28A61P25/16A61P35/00A61P25/06A61P19/08A61P25/00
CPCC07D471/04A61P17/10A61P11/06A61P13/08A61P13/12A61P1/00A61P15/00A61P19/02A61P37/06A61P9/00A61P11/00A61P13/10A61P37/08A61P29/00A61P9/10A61P25/28A61P25/16A61P35/00A61P25/06A61P19/08A61P25/00C07B2200/13
Inventor 郭睿智王健松罗志波黄海文秦飞王玮叶海鸿钱日彬
Owner GUANGZHOU BAIYUNSHAN PHARMA HLDG CO LTD BAIYUNSHAN PHARMA GENERAL FACTORY
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