Crystal form of quinazoline compound and preparation method thereof

A quinazoline-based, crystal-form technology, applied in the field of drug crystals, can solve the problems of affecting drug efficacy, restricting dissolution and bioavailability, and low solubility, achieving good bioavailability, improving drug efficacy, and low hygroscopicity Effect

Pending Publication Date: 2021-11-30
CRYSTAL PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, the existing crystal form of the compound of formula (I) has low solubility, which will greatly restrict its dissolution and bioavailability, thereby affecting the efficacy of the drug

Method used

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  • Crystal form of quinazoline compound and preparation method thereof
  • Crystal form of quinazoline compound and preparation method thereof
  • Crystal form of quinazoline compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Weigh about 20 mg of (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4-(1-piper (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7- Methoxy-6-quinazolinyl]-4-(1-piperidinyl)-2-butenamide was heated (heating rate was 10°C / min) to about 180°C, then naturally cooled to room temperature (approx. 25°C) to obtain a solid product.

[0083] After testing, the X-ray powder diffraction data of the solid obtained in this embodiment are shown in Table 1, and its XRPD pattern is as follows figure 1 As shown, the results show that the obtained solid product is the crystal form C described in the application.

[0084] Table 1

[0085] Numbering Diffraction angle 2θ(±0.2°) d value Relative Strength% 1 5.62 15.72 100.00 2 6.76 13.09 23.66 3 8.33 10.61 4.71 4 10.46 8.46 73.12 5 12.85 6.89 85.63 6 13.56 6.53 3.45 7 15.40 5.75 2.31 8 16.74 5.30 22.67 9 17.41 5.09 4.91 10 18.04 4.92 10.20...

Embodiment 2

[0087] Weigh about 20 mg of (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4-(1-piper (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7- Methoxy-6-quinazolinyl]-4-(1-piperidinyl)-2-butenamide was heated (heating rate: 10°C / min) to 180°C, then naturally cooled to room temperature (about 25°C ) to obtain a solid product, parallel test 20 times, the solid product obtained in 20 times was mixed homogeneously, and sampling was detected.

[0088] After testing, the X-ray powder diffraction data of the resulting solid product are shown in Table 2, and its XRPD pattern is as follows figure 2 As shown, the TGA image as image 3 As shown, the DSC image is as Figure 4 As shown, the results show that the obtained solid product is the crystalline form C described in this application, and the TGA data shows that the crystalline form sample loses about 1.8% in weight when heated to 160°C, and there is a single melting endothermic peak at 167°C to 200°C in DSC, It shows...

Embodiment 3

[0092] Weigh about 1 gram of (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4-(1-piper Pyridyl)-2-butenamide solid is placed in a vacuum drying oven, and (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy Base-6-quinazolinyl]-4-(1-piperidinyl)-2-butenamide was heated to 170°C, and then naturally cooled to room temperature (about 25°C) to obtain a solid product, which was sampled for detection.

[0093] After testing, the X-ray powder diffraction data of the resulting solid product are shown in Table 3, and its XRPD pattern is as follows Figure 5 As shown, the results show that the obtained solid product is the crystal form C described in the application, and the crystal form is (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-form Oxy-6-quinazolinyl]-4-(1-piperidinyl)-2-butenamide anhydrate.

[0094] table 3

[0095] Numbering Diffraction angle 2θ(±0.2°) d value Relative Strength% 1 5.59 15.82 100.00 2 6.72 13.16 15.49 ...

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Abstract

The invention relates to a crystal form C of (2E)-N-[4-[(3-chloro-4-fluorophenyl) amino]-7-methoxy-6-quinazolinyl]-4-(1-piperidinyl)-2-buteneamide, a preparation method thereof and a medicine containing the crystal form C. The crystal form C is an anhydrous substance, Cu-K alpha radiation is used, and the crystal form C has an X-ray powder diffraction pattern with characteristic peaks at diffraction angles 2theta of 5.6 +/- 0.2 degrees, 10.5 +/- 0.2 degrees and 12.8 +/- 0.2 degrees. The crystal form C is the anhydrous substance and has obvious advantages in medicine development compared with an existing solvate, in addition, the solubility of the crystal form C is remarkably improved compared with that of the existing solvate on the premise that good stability is kept.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical crystals. Specifically, it relates to quinazoline compounds (2E)-N-[4-[(3-chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-4- A new crystal form of (1-piperidinyl)-2-butenamide and its preparation method and use. [0002] technical background [0003] The pan-ErbB kinase family consists of four receptors, including Her1 (EGFR, ErbB1), Her2 (Neu, ErbB2), Her3 (ErbB3) and Her4 (ErbB4). In the process of cell signal transduction, the binding of ErbB kinase family proteins to the corresponding ligands will induce the cascade reaction of the downstream signal transduction pathway of tyrosine kinases, such as Ras-Raf-MAPK or PI3-K / AKT, etc. Inhibition of the process of apoptosis and promotion of the process of cell proliferation. The occurrence and development of various tumors are accompanied by the overexpression of pan-ErbB family proteins, and this receptor has also become an importan...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/94A61K31/517A61P35/00
CPCC07D239/94A61P35/00C07B2200/13A61K31/517
Inventor 鲁霞樊孝天张晓宇
Owner CRYSTAL PHARMATECH CO LTD
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