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Dimethyl sulfonate of compound A, crystal form of dimethyl sulfonate, and medicinal composition containing dimethyl sulfonate

A kind of technology of dimethanesulfonic acid salt and compound, applied in the field of pharmaceutical composition containing this salt, can solve problems such as unknown compound A

Inactive Publication Date: 2017-05-17
HUIZHOU XINLITAI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] It is not known in the prior art how to obtain other salts of compound A and a plurality of salts

Method used

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  • Dimethyl sulfonate of compound A, crystal form of dimethyl sulfonate, and medicinal composition containing dimethyl sulfonate
  • Dimethyl sulfonate of compound A, crystal form of dimethyl sulfonate, and medicinal composition containing dimethyl sulfonate
  • Dimethyl sulfonate of compound A, crystal form of dimethyl sulfonate, and medicinal composition containing dimethyl sulfonate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] The preparation of embodiment 1 compound A

[0071] According to the method of Example 28 and 28A of the PCT / GB2012 / 051783 instruction manual, the following technical synthesis route was used to prepare compound A-methanesulfonate and its crystal form B:

[0072]

[0073] The reaction conditions and parameters are:

[0074] to N at 0°C 1 -(2-Dimethylaminoethyl)-5-methoxy-N 1 -Methyl-N 4 -[4-(1-Methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (Intermediate 100, 10 g, 21.32 mmol) in THF (95 mL) and water ( To the stirred solution in 9.5 mL) was added 3-chloropropionyl chloride (3.28 g, 25.59 mmol). The mixture was stirred at room temperature for 15 minutes, then NaOH (3.48 g, 85.28 mmol) was added. The resulting mixture was heated to 65°C for 10 hours. The mixture was then cooled to room temperature and CH was added 3 OH (40 mL) and water (70 mL). The resulting mixture was stirred overnight. The resulting solid was collected by filtration, washed with wa...

Embodiment 2

[0079] The preparation of embodiment 2 compound A dimesylate

[0080] Add 12g of compound A-methanesulfonate to 125ml of ethanol and 25ml of water, stir at 60°C for 0.75h, dissolve, add 5.5g of methanesulfonic acid dropwise, keep stirring for 5h, then move to 20°C and stir for 14h , a pale yellow solid was precipitated, and dried at 42.5°C for 3.5 hours to obtain compound A dimesylate.

[0081] Described compound is determined by NMR, 1 H-NMR test spectrum such as figure 2 As shown in the figure, it is found that the dimethyl proton signal peak of dimethanesulfonic acid appears in the high field, indicating that there are 6 hydrogens, indicating that the obtained product is a double salt, namely dimethanesulfonate.

[0082] 1 H-NMR testing equipment and conditions: testing equipment: Bruker AVANCE III HD 500 superconducting pulse Fourier transform nuclear magnetic resonance spectrometer; testing conditions: solvent: MeOD-d4; temperature: 25°C; testing basis: JY / T 007- 1996...

Embodiment 3

[0083] Example 3 Preparation of compound A dimesylate salt crystal form α

[0084] Add 10 g of compound A dimesylate of Example 2 into 100 ml of acetonitrile, add 30 ml of water at room temperature, stir and react at 60°C for 0.5 h, and dissolve; add 100 g of acetonitrile at 30°C, stir for 1.5 h, and then Move it to an ice bath and stir for another 2 hours, a light yellow solid precipitates out, and dry at 50°C for 5 hours to obtain the product, which is the dimesylate α crystal form.

[0085] The solid material is defined as dimesylate salt α crystal form.

[0086] The X-ray diffraction pattern of obtained compound A dimesylate salt crystal form α is as follows: Figure 4 shown. The specific characteristic absorption peaks are shown in Table 1, with an error of ±0.2°.

[0087] The DSC spectrum of obtained compound A dimesylate salt crystal form α is as follows Figure 5 As shown, there is a maximum absorption peak at 262.1°C±2°C.

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Abstract

The invention provides dimethyl sulfonate of a compound A, a crystal form of the dimethyl sulfonate, application of the dimethyl sulfonate of the compound A in preparation of a medicine for preventing and / or treating mammal diseases, and a medicinal composition containing the dimethyl sulfonate of the compound A, wherein the mammals comprise human beings, and the diseases comprise various cancers, preferably non-small cell lung cancer, particularly mutated non-small cell lung cancer.

Description

technical field [0001] The invention belongs to the field of chemical drug preparation, and in particular relates to a dimesylate salt of EGFR inhibitor compound A and its crystal form, and a pharmaceutical composition containing the salt. Background technique [0002] EGFR is a transmembrane protein tyrosine kinase member of the erbB receptor family. When bound to a growth factor ligand such as epidermal growth factor (EGF), the receptor can homodimerize with an additional EGFR molecule, or with another family member such as erbB2 (HER2), erbB3 (HER3), Or erbB4 (HER4)) undergoes heterodimerization. [0003] Homodimerization and / or heterodimerization of ErbB receptors leads to phosphorylation of key tyrosine residues in the intracellular domain and to stimulation of many intracellular signaling pathways involved in cell proliferation and survival. Dysregulation of erbB family signaling promotes proliferation, invasion, metastasis, angiogenesis, and tumor cell survival, and...

Claims

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Application Information

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IPC IPC(8): C07D403/04A61K31/506A61P35/00
CPCC07D403/04C07B2200/13
Inventor 颜杰李松许文杰华怀杰
Owner HUIZHOU XINLITAI PHARMA
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