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Novel crystal form of phosphorus-containing substituted quinazoline derivative as well as preparation method and application of novel crystal form

A technology of quinazoline and chlorination, which is applied in the field of new crystal forms of quinazoline derivatives and its preparation, can solve the problems of low bioavailability and blank basic drug research, and achieve improved bioavailability and improved drug production. active effect

Active Publication Date: 2015-04-29
JIANGSU KANION PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But at present, there is no p-N-(3-chloro-4-(3-fluorobenzoyloxy)phenyl)-6-(3-(4-methyl-1,4azaphosphin-1-yl) )prop-1-ynyl)quinazolin-4-amine p-toluenesulfonate drug crystal form, making the basic research of the drug blank
And, N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(3-(4-methyl-1,4azaphosphin-1-yl)propan-1 -alkynyl) quinazoline-4-amine p-toluenesulfonate still has certain deficiencies in drug metabolism, and the bioavailability is not high

Method used

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  • Novel crystal form of phosphorus-containing substituted quinazoline derivative as well as preparation method and application of novel crystal form
  • Novel crystal form of phosphorus-containing substituted quinazoline derivative as well as preparation method and application of novel crystal form
  • Novel crystal form of phosphorus-containing substituted quinazoline derivative as well as preparation method and application of novel crystal form

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Embodiment 1: Preparation of N-(3-chloro-4-(3-fluorobenzoyloxy)phenyl)-6-(3-(4-methyl-1,4azaphosphine- 1-yl)prop-1-ynyl)quinazolin-4-amine p-toluenesulfonate crystal form

[0042] 100mg of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(3-(4-methyl-1,4azaphosphin-1-yl)propan-1- Alkynyl)quinazolin-4-amine p-toluenesulfonate sample was completely dissolved in 8.0mL mixed solvent (water:methanol volume ratio 1:2) at 40°C, and 88mg of the crystal form was obtained by cold spray method , carry out powder X-ray diffraction analysis to the obtained crystal form, and its diffraction pattern is as follows figure 1 As shown, the infrared spectrum as figure 2 shown.

Embodiment 2

[0043] Embodiment 2: Preparation of N-(3-chloro-4-(3-fluorobenzoyloxy)phenyl)-6-(3-(4-methyl-1,4azaphosphine- 1-yl)prop-1-ynyl)quinazolin-4-amine p-toluenesulfonate crystal form

[0044] 100mg of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(3-(4-methyl-1,4azaphosphin-1-yl)propan-1- Alkynyl)quinazolin-4-amine p-toluenesulfonate sample was completely dissolved in 10.0mL mixed solvent (water:ethanol volume ratio 1:1) at 60°C, and 84mg of the crystal form was obtained by cold spray method , powder X-ray diffraction analysis was performed on the obtained sample, and the diffraction pattern was basically as figure 1 As shown, the infrared spectrum is basically as figure 2 Shown, consistent with the identification result of embodiment 1.

Embodiment 3

[0045] Example 3: Preparation of N-(3-chloro-4-(3-fluorobenzoyloxy)phenyl)-6-(3-(4-methyl-1,4azaphosphine- 1-yl)prop-1-ynyl)quinazolin-4-amine p-toluenesulfonate crystal form

[0046] 100mg of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(3-(4-methyl-1,4azaphosphin-1-yl)propan-1- Alkynyl) quinazoline-4-amine p-toluenesulfonate sample was completely dissolved in 5.0mL mixed solvent (water:isopropanol volume ratio 1:3) at a temperature of 55°C, and the cold spray method was used to obtain 80mg of the crystal form, powder X-ray diffraction analysis was carried out on the obtained sample, and its diffraction pattern was basically as follows: figure 1 As shown, the infrared spectrum is basically as figure 2 Shown, consistent with the identification result of embodiment 1.

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Abstract

The invention relates to the field of compound preparation and particularly relates to a novel crystal form of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(3-(4-methyl-1,4-azaphosphine-1-yl)propyl-1-alkynyl)quinazoline-4-p-toluidine sulfonate as well as a preparation method and application of the novel crystal form. The novel crystal form of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(3-(4-methyl-1,4-azaphosphine-1-yl)propyl-1-alkynyl)quinazoline-4-p-toluidine sulfonate having a better treating effect for excessive proliferative diseases is further obtained through crystallizing a mixed solvent prepared by mixing water and methanol, ethanol, n-propanol, isopropanol, acetone, acetonitrile, tetrahydrofuran or dioxane according to different proportions, so that not only is the pharmaceutical activity of the phosphorus-containing substituted quinazoline derivative improved, but also the bioavailability of the phosphorus-containing substituted quinazoline derivative is increased, and the blank for researching a drug with the crystal form of the phosphorus-containing substituted quinazoline derivative is made up.

Description

technical field [0001] The invention relates to the technical field of crystal form compounds, in particular to a new crystal form of a phosphorus-containing substituted quinazoline derivative and a preparation method and application thereof. Background technique [0002] N-(3-Chloro-4-(3-fluorobenzyloxy)phenyl)-6-(3-(4-methyl-1,4azaphosphin-1-yl)prop-1-yne Base) quinazoline-4-amine p-toluenesulfonate, which is a phosphorus-substituted quinazoline derivative. Its structural formula is as follows. It is a drug for the treatment of hyperproliferative diseases developed by Newkin Pharmaceuticals. The compound It is a type I receptor protein kinase inhibitor, which can be used to treat diseases related to abnormal protein kinase activity in mammals, such as cancer and inflammation. [0003] [0004] Chinese patent CN102711472A discloses a phosphorus-containing quinazoline derivative and a method of use thereof, including N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(3- (4-Met...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6584A61K31/675A61P35/00A61P29/00
Inventor 萧伟吕扬杜冠华杨世颖张国顺王振中郭庆明李瑛光
Owner JIANGSU KANION PHARMA CO LTD
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