New crystal form of phosphorus-substituted quinazoline derivatives and its preparation method and application

A technology of quinazoline and crystal form, which is applied to the new crystal form of quinazoline derivatives and the field of preparation thereof, can solve the problems of low bioavailability, blanks in basic research of drugs, etc., so as to improve bioavailability and improve drug active effect

Active Publication Date: 2017-03-29
JIANGSU KANION PHARMA CO LTD
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  • Summary
  • 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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  • New crystal form of phosphorus-substituted quinazoline derivatives and its preparation method and application
  • New crystal form of phosphorus-substituted quinazoline derivatives and its preparation method and application
  • New crystal form of phosphorus-substituted quinazoline derivatives and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] 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

[0045] 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 dissolved in 6.0mL mixed solvent (water:methanol volume ratio 1:1), and the solvent was removed with a rotary evaporator, the pressure was -0.01Mpa, the speed was 90rpm, The time was 30min to obtain 83mg of the crystal form, and the obtained crystal form was subjected to powder X-ray diffraction analysis, and its diffraction pattern was as follows: figure 1 As shown, the infrared spectrum as figure 2 shown.

Embodiment 2

[0046] 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

[0047] 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 dissolved in 8.0mL mixed solvent (water: ethanol volume ratio 1:2), and the solvent was removed with a rotary evaporator, the pressure was -0.01Mpa, the speed was 90rpm, The time is 30min to obtain 85mg of the crystal form, and the obtained sample is subjected to powder X-ray diffraction analysis, and the diffraction pattern is basically as follows: figure 1 As shown, the infrared spectrum is basically as figure 2 Shown, consistent with the identification result of embodiment 1.

Embodiment 3

[0048] 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

[0049] 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 dissolved in 4.0mL mixed solvent (water: isopropanol volume ratio 1:3), and the solvent was removed with a rotary evaporator, the pressure was -0.01Mpa, and the rotation speed was 90rpm, the time is 30min to obtain 82mg of the crystal form, and the obtained sample is subjected to powder X-ray diffraction analysis, and its diffraction pattern is 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 or adopting a grinding and physical rotating crystal method, 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 & AuthorityPatents(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
OwnerJIANGSU KANION PHARMA CO LTD