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

A technology of quinazoline and crystal form, which is applied in the field of new crystal form of quinazoline derivatives and its preparation, and can solve problems such as low bioavailability and blank basic drug research

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

[0056] 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

[0057] 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 is 30min to obtain 83mg transition crystal form, powder X-ray diffraction analysis is carried out to the transition crystal form obtained, and its diffraction pattern is as follows Figure 5 As shown, the infrared spectrum as Figure 6 shown.

[0058] Spread 100 mg of the transitional crystal form sample on a petri dish, place it for 1 day at an ambient temperature of 10°C and an ambient relative humidity of 90% to obtain the new crystal form, and perform powder X...

Embodiment 2

[0059] 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

[0060] 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, Time is 30min to obtain 85mg transition crystal form, powder X-ray diffraction analysis is carried out to the transition crystal form obtained, and its diffraction pattern is basically as follows Figure 5 As shown, the infrared spectrum is basically as Figure 6 Shown, consistent with the identification result of embodiment 1.

[0061] Spread 100 mg of the transitional crystal form sample on a petri dish, place it for 2 days at an ambient temperature of 20°C and an ambien...

Embodiment 3

[0062] 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

[0063] 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 transition crystal form, powder X-ray diffraction analysis is carried out to the transition crystal form obtained, and its diffraction pattern is basically as follows Figure 5 As shown, the infrared spectrum is basically as Figure 6 Shown, consistent with the identification result of embodiment 1.

[0064] Spread 100 mg of the transitional crystal form sample on a petri dish, place it for 3 days at an ambient temperature of ...

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Abstract

The invention relates to the field of preparation of compounds 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-amine p-toluene sulfonate as well as a preparation method and application of the novel crystal form. According to the preparation method, a transition crystal form is obtained by crystallizing or carrying out grinding physical crystal transformation on a mixed solvent of water, methanol, ethanol, n-propanol, isopropanol, acetone, acetonitrile, tetrahydrofuran or dioxane at different proportions and is further converted under special environmental conditions to obtain the novel crystal form of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(3-(4-methyl-1,4-azaphosphine-1-yl)prop-1-alkynyl)quinazoline-4-amine p-toluene sulfonate which has better treatment effect on treatment of hyperproliferative diseases. The drug activity is improved, the bioavailability of the crystal form is improved and the crystal form fills the gap in research on drugs containing the crystal form.

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 Patents(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