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

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

Active Publication Date: 2017-01-11
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)quinazolin-4-amine p-toluenesulfonate sample is completely dissolved in 7.0mL of methanol, placed in a water bath at 60°C to dissolve the sample completely, placed at 10°C, with a relative humidity of 42.5%, and normal pressure In a constant temperature box, let it stand for 24 hours to crystallize, place the collected solid at 60°C and dry it under normal pressure for 24 hours to obtain the product, and the yield is 75%. The obtained sample is analyzed by powder X-ray diffraction, and its diffraction pattern is as follows: figure 1 As shown, the infrared spectrum as figure 2 As shown, the differential scanning calorimetry spectrum is shown as image 3 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] 200mg 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 is completely dissolved in 13.0mL of methanol, placed in a water bath at 40°C to dissolve the sample completely, placed at 20°C, with a relative humidity of 10%, and normal pressure In a constant temperature box, let stand for 24 hours to crystallize, put the collected solid at 60°C and dry it under normal pressure for 24 hours to get it, the yield is 80%. The obtained sample is analyzed by powder X-ray diffraction, and the diffraction pattern is basically as follows: figure 1 As shown, the infrared spectrum is basically as figure 2 As shown, the differential scanning calorimetry map is basically as image 3 Shown, consistent with the identificat...

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] 1g 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 is completely dissolved in 65.0mL of methanol, placed in a water bath at 80°C to dissolve the sample completely, placed at 4°C, with a relative humidity of 75%, and normal pressure In a constant temperature box, let it stand for 24 hours to crystallize, put the collected solid at 60°C and dry it under normal pressure for 24 hours to get it. The yield is 82%. The obtained sample is analyzed by powder X-ray diffraction, and the diffraction pattern is basically as follows: figure 1 As shown, the infrared spectrum is basically as figure 2 As shown, the differential scanning calorimetry map is basically as image 3 Shown, consistent with the identificatio...

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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 methanol solvent, 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