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

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...

Examples

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.

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...

Examples

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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