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 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...

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)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...

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)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...

Images