Crystal forms of 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1h,3h)-dione and preparation thereof
AssigneeImpact Therapeutics (Shanghai), Inc
InventorsSui Xiong CAI, Ning MA, Yisheng YANG, Kai YANG
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Abstract
Provide crystal forms of 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl) piperazine-1-carbonyl) benzyl) quinazoline-2, 4 (1H,3H)-dione and preparation method thereof.
Claims20
A crystal form of 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione selected from crystal forms VIII, I, II, III, V, VI, “VIII”, IX, X, XI, XII, or a mixture of two or more of the above crystal forms;
- wherein, the XRPD of the crystal form VIII includes diffraction peaks at 2θ=6.7°±0.2°, 11.0°±0.2°, 22.2°±0.2° and 25.7°±0.2°;
- the XRPD of the crystal form I includes diffraction peaks at 2θ=5.2°±0.2°, 6.6°±0.2°, 13.3°±0.2° and 19.9°±0.2°;
- the XRPD of the crystal form II includes diffraction peaks at 2θ=10.6°±0.2°, 11.0°±0.2°, 15.5°±0.2° and 16.8°±0.2°;
- the XRPD of the crystal form III includes diffraction peaks at 2θ=12.5°±0.2°, 13.5°±0.2°, 16.7°±0.2°, and 17.6°±0.2°;
- the XRPD of the crystal form V includes diffraction peaks at 2θ=7.0°±0.2°, 13.9°±0.2°, 15.8°±0.2° and 24.9°±0.2°;
- the XRPD of the crystal form VI includes diffraction peaks at 2θ=12.8°±0.2°, 13.3°±0.2°, 14.0°±0.2° and 17.3°±0.2°;
- the XRPD of the crystal form “VIII” includes diffraction peaks at 2θ=6.8°±0.2°, 10.9°±0.2°, 11.7°±0.2°, 16.1°±0.2°, 17.2°±0.2°, 22.1°±0.2°, 25.8°±0.2°, 27.2°±0.2° and 30.0°±0.2°;
- the XRPD of the crystal form IX includes diffraction peaking at 2θ=14.5°±0.2°, 20.0°±0.2°, 21.6°±0.2° and 26.7°±0.2°;
- the XRPD of the crystal form X includes diffraction peaks at 2θ=7.5°±0.2°, 9.8°±0.2°, 11.3°±0.2° and 14.8°±0.2°;
- the XRPD of the crystal form XI includes diffraction peaks at 2θ=6.8°±0.2°, 9.2°±0.2°, 11.0°±0.2° and 17.2°±0.2°;
- and
- the crystal form XII is the dehydrated form of the crystal form VIII.
A crystal form of 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione, wherein the crystal form is form VIII, and its XRPD includes diffraction peaks in 2θ=6.7°±0.2°, 10.5°±0.2°, 11.0°±0.2°, 15.5°±0.2°, 16.7°±0.2°, 18.9°±0.2°, 20.7°±0.2°, 22.2°±0.2°, 23.3°±0.2°, 25.7°±0.2°, 27.0°±0.2° and 29.7°±0.2°.
-14. (canceled)
A method of preparing 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione represented by Formula I, wherein the method includes:
- (1) preparing a compound of Formula III from a compound of Formula IV and a compound of Formula V:
- (2) hydrolyzing the compound of Formula III to obtain a compound of Formula II:
- (3) preparing 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl) benzyl)quinazoline-2,4(1H,3H)-dione represented by Formula I via a condensation reaction between the compound of Formula II and a compound of Formula A:
- wherein in step (3), the compound of Formula II is dissolved in ethyl acetate, the temperature of a reactor is controlled at 15-25° C., and an ethyl acetate solution of the compound of Formula II is added to the reactor;
- then the temperature of the reactor is adjusted to 20±2° C. and a condensation agent and an organic base are added, and then the reaction mixture is heated to 35-45° C.;
- a solution of Compound A in ethyl acetate is added and stirred for 15-25 hours;
- after the completion of reaction, process water is added to the reaction mixture, stirred for 1-3 hours, and filtered;
- the filter cake is rinsed with ethyl acetate, the wet product is returned to the reactor, dimethyl sulfoxide is added and stirred for 1-3 hours, then purified water and crystal seeds of the compound of Formula I are added and stirred for 4-6 hours and filtered;
- the filter cake is rinsed with process water, and dried under reduced pressure at 50-60° C. for 50-70 hours to give 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione (Formula I).
Dependencies are inferred from the claim text.