CRYSTAL OF SALT OF QUINAZOLINE DERIVATIVE

Abstract

Disclosed are a crystal of a maleate of a compound of formula (I), a preparation method for the crystal, a crystallization composition of same, a pharmaceutical composition of same, and uses thereof in preventing and treating a tumor.

##STR00001##

Claims

1. A crystal of a maleate of a compound of Formula (I) ##STR00005##

2. The crystal of the maleate of the compound of Formula (I) according to claim 1, being a crystalline Form A, and having diffraction peaks at 2=6.24, 7.19, 14.26, 18.50, and 26.800.2 in an X-ray powder diffraction pattern, preferably having diffraction peaks at 2=6.24, 7.19, 14.26, 18.50, 22.59, 26.80, and 27.640.2, and more preferably having diffraction peaks at 2=6.24, 7.19, 14.26, 14.65, 17.09, 18.50, 21.38, 22.59, 24.70, 25.83, 26.80, and 27.640.2.

3. The crystal of the maleate of the compound of Formula (I) according to claim 2, having a melting point of 196 C.-198 C.

4. The crystal of the maleate of the compound of Formula (I) according to claim 1, being a crystalline Form B, and having diffraction peaks at 2=6.39, 7.35, 16.00, 21.21, 22.65, and 27.030.2 in an X-ray powder diffraction pattern, preferably having diffraction peaks at 2=6.39, 7.35, 13.37, 14.97, 16.00, 18.58, 21.21, 22.65, 23.98, 26.12, 26.50, 27.03, and 27.450.2, and more preferably having diffraction peaks at 2=6.39, 7.35, 13.37, 14.49, 14.97, 16.00, 17.71, 18.58, 19.13, 21.21, 22.65, 23.98, 24.42, 26.12, 26.50, 27.03, 27.45 and 28.05+0.2.

5. A process for preparing the crystal of the maleate of the compound of Formula (I) according to claim 2, comprising: (1) dissolving the compound of Formula (I) in a mixed solvent of ethyl acetate and an alcohol; (2) dissolving maleic acid in an alcohol and contacting the acid with the solution of the compound of Formula (I) obtained from step (1); and (3) crystallizing.

6. The process according to claim 5, wherein the alcohol in step (1) and the alcohol in step (2) are independently selected from one or a mixture of two or more of methanol, ethanol, and isopropanol, and preferably, both the alcohol in step (1) and the alcohol in step (2) are ethanol.

7. The process according to claim 5, wherein a molar ratio of the compound of Formula (I) to maleic acid is 1:110, preferably 1:28, and more preferably 1:5.

8. The process according to claim 5, wherein a volume ratio of the alcohol to ethyl acetate in step (1) is 151:1, preferably 81:1, and more preferably 2:1.

9. A process for preparing the crystal of the maleate of the compound of Formula (I) according to claim 4, comprising: dissolving the crystal of the maleate of the compound of Formula (I) according to claim 2 in an organic solvent, and cooling for crystallization.

10. The process according to claim 9, wherein the organic solvent is selected from the group consisting of dimethyl sulfoxide, N,N-dimethylformamide and N,N-dimethylacetamide, and preferably, N,N-dimethylformamide.

11. A crystalline composition, comprising the crystal of the maleate of the compound of Formula (I) according to claim 1, which accounts for 50 wt % or more, preferably 80 wt % or more, more preferably 90 wt % or more, and most preferably 95 wt % or more by weight of the crystalline composition.

12. A pharmaceutical composition, comprising a therapeutically effective amount of the crystal of the maleate of the compound of Formula (I) according to claim 1.

13. A method for the treatment of a tumor in a subject in need thereof, comprising administering to the subject the crystal of the maleate of the compound of Formula (I) according to claim 1.

14. A crystalline composition, comprising the crystal of the maleate of the compound of Formula (I) according to claim 2, which accounts for 50 wt % or more, preferably 80 wt % or more, more preferably 90 wt % or more, and most preferably 95 wt % or more by weight of the crystalline composition.

15. A crystalline composition, comprising the crystal of the maleate of the compound of Formula (I) according to claim 4, which accounts for 50 wt % or more, preferably 80 wt % or more, more preferably 90 wt % or more, and most preferably 95 wt % or more by weight of the crystalline composition.

16. A pharmaceutical composition, comprising a therapeutically effective amount of the crystal of the maleate of the compound of Formula (I) according to claim 2.

17. A pharmaceutical composition, comprising a therapeutically effective amount of the crystal of the maleate of the compound of Formula (I) according to claim 4.

18. A method for the treatment of a tumor in a subject in need thereof, comprising administering to the subject the crystal of the maleate of the compound of Formula (I) according to claim

19. A method for the treatment of a tumor in a subject in need thereof, comprising administering to the subject the crystal of the maleate of the compound of Formula (I) according to claim 4.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0041] FIG. 1 shows the X-ray powder diffraction pattern (XRPD) of the crystalline Form A of the maleate of the compound of Formula (I).

[0042] FIG. 2 shows the XRPD of the crystalline Form B of the maleate of the compound of Formula (I).

EXAMPLES

[0043] The present application is described in more detail below through (but not limited to) the following examples and experiments. The compound of Formula (I) used in the examples was prepared according to Example 2 in CN104513229A.

[0044] The XRPD was measured using a PHASER BRUKER D2 X-ray powder diffractometer with a wavelength of 1.54060 . The melting point was measured using an YRT-3 melting point apparatus (manufactured by Tianjin University). The content was determined by HPLC with reference to Chinese Pharmacopoeia, 2010 edition, Part II, Appendix V D, using octadecylsilane bonded silica gel as a filler, and ammonium formate buffer solution and acetonitrile as a mobile phase; detection wavelength of 260 nm and column temperature of 40 C. The moisture content was determined using a METTLER TOLEDO DL31 Karl Fischer moisture analyzer.

Example 1: Preparation of the Crystalline Form A of the Maleate of the Compound of Formula (I)

[0045] ##STR00004##

[0046] 83.1 g of the compound of Formula (I) was dissolved in a mixed solvent of 910 mL of anhydrous ethanol and 455 mL of ethyl acetate at 60 C. 105.8 g of maleic acid and 910 mL of anhydrous ethanol were added to a 3 L reaction flask, and stirred until completely dissolved. To the resulting mixture was added the above solution of the compound of Formula (I) at room temperature, and reacted for 20-24 h at 20-30 C. A large amount of yellow solid was precipitated out, and then filtered. The filter cake was washed with 200 mL of anhydrous ethanol and dried for 24 h in vacuo at 45-55 C. to afford 102.5 g of the crystalline Form A of the maleate of the compound of Formula (I) as a bright yellow solid with a melting point of 196-198 C.

[0047] .sup.1H-NMR (500 MHz, DMSO-d.sub.6): 15.39 (s, 2H), 10.26 (s, 1H), 8.63 (s, 1H), 8.01 (dd, 1, J=2.4, 6.75 Hz), 7.69-7.72 (m, 1H), 7.52 (t, 1H, J=9 Hz), 7.38 (s, 1H), 7.14 (s, 1H), 6.86 (dd, 1H, J=10.45, 16.65 Hz), 6.15 (s, 2H), 6.12 (d, 1H, J=2.35 Hz), 5.75 (s, 1H), 5.70 (dd, 1H, J=2.15, 10.4 Hz), 4.47 (d, 1H, J=11.2 Hz), 4.14 (d, 1H, J=11.65 Hz), 4.02 (s, 3H), 3.81 (s, 1H), 3.25 (t, 1H, J=11.5 Hz), 2.89 (t, 1H, J=11.2 Hz), 2.06 (s, 2H), 1.50 (s, 2H).

Example 2: Preparation of the Crystalline Form B of the Maleate of the Compound of Formula (I)

[0048] 10 g of the crystalline Form A prepared in Example 1 was weighed, added to N,N-dimethylformamide, heated to 80 C. and dissolved under stirring, and then hot-filtered. The filtrate was slowly cooled and crystallized for 7 h, and then filtered. The resulting filter cake was washed with 10 ml DMF and dried under for 24 h in vacuo at 55 C. to afford 6.5 g of the crystalline Form B of the maleate of the compound of Formula (I) as a yellow solid.

Example 3: Stability Test of Crystal

[0049] The conditions and methods for the stability test of crystal were performed according to the requirements of the Chinese Pharmacopoeia (2010 edition), Part II, Appendix XIX C, Guidelines for Stability Tests of Active Pharmaceutical Ingredients and Pharmaceutical Preparations. The crystalline Form A prepared in Example 1 was used as a test sample. A medicinal low-density polyethylene bag was used as an inner package for a sample, and polyester/aluminum/polyethylene composite bag for pharmaceutical packaging was used as an outer packaging material for a sample. The specific results were shown below.

TABLE-US-00001 TABLE 1 Accelerated test (40 C. 2 C., relative humidity of 75% 5%) Time (Month) Test items (%) 0 1 2 3 6 Moisture 0.17 0.19 0.18 0.19 0.20 the crystalline Form A of 99.4 99.3 99.2 99.2 99.3 the maleate of the compound of Formula (I)

TABLE-US-00002 TABLE 2 Long-term test (25 C. 2 C., relative humidity of 60% 10%) Time (Month) Test items (%) 0 3 6 9 12 18 Moisture 0.17 0.19 0.20 0.21 0.22 0.24 the crystalline Form A of 99.4 99.3 99.4 99.2 99.4 99.2 the maleate of the compound of Formula (I)