Crystal form of orexin receptor antagonist compound, and preparation method and application thereof
Disclosed are a preparation method of an orexin receptor antagonist compound 5-3, Crystalline forms I-IV of an orexin receptor antagonist compound 5-3 are provided. Also provided are processes of the preparing the orexin receptor antagonist compound 5-3 and its crystalline forms, as well as methods of using the crystalline forms I-IV for treating an orexin-related disease.
1. A crystal form of compound 5-3, wherein the crystal form is crystal form II, and the crystal form II has an XRPD pattern analysis as follows
diffraction
relative
diffraction
relative
angle 2θ
intensity (%)
angle 2θ
intensity (%)
10.428
60.0
25.533
8.2
11.968
100.0
26.083
11.0
13.542
17.8
27.133
3.1
14.238
3.4
27.506
17.7
14.767
12.1
28.316
3.0
15.851
73.9
29.557
2.2
16.818
72.0
30.740
4.2
18.003
9.2
31.846
5.1
19.087
2.1
32.550
2.0
19.755
47.6
33.775
3.1
20.900
25.7
34.682
2.2
22.652
2.9
36.422
3.4
23.858
49.2
36.953
3.4
24.844
23.2
38.569
3.0.
2. The crystal form of compound 5-3 of claim 1 , wherein the crystal form is crystal form II whose XRPD pattern is shown in FIG. 2 .
3. A process for preparing the crystal form of compound 5-3 of claim 1 , comprising:
adding compound 5-3 into a polar organic solvent,
heating to a temperature of 40° C. to reflux temperature for dissolution,
then slowly adding a weak polar or non-polar organic solvent dropwise, and
after the addition is completed, cooling to a temperature of 0° C. to 20° C. in 1-10 hours, thereby forming the crystal; or
adding compound 5-3 into a single organic solvent, a mixed organic solvent, a mixed solvent of a single organic solvent and water, or a mixed solvent of a mixed organic solvent and water, and conducting recrystallization or crystallization.
4. The process of claim 3 ,
wherein the organic solvent is selected from C 1-6 alkyl alcohol, C 5-10 alkane or cycloalkane, C 4-10 ether or cyclic ether, C 3-7 ketone, C 2-6 ester, acetonitrile, or benzene optionally substituted by methyl, ethyl or halogen atoms, wherein the number of substituent is selected from 1, 2 or 3,
wherein the polar organic solvent is selected from C 1-6 alkyl alcohols, C 2-6 esters, acetonitrile or dichloromethane, and
wherein the weak polar or non-polar organic solvent is selected from C 5-10 alkane or cycloalkane, C 4-10 ether or cyclic ether, petroleum ether, or benzene optionally substituted by methyl or ethyl or halogen atoms, wherein the number of substituent is selected from 1, 2 or 3.
5. The process of claim 4 ,
wherein the organic solvent is selected from methanol, ethanol, isopropanol, butanol, pentane, n-hexane, n-heptane, cyclohexane, methyl tert-butyl ether, tetrahydrofuran, dimethyl tetrahydrofuran, 1,4-dioxane, acetone, methyl isobutyl ketone, methyl ethyl ketone, acetonitrile, ethyl acetate, isopropyl acetate, toluene, xylene and/or chlorobenzene,
wherein the polar organic solvent is selected from methanol, ethanol, isopropanol, n-butanol, ethyl formate, ethyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, acetonitrile and/or dichloromethane, or a mixture thereof, and
wherein the weak polar or non-polar organic solvent is selected from pentane, n-hexane, cyclohexane, n-heptane, isooctane, ethyl ether, methyl tert-butyl ether, n-propyl ether, n-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, dimethyl tetrahydrofuran, dioxane, toluene, xylene or chlorobenzene.
6. The process of claim 3 ,
wherein the mixed organic solvent is selected from ethyl acetate/isopropanol
wherein the mixed solvent of an organic solvent and water is selected from methanol/water, ethanol/water, isopropanol/water, acetonitrile/water, acetone/water, tetrahydrofuran/water or 1,4-dioxane/water, and
wherein the volume ratio of organic solvent to water is 0.1-20:1.
7. The process of claim 3 , wherein the volume ratio of organic solvent to water is 0.5-5:1.