Crystal form I of salt of a dipeptidyl peptidase-IV inhibitor and preparation method and use thereof
The present invention relates to the crystal form I of salt of a dipeptidyl peptidase-IV inhibitor, and the preparation method and use thereof. In particular, it relates to the crystal form I of dihydrochloride salt of the compound (R)-2-[[7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl]methyl]benzonitrile represented by formula (1), which is a dipeptidyl peptidase-IV inhibitor, and the preparation method and use thereof. The crystal form I of dihydrochloride salt of the dipeptidyl peptidase-IV inhibitor represented by formula (1) is characterized in that it has characteristic peaks at 8.7±0.2°, 19.4±0.2°, 23.5±0.2° and 27.2±0.2° in X-ray powder diffraction indicated by an angle 2θ (°) using Cu—Kα irradiation.
1. A crystal form I of dihydrochloride salt of the compound (R)-2-[[7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl]methyl]benzonitrile represented by formula (1), wherein its characteristic peaks at 8.7±0.2°, 19.4±0.2°, 23.5±0.2° and 27.2±0.2° in X-ray powder diffraction indicated by an angle 2θ(°) using Cu—Kα irradiation,
2. The crystal form I according to claim 1 , wherein by its characteristic peaks at 12.5±0.2°, 22.5±0.2° and 25.5±0.2° in X-ray powder diffraction indicated by an angle 2θ(°) using Cu—Kα irradiation.
3. The crystal form I according to claim 2 , wherein by its characteristic peaks at 11.7±0.2°, 14.6±0.2° and 26.0±0.2° in X-ray powder diffraction indicated by an angle 2θ(°) using Cu—Kα irradiation.
4. A preparation method for the crystal form I according to claim 1 , comprising in that dissolving the compound (R)-2-[[7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl]methyl]benzonitrile in an organic solvent and increasing the temperature, then adding dropwise hydrochloric acid in a certain stoichiometric ratio thereto, thereafter stirring, filtering and drying to obtain the crystal form I of dihydrochloride salt of the compound.
5. The preparation method according to claim 4 , comprising the organic solvent is selected from lower alcohols containing 1-4 carbon atom(s), lower ketones containing 3-6 carbon atoms, acetonitrile, propionitrile or tetrahydrofuran.
6. The preparation method according to claim 5 , comprising the organic solvent is a lower alcohol containing 1-4 carbon atom(s) selected from methanol, ethanol, propanol, isopropanol, n-butanol or isobutanol.
7. The preparation method according to claim 6 , comprising the organic solvent is ethanol.
8. The preparation method according to claim 4 , comprising the organic solvent is a mixed solvent consisting of two or more organic solvents selected from lower alcohols containing 1-4 carbon atom(s), lower ketones containing 3-6 carbon atoms, acetonitrile, propionitrile or tetrahydrofuran.
9. The preparation method according to claim 8 , comprising the organic solvent is an ethanol/water mixed solvent.
10. The preparation method according to claim 4 , comprising the molar ratio of the compound (R)-2-[[7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl]methyl]benzonitrile to hydrochloric acid is less than or equals to 1:2.
11. The preparation method according to claim 10 , comprising the molar ratio of the compound (R)-2-[[7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl]methyl]benzonitrile to hydrochloric acid is 1:4-1:2.
12. A pharmaceutical composition, wherein it includes the crystal formal I of dihydrochloride salt of the compound represented by formula (1) according to claim 1 .
13. A preparation method for the crystal form I according to claim 2 , characterized in that dissolving the compound (R)-2-[[7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl]methyl]benzonitrile in an organic solvent and increasing the temperature, then adding dropwise hydrochloric acid in a certain stoichiometric ratio thereto, thereafter stirring, filtering and drying to obtain the crystal form I of dihydrochloride salt of the compound.
14. A preparation method for the crystal form I according to claim 3 , comprising dissolving the compound (R)-2-[[7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl]methyl]benzonitrile in an organic solvent and increasing the temperature, then adding dropwise hydrochloric acid in a certain stoichiometric ratio thereto, thereafter stirring, filtering and drying to obtain the crystal form I of dihydrochloride salt of the compound.
15. The preparation method according to claim 13 , wherein the organic solvent is selected from lower alcohols containing 1-4 carbon atom(s), lower ketones containing 3-6 carbon atoms, acetonitrile, propionitrile or tetrahydrofuran.
16. The preparation method according to claim 14 , wherein the organic solvent is selected from lower alcohols containing 1-4 carbon atom(s), lower ketones containing 3-6 carbon atoms, acetonitrile, propionitrile or tetrahydrofuran.
17. A pharmaceutical composition, wherein it includes the crystal formal I of dihydrochloride salt of the compound represented by formula (1) according to claim 2 .
18. A pharmaceutical composition, wherein it includes the crystal formal I of dihydrochloride salt of the compound represented by formula (1) according to claim 3 .