Angiotensin II receptor 2 antagonist salt form and crystalline form, and preparation method therefor
View Patent ↗Disclosed are an angiotensin II receptor 2 (AT 2 R) antagonist salt form and crystalline form, a preparation method therefor, and an application of the salt form and crystalline form in preparing a drug which treats chronic pain.
1. Crystalline form “A” of a compound represented by formula (I), wherein an X-ray powder diffraction pattern of the crystalline form “A” has characteristic diffraction peaks at the following 2θ angles: 3.52±0.20°, 6.04±0.20°, and 18.21±0.20°
2. The crystalline form “A” according to claim 1 , wherein the X-ray powder diffraction pattern of the crystalline form “A” has characteristic diffraction peaks at the following 2θ angles: 3.52±0.20°, 6.04±0.20°, 14.40±0.20°, 15.11±0.20°, 18.21±0.20°, 18.46±0.20°, 20.12±0.20°, and 24.13±0.20°.
3. The crystalline form “A” according to claim 1 , wherein a differential scanning calorimetry curve of the crystalline form “A” has an endothermic peak starting at 155.36° C.±3° C.
4. The crystalline form “A” according to claim 1 , wherein a thermal gravimetric analysis curve of the crystalline form “A” has a weight loss of 0.1489% at 100.00° C.±3° C.
5. A method for preparing the crystalline form “A” of the compound represented by formula (I) according to claim 1 , comprising steps of:
(a) dissolving the compound represented by formula (I) in a mixed solvent to obtain a first mixture;
(b) stirring the first mixture at 30˜50° C. for 10-30 hours to obtain a second mixture; and
(c) filtering the second mixture to obtain a filter cake, and then drying the filter cake at 30-50° C. for 15-25 hours;
wherein, the mixed solvent is a mixture of acetone and water at a volume ratio of 1:(1.5-2.5).
6. Crystalline form “B” of a compound represented by formula (I), wherein an X-ray powder diffraction pattern of the crystalline form “B” has characteristic diffraction peaks at the following 2 θ angles: 6.08±0.20°, 12.12±0.20°, and 18.19±0.20°.
7. The crystalline form “B” according to claims. 6 , wherein a differential scanning calorimetry curve of the crystalline form “B” has an endothermic peak starting at 150.95° C.±3 20 C.
8. The crystalline form “B” according to claims 6 , wherein a thermal gravimetric analysis curve of the crystalline form “B” has a weight loss of 0.0558% at 120.00° C.±3° C.
9. A method for preparing the crystalline form “B” of the compound represented by formula (I) according to claim 6 , comprising steps of:
(a) adding the compound represented by formula (I) to a solvent to obtain a first suspension;
(b) stirring the first suspension at 35-45° C. for 30-60 hours to obtain a second suspension; and
(c) centrifuging the second suspension to obtain a filter cake, and then drying the filter cake for 8-16 hours;
wherein, the solvent is selected from the group consisting of methanol, ethanol and acetonitrile; or
the solvent is a mixture of acetone and water at a volume ratio of 3:2.
10. A method for the treatment of chronic pain, comprising a step of administering the crystalline form “A” according to claim 1 to a subject in need.
11. A method for the treatment of chronic pain, comprising a step of administering the crystalline form “B” according to claim 6 to a subject in need.
12. A method for preparing a compound represented by formula (I),
comprising steps of:
wherein,
R1 is selected from Cl, Br and I;
solvent F is selected from n-heptane, dichloromethane, tetrahydrofuran, cyclohexane and dioxane; and
reagent G is selected from silver oxide, magnesium sulfate, calcium sulfate and sodium sulfate.
13. The method according to claim 12 , comprising steps of:
wherein,
solvent H is selected from tetrahydrofuran, methanol and water;
reagent I is selected from lithium hydroxide monohydrate and sodium hydroxide;
solvent J is selected from dichloromethane;
catalyst K is selected from N,N-dimethylformamide;
reagent L is selected from oxalyl chloride;
solvent M is selected from dichloromethane;
reagent N is selected from pyrazole;
reagent O is selected from N-methylmorpholine;
solvent P is selected from N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane and tetrahydrofuran; and
reagent Q is selected from tetramethylguanidine, 1,8-diazabicycloundec-7-ene, triethylamine, diisopropylethylamine and 2,6-lutidine.
14. The method according to claim 13 , wherein a molar ratio of compound 1E to compound 1-0 is (1.2-5):1.
15. The method according to claim 13 , wherein a molar ratio of compound 1-4 to compound D1-1 is (1.1-1.5):1.
16. The method according to claim 13 , wherein reaction systems for preparing compounds 1-1, 1-2and 1-3 are controlled at a temperature of 25±5° C.
17. The method according to claim 13 , wherein preparing the compound 1-4 comprises steps a and b, wherein a reaction system in the step a is controlled to a temperature of 25±5° C.; and a reaction system in the step b is controlled to a temperature of 5±5° C. when feeding reagents into the reaction system, and the reaction system is controlled to a temperature of 25±5° C. after the reagents feeding is completed.
18. The method according to claim 13 , wherein the solvent F is selected from n-heptane, a ratio of n-heptane by volume to compound 1-0 by weight being (8.0-10.0):1, and the reagent G is selected from silver oxide and magnesium sulfate, a molar ratio of silver oxide and magnesium sulfate to compound 1-0 being (1.0-5.0):1.
19. The method according to claim 12 , wherein the reagent G is fed in batches.
20. The method according to claim 13 , wherein the solvent H is a mixture of tetrahydrofuran and water at a volume ratio of (1-2):1, the reagent I is lithium hydroxide monohydrate, wherein a molar ratio of lithium hydroxide monohydrate to compound 1-0 is (1.0-2.0):1, a weight ratio of solvent J to compound 1-3 is 10:1, a molar ratio of catalyst K to compound 1-3 is (0.002-0.004):1, a molar ratio of reagent L to compound 1-3 is (1.2-2.0):1, a weight ratio of solvent M to compound 1-3 is (6-10):1, a molar ratio of reagent N to compound 1-3 is (1.0-1.5):1, and a molar ratio of reagent O to compound 1-3 is (1.0-1.5):1; and solvent P is selected from N,N-dimethylformamide, wherein a weiht ratio of N,N-dimethylformamide to compound 1-4 is 10:1; and the reagent Q is selected from tetramethylguanidine, wherein a molar ratio of tetramethylguanidine to compound 1-4 is (1-1.2):1.
21. The crystalline form “B” according to claim 6 , wherein the X-ray powder diffraction pattern of the crystalline form “B” has characteristic diffraction peaks at the following 2θ angles: 6.08±0.20°, 12.12±0.20°, 18.19±0.20°, 24.31±0.20°, and 30.50±0.20°.
22. The crystalline form “B” according to claim 6 , wherein the X-ray powder diffraction pattern of the crystalline form “B” has characteristic diffraction peaks at the following 2θ angles: 3.52±0.20°, 6.08±0.20°, 9.25±0.20°, 12.12±0.20°, 14.00±0.20°, 18.19±0.20°, 24.31±0.20°, and 30.50±0.20°.