Salt, solvate and polymorphic substance of benzazepine derivative, and preparation method and application of salt, solvate and polymorphic substance of benzazepine derivative
A crystal form and compound technology, applied in the field of salts of benzazepine derivatives, can solve the problems of poor solubility and stability, and achieve the best absorption and metabolism effect
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Embodiment 1
[0155] Example 1 2-amino-8-(2-(2-(methylsulfonyl)ethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-N,N-diisopropyl Synthesis of yl-3H-benzazepine-4-carboxamide (Compound A)
[0156] method 1:
[0157]
[0158] Step 1: To a solution of compound 1.10 (2.1 g, 1 eq) in tetrahydrofuran (90 mL) under nitrogen protection, compound 22.7 (2.7 g, 1.5 eq), aqueous sodium carbonate solution (29.2 mL, 2.0 M) and Pd(dppf) were sequentially added 2 Cl 2 (369 mg, 0.1 equiv), the addition was complete, the reaction system was replaced with nitrogen three times, and the reaction system was stirred at 70°C until the reaction was complete by TLC (about 1.5 hours). Water (50 mL) was added to the reaction system to quench the reaction, the mixture was extracted with ethyl acetate (150 mL×3), the organic phases were combined, the organic phases were washed with saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, After concentration, the obtained residue was ...
Embodiment 2
[0161] Example 2 Crystal Form I of Compound A
[0162]Compound A (1 g) was added to absolute ethanol (40 mL), sonicated for 5-10 minutes after dissolving, and the solid was precipitated and stirred for 1 hour, filtered, and the filter cake was vacuum-dried at room temperature overnight to obtain compound A, which was an off-white solid, It is the crystalline form I of compound A. And carried out XRPD, DSC, TGA and 1 H NMR characterization, the results were as follows figure 2 , image 3 , Figure 4 and Figure 5 shown.
Embodiment 3
[0163] Example 3 The acetic acid solvate crystal form I of compound A
[0164] Compound A (1 g, 1 eq) was dissolved in a mixed solvent of dichloromethane (8 mL) and methanol (4 mL), acetic acid (224 mg, 2 eq) was added, the resulting solution was stirred at room temperature for 0.5 hours, and then ethyl acetate (20 mL) was added to continue After stirring for 1 hour for crystallization, the obtained solid was vacuum-dried at 50° C. for 4 hours to obtain the corresponding acetic acid solvate crystal form I of Compound A. The samples were off-white powders, and were subjected to XRPD, DSC, TGA and 1 H NMR characterization.
[0165] like Figure 9 shown, 1 H NMR results showed that the sample had no solvent residue and the ratio of free base to acetic acid was approximately 1:1. like Figure 8 As shown, TGA had a weight loss of 10.16% before 175°C. like Figure 7 As shown, the DSC spectrum shows that the temperature of its endothermic peaks is about 167.21°C and 238.50°C. ...
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