Crystals of Disspiropyrrolidine Derivatives
A technology of crystallization and pyran, applied in the field of crystallization of disspiropyrrolidine compounds or their salts, can solve the problems of p53 function inactivation, canceration, etc.
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Embodiment 1
[0132] [Formula 3]
[0133]
[0134] (3'R,4'S,5'R)-N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6''-chloro-4'-(2 -Chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'- Pyrrolidine-3',3''-indole]-5'-carboxamide
[0135] The compound obtained in Step 3 of Reference Example 2 (35 mg, 0.24 mmol), triethylamine (0.04ml, 0.30 mmol), 1-hydroxybenzotriazole (27 mg, 0.20 mmol) and 1-ethane Dimethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (46 mg, 0.24 mmol) was added to the N of the compound (100 mg, 0.20 mmol) obtained in Step 3 of Reference Example 1 , N-dimethylformamide (4 ml) solution, and the resulting mixture was stirred at 50°C for 1 hour. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution and brine in that order, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by NH-silica g...
Embodiment 1-1
[0139] A trichlorethylene / ethanol mixture (95 / 5) (4.75 ml) was added to the compound obtained in Example 1 (302 mg, 0.49 mmol), and the resulting mixture was heated to about 50°C for dissolution. The reaction mixture was left standing at room temperature to precipitate crystals. Precipitated crystals were collected by filtration, and dried at room temperature to obtain crystals. The crystals were subjected to X-ray powder diffraction, simultaneous thermogravimetry and differential thermal analysis (TG / DTA), and measurements of adsorption and desorption behavior.
[0140] Alternatively, crystals can also be obtained using ethyl formate and acetonitrile.
[0141] The X-ray powder diffraction pattern is shown in figure 1 , the adsorption-desorption isotherm is shown at Figure 10 , and thermal analysis data (TG / DTA) are displayed in Figure 17 middle.
[0142] [Table 1]
[0143] Peaks in X-ray powder diffraction pattern (relative intensity of 22 or higher)
[0144]
Embodiment 1-2
[0146] Methanol (3.6 ml) was added to the compound obtained in Example 1 (301 mg, 0.49 mmol), and the resulting mixture was heated to about 50°C for dissolution. The reaction mixture was left standing at room temperature to precipitate crystals. Precipitated crystals were collected by filtration, and dried at room temperature to obtain crystals. The crystals were subjected to measurements of X-ray powder diffraction, TG / DTA, and adsorption and desorption behavior.
[0147] Alternatively, crystals can also be obtained using 2-butanone.
[0148] The X-ray powder diffraction pattern is shown in figure 2 , the adsorption-desorption isotherm is shown at Figure 11 , and thermal analysis data (TG / DTA) are displayed in Figure 18 middle.
[0149] [Table 2]
[0150] Peaks in X-ray powder diffraction pattern (relative intensity of 14 or higher)
[0151]
PUM
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