Spirochromane derivatives
A technology of compounds and hydrates, which can be used in drug combinations, organic active ingredients, nervous system diseases, etc., and can solve the problem of suboptimal clinical efficacy
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Embodiment 1
[0571]
[0572] 6'-fluoro-N-[(2-methyl-1H-indol-5-yl)methyl]-4'-oxo-3',4'-dihydrospiro[azetidine-3,2 '-[1]benzopyran]-1-carboxamide
[0573] Add 4-nitrophenyl chloroformate (1020 mg, 5.06 mmol) to 800 mg (5.0 mmol) of 2-(methyl-1H-indol-5-yl)methanamine (intermediate 26) at 0 °C under argon atmosphere ) and 1.295g (1.75mL, 10mmol) of DIPEA in 120mL of dichloromethane (CH 2 Cl 2 )mixture. The pale yellow suspension was stirred under these conditions for 1 hour. After the pot life, 6'-fluoro-3',4'-dihydrospiro[azetidine-3,2'-[1]benzopyran]-4'-one hydrochloride (1.22 g, 5 mmol , Intermediate 6) and 1.75 mL DIPEA (7.75 mmol) in 30 mL CH 2 Cl 2 in the mixture. After the addition, the mixture was allowed to warm to room temperature and stirred at this temperature for 22 hours. After completion of the reaction (monitored by TLC), the mixture was washed with water (2 x 40 mL), followed by brine. The organic layer was washed with anhydrous Na 2 SO 4 Dry, filter and concen...
Embodiment 66b
[0589]
[0590] 6'-Chloro-N-[(2-methyl-1H-indol-5-yl)methyl]-4'-oxo-3',4'-dihydrospiro[azetidine-3,2 '-[1]benzopyran]-1-carbothioamide (carbothioamide)
[0591] 1,1'-thiocarbonyl-diimidazole (98 mg, 0.55 mmol) was added to 80.1 mg (0.5 mmol) of 2-(methyl-1H-indol-5-yl)methanamine ( Intermediate 28) in 2 mL of DMF. The tan solution was stirred under these conditions for 1 hour. After the activation period, 6'-chloro-3',4'-dihydrospiro[azetidine-3,2'-[1]benzopyran]-4'-one hydrochloride (130mg, 0.5mmol , a mixture of intermediate 1) and 0.131 mL of DIPEA (0.75 mmol) in 2 mL of DMF, and the mixture was stirred at this temperature for 20 hours. After completion of the reaction (monitored by TLC), the mixture was poured into water (8 mL) and extracted with EtOAc (2 x 15 mL). The organic layer was washed with anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. The residue was placed on silica gel with CH 2 Cl 2 Chromatography was performed eluting with a mixture of ...
Embodiment 71c
[0593]
[0594] 7'-fluoro-N-[(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)methyl]-4'-oxo-3',4'-dihydrospiro [Azetidine-3,2'-[1]benzopyran]-1-carboxamide
[0595] Add 4-nitrophenyl chloroformate (111 mg, 0.55 mmol) to 88 mg (0.5 mmol) of 1-(1-methyl-1,2,3,4-tetrahydroquinoline- 6-yl)methylamine (Intermediate 39) and 175 μL (1.0 mmol) of DIPEA in 20 mL of dichloromethane (CH 2 Cl 2 ) in the mixture. The pale yellow suspension was stirred under these conditions for 1.5 hours. After the activation period, 7'-fluoro-3',4'-dihydrospiro[azetidine-3,2'-[1]benzopyran]-4'-one hydrochloride (122mg, 0.5mmol , Intermediate 19) and 131 μL DIPEA (0.75 mmol) in 5 mL CH 2 Cl 2 in the mixture. After the addition, the mixture was allowed to warm to room temperature and stirred at this temperature for 24 hours. After completion of the reaction (monitored by TLC), the mixture was washed with water (2 x 20 mL), followed by brine. The organic layer was washed with anhydrous Na 2 SO 4 Dry,...
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