Novel Renin Inhibitors
A halogen and group technology, applied in the field of new compounds, can solve the problem of not involving the details of morpholine compounds, and achieve the effect of excellent renin inhibition
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Embodiment 1
[0286] [Chemical formula 5]
[0287]
[0288] (1) Add (3-{3-[(1R)-1-(cyclopropylamino)ethyl]-6-methyl-1H-pyrazolo[3,4-b]pyridine- 1-yl}propyl)carbamate (4.00g), and (2R,6S)-4-(tert-butoxycarbonyl)-6-(methoxymethyl)morpholine-2-carboxylic acid (3.66 g) g) To a solution of N,N-dimethylformamide (80 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.45 g), 1-hydroxyl Benzotriazole (1.63 g) was then stirred at room temperature for 5 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic phase was washed with water and saturated brine in this order, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=1 / 1→ethyl acetate) to obtain (2R,6S)-2-{cyclopropyl[(1R) )-1-(1-{3-[(methoxycarbonyl)amino]propyl}-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)ethyl]aminomet...
Embodiment 2
[0293] [Chemical formula 6]
[0294]
[0295] (1) To (2R,6S)-4-(tert-butoxycarbonyl)-6-(methoxymethyl)morpholine-2-carboxylic acid (7.59 g) in dichloromethane (70 mL) under ice-cooling To the solution, diisopropylethylamine (9.60 mL) and diphenyl chlorophosphate (5.71 mL) were added, followed by stirring under ice-cooling for 15 minutes. Under ice-cooling, methyl (3-{4-[(1R)-1-(cyclopropylamino)ethyl]-6-methoxypyridin-2-yl}propyl)carbamate (5.65 g) was added dropwise. ) in dichloromethane (20 mL), and then stirred at room temperature for 20 hours. Under ice-cooling, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, followed by extraction with chloroform. The organic phase was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=1 / 1→ethyl acetate) to obtain (2R,6S)-2-{cyclopropyl[(1R) )-1-...
Embodiment 3
[0300] [Chemical formula 7]
[0301]
[0302] (1) Under nitrogen flow and ice cooling, to a dichloromethane solution (20 mL) of (2R,6S)-4-(tert-butoxycarbonyl)-6-(methoxycarbonyl)morpholine-2-carboxylic acid (289 mg) ), diisopropylamine (523 μL) and diphenyl chlorophosphate (415 μL) were added, followed by stirring under ice cooling for 30 minutes, after which (3-{2-bromo-5-[(1R)-1-(cyclohexane) was added A solution of methyl propylamino)ethyl]thiophen-3-yl}propyl)carbamate (361 mg) in dichloromethane (3 mL) was stirred at room temperature for 4 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, followed by extraction with chloroform. The organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate=75 / 25→40 / 60) to obtain (2S,6R)-6-{[(1R)-1 -(5-Bromo...
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