Quinuclidines-substituted-multi-cycli-heteroaryls for treatment of disease
A technology of compounds and substituents, applied in the field of quinuclidine-substituted polycyclic heteroaryl compounds for the treatment of diseases, capable of solving problems such as calcium ion blockade
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Embodiment 1
[0235] Example 1: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2,3-dihydrofuro[2,3-c]pyridine-5-carboxamide Dihydrochloride:
[0236]
[0237] Acid preparation:
[0238] 2-chloro-3-pyridinol (20.0g, 0.154mol), NaHCO 3 (19.5g, 0.232mol, 1.5equ) and 150ml of water were placed in the flask. Place the flask in an oil bath at 90°C, and after 5 minutes, add six different doses of 37% aqueous formaldehyde (40.5ml, 0.541mol, 3.5equ) in the following order: 12ml, 3×8ml and then 2.2ml, all A final 2.3 ml was added after 90 minute intervals followed by stirring at 90°C for 15 hours. The reaction was stirred at 90°C for an additional 4 hours, then the flask was cooled in an ice bath. The pH of the reaction was then adjusted to 1 with 6N HCl. The reaction was stirred in an ice bath for 1.5 hours, an unwanted solid formed. Unwanted solids were removed by filtration and the filtrate was extracted seven times with EtOAc. Combine the organic extracts, concentrate in vacuo, add toluene to the...
Embodiment 2
[0247] Example 2: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[3,2-c]pyridine-2-carboxamide:
[0248]
[0249] Acid preparation:
[0250] Add 4-hydroxypyridine (23.8g, 250mmol) and Na to 80ml of water 2 CO 3 (7.4 g, 70 mmol). The reaction mixture was heated to reflux, and 250 ml of an aqueous solution of iodine (23.2 g, 92 mmol) and potassium iodide (80 g, 482 mmol) was slowly added dropwise. After the addition, the reaction was refluxed for 1 hour. The mixture was filtered hot to remove by-products, the filtrate was cooled to room temperature, solids were removed and dried to give 3-iodo-4-pyridinol (C10) (32% yield). C 5 h 4 The HRMS (FAB) calculated value of INO+H is 221.9418, and the measured value is 221.9416 (M+H) + .
[0251] in N 2 To a suspension of triphenylphosphine (166mg, 0.63mmol) and palladium acetate (71mg, 0.32mmol) in 25ml DMF in a dry flask was added C10 (3.5g, 15.8mmol). Propionaldehyde diethyl acetal (2.3ml, 15.8mmol), cuprous iodide (120mg, 0.63m...
Embodiment 3
[0256] Example 3: N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-chlorofuro[2,3-c]pyridine-5-carboxamide hydrochloride :
[0257]
[0258] Method B:
[0259] Acid C7 (435mg, 2.2mmol) and TEA (307μl, 2.2mmol) in CH 2 Cl 2 (10ml) was stirred until dissolved, diphenylphosphoryl azide (431μl, 2.0mmol) was added, and the reaction was stirred at room temperature for 20 minutes. Add R-(+)-3-aminoquinucidine (252 mg, 2.0 mmol) in 2 Cl 2 (3 mL) solution and the reaction was stirred at room temperature for 18 hours. The solution was diluted with MeOH and loaded on an AG 50W-X2 resin column (hydrogen form). The column was flushed with MeOH and the product was eluted with 5% TEA / MeOH solution onto an AMBERJET 4400 OH resin column. The eluted product was concentrated to an oil. The crude product was purified by chromatography on 25 g of slurry packed silica gel with 0.3% ammonium hydroxide / 4% MeOH / CH 2 Cl 2 , then with 0.5% Ammonium Hydroxide / 5% MeOH / CH 2 Cl 2 , and finally with 0.5...
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