Tetrahydropyridinyl and Dihydropyrrolyl Compounds and the Use Thereof
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example 1
N-Cyclopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)picolinamide hydrochloride (5)
[0363]
[0364]a) To a stirred suspension of compound 1 (500 mg, 3.18 mmol, Aldrich), 1-hydroxybenzotriazole hydrate (HOBt) (430 mg, 3.18 mmol, Aldrich), and N-(3-dimethylaminopropyl)N′ethylcarbodiimide hydrochloride (EDCl) (672 mg, 3.50 mmol, Aldrich) in dichloromethane was added sequentially diisopropyl ethyl amine (1.1 ml, 6.4 mmol) and cyclopropyl amine (245 μl, 3.5 mmol, Aldrich). The resulting mixture was slowly warmed to room temperature and stirred for 12 hours. The crude mixture was purified on CombiFlash® (Teledyne Isco, Inc., Lincoln, Nebr.) with a gradient of 20% to 80% EtOAc in hexane to provide compound 2 as a white solid (483 mg, yield 77%).
[0365]b) The suspension of compound 2 (180 mg, 0.92 mmol), 3,6-dihydro-2H-pyridine-1-tert-butoxycarbonyl-4-boronic acid pinacol ester (3) (284 mg, 0.92 mmol, Carbocore), potassium carbonate (254 mg, 1.84 mmol) and palladium bistriphenylphosphine dichloride (...
example 2
1′-(3-Trifluoromethylbenzenesulfonyl)-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-carboxylic acid cyclopropylamide (7)
[0367]
[0368]Diisopropyl ethyl amine (66 ml, 0.36 mmol) and 3-(trifluoromethyl)benzene sulfonyl chloride (6) (44 mg, 0.18 mmol, Aldrich) were sequentially added to a suspension of compound 5 (50 mg, 0.18 mmol) in dichloromethane at 0° C. while stirring. The reaction was completed within 0.5 hour and the crude product was purified without work-up on CombiFlash® with a gradient of 50-100% EtOAc in hexane to provide the title compound 7 as a white solid (50 mg, yield 64%). 1H NMR (400 MHz, CD3OD): δ 8.15 (m, 2H), 8.02-7.83 (m, 4H), 7.67 (dd, 1H, J=1.2, 7.6 Hz), 6.78 (m, 1H), 3.92 (m, 2H), 3.45 (m, 2H), 2.87 (m, 1H), 2.77 (m, 2H), 0.86 (m, 2H), 0.70 (m, 2H); MS: 452 (M+H+), 474 (M+Na).
[0369]Similarly, the following compounds were prepared by reacting compound 5 with an appropriate reagent (in parenthesis):
[0370]1′-(4-Trifluoromethoxybenzenesulfonyl)-1′,2′,3′,6′-tetrahydro-...
example 3
[0390]1′-(4-Trifluoromethoxybenzyl)-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-carboxylic acid cyclopropylamide (9)
[0391]1′-(4-Trifluoromethoxybenzyl)-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-carboxylic acid cyclopropylamide (9) was prepared by adding diisopropyl ethyl amine to a suspension of compound 5 (72 mg, 0.25 mmol), 4-trifluoromethoxybenzaldehyde (8) (Aldrich) and 3 Å molecular sieves (200 mg, Aldrich). The mixture was stirred for 12 hours and NaCNBH3 was added. The crude product was filtered and then purified on Prep TLC (10% MeOH in dichloromethane with 1% NH4OH) to provide the title compound 9 (25 mg, yield 23%): 1H NMR (400 MHz, CD3OD, HCl-salt): δ 8.48 (bd, 1 h, NH), 7.88 (d, 1H, J=7.6 Hz), 7.83 (t, 1H, J=7.6 Hz), 7.65 (d, 1H, J=7.6 Hz), 7.57 (m, 2H), 7.32 (d, 2H, J=8.8 Hz), 6.68 (m, 1H), 4.39 (m, 2H), 3.85 (m, 2H), 3.68 (m, 1H), 3.26 (m, 1H), 3.12 (m, 1H), 2.82 (m, LH), 2.71 (m, 1H), 0.72 m, 2H), 0.54 (m, 2H); MS: 418.
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