Triethylamine → 1-(8-{2-[1-(isoxazol-3-ylcarbonyl)-4-phenylpiperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole

HRID 1992081Notes

Reaction equation

HRID 1992081 reaction equation
Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.[O:35]1[C:39](C(Cl)=O)=[CH:38][CH:37]=[N:36]1.C(N(CC)CC)C.[C:50](OCC)(=[O:52])C>ClCCl>[O:35]1[CH:39]=[CH:38][C:37]([C:50]([N:22]2[CH2:21][CH2:20][C:19]([CH2:18][CH2:17][N:16]3[CH:14]4[CH2:13][CH2:12][CH:11]3[CH2:10][CH:9]([N:8]3[C:7]5[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=5[N:5]=[C:4]3[CH3:3])[CH2:15]4)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:24][CH2:23]2)=[O:52])=[N:36]1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 8857Ethyl AcetateHCID 2736707Isoxazole-5-carbonyl chlorideHCID 686757782-methyl-1-{8-[2-(4-phenyl piperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride

Product 1

HCID 587287631-(8-{2-[1-(isoxazol-3-ylcarbonyl)-4-phenylpiperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazoleYield 68%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a pre-cooled (0° C.) solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride (25.3 mg, 0.05 mmol) in dichloromethane (3 mL) was added isoxazole-5-carbonyl chloride (7.2 mg, 0.055 mmol) and triethylamine (15 μL, 0.11 mmol). The resulting mixture was stirred overnight at ambient temperature and was then diluted with ethyl acetate (20 mL). After being washed with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate and evaporated. The crude product was purified by flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford 1-(8-{2-[1-(isoxazol-3-ylcarbonyl)-4-phenylpiperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole as amorphous solid (18.4 mg, 68%). 1H NMR (300 MHz, CDCl3) δ 8.32 (d, J=1.8 Hz), 7.67 (dd, J=2.6, 7.0 Hz, 1H), 7.43-7.38 (m, 2H), 7.34-7.24 (m, 4H), 7.21-7.13 (m, 2H), 6.74 (d, J=1.8 Hz), 4.64 (br, 1H), 4.23-4.18 (m, 1H), 3.93-3.89 (m, 1H), 3.45-3.27 (m, 4H), 2.58 (s, 3H), 2.44-2.31 (m, 4H), 1.96-1.86 (m, 10H), 1.67-1.60 (m, 2H). HRMS m/z (M+H)+ calcd: 524.3026, obsd: 524.3024.

Workup

  1. washAfter being washed with saturated sodium bicarbonate solution
  2. dry with materialthe organic phase was dried over anhydrous sodium sulfate
  3. customevaporated
  4. customThe crude product was purified by flash chromatography on silical gel
  5. washeluting with a gradient of 0-10% methanol in ethyl acetate

Sources & evidence

ORD record
ord-9a8c1f1dd29349749ff08d13de947e74
Source dataset
uspto-grants-2010_01
Patent number
US07645771B2

Reaction notes

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