Tetrahydrofuran → (1-(tert-Butoxycarbonyl)-4-(4-fluorophenyl)piperidin-4-yl)methyl 6-chloro-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate

HRID 913938Notes

Reaction equation

HRID 913938 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[O:13])[C:5]2[NH:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.C1(N(C)C2CCCCC2)CCCCC1.Cl[CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56].[O:59]1[CH2:63][CH2:62]C[CH2:60]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH2:15][C:16]2([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[O:13])[C:5]2[N:9]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[C:8](=[O:10])[N:7]([CH2:60][O:59][CH2:63][CH2:62][Si:55]([CH3:57])([CH3:56])[CH3:54])[C:6]=2[CH:11]=1

Participants

5

Reactant 4

HCID 8028TetrahydrofuranHCID 24210N-Methyl dicyclohexylamineHCID 27242712-Chloromethyl 2-(trimethylsilyl)ethyl etherHCID 57546031(1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperidin-4-yl)methyl 6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate

Product 1

HCID 57546185(1-(tert-Butoxycarbonyl)-4-(4-fluorophenyl)piperidin-4-yl)methyl 6-chloro-2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate

Procedure

To a solution of (1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperidin-4-yl)methyl 6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (0.5 g, 0.99 mmol) and N-cyclohexyl-N-methylcyclohexanamine (0.70 mL, 3.3 mmol) in tetrahydrofuran (6.5 mL) at 0° C. was added (2-(chloromethoxy)ethyl)trimethylsilane (0.56 mL, 3.2 mmol). After 5 min, the ice bath was removed and stirring continued at room temperature for 24 h. The reaction was allowed to stir overnight. The reaction was diluted with diethyl ether, washed with water, then 1M potassium bisulfate, then water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12%→25% ethyl acetate/n-hexane) gave 580 mg (76%) as an amorphous white foam solid. 1H-NMR (CDCl3, 500 MHz) δ 7.37 (dd, J=8.9, 5.2 Hz, 2H), 7.27 (d, J=2.1 Hz, 1H), 7.08 (m, 3H), 5.43 (s, 2H), 5.27 (s, 2H), 4.26 (s, 2H), 3.78 (m, 2H), 3.55 (t, J=8.1 Hz, 2H), 3.27 (t, J=8.1 Hz, 2H), 3.08 (m, 2H), 2.23 (m, 2H), 1.88 (m, 2H), 1.42 (s, 9H), 0.89 (t, J=8.2 Hz, 2H), 0.71 (t, J=8.1 Hz, 2H), −0.05 (s, 9H), −0.12 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 164.6, 161.7 (d, J=247 Hz), 154.9, 154.7, 137.1 (d, J=3.8 Hz), 131.3, 128.9 (d, J=7.7 Hz), 127.1, 125.4, 122.8, 116.9, 115.7 (d, J=20 Hz), 112.3, 79.7, 73.3, 71.9, 70.9, 66.5, 65.6, 40.6, 39.9, 32.2, 28.5, 17.8, 17.7, −1.3, ″1.4. Mass spec.: 786.00 (MNa)+.

Workup

  1. customthe ice bath was removed
  2. waitcontinued at room temperature for 24 h
  3. stirringto stir overnight
  4. additionThe reaction was diluted with diethyl ether
  5. washwashed with water
  6. dry with material1M potassium bisulfate, then water, then brine, dried over magnesium sulfate
  7. concentrationconcentrated
  8. customColumn chromatography (12%→25% ethyl acetate/n-hexane) gave 580 mg (76%) as an amorphous white foam solid

Sources & evidence

ORD record
ord-868b434594154b55bf5ef1e4816d0a3d
Source dataset
uspto-grants-2011_09
Patent number
US08026257B2

Reaction notes

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