Dimethylformamide → 1-[4-(2-(Azepan-1-yl)ethoxy)benzyl]-5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indole

HRID 1862561Notes

Reaction equation

HRID 1862561 reaction equation
[H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:22][CH:21]=1)=[C:14]2[CH3:34])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:35](Cl)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CCO[C:46]([CH3:48])=[O:47].[CH3:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54].C[N:56](C=O)C>O>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:47][CH2:46][CH2:48][N:56]3[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)=[CH:38][CH:37]=1)[C:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:22][CH:21]=1)=[C:14]2[CH3:34])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1

Participants

7

Reactant 5

HCID 6228Dimethylformamide2×HCID 7503Benzyl ChlorideHCID 24758Sodium hydrideHCID 38247451H-Indole, 3-methyl-5-(phenylmethoxy)-2-[4-(phenylmethoxy)phenyl]-HCID 21226206Ethyl acetate hexane

Product 1

HCID 98958311-[4-(2-(Azepan-1-yl)ethoxy)benzyl]-5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indoleYield 76%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

To a slurry of NaH (20.0 g, 60% oil dispersion, 0.5 mol, 2.5 eq.) solution of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole (84 g, 0.2 mol, 1.0 eq.) in DMF (100 mL) was added at 0/+10° C. over 1 h. The reaction mixture was stirred for 30 min. A solution of the benzylchloride (synthesis shown in scheme 7 and details given in the following experimental) (67 g, 0.22 mol, 1.1 eq.) in DMF (200 mL) was added dropwise at 0/+10° C. over 2 h. The reaction mixture was stirred at 25° C. for 2 h. TLC at this point showed no starting material, mostly product (EtOAc/hexane 1:5). The reaction mixture was diluted with water (1 L), extracted with EtOAc (3×1 L), and dried over MgSO4. The solution was concentrated to 150 mL, poured in MeOH (750 mL), and stirred overnight. The precipitate was filtered and dried to give the title compound (99 g, 76%): Mp=106-107° C.; 1H NMR (DMSO) δ 7.47 (d, 4 H, J=8.3 Hz), 7.41-7.36 (m, 4 H), 7.36-7.30 (m, 2 H), 7.29 (d, 2 H, J=8.8 Hz), 7.19 (d, 1 H, J=8.8 Hz), 7.14-7.10 (m, 3 H, 6.80 (dd, 1 H, J=8.8 Hz), 6.73 (s, 4 H),5.15 (s, 2 H), 5.13 (s, 2 H), 5.11 (s, 2 H), 3.90 (t, 2 H, J=5.9 Hz), 2.76 (t, 2 H, J=5.9 Hz), 2.64-2.56 (m, 4 H), 2.15 (s, 3 H), 1.58-1.44 (m, 8 H); MS FAB m/z 651 (M+H+).

Workup

  1. additionwas added dropwise at 0/+10° C. over 2 h
  2. stirringThe reaction mixture was stirred at 25° C. for 2 h
  3. extractionextracted with EtOAc (3×1 L)
  4. dry with materialdried over MgSO4
  5. concentrationThe solution was concentrated to 150 mL
  6. additionpoured in MeOH (750 mL)
  7. stirringstirred overnight
  8. filtrationThe precipitate was filtered
  9. customdried

Sources & evidence

ORD record
ord-bf71f0fdcacb45278c2d21edeec814ee
Source dataset
uspto-grants-2003_03
Patent number
US06537971B2

Reaction notes

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