Sodium hydride → 1-(((5S,7S)-3-((5-ethoxypyrazin-2-yl)methyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

HRID 715541Notes

Reaction equation

HRID 715541 reaction equation
[CH3:1][C@:2]1([CH2:13][N:14]2[C:18]3[CH:19]=[C:20]([C:23]#[N:24])[CH:21]=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH2:12][CH2:11][CH2:10][C@:4]2([O:8][C:7](=[O:9])[NH:6][CH2:5]2)[CH2:3]1.[H-].[Na+].Br[CH2:28][C:29]1[CH:34]=[N:33][C:32]([O:35][CH2:36][CH3:37])=[CH:31][N:30]=1>CN(C)C=O.[NH4+].[Cl-]>[CH2:36]([O:35][C:32]1[N:33]=[CH:34][C:29]([CH2:28][N:6]2[CH2:5][C@@:4]3([CH2:10][CH2:11][CH2:12][C@@:2]([CH2:13][N:14]4[C:18]5[CH:19]=[C:20]([C:23]#[N:24])[CH:21]=[CH:22][C:17]=5[N:16]=[CH:15]4)([CH3:1])[CH2:3]3)[O:8][C:7]2=[O:9])=[N:30][CH:31]=1)[CH3:37]

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 712269671-(((5S,7S)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrileHCID 867175972-(Bromomethyl)-5-ethoxypyrazine

Product 1

HCID 712276351-(((5S,7S)-3-((5-ethoxypyrazin-2-yl)methyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrileYield 58.8%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 25517Ammonium ChlorideSolvent

Procedure

To a solution of 1-{[(5S,7S)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile (150 mg, 0.462 mmol) in N,N-Dimethylformamide (DMF) (2 mL) was added 60% sodium hydride in mineral oil (24.04 mg, 0.601 mmol) and stirred for 30 minutes. To the mixture was added 2-(bromomethyl)-5-ethoxypyrazine (120 mg, 0.555 mmol) and stirred overnight. The reaction was diluted with saturated NH4Cl and extracted with ethyl acetate (3×). The combined organic extracts were washed with saturated NaCl (2×), dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel ISCO chromatography (40 g silica gel, 40 mL/min, 0-10% MeOH/CH2Cl2 over 25 min) to afford 1-(((5S,7S)-3-((5-ethoxypyrazin-2-yl)methyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (125 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.35 (d, J=0.75 Hz, 1H), 8.21 (d, J=1.25 Hz, 1H), 8.13 (d, J=1.51 Hz, 1H), 7.83 (d, J=8.28 Hz, 1H), 7.59 (dd, J=8.28, 1.51 Hz, 1H), 4.31-4.41 (m, 4H), 4.12 (s, 2H), 3.21 (dd, J=23.09, 9.03 Hz, 2H), 1.81 (d, J=13.30 Hz, 1H), 1.49-1.74 (m, 4H), 1.22-1.46 (m, 6H), 1.02 (s, 3H). MS (m/z) 461.2 (M+H+).

Workup

  1. stirringstirred overnight
  2. extractionextracted with ethyl acetate (3×)
  3. washThe combined organic extracts were washed with saturated NaCl (2×)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified via silica gel ISCO chromatography (40 g silica gel, 40 mL/min, 0-10% MeOH/CH2Cl2 over 25 min)

Sources & evidence

ORD record
ord-a5d5c83e7e0047849618ce7c1c6ede18
Source dataset
uspto-grants-2015_11
Patent number
US09187464B2

Reaction notes

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