Trimethylacetamide → HCID 178432101, compound

HRID 1992092Notes

Reaction equation

HRID 1992092 reaction equation
[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].[H-].[Na+].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=S)=[CH:13][CH:12]=1.[CH3:20][C:21]1[N:25]([CH:26]2[CH2:32][CH:31]3[N:33]([CH2:34][CH2:35][C:36]4([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[CH:28]([CH2:29][CH2:30]3)[CH2:27]2)[C:24]2[CH:48]=[CH:49][CH:50]=[CH:51][C:23]=2[N:22]=1.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17]/[C:18](/[N:39]2[CH2:38][CH2:37][C:36]([CH2:35][CH2:34][N:33]3[CH:28]4[CH2:29][CH2:30][CH:31]3[CH2:32][CH:26]([N:25]3[C:24]5[CH:48]=[CH:49][CH:50]=[CH:51][C:23]=5[N:22]=[C:21]3[CH3:20])[CH2:27]4)([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:41][CH2:40]2)=[N:5]\[C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[CH:13][CH:12]=1

Participants

8

Reactant 5

HCID 12957TrimethylacetamideHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 164804-Chlorophenyl isothiocyanateHCID 24758Sodium hydrideHCID 587278272-Methyl-1-{8-[2-(4-phenyl-4-piperidinyl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole

Product 1

HCID 178432101HCID 178432101, compoundYield 38%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent

Procedure

To a solution of trimethylacetamide (10 mg, 0.1 mmol) in DMF (0.5 mL) was added sodium hydride (60%, 5.2 mg, 0.13 mmol). After stirring for 5 minutes, 4-chlorophenylisothiocyanate (17 mg, 0.1 mmol) was added. The reaction mixture was stirred at 60° C. for one hour before being cooled down to room temperature. To this reaction mixture was then added 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]-oct-3-yl}-1H-benzimidazole (35 mg, 0.08 mmol), EDCI (19 mg, 0.1 mmol) and a catalytic amount of DMAP. After stirring at ambient temperature overnight, the reaction was quenched with water and extracted with dichloromethane (4×10 mL). The organic phase was washed with brine and dried over sodium sulfate. The solvent was removed and the residue was purified by flash chromatography on silical gel, eluting with a gradient of 0-15% methanol in ethyl acetate to afford N-[(1E)-[(4-chlorophenyl)amino](4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl) methylidene]-2,2-dimethylpropanamide as amorphous solid (20 mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ 8.9 (s, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.39-7.33 (m, 6H), 7.22-7.19 (m, 1H), 7.13-7.05 (m, 3H), 6.61 (d, J=8.6 Hz, 2H), 4.51-4.47 (m, 1H), 3.80-3.40 (m, 2H), 3.26-3.13 (m, 4H), 2.46 (s, 3H), 2.37-2.30 (m, 2H), 2.14 (br, 2H), 1.85-1.71 (m, 10H), 1.56 (d, J=7.4 Hz, 2H), 0.88 (s, 9H). HRMS m/z (M+H)+ calcd: 665.3735, obsd: 665.3741.

Workup

  1. stirringThe reaction mixture was stirred at 60° C. for one hour
  2. stirringAfter stirring at ambient temperature overnight
  3. customthe reaction was quenched with water
  4. extractionextracted with dichloromethane (4×10 mL)
  5. washThe organic phase was washed with brine
  6. dry with materialdried over sodium sulfate
  7. customThe solvent was removed
  8. customthe residue was purified by flash chromatography on silical gel
  9. washeluting with a gradient of 0-15% methanol in ethyl acetate

Sources & evidence

ORD record
ord-5428d4d3462e4f36963003d1270dc9c7
Source dataset
uspto-grants-2010_01
Patent number
US07645771B2

Reaction notes

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