Trifluoroacetic acid → 6-(adamantan-1-ylmethoxy)-5-cyclopropyl-N-(N-methylsulfamoyl)nicotinamide

HRID 1849697Notes

Reaction equation

HRID 1849697 reaction equation
[C:1]12([CH2:11][O:12][C:13]3[C:25]([CH:26]4[CH2:28][CH2:27]4)=[CH:24][C:16]([C:17](OC(C)(C)C)=[O:18])=[CH:15][N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.FC(F)(F)C(O)=O.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:48][NH:49][S:50]([NH2:53])(=[O:52])=[O:51].N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>ClCCl.C(OCC)(=O)C>[C:1]12([CH2:11][O:12][C:13]3[C:25]([CH:26]4[CH2:28][CH2:27]4)=[CH:24][C:16]([C:17]([NH:53][S:50](=[O:52])(=[O:51])[NH:49][CH3:48])=[O:18])=[CH:15][N:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2

Participants

8

Reactant 5

HCID 6422Trifluoroacetic acidHCID 5250894Bis-(1H-imidazol-2-YL)-methanoneHCID 13168287(Methylsulfamoyl)amineHCID 86703569Tert-butyl 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinateHCID 1296629601,8-Diazabicycloundec-7ene

Product 1

HCID 867035686-(adamantan-1-ylmethoxy)-5-cyclopropyl-N-(N-methylsulfamoyl)nicotinamideYield 22%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of tert-butyl 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinate (0.50 g, 1.30 mmol) in dichloromethane (20 mL) was treated with trifluoroacetic acid (5.0 mL). The resulting mixture was stirred for 30 minutes and then concentrated in vacuo. The residue was treated with methanol (20 mL) and concentrated in vacuo. The residue was dissolved in anhydrous tetrahydrofuran (20 mL), treated with carbonyl diimidazole (0.42 g, 2.60 mmol), and refluxed under nitrogen for 30 min. The reaction mixture was cooled to ambient temperature and added (methylsulfamoyl)amine (0.43 g, 3.90 mmol) and 1,8-diazabicycloundec-7-ene (0.58 mL, 3.90 mmol). The reaction mixture was refluxed under nitrogen for 30 minutes. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (50 mL), washed with 1 M aqueous hydrochloric acid solution (2×30 mL) and brine (30 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) to provide the title compound (0.12 g, 22%): 1H NMR (300 MHz, DMSO-d6) δ 11.65 (br s, 1H), 8.46 (d, J=2.3 Hz, 1H), 7.73 (d, J=2.3 Hz, 1H), 7.58-7.51 (m, 1H), 3.92 (s, 2H), 2.52-2.48 (m, 3H), 2.07-1.98 (m, 1H), 1.97-1.90 (m, 3H), 1.72-1.55 (m, 12H), 0.98-0.90 (m, 2H), 0.77-0.70 (m, 2H); MS (ES+) m/z 420.2 (M+1).

Workup

  1. concentrationconcentrated in vacuo
  2. additionThe residue was treated with methanol (20 mL)
  3. concentrationconcentrated in vacuo
  4. dissolutionThe residue was dissolved in anhydrous tetrahydrofuran (20 mL)
  5. temperaturerefluxed under nitrogen for 30 min
  6. temperatureThe reaction mixture was refluxed under nitrogen for 30 minutes
  7. temperatureThe reaction mixture was cooled to ambient temperature
  8. washwashed with 1 M aqueous hydrochloric acid solution (2×30 mL) and brine (30 mL)
  9. dry with materialdried over anhydrous sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customThe residue was purified by silica gel column chromatography (2:1 hexanes

Sources & evidence

ORD record
ord-dd6c74f13a9d4a19b4f7c6521d96811c
Source dataset
uspto-grants-2015_02
Patent number
US08952169B2

Reaction notes

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