Cyclopropylamine → N-Cyclopropyl-1-{[2-(1,1-difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carboxamide

HRID 1435547Notes

Reaction equation

HRID 1435547 reaction equation
OOS([O-])=O.[K+].[F:7][C:8]([C:11]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:14]2[CH:23]=[CH:24][C:25]([S:27]([N:30]3[CH:34]=[CH:33][C:32]([CH:35]=[O:36])=[CH:31]3)(=[O:29])=[O:28])=[CH:26][C:13]=2[N:12]=1)([F:10])[CH3:9].[CH:37]1([NH2:40])[CH2:39][CH2:38]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[CH:37]1([NH:40][C:35]([C:32]2[CH:33]=[CH:34][N:30]([S:27]([C:25]3[CH:24]=[CH:23][C:14]4[N:15]([CH2:16][CH:17]5[CH2:18][CH2:19][O:20][CH2:21][CH2:22]5)[C:11]([C:8]([F:7])([F:10])[CH3:9])=[N:12][C:13]=4[CH:26]=3)(=[O:28])=[O:29])[CH:31]=2)=[O:36])[CH2:39][CH2:38]1

Participants

8

Reactant 5

HCID 69828CyclopropylamineHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 23707502Potassium hydroxy sulfiteHCID 579373571-{[2-(1,1-difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carbaldehyde

Product 1

HCID 57937306N-Cyclopropyl-1-{[2-(1,1-difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carboxamide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

Oxone (1.33 g, 2.17 mmol) was added to a solution of 1-{[2-(1,1-difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carbaldehyde (0.86 g, 11.97 mmol) (see following step B for preparation) in DMF (15 mL). The reaction mixture was stirred overnight at room temperature and then cooled down to 0° C. Cyclopropylamine (0.23 g, 0.27 ml, 3.94 mmol) and N,N-diisopropylethylamine (1.02 g, 1.37 ml, 7.88 mmol) were added. Stirring for 20 min, HATU (1.35 g, 3.55 mmol) was added portionwise and the reaction was allowed to warm to room temperature. The reaction mixture was diluted with water (200 mL), and extracted with EtOAc (3×100 mL). The combined organic phases washed with NaCl (2×20 mL) and dried over Na2SO4. The crude product was purified by normal-phase MPLC using EtOAc to provide the title compound as a light brown solid. Yield: 0.70 g (72%). 1H NMR (400 MHz, METHANOL-D4) δ 0.51-0.59 (m, 2 H), 0.68-0.78 (m, 2 H), 1.37-1.54 (m, 5 H), 2.25 (t, J=19.43 Hz, 3 H), 2.68-2.77 (m, 1 H), 3.27 (d, J=2.54 Hz, 1 H), 3.33 (d, J=2.93 Hz, 1 H), 3.84-3.94 (m, 2 H), 4.38 (d, J=7.62 Hz, 2 H), 6.65 (dd, J=3.32, 1.56 Hz, 1 H), 7.30 (dd, J=3.32, 2.34 Hz, 1 H), 7.81-7.84 (m, 1 H), 7.88-7.94 (m, 1 H), 7.94-8.00 (m, 1 H), 8.39 (d, J=1.56 Hz, 1 H); MS (APPI) (M+H)+=493.3; Anal. Calc. for C23H26F2N4O4S+0.8 TFA: C, 50.61; H, 4.63; N, 9.60. Found: C, 50.84; H, 3.87; N, 9.39.

Workup

  1. temperaturecooled down to 0° C
  2. stirringStirring for 20 min
  3. temperatureto warm to room temperature
  4. extractionextracted with EtOAc (3×100 mL)
  5. washThe combined organic phases washed with NaCl (2×20 mL)
  6. dry with materialdried over Na2SO4
  7. customThe crude product was purified by normal-phase

Sources & evidence

ORD record
ord-e8a68930eef04353a5022b6784d3e823
Source dataset
uspto-grants-2009_11
Patent number
US07615642B2

Reaction notes

Loading…