Epichlorohydrin → 1-[3-(4-Bromo-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

HRID 967363Notes

Reaction equation

HRID 967363 reaction equation
C([O-])([O-])=O.[Cs+].[Cs+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]3[CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22][C:17]=3[NH:16][N:15]=2)=[CH:10][CH:9]=1.[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>CN(C=O)C.CCOC(C)=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:18]3[CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22][C:17]=3[N:16]([CH2:26][CH:28]3[CH2:29][O:30]3)[N:15]=2)=[CH:12][CH:13]=1

Participants

6

Reactant 3

HCID 7835EpichlorohydrinHCID 10796Cesium carbonateHCID 222936551-[3-(4-Bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone

Product 1

HCID 222936301-[3-(4-Bromo-phenyl)-1-oxiranylmethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanoneYield 56%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

Cs2CO3 (11.58 g, 35.5 mmol) was added to a solution of 1-[3-(4-bromo-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (7.59 g, 23.7 mmol) and epichlorohydrin (20 mL, 234 mmol) in DMF (100 mL). The mixture was stirred for 18 h then diluted with EtOAc (800 mL) and washed with saturated aqueous NaHCO3 (2×100 mL), H2O (2×100 mL), and brine (100 mL). The NaHCO3 layer was extracted with EtOAc (2×150 mL). The combined washes were extracted with EtOAc (2×100 mL). The combined extracts were dried over Na2SO4 and concentrated. Column chromatography (silica, 10-20% acetone/CH2Cl2) afforded 4.98 g (56%) of the title compound. HPLC, tR=4.90 min. (Reverse phase conditions: HP 1100 LCMS, Phenomenex luna 2.1×150 mm column, 60% MeOH/H2O (0.5% AcOH) to 90% MeOH/H2O (0.5% AcOH), held at initial conditions for 2 min then ramped to final conditions over 5 min.) MS (electrospray): m/z calculated for C17H1979BrN3O2, [M+H]+, 376.07. found 376.0. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 7.47 (d with fine splittings, J=8.5, Hz, 2H), 7.44 (m, 4H), 7.38 (d with fine splittings, J=8.5, Hz, 2H), 4.71 and 4.64 (A and B of AB quartet, Jab=15.7 Hz, 2H), 4.51 (s, 2H), 4.39 (dd, J=15.1, 2.5 Hz, 1H), 4.34 (dd, J=15.0, 2.9 Hz, 1H), 4.02 (dd, J=5.2, 3.9 Hz, 1H), 3.98 (dd, J=5.3, 3.7 Hz, 1H), 3.83 (m, 2H), 3.64 (m, 2H), 3.25 (br m, 2H), 2.80-2.60 (m, 6H), 2.46 (dd, J=4.6, 2.6 Hz, 1H), 2.38 (dd, J=4.6, 2.6 Hz, 1H), 2.10 (s, 3H), 2.06 (s, 3H).

Workup

  1. washwashed with saturated aqueous NaHCO3 (2×100 mL), H2O (2×100 mL), and brine (100 mL)
  2. extractionThe NaHCO3 layer was extracted with EtOAc (2×150 mL)
  3. extractionThe combined washes were extracted with EtOAc (2×100 mL)
  4. dry with materialThe combined extracts were dried over Na2SO4
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-5c95b3d2cb5d41119aa2ec327fd4f956
Source dataset
uspto-grants-2005_10
Patent number
US06953793B2

Reaction notes

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