(Diethylamino)sulfur trifluoride → 2-(4-ethyl-1H-imidazol-1-yl)-9-(1-fluorocyclobutyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

HRID 532951Notes

Reaction equation

HRID 532951 reaction equation
[CH2:1]([C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:27]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:28])[CH2:10][N:9]=2)=[C:18]([C:22]2(O)[CH2:25][CH2:24][CH2:23]2)[CH:17]=[CH:16][CH:15]=4)[CH:7]=1)[CH3:2].CCN(S(F)(F)[F:35])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:27]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:28])[CH2:10][N:9]=2)=[C:18]([C:22]2([F:35])[CH2:25][CH2:24][CH2:23]2)[CH:17]=[CH:16][CH:15]=4)[CH:7]=1)[CH3:2]

Participants

5

Reactant 3

HCID 123472(Diethylamino)sulfur trifluorideHCID 516892Sodium BicarbonateHCID 867113932-(4-ethyl-1H-imidazol-1-yl)-9-(1-hydroxycyclobutyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

Product 1

HCID 867113942-(4-ethyl-1H-imidazol-1-yl)-9-(1-fluorocyclobutyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-oneYield 34.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Example 113. A solution of 2-(4-ethyl-1H-imidazol-1-yl)-9-(1-hydroxycyclobutyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (120 mg, 0.32 mmol) in DCM was cooled to 0° C. under N2 and treated with DAST (0.42 mL, 3.19 mmol) dropwise. The mixture was stirred for 20 min at 0° C., and the allowed to warm to RT. The reaction mixture was then slowly poured onto a cooled saturated aq. solution of NaHCO3 and extracted with DCM. The combined org layers were then dried over Na2SO4, filtered and concentrated in vacuo. The crude product obtained was purified by flash chromatography (SiO2, heptane to AcOEt to AcOEt/MeOH 9:1) and SFC (column: 2-Ethylpyridine 5 μm, 250×30 mm, 60A, Princeton; eluent: isocratic 6% MeOH/CO2 for 11 min; flow 100 mL/min; UV detection at 220 nm) to afford the title compound (42 mg) as a beige solid. UPLC-MS: MS 379.2 (M+H+); UPLC rt 0.95 min. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.10-1.19 (m, 3 H); 1.46-1.64 (m, 1 H); 1.88-2.09 (m, 1 H); 2.47 (m, 2 H); 2.51-2.79 (m, 4 H); 2.95 (t, J=5.28 Hz, 2 H); 3.73 (t, J=6.06 Hz, 2 H); 4.22 (br. s., 2 H); 7.07 (s, 1 H); 7.33-7.48 (m, 2 H); 7.58-7.67 (m, 1 H); 7.95 (d, J=8.21 Hz, 1 H); 8.13 (s, 1 H).

Workup

  1. temperatureto warm to RT
  2. extractionextracted with DCM
  3. dry with materialThe combined org layers were then dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe crude product obtained
  7. customwas purified by flash chromatography (SiO2, heptane to AcOEt to AcOEt/MeOH 9:1) and SFC (column: 2-Ethylpyridine 5 μm, 250×30 mm, 60A, Princeton; eluent: isocratic 6% MeOH/CO2 for 11 min; flow 100 mL/min; UV detection at 220 nm)

Sources & evidence

ORD record
ord-5cec4b6538e04af38ec5cda9024a799a
Source dataset
uspto-grants-2014_10
Patent number
US08853203B2

Reaction notes

Loading…