(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 926324Notes

Reaction equation

HRID 926324 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, 60 A, 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, 60 A, Princeton; eluent: isocratic 6% MeOH/CO2 for 11 min; flow 100 mL/min; UV detection at 220 nm)

Sources & evidence

ORD record
ord-a90373e1ecb743158bf3b4851c297f6f
Source dataset
uspto-grants-2016_03
Patent number
US09284331B2

Reaction notes

Loading…