Pyridine → 2-(4-cyclopropyl-1H-imidazol-1-yl)-9-iodo-1-methyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

HRID 926312Notes

Reaction equation

HRID 926312 reaction equation
[I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=O)[C:12]([CH3:19])=[C:7]12.O=P(Cl)(Cl)Cl.[CH:25]1([C:28]2[N:29]=[CH:30][NH:31][CH:32]=2)[CH2:27][CH2:26]1.N1C=CC=CC=1>ClCCCl>[CH:25]1([C:28]2[N:29]=[CH:30][N:31]([C:13]3[C:12]([CH3:19])=[C:7]4[C:8]5[C:3]([CH2:4][CH2:5][N:6]4[C:16](=[O:17])[CH2:15][N:14]=3)=[C:2]([I:1])[CH:11]=[CH:10][CH:9]=5)[CH:32]=2)[CH2:27][CH2:26]1

Participants

6

Reactant 4

HCID 1049PyridineHCID 24813Phosphorus oxychlorideHCID 867113849-Iodo-1-methyl-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dioneHCID 178420870HCID 178420870, compound

Product 1

HCID 867113832-(4-cyclopropyl-1H-imidazol-1-yl)-9-iodo-1-methyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-oneYield 29.6%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent2×

Conditions

Temperature
100 °C

Procedure

107-1. A mixture of 9-iodo-1-methyl-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (30 mg, 81 μmol) in DCE (2 mL) is treated with POCl3 (15 μL, 0.16 mmol) and heated to 100° C. for 3 h. The mixture was then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. phases were dried over Na2SO4, filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (2 mL) and 4-cyclopropyl-1H-imidazole (31 mg, 0.28 mmol) and pyridine (20 μL, 0.24 mmol) were then added. The mixture was heated to 100° C. for 4.5 h, and then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. Filtration through a pad of SiO2 (AcOEt) afforded a brown solid that was purified by SFC (column: Diol 5 μm, 250×30 mm, 60 A, Princeton; eluent: 13% MeOH/CO2 for 1 min, then from 13% MeOH/CO2 to 18% MeOH/CO2 in 6 min; then from 18% MeOH/CO2 to 50% MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) to give the title compound (11 mg) as a white powder. UPLC-MS: MS 459.0 (M+H+); UPLC rt 0.98 min.

Workup

  1. temperatureto cool to RT
  2. additionpoured onto H2O
  3. extractionextracted with DCM
  4. dry with materialphases were dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe brown residue obtained
  8. temperatureThe mixture was heated to 100° C. for 4.5 h
  9. temperatureto cool to RT
  10. additionpoured onto H2O
  11. extractionextracted with DCM
  12. dry with materiallayers were then dried over Na2SO4
  13. filtrationfiltered
  14. concentrationconcentrated in vacuo
  15. filtrationFiltration through a pad of SiO2 (AcOEt)
  16. customafforded a brown solid that
  17. customwas purified by SFC (column
  18. waitfrom 13% MeOH/CO2 to 18% MeOH/CO2 in 6 min
  19. waitthen from 18% MeOH/CO2 to 50% MeOH/CO2 in 1 min

Sources & evidence

ORD record
ord-059a1a3e5bfd44d7bacc8622c244f283
Source dataset
uspto-grants-2016_03
Patent number
US09284331B2

Reaction notes

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