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

HRID 926331Notes

Reaction equation

HRID 926331 reaction equation
[C:1]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9]1[C:19](=[O:20])[CH2:18][NH:17][C:16](=O)[CH:15]=[C:10]12)(=[O:4])[CH2:2][CH3:3].O=P(Cl)(Cl)Cl.[CH:27]1([C:31]2[N:32]=[CH:33][NH:34][CH:35]=2)[CH2:30][CH2:29][CH2:28]1.N1C=CC=CC=1>ClCCCl.C(Cl)Cl>[CH:27]1([C:31]2[N:32]=[CH:33][N:34]([C:16]3[CH:15]=[C:10]4[C:11]5[C:6]([CH2:7][CH2:8][N:9]4[C:19](=[O:20])[CH2:18][N:17]=3)=[C:5]([C:1](=[O:4])[CH2:2][CH3:3])[CH:14]=[CH:13][CH:12]=5)[CH:35]=2)[CH2:30][CH2:29][CH2:28]1

Participants

7

Reactant 4

HCID 1049PyridineHCID 24813Phosphorus oxychlorideHCID 867113999-Propionyl-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dioneHCID 178420872HCID 178420872, compound

Product 1

HCID 867114012-(4-cyclobutyl-1H-imidazol-1-yl)-9-propionyl-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-oneYield 12%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
110 °C

Procedure

Example 124. A solution of 9-propionyl-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (225 mg, 0.77 mmol) in DCE (20 mL) was treated with POCl3 (0.22 mL, 2.30 mmol) and the mixture was heated to 110° C. for 1 h. The mixture was then allowed to cool to RT, diluted with DCM and washed with H2O. The org. phase was then dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was taken up in DCE (20 mL) and 4-cyclobutyl-1H-imidazole (188 mg, 1.54 mmol) and pyridine (0.12 mL, 1.54 mmol) were then added. The mixture was heated to 110° C. for 1 h, and then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. layer was then dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, heptane to AcOEt to AcOEt/MeOH 85:15) and SFC (column: 2-Ethylpyridine 5 μm, 250×30 mm, 60 A, Princeton; eluent: 7% MeOH/CO2 for 1 min, then from 7% MeOH/CO2 to 12% MeOH/CO2 in 6 min; then from 12% MeOH/CO2 to 50% MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) afforded the title compound (36 mg). UPLC-MS: MS 389.2 (M+H+); UPLC rt 0.95 min. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.06 (t, J=7.23 Hz, 3 H); 1.55-1.90 (m, 2 H); 1.99-2.27 (m, 4 H); 2.91-3.05 (m, 4 H); 3.36 (m, 1 H); 3.70 (t, J=6.06 Hz, 2 H); 4.22 (s, 2 H); 7.10 (s, 1 H); 7.41 (s, 1 H); 7.49 (t, J=8.02 Hz, 1 H); 7.88 (d, J=7.43 Hz, 1 H); 8.05-8.20 (m, 2 H).

Workup

  1. temperatureto cool to RT
  2. washwashed with H2O
  3. dry with materialphase was then dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue obtained
  7. temperatureThe mixture was heated to 110° C. for 1 h
  8. temperatureto cool to RT
  9. additionpoured onto H2O
  10. extractionextracted with DCM
  11. dry with materiallayer was then dried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo
  14. customPurification by flash chromatography (SiO2, heptane to AcOEt to AcOEt/MeOH 85:15) and SFC (column
  15. waitfrom 7% MeOH/CO2 to 12% MeOH/CO2 in 6 min
  16. waitthen from 12% MeOH/CO2 to 50% MeOH/CO2 in 1 min

Sources & evidence

ORD record
ord-08f3a02a4d39442990bc115c4bc01009
Source dataset
uspto-grants-2016_03
Patent number
US09284331B2

Reaction notes

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