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

HRID 532946Notes

Reaction equation

HRID 532946 reaction equation
[O:1]1[C:5]([C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][N:10]2[C:20](=[O:21])[CH2:19][NH:18][C:17](=O)[CH:16]=[C:11]23)=[CH:4][N:3]=[CH:2]1.O=P(Cl)(Cl)Cl.[CH:28]1([C:31]2[N:32]=[CH:33][NH:34][CH:35]=2)[CH2:30][CH2:29]1.N1C=CC=CC=1>ClCCCl.O>[CH:28]1([C:31]2[N:32]=[CH:33][N:34]([C:17]3[CH:16]=[C:11]4[C:12]5[C:7]([CH2:8][CH2:9][N:10]4[C:20](=[O:21])[CH2:19][N:18]=3)=[C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)[CH:15]=[CH:14][CH:13]=5)[CH:35]=2)[CH2:30][CH2:29]1

Participants

7

Reactant 4

HCID 1049PyridineHCID 24813Phosphorus oxychlorideHCID 867113899-(Oxazol-5-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dioneHCID 178420870HCID 178420870, compound

Product 1

HCID 867113902-(4-cyclopropyl-1H-imidazol-1-yl)-9-(oxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-oneYield 3%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolvent2×HCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

Example 109. A mixture of 9-(oxazol-5-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (180 mg, 0.61 mmol) in DCE (10 mL) was treated with POCl3 (114 μL, 1.22 mmol) and heated to 100° C. for 1 h. The mixture was then allowed to cool to RT, poured onto cold 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 (5 mL) and 4-cyclopropyl-1H-imidazole (79 mg, 0.73 mmol) and pyridine (148 μL, 1.83 mmol) were then added. The mixture was heated to 100° C. for 1 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. Purification by SFC (column: 2-Ethylpyridine 5 μm, 250×30 mm, 60A, Princeton; eluent: 9% MeOH/CO2 for 1 min, then from 9% MeOH/CO2 to 14% MeOH/CO2 in 6 min; then from 14% MeOH/CO2 to 50% MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) afforded the title compound (7 mg) as pale brown solid. UPLC-MS: MS 386.1 (M+H+); UPLC rt 0.79 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 0.78 (m, 2 H); 0.81-0.87 (m, 2 H); 1.79-1.93 (m, 1 H); 3.14 (t, J=6.02 Hz, 2 H); 3.94 (t, J=6.15 Hz, 2 H); 4.38 (br. s., 2 H); 6.66 (s, 1 H); 7.20 (s, 1 H); 7.30 (s, 1 H); 7.42-7.60 (m, 1 H); 7.77 (d, J=7.78 Hz, 1 H); 7.74 (d, J=8.03 Hz, 1 H); 7.90 (s, 1 H); 8.03 (s, 1 H).

Workup

  1. temperatureto cool to RT
  2. extractionextracted with DCM
  3. dry with materialphases were dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe brown residue obtained
  7. temperatureThe mixture was heated to 100° C. for 1 h
  8. temperatureto cool to RT
  9. additionpoured onto H2O
  10. extractionextracted with DCM
  11. dry with materiallayers were then dried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo
  14. customPurification by SFC (column
  15. waitfrom 9% MeOH/CO2 to 14% MeOH/CO2 in 6 min
  16. waitthen from 14% MeOH/CO2 to 50% MeOH/CO2 in 1 min

Sources & evidence

ORD record
ord-b6fd08a45ec94d498f670f235f258d86
Source dataset
uspto-grants-2014_10
Patent number
US08853203B2

Reaction notes

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