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

HRID 926317Notes

Reaction equation

HRID 926317 reaction equation
[CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][N:11]2[C:21](=[O:22])[CH2:20][NH:19][C:18](=O)[CH:17]=[C:12]23)[N:6]=1.O=P(Cl)(Cl)Cl.[CH:29]1([C:32]2[N:33]=[CH:34][NH:35][CH:36]=2)[CH2:31][CH2:30]1.N1C=CC=CC=1>ClCCCl.O>[CH:29]1([C:32]2[N:33]=[CH:34][N:35]([C:18]3[CH:17]=[C:12]4[C:13]5[C:8]([CH2:9][CH2:10][N:11]4[C:21](=[O:22])[CH2:20][N:19]=3)=[C:7]([C:5]3[N:6]=[C:2]([CH3:1])[O:3][CH:4]=3)[CH:16]=[CH:15][CH:14]=5)[CH:36]=2)[CH2:31][CH2:30]1

Participants

7

Reactant 4

HCID 1049PyridineHCID 24813Phosphorus oxychlorideHCID 867113879-(2-Methyloxazol-4-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dioneHCID 178420870HCID 178420870, compound

Product 1

HCID 867113882-(4-cyclopropyl-1H-imidazol-1-yl)-9-(2-methyloxazol-4-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-oneYield 23.4%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolvent2×HCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

Example 108. A mixture of 9-(2-methyloxazol-4-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (140 mg, 0.45 mmol) in DCE (10 mL) was treated with POCl3 (84 μL, 0.91 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 (59 mg, 0.54 mmol) and pyridine (110 μL, 1.36 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, 60 A, Princeton; eluent: 10% MeOH/CO2 for 1 min, then from 10% MeOH/CO2 to 15% MeOH/CO2 in 6 min; then from 15% MeOH/CO2 to 50% MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) afforded the title compound (42 mg) as beige powder. UPLC-MS: MS 400.2 (M+H+); UPLC rt 0.86 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 0.61-0.82 (m, 2 H); 0.82-0.91 (m, 2 H); 1.78-1.96 (m, 1 H); 2.56 (s, 3 H); 3.16 (t, J=6.02 Hz, 2 H); 3.89 (t, J=6.15 Hz, 2 H); 4.37 (br. s., 2 H); 6.62 (s, 1 H); 7.19 (d, J=1.25 Hz, 1 H); 7.38-7.48 (m, 1 H); 7.63-7.70 (m, 2 H); 7.78 (dd, J=7.65, 1.13 Hz, 1 H); 7.89 (d, J=1.26 Hz, 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 10% MeOH/CO2 to 15% MeOH/CO2 in 6 min
  16. waitthen from 15% MeOH/CO2 to 50% MeOH/CO2 in 1 min

Sources & evidence

ORD record
ord-de5cd596ee294bfe911685753f4d4c5c
Source dataset
uspto-grants-2016_03
Patent number
US09284331B2

Reaction notes

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