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

HRID 532936
Notes
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Reaction equation

HRID 532936 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][CH:3]=[N: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>[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][N:2]=[CH:3][CH:4]=3)[CH:15]=[CH:14][CH:13]=5)[CH:35]=2)[CH2:30][CH2:29]1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 1049PyridineHCID 24813Phosphorus oxychlorideHCID 867113819-(Isoxazol-5-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dioneHCID 178420870HCID 178420870, compound

Product 1

HCID 733358292-(4-cyclopropyl-1H-imidazol-1-yl)-9-(isoxazol-5-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-oneYield 35.2%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent2×

Conditions

Temperature
100 °C

Procedure

Example 100. A solution of 9-(isoxazol-5-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (90 mg, 0.31 mmol) in DCE (4 mL) was treated with POCl3 (57 μL, 0.61 mmol) and the mixture was heated to 100° C. for 1 h. The mixture was then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. phases were then dried over Na2SO4, filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (4 mL) and 4-cyclopropyl-1H-imidazole (50 mg, 0.46 mmol) and pyridine (74 μL, 0.91 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. layers were then dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, cHex/AcOEt 100:0 to 0:100 and DCm/MeOH 99:1 to 90:10) afforded the title compound (42 mg) as a pale red solid. UPLC-MS: MS 386.2 (M+H+); UPLC rt 0.85 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 0.67-0.79 (m, 2 H); 0.80-0.91 (m, 2 H); 1.80-1.91 (m, 1 H); 3.17 (t, J=6.06 Hz, 2 H); 3.90 (t, J=6.19 Hz, 2 H); 4.37 (s, 2 H); 6.47 (s, 1 H); 6.63 (s, 1 H); 7.18 (s, 1 H); 7.50 (t, J=7.83 Hz, 1 H); 7.70-7.83 (m, 2 H); 7.88 (s, 1 H); 8.38 (s, 1 H).

Workup

  1. temperatureto cool to RT
  2. additionpoured onto H2O
  3. extractionextracted with DCM
  4. dry with materialphases were then dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe brown residue obtained
  8. temperatureThe mixture was heated to 110° C. for 1 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. customPurification by flash chromatography (SiO2, cHex/AcOEt 100:0 to 0:100 and DCm/MeOH 99:1 to 90:10)

Sources & evidence

ORD record
ord-80537f838828483ca79cf430efb33180
Source dataset
uspto-grants-2014_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08853203B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes