Phosphorus oxychloride → methyl 2-(4-cyclopropyl-1H-imidazol-1-yl)-5-oxo-4,5,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-9-carboxylate

HRID 532963Notes

Reaction equation

HRID 532963 reaction equation
O=[C:2]1[CH:20]=[C:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[C:13]=3[CH2:14][CH2:15][N:6]2[C:5](=[O:21])[CH2:4][NH:3]1.O=P(Cl)(Cl)Cl.[CH:27]1([C:30]2[N:31]=[CH:32][NH:33][CH:34]=2)[CH2:29][CH2:28]1>ClCCCl.C(Cl)Cl>[CH:27]1([C:30]2[N:31]=[CH:32][N:33]([C:2]3[CH:20]=[C:7]4[C:8]5[CH:9]=[CH:10][CH:11]=[C:12]([C:16]([O:18][CH3:19])=[O:17])[C:13]=5[CH2:14][CH2:15][N:6]4[C:5](=[O:21])[CH2:4][N:3]=3)[CH:34]=2)[CH2:29][CH2:28]1

Participants

6

Reactant 3

HCID 24813Phosphorus oxychlorideHCID 86711409Methyl 2,5-dioxo-2,3,4,5,7,8-hexahydro-[1,4]diazepino[7,1-a]isoquinoline-9-carboxylateHCID 178420870HCID 178420870, compound

Product 1

HCID 86711408methyl 2-(4-cyclopropyl-1H-imidazol-1-yl)-5-oxo-4,5,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-9-carboxylateYield 39%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
100 °C

Procedure

Example 132. A solution of methyl 2,5-dioxo-2,3,4,5,7,8-hexahydro-[1,4]diazepino[7,1-a]isoquinoline-9-carboxylate (225 mg, 0.79 mmol) in DCE (20 mL) was treated with POCl3 (0.37 mL, 3.93 mmol) and the mixture was heated to 100° C. for 1 h. The mixture was then allowed to cool to RT, and then concentrated in vacuo, and dried azeotropically with toluene. The residue obtained was taken up in DCE (40 mL) and 4-cyclopropyl-1H-imidazole (261 mg, 2.41 mmol) were added. The mixture was heated to to 100° C. for 1 h and then allowed to cool to RT, diluted with DCM and washed with a saturated aq, solution of NaHCO3. The org. layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, AcOEt/MeOH 100:0 to 90:10) and crystallization in Et2O/petroleum ether gave the title compound (116 mg). UPLC-MS: MS 377.2 (M+H+); UPLC rt 0.88 min. 1H NMR (600 MHz, DMSO-d6): δ ppm 0.54-0.73 (m, 2H); 0.73-0.88 (m, 2H); 1.74-1.89 (m, 1H); 3.25 (br s, 2H); 3.67-3.82 (m, 2H); 3.88 (s, 3H); 4.25 (br s, 2H); 7.13 (s, 1H); 7.44 (s, 1H); 7.48-7.57 (m, 1H); 7.96 (d, J=7.65 Hz, 1H); 8.09 (s, 1H); 8.19 (d, J=7.91, 1H).

Workup

  1. temperatureto cool to RT
  2. concentrationconcentrated in vacuo
  3. dry with materialdried azeotropically with toluene
  4. customThe residue obtained
  5. temperatureThe mixture was heated to to 100° C. for 1 h
  6. temperatureto cool to RT
  7. washwashed with a saturated aq, solution of NaHCO3
  8. dry with materiallayer was dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customPurification
  12. customby flash chromatography (SiO2, AcOEt/MeOH 100:0 to 90:10) and crystallization in Et2O/petroleum ether

Sources & evidence

ORD record
ord-5ca706cf0c244843ba7f4b71b8c681fc
Source dataset
uspto-grants-2014_10
Patent number
US08853203B2

Reaction notes

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