Phosphorus oxychloride → HCID 73335545, compound

HRID 532917Notes

Reaction equation

HRID 532917 reaction equation
[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]1[C:17](=[O:18])[CH2:16][NH:15][C:14](=O)[CH:13]=[C:8]12.O=P(Cl)(Cl)Cl.[CH:25]([C:28]1[N:29]=[CH:30][NH:31][CH:32]=1)([CH3:27])[CH3:26].C([O-])(O)=O.[Na+]>ClCCCl>[CH:25]([C:28]1[N:29]=[CH:30][N:31]([C:14]2[CH:13]=[C:8]3[C:9]4[C:4]([CH2:5][CH2:6][N:7]3[C:17](=[O:18])[CH2:16][N:15]=2)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][CH:10]=4)[CH:32]=1)([CH3:27])[CH3:26]

Participants

6

Reactant 4

HCID 24813Phosphorus oxychlorideHCID 516892Sodium BicarbonateHCID 86711362HCID 86711362, compoundHCID 178439626HCID 178439626, compound

Product 1

HCID 73335545HCID 73335545, compoundYield 13.8%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Conditions

Temperature
100 °C

Procedure

To a stirred solution of 9-methoxy-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (80 mg, 0.31 mmol) in 1,2-dichloroethane (8 mL) was added POCl3 (0.058 mL, 0.62 mmol) and the resulting yellow suspension was stirred at 100° C. for 1 h. The reaction mixture was cooled to RT and concentrated under reduced pressure to dryness. The resulting crude chloro compound was dissolved in 1,2-dichloroethane (8 mL), 4-isopropyl-1H-imidazole (102 mg, 0.93 mmol) was added and the mixture was stirred at 100° C. for 2 h. The reaction mixture was allowed to warm to RT. Saturated aqueous NaHCO3 solution was added and the mixture was extracted twice with DCM. The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (eluent: gradient 0% to 100% ethyl acetate/cyclohexane in 30 min) to yield 15 mg of a brown solid. Further purification by SFC (column: Diol 5 μm, 250×30 mm, 60A, Princeton; eluent: 13% MeOH/CO2 for 0.5 min, then from 13% MeOH/CO2 to 18% MeOH/CO2 in 6 min; then from 18% MeOH/CO2 to 50% MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) yielded the title compound (9 mg). UPLC-MS: MS 351.3 (M+H+); UPLC rt 0.90 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.35 (d, J=6.8 Hz, 6 H), 2.95 (t, J=6.2 Hz, 2 H), 3.03-3.19 (m, 1 H), 3.88 (s, 3 H), 3.92-4.05 (m, 2 H), 4.40 (s, 2 H), 6.87-7.05 (m, 2 H), 7.19-7.58 (m, 4 H).

Workup

  1. temperatureThe reaction mixture was cooled to RT
  2. concentrationconcentrated under reduced pressure to dryness
  3. dissolutionThe resulting crude chloro compound was dissolved in 1,2-dichloroethane (8 mL)
  4. stirringthe mixture was stirred at 100° C. for 2 h
  5. temperatureto warm to RT
  6. extractionthe mixture was extracted twice with DCM
  7. dry with materialThe combined organic layers were dried with sodium sulfate
  8. filtrationfiltered
  9. customthe solvent was removed under reduced pressure
  10. customThe crude product was purified by flash-column chromatography over silicagel (eluent: gradient 0% to 100% ethyl acetate/cyclohexane in 30 min)

Sources & evidence

ORD record
ord-b5ec079086404cb4be3fea789c7a74bd
Source dataset
uspto-grants-2014_10
Patent number
US08853203B2

Reaction notes

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