Cyclobutanone → 2-(4-ethyl-1H-imidazol-1-yl)-9-(1-hydroxycyclobutyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one

HRID 926323Notes

Reaction equation

HRID 926323 reaction equation
[CH2:1]([C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:23]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:24])[CH2:10][N:9]=2)=[C:18](I)[CH:17]=[CH:16][CH:15]=4)[CH:7]=1)[CH3:2].C([Mg]Cl)(C)C.[C:30]1(=[O:34])[CH2:33][CH2:32][CH2:31]1.[NH4+].[Cl-]>C1COCC1>[CH2:1]([C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:23]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:24])[CH2:10][N:9]=2)=[C:18]([C:30]2([OH:34])[CH2:33][CH2:32][CH2:31]2)[CH:17]=[CH:16][CH:15]=4)[CH:7]=1)[CH3:2]

Participants

6

Reactant 4

HCID 14496CyclobutanoneHCID 25517Ammonium ChlorideHCID 867113912-(4-ethyl-1H-imidazol-1-yl)-9-iodo-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-oneHCID 178418918HCID 178418918, compound

Product 1

HCID 867113932-(4-ethyl-1H-imidazol-1-yl)-9-(1-hydroxycyclobutyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-oneYield 59.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

113-1. A solution of 2-(4-ethyl-1H-imidazol-1-yl)-9-iodo-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (250 mg, 0.58 mmol) in dry THF was cooled to −78° C. under Ar and a solution of iPrMgCl*LiCl (1.78 mL, 2.31 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 min and cyclobutanone (0.22 mL, 2.90 mmol) was then added dropwise. The mixture was stirred at −78° C. for another 30 min and then at RT for 4 h. The mixture was poured onto a saturated aq. solution of NH4Cl and the mixture was extracted with AcOEt. The combined org. phases were then dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was purified by flash chromatography (SiO2, heptane to AcOEt to AcOEt/MeOH 9:1) gave the title compound (129 mg) as a red solid. UPLC-MS: MS 377.3 (M+H+); UPLC rt 0.76 min.

Workup

  1. stirringThe mixture was stirred at −78° C. for another 30 min
  2. waitat RT for 4 h
  3. extractionthe mixture was extracted with AcOEt
  4. dry with materialphases were then dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe residue obtained
  8. customwas purified by flash chromatography (SiO2, heptane to AcOEt to AcOEt/MeOH 9:1)

Sources & evidence

ORD record
ord-05514c4e246245aab13d3a85fbbbe861
Source dataset
uspto-grants-2016_03
Patent number
US09284331B2

Reaction notes

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