Sulfuric Acid → 9-Bromo-10-fluoro-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione

HRID 926258Notes

Reaction equation

HRID 926258 reaction equation
BrC1C(F)=CC=C2C=1CC[NH:6]C2CC(OC)=O.S(=O)(=O)(O)O.[C:23]([N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([F:37])[C:32]=2[Br:36])[CH:27]1[CH2:38][C:39]([O:41]C)=O)(=[O:25])[CH3:24].C([O-])(O)=O.[Na+]>O.CO>[Br:36][C:32]1[C:31]([F:37])=[CH:30][CH:29]=[C:28]2[C:33]=1[CH2:34][CH2:35][N:26]1[C:23](=[O:25])[CH2:24][NH:6][C:39](=[O:41])[CH:38]=[C:27]12

Participants

7

Reactant 4

HCID 1118Sulfuric AcidHCID 516892Sodium BicarbonateHCID 86711334Methyl 2-(2-acetyl-5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetateHCID 86711336Methyl 2-(5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate

Product 1

HCID 867113419-Bromo-10-fluoro-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Procedure

methyl 2-(5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate. MeOH (620 mL) was cooled to −15° C. and conc. Sulfuric acid (73.7 mL, 1383 mmol) was added slowly (exotherm) under cooling. To this solution, methyl 2-(2-acetyl-5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate (47.6 g, 138 mmol) was added and the reaction mixture was stirred under reflux for 96 h. The reaction mixture was cooled to RT and slowly added to a solution of NaHCO3 (244 g) in water (500 mL). The slightly basic aqueous solution was extracted with AcOEt (3×). The combined organic layers were washed with saturated aqueous NaHCO3 and brine. The organic layer was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was dried under high vacuo to yield the title compound as yellow foam (41.58 g) which was used without further purification. UPLC-MS: MS 302.1/304.1 (M+H+); UPLC rt 0.51 min.

Workup

  1. temperatureunder cooling
  2. temperatureunder reflux for 96 h
  3. extractionThe slightly basic aqueous solution was extracted with AcOEt (3×)
  4. washThe combined organic layers were washed with saturated aqueous NaHCO3 and brine
  5. dry with materialThe organic layer was dried with sodium sulfate
  6. filtrationfiltered
  7. customthe solvent was removed under reduced pressure
  8. dry with materialThe crude product was dried under high vacuo

Sources & evidence

ORD record
ord-039570e8606847078a56c085ba40c634
Source dataset
uspto-grants-2016_03
Patent number
US09284331B2

Reaction notes

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