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

HRID 926256Notes

Reaction equation

HRID 926256 reaction equation
[C:1]([N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:15])[C:10]=2[Br:14])[CH:5]1[CH2:16][C:17]([O:19]C)=O)(=[O:3])[CH3:2].BrC1C(F)=CC=C2C=1C=C[N:26]=C2.C([Si](OC(OC)=C)(C)C)(C)(C)C.Cl>C(Cl)Cl>[Br:14][C:10]1[C:9]([F:15])=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][CH2:13][N:4]1[C:1](=[O:3])[CH2:2][NH:26][C:17](=[O:19])[CH:16]=[C:5]12

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 45644911-(tert-Butyldimethylsilyloxy)-1-methoxyetheneHCID 687577385-broMo-6-fluoroisoquinolineHCID 86711335Methyl 2-(2-acetyl-5-bromo-6-fluoro-1,2-dihydroisoquinolin-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 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
-78 °C

Procedure

methyl 2-(2-acetyl-5-bromo-6-fluoro-1,2-dihydroisoquinolin-1-yl)acetate. To a stirred solution of 5-bromo-6-fluoroisoquinoline (43.9 g, 194 mmol) in DCM (880 mL) acetyl chloride (14.49 mL, 204 mmol) was dropped at RT and the solution was stirred for 60 min. The solution was cooled to −78° C. (yellow suspension) and then a solution of tert-butyl((1-methoxyvinyl)oxy)dimethylsilane (38.4 g, 204 mmol) in DCM (220 mL) was added in one portion. The resulting yellow solution was stirred at −78° C. for 1 h and then allowed to warm to rt overnight. 2N aqueous HCl was added and the reaction mixture was stirred for 10 min. The organic layer was separated and washed with brine (2×). The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The residue was dissolved in diethyl ether, charcoal was added and the mixture was filtrated through a pad of celite. The solvent was evaporated and the crude product was dried under high vacuo overnight to yield the title compound (70.6 g) which was used without further purification. UPLC-MS: MS 342.2/344.2 (M+H+); UPLC rt 1.05 min.

Workup

  1. stirringThe resulting yellow solution was stirred at −78° C. for 1 h
  2. temperatureto warm to rt overnight
  3. stirringthe reaction mixture was stirred for 10 min
  4. customThe organic layer was separated
  5. washwashed with brine (2×)
  6. dry with materialThe combined organic layers were dried with sodium sulfate
  7. filtrationfiltered
  8. customthe solvent was removed under reduced pressure
  9. dissolutionThe residue was dissolved in diethyl ether
  10. additioncharcoal was added
  11. filtrationthe mixture was filtrated through a pad of celite
  12. customThe solvent was evaporated
  13. dry with materialthe crude product was dried under high vacuo overnight

Sources & evidence

ORD record
ord-6b6a6d0f3b174a1f95ffa8b2eb4d3b17
Source dataset
uspto-grants-2016_03
Patent number
US09284331B2

Reaction notes

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