Hydrochloric Acid → 6-cyclopropyl-8-fluoroisoquinolin-1(2H)-one

HRID 2069707Notes

Reaction equation

HRID 2069707 reaction equation
[CH:1]1([C:4]2[CH:12]=[C:11]([CH3:13])[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([F:14])[CH:5]=2)[CH2:3][CH2:2]1.[CH3:15]OC(OC)N(C)C.CC(C)([O-])C.[K+].C1COCC1.Cl>CC1CCCO1>[CH:1]1([C:4]2[CH:12]=[C:11]3[C:7](=[C:6]([F:14])[CH:5]=2)[C:8](=[O:9])[NH:10][CH:15]=[CH:13]3)[CH2:2][CH2:3]1

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 8028TetrahydrofuranHCID 78373Dimethylformamide dimethyl acetalHCID 23665647Potassium tert-butoxideHCID 594738034-Cyclopropyl-2-fluoro-6-methylbenzamide

Product 1

HCID 594737616-cyclopropyl-8-fluoroisoquinolin-1(2H)-oneYield 78%

Reagents, catalysts & solvents 1

HCID 73012-MethyltetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of 4-cyclopropyl-2-fluoro-6-methylbenzamide (37.2 g, 0.19 mol) in 2-methyltetrahydrofuran (MeTHF; 223 ml) was added 1,1-dimethoxy-N,N-dimethylmethanamine (29.8 g, 0.25 mol). The mixture was heated to 60° C. for 2 hours, then around 100 mL of MeTHF was distilled out under vacuum in order to remove Methanol. The reaction mixture was heated to 55° C. again, and potassium tert-butoxide, 1 M solution in THF (289 ml, 0.29 mol) was added dropwise. After 1 hr stirring at 60° C., the reaction mixture was allowed to cool down to room temperature and poured into HCl, 1 M solution (289 ml, 0.29 mol), and then THF/MeTHF was distilled out at 60° C. for crystallization. During the distillation, IPA (223 ml) was added slowly. After most of THF/MeTHF was removed, the solution was cooled down to ambient temperature. The desired product was crystallized out from IPA/water, collected by filtration and washed with water and cold IPA. The filter cake was dried under vacuum at 50° C. to afford 30.1 g of the title compound (77% isolated yield) as a white solid. MS (ESI) 204 (M+H)+.

Workup

  1. distillationaround 100 mL of MeTHF was distilled out under vacuum in order
  2. customto remove Methanol
  3. temperatureThe reaction mixture was heated to 55° C. again
  4. temperatureto cool down to room temperature
  5. distillationTHF/MeTHF was distilled out at 60° C. for crystallization
  6. distillationDuring the distillation, IPA (223 ml)
  7. additionwas added slowly
  8. customAfter most of THF/MeTHF was removed
  9. temperaturethe solution was cooled down to ambient temperature
  10. customThe desired product was crystallized out from IPA/water
  11. filtrationcollected by filtration
  12. washwashed with water and cold IPA
  13. customThe filter cake was dried under vacuum at 50° C.

Sources & evidence

ORD record
ord-27d6d94d75d1447daf12d13d5e2f52af
Source dataset
uspto-grants-2012_10
Patent number
US08299077B2

Reaction notes

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