Water → 8-bromo-7-fluoroisoquinoline

Temperature

130 °C

A mixture of 2-bromo-3-fluorobenzaldehyde (4.06 g, 20 mmol, 1 eq.) and aminoacetaldehyde dimethyl acetal (2.18 mL, 20 mmol, 1 eq.) in toluene (50 mL) was stirred at 130° C. with concomitant removal of H2O (Dean-Stark) for 1 hour. The mixture was concentrated in vacuo and dried under h.v. The resulting imine was added dropwise over 20 min to hot H2SO4 (20 mL) at 140° C. After addition completion, the mixture was stirred at 130° C. for another 30 min. The mixture was allowed to cool to r.t., poured on ice (1 kg). Some black tar was removed by filtration over Celite. The filtrate was basified by addition of 32% aq. NaOH soln. The mixture was extracted with AcOEt (3×200 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by prep. HPLC (column: Water X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound.

1. concentrationThe mixture was concentrated in vacuo
2. customdried under h.v
3. additionThe resulting imine was added dropwise over 20 min to hot H2SO4 (20 mL) at 140° C
4. additionAfter addition completion
5. temperatureto cool to r.t.
6. additionpoured on ice (1 kg)
7. customSome black tar was removed by filtration over Celite
8. additionThe filtrate was basified by addition of 32% aq. NaOH soln
9. extractionThe mixture was extracted with AcOEt (3×200 mL)
10. dry with materialphases were dried over MgSO4
11. concentrationconcentrated in vacuo
12. customThe residue was purified by prep
13. concentrationHPLC (column: Water X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo

ORD record

ord-74c3bf81ee364a7c947bc97427a56f58

Source dataset

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09255090B2