Acetic Acid → Methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylate

Temperature

100 °C

Piperidine (7 mL, 70.9 mmol) and acetic acid (5.5 mL, 95 mmol) were added to a solution of 2-(4-chloro-3-methylpyridin-2-yl)-2-cyclopropylacetaldehyde (4.98 g, 23.75 mmol) in absolute ethanol (200 mL). Dimethyl malonate (16.44 mL, 144 mmol) was added and the reaction mixture was stirred at 100° C. for 5 h (the reaction mixture turned into a red solution). The solvent was evaporated under reduced pressure. The resulting mixture was diluted with ether (100 mL) and washed with water (100 mL) and brine (50 mL). The organic layer was separated and dried over sodium sulfate. The mixture was evaporated to dryness. Dowtherm A (110 mL) was added. This reaction mixture was heated to 240° C. under microwave irradiation and stirred at this temperature for 0.5 h during which the reaction mixture turned into a black solution. The residue was purified by reversed phase flash chromatography using a 5%-100% ACN gradient in water with 1% TFA yielding the cyclized methyl ester (4 g, 51.4%).

1. customThe solvent was evaporated under reduced pressure
2. additionThe resulting mixture was diluted with ether (100 mL)
3. washwashed with water (100 mL) and brine (50 mL)
4. customThe organic layer was separated
5. dry with materialdried over sodium sulfate
6. customThe mixture was evaporated to dryness
7. additionDowtherm A (110 mL) was added
8. temperatureThis reaction mixture was heated to 240° C. under microwave irradiation
9. stirringstirred at this temperature for 0.5 h during which the reaction mixture
10. customThe residue was purified by reversed phase flash chromatography

ORD record

ord-aa8a16c40fef41f3b7e2f4e12a2d6205

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09403818B2