Formic Acid → HCID 118699729, compound

Temperature

-18 °C

A 2 L, three-necked, round-bottomed flask was equipped with a heating/cooling bath, magnetic stirrer and stir bar, 60 mL addition funnel, thermocouple, thermocouple adapter with a nitrogen inlet. The flask was charged with triethylamine (43 mL, 31.2 g, 308 mmol), 3-benzoyl-8,9-dimethoxy-2,3,4,6-tetrahydrobenzo[c]-2,7-naphthyridin-5(1H)-one (30.2 g, 83 mmol), and dichloromethane (850 mL). The resulting slurry was stirred for 15 minutes at 22° C. and cooled to −18° C. Neat trifluoromethanesulfonic anhydride (34 mL, 202 mmol) was added drop-wise via an addition funnel over 40 minutes, keeping the temperature at −12 to −18° C. Upon completion of the addition, the mixture was warmed to 0° C. over 40 minutes and stirred at 0° C. for 2 hours. Solvents were stripped under reduced pressure. A solution of dichloro[1,1′-bis(diphenylphos-phino)ferrocene]palladium(II) dichloromethane adduct (4.72 g, 5.78 mmol) in a solution of degassed N,N-dimethylformamide (520 mL) and Et3N (120 mL, 87.1 g, 861 mmol) was added to the residue and the batch was degassed by bubbling N2 through it for 10 minutes. Degassed formic acid (15.8 mL, 419 mmol) was added over 1 minute via syringe and the stirred solution was heated to 55° C. Additional dichloro[1,1′-bis(diphenylphosphino) ferrocene]palladium(II) dichloromethane adduct (3.20 g, 3.92 mmol) was added after 20 minutes and the batch was heated at 55° C. for another 1 hour. At that time, assay by HPLC showed the reaction to be complete. Concentration in vacuo afforded 149 g of crude dark brown oil, which was dissolved in dichloromethane (180 mL) and loaded into a Biotage® unit (340 g KP-Sil cartridge equilibrated with dichloromethane). The column was eluted isocratically with dichloromethane (8 CV). The product containing fractions were combined and concentrated under reduced pressure; the resulting oil (105 g) was swished with ethyl acetate (520 mL) to give the title compound as a grey solid (13.0 g, 45% yield).

1. customA 2 L, three-necked, round-bottomed flask was equipped with a heating/cooling bath, magnetic stirrer
2. additionbar, 60 mL addition funnel
3. stirringThe resulting slurry was stirred for 15 minutes at 22° C.
4. customat −12 to −18° C
5. additionUpon completion of the addition
6. temperaturethe mixture was warmed to 0° C. over 40 minutes
7. stirringstirred at 0° C. for 2 hours
8. customthe batch was degassed
9. customby bubbling N2 through it for 10 minutes
10. temperaturethe stirred solution was heated to 55° C
11. temperaturethe batch was heated at 55° C. for another 1 hour
12. customthe reaction
13. concentrationConcentration in vacuo
14. customafforded 149 g of crude dark brown oil, which
15. washThe column was eluted isocratically with dichloromethane (8 CV)
16. additionThe product containing fractions
17. concentrationconcentrated under reduced pressure

ORD record

ord-e74fbc8341ce4973abae49c42be95110

Source dataset

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09255096B1