Methane → tert-butyl (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylate

Temperature

77.5 °C

A 22-L three-necked round-bottomed flask with a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet was flushed with N2. The flask was charged with acetonitrile (8 L, 5 v), dimethylformamide (93.2 L, 2 v) and 6-bromo-3,4-dihydro-1,8-naphthyridin-2(1H)-one bromide (1.6 kg, 7.05 mol, 1 eq.). To the suspension were added diisopropylethylamine (1.33 kg, 10.57 mol, 1.5 eq.) and tert-butylacrylate (1.33 kg, 10.57 mol, 1.5 eq.). The suspension was then purged with a slow stream of N2 for 10 min. Trio-tolylphosphine (0.214 kg, 0.705 mol, 0.1 eq) and palladium diacetate (0.079 kg, 0.352 mol, 0.05 eq) were added to the reaction mixture. The reaction mixture was heated to 75-80° C. and stirred at 75-80° C. for 20 h. The reaction mixture was cooled to 20-25° C., diluted with water (10 v) and stirred for one hour. The solid was collected by vacuum filtration using a Buchnner funnel with a cloth filter and 20-L glass receiver flask. The solids were then washed with water (3×1 v) followed by heptane (2×1v). The light brown damp solid was dried under vacuum at 30-35° C. with a slow N2 bleed for 48 h to a constant weight to give 2.11 kg of light brown solid. This solid was then suspended DCM/MeOH (10v/1v) under N2 in two 22-L three necked RBFs with a mechanical stirrer, a thermocouple and a reflux condenser. To each of these RBFs charcoal (100 g, ALDRICH Activated Darco G 60-100 mesh) was added and the mixture allowed to stir at 20-25° C. for 20 h. The suspensions were filter through a pad of celite (500 g)/silica gel (500 g) using a cintered glass funnel and a 20-L glass filter flask. The solid cake was rinsed with DCM (3×1 v). The combined filtrate was concentrated under vacuum ˜30-35° C. and the residue was diluted with heptane/ethyl acetate (3v/3v) and further concentrated to a suspension. The solid product was collected under vacuum by filtration using a Buchnner funnel with a cloth filter. The solids were rinsed with heptane (3×1.25 v) and the damp solid was dried under vacuum at 30-35° C. with a slow N2 bleed for 90 h to a constant weight to give 1.58 kg (82%) of the desired product as a yellow solid.

1. customA 22-L three-necked round-bottomed flask with a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet was flushed with N2
2. customThe suspension was then purged with a slow stream of N2 for 10 min
3. temperatureThe reaction mixture was cooled to 20-25° C.
4. stirringstirred for one hour
5. filtrationThe solid was collected by vacuum filtration
6. filtrationfilter
7. washThe solids were then washed with water (3×1 v)
8. dry with materialThe light brown damp solid was dried under vacuum at 30-35° C. with a slow N2
9. waitbleed for 48 h to a constant weight
10. customto give 2.11 kg of light brown solid
11. stirringto stir at 20-25° C. for 20 h
12. filtrationThe suspensions were filter through a pad of celite (500 g)/silica gel (500 g)
13. filtrationa 20-L glass filter flask
14. washThe solid cake was rinsed with DCM (3×1 v)
15. concentrationThe combined filtrate was concentrated under vacuum ˜30-35° C.
16. additionthe residue was diluted with heptane/ethyl acetate (3v/3v)
17. concentrationfurther concentrated to a suspension
18. filtrationThe solid product was collected under vacuum by filtration
19. filtrationfilter
20. washThe solids were rinsed with heptane (3×1.25 v)
21. dry with materialthe damp solid was dried under vacuum at 30-35° C. with a slow N2
22. waitbleed for 90 h to a constant weight

ORD record

ord-c1751d75ac434e51a797d3e611e064f3

Source dataset

uspto-grants-2012_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08263613B2