8-Hydroxyquinoline → (3aR,6aR)-ethyl 1-(4'-(6-oxopyridazin-1(6H)-yl)biphenyl-4-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate

Temperatur

140 °C

A mixture of 1.98 g of copper (I) iodide (10.4 mmole, 0.10 eq.), 1.66 g of 8-hydroxyquinoline (11.44 mmole, 0.11 eq.), 4.0 g of potassium carbonate (28.94 mmole, 0.29 eq.) in 18.8 g of dimethylformamide (DMF) was mixed at ambient temperature. The mixture was added to another flask containing 41.6 g of the product of Example 41D (100.16 mmole, 1.00 eq.), 23.6 g of potassium carbonate (170.75 mmole, 1.70 eq.), and 14.4 g of pyridazinone (149.86 mmole, 1.50 eq.). Additional DMF (226 g) was used to transfer the catalyst slurry. The resulting mixture was deoxygenated then heated to 140° C. for about 18 hours. After cooling to ambient temperature the mixture was diluted with 567 g of THF and 384 g of 10% sodium chloride solution. The mixture was filtered to remove excess salts and the aqueous phase was separated and back extracted with an additional 177 g of THF. The combined organic phases were then washed with 10% sodium chloride solution (3×384 g). The organic phase was concentrated under reduced pressure and methanol (253 g) was added and the contents were concentrated under reduced pressure. After adding additional methanol (158 g) the contents were cooled to 0° C., filtered, and washed with cold methanol. The resulting solids were transferred to a vacuum oven to yield 35.31 g (81.9% yield). Mass Spectroscopy: 431.5 (m.w. 430.5). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (s, 3H), 1.78-1.88 (m, 1H), 2.10 (ddd, J=12.49, 6.17, 6.04 Hz, 1H), 3.03 (s, 1H), 3.24-3.35 (m, 5H), 3.53 (ddd, J=9.23, 6.86, 6.69 Hz, 2H), 3.67 (s, 1H), 4.00 (s, 2H), 4.22 (s, 1H), 6.63 (d, J=8.51 Hz, 2H), 7.07 (dd, J=9.47, 1.51 Hz, 1H), 7.48 (dd, J=9.47, 3.84 Hz, 1H), 7.53-7.60 (m, 4H), 7.68 (d, J=8.64 Hz, 2H), 8.06 (dd, J=3.84, 1.51 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 14.79 (CH3), 28.89 (CH2), 47.71 (CH2), 60.24 (CH2), 112.34 (CH), 124.87 (CH), 125.27 (CH), 126.02 (C), 126.89 (CH), 130.05 (CH), 131.69 (CH), 136.87 (CH), 138.78 (C), 139.31 (C), 145.61 (C), 153.53 (C), 158.64 (C).

1. additionwas mixed at ambient temperature
2. additionThe mixture was added to another flask
3. customThe resulting mixture was deoxygenated
4. temperatureAfter cooling to ambient temperature the mixture
5. additionwas diluted with 567 g of THF and 384 g of 10% sodium chloride solution
6. filtrationThe mixture was filtered
7. customto remove excess salts
8. customthe aqueous phase was separated
9. extractionback extracted with an additional 177 g of THF
10. washThe combined organic phases were then washed with 10% sodium chloride solution (3×384 g)
11. concentrationThe organic phase was concentrated under reduced pressure and methanol (253 g)
12. additionwas added
13. concentrationthe contents were concentrated under reduced pressure
14. additionAfter adding additional methanol (158 g) the contents
15. temperaturewere cooled to 0° C.
16. filtrationfiltered
17. washwashed with cold methanol
18. customto yield 35.31 g (81.9% yield)

ORD-Eintrag

ord-145d1967d4f44cb89cea776b8f8cf9b2

Quelldatensatz

uspto-grants-2013_03

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08399468B2