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 1D (100.16 mmole, 1.00 eq.), 23.6 g of potassium carbonate (170.75 mmole, 1.70 eq.), and 14.4 g of 3(2H)-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% NaCl 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% NaCl solution (3×384 g). The organic phase was concentrated under reduced pressure and MeOH (253 g) was added and the contents were concentrated under reduced pressure. After adding additional MeOH (158 g), the contents were cooled to 0° C., filtered, and washed with cold MeOH. 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, 3 H), 1.78-1.88 (m, 1 H), 2.10 (ddd, J=12.49, 6.17, 6.04 Hz, 1H), 3.03 (s, 1 H), 3.24-3.35 (m, 5 H), 3.53 (ddd, J=9.23, 6.86, 6.69 Hz, 2 H), 3.67 (s, 1 H), 4.00 (s, 2 H), 4.22 (s, 1 H), 6.63 (d, J=8.51 Hz, 2 H), 7.07 (dd, J=9.47, 1.51 Hz, 1 H), 7.48 (dd, J=9.47, 3.84 Hz, 1 H), 7.53-7.60 (m, 4 H), 7.68 (d, J=8.64 Hz, 2 H), 8.06 (dd, J=3.84, 1.51 Hz, 1 H). 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
5. additionthe mixture was diluted with 567 g of THF and 384 g of 10% NaCl 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% NaCl solution (3×384 g)
11. concentrationThe organic phase was concentrated under reduced pressure and MeOH (253 g)
12. additionwas added
13. concentrationthe contents were concentrated under reduced pressure
14. additionAfter adding additional MeOH (158 g)
15. temperaturethe contents were cooled to 0° C.
16. filtrationfiltered
17. washwashed with cold MeOH
18. customto yield 35.31 g (81.9% yield)

ORD-Eintrag

ord-ff578ea522604ea0ae3324d1cd9ef64a

Quelldatensatz

uspto-grants-2011_09

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08026240B2