Water → HCID 86722466, compound

Temperature

19 °C

A flask was charged with 1-(4-fluorophenyl)-5-methylene-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinoline (113, R1=4-Fluorophenyl) (44.0 g, 158 mmol), MeOH (1050 mL) and water (105 mL). [Hydroxy(tosyloxy)iodo]benzene (61.8 g, 158 mmol) was dissolved in MeOH (160 mL) then the solution was added dropwise to the stirred 1-(4-fluorophenyl)-5-methylene-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinolone slurry. The internal temperature of the reaction mixture was maintained at about 18 to 20° C. during the addition. The addition was carried out over about 1 h. After about 90 min [hydroxy(tosyloxy)iodo]benzene (3.09 g, 7.88 mmol) was added and the mixture was stirred for about 1 h. A third portion of [hydroxy(tosyloxy)iodo]benzene (2.5 g, 6.37 mmol) was added then after about 15 min the reaction mixture was concentrated under reduced pressure to remove about 1 L solvent (˜70 torr, bath temp ˜40° C.). Water (1.5 L) was added to the mixture and the resulting slurry was stirred for about 4 h at rt. The solids were collected by filtration then the pad was washed with about 150 mL water. The material was air dried then dissolved in DCM (500 mL) then washed with a mixture of water (100 mL) with sat. aq. NaHCO3 (100 mL). The organic solution was dried over MgSO4, filtered and the filtrate concentrated to dryness under reduced pressure. The material was treated with DCM (100 mL) then the slurry was poured onto a filter funnel containing 500 gram silica gel pre-gelled with DCM. The pad was washed with DCM (500 mL) then 9:1 DCM/EtOAc (2 L). Filtrate containing desired product was concentrated under reduced pressure then the material was treated with DCM (50 mL) and heptane (250 mL). The solids were collected by filtration and washed with heptane (100 mL). The material was dried under vacuum at about 70° C. to yield 1-(4-fluorophenyl)-5,7,8,9-tetrahydrocyclohepta[b]pyrazolo[4,3-e]pyridin-6(1H)-one (114, R1=4-Fluorophenyl) (36.78 g, 79%). LC/MS, method 3, Rt=2.31 min, MS m/z 296 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 8.34-8.28 (m, 2H), 8.16 (s, 1H), 7.46-7.38 (m, 2H), 3.92 (s, 2H), 3.36-3.28 (m, 2H), 2.57 (t, J=6.9 Hz, 2H), 2.05-1.94 (m, 2H).

1. additionThe addition
2. concentrationafter about 15 min the reaction mixture was concentrated under reduced pressure
3. customto remove about 1 L solvent (˜70 torr, bath temp ˜40° C.)
4. additionWater (1.5 L) was added to the mixture
5. stirringthe resulting slurry was stirred for about 4 h at rt
6. filtrationThe solids were collected by filtration
7. washthe pad was washed with about 150 mL water
8. customdried
9. dissolutionthen dissolved in DCM (500 mL)
10. washthen washed with a mixture of water (100 mL) with sat. aq. NaHCO3 (100 mL)
11. dry with materialThe organic solution was dried over MgSO4
12. filtrationfiltered
13. concentrationthe filtrate concentrated to dryness under reduced pressure
14. additionThe material was treated with DCM (100 mL)
15. additionthe slurry was poured onto a filter funnel
16. additioncontaining 500 gram silica gel pre-gelled with DCM
17. washThe pad was washed with DCM (500 mL)
18. additionFiltrate containing desired product
19. concentrationwas concentrated under reduced pressure
20. additionthe material was treated with DCM (50 mL) and heptane (250 mL)
21. filtrationThe solids were collected by filtration
22. washwashed with heptane (100 mL)
23. customThe material was dried under vacuum at about 70° C.

ORD record

ord-5d0ee16ae4034f48ae41dbeb4318c314

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09193744B2