HCID 67185468, compound → HCID 67186464, compound

Temperature

0 °C

Intermediate 49 (0.726 g, 2.92 mmol) was dissolved in THF (100 mL) and cooled to 0° C. in an ice bath. BH3.Me2S complex (0.61 mL, 6.40 mmol) was added dropwise and the reaction mixture allowed to warm to r.t. The reaction mixture was heated to reflux for 5 h and allowed to cool to r.t. The reaction mixture was quenched with aqueous 2N NaOH (25 mL) and stirred at r.t. for 72 h. The reaction mixture was concentrated in vacuo and dissolved in EtOAc (100 mL), washed with aqueous 2N HCl (2×50 mL) and the combined aqueous fractions basified with solid NaOH pellets (ca 10 g) to raise the pH to pH 12. The aqueous fraction was extracted with EtOAc (3×50 mL) and the combined organic fractions were dried (MgSO4), filtered and concentrated in vacuo. The material from the initial EtOAc extraction was combined with the concentrated material and purified by column chromatography (SiO2, 0-25% [MeOH/DCM/NH4OH (50:50:1)]/DCM) to afford 0.493 g as a mixture of 6-fluoro-3-(morpholin-3-ylmethyl)indoline and title compound (1:3). The resulting mixture was dissolved in THF (7.5 mL) followed by the addition of DDQ (0.102 g, 0.452 mmol). The reaction mixture was irradiated in the microwave at 100° C. for 10 minutes. The reaction mixture was diluted with EtOAc (50 mL), washed with aqueous 2N NaOH (20 mL), brine (20 mL), dried (MgSO4), filtered, concentrated in vacuo and purified by column chromatography (SiO2, 0-25% [MeOH/DCM/NH4OH (50:50:1)]/DCM) to give the title compound (0.430 g, 61%) as an amber oil. δH (CDCl3) 8.04 (1H, br. s), 7.52 (1H, dd, J 8.7 and J 5.3 Hz), 7.00-7.09 (2H, m), 6.85-6.95 (1H, m), 3.90 (1H, dd, J 10.9 and J 2.8 Hz), 3.76-3.85 (1H, m), 3.49-3.61 (1H, m), 3.24-3.36 (1H, m), 3.17-3.03 (1H, m), 2.95-2.76 (3H, m), 2.62 (1H, dd, J 14.3 and J 9.0 Hz), 1.78 (1H, br. s). LCMS (ES+) 235.0 (M+H)+, RT 1.85 minutes (Method 2).

1. additionMe2S complex (0.61 mL, 6.40 mmol) was added dropwise
2. temperatureto warm to r.t
3. temperatureThe reaction mixture was heated
4. temperatureto reflux for 5 h
5. temperatureto cool to r.t
6. customThe reaction mixture was quenched with aqueous 2N NaOH (25 mL)
7. concentrationThe reaction mixture was concentrated in vacuo
8. dissolutiondissolved in EtOAc (100 mL)
9. washwashed with aqueous 2N HCl (2×50 mL)
10. temperatureto raise the pH to pH 12
11. extractionThe aqueous fraction was extracted with EtOAc (3×50 mL)
12. dry with materialthe combined organic fractions were dried (MgSO4)
13. filtrationfiltered
14. concentrationconcentrated in vacuo
15. extractionThe material from the initial EtOAc extraction
16. custompurified by column chromatography (SiO2, 0-25% [MeOH/DCM/NH4OH (50:50:1)]/DCM)
17. customto afford 0.493 g

ORD record

ord-6953b006efdd435a9dcc66c4df8ce021

Source dataset

uspto-grants-2012_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08242116B2