Sodium Carbonate → 2-(2-Chloro-5-methylpyrimidin-4-yl)benzo[b]thiophen-4-ol

Temperatur

-70 °C

To a −65° C. solution of (benzo[b]thiophen-4-yloxy)(tert-butyl)dimethylsilane (6.25 g, 23.6 mmol) and triisopropylborate (4.89 g, 26.0 mmol) in THF (60 mL) is added lithium diisopropylamide (13.0 mL of a 2 M solution in heptane/THF/ethylbenzene, 26.0 mmol) dropwise over 5 minutes. The mixture is stirred for 2 hours at −70° C., whereupon the cold bath is removed and the mixture is allowed to warm to room temperature. After 2 hours, to the mixture is then added 2,4-dichloro-5-methylpyrimidine (3.85 g, 23.6 mmol), 2M Na2CO3 (23.6 mL, 47.2 mmol), 1,1′-bis(diphenylphosphino) ferrocene (655 mg, 1.18 mmol) and palladium(II) acetate (265 mg, 1.18 mmol) and the mixture is heated to reflux for 18 hours. Upon cooling to room temperature, the mixture is concentrated under reduced pressure, extracted from water (100 mL) with dichloromethane (3×150 mL) and the organic extracts are concentrated under reduced pressure. The crude material is subjected to chromatography on silica gel, eluting with dichloromethane in hexanes 50-100%, followed by CHCl3 in MeOH 0-100%, to obtain a dark solid. The crude material is extracted from 1 N NaOH (125 mL) with dichloromethane (3×100 mL). The aqueous layer is acidified with 5 N HCl, exhaustively extracted with 10% CHCl3/MeOH followed by 1:1 THF/dichloromethane and concentrated to yield a dark solid. Sonication of the solid in dichloromethane and filtration yielded the title compound as a brown solid (1.10 g, 12% yield).

1. customis removed
2. temperatureto warm to room temperature
3. waitAfter 2 hours
4. temperatureto reflux for 18 hours
5. temperatureUpon cooling to room temperature
6. concentrationthe mixture is concentrated under reduced pressure
7. extractionextracted from water (100 mL) with dichloromethane (3×150 mL)
8. concentrationthe organic extracts are concentrated under reduced pressure
9. washeluting with dichloromethane in hexanes 50-100%
10. customto obtain a dark solid
11. extractionThe crude material is extracted from 1 N NaOH (125 mL) with dichloromethane (3×100 mL)
12. extractionexhaustively extracted with 10% CHCl3/MeOH
13. concentrationconcentrated
14. customto yield a dark solid
15. filtrationfiltration

ORD-Eintrag

ord-7f6f18166168476f992db4e5ed633239

Quelldatensatz

uspto-grants-2009_06

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07547691B2