Chlorotrimethylsilane → (4-(1H-indol-5-yloxy)pyrimidin-2-yl)methyl acetate

Temperature

60 °C

To a suspension of nano zinc metallic powder (Strem Chemicals; average particle size 75-125 nm) (1.34 g, 20.52 mmol) in DMF (8 ml) is added 1,2-dibromoethane (0.19 mL, 2.2 mmol). The heterogeneous mixture is heated to 60° C. and then stirred for 10 min. The mixture is cooled to room temperature and charged with chlorotrimethylsilane (0.24 mL, 1.8 mmol). The reaction vessel is then sonicated in a room temperature water bath for 30 min. The suspension is then left standing for ca. 30 min to permit the solid to settle and the supernatant is then removed via syringe. DMF (8 ml) is then added, followed by bromomethyl acetate (1.00 mL, 10.3 mmol). The reaction mixture is then stirred for 2 hr at room temperature. The suspension is then left standing for 1 hour to permit the solid to settle. Next a separate flask is charged with 5-(2-chloropyrimidin-4-yloxy)-1H-indole (450 mg, 1.83 mmol), prepared as described in Example 73-A, DMF (3 mL) is then added to the 5-(2-chloropyrimidin-4-yloxy)-1H-indole followed by Pd(dppf)Cl2.CH2Cl2 (230 mg, 0.28 mmol). To this solution is added a portion of the supernatant (6 mL), from the flask containing the organozincate, via syringe. The reaction is heated at 50° C. for 16 h then cooled to room temperature and diluted with DCM and saturated aqueous NH1Cl. The layers are separated and the aqueous layer is extracted 2 additional times with DCM. The organic layers are combined dried over anhydrous Na2SO4, filtered, and concentrated.

1. temperatureThe mixture is cooled to room temperature
2. customThe reaction vessel is then sonicated in a room temperature water bath for 30 min
3. waitThe suspension is then left
4. waitstanding for ca. 30 min
5. customthe supernatant is then removed via syringe
6. additionDMF (8 ml) is then added
7. stirringThe reaction mixture is then stirred for 2 hr at room temperature
8. waitThe suspension is then left
9. waitstanding for 1 hour
10. customprepared
11. additionTo this solution is added a portion of the supernatant (6 mL)
12. additionfrom the flask containing the organozincate
13. temperatureThe reaction is heated at 50° C. for 16 h
14. temperaturethen cooled to room temperature
15. customThe layers are separated
16. extractionthe aqueous layer is extracted 2 additional times with DCM
17. dry with materialThe organic layers are combined dried over anhydrous Na2SO4
18. filtrationfiltered
19. concentrationconcentrated

ORD record

ord-8123e138a20e4c2bb38d0ed82b487dbd

Source dataset

uspto-grants-2013_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08541432B2