1-(3-Fluorophenyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane → 1,1-Dimethylethyl 4-(4-amino-2-fluorophenyl)-3,6-dihydro-1(2h)-pyridinecarboxylate

Temperature

-78 °C

A solution of 1-(3-fluorophenyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (EXAMPLE 20, Step 1, 19.1 g) in dry tetrahydrofuran (150 mL) at −78° C. under N2 is treated with sec-butyllithium (1.3 M in cyclohexane, 60.3 mL) dropwise over ten minutes, and the resulting mixture is stirred at −78° C. for 2.25 hours. A solution of zinc chloride (0.5 M in tetrahydrofuran, 150 mL) is then added over 15 minutes, and the mixture is allowed to warm to ambient temperature over one hour with stirring. A solution of 3,6-dihydro-4-[[(trifluoromethyl)-sulfonyl]oxy]1(2 H)-pyridinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step, 2, 20.8 g) in dry tetrahydrofuran (63 mL) and tetrakis(triphenylphosphine)palladium(0) (1.45 g) is added, and the mixture is degassed, heated up to reflux, refluxed for five minutes, cooled to ambient temperature and stirred for 12 hours. The mixture is then diluted with water (150 mL), the layers are separated, the aqueous phase is extracted with diethyl ether (2×100 mL) and the combined organic phase is washed with water (100 mL) and saline (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is then dissolved in methanol (630 mL) and treated with anhydrous potassium carbonate (17.3 g), and the mixture is stirred at ambient temperature for 40 minutes, concentrated under reduced pressure, diluted with water (100 mL) and extracted with diethyl ether (2×150 mL). The combined organic phase is washed with water (50 mL) and saline (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 1 kg), eluting with a gradient of ethyl acetate/hexane (15/85-50/50). Pooling and concentration of those fractions with an Rf=0.17 by TLC (ethyl acetate/hexane, 26/75) gives the title compound, mp 123-125° C.

1. temperatureto warm to ambient temperature over one hour
2. stirringwith stirring
3. customthe mixture is degassed
4. temperatureheated up
5. temperatureto reflux
6. temperaturerefluxed for five minutes
7. temperaturecooled to ambient temperature
8. stirringstirred for 12 hours
9. additionThe mixture is then diluted with water (150 mL)
10. customthe layers are separated
11. extractionthe aqueous phase is extracted with diethyl ether (2×100 mL)
12. washthe combined organic phase is washed with water (100 mL) and saline (100 mL)
13. dry with materialdried over anhydrous magnesium sulfate
14. concentrationconcentrated under reduced pressure
15. dissolutionThe residue is then dissolved in methanol (630 mL)
16. additiontreated with anhydrous potassium carbonate (17.3 g)
17. stirringthe mixture is stirred at ambient temperature for 40 minutes
18. concentrationconcentrated under reduced pressure
19. additiondiluted with water (100 mL)
20. extractionextracted with diethyl ether (2×150 mL)
21. washThe combined organic phase is washed with water (50 mL) and saline (50 mL)
22. dry with materialdried over anhydrous magnesium sulfate
23. concentrationconcentrated under reduced pressure
24. customto give the crude product which
25. customis chromatographed on silica gel (230-400 mesh, 1 kg)
26. washeluting with a gradient of ethyl acetate/hexane (15/85-50/50)

ORD record

ord-b13b6b16c4034c13b155d21c099da0a5

Source dataset

uspto-grants-2001_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06313307B1