反应详情

To a stirred mixture of [3-(5-trifluoromethyl-pyridin-2-yloxy)-benzyl]-phosphonic acid diethyl ester (155.7 g, 0.40 mol) in tetrahydrofuran (800 mL) at −10° C. was added dropwise over a 5 min period 1.0 M tBuOK in tetrahydrofuran (420.0 mL, 0.42 mol). The temperature rose to −3° C. during the addition. The resulting red mixture was stirred between −6° C. and −10° C. for 2.5 h. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (79.7 g, 0.40 mol) in tetrahydrofuran (300 mL) was added dropwise over a 5 min period. The temperature rose to 2° C. The resulting red mixture was stirred at temperatures reaching 21° C. over the next 16 h. TLC showed product with no phosphonate present. The mixture was poured into 3.5 L of stirred ice-water. The resulting suspension was stirred at ambient temperature for 2.5 h and then was extracted with successive 1.0 L and 0.6 L portions of dichloromethane. The combined extracts were washed with 500 mL of brine, dried over magnesium sulfate and concentrated in vacuo to a thick semi solid residue. 250 mL of methyl t-butyl ether was added. The suspension was stirred at −10° C. for 2 h and filtered. Drying in vacuo at 25° C. for 66 h provided 85 g (49%) of product. The filtrate was concentrated in vacuo to a damp solid residue. This was taken up in 100 mL of methyl t-butyl ether. To the stirred suspension was added 300 mL of heptane and the resulting suspension was stirred at −10° C. for 2 h. The solid was filtered off, rinsed with 50 mL of methyl t-butyl ether:heptane (1:3) and pressed dry under suction. Further drying in vacuo at 34° C. for 6 h provided an additional 34.2 g (19.5%) of product. Total yield=119.2 g (68.5%).

1. additionThe temperature rose to −3° C. during the addition
2. customrose to 2° C
3. stirringThe resulting red mixture was stirred at temperatures
4. customreaching 21° C. over the next 16 h
5. stirringThe resulting suspension was stirred at ambient temperature for 2.5 h
6. extractionwas extracted with successive 1.0 L and 0.6 L portions of dichloromethane
7. washThe combined extracts were washed with 500 mL of brine
8. dry with materialdried over magnesium sulfate
9. concentrationconcentrated in vacuo to a thick semi solid residue
10. addition250 mL of methyl t-butyl ether was added
11. stirringThe suspension was stirred at −10° C. for 2 h
12. filtrationfiltered
13. customDrying in vacuo at 25° C. for 66 h