Diisopropylethylamine → Ethyl 1-benzyl-4-fluoropiperidine-4-carboxylate

Temperature

-78 °C

A flask was charged with DIEA (8.64 mL, 60.6 mmol) and THF (100 mL). The mixture was cooled to about −78° C. followed by the addition of n-BuLi (24.3 mL, 60.6 mmol) over about 5 min. The mixture was warmed to about 0° C. and stirred for about 30 min and then cooled to about −40° C. To the mixture was added a solution of ethyl 1-benzylpiperidine-4-carboxylate (10.0 g, 40.4 mmol, Oakwood) in THF (75 mL) over about 10 min such that the solution is kept between −40 to −30° C. The mixture was stirred for about 1 h at about −10° C. before being cooled to about −78° C. A solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (14.0 g, 44.5 mmol) in THF (75 mL) was added over about 20 min while keeping the mixture between about −65 and −78° C. The mixture was then stirred for about 1 h at about −78° C. The mixture was poured into a separatory funnel containing ice water (30 mL) and EtOAc (30 mL) was added. The aqueous layer was extracted with EtOAc (3×25 mL) and the combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting mixture was adsorbed onto silica gel and purified by flash silica gel chromatography eluting with hexanes/EtOAc (10:1) to afford ethyl 1-benzyl-4-fluoropiperidine-4-carboxylate (7.13 g, 66%): LC/MS (Table 2, Method h) Rt=2.21 min; MS m/z: 266 (M+H)+.

1. temperatureThe mixture was warmed to about 0° C.
2. temperaturecooled to about −40° C
3. customis kept between −40 to −30° C
4. stirringThe mixture was stirred for about 1 h at about −10° C.
5. temperaturebefore being cooled to about −78° C
6. customthe mixture between about −65 and −78° C
7. stirringThe mixture was then stirred for about 1 h at about −78° C
8. additionThe mixture was poured into a separatory funnel
9. additionwas added
10. extractionThe aqueous layer was extracted with EtOAc (3×25 mL)
11. washthe combined organic extracts were washed with brine
12. dry with materialdried over anhydrous Na2SO4
13. filtrationfiltered
14. concentrationconcentrated under reduced pressure
15. custompurified by flash silica gel chromatography
16. washeluting with hexanes/EtOAc (10:1)

ORD record

ord-ac7d0fa03fcd4542aa0c1da292601c9f

Source dataset

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08551981B2