2-(4-Fluorophenyl)acetic acid → 6-Chloro-2-(4-fluorophenyl)hexanoic acid

Step AE (1): NaHMDS (1.0 M in THF, 200 mL, 200 mmol) was added to a stirred solution of 2-(4-fluorophenyl)acetic acid (15.41 g, 100 mmol) in THF (200 mL) at 0° C. The resulting mixture was aged for 20 min at 0° C. and neat 1-chloro-4-iodobutane (21.85 g, 100 mmol) was added. The mixture was allowed to warm to rt. After 16 hr, the reaction was quenched with water (3 mL). The crude mixture was concentrated in vacuo. Aqueous NaOH (1 M, 150 mL) was added to the residue and the resulting mixture was extracted with Et2O (2×250 mL). The basic layer was acidified with aqueous HCl (1 M, 200 mL) and the resulting solution was extracted with Et2O (2×250 mL). The combined organic layers from the acidic extraction were washed with mixture of brine/1N HCl/sodium sulfite, dried (MgSO4), filtered, and concentrated in vacuo to afford 6-chloro-2-(4-fluorophenyl)hexanoic acid (22.8 g, 84 mmol, 84% yield) as a viscous oil that slowly solidified upon standing to provide a light brown solid. LC-MS (M−H)− 243.1. 1H NMR (500 MHz, chloroform-d) δ ppm 7.29 (dd, J=8.70, 5.34 Hz, 2 H) 7.03 (t, J=8.70 Hz, 2 H) 3.56 (t, J=7.63 Hz, 1 H) 3.51 (t, J=6.56 Hz, 2 H) 2.06-2.14 (m, 1 H) 1.74-1.85 (m, 3 H) 1.33-1.51 (m, 2 H).

1. waitAfter 16 hr
2. customthe reaction was quenched with water (3 mL)
3. concentrationThe crude mixture was concentrated in vacuo
4. additionAqueous NaOH (1 M, 150 mL) was added to the residue
5. extractionthe resulting mixture was extracted with Et2O (2×250 mL)
6. extractionthe resulting solution was extracted with Et2O (2×250 mL)
7. extractionThe combined organic layers from the acidic extraction
8. washwere washed with mixture of brine/1N HCl/sodium sulfite
9. dry with materialdried (MgSO4)
10. filtrationfiltered
11. concentrationconcentrated in vacuo

ORD record

ord-9a0eaba463f7410485c0bd7e6631d2ad

Source dataset

uspto-grants-2013_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08349880B2