Isobutyric Acid → HCID 62397071, compound

Temperature

-78 °C

To a solution of diisopropylamine (3.31 mL, 23.22 mmol) in THF (5 mL) was added n-BuLi/hexane (9.29 mL, 23.22 mmol) dropwise at −78° C. The reaction mixture was stirred at −78° C. for 5 min and then stirred in ice bath for 20 min. The reaction mixture was added dropwise with a solution of isobutyric acid (1.055 mL, 11.61 mmol) in THF (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 30 min and 60° C. for 2 h. The flask was recooled to 0° C., and a solution of 2-fluorobenzaldehyde (1.441 g, 11.61 mmol) in THF (5 mL) was added dropwise. Then the solution was allowed to warm to rt and stirred for 16 h. The reaction was quenched with 1 N HCl until pH˜3 and extracted with EtOAc. The combined organic layers were washed with 1 N NaOH. The combined basic washes were acidified with HCl and extracted with EtOAc. Then organic phase was washed with sat. NaCl, dried over anhydrous MgSO4, and concentrated to yield 3-(2-fluorophenyl)-3-hydroxy-2,2-dimethylpropanoic acid (1.5 g, 60.9% yield) as Cap N-9. 1H NMR (400 MHz, DMSO-d6) ppm 7.50 (td, J=7.5, 1.8 Hz, 1H), 7.32 (tdd, J=7.7, 5.4, 1.8 Hz, 1H), 7.22 (td, J=7.5, 1.0 Hz, 1H), 7.14 (ddd, J=10.5, 8.3, 1.3 Hz, 1H), 5.28-5.11 (m, 1H), 3.33 (br. s., 1H), 1.06-0.97 (m, 3H), 0.93 (d, J=2.8 Hz, 3H).

1. stirringstirred in ice bath for 20 min
2. stirringThe reaction mixture was stirred at 0° C. for 30 min and 60° C. for 2 h
3. customwas recooled to 0° C.
4. temperatureto warm to rt
5. stirringstirred for 16 h
6. customThe reaction was quenched with 1 N HCl until pH˜3
7. extractionextracted with EtOAc
8. washThe combined organic layers were washed with 1 N NaOH
9. extractionextracted with EtOAc
10. washThen organic phase was washed with sat. NaCl
11. dry with materialdried over anhydrous MgSO4
12. concentrationconcentrated

ORD record

ord-79350993b2954ee89080322b0175dfcc

Source dataset

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09326973B2