Aluminium lithium hydride → (3,3-Difluoro-1-methyl-cyclobutyl)methanol

Temperature

-40 °C

To a solution of the 3,3-difluoro-1-methylcyclobutanecarboxylic acid (150 mg, 0.999 mmol) in diethyl ether (5 mL) was added to a suspension of LAH (2.198 mL, 2.198 mmol, 1M in THF) in diethyl ether (2 mL) at −40° C. The reaction mixture was stirred at −40° C. for 1 h and allowed to warm to RT and stirred for 15 h. The reaction mass cooled to −40° C. and quenched with sequential addition of water (10 mL), 10% aqueous solution of NaOH (10 mL) and water (10 mL). Diethyl ether (15 mL) was then added and the solution was stirred for 2 h. The organic layer was separated and the aqueous phase was extracted with diethyl ether (3×15 mL). The combined organic layer was dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The crude sample was purified by silica gel chromatography (12 g REDISEP® column, eluting with 30% EtOAc in petroleum ether). Fractions containing the product were combined and evaporated to afford the Intermediate 229A as a pale yellow oil (100 mg, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.92 (t, J=5.52 Hz, 1H) 3.27 (d, J=4.02 Hz, 2H), 2.55-2.45 (m, 2H), 2.07-2.21 (m, 2H), 1.07-1.17 (m, 3H).

1. temperatureto warm to RT
2. stirringstirred for 15 h
3. temperatureThe reaction mass cooled to −40° C.
4. customquenched with sequential addition of water (10 mL), 10% aqueous solution of NaOH (10 mL) and water (10 mL)
5. additionDiethyl ether (15 mL) was then added
6. stirringthe solution was stirred for 2 h
7. customThe organic layer was separated
8. extractionthe aqueous phase was extracted with diethyl ether (3×15 mL)
9. dry with materialThe combined organic layer was dried over Na2SO4
10. filtrationfiltered
11. concentrationthe filtrate concentrated under reduced pressure
12. customThe crude sample was purified by silica gel chromatography (12 g REDISEP® column, eluting with 30% EtOAc in petroleum ether)
13. additionFractions containing the product
14. customevaporated

ORD record

ord-20e09ad49f8f4fea879e89fb649be1a4

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09273058B2