Boron trifluoride → HCID 67430748, compound

Temperature

-78 °C

To a solution of methyl (1S)-2,2-dimethyl-4-oxocyclohexanecarboxylate (10 g, 54.28 mmol)) in THF (16.3 g) was added additional THF (184 mL) followed by thiazole (6.93 g, 81.42 mmol). The resulting solution was then cooled to −78° C. Boron trifluoride diethyletherate (9.24 g, 65.14 mmol) was added over 24 minutes and the resulting mixture aged at −78° C. for 5 minutes. n-Butyllithium (2.5M in hexanes, 20.05 g, 71.98 mmol) was added to the mixture subsurface over 4 hours and the mixture was aged for 15 mins. Sodium hydroxide (1M aqueous solution, 54.3 mL, 54.3 mmol) was added followed by MTBE (54 mL) and the mixture was warmed to 20° C. The aqueous layer was separated and the organic layer was washed with a half saturated aqueous solution of sodium chloride (54 mL) resulting in a light yellow solution of methyl (1S,4R)-4-hydroxy-2,2-dimethyl-4-(1,3-thiazol-2-yl)cyclohexanecarboxylate, which was then concentrated under partial vacuum to a low volume. Methanol (124 mL) was added and the solution concentrated to an oil under partial vacuum. The solution was then diluted with methanol (124 mL) and heated to 40° C. A solution of 1M sodium hydroxide (92 mL, 92.0 mmol) was added over 5 minutes and the resulting mixture heated to 50° C. then aged for 16 hours before being cooled to 20° C. The solution was washed three times with dichloromethane (124 mL, 62 mL, 62 mL) and the aqueous methanol solution of the product was crystallised by addition of 6M aqueous HCl (15.3 mL, 92 mmol) over 30 mins. The slurry was aged for 2 hours then the mixture was concentrated under partial vacuum to a total volume of 124 mL. The solid was collected by filtration and washed with water-methanol (1:1 v:v, 62 mL) then water (62 mL) to give the title compound (11.44 g, 41.86 mmol, 99.9% ee) as a pale yellow solid. MS ESI: [M+H]+ 256.1 1H NMR (400 MHz, DMSO-d6): 11.89-12.09 (br s, 1H), 7.67 (d, J=3.5 Hz, 1H), 7.53 (d, J=3.5 Hz, 1H), 5.79 (s, 1H), 3.36 (br s, 2H), 2.13-2.20 (m, 2H), 1.95-2.09 (m, 1H), 1.76-1.91 (m, 3H), 1.53-1.65 (m, 2H), 1.11 (s, 3H), 0.99 (s, 3H).

1. waitthe mixture was aged for 15 mins
2. temperaturethe mixture was warmed to 20° C
3. customThe aqueous layer was separated
4. washthe organic layer was washed with a half saturated aqueous solution of sodium chloride (54 mL)

ORD record

ord-b916e3b9b344466c843291c0382083ef

Source dataset

uspto-grants-2014_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08759366B2