Hydrochloric Acid → HCID 67433711, compound

Temperature

40 °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 GM 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 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. concentrationwas then concentrated under partial vacuum to a low volume
2. additionMethanol (124 mL) was added
3. concentrationthe solution concentrated to an oil under partial vacuum
4. additionThe solution was then diluted with methanol (124 mL)
5. temperaturethe resulting mixture heated to 50° C.
6. temperaturebefore being cooled to 20° C
7. washThe solution was washed three times with dichloromethane (124 mL, 62 mL, 62 mL)
8. waitThe slurry was aged for 2 hours
9. concentrationthe mixture was concentrated under partial vacuum to a total volume of 124 mL
10. filtrationThe solid was collected by filtration
11. washwashed with water-methanol (1:1 v:v, 62 mL)

ORD record

ord-e18c777579cc4cdca2d247075940613f

Source dataset

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08551984B2