Sodium hydride → Trifluoromethanesulfonate

Temperature

23 °C

A solution of (1R,3R,4S)-p-menth-3-yl(1R,6S)-4-methoxy-6-methyl-2-oxo-3-cyclohexene-1-carboxylate (4, 35.5 g, 110 mmol, 1 equiv) in ether (300 mL) was transferred by cannula over 15 min to a stirring suspension of sodium hydride (3.96 g, 165 mmol, 1.50 equiv) in ether (100 mL) at 0° C. The slurry was allowed to warm to 23° C. over approximately 10 min, and was stirred at that temperature for 5 h. Excess sodium hydride was quenched by the addition of 10-mL aliquots of water to the suspension at 30-min intervals until such point as gas evolution was no longer evident. The reaction mixture was then cooled to -78° C. and trifluoromethanesulfonic anhydride (29.6 mL, 176 mmol, 1.60 equiv) was added by syringe over 10 min. Upon completion of the latter addition, the reaction mixture was placed in an ice bath and was stirred for 30 min. The product solution was partitioned between aqueous phosphate buffer solution (pH 7, 0.05M in sodium hydrogen phosphate and 0.05M in potassium dihydrogen phosphate, 400 mL) and ether (400 mL). The aqueous layer was separated and extracted further with ether (2×400 mL). The combined organic layers were dried over sodium sulfate, and then were concentrated. The residue was purified by flash column chromatography (10% ethyl acetate-hexanes) to afford (1R,3R,4S)-p-menth-3-yl(S)-2-hydroxy-4-methoxy-6-methyl-1,3-cyclohexadiene-1-carboxylate, trifluoromethane-sulfonate (6) as a pale yellow oil (47.3 g, 95%). Due to its instability to storage, product 6 was typically carried directly on to the next step in the sequence. ##STR17##

1. customExcess sodium hydride was quenched by the addition of 10-mL aliquots of water to the suspension at 30-min intervals until such point as gas evolution
2. temperatureThe reaction mixture was then cooled to -78° C.
3. additionUpon completion of the latter addition
4. customthe reaction mixture was placed in an ice bath
5. stirringwas stirred for 30 min
6. customThe product solution was partitioned between aqueous phosphate buffer solution (pH 7, 0.05M in sodium hydrogen phosphate and 0.05M in potassium dihydrogen phosphate, 400 mL) and ether (400 mL)
7. customThe aqueous layer was separated
8. extractionextracted further with ether (2×400 mL)
9. dry with materialThe combined organic layers were dried over sodium sulfate
10. concentrationwere concentrated
11. customThe residue was purified by flash column chromatography (10% ethyl acetate-hexanes)

ORD record

ord-b427526166a14576866e5b65dcf5e53c

Source dataset

uspto-grants-1998_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05763451