Water → 2-Methoxybenzoic acid

Temperature

125 °C

(S)-5-(6-Methoxy-1-methyl-2,3-dihydro-1H-inden-1-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione (290 mg, 960 μmol) was dissolved in N-methylpyrrolidinone (2 mL). Water (17.2 μL, 960 μmol) was added, and the reaction was heated and stirred at 125° C. for one hour to give the intermediate anisole carboxylic acid. The reaction was cooled and NaOH (170 mg, 4.3 mmol) and 1-dodecanethiol (0.80 mmol, 3.3 mmol) were added. The reaction was reheated to 125° C. and stirred for 2.5 days. Another 2.25 equivalents of NaOH was added along with 1.75 equivalents of the thiol. The resulting mixture was stirred at 125° C. for an additional 16 hours. The reaction was then cooled to room temperature and diluted with water (about 25 mL). The resulting mixture was extracted with diethyl ether (2×50 mL) and then the aqueous layer was acidified with hydrochloric acid. The aqueous layer was extracted with EtOAc (2×75 mL). The combined EtOAc layers were washed with water (2×75 mL) and brine (1×25 mL) and dried over magnesium sulfate. The organic layer was filtered and the solvent was removed. The residue was used directly in the next step (S)-2-(6-hydroxy-1-methyl-2,3-dihydro-1H-inden-1-yl)acetic acid (370 mg, 190% yield) (contains residual NMP). The (S)-2-(6-hydroxy-1-methyl-2,3-dihydro-1H-inden-1-yl)acetic acid (197 mg, 955 mmol) was dissolved in MeOH (10 mL) and a catalytic amount of sulfuric acid was added. The mixture was heated at reflux and stirred for three hours. The reaction was cooled, basified with saturated sodium bicarbonate, and the solvent was removed. The residue was then partitioned between EtOAc and water, and the layers were separated. The aqueous layer was extracted with EtOAc (1×50 mL), and the combined organic layers were washed with brine (1×25 mL) and dried over magnesium sulfate. After filtration and solvent removal, the residue was purified by medium pressure chromatography (silica, 0 to 15% EtOAc:DCM) to give (S)-methyl 2-(6-hydroxy-1-methyl-2,3-dihydro-1H-inden-1-yl)acetate (141 mg, 67% yield). LCMS ESI (neg.) m/e: 219.1 (M−1)−. Chiral Analytical HPLC (ChiralPak AD-H column, 8% isopropanol:hexanes): retention time=18.1 minutes (second peak).

1. temperaturethe reaction was heated

ORD record

ord-823fa2c9fce74ef9ab8dd09efa5f44b0

Source dataset

uspto-grants-2013_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08450522B2