Oxalyl chloride → HCID 23113855, compound

To a solution of 2-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)-2-methylpropanoic acid obtained in Reference Example 156 (5.55 g, 16.3 mmol) in THF (50 mL) was added dropwise oxalyl chloride (2.13 mL, 24.5 mmol) with ice-cooling. The mixture was stirred for 20 minutes, and DMF (3 drops) was added thereto, and the mixture was stirred with ice-cooling for 30 minutes, and then, was warmed to room temperature. The solvent was removed by concentration under reduced pressure, and to a solution of the residue in dichloromethane (50 mL) was added aluminum chloride (3.26 g, 24.5 mmol) at −78° C., and the mixture was slowly warmed to room temperature. Ice was added to the reaction solution to separate the organic layer, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with a saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 3.35 g (yield 64%) of 7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one as crude product. To a solution of this compound (3.35 g, 10.4 mmol) in acetonitrile (40 mL) was added N-bromosuccinimide (1.85 g, 10.4 mmol) with ice-cooling, and the mixture was stirred for 30 minutes. The reaction solution was warmed to room temperature, to which water was added, which was extracted with ethyl acetate. The combined organic layer was washed with a saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19) to obtain 2.76 g (yield 66%) of 5-bromo-7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one as crude product. The compound (2.76 g, 6.89 mmol), palladium acetate (31 mg, 0.14 mmol) and BINAP (257 mg, 0.41 mmol) were mixed at room temperature, and the mixture was stirred under argon stream for 15 minutes. To the reaction solution was added sodium tert-butoxide (926 mg, 9.63 mmol) at room temperature, and the mixture was heated under argon stream at 110° C. for 16 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The combined organic layer was washed with water and a saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain 675 mg (yield 23%) of the title compound. Oily matter.

1. temperaturecooling
2. stirringthe mixture was stirred with ice-
3. temperaturecooling for 30 minutes
4. customThe solvent was removed by concentration under reduced pressure
5. temperaturethe mixture was slowly warmed to room temperature
6. additionIce was added to the reaction solution
7. customto separate the organic layer
8. extractionthe aqueous layer was extracted with ethyl acetate
9. washThe combined organic layer was washed with a saturated sodium hydrogen carbonate solution
10. dry with materialdried over anhydrous sodium sulfate
11. filtrationfiltered
12. concentrationconcentrated under reduced pressure
13. customThe obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4)

ORD record

ord-81d75eec7bbf4269b79ba5de21a54f97

Source dataset

uspto-grants-2009_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07507841B2