Acetyl chloride → 2-Hydroxy-4,4-dimethylpentanoic acid

A solution of (±)-4,4-dimethyl-2-hydroxypentanoic acid (f) (40.0 g, 0.274 mol) is prepared in acetyl chloride (70.0 mL, 0.984 mol) and stirred at room temperature for 2 hours. The solution is concentrated (40° C., 20 mm Hg), the residue dissolved in dichloromethane (300 mL), and treated sequentially with oxalyl chloride (30.0 mL, 0.344 mol) and dimethylformamide (0.2 mL, 3 mmol). After stirring overnight at room temperature, the solution is concentrated (40° C., 20 mm Hg), stirred in dichloromethane (400 mL), and treated with N,N-diisopropylethylamine (120 mL, 0.689 mol), dimethylaminopyridine (0.50 g, 4.1 mmol), and (R)-(−)-4-phenyl-2-oxazolidinone (50.0 g, 0.306 mol), resulting in a gentle reflux. After stirring overnight at room temperature, the mixture is washed with hydrochloric acid (1 N, 2×500 mL). The aqueous layer is extracted with dichloromethane (100 mL) and the organic layers are washed with sodium chloride (saturated aqueous, 200 mL), dried (magnesium sulfate), filtered, and the filtrate evaporated (40° C., 20 mm Hg) to provide 100 g of the crude diastereomers as a paste. The paste is divided into two 50 g portions and chromatographed on silica gel [1 kg, 100 mm column, 4:1:1 tert-butyl methyl ether/dichloromethane/hexanes] to provide 42.5 g of oxizolidinone (h) as a colorless solid (47%). An analytical sample is prepared by recrystallizing 0.78 g from 40 mL of 1:1 tBuOMe/hexanes to afford 0.61 g of pure (h) as white needles.

1. concentrationThe solution is concentrated (40° C., 20 mm Hg)
2. dissolutionthe residue dissolved in dichloromethane (300 mL)
3. stirringAfter stirring overnight at room temperature
4. concentrationthe solution is concentrated (40° C., 20 mm Hg)
5. stirringstirred in dichloromethane (400 mL)
6. customresulting in a gentle reflux
7. stirringAfter stirring overnight at room temperature
8. washthe mixture is washed with hydrochloric acid (1 N, 2×500 mL)
9. extractionThe aqueous layer is extracted with dichloromethane (100 mL)
10. washthe organic layers are washed with sodium chloride (saturated aqueous, 200 mL)
11. dry with materialdried (magnesium sulfate)
12. filtrationfiltered
13. customthe filtrate evaporated (40° C., 20 mm Hg)
14. customto provide 100 g of the crude diastereomers as a paste
15. customchromatographed on silica gel [1 kg, 100 mm column, 4:1:1 tert-butyl methyl ether/dichloromethane/hexanes]

ORD record

ord-779b36e60df446cfb127ac06fea246f3

Source dataset

uspto-grants-2004_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06747021B2