Citric Acid → 6-[4-(2-Bromo-5-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one

663 mg (1.56 mol) of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin-periodinane, cf. D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277) is added to a solution of 250 mg (0.78 mmol) of 4-(2-bromo-5-fluorophenyl)-2-hydroxy-4-methylvaleric acid-methyl ester in 10 ml of dichloromethane. After 1.5 hours at room temperature, the batch is diluted with 150 ml of MTBE, washed with a solution of 1.2 g of NaHCO3 and 4.0 g of Na2SO3 in 50 ml of water, saturated NaHCO3 and saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. The residue (250 mg) is taken up in 16 ml of THF-EtOH (1:1) and mixed with 3.9 ml (3.9 mmol) of a 1 M sodium hydroxide solution. After 30 minutes, the batch is concentrated in a vacuum, diluted with 20 ml of water and washed with MTBE. The aqueous phase is acidified with 10% sulfuric acid (pH 2) and extracted with 100 ml of ethyl acetate and 100 ml of dichloromethane. The combined extracts are dried (NaSO4) and concentrated by evaporation in a vacuum. 0.06 ml (0.92 mmol) of thionyl chloride is added in drops at −6° C. to the solution of the residue (230 mg) in 5 ml of dimethyl acetamide. After 20 minutes at −6° C., 201 mg (1.14 mmol) of 6-amino-4-methyl-2,3-benzoxazin-1-one is added to it. The batch is stirred for 15 hours at room temperature, acidified with 50 ml of 10% citric acid and shaken out with 150 ml of MTBE. The organic phase is washed with saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 290 mg of product.

1. washwashed with a solution of 1.2 g of NaHCO3 and 4.0 g of Na2SO3 in 50 ml of water, saturated NaHCO3 and saturated NaCl
2. dry with materialdried (Na2SO4)
3. concentrationconcentrated by evaporation in a vacuum
4. additionmixed with 3.9 ml (3.9 mmol) of a 1 M sodium hydroxide solution
5. waitAfter 30 minutes
6. concentrationthe batch is concentrated in a vacuum
7. additiondiluted with 20 ml of water
8. washwashed with MTBE
9. extractionextracted with 100 ml of ethyl acetate and 100 ml of dichloromethane
10. dry with materialThe combined extracts are dried (NaSO4)
11. concentrationconcentrated by evaporation in a vacuum
12. waitAfter 20 minutes at −6° C.
13. washThe organic phase is washed with saturated NaCl
14. dry with materialdried (Na2SO4)
15. concentrationconcentrated by evaporation in a vacuum

ORD record

ord-73b52b98312d48788643857ee078b523

Source dataset

uspto-grants-2006_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07129270B2