Hexamethyldisilazane → (R)-4-benzyl-3-((R)-2-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-3-methylbutanoyl)-oxazolidin-2-one

To a stirred solution of hexamethyldisilazane (200 mg, 1.24 mmol) in anhydrous THF (2 mL) cooled to −78° C. under N2 was added dropwise 2.5 M n-BuLi (0.5 mL, 1.25 mol) over 30 min. After stirring for an additional 30 min, a solution of (R)-4-benzyl-3-(3-methylbutanoyl)oxazolidin-2-one (313 mg, 1.2 mmol) in THF (2 mL) was added dropwise to the reaction mixture. The mixture was stirred at −78° C. for 2 h and a solution of 6-(bromomethyl)-1-(3-methoxypropyl)-1H-indazole (300 mg, 1.1 mmol) in THF (2 mL) was added. The mixture was allowed to warm from −78° C. to 0° C. over 2 h and stirred at it for 18 h. 10% aq NH4Cl was added and the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel to give (R)-4-benzyl-3-((R)-2-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-3-methylbutanoyl)-oxazolidin-2-one (250 mg, 49%). 1H NMR (400 MHz, CDCl3): 1.09 (m, 6H), 1.96 (m, 1H), 2.09 (m, 3H), 2.61 (m, 1H), 3.12 (m, 2H), 3.22 (m, 2H), 3.29 (s, 3H), 3.89 (m, 1H), 4.02 (m, 1H), 4.35 (m, 1H), 4.40 (m, 1H), 4.59 (m, 1H), 6.75 (m, 2H), 7.07 (m, 3H), 7.13 (m, 1H), 7.26 (m, 1H), 7.33 (m, 1H), 7.61 (m, 1H), 7.91 (m, 1H); MS: 464 (M++1)

1. stirringThe mixture was stirred at −78° C. for 2 h
2. temperatureto warm from −78° C. to 0° C. over 2 h
3. stirringstirred at it for 18 h
4. extractionthe mixture was extracted with EtOAc (3×10 mL)
5. washThe combined organic layers were washed with brine
6. dry with materialdried over Na2SO4
7. concentrationconcentrated
8. customThe residue was purified by flash chromatography on silica gel

ORD record

ord-b909c1a4ba1140f49675c957a2b5003d

Source dataset

uspto-grants-2011_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08084485B2