1,1,3,3-Tetramethylguanidine → (R)-5,5-difluoro-4-[5-fluoro-2-(4-methoxy-benzyl)-1H-indol-6-yl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine

関与物質

反応条件

反応手順

A solution of (R)-4-(5-amino-2-fluoro-4-iodo-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate B6.1) (100 mg, 260 μmol) N,N-dimethylformamide (0.5 ml) was purged with argon for 10 minutes. Thereafter, 1,1,3,3-tetramethylguanidine (74.8 mg, 81.3 μl, 649 μmol), bis-(triphenylphosphin)-palladium(II)dichlorid (9.11 mg, 13.0 μmol) and copper (I) iodide (7.42 mg, 38.9 μmol) were added. After 5 minutes at room temperature, a solution of 1-methoxy-4-prop-2-ynyl-benzene (CAS [13540-76-6]) (45.5 mg, 312 μmol) in N,N-dimethylformamide (0.2 ml) was added and the reaction mixture was stirred at 80° C. for 15 hours. For the workup, the reaction mixture was allowed to cool to room temperature, then it was diluted with a saturated solution of sodium hydrogencarbonate and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated at reduced pressure. The crude product was purified by flash chromatography on a silica-NH2 phase using a gradient of heptane/ethyl acetate=100:0 to 0:100 as the eluent. The (R)-5,5-difluoro-4-[5-fluoro-2-(4-methoxy-benzyl)-1H-indol-6-yl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (35 mg, 33% yield) was obtained as a light green foam. MS (ISP): m/z=404.4 [M+H]+.

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