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With sodium hydride; In 1-methyl-pyrrolidin-2-one; mineral oil; at 90℃; for 1h; |
(Boc)20 (535 mg, 2.45 mmol) was added to a stirred solution of 4-(3-(3-amino-4- methylphenyl)-1 ,2,4-oxadiazol-5-yl)butan-2-one (88c) (200 mg, 0.82 mmol) and DMAP (catalytical amount) in dichloromethane (2 mL). The reaction was stirred at room temperature overnight. The mixture was diluted with dichloromethane (20 mL) and washed with brine. The organic layers were combined, dried over Na2S04, filtered and concentrated to give 4-(3-(3-[bis[(1 ,1 -dimethylethoxy)carbonyl]amino]-4-methylphenyl)- 1 ,2,4-oxadiazol-5-yl)butan-2-one (139) (200 mg, 55% yield). MS m/z 468.1 (M+23)+. To a solution of 4-(3-(3-[bis[(1 ,1 -dimethylethoxy)carbonyl]amino]-4-methylphenyl)- 1 ,2,4-oxadiazol-5-yl)butan-2-one (139) (200 mg, 0.45 mmol) and TBAF (0.5 M in THF, 0.9 mL) in anydrous THF (2.5 mL) at 0 C was added trifluoromethyltrimethylsilane dropwise (excess) and the reaction was stirred to room temperature for 15 minutes. The reaction was checked by LCMS. More trifluoromethyltrimethylsilane was added dropwise until reaction was completed by LCMS. The reaction was quenched with water, then the solvent was removed and the crude product was dissolved in ethyl acetate. The organic phase was washed with water then brine and dried over anhydrous sodium sulfate. The crude product was purified by silica chromatography to yield 4-(3-(3-[bis[(1 ,1 - dimethylethoxy)carbonyl]amino]-4-methylphenyl)-1 ,2,4-oxadiazol-5-yl)-1 ,1 ,1 -trifluoro-2- methylbutan-2-ol (140) 1 H NMR (400MHz, CDCI3) delta 7.89 (d, J = 8.0 Hz, 1 H), 7.77 (s, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 3.16 (m, 2H), 2.16-2.44 (m, 5H), 1 .39 (m, 18H), 1 .24 (s, 3H). MS m/z 538.1 (M+23) +. To a solution of 4-(3-(3-[bis[(1 ,1 -dimethylethoxy)carbonyl]amino]-4-methylphenyl)- 1 ,2,4-oxadiazol-5-yl)-1 ,1 ,1 -trifluoro-2-methylbutan-2-ol (140) (27 mg, 0.052 mmol) in NMP (1 .0 mL) was added NaH (12.5 mg, 60% wt in mineral oil, 0.312 mmol) and Mel (44 mg, 0.312 mmol). The resulting mixture was heated at 90 C for 1 hour. The reaction was quenched with water and extracted with EtOAc. The organic layers were combined and concentrated to yield a residue which was dissolved in TFA (0.5 mL) and stirred at room temperature for 10 minutes. Then 2M aqueous Na2C03 (5 mL) was added and extrated with EtOAc. The organic layers were dried over Na2S04, filtered and concentrated to give crude 2-methyl-5-(5-(4,4,4-trifluoro-3-methoxy-3-methylbutyl)-1 ,2,4-oxadiazol-3-yl)aniline (141 ) which was used without further purification. MS m/z 344.1 (M+1 ) +. |