(3S)-3-amino-2-methylbutan-2-ol

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (3) (1.193 g, 8.56 mmol) at 0° C. in pyridine (24 ml) was added trichloroacetyl chloride (1.05 ml, 9.41 mmol). After stirring at this temperature for 10 minutes, the reaction mixture was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous sodium chloride solution, after which the product was extracted with dichloromethane and the combined organic extracts were washed with hydrochloric acid (1M). Concentration in vacuo and purification by flash column chromatography using 30% ethyl acetate/40-60 petroleum ether as eluant furnished the title compound (4) (1.992 g, 94%) as an oil; νmax (CH2Cl2) 1713 cm-1 ; [α]D24 (c 1.2 in CHCl3)=+6.3; (Found: C, 33.71; H, 5.12; N, 5.72. C7H12Cl3NO2 requires C, 33.83; H, 4.87; N, 5.64%); δH (200 MHz; CDCl3) 1.21 (3H, d, J=3.4, CH3CH), 1.25 (3H, s, C(CH3)2), 1.26 (3H, s, C(CH3)2), 2.31 (1H, s, OH), 3.82 (1H, dq, J=6.7 and 8.8, CHCH3NH), 7.1 (1H, s, NH); δC (125 MHz; CDCl3) 14.89 (CH3), 26.68 (CH3), 27.56 (CH3), 55.19 (CH), 72.01 (C), 92.82 (CCl3), 161.56 (CO); m/z (CI+, NH3) 248 (M+). the reaction mixture was stirred overnight at room temperature The reaction was quenched by the addition of saturated aqueous sodium chloride solution after which the product was extracted with dichloromethane the combined organic extracts were washed with hydrochloric acid (1M) Concentration in vacuo and purification by flash column chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (3) (1.193 g, 8.56 mmol) at 0° C. in pyridine (24 ml) was added trichloroacetyl chloride (1.05 ml, 9.41 mmol). After stirring at this temperature for 10 minutes, the reaction mixture was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous sodium chloride solution, after which the product was extracted with dichloromethane and the combined organic extracts were washed with hydrochloric acid (1M). Concentration in vacuo and purification by flash column chromatography using 30% ethyl acetate/40-60 petroleum ether as eluant furnished the title compound (4) (1.992 g, 94%) as an oil; νmax (CH2Cl2) 1713 cm-1 ; [α]D24 (c 1.2 in CHCl3)=+6.3; (Found: C, 33.71; H, 5.12; N, 5.72. C7H12Cl3NO2 requires C, 33.83; H, 4.87; N, 5.64%); δH (200 MHz; CDCl3) 1.21 (3H, d, J=3.4, CH3CH), 1.25 (3H, s, C(CH3)2), 1.26 (3H, s, C(CH3)2), 2.31 (1H, s, OH), 3.82 (1H, dq, J=6.7 and 8.8, CHCH3NH), 7.1 (1H, s, NH); δC (125 MHz; CDCl3) 14.89 (CH3), 26.68 (CH3), 27.56 (CH3), 55.19 (CH), 72.01 (C), 92.82 (CCl3), 161.56 (CO); m/z (CI+, NH3) 248 (M+). the reaction mixture was stirred overnight at room temperature The reaction was quenched by the addition of saturated aqueous sodium chloride solution after which the product was extracted with dichloromethane the combined organic extracts were washed with hydrochloric acid (1M) Concentration in vacuo and purification by flash column chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (S)-3-amino-2-methylbutan-2-ol (4 g, 38.8 mmol) and imidazole (5.20 g, 77.7 mmol) in CH2Cl2 (50 mL) was added TBSCl (8.7 g, 57.7 mmol) at 0° C. The mixture was stirred overnight. The mixture was washed with brine. The organic phase was separated and concentrated to give (S)-3-(tert-butyldimethylsilyloxy)-3-methylbutan-2-amine (8.4 g, 100%), which was used for the next step without purification. 1H NMR (CDCl3): 0.00 (s, 6H), 0.73 (s, 9H), 1.08 (s, 3H), 1.12 (d, 3H), 1.21 (s, 3H), 2.83 (q, 1H), 4.08 (brs, 1H). The mixture was washed with brine The organic phase was separated concentrated

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: An oven-dried vial was charged with (S)-3-amino-2-methylbutan-2-ol (Example 21G) (0.064 g, 0.622 mmol), 4-fluoro-3-((trimethylsilyl)ethynyl)phthalonitrile (0.126 g, 0.518 mmol), and K2CO3 (0.143 g, 1.036 mmol) and sealed with a rubber septum. Anhyd NMP (3 mL) was added via syringe and the mixture was stirred in a heating block at 60° C. under N2. After 30 min, the vial was sealed with a PTFE-faced crimp top and the mixture was subjected to microwave heating (140° C.) for 15 min. The mixture was poured into water and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording (S)-1-(3-hydroxy-3-methylbutan-2-yl)-1H-indole-4,5-dicarbonitrile (0.0659 g, 50% yield) as a tan solid: 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=8.7 Hz, 1H), 7.69 (d, J=3.3 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 6.84 (d, J=3.2 Hz, 1H), 4.47 (q, J=7.0 Hz, 1H), 1.63 (d, J=7.0 Hz, 3H), 1.53 (s, 1H), 1.34 (s, 3H), 1.11 (s, 3H). sealed with a rubber septum heating (140° C.) for 15 min extracted with EtOAc (×3) Combined organics were washed (water, brine) dried over Na2SO4 concentrated in vacuo The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2-chloro-4-fluoro-3-((trimethylsilyl)ethynyl)benzonitrile, (0.229 g, 0.91 mmol), (S)-3-amino-2-methylbutan-2-ol (Example 21E) (0.113 g, 1.092 mmol), and K2CO3 (0.252 g, 1.820 mmol) in anhyd NMP (3 mL) was stirred in a heating block at 60° C. under N2 for 2 h. CuI (0.017 g; 0.091 mmol) was added and the mixture was subjected to microwave heating (140° C.) for 30 min. The reaction mixture was poured into EtOAc/water and the whole was filtered through a pad of Celite. Layers of the filtrate were separated and the aqueous layer was extracted with EtOAc (×2). Combined organics were filtered (Whatman #2), washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording (S)-4-chloro-1-(3-hydroxy-3-methylbutan-2-yl)-1H-indole-5-carbonitrile (0.148 g, 62% yield) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.50 (d, 1H), 7.42-7.39 (m, 1H), 7.39-7.34 (m, 1H), 6.74 (d, J=3.3 Hz, 1H), 4.41 (q, J=7.0 Hz, 1H), 1.60 (d, J=7.1 Hz, 3H), 1.41 (s, 1H), 1.33 (s, 3H), 1.09 (s, 3H); MS (LCMS ES+) m/z 263 ([M+H]+, 88%), 304 ({[M+H]+MeCN}+, 100%). heating (140° C.) for 30 min the whole was filtered through a pad of Celite Layers of the filtrate were separated the aqueous layer was extracted with EtOAc (×2) Combined organics were filtered (Whatman #2) washed (water, brine) dried over Na2SO4 concentrated in vacuo The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution)

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-Fluoro-2-(trifluoromethyl)-3-((trimethylsilyl)ethynyl)benzonitrile (0.063 g, 0.221 mmol), (S)-3-amino-2-methylbutan-2-ol (0.060 g, 0.582 mmol) and DIEA (0.077 mL, 0.442 mmol) were combined in NMP (0.5 mL) and heated to 90° C. LCMS after heating for 9 h showed good conversion to the aniline intermediate and some desired indole formation. The mixture was cooled to rt and then treated with KOtBu (1.98 mL, 1 M in THF). The base did not afford conversion to the desired indole despite heating. The mixture was quenched with sat. aqueous NH4Cl, and then extracted with EtOAc. The combined organic fractions were concentrated to a yellow oil and then diluted with NMP (1 mL). Addition of more KOtBu (1.98 mL, 1 M in THF) afforded a dark brown solution that was heated to 50° C. LCMS after 0.5 h showed conversion to the desired indole. The reaction was again quenched with sat. aqueous NH4Cl and then extracted with EtOAc. The combined organic portions were concentrated to a yellow oil and then chromatographed (ISCO, std grad, hex/EtOAc, 24 g silica) to afford the desired product. The mixture was next subjected to reverse phase semiprep (Agilent, 230 nm detection) to afford the desired product as a colorless gum: MS (ESI): m/z 297 (MH+). LCMS after heating for 9 h The mixture was cooled to rt