| 92% | With sodium tris(acetoxy)borohydride; acetic acid; In 1,2-dichloro-ethane; at 20 - 24℃; for 24h;Under nitrogen; | Preparation IV S-6-(tert-butoxycarbonyl)-5-(tert-Butoxy)methyl-5,6-dihydro-6H-[1,4]diazepino[6,7,1-hi]indole S-3-(tert-Butoxy)-2-(N-[(1H-indol-7-yl)methyl]amino)-propionic Acid Methyl Ester [0158] To a solution of indole-7-carboxaldehyde (0.500 g, 3.44 mmol) in 1,2-dichloroethane (30 mL) under nitrogen was added <strong>[17114-97-5]S-(O-tert-butyl)serine methyl ester hydrochloride</strong> (1.09 g, 5.16 mmol), acetic acid (0.206 g, 0.197 mL, 3.44 mMol), and sodium triacetoxyborohydride (1.46 g, 6.88 mmol). The resulting mixture was stirred at 20-24° C. for 24 hours. The reaction mixture was then quenched by the addition of aqueous saturated sodium bicarbonate. The organic phase was extracted with dichloromethane and washed with saturated aqueous sodium chloride. The organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with ethyl acetate hexane (37). Fractions containing product were combined and concentrated under reduced pressure to give 0.96 g (92percent) of the desired product as an oil. [0159] MS (ES, m/z) (M+1)=305.0 [0160] S-3-(tert-Butoxy)-2-(N-[(1H-indol-7-yl)methyl]amino)propan-1-ol [0161] To a solution of S-3-(tert-Butoxy)-2-(N-[(1H-indol-7-yl)methyl]amino)propionic acid methyl ester (0.960 g, 3.15 mmol) in tetrahydrofuran (20 ml) at -78° C. was added lithium aluminum hydride (1 M in toluene, 6.31 mL) dropwise. The resulting reaction solution was warmed to 0° C. and stirred for 1 hour then warmed to 20-24° C. and stirred for 1 hour. It was cooled to 0° C., and was then quenched by the sequential addition of methanol followed by water. The suspension was filtered, washed with methanol and the filtrate concentrated under reduced pressure. The residue was dissolved in ethyl acetate, dried over magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with methanol:ethylacetate (1:9). Fractions containing product were combined and concentrated under reduced presuure to provide 0.51 g (59percent) of the desired compound. [0162] MS (ES, m/z) (M-1)=275.1, (M+1)=277.1. [0163] S-3-(tert-Butoxy)-2-(N-[(1H-indol-7-yl)methyl]-N-[tert-butoxycarbonyl]amino)propan-1-ol [0164] A solution of S-3-(tert-Butoxy)-2-(N-[(1H-indol-7-yl)methyl]amino)propan-1-ol (0.510 g, 1.85 mmol) and di(tert-butyl) dicarbonate (0.480 g, 2.21 mmol) in tetrahydrofuran (20 ml) was refluxed under nitrogen for 1.5 hours. The reaction mixture was cooled to room temperature and was then concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with ethyl acetate:hexane (1:1). Fractions containing product were combined to provide 0.58 g (84percent) of the desired product as an oil. [0165] MS (ES, m/z) (M+1)=377.1, (M-1)=375.1. [0166] S-3-(tert-Butoxy)-2-(N-[(1H-indol-7-yl)methyl]-N-[tert-butoxycarbonyl]amino)-1-(methanesulfonyloxy)propane [0167] To a solution S-3-(tert-Butoxy)-2-(N-[(1H-indol-7-yl)methyl]-N-[tert-butoxycarbonyl]amino)propan-1-ol (0.522 g, 1.39 mmol) in dichloromethane (15 ml) at 0° C. under nitrogen was added triethylamine (0.94 mL, 0.680 g, 6.70 mMol) followed by the dropwise addition of a solution of methanesulfonyl chloride (0.159 g, 1.39 mmol) in dichloromethane (5 ml). The resulting solution was stirred at 0° C. for 1 hour. Ice-cooled water was added and the resulting mixture was extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was used without further purification. [0168] MS (ES, m/z) (M-1)=453.1 [0169] Ring Closure [0170] To a solution of S-3-(tert-Butoxy)-2-(N-[(1H-indol-7-yl)methyl]-N-[tert-butoxycarbonyl]amino)-1-(methanesulfonyloxy)propane in dimethylformamide at 0° C. under nitrogen was added sodium hydride (0.083 g, 2.09 mmol, 60percent suspension in oil). The mixture was stirred for 1 hour and then it was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic phase was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with ethyl acetate:hexane (1:1). Fractions containing product were combined and concentrated under reduced pressure to provide 0.34 g (68percent) of the title compound as a white solid. [0171] MS (ES, m/z) (M+1)=359.1 |
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