Imidazo-benzazepine

The imidazo-benzazepine 43 was prepared in moderate yield by a combination reaction sequence involving an initial van Leusen reaction to prepare the imidazole 42 followed by a microwave-promoted intramolecular Heck reaction <06TL3225>. 

Chemical Name trans-(+/-)-4,5,6,7-Tetrahydro-7-hydroxy-6-[(l-methylethyl)amino]imidazo[4,5,l-j k][l]benzazepin-2-(lH)-one monohydrochloride... 

A mixture of 29.2 g of the 5,6-dihydro-l-benzyl-imidazo[4,5,l-j-k][l]benzazepin-2,7-[lH,4H]-dione, 292.0 g of o-phosphoric acid and 14.1 g of phenol were heated at 150°C under an inert atmosphere for 2 h, was cooled to about 35°C and was poured into 1200 ml of iced water with stirring. 2 L of methylene chloride were added to the mixture which was then made alkaline with sodium hydroxide. The mixture was filtered and the solids were washed with methylene chloride. The combined organic phases were washed, dried and evaporated to dryness under reduced pressure. The residue was crystallized and was chromatographed over silica gel. Elution with a 90 2 2 ethyl acetate-methanol-triethylamine mixture yielded 9.7 g of 5,6-dihydro-imidazo[4,5,l-j-k][l]benzazepin-2,7-[lH,4H]-dione, melting point 235°C. 

A suspension of 4.0 g of the 6-oxime of 4,5-dihydroimidazo[4,5,l-j-k][l]benzazepin-2,6,7[lH]-trione 2.0 g of 10% palladium carbon and 150 ml of methanol was stirred under hydrogen for 2,5 h and was then filtered. The filtrate was cooled in an ice bath while slowly adding with mild stirring 0.66 g of sodium borohydride and the mixture was stirred at 5°C for 90 min. The mixture was evaporated to dryness under reduced pressure at 30°C and the residue was dissolved in 15 ml of methanol. The solution was acidified to a pH of 1-2 by addition of hydrogen chloride in ethyl acetate and the mixture was vacuum filtered to obtain 3.6 g of (6RS, trans)-6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,l-j-k][l]benzazepin-2[lH]-one hydrochloride melting at >260°C (crystallization from methanol and then from ethanol). The base (6RS, trans)-6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,l-j-k][l]benzazepin-2[lH]-one may be produced from (6RS,trans)-6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,l-j-k][l]benzazepin-2[lH]-one hydrochloride by treatment of salt with sodium hydroxide. 

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