SYNTHESIS OF BENZAZEPINONE AND 3-METHYLBENZOTHIAZEPINONE ANALOGS OF DILTIAZEM

One of the most important calcium channel blocking agents in clinical use is diltiazem, a l,5-benzothiazepin-2-one derivative. Synthetic methods to prepare both benzazepinone and novel benzothiazepinone analogues have been developed. The initial step in the synthesis of the l-benzazepin-2-one analogues of diltiazem involves the base-induced addition of 2-nitrotoluene to a benzylidenemalonate to afford the addition product 1. This reaction has not been previously described in the literature. Critical to the success of this synthetic scheme was the observation that the decarboxymethylation of 4 with Lil in aqueous pyridine affords predominantly the desired cis-3-hydroxybenzazepinone 5. The importance of a proton source during this reaction is discussed. With the use of X-ray crystallographic methods, C-3/C-4 relative stereochemistry was found to impart a profound effect on molecular shape, which is, most likely, ultimately relevant to the differences in biological activity between cis and trans isomers in this series. The conversion of intermediate 1 to the 3-methyl analogue 12 is also described, which, again, relies on a decarboxylation reaction to set the desired cis relationship between the substituents on C-3 and C-4. The results obtained in these studies were applied to the development of a new method to prepare 18, the cis-3-methylbenzothiazepinone analogue of diltiazem. The key step in this process involves the two-step decarboxylation of 15, affording a good yield of the cis-2-aryl-3-methylbenzothiazepinone 17. Both 8 and 12 have potency in vitro similar to diltiazem, whereas the benzothiazepinone 18 was found to be significantly more potent than diltiazem and the benzazepinone derivatives. The procedures described in this paper represent general methods to prepare cis-3,4-disubstituted-l-benzazepin-2-ones and analogous 3-methylbenzothiazepinones. © 1990, American Chemical Society. All rights reserved.