Phthalamic acid, cyclization

Requests for larger samples for field testing necessitated the examination of alternate routes to AC 94,377. One of these started with 1-amino-1-cyclohexanecarboxamide and 3-chloro-phthalic anhydride. Attempted cyclization of the intermediate phthalamic acid 4 with cold trifluoroacetic anhydride gave, albeit in low yield, the readily isolated imidazoisoindole Biological evaluation of indicated that it had very similar PGR properties to that of AC 94,377 yet was perhaps slower acting. This was attributed to the slow hydrolysis of back to AC 94,377. 

Another procedure recommended for avoidance of racemization involves reaction of the amino acid with phthalic anhydride in aqueous dioxane in the presence of triethylamine to produce the N-substituted phthalamic acid and cyclization by addition of more triethylamine and dioxane and distillation until the boiling point of dioxane is reached. 

Other methods of obtaining IA include oxidizing phthalamic acid (8) with Pb(OAc)4.,4 2-43 thermally cyclizing the phthalamic acid derivative (10),44 or treating N-hydroxyphthalimide (11) with benzenesulfonyl chloride (12)45 (Schemes 1 and 2). 

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