Benzonorbomadienes, synthesis

Synthesis. The unsymmetrical norbomadiene substituted pz (34) (Scheme 7) (34%) (36), was prepared by a mixed cyclization of benzonorbomadiene phthalonitrile (32) (93) with a sevenfold excess of dipropylmaleonitrile (33) (28) (Scheme 7). 

Over the course of 10 months, this synthesis generated 4.7 kilograms of varenicline (17% yield overall from benzonorbomadiene) from 50 kilograms of fluorobromobenzene 2 and 20 kilograms of dicyclopentadiene. This material fueled a fast-paced development program through the 6-month toxicological evaluation, salt selection, formulation and stability studies, and Phase 2 clinical trials. 

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