Preparation of Ethynylbenzene Derivatives from Substituted Benzaldehydes

We have tested a number of synthetic methods for large-scale synthesis of targeted substituted aromatic alkyne (S)-[4-(3-chloro-5-ethynyl-4-fluoro-phenyl)-1-methyl-butyl]-carbamic acid benzyl ester (1). This research resulted in an improved method for the Corey–Fuchs approach to alkyne synthesis from aldehydes. Importantly, we have shown that the use of P­(OCH₃)₃/CBr₄ in toluene for the synthesis of the dibromo-methylene intermediate (S)-{4-[3-chloro-5-(2,2-dibromo-vinyl)-4-fluoro-phenyl]-1-methyl-butyl}-carbamic acid benzyl ester (5) allows the synthesis of alkyne 1 under conditions that may be amenable for scaling-up. Since this method was developed, multiple batches of alkyne 1, each approaching 100 g in size, have been prepared under process-friendly conditions, as well as multigram batches of other alkynes.