Which of two Sonogashira coupling pathways to tazarotene works best?
Tazarotene is a synthetic receptor-selective retinoid that is topically effective for treating acne, psoriasis, and photoaging. The two substituents (a thiochromane structure and a nicotinic acid ester) on the acetylenic “backbone” of tazarotene can be added in two ways, as described by S. Serra and co-workers at the Polytechnic Institute of Milan, Italy. Coupling a bicyclic bromosulfoxide with 2-methyl-3-butyn-2-ol, followed by removing the protecting group and coupling with ethyl 6-chloronicotinate proceeded in 55% yield over the three steps; the individual step yields were 83, 84, and 79%, respectively. The alternative route—coupling ethyl 6-chloronicotinate with 2-methyl-3-butyn-2-ol, deprotection, and coupling with the bromosulfoxide—gave a significantly lower overall yield (28%); the yields were lower in every step (69, 72, and 57%, respectively). The first route was operationally simple and robust and was therefore chosen for scale-up. (Org. Process Res. Dev. 2005, 9, 646–650 Wi
