Over the past decades, (+)-biotin (1) has received increasing interest due to the significance in human nutrition and animal health. Unlike other vitamins, as much as 200 MTN of 1 are currently being produced via total synthetic method due to lack of an efficient fermentation technology. Among a number of synthetic approaches hitherto developed, synthesis using thiolactone 2 as a key intermediate has been considered the most viable method for large scale production of 1.<br/>In the course of our ongoing studies on process development of pharmaceuticals, we have developed an expedient synthesis of 2 by the use of inexpensive R-α-methylbenzylamine as a chiral source and temperature-dependent purity upgrade of an intermediate during crystallization. Installation of 4-carboxylbutyl side chain was achieved through Fukuyama coupling reaction of 2 using readily available ethyl 5-bromovalerate where an efficient Finkelstein reaction in non-polar organic solvent was performed to transform it to the corresponding iodide effectively. The new process has already been scaled up successfully and is ready for commercial production.

Development of a practical synthesis of (+)-biotin

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