Thionyl Chloride–Mediated Synthesis of tert-Butyl ((S)-1-((R)-Oxiran-2-yl)-2-phenylethyl)carbamate with Boc-Involved Neighboring Group Participation

Abstract A convenient, high-yielding preparation of tert-butyl ((S)-1-((R)-oxiran-2-yl)-2-phenylethyl)carbamate is described. An efficient chiral inversion as the key step is furnished via Boc-involved neighboring group participation mediated by thionyl chloride. This preparation has significant advantages over the previously reported methods with respect to simplicity, cost efficiency, yield, and purification procedure as well as industry reliability. GRAPHICAL ABSTRACT


INTRODUCTION
Chiral N-protected a-amino epoxides or their derivatives are key building blocks or essential starting materials for a series of HIV protease inhibitors, including atazanavir, [1,2] ritonavir, [3] fosamprenavir, [4] darunavir, [5] saguinavir, [6] amprenavir, [7] and nelfanavir. [8] As a result, the synthesis of related compounds has attracted considerable attention from both academia and the pharmaceutical industry in recent years.
further verification in the plant confirmed that the quality of compound 1 could completely meet the quality specification set before.

CONCLUSION
A new industrially reliable process was developed for the manufacturing of tertbutyl ((S)-1-((R)-oxiran-2-yl)-2-phenylethyl)carbamate (1). Two important intermediates were isolated and characterized, and the reaction mechanism was elucidated. With this process route, product 1 could be conveniently manufactured with good quality. By preliminary estimate, the manufacture cost could be reduced at least 20-30% with the current process compared to the early routes. Further study on the mechanism, process optimization, and process development are still in progress.

ACKNOWLEDGMENTS
We thank Min Li, Yinli Lv, Weixia Liu, Wenlong Wang, and Xiangjun Wang for their support with NMR, HPLC, and LC-MS analysis. We also thank Jun He and Hai Sun for their help in the manuscript preparation.

SUPPORTING INFORMATION
Full experimental detail, 1 H and 13 C NMR spectra, HPLC conditions, and charts for this article can be accessed on the publisher's website.