Development of a Scalable Process for the Synthesis of Cyclopropyl-Methyl-Proline with Complex Stereochemistry: A Key Building Block of Factor D Inhibitors

Abstract

The development of a scalable process for a complex intermediate featuring a chiral, quaternary cyclopropane moiety presented significant challenges. We report two generations of synthetic strategies appropriate for the respective stages of development. The initial approach utilized a stereoselective Simmons–Smith cyclopropanation of (R)-pyroglutamic acid ester, which predominantly yielded the undesired stereoisomer. To circumvent this issue, we implemented a strategy that combined isomerization, recycling of the undesired isomer, and selective crystallization to improve the yield of the desired product. An important insight was that the Simmons–Smith cyclopropanation exhibited opposite stereoselectivity with a benzoyl ester of a prolinol substrate, resulting in the desired stereoisomer as the major product. This understanding enabled the development of a second-generation process that facilitated the large-scale production of the targeted intermediate, thus supporting the advancement of clinical trials.