Diastereoselective Synthesis of a -1,3-Disubstituted Cyclobutane Carboxylic Acid Scaffold for TAK-828F, a Potent Retinoic Acid Receptor-Related Orphan Receptor (ROR)-γt Inverse Agonist.

A scalable synthesis of the -1,3-disubstituted cyclobutane carboxylic acid scaffold of TAK-828F () has been developed, featuring the diastereoselective reduction of a cyclobutylidene Meldrum's acid derivative with NaBH. Controlling acidic impurities was crucial for improving the diastereomeric ratio by recrystallization. Furthermore, reaction optimization and the streamlining of several steps established a scalable synthetic method free from column chromatography purification with an overall yield improved from 23 to 39%.