Open AccessDiastereoselective Synthesis of a cis-1,3-Disubstituted Cyclobutane Carboxylic Acid Scaffold for TAK-828F, a Potent Retinoic Acid Receptor-Related Orphan Receptor (ROR)-γt Inverse Agonist
Author(s) -
Keisuke Majima,
Mitsuhisa Yamano
Publication year - 2021
Publication title -
journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.2
H-Index - 228
eISSN - 1520-6904
pISSN - 0022-3263
DOI - 10.1021/acs.joc.1c00970
Subject(s) - cyclobutane , chemistry , retinoic acid , carboxylic acid , diastereomer , derivative (finance) , agonist , stereochemistry , recrystallization (geology) , receptor , combinatorial chemistry , organic chemistry , biochemistry , biology , ring (chemistry) , paleontology , financial economics , economics , gene
A scalable synthesis of the cis -1,3-disubstituted cyclobutane carboxylic acid scaffold of TAK-828F ( 1 ) has been developed, featuring the diastereoselective reduction of a cyclobutylidene Meldrum's acid derivative with NaBH 4 . 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%.