Expedited Kilolab Development of AZD7624 Using Kulinkovich-de Meijere Cyclopropanation

AZD7624 is a small molecule compound developed for the treatment of chronic obstructive pulmonary disease. This study describes the lab development and kilolab manufacture of the drug substance. A small number of route options were evaluated using lab proof-of-concept and predictive studies, before a Kulinkovich-de Meijere cyclopropanation of an aromatic nitrile with little precedent was explored as a means of shortening the medicinal chemistry route. In the synthesis of the cyclopropanation substrate, an SNAr-carbamoylation telescope sequence was used. The lab development activities devised procedures to make two of the reagents in the kilolab facility, addressed critical safety concerns, and prevented the coating of the reactor with titanium dioxide. Although cyclopropanation only proceeded in 37% yield, it still made the manufacturing target for its subunit, enabling 5.3 kg of in-specification AZD7624 to feed preclinical testing and phase 1 studies.