Steven A.
*
et al.
AstraZeneca R&D, Macclesfield, UK
Expedited Kilolab Development of AZD7624 Using Kulinkovich–de Meijere Cyclopropanation.
Org. Process Res. Dev. 2021;
25: 2351-2366
DOI:
10.1021/acs.oprd.1c00283
Key words
AZD7624 - cyclopropanation - Buchwald–Hartwig reaction - de Meijere reaction - Kulinkovich
reaction
Significance
The p38α mitogen-activated protein kinase is expressed and activated in several cell
types associated with chronic obstructive pulmonary disease (COPD). AZD7624 inhibits
p38a but its development was halted after phase 2a trials failed to show any benefit
over placebo. The synthesis depicted delivered 5.3 kg of API.
Comment
A noteworthy feature of the synthesis is the implementation of the de Meijere modification
of the Kulinkovich cyclopropanation that converts the benzonitrile G to the cyclopropylamine H in 37% yield on a 22.6 mol scale. On a laboratory scale the yield was 57%. For an
alternative synthesis of AZD7624, see: WO 2017 162304 A1.
