Mitchell D.
* et al. Eli Lilly and Company, Indianapolis, USA
Double Heck Route to a Dibenzoxepine and Convergent Suzuki Cross-Coupling Strategy
for the Synthesis of an MR Antagonist.
Org. Process Res. Dev. 2017;
21: 208-217
Key words
LY2623091 - mineralocorticoid receptor antagonist - intramolecular Heck reaction -
Suzuki–Miyaura cross-coupling - dibenzoxepine ring formation
Significance
LY2623091 is a mineralocorticoid receptor antagonist that was of interest for the
treatment of resistant hypertension. The kilogram-scale synthesis depicted features
two sequential Heck reactions to construct the (E)-dihydrodibenzo[b,e]oxepine ring system. Note the clean retention of stereochemistry in the conversion
of (E)-F into bromoalkene (E)-G.
Comment
An investigation of the conversion of A into (E)-F through a one-pot, double Heck reaction revealed that the first Heck reaction (A → C) was fast and occurred at 60 °C whereas the second Heck reaction [C → (E)-F] required a much higher temperature (145 °C) owing to iodide acting as a catalyst
poison. Better yields and stereoselectivity were obtained in the two-pot process shown.
