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Synfacts 2017; 13(05): 0451
DOI: 10.1055/s-0036-1590207
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of LY2623091

Contributor(s):
Philip Kocienski
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
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Publication History

Publication Date:
18 April 2017 (online)

 
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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.


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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.


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