Three natural pyrrolizidines, (+)-amphorogynines A and D and (+)-retronecine, have been prepared from a common lactam intermediate. This central compound, in turn, was synthesized in diastereomerically enriched form through a highly selective [2 + 2]-cycloaddition of dichloroketene with a chiral enol ether, followed by Beckmann ring expansion and reduction. Subsequent stereocenters were then cleanly introduced through internal induction.
The evolution from early medicinal
chemistry to large-scale production
of the chemical synthesis of Lilly D1-positive allosteric modulator
(PAM) mevidalen (LY3154207) and its hydroxybenzoate co-crystal is
outlined. The issues and steps taken to resolve them are outlined
across several generations of synthesis, including unexpected issues
that arose during cryogenic addition of MeLi to a key imine intermediate
and the use of flow chemistry to enable large-scale production. Ultimately,
a process that was used to deliver >100 kg of API to support ongoing
clinical trials is described.
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