Journal
ORGANIC PROCESS RESEARCH & DEVELOPMENT
Volume 24, Issue 11, Pages 2549-2564Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.oprd.0c00229
Keywords
continuous processing; flow chemistry; tetrahydroisoquinoline; mevidalen; process development; co-crystal; D1 PAM; LY3154207
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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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