Development of a Manufacturing Process for a Key (S)-5-(2,2-Dimethyltetrahydro-2H-pyran-4-yl)-1H-indole Intermediate for Orforglipron. Part I. Selection of an Evans Auxiliary-Assisted Asymmetric 1,4-Addition Route

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Two synthetic strategies for key ( S )-5-(2,2-dimethyltetrahydro-2 H -pyran-4-yl)-1 H -indole intermediate 1 for orforglipron were demonstrated. The Negishi cross-coupling route was initially scaled up to deliver a total of 36.6 kg of compound 1 to support the production of orforglipron to fund early clinical trials. However, this route was nonenantioselective and required laborious chiral SFC purification to obtain an optically pure intermediate. An enantioselective route featuring Evans auxiliary-assisted asymmetric 1,4-addition successfully produced the desired product without necessitating nonscalable chromatographic purification throughout the synthesis, which was selected for further development into a robust process for large-scale production.