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Zinc Binding Enhances the SNAr Route to GSK332
Gregg A Barcan1, Rebecca J W Beck1, John Jin Lim1
1GSK, Drug Substance Development Chemistry, 1250 Collegeville Road, Collegeville, Pennsylvania 19426, United States.
Abstract:
The route and process for the penultimate intermediate toward an mTOR inhibitor GSK332 in GSK's respiratory portfolio is described. It relies on a heterocycle formation from a crystalline sodium ketoester enolate and an amidine derived from Pd-catalyzed cyanation of an azaindole. The final step involves an SNAr reaction through selective activation by a hindered sulfonyl chloride and Lewis acid activation to accelerate the rate.
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