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An Improved Convergent Synthesis of AZD7762: A One-Pot Construction of a Highly Substituted Thiophene at the Multikilogram Scale

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journal contribution
posted on 15.02.2017, 18:51 by Matthew Ball, Martin F. Jones, Fiona Kenley, J. David Pittam
A multikilogram synthesis of AZD7762 has been achieved using a highly convergent route employing two efficient telescoped sequences to generate the key intermediates. Aminothiophene 11 is formed in a four-step, one-pot addition–elimination–cyclization sequence from cinnamonitrile 9, constructing the trisubstituted thiophene ring with the desired API substitution pattern in place. Cinnamonitrile 9 is derived by elaboration of 3-fluoroacetophenone. Generation of the urea function, followed by deprotection, affords AZD7762 in 49% yield over 5 isolated stages from chiral piperidine 5, a 5-fold increase in yield versus the first generation route, reducing the starting material burden and eliminating the previous requirement for metal-mediated couplings and chromatography.