An Improved Convergent Synthesis of AZD7762: A One-Pot Construction of a Highly Substituted Thiophene at the Multikilogram Scale
2017-02-15T18:51:30Z (GMT) by
A multikilogram synthesis of AZD7762 has been achieved using a highly convergent route employing two efficient telescoped sequences to generate the key intermediates. Aminothiophene <b>11</b> is formed in a four-step, one-pot addition–elimination–cyclization sequence from cinnamonitrile <b>9</b>, constructing the trisubstituted thiophene ring with the desired API substitution pattern in place. Cinnamonitrile <b>9</b> 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 <b>5</b>, 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.