An Improved Convergent Synthesis of AZD7762: A One-Pot
Construction of a Highly Substituted Thiophene at the Multikilogram
Scale
Matthew Ball
Martin F. Jones
Fiona Kenley
J. David Pittam
10.1021/acs.oprd.6b00364.s001
https://acs.figshare.com/articles/journal_contribution/An_Improved_Convergent_Synthesis_of_AZD7762_A_One-Pot_Construction_of_a_Highly_Substituted_Thiophene_at_the_Multikilogram_Scale/4654561
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.
2017-02-15 18:51:30
generation
trisubstituted thiophene ring
sequence
chiral piperidine 5
API substitution pattern
AZD 7762