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Synthesis 2022; 54(09): 2267-2281
DOI: 10.1055/s-0040-1719873
paper

Synthesis of Novel Pyrazine-Substituted 1H-Pyrrole-2-carboxamides and Related Tethered Heterocycles

Rachel L. Howells∗
a   AstraZeneca R & D, Darwin Building (310), Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK
,
Scott G. Lamont
a   AstraZeneca R & D, Darwin Building (310), Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK
,
Thomas M. McGuire
a   AstraZeneca R & D, Darwin Building (310), Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK
,
Samantha Hughes
a   AstraZeneca R & D, Darwin Building (310), Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK
,
Rachel Borrows
a   AstraZeneca R & D, Darwin Building (310), Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK
,
Gary Fairley
a   AstraZeneca R & D, Darwin Building (310), Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK
,
Lyman J. L. Feron
a   AstraZeneca R & D, Darwin Building (310), Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK
,
Ryan D. R. Greenwood
a   AstraZeneca R & D, Darwin Building (310), Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK
,
Eva Lenz
a   AstraZeneca R & D, Darwin Building (310), Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK
,
Emma Grant
b   Formerly of AstraZeneca R & D, Cambridge, UK
,
Iain Simpson
b   Formerly of AstraZeneca R & D, Cambridge, UK
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Abstract

As part of a drug discovery program, 4-pyrazin-2-yl-1H-pyrrole-2-carboxamides were accessed along with a number of bicyclic analogues. Routes to these compounds were largely absent from the scientific literature. The synthesis of a 4-(pyrazin-2-yl)-1H-pyrrole-2-carboxamide and several fused bicyclic analogues all using standard procedures (SNAr, borylation, C–C cross couplings, hydrolysis, amide bond formation, cyclisation, halogenation, and alkylation) from readily available starting materials is reported. The synthetic sequences range from 4–12 steps per final compound, with yields of isolated intermediates ranging from 20 to ∼100%.

Key words

heterocycle - bicyclic - fused - pyrazine - pyrrole - drug discovery - tethered - core

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0040-1719873.
  • Supporting Information


Publication History

Received: 01 October 2021

Accepted after revision: 29 November 2021

Article published online:
26 January 2022

© 2022. Thieme. All rights reserved

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