Optimized scale up of 3-pyrimidinylpyrazolo[1,5-a]pyridine via Suzuki coupling; a general method of accessing a range of 3-(hetero)arylpyrazolo[1,5-a]pyridines Paul A. Bethel, Andrew D. Campbell, Frederick W. Goldberg, Paul D. Kemmitt * , Gillian M. Lamont, Abid Suleman AstraZeneca, Oncology iMed, Mereside, Alderley Park, Macclesfield SK10 4TG, UK article info Article history: Received 31 January 2012 Received in revised form 23 March 2012 Accepted 24 April 2012 Available online 2 May 2012 Keywords: 3-(Hetero)aryl pyrazolo[1,5-a]pyridines Boronic esters Suzuki coupling High throughput chemistry abstract We have developed an improved synthesis of 3-(hetero)aryl pyrazolo[1,5-a]pyridines (such as 3-(2,5- dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (8)) via an optimized synthesis and Suzuki coupling of 3-pyrazolo[1,5-a]pyridine boronic ester 10. These conditions are applicable to both high throughput chemistry and large scale synthesis of these medicinally important compounds. The scope of this chemistry has been further extended to include the synthesis and coupling of a novel boronic ester, 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (43). Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction Many compounds containing 3-substituted pyrazolo[1,5-a]pyr- idines have been found to possess biological activity, with over 400 publications including this bicycle over the last 5 years. 1 Certain 3- substituted pyrazolo[1,5-a]pyridine derivatives have been shown to be effective adenosine A1 antagonists, e.g., FK-838 (1), 2 while others have been found to be effective as kinase inhibitors (e.g., 2e4) 3e5 (Fig. 1). As part of ongoing discovery chemistry efforts, we were interested to investigate improvements to the synthetic methodology towards 3-arylpyrazolo[1,5-a]pyridines. 1.1. Synthesis of 3-aryl and heteroaryl-pyrazolo[1,5-a]pyridines 3-Substituted pyrazolopyridines are typically made via a 1,3- dipolar cycloaddition between an azomethine imine 5 (formed by deprotonation of a 1-amino-pyridinium ion 6) with an appropriate dipolarophile. 6 More recently their synthesis by a Michael reaction between vinylether 7 and 1-amino-pyridinium ion 6, followed by a cyclizationdoxidative aromatization sequence has been reported, Scheme 1 . 7 As part of an ongoing discovery campaign we required multi gram quantities of 3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a] pyridine (8) as a key intermediate. We also wanted to be able to vary the 3-substituent by high throughput chemistry. Initially we followed the published route to compound 8, which starts with the N N O N N O OH N N N N N H NH MeO N N S N O N F F NH 2 Cl N N Cl N H OMe N N O N N FK-838, 1 3 2 4 1 2 3 4 5 6 7 3a Fig. 1. Structures of some bioactive compounds containing a pyrazolo[1,5-a]pyridine motif. * Corresponding author. Tel.: þ44 (0) 1625 516128; e-mail address: paul.kemmitt@ astrazeneca.com (P.D. Kemmitt). Contents lists available at SciVerse ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2012.04.094 Tetrahedron 68 (2012) 5434e5444