Process Research and Development for Heterocyclic p38 MAP Kinase Inhibitors

Dedicated to Professor Barry M. Trost on the occasion of his 70th birthday.

Abstract

The need to access different heterocyclic cores as part of p38 MAP kinase inhibitors led to the discovery and development of several efficient approaches to three separate classes of heterocycles, namely phthalazines, pyrazolopyridinones, and triazolopyridines. This account summarizes our studies in this field in a comprehensive fashion.

1 Introduction

2 Synthesis of Phthalazine-Based p38 Inhibitors

2.1 Synthesis of Clinical Candidate 2

2.2 Synthesis of Clinical Candidate 3

3 Synthesis of Pyrazolopyridinone-Based p38 Inhibitors

4 Synthesis of Triazolopyridine-Based p38 Inhibitors

4.1 Synthesis through Pd-Catalyzed Benzhydrazide Couplings

4.2 Synthesis through Pd-Catalyzed Benzhydrazone Couplings

5.0 Conclusions

Key words

green chemistry - catalysis - heterocycles - Suzuki reaction - process chemistry

• References


For leading references regarding principles and green chemistry and the concept of atom economy, see:
• 1a Anastas PT, Warner JC. Green Chemistry: Theory and Practice . Oxford University Press; New York: 1998
• 1b Trost BM. Science 1995; 254: 1471
• 1c Trost BM. Angew. Chem., Int. Ed. Engl. 1995; 34: 259
• 2a Chen Z, Gibson TB, Robinson F, Silvestro L, Pearson G, Xu B, Wright A, Vanderbilt C, Cobb MH. Chem. Rev. 2001; 101: 2449
• 2b Raingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ, Davis RJ. J. Biol. Chem. 1995; 270: 7420
• 3a Gaestal M, Mengel A, Bothe U, Asadullah K. Curr. Med. Chem. 2007; 14: 2214
• 3b Peifer C, Wagner G, Laufer SA. Curr. Top. Med. Chem. (Sharjah, United Arab Emirates) 2006; 6: 113
• 3c Margutti S, Laufer SA. ChemMedChem 2007; 2: 1116
• 3d Schett G, Zwerina J, Firestein G. Ann. Rheum. Dis. 2008; 67: 909
• 4 Dominquez C, Powers DA, Tamayo N. Curr. Opin. Drug Discovery Dev. 2005; 8: 421
• 5 Herberich B, Cao G.-Q, Chakrabarti PP, Falsey JR, Pettus L, Rzasa RM, Reed AB, Reichelt A, Sham K, Thaman M, Wurz RP, Xu S, Zhang D, Hsieh F, Lee MR, Syed R, Li V, Grosfeld D, Plant MH, Henkle B, Sherman L, Middleton S, Wong LM, Tasker AS. J. Med. Chem. 2008; 51: 6271
• 6 Achmatowicz M, Thiel OR, Wheeler P, Bernard C, Huang J, Larsen RD, Faul MM. J. Org. Chem. 2009; 74: 795
• 7 Thiel OR, Achmatowicz M, Bernard C, Wheeler P, Savarin C, Correll T, Kasparian A, Allgeier A, Bartberger MD, Tan H, Larsen RD. Org. Process Res. Dev. 2009; 13: 230
• 8 Pettus LH, Wurz RP, Xu S, Herberich B, Henkle B, Liu Q, McBride HJ, Mu S, Plant MH, Saris CJ. M, Sherman L, Wong LM, Chmait S, Lee MR, Mohr C, Hsieh F, Tasker AS. J. Med. Chem. 2010; 53: 2973
• 9 Milburn RR, Thiel OR, Achmatowicz M, Wang X, Zigterman J, Bernard C, Colyer JT, DiVirgilio E, Crockett R, Correll TL, Nagapudi K, Ranganathan K, Hedley SJ, Allgeier A, Larsen RD. Org. Process Res. Dev. 2011; 15: 31
• 10 Zhang D, Tasker A, Sham KK. C, Chakrabarti PP, Falsey RJ, Herberich BJ, Pettus LH, Rzasa RM. PCT Int. Appl WO 2008045393, 2008 ; Chem. Abstr. 2008, 479605
• 11 Reichelt A, Falsey JR, Rzasa RM, Thiel OR, Achmatowicz MM, Larsen RD, Zhang D. Org. Lett. 2010; 12: 792
• 12 Thiel OR, Achmatowicz MM, Reichelt A, Larsen RD. Angew. Chem. Int. Ed. 2010; 49: 8277
• 13 Garrett CE, Prasad K. Adv. Synth. Catal. 2004; 346: 889
• 14 Epsztajn J, Brzezinski JZ, Czech K. Monatsh. Chem. 1993; 124: 549
• 15 Snieckus V. Chem. Rev. 1990; 90: 879
• 16 A recent review on large-scale applications of Suzuki couplings has two examples for kilogram-scale Suzuki couplings of aryl chlorides (one being synthesis of compound 3), compared to thirteen examples for arylbromides: Magano J, Dunetz JR. Chem. Rev. 2011; 111: 2177

For the use of 2-dicyclohexylphosphinobiphenyl ligands in Suzuki coupling reactions, see:
• 17a Old DW, Wolfe JP, Buchwald SL. J. Am. Chem. Soc. 1998; 120: 9722
• 17b Barder TE, Walker SD, Martinelli JR, Buchwald SL. J. Am. Chem. Soc. 2005; 127: 4685
• 18a Rosen TC, Feldmann R, Dünkelmann P, Daußmann T. Tetrahedron Lett. 2006; 47: 4803
• 18b Doderer K, Gröger HMay O. DE 2005100054282, 2005 ; Chem. Abstr. 2007: 531999
• 19 For a detailed study on the quenching of phosphorus oxychloride, see: Achmatowicz MM, Thiel OR, Colyer JT, Hu J, Elipe MV. S, Tomaskevitch J, Tedrow JS, Larsen RD. Org. Process Res. Dev. 2010; 14: 1498
• 20 For a related concurrent application of this approach, see: Norris T, Bezze C, Franz SZ, Stivanello M. Org. Process Res. Dev. 2009; 13: 354
• 21 Guram AS, Wang X, Bunel EE, Faul MM, Larsen RD, Martinelli MJ. J. Org. Chem. 2007; 72: 5104
• 22 Abad A, Agulló C, Cuñat AC, Vilanova C. Synthesis 2005; 915