Development of a general process for the synthesis of highly substituted imidazoles

Abstract

Several highly substituted imidazoles have been under investigation at GlaxoSmithKline as potential therapies for the treatment of rheumatoid arthritis and have spawned the need for a general synthetic method for their preparation on a multikilogram scale. We describe herein the optimization of a general method for the preparation of aryl-substituted TosMIC reagents and the ease with which they undergo [3+2] cycloadditions with a host of imines, prepared in situ, to generate densely functionalized imidazoles with various substitution patterns in a completely regioselective manner.

Discovery Of Pyrroloimidazoles As Agents Stimulating Neurite Outgrowth

“…Cinnamic aldehyde, glyoxylic acids, dialdehyde, aminoacetaldehyde dimethyl acetal, glyoxales, and a-amino acid derived aldehydes have been shown to react as aldehyde component. Moreover the scalability of this reaction has been proven by the recent multi kilogram synthesis of a p38 kinase inhibitor [12]. This particular reaction and other MCRs therefore are perfectly suited for the production of a diverse library of small molecules [13].…”

Parallel synthesis of arrays of 1,4,5-trisubstituted 1-(4-piperidyl)-imidazoles by IMCR: A novel class of aspartyl protease inhibitors

“…One specific Tosmic derivative for the production of a p38 inhibitor in phase III clinical trails has been described even on a 500 kg scale. 22 Gratifyingly, Tosmic and its derivatives are solids and devoid of the otherwise characteristic isocyanide odor. However, the chemistry of Tosmic is much more broadly usable than for the synthesis of imidazoles alone.…”

Current advances in the synthesis and biological potencies of tri- and tetra-substituted 1H-imidazoles

“…As a result, both the introduction of new methodologies and the developments of the already reported synthesis of imidazoles have created great interest in universities' research laboratories as well as in industry. Consequently, an increasing amount of worldwide research has grown in the area of synthesis, functionalization, and derivatization of the imidazole scaffold [8][9][10][11][12][13][14][15][16][17][18][19][20][21]. A literature survey revealed several useful reviews on the synthesis of imidazoles [22][23][24][25][26]-among them a comprehensive review published in Tetrahedron in 2007 [22].…”