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Preparation of a clinically investigated ras farnesyl transferase inhibitor
Author(s) -
Maligres Peter E.,
Waters Marjorie S.,
Weissman Steven A.,
McWilliams J. Christopher,
Lewis Stephanie,
Cowen Jennifer,
Reamer Robert A.,
Volante R. P.,
Reider Paul J.,
Askin David
Publication year - 2003
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570400206
Subject(s) - imidazole , chemistry , retrosynthetic analysis , mitsunobu reaction , combinatorial chemistry , stereochemistry , organic chemistry , total synthesis
The synthesis of ras farnesyl‐protein transferase inhibitor 1 is described on a multi‐kilogram scale. Retrosynthetic analysis reveals chloromethylimidazole 2 and a piperazinone 3 as viable precursors. The 1,5‐disubstituted imidazole system was regioselectively assembled via an improved Marckwald imidazole synthesis. A new imidazole dethionation procedure has been developed to convert the Marckwald mercaptoim‐idazole product to the desired imidazole. This methodology was found to be tolerant of a variety of functional groups providing good to excellent yields of 1,5‐disubstituted imidazoles. A new Mitsunobu cycliza‐tion strategy was developed to prepare the arylpiperazinone fragment 3 .