Regioselective alkylation at the N4 position of a 3-oxo-1,4-benzodiazepine on solid support.
An efficient solid phase regioselective alkylation at the N4 position of a 3-oxo-1,4-benzodiazepine template exemplified by 4-H-2,3,4,5-tetrahydro-7-iodo-3-oxo-1H-1,4-benzodiazepine-2-acetate-polymer ester is described. Further chemical elaboration at position 7, utilizing a modified Heck reaction, allows the incorporation of amides from primary or secondary amines. The two diversity points at positions 4 and 7 were utilized to synthesize a 28-membered, combinatorial array on Sasrin resin in moderate yields and > 80% purity. Having validated the chemistry on solid support, a combine and split approach to prepare a bead-bound combinatorial library is achievable utilizing similar experimental practices and procedures as in the array synthesis.
Ali
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Department of Medicinal Chemistry, Research and Development Division, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA 19406-0939, USA. fadia_e_ali@sbphrd.com
Yuan
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Ross
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Hall
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D000478:Alkylation; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000737:chemistry*; D020650:Combinatorial Chemistry Techniques; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure
D001570:Benzodiazepinones