Regioselective alkylation at the N4 position of a 3-oxo-1,4-benzodiazepine on solid support
Fadia E. Ali
Department of Medicinal Chemistry, Research and Development Division,
SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, P.O. Box 1539,
King of Prussia, PA 19406-0939, U.S.A.
To whom correspondence should be addressed.
E-mail:
fadia_e_ali@sbphrd.com
Catherine C.K. Yuan
Department of Medicinal Chemistry, Research and Development Division,
SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, P.O. Box 1539,
King of Prussia, PA 19406-0939, U.S.A.
Stephen T. Ross
Department of Medicinal Chemistry, Research and Development Division,
SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, P.O. Box 1539,
King of Prussia, PA 19406-0939, U.S.A.
Leon B. Hall
Department of Medicinal Chemistry, Research and Development Division,
SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, P.O. Box 1539,
King of Prussia, PA 19406-0939, U.S.A.
Abstract
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.
Keywords
benzodiazepine, combinatorial array, diversity, Heck reaction,
regioselective alkylation, Sasrin.
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