Issue 42, 2015

Application of design of experiments (DoE) optimization to the one-pot synthesis of 4,6-dihydropteridinones

Abstract

A design of experiments (DoE) analysis of a tandem SnAr-amidation cyclization reaction between 4-chloropyrimidin-5-amine and (S)-N-methylalanine to form (S)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one is reported. Five reaction variables were optimized using DoE and conversion was improved from 26% to 74%, with a significant reduction in reaction time while retaining high optical purity. The optimized conditions were applied to the synthesis of a wide variety of analogs and the expanded reaction substrate scope included a variety of amino acids and pyrimidines. Products were obtained in isolated yields up to 95% and enantiomeric excess as high as 98%.

Graphical abstract: Application of design of experiments (DoE) optimization to the one-pot synthesis of 4,6-dihydropteridinones

Supplementary files

Article information

Article type
Paper
Submitted
08 Jun 2015
Accepted
13 Aug 2015
First published
01 Sep 2015

Org. Biomol. Chem., 2015,13, 10471-10476

Application of design of experiments (DoE) optimization to the one-pot synthesis of 4,6-dihydropteridinones

S. Stone, T. Wang, J. Liang, J. Cochran, J. Green and W. Gu, Org. Biomol. Chem., 2015, 13, 10471 DOI: 10.1039/C5OB01154J

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