Application of design of experiments (DoE) optimization to the one-pot synthesis of 4,6-dihydropteridinones.
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%.
Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, MA 02210, USA. Wenxin_Gu@vrtx.com.
Steven
S
Stone
Tiansheng
T
Wang
Jianglin
J
Liang
John
J
Cochran
Jeremy
J
Green
Wenxin
W
Gu
D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D011621:Pteridines / Q000138:chemical synthesis* / Q000737:chemistry
C000609654:7,8-dimethyl-7,8-dihydropteridin-6(5H)-one; D011621:Pteridines