An efficient and large-scale enantioselective synthesis of PNP405: a purine nucleoside phosphorylase inhibitor |
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Authors: | Prashad Mahavir Har Denis Chen Lijian Kim Hong-Yong Repic Oljan Blacklock Thomas J |
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Institution: | Process Research and Development, Chemical and Analytical Development, Novartis Institute for Biomedical Research, One Health Plaza, East Hanover, New Jersey 07936, USA. mahavir.prashad@pharma.novartis.com |
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Abstract: | An efficient and large-scale enantioselective synthesis of PNP405 (1), a purine nucleoside phosphorylase inhibitor, is described. This synthesis of 1 involved eight steps starting from o-fluorophenylacetic acid with a 21.6% overall yield and >99.5% enantiopurity. The key stereogenic center with (R)-configuration was created using Evans' asymmetric alkylation methodology. This synthesis also features the racemization-free reductive removal of the chiral auxiliary in 5 using sodium borohydride, protection of the gamma-cyano alcohol 6 as the trityl ether by a new water-assisted tritylation with trityl chloride and triethylamine or with trityl alcohol and catalytic trifluoroacetic acid, and an efficient one-pot cyclo-guanidinylation of 10 using cyanamide as the guanidinylating agent. |
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