An efficient and large-scale enantioselective synthesis of PNP405: a purine nucleoside phosphorylase inhibitor.
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.
Prashad
Mahavir
M
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
Har
Denis
D
Chen
Lijian
L
Kim
Hong-Yong
HY
Repic
Oljan
O
Blacklock
Thomas J
TJ
D002384:Catalysis; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005464:Fluorobenzenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
D004791:Enzyme Inhibitors; D005464:Fluorobenzenes; C472761:PNP405; D011744:Pyrimidinones; D011683:Purine-Nucleoside Phosphorylase