title: Parallel solid-phase synthesis and high-throughput 1H NMR evaluation of a 96-member 1,2,4-trisubstituted-pyrimidin-6-one-5-carboxylic acid library.
abstract: A solid-phase organic synthesis method has been developed for the preparation of trisubstituted pyrimidin-6-one carboxylic acids 12, which allows elaboration to a 3-dimensional combinatorial library. Three substituents are introduced by initial Knoevenagel condensation of an aldehyde and malonate ester resin 7 to give resin bound 1. Cyclization of 1 with an N-substituted amidine 10, oxidation, and cleavage afforded pyrimidinone 12. The initial solid-phase reaction sequence was followed by gel-phase (19)FNMR and direct-cleavage (1)H NMR of intermediate resins to determine the optimal conditions. The scope of the method for library production was determined by investigation of a 3 x 4 pilot library of twelve compounds. Cyclocondensation of N-methylamidines and 7 followed by CAN oxidation gave mixtures of the resin bound pyrimidin-6-one 11 and the regioisomeric pyrimidin-4-one 15, which after cleavage from the resin afforded a nearly 1:1 mixture of pyrimidin-6-one and pyrimidin-4-one carboxylic acids 12 and 16, respectively. The regiochemical assignment was confirmed by ROESY1D and gHMBC NMR experiments. A library was prepared using 8 aldehydes, 3 nitriles, and 4 amines to give a full combinatorial set of 96 pyrimidinones 12. Confirmation of structural identity and purity was carried out by LCMS using coupled ELS detection and by high-throughput flow (1)H NMR.
authors.affiliation: Pfizer Inc., Global Research and Development, Medicinal Chemistry, Chesterfield, Missouri 63017, USA. brucehamper@gmail.com
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Hamper
authors.forename: Allen S
authors.initials: AS
authors.lastname: Kesselring
authors.forename: Robert C
authors.initials: RC
authors.lastname: Chott
authors.forename: Shengtian
authors.initials: S
authors.lastname: Yang
mesh_terms: D000447:Aldehydes / Q000138:chemical synthesis / Q000737:chemistry; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000447:Aldehydes; D000588:Amines; D009570:Nitriles; D011744:Pyrimidinones; D054852:Small Molecule Libraries