A novel synthetic approach to nemtabrutinib (MK-1026) was recently developed in our laboratories. The chemistry goes through a cyrene amine intermediate which does not contain any chromophore. As a result, analysis of this key chiral intermediate by HPLC-UV is not feasible.
View Article and Find Full Text PDFThe introduction of molecular complexity in an atom- and step-efficient manner remains an outstanding goal in modern synthetic chemistry. Artificial biosynthetic pathways are uniquely able to address this challenge by using enzymes to carry out multiple synthetic steps simultaneously or in a one-pot sequence. Conducting biosynthesis ex vivo further broadens its applicability by avoiding cross-talk with cellular metabolism and enabling the redesign of key biosynthetic pathways through the use of non-natural cofactors and synthetic reagents.
View Article and Find Full Text PDFAn operationally simple protocol for a palladium-catalyzed CO and CO exchange with activated aliphatic and benzoic carbonyls is presented. Several C and C building blocks, natural product derivatives, and pharmaceuticals have been prepared to showcase the method for late-stage carbon isotope incorporation and its functional group compatibility.
View Article and Find Full Text PDFAngew Chem Int Ed Engl
February 2018
Tritium-labeled molecules are critical tools for elucidating the binding and metabolic properties of bioactive compounds, particularly during pharmaceutical discovery. Direct tritiation of inert C-H bonds with T gas is an ideal approach for tritium labeling, but significant gaps remain for direct tritiation of structurally complex molecules with diverse functional groups. Here we report the first application of palladium(II) C-H activation chemistry for tritiation with T gas.
View Article and Find Full Text PDFDeuterium- and tritium-labeled pharmaceutical compounds are pivotal diagnostic tools in drug discovery research, providing vital information about the biological fate of drugs and drug metabolites. Herein we demonstrate that a photoredox-mediated hydrogen atom transfer protocol can efficiently and selectively install deuterium (D) and tritium (T) at α-amino sp carbon-hydrogen bonds in a single step, using isotopically labeled water (DO or TO) as the source of hydrogen isotope. In this context, we also report a convenient synthesis of TO from T, providing access to high-specific-activity TO.
View Article and Find Full Text PDFThe development of a convergent and highly stereoselective synthesis of an HCV NS3/4a protease inhibitor possessing a unique spirocyclic and macrocyclic architecture is described. A late-stage spirocyclization strategy both enabled rapid structure-activity relationship studies in the drug discovery phase and simultaneously served as the basis for the large scale drug candidate preparation for clinical use. Also reported is the discovery of a novel InCl3-catalyzed carbonyl reduction with household aluminum foil or zinc powder as the terminal reductant.
View Article and Find Full Text PDFA thorough understanding of the pharmacokinetic and pharmacodynamic properties of a drug in animal models is a critical component of drug discovery and development. Such studies are performed in vivo and in vitro at various stages of the development process--ranging from preclinical absorption, distribution, metabolism and excretion (ADME) studies to late-stage human clinical trials--to elucidate a drug molecule's metabolic profile and to assess its toxicity. Radiolabelled compounds, typically those that contain (14)C or (3)H isotopes, are one of the most powerful and widely deployed diagnostics for these studies.
View Article and Find Full Text PDFWe report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.
View Article and Find Full Text PDFJ Labelled Comp Radiopharm
January 2015
Radiolabeled steroid derivative 1 was successfully prepared using a Horner-Wadsworth-Emmons approach: a [(14) C]-label was efficiently incorporated into the C-18 position of the molecule. Previously published procedures employing other olefination methods are either not applicable due to unavailability of [(14) C]-precursors or suffer from poor reactivity.
View Article and Find Full Text PDFA microscale chemistry improvement engine: a pre-dosed microscale high-throughput experimentation additives platform enables rapid, serendipitous reaction improvement. This platform allowed one chemist to set up 475 experiments and analyze the results using MISER chromatography in a single day, thus resulting in two high-quality catalytic systems for the construction of the title compound 1. Support for a single-electron transfer mechanism was obtained.
View Article and Find Full Text PDFMK-7655 (1) is a β-lactamase inhibitor in clinical trials as a combination therapy for the treatment of bacterial infection resistant to β-lactam antibiotics. Its unusual structural challenges have inspired a rapid synthesis featuring an iridium-catalyzed N-H insertion and a series of late stage transformations designed around the reactivity of the labile bicyclo[3.2.
View Article and Find Full Text PDFA highly efficient synthesis of sitagliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM), has been developed. The key dehydrositagliptin intermediate 9 is prepared in three steps in one pot and directly isolated in 82% yield and >99.6 wt % purity.
View Article and Find Full Text PDFAryl carboxylic esters were synthesized by Pd-catalyzed carbonylation of aryl p-fluorobenzenesulfonates or -tosylates. A unique Josiphos ligand was discovered through high-throughput catalyst screening, which was the key for the successful carbonylation of various substrates. This catalyst is effective and works well for both electron-rich and electron-poor aryl arenesulfonates.
View Article and Find Full Text PDFThe asymmetric synthesis of a Merck anti-HIV drug candidate is described. The target molecule contains four stereogenic centers, three of which are located in a highly functionalized cyclopentane unit. The convergent synthesis involves the preparation of two key advanced intermediates: the cyclopentane unit and a substituted pyrazole unit.
View Article and Find Full Text PDFThe preparation of 3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propan-1-amine 2a and 3-[(7R)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl]propan-1-amine 2b, key intermediates in the synthesis of alpha(V)beta(3) antagonists, is described. The syntheses rely on the efficient double Sonogashira reactions of 2,5-dibromopyridine 3 with acetylenic alcohols 4a/4b and protected propargylamines 10a-e followed by Chichibabin cyclizations of 3,3'-pyridine-2,5-diyldipropan-1-amines 9a/9b.
View Article and Find Full Text PDFA practical preparation of an alpha(v)beta(3) antagonist is reported. The antagonist consists of three key components, a tetrahydronaphthyridine moiety, a beta-alanine moiety, and a central imidazolidone moiety. The tetrahydronaphthyridine component was prepared using two different methods, both of which relied on variations of the Friedländer reaction to establish the desired regiochemistry.
View Article and Find Full Text PDFPure (Z)-enamines readily prepared from beta-ketoesters and amides using (S)-phenylglycine amide were hydrogenated with very high diastereoselectivities (up to 200:1) using heterogeneous catalysis. Hydrogenolytic cleavage of the (S)-phenylglycine amide afforded the corresponding chiral beta-aminoesters and amides. The high geometrical purity of the (Z)-enamine and a simple activation procedure for the PtO2 catalyst are essential in achieving high selectivity.
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