Two closely related classes of oxindole-based compounds, 1H-indole-2,3-dione 3-phenylhydrazones and 3-(anilinomethylene)-1,3-dihydro-2H-indol-2-ones, were shown to potently inhibit cyclin-dependent kinase 2 (CDK2). The initial lead compound was prepared as a homologue of the 3-benzylidene-1,3-dihydro-2H-indol-2-one class of kinase inhibitor. Crystallographic analysis of the lead compound bound to CDK2 provided the basis for analogue design. A semiautomated method of ligand docking was used to select compounds for synthesis, and a number of compounds with low nanomolar inhibitory activity versus CDK2 were identified. Enzyme binding determinants for several analogues were evaluated by X-ray crystallography. Compounds in this series inhibited CDK2 with a potency approximately 10-fold greater than that for CDK1. Members of this class of inhibitor cause an arrest of the cell cycle and have shown potential utility in the prevention of chemotherapy-induced alopecia.

A one-step diastereoselective (up to 98:2) synthesis of the bis-furan alcohol of Darunavir and other HIV drug candidates has been achieved utilizing the novel cyclization of glycolaldehyde and 2,3-dihydrofuran. The cycloaddition was catalyzed by a variety of catalysts including those formed from tin(II) triflate and common chiral ligands such as BINAP and Evans's box ligands. An efficient and unique enzymatic process enhanced the enantiomeric purity to provide the target in optically pure form.

Two short, high-yielding routes to the selective PPARγ agonist GSK376501A were developed and carried out on scale. The key bond -forming reaction in each synthesis was the substitution of a 3,5-difluoro or 3,5-dibromo aryl intermediate with 2-methoxyethanol. A nucleophilic aromatic (S N Ar) substitution reaction under basic conditions was developed for the aryl fluoride substrate. The 3,5-dibromo aryl halide intermediate required copper-catalyzed conditions to achieve substitution of the second bromide. In addition, a 2-methoxyethanol decomposition pathway to generate methanol and ethylene oxide under basic reaction conditions as well as its effect on impurity formation, was elucidated. Both the difluoro and dibromo intermediates were considered as the basis for the final route of manufacture. The difluoro substrates were chosen due to straightforward chemistry, controllable impurity profile, and ease of fluoride removal.

Parallel microreactor screening enabled rapid identification of effective conditions for PTC-mediated Knoevenagel condensation between aldehyde (1) and thiazalone (2), affording a dramatic reduction in cycle time when compared to traditional conditions. Interesting facets of the reaction mechanism were revealed from kinetic profiling, specifically the operation of an extractive PTC mechanism with a pH optimum for the Knoevenagel condensation, a pK a optimum for the elimination reaction and the requirement for crystallization of aldol tautomer (4) to drive the reaction to completion.

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Ring closure reactions O 0130Solvent-Free Friedel-Crafts Cyclization with Trichloroacetic Anhydride. -The scope of the title reaction is explored with the synthesis of tetralones (II), benzothiopyrans (IV), benzoxepins and benzothiepines (VIII) as well as dibenzoxepins and dibenzothiepins (VI). Phenoxy-or phenylthiopropanoic acids do not react to the corresponding benzofuran or benzothiophene derivatives and the formation of eight-membered heterocycles such as (VIIIc) also fails. -(ANDREWS, B.; BULLOCK, K.; CONDON, S.; CORONA, J.; DAVIS*, R.; GRIMES, J.; HAZELWOOD, A.; TABET, E.; Synth. Commun. 39 (2009) 15, 2664-2673; Chem. Dev., GlaxoSmithKline, Research Triangle Park, NC 27709, USA; Eng.) -H. Haber 51-039

Aus 2‐Aminomethyl‐pyridin (I) erhält man mit Carbonsäuren (II) über die Amide (III) mit Phosphoroxychlorid die Imidazo‐pyridine (IV), die auch direkt aus (I) und (II) mit Polyphosphorsäure erhalten werden können.

Cyclization of amides of 2‐aminomethylpyridine gave imidazo[1,5‐a]pyridines. In several examples the literature preparation (phosphorus oxychloride) gave extensive tar formation. The use of phosphorus trichloride‐triethylamine (−20°) gave the desired imidazo[1,5‐a]pyridines.