ABBV-3748 is a C2 corrector for the treatment of cystic fibrosis profiled among AbbVie’s CFTR portfolio. A decagram-scale enabling asymmetric synthesis is described which addresses numerous ...shortcomings of the original route. Highlights include an InBr3-catalyzed intramolecular hydroarylation reaction that rapidly assembles the chromane core, an exceptionally efficient asymmetric hydrogenation of a primary enamide, and identification of tBuMgCl as a uniquely effective base in a challenging acyl sulfonamide formation.
The tetrasubstituted pyrrolidine core of ABBV-3221 was synthesized by catalytic, enantioselective cycloaddition. A Cu(I) catalyst system was identified as ideal for further development, which gave a ...78% yield of 99% purity product after optimization. The processes of catalyst selection, optimization, and crystallization of the cycloaddition product are described herein.
An enabling preclinical synthetic route to cystic fibrosis candidate ABBV-2222 is described. Two stereoselective steps provide access to an aminochroman intermediate with excellent control, and a ...late-stage demethylation/difluoromethylation sequence provides efficient access to the target molecule.
A scalable
-selective synthesis of 2,3,4,5-tetrasubstituted pyrrolidines via cycloaddition of nitroalkenes and azomethine ylides is reported using a P,N-type ferrocenyl ligand and Cu(OTf)
·C
H
. The ...robust method is tolerant of a wide range of functionalities, including rarely reported quaternary nitroalkene substitution and heteroaromatic and hindered
-substituted arenes on the azomethine ylide. Subsequent transformations highlight the utility of the method in the synthesis of densely functionalized small molecules suitable for fragment-based drug discovery and the cystic fibrosis C2-corrector clinical candidate ABBV-3221.
The room temperature palladium-catalyzed cross-coupling of aromatic and heteroaromatic halides with Reformatsky reagents derived from 1-bromocyclopropanecarboxylates provides an exceptionally mild ...method for enolate α-arylation. The method is tolerant of a wide range of functionalities and dramatically shortens many of the existing routes to access widely used 1,1-disubstituted cyclopropanecarboxylate derivatives.
The paramount importance of synthetic organic chemistry in the pharmaceutical industry arises from the necessity to physically prepare all designed molecules to obtain key data to feed the ...design–synthesis–data cycle, with the medicinal chemist at the center of this cycle. Synthesis specialists accelerate the cycle of medicinal chemistry innovation by rapidly identifying and executing impactful synthetic methods and strategies to accomplish project goals, addressing the synthetic accessibility bottleneck that often plagues discovery efforts. At AbbVie, Discovery Synthesis Groups (DSGs) such as Centralized Organic Synthesis (COS) have been deployed as embedded members of medicinal chemistry teams, filling the gap between discovery and process chemistry. COS chemists provide synthetic tools, scaffolds, and lead compounds to fuel the pipeline. Examples of project contributions from neuroscience, cystic fibrosis, and virology illustrate the impact of the DSG approach. In the first ten years of innovative science in pursuit of excellence in synthesis, several advanced drug candidates, including ABBV-2222 (galicaftor) for cystic fibrosis and foslevodopa/foscarbidopa for Parkinson’s disease, have emerged with key contributions from COS.
The pentacyclic core skeleton of the cortistatins has been prepared in a stereoselective fashion by strategic use of an alkoxide-directed metallacycle-mediated annulative cross-coupling. This ...metal-centered tandem reaction delivers a polyunsaturated hydrindane and establishes the C13 stereodefined quaternary center with high levels of stereocontrol. Subsequent regio- and stereoselective global hydroboration results in the realization of the DE-trans ring fusion and a tertiary alcohol at C8. Establishment of the ABC-tricyclic subunit was then accomplished through phenolic oxidation/trans-acetalization, chemoselective reduction, regioselective cleavage, and intramolecular alkylation at C5.
Three contiguous stereocenters can be established with remarkable diastereoselectivity in a double Reformatsky sequence. Densely functionalized γ-butyrolactones were assembled rapidly by this ...approach, in which a ketone is used as the terminal electrophile (see scheme). Secondary transformations of the lactone products enhance their synthetic utility. R¹=Me, H; R²=alkyl, aryl, CF₃; Bn=benzyl, TBS=tert-butyldimethylsilyl.
We report operationally facile methods for the synthesis of substituted dihydroisoquinolinones and tetrahydroisoquinolines from readily accessible o-bromobenzyl bromides and o-bromobenzaldehydes, ...respectively. While classical electrophilic aromatic substitution reactions are tailored to the construction of saturated isoquinolines derived from electron-rich precursors, we demonstrate efficient syntheses from electronically diverse substrates to produce cyclized products as single regioisomers.
A convergent synthesis of highly substituted and stereodefined dihydroindanes is described from alkoxide-directed Ti-mediated cross-coupling of internal alkynes with substituted 4-hydroxy-1,6-enynes ...(substrates that derive from 2-directional functionalization of readily available epoxy alcohol derivatives). In addition to describing a new and highly stereoselective approach to bimolecular 2 + 2 + 2 annulation that delivers products not available with other methods in this area of chemical reactivity, evidence is provided to support annulation by way of regioselective alkyne–alkyne coupling, followed by metal-centered 4 + 2 rather than stepwise alkene insertion and reductive elimination. Overall, the reaction proceeds with exquisite stereochemical control and defines a convenient, convergent, and enantiospecific entry to fused carbocycles of great potential value in target-oriented synthesis and medicinal chemistry.
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