Microwave-assisted synthesis of 4-amino-3,5-dihalopyridines

Pichowicz, Mark; Crumpler, Simon; McDonald, Edward; Blagg, Julian

doi:10.1016/j.tet.2010.01.101

Cited by 8 publications

(4 citation statements)

References 6 publications

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“…The selective displacement of 3,4,5-trichloropyridine ( 3 ) with varying equivalents of morpholine ( 4 ) to afford pyridine amine 5 was screened in a STR using nitrogen as the spacer between segments (Scheme ). The STR set up, execution, and sampling sequences were performed as described above.…”

Section: Resultssupporting

confidence: 92%

Segmented Tube Reactors (STR): A Simple Tool To Screen Multiple Reactions in Parallel in Batch Mode within a Single Tube

Weiberth

Powers

Gallin

et al. 2018

Org. Process Res. Dev.

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A simple tool to perform multiple reactions in parallel in batch mode in static segments within a single tube is described. The Segmented Tube Reactor (STR) involves using syringe pumps to load a section of Teflon tubing with solutions of reaction components while forming a preprogrammed gradient of one of the components (e.g., equivalents, concentration) along its length. Simultaneously, a chemically inert spacer is loaded to break the gradient into discrete static segments. Ten or more distinct sets of conditions can be quickly set up in a single experiment. Although the STR is set up in flow mode, reactions occur in batch mode within the tubes, usually by heating the STR for a desired duration. Segments are then individually sampled and analyzed to identify the conditions that provide the best performance. The technology is translatable: the STR was employed to screen for preferred reaction stoichiometries that were then duplicated on larger scale in batch mode in traditional lab equipment.

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Section: Resultssupporting

confidence: 92%

Segmented Tube Reactors (STR): A Simple Tool To Screen Multiple Reactions in Parallel in Batch Mode within a Single Tube

Weiberth

Powers

Gallin

et al. 2018

Org. Process Res. Dev.

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“…Our synthetic strategy to most desired 3,4,5-trisubstituted pyridines involved S N Ar displacement of the 4-chloro substituent in either 3,4,5-trichloropyridine (10) or 3-bromo-4,5-dichloropyridine (11) using the appropriate N-bocprotected pyrrolidine 12, piperidine 13, or NH-piperidine 14 to give the 4-substituted analogues 9, 15−22, 39, 41, 43, 45, 47, 49, 51, 53, 57, and 84 according to our previously published methodology. 31 Subsequent palladium-mediated cross-coupling of appropriate aryl boronic acids or esters gave the corresponding 3,4,5-trisubstituted pyridines 26, 28−38, 40, 42, 44, 46, 48, 50, 52, 54, and 65−81 (Scheme 1). Compounds 59, 60, and 62 described in Table 5 were prepared by sequential cross-coupling at the 3-and 5-positions of 8-(3bromo-5-chloropyridin-4-yl)-2,8-diazaspiro [4.5]decan-1-one (57).…”

Section: ■ Chemistrymentioning

confidence: 99%

Discovery of Potent, Orally Bioavailable, Small-Molecule Inhibitors of WNT Signaling from a Cell-Based Pathway Screen

et al. 2015

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WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted pyridine 9 using a high-throughput cell-based reporter assay of WNT pathway activity. We demonstrate a twisted conformation about the pyridine–piperidine bond of 9 by small-molecule X-ray crystallography. Medicinal chemistry optimization to maintain this twisted conformation, cognisant of physicochemical properties likely to maintain good cell permeability, led to 74 (CCT251545), a potent small-molecule inhibitor of WNT signaling with good oral pharmacokinetics. We demonstrate inhibition of WNT pathway activity in a solid human tumor xenograft model with evidence for tumor growth inhibition following oral dosing. This work provides a successful example of hypothesis-driven medicinal chemistry optimization from a singleton hit against a cell-based pathway assay without knowledge of the biochemical target.

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“…After subsequent experiments, said it was concluded that the batch microwave reactor (1-2 l range) is a useful tool for the scale-up of organic reactions and suitable for the delivery of several hundred grams of product per day for medicinal chemistry needs. Encouraged by these results, Blagg and co-workers were particularly interested in the 4-substitution of 3,4,5-trihalopyridines in order to maximize the opportunity for subsequent iterative diversification of the pyridine template [155]. After optimization of the reaction conditions with morpholine (isolated yield 99%), they explored the scope of the reaction with other cyclic amines, including pyrrolidine, piperidine, and N-methylpiperazine (Table 16.11).…”

Section: Microwave-assisted Nucleophilic Aromatic Substitution (S N Ar)mentioning

confidence: 99%

Microwaves in Heterocyclic Chemistry

Bazureau

Paquin

Carrié

et al. 2012

Microwaves in Organic Synthesis

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Microwave-assisted synthesis of 4-amino-3,5-dihalopyridines

Cited by 8 publications

References 6 publications

Segmented Tube Reactors (STR): A Simple Tool To Screen Multiple Reactions in Parallel in Batch Mode within a Single Tube

Segmented Tube Reactors (STR): A Simple Tool To Screen Multiple Reactions in Parallel in Batch Mode within a Single Tube

Discovery of Potent, Orally Bioavailable, Small-Molecule Inhibitors of WNT Signaling from a Cell-Based Pathway Screen

Microwaves in Heterocyclic Chemistry

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