1010075-63-4

Upstream product

• 14432-12-3 4-Amino-2-chloropyridine 
• 5720-05-8 4-methylphenylboronic acid 

Relevant academic research and scientific papers

Discovery of 4-aminoquinolines as highly selective TGFβR1 inhibitors with an attenuated MAP4K4 profile for potential applications in immuno-oncology

The tumor microenvironment contains high concentrations of TGFβ, a crucial immunosuppressive cytokine. TGFβ stimulates immune escape by promoting peripheral immune tolerance to avoid tumoricidal attack. Small-molecule inhibitors of TGFβR1 are a prospective method for next-generation immunotherapies. In the present study, we identified selective 4-aminoquinoline-based inhibitors of TGFβR1 through structural and rational-based design strategies. This led to the identification of compound 4i, which was found to be selective for TGFβR1 with the exception of MAP4K4 in the kinase profiling assay. The compound was then further optimized to remove MAP4K4 activity, since MAP4K4 is vital for proper T-cell function and its inhibition could exacerbate tumor immunosuppression. Optimization efforts led to compound 4s that inhibited TGFβR1 at an IC50 of 0.79 ± 0.19 nM with 2000-fold selectivity against MAP4K4. Compound 4s represents a highly selective TGFβR1 inhibitor that has potential applications in immuno-oncology.

Pd-Catalyzed Suzuki coupling reactions of aryl halides containing basic nitrogen centers with arylboronic acids in water in the absence of added base

The Pd-catalyzed Suzuki coupling reactions of a series of aryl chlorides and aryl bromides containing basic nitrogen centers with arylboronic acids in water in the absence of added base are reported. The reactions proceed either partially or entirely under acidic conditions. After surveying twenty-two phosphorus ligands, high yields of products were obtained with aryl chlorides only when a bulky ligand, 2-(di-tert-butyl-phosphino)-1-phenyl-1H-pyrrole (cataCXiumPtB) was used. In contrast, aryl bromides produced high yields of products in the absence of both added base and added ligand. In order to explore the Suzuki coupling process entirely under acidic conditions, a series of reactions were conducted in buffered acidic media using several model substrates. 4-Chlorobenzylamine, in the presence of cataCXiumPtB, produced high yields of product at buffered pH 6.0; the yields dropped off precipitously at buffered pH 5.0 and lower. The fall-off in yield was attributed to the decomposition of the Pd-ligand complex due to the protonation of the ligand in the more acidic aqueous media. In contrast, in the absence of an added ligand, 4-amino-2-chloropyridine produced quantitative yields at buffered pH 3.5 and 4.5 while 4-amino-2-bromopyridine produced quantitative yields in a series of buffered media ranging from pH 4.5 to 1.5. These substrates are only partially protonated in acidic media and can behave as active Pd ligands in the Suzuki catalytic cycle.

Highly efficient suzuki-miyaura coupling of heterocyclic substrates through rational reaction design

A dicyclohexyl(2-sulfo-9-(3-(4-sulfophenyl)propyl)-9H-fluoren-9-yl) phosphonium salt was synthesized in 64% overall yield in three steps from simple commercially available starting materials. The highly water-soluble catalyst obtained from the corresponding phosphine and [Na2PdCl4] enabled the Suzuki coupling of a broad variety of N- and S-heterocyclic substrates. Chloropyridines (-quinolines) and aryl chlorides were coupled with aryl-, pyridineor indoleboronic acids in quantitative yields in water/n-butanol solvent mixtures in the presence of 0.005-0.05 mol% of Pd catalyst at 100°C, chloropurines were quantitatively Suzuki coupled in the presence of 0.5 mol% of catalyst, and S-heterocyclic aryl chlorides and aryl- or 3-pyridylboronic acids required 0.01-0.05 mol % Pd catalyst for full conversion. The key to the high activity of the Pd-phosphine catalyst is the rational design of the reaction parameters (i.e., the presence of water in the reaction mixture, good solubility of reactants and catalyst in n-butanol/water (3:1), and the electron-rich and sterically demanding nature of the phosphine ligand).

New cyclopentadienyl, indenyl or fluorenyl substituted phosphine compounds and their use in catalytic reactions

The invention is directed to a phosphine compound represented by general formula (1) wherein R' and R" independently are selected from alkyl, cycloalkyl and 2-furyl radicals, or R' and R" are joined together to form with the phosphorous atom a carbon-phosphorous monocycle comprising at least 3 carbon atoms or a carbon-phosphorous bicycle; the alkyl radicals, cycloalkyl radicals, and carbon-phosphorous monocycle being unsubstituted or substituted by at least one radical selected from the group of alkyl, cycloalkyl, aryl, alkoxy, and aryloxy radicals; Cps is a partially substituted or completely substituted cyclopentadien-1-yl group, including substitutions resulting in a fused ring system, and wherein a substitution at the 1-position of the cyclopentadien-1-yl group is mandatory when the cyclopentadien-1-yl group is not part of a fused ring system or is part of an indenyl group. Also claimed is the use of these phosphines as ligands in catalytic reactions and the preparation of these phosphines.

9-Fluorenylphosphines for the Pd-catalyzed Sonogashira, Suzuki, and Buchwald-Hartwig coupling reactions in organic solvents and water

The lithiation/alkylation of fluorene leads to various 9-alkyl-fluorenes (alkyl = Me. Et, /Pr, -Pr. -C18H25) in > 95% yields, for which lithiation and reaction with R2PCl (R = Cy, iPr, tBu) generates 9-alkyl, 9-PR2fluorenes which constitute electron-rich and bulky phosphine ligands. The in-situ-formed palladium-phosphinc complexes ([Na2PdCl4], phosphonium salt, base, substrates) were tested in the Sonogashira. Suzuki, and Buchwald-Hartwig reactions of aryl chlorides and aryl bromides in organic solvents. The Sonogashira coupling of aryl chlorides at 100-120°C leads to >90% yields with 1 mol % of Pd catalyst. The Suzuki coupling of aryl chlorides typically requires 0.05 mol % of Pd catalyst at 100°C in dioxane for quantitative product formation. To carry out "green" cross-coupling reactions in water, 9-ethylfluorenyldicyclohexylphosphine was reacted in sulphuric acid to generate the respective 2-sulfonated phosphonium salt. The Suzuki coupling of activated aryl chlorides by using this water-soluble catalyst requires only 0.01 mol% of Pd catalyst, while a wide range of aryl chlorides can be quantitatively converted into the respective coupling products by using 0.1-0.5 mol % of catalyst in pure water at 100°C. Difficult substrate combinations, such as naphthylboronic acid or 3-pyridylboronic acid and aryl chlorides are coupled at 100°C by using 0.1-0.5 mol % of catalyst in pure water to obtain the respective N-heterocycles in quantitative yields. The copper-free aqueous Sonogashira coupling of aryl bromides generates the respective tolane derivatives in > 95 % yield.