An Efficient Approach to 3,4-Disubstituted Pyridin-2-ones. Formal Synthesis of Mappicine Ketone

Lin, Ching Hsuan; Tsai, Min R.; Wang, Yung S.; Chang, Nein Chen

doi:10.1021/jo034042s

Cited by 21 publications

(3 citation statements)

References 10 publications

(6 reference statements)

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“…38 The silver carbonate directed O-alkylation was selected as a deliberate synthesis strategy since O-debenzylation of the alkylated 2-pyridone was expected to be a facile process using TFA. In contrast, deprotection of Nbenzyl 2-pyridone would likely require more forcing or hydrogenolysis conditions 39 which might cause cleavage of the aryl chlorides. Alkylation of the 2-OBn intermediate with methyl iodide in the presence of K 2 CO 3 gave methyl ether 29.…”

Section: ■ Chemistrymentioning

confidence: 99%

Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497)

Kung¹,

Bingham²,

Brooun³

et al. 2017

J. Med. Chem.

102

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A new series of lactam-derived EZH2 inhibitors was designed via ligand-based and physicochemical-property-based strategies to address metabolic stability and thermodynamic solubility issues associated with previous lead compound 1. The new inhibitors incorporated an sp hybridized carbon atom at the 7-position of the lactam moiety present in lead compound 1 as a replacement for a dimethylisoxazole group. This transformation enabled optimization of the physicochemical properties and potency compared to compound 1. Analysis of relationships between calculated log D (clogD) values and in vitro metabolic stability and permeability parameters identified a clogD range that afforded an increased probability of achieving favorable ADME data in a single molecule. Compound 23a exhibited the best overlap of potency and pharmaceutical properties as well as robust tumor growth inhibition in vivo and was therefore advanced as a development candidate (PF-06821497). A crystal structure of 23a in complex with the three-protein PRC2 complex enabled understanding of the key structural features required for optimal binding.

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Section: ■ Chemistrymentioning

confidence: 99%

Optimization of Orally Bioavailable Enhancer of Zeste Homolog 2 (EZH2) Inhibitors Using Ligand and Property-Based Design Strategies: Identification of Development Candidate (R)-5,8-Dichloro-7-(methoxy(oxetan-3-yl)methyl)-2-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (PF-06821497)

Kung¹,

Bingham²,

Brooun³

et al. 2017

J. Med. Chem.

102

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“…Polycyclic quinolines can be found in a number of commercial drugs and other bioactive compounds, such as the natural alkaloid Mappicine [ 108 ], the poly ADP ribose polymerase (PARP) inhibitor for cancer Talazoparib [ 109 ], the antibacterial drug Levofloxacin [ 110 ], the natural product Flindersine [ 111 ], and the immune response modifier Imiquimod ( Figure 3 ) [ 112 ]. The cyclization of 2-azidobenzaldehydes can be integrated into multistep synthesis, one-pot synthesis, or a multi-component reaction (MCR) to make N -heterocycles [ 63 , 68 , 113 , 114 ].…”

Section: Resultsmentioning

confidence: 99%

2-Azidobenzaldehyde-Based [4+2] Annulation for the Synthesis of Quinoline Derivatives

Zhang,

Liu,

Qiu

et al. 2024

Molecules

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Quinoline is a privileged heterocyclic ring which can be found in many drug molecules and bioactive compounds. The development of synthetic methods for making quinoline derivatives continuously attracts the interest of organic and medicinal chemists. This paper highlights 2-azidobenzaldehyde-based [4+2] annulation for the synthesis of quinoline derivatives including fused and spiro-quinolines, quinoline-4-ols, 4-aminoquinolines, and related compounds.

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“…An efficient route to unsymmetrical glutarimides, with a sulfonyl group at C-3 position [70], has allowed an efficient approach to 2-pyridone ring [71]. Regioselective reduction (8)).…”

Section: From Other Aromatic Heterocyclic Ringsmentioning

confidence: 99%

New Synthetic Methods to 2-Pyridone Rings

Torres¹,

Gil²,

Parra

2005

COC

200

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The synthesis of a substituted 2-pyridone ring is a topical area of continuing interest due to the number of biologically active molecules containing this moiety. Over the last decade, natural compounds with this structure have emerged as potent antitumor antiviral and attention, because those compounds may be studied as a simple model for investigating mechanisms of some enzymatic reactions or for discerning the behavior of nucleic acids bases in connection with mutation due to base mispairing or other mistaken helices. Recent studies have shown the usefulness of 2-pyridones as intermolecular connectors between building blocks in material science. Thus, despite the large number of methods known for their synthesis, new procedures are continuously being developed. Two main synthetic approaches can be found in the literature: from other heterocycles systems or condensation of acyclic systems. The latter can be further classified depending on the bond formed in the cyclization step: by C-C or C-N bond generation. The latter can be subclassified depending on the first condensation step. This is a review of new or improved methods for constructing 2-pyridone rings. This article will be restricted to ring formation, which can be included in the total synthesis of several compounds with specific biological or material properties.The pursuit of these properties requires efficient synthetic routes that allow rapid assembly and variation of multiple pendant substituents on the heteroaromatic case, which permits rapid analogsynthesis (RAS) [1].

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An Efficient Approach to 3,4-Disubstituted Pyridin-2-ones. Formal Synthesis of Mappicine Ketone

Abstract: Treatment of 3,4-dihydro-3-tosylpyridin-2-one 5 with sodium hydride and then alkyl halides gave various 3,4-disubstituted pyridin-2-ones 6. Formal synthesis of mappicine ketone (1) was also reported.

Cited by 21 publications

References 10 publications

2-Azidobenzaldehyde-Based [4+2] Annulation for the Synthesis of Quinoline Derivatives

New Synthetic Methods to 2-Pyridone Rings

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