A Scaleable Synthesis of Methyl 3-Amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate

Boros, Eric E.; Burova, Svetlana A.; Erickson, Greg A.; Johns, Brian A.; Koble, Cecilia S.; Kurose, Noriyuki; Sharp, Matthew J.; Tabet, Elie A.; Thompson, James B.; Toczko, Matthew A.

doi:10.1021/op7001326

Cited by 14 publications

(12 citation statements)

References 12 publications

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“…Alternatively, it was found that the electron deficient 2-bromoquinoline was an excellent partner for cross-coupling with Pd(0) where carbonylation was achieved yielding the methyl ester 11 . 58 Subsequent saponification provided the requisite acid 7c , which led to the desired 4-CF 3 -quinox 8c . An alternative method was utilized to obtain the 4-chloro-quinox derivative 8d .…”

Section: Resultsmentioning

confidence: 99%

On the Mechanism of the Palladium-Catalyzed tert-Butylhydroperoxide-Mediated Wacker-Type Oxidation of Alkenes Using Quinoline-2-Oxazoline Ligands

2011

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The mechanism of the tert-butylhydroperoxide-mediated, Pd(quinox)-catalyzed Wacker-type oxidation was investigated to evaluate the hypothesis that a selective catalyst-controlled oxidation could be achieved by rendering the palladium coordinatively saturated using a bidentate amine ligand. The unique role of the quinox ligand framework was probed via systematic ligand modifications. The modified ligands were evaluated through quantitative Hammett analysis, which supports a “push-pull” relationship between the electronically asymmetric quinoline and oxazoline ligand modules.

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Section: Resultsmentioning

confidence: 99%

On the Mechanism of the Palladium-Catalyzed tert-Butylhydroperoxide-Mediated Wacker-Type Oxidation of Alkenes Using Quinoline-2-Oxazoline Ligands

2011

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“…This compound was first treated with n -BuLi in anhydrous diethyl ether at −50° C, followed by the addition of 2,6-difluorobenzaldehyde, 12 which afforded the alcohol 3 in 90% yield (Scheme 1). In the next step, deoxygenation of the benzylic hydroxyl group and deprotection of the methoxy group was achieved with trimethylsilyl iodide (generated in situ from TMSCl and NaI), trifluoroacetic acid (TFA) and triethylsilane (TES) 12,13 to give the pyridinone 4 in 88% yield. The reagents used in this step were in excess to ensure completion of both alterations in the molecule.…”

Section: Resultsmentioning

confidence: 99%

Approaches to the synthesis of a novel, anti-HIV active integrase inhibitor

et al. 2013

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The novel HIV-1 integrase inhibitor 1, discovered in our laboratory, exhibits potent anti-HIV activity against a diverse set of HIV-1 isolates and also against HIV-2 and SIV. In addition, this compound displays low cellular cytotoxicity and possesses a favorable in vitro drug interaction profile with respect to isozymes of cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT). However, the total synthesis of this significant HIV integrase inhibitor has not been reported. This contribution describes an optimized, reproducible, multi-step, synthetic route to inhibitor 1. The yield for the separate steps averaged about 80%. The methodologies utilized in the synthesis were, among others, a palladium-catalyzed cross-coupling reaction, a crossed-Claisen condensation, and a hydrazino amide synthesis step. Successful alternative synthetic methodologies for some of the steps are also described.

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“…The 6-substituted 2(1H)-pyridones were synthesized starting with a Sonogashira coupling [37] between 6-bromo-2-methoxypyridine 5 and the corresponding terminal alkyne (6-8), obtaining 2-methoxypyridines (9-11) in good yields. The 6-substituted 2(1H)-pyridone receptors (12)(13)(14) were obtained in modest yields by adding TMSCl and dry NaI at room temperature in dry acetonitrile (Scheme 1) [38,39].…”

Section: Synthesismentioning

confidence: 99%

Study of CH/π Interactions in the Molecular Recognition between Acetyl Galactopyranoside and 6-substituted 2-Methoxypyridines and 2(1H)-Pyridones

2017

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A series of 6-substituted 2-methoxypyridine and 2(1H)-pyridones was designed and synthesized for its evaluation in the molecular recognition of acetyl 2,3,4,6-tetra-O-methyl-b-D-galactopyranoside substrate. 1H-NMR titration (affinity constant Ka determination) and chemical shift perturbation experiments were performed to evaluate the capacity of these receptors to form CH/π interactions with the substrate. The addition of 2-methoxypyridines to the substrate effected up-field shift for the H3, H4 and H5 proton signals and down-field shift for the H2 proton signal of galactopyranoside substrate. The determined affinity constant Ka values for the association between 2(1H)-pyridones and galactopyranoside showed that molecular recognition was weak. These results have demonstrated the existence of weak CH/π interactions and have reflected their weak intermolecular nature. Finally DFT calculations were performed to illustrate the geometry of the molecular recognition between 2(1H)-pyridones and galactopyranoside.

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A Scaleable Synthesis of Methyl 3-Amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate

Cited by 14 publications

References 12 publications

On the Mechanism of the Palladium-Catalyzed tert-Butylhydroperoxide-Mediated Wacker-Type Oxidation of Alkenes Using Quinoline-2-Oxazoline Ligands

On the Mechanism of the Palladium-Catalyzed tert-Butylhydroperoxide-Mediated Wacker-Type Oxidation of Alkenes Using Quinoline-2-Oxazoline Ligands

Approaches to the synthesis of a novel, anti-HIV active integrase inhibitor

Study of CH/π Interactions in the Molecular Recognition between Acetyl Galactopyranoside and 6-substituted 2-Methoxypyridines and 2(1H)-Pyridones

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