A Practical Procedure for the Synthesis of Esonarimod, (R,S)-2-Acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic Acid, an Antirheumatic Agent. (Part 1).

Noguchi, Toshiya; Onodera, Akira; Tomisawa, Kazuyuki; Yokomori, Sadakazu

doi:10.1248/cpb.50.1407

Cited by 10 publications

(6 citation statements)

References 10 publications

(15 reference statements)

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“…The combined organic material was chromatographed with ethyl acetate/hexane to afford 3b (4 mg, 4% yield). Compound 3a was fully characterized spectrally and the data were consistent with that previously published [13]. Compound 3b was characterized spectrally and gave consistent 1 + was also observed.…”

Section: -(4-methoxyphenyl)-2-methylsulfanylmethyl-4-oxobutyric Acidsupporting

confidence: 85%

“…The components of the NADPH-generating system were obtained from Sigma Chemical Co. Buffers and other agents were purchased from VWR Scientific, Inc., (San Diego, CA). The synthesis of test compounds 3a, 3b, 3-DPT, 5-DPT, and 8-DPT has been previously reported [13][14][15], as well as is reported in the following. For chemical synthesis, moisture-sensitive reactions were carried out in flamedried glassware under an argon atmosphere.…”

Section: Methodsmentioning

confidence: 95%

“…Chemical synthesis of (±)-2-methylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid (S-methylesonarimod, compound 3a, Scheme 1) has been previously described [13]. An analog of S-methylesonarimod (i.e., (±)-4-(4-methoxyphenyl)-2-methylsulfanylmethyl-4-oxobutyric acid (compound 3b)) was also synthesized with the same procedure by a slight modification of the starting material (Scheme 1) [13].…”

Section: Chemical Synthesismentioning

confidence: 99%

“…An analog of S-methylesonarimod (i.e., (±)-4-(4-methoxyphenyl)-2-methylsulfanylmethyl-4-oxobutyric acid (compound 3b)) was also synthesized with the same procedure by a slight modification of the starting material (Scheme 1) [13].…”

Section: Chemical Synthesismentioning

confidence: 99%

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Functional activity of the mouse flavin‐containing monooxygenase forms 1, 3, and 5

Zhang

Cerny

Lawson

et al. 2007

J Biochem & Molecular Tox

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Three functional mouse flavin-containing monooxygenases (mFMOs) (i.e., mFMO1, mFMO3, and mFMO5) have been reported to be the major FMOs present in mouse liver. To examine the biochemical features of these enzymes, recombinant enzymes were expressed as maltose-binding protein fusion proteins (i.e., MBP-mFMO1, MBP-mFMO3, and MBP-mFMO5) in Escherichia coli and isolated and purified with affinity chromatography. The substrate specificity of these three mouse hepatic FMO enzymes were examined using a variety of substrates, including mercaptoimidazole, trimethylamine, S-methyl esonarimod, and an analog thereof, and a series of 10-(N,N-dimethylaminoalkyl)-2-(trifluoromethyl)phenothiazine analogs. The kinetic parameters of the three mouse FMOs for these substrates were compared in an attempt to explore substrate structure--function relationships specific for each mFMO. Utilizing a common phenothiazine substrate for all three enzymes, we compared the pH dependence for the recombinant enzymes under similar conditions. In addition, thermal stability for mFMO1, mFMO3, and mFMO5 enzymes was examined in the presence and absence of NADPH. The results revealed unique features for mFMO5, suggesting possible impact on the functional significance of this abundantly expressed FMO5 isoform in both human and mouse liver.

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Section: -(4-methoxyphenyl)-2-methylsulfanylmethyl-4-oxobutyric Acidsupporting

confidence: 85%

Section: Methodsmentioning

confidence: 95%

Section: Chemical Synthesismentioning

confidence: 99%

Section: Chemical Synthesismentioning

confidence: 99%

See 2 more Smart Citations

Functional activity of the mouse flavin‐containing monooxygenase forms 1, 3, and 5

Zhang

Cerny

Lawson

et al. 2007

J Biochem & Molecular Tox

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“…It has a variety of effects on cellular and mediator events in inflammatory processes including the inhibition of inflammatory cytokine production, [25] and it suppresses the development of arthritis in various animal models [26] . Esonarimod has been initially employed clinically as a racemate that was prepared via a multistep procedure relying on a Friedel‐Crafts acylation in the presence of AlCl 3 and nitrobenzene as key step [24,27] . The involvement of hazardous reagents in this synthetic route as well as the low yield obtained were acting as significant obstacles to large scale production.…”

Section: Resultsmentioning

confidence: 99%

Merger of Visible Light‐Driven Chiral Organocatalysis and Continuous Flow Chemistry: An Accelerated and Scalable Access into Enantioselective α‐Alkylation of Aldehydes

2023

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The electron donor-acceptor complex-enabled asymmetric photochemical alkylation strategy holds potential to attain elusive chiral α-alkylated aldehydes without an external photoredox catalyst. The photosensitizer-free conditions are beneficial concerning process costs and sustainability. However, lengthy organocatalyst preparation steps as well as limited productivity and difficult scalability render the current approaches unsuitable for synthesis on enlarged scales. Inspired by these limitations, a protocol was developed for the enantioselective α-alkylation of aldehydes based on the synergistic combination of visible light-driven asymmetric organocatalysis and a controlled continuous flow reaction environment. With the aim to reduce process costs, a commercially available chiral catalyst has been exploited to achieve photosensitizer-free enantioselective α-alkylations using phenacyl bromide derivates as alkylating agents. As a result of elaborate optimization and process development, the present flow strategy furnishes an accelerated and inherently scalable entry into enantioenriched α-alkylated aldehydes including a chiral key intermediate of the antirheumatic esonarimod.

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