A Practical Synthesis of a COX-2-Specific Inhibitor

Davies, Ian W.; Marcoux, Jean-François; Corley, Edward G.; Journet, Michel; Cai, D.; Palucki, Michael; Wu, Jimmy; Larsen, Robert D.; Rossen, Kai; Pye, Philip J.; DiMichele, Lisa; Dormer, Peter G.; Reider, Paul J.

doi:10.1021/jo000870z

Cited by 93 publications

(50 citation statements)

References 23 publications

(23 reference statements)

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“…We speculate that the reaction mechanism is that the 2-cyano-N-(2-cyanophenyl) acetamide (2k) was first formed the carbon-anion 2k' in the presence of NaOEt, which could react with 2-aryl vinamidinium salt 1 to generate the intermediate 3ak 8,9 and further underwent a 1,6-addition followed by an elimination of dimethylamine to yield the target compound 4ak. On the other hand, the 2k' may convert into the compound 4ak'…”

Section: Resultsmentioning

confidence: 99%

One step synthesis of 1,5-diaryl pyridin-2(1H)-ones from 2-aryl vinamidinium salts and N-aryl cyanoacetamides

Yang

Su²,

Ren³

et al. 2014

Tetrahedron

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Section: Resultsmentioning

confidence: 99%

One step synthesis of 1,5-diaryl pyridin-2(1H)-ones from 2-aryl vinamidinium salts and N-aryl cyanoacetamides

Yang

Su²,

Ren³

et al. 2014

Tetrahedron

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“…Hydrolysis of thioester 9 generated the free thiol 10, which was used, without isolation, in the displacement of the bromide. Bromoketone 14 preparation started with the addition of benzylmagnesium chloride 12 to iodo Weinreb amide 11 (9), producing iodoketone 13 in 80% yield. Selective bromination of 13 to give bromoiodoketone 14 was accomplished with phenyltrimethylammonium tribromide in 1,2-dimethoxyethane in quantitative yield.…”

Section: Preparation Of Benzoxathiin 6 Preparation Of This Key Intermentioning

confidence: 99%

An efficient asymmetric synthesis of an estrogen receptor modulator by sulfoxide-directed borane reduction

Song

King²,

Waters³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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An efficient asymmetric synthesis of a selective estrogen receptor modulator (SERM) that has a dihydrobenzoxathiin core structure bearing two stereogenic centers is reported. The stereogenic centers were established by an unprecedented chiral sulfoxide-directed stereospecific reduction of an ␣,␤-unsaturated sulfoxide to the saturated sulfide in one step. Studies to elucidate the mechanism for this reduction are reported. Highly efficient Cu(I)-mediated ether formation was used to install the ether side chain, and selective debenzylation conditions were developed to remove the benzyl protecting groups on the phenols. E strogen receptors (ERs) are members of the steroid hormone nuclear receptor superfamily. They are ligand-dependent transcription factors that bind to specific DNA sequences and regulate gene expression. There are two known members of the estrogen receptor family, ER␣ and ER␤, encoded by distinct genes. ER modulators are potentially useful agents for treatment or prevention of a variety of conditions related to estrogen functions, including bone loss, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of low-density lipoprotein cholesterol, cardiovascular disease, obesity, incontinence, and cancer (refs. 1-4 and references cited in ref. 4). SERMs are ER ligands that act like estrogens in some tissues, but block estrogen action in others. Thus, SERMs may exhibit an agonistic or antagonistic activity, depending on the context in which their activity is examined. Fig. 1) is a potent ER␣ SERM being evaluated as part of the selective ER antagonist program at Merck (1-4). Although there are several methods for the synthesis of the core cis-2,3-disubstituted-dihydrobenzoxathiin, the asymmetric synthesis of these compounds has not been reported (1-7). Herein, we report an enantioselective synthesis of 1. Experimental ProceduresGeneral. Chemicals were used as received from commercial sources unless otherwise noted. NMR data were collected on Bruker Avance NMR spectrometers. Chemical shifts are reported in ppm downfield from tetramethylsilane. HPLC purity data are reported as area percentage of the desired peak from the total peaks. HPLC conditions are listed in supporting information, which is published on the PNAS web site. High-resolution mass spectrometer (HRMS) data were collected on a Micromass API US Ultima quadrupole time-of-flight (QTOF) mass spectrometer. Vinyl Sulfide 6.A 100-liter round-bottom flask was charged with ketone 7 (8.01 kg, 12.2 mol) and 48 liters of acetonitrile followed by phenylphosphonic dichloride (2.50 kg, 12.9 mol). The flask was fitted with a reflux condenser with off-gases vented through a caustic scrubber, and the reaction mixture was heated to reflux (75°C). After about 2 h, HPLC assay showed Ͼ99% conversion. The reaction mixture was concentrated under reduced pressure at 20-50°C to 28 liters. Diisopropylethylamine (786 g, 6.08 mol) was added, followed by 28 liters of denatured ethanol (denatured with 0.5% toluene). The solution was ...

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“…The other selective inhibitors of COX-2 enzyme are celecoxib 18 . valdecoxib 19,20 and etoricoxib [21][22][23] . The follow-up studies of this class of compounds [24][25][26][27][28][29] have pointed out that the mechanism of action as probable cause of adverse effects 30,31 .…”

Section: Introductionmentioning

confidence: 99%

QSAR of 2-(4-methylsulphonylphenyl)pyrimidine derivatives as cyclooxygenase-2 inhibitors: simple structural fragments as potential modulators of activity

Sharma

Singh

Pilania

et al. 2011

Journal of Enzyme Inhibition and Medicinal Chemistry

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A Practical Synthesis of a COX-2-Specific Inhibitor

Cited by 93 publications

References 23 publications

One step synthesis of 1,5-diaryl pyridin-2(1H)-ones from 2-aryl vinamidinium salts and N-aryl cyanoacetamides

One step synthesis of 1,5-diaryl pyridin-2(1H)-ones from 2-aryl vinamidinium salts and N-aryl cyanoacetamides

An efficient asymmetric synthesis of an estrogen receptor modulator by sulfoxide-directed borane reduction

QSAR of 2-(4-methylsulphonylphenyl)pyrimidine derivatives as cyclooxygenase-2 inhibitors: simple structural fragments as potential modulators of activity

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