An efficient synthesis of highly substituted pyrrole and bis pyrrole derivatives

Sagyam, Rajeshwar Reddy; Padi, Pratap Reddy; Ghanta, Mahesh Reddy; Himabindu, V.

doi:10.1002/jhet.5570440429

Cited by 24 publications

(20 citation statements)

References 25 publications

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“…The synthesis of the benzyl ether pyrrole intermediate 6, as well as the atorvastatin precursor 11, was performed by the treatment of the corresponding 1,4-diketone intermediates 4 and 10, respectively, with the commercially available primary amine 5 in a pivalic acidcatalyzed Paal-Knorr condensation reaction (Scheme 1). The 1,4-diketone intermediates 4 and 10 were synthesized via a Stetter reaction [61,62]. In summary, the α,βunsaturated ketone 1 was combined with benzaldehydes 2 and 9, respectively, in the presence of triethylamine and the thiazolium bromide catalyst 3 to afford the corresponding 1,4-diketone intermediates 4 and 10, respectively.…”

Section: Synthesis Of Precursors and 18 F-fluorination Strategymentioning

confidence: 99%

[18F]Atorvastatin: synthesis of a potential molecular imaging tool for the assessment of statin-related mechanisms of action

et al. 2020

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Background: Statins are lipid-lowering agents that inhibit cholesterol synthesis and are clinically used in the primary and secondary prevention of cardiovascular diseases. However, a considerable group of patients does not respond to statin treatment, and the reason for this is still not completely understood. [ 18 F]Atorvastatin, the 18 Flabeled version of one of the most widely prescribed statins, may be a useful tool for statin-related research. Results: [ 18 F]Atorvastatin was synthesized via an optimized ruthenium-mediated late-stage 18 F-deoxyfluorination. The defluoro-hydroxy precursor was produced via Paal-Knorr pyrrole synthesis and was followed by coordination of the phenol to a ruthenium complex, affording the labeling precursor in approximately 10% overall yield. Optimization and automation of the labeling procedure reliably yielded an injectable solution of [ 18 F]atorvastatin in 19% ± 6% (d.c.) with a molar activity of 65 ± 32 GBq·μmol −1 . Incubation of [ 18 F]atorvastatin in human serum did not lead to decomposition. Furthermore, we have shown the ability of [ 18 F]atorvastatin to cross the hepatic cell membrane to the cytosolic and microsomal fractions where HMG-CoA reductase is known to be highly expressed. Blocking assays using rat liver sections confirmed the specific binding to HMG-CoA reductase. Autoradiography on rat aorta stimulated to develop atherosclerotic plaques revealed that [ 18 F]atorvastatin significantly accumulates in this tissue when compared to the healthy model. Conclusions: The improved ruthenium-mediated 18 F-deoxyfluorination procedure overcomes previous hurdles such as the addition of salt additives, the drying steps, or the use of different solvent mixtures at different phases of the process, which increases its practical use, and may allow faster translation to clinical settings. Based on tissue uptake evaluations, [ 18 F]atorvastatin showed the potential to be used as a tool for the understanding of the mechanism of action of statins. Further knowledge of the in vivo biodistribution of [ 18 F]atorvastatin may help to better understand the origin of off-target effects and potentially allow to distinguish between statin-resistant and non-resistant patients.

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Section: Synthesis Of Precursors and 18 F-fluorination Strategymentioning

confidence: 99%

[18F]Atorvastatin: synthesis of a potential molecular imaging tool for the assessment of statin-related mechanisms of action

et al. 2020

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“…Although they are scientifically very interesting, they will not be discussed here in any greater detail. [395,396] The key step for building the 1,4-diketone, subsequently used in the Paal-Knorr pyrrole synthesis, is a Stetter reaction, whereby p-fluorobenzaldehyde is added to a β-ketoamide in presence of a thiazolium salt.…”

Section: Pravastatinmentioning

confidence: 99%

Pharmaceuticals

Schaefer

2014

Natural Products in the Chemical Industry

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A boy who is born in Germany today has a probable life expectancy of around 77 years, and a girl one of 82 years -twice as long as in the year 1880. This increase is a consequence of both, better living circumstances -working conditions, food, clothing, housing -, and also a result of more comprehensive medical care. Thus, a whole range of infectious diseases has been wiped out, or brought at least under control, and the mortality rate for civilisation-and age-related diseases has dropped. Vaccinations and drugs play a key role in this outcome. The 20th century is characterised especially by the worldwide blossoming of the pharmaceutical industry. More and more, the targeted search for and development of new drugs have replaced serendipitous discoveries (Fig. 5.1). Pharmaceuticals of the last century.

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“…Schlüssel-schritt hierbei ist eine Paal-Knorr-Synthese (Abbildung 36). Diese gelingt nur unter eigens hierfür entwickelten Bedingungen und stellte anfänglich eine scheinbar unüberwind-bare Hürde dar, so dass auch eine Reihe linearer Synthesen entwickelt wurde, auf die aber hier nicht näher eingegangen werden soll [48,49].…”

Section: Synthese Von Racemischem Fluvastatinunclassified

Statine. Cholesterolsenker

Schäfer

2010

Chemie in nserer Zeit

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An efficient synthesis of highly substituted pyrrole and bis pyrrole derivatives

Abstract: An efficient synthesis of highly substituted pyrrole and bis pyrrole derivatives is reported.

Cited by 24 publications

References 25 publications

[18F]Atorvastatin: synthesis of a potential molecular imaging tool for the assessment of statin-related mechanisms of action

[18F]Atorvastatin: synthesis of a potential molecular imaging tool for the assessment of statin-related mechanisms of action

Pharmaceuticals

Statine. Cholesterolsenker

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