125971-58-6Relevant articles and documents
[18F]Atorvastatin: synthesis of a potential molecular imaging tool for the assessment of statin-related mechanisms of action
Antunes, Inês F.,Clemente, Gon?alo S.,D?mling, Alexander,Elsinga, Philip H.,Rickmeier, Jens,Ritter, Tobias,Zarganes-Tzitzikas, Tryfon
, (2020/04/24)
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. [18F]Atorvastatin, the 18F-labeled version of one of the most widely prescribed statins, may be a useful tool for statin-related research. Results: [18F]Atorvastatin was synthesized via an optimized ruthenium-mediated late-stage 18F-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 [18F]atorvastatin in 19% ± 6% (d.c.) with a molar activity of 65 ± 32 GBq·μmol?1. Incubation of [18F]atorvastatin in human serum did not lead to decomposition. Furthermore, we have shown the ability of [18F]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 [18F]atorvastatin significantly accumulates in this tissue when compared to the healthy model. Conclusions: The improved ruthenium-mediated 18F-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, [18F]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 [18F]atorvastatin may help to better understand the origin of off-target effects and potentially allow to distinguish between statin-resistant and non-resistant patients.
Atorvastatin key intermediate for preparing environmental protection
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Paragraph 0051-0054; 0057-0058, (2019/07/01)
The present invention provides a kind of atorvastatin key intermediate of environmental protection preparation method, the intermediate body is 4 - fluoro - alpha - [2 - methyl - 1 - oxygen propyl] - gama - oxo - N, beta - diphenyl benzene ding amide, the method uses hydrogen peroxide oxidation of an alkali metal salt of bromide, bromine generated in-situ, brominated 4 '- fluorophenyl - 2 - acetophenone synthesis of 2 - bromo - 1 - (4' - fluoro phenyl) - 2 - acetophenone; above brominated alkali metal salt can be the recovery of the condensation reaction by-product, the obtained 2 - bromo - 1 - (4' - fluoro phenyl) - 2 - acetophenone with isobutyryl acetyl aniline under the action of the acid condensation reaction to obtain the target product, 4 - fluoro - alpha - [2 - methyl - 1 - oxygen propyl] - gama - oxo - N, beta - diphenyl benzene ding amide. When the condensation reaction to form a brominated alkali metal salt recovery, is used for the next batch 4' - fluorophenyl - 2 - acetophenone of the bromination reaction. The method epihalogenohydrine atomic access to fully recycle, greatly reduce the emission of halogen-containing waste. The utilization rate of higher than 80%, saving, full use of resources, reduce environmental pollution, truly environmental protection.
Preparation technology of atorvastatin
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, (2017/08/27)
The invention discloses preparation technology of atorvastatin. The preparation technology comprises the following steps: a first step, the reaction of phenylacetic acid and thionyl chloride is carried out in order to obtain phenylacetyl chloride; a second step, the Friedel-Crafts acylation reaction of phenylacetyl chloride and fluorobenzene is carried out under the action of catalyst, in order to obtain 4-fluorophenyl acetophenone; a third step, 4-fluorophenyl acetophenone is brominated and the brominated 4-fluorophenyl acetophenone is reacted with N-phenyl-isobutyloylacetamide in order to obtain M-4; a fourth step, a reaction is carried out for M-4 and ATS-9 in a cyclohexane, toluene or a mixed solvent of cyclohexane and toluene, pivalic acid is used for catalysis, and a condensation product is obtained. Phenylacetyl chloride and fluorobenzene are reacted in a catalytic action of zeolite molecular sieve, a complexation reaction of the catalyst and products is avoided, reaction yield is improved, and side reactions are few in order to facilitate purification; post-treatment can be carried out for excess M-4 for recycling and reusing, reaction yield is improved, mole proportion of M-4 to ATS-9 and the addition amount of pivalic acid can be adjusted, and final yield of the reaction is improved.
