125971-96-2Relevant 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.
Method for synthesizing atorvastatin calcium intermediate by multi-component one-pot method
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Paragraph 0152-0179, (2020/11/23)
The invention provides a method for synthesizing an atorvastatin calcium intermediate by a multi-component one-pot method, and particularly provides a one-pot method for synthesizing 4-(4-fluorophenyl)-2-(2methylpropionyl)-3-phenyl 4-oxo-N-phenyl butyramide. The preparation method is characterized in that N-phenyl phenylpropiolamide, 4-fluorobenzaldehyde and isobutyraldehyde are synthesized by a one-pot method under the action of Cu(SbF6)2 and a Pd-ligand catalyst to obtain a target compound. The one-pot method conforms to the characteristics of green chemistry and high atom economy, and emission of three wastes and pollution factors is remarkably reduced; the reaction steps are short, and the yield (about 80-87%) is obviously higher than that of the technical scheme of the existing multi-step synthesis method; raw materials are easily available; the process operation is simple; the EHS risk is low; and the industrialized feasibility is high.
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 method of atorvastatin calcium
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, (2018/07/30)
The invention belongs to the technical field of medicine preparation and particularly relates to a patent application about a novel preparation method of atorvastatin calcium. The method includes steps of preparing intermediates including: 2-methyl-3-carbonyl-methyl pentanoate, 2-methyl-3,5-dicarbonyl-5-anilino-butane, 4-methyl-3-oxo-N-phenyl-2-benzylidene pentanamide, 4-(4-fluorophenyl)-2-(2-methylpropionyl)-4-oxo-N-beta-diphenyl butyrylamide. The preparation method employs cheap and easy-to-obtained raw materials, has simple reactions and operations, and has great industrial application prospect. In conclusion, the preparation method has high reaction efficiency and product yield, is good in repeatability, is suitable for industrial production and has great application value and promotion and application significance.
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.
The total synthesis of calcium atorvastatin
Dias, Luiz C.,Vieira, Adriano S.,Barreiro, Eliezer J.
, p. 2291 - 2296 (2016/03/01)
A practical and convergent asymmetric route to calcium atorvastatin (1) is reported. The synthesis of calcium atorvastatin (1) was performed using the remote 1,5-anti asymmetric induction in the boron-mediated aldol reaction of β-alkoxy methylketone (4) with pyrrolic aldehyde (3) as a key step. Calcium atorvastatin was obtained from aldehyde (3) after 6 steps, with a 41% overall yield.
Efficient Synthesis of the Nucleus of Atorvastatin Calcium
Xing, Yuzhi,Chen, Shipeng,Zhou, Yingtao,Liu, Na,Chen, Ligong,Li, Yang
, p. 2832 - 2840 (2015/12/23)
An efficient synthetic route for the parent nucleus of atorvastatin calcium was successfully established through the modification of the related reactions. Under the optimized conditions, compound 1 was obtained in 61.2% yield (lit. 51.4%) from methyl isopropyl ketone via five steps. Two impurities generated by the aldol condensation of methyl isopropyl ketone were identified by gas chromatography-mass spectrometry and their generation can be inhibited by reducing the mixing time of methyl isopropyl ketone and NaH. One oxybromination protocol with hydrogen peroxide was employed to make the best of bromine. A debromination by-product was isolated and confirmed by 1H NMR, 13C NMR, and high-resolution mass spectrometry and its generation mechanism was discussed. The impurity can be inhibited by protecting the reaction from light and easily removed by recrystallization.
A PROCESS FOR PREPARATION OF 4-FLUORO-α-[2-METHYL-L-OXOPROPYL]-γ-OXO-N-β-DIPHENYLBENZENE BUTANE AMIDE
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, (2012/11/07)
A process for preparation of 4-fluoro-alpha-[2-methyl-l -oxopropyl]-gama-oxo-N- beta-diphenylbenzene butane amide also known as a diketone intermediate of atorvastatin, completely devoid of impurities 3,4-difluoro-alpha-[2-methyl-l-oxopropyl]-gama-oxo-n-beta-diphenylbenzene butane amide; methyl, 2 {-2[-(4-fluorophenyl)-2-oxo- 1 -phenyl ethyl)] } -4-methyl-3-oxo pentanoate; 1,4-bis(4-fluorophenyl)-2,3-diphenylbutane- 1,4-dione, 1 -(4-fluorophenyl)-2-phenyl ethanone; l-(4-fluorophenyl)-2-phenyl ethanone and containing about 0.05% or less of 2-methyl- l-oxopropyl]-gama-oxo-N-beta- diphenylbenzene butane amide. In that process the said diketone intermediate of formula 1 is obtained by maintaining temperature -25° C to 50° C during Friedel-Crafts acylation, in situ halogenation of formula II in presence of a solvent and nucleophilic substitution from a compound of formula III with formula IV in presence of a base.
METHOD FOR THE PREPARATION OF 4-FLUORO-ALPHA-[2-METHYL-1-OXOPROPYL]-y-OXO-N-BETA-DIPHENYLBENZENEBUTANAMIDE AND PRODUCTS THEREFROM
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Page/Page column 7, (2009/12/23)
A method for the preparation of 4-fluoro-α-[2-methyl-1-oxopropyl]-y-oxo-N-β-diphenylbenzenebutanamide also known as 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid phenylamide of the formula I containing about 0.1% or less of α-[2-methyl-1-oxopropyl]-γ-oxo-N-p-diphenylbenzene butanamide, about 0.05% or less of difluoro-α-[2-methyl-1-oxopropyl]-y-oxo-N-β-diphenylbenzene butanamide and about 0.1% or less of 3-[2-(4-Fluorophenyl)-2-oxo-1-phenyl-ethoxy]-4-methyl-pent-2-enoic acid phenylamide.
An efficient synthesis of highly substituted pyrrole and bis pyrrole derivatives
Sagyam, Rajeshwar Reddy,Vurimidi, Himabindu,Padi, Pratap Reddy,Ghanta, Mahesh Reddy
, p. 923 - 926 (2008/03/29)
(Chemical Equation Presented) An efficient synthesis of highly substituted pyrrole and bis pyrrole derivatives is reported.
