110862-48-1

Usage

Clinical Use

Hyperlipidaemia and hypercholesterolaemia

Drug interactions

Potentially hazardous interactions with other drugs Anti-arrhythmics: concentration possibly increased by dronedarone. Antibacterials: azithromycin, erythromycin, clarithromycin or fusidic acid possibly increased risk of myopathy - avoid atorvastatin for at least 7 days after fusidic acid stopped; concentration increased by clarithromycin - do not exceed 20 mg of atorvastatin1 ; avoid with telithromycin; increased risk of myopathy with daptomycin; concentration possibly reduced by rifampicin. Anticoagulants: may transiently reduce anticoagulant effect of warfarin. Antifungals: increased risk of myopathy with itraconazole - do not exceed 40 mg of atorvastatin1 ; increased risk of myopathy with fluconazole, ketoconazole, posaconazole, voriconazole and possibly other imidazoles and triazoles - avoid. Antivirals: increased risk of myopathy with atazanavir, boceprevir (reduce atorvastatin dose), and possibly darunavir, fosamprenavir, indinavir, lopinavir, ritonavir, saquinavir or tipranavir (max dose of atorvastatin 10 mg); concentration reduced by efavirenz and possibly etravirine; avoid with dasabuvir, ombitasvir, paritaprevir and telaprevir; possible increased risk of myopathy with ledipasvir - reduce atorvastatin dose; concentration increased by simeprevir - consider reducing atorvastatin dose. Calcium channel blockers: concentration increased by diltiazem - increased risk of myopathy; concentration of verapamil increased also possible increased risk of myopathy - consider reducing atorvastatin dose. Ciclosporin: increased risk of myopathy - do not exceed 10 mg of atorvastatin.1 Cobicistat: reduce atorvastatin dose. Colchicine: possible increased risk of myopathy. Grapefruit juice: concentration possibly increased. Lipid lowering agents: increased risk of myopathy with fibrates, gemfibrozil (avoid) and nicotinic acid.

Metabolism

Atorvastatin undergoes extensive presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Atorvastatin is metabolised by cytochrome P450 3A4 to ortho- and parahydroxylated derivatives and various beta-oxidation products. These products are further metabolised via glucuronidation. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. Atorvastatin is eliminated primarily in bile as active metabolites following hepatic and/or extrahepatic metabolism, but does not appear to undergo significant enterohepatic recirculation.

InChI:InChI=1/C33H34FNO5.Ca/c1-21(2)31-30(33(40)24-11-7-4-8-12-24)29(22-9-5-3-6-10-22)32(23-13-15-25(34)16-14-23)35(31)18-17-26(36)19-27(37)20-28(38)39;/h3-16,21,26-27,36-37H,17-20H2,1-2H3,(H,38,39);/q;+2/p-1/t26-,27-;/m1./s1

Upstream product

• 125971-86-0 tert-butyl [(4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate 
• 459-57-4 4-fluorobenzaldehyde 
• 581772-29-4 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetic acid 
• 472967-95-6 tert-butyl (4S,6S)-6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]ethyl}-2,2-dimethyl-1,3-dioxane-4-acetate 
• 134394-96-0 *,S^*)>-5-<2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-<(phenylamino)carbonyl>-1H-pyrrol-1-yl>-3-hydroxy-1-pentanoic acid, 2-hydroxy-1,2,2-triphenylethyl ester 
• 103-82-2 phenylacetic acid 
• 347-84-2 1-(4-fluorophenyl)-2-phenylethanone 
• 103-80-0 phenylacetyl chloride 
• 125971-96-2 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxopentanoic acid phenylamide 
• 134523-01-6 atorvastatin sodium 
• 1146977-93-6 ethyl (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate 
• 1447820-23-6 C₁₈H₂₇NO₄ 
• 1447820-21-4 C₃₀H₃₅NO₂ 
• 442851-51-6 tert-butyl 2-((2R,4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)ethyl)-2-phenyl-1,3-dioxan-4-yl)acetate 

Downstream Products

• 345891-62-5 (3R,5R)-methyl 7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate 
• 214217-88-6 p-Hydroxyatorvastatin 
• 214217-86-4 o-Hydroxyatorvastatin 
• 1440755-31-6 1-((19R,21R)-1-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthene]-5-ylamino)-19,21-dihydroxy-17-oxo-1-thioxo-6,9,12-trioxa-2,16-diazatricosan-23-yl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide 
• 1174332-81-0 1-((3R,5R)-3,5-dihydroxy-7-(hydroxyamino)-7-oxoheptyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-7H-pyrrole-3-carboxamide 

Relevant academic research and scientific papers

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

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.

Synthesis method of atorvastatin calcium

The invention relates to a synthesis method of an atorvastatin calcium. A cheap and easy-to-get Paal-Knorr cyclization product formula-V compound is subjected to hydroxyl deprotection, esterolysis andsalinization so as to obtain a target product atorvasta

Preparation technology of atorvastatin

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.

METHODS FOR PROVIDING INTERMEDIATES IN THE SYNTHESIS OF ATORVASTATIN.

The invention relates to the field of medicinal chemistry, In particular, it relates to methods for providing intermediates in the synthesis of Atorvastatin, a competitive inhibitor of HMG-Co A reductase. Provided is a process for providing a compound having a Formula (I) or a pharmaceutically acceptable salt, ester, amide or stereoisomer thereof, comprising reacting in a 4 component Ugi-reaction in a single reaction mixture the compounds of formula A, formula B, formula C and formula D.

A decongestant atorvastatin

The invention relates to an atorvastatin amino acid and a preparation method thereof. Atorvastatin acid reacts with alkaline amino acid to obtain the compound. The preparation method comprises the following steps: (1) weighing the atorvastatin acid, and d

Enantioselective synthesis of allylboronates and allylic alcohols by copper-catalyzed 1,6-boration

Chiral secondary allylboronates are obtained in high enantioselectivities and 1,6:1,4 ratios by the copper-catalyzed 1,6-boration of electron-deficient dienes with bis(pinacolato)diboron (B2(pin)2). The reactions proceed efficiently using catalyst loadings as low as 0.0049 mol %. The allylboronates may be oxidized to the allylic alcohols, and can be used in stereoselective aldehyde allylborations. This process was applied to a concise synthesis of atorvastatin, in which the key 1,6-boration was performed using only a 0.02 mol % catalyst loading. 1,6-Borations of electron-deficient dienes with bis(pinacolato)diboron using copper catalyst loadings as low as 0.0049 mol % provided chiral allylboronates that, after oxidation, result in allylic alcohols in high enantioselectivities and 1,6:1,4 ratios. The allylboronates can also be used in stereoselective allylations of aldehydes. This process was applied to a concise synthesis of atorvastatin.

Streamlined catalytic asymmetric synthesis of atorvastatin

An efficient enantioselective synthetic route to atorvastatin was developed based on a direct catalytic asymmetric aldol reaction. The expensive chiral ligand used in the initial aldol reaction was readily recovered (91 %) and reused. Implementation of an oxy-Michael reaction for the construction of the syn-1,3-diol unit eliminated several redundant steps, allowing for rapid access to the common intermediate in six steps (see scheme). Copyright

A simplified catalytic system for direct catalytic asymmetric aldol reaction of thioamides; Application to an enantioselective synthesis of atorvastatin

A new catalytic system was developed for the direct catalytic asymmetric aldol reaction of thioamides. The new lithium-free Cu catalyst (second-generation catalyst) exhibited enhanced catalytic efficiency over the previously developed catalyst comprising [Cu(CH3CN) 4]PF6/Ph-BPE/LiOAr (first-generation catalyst), which required a tedious catalyst preparation process. In the reaction with the second-generation catalyst, the intermediate Cu-aldolate functioned as a Bronsted base to generate thioamide enolate, efficiently driving the catalytic cycle. The present aldol methodology culminated in a concise asymmetric synthesis of atorvastatin (Lipitor: atorvastatin calcium), a widely prescribed HMG-CoA reductase inhibitor for lowering low-density lipoprotein cholesterol.

Methods for predicting the response to statins

The invention provides methods for optimizing therapeutic efficacy for treating hypercholesterolemia in a subject having a cardiovascular disease (CVD), comprising (a) determining subject characteristics that affect the likelihood of reaching a goal level of low density lipoprotein (LDL); and (b) obtaining success probabilities of a variety of statin treatments for reaching said goal level of LDL using said subject characteristics and a multivariate model; and (c) administrating the optimal statin treatment with the highest success probability of step (b) to said subject thereby optimizing therapeutic efficacy for treating hypercholesterolemia in said subject.

Drug or Supplement Combination with Conjugated Linoleic Acid for Fat Loss in Mammals

Food, feed or drug combinations with conjugated linoleic acid are described that cause enhanced fat loss in mammals more efficiently than any of the individual components of the combination. Food, feed, or drugs that activate AMP activated protein kinase, agonists of nuclear receptors that bind RXR in adipocytes, or statin inhibitors were found to be more effective for fat loss when combined with conjugated linoleic acid.