- [18F]Atorvastatin: synthesis of a potential molecular imaging tool for the assessment of statin-related mechanisms of action
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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. [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.
- Antunes, Inês F.,Clemente, Gon?alo S.,D?mling, Alexander,Elsinga, Philip H.,Rickmeier, Jens,Ritter, Tobias,Zarganes-Tzitzikas, Tryfon
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- Synthesis method of atorvastatin calcium
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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
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Paragraph 0051-0053
(2018/12/02)
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- Preparation technology of atorvastatin
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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.
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- A decongestant atorvastatin
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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
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Paragraph 0094-0099
(2017/01/17)
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- Enantioselective synthesis of allylboronates and allylic alcohols by copper-catalyzed 1,6-boration
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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.
- Luo, Yunfei,Roy, Iain D.,Madec, Amael G. E.,Lam, Hon Wai
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supporting information
p. 4186 - 4190
(2014/05/06)
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- Streamlined catalytic asymmetric synthesis of atorvastatin
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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
- Kawato, Yuji,Chaudhary, Sandeep,Kumagai, Naoya,Shibasaki, Masakatsu
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supporting information
p. 3802 - 3806
(2013/04/24)
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- A simplified catalytic system for direct catalytic asymmetric aldol reaction of thioamides; Application to an enantioselective synthesis of atorvastatin
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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.
- Kawato, Yuji,Iwata, Mitsutaka,Yazaki, Ryo,Kumagai, Naoya,Shibasaki, Masakatsu
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experimental part
p. 6539 - 6546
(2011/09/20)
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- Methods for predicting the response to statins
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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.
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- Drug or Supplement Combination with Conjugated Linoleic Acid for Fat Loss in Mammals
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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.
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- PROCESS FOR THE MODIFICATION OF THE SOLID STATE OF A COMPOUND AND CO-AMORPHOUS COMPOSITIONS PRODUCED WITH SAME
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The invention provides a process for preparing non-crystalline organic compositions and non-crystalline, co-amorphous blends of organic compounds.
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Page/Page column 28-30
(2009/05/28)
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- Pharmaceutically acceprable salts of aporphine compounds of carboxyl group-containing agents and methods for preparing the same
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The present invention discloses novel pharmaceutically acceptable salts of aporphine compounds and carboxyl-group containing agents. Also, the present invention discloses methods for preparing the pharmaceutically acceptable salts. These pharmaceutically acceptable salts are suitable for use in treating and/or preventing hyperglycemic disease and/or several oxidative stress related diseases.
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- Crystalline forms of atorvastatin magnesium
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The present invention relates to crystalline forms of Atorvastatin magnesium and processes for their preparation. The crystalline forms of the present invention are designated as form X, form Y, form Z and form P of atorvastatin magnesium. The present inv
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Page/Page column 6-7
(2009/12/24)
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- CRYSTALLINE FORMS OF ATORVASTATIN MAGNESIUM
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The present invention relates to crystalline forms of Atorvastatin magnesium and processes for their preparation. The crystalline forms of the present invention are designated as form X, form Y, form Z and form P of atorvastatin magnesium. The present inv
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Page/Page column 4
(2009/12/24)
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- Synthesis of some impurities and/or degradation products of atorvastatin
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Synthesis of some impurities and/or degradation products of atorvastatin, calcium (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl) pyrrol-1-yl]-3,5-dihydroxyheptanoate, is described. These include its desfluoro analog, the corresponding (3S,5S)-and (3S,5R)-epimers, atorvastatin lactone, and some other potential impurities. The synthesized compounds as well as the corresponding intermediates were characterized by 1H NMR, 13C NMR and MS.
- Stach, Jan,Havlicek, Jaroslav,Placek, Lukas,Radl, Stanislav
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p. 229 - 246
(2008/12/22)
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- ATORVASTATIN INTERMEDIATES AND METHOD FOR PRODUCING THE SAME
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The present invention provides a novel boronate ether of Formula 1 useful for the synthesis of atorvastatin, and a preparation method thereof.
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Page/Page column 10-11
(2008/12/08)
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- NEW COMBINATION FOR USE IN THE TREATMENT OF INFLAMMATORY DISORDERS
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There is provided combination products comprising (a) pemirolast, or a pharmaceutically-acceptable salt or solvate thereof; and (b) a statin, or a pharmaceutically-acceptable salt or solvate thereof. Such combination products find particular utility in th
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Page/Page column 41-42
(2008/12/06)
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- Drug or Pharmaceutical Compounds and a Preparation Thereof
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The administration of pharmaceuticals of drugs which are having less solubility, lower bioavailability, lower bioabsorbability, less rate of absorption has become a big challenge in day to day life. Therefore an attempt has been made to prepare a complex modified form of the said pharmaceutical or drug such that the modified complex drugs or pharmaceuticals exhibits the enhanced properties of solubility, bioavailability, bioabsorbability and rate of absorption despite the increased complexity of the molecule. Surprisingly such modification was found to enhance retentivity of the active drug ingredient in the blood. Higher amounts of the active drug ingredient has shown lower toxicity.
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Page/Page column 5-6
(2008/12/08)
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- Atorvastatin calcium propylene glycol solvates
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Atorvastatin calcium propylene glycol solvates and processes to prepare these novel solvates which are particularly useful and suitable for pharmaceutical applications.
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Page/Page column 5-6
(2008/12/07)
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- PREPARATION OF AN ATORVASTATIN INTERMEDIATE
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Atorvastatin lactone is prepared by hydrogenating tert-butyl isopropylidene nitrile to tert-butyl isopropylidene amine and condensing the amine with the diketone of atorvastatin to form acetonide ester. The diol protecting acetonide ester is deprotected to form a diol ester by dissolving the acetonide ester in methanol and treating with an acid. The diol ester is saponified to form a sodium salt. Methanol is removed from the reaction mixture by distillation. The sodium salt is reacidified to the free diol acid and atorvastatin lactone is formed from the diol acid. The atorvastatin lactone is directly dried without further purification.
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Page/Page column 6-9; 11
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM SALT
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Disclosed is a novel process for preparing pure amorphous form of Atorvastatin employing a suitable solvent system selected from water, water miscible solvents or water immiscible solvents or mixture thereof.
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Page/Page column 9
(2008/06/13)
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- IMPROVED DRUG OR PHARMACEUTICAL COMPOUNDS AND A PREPARATION THEREOF
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The administration of pharmaceuticals of drugs which are having less solubility, lower bioavailability, lower bioabsorbability, less rte of absorption has become a big challenge in day today life. Therefore anattempt has been made to prepare a complex modified form of the said pharmaceutical or drug such that the modified complex drugs or pharmaceuticals exhibits the enhanced properties of solubility, bioavailability, bioabsorbability and rate of absorption despite the increased complexity of the molecule. Surprisingly such modification was found to enhance retentivity of the active drug ingredient in the blood. Higher amounts of the active drug ingredient has shown lower toxicity.
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Page/Page column 20-23
(2008/06/13)
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- POLYMORPHS OF ATORVASTATIN TERT.-BUTYLESTER AND USE AS INTERMEDIATES FOR THE PREPARATION OF ATORVASTATIN
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The invention relates to crystalline forms and 1 and 2 of atorvastatin tert.-butyl ester (Formula (II)), processes for their preparation and their conversion to highly pure atorvastatin hemi calcium in non-crystalline, in particular amorphous form.
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Page/Page column 19-22
(2008/06/13)
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- CRYSTALLINE FORMS OF `R-(R*,R*)]-2-(4-FLUOROPHENYL)-BETA,DELTA-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-`(PHENYLAMINO)CARBONYL!-1H-PYRROLE-1-HEPTANOIC ACID
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Novel crystalline forms of [R-(R*,R*)]-2-(4-fluorophenyl)-?,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-l-heptanoic acid (atorvastatin free acid) designated Form A and Form B, characterized by their X-ray powder diffraction
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Page/Page column 15-16
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF ATORVASTATIN
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The invention relates to processes for the preparation of atorvastatin. Atorvastatin is known by the chemical name [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid. The hemi-calcium salt of atorvastatin is useful as an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase). The invention also relates to pharmaceutical compositions that include the atorvastatin or a pharmaceutically acceptable salt thereof and to use of said compositions for treating hypolipidemia, hypocholesterolemia and atherosclerosis.
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Page/Page column 12
(2008/06/13)
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- PROCESS FOR PREPARING 5-(4-FLUOROPHENYL)-1-[2-((2R,4R)-4-HYDROXY -6-OXO-TETRAHYDRO-PYRAN-2-YL)ETHYL]-2-ISOPROPYL-4-PHENYL-1H-PYRROLE-3-CARBOXYLIC ACID PHENYLAMIDE
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A method for preparing 5-(4-fluorophenyl)-I-[2-((2R, 4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide (I), a key intermediate in the synthesis of atorvastatin calcium, is described.
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- Treatment of type 1 diabetes with PDE5 inhibitors
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The use of a PDE5 inhibitor without substantial PDE2 inhibiting activity, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of Type 1 Diabetes. A method of treating Type 1 Diabetes in an individual suffering from Type 1 Diabetes, which method comprises administering to said individual an effective amount of a PDE5 inhibitor without substantial PDE2 inhibiting activity, or a pharmaceutically acceptable salt thereof.
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- Process for the production of amorphous atorvastatin calcium
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A process for the preparation of amorphous atorvastatin calcium and hydrates thereof which comprises: (a) dissolving crystalline atorvastatin calcium in a non-hydroxylic solvent; (b) adding a non-polar hydrocarbon anti-solvent or adding the dissolved ator
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- Novel crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms
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The present invention provides novel forms of atorvastatin designated Forms VI, VII, VIII, IX, IXa, X, XI, XII, XIV, XVI and XVII and novel processes for their preparation as well as processes for preparing atorvastatin Forms I, II, IV, V and amorphous at
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- Method for producing pharmaceutical dosage forms
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The invention relates to a method for producing a granulate while using spray-dried D-mannitol and to the production of pharmaceutical dosage forms comprised of granulates of this type. The invention additionally relates to granulates obtained by using this method and to pharmaceutical dosage forms, which contain statins, especially cerivastatin, and which can be produced from said granulates.
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- Crystalline forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1)
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Novel crystalline forms of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid hemi calcium salt designated Form V, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII,
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- NEW ATORVASTATIN SALTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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The invention relates to salts of atorvastatin formed with a basic amino acid of the general formula (I), where the meaning of R is a group originated from lysine, arginine or ornithine, and the amorphous or polymorph modifications thereof. The inventi
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Page/Page column 8; 9-10
(2008/06/13)
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- Synthesis of deuterium-labeled atorvastatin and its metabolites for use as internal standards in a LC/MS/MS method developed for quantitation of the drug and its metabolites in human serum
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D5-labeled isotopomers of atorvastatin, atorvastatin lactone and its hydroxy metabolites were synthesized as internal standards for use in a LC/MS/MS method developed for the simultaneous quantitative determination of atorvastatin and its hydroxy metabolites in human serum. d5-Atorvastatin and d5-atorvastatin lactone were prepared from d5-aniline whereas their corresponding hydroxy metabolites were synthesized using d5-benzaldehyde.
- Chen, Bang-Chi,Sundeen, Joseph E.,Guo, Peng,Bednarz, Mark S.,Hangeland, Jon J.,Ahmed, Syed Z.,Jemal, Mohammed
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p. 261 - 270
(2007/10/03)
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- Process for the synthesis of protected esters of (S)-3,4-dihydroxybutyric acid
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The invention is an improved process for the preparation of a compound of formula I wherein R and R1 are each independently alkyl of from 1 to 3 carbon atoms; and R2 is alkyl of from 1 to 8 carbon atoms. STR1
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- Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis
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An improved process for the preparation of trans-6-[2-(substituted-pyrrole-1-yl)alkyl]pyran-2-ones by a novel synthesis is described where α-metalated N,N-disubstituted acetamide is converted in seven operations to the desired products, and specifically,
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