- PROCESS FOR THE CONTINUOUS MANUFACTURE OF STATINS
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The present invention relates to process for the continuous manufacture of Statins or salts thereof. The present invention relates to process for the continuous manufacture of Atorvastatin or a salt thereof. The present invention relates to a continuous m
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Page/Page column 25-31
(2021/06/04)
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- Method for purifying atorvastatin calcium intermediate
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The atorvastatin calcium intermediate is subjected to hydrolysis reaction to obtain the reaction liquid of atorvastatin calcium intermediate. The reaction liquid is extracted with a stripping solvent and is separated and separated to obtain an aqueous pha
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Paragraph 0043; 0046; 0049; 0052; 0055; 0058; 0062
(2021/09/01)
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- AN IMPROVED AND COMMERCIALLY VIABLE PROCESS FOR PREPARATION OF PYRROLE DERIVATIVES WITH IMPROVED IMPURITY PROFILE & MINIMISATION OF UNIT OPERATIONS.
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The present invention relates to improved process for the preparation of a pyrrole derivative as a racemic mixture, an enantiomer, a diastereoisomer, a mixture thereof, a tautomer thereof or a pharmaceutically acceptable salt and hydrates thereof and also intermediates involved therein. Particularly invention is directed to improved processes for the preparation of pyrrole derivatives such as (4R,cis)-6-[2-[3-phenyl-4-(phenyl-carbamoyl)-2-(4-fluorophenyl)-5-(1-methyl-ethyl)-pyrrole-1-yl]-2,2-dimethyl-[1,3]dioxane-4-yl-acetic acid-tertiary butyl ester of formula IV followed by its conversion into [R-(R*, R*]-2-(4-fluorophenyl)- β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1- heptanoic acid particularly calcium salt and its hydrate represented by Formulae I/IA respectively wherein formation of the impurities is either eliminated or minimized in the corresponding intermediaries.
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- Structure-activity relationship of atorvastatin derivatives for metabolic activation by hydrolases
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1. We investigated the structure-activity relationship of 31 kinds of synthesized atorvastatin esters, thioesters, amides and lactone, selected as prodrug models, for metabolic activation by microsomes and hydrolases. 2. The susceptibility to human carboxylesterase 1 (hCES1) was influenced not only by the size of the acyl group and alkoxy group but also by the degree of steric crowding around the alkoxy group. 3. The susceptibility to human carboxylesterase 2 (hCES2) increased with a decrease in electron density around the alkoxy group of the substrate. 4. Lactone was specifically hydrolyzed by paraoxonase 3 (PON3). 5. These findings should be useful in prodrug design for controlling metabolic activation.
- Mizoi, Kenta,Takahashi, Masato,Sakai, Sachiko,Ogihara, Takuo,Haba, Masami,Hosokawa, Masakiyo
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p. 261 - 269
(2019/06/27)
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- Preparation method of crystal form I atorvastatin calcium
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The invention discloses a preparation method of crystal form I atorvastatin calcium. The method includes the steps of: preparation of atorvastatin ester; preparation of an atorvastatin salt; preparation of atorvastatin calcium; refining an atorvastatin ca
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Paragraph 0043; 0052; 0058; 0064; 0069
(2020/02/29)
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- A high-quality HMG - CoA reductase inhibitor atorvastatin calcium preparation method
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The invention discloses a high-quality HMG - CoA reductase inhibitor atorvastatin calcium preparation method, which belongs to the field of treatment of cardiovascular medicine. Of formula (I) compounds soluble in organic solvent, then adding the alkaline
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Paragraph 0030-0039
(2019/02/13)
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- Preparing method of high-purity atorvastatin calcium
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The invention discloses a preparing method of high-purity atorvastatin calcium, and belongs to the technical field of organic synthesis. The method includes the steps of making a compound V and calcium acetate react in a water and alcohol mixed solvent system, and conducting cooling crystallization and filtration after the reaction is completed to obtain an atorvastatin calcium crude product, wherein the reaction temperature is 40-70 DEG C, the volume ratio of alcohols to water in the reaction system is 1:(2-8), and the mass percentage concentration of the compound V in a mixed solvent is 5-10%; dissolving the atorvastatin calcium crude product in a recrystallization solvent A, adding I-type atorvastatin calcium crystals at 45-85 DEG C for crystal transformation, and conducting cooling crystallization, filtration, washing and drying after crystal transformation is completed to obtain a fine product, wherein the mass percentage concentration of the atorvastatin calcium crude product inthe recrystallization solvent A is 5-10%. The method has the advantages of being high in product purity, easy and safe to operate, high in yield and the like and is suitable for large-scale industrialproduction.
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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 0036; 0037; 0042; 0047
(2018/12/02)
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- AN IMPROVED PROCESS FOR PREPARATION OF ATORVASTATIN OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The present invention provides an improved process for the preparation of Atorvastatin or pharmaceutically acceptable salts thereof in high yield and purity.
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- Production technology of atorvastatin calcium
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The invention relates to a production technology of atorvastatin calcium.The production technology comprises the steps that (4R-Cis)-2.2-dimethyl-6-(2-aminoethyl)-1,3-dioxane-4-tert-butyl acetate and 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-o
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Paragraph 0020; 0021
(2016/10/08)
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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 0084-0093
(2017/01/17)
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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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p. 3802 - 3806
(2013/04/24)
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- Spectroscopic characterization and quantitative determination of atorvastatin calcium impurities by novel HPLC method
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Seven process related impurities were identified by LC-MS in the atorvastatin calcium drug substance. These impurities were identified by LC-MS. The structure of impurities was confirmed by modern spectroscopic techniques like 1H NMR and IR and physicochemical studies conducted by using synthesized authentic reference compounds. The synthesized reference samples of the impurity compounds were used for the quantitative HPLC determination. These impurities were detected by newly developed gradient, reverse phase high performance liquid chromatographic (HPLC) method. The system suitability of HPLC analysis established the validity of the separation. The analytical method was validated according to International Conference of Harmonization (ICH) with respect to specificity, precision, accuracy, linearity, robustness and stability of analytical solutions to demonstrate the power of newly developed HPLC method.
- Gupta, Lokesh Kumar
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p. 495 - 501,7
(2012/12/11)
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- Spectroscopic characterization and quantitative determination of atorvastatin calcium impurities by novel HPLC method
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Seven process related impurities were identified by LC-MS in the atorvastatin calcium drug substance. These impurities were identified by LC-MS. The structure of impurities was confirmed by modern spectroscopic techniques like 1H NMR and IR and physicochemical studies conducted by using synthesized authentic reference compounds. The synthesized reference samples of the impurity compounds were used for the quantitative HPLC determination. These impurities were detected by newly developed gradient, reverse phase high performance liquid chromatographic (HPLC) method. The system suitability of HPLC analysis established the validity of the separation. The analytical method was validated according to International Conference of Harmonization (ICH) with respect to specificity, precision, accuracy, linearity, robustness and stability of analytical solutions to demonstrate the power of newly developed HPLC method.
- Gupta, Lokesh Kumar
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p. 495 - 501
(2013/01/13)
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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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p. 6539 - 6546
(2011/09/20)
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- PREPARATION PROCESS USEFUL IN SYNTHESIS OF ATORVASTATIN
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The present invention relates to a preparation process useful in synthesis of atorvastatin, more particularly a process for preparing atorvastatin is effective in treating hyperlipemia, comprising protecting the dihydroxy group at C3 and C5 positions of t
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Page/Page column 9
(2011/05/16)
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- PROCESS FOR THE PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM
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The present invention also provides the amorphous form of hemi-calcium salt of atorvastatin with high purity and processes for preparation thereof.
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Page/Page column 6
(2010/08/07)
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- USE OF AMPHIPHILIC COMPOUNDS FOR CONTROLLED CRYSTALLIZATION OF STATINS AND STATIN INTERMEDIATES
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The invention relates to an improved process comprising amphiphilic compounds for the crystallization of an intermediate used in the process for the preparation of statins and statin intermediates.
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Page/Page column 25
(2010/08/05)
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- PREPARATION PROCESS USEFUL IN SYNTHESIS OF ATORVASTATIN
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The present invention relates to a preparation process useful in synthesis of atorvastatin, more particularly a process for preparing atorvastatin is effective in treating hyperlipemia, comprising protecting the dihydroxy group at C3 and C5 positions of t
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Page/Page column 16
(2009/08/14)
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- A METHOD FOR PRODUCING STATINS IN PURE FORM
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This invention provides a new method for the preparation of statins comprising hydrolyzing a mixture of compounds of the following formulas (Formula III and IV).
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Page/Page column 10
(2009/07/25)
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- PROCESS FOR THE PRODUCTION OF ATORVASTATIN CALCIUM IN AMORPHOUS FORM
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A process for the production of amorphous atorvastatin calcium and stabilized, amorphous atorvastatin calcium is provided.
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Page/Page column 8; 11
(2009/09/07)
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- NOVEL PROCESS FOR THE SYNTHESIS OF [R-(R*, R*)]-2-(4-FLUOROPHENYL)-BETA, DELTA-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROLE-1-HEPTANOIC ACID OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
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An improved synthesis for the preparation of [R-(R*, R*)]-2-(4-fluorophenyl)- β, δ-dihydroxy-5-(1- methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole-1-heptanoic acid or a pharmaceutically acceptable salt thereof, as well as other valuable interm
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Page/Page column 21
(2008/12/06)
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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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- CRYSTALLINE FORMS OF ATORVASTATIN
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Novel forms of atorvastatin hemi-calcium have been prepared and characterized. These novel forms are particularly useful in pharmaceutical compositions.
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Page/Page column 15
(2008/06/13)
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- A NOVEL CRYSTALLINE FORM OF ATORVASTATIN SODIUM
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A novel crystalline form of atorvastatin sodium. The said crystalline atorvastatin sodium has characteristic X-ray powder diffraction pattern and is highly pure with purity above 99.5%.
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Page/Page column 4
(2008/12/05)
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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 13
(2008/06/13)
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- AMORPHOUS ATORVASTATIN CALCIUM
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Amorphous atorvastatin calcium having an enhanced stability contains about 2 to about 8 percent by weight water. A process for preparing the amorphous atorvastatin calcium and a packaging system for maintaining the stability are described.
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Page/Page column 9; 2/2
(2008/06/13)
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- Process for producing atorvastatin hemicalcium
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A process is provided for preparing pharmaceutical grade atorvastatin hemicalcium salt comprising: (a) deesterifying, wherein R is an ester protecting group to (b) extracting R(R*,R*)-3 into an organic solvent or mixture of solvents, (c) adding a base of formula NR1R2R3 wherein R1, R2 and R3 are independently selected from H, substituted or non-substituted C1 to C7 alkyl, C6 to C9 aryl, C8 to C10 aralkyl or aminoalkyl to form atorvastatin base salt, (d) isolating by precipitation of the above atorvastatin base salt and purifying when necessary,
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Page/Page column 8
(2008/06/13)
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- PROCESSES FOR THE PREPARATION OF PYRROLE DERIVATIVES
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A process for the preparation of a pyrrole derivative or a racemic mixture, an enantiomer, a diastereoisomer, a mixture thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof comprising reacting an amino compound of the general formula (I), wherein each R is independently hydrogen or a hydrolyzable protecting group, or each R, together with the oxygen atom to which each is bonded, form a hydrolyzable cyclic protecting group, or each R is bonded to the same substituent which is bonded to each oxygen atom to form a hydrolyzable protecting group and R1 is hydrogen, a lower alkyl or a cation capable of forming a non-toxic pharmaceutically acceptable salt, with a di-oxo compound of the general formula (II), wherein R2 is 1-naphthyl, 2-naphthyl, a C3-C25 cycloalkyl group, norbornenyl, a substituted or unsubstituted aryl group, benzyl, 2-, 3-, or 4-pyridinyl, or 2-, 3-, 4-pyridinyl-N-oxide, R3 and R4 are independently hydrogen, a lower alkyl, a C3-C25 cycloalkyl group, a substituted or unsubstituted aryl group, cyano, trifluoromethyl, or -CONR6R7 wherein R6 and R7 are independently hydrogen, a lower alkyl or a substituted or unsubstituted aryl group and R5 is a lower alkyl, a C3-C25 cycloalkyl or trifluoromethyl; in the presence of a catalyst and in at least one solvent. Also disclosed is a process for hydrolyzing the pyrrole derivative to provide, for example, atorvastatin or pharmaceutically acceptable salts thereof.
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Page/Page column 12-13
(2008/06/13)
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- A PROCESS FOR SYNTHESIS OF LARGE PARTICLE SIZE STATIN COMPOUNDS.
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This invention discloses a process for synthesis of with large size statin compounds comprising adding solution of desired statin compound either crystalline or amorphous form, optionally obtained from, their intermediates by known methods, in organic solvent to anti-solvent, under stirring, optionally the solvent was being evaporated, isolating the title compound by centrifugation followed by drying under vacuum. Specifically the process was directed to the synthesis of Atorvastatin calcium and Fluvastatin Sodium.
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Page/Page column 3
(2008/06/13)
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- Process for the production of atorvastatin calcium un amorphous form
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A process for the production of amorphous atorvastatin calcium and stabilized, amorphous atorvastatin calcium is provided.
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Page/Page column 3; 14; 18
(2010/11/30)
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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 18
(2008/06/13)
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- Process for the production of atorvastatin calcium in amorphous form
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A process for the production of amorphous atorvastatin calcium and stabilized, amorphous atorvastatin calcium is provided.
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Page/Page column 5; 6; 9
(2010/02/14)
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- CRYSTALLINE FORM OF ATORVASTATIN HEMI CALCIUM
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The present invention relates to novel crystalline form R of atorvastatin hemi calcium salt and hydrates thereof useful as pharmaceutical agents, to methods for their production and isolation, to pharmaceutical compositions which include novel crystalline form R of atorvastatin hemi calcium salt and hydrates thereof and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment.
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Page/Page column 6; 13-14
(2010/02/14)
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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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- 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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- The convergent synthesis of CI-981, an optically active, highly potent, tissue selective inhibitor of HMG-CoA reductase
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The synthesis of CI-981 is described starting from isobutyrylacetanilide (3) and the key chiral intermediate 2.
- Baumann,Butler,Deering,Mennen,Millar,Nanninga,Palmer,Roth
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p. 2283 - 2284
(2007/10/02)
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