cas 125971-95-1, tert-Butyl (4R,6R)-2-[[[6-(2-4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl]acetate

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AN IMPROVED AND COMMERCIALLY VIABLE PROCESS FOR PREPARATION OF PYRROLE DERIVATIVES WITH IMPROVED IMPURITY PROFILE & MINIMISATION OF UNIT OPERATIONS.
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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(2020/02/14)

[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.
Antunes, Inês F.,Clemente, Gon?alo S.,D?mling, Alexander,Elsinga, Philip H.,Rickmeier, Jens,Ritter, Tobias,Zarganes-Tzitzikas, Tryfon
(2020/04/24)

Atorvastatin calcium intermediate as well as preparation method and application thereof
The invention discloses an atorvastatin calcium intermediate as well as a preparation method and application thereof. A synthesis process of the intermediate is environmentally-friendly, simple to operate and low in EHS risk; raw materials are easy to obtain; a used chemical reagent is small in toxicity and low in cost; and the synthesis process is a green synthesis process suitable for the industrial production. Moreover, the intermediate provided by the invention is applied to the synthesis of atorvastatin calcium and a key intermediate thereof, the route is relatively short, the yield is high, the industrial production cost of the atorvastatin calcium is effectively reduced, and the atorvastatin calcium intermediate has a relatively high industrial application prospect.
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(2019/04/04)

Novel method for preparing atorvastatin key intermediate L1 through solvent-free method
The invention discloses a novel method for preparing an atorvastatin key intermediate L1 through a solvent-free method and belongs to the technical field of drug chemical synthesis. The novel method comprises the following steps that M4 and A9 are taken as raw materials, under the effects of a phase transfer catalyst and an acid catalyst, constant-temperature stirring melting reaction is directlyconducted for 5-7 hours under the solvent-free condition, the reaction temperature is 80-140 DEG C, water distribution is conducted in the reaction process, after reaction is completed, cooling is conducted, then recrystallization is conducted, and thus the atorvastatin key intermediate L1 is obtained. According to the novel method, the phase transfer catalyst and the acid catalyst are adopted, aparent nucleus M4 and a chiral side chain A9 are subjected to stirring melting reaction under the solvent-free condition, after reaction, recrystallization is conducted directly through ethyl alcohol/water, and thus L1 is obtained; and as for the process, the reaction time can be shortened to be 5 h, the conversion rate can reach up to 90%, operation and aftertreatment are easy, no mixed solvent is recovered, pollution is reduced remarkably, and the method is suitable for amplification production.
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Paragraph 0037-0086

(2019/11/12)

Separating method for impurity A and impurity B and method for effectively reducing content of impurity A in atorvastatin calcium condensate
The invention discloses a separating method for an impurity A and an impurity B and a method for effectively reducing the content of an impurity A in an atorvastatin calcium condensate, and belongs tothe technical field of impurity separating in medicinal chemistry. The invention specifically discloses the impurity A in the atorvastatin calcium condensate, and a method for separating the impurityA from the atorvastatin calcium condensate, further studies that the impurity A of the atorvastatin calcium condensate is introduced by the impurity B in a starting material ATS-9 crude product, anddiscloses a method for separating the impurity B in the ATS-9 crude product, so as to reduce the content of impurity A in the atorvastatin calcium condensate, and further provide the basis for reducing the content of impurities in atorvastatin calcium diamine. The purity of the impurity A in the atorvastatin calcium condensate obtained by the separating method is at least 99.5%, and the purity ofthe impurity B in ATS-9 is at least 99.5%.
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Paragraph 0071; 0072; 0073

(2019/01/16)

Method for preparing atorvastatin intermediate
The invention provides a method for preparing an atorvastatin intermediate, belongs to the technical field of preparation of drug intermediates, and can solve the problems that an existing preparationmethod for the atorvastatin is long in route and complicated in operation, and raw materials are expensive. The method for preparing the atorvastatin intermediate comprises the steps of condensing fluorobenzaldehyde and ATS-9 by using a 'one-pot method' to generate imine; carrying out N-acylation reaction by using the imine and isobutyryl chloride; then reacting with t-butylisonitrile; and finally carrying out 1,3-dipole ring addition-desorption reaction on the reactant and 3-phenylpropargyl aniline to generate a target (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-isopropyl)-3-phenyl-4-[(aniline) carboxyl]-1H-pyrrole-1-yl] ethyl]-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate. The yield of a final product obtained by the synthetic method is high, and can reach up to 70-75%.
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Paragraph 0020-0022

(2018/11/03)

Method for preparing atorvastatin calcium intermediate
The invention discloses a method for preparing an atorvastatin calcium intermediate, and belongs to the technical field of synthesis of medicinal intermediates. The problems that an existing synthesismethod of the atorvastatin calcium intermediate is long in synthesis line and complicated in operation and raw materials are expensive can be solved. By adoption of a 'one-pot' method, firstly, isobutyraldehyde and ATS-9 are condensed to generate imine, and the imine and fluorobenzoyl chloride generate N-acylation reaction and then react with tertiary butyl isonitrile; and finally, the product and 3-phenyl propylene aniline generate 1,3-dipolar cycloaddition-removal reaction to generate a target (4R-cis)-6-[2-[2-(4-fluorinated phenyl)-5-(1-isopropyl)-3-phenyl-4-[( anilino) carboxyl]-1H-pyrrole-1-radical]-ethyl]-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate. The yield of the final product obtained by the synthesis method disclosed by the invention is as high as 72 to 75 percent.
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Paragraph 0016; 0017; 0018

(2018/09/12)

A atorvastatin calcium intermediate preparation method
An Atorvastatin calcium intermediate preparation method comprises the following steps: selecting 1-p-fluorophenyl-2-phenyl-ethyl ketone, 1-anilino-4-methyl-(1,3-pentanedione) and (4R,6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate under the protection of nitrogen; and placing the above three raw materials in a synthesis kettle, adding formic acid as a catalyst, adding benzene as a solvent, gradually heating to 100-110DEG C, refluxing for 10h, cooling, adding an aqueous solution of HCl to wash the obtained organic layer to neutrality, evaporating the solvent by reducing the pressure to a pressure p of below -0.090Mpa at below 50DEG C, adding ethanol and cyclohexane, crystallizing at 0-5DEG C for 24h, carrying out pumping filtration, and carrying out reduced pressure drying on the obtained filter cake to prepare (4R-cis)-6-[2-[2-(4-fluorophenyl)-5-(1-isopropyl)-3-phenyl-4-[(aniline)carbonyl]-1H-pyrryl-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate. The preparation method adopting a one step process has the advantages of less synthesis steps, low price of the above used reagents, abundant sources of raw materials, safe operation, and suitableness for large scale industrial production.
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Paragraph 0041; 0047; 0048; 0049

(2018/05/30)

Preparing method of high-purity atorvastatin calcium
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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Paragraph 0006; 0024

(2018/10/19)

A method for the preparation of atorvastatin (by machine translation)
The invention discloses a method for the preparation of atorvastatin. To 2 - methyl tetrahydrofuran as solvent, in the high pressure autoclave adding [(4 R, 6 R) - 2, 2 - dimethyl - 6 - (2 - aminoethyl) - [1, 3] - dioxan - 4 - yl - acetic acid tert-butyl (ATS - 9) and [5 - methyl - 4 - isopropyl - 2 - phenyl - 1 - (4 - fluorophenyl) - 3 - (phenyl-carbamoyl) - 1, 4 - Cyclohexanedione] (M4), slowly added under stirring [...] anhydride, replace the nitrogen reaction kettle air 2 - 3 time, raising the temperature to 150 - 200 °C, reaction 2 - 4 hours, after the reaction, the solvent is recovered concentrating under reduced pressure, to obtain the sheet sticks the thick oil, in oily adding water, isopropanol, heating to 40 - 60 °C, slow cooling to 20 - 30 °C, precipitated yellow solid, filtered, dried to obtain atorvastatin intermediate (4 R, 6 R) - 6 - {2 - [5 - isopropyl - 3 - phenyl - 2 - (4 - fluorophenyl) - 4 - (phenyl-carbamoyl) - pyrrole - 1 - yl - ethyl} - 2, 2 - dimethyl - [1, 3] - dioxan - 4 - yl - acetic acid tert-butyl. The operation of the invention low cost, high selectivity, does not pollute the environment, and is suitable for industrial production. (by machine translation)
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Paragraph 0012; 0013; 0014; 0016; 0018

(2018/06/26)

α-Unsubstituted Pyrroles by NHC-Catalyzed Three-Component Coupling: Direct Synthesis of a Versatile Atorvastatin Derivative
A practical one-pot cascade reaction protocol provides direct access to valuable 1,2,4-trisubstituted pyrroles. The process involves an N-heterocyclic carbene (NHC)-catalyzed Stetter-type hydroformylation using glycolaldehyde dimer as a novel C1 building-block, followed by a Paal-Knorr condensation with primary amines. The reaction makes use of simple and commercially available starting-materials and catalyst, an important feature regarding applicability and utility. Low catalyst loading under mild reaction conditions afforded a variety of 1,2,4-substituted pyrroles in a transition-metal-free reaction with high step economy and good yields. This methodology is applied in the synthesis of a versatile Atorvastatin precursor, in which a variety of modifications at the pyrrole core structure are possible.
Fleige, Mirco,Glorius, Frank
p. 10773 - 10776
(2017/08/22)

AN IMPROVED PROCESS FOR PREPARATION OF ATORVASTATIN OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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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Page/Page column 14; 15; 16

(2017/05/07)

Spectroscopic characterization and quantitative determination of atorvastatin calcium impurities by novel HPLC method
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
p. 495 - 501,7
(2012/12/11)

Spectroscopic characterization and quantitative determination of atorvastatin calcium impurities by novel HPLC method
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
p. 495 - 501
(2013/01/13)

A novel and efficient route for the preparation of atorvastatin
A novel and efficient synthetic method of atorvastatin was described. The key step of the synthesis was the construction of the olefin linkage between the chiral side chain and skeleton via a Horner-Wadsworth-Emmons reaction, resulting in the advanced intermediate of atorvastatin under hydrogenation of the olefin over Pd/C. This novel method is more useful for the practical synthesis of atorvastatin than its document reported methods.
Gao, Jian,Guo, Yang Hui,Wang, Ya Ping,Wang, Xiang Jing,Xiang, Wen Sheng
scheme or table
p. 1159 - 1162
(2012/01/16)

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.
Kawato, Yuji,Iwata, Mitsutaka,Yazaki, Ryo,Kumagai, Naoya,Shibasaki, Masakatsu
experimental part
p. 6539 - 6546
(2011/09/20)

METHOD FOR THE PREPARATION OF ATORVASTATIN AND INTERMEDIATES USED THEREIN
The present invention relates to a novel method for preparing atorvastatin. According to the present invention, provided are a novel intermediate of the preparation of atorvastatin and a method of preparing large amounts of atorvastatin in a safe manner using the intermediate.
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Page/Page column 12-13

(2011/02/18)

A NOVEL POLYMORPHIC FORM OF ATORVASTATIN SALTS
The present invention provides an improved process for the preparation of Atorvastatin of formula (I) or its salts, preferably hemicalcium salt with purity greater than 99.5% using novel salts of Atorvastatin such as N,N- dicyclohexylethylenediamine salt of Atorvastatin and novel polymorph of Atorvastatin sodium salt. Formula (I).
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Page/Page column 17

(2011/08/08)

SYNTHETIC INTERMEDIATES, PROCESS FOR PREPARING PYRROLYLHEPTANOIC ACID DERIVATIVES THEREFROM
There are provided intermediates used to prepare a derivative, (3R,5R)-7-[2-(4-fluorphenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-lH-pyrrol-l-yl]-3,5-di hydroxyheptanoic acid, which has an effect to suppress cholesterol in blood, and a process for preparing pyrrolylheptanoic acid derivatives therefrom. In accordance with the present invention, the 5-(4-fluorphenyl)-2-isopropyl-4-phenyl-lH-pyrrole-3-carbonyl derivative is provided as one of the novel synthetic intermediates that are used to prepare pyrrolylheptanoic acid derivatives including a derivative, (3R,5R)-7-[2-(4-fluorphenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-lH-pyrrol-l-yl]-3,5-di hydroxyheptanoic acid. Therefore, the (3R,5R)-7-[2-(4-fluorphenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-lH-pyrrol-l-yl]-3,5-di hydroxyheptanoic acid derivative may be prepared from the carbonyl derivative in a high yield for a short time period under a moderate condition.
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Page/Page column 11

(2009/08/14)

A process for preparation of amorphous form of atorvastatin hemi-calcium salt
The present invention relates to a process for preparation of atorvastatin hemi-calcium salt in its amorphous form.
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Page/Page column 19

(2009/08/13)

AN IMPROVED PROCESS FOR SYNTHESIS OF PYRROLE DERIVATIVE, AN INTERMEDIATE FOR ATORVASTATIN
The present invention also relates to a novel impurity, (6-{2-[2-(6-{2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-ethyl }-2,2-dimethyl-[1,3]-dioxan-4-yl)-acetylamino]-ethyl}-2,2-dimethyl-[1,3]-dioxan-4-yl)-acetic acid tert-butyl ester, the compound of formula IV, having the following structure: The present invention also provides methods of preparing the compound of formula rv as well as methods of using the compound of formula IV as a reference marker and a reference standard. The present invention also provides an improved process for preparing (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, the compound of formula I, said process comprising the step of condensing 4-fluoro-α-[2-methyl-1- oxopropyl]-γ-oxo-N,β-diphenylbenzene butanamide, the compound of formula III, with (4R,Cis)-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4- acetate, the compound of formula II, in the presence of a catalytic amount of an acid in the presence of a solvent system, preferably a binary solvent system, to obtain the desired compound (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.
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Page/Page column 19-20

(2009/04/25)

METHOD FOR THE PREPARATION OF ATORVASTATIN AND INTERMEDIATES USED THEREIN
The present invention relates to a novel method for preparing atorvastatin. According to the present invention, provided are a novel intermediate of the preparation of atorvastatin and a method of preparing large amounts of atorvastatin in a safe manner using the intermediate.
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Page/Page column 28

(2009/09/05)

NOVEL PROCESS FOR THE PREPARATION OF 4-FLUORO-ALPHA-[2-METHYL -1-OXOPROPYL]-GAMMA-OXO-N-?-DIPHENYLBENZENEBUTANAMIDE AND PRODUCTS THEREFROM
A novel process for the preparation of 4-fluoro-α-[2-methyl-1-oxopropyl]-γ-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-β-diphenylbenzene butanamide, about 0.05 % or less of difluoro -α-[2-methyl-1-oxopropyl]-γ-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.
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Page/Page column 18

(2009/12/27)

PROCESS FOR THE PRODUCTION OF ATORVASTATIN CALCIUM IN AMORPHOUS FORM
A process for the production of amorphous atorvastatin calcium and stabilized, amorphous atorvastatin calcium is provided.
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Page/Page column 8

(2009/09/07)

Synthesis of some impurities and/or degradation products of atorvastatin
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
p. 229 - 246
(2008/12/22)

PROCESS FOR PREPARING AMORPHOUS ATORVASTATIN HEMI CALCIUM SALT AND ITS INTERMEDIATE
The invention relates to the HMG-CoA reductase inhibitor in particular to Atorvastatin Hemi-calcium. The present invention is directed to novel processes for preparing amorphous form of Atorvastatin hemi calcium and their intermediate in high purity.
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Page/Page column 11-12

(2008/12/05)

A NOVEL CRYSTALLINE FORM OF ATORVASTATIN SODIUM
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)

PREPARATION OF AN ATORVASTATIN INTERMEDIATE
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)

PROCESS FOR THE PREPARATION OF AMORPHOUS ATORVASTATIN CALCIUM SALT
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)

PROCESS FOR THE PREPARATION OF ATORVASTATIN CALCIUM
The present invention relates to process for the preparation of atorvastatin calcium. The process provides the novel approach for the synthesis of an important intermediate atorvastatin protected diol chemically (4R-cis)-6-[-2-[3-phenyl-4-(phenyl- carbamoyl)-2-(4-flourophenyl)-5-(1-methyl-ethyl)-pyrrol-1-yl]-ethyl]-2,2-dimethyl- [1,3]dioxane-4-yl-acetic acid-tertriay butyl ester for atorvastatin calcium i.e. [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). The present invention relates the use of amino side chain i.e [6-(2-aminoethyl)-2,2,-dimethyl- [1,3]dioxan-4-yl]-acetic acid tert-butyl ester and stetter compound i.e. 4-(4- Fluoroρhenyl)-2-isobutryl-4-oxo-N-phenyl butryl amide as an important starting materials for the preparation of atorvastatin protected diol in the high yield and thereby the recovery of amino side chain with an industrially applicable process.
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Page/Page column 5-7

(2008/06/13)

PROCESSES FOR THE PREPARATION OF PYRROLE DERIVATIVES
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 11-12

(2008/06/13)

A PROCESS FOR SYNTHESIS OF LARGE PARTICLE SIZE STATIN COMPOUNDS.
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 17

(2008/06/13)

PREPARATION OF AN ATORVASTATIN INTERMEDIATE USING A PAAL-KNORR CONDENSATION
A process for preparing a compound of formula (I): comprises reacting a 1,4-diketone of the formula (II): with a primary amine of the formula (III): wherein R1 and R2 may be the same or different and are selected from any one or more of H; C1-C6 alkyl which may be straight or branched, substituted or unsubstituted with a halogen group; C1-C6 alkoxy group; or R1 and R2 together represent an alkylidene group of the formula CRaRb wherein Ra and Rb may be the same or different and are selected from any one or more of a C1-C11 alkyl group, and R3 is selected from any one or more of a C1-C6 alkyl group, in the presence of a catalyst, the catalyst comprising a salt wherein the salt comprises an amine salt or an inorganic salt of an organic acid.
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Page/Page column 9

(2008/06/13)

AMORPHOUS ATORVASTATIN CALCIUM
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 8-9; 2/2

(2008/06/13)

Process for the production of atorvastatin calcium un amorphous form
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

(2010/11/30)

POLYMORPHS OF ATORVASTATIN TERT.-BUTYLESTER AND USE AS INTERMEDIATES FOR THE PREPARATION OF ATORVASTATIN
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 14-15

(2008/06/13)

PROCESS FOR THE PREPARATION OF ATORVASTATIN
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 11

(2008/06/13)

Process for the production of atorvastatin calcium in amorphous form
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

(2010/02/14)

CRYSTALLINE FORM OF ATORVASTATIN HEMI CALCIUM
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 5-6

(2010/02/14)

SYNTHESIS OF 3,5-DIHYDROXY-7-PYRROL-1-YL HEPTANOIC ACIDS
Atorvastatin and related 3,5-dihydroxy-7-pyrrol-1-yl heptanoic acids can be made by oxidation of a 3,5-dihydroxy-7-pyrrol-1-yl heptanol precursor from novel but readily accessible starting materials. Silylether-protected 7-amino-3,5-dihydroxy heptanoic acid esters undergo Paal Knorr reaction with 1,4-diketones to give valuable silylether-diprotected 3,5-dihydroxy-7-pyrrol-1-yl heptanoic acid ester intermediates for preparing atorvastatin. The Paal Knorr reaction of ketal-proctected 7-amino-3R, 5R-dihydroxy heptanoic acid esters with 4-fluoro-α-(2-methyl-1-oxopropyl-γ-oxo-N,β-diphenylbenzenebutanamide occurs in high yield with few side products when it is conducted in a low boiling point ether.
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Page 36-37

(2010/02/07)

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
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
p. 261 - 270
(2007/10/03)

Process for the synthesis of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate
An improved process for the preparation of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate is described where a hydroxy ester derivative is converted in two steps to the desired product, as well as valuable intermediates used in the process.
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(2008/06/13)

Process for the synthesis of (5R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate
An improved process for the preparation of (5R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate is described where a halo hydroxyester or other activated dihydroxyester is converted in two steps to the desired product.
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(2008/06/13)

The convergent synthesis of CI-981, an optically active, highly potent, tissue selective inhibitor of HMG-CoA reductase
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
p. 2283 - 2284
(2007/10/02)

Process for trans-6-(2-(substituted-pyrrol-1-yl)alkyl)pryan-2-one inhibitors of cholesterol synthesis
An improved process for the preparation of trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones by a novel synthesis is described where 1,6-heptadien-4-ol is converted in eight operations to the desired products, as well as an improved process for the preparation of (2R-trans) and trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N-4-diphenyl-1-[2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide by a novel synthesis where 4-methyl-3-oxo-N-phenylpentanamide is converted in eight operations to the desired product or alternatively 4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N,β-diphenylbenzenebutaneamide is converted in one step to the desired product, and additionally, a process for preparing (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide from (R)-4-cyano-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]butanoic acid, as well as other valuable intermediates used in the processes.
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(2008/06/13)