125971-95-1Relevant articles and documents
AN IMPROVED AND COMMERCIALLY VIABLE PROCESS FOR PREPARATION OF PYRROLE DERIVATIVES WITH IMPROVED IMPURITY PROFILE & MINIMISATION OF UNIT OPERATIONS.
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Page/Page column 68-69; 71, (2020/02/14)
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.
[18F]Atorvastatin: synthesis of a potential molecular imaging tool for the assessment of statin-related mechanisms of action
Antunes, Inês F.,Clemente, Gon?alo S.,D?mling, Alexander,Elsinga, Philip H.,Rickmeier, Jens,Ritter, Tobias,Zarganes-Tzitzikas, Tryfon
, (2020/04/24)
Background: Statins are lipid-lowering agents that inhibit cholesterol synthesis and are clinically used in the primary and secondary prevention of cardiovascular diseases. However, a considerable group of patients does not respond to statin treatment, and the reason for this is still not completely understood. [18F]Atorvastatin, the 18F-labeled version of one of the most widely prescribed statins, may be a useful tool for statin-related research. Results: [18F]Atorvastatin was synthesized via an optimized ruthenium-mediated late-stage 18F-deoxyfluorination. The defluoro-hydroxy precursor was produced via Paal-Knorr pyrrole synthesis and was followed by coordination of the phenol to a ruthenium complex, affording the labeling precursor in approximately 10% overall yield. Optimization and automation of the labeling procedure reliably yielded an injectable solution of [18F]atorvastatin in 19% ± 6% (d.c.) with a molar activity of 65 ± 32 GBq·μmol?1. Incubation of [18F]atorvastatin in human serum did not lead to decomposition. Furthermore, we have shown the ability of [18F]atorvastatin to cross the hepatic cell membrane to the cytosolic and microsomal fractions where HMG-CoA reductase is known to be highly expressed. Blocking assays using rat liver sections confirmed the specific binding to HMG-CoA reductase. Autoradiography on rat aorta stimulated to develop atherosclerotic plaques revealed that [18F]atorvastatin significantly accumulates in this tissue when compared to the healthy model. Conclusions: The improved ruthenium-mediated 18F-deoxyfluorination procedure overcomes previous hurdles such as the addition of salt additives, the drying steps, or the use of different solvent mixtures at different phases of the process, which increases its practical use, and may allow faster translation to clinical settings. Based on tissue uptake evaluations, [18F]atorvastatin showed the potential to be used as a tool for the understanding of the mechanism of action of statins. Further knowledge of the in vivo biodistribution of [18F]atorvastatin may help to better understand the origin of off-target effects and potentially allow to distinguish between statin-resistant and non-resistant patients.
Novel method for preparing atorvastatin key intermediate L1 through solvent-free method
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Paragraph 0037-0086, (2019/11/12)
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.
Separating method for impurity A and impurity B and method for effectively reducing content of impurity A in atorvastatin calcium condensate
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Paragraph 0071; 0072; 0073, (2019/01/16)
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%.
Atorvastatin calcium intermediate as well as preparation method and application thereof
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Paragraph 0104-0106, (2019/04/04)
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.
Preparing method of high-purity atorvastatin calcium
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Paragraph 0006; 0024, (2018/10/19)
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.
A method for the preparation of atorvastatin (by machine translation)
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Paragraph 0012; 0013; 0014; 0016; 0018, (2018/06/26)
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)
Method for preparing atorvastatin intermediate
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Paragraph 0020-0022, (2018/11/03)
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%.
Method for preparing atorvastatin calcium intermediate
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Paragraph 0016; 0017; 0018, (2018/09/12)
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.
A atorvastatin calcium intermediate preparation method
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Paragraph 0041; 0047; 0048; 0049, (2018/05/30)
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.
