280 results about "Rosuvastatin Calcium" patented technology

The invention provides a synthetic method of rosuvastatin calcium, which is characterized in that a compound 6 and branched chain react under the action of 2,2,6,6,-tetramethylpiperidine and n-butyl lithium to generate a compound 7, the reaction temperature is increased to minus 30 DEG C and the aspects such as reaction solvent and reaction reagent are improved so that the total reaction route has the advantages of mild condition, low device requirement and suitability for industrial production. Meanwhile, another improved synthetic route of rosuvastatin calcium comprises the following steps: converting esters into acids, synthesizing esters again, and synthesizing the rosuvastatin calcium. The rosuvastatin calcium purity is as high as 99.8%.

The present invention relates to novel anhydrous amorphous forms of bis[(E)[4-(4-fluorophenyl)isopropyl[methyl(methylsulfonyl)amino]pyrimidinyl](3R,5S)-3,5-dihydroxyhept enoic acid]calcium salt (rosuvastatin calcium), (±)7-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl)3,5-dihydroxy heptenoic acid monosodium salt (fluvastatin sodium) and bis[(E)-3,5-dihydroxy-7-[4′-(4″-fluorophenyl)-2′-cyclopropyl-quinolin-3′-hept-6-enoic acid]calcium salt (pitavastatin calcium), to processes for their preparation, to pharmaceutical compositions containing them and to methods of treatment using the same. The rosuvastatin calcium, pitavastatin calcium and fluvastatin sodium obtained are known valuable agents useful in treating hyperlipidemia and hypercholestrolemia.

This invention provides a method for preparing rosuvastatin intermediate compound I-XI. The method can ensure a high purity of I-XI, thus ensuring the completeness of the stereoselectivity in subsequent reactions. Although the yield of I-XII from I-X in this invention is a little lower than that in the invention EP 0,521,471 A1, the purification of I-XII only needs a low-efficiency chromatographic column. The method thus has such advantages as low cost and high efficiency.

The invention discloses a preparation method of a key intermediate of rosuvastatin calcium side chains. (S)-3-hydroxy-4-chlorine-butyronitrile is taken as a starting material and subject to four steps condensation, reduction, hydroxyl protection and condensation reactions to obtain the intermediate. The method has simple operation during the reaction, products in the steps are easily separated and purified, no silica gel column is needed for purification and separation, the yield is above 80%, an intermediate with high chemical purity and optical purity can be obtained, and conclusion of GC determination is that the chemical purity is not less than 99.4%, and the optical purity is not less than 99.3%ee.

This invention discloses a method for preparing methyl (R)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-mesylamino)pyrimidin-5-yl]-3-tert-butyldimethylsiloxyl-5-carbonyl-6(E)-hepetnate as the intermediate for synthesizing rosuvastatin calcium. The method comprises: reducing pyrimidine carbonate (II) by borohydride/chloride to obtain pyrimidine methanol (III), oxidizing by potassium dichromate to obtain pyrimidine formaldehyde, and condensing in the presence of chiral phosphonate to obtain methyl (R)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-mesylamino)pyrimidin-5-yl]-3-tert-butyldimethylsiloxyl-5-carbonyl-6(E)-hepetnate (VI). The method has such advantages as abundant raw materials, low cost, mild reaction conditions, short time and high yield. The byproduct is water-soluble.

The invention relates to a rosuvastatin calcium tablet and a preparation method, the tablet is composed of a tablet core and a coating layer, the tablet core is composed of rosuvastatin calcium, lactose, microcrystalline cellulose, a disintegrating agent and a lubricant, the lactose is spray dried lactose or particle lactose, and the microcrystalline cellulose is flowing steam dried microcrystalline cellulose or spray dried microcrystalline cellulose. The rosuvastatin calcium tablet is not required for adding a stabilizing agent or aerosil or preparing to a special preparation, the rosuvastatin calcium preparation with good stability, excellent dissolution and content uniformity can be obtained by a direct tabletting technology, and the method of the invention has the advantages of simple technology and low cost, and is suitable for large scale production.

The present invention publicly discloses a synthetic method and intermediates of rosuvastatin calcium and synthetic methods of the intermediates. The synthetic method uses 4-4′-fluorophenyl-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyridine-5-formaldehyde as the raw material, includes 4-4′-fluorophenyl-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyridine-5-acrylonitrile (intermediate I) from a nitrilized reaction, and 4-4′-fluorophenyl-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyridine-5-acraldehyde (intermediate II) from an aldehydized reaction of the intermediate I, and further goes through such unit processes as side-chain extension, ketone-group reduction, ethyl-group hydrolysis and neutralization reaction or decomposition reaction to obtain rosuvastatin calcium. The nitrilized reagent can be phosphate diethylacetonitrile, acetonitrile, etc.; the aldehyde reductant can be diisobutyl aluminum hydride, red aluminum, etc.; and the ketone-group reductant can be diethylmethoxyborane, NaBH₄, KBH₄, etc.

The invention discloses a preparation method of rosuvastatin calcium. The method comprises the following steps of: synthesizing an important intermediate, i.e., [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-mesyl amino)pyrimidine-5-radical]methanol (compound IV); and preparing the rosuvastatin calcium (compound I). The method has the advantages of readily available raw materials, high stereoselectivity, high yield and suitability for industrial production.

The invention relates to a preparation detection method for substances related to rosuvastatin calcium preparation. The preparation detection method comprises the following steps: preparing (3S,5S)-rosuvastatin calcium diastereoisomer, rosuvastatin-5S-lactone, rosuvastatin-5R-lactone, rosuvastatin-5-oxide, a rosuvastatin photodegradation product 1, a rosuvastatin photodegradation product 2, rosuvastatin photodegradation product 1-lactone and rosuvastatin photodegradation product 2-lactone, which are used as comparison products of the substances related the rosuvastatin calcium preparation; metering a test sample solution, a comparison product solution and a blank solution; and injecting the solutions into a liquid chromatograph respectively. The chromatographic conditions are as follows: a chromatographic column is a C18 chromatographic column; the column temperature is 30-40 DEG C, the flow speed is 0.6-1.0ml/min and the detection wavelength is 210-260nm. The content of the substances related to the rosuvastatin calcium preparation can be detected so as to be good for improving the quality standard of the rosuvastatin calcium preparation.

The invention relates to a method for preparing a tablet drug composition containing Rosuvastatin calcium. The preparation forms of the drug composition can be administered to the patients safely and the stability of Rosuvastatin calcium and the absorbability in gastrointestinal tract can be improved. Specifically, the invention relates to a method for preparing the drug composition containing amorphous Rosuvastatin calcium and beta-cyclodextrin. The method is characterized by grinding Rosuvastatin calcium and beta-cyclodextrin under alkaline condition, drying and crashing to obtain (80-100)-mesh fine powder, mixing the fine powder with appropriate auxiliary materials, preparing granules, carrying out tabletting and carrying out coating, thus preparing the drug composition. The in vitro release of the composition is improved to a greater degree, thus improving the bioavailability; and the composition can effectively treat hyperlipidemia, is convenient to take orally, covers the bad taste and is fast to disintegrate and absorb and convenient to carry.

The present invention relates to a process for the preparation of rosuvastatin calcium, a promising new HMG-CoA reductase inhibitor.

The invention relates to a method for preparing (3R, 5S, E)-7-{2-(N-methylsulphonylamino) -4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-yl}-2,2-dimethyl-3,5-dioxane-6-heptenoic acid (compound shown by a formula 4) which is an important intermediate of Rosuvastatin Calcium in a one-pot way. The method comprises the steps of adding a compound in the formula 1 and a compound in the formula 2 into a solvent under protection of dried inert gas, adding a certain amount of strong base at minus 60 DEG C, then slowly increasing temperature to room temperature, supplementing the strong base after a compound in the formula 3 is completely produced, adding N-methylsulphonylamino, and reacting to produce a compound in the formula 4 at the room temperature. The method is stable in yield and easy to operate, and provides a method for preparing Rosuvastatin, and the method has lower cost, is simplified for operation and easy for industrialization. The formula 1, 2, 3, and 4 are shown in the description, wherein R1 is shown in description, and R2 is alkyl, naphthenic base or benzyl, and preferably methyl, ethyl or tertiary butyl.

The present invention relates to an improved process for preparing (2E)-3-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-propenal of Formula I which is an intermediate useful in the preparation of bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methyl-sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid] calcium salt of Formula II

The invention relates to commercially viable process for the preparation of Rosuvastatin by an early introduction of correct absolute stereochemistry at C-5 (S) of Rosuvastatin side chain followed by regioselective chain extension using novel side chain building blocks and less expensive reagents. It is yet another object of the invention is to provide novel intermediates that may be used for the preparation of Calcium salt of Rosuvastatin.Formula (I).

The invention relates to a rosuvastatin calcium oral drug composition and a preparation method thereof. The rosuvastatin calcium oral drug composition is characterized by comprising the following components in proportion: 10-80mg of rosuvastatin calcium, 20-160mg of hydroxypropyl betadex, 5-40mg of meglumine, 2-16mg of sodium sulfite, 100-800mg of lactose, 50-400mg of microcrystalline cellulose, 20-160mg of croscarmellose sodium, 2-16mg of magnesium stearate and a proper amount of 80 percent ethanol solution. The preparation method comprises the following steps of: dissolving hydroxypropyl betadex, meglumine and magnesium stearate into a proper amount of 80% ethanol solution; adding rosuvastatin calcium and mixing until the rosuvastatin calcium is completely dissolved; evenly mixing lactose, microcrystalline cellulose and croscarmellose sodium for later use; quantitatively adding the solution into an evenly-mixed accessory for pelletization; and obtaining a finished product by drying, palletizing, totally mixing, checking an intermediate body, pressing into pieces, coating and packing. The prepared rosuvastatin calcium tablet has good stability and high bioavailability.

The invention discloses a method for determining content of rosuvastatin calcium and related substances thereof by employing an HPLC (high performance liquid chromatography) method. By adopting the method, octadecylsilane chemically bonded silica is selected as a chromatographic column of a filler, and a mobile phase is formed by methanol and water (containing 0.1-0.8% of trifluoroacetic acid). The content of the rosuvastatin calcium and the related substances thereof can be accurately determined under a chromatographic condition, so that the quality of materials and preparation of the rosuvastatin calcium is well controlled.

The invention relates to a rosuvastatin calcium sustained-release preparation and a preparation method thereof. The rosuvastatin calcium sustained-release preparation basically contains 5 to 10mg of rosuvastatin calcium, and the balance of sustained-release framework material and other pharmaceutical excipients. The preparation method is simple; and all the materials are proportioned and the preparation is prepared by the preparation method for common tablets, granules or capsules. The rosuvastatin calcium sustained-release preparation prepared by the method avoids adverse reactions such as rhabdomyolysis, proteinuria, nephrosis, kidney failure, hepatotoxicity and the like caused by overdosage of medicaments; meanwhile, due blood concentration and time for treating diseases after the medicaments are taken can be maintained, and the peak valley phenomenon of the blood concentration is effectively avoided.

The invention discloses a preparation method of an intermediate of a rosuvastatin calcium side chain, which comprises the following steps: firstly allowing (R)-4-cyano-3- methyl hydroxybutyrate to react with tert-butyl-dimethylchlorosilane, performing nitrile group hydrolysis in water phase under the action of an enzyme with the obtained (R)-4-cyano-3-tert-butyl dimethylsiloxyl methyl butyrate (II) as a substrate to generate a target product with a structure (I). The invention has the characteristics of being mild in reaction, high in yield, environment friendly, low in cost, and high in chiral purity of the prepared product.

The present invention relates to preparation methods for rosuvastatin calcium and intermediates thereof, and specifically discloses intermediate compounds for preparing rosuvastatin calcium, and preparation methods thereof, wherein the structures of the intermediates are respectively represented by a formula II, a formula III, a formula IV, a formula VI and a formula VII in an instruction. The present invention further discloses a preparation method for rosuvastatain or a salt thereof, wherein the preparation method is based on the preceding five intermediate compounds and the preparation methods thereof, has characteristics of simple and safe operation and low production cost, and is suitable for industrial production.

The invention discloses a recycling method of 1-phenyl-5-hydroxytetrazole, and belongs to the technical field of medicinal chemistry. The preparation method comprises the following steps: a byproduct1-phenyl-5-hydroxytetrazole generated in preparation process of a rosuvastatin calcium intermediate is converted into 1-phenyl-5-mercaptotetrazole; and meanwhile, the 1-phenyl-5-mercaptotetrazole is further used for preparing a rosuvastatin calcium intermediate or rosuvastatin calcium. According to the method disclosed by the invention, reasonable recycling of the byproduct 1-phenyl-5-hydroxytetrazole is realized, the raw materials are fully utilized, the production cost of rosuvastatin calcium and the intermediate thereof is reduced, and the emission of three wastes is reduced.

A pure amorphous form of rosuvastatin calcium substantially free from alkali metal impurities is disclosed. A process of preparing a pure amorphous form of rosuvastatin calcium is disclosed, which comprises hydrolysis of C₁-C₅ alkyl esters of rosuvastatin, preferably tert-butyl ester of rosuvastatin, with an organic nitrogen base, e.g. guanidines, amidines, amines and quaternary ammonium hydroxides, in the presence of water, optionally containing aprotic solvent, following the conversion of thus obtained rosuvastatin salt with a source of calcium to obtain rosuvastatin calcium, which is then isolated. An alternative process is disclosed, which comprises the conversion of numerous novel ammonium salts of rosuvastatin, preferably tert-octylammonium salt of rosuvastatin, with the source of calcium to desired commercial rosuvastatin calcium. Rosuvastatin calcium is an inhibitor of HMG CoA reductase, useful in the treatment of hyperlipidemia, hypercholesterolemia and atherosclerosis.