- Method for preparing rosuvastatin and pitavastatin 2, 5-diene heptanoate compound
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The invention discloses a method for preparing rosuvastatin and pitavastatin 2, 5-diene heptanoate compound. (4R, 6S)-6-[(1E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methanesulfonyl)amino]-5-pyrimidine] vinyl]-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate and (4R, 6S)-6-[[(1E)-2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl] vinyl]-2, 2-dimethyl-1, 3-dioxane-4-tert-butyl acetate are respectivelytaken as starting materials of rosuvastatin and pitavastatin, deprotection and a hydrolyzation one-step method is adopted to prepare statin acid, then the statin acid is taken as a reaction substratefor dehydration and substitution two-step reaction to prepare the 2, 5-diene heptanoate compound. The preparation and synthesis routes of rosuvastatin and pitavastatin 2, 5-diene heptanoate involved in the invention are short and feasible, the operation is simple and convenient, the product yield is high, and the rosuvastatin and pitavastatin 2, 5-diene heptanoate is more suitable for large-scaleindustrial production.
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Paragraph 0031-0033
(2020/05/14)
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- Palladium-Catalyzed Stereoselective Cyclization of in Situ Formed Allenyl Hemiacetals: Synthesis of Rosuvastatin and Pitavastatin
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A diastereoselective palladium-catalyzed cyclization of allenyl hemiacetals is described. It permits the selective synthesis of 1,3-dioxane derivatives, precursors for syn-configured 1,3-diols which make an appearance in all of the statin representatives. The reaction allows the total synthesis of Rosuvastatin and Pitavastatin in a straightforward fashion.
- Spreider, Pierre A.,Breit, Bernhard
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p. 3286 - 3290
(2018/06/11)
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- New crystal form of pitavastatin hemicalcium salt and preparation method thereof
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The invention provides a new crystal form of a pitavastatin hemicalcium salt. The new crystal form is named as a crystal form I. In an X-ray powder diffraction spectrum measured by using a Cu-K alpharay, the new crystal form of the pitavastatin hemicalciu
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Paragraph 0052-0061
(2019/01/08)
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- Multi-substituted dihydroisoquinolines he the sandbank contains the fluorine derivative and use thereof
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The invention belongs to the field of pharmaceutical chemistry, and provides a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor. The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor is a polysubstituted miazine statin fluorine-containing modifier of 1-fluoro-3-hydroxypentanoic acid and its salt or ester formed after ring opening of 3-fluoro-caprolactone fragment and its lactone. The structural formula of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor is shown in the specification. A result of test of like compounds shows that the compounds have an HMG-CoA reductase activity inhibition effect, and can be used as a new-generation latent HMG-CoA reductase inhibitor.
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Paragraph 0135; 0136
(2018/06/04)
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- For production of the precursor [...]
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PROBLEM TO BE SOLVED: To provide a precursor compound of pitavastatin calcium excellent in safety and cost with high yield and high selectivity in a mild condition.SOLUTION: A method for producing a precursor compound of pitavastatin calcium of formula 1 is characterized by reacting a compound of formula 2 with a compound of formula 3 in the presence of an alkali metal salt selected from alkali metal carbonate, alkali metal acetate, and alkali metal propionate. (In the formulae, Ris a C-Calkyl group, and Ris an aryl group, an aralkyl group, or an alkyl group.)
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- Method for preparing statin raw material drug intermediate by use of improved Julia olefination as key step
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The invention relates to a method for preparing a statin raw material drug intermediate by use of improved Julia olefination as a key step, and mainly solves the problems of high construction cost of a chiral center for preparing of the statin raw materia
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- Pitavastatin calcium method for the preparation of
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The invention relates to a preparation method of a cholesterol reduction drug, particularly relates to a preparation method of pitavastatin calcium as a crude drug of the cholesterol reduction drug, and aims at the problems that the pitavastatin calcium synthetic technology in the prior art is long in steps and complicated in operation, and uses strongly corrosive reagents which is environmentally unfriendly, causes serious corrosion to equipment, and may not facilitate industrial production. The invention provides the new preparation method of the pitavastatin calcium, the new preparation method is as follows: 3-bromomethyl-2-cyclopropyl-4-(4-fluorophenyl)quinoline is prepared from 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarboxaldehyde by a one step reaction, and then reacts with an organophosphorus reagent to obtain pitavastatin calcium intermediate phosphorus ylide, on the basis of improving of the yield to 80%, the reaction steps are reduced, and the reaction difficulty is reduced, and hydroxylamine hydrochloride is selected as a deprotection reagent, so that the new preparation method is mild in reaction conditions, environmentally friendly, high in yield, and beneficial to industrial production.
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- 3,5-dihydroxyhept-6-enoic acid derivative preparation method
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The invention relates to a preparation method of 3, 5-dihydroxy-6-heptenoic acid derivatives. The preparation method comprises the steps of hydrolyzing crude statin ester to form a water-soluble alkali metal salt, extracting by using a solvent to remove impurities which cannot be dissolved into water, and converting at high yield to form ester with relatively high purity; then, purifying the ester by using a recrystallization way to obtain pure statin ester; and finally, converting the pure statin ester at high yield to form statin calcium, namely the 3, 5-dihydroxy-6-heptenoic acid derivatives. The 3, 5-dihydroxy-6-heptenoic acid derivatives, namely rosuvastatin calcium and pitavastatin calcium, synthesized by using the preparation method are high in purity and total yield, relatively low in cost and beneficial to mass production.
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Paragraph 0079 - 0081
(2017/04/19)
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- Method for preparing pitavastatin lactone impurity
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The invention discloses a method for preparing pitavastatin lactone impurity. 4-(1-(4-chlorobenzoyl))-6-imino-3-methyl-1,4,6,7-tetrahydropyrazolo[3,4-D][1,3]thiazol-4-yl)-2-methoxyphenol is one main impurity during production of pitavastatin calcium. The impurity can be prepared through dehydration condensation of a compound (E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3R,5S-dihydroxy-6-heptenoic acid. The condensation reaction conditions are mild, the product purity is high, and research demand on pitavastatin calcium quality is satisfied.
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Paragraph 0007
(2016/11/17)
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- NOVEL BORONATE ETHER INTERMEDIATES FOR PREPARATION OF STATIN COMPOUNDS, PREPARATION METHOD THEREOF AND PREPARATION METHOD OF STATIN COMPOUNDS USING SAID BORONATE ETHER INTERMEDIATES
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The present invention relates to a novel boronate ether compound and a manufacturing method thereof. Provided is a novel boronate ether compound denoted by chemical formula 1 or chemical formula 2 as an intermediate to manufacture rosuvastatin calcium or pitavastatin calcium which is one of the statin based compounds to reduce the level of low density lipoprotein (LDL) of patients who have hyperlipidemia and are accordingly cured, and statin compounds with high purity are easily manufactured and separated compared with an existing patented method and are easily provided in a method of mass production.
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- The synthesis of [18F]pitavastatin as a tracer for hOATP using the Suzuki coupling
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Fluorine-18 labeled radiotracers, such as [18F]fluorodeoxyglucose, can be used as practical diagnostic agents in positron emission tomography (PET). Furthermore, the properties of pharmaceuticals can be enhanced significantly by the introduction of fluorine groups into their original structures, and significant progress has been made during the last three decades towards the development of practical procedures for the introduction of fluorine. The replacement of the fluorine atoms present in pharmaceuticals with radioactive 18F atoms is a rational approach for designing novel PET tracers. As a fluorine-containing pharmaceutical agent, pitavastatin has attracted considerable interest from researchers working in the life sciences because it can act as an antihyperlipidemic agent as well as a substrate for hepatic organic anion transporting polypeptides (hOATP). With this in mind, it was envisaged that [18F]pitavastatin would be used as an excellent imaging agent for hOATP, which prompted us to investigate the synthesis of this agent. Herein, we report a practical method for the synthesis of [18F]pitavastatin by the Suzuki coupling reaction of p-iodofluorobenzene and a quinoline boronate derivative, with the desired product being formed in a radiochemical yield of 12 ± 3% (decay corrected from [18F]fluoride ions, n = 3). This journal is
- Yagi, Yusuke,Kimura, Hiroyuki,Arimitsu, Kenji,Ono, Masahiro,Maeda, Kazuya,Kusuhara, Hiroyuki,Kajimoto, Tetsuya,Sugiyama, Yuichi,Saji, Hideo
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p. 1113 - 1121
(2015/02/19)
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- PHARMACEUTICALLY ACCEPTABLE AMINE SALTS OF PITAVASTATIN
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The present invention relates to pharmaceutically acceptable amine salts of pitavastatin and a method for producing pharmaceutically acceptable amine salts of pitavastatin. Also provided are pharmaceutical compositions of these amine salts or solvates thereof, and methods of their use as HMG-CoA reductase inhibitors.
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Page/Page column 12; 13
(2014/10/15)
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- AMINE SALTS OF PITAVASTATIN AND ROSUVASTATIN
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The present invention relates to oxygen-comprising amine salts of HMG-CoA reductase inhibitors, to a method of producing said amine salts and to the use of said amine salts in the production of pharmaceutically acceptable salts of HMG-CoA reductase inhibi
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Page/Page column 15; 16
(2014/10/15)
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- AMINE SALTS OF PRAVASTATIN AND ROSUVASTATIN
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The present invention relates to unsaturated amine salts of HMG-CoA reductase inhibitors, to a method of producing said amine salts and to the use of said amine salts in the production of pharmaceutically acceptable salts of HMG-CoA reductase inhibitors.
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Page/Page column 14; 15
(2014/10/15)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF CHIRAL DIOL SULFONES AND STATINS
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The present invention relates to an improved process to prepare chiral diol sulfones of formula (I), wherein R1 and R2 each independently represent group selected from C1-4 alkyl, C1-4 alkenyl, C3-6 cycloalkyl, C6-10 aryl or C7-12 aralkyl, each of R1 and R2 may be substituted and wherein R1 and R2 may form a ring together with the C-atom; R3 represents group selected from C1-5 alkyl, aryl or aralkyl.
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- METHOD FOR PREPARING AN INTERMEDIATE OF PITAVASTATIN OR OF THE SALT THEREOF
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The present invention relates to a method for preparing (4R,6S)-(E)-6-[2-(2-cyclopropyl)-4-(4-fluorophenyl)quinolin-3-yl)-vinyl-2,2-dimethyl-1,3-dioxan-4-yl]acetic acid ester derivative, which is an intermediate of pitavastatin or of the salt thereof, into a crystalline solid form. In addition, the present invention relates to a novel solvate of the intermediate, and to a method for preparing pitavastatin or the salt thereof using the intermediate.
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- POLYMORPHIC FORM OF PITAVASTATIN CALCIUM
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The present invention relates to a new polymorphic form of pitavastatin calcium, a process for its preparation and a pharmaceutical composition comprising it. The new polymorphic form is characterized by an X-ray powder diffraction pattern as shown in Fig
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Page/Page column 27; 28
(2013/03/28)
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- PITAVASTATIN CALCIUM AND PROCESS FOR ITS PREPARATION
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The invention provides the process for the preparation of pitavastatin and its pharmaceutically acceptable salts thereof. In particular, the invention provides a process for the preparation of stable pitavastatin calcium in crystalline form having water content less than 5% wt/wt. The present invention also provides stable crystalline form of pitavastatin calcium substantially free from crystal Form-A and use thereof for pharmaceutical compositions.
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Page/Page column 22
(2012/03/26)
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- Process for Preparing Pitavastatin, Intermediates and Pharmaceuctically Acceptable Salts Thereof
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Processes for preparing pravastatin, intermediates and pharmaceutically acceptable salts thereof are provided Crystalline forms of pravastatin, intermediates and pharmaceutically acceptable salts thereof are also disclosed.
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- NOVEL POLYMORPHS OF PITAVASTATIN CALCIUM
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The present invention provides a solid of pitavastatin tert-butyl ester and process for its preparation. The present invention also provides a novel crystalline form of pitavastatin calcium, process for its preparation and pharmaceutical compositions comprising it.
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- PROCESS FOR PREPARING QUINOLINE DERIVATIVE
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The present invention relates to a novel process for preparing Pitavastatin calcium salt of formula (I).
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- PITAVASTATIN SALTS
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The present disclosure includes salt of pitavastatin, and processes for their preparation and isolation. It further relates to crystalline forms of pitavastatin salts and hydrates thereof, and process for preparing an amorphous form of pitavastatin
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Page/Page column 27
(2012/08/27)
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- Process for the preparation of statins
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Process for the preparation of ?-ketoester synthetic intermediates useful in the preparation of statins, in particular Pitavastatin.
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Page/Page column 10
(2011/11/12)
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- PROCESS FOR PREPARING STATINS
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Process for the preparation of β-ketoester synthetic intermediates useful in the preparation of statins, in particular Pitavastatin.
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Page/Page column 7
(2011/11/12)
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- PREPARATION METHOD OF STATIN COMPOUND AND BENZOTHIAZOLYL SULFONE COMPOUND USED THEREIN
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The inventive method comprising subjecting a novel benzothiazolyl sulfone compound to a reaction with an aldehyde to obtain a vinyl intermediate and removing the hydroxy and carboxy protective groups of the vinyl intermediate is simple and efficient in preparing a statin compound or a salt thereof which is useful for treating hyperlipemia.
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Page/Page column 18-19
(2010/08/04)
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- Drug or Supplement Combination with Conjugated Linoleic Acid for Fat Loss in Mammals
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Food, feed or drug combinations with conjugated linoleic acid are described that cause enhanced fat loss in mammals more efficiently than any of the individual components of the combination. Food, feed, or drugs that activate AMP activated protein kinase, agonists of nuclear receptors that bind RXR in adipocytes, or statin inhibitors were found to be more effective for fat loss when combined with conjugated linoleic acid.
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- A new and efficient synthesis of the HMG-CoA reductase inhibitor pitavastatin
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A new synthetic method for the preparation of pravastatin is described. The approach circumvents various synthetic problems associated with the buildup of the 3,5-dihydroxy-C7 acid side chain of HMG-CoA reductase inhibitors (statins). The use of the C6-amide derivative 5 instead of ester derivatives in the coupling reaction with carboxaldehyde 8 (Scheme 3) prevents undesired side reactions, such as eliminations and retro-aldol reactions. The method provides synthetic statins, such as pitavastatin, in >99% ee and exceptionally high overall yield. The enantiomerically pure starting material, (3S)-3-{[(tert-butyl)dimethylsilyl]oxy}-5-oxo-5-{[(1S)-1-phenylethyl]amino} pentanoic acid (3c), is prepared by an improved procedure from 3-{[(tert-butyl)dimethylsilyl]oxy}glutaric anhydride (1) and (1S)-1-phenylethylamine (2c; Scheme 1).
- Acemoglu, Murat,Brodbeck, Andre,Garcia, Angel,Grimier, Dominique,Hassel, Marc,Riss, Bernhard,Schreiber, Robert
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p. 1069 - 1081
(2008/03/12)
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- NOVEL PROCESS FOR STATINS AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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Novel process for statins and its pharmaceutically acceptable salts thereof represented by general formula (I).
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Page/Page column 54; 70
(2008/06/13)
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- NOVEL PROCESS FOR THE PREPARATION OF PITAVASTATIN AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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Novel Process for the preparation of Pravastatin and its pharmaceutically acceptable salts compound of formula- 1 via novel triphenyl phosphonium bromide salt compound of formula-3 or tributyl phosphonium bromide salt compound of formula-7 by employing Wittig reagents. Formula (I): Wherein M is H, Na+,K+,Mg+2,Ca+2.
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Page/Page column 16
(2010/11/29)
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- CRYSTAL FORM OF QUINOLINE COMPOUND AND PROCESS FOR ITS PRODUCTION
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A method for producing a drug substance of crystalline pitavastatin calcium excellent in stability, is presented. In the production of a compound (pitavastatin calcium) represented by the formula (1): The water content is adjusted to a level of from 5 to
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- Novel anhydrous amorphous forms of rosuvastatin calcium, pitavastatin calcium and fluvastatin sodium
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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-methyle
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Page/Page column 6
(2008/06/13)
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- Process for producing (3R,5S)-(E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-quinolin- 3-yl]-3, 5-dihydroxyhept-6-enic acid esters
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A process for producing a compound represented by the following formula (IV): (wherein R denotes a hydrogen atom, an alkyl group, or an aryl group), comprising reducing a compound selected from the group consisting of: a compound represented by the following formula (I): (wherein R is as defined in the formula); a compound represented by the following formula (II): (wherein R is as defined in the formula); and a compound represented by the following formula (III): (wherein R is as defined in the formula), by reacting the compound with a cell of a microorganism and/or a cell preparation thereof capable of stereo-selectively reducing a keto group.
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- CRYSTALLINE FORMS OF PITAVASTATIN CALCIUM
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The present invention is directed to new crystalline forms of Pitavastatin hernicalcium salt, referred to hereinafter as polymorphic Forms A, B, C, D, E and F, as well as the amorphous form. Furthermore, the present invention is directed to processes for
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- Treatment of type 1 diabetes with PDE5 inhibitors
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The use of a PDE5 inhibitor without substantial PDE2 inhibiting activity, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of Type 1 Diabetes. A method of treating Type 1 Diabetes in an individual suffering from Type 1 Diabetes, which method comprises administering to said individual an effective amount of a PDE5 inhibitor without substantial PDE2 inhibiting activity, or a pharmaceutically acceptable salt thereof.
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- Process for the manufacture of organic compounds
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A method for preparing an alkali metal salt comprising: (a) condensing a disilyloxydiene with an aldehyde in the presence of a titanium (IV) catalyst in an inert solvent to form a 5(S)-hydroxy-3-ketoester; (b) reducing the 5(S)-hydroxy-3-ketoester to a 3(
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Page/Page column 10, 11 - 12
(2008/06/13)
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- Method for producing pharmaceutical dosage forms
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The invention relates to a method for producing a granulate while using spray-dried D-mannitol and to the production of pharmaceutical dosage forms comprised of granulates of this type. The invention additionally relates to granulates obtained by using this method and to pharmaceutical dosage forms, which contain statins, especially cerivastatin, and which can be produced from said granulates.
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- First systematic chiral syntheses of two pairs of enantiomers with 3,5-dihydroxyheptenoic acid chain, associated with a potent synthetic statin NK-104
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First systematic chiral syntheses of two pairs of enantiomers with 3,5-dihydroxyheptenoic acid chain, associated with a potent synthetic statin NK-104 are reported. A pair of syn diol isomers (NK-104 and its enantiomer) was obtained efficiently by diastereomeric resolution. The synthesis of a pair of anti diol isomers (3-epimer and 5-epimer) was accomplished effectively by the asymmetric aldol reaction followed by anti stereoselective reduction as key steps. Their purity determinations were effected by chiral HPLC analysis.
- Suzuki, Mikio,Yanagawa, Yoshinobu,Iwasaki, Hiroshi,Kanda, Hiroyasu,Yanagihara, Kazufumi,Matsumoto, Hiroo,Ohara, Yoshio,Yazaki, Yukari,Sakoda, Ryozo
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p. 2977 - 2982
(2007/10/03)
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- Stereoselective reduction of β,δ-diketo esters. A novel strategy for the synthesis of artificial HMG-CoA reductase inhibitors
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Condensation of N-methoxy-N-methyl amides with the dianions of acetoacetates gives in good yields β,δ-diketo esters, which are reduced with Et2BOMe-NaBH4 in tetrahydrofuran-methanol highly selectively to give syn-β,δ-dihydroxy esters in one step. Similarly, the β,δ-diketo esters of the Taber's chiral alcohol or its enantiomer respectively are reduced to give syn-β,δ-dihydroxy esters of moderate enantiomeric excess. Higher diastereo- and enantioselectivity were achieved by reduction of the β,δ-diketo esters of the Taber's chiral alcohol or its enantiomer successively with diisobutylalane and with Et2BOMe-NaBH4. The resulting syn-diol esters were hydrolyzed and lactonized to give various types of β-hydroxy-δ-lactones commonly found in artificial HMG-CoA reductase inhibitors.
- Hiyama,Reddy,Minami,Hanamoto
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p. 350 - 363
(2007/10/02)
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