- Preparation method of pitavastatin calcium intermediate
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The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of a pitavastatin calcium intermediate. The preparation method comprises the following steps: 1,carrying out a chemical reaction on a compound II and triphenylphosphine at a temperature of 10-150 DEG C to prepare a compound III; 2, in the presence of triethylamine, with oxalyl chloride and dimethyl sulfoxide as oxidants, subjecting a compound IV to a chemical reaction to prepare a compound V; and 3, subjecting the compound III and the compound V to a chemical reaction at 20-150 DEG C in thepresence of a basic catalyst so as to prepare a compound I. The intermediate prepared by using the method provided by the invention has the advantages of easy availability of raw materials, simple operation, high yield and high purity. The specific synthetic route of the method is shown in the specification.
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Paragraph 0056; 0057
(2020/02/14)
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- Synthetic method of pitavastatin tert-butyl ester
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The invention discloses a synthesis method of pitavastatin tert-butyl ester, which comprises the following steps: carrying out a reaction on (4R-Cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxolane-4-tert-butyl acetate with a substance A under the action of a first base catalyst to obtain a substance B; oxidizing the substance B with an oxidizing agent to obtain a substance C; carrying out a reaction with 2-Cyclopropyl-4-(4-fluorophenyl)-quinoline-3-formaldehyde under the action of a second base catalyst to obtain a substance D; and finally, performing acid deprotection to obtain the pitavastatin tert-butyl ester. The method has the advantages of mild and controllable reaction conditions, wherein the reaction conditions of Julia olefination are free of requirement of ultralow-temperature reaction, so that the synthesis method has advantages of convenience and simplicity in operation, good stereoselectivity and high yield, and the synthesized pitavastatin tert-butyl ester is completely free of cis-isomer and high in purity.
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- Synthetic method for pitavastatin calcium intermediate
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The invention discloses a synthetic method for a pitavastatin calcium intermediate. The method includes the following steps: reacting 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-bromomethyl with trithiocyanuric acid under catalysis of sodium hydroxide to obtain a substance A; then oxidizing by the effect of an oxidizing agent to obtain a substance B; and reacting with (4R-Cis)-6-aldehyde group-2,2-dimethyl-1,3-dioxane-4-tert-butyl acetate under the catalysis of sodium hydride to obtain the pitavastatin calcium intermediate. The synthetic method for the pitavastatin calcium intermediate is cheap and easily available in raw material, is novel in route, is good in atom economy, is green and environmentally friendly, is mild and controllable in reaction condition, is convenient and simple inoperation, is simple in purification treatment, is suitable for industrialization production, is good in stereoselectivity, is high in yield, and is good in purity of the prepared pitavastatin calciumintermediate.
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Paragraph 0045; 0050; 0054; 0055; 0059; 0060; 00640065; 0069
(2019/04/17)
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- A process for preparing pitavastatin calcium key intermediate of
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The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of a pitavastatin calcium key intermediate. The method comprises a step of preparing an organic zinc reagent by using high-activity zinc and 2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline methylene bromide. The organic zinc reagent generates a Witting reaction with (3R, 5S)-6-oxo-3,5-dihydroxyl-3,5-O-isopropylidene tert-butyl caproate to generate (3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolone-3-yl]-3,5-dihydroxyl-3,5- O-isopropylidene-6-tert-butyl heptenate which is recrystallized to obtain the pitavastatin calcium key intermediate. The synthesis method provided by the invention has the characteristics of high purity of E construction, simple process, high yield and the like.
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Paragraph 0028; 0034-0038; 0039; 0043-0047; 0048; 0054-0058
(2018/09/12)
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- Preparation method of statins intermediate
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The invention discloses a preparation method of a statins intermediate, comprising the following steps: a phosphate compound and an aldehyde compound are subjected to a condensation reaction under theaction of a catalyst and alkali; after the reaction, post-treatment is conducted to obtain the statins intermediate. The statins intermediate includes a rosuvastatin intermediate (Compound A) and a pitavastatin calcium intermediate (Compound B). The preparation method has the advantages of low cost, simple operation and good yield, is environmentally friendly, and is suitable for industrial production.
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Paragraph 0057-0060; 0067-0070; 0077-0080; 0087-0090
(2018/11/27)
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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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- 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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Paragraph 0075-0082
(2017/03/14)
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- A NOVEL, GREEN AND COST EFFECTIVE PROCESS FOR SYNTHESIS OF TERT-BUTYL (3R,5S)-6-OXO-3,5-DIHYDROXY-3,5-O-ISOPROPYLIDENE-HEXANOATE
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The present invention provides a process of preparation of an intermediate useful for the preparation of statins more particularly the present invention relates to an eco-friendly and cost effective process for the preparation of tert -butyl (3R,5S)-6-oxo-3,5-dihydroxy- 3,5-O-isopropylidene-hexanoate [I].
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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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Paragraph 0046-0050
(2013/03/28)
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- METHOD FOR PREPARATION OF PITAVASTATIN AND ITS PHARMACEUTICAL ACCEPTABLE SALTS THEREOF
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The present invention discloses a compound, which is alkali or alkaline earth metal salts of pitavastatin, wherein the alkali or earth metal comprise one or more of magnesium, zinc, potassium, strontium and barium.
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Page/Page column 10
(2012/02/03)
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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 21
(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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Page/Page column 13
(2012/02/01)
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- PROCESS FOR PREPARING PITAVASTATIN AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The present invention discloses a compound, which is alkali or alkaline earth metal salts of pitavastatin, wherein the alkali or earth metal comprise one or more of magnesium, zinc, potassium, strontium and barium.
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Page/Page column 21; 22
(2011/08/08)
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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 13-14
(2010/08/04)
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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 13
(2010/11/29)
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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; 71-72
(2008/06/13)
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- Synthesis of an artificial HMG-CoA reductase inhibitor NK-104 via a hydrosilylation-cross-coupling reaction
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The hydrosilylation of t-butyl (3R,5S)-3,5-isopropylidenedioxy-6-heptynoate with ClMe2SiH and a platinum catalyst, t-Bu3P·Pt(CH2 = CHSiMe2)2O, gave an (E)-vinylsilane in high yield with high regioselectivity. A subsequent cross-coupling reaction with an aryl halide afforded t-butyl (3R,5S,6E)-7-aryl-3,5-isopropylidene-dioxy-6-heptenoate. This sequence was applied to the synthesis of a potent HMC-CoA reductase inhibitor, NK-104.
- Takahashi,Minami,Ohara,Hiyama
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p. 2649 - 2656
(2007/10/03)
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- Synthesis of artificial HMG-CoA reductase inhibitors based on the olefination strategy
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Synthetic methods were studied for optically active 6-oxo-3,5-isopropylidenedioxyhexanoate esters (4), which could be used as a key precursor of various kinds of artificial analogs of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. An enantiomer (+)-4 was prepared by asymmetric reduction of β,δ-diketo esters derived from the Taber's alcohol or L-tartrate followed by a series of chemical transformations, and the desired enantiomer (-)-4 was prepared by the same asymmetric reduction starting from D-tartrate. The key intermediate (-)-4 was finally converted into a highly potent HMG-CoA reductase inhibitor, NK-104.
- Hiyama,Minami,Takahashi
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p. 364 - 372
(2007/10/02)
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- STEREOSELECTIVE REDUCTION OF β,δ-DIKETO ESTERS DERIVED FROM TARTARIC ACID. A FACILE ROUTE TO OPTICALLY ACTIVE 6-OXO-3,5-syn-ISOPROPYLIDENEDIOXYHEXANOATE, A VERSATILE SYNTHETIC INTERMEDIATE OF ARTIFICIAL HMG Co-A REDUCTASE INHIBITORS.
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Reduction of β,δ-diketo esters derived from tartaric acid with HAl(i-Bu)2 gave stereoselectively β-hydroxy-δ-keto esters which were reduced with NaBH4 and Et2BOMe to β,δ-syn-dihydroxy esters.This strategy was successfully applied to the synthesis of t-butyl (3R,5S)-6-oxo-3,5-isopropylidenedioxyhexanoate starting from D-tartrate.
- Minami, Tatsuya,Takahashi, Kyoko,Hiyama, Tamejiro
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p. 513 - 516
(2007/10/02)
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- A new synthesis of HMG-CoA reductase inhibitor NK-104 through hydrosilylation-cross coupling reaction
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Regioselective hydrosilylation of t-butyl (3R,5S)-3,5-syn-isopropylidenedioxy-6-heptynoate with CLME2SiH and a catalyst t-Bu3P·Pt(CH2=CHSiMe2)2O gives an (E)-vinylsilane which undergoes cross coupling reaction with aryl halide to afford t-butyl (3R,5S,6E)-7-aryl-3,5-syn-isopropylidenedioxy-6-heptenoate, a precursor of a highly potent HMG-CoA reductase inhibitor NK-104.
- Takahashi,Minami,Ohara,Hiyama
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p. 8263 - 8266
(2007/10/02)
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