- Synthesis, characterization of 3-(bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)quinoline and its crystal structure
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3-(Bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)quinoline (I), an important intermediate to synthesize pitavastatin calcium. It was prepared from ethyl 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxylate via reduction by KBH4/ZnCl2 and then bromide by PBr3. The product was characterized by NMR and LC-MS. The crystal structure of compound I was investigated using X-ray diffraction and SHELXTL-97 software. The result indicated that compound I crystallized in the triclinic system, space group P-1 with a = 9.6150(19), b = 9.868 (2), c = 10.060(2) ?, V = 783.3 (4) ?3; Z 2.
- Xu, Jia-Ying,Cheng, Wei-Hua,Wang, Lan,Wu, Jian-Guo,Wang, Kai
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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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supporting information
p. 3286 - 3290
(2018/06/11)
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- Pitavastatin calcium method for the preparation of intermediates
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The invention discloses a preparation method for a pitavastatin calcium intermediate shown in the formula (I) of the Specification. According to the invention, the pitavastatin calcium intermediate is prepared from ester compounds shown in the formula (II) of the Specification through hydrolysis and reduction; alcohol is used as hydrolysis medium, alcoholate can be formed by the alcohol and hydroxide, and the alkalinity of the alcoholate is stronger than that of the hydroxide, so that hydrolysis reaction is relatively facilitated; the hydrolysis time is 3-4 days when the hydrolysis medium in the prior art is an aqueous solution, while the hydrolysis time of the preparation method provided by the invention is less than 20 h.
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Page/Page column 0046-0047
(2017/01/23)
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- Substrate stereocontrol in bromine-induced intermolecular cyclization: Asymmetric synthesis of pitavastatin calcium
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A novel approach to synthesize pitavastatin calcium (1), an effective HMG-CoA reductase inhibitor, based on readily available and attractively functionalized (R)-3-chloro-1,2-propanediol is reported. This work highlights an intermolecular diastereoselective bromine-induced cyclization of homoallylic carbonate to meet stereochemical challenges in the synthesis of statins. An efficient route to a new triphenylphosphonium tetrafluoroborate salt of a quinoline core is also presented.
- Chen, Weiqi,Xiong, Fangjun,Liu, Qian,Xu, Lingjun,Wu, Yan,Chen, Fener
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p. 4730 - 4737
(2015/07/27)
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- Palladium-Catalyzed Carbonylative Couplings of Vinylogous Enolates: Application to Statin Structures
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The first Pd-catalyzed carbonylative couplings of aryl and vinyl halides with vinylogous enolates are reported generating products derived from C-C bond formation exclusively at the γ-position. Good results were obtained with a dienolate derivative of acetoacetate (1,3-dioxin-4-one). These transformations occurred at room temperature and importantly with only stoichiometric carbon monoxide in a two-chamber reactor. The methodology was applied to the synthesis of two members of the statin family generating the cis-3,5-diol acid motif by a γ-selective carbonylation followed by a cis-stereoselective reduction of the 3,5-dicarbonyl acid intermediates.
- Makarov, Ilya S.,Kuwahara, Takashi,Jusseau, Xavier,Ryu, Ilhyong,Lindhardt, Anders T.,Skrydstrup, Troels
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supporting information
p. 14043 - 14046
(2015/11/25)
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- Diastereoselective synthesis of pitavastatin calcium via bismuth-catalyzed two-component hemiacetal/oxa-Michael addition reaction
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An efficient and concise asymmetric synthesis of pitavastatin calcium (1) starting from commercially available (S)-epichlorohydrin is described. A convergent C1 + C6 route allowed for the assembly of the pitavastatin C7 side chain via a Wittig reaction between phosphonium salt 2 and the enantiomerically pure C6-formyl side chain 3. The 1,3-syn-diol acetal motif in 3 was established with excellent stereo control by a diastereoselective bismuth-promoted two-component hemiacetal/oxa-Michael addition reaction of (S)-α,β-unsaturated ketone 4 with acetaldehyde.
- Xiong, Fangjun,Wang, Haifeng,Yan, Lingjie,Xu, Lingjun,Tao, Yuan,Wu, Yan,Chen, Fener
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p. 9813 - 9819
(2015/10/05)
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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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Page/Page column 9
(2012/05/31)
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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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- PROCESS FOR THE PREPARATION OF KEY INTERMEDIATES FOR THE SYNTHESIS OF STATINS OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The invention relates to commercially viable process for the synthesis of key intermediates for the preparation of statins, in particular Rosuvastatin and Pitavastatin or respective pharmaceutically acceptable salts thereof. A new simple and short synthetic route for key intermediates is presented which benefits from the use of cheap and readily available starting materials, by which the conventionally most frequently used DIBAL-H as reducing agent can be avoided.
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- The use of a lactonized statin side-chain precursor in a concise and efficient assembly of pitavastatin
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A concise and simple synthetic route to pitavastatin is described. The approach involves a highly stereoselective Wittig olefination reaction between a lactonized statin side-chain precursor and the triphenylphosphonium bromide salt of the corresponding quinoline heterocyclic core. The necessary O-tert-butyl(dimethyl)silyl-protected pitavastatin lactone was obtained in 75% yield and high purity by simple crystallization from aqueous methanol. Subsequent deprotection, hydrolysis, and cation exchange in a one-pot operation provided pitavastatin calcium in 93% yield. Georg Thieme Verlag Stuttgart · New York.
- Fabris, Jan,Casar, Zdenko,Smilovic, Ivanagazi
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experimental part
p. 1700 - 1710
(2012/07/27)
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- A practical and efficient procedure for reduction of carboxylic acids and their derivatives: use of KBH4-MgCl2
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The use of KBH4-MgCl2 to reduce carboxylic acids and their derivatives to the corresponding alcohols or the respective reduced products is described. Methyl (S)-3,4-O-isopropylidene-3,4-dihydroxy butanoate 2 used as a reference substrate was reduced with KBH4 and MgCl2 in 1:1 mol ratio to (S)-1,2-O-isopropylidene-1,2,4-butanetriol 1.
- Qiu, You-Chun,Zhang, Fu-Li,Zhang, Chun-Nian
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p. 7595 - 7598
(2008/03/14)
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- Synthesis and biological evaluations of quinoline-based HMG-CoA reductase inhibitors
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A series of quinoline-based 3,5-dihydroxyheptenoic acid derivatives were synthesized from quinolinecarboxylic acid esters by homologation, aldol condensation with ethyl acetoacetate dianion, and reduction of 3-hydroxyketone to evaluate their ability to inhibit the enzyme HMG-CoA reductase in vitro. In agreement with previous literature, a strict structural requirement exists on the external ring, and 4-fluorophenyl is the most active in this system. For the central ring, substitution on positions 6, 7, and 8 of the central quinoline nucleus moderately affected the potency, whereas the alkyl side chain on the 2-position had a more pronounced influence on activity. Among the derivatives, NK-104 (pitavastatin calcium), which has a cyclopropyl group as the alkyl side chain, showed the greatest potency. We found that further modulation and improvement in potency at inhibiting HMG-CoA reductase was obtained by having the optimal substituents flanking the desmethylmevalonic acid portion, that is, 4-fluorophenyl and cyclopropyl, instead of the usual isopropyl group.
- Suzuki,Iwasaki,Fujikawa,Kitahara,Sakashita,Sakoda
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p. 2727 - 2743
(2007/10/03)
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- Enantioconvergent Synthesis of a Promising HMG Co-A Reductase Inhibitor NK-104 from Both Enantiomers of Epichlorohydrin
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An enantioconvergent synthesis of (+)-NK-104 (3), a promising HMG Co-A reductase inhibitor, has been developed from both enantiomers of epichlorohydrin.
- Takano, Seiichi,Kamikubo, Takashi,Sugihara, Takumichi,Suzuki, Mikio,Ogasawara, Kunio
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p. 201 - 204
(2007/10/02)
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