- Total synthesis of (±)-paroxetine by diastereoconvergent cobalt-catalysed arylation
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A total synthesis of paroxetine is reported, with a diastereoselective and diastereoconvergent cobalt-catalysed sp3-sp2 coupling reaction involving a 3-substituted 4-bromo-N-Boc-piperidine (Boc = tert-butoxycarbonyl) substrate as a key step. A 9:1 diastereoselectivity was obtained, while a control experiment involving a conformationally locked 3-substituted 4-bromo-tert-butyl cyclohexane ring proceeded with essentially complete stereoselectivity.
- Despiau, Carole F.,Dominey, Andrew P.,Harrowven, David C.,Linclau, Bruno
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Read Online
- Diastereoconvergent Synthesis of (–)-Paroxetine
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A diastereoconvergent approach to (–)-paroxetine from diastereomeric 3,4-epoxy-2-piperidones is reported. For this synthesis, a regioselective and stereodivergent CuI-catalyzed epoxide-ring-opening reaction of epoxyamide precursors to give the 4-(4-fluorophenyl)-2-piperidone skeleton with the correct absolute configuration is crucial. Using CuBr·SMe2 as a catalyst, the epoxide-ring-opening reaction takes place with inversion of configuration; the configuration is retained when CuI is used.
- Chamorro-Arenas, Delfino,Fuentes, Lilia,Quintero, Leticia,Cruz-Gregorio, Silvano,H?pfl, Herbert,Sartillo-Piscil, Fernando
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p. 4104 - 4110
(2017/08/07)
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- Stereodivergent α-allylation of linear aldehydes with dual iridium and amine catalysis
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We describe the fully stereodivergent, dual catalytic α-allylation of linear aldehydes. The reaction proceeds via direct iridium-catalyzed substitution of racemic allylic alcohols with enamines generated in situ. The use of an Ir(P,olefin) complex and a diarylsilyl prolinol ether as catalysts in the presence of dimethylhydrogen phosphate as the promoter proved to be crucial for achieving high enantio- and diastereoselectivity (>99% ee, up to >20:1 dr). The utility of the method is demonstrated in a concise enantioselective synthesis of the antidepressant (-)-paroxetine.
- Krautwald, Simon,Schafroth, Michael A.,Sarlah, David,Carreira, Erick M.
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p. 3020 - 3023
(2014/03/21)
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- Improved process for paroxetine hydrochloride substantially free from potential impurities
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An efficient process for production of paroxetine hydrochloride hemihydrate 1, a selective 5-hydroxytryptamine (serotonin) reuptake inhibitor, is described. Identification and control of potential impurities and establishment of efficient downstream workup procedures enabled us to produce paroxetine hydrochloride hemihydrate 1 efficiently.
- Gangula, Srinivas,Kolla, Naveen Kumar,Elati, Chandrasekar,Dongamanti, Ashok,Bandichhor, Rakeshwar
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p. 3344 - 3360
(2012/10/08)
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- SULFATED GALACTANS WITH ANTITHROMBOTIC ACTIVITY, PHARMACEUTICAL COMPOSITION, METHOD FOR TREATING OR PROPHYLAXIS OF ARTERIAL OR VENOUS THROMBOSIS, METHOD OF EXTRACTION AND USE THEREOF
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The present invention relates to low molecular weight sulfated galactans, obtained from algae, particularly genus Botryocladia, preferably species Botryocladia occidentallis, which have no effect on the factor XII activation of the clotting cascade, having antithrombotic heparinoid activity. The present invention also refers to a pharmaceutical composition comprising said sulfated galactans and the use thejreof, as heparin substitute, in the treatment or prophylaxis of arterial or venous thrombosis in humans and animals. Furthermore, the present invention provides a method of extraction of the said sulfated galactans.
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(2009/12/23)
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- Controlled Release Compositions of an Antidepressant Agent
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The present invention relates to controlled release compositions comprising an anti-depressant compound. More particularly, the present invention relates to controlled release compositions comprising paroxetine hydrochloride.
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- A PROCESS FOR THE PREPARATION OF (-)-TRANS-4-(P-FLUOROPHENYL)-3-[[3,4-(METHYLENEDIOXY)PHENOXY]METHYL)]PIPERIDINE
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A process for preparing (-)-trans-4-(4-fluorophenyl)-3-[[3,4-(methylenedioxy)phenoxy]methyl]-piperidine, a compound of formula (I) or pharmaceutically acceptable salts thereof, said process comprising hydrolyzing a compound of formula (II), wherein R may be selected from halo substituted or unsubstituted linear, branched or cyclic alkyl, alkylaryl, arylalkyl, by treatment with a base in a solvent system comprising a polar aprotic water miscible solvent and a hydrocarbon solvent wherein the polar aprotic water miscible solvent is selected from a sulfoxide solvent, an amide solvent or mixture thereof.
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Page/Page column 18
(2008/06/13)
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- Enantioselective total and formal syntheses of paroxetine (PAXIL) via phosphine-catalyzed enone α-arylation using arylbismuth(V) reagents: a regiochemical complement to Heck arylation
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Exposure of dihydropyridinone 1 to the arylbismuth(V) reagent (p-F-Ph)3BiCl2 in the presence of substoichiometric quantities of tributylphosphine (10 mol %) results in aryl transfer to the transiently generated (β-phosphonio)enolate to provide the α-arylated enone 2. This transformation, which represents a regiochemical complement to the Mizoroki-Heck arylation, is used strategically in concise formal and enantioselective total syntheses of the blockbuster antidepressant (-)-paroxetine (PAXIL).
- Koech, Phillip K.,Krische, Michael J.
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p. 10594 - 10602
(2007/10/03)
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- PREPARATION OF PAROXETINE HYDROCHLORIDE HEMIHYDRATE
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A process for preparing paroxetine hydrochloride hemihydrate.
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(2008/06/13)
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- METHODS OF CRYSTAL PRECIPITATION
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Crystals of paroxetine hydrochloride 1/2-hydrate are allowed to separate out by adding water to a solution or suspension comprising paroxetine hydrochloride and a polar organic solvent which contains no water or at most 60% by weight of water to adjust the water content to at least 70% by weight when crystals of paroxetine hydrochloride 1/2-hydrate are allowed to separate out in a water-containing polar organic solvent. Crystals of paroxetine hydrochloride 1/2-hydrate being not colored in pink can be allowed to separate out in the presence of hydrogen chloride when crystals of paroxetine hydrochloride 1/2-hydrate are allowed to separate out in water or a water-containing polar organic solvent.
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Page/Page column 9
(2008/06/13)
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- NOVEL FORM OF ANHYDROUS PAROXETINE HYDROCHLORIDE AND METHOD FOR PREPARATION THEREOF
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A novel form of anhydrous Paroxetine hydrochloride is prepared by dissolving Paroxetine base in isopropanol, which is treated with a solution of hydrogen chloride in isopropanol. 50 to 60% of isopropanol used in the reaction is then distilled at atmospheric pressure. The product thus obtained after drying contains isopropanol not more than 3% and water content which is less than 2.0%. The product is found to be stable even after 3 days upon direct exposure to 75% RH at 40°C and the crystallinity of product is unchanged as confirmed by X-ray powder difractogram. The product is also found to be stable for three months as per ICH satiability conditions.
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(2008/06/13)
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- A convenient synthesis of (-)-paroxetine
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A convenient synthesis of the antidepressant paroxetine starting from 1-benzyl-4-piperidone (2) is reported. A stereoselective reduction resulted in cis-piperidine-3-methanol [(+)-6]. The reaction between cis-piperidine-3- methanol mesylate (7) and sesamol led to benzyl-protected trans-paroxetine (9) through an inversion reaction of the stereogenic center at position 3. The latter compound was deprotected by hydrogenolysis. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.
- Czibula, Laszlo,Nemes, Andras,Seboek, Ferenc,Szantay Jr., Csaba,Mak, Marianna
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p. 3336 - 3339
(2007/10/03)
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- Practical syntheses of chiral trans-3, 4-disubstituted piperidines and the intermediates
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A new method for the preparation of chiral 4-substituted 2-piperidinones, trans-3,4-disubstituted 2-piperidinones, and trans-3,4-disubstituted piperidines is invented. Chiral paroxetine can be obtained from a chiral trans-3,4-disubstituted piperidine intermediate in high purity and good selectivity.
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- Enantioselective Michael additions to α,β-unsaturated imides catalyzed by a salen-al complex
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(Salen)aluminum complex 1b is an efficient catalyst for the conjugate addition of di- and trisubstituted nitriles to a wide range of acyclic alkyl- and aryl-substituted α,β-unsaturated imides. This new methodology provides access to multifunctional compounds that previously have not been readily accessible in enantioenriched form. Synthetic applications of these products include the preparation of enantiomerically enriched piperidines, as exemplified by an expedient asymmetric catalytic synthesis of (-)-paroxetine. Copyright
- Taylor, Mark S.,Jacobsen, Eric N.
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p. 11204 - 11205
(2007/10/03)
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- N-benzylpiperidine and tetrahydropyridine derivatives
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A process is disclosed for the preparation of compounds of the formula (I), which compounds are useful as intermediates for the preparation of paroxetine of formula(V).
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Page column 13
(2010/11/30)
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- Process for producing paroxetine salts substantially free from organic solvents
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A paroxetine salt free from an organic solvent is produced by substantially and safely removing the organic solvents from paroxetine hydrochloride. A process for producing a paroxetine salt, which comprises neutralizing paroxetine hydrochloride containing an organic solvent into paroxetine, then forming a salt of paroxetine with an acid other than hydrochloric acid, and crystallizing the salt from an organic solvent.
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- Preparation of paroxetine involving novel intermediates
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Disclosed are processes for preparing novel carbamate intermediates of paroxetine comprising dealkylating N-alkylparoxetine by reaction thereof with a haloalkyl ester of a haloformic acid, in a suitable organic solvent. Also disclosed are processes for preparing paroxetine comprising hydrolyzing the novel carbamate intermediates in a suitable solvent. Paroxetine prepared by the above processes can be neutralized with hydrogen chloride and crystallized as paroxetine hydrochloride anhydrous, hemihydrate or as a solvate of isopropanol. The invention is further directed to the novel carbamate intermediates formed by the disclosed processes.
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- Process for preparing paroxetine HCl which limits formation of pink colored compounds
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The present invention provides a process for preparing paroxetine HCl from paroxetine base which provides paroxetine HCl substantially free of pink-colored compounds or an impurity identified by an HPLC RRT of about 1.5. The processes of the present invention utilize a buffer, a molar ratio of HCl to paroxetine base of less than one, and crystallize/recrystallize in the presence of an effective amount of an anti-oxidants. A preferred way to create a buffer is by using ammonium chloride. A preferred anti-oxidant is ascorbic acid. The present invention also provides for re-crystalizing paroxetine HCl prepared by the above methods or any other methods in the presence of an effective amount of an anti-oxidant such as ascorbic acid. A preferred solvent system for recrystallization is a mixture of acetone and methanol. Processes of the present invention can combine these various features.
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- Process for the production of paroxetine
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A process for the production of paroxetine is described, wherein N-substituted derivatives of 4-(p-fluorophenyl)-3-hydroxymethyl-1,2,3,6-tetrahydropyridine are treated according to the following sequence of reactions: (a) hydrogenation catalyzed by transition metal complexes with chiral diphosphinic ligands; (b) —OH derivatisation and nucleophilic substitution, the substituent being sesamol; (c) N-dealkylation. The process is highly stereospecific and brings about the formation of intermediates enriched with the desired isomeric components, which are converted into paroxetine in quantitative yields.
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- MIXED PAROXETINE PROPAN-2-OL SOLVATES
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A crystalline paroxetine hydrochloride mixed solvate, that is more easily desolvated than the propan-2-ol solvate to form the anhydrate, is obtained by contacting crystalline propan-2-ol solvate with a transformation solvent. Suitable transformation solvents are an ether, ketone, chlorinated hydrocarbon, nitrile, lower alcohol, or ester, or a mixture thereof. Crystalline paroxetine hydrochloride anhydrate is obtained by heating the mixed solvate in a vacuum oven.
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- Serotonin reuptake inhibitor formulations
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A process for preparing amorphous paroxetine hydrochloride or sertraline hydrochloride is provided, which comprises preparing a solution in which paroxetine hydrochloride or sertraline hydrochloride and a water-soluble polymer are dissolved in a co-solvent of a volatile organic solvent and water. Said solution is dried to obtain a composition comprising amorphous paroxetine hydrochloride or sertraline hydrochloride and the water-soluble matrix.
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- Useful form of anhydrous paroxetine hydrochloride
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Paroxetine hydrochloride anhydrous designated as Form IV having at least one, some or all of the following characteristics: a) Infrared spectra as shown in FIG. 1 and 2, b) A X-ray powder diffraction pattern as shown in Schedule “C”, c) A melting point of between about 80°0 C. to about 95° C.
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- Practical syntheses of chiral trans-3, 4-disubstituted piperidines and the intermediates
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A new method for the preparation of chiral 4-substituted 2-piperidinones, trans-3,4-disubstituted 2-piperidinones, and trans-3,4-disubstituted piperidines is invented. Chiral paroxetine can be obtained from a chiral trans-3,4-disubstituted piperidine intermediate in high purity and good selectivity.
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- Asymmetric syntheses of trans-3,4-disubstituted 2-piperidinones and piperidines
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A convenient and practical method for the preparation of chiral 4-aryl-2-piperidinone from 3-arylglutaric anhydride and (S)-methylbenzylamine is described. Acylation or alkylation at the α-carbon of the chiral 4-aryl-2-piperidinone product afforded chiral trans-3,4-disubstituted 2-piperidinone derivatives and reduction of the chiral 2-piperidinones with lithium aluminum hydride provided the corresponding enantiomerically pure trans-3,4-disubstituted piperidines. This methodology has been successfully applied to the synthesis of the anti-depressant paroxetine.
- Liu, Lee Tai,Hong, Pao-Chiung,Huang, Hsiang-Ling,Chen, Shyh-Fong,Wang, Chia-Lin Jeff,Wen, Yuh-Sheng
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p. 419 - 426
(2007/10/03)
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- Improved synthesis of paroxetine hydrochloride propan-2-ol solvate through one of metabolites in humans, and characterization of the solvate crystals
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Paroxetine, a potent and selective inhibitor of 5-hydroxytryptamine (serotonin) uptake, was prepared through a piperidine derivative, which was reported to be one of the paroxetine metabolites in humans. Thus, the piperidine derivative was converted to its N-tert-butoxycarbonyl (N-Boc) derivative, which was then converted to N-Boc paroxetine. Paroxetine hydrochloride propan-2-ol (isopropyl alcohol (IPA)) solvate crystals were directly obtained from the N-Boc paroxetine by adding hydrogen chloride to the N-Boc paroxetine IPA solution. The amount of IPA content in the crystals was reduced by drying with a continuous change of powder X-ray diffraction patterns. Other characterizations of the solvate crystals were also conducted.
- Sugi, Kiyoshi,Itaya, Nobushige,Katsura, Tadashi,Igi, Masami,Yamazaki, Shigeya,Ishibashi, Taro,Yamaoka, Teiji,Kawada, Yoshihiro,Tagami, Yayoi,Otsuki, Michiya,Ohshima, Takao
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p. 529 - 536
(2007/10/03)
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- Asymmetric synthesis of (-)-paroxetine using PLE hydrolysis
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(-)-Paroxetine hydrochloride was produced asymmetrically in seven steps starting from 4-fluoro-benzaldehyde. The stereocenter at C-4 was initially set through desymmetrization of glutaric acid bis methyl ester 4 by PLE hydrolysis. A unique one-pot reduction-alkylation procedure was then developed to provide entry to lactam 2 with the appropriate absolute stereochemistry. (C) 2000 Elsevier Science Ltd.
- Yu, Marvin S.,Lantos, Ivan,Peng, Zhi-Qiang,Yu,Cacchio, Thomas
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p. 5647 - 5651
(2007/10/03)
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- Process for manufacturing paroxetine solid dispersions
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Solid dispersions of poorly soluble drugs are disclosed which are prepared using a solvent or fusion process. Such dispersions are manufactured with the free base of the drug, specifically paroxetine free base, an oil, allowing for a low temperature for the fusion process, decreased organic solvent volumes for the solvent process and the formation of a paroxetine salt during the solid dispersion manufacture process.
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- Synthesis and 5HT modulating activity of stereoisomers of 3-phenoxymethyl-4-phenylpiperidines
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A series of pairs of enantiomers of substituted 3-phenoxymethyl-4-phenylpiperidines has been prepared from arecoline or α-methylstyrene by a combination of stereospecific reactions and optical resolutions. The ability of the compounds to modulate serotonin (5HT) neurotransmission in vitro was determined. Several derivatives, among which is the antidepressant paroxetine, are very potent inhibitors of 5HT reuptake. These compounds exhibit a pronounced steric requirement for inhibition of 5HT reuptake and binding to 5HT2A and 5HT2C receptors. Acta Chemica Scandinavica 1996.
- Engelstoft, Mogens,Hansen, John Bondo
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p. 164 - 169
(2007/10/03)
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- ANTI-DEPRESSANT CRYSTALLINE PAROXETINE HYDROCHLORIDE HEMIHYDRATE
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The invention provides crystalline paroxetine hydrochloride hemihydrate, processes for its preparation, compositions containing the same and its therapeutic use as an anti-depressant
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