- Single point activation of pyridines enables reductive hydroxymethylation
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The single point activation of pyridines, using an electron-deficient benzyl group, facilitates the ruthenium-catalysed dearomative functionalisation of a range of electronically diverse pyridine derivatives. This transformation delivers hydroxymethylated piperidines in good yields, allowing rapid access to medicinally relevant small heterocycles. A noteworthy feature of this work is that paraformaldehyde acts as both a hydride donor and an electrophile in the reaction, enabling the use of cheap and readily available feedstock chemicals. Removal of the activating group can be achieved readily, furnishing the free NH compound in only 2 steps. The synthetic utility of the method was illustrated with a synthesis of (±)-Paroxetine.
- Marinic, Bruno,Hepburn, Hamish B.,Grozavu, Alexandru,Dow, Mark,Donohoe, Timothy J.
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p. 742 - 746
(2021/01/28)
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- Preparation method of paroxetine and analogues thereof
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The invention provides a preparation method for synthesizing paroxetine and analogues thereof. The invention also provides an intermediate compound for synthesizing paroxetine and analogues thereof. According to the method, a chiral center is creatively constructed firstly, and a required trans-product can be efficiently formed without a chiral catalyst in the reduction process because the positions of the two chiral centers needing to be constructed are adjacent, and due to the influence of steric hindrance of a first chiral group Rb (such as 4-F-phenyl). Meanwhile, R2NH- is adopted as an N protecting group on a piperidine ring from the beginning of the reaction, so that three toxic methyl-containing impurities inevitably generated during demethylation due to the adoption of methyl protection are avoided. A brand-new reaction route is opened up for synthesis of paroxetine and analogues thereof, and the yield and the chiral purity of the products are improved; meanwhile, intermediatesfor synthesizing paroxetine and analogues of paroxetine are enriched.
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- Organocatalytic Hantzsch Type Reaction Using Aryl Hydrazines, Propiolic Acid Esters and Enals: Enantioselective Synthesis of Paroxetine
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Aryl hydrazines, propiolic acid esters and enals serve as a viable substrate combination for an organocatalytic enantioselective Hantzsch type reaction. The method converts readily available starting materials into important chiral heterocycles with good to excellent yields and enantioselectivities, and has addressed the longstanding scope limitation of the classic Hantzsch reaction in the asymmetric synthesis of 2,6-unsubstituted hydropyridines. The synthetic utility has been demonstrated by the concise enantioselective synthesis of paroxetine. (Figure presented.).
- Chen, Lu,Zhang, Zhi,Zu, Liansuo
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p. 5385 - 5390
(2020/12/01)
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- Total Asymmetric Synthesis of (+)-Paroxetine and (+)-Femoxetine
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Total, asymmetric synthesis of (+)-Paroxetine and (+)-Femoxetine, selective serotonin reuptake inhibitors, used for the treatment of depression, anxiety, and panic disorders is reported. The key step is organocatalytic Michael addition of aldehydes to trans-nitroalkenes realized in bath or continues flow. High efficiency and selectivity in the Michael addition was achieved by application of Wang resin-supported Hayashi–J?rgensen catalyst.
- Szcze?niak, Piotr,Buda, Szymon,Lefevre, Laura,Staszewska-Krajewska, Olga,Mlynarski, Jacek
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p. 6973 - 6982
(2019/11/20)
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- 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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- A Tobramycin Vector Enhances Synergy and Efficacy of Efflux Pump Inhibitors against Multidrug-Resistant Gram-Negative Bacteria
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Drug efflux mechanisms interact synergistically with the outer membrane permeability barrier of Gram-negative bacteria, leading to intrinsic resistance that presents a major challenge for antibiotic drug development. Efflux pump inhibitors (EPIs) which block the efflux of antibiotics synergize antibiotics, but the clinical development of EPI/antibiotic combination therapy to treat multidrug-resistant (MDR) Gram-negative infections has been challenging. This is in part caused by the inefficiency of current EPIs to penetrate the outer membrane and resist efflux. We demonstrate that conjugation of a tobramycin (TOB) vector to EPIs like NMP, paroxetine, or DBP enhances synergy and efficacy of EPIs in combination with tetracycline antibiotics against MDR Gram-negative bacteria including Pseudomonas aeruginosa. Besides potentiating tetracycline antibiotics, TOB-EPI conjugates can also suppress resistance development to the tetracycline antibiotic minocycline, thereby providing a strategy to develop more effective adjuvants to rescue tetracycline antibiotics from resistance in MDR Gram-negative bacteria.
- Yang, Xuan,Goswami, Sudeep,Gorityala, Bala Kishan,Domalaon, Ronald,Lyu, Yinfeng,Kumar, Ayush,Zhanel, George G.,Schweizer, Frank
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p. 3913 - 3932
(2017/05/19)
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- Catalytic Michael/Ring-Closure Reaction of α,β-Unsaturated Pyrazoleamides with Amidomalonates: Asymmetric Synthesis of (?)-Paroxetine
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A highly enantioselective tandem Michael/ring-closure reaction of α,β-unsaturated pyrazoleamides and amidomalonates has been accomplished in the presence of a chiral N,N′-dioxide–Yb(OTf)3complex (Tf: trifluoromethanesulfonyl) to give various substituted chiral glutarimides with high yields and diastereo- and enantioselectivities. Moreover, this methodology could be used for gram-scale manipulation and was successfully applied to the synthesis of (?)-paroxetine. Further nonlinear and HRMS studies revealed that the real catalytically active species was a monomeric L-PMe2–Yb3+complex. A plausible transition state was proposed to explain the origin of the asymmetric induction.
- Zhang, Yu,Liao, Yuting,Liu, Xiaohua,Yao, Qian,Zhou, Yuhang,Lin, Lili,Feng, Xiaoming
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p. 15119 - 15124
(2016/10/11)
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- Enantioselective Synthesis of Chiral Piperidines via the Stepwise Dearomatization/Borylation of Pyridines
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We have developed a novel approach for the synthesis of enantioenriched 3-boryl-tetrahydropyridines via the Cu(I)-catalyzed regio-, diastereo-, and enantioselective protoborylation of 1,2-dihydropyridines, which were obtained by the partial reduction of the pyridine derivatives. This dearomatization/enantioselective borylation stepwise strategy provides facile access to chiral piperidines together with the stereospecific transformation of a stereogenic C-B bond from readily available starting materials. Furthermore, the utility of this method is demonstrated for the concise synthesis of the antidepressant drug (-)-paroxetine. A theoretical study of the reaction mechanism is also described.
- Kubota, Koji,Watanabe, Yuta,Hayama, Keiichi,Ito, Hajime
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p. 4338 - 4341
(2016/05/09)
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- Enantioselective Synthesis of Carbo- and Heterocycles through a CuH-Catalyzed Hydroalkylation Approach
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The enantioselective, intramolecular hydroalkylation of halide-tethered styrenes has been achieved through a copper hydride-catalyzed process. This approach allowed for the synthesis of enantioenriched cyclobutanes, cyclopentanes, indanes, and six-membered N- and O-heterocycles. This protocol was applied to the synthesis of the commercial serotonin reuptake inhibitor (ˉ)-paroxetine.
- Wang, Yi-Ming,Bruno, Nicholas C.,Placeres, ángel L.,Zhu, Shaolin,Buchwald, Stephen L.
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p. 10524 - 10527
(2015/09/28)
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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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- Highly enantioselective organocatalytic cascade reaction for the synthesis of piperidines and oxazolidines
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The synthesis of piperidines and piperidines derivatives in enantiopure fashion has been a challenging goal for organic chemists. In this report we developed a nice cascade reaction for piperidine derivatives based in an amidomalonate Michael addition to enals followed by an intramolecular hemiaminal formation with good yields and enantioselectivities. Moreover we studied the 'in situ' intramolecular cyclization of this hemiaminals with alcohols forming fused piperidine-oxazolidines.
- ?íhalová, Sylva,Valero, Guillem,Schimer, Ji?í,Humpl, Marek,Dra?ínsky, Martin,Moyano, Albert,Rios, Ramon,Vesely, Jan
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p. 8942 - 8950
(2011/12/01)
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- Synthesis of (-)-paroxetine via enantioselective phase-transfer catalytic monoalkylation of malonamide ester
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(Figure presented) A new enantioselective synthetic method of (-)-paroxetine is reported. (-)-Paroxetine could be obtained in 15 steps (95% ee and 9.1% overall yield) from N,N-bis(p-methoxyphenyl)malonamide tert-butyl ester via the enantioselective phase-transfer catalytic alkylation and the diastereoselective Michael addition as the key steps.
- Kim, Mi-Hyun,Park, Yohan,Jeong, Byeong-Seon,Park, Hyeung-Geun,Jew, Sang-Sup
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supporting information; experimental part
p. 2826 - 2829
(2010/08/07)
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- Chimeric Nitrate Esters and Use of the Same in a Treatment for Depression
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Chimeric nitrate esters and their use in the treatment of depression are disclosed. The chimeric nitrate esters also are useful in the treatment of depression and comorbidity associated with aging.
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Page/Page column 14
(2009/07/25)
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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 18-19
(2008/06/13)
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- Stereospecific construction of substituted piperidines. Synthesis of (-)-paroxetine and (+)-laccarin
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Short and efficient enantioselective syntheses of (-)-paroxetine and (+)-laccarin are described based on the highly stereospecific cleavage of C(3)-substituted 1,3-cyclic sulfamidates. The Royal Society of Chemistry.
- Bower, John F.,Riis-Johannessen, Thomas,Szeto, Peter,Whitehead, Andrew J.,Gallagher, Timothy
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p. 728 - 730
(2007/10/03)
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- Efficient Heck arylations of cyclic and acyclic acrylate derivatives using arenediazonium tetrafluoroborates. A new synthesis of the antidepressant drug (±)-paroxetine
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The Heck arylation of acyclic- and cyclic-substituted acrylates using several arenediazonium tetrafluoroborates was investigated. Arylations were carried out under aerobic, ligand-free conditions to provide the corresponding substituted acrylates in moderate to high isolated yields. Heck arylations were usually completed in less than 2 h in refluxing methanol. The aza-endocyclic acrylate derivative 11a was converted into the antidepressant drug (±)-paroxetine in a concise new route in good overall yield.
- Pastre, Julio Cezar,Correia, Carlos Roque Duarte
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p. 1657 - 1660
(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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Page/Page column 7
(2008/06/13)
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- Anti-proliferative drugs
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The present invention relates to methods for the treatment of diseases associated with hyper-proliferation of cells by administering to a subject in need a therapeutically effective amount of at least one psychotropic agent. Specific proliferative diseases against which psychotropic agents were found to be effective are cancer, including multi-drug resistant cancer and diseases associated with hyper-proliferation of the skin cells, such as psoriasis and hyperkeratosis.
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- Catalytic enantioselective conjugate reduction of lactones and lactams
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A dramatic acceleration of the enantioselective copper-catalyzed conjugate reduction of α,β-unsaturated lactones, lactams, and esters is reported upon addition of alcohol additives. Good to excellent yields and enantioselectivities were realized using a catalyst generated in situ from CuCl2·H2O, t-BuONa, p-tol-BINAP, and PMHS, and this methodology was applied to the synthesis of (-)-Paroxetine.
- Hughes, Gregory,Kimura, Masanari,Buchwald, Stephen L.
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p. 11253 - 11258
(2007/10/03)
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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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- Paroxetine maleate
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Paroxetine maleate and its preparation and use in the treatment and prevention of inter alia depression.
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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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- Synthesis of the major metabolites of Paroxetine
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Paroxetine is a well-known antidepressant, used worldwide in therapeutics. In comparison with other selective serotonin reuptake inhibitors, it exhibits the highest activity in serotonin reuptake inhibition. Paroxetine metabolism initially involves its demethylenation to the catechol intermediate, which is then O-methylated at positions C3 or C4. Herein, the chemistry resulting in the syntheses of these metabolites (3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)piperidine and (3S,4R)-4-(4-fluorophenyl)-3-(4-hydroxy-3-methoxyphenoxymethyl)piperidine is described starting from the common intermediate (3S,4R)-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine. Additionally, the common intermediate was used to synthesize paroxetine, which had the same structure and stereochemistry as commercial paroxetine, thereby confirming our synthetic route.
- Segura, Mireia,Roura, Lidia,De La Torre, Rafael,Joglar, Jesus
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p. 248 - 258
(2007/10/03)
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- Application of the chiral base desymmetrisation of imides to the synthesis of the alkaloid jamtine and the antidepressant paroxetine
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The synthesis of the alkaloid jamtine and the antidepressant paroxetine have been addressed by a strategy involving asymmetric desymmetrisation of prochiral imides by a chiral lithium amide base. A short reaction sequence, starting with a cyclohexane fused succinimide, led to the structures originally reported for the alkaloid jamtine and its derived N-oxide. The structures synthesised are shown not to correspond with those originally reported. A second sequence involves desymmetrisation of a 4-arylglutarimide, and provides a short enantioselective synthesis of the drug substance paroxetine.
- Gill, Christopher D.,Greenhalgh, Daniel A.,Simpkins, Nigel S.
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p. 9213 - 9230
(2007/10/03)
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- Process for producing paroxetine
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A process for producing a paroxetine represented by the following formula (4), which comprises reacting an N-alkylpiperidine represented by the following general formula (1) with a haloformic acid ester represented by the general formula (2) to prepare an alkoxycarbonylpiperidine represented by the general formula (3), and hydrolyzing the alkoxycarbonylpiperidine under alkaline conditions: wherein each of R1and R2is a lower alkyl group, a lower cycloalkyl group, an aralkyl group or CmF2m+1(wherein m is an integer of from 1 to 6), and X is a halogen atom.
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- Process for the production of paroxetine
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The synthesis of paroxetine can be made more convenient by using a solvent system comprising an aliphatic alcohol and a hydrocarbon co-solvent. The solvent system is used particularly in the hydrolysis of paroxetine phenylcarbamate and preferably uses butanol and toluene as the system.
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- Synthesis of Enantiopure trans-3,4-Disubstituted Piperidines. An Enantiodivergent Synthesis of (+)- And (-)-Paroxetine
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Reaction of (R)-phenylglycinol with methyl 5-oxopentanoate gave either bicyclic lactam cis-1 (the kinetic product) or its isomer trans-1 (under equilibrating conditions) as the major products, which were converted to the corresponding (cis or trans) unsaturated lactams 4 and 5. On treatment with lithium alkyl (or aryl) cyanocuprates, these chiral building blocks undergo conjugate addition to give enantiopure trans-3,4-substituted 2-piperidone derivatives in high yield and stereoselectivity. The synthetic potential of this transformation is illustrated by the synthesis of (+)-femoxetine and the two enantiomers of the known antidepressant paroxetine.
- Amat, Mercedes,Bosch, Joan,Hidalgo, Jose,Canto, Margalida,Perez, Maria,Llor, Nuria,Molins, Elies,Miravitlles, Carles,Orozco, Modesto,Luque, Javier
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p. 3074 - 3084
(2007/10/03)
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- Process for the preparation of optically enriched 4-aryl-3-hydromethyl substituted piperidines to be used as intermediates in the synthesis of paroxetine
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The subject invention pertains to optically-enriched compounds of formula (1), wherein Ar is a C6-20 aryl group; and R1 and R2 are independently H, alkyl or aryl. The subject invention also pertains to method of preparing these compounds. The subject compounds can be prepared by reduction of the corresponding 1,4-dihydropyridine-3-aldehyde, e.g., using hydrogen an a catalyst. The aldehyde can be prepared by hydrolytic cleavage of an aminal obtainable by the reaction of 3-pyridinecarboxaldehyde and a chiral C-2 symmetric diamine, an then stereoselective introduction of the Ar and COOCHR1 R2 groups. STR1
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- Piperidine derivative and process for preparing the same
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A piperidine derivative, which can be used as an intermediate for pharmaceuticals such as paroxetine useful as antidepressants, represented by the general formula (I): STR1 wherein R1 is hydrogen atom, benzyloxycarbonyl group or tert-butoxycarbonyl group; R2 is hydroxymethyl group, an alkylsulfonyloxymethyl group having an alkyl moiety of 1 to 2 carbon atoms, phenylsulfonyloxymethyl group which may have methyl group at the 4-position, (3,4-methylenedioxyphenyl)oxymethyl group, carboxyl group or --CO2 R7 group in which R7 is an alkyl group having 1 to 5 carbon atoms, and Z is methylene group or carbonyl group.
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- 4-Phenylpiperidine compounds for treating depression
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The invention relates to a compound, and pharmaceutically acceptable salts, having the formula I: STR1 wherein: R represents an alkyl or alkynyl group having 1-4 carbon atoms, or a phenyl group optionally substituted by C1-4 alkyl, alkylthio, alkoxy, halogen, nitro, acylamino, methylsulfonyl or methylenedioxy, or represents tetrahydronaphthyl, R1 represents hydrogen, trifluoro (C1-4) alkyl, alkyl or alkynyl, X represents hydrogen, alkyl having 1-4 carbon atoms, alkoxy, trifluoroalkyl, hydroxy, halogen, methylthio or aralkoxy, R2 represents: a C1-C10 alkyl group, a phenyl group optionally substituted by one or more of the following groups: a C1-C10 alkyl group, a halogen group, a nitro group, hydroxy group, and/or an alkoxy group.
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