- Preparation method of cefamoxetine hydrochloride
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The invention discloses a preparation method of tamoxidectin hydrochloride, belongs to the technical field of drug synthesis, and uses 3 - chlorine -1 - phenylpropanone as a raw material to undergo a reduction reaction. The synthesis route has the advantages of few reaction steps, mild reaction conditions,3 - simple 2 - operation, cheap -3 - and easily available raw materials, and low production cost 3 - and -1 - R-chloro - N - phenylpropanone is used as a raw material.
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Paragraph 0008; 0018-0019; 0022; 0025; 0028
(2021/10/27)
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- Preparation method of N-methyl-3-(2-methylphenoxy)amphetamine
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The invention discloses a preparation method of N-methyl-3-(2-methylphenoxy)amphetamine as shown in a formula III. The preparation method comprises the following step: in DMSO, (S)-N-methyl-3-(2-methylphenoxy)amphetamine as shown in a formula II and potassium tert-butoxide are subjected to racemization reaction to obtain the N-methyl-3-(2-methylphenoxy)amphetamine. Chiral N-methyl-3-(2-methylphenoxy)amphetamine is subjected to efficient racemization under mild conditions, no obvious impurities are generated, and the obtained racemization product can be further split to obtain required (R)-atomoxetine, so that the splitting efficiency of atomoxetine is improved.
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Paragraph 0081-0092
(2021/09/04)
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- Preparation method of atomoxetine hydrochloride
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The invention belongs to the technical field of medicines, and particularly relates to a preparation method of atomoxetine hydrochloride serving as a medicine for treating attention deficit hyperactivity. According to the invention, commercially available (E)-N-methyl-3-phenyl-2-propylene-1-amine is adopted as a starting material, and addition, substitution and salification are carried out so as to prepare atomoxetine hydrochloride. The preparation method provided by the invention is simple in preparation process, simple and convenient to operate, relatively high in yield and suitable for industrial production, and can provide sufficient bulk drugs for research and development of medicines.
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- Enantioselective Heck Arylation of Acyclic Alkenol Aryl Ethers: Synthetic Applications and DFT Investigation of the Stereoselectivity
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Herein we report the enantioselective Heck-Matsuda arylation of acyclic E and Z-alkenyl aryl ethers. The reactions were carried out under mild conditions affording the enantioenriched benzyl ethers in a regioselective manner, moderate to good yields (up to 73%), and in good to excellent enantiomeric ratios (up to 97:3). The enantioselective Heck-Matsuda arylation has shown a broad scope (25 examples), and some key Heck-Matsuda adducts were further converted into more complex and valuable scaffolds including their synthetic application in the synthesis of (R)-Fluoxetine, (R)-Atomoxetine, and in the synthesis of an enantioenriched benzo[c]chromene. Finally, in silico mechanistic investigations into the reaction's enantioselectivity were performed using density functional theory. (Figure presented.).
- Polo, Ellen Christine,Wang, Martí Fernández,Angnes, Ricardo Almir,Braga, Ataualpa A. C.,Correia, Carlos Roque Duarte
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p. 884 - 892
(2019/12/30)
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- Preparation method of atomoxetine
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The invention belongs to the technical field of medicines, and particularly relates to a preparation method of atomoxetine hydrochloride serving as a medicine for treating attention deficit hyperactivity. Commercially available 3-(methylamino)-1-phenylacetone is adopted as a starting material, and undergoes asymmetric reduction, substitution and other reactions to prepare the atomoxetine. The invention mainly aims to prepare the atomoxetine by an asymmetric synthesis method and expand a preparation method of the atomoxetine hydrochloride.
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Paragraph 0003; 0012; 0013
(2020/06/05)
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- Selective Monomethylation of Amines with Methanol as the C1 Source
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The N-monomethyl functionality is a common motif in a variety of synthetic and natural compounds. However, facile access to such compounds remains a fundamental challenge in organic synthesis owing to selectivity issues caused by overmethylation. To address this issue, we have developed a method for the selective, catalytic monomethylation of various structurally and functionally diverse amines, including typically problematic primary aliphatic amines, using methanol as the methylating agent, which is a sustainable chemical feedstock. Kinetic control of the aliphatic amine monomethylation was achieved by using a readily available ruthenium catalyst at an adequate temperature under hydrogen pressure. Various substrates including bio-related molecules and pharmaceuticals were selectively monomethylated, demonstrating the general utility of the developed method.
- Choi, Geunho,Hong, Soon Hyeok
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supporting information
p. 6166 - 6170
(2018/04/30)
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- Minimizing Aryloxy Elimination in RhI-Catalyzed Asymmetric Hydrogenation of β-Aryloxyacrylic Acids using a Mixed-Ligand Strategy
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The first example of efficient asymmetric hydrogenation of challenging β-aryloxyacrylic acids was realized using a RhI-complex based on the heterocombination of a readily available chiral monodentate secondary phosphine oxide (SPO) and an achiral monodentate phosphine ligand as the catalyst. Excellent enantioselectivities (92->99% ee) were achieved for a wide variety of chiral β-aryloxypropionic acids with minor aryloxy elimination in most cases. The resultant products were readily transformed into biologically active compounds through simple synthetic manipulations.
- Li, Yang,Wang, Zheng,Ding, Kuiling
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supporting information
p. 16387 - 16390
(2015/11/09)
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- A method for preparing optically active 3-amino-1-phenylpropanol derivatives as an intermediate and a method for preparing optically active pharmaceutical products using the same
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The present invention relates to a method for preparing a 3-amino-1-phenylpropanol derivative having (R) or (S) optical activity with 80% or more of an enantiomeric excess (ee), which includes a step of performing an asymmetric reduction reaction in the presence of a spiroborate ester catalyst and a hydrogen donor. The invention also relates to a method for preparing an optically active pharmaceutical product, which includes a step of preparing a (R)- or (S)-3-amino-1-phenylpropanol derivative, that is an intermediate, by using the catalyst.(AA) 3-amino-1-phenylpropanol(BB) Tomoxetine(CC) Nisoxetine(DD) FluoxetineCOPYRIGHT KIPO 2016
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Paragraph 0207; 0208
(2016/11/09)
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- ALDEHYDE-SELECTIVE WACKER-TYPE OXIDATION OF UNBIASED ALKENES
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This disclosure is directed to methods of preparing organic aldehydes, each method comprising contacting a terminal olefin with an oxidizing mixture comprising: (a) a dichloro-palladium complex; (b) a copper complex; (c) a source of nitrite; under aerobic reaction conditions sufficient to convert at least a portion of the terminal olefin to an aldehyde.
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Paragraph 0217; 0220
(2014/10/29)
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- Catalyst-controlled wacker-type oxidation: Facile access to functionalized aldehydes
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The aldehyde-selective oxidation of alkenes bearing diverse oxygen groups in the allylic and homoallylic position was accomplished with a nitrite-modified Wacker oxidation. Readily available oxygenated alkenes were oxidized in up to 88% aldehyde yield and as high as 97% aldehyde selectivity. The aldehyde-selective oxidation enabled the rapid, enantioselective synthesis of an important pharmaceutical agent, atomoxetine. Finally, the influence of proximal functional groups on this anti-Markovnikov reaction was explored, providing important preliminary mechanistic insight.
- Wickens, Zachary K.,Skakuj, Kacper,Morandi, Bill,Grubbs, Robert H.
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p. 890 - 893
(2014/02/14)
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- Chemoenzymatic asymmetric synthesis of fluoxetine, atomoxetine, nisoxetine, and duloxetine
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The asymmetric synthesis of two well-known anti-depressant drugs, fluoxetine and duloxetine has been accomplished in a chemoenzymatic manner. The main highlight of the synthesis is the enantioselective cyanohydrin formation by a plant (R)-HNL (hydroxynitrile lyase). The enantiopure cyanohydrins are then synthetically manipulated into the above two drug molecules and two of their structural analogues, atomoxetine and nisoxetine.
- Rej, Rohan Kalyan,Das, Tapas,Hazra, Suman,Nanda, Samik
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p. 913 - 918
(2013/09/23)
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- Candida tenuis xylose reductase catalyzed reduction of aryl ketones for enantioselective synthesis of active oxetine derivatives
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Candida tenuis xylose reductase shows high catalytic efficiencies in carbonyl reduction of acetophenone and 1-phenyl-1-propanone derivatives. The quite low substrate solubility in aqueous buffer systems is circumvented by addition of methanol or by two-phase solvent systems. In the latter, methanol improves the substrate phase transfer as solvent mediator and leads to reasonable space/time yields. Resulting enantiomerically pure chiral alcohols are key intermediates for synthesis of active pharmaceutical ingredients. (R)-Atomoxetine is exemplarily synthesized in four steps, and the further use for generation of other oxetine derivatives and a polo-like kinase 1 inhibitor are discussed. Copyright
- Vogl, Michael,Brecker, Lothar,Kratzer, Regina,Nidetzky, Bernd
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p. 847 - 853,7
(2020/07/31)
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- METHOD FOR PREPARING ATOMOXETINE
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The present invention provides an efficient method for preparing atomoxetine in high yield. (R)-methylhydroxylaminopropanol compound of formula (II) in the present invention is used as an intermediate without the need for resolution processes.
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- Process for the preparation of enantiomerically pure 3-hydroxy-3-arylpropylamines and their optical stereoisomers
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The invention provides a process for the preparation of enantiomerically pure 3-hydroxy-3-arylpropylamines via novel semiester derivatives containing o-carboxy benzoyl group as intermediates. The 3-hydroxy-3-arylpropylamines serve as precursor for the preparation of serotonin or noradrenalin reuptake inhibitors such as duloxetine, atomoxetine, fluoxetine, nisoxetine and norfluoxetine.
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Page/Page column 10
(2009/06/27)
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- AN IMPROVED PROCESS FOR SYNTHESIZING HIGHLY PURE ATOMOXETINE
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The present invention relates to a process for the preparation of highly pure atomoxetine of formula (I) and pharmaceutically acceptable salts thereof Formula (I) The present invention also aims at novel processes for the preparation and purification of intermediates involved in the process of the present invention.
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Page/Page column 15
(2009/12/27)
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- Nucleophilic addition of phenol derivatives to methyl 1- nitrocyclopropanecarboxylates
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(Chemical Equation Presented) Nucleophilic ring opening of methyl 1-nitrocyclopropane-carboxylates by phenol derivatives in the presence of Cs2CO3 is described. The reaction tolerates a variety of substituents on both the aromatic alcohol and the cyclopropane and affords the products in good yields (53-84%) and with complete preservation of the enantiomeric excess at C-4. The methodology was applied in an enantioselective synthesis of the norepinephrine reuptake inhibitor atomoxetine (Strattera).
- Lifchits, Olga,Alberico, Dino,Zakharian, Irina,Charette, Andre B.
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p. 6838 - 6840
(2008/12/22)
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- PROCESS FOR PREPARING ATOMOXETINE HYDROCHLORIDE
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The present invention relates to the process for preparing Atomoxetine hydrochloride which is a selective norepinephrine reuptake inhibitor. Atomoxetine HCl is chemically known as (-)-iV-Methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride and represented by formula (I). More particularly, the invention relates to crystalline form of N-methyl-3-phenyl-3-(o- tolyloxy) propylamine oxalate (here in after referred as "(±) Atomoxetine Oxalate"), which is an useful intermediate for the synthesis of Atomoxetine hydrochloride.
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Page/Page column 19; 20
(2008/12/05)
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- 3-ARYLOXY-3-ARYLPROPYLAMINE SYNTHESIS
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A process for preparing a 3-aryloxy-3-arylpropylamine comprises reacting a 3-hydroxy-3-arylpropylamine with a substituted aryl compound, in a solvent comprising N-N-dimethylacetamide or hexamethylphosphorous triamide.
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Page/Page column `3
(2008/06/13)
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- Process for the preparation of atomoxetine hydrochloride
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The present invention provides improved processes for the preparation of atomoxetine hydrochloride under reaction conditions that improve reaction yields and facilitate commercial synthesis. In particular, the invention is directed to the synthesis of atomoxetine HCl by adding HCl to a mixture of (R)-(?)-tomoxetine (S)-(+)-mandelate with an organic solvent, with or without a base and water.
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Page/Page column 4
(2008/06/13)
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- Candida Rugosa lipase-catalyzed kinetic resolution of β-hydroxy- β-arylpropionates and δ-hydroxy-δ-aryl-β-oxo-pentanoates
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A simple and convenient method was reported for the preparation of optically active β-hydroxy-β-arylpropionates, δ-hydroxy-δ- aryl-β-oxo-pentanoates and their butyryl derivatives via CRL-catalyzed hydrolysis. The optically active products are potential precursors of some chiral pharmaceuticals and natural products.
- Xu, Chengfu,Yuan, Chengye
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p. 2169 - 2186
(2007/10/03)
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- Asymmetric reduction of prochiral ketones using in situ generated oxazaborolidine derived from (1S,2S,3R,4R)-3-amino-7,7-dimethoxynorbornan-2-ol. An efficient synthesis of enantiopure (R)-tomoxetine
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In this work, we report our results on the asymmetric reduction of prochiral aromatic and aliphatic ketones 3, 5-8 catalyzed by the novel in situ generated oxazaborolidine 2 derived from (1S,2S,3R,4R)-3-amino-7,7- dimethoxybornan-2-ol (1) and BH3?Me2S. This methodology was applied to the synthesis of the anti-depressant drug (R)-tomoxetine in three steps and 47% overall yield from 3-chloropropiophenone (3h). Catalytic asymmetric reduction of prochiral ketones was examined in the presence of chiral oxazaborolidine catalyst 2 prepared in situ from (1S,2S,3R,4R)-3-amino-7,7-dimethoxynorbornan-2-ol (1). The optically active secondary alcohols were generally obtained in moderate to high enantiomeric excesses (ee 43-95%) and good yields (75-94%), except for ketones bearing electron-withdrawing groups. The methodology was applied to the synthesis of enantiopure (R)-tomoxetine, a potent anti-depressant drug.
- Lapis, Alexandre A. M.,De Fátima, ?ngelo,Martins, José E. D.,Costa, Valentim E. U.,Pilli, Ronaldo A.
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p. 495 - 498
(2007/10/03)
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- Chemoenzymatic synthesis2 of both enantiomers of fluoxetine, tomoxetine and nisoxetine: Lipase-catalyzed resolution of 3-aryl-3-hydroxypropanenitriles
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A facile preparation of (±)-3-hydroxy-3-phenylpropanenitrile has been carried out by ring-opening of styrene oxide with NaCN in aqueous ethanol. Subsequent kinetic resolution of this material via lipase-mediated transesterification gave the S-alcohol and R-acetate in excellent yields and high enantioselectivities, particularly with lipase PS-C 'Amano' II. The effect of solvents and immobilization of the lipase has also been investigated. It is interesting to note that the use of immobilized lipase for this transesterification process in hydrophobic solvents (diisopropyl ether, toluene and hexane) enhanced the reaction rate drastically and gave optimal yields with high enantioselectivity (>99%). Moreover, enantiopure 3-hydroxy-3-phenylpropanenitrile products have been converted via enantioconvergent routes into the (R)- and (S)-enantiomers of the important anti-depressants fluoxetine, tomoxetine, nisoxetine and norfluoxetine.
- Kamal, Ahmed,Khanna,Ramu
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p. 2039 - 2051
(2007/10/03)
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- A stereospecific ruthenium-catalyzed allylic alkylation
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Good regioselectivity and chirality transfer for aryl-substituted allyl units is achieved in allylic alkylations with a wide range of nucleophiles by using the highly active ruthenium catalyst 1. This method provides a route to antidepressants such as (-)-fluoxetine from (S)-ephedrine (see scheme; Cp* = η5-C5Me5, TBAT = tetrabutylammonium triphenyldifluorosilicate).
- Trost, Barry M.,Fraisse, Pierre L.,Ball, Zachary T.
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p. 1059 - 1061
(2007/10/03)
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- Chemoenzymatic synthesis of the non-tricyclic antidepressants Fluoxetine, Tomoxetine and Nisoxetine
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3-Chloro-1-phenylpropan-1-ol and the corresponding butanoate, 3-chloro-1-phenyl-1-propyl butanoate, were kinetically resolved using lipase B from Candida antarctica catalysis by transesterification and hydrolysis respectively. The resulting chiral building blocks (S)- and (R)-3-chloro-1-phenylpropanol were converted into both enantiomers of the antidepressant drugs, Fluoxetine, Tomoxetine and Nisoxetine. The Royal Society of Chemistry 2000.
- Liu, Hui-Ling,Hoff, Bard Helge,Anthonsen, Thorleif
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p. 1767 - 1769
(2007/10/03)
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- An efficient route to enantiomerically pure antidepressants: Tomoxetine, nisoxetine and fluoxetine
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Both enantiomers (R)- and (S)-3-chloro-1-phenyl-1-propanol can be obtained conveniently by an efficient enzymatic resolution process. They can be converted via enantioconvergent routes into all enantiomers of the important antidepressants (R)- and (S)-Tomoxetine, Fluoxetine and Nisoxetine.
- Schneider,Goergens
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p. 525 - 528
(2007/10/02)
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- Iodinated tomoxetine derivatives as selective ligands for serotonin and norepinephrine uptake sites
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In order to develop selective radioactive ligands for the study of presynaptic monoamine uptake sites, iodinated derivatives of tomoxetine were synthesized and evaluated in radioligand binding assays. Iodotomoxetine derivatives showed high affinity for serotonin (5-HT) uptake sites using a rat cortical membrane preparation. Compound 1R, (R)-(-)-N-methyl-3-(4-iodo-2- methyl]phenoxy)-3-phenylpropanamine, was the most potent and showed high stereoselectivity for 5-HT uptake sites (K(i), R isomer = 0.65 nM, S isomer = 13.9 nM). Changing the position of the methyl group or eliminating the methyl group at the phenoxy ring resulted in a loss of stereoselectivity. Substitution of the methyl group of tomoxetine with iodine gave the R and S isomers of N-methyl-3-(2-iodophenoxy)-3-phenylpropanamine 4R and 4S. These compounds displayed stereoselectivity for the norepinephrine (NE) (K(i) values = 0.24 and 9.35 nM for R and S isomers, respectively). The in vitro binding data suggest that 1R and 4R are potential radioiodinated ligands for pharmacological studies of 5-HT and NE uptake sites, respectively.
- Chumpradit,Kung,Panyachotipun,Prapansiri,Foulon,Brooks,Szabo,Tejani-Butt,Frazer,Kung
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p. 4492 - 4497
(2007/10/02)
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- Asymmetric Synthesis of Both Enantiomers of Tomoxetine and Fluoxetine. Selective Reduction of 2,3-Epoxycinnamyl Alcohol with Red-Al.
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Both enantiomers of tomoxetine 7a,7b and fluoxetine 8a,8b (as their hydrochloride salts) have been synthetized from cinnamyl alkohol by asymmetric epoxidation, and their absolute configurations have been established.Optimal conditions for regioselective Red-Al reduction at C-2 of 2,3-epoxycinnamyl alcohol are discussed.
- Gao, Y.,Sharpless, K. B.
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p. 4081 - 4084
(2007/10/02)
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