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Truly-Biocompatible Gold Catalysis Enables Vivo-Orthogonal Intra-CNS Release of Anxiolytics
Being recognized as the best-tolerated of all metals, the catalytic potential of gold (Au) has thus far been hindered by the ubiquitous presence of thiols in organisms. Herein we report the development of a truly-catalytic Au-polymer composite by assembling ultrasmall Au-nanoparticles at the protein-repelling outer layer of a co-polymer scaffold via electrostatic loading. Illustrating the in vivo-compatibility of the novel catalysts, we show their capacity to uncage the anxiolytic agent fluoxetine at the central nervous system (CNS) of developing zebrafish, influencing their swim pattern. This bioorthogonal strategy has enabled -for the first time- modification of cognitive activity by releasing a neuroactive agent directly in the brain of an animal.
Adam, Catherine,Becker, Catherina G.,Hamilton, Lloyd,Ortega-Liebana, M. Carmen,Porter, Nicola J.,Sieger, Dirk,Unciti-Broceta, Asier,Valero, Teresa
supporting information

(2021/11/22)

Method for synthesizing chiral secondary alcohol compound
The invention discloses a method for synthesizing a chiral secondary alcohol compound. The method comprises the following step of: reacting a ketone compound in an aprotic organic solvent at room temperature and inert gas atmosphere under the action of a chiral cobalt catalyst and an activating agent by taking a combination of bis(pinacolato)diboron and alcohol or water as a reducing agent to obtain the chiral secondary alcohol compound. According to the method disclosed by the invention, a combination of pinacol diborate and alcohol or water which are cheap, stable and easy to obtain is taken as a reducing agent, and a ketone compound is efficiently reduced to synthesize a corresponding chiral secondary alcohol compound in an aprotic organic solvent under the action of a chiral cobalt catalyst; in a chiral cobalt catalyst adopted by the method, when a chiral ligand is PAOR, an activating agent is NaBHEt3 or NaOtBu and an adopted raw material is aromatic ketone, the yield is 80% or above, and the optical purity is 90% or above; and when the adopted raw material is alkane ketone, the yield can reach 70% or above, and the optical purity can reach 80% or above.
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Paragraph 0160-0166

(2021/05/29)

Tuning the activity of known drugs via the introduction of halogen atoms, a case study of SERT ligands – Fluoxetine and fluvoxamine
The selective serotonin reuptake inhibitors (SSRIs), acting at the serotonin transporter (SERT), are one of the most widely prescribed antidepressant medications. All five approved SSRIs possess either fluorine or chlorine atoms, and there is a limited number of reports describing their analogs with heavier halogens, i.e., bromine and iodine. To elucidate the role of halogen atoms in the binding of SSRIs to SERT, we designed a series of 22 fluoxetine and fluvoxamine analogs substituted with fluorine, chlorine, bromine, and iodine atoms, differently arranged on the phenyl ring. The obtained biological activity data, supported by a thorough in silico binding mode analysis, allowed the identification of two partners for halogen bond interactions: the backbone carbonyl oxygen atoms of E493 and T497. Additionally, compounds with heavier halogen atoms were found to bind with the SERT via a distinctly different binding mode, a result not presented elsewhere. The subsequent analysis of the prepared XSAR sets showed that E493 and T497 participated in the largest number of formed halogen bonds. The XSAR library analysis led to the synthesis of two of the most active compounds (3,4-diCl-fluoxetine 42, SERT Ki = 5 nM and 3,4-diCl-fluvoxamine 46, SERT Ki = 9 nM, fluoxetine SERT Ki = 31 nM, fluvoxamine SERT Ki = 458 nM). We present an example of the successful use of a rational methodology to analyze binding and design more active compounds by halogen atom introduction. ‘XSAR library analysis’, a new tool in medicinal chemistry, was instrumental in identifying optimal halogen atom substitution.
Bojarski, Andrzej J.,Bugno, Ryszard,Duszyńska, Beata,Hogendorf, Adam S.,Hogendorf, Agata,Kurczab, Rafa?,Lenda, Tomasz,Pietru?, Wojciech,Sata?a, Grzegorz,Staroń, Jakub,Wantuch, Anna,Warszycki, Dawid
supporting information

(2021/06/02)

Enantioselective Heck Arylation of Acyclic Alkenol Aryl Ethers: Synthetic Applications and DFT Investigation of the Stereoselectivity
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
supporting information
p. 884 - 892
(2019/12/30)

Systems and methods for synthesizing chemical products, including active pharmaceutical ingredients
Systems and methods for synthesizing chemical products, including active pharmaceutical ingredients, are provided. Certain of the systems and methods described herein are capable of manufacturing multiple chemical products without the need to fluidically connect or disconnect unit operations when switching from one making chemical product to making another chemical product.
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Page/Page column 37-39

(2020/12/14)

Copper-catalyzed and additive free decarboxylative trifluoromethylation of aromatic and heteroaromatic iodides
A copper-catalyzed decarboxylative trifluoromethylation of (hetero)aromatic iodides has been developed. Importantly, this new copper-catalyzed reaction operates in the absence of any ligands and metal additives. The protocol shows good functional group tolerance and is compatible with heteroaromatic systems. The reaction proved scalable to a 15 mmol scale with increased yield. Finally, late-stage installation of the trifluoromethyl functionality afforded the N-trifluoroacetamide variant of the antidepressant agent, Prozac, demonstrating the applicability of the developed method.
Johansen, Martin B.,Lindhardt, Anders T.
p. 1417 - 1425
(2020/03/03)

Enantioseparation of chiral pharmaceuticals by vancomycin-bonded stationary phase and analysis of chiral recognition mechanism
The drug chirality is attracting increasing attention because of different biological activities, metabolic pathways, and toxicities of chiral enantiomers. The chiral separation has been a great challenge. Optimized high-performance liquid chromatography (HPLC) methods based on vancomycin chiral stationary phase (CSP) were developed for the enantioseparation of propranolol, atenolol, metoprolol, venlafaxine, fluoxetine, and amlodipine. The retention and enantioseparation properties of these analytes were investigated in the variety of mobile phase additives, flow rate, and column temperature. As a result, the optimal chromatographic condition was achieved using methanol as a main mobile phase with triethylamine (TEA) and glacial acetic acid (HOAc) added as modifiers in a volume ratio of 0.01% at a flow rate of 0.3?mL/minute and at a column temperature of 5°C. The thermodynamic parameters (eg, ΔH, ΔΔH, and ΔΔS) from linear van 't Hoff plots revealed that the retention of investigated pharmaceuticals on vancomycin CSP was an exothermic process. The nonlinear behavior of lnk′ against 1/T for propranolol, atenolol, and metoprolol suggested the presence of multiple binding mechanisms for these analytes on CSP with variation of temperature. The simulated interaction processes between vancomycin and pharmaceutical enantiomers using molecular docking technique and binding energy calculations indicated that the calculated magnitudes of steady combination energy (ΔG) coincided with experimental elution order for most of these enantiomers.
Li, Jiaxi,Liu, Ruixia,Wang, Liyang,Liu, Xiaoling,Gao, Hongjie
p. 236 - 247
(2019/02/01)

Simultaneous enantioselective determination of seven psychoactive drugs enantiomers in multi-specie animal tissues with chiral liquid chromatography coupled with tandem mass spectrometry
In stock farming, illegal use of antipsychotics has caused the food safety problem. This paper presents for the first time, a multi-residues method for the simultaneous enantioselective determination of seven antipsychotics in pork, beef and lamb muscles. The behaviors of Chiralpak AGP toward changes in pH and organic modifier in mobile phase were studied, and all analytes were rapidly separated within 30 min. The calibration curves of all enantiomers were linear in the range of 1–250 ng g?1, with correlation coefficient above 0.9931. The recoveries of the targeted compounds were higher than 82.1%, with repeatability and intermediate precision lower than 18.2% and 17.4%, respectively. In three matrices, the limit of detection and limit of quantification ranged from 0.20 to 0.65 ng g?1 and from 0.40 to 1.00 ng g?1, respectively. The proposed method can be used to provide additional information for the reliable risk assessment of chiral antipsychotics.
Zhu,Li, Shuang,Zhou, Li,Li, Qing,Guo, Xingjie
(2019/07/31)

Evaluation of the Edman degradation product of vancomycin bonded to core-shell particles as a new HPLC chiral stationary phase
A modified macrocyclic glycopeptide-based chiral stationary phase (CSP), prepared via Edman degradation of vancomycin, was evaluated as a chiral selector for the first time. Its applicability was compared with other macrocyclic glycopeptide-based CSPs: TeicoShell and VancoShell. In addition, another modified macrocyclic glycopeptide-based CSP, NicoShell, was further examined. Initial evaluation was focused on the complementary behavior with these glycopeptides. A screening procedure was used based on previous work for the enantiomeric separation of 50 chiral compounds including amino acids, pesticides, stimulants, and a variety of pharmaceuticals. Fast and efficient chiral separations resulted by using superficially porous (core-shell) particle supports. Overall, the vancomycin Edman degradation product (EDP) resembled TeicoShell with high enantioselectivity for acidic compounds in the polar ionic mode. The simultaneous enantiomeric separation of 5 racemic profens using liquid chromatography-mass spectrometry with EDP was performed in approximately 3?minutes. Other highlights include simultaneous liquid chromatography separations of rac-amphetamine and rac-methamphetamine with VancoShell, rac-pseudoephedrine and rac-ephedrine with NicoShell, and rac-dichlorprop and rac-haloxyfop with TeicoShell.
Hellinghausen, Garrett,Lopez, Diego A.,Lee, Jauh T.,Wang, Yadi,Weatherly, Choyce A.,Portillo, Abiud E.,Berthod, Alain,Armstrong, Daniel W.
p. 1067 - 1078
(2018/08/01)

Determination of fluoxetine hydrochloride via ion-pair complexation with alizarin red S
Two UV-Vis spectrophotometric methods and one fluorimetric method have been developed for the quantitative determination of fluoxetine hydrochloride in bulk and pharmaceutical formulations. These methods are based on the ion-pair complex formation between alizarin red S and fluoxetine hydrochloride. In the first method (method A), the yellow-colored complex obtained in acidic medium was extracted with chloroform and the absorbance of the chloroformic solution was measured at 425 nm. Beerís law limits (9.5 ? 48 μg/mL), the molar absorptivity (5256 L ∑ mol-1 ∑ cm-1), and the complex composition (1: 1) were determined. In the second method (method B), the yellow complex fluoxetine ? alizarin red S extracted in chloroform was broken in alkaline medium, and the absorbance of the resulting violet-colored free dye was measured at 524 nm. A linear relationship was observed in the range of 9.0 ? 54 μg/mL. In the third method (method C) the fluorescence intensity of the fluoxetine ? alizarin red S complex, obtained in the same manner as for method A, was measured at 594 nm after excitation at 425 nm. The fluorescence intensity was proportional to the drug concentration in the linear range of 2.7-10.2 μg/mL. The limits of detection and quantification have also been calculated. Furthermore, the proposed methods have been successfully applied for the assay of the drug in pharmaceutical dosage forms.
Constantinescu, Ioana Clementina,Neagu, Alexandra Filareta,Uivarosi, Valentina
p. 1293 - 1303
(2019/01/04)

Chiral resolution of the method for preparing single configuration fluoxetine
The invention discloses a method for preparing single-configuration fluoxetine through chiral resolution, and belongs to the technical field of medicinal chemistry. According to the method, chirality mandelic acid and analog of the chirality mandelic acid are used as resolving agents, micromolecule aldehyde or ketone compounds are used as additives, racemic fluoxetine is resolved through the resolving agents and the additives, the single-configuration fluoxetine is integrally prepared through conversion and resolving in the preparation process, the e.e. value (enantiomeric excess) of the prepared single-configuration fluoxetine is larger than 99%, and the yield of the prepared single-configuration fluoxetine is larger than 85%. The preparation method is simple, low in cost, efficient, capable of being circulated many times and suitable for industrial production.
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Paragraph 0045-0046

(2017/08/25)

Fe(OTf)3-catalyzed tandem Meyer-Schuster rearrangement/intermolecular hydroamination of 3-aryl propargyl alcohols for the synthesis of acyclic β-Aminoketones
Fe(OTf)3-catalyzed synthesis of acyclic β-aminoketones from 3-aryl propargyl alcohols and nitrogen nucleophiles were investigated. Results showed that propargyl alcohols without bulky groups α to the hydroxyl group underwent the transformation smoothly. Sulphonamides exhibited the higher reactivity than amides as the nitrogen nucleophiles and the transformation of acyclic β-aminoketones were finished in shorter reaction time and higher yields. Finally, racemic fluoxetine was efficiently accessed with the present reaction as the first step. This novel synthesis of acyclic β-aminoketones probable proceeded a Fe(OTf)3-catalyzed Meyer-Schuster rearrangement of 3-aryl propargyl alcohols, followed by a intermolecular hydroamination between nitrogen nucleophiles and α, β-unsaturated ketones.
Tao, Ruiheng,Yin, Yan,Duan, Yongbin,Sun, Yuxing,Sun, Yue,Cheng, Fengkai,Pan, Jinpeng,Lu, Cheng,Wang, Yuan
p. 1762 - 1768
(2017/03/08)

A model target anti-tumor medicament and its preparation method and application (by machine translation)
This invention relates to the targeting of antineoplastic eEF2K of a small molecule inhibitor, its formula (I), formula (II) the structure of the formula (III): Formula (I), formula (II) compound of the formula (III) structure and its pharmaceutically acceptable salt thereof can kill cancer cells, the healthy organism cells are not affected, to various tumor is markedly inhibited, in particular breast cancer, glioma, stomach cancer, liver cancer cells is markedly inhibited. (by machine translation)
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(2016/10/10)

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
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 0198; 0199

(2016/11/09)

Total synthesis of fluoxetine and duloxetine through an in situ imine formation/borylation/transimination and reduction approach
We report efficient, catalytic, asymmetric total syntheses of both (R)-fluoxetine and (S)-duloxetine from α,β-unsaturated aldehydes conducting five sequential one-pot steps (imine formation/copper mediated β-borylation/transimination/reduction/oxidation) followed by the specific ether group formation which deliver the desired products (R)-fluoxetine in 45% yield (96% ee) and (S)-duloxetine in 47% yield (94% ee). This journal is the Partner Organisations 2014.
Calow, Adam D. J.,Fernandez, Elena,Whiting, Andrew
p. 6121 - 6127
(2014/08/05)

Copper(ii)-catalyzed enantioselective hydrosilylation of halo-substituted alkyl aryl and heteroaryl ketones: Asymmetric synthesis of (R)-fluoxetine and (S)-duloxetine
A set of reaction conditions has been established to facilitate the non-precious copper-catalyzed enantioselective hydrosilylation of a number of structurally diverse β-, γ- or ε-halo-substituted alkyl aryl ketones and α-, β- or γ-halo-substituted alkyl heteroaryl ketones under air to afford a broad spectrum of halo alcohols in high yields and good to excellent enantioselectivities (up to 99% ee). The developed procedure has been successfully applied to the asymmetric synthesis of antidepressant drugs (R)-fluoxetine and (S)-duloxetine, which highlighted its synthetic utility.
Zhou, Ji-Ning,Fang, Qiang,Hu, Yi-Hu,Yang, Li-Yao,Wu, Fei-Fei,Xie, Lin-Jie,Wu, Jing,Li, Shijun
p. 1009 - 1017
(2014/02/14)

From precursor to catalyst: The involvement of [Ru(η5-Cp?)Cl2]2 in highly branch selective allylic etherification of cinnamyl chlorides
(RuCp?Cl2)2, a general entry into Cp?Ru sandwich and half-sandwich chemistry was first used as a precatalyst in allylic etherification of cinnamyl chlorides with up to 98:2 regioselectivity (19 examples). Both the solvent effect and the exsiccant reaction condition are crucial to the reactivity and selectivity. Preliminary mechanism studies and the demonstration of Fluoxetine synthesis were presented in this work as well.
Siddappa, Ravi Kumara Guralamatta,Chang, Chih-Wei,Chein, Rong-Jie
p. 1031 - 1035
(2015/02/19)

Molecular basis for selective serotonin reuptake inhibition by the antidepressant agent fluoxetine (Prozac)
Inhibitors of the serotonin transporter (SERT) are widely used antidepressant agents, but the structural mechanism for inhibitory activity and selectivity over the closely related norepinephrine transporter (NET) is not well understood. Here we use a combination of chemical, biological, and computational methods to decipher the molecular basis for high-affinity recognition in SERT and selectivity over NET for the prototypical antidepressant drug fluoxetine (Prozac; Eli Lilly, Indianapolis, IN). We show that fluoxetine binds within the central substrate site of human SERT, in agreement with recent X-ray crystal structures of LeuBAT, an engineered monoamine-like version of the bacterial amino acid transporter LeuT. However, the binding orientation of fluoxetine is reversed in our experimentally supported model comparedwith the LeuBAT structures, emphasizing the need for careful experimental verification when extrapolating findings from crystal structures of bacterial transporters to human relatives. We find that the selectivity of fluoxetine and nisoxetine, a NET selective structural congener of fluoxetine, is controlled by residues in different regions of the transporters, indicating a complex mechanism for selective recognition of structurally similar compounds in SERT and NET. Our findings add important new information on the molecular basis for SERT/NET selectivity of antidepressants, and provide the first assessment of the potential of LeuBAT as a model system for antidepressant binding in human transporters, which is essential for future structure-based drug development of antidepressant drugs with fine-tuned transporter selectivity. Copyright
Andersen, Jacob,Stuhr-Hansen, Nicolai,Zachariassen, Linda Gronborg,Koldso, Heidi,Schiott, Birgit,Stromgaard, Kristian,Kristensen, Anders S.
p. 703 - 714
(2014/04/17)

Room temperature, metal-free arylation of aliphatic alcohols
Diaryliodonium salts are demonstrated as efficient arylating agents of aliphatic alcohols under metal-free conditions. The reaction proceeds at room temperature within 90 min to give alkyl aryl ethers in good to excellent yields. Aryl groups with electron
Ghosh, Raju,Lindstedt, Erik,Jalalian, Nazli,Olofsson, Berit
p. 54 - 57
(2014/05/06)

From precursor to catalyst: The involvement of [Ru(η5- Cp*)Cl2]2 in highly branch selective allylic etherification of cinnamyl chlorides
(RuCp*Cl2)2, a general entry into Cp*Ru sandwich and half-sandwich chemistry was first used as a precatalyst in allylic etherification of cinnamyl chlorides with up to 98:2 regioselectivity (19 examples). Both the solvent effect and the exsiccant reaction condition are crucial to the reactivity and selectivity. Preliminary mechanism studies and the demonstration of Fluoxetine synthesis were presented in this work as well.
Siddappa, Ravi Kumara Guralamatta,Chang, Chih-Wei,Chein, Rong-Jie
supporting information
p. 1031 - 1035
(2014/02/14)

Influence of gasoline inhalation on the enantioselective pharmacokinetics of fluoxetine in rats
Fluoxetine is used clinically as a racemic mixture of (+)-(S) and (-)-(R) enantiomers for the treatment of depression. CYP2D6 catalyzes the metabolism of both fluoxetine enantiomers. We aimed to evaluate whether exposure to gasoline results in CYP2D inhibition. Male Wistar rats exposed to filtered air (n = 36; control group) or to 600 ppm of gasoline (n = 36) in a nose-only inhalation exposure chamber for 6 weeks (6 h/day, 5 days/week) received a single oral 10-mg/kg dose of racemic fluoxetine. Fluoxetine enantiomers in plasma samples were analyzed by a validated analytical method using LC-MS/MS. The separation of fluoxetine enantiomers was performed in a Chirobiotic V column using as the mobile phase a mixture of ethanol:ammonium acetate 15 mM. Higher plasma concentrations of the (+)-(S)-fluoxetine enantiomer were found in the control group (enantiomeric ratio AUC(+)-(S)/(-)-(R) = 1.68). In animals exposed to gasoline, we observed an increase in AUC0-??? for both enantiomers, with a sharper increase seen for the (-)-(R)-fluoxetine enantiomer (enantiomeric ratio AUC(+)-(S)/(-)-(R) = 1.07), resulting in a loss of enantioselectivity. Exposure to gasoline was found to result in the loss of enantioselectivity of fluoxetine, with the predominant reduction occurring in the clearance of the (-)-(R)-fluoxetine enantiomer (55% vs. 30%). Chirality 25:206-210, 2013. 2013 Wiley Periodicals, Inc. Copyright
Cardoso, Juciane Lauren Cavalcanti,Lanchote, Vera Lucia,Pereira, Maria Paula Marques,Capela, Jorge Manuel Vieira,Lepera, José Salvador
p. 206 - 210
(2013/08/25)

Chemoenzymatic asymmetric synthesis of fluoxetine, atomoxetine, nisoxetine, and duloxetine
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
p. 913 - 918
(2013/09/23)

Reversal of selectivity in acetate aldol reactions of N-acetyl-(S)-4- isopropyl-1-[(R)-1-phenylethyl]imidazolidin-2-one
Synergistic effects of the exo- and endocyclic chiral centers of an imidazolidinone-based auxiliary were investigated in the perspective of acetate aldol reactions. The reversal in diastereoselectivity was accomplished by lithium and titanium enolate reactions, which proceed through proposed open and closed transitions states, respectively. The aldol adducts were used in the stereoselective synthesis of fluoxetine.
Khatik, Gopal L.,Kumar, Varun,Nair, Vipin A.
p. 2442 - 2445
(2012/07/03)

NO-SSRIs: Nitric oxide chimera drugs incorporating a selective serotonin reuptake inhibitor
Hybrid nitrate drugs have been reported to provide NO bioactivity to ameliorate side effects or to provide ancillary therapeutic activity. Hybrid nitrate selective serotonin reuptake inhibitors (NO-SSRIs) were prepared to improve the therapeutic profile of this drug class. A synthetic strategy for use of a thiocarbamate linker was developed, which in the case of NO-fluoxetine facilitated hydrolysis to fluoxetine at pH 7.4 within 7 h. In cell culture, NO-SSRIs were weak inhibitors of the serotonin transporter; however, in the forced swimming task (FST) in rats, NO-fluoxetine demonstrated classical antidepressant activity. Comparison of NO-fluoxetine, with fluoxetine, and an NO-chimera nitrate developed for Alzheimer's disease (GT-1061) were made in the step through passive avoidance (STPA) test of learning and memory in rats treated with scopolamine as an amnesic agent. Fluoxetine was inactive, whereas NO-fluoxetine and GT-1061 both restored long-term memory. GT-1061 also produced antidepressant behavior in FST. These data support the potential for NO-SSRIs to overcome the lag in onset of therapeutic action and provide cotherapy of neuropathologies concomitant with depression.
Abdul-Hay, Samer,Schiefer, Isaac T.,Chandrasena, R. Esala P.,Li, Min,Abdelhamid, Ramy,Wang, Yue-Ting,Tavassoli, Ehsan,Michalsen, Bradley,Asghodom, Rezene T.,Luo, Jia,Thatcher, Gregory R. J.
p. 656 - 661
(2011/11/07)

Preparation of fluoxetine by multiple flow processing steps
Microflow technology is established as a modern and fashionable tool in synthetic organic chemistry, bringing great improvement and potential, on account of a series of advantages over flask methods. The study presented here focuses on the application of flow chemistry process in performing an efficient multiple step syntheses of (±)-fluoxetine as an alternative to conventional synthetic methods, and one of the few examples of total synthesis accomplished by flow technique.
Ahmed-Omer, Batoul,Sanderson, Adam J.
p. 3854 - 3862
(2011/06/23)

Direct catalytic asymmetric aldol reaction of thioamides: A concise asymmetric synthesis of (R)-fluoxetine
A direct catalytic asymmetric aldol reaction of aromatic aldehydes and thioamides is described. A soft Lewis acid/hard Bronsted base cooperative catalyst comprising (R,R)-Ph-BPE/[Cu(CH3CN)4]PF 6/Li(OC6H4-p-OMe) promoted the title reaction efficiently, triggered by in situ generation of the active thioamide enolate through a soft-soft interaction of Cu(I) and the thioamide. The aldol product was transformed into (R)-fluoxetine, an antidepressant agent.
Iwata, Mitsutaka,Yazaki, Ryo,Kumagai, Naoya,Shibasaki, Masakatsu
experimental part
p. 1688 - 1694
(2010/10/19)

METHOD FOR THE PREPARATION OF N-METHYL-ARYLOXY-PROPANAMINE DERIVATIVES
The present invention is related to a method for the preparation of N-methyl-aryloxy-propanamine derivatives, which comprises reacting a suitable uretane derivative of the Formula (XXIV) with a Grignard reagent.
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Page/Page column 35-36

(2010/04/03)

Novel synthetic route to fluoxetine
Racemic fluoxetine was synthesized from 3-benzoylpropionic acid in five steps in 54% overall yield. Copyright
Schulze, Matthias
experimental part
p. 3415 - 3422
(2011/01/12)

Chimeric Nitrate Esters and Use of the Same in a Treatment for Depression
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 20

(2009/07/25)

Enantioselective hydrogenation of β-ketoesters using a MeO-PEG-supported Biphep ligand under atmospheric pressure: A practical synthesis of (S)-fluoxetine
The preparation of a novel chiral 2,2′-bis(MeO-PEG-supported)-6, 6′-bis(diphenylphosphanyl)biphenyl (MeO-PEG-Biphep) ligand is described. The derived ruthenium complex catalyzes the hydrogenation of β-ketoesters in up to 99% yield and 99% ee under atmospheric pressure. The accelerating effects exerted by the PEG linkage are dramatic when compared to the unsupported analogue, MeO-Biphep-RuBr2. Furthermore, the catalyst can be recovered easily and the recycled catalysts were shown to maintain their efficiency in two consecutive runs, albeit with declining activity. One of the products, (S)-ethyl-3-hydroxy-3-phenylpropanoate, is useful in the preparation of (S)-fluoxetine. Georg Thieme Verlag Stuttgart.
Chai, Liting,Chen, Huansheng,Li, Zhiming,Wang, Quanrui,Tao, Fenggang
p. 2395 - 2398
(2008/02/09)

Candida Rugosa lipase-catalyzed kinetic resolution of β-hydroxy- β-arylpropionates and δ-hydroxy-δ-aryl-β-oxo-pentanoates
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
p. 2169 - 2186
(2007/10/03)

Polymer-supported chiral sulfonamide catalyzed one-pot reduction of β-keto nitriles: A practical synthesis of (R)-fluoxetine and (R)-duloxetine
Enantioselective reduction of β-keto nitriles to optically active 1,3-amino alcohols has been carried out in one step using an excess of borane-dimethyl sulfide complex as a reductant and a polymer-supported chiral sulfonamide as a catalyst with moderate to high enantioselectivity. The facile and enantioselective method to prepare optically active 1,3-amino alcohols to be converted into 3-aryloxy-3-arylpropylamine-type antidepressant drugs (R)-fluoxetine, and (R)-duloxetine is also reported.
Wang, Guangyin,Liu, Xingshun,Zhao, Gang
p. 1873 - 1879
(2007/10/03)

Substituted propanolamines and alkylamines derived from fluoxetine as potent appetite suppressants
A series of propanolamine and alkylamine analogues of fluoxetine (7-26, 28-31) were synthesized and assessed for their anorexigenic and antidepressant activities. Effect of various substituents at C-4 aryl position of fluoxetine has also been studied. Most of the propanolamine analogues (7-13, 16-26) displayed significant anorexigenic activity but interestingly they were devoid of antidepressant activity whereas anorexigenic as well as antidepressant activity was retained in the alkylamine series (28-31). Compounds 10 and 26 emerged as the most active compound and anorexigenic activity was better (83.67% and 82.45%) compared to fluoxetine (81.25%).
Bhandari, Kalpana,Srivastava, Shipra,Shanker, Girija,Nath, Chandishwar
p. 1739 - 1747
(2007/10/03)

Asymmetric dihydroxylation route to (R)-isoprenaline, (R)-norfluoxetine and (R)-fluoxetine
An efficient asymmetric synthesis of enantiomerically pure (R)-isoprenaline, (R)-norfluoxetine and (R)-fluoxetine is described using Sharpless asymmetric dihydroxylation as the key step.
Kumar, Pradeep,Upadhyay, Rajesh Kumar,Pandey, Rajesh Kumar
p. 3955 - 3959
(2007/10/03)

Pulmonary delivery for bioconjugation
Methods of and compositions for pulmonary delivery of therapeutic agents which are capable of forming covalent bonds with a site of interest or which have formed a covalent bond with a pulmonary solution protein are disclosed. Therapeutic agents useful in the invention include wound healing agents, antibiotics, anti-inflammatories, anti-oxidants, anti-proliferatives, immunosupressants, anti-infective and anti-cancer agents.
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(2008/06/13)

Synthesis of 3-aminomethyl-1-propanol, a fluoxetine precursor
The present invention concerns a method of synthesizing fluoxetine hydrochloride. The method includes the synthesis of 3-methylamino-1-phenyl-1-propanol by reduction of 1-phenyl-3-methylamino-1-propen-1-one with sodium borohydride and acetic acid.
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Page 4

(2010/02/07)

Anti-proliferative drugs
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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(2008/06/13)

Methods and compounds for treating depression and other disorders
The present invention features compounds active at both the serotonin reuptake site and the N-methyl-D-aspartate (NMDA) receptor and the use of such compounds for treating different disorders. Compounds having activity at the serotonin reuptake site and the NMDA receptor (“multi-active compounds”) can be used to treat different types of disorders such as depression, obsessive-compulsive disorders (OCD), sleep, disorders, sexual dysfunction, and eating disorders. Preferably, the multi-active compounds are used to treat depression.
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(2008/06/13)

Synthesis, anorexigenic activity and QSAR of substituted aryloxypropanolamines
Substituted aryloxypropanolamines (6-20) were synthesized and evaluated for their anorexigenic activity. Among them 4-cyanoaryloxy (7), 2-methylaryloxy (9), 2-methoxyl aryloxy (10), 4-acetamidoaryloxy (15), 4-bromoaryloxy (16) and 4-ethylaminoaryloxy (20) exhibited potent anorexigenic activity. According to QSAR studies, the electronic parameter 'σ' plays an important role in describing the variance in activity. Birkhaeuser Boston 2004.
Srivastava, Shipra,Bhandari, Kalpana,Shankar, Girija,Singh,Saxena, Anil K.
p. 631 - 642
(2007/10/03)

Enantioselective Hydrogenation of β-Keto Esters using Chiral Diphosphine-Ruthenium Complexes: Optimization for Academic and Industrial Purposes and Synthetic Applications
Enantioselective hydrogenation using chiral complexes between atropisomeric diphosphines and ruthenium is a powerful tool for producing chiral compounds. Using a simple and straightforward in situ catalyst preparation, the conditions were optimized using molecular hydrogen for both academic and industrial purposes. This led to the best conditions and the lowest catalytic ratio required for the pressure used. Hydrogenation of various β-keto esters was efficiently performed at atmospheric and higher pressures, leading to the use of very low catalyst-substrate ratios up to 1/20,000. Asymmetric hydrogenations were used in key-steps towards the total synthesis of corynomycolic acid, Duloxetine and Fluoxetine.
Ratovelomanana-Vidal,Girard,Touati,Tranchier,Ben Hassine,Genet
p. 261 - 274
(2007/10/03)

Method and pharmaceutical composition for the treatment of cancer
A method of chemosensitization which comprises administering at least one chemotherapeutic agent and at least one 3-aryloxy-3-phenylpropylamine to a subject in need thereof.
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(2008/06/13)

Pure S(+)isomer fluoxetine
Methods and compositions are disclosed utilizing the pure S(+) isomer of fluoxetine which is a potent antidepressant and appetite suppressant substantially free of unwanted, adverse toxic or psychological effects, for the treatment of human depression. In addition, methods and compositions are disclosed utilizing the pure S(+) isomer of fluoxetine which is useful in treating migraine headaches, pain, in particular chronic pain, and obsessive-compulsive disorders. Further, methods and compositions for treating a condition alleviated or improved by inhibition of serotonin uptake in serotonergic neurons and platelets in a human using optically pure S(+) fluoxetine are disclosed.
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(2008/06/13)

An asymmetric dihydroxylation route to enantiomerically pure norfluoxetine and fluoxetine
An efficient, practical asymmetric synthesis of (R)-norfluoxetine 1 and (R)-fluoxetine 2 has been achieved. The synthetic strategy features a Sharpless asymmetric dihydroxylation (SAD) route to the common building block 1,3-amino alcohol 9, from which (R)-norfluoxetine, (R)-fluoxetine and other related analogs can be synthesized.
Pandey, Rajesh Kumar,Fernandes, Rodney A.,Kumar, Pradeep
p. 4425 - 4426
(2007/10/03)

A stereospecific ruthenium-catalyzed allylic alkylation
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.
p. 1059 - 1061
(2007/10/03)

Chemoenzymatic synthesis2 of both enantiomers of fluoxetine, tomoxetine and nisoxetine: Lipase-catalyzed resolution of 3-aryl-3-hydroxypropanenitriles
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
p. 2039 - 2051
(2007/10/03)

Enantioselective synthesis of (S)- and (R)-fluoxetine hydrochloride
The enantioselective synthesis of fluoxetine hydrochloride, a potent serotonin-uptake inhibitor, is described. The synthesis of (S)-fluoxetine hydrochloride begins with the asymmetric carbonyl-ene reaction of benzaldehyde with 3-methylene-2,3-dihydrofuran (1) catalyzed by Ti[OCH(CH3)2]4/(S)-BINOL to give (S)-2-(3-furyl)-1-phenyl-1-ethanol (2) in 90% yield and 95% ee. In five steps, alcohol 2 was converted into (S)-fluoxetine hydrochloride (97% ee and 56% overall yield from benzaldehyde). (R)-fluoxetine hydrochloride was prepared by the same sequence except that Ti[OCH(CH3)2]4/(R)-BINOL was used in the first reaction to give the enantiomer of 2.
Miles, William H,Fialcowitz, Elizabeth J,Scott Halstead
p. 9925 - 9929
(2007/10/03)

A practical asymmetric synthesis of (R)-fluoxetine and its major metabolite (R)-norfluoxetine
A convenient and chromatography-free synthesis for the enantiomers of fluoxetine and norfluoxetine is described. The synthesis relied on the use of the CBS reduction, and Hofman rearrangement to establish the key common intermediate 5, and enrichment of optical purity of the final product by crystallization as the tartrate salt.
Hilborn, James W.,Lu, Zhi-Hui,Jurgens, Alex R.,Fang,Byers, Paul,Wald, Stephen A.,Senanayake, Chris H.
p. 8919 - 8921
(2007/10/03)

Chemoenzymatic synthesis of the non-tricyclic antidepressants Fluoxetine, Tomoxetine and Nisoxetine
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
p. 1767 - 1769
(2007/10/03)

Fluoxetine process from benzoylacetonitrile
A synthesis of fluoxetine is disclosed. The process begins with benzoylacetonitrile, which is reduced, optionally in the presence of a chiral ligand, to produce the corresponding aminoalcohol, and the amine is carbamoylated without isolation. The alcohol is deprotonated and reacted with 4-chloro- or 4-fluoro benzotrifluoride or with 4-trifluoromethylphenol to provide a carbamate of fluoxetine. The carbamate is reduced with a hydride or with borane to provide fluoxetine free base. The process may be employed for the synthesis of individual enantiomers of fluoxetine.
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(2008/06/13)

Preparation and uses of hydrocarbylnitrones
Nitrones are produced by reaction of primary amine with aldehyde or ketone, in the presence of a transition metal-containing oxidation catalyst, and a peroxidic compound. The nitrone can then be reacted with a vinylaromatic compound to produce a 2-hydrocarbyl-5-arylisoxazolidine. Both such reactions can be conducted concurrently by including the vinylaromatic compound in the initial reaction mixture. Hydrogenation of the 2-hydrocarbyl-5-arylisoxazolidine, e.g., using hydrogen and a palladium-carbon catalyst, forms an N-hydrocarbyl-3-aryl-3-hydroxypropylamine. Such reactions enable, inter alia, synthesis of the racemic hydrochloride salt of N-methyl-3-phenyl-3-[4-trifluoromethyl)phenoxy]-propylamine, known generically as fluoxetine hydrochloride, a widely used antidepressant.
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(2008/06/13)