- A Michael Addition-Asymmetric Transfer Hydrogenation One-Pot Enantioselective Tandem Process for Syntheses of Chiral γ-Secondary Amino Alcohols
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An aza-Michael addition-asymmetric transfer hydrogenation tandem process for preparation of chiral γ-secondary amino alcohols has been developed. This one-pot tandem process involves an aza-Michael addition of aryl-substituted enones and amines to form aryl-substituted γ-secondary amino ketones, followed by a Ru-catalyzed asymmetric transfer hydrogenation to form aryl-substituted γ-secondary amino alcohols. An advantageous feature of this tandem reaction is that it provides various γ-secondary amino alcohols in high yields with high enantioselectivities.
- Wu, Liang,Jin, Ronghua,Li, Liang,Hu, Xiaoying,Cheng, Tanyu,Liu, Guohua
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Read Online
- Method for synthesizing chiral secondary alcohol compound
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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 0038-0043; 0114-0117
(2021/05/29)
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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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Paragraph 0013
(2020/06/09)
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- A site isolation-enabled organocatalytic approach to enantiopure γ-amino alcohol drugs
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Solid support-enabled site isolation has previously allowed to use paraldehyde as an acetaldehyde surrogate in aldol reactions. However, only electron-poor aldehydes were tolerated by the system. Herein, we show that the temporary conversion of benzaldehyde into η6-benzaldehyde Cr(CO)3 circumvents this limitation. Asymmetric synthesis of (R)-Phenoperidine, as well as formal syntheses of (R)-Fluoxetine and (R)-Atomoxetine, illustrate the benefits of this strategy.
- Wang, Shoulei,Rodríguez-Escrich, Carles,Fan, Xinyuan,Pericàs, Miquel A.
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supporting information
p. 3943 - 3946
(2018/04/20)
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- Method for preparation of optically active 3-amino-arylpropan-1-ol derivatives from 3-chloro-1-arylpropan-1-ol derivatives
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The present invention relates to a method for preparing an optically active 3-amino-1-arylpropan-1-ol derivative, including the step of making an optically active 3-chloro-1-arylpropan-1-ol compound react with an amine derivative. The method according to the present invention allows direct amination of an optically active 3-chloro-1-arylpropan-1-ol derivative through a single-step reaction. Thus, it is possible to provide a compound functioning as a key intermediate of various optically active molecules through a simple process with high yield, while maintaining the optical purity of the reactant. Therefore, the method may be used for preparing medicines, such as (S)-Duloxetin, (R)-Fluoxetine, (R)- Tomoxetine or (R)- Nisoxetine, with high optical purity by combining the method for preparing an optically active 3-chloro-1-arylpropan-1-ol derivative as a reactant of the method with an additional substitution reaction.(AA) Tomoxetine(BB) Fluoxetine(CC) 3-amino-1-propanol(DD) Nisoxetine(EE) DuloxetineCOPYRIGHT KIPO 2016
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Paragraph 0103-0105
(2016/12/01)
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- Method for preparing atomoxetine hydrochloride
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The invention belongs to the technical field of medicines, and particularly relates to a method for preparing atomoxetine hydrochloride which is a medicine for treating attention deficit hyperactivity disorder. The atomoxetine hydrochloride is made of commercially easily available intermediates 3-methylamino-1-propiophenone hydrochloride. The method includes carrying out reduction, salt decomposition, resolving, substitution and salt forming to obtain the atomoxetine hydrochloride. The method has the advantages that technologies for preparing the atomoxetine hydrochloride are simple and stable and are easy and convenient to implement, high in yield and applicable to industrial production, and sufficient raw materials can be provided for research and development of medicines.
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Paragraph 0010
(2017/05/20)
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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 0193; 0194
(2016/11/09)
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- ZnCl2-promoted asymmetric hydrogenation of β-secondary-amino ketones catalyzed by a P-chiral rh-bisphosphine complex
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A new catalytic system has been developed for the asymmetric hydrogenation of β-secondary-amino ketones using a highly efficient P-chiral bisphosphine-rhodium complex in combination with ZnCl2 as the activator of the catalyst. The chiral γ-secondary-amino alcohols were obtained in 90-94% yields, 90-99% enantioselectivities, and with high turnover numbers (up to 2000 S/C; S/C = substrate/catalyst ratio). A mechanism for the promoting effect of ZnCl2 on the catalytic system has been proposed on the basis of NMR spectroscopy and HRMS studies. This method was successfully applied to the asymmetric syntheses of three important drugs, (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine, in high yields and with excellent enantioselectivities.
- Hu, Qiupeng,Zhang, Zhenfeng,Liu, Yangang,Imamoto, Tsuneo,Zhang, Wanbin
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supporting information
p. 2260 - 2264
(2015/02/19)
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- HYDROXY ALIPHATIC SUBSTITUTED PHENYL AMINOALKYL ETHER DERIVATIVES
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New hydroxy aliphatic substituted phenyl aminoalkyl ether compounds of formula (I), compositions thereof and their use as a medicament in the treatment of nervous system diseases and/or the treatment of developmental, behavioral and/or mental disorders associated with cognitive deficits.
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Paragraph 0307-0308; 0322
(2015/12/24)
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- Copper(ii)-catalyzed enantioselective hydrosilylation of halo-substituted alkyl aryl and heteroaryl ketones: Asymmetric synthesis of (R)-fluoxetine and (S)-duloxetine
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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
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p. 1009 - 1017
(2014/02/14)
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- Total synthesis of fluoxetine and duloxetine through an in situ imine formation/borylation/transimination and reduction approach
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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
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p. 6121 - 6127
(2014/08/05)
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- Reversal of selectivity in acetate aldol reactions of N-acetyl-(S)-4- isopropyl-1-[(R)-1-phenylethyl]imidazolidin-2-one
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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.
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supporting information; experimental part
p. 2442 - 2445
(2012/07/03)
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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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Page/Page column 4
(2012/01/13)
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- Ruthenium-catalyzed asymmetric hydrogenation of β-keto- enamines: An efficient approach to chiral γ-amino alcohols
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A highly efficient and enantioselective hydrogenation of unprotected β-ketoenamines catalyzed with ruthenium(II) dichloro{(S)-(-)-2,2′- bis[di(3,5-xylyl)phosphino]-1,1′-binaphthyl}[(2S)-(+)-1, 1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine] {Ru[(S)-xylbinap][(S)-daipen] Cl2} has been successfully developed. This methodology provides a straightforward access to free γ-secondary amino alcohols, which are key building blocks for a variety of pharmaceuticals and natural products, with high yields (>99%) and excellent enantioselectivities (up to 99% ee) in all cases. Copyright
- Geng, Huiling,Zhang, Xiaowei,Chang, Mingxin,Zhou, Le,Wu, Wenjun,Zhang, Xumu
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supporting information; experimental part
p. 3039 - 3043
(2012/01/02)
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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 9-10
(2009/06/27)
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- AN EFFICIENT METHOD FOR PREPARING 3-ARYLOXY-3- ARYLPROPYLAMINES AND THEIR OPTICAL STEREOISOMERS
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Provided is an efficient method for the preparation of 3-aryloxy-3- arylpropylamines, their optical stereoisomers, and pharmaceutically acceptable salts thereof. The process allows for the isolation of 3-aryloxy-3- arylpropylamines in high yield and purity. The present invention further relates to a process for producing fluoxetine, tomoxetine, norfluoxetine, duloxetine, nisoxetine, and their optically enriched (R)- and (S)-enantiomers.
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Page/Page column 18-19
(2010/11/25)
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- PROCESS FOR PREPARING A 3-ARYLOXY-3-ARYLPROPYLAMINE
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The invention relates to the use of copper-catalyzed nucleophilic aromatic substitution reaction for preparing 3-aryloxy-3-arylpropylamines and more specifically to a method of preparing certain 3-aryloxy-3-arylpropylamines and the pharmaceutically acceptable addition salts thereof, comprising reacting an amino alcohol with a haloaromatic compound in the presence of a base and a catalytic copper source, and in the absence of a separate ligand.
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Page/Page column 14
(2008/06/13)
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- Efficient method for preparing 3-aryloxy-3-arylpropylamines and their optical stereoisomers
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Provided is an efficient method for the preparation of 3-aryloxy-3-arylpropylamines, their optical stereoisomers, and pharmaceutically acceptable salts thereof. The process allows for the isolation of 3-aryloxy-3-arylpropylamines in high yield and purity. The present invention further relates to a process for producing fluoxetine, tomoxetine, norfluoxetine, duloxetine, nisoxetine, and their optically enriched (R)— and (S)-enantiomers.
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Page/Page column 6-7
(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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- Polymer-supported chiral sulfonamide catalyzed one-pot reduction of β-keto nitriles: A practical synthesis of (R)-fluoxetine and (R)-duloxetine
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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
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p. 1873 - 1879
(2007/10/03)
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- Synthesis of enantiomerically pure (S)- and (R)-fluoxetine (Prozac) via a hetero Diels-Alder strategy
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A new route to enantiomerically pure (R)- and (S)-fluoxetine is described using a hetero Diels-Alder strategy.
- Panunzio, Mauro,Rossi, Katia,Tamanini, Emiliano,Campana, Eileen,Martelli, Giorgio
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p. 3489 - 3493
(2007/10/03)
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- Enantioselective Hydrogenation of β-Keto Esters using Chiral Diphosphine-Ruthenium Complexes: Optimization for Academic and Industrial Purposes and Synthetic Applications
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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
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p. 261 - 274
(2007/10/03)
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- Pure S(+)isomer fluoxetine
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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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- 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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- Pd-catalyzed kinetic resolution of benzylic alcohols: A practical synthesis of (R)-tomoxetine and (S)-fluoxetine hydrochlorides
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A convenient synthetic route to (R)-tomoxetine hydrochloride (90% ee) and (S)-fluoxetine hydrochloride (84% ee) is described. (S)-3-Phenyl-3-hydroxypropyl p-toluenesulphonate, the key intermediate, is obtained by the oxidative kinetic resolution of the corresponding racemic 3-phenyl-3-hydroxypropyl p-toluenesulphonate using (-)-sparteine/Pd(II)/O2 (1 atm) catalytic system.
- Ali, Iliyas Sayyed,Sudalai, Arumugam
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p. 5435 - 5436
(2007/10/03)
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- A practical asymmetric synthesis of (R)-fluoxetine and its major metabolite (R)-norfluoxetine
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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.
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p. 8919 - 8921
(2007/10/03)
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- Process to make chiral compounds
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The present invention relates to processes for resolving N-methyl-3(R,S)-hydroxy-3-phenylpropylamine and N,N-dimethyl-3 (R,S) -hydroxy-3-phenylpropylamine with the isomers of mandelic acid and the resulting salts.
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- Process to make chiral compounds
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A process to make the S(+)mandelic acid salt of N-methyl-3R-hydroxy-3-phenylpropylamine comprising reacting N-methyl-3(R,S)-hydroxy-3-phenylpropylamine with S(+)mandelic acid is described and claimed. Also described and claimed are processes to make N-methyl-3R-(2-methylthiophenoxy)-3-phenylpropylamine and N-methyl-3R-(2-methylphenoxy)-3-phenylpropylamine.
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- Methods for treating depression and other disorders using optically pure R (-) fluoxetine and monoamine oxidase inhibitor
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A method and composition are utilizing the pure R(-) isomer of fluoxetine which is a potent antidepressant and appetite suppressant substantially free of adverse effects. In addition, a method and composition are disclosed utilizing the pure R(-) isomer of fluoxetine which is useful to treat migraine headaches, pain, in particular chronic pain, psychoactive substance abuse disorders and obsessive compulsive disorders.
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- Efficient asymmetric hydrogenation of β- and γ-amino ketone derivatives leading to practical synthesis of fluoxetine and eprozinol
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N-(Methylcarbamoyl)-4-(dicyclohexylphosphino)-2-[(diphenylphosphino)me thyl]pyrrolidine (MCCPM)- and N-(tert-butoxycarbonyl)-4-(dicyclohexylphosphino)-2-[(diphenylphosphin o)methyl]pyrrolidine (BCPM)-rhodium(I) complexes were efficient catalysts for asymmetric hydrogenations of β- and γ-amino ketone hydrochloride derivatives. Utilizing this methodology, we have developed efficient syntheses of fluoxetine and eprozinol from intermediate optically active amino alcohols.
- Sakuraba,Achiwa
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p. 748 - 753
(2007/10/02)
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- A convenient method for preparing enantiomerically pure norfluoxetine, fluoxetine and tomoxetine
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A convenient synthesis for enantiomers of norfluoxetine, fluoxetine and tomoxetine is described. All final products were derived from a common intermediate, 3-phenyl-3-hydroxypropylamine.
- Koenig, Thomas M.,Mitchell, David
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p. 1339 - 1342
(2007/10/02)
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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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- Methods and compositions for treating depression using optically pure fluoxetine
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A method and composition are disclosed utilizing the pure S(+) isomer of fluoxetine, which is a potent antidepressant substantially free of adverse toxic or psychological effects, having a rapid onset of action and a high response rate.
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- ENANTIOSELECTIVE AND PRACTICAL SYNTHESES OF R- AND S-FLUOXETINES
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An efficient synthetic route to either R- or S-fluoxetine is described which depends on the use of a chiral, enzyme-like catalyst (chemzyme) to establish the stereocenter and which makes these important therapeutic agents readily available in enantiomerically pure form.
- Corey, E. J.,Reichard, Gregory A.
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p. 5207 - 5210
(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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