- Direct catalytic asymmetric aldol reaction of thioamides: A concise asymmetric synthesis of (R)-fluoxetine
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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
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experimental part
p. 1688 - 1694
(2010/10/19)
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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 7
(2008/06/13)
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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 19
(2010/11/25)
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- An asymmetric dihydroxylation route to enantiomerically pure norfluoxetine and fluoxetine
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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
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p. 4425 - 4426
(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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- 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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- Enantioselective synthesis of (S)- and (R)-fluoxetine hydrochloride
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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
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p. 9925 - 9929
(2007/10/03)
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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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- A novel chemoenzymatic enantioselective synthesis of some clinically effective CNS drugs and related compounds
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We have demonstrated in this study a novel route for the synthesis of benzothiopyran and benzothiazepin ring systems along with the synthesis of optically pure, clinically effective drugs tomoxetine, fluoxetine and thiazesim.
- Kumar, Ashok,Ner, D H,Dike, Suneel
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p. 803 - 809
(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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- Asymmetric Synthesis of Both Enantiomers of Fluoxetine via Microbiological Reduction of Ethyl Benzoylacetate
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Microbiological reduction of ethyl benzoylacetate by bakers' yeast (Saccharomyces cerevisiae), Beauveria sulfurescens or Geotrichum candidum afforded ethyl (S)-3-hydroxy-3-phenylpropionate in high optical yield.This enantiomerically pure alcohol was converted into both enantiomers of fluoxetine (7).The product resulting from the bakers' yeast reduction had ee values (87-93percent) lower than the 100percent value erroneously attributed in earlier studies.Key Words: Fluoxetine; asymmetric synthesis; bioreduction; bakers' yeast; Beauveria sulfurescens; Geotrichum candidum.
- Chenevert, Robert,Fortier, Genevieve,Rhlid, Rachid Bel
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p. 6769 - 6776
(2007/10/02)
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- A new chemoenzymatic enantioselective synthesis of R-(-)-tomoxetine, (R)- and (S)-fluoxetine
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A new chemoenzymatic synthesis of optically pure (R)-Tomoxetine and both the enantiomers of Fluoxetine starting from (S)-ethyl-3-hydroxy-3-phenyl propionate obtained by enzymatic methods, is described.
- Kumar, Ashok,Ner, Dilip H.,Dike, Suneel Y.
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p. 1901 - 1904
(2007/10/02)
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- Chemoenzymatic Synthesis of Both Enantiomers of Fluoxetine
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Both enantiomers of fluoxetine have been synthesized from ethyl benzoylacetate.The key step is the enantioselective reduction of the starting material by baker's yeast.
- Chenevert, Robert,Fortier, Genevieve
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p. 1603 - 1606
(2007/10/02)
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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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- Novel process of producing phenyl or substituted phenylalkylamine pharmaceutical agents and novel chiral intermediates of high enantiomeric purity useful therein
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A process for producing the optically pure (+)- or (-) isomer of a phenyl- or substituted- phenylalkanolamine compounds having pharmacologic activity without the need for resoltuion processes ad novel intermediates useful in the process including optically pure haloalcohols are provided.
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- Chiral Synthesis via Organoboranes. 18. Selective Reductions. 43. Diisopinocampheylchloroborane as an Excellent Chiral Reducing Reagent for the Synthesis of Halo Alcohols of High Enantiomeric Purity. A Highly Enantioselective Synthesis of Both Optical Isomers of Tomoxetine, Fluoxetine, a
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Diisopinocampheylchloroborane, dIpc2BCl, reduces ring and chain sustituted haloaralkyl ketones to the corresponding halo alcohols in excellent enantiomeric excess.In certain cases these alcohols can be upgraded by simple methods to essentially 100percent ee.For instance, (+)- or (-)-3-chloro-1-phenyl-1-propanol is initially obtained in 97percent ee.Simple recrystallisation then furnishes the pure enantiomers.These chiral halo alcohols are highly versatile intermediates.They can be readily cyclized to oxiranes and 2-substituted tetrahydrofurans with retention of chirality.Utilizing this methodology, we have developed an efficient, highly enantioselective synthesis of both optical isomers of the antidepressant drugs, Tomoxetine, Fluoxetine, and Nisoxetine, from the common intermediates (+)-or (-)-3-chloro-1-phenyl-1-propanol.
- Srebnik, Morris,Ramachandran, P.V.,Brown, Herbert C.
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p. 2916 - 2920
(2007/10/02)
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