- Bioreductive production of enantiopure (S)-duloxetine intermediates catalyzed with ketoreductase ChKRED15
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The blockbuster antidepressant drug duloxetine contains one stereo-center derived from chiral alcohol intermediates. The stereoselective bioreductive production of five of such intermediates could be achieved using the recombinant ketoreductase ChKRED15, yielding the enantiopure (S)-alcohols with >99% ee. Sequence alignment indicated that ChKRED15 lacks the conserved G-rich motif, which was then amended by a single mutation of S12G. The resulting S12G mutant displayed significantly improved catalytic activity and protein stability. When coupled with a cofactor recycling system, the S12G mutant was able to catalyze the complete conversion of ethyl 3-oxo-3-(thiophen-2-yl)propanoate within 6 h and N-methyl-3-oxo-3-(thiophen-2-yl)propanamide within 24 h at substrate concentrations of 10 and 50 g/l, respectively, without the compromise of enantioselectivity.
- Ren, Zhi-Qiang,Liu, Yan,Pei, Xiao-Qiong,Wang, Hai-Bo,Wu, Zhong-Liu
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- Chemoenzymatic synthesis of (S)-duloxetine using carbonyl reductase from Rhodosporidium toruloides
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A chemoenzymatic strategy was developed for (S)-duloxetine production employing carbonyl reductases from newly isolated Rhodosporidium toruloides into the enantiodetermining step. Amongst the ten most permissive enzymes identified, cloned, and overexpressed in Escherichia coli, RtSCR9 exhibited excellent activity and enantioselectivity. Using co-expressed E. coli harboring both RtSCR9 and glucose dehydrogenase, (S)-3-(dimethylamino)-1-(2-thienyl)-1-propanol 3a was fabricated with so far the highest substrate loading (1000 mM) in a space-time yield per gram of biomass (DCW) of 22.9 mmol L-1 h-1 g DCW-1 at a 200-g scale. The subsequent synthetic steps from RtSCR9-catalyzed (S)-3a were further performed, affording (S)-duloxetine with 60.2% overall yield from 2-acethylthiophene in >98.5% ee.
- Chen, Xiang,Liu, Zhi-Qiang,Lin, Chao-Ping,Zheng, Yu-Guo
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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 0054-0057
(2016/12/01)
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- A method for preparing optically active 3-amino-1-propanol derivatives as an intermediate and a method for preparing (S)-duloxetine using the same
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The present invention relates to a method for preparing optically active 3-AMNO1-propanol derivatives as an intermediate and a method for preparing (s)-duloxetine using the same. This method can obtain optically active 3-AMNO1-propanol with higher yield and optical purity (ee) than any other conventional methods. Using this as an intermediate compound, it is possible to manufacture duloxetine which is enantiomerically pure and has high optical purity (ee).(DD) Nisoxetine(EE) Duloxetine(CC) 3-amino-1-propanol(BB) Fluoxetine(AA) TomoxetineCOPYRIGHT KIPO 2015
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Paragraph 0158-0161
(2016/12/01)
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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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- PERMANENTLY POSITIVELY CHARGED ANTIDEPRESSANTS
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The present invention provides compounds comprising a substructure of below formula 3: or a salt or prodrug thereof and the use of such compounds in treatment of e.g. CNS disorders.
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Page/Page column 68; 69
(2013/03/26)
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- Corey-itsuno reduction of ketones: A development of safe and inexpensive process for synthesis of some API intermediates
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A safe and inexpensive procedure for asymmetric reduction of ketones using in situ prepared N,N-diethylaniline borane (DEANB) and oxazaborolidine catalyst from sodium borohydride, N,N-diethylaniline hydrochloride and (S)-α,α-diphenylprolinol is described. This protocol is demonstrated successfully to manufacture enantiopure dapoxetine at the plant scale.
- Mahale, Rajendra D.,Chaskar, Sudhir P.,Patil, Kiran E.,Maikap, Golak C.,Gurjar, Mukund K.
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supporting information; experimental part
p. 710 - 713
(2012/07/27)
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- Method for Production of Optically Active (1S)-3-Chloro-1-(2-Thienyl)-Propan-1-Ol
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A process for preparing optically active (1S)-3-chloro-1-(2-thienyl)propan-1-ol of the formula I by, in a medium comprising 3-chloro-1-(2-thienyl)propan-1-one of the formula II reducing this compound to the compound of the formula I by means of an alcohol dehydrogenase from the Thermoanaerobacter genus, and isolating the product formed in substantially enantiomerically pure form.
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Page/Page column 3
(2009/01/24)
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- Duloxetine (Cymbalta), a dual inhibitor of serotonin and norepinephrine reuptake.
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A series of naphthalenyloxy-arylpropylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake. One member of this series, duloxetine (Cymbalta) has proven to be effective in clinical trials for the treatment of depression.
- Bymaster,Beedle,Findlay,Gallagher,Krushinski,Mitchell,Robertson,Thompson,Wallace,Wong
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p. 4477 - 4480
(2007/10/03)
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- An asymmetric synthesis of duloxetine hydrochloride, a mixed uptake inhibitor of serotonin and norepinephrine, and its C-14 labeled isotopomers
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Two 14C-isotopomers of duloxetine HCl (S-(+)-N-methyl-3(1-naphthalenyloxy)-3(2-thiophene)propanamine hydrochloride), a potent mixed serotonin/norepinephrine Uptake inhibitor have been prepared by an asymmetric synthesis. The palladium catalyzed cross-coupling of 2-thienoyl chloride (3c) (or its [carbonyl-14C] isotopomer 3d) with vinyl tri-n-butylstannane, followed by addition of HCl afforded the key pro-chiral intermediate chloroketone (5a,b). Chiral reduction with borane in the presence of the appropriate oxazaborolidine catalyst (14a or b) provided the S-chloroalcohol (7a) and its 14C-labeled counterpart 7b or the analogous R-chloroalcohol (6). Activation of 7a,b by reaction with NaI/acetone, followed by reaction of the corresponding iodoalcohol with methylamine yielded the penultimate aminoalcohols (8a,b). Formation of the alkoxide with NaH, followed by reaction with 1-fluoronaphthalene yielded duloxetine or its 14C-labeled isotopomer 9. Alternatively, reaction of 6 with 1-naphthol-[1-14C] under Mitsunobu conditions afforded aryl-ether 10a,b, which was in turn activated by reaction with NaI/acetone Subsequent reaction of 10c,d with methylamine followed by salt formation yielded duloxetine or its naphthalene-labeled isotopomer (13) as their HCl salts.
- Wheeler,Kuo
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p. 213 - 223
(2007/10/02)
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