- A chemoenzymatic dynamic kinetic resolution approach to enantiomerically pure (R)- and (S)-duloxetine
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The synthesis of (R)-duloxetine is described. Dynamic kinetic resolution of β-hydroxynitrile rac-1 using Candida antarctica lipase B (CALB, N435) and ruthenium catalyst 6 afforded β-cyano acetate (R)-2 in high yield and in excellent enantioselectivity (98% ee). The subsequent synthetic steps were straightforward and (R)-duloxetine was isolated in 37% overall yield over 6 steps. The synthetic route also constitute a formal total synthesis of (S)-duloxetine.
- Traeff, Annika,Lihammar, Richard,Baeckvall, Jan-E.
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Read Online
- ORTHO SUBSTITUTED PHENOXYPROPYLAMINO AND BENZYLOXYPROPYLAMINO DERIVATIVES HAVING MULTIMODAL ACTIVITY AGAINST PAIN
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The present invention relates to ortho substituted phenoxypropylamino and benzyloxypropylamino derivatives having pharmacological activity towards the α2δ subunit of the voltage-gated calcium channel, in particular to ortho substituted phenoxypropylamino and benzyloxypropylamino derivatives having dual pharmacological activity towards both the α2δ subunit of the voltage-gated calcium channel and the sigma-1 (σ1 ) receptor, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.
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Page/Page column 190
(2020/02/17)
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- COMPOUNDS HAVING MULTIMODAL ACTIVITY AGAINST PAIN
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The present invention relates to a compound of formula (I): wherein the meanings for the various substituents are as disclosed in the description, having dual pharmacological activity towards both the α2δ subunit, in particular the α2δ- 1 subunit, of the voltage-gated calcium channel and the NET receptor, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.
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- AMINOPROPOXYPHENYL AND BENZYL 3,4-DIHYDRO-2H-SPIRO[ISOQUINOLINE-1,4'-PIPERIDIN]-1'-YL DERIVATIVES HAVING MULTIMODAL ACTIVITY AGAINST PAIN
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The present invention relates to aminopropoxyphenyl and benzyl 3,4-dihydro-2H- spiro[isoquinoline-1,4'-piperidin]-1'-ylderivatives having dual pharmacological activity towards both the α2δ-subunit, in particular the α2δ-1 subunit, of the voltage-gated calcium channel and the μ-opioid receptor, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.
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Page/Page column 288
(2019/10/15)
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- NITROGEN CONTAINING BICYCLIC DERIVATIVES FOR TREATING PAIN AND PAIN RELATED CONDITIONS
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The present invention relates to new compounds of formula (I): showing great affinity and activity towards the subunit α2δ of voltage-gated calcium channels (VGCC), especially the α2δ-1 subunit of voltage-gated calcium channels or dual activity towards the subunit α2δ of voltage-gated calcium channels (VGCC), especially the α2δ-1 subunit of voltage-gated calcium channels, and the noradrenaline transporter (NET).
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Paragraph 0120; 0121
(2018/07/06)
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- west Luo river sandbank chiral method for the preparation of intermediates
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The invention relates to a preparation method of a chiral duloxetine intermediate, namely (S)-N-methyl-3-hydroxy-(2-thienyl)-1-propylamine, belonging to the technical field of drug synthesis. The preparation method comprises the following steps: reacting trans-N-methyl-3-(2-thienyl)-crotonamide with a boron compound in a solvent in the presence of a chiral catalyst, copper salt and alkali under the nitrogen protection to obtain a reaction product, and performing oxidation reduction on the reaction product to obtain (S)-N-methyl-3-hydroxy-(2-thienyl)-1-propylamine. The preparation method is easy and feasible; the prepared target product is high in yield and optical purity, low in purification difficulty and suitable for a research on scale production.
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Paragraph 0034
(2017/03/08)
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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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supporting information
p. 82 - 89
(2016/02/23)
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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 making duloxetine and related compounds
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A compound of formula 10 is useful in making duloxetine.
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Page/Page column 7
(2008/12/06)
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- 5-Phenylthio-1,3-oxazinan-4-ones via hetero Diels-Alder reactions: synthesis of (R)- and (S)-Duloxetines and Fluoxetines
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The synthesis of 5-phenylthio-1,3-oxazinan-4-ones, through a hetero Diels-Alder strategy, is described. The cycloadducts thus prepared have been shown to be useful intermediates for the synthesis of 1,3-aminoalcohols, valuable intermediates in the preparation of biologically significant molecules, e.g., optically active Duloxetines and Fluoxetines. In the course of this elaboration a novel microwave assisted desulfurization reaction is reported.
- Panunzio, Mauro,Tamanini, Emiliano,Bandini, Elisa,Campana, Eileen,D'Aurizio, Antonio,Vicennati, Paola
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p. 12270 - 12280
(2007/10/03)
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- METHODS FOR THE PRODUCTION OF 3-METHYLAMINO-1-(THIENE-2-YL)-PROPANE-1-OL
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The invention relates to enzymatic and non-enzymatic methods for the production of 3-methylamino-1-(thiene-2-yl)-propane-1-ol; in addition to enzymes for carrying out said method; nucleic acid sequences coding for said enzymes, expression cassettes containing them, vectors and recombinant hosts.
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Page/Page column 43-44
(2008/06/13)
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- Process for the asymmetric hydrogenation of beta-amino ketones
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The invention relates to a process for the preparation of enantiomerically enriched or enantiomerically pure (S)- or (R)-N-monosubstituted β-amino alcohols of formula ???and enantiomers and their addition salts of proton acids, X represents S or O, and R represent C1-6-alkyl, C3-8-cycloalkyl, aryl or aralkyl.
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Page/Page column 8
(2008/06/13)
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- Practical synthesis of enantiopure γ-amino alcohols by rhodium-catalyzed asymmetric hydrogenation of β-secondary-amino ketones
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(Chemical Equation Presented) Another way to antidepressants: A series of β-secondary-amino ketone hydrochlorides (e.g. 1) were hydrogenated with remarkably high enantioselectivities by using a Rh complex containing P-chiral bisphospholane 2. These results establish a short and practical means for the synthesis of enantiopure N-monosubstituted γ-amino alcohols (e.g. 3), which are key intermediates in the synthesis of important antidepressants. (nbd = norbornadiene; TON = turnover number).
- Liu, Duan,Gao, Wenzhong,Wang, Chunjiang,Zhang, Xumu
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p. 1687 - 1689
(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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- PROCESSES AND INTERMEDIATES FOR THE PREPARATION OF OPTICALLY ACTIVE 3-AMINO-1-(2-THIENYL)-1-PROPANOL DERIVATIVES
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Enantiomerically enriched 3-amino-1-(2-thienyl)-1-propanols of the fomulae (S)-I or (R)-I wherein R1 and R2 independently denote H, C1-6-alkyl, C5-7-cycloalkyl, aralkyl or aryl, were prepared by reducing a 3-amino-1-(2-thienyl)-1-propanone of the formula (II) wherein R1 and R2 are defined as above, using a hydrogen donor in the presence of a metal catalyst, an optically active nitrogen-containing ligand and optionally a base.
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- 3-METHYLAMINO-1-(2-THIENYL)-1-PROPANONE, PRODUCTION AND USE THEREOF
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The invention relates to the production of 3-methylamino-1-(2-thienyl)-1-propanone and the use thereof for producing the pharmaceutical (+)-(S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine oxalate (trade name Duloxetine?).
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Page/Page column 4
(2008/06/13)
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- Chemoenzymatic synthesis of duloxetine and its enantiomer: Lipase-catalyzed resolution of 3-hydroxy-3-(2-thienyl) propanenitrile
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An efficient and facile chemoenzymatic synthesis of duloxetine by lipase mediated resolution of 3-hydroxy-3-(2-thienyl)propanenitrile has been achieved. This process also describes an enantioconvergent synthesis of duloxetine via a Mitsunobu reaction.
- Kamal, Ahmed,Khanna, G. B. Ramesh,Ramu,Krishnaji
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p. 4783 - 4787
(2007/10/03)
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- Resolution of 3-(methylamino)-1-(2-thienyl)propan-1-ol, a new key intermediate for duloxetine, with (S)-mandelic acid
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The resolution of racemic 3-(methylamino)-1-(2-thienyl)propan-1-ol 3, a new key intermediate for duloxetine 1, was studied. The conditions were optimized for an industrial-scale resolution of 3 by using (S)-mandelic acid 4 as a resolving agent and 2-butanol containing 2 equimolar amounts of water as a solvent. The (S)-3·(S)-4·H2O diastereomeric salt was crystallized to give pure (S)-3 with >99.9% e.e. after liberation of the amine. The absolute configuration of liberated (-)-3 was determined as (S) by X-ray crystallography.
- Sakai, Kenichi,Sakurai, Rumiko,Yuzawa, Atsushi,Kobayashi, Yuka,Saigo, Kazuhiko
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p. 1631 - 1636
(2007/10/03)
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