- Preparation method of S-(+)duloxetine hydrochloride intermediate
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The invention discloses a preparation method of a compound of a formula B (shown in the description). The preparation method comprises the steps of dissolving a compound of a formula A (shown in the description) in a solvent, and reacting under the effect of a reducing agent. Furthermore, the ee value of the compound of the formula B obtained by reducing in the presence of a complex, namely ferrocene, is over 98%. The preparation method provided by the invention is simple and feasible, the resolution or the chiral catalysis induction is not required, the product yield and the chiral purity arehigh, and the preparation method is suitable for the industrial production of S-(+)duloxetine hydrochloride intermediate.
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Paragraph 0066-0068
(2019/04/09)
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- Synthesis method of key intermediate for preparing duloxetine hydrochloride from 2-acetylthiophene
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The invention provides a synthesis method of a key intermediate for preparing duloxetine hydrochloride from 2-acetylthiophene and belongs to the technical field of chemical synthesis. The synthesis method comprises the following steps: reacting cyanuric chloride and N,N-dimethylformamide with 2-acetylthiophene to obtain 3-(dimethylamino)-1-(2-thienyl)-2-propenyl-1-one; reducing 3-(dimethylamino)-1-(2-thienyl)-2-propenyl-1-one through lithium aluminum hydride to obtain a duloxetine hydrochloride intermediate which is (R,S)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine. The synthesis method iscapable of synthesizing a target product which is a key intermediate of duloxetine hydrochloride through two-step reaction, is cheap in raw materials, simple in process, simple and convenient to operate, mild in reaction condition, short in reaction period and free of expensive catalysts, is environmentally friendly, and is suitable for industrial production; the prepared products are high in yield and purity.
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Paragraph 0025; 0026; 0027; 0028; 0029; 0030
(2018/11/03)
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- New amine compound and use thereof in treatment of depression
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The invention relates to a new amine compound and a use thereof in the treatment of depression, and concretely relates to a compound represented by formula I, optical isomers, solvates or pharmaceutically acceptable salts thereof, and a use thereof in the preparation of antidepressant drugs. Preclinical pharmacological studies show that the compound is comparable to and even better than first-line antidepressants (such as duloxetine).
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Paragraph 0073; 0074
(2017/09/19)
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- A west Luo river sandbank chiral intermediate mandelic acid salt preparation method
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A purpose of the present invention is to provide a method for simultaneously recycling (R)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropylamine (II) and S-mandelic acid to prepare a duloxetine chiral intermediate (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropylamine S-mandelate (I). The formulas (I) and (II) are defined in the instruction.
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Paragraph 0037; 0048-0051
(2017/07/19)
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- Preparation method of (S)-3-N,N-disubstituted amino-1-(2-thienyl)-1-propanol
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The invention discloses a preparation method of (S)-3-N,N-disubstituted amino-1-(2-thienyl)-1-propanol shown as the formula (I). The method comprises: taking 2-acetyl thiophene shown in the formula (II) as a raw material, and allowing 2-acetyl thiophene to completely react with di(trichloromethyl)carbonic ester (III) and N,N-disubstituted methanamide (IV) in an organic solvent under the catalysis of an organic base to obtain N,N-disubstituted amino-1-(2-thienyl)-1-acrylketone shown as the formula (V); and performing hydrogenation reduction with lithium aluminium hydride to obtain N,N-disubstituted amino-1-(2-thienyl)-1-propanol shown as the formula (VI); and performing splitting with S-mandelic acid and recrystallization with ethyl acetate to obtain the target product shown as the formula (I). The preparation method is low in cost, mild in reaction condition, less in waste water, waste gas and industrial residue, small in energy consumption, and high in yield. The preparation method is safe and is suitable for industrial production.
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Paragraph 0040
(2018/03/24)
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- Preparation of duloxetine hydrochloride
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The invention belongs to the fields of organic chemistry and pharmaceutical chemistry, and particularly relates to a synthesis technique of duloxetine hydrochloride. By converting the R configuration compound into S configuration, compared with the duloxetine hydrochloride prepared from the single S-configuration compound, the total yield is enhanced by nearly 47%, and the production cost is lowered. 1-chloroethylchloroformate is used instead of phenyl chloro-formate to directly generate the duloxetine hydrochloride during demethylation, thereby reducing the salification step, shortening the production cycle and saving the cost.
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Paragraph 0053-0054
(2017/08/26)
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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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- METHOD FOR PRODUCING DULOXETINE HYDROCHLORIDE
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PROBLEM TO BE SOLVED: To provide a new method for producing (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride (general name: duloxetine hydrochloride) useful as an antidepressant. SOLUTION: In a method for producing duloxetine hydrochloride, a solution obtained by dissolving a crude product containing duloxetine hydrochloride in a dissolving solvent (a first dissolution step) and acetone are mixed (a mixing step), the duloxetine hydrochloride precipitated in the obtained mixed solution is temporarily dissolved (a second dissolution step), and then the duloxetine hydrochloride is precipitated. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
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Paragraph 0063
(2017/05/05)
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- OLIGOMER-ARYLOXY-SUBSTITUTED PROPANAMINE CONJUGATES
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The invention relates to (among other things) oligomer- aryloxy-substituted propanamine conjugates and related compounds. A conjugate of the invention, when administered by any of a number of administration routes, exhibits advantages over un-conjugated aryloxy-substituted propanamine compounds.
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Paragraph 0245; 0251
(2016/11/17)
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- ARALKYL DIAMINE DERIVATIVES AND USES THEREOF AS ANTIDEPRESSANT
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Aralkyl diamine derivative of the following formula, pharmaceutically acceptable salts or uses thereof as antidepressants. The derivatives have triplex inhibiting activities of the reuptake of 5-HT, dopamine and noradrenalin, which can be administered to the patients in need of such treatment in the form of compositions orally or injectedly et al.
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Paragraph 0031; 0161
(2013/03/28)
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- Synthesis and dual 5-ht1a/ssri activities of some novel arylpiperazine derivatives of duloxetine
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A series of novel arylpiperazine derivatives of duloxetine were designed and synthesized from the key intermediate 5 by acylation, alkylation and reduction based on 5-HT1A/SSRI drugs design strategies. Compound 5 was obtained through the reaction sequence including condensation, reduction, O-etherification, Von Braun reaction, hydrolysis reaction. Structures of the synthesized compounds were confirmed by MS, 1H NMR and HRMS. Furthermore, these compounds were evaluated for their dual 5-HT1A/5-HTT activities. The results indicated that all the compounds exhibited certain affinity to 5-HTT and 5-HT1A receptor.
- Chen, Shao-Rui,Li, Ai-Jun,Chen, Ming-Ming
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experimental part
p. 1680 - 1684
(2012/08/28)
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- AMINE COMPOUNDS AND THEIR PHARMACEUTICAL USE
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The present invention relates to a new amine compound or a pharmaceutically acceptable salt thereof, wherein the definitions of X, R1, R2 and n are given in the description, to a pharmaceutical composition containing the compound as active ingredient, and to use of the amine compound or its pharmaceutically acceptable salt for the manufacture of an anti-depressent drug.
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Page/Page column 6
(2011/04/25)
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- IMPROVED PROCESS FOR THE PREPARATION OF DULOXETINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALT
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The present invention relates to an improved process for racemizing one of the enantiomers, or an enantiomerically enriched mixture, of an optically active compound (S)-N, N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine, a key intermediate used for the preparation of (S)-N-methyl-3-(1-naphthalenyloxy)-3-(2- thienyl) propanamine (duloxetine) or its hydrochloride salt. Moreover, the present invention also relates to an improved process for the preparation of (S)-N-methyl-3- (1-naphthalenyloxy)-3-(2-thienyl) propanamine (duloxetine) or its hydrochloride salt having low content of undesired R-isomer and chiral purity not less than 99%.
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Page/Page column 23
(2011/04/19)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF DULOXETINE AND SALTS THEREOF
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The present invention relates to improved process for the preparation of Duloxetine of formula (I) and salts thereof wherein said improvement takes place in step of condensation.
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Page/Page column 7
(2010/08/04)
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- PROCESS FOR THE PREPARATION ENANTIOMERICALLY PURE SALTS OF N-METHYL-3-(1-NAPHTHALENEOXY)-3-(2-THIENYL)PROPANAMINE
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The present invention relates to duloxetine salts having enantiomeric purity of 98% or more and a process for such salts.
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Page/Page column 3
(2010/12/29)
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- PROCESS FOR THE PREPARATION OF 3-ARYLOXY-3-ARYLPROPANAMINES
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The present invention provides a process for the preparation of 3-aryloxy-3-arylρropanamine derivatives. Particularly the present invention provides a process for the preparation of duloxetine and pharmaceutically acid addition salts thereof specifically, duloxetine hydrochloride of formula (I), using 3-O-protected propanolamine derivatives. The invention also aims at providing a process for the preparation of highly pure duloxetine hydrochloride of formula (I) from duloxetine free base via its acid addition salts The invention further aims at providing a process for the purification of duloxetine hydrochloride, wherein the level of unwanted R-enantiomer is reduced to nearly 0%.
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Page/Page column 16
(2009/04/25)
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- PROCESS FOR THE PREPARATION OF DULOXETINE AND ITS SALTS
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The present invention relates to duloxetine salts having enantiomeric purity of 98% or more and a process for such salts.
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Page/Page column 6-7
(2008/06/13)
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- A PROCESS FOR PREPARATION OF (S)-(+)-N-METHYL-3(1-NAPHTHYLOXY)-3(2-THIENYL)PROPYLAMINE HYDROCHLORIDE
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The present invention provides an improved process for preparation of intermediate of Duloxetine base and hydrochloride salt thereof.
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Page/Page column 9-10
(2008/12/07)
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- Process for the preparation of (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropananine, a duloxetine intermediate
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A chiral resolution process for the preparation of (S)-AT-OL, and a process for the racemization of AT-OL are provided.
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Page/Page column 2-3; 5
(2008/06/13)
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- A process for the preparation of an intermediate useful for the asymmetric synthesis of (+)duloxetine
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A process for the preparation of (+)duloxetine, or an acid addition salt thereof, comprising: (i) Resolving racemic (±)N-methyl duloxetine with a less than stoichiometric amount of a chiral acid in combination with suitable amounts of a hydrohalogen acid to give a salt of the chiral acid and (+)N-methyl duloxetine, substantially free from (-)N-methyl duloxetine; (ii) Demethylating the (+)N-methyl duloxetine prepared in step (i) to give (+)duloxetine or another acid addition salt in enantiomerically pure form.
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Page/Page column 4-5
(2010/11/28)
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- IMPROVED PROCESS FOR PURE DULOXETINE HYDROCHLORIDE
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A process for the preparation of pure Duloxetine hydrochloride comprises the steps of : a) reacting 1-(thiophen-2-yl)ethanone with dimethylamine hydrochloride, b) purifying the component in a solvent, c) reducing the component with an alkali metal borohydride, d) resolving the compound with a chiral acid, and treating the obtained compound with weak inorganic base, e) reacting the compound to give Duloxetine oxalate salt and f) converting the Duloxetine salt into its hydrochloride salt. Further the purifications of the obtained compound and of two intermediate products are described.
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Page/Page column 15
(2008/06/13)
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- Process for preparing duloxetine and intermediates thereof
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Processes for preparing chemically pure duloxetine and chemically pure duloxetine intermediates are provided.
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Page/Page column 5
(2010/11/29)
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- Synthesis of (S)-3-(N-methylamino)-1-(2-thienyl)propan-1-ol: Revisiting Eli Lilly's resolution-racemization-recycle synthesis of duloxetine for its robust processes
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(±)-3-(N,N-Dimethylamino)-1-(2-thienyl)propan-1-ol (6), prepared from 2-acetylthiophene (4) in a two-step overall yield of 79%, is resolved into (S)-6 of 93% ee as its diastereomeric salt (8) with (S)-mandetic acid (7) according to Eli Lilly's procedures developed for the resolution-racemization- recycle (RRR) synthesis of duloxetine (2) with some modifications in terms of practicality. On its liberation from 8, (S)-6 undergoes N-demethylative ethyl carbamate formation in two discrete but successive steps in an overall yield of 87% from 8: (1) O-ethyl carbonate formation and (2) ethyl carbamate formation with concomitant loss of the N-methyl group. Alkaline hydrolysis then affords (S)-3-(N-methylamino)-1-(2-thienyl)propan-1-ol (1) of 100% ee, an alleged penultimate precursor to duloxetine (2), in 75% yield after a single recrystallization from ethylcyclohexane. In the overall process thus developed, PhMe is substituted successfully for t-BuOMe, a solvent that has been used favorably in Eli Lilly's original RRR synthesis of 2.
- Fujima, Yoshito,Ikunaka, Masaya,Inoue, Toru,Matsumoto, Jun
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p. 905 - 913
(2012/12/23)
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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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- Chiral synthesis of 1-aryl-3-aminopropan-1-ols
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This invention is directed to a process for preparing chiral 1-aryl-3-amino-propan-1-ols. These compounds are important intermediates in the synthesis of pharmacologically active compounds.
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- 3-aryloxy-3-substituted propanamines
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The present invention provides 3-aryloxy-3-substituted propanamines capable of inhibiting the uptake of serotonin and norepinephrine.
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