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WO2011033366A2 - Procédé amelioré pour la préparation de duloxetine et de sel acceptable sur le plan pharmaceutique de celle-ci - Google Patents

Procédé amelioré pour la préparation de duloxetine et de sel acceptable sur le plan pharmaceutique de celle-ci Download PDF

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Publication number
WO2011033366A2
WO2011033366A2 PCT/IB2010/002320 IB2010002320W WO2011033366A2 WO 2011033366 A2 WO2011033366 A2 WO 2011033366A2 IB 2010002320 W IB2010002320 W IB 2010002320W WO 2011033366 A2 WO2011033366 A2 WO 2011033366A2
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Prior art keywords
acid
thienyl
process according
formula
dimethyl
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Ceased
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WO2011033366A8 (fr
WO2011033366A3 (fr
Inventor
Sujay Biswas
Archana Trivedi
Manlta Kharbanda
Shailendra Dubey
Sandeep Singla
Mansukhlal Bodheka Yogiraj
Dharam Vir
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Jubilant Pharmova Ltd
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Jubilant Life Sciences Ltd
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Publication of WO2011033366A8 publication Critical patent/WO2011033366A8/fr
Publication of WO2011033366A3 publication Critical patent/WO2011033366A3/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms

Definitions

  • the present invention relates to an improved and environment friendly 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 in the preparation of (S)-N-methyl-3-(l -naphthalenyloxy)-3- (2-thienyl)propanamine (duloxetine) or its hydrochloride salt.
  • the present invention also relates to an improved process for the preparation of (S)-N-methyl-3- ( l -naphthalenyloxy)-3-(2-thienyl) propanamine (duloxetine) or its hydrochloride salt.
  • Duloxetine belongs to the class of selective serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors and exhibits antidepressant activity.
  • Duloxetine selectively prevents the reuptake of 5-HT and NE via transporter complexes on the pre-synaptic membrane, thereby increasing the level of these neurotransmitters within the synaptic cleft.
  • Duloxetine is chemically known as (S)-N- methyl-3-( l -naphthalenyloxy)-3-(2-thienyl)propanamine and represented by Formula
  • duloxetine and its pharmaceutically acceptable salt are prepared by converting 2-acetylthiophene to 3-dimethylamino- l -(2-thienyl)- l - propanone hydrochloride of Formula A via Mannich reaction, followed by reducing the resultant to obtain the corresponding alcohol of N,N-dimethyl-3-(2-thienyl)-3- hydroxypropanamine of Formula B.
  • the resulting alcohol i. e.
  • N,jV-dimethyl-3-(2- thienyl)-3-hydroxypropanamine of Formula B is then reacted with 1 - fluoronaphthalene in presence of sodium hydride to form yV,N-dimethyI-3-( l - naphthalenyloxy)-3-(2-thienyl) propanamine of Formula C, which undergoes demethvlation to form carbamate intermediate of Formula D, which after hydrolysis yields duloxetine.
  • US '269 patent does not provide specific method for obtaining the optically active isomer i. e S-isomer of duloxetine.
  • optically active isomers of the racemates may be prepared from optically active precursors or by resolving the racemic mixture.
  • the resolving agent disclosed are dibenzoyl-D and L- tartaric acid. Further, it has been observed that dibenzoyl-D and L-tartaric acid are poor resolving agents for resolving N, N-dimethyl-3-( l -naphthalenyloxy)-3-(2- thienyl) propanamine compound.
  • US 5,362,886 and WO200403 1 168 discloses chiral resolution of racemic N, A -dimethyl-3-(2-thienyl)-3-hydroxypropanamine by the use of (S)-(+) mandelic acid and (-)-2,3 :4,6-di-0-isopropylidene-2-keto-L-gulonic acid respectively.
  • US'886 describes the preparation of duloxetine by the chiral resolution of N, N-dimethyl-3-(2- thienyl)-3-hydroxypropanamine using (S)-mandelic acid, followed by reaction with 1 - fluoronaphthalene to obtain N,N-dimethyl-3-( l -naphthalenyloxy)-3-(2-thienyl) propanamine.
  • the resulting jV,N-dimethyl-3-( l -naphthalenyloxy)-3-(2-thienyl) propanamine is demethylated using phenyl chloroformate followed by basic hydrolysis to obtain (S)-duloxetine, which is further converted to its hydrochloride salt.
  • US' 886 patent does not specifically disclose the enantiomeric excess of duloxetine hydrochloride prepared according to ' Preparation 2' from the (S)-(+)-N,N-dimethyl-3-( l -naphthalenyloxy)-3- (2-thienyl) propanamine phosphoric acid salt, and the yield of duloxetine hydrochloride is also very poor (overall yield 33%).
  • WO2007045405 discloses process for the preparation of duloxetine and its pharmaceutically acceptable salt by reacting N, N-dimethyl-3-hydroxy-3-(2-thienyl) propanamine with 1 -fluoronaphthalene using l ,3-dimethyl-2-oxo- hexahydropyrimidine (DMPU) as a solvent at a temperature 70 to 120°C to form N- methyl duloxetine, which is further isolated as oxalate salt.
  • DMPU l ,3-dimethyl-2-oxo- hexahydropyrimidine
  • the resulting N-methyl duloxetine oxalate undergoes hydrolysis, resolution with tartaric acid and demethylation to form duloxetine, which is further converted to its hydrochloride salt.
  • the main drawback of the process is the use of l ,3-dimethyl-2-oxo- hexahydropyrimidine (DMPU) as a solvent, which makes the process unsuitable on commercial scale as this solvent can cause irritation to the skin, eyes and respiratory tract.
  • DMPU l ,3-dimethyl-2-oxo- hexahydropyrimidine
  • the other drawback is the resolution in the final stage with costly chiral acid and consumption of the expensive 1 -fluoronaphthalene compound, which not only affect the yield of the final duloxetine hydochloride, but also makes the process costly and uneconomical on large scale.
  • 2006 ( 10) 905-91 3 provides the process for resolution of racemic N, N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine and racemization of undesired ?-enantiomer in the presence of acid in an organic solvent.
  • the preferred acid is selected from the group consisting of hydrochloric acid and sulphuric acid.
  • WO'250 require more than 20 hours during the racemization, which increases reaction cycle and hence it is unsuitable on industrial scale.
  • WO2006045255 discloses the resolution of the duloxetine using D-tartaric acid.
  • WO2004056795 discloses resolution of racemic duloxetine using various chiral acids like mandelic acid, tartaric acid, di- -toluyl tartaric acid, dibenzoyl tartaric acid and camphor sulphonic acid with preference to di- -toluyl tartaric acid and the conversion of the resulting salt either into free base or other addition salts like hydrochloride etc.
  • Use of resolving agent in the final step is not very economical due to the loss of undesired (R)-isomer of duloxetine, which is not environment friendly as well as chemically unviable as the reagents, solvents etc.
  • WO2004005307 discloses a process for the preparation of duloxetine and its pharmaceutically acceptable salt by subjecting the enantiomeric mixture of (S)- (-)-3-N-methylamino- 1 -(2-thienyl)- 1 -propanol and (R)-(+)-3-N-methylamino- 1 -(2- thienyl)- l -propanol of Formula la and lb
  • the final duloxetine product prepared by most of the prior art processes show the presence of therapeutically inactive R-isomer, which result in the contamination of the final duloxetine product and in extreme cases might even be harmful to a patient being treated with a dosage form of the said API.
  • the process disclosed in the prior arts is not industrially feasible and cost effective as it requires substantial work up and treatment using multiple solvent systems for the racemization of undesired R- isomer. This not only lowers the yield on plant scale, but also increases the overall production cost of the final duloxetine hydrochloride.
  • an optically active compound (S)- N, N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine and the use of said optically active compound for producing (S)-A ⁇ -methyl-3-( l -naphthalenyloxy)-3-(2- thienyl)propanamine (duloxetine) or its hydrochloride salt in high chiral purity and having low amount
  • the present invention provides an improved process for producing (S)-N,N-dimethyl-3-(2-thienyl)-3- hydroxypropanamine of Formula III or its salt,
  • the present invention provides an improved process for producing (S)-N,jV-dimethyl-3-(2-thienyl)-3- hydroxypropanamine of Formula III or its salt,
  • HA is an optically active acid
  • and 2 independently represent an optionally substituted alkyl, cycloalkyl, aralkyl or aryl radical ; and R 3 in addition to these radicals, can also be a hydrogen, converting the resultant isourea ether of Formula V with the carboxylic acid in an aprotic solvent to obtain corresponding ester of Formula VI,
  • R represents hydrogen or an optionally substituted saturated or unsaturated aliphatic or cycloaliphatic hydrocarbon radicals or an optionally substituted araliphatic or aromatic hydrocarbon radicals and hydrolysis of the corresponding ester of Formula VI in presence of base using protic solvent, to obtain racemic N, N- dimethyl-3-(2-thienyl)-3-hydroxypropanamine, followed by resolving the racemic N, ;V-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with an optically active acid to precipitate (S)-N,yV-dimethyl-3-(2-thienyl)-3-hydroxypropanamine of Formula III or its salt.
  • the present invention provides an improved process for the preparation of (S)-N-methyl-3-( l -naphthalenyloxy)-3-(2- thienyl) propanamine (duloxetine) of Formula I or its hydrochloride salt,
  • the present invention provides an improved process for producing (S)-N,N-dimethyl-3-(2-thienyl)-3- hydroxypropanamine of Formula III or its salt, a key intermediate used for the preparation of (5)-N-methyl-3-( l -naphthalenyloxy)-3-(2-thienyl)propanamine (duloxetine) of Formula I or its hydrochloride salt, the process comprising the steps of;
  • HA is an optically active acid
  • the optically active acid used herein is selected from the group comprising of mandelic acid, tartaric acid, camphor sulphonic acid, dibenzoyl tartaric acid, toluoyl tartaric acid and the like.
  • the solvent employed during the resolution is selected from a group comprising of alcohol such as methanol, ethanol, n-propanol, isopropanol n-butanol, isobutanol and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and the like; ethers such as diethyl ether, methyl tertiary butyl ether, tetrahydrofuran, dioxane and the like; esters such as ethyl acetate, isopropyl acetate, butyl acetate and the like; or mixture thereof.
  • the resolution takes place at a temperature between 40- 100°C, preferably 45 to 90°C
  • the desired (S)-N,N-dimethyl-3-(2- thienyl)-3-hydroxypropanamine of Formula III or its salt is separated and the resulting mother liquor enriched with (R)-N, N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine or its salt is racemized using organic or inorganic acid or its mixture thereof.
  • the organic acid is selected from group comprising of formic acid, acetic acid, /?-toluene sulphonic acid, trifluoroacetic acid, camphorsulphonic acid and the like.
  • the inorganic acid is selected from the group comprising of hydrochloric acid, hydrobromic acid, perchloric acid, phosphoric acid, sulphamic acid, nitric acid, boron trifluoride, potassium hydrogen sulphate and the like.
  • a mixture of organic and inorganic acid such as hydrobromic acid in acetic acid can also be used.
  • the solvents used for racemization are selected from the group comprising of chlorinated hydrocarbons, alicyclic hydrocarbons, amides, sulphoxide, nitriles and the like or mixture thereof.
  • the solvent is selected from chloroform, dichloromethane, cyclohexane, dimethylformamide, dimethylacetamide, dimethylsulphoxide, acetonitrile, propionitrile and the like or mixture thereof.
  • the racemization takes place at a temperature between 20-100°C, preferably 20 to 60°C, more preferably between 20-30°C for 4- 1 Oh, preferably 6-8h.
  • the reaction temperature and reaction time depends upon the type of solvent chosen for the racemization.
  • HA is an optically active acid
  • Ri and R2 independently represent an optionally substituted alkyl, cycloalkyl, aralkyl or aryl radical; and R3 in addition to these radicals, can also additionally be hydrogen;
  • R4 represent hydrogen or an optionally substituted saturated or unsaturated aliphatic or cycloaliphatic hydrocarbon radicals or an optionally substituted araliphatic or aromatic hydrocarbon radicals
  • optically active acid used for resolving N, N-dimethyl-3-(2-thienyl)-3- hydroxypropanamine of Formula II or its salt is selected from the group comprising of mandelic acid, tartaric acid, camphor sulphonic acid, dibenzoyl tartaric acid, di- - toluoyl tartaric acid and the like.
  • the suitable solvent employed during the resolution is selected from a group comprising of alcohols such as methanol, ethanol, n- propanol, isopropanol n-butanol, isobutanol and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and the like; ethers such as diethyl ether, methyl tertiary butyl ether, tetrahydrofuran, dioxane and the like; esters such as ethyl acetate, isopropyl acetate, butyl acetate and the like; or mixture thereof.
  • the resolution takes place at a temperature between 40- 100°C, preferably 45 to 90°C, more preferably between 70-80°C for 1 -4 h, preferably 1 -2 h.
  • the resulting mother liquor enriched with (R)-N, N-dimethyl-3-(2-thienyl)-3- hydroxypropanamine or its salt is treated with a coupling agent which is selected from a group comprising of N, N -dicyclohexylcarbodimide, N.
  • the reaction optionally takes place in presence of catalyst selected from metal chloride preferably copper (I) and copper (II) halide, titanium (IV) alcoholates, titanium (IV) halides, zinc halide, tin halide, iron halide, boron halide, chromium chloride and the like, preferably copper (I) or copper (II) halide.
  • metal chloride preferably copper (I) and copper (II) halide, titanium (IV) alcoholates, titanium (IV) halides, zinc halide, tin halide, iron halide, boron halide, chromium chloride and the like, preferably copper (I) or copper (II) halide.
  • the solvent used for coupling reaction is selected from the group comprising of aromatic hydrocarbons such as toluene, xylene and the like; chlorinated hydrocarbons such as chloroform, dichloromethane, chlorobenzene and the like; esters such as ethyl acetate, propyl acetate and the like; ethers such as methyl tertiary butyl ether, tetrahydrofuran, 1 ,4-dioxane and the like; amides such as dimethyl formamide, dimethylacetamide and the like; sulphoxide such as dimethylsulphoxide and the like, nitriles such as acetonitrile, propionitrile and the like or mixture thereof.
  • the reaction is carried out under inert atmosphere at temperature 0-200°C, preferably 20- 100°C for 1 5-25 h, preferably 20-22 h.
  • R_t represent hydrogen or an optionally substituted saturated or unsaturated aliphatic or cycloaliphatic hydrocarbon radicals or an optionally substituted araliphatic or aromatic hydrocarbon radicals.
  • the carboxylic acid is selected from the group comprising of formic acid, acetic acid, benzoic acid, methane sulphonic acid, -toluene sulphonic acid and the like.
  • the aprotic solvent used for esterification is selected from, aliphatic hydrocarbons such as hexane, cyclohexane and the like; aromatic hydrocarbons such as toluene, xylene and the like; chlorinated hydrocarbons such as chloroform, dichloromethane and the like; esters such as ethyl aceate, propyl acetate, butyl acetate and the like; ethers such as tetrahydrofuran or dioxane and the like; amides such as dimethyl formamide and the like; sulphoxide such as dimethylsulphoxide and the like, nitriles such as acetonitrile, propionitrile and the like or mixture thereof.
  • the resulting ester of Formula VI undergoes hydrolysis to obtain racemic N, yV-dimethyl-3-(2-thienyl)-3-hydroxypropanamine of Formula II in presence of a base and optionally in a solvent.
  • the base is selected from the group comprising of an alkali metal or alkaline earth metal hydroxide, bicarbonates, carbonate and the like, wherein alkali metal or alkaline earth metal is selected from a group comprising of lithium, sodium, potassium, magnesium, calcium, barium and the like.
  • the solvent used herein is selected from protic solvents such as methanol, ethanol, propanol, butanol and the like.
  • the racemic N ⁇ V-dimethyl-3-(2- thienyl)-3-hydroxypropanamine compound of Formula II is further resolved using optically active acid to give the diasteriomerically enriched salt of the optically pure acid.
  • This salt is filtered and separated from the undesired (R) isomer to obtain enantiomerically pure (S)- ,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine of Formula III or its salt.
  • the present invention also provides an improved process for the preparation of (S)-N-methyl-3-( l - naphthalenyloxy)-3-(2-thienyl)propanamine (duloxetine) of Formula I or its hydrochloride salt
  • the reaction of desired (S)-jV,N-dimethyl-3-(2-thienyl)-3- hydroxypropanamine of Formula III or its salt with 1 -fluoronaphthalene takes place in presence of a base, wherein the base is selected from organic or inorganic.
  • the organic base is selected from diethylamine, triethylamine, pyridine and the like.
  • the inorganic base is selected from the group comprising of alkali metal or alkaline earth metal hydroxide, hydride, carbonate and the like, wherein alkali metal or alkaline earth metal is selected from a group comprising of lithium, sodium, potassium, magnesium, calcium, barium and the like.
  • the solvent used in the reaction is selected from the group comprising of amides such as dimethylformamide, dimethyl acetamide; sulphoxide such as dimethylsulphoxide and the like; esters such as ethyl acetate, propyl acetate, butyl acetate and the like or mixture thereof.
  • the resulting (S)-N,N-dimethyl-3-( l -naphthalenyloxy)-3-(2- thienyl)propanamine of Formula VII is converted into (S)-N,N-dimethyl-3-( l - naphthalenyloxy)-3-(2-thienyl)propanamine oxalate salt of Formula VIII using organic solvent, wherein the organic solvent is selected from esters such as ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate and the like, chlorinated hydrocarbons such as chloroform, dichloromethane and the like or mixture thereof.
  • organic solvent is selected from esters such as ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate and the like, chlorinated hydrocarbons such as chloroform, dichloromethane and the like or mixture thereof.
  • (2-thienyl)propanamine oxalate salt of Formula VIII is carried out without isolating intermediate compound (S)-jV,jV-dimethyI-3-(l -naphthalenyloxy)-3-(2- thieny propanamine of Formula VII, thereby reduces a step during the synthesis of duloxetine hydrochloride.
  • the resulting (5)-NJv r -dimethyl-3-( 1 -naphthalenyloxy)-3-(2-thienyl) propanamine oxalate salt of Formula VIII undergoes demethylation via carbamate formation by treatment with chloroformate, preferably phenyl chloroformate using diisopropylamine as a base to obtain carbamate intermediate, which in situ is subjected to hydrolysis with an alkali metal hydoxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide barium hydroxide, cesium hydroxide and the like in an hydrocarbon solvents, preferably aromatic hydrocarbons selected from the group comprising of toluene, xylene, and the like, preferably in toluene to obtain duloxetine base, as an oily residue.
  • chloroformate preferably phenyl chloroformate using diisopropylamine as a base
  • duloxetine base is further converted to duloxetine hydrochloride, free from the acidic impurity by treating the duloxetine free base with solvent preferably ethyl aceate followed by addition of concentrated hydrochloric acid.
  • solvent preferably ethyl aceate followed by addition of concentrated hydrochloric acid.
  • the resulting solid was washed with ethyl acetate till the pH of the filtrate becomes neutral (pH 6 to 7). Washing with excess of ethyl aceate of the crude duloxetine hydrochloride not only removes the residual hydrochloride, which adhere on the surface of duloxetine hydrochloride molecules but also enhances the purity and stability of the final duloxetine hydrochloride.
  • the resulting crude duloxetine hydrochloride is then optionally purified by treating the resultant with ester solvent, preferably ethyl acetate followed by addition of water to obtain pure duloxetine hydrochloride.
  • ester solvent preferably ethyl acetate
  • racemic N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine of Formula II used as starting material is prepared from 2-acetyl thiophene by the methods known in the prior arts.
  • the present invention provides a safe, environment and industrial friendly and commercially viable process for the production of duloxetine hydrochloride having low content of undesired R-isomer and chiral purity not less than 99%.
  • Example 1 The following examples are provided only to exemplify, but not to limit the scope of the invention.
  • Example 1 The following examples are provided only to exemplify, but not to limit the scope of the invention.
  • N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine obtained from Example 1 was taken in 3 1 5 ml of ethanol and 60 ml of methyl tertiary butyl ether at room temperature and 77g of 5"-(+)-mandelic acid was added. The reaction mixture was heated at 70-80°C under stirring for 1 hr. The reaction mass was cooled to 1 5-20°C under stirring for 2h and the resulting solid was filtered, washed with methyl tertiary butyl ether and dried under vacuum. To the resulting solid, 180 ml ethanol and 45 ml methyl tertiary butyl ether was added and heated to 70-75°C under stirring for 1 h.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé amélioré pour racémiser un des énantiomères, ou un mélange enrichi de manière énantiomérique, d'un composé optiquement actif (S)-N, N-diméthyl-3-(2-thiényl)-3-hydroxypropanamine, un intermédiaire clé utilisé pour la préparation de (S)-N-méthyl-3-(1-naphthalènyloxy)-3-(2- thiényl) propanamine (duloxétine) ou un chlorhydrate de celle-ci. L'invention concerne également un procédé amélioré pour la préparation de (S)-N-méthyl-3- (1-naphthalènyloxy)-3-(2-thiényl) propanamine (duloxétine) ou un chlorhydrate de celle-ci présentant une faible teneur en R-isomères non désirés et une pureté chirale non inférieure à 99 %.
PCT/IB2010/002320 2009-09-16 2010-09-16 Procédé amelioré pour la préparation de duloxetine et de sel acceptable sur le plan pharmaceutique de celle-ci Ceased WO2011033366A2 (fr)

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Cited By (4)

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CN104163811A (zh) * 2013-05-16 2014-11-26 重庆圣华曦药业股份有限公司 一种制备度洛西汀盐酸盐的新方法
CN104829587A (zh) * 2015-05-08 2015-08-12 上海万巷制药有限公司 盐酸度洛西汀的制备
CN107382958A (zh) * 2017-07-05 2017-11-24 浙江华海药业股份有限公司 一种度洛西汀中间体的结晶方法
CN114790146A (zh) * 2022-05-19 2022-07-26 河南省科学院高新技术研究中心 一种3-(甲基氨基)-1-芳香基丙酮的制备方法

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WO2004056795A1 (fr) 2002-12-19 2004-07-08 Cipla Ltd Procede de preparation de la duloxetine et intermediaires destines a etre utilises dans ledit procede
WO2006045255A1 (fr) 2004-10-26 2006-05-04 Zentiva, A.S. Procede de fabrication de (s)-n-methyl-3-(1-naphtyloxy)-3-(2-thienyl)propylamine hydrochlorure (duloxetine)
WO2007045405A1 (fr) 2005-10-18 2007-04-26 Solmag S.P.A. Procede de fabrication de duloxetine
WO2007098250A2 (fr) 2006-02-21 2007-08-30 Teva Pharmaceutical Industries Ltd. Procédé de préparation de (s)-(-)-n,n-diméthyl-3-(2-thiényl)-3-hydroxypropanamine, un composant de la duloxétine

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WO2006126213A1 (fr) * 2005-05-24 2006-11-30 Matrix Laboratories Ltd Ameliorations apportees a un procede de preparation de duloxetine
WO2008093360A2 (fr) * 2007-01-31 2008-08-07 Usv Limited Procédé de préparation d'hydrochlorure de (s)-(+)-n-méthyl-3(1-naphthyloxy)-3(2-thienyl)propylamine

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US4956388A (en) 1986-12-22 1990-09-11 Eli Lilly And Company 3-aryloxy-3-substituted propanamines
US5023269A (en) 1986-12-22 1991-06-11 Eli Lilly And Company 3-aryloxy-3-substituted propanamines
US5362886A (en) 1993-10-12 1994-11-08 Eli Lilly And Company Asymmetric synthesis
WO2004005307A1 (fr) 2002-07-09 2004-01-15 Lonza Ag Procede de preparation de 3-n-methylamino-1-(2-thienyl)-1-propanol optiquement actif
WO2004031168A2 (fr) 2002-10-07 2004-04-15 Lonza Ag Procedes et produits intermediaires pour la preparation de derives de 3-amino-1-(2-thienyl)-1-propanol optiquement actifs
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CN104829587A (zh) * 2015-05-08 2015-08-12 上海万巷制药有限公司 盐酸度洛西汀的制备
CN107382958A (zh) * 2017-07-05 2017-11-24 浙江华海药业股份有限公司 一种度洛西汀中间体的结晶方法
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CN114790146A (zh) * 2022-05-19 2022-07-26 河南省科学院高新技术研究中心 一种3-(甲基氨基)-1-芳香基丙酮的制备方法
CN114790146B (zh) * 2022-05-19 2024-03-29 河南省科学院高新技术研究中心 一种3-(甲基氨基)-1-芳香基丙酮的制备方法

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