[go: up one dir, main page]

WO2006126213A1 - Ameliorations apportees a un procede de preparation de duloxetine - Google Patents

Ameliorations apportees a un procede de preparation de duloxetine Download PDF

Info

Publication number
WO2006126213A1
WO2006126213A1 PCT/IN2006/000174 IN2006000174W WO2006126213A1 WO 2006126213 A1 WO2006126213 A1 WO 2006126213A1 IN 2006000174 W IN2006000174 W IN 2006000174W WO 2006126213 A1 WO2006126213 A1 WO 2006126213A1
Authority
WO
WIPO (PCT)
Prior art keywords
dimethyl
thienyl
propanamine
naphthalenyloxy
salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2006/000174
Other languages
English (en)
Inventor
Chava Satyanarayana
Gorantla Seeta Ramanjaneyulu
Chavakula Ramdas
Konudula Babu Rao
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mylan Laboratories Ltd
Original Assignee
Matrix Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Matrix Laboratories Ltd filed Critical Matrix Laboratories Ltd
Publication of WO2006126213A1 publication Critical patent/WO2006126213A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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 process for the preparation of (S)-(+)-N, N- dimethyl-3- (1-naphthalenyloxy) -3-(2-thienyl) propanamine, a key intermediate for the preparation of Duloxetine or an acid addition salt.
  • Duloxetine [(+)-N-methyl-3- (l-naphthalenyloxy)-3-(2-thienyl) propanamine] has the following structure
  • Duloxetine hydrochloride is the active ingredient of 'CYMBALTA', which inhibits the uptake of both norepinephrine and serotonin.
  • Duloxetine was first disclosed in U.S. Pat. No. 4,956,388 by Robertson, et al., and the synthesis of it was discussed in more detail by Deeter, et al., in Tetrahedron Letters, 31 (49), 7101 -04 ( 1990).
  • PCT publication WO 2004/056795 discloses a process for the preparation of Duloxetine, or an acid addition salt thereof, which process comprises resolving racemic Duloxetine with a chiral acid so as to obtain a salt of the chiral acid and (+) Duloxetine, substantially free of (-) Duloxetine; and also disclosed a process for preparing (+) Duloxetine, or an acid addition salt thereof, comprise an O-alkylation intermediate process step which is carried out in the presence of a base and a phase transfer catalyst.
  • EP 0457559 discloses a process for the preparation of D (+) Duloxetine oxalate as shown in the following scheme-3.
  • the present invention provides a process for preparation of Duloxetine, or an acid addition salt by coupling N, N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with 1- fluoro naphthalene in presence of an alkoxide in an organic polar solvent followed by resolution and demethylation yields Duloxetine or coupling (S)-(-)-N,N-dimethyl-3-(2- thienyl)-3 -hydroxy propanamine with 1-fiuoronaphthalene in presence of an alkoxide in an organic polar solvent followed by demethylation yields Duloxetine and also recycling the unwanted isomer in the preparation of Duloxetine.
  • N, N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with 1- fluoro naphthalene in presence of an alkoxide in an organic polar solvent followed by resolution and demethylation yields Duloxetine
  • a process for the preparation of Duloxetine, or an acid addition salt comprising steps; i. Condensation of N, N-dimethyl-3 ⁇ (2-thienyI)-3-hydroxypropanamine with 1- fluoro naphthalene so as to obtain N,N-dimethyl-3-(l-naphthalenyloxy) -3-(2- thienyl) propanamine (optionally converting it to its oxalate salt), ii.
  • Condensation of N,N-dimethyI-3-(2-thienyl)-3-hydroxy propanamine with 1-fluoro naphthalene is carried out in presence of an alkoxide selected from potassium tert.butoxide, sodium methoxide and sodium ethoxide in an organic polar solvent selected from Dimethyl sulphoxide, N,N-Dimethyl formamide and N,N-Dimethyl acetamide at a temperature ranging from room temperature to 70°C, preferably at 50-60°C.
  • an alkoxide selected from potassium tert.butoxide, sodium methoxide and sodium ethoxide
  • organic polar solvent selected from Dimethyl sulphoxide, N,N-Dimethyl formamide and N,N-Dimethyl acetamide
  • N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine prepared according to the present invention as described above can be isolated as its acid addition salts which includes oxalate salt, phosphate salt, hydrochloride salt, nitrate salt and tartrate salt among which preferable one is the oxalate salt.
  • N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine is achieved with a suitable chiral acid in a suitable solvent.
  • the chiral acids employed in a process according to the present invention are Tartaric acid, Mandelic acid, camphor sulphonic acid, Dibenzyl tartaric acid and Diparatolyl tartaric acid.
  • the solvents employed are alkanols, esters or a mixture of alkanol, ester and water.
  • the present invention further relates to a process for the preparation of Duloxetine, or an acid addition salt comprising steps:
  • the present invention further relates to a process for the preparation of Duloxetine, or an acid addition salt comprising steps:
  • Racemization of the (-)-N,N-dimethyl-3-( 1-naphthalenyloxy) -3-(2 -thienyl) propanamine is carried out in alkanols or polar aprotic solvents in presence of a base selected from alkali metal hydroxides preferably potassium hydroxide and alkoxide of alkali metals to get N,N-dimethyl-3-( 1-naphthalenyloxy) -3 -(2 -thienyl) propanamine.
  • a base selected from alkali metal hydroxides preferably potassium hydroxide and alkoxide of alkali metals to get N,N-dimethyl-3-( 1-naphthalenyloxy) -3 -(2 -thienyl) propanamine.
  • N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine is achieved with a suitable chiral acid in a suitable solvent.
  • the chiral acids employed in a process according to the present invention are Tartaric acid, Mandeiic acid, camphor sulphonic acid, Dibenzyl tartaric acid and Diparatolyl tartaric acid.
  • the solvents employed are alkanols, esters or a mixture of alkanol, ester and water.
  • the invention can be further illustrated by the below non-limiting examples.
  • N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine (25.0gm) is dissolved in DMSO (150ml) at room temperature.
  • Potassium.tertButoxide (15.5gm) is added over a period of 30min at room temperature.
  • the reaction mixture is stirred for 30min at 25-30 C and 4- Fluoronaphthalene (24.45gm) is added slowly over a period of lhour.
  • Reaction mass temperature is slowly raised to 50-55 0 C and maintained for about ⁇ hours at that temperature.
  • After the reaction is completed reaction mass is cooled to room temperature and Acetic acid (10ml) is slowly added over a period of lOmin and quenched in water at 20 0 C.
  • Reaction mass pH is adjusted to about 5.0 with acetic acid and extracted with n-Hexane. Aq layer is separated and pH is adjusted to 11.5 with 5N NaOH and extracted with ethyl acetate. The ethyl acetate layer is washed and concentrated under vacuum. The residue is dissolved in ethyl acetate and treated with activated charcoal. To the clear filtrate Oxalic acid (15.3gm) is added. The reaction mixture is stirred for 2hrs and the precipitated Oxalate salt is filtered. Out put: 44.0gm (81.5 % yield)
  • Duloxetine (27gm) is dissolved in ethyl acetate (90ml) and cooled the mass to 10 0 C. pH is adjusted to below 2.0 with IPA.HC1 over a period of one hour. Stirred the reaction mass for lhour at 10 0 C and lhour at O 0 C. Precipitated hydrochloride salt is filtered, washed with 100ml ethyl acetate and dried the product at 50-55 0 C. Out put: 14.0 gm.
  • Example-4 (+)-N-methyI-3-(l-naphthalenyloxy)-3-(2-thie ⁇ yl) propanamine (Duloxetine)
  • reaction mass After the reaction is completed cooled the reaction mass to 20 0 C and slowly quenched in DM water at 20°C.Reaction mass pH is adjusted to 7.7 with Acetic acid and washed the reaction mass with n-hexane. Aq.layer is separated and pH is adjusted to 10.5 with caustic lye. Extracted with ethyl acetate and ethyl acetate is concentrated under vacuum to get residue. The obtained residue is dissolved in ethyl acetate and treated with activated charcoal. The filtered ethyl acetate layer is concentrated to give Duloxetine. Out put: 26gm (Yield; 95.0 %)
  • Duloxetine (26gm) is dissolved in ethyl acetate (90ml) and cooled the mass to 10 0 C. pH is adjusted to below 2.0 with IPA.HC1 over a period of one hour. Stirred the reaction mass for lhour at 10 0 C and lhour at O 0 C. Precipitated hydrochloride salt is filtered, washed with 100ml ethyl acetate and dried the product at 50-55 0 C. Out put: 13.8gm.

Landscapes

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

Abstract

L'invention concerne un procédé destiné à la préparation de la duloxétine ou de son sel d'addition acide, comprenant (i) une condensation de la (S)-(-)-N, N-diméthyl-3-(2-thiényl)-3-hydroxy propanamine avec du 1-fluoronaphtalène suivie d'une déméthylation ou d'une condensation de la N, N-diméthyl-3-(2-thiényl)-3-hydroxy propanamine avec du 1-fluoronaphtalène suivie d'une résolution et d'une déméthylation ; et (ii), si on le souhaite, une conversion de la duloxétine en sel d'addition acide de la duloxétine.
PCT/IN2006/000174 2005-05-24 2006-05-23 Ameliorations apportees a un procede de preparation de duloxetine Ceased WO2006126213A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN623/CHE/2005 2005-05-24
IN623CH2005 2005-05-24

Publications (1)

Publication Number Publication Date
WO2006126213A1 true WO2006126213A1 (fr) 2006-11-30

Family

ID=37451674

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2006/000174 Ceased WO2006126213A1 (fr) 2005-05-24 2006-05-23 Ameliorations apportees a un procede de preparation de duloxetine

Country Status (1)

Country Link
WO (1) WO2006126213A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007067581A1 (fr) * 2005-12-05 2007-06-14 Teva Pharmaceutical Industries Ltd. 2-(n-methyl-propanamine)-3-(2-naphtol)thiophene, une impurete du duloxetine chlorhydrate
WO2007076733A3 (fr) * 2006-01-04 2007-08-23 Zentiva As Procédé pour la préparation de chlorhydrate de (s)-n-métηyl-3-(1-naphtyloxy)-3-(2-thiényl)propylamine (duloxétine)
WO2007095200A3 (fr) * 2006-02-13 2008-08-21 Teva Pharma nouveau processus pour la preparation de (S)-(+)-N,N-DIMETHYL-3-(1-NAPHTHALENYLOXY)-3-(2-THIENYL)PROPANAMINE, un intermediaire de la duloxetine
WO2008107911A3 (fr) * 2007-03-05 2008-11-20 Lupin Ltd Nouveau procédé de préparation du chlorhydrate de duloxétine
US7534900B2 (en) 2005-03-14 2009-05-19 Teva Pharmaceutical Industries Ltd Process for the purification of duloxetine hydrochloride
WO2009074883A3 (fr) * 2007-11-06 2009-08-06 Medichem Sa Procédé amélioré pour la préparation de duloxétine
US7842717B2 (en) 2005-09-22 2010-11-30 Teva Pharmaceutical Industries Ltd. DNT-maleate and methods of preparation thereof
WO2011033366A3 (fr) * 2009-09-16 2011-09-01 Jubilant Life Sciences Limited Procédé amelioré pour la préparation de duloxetine et de sel acceptable sur le plan pharmaceutique de celle-ci
JP2011236195A (ja) * 2010-05-06 2011-11-24 Sci Pharmatech Inc 光学活性のメチルヒドロキシルアミノプロパノール化合物を中間体として用いる（ｓ）−（＋）−ｎ−メチル−３−（１−ナフチルオキシ）−３−（２−チエニル）プロピルアミンの製造方法
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
CN114163415A (zh) * 2021-12-01 2022-03-11 珠海润都制药股份有限公司 一种盐酸度洛西汀中间体的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5362886A (en) * 1993-10-12 1994-11-08 Eli Lilly And Company Asymmetric synthesis
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)

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5362886A (en) * 1993-10-12 1994-11-08 Eli Lilly And Company Asymmetric synthesis
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)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7534900B2 (en) 2005-03-14 2009-05-19 Teva Pharmaceutical Industries Ltd Process for the purification of duloxetine hydrochloride
US7842717B2 (en) 2005-09-22 2010-11-30 Teva Pharmaceutical Industries Ltd. DNT-maleate and methods of preparation thereof
US7759500B2 (en) 2005-12-05 2010-07-20 Teva Pharmaceutical Industries Ltd. 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene, an impurity of duloxetine hydrochloride
WO2007067581A1 (fr) * 2005-12-05 2007-06-14 Teva Pharmaceutical Industries Ltd. 2-(n-methyl-propanamine)-3-(2-naphtol)thiophene, une impurete du duloxetine chlorhydrate
EA014559B1 (ru) * 2006-01-04 2010-12-30 ЗЕНТИВА, а.с. Способ получения (s)-n-метил-3-(1-нафтилокси)-3-(2-тиенил)пропиламина гидрохлорида (дулоксетина)
US8207356B2 (en) 2006-01-04 2012-06-26 Zentiva K.S. Method for the preparation of (S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride (duloxetine)
WO2007076733A3 (fr) * 2006-01-04 2007-08-23 Zentiva As Procédé pour la préparation de chlorhydrate de (s)-n-métηyl-3-(1-naphtyloxy)-3-(2-thiényl)propylamine (duloxétine)
US8071791B2 (en) 2006-01-04 2011-12-06 Zentiva K.S. Method for the preparation of (S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride (duloxetine)
EP2172464A3 (fr) * 2006-01-04 2010-05-12 Zentiva, k.s. Procédé de préparation du sel chlorhydrate de Duloxetin
WO2007095200A3 (fr) * 2006-02-13 2008-08-21 Teva Pharma nouveau processus pour la preparation de (S)-(+)-N,N-DIMETHYL-3-(1-NAPHTHALENYLOXY)-3-(2-THIENYL)PROPANAMINE, un intermediaire de la duloxetine
US8269023B2 (en) 2007-03-05 2012-09-18 Lupin Ltd. Process for preparation of duloxetine hydrochloride
WO2008107911A3 (fr) * 2007-03-05 2008-11-20 Lupin Ltd Nouveau procédé de préparation du chlorhydrate de duloxétine
WO2009074883A3 (fr) * 2007-11-06 2009-08-06 Medichem Sa Procédé amélioré pour la préparation de duloxétine
WO2011033366A3 (fr) * 2009-09-16 2011-09-01 Jubilant Life Sciences Limited Procédé amelioré pour la préparation de duloxetine et de sel acceptable sur le plan pharmaceutique de celle-ci
JP2011236195A (ja) * 2010-05-06 2011-11-24 Sci Pharmatech Inc 光学活性のメチルヒドロキシルアミノプロパノール化合物を中間体として用いる（ｓ）−（＋）−ｎ−メチル−３−（１−ナフチルオキシ）−３−（２−チエニル）プロピルアミンの製造方法
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
CN114163415A (zh) * 2021-12-01 2022-03-11 珠海润都制药股份有限公司 一种盐酸度洛西汀中间体的制备方法
CN114163415B (zh) * 2021-12-01 2023-03-03 珠海润都制药股份有限公司 一种盐酸度洛西汀中间体的制备方法

Similar Documents

Publication Publication Date Title
KR100926723B1 (ko) 둘록세틴의 제조 방법 및 이에 이용하기 위한 중간체
WO2006126213A1 (fr) Ameliorations apportees a un procede de preparation de duloxetine
US20100286412A1 (en) Synthesis and preparations of duloxetine salts
JP2002541235A (ja) ３−アリールオキシ−３−アリールプロピルアミン及びその中間体の製造方法
US20110004007A1 (en) PROCESS FOR THE PREPARATION OF N-MONOSUBSTITUTED beta-AMINO ALCOHOLS
IE911677A1 (en) Chiral synthesis of 1-aryl-3-aminopropan-1-ols
US20060270861A1 (en) Process for the preparation of optically active (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine
US7550605B2 (en) Process for preparation of an anitdepressant compound
WO2006045255A1 (fr) Procede de fabrication de (s)-n-methyl-3-(1-naphtyloxy)-3-(2-thienyl)propylamine hydrochlorure (duloxetine)
US8269023B2 (en) Process for preparation of duloxetine hydrochloride
EP1476439A1 (fr) Preparation de derives de n-methyl-3-hydroxy- 3-(2-thienyl)propylamine via de nouveaux derives de thiophene contenant des groupes carbamates en tant qu'intermediaires
WO2011033366A8 (fr) Procédé amelioré pour la préparation de duloxetine et de sel acceptable sur le plan pharmaceutique de celle-ci
WO2008093360A2 (fr) Procédé de préparation d'hydrochlorure de (s)-(+)-n-méthyl-3(1-naphthyloxy)-3(2-thienyl)propylamine
US20100280093A1 (en) Process for the preparation enantiomerically pure salts of n-methyl-3-(1-naphthaleneoxy)-3-(2-thienyl)propanamine
US20080015363A1 (en) Process for the preparation of (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropananine, a duloxetine intermediate
WO2007076733A2 (fr) Procédé pour la préparation de chlorhydrate de (s)-n-métηyl-3-(1-naphtyloxy)-3-(2-thiényl)propylamine (duloxétine)
WO2009087463A2 (fr) Procédé d'élaboration de duloxétine hydrochlorure
EP2125772B1 (fr) Procédé de préparation de duloxétine et nouveaux intermédiaires clés pour une utilisation dans celui-ci.
EP2060559A1 (fr) Procédé pour la préparation de 3-hyxdroxy-3-arylpropylamines énantiomériquement pures et leurs stéréoisomères optiques
EP2376471A2 (fr) Procédé amélioré de préparation de duloxétine et de sels de celle-ci
EP2393799A1 (fr) Procédés de préparation du chlorhydrate de duloxétine
WO2009130708A2 (fr) Préparation de duloxétine et de ses sels
CZ296345B6 (cs) Zpusob výroby hydrochloridu (R)-N-methyl-3-(2-methylfenoxy)-3-fenylpropylaminu (atomoxetinu)
WO2009019719A2 (fr) Procédé de préparation de 3-aryloxy-3-arylpropanamines
WO2009109992A1 (fr) Nouveau procédé de préparation de duloxétine et intermédiaires pour l'utiliser

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

NENP Non-entry into the national phase

Ref country code: RU

WWW Wipo information: withdrawn in national office

Country of ref document: RU

122 Ep: pct application non-entry in european phase

Ref document number: 06745223

Country of ref document: EP

Kind code of ref document: A1