WO2011077443A1 - Procédé amélioré pour la préparation de chlorhydrate de duloxétine - Google Patents

Procédé amélioré pour la préparation de chlorhydrate de duloxétine Download PDF

Info

Publication number
WO2011077443A1
WO2011077443A1 PCT/IN2010/000061 IN2010000061W WO2011077443A1 WO 2011077443 A1 WO2011077443 A1 WO 2011077443A1 IN 2010000061 W IN2010000061 W IN 2010000061W WO 2011077443 A1 WO2011077443 A1 WO 2011077443A1
Authority
WO
WIPO (PCT)
Prior art keywords
amine
thiophen
yloxy
naphthalen
propan
Prior art date
Application number
PCT/IN2010/000061
Other languages
English (en)
Inventor
Chandrashekar Aswathanarayanappa
Pullela Venkata Srinivas
Guruprasad Tadapatri
Original Assignee
Biocon Limited
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 Biocon Limited filed Critical Biocon Limited
Publication of WO2011077443A1 publication Critical patent/WO2011077443A1/fr

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
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • 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 disclosure is related to a process for preparation of duloxetine hydrochloride, an Active Pharmaceutical Ingredient [API].
  • the present disclosure relates to an improved process for the preparation of Duloxetine Hydrochloride, (S)-(+)-N-methyl-3(l-naphthalenyloxy)-3-(2-thienyl)propanamine hydrochloride, compound of formula (VI).
  • Duloxetine hydrochloride is currently marketed as an anti-depressant and inhibits the uptake of both norepinephrine and serotonin.
  • Duloxetine is disclosed in U.S. Pat. Nos. 5,023,269 and 4,956,388 by Robertson, et al. The synthesis of duloxetine is discussed in more detail by Berglund, R. A., Org. Proc. Res. Devel., 1, 328 (1997) and Deeter, et al., in Tetrahedron Letters, 31(40), 7101-04 (1990) and aspects patented in U.S. Pat. Nos. 5,362,866 and 5,491,243.
  • U.S. Pat. No. 5,362,866 discloses a process to synthesize duloxetine via arylation of a dimethylamino alcohol, with 1-fluoronaphthalene which may be recovered as the phosphoric acid salt if desired.
  • the dealkylation yields duloxetine as a final product.
  • the present invention is advantageous in reducing the racemization caused due to elevated temperature formation and hydrolysis in polyethylene glycol.
  • the first objective of the disclosure is to provide an improved process for the preparation of duloxetine hydrochloride.
  • Second objective of the disclosure is to prevent racemization of duloxetine hydrochloride followed by preventing the formation of its unwanted isomer.
  • the present disclosure is in relation to a process for preparation of (S)-(+)-N-methyl-3-(naphthalen- l-yloxy)-3-(thiophen-2- yl)propan- l -amine hydrochloride, comprising steps of: preparing (S)-(+)- N,N-dimethyl-3-(naphthalen- 1 -yloxy)-3-(thiophen-2-yl)propan- 1 -amine by reacting (S)-(-)-3-(dimethylamino)-l -(thiophen-2-yl)propan-l-ol and 1-Flouoro Naphthalene in the presence of Potassium benzoate and NaH at room temperature in an organic solvent; reacting (S)-(+)-N,N-dimethyl-3-(naphthalen-l-yloxy)-3-(thiophen-2- yl)propan-l -amine with ethychloro formate in the presence
  • This invention is to provide an improved process for the synthesis of Duloxetine hydrochloride, (S)-(+)-N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan -1- amine hydrochloride in good yield, in large amounts and with desired purity.
  • This invention includes a process for preparing (S)-(+)-N,N-dimethyl-3-(naphthalen-l- yloxy)-3-(thiophen-2-yl)propan-l -amine comprising reacting (S)-(-)-3- (dimethylamino)-l-(thiophen-2-yl)propan-l-ol with sodium hydride and 1- fluoronaphthalene in dimethylsulfoxide at ambient temperature. This process reduces the racemization caused due to elevated temperature.
  • Another embodiment of this invention includes a process for preparing (S)-(+)-ethyl methyl(3-(naphthalen-l -yloxy)-3-(thiophen-2-yl)propyl)carbamate comprising reacting (S)-(+)-N,N-dimethyl-3-(naphthalen- 1 -yloxy)-3-(thiophen-2-yl)propan- 1 -amine with ethyl chloroformate in toluene in presence of diisopropyl ethyl amine at reflux temperature.
  • a further embodiment of the present invention includes a process for preparing (S)-(+)- N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine comprising hydrolysis of (S)-(+)-ethyl methyl(3-(naphthalen-l-yIoxy)-3-(thiophen-2- yl)propyl)carbamate using potassium hydroxide in polyethylene glycol-400 at 65-70° C.
  • the present invention provides a process for preparing (S)-(+)-N-methyl- 3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l -amine hydrochloride from (S)-(+)- N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine by converting it into its oxalate salt or by direct conversion to Duloxetine hydrochloride.
  • the disclosed workup procedure includes adjusting the pH of the reaction mixture to acidic by using Acetic acid.
  • 1-Fluoronaphthalene was extracted to n-hexane.
  • the product was then extracted from its acetate salt by adjusting the pH to basic using liq. ammonia solution.
  • acid base work up is avoided and the product is directly extracted to ethyl acetate.
  • Unreacted 1-Fluoronaphthalene is subsequently removed by oxalate salt formation or hydrochloride formation.
  • Another embodiment of this invention includes a process for the preparation of (S)-(+)- ethyl methyl(3-(naphthalen- 1 -yloxy)-3-(thiophen-2-yI)propyl)carbamate comprising reacting (S)-(+)-N,N-dimethyl-3-(naphthalen- 1 -yloxy)-3-(thiophen-2-yl)propan- 1 - amine with ethyl chloroformate in toluene in presence of diisopropyl ethyl amine at reflux temperature.
  • reaction time is about 15 minutes to Ihour.
  • this process provides a better pathway to obtain (S)-(+)-ethyl methyl(3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propyl)carbamate in its pure form in good yields.
  • a further embodiment of the present invention includes a process for preparing (S)-(+)- N-methyl-3 -(naphthalen- 1 -yloxy)-3-(thiophen-2-y l)propan- 1 -amine comprising hydrolysis of (S)-(+)-ethyl methyl(3 -(naphthalen- l-yloxy)-3 -(thiophen-2- yl)propyl)carbamate using potassium hydroxide in polyethylene glycol-400 at 30° C to 100° C.
  • This process is very effective in hydrolyzing (S)-(+)-ethyl methyl(3- (naphthalen-l-yloxy)-3-(thiophen-2-yl)propyl)carbamate to secondary amine.
  • the process followed is novel, introduces the use of Polyethylene glycol-400 as a solvent in hydrolysis of (S)-(+)-ethyl methyl(3-(naphthalen-l-yloxy)-3-(thiophen-2- yl)propyl)carbamate.
  • the present invention provides a process for preparing (S)-(+)-N-methyl- 3-(l-naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l-amine hydrochloride from (S)- (+)-N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl)propan-l -amine by converting into its oxalate salt.
  • This process provides a pathway to remove unreacted 1- Fluoronaphthalene which was carried over from O-arylation stage and improves the purity of Duloxetine free amine in good yields.
  • (S)-(+)-N-methyl-3-(naphthalen-l-yloxy)-3-(thiophen-2-yl) propan-1 -amine is directly converted into Duloxetine hydrochloride avoiding oxalate salt formation.
  • This process reduces the process time by one step providing required quality of Duloxetine hydrochloride. Efforts were made to circumvent the purification step as it involves the loss of yield to as much as 45% in oxalate salt formation.
  • the amine is directly converted to its Hydrochloride salt by treating it with Cone. Hydrochloric acid in a mixture of Ethyl acetate and Acetone.
  • the duloxetine amine was purified by converting into its oxalate salt in a mixture of ethyl acetate and acetone. This process provides a new method for purification of Duloxetine amine which also removes unreacted 1- Fluoronaphthalene which was carried over from O-arylation stage. The oxalate salt thus obtained is further converted into Duloxetine hydrochloride in its pure form.
  • Duloxetine free amine is converted into Duloxetine hydrochloride in the mixture of Ethyl acetate and Acetone in presence of Cone. Hydrochloric acid.
  • This improved process provides a method for hydrochloride formation in its purest form. This improved process avoids purification of Duloxetine hydrochloride.
  • stepl the reaction was carried out at 25 to 30° C to avoid partial racemization as against other processes which were carried out at 65-70° C. This is advantageous as the reagent used here is sodium hydride.
  • step 1 the workup procedure in step 1 to remove unreacted 1-Fluoronaphthalene is avoided as it can be removed in subsequent steps by oxalate formation or hydrochloride formation.

Landscapes

  • 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 fournit une solution au problème associé à la préparation de chlorhydrate de duloxétine. La présente invention permet d'empêcher la racémisation et donc d'inhiber la formation d'isomère indésirable de chlorhydrate de duloxétine. La présente invention concerne également une technique simple pour l'élimination de réactif n'ayant pas réagi, du 1-fluoronapthalène étant utilisé comme réactif dans le procédé pour obtenir du chlorhydrate de (S)-(+)-N-méthyl-3(1-naphthalényloxy)-3-(2-thienyl)propanamine, un composé de formule (VI).
PCT/IN2010/000061 2009-12-22 2010-02-03 Procédé amélioré pour la préparation de chlorhydrate de duloxétine WO2011077443A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3159CH2009 2009-12-22
IN3159/CHE/2009 2009-12-22

Publications (1)

Publication Number Publication Date
WO2011077443A1 true WO2011077443A1 (fr) 2011-06-30

Family

ID=44195033

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2010/000061 WO2011077443A1 (fr) 2009-12-22 2010-02-03 Procédé amélioré pour la préparation de chlorhydrate de duloxétine

Country Status (1)

Country Link
WO (1) WO2011077443A1 (fr)

Citations (3)

* 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
WO2006071868A2 (fr) * 2004-12-23 2006-07-06 Teva Pharmaceutical Industries Ltd. Processus de preparation de sels de duloxetine repondant aux normes pharmaceutiques et d'intermediaires de ceux-ci
WO2007134168A2 (fr) * 2006-05-10 2007-11-22 Dr. Reddy's Laboratories Ltd. Procédé de préparation de duloxétine

Patent Citations (3)

* 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
WO2006071868A2 (fr) * 2004-12-23 2006-07-06 Teva Pharmaceutical Industries Ltd. Processus de preparation de sels de duloxetine repondant aux normes pharmaceutiques et d'intermediaires de ceux-ci
WO2007134168A2 (fr) * 2006-05-10 2007-11-22 Dr. Reddy's Laboratories Ltd. Procédé de préparation de duloxétine

Similar Documents

Publication Publication Date Title
EP0650965B1 (fr) Synthèse asymétrique de (S)-(+)-N,N-dimethyl-3-(1-naphtalényloxy)-3-(2-thiènyl)propénamine un produit intermédiaire pour la préparation de duloxetine
US8158808B2 (en) Synthesis and preparations of duloxetine salts
US7550605B2 (en) Process for preparation of an anitdepressant compound
EP1758879B1 (fr) Procede de fabrication de (s)-n-methyl-3-(1-naphtyloxy)-3-(2-thienyl)propylamine hydrochlorure (duloxetine)
US7538232B2 (en) Process for the asymmetric synthesis of duloxetine
US8362279B2 (en) Process for pure duloxetine hydrochloride
EP2114912B1 (fr) Procede de fabrication de la duloxetine et de composes apparentes
US8207356B2 (en) Method for the preparation of (S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride (duloxetine)
WO2011077443A1 (fr) Procédé amélioré pour la préparation de chlorhydrate de duloxétine
US8269023B2 (en) Process for preparation of duloxetine hydrochloride
US20100280093A1 (en) Process for the preparation enantiomerically pure salts of n-methyl-3-(1-naphthaleneoxy)-3-(2-thienyl)propanamine
EP2060559A1 (fr) Procédé pour la préparation de 3-hyxdroxy-3-arylpropylamines énantiomériquement pures et leurs stéréoisomères optiques
CN1678564A (zh) 制备单烷基氨基酮的方法
KR101353820B1 (ko) (ｓ)-3-메틸-6-(2-티에닐)-1,3-옥사지난-2-온을 통한 (+)염산 둘록세틴의 새로운 제조방법
WO2009019719A2 (fr) Procédé de préparation de 3-aryloxy-3-arylpropanamines
WO2009109992A1 (fr) Nouveau procédé de préparation de duloxétine et intermédiaires pour l'utiliser
US20100267968A1 (en) Method for the preparation of duloxetine hydrochloride
WO2011145102A1 (fr) Procédé pour la préparation de dérivés de n-méthyl-o-aryloxypropanamine et de sel pharmaceutiquement acceptable de ceux-ci

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10838828

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10838828

Country of ref document: EP

Kind code of ref document: A1