WO2009109992A1 - Nouveau procédé de préparation de duloxétine et intermédiaires pour l'utiliser - Google Patents

Nouveau procédé de préparation de duloxétine et intermédiaires pour l'utiliser Download PDF

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Publication number
WO2009109992A1
WO2009109992A1 PCT/IN2009/000058 IN2009000058W WO2009109992A1 WO 2009109992 A1 WO2009109992 A1 WO 2009109992A1 IN 2009000058 W IN2009000058 W IN 2009000058W WO 2009109992 A1 WO2009109992 A1 WO 2009109992A1
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WO
WIPO (PCT)
Prior art keywords
propanamine
thiophenyl
naphthalenyloxy
lewis acid
methyl
Prior art date
Application number
PCT/IN2009/000058
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English (en)
Inventor
Nishikant Digambar Ghadge
Bapu Atmaram Chaudhari
Ganesh Gurpur Pai
Original Assignee
Arch Pharmalabs 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 Arch Pharmalabs Limited filed Critical Arch Pharmalabs Limited
Publication of WO2009109992A1 publication Critical patent/WO2009109992A1/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

  • Duloxetine hydrochloride comprising the preparation of substantially pure S isomer of lewis acid salts of Duloxetine of the formula- II which owing to difference in selectivity of R and S isomers towards Lewis acid thereby resulting into enrichment of S isomer.
  • Lewis salt of Duloxetine in organic solvent selectively gets enriched in S isomer by minimizing the unwanted R isomer obtained as impurity due to epimerization during the arylation of (S)-(+)-N,N-dimethyl-3-Hydroxy-3-(2-thiophenyl) propanamine of Formula-Ill with 1-Fluoro naphthalene.
  • the lewis acid salt of the Duloxetine can be converted into substantially pure Duloxetine hydrochloride by converting the lewis acid salt to free base which is converted into the corresponding hydrochloride salt or optionally converting the lewis acid salt of Duloxetine into corresponding hydrochloride salt in situ without the isolation of the free base.
  • lewis salt of (S)-(+)-N,N-dimethyl-3-(l- naphthalenyloxy)-3-(2-thiophenyl)-propanamine in organic solvent gets enriched in S isomer by minimizing the unwanted R isomer obtained as an impurity due to epimerization during the arylation of (S)-(+)-N,N-dimethyl-3-Hydroxy-3-(2-thiophenyl) propanamine of Formula III with 1-Fluoro naphthalene.
  • Another aspect of the invention is a novel process for the preparation of substantially pure (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyI) propanamine hydrochloride of Formula-I comprising converting the said lewis acid salt of (S)-(+)-N,-methyl-3-(l- naphthalenyloxy)-3-(2-thiophenyl) propanamine into Duloxetine hydrochloride by its conversion into free base which is then further converted into the corresponding hydrochloride salt or optionally converting the lewis acid salt of Duloxetine into corresponding hydrochloride salt in situ without the isolation of the free base.
  • Duloxetine is a selective inhibitor of serotonin and nor epinephrine uptake in the human body. It is used as antidepressant in the clinical practice. Duloxetine is an efficient active pharmaceutical ingredient, which inhibits the metabolism of serotonin, the decreased level of which is responsible for depression and anxiety. Duloxetine hydrochloride salt of Formula I is most suitable for use in clinical practice as antidepressant.
  • US5023269 and US4956388 disclose chemical synthesis of Duloxetine. These describe the use of optically active precursor key intermediate or resolution of racemates of Duloxetine.
  • US5491243 discloses a stereospecific process for the synthesis of dimethyl precursor of Duloxetine (Formula- IV) and isolating it as a phosphoric acid salt (98.1% potency, adjusted yield of 79.6% with EE % 91. The obtained phosphoric acid salt is then converted into corresponding base followed by demethylation to get Duloxetine and isolating it as hydrochloride with potency of 99.8%. However, there is no mention of chiral purity.
  • WO2004/056795 discloses resolution of racemic Duloxetine using various chiral acids like mandelic acid, tartaric acid, di-p-toluyl tartaric acid, dibenzoyl tartaric acid and camphor sulphonic acid with preference to di-p-toluyl tartaric acid and conversion of these salts either into free base or other addition salts like hydrochloride as appropriate. It also describes racemisation and recycling of the non-desired enantiomer thereby increasing the economy of the process.
  • US5362886 discloses a process for the preparation of (S)-(+)-N,N-dimethyl-3-(l- naphthalenyloxy)-3-(2-thiophenyl) propanamine by arylation of (S)-(+)-N,N-dimethyl-3-(l- hydroxy )-3-(2-thiophenyl) propanamine with 1- fluoronaphthalene using sodium hydride in presence of certain potassium salts in an organic solvent and recovering the product as the phosphoric acid salt.
  • the substantially pure S)-(+)-N-methyl- 3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine can only be obtained if R impurity is removed from the mixture.
  • the Prior art also discloses the phenomenon of racemisation during the arylation of 3 -hydroxy propanamine with 1-fluoro naphthalene in presence of strong base like sodium hydride that attribute towards R isomer as an impurity. This recurrence of R-isomer motivated the inventors to give a method that minimizes this impurity resulting into enhancement of chiral purity.
  • salt preparation is preferable as a way of purification Transformation of the crude base of the active ingredient into salt is advantageous in following aspects.
  • salts have higher melting temperatures than the corresponding bases; therefore salts can be isolated and purified more efficiently and conveniently.
  • the convenience of the purification process is justified by the strict requirements towards purity of the active pharmaceutical ingredient.
  • the second advantage of the present invention in using Lewis acid more preferably Zinc chloride salts resides in fact that two optical enantiomeric Zinc chloride salts of N-methyl-3- (l-naphthalenyloxy)-3-(2-thiophenyl) propanamine and N,N-dimethyl-3-(l- naphthalenyloxy)-3-(2-thiophenyl) propanamine differ in their selectivity towards Lewis acid in the given solvent.
  • This feature enables to minimize the undesired R isomer in both cases mentioned herein thereby resulting into enrichment of S isomer.
  • the disadvantage associated with methods used in state of art to get the stereo specific enantiomer is the high cost of the chiral acids used for isolating the chiral salts of Duloxetine or precursors thereby requiring enhanced raw material consumption, conversion of chiral salts into Duloxetine base, its isolation and further conversion into addition salts increases unit operation beside the problems like racemisation and yield loss.
  • the associated problem is its stability.
  • Process disclosed in the prior art comprises the reaction between molecules of structure III and V via IV to give the Duloxetine free base as shown below.
  • epimerization takes place which results in the formation of R isomer which is carried forward till the formation of free base.
  • the present invention provides a novel method of preparing Duloxetine comprising formation of lewis acid salt of molecules of structures IV or Ia.
  • the lewis acid salt of R isomer formed as an impurity during the condensation process to form IV or in Ia is selectively removed in organic solvent during their lewis acid salt formation thereby causing the enrichment of S isomer either at stage IV or Ia resulting in the formation of substantially pure S isomer of Duloxetine free from the R impurity formed during the formation of molecule of structure IV or Ia.
  • the present invention has following advantages over the existing prior art, namely:
  • the resultant product thus obtained is of high chiral and chemical purity with good yield.
  • One of the embodiments of the present invention comprises a process for preparing substantially pure (+) Duloxetine Hydrochloride of high optical purity comprising use of Lewis acid salts.
  • Lewis acid salt can be Aluminium chloride, Stannic chloride, Ferric chloride preferably Zinc chloride salt of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2- thiophenyl) propanamine or (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine.
  • Zinc chloride salts obtained either from (S)-(+)-N,N- dimethyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine or from (S)-(+)-N-methyl-3- (l-naphthaleny!oxy)-3-(2-thiophenyl) propanamine are converted into the corresponding hydrochloride salt either by treating the respective Zinc chloride salt directly with IPA/HC1 or optionally by isolating Duloxetine base by treating with an inorganic base
  • the (S)-(+)-N,N-dimethyl-3-(l-hydroxy)-3-(2-thiophenyl) propanamine used in the present invention can be prepared by any of the process available in the prior art and forms no part of the present invention.
  • the R and S isomers of the said lewis acid salt of (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine and (S)-(+)-N,N-dimethyl-3-(l -naphthalenyloxy)-3-(2-thiophenyl) propanamine differ in their selectivity pattern towards lewis acid by resulting into enrichment of S isomer in an organic solvent.
  • Organic solvent can be selected from aliphatic alcohol, aliphatic ketone or aliphatic ester and the like.
  • the organic solvent is aliphatic primary alcohol of primary aliphatic ester. More preferably the organic solvent is aliphatic primary alcohol. Most preferable is isopropanol.
  • the lewis acid salt is selected from aluminium chloride, tin chloride, zinc chloride, Ferric chloride and the like. More preferably the lewis acid salt is zinc chloride of (S)-(+)-N- methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine hereinbefore and hereinafter referred as Duloxetine lewis acid can be converted into corresponding Duloxetine hydrochloride salt comprising either by treating the said lewis acid salt with a base, preferably with an inorganic base into the corresponding free base which can be converted into the corresponding hydrochloride salt optionally insitu or by isolating the free base by treating the said Duloxetine base with hydrochloric said in an organic solvent preferably aliphatic alcoholic solvent or by directly treating with alcoholic HCl preferably isopropanolic HCl.
  • Duloxetine Hydrochloride optionally isolating Duloxetine base that again comprises treatment of an inorganic base with (S)-(+)-N-methyl-3-(l-naphthalenyloxy)-3-(2-thiophenyl) propanamine Zinc chloride.
  • the solution was stirred at 60 ⁇ C to 65 ⁇ C and the progress of the reaction was monitored by TLC. After complete conversion, cooled the reaction mass followed by the reaction mixture was poured into mixture of 10 ml acetic acid in 1000 ml water. Allow the temperature raise to ambient temperature. 10 ⁇ C to 20 ⁇ C and stirred for 15 to 20 minutes. Adjust the pH of the reaction mixture to 12 using 30% caustic solution. Extract the reaction mixture with toluene (3 X 150 ml). Combined organic layer washed with water (1 X 50 ml). Dry over anhydrous sodium sulphate. Use the organic layer as such for the next step.

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

Abstract

L'invention concerne un nouveau procédé pour préparer essentiellement du chlorhydrate de (S)-(+)-N-méthyl-3-(l-naphtalènyloxy)-3-(2-thiophényl)propanamine comprenant la formation d'un sel d'acide de Lewis de (S)-(+)-N-méthyl-3-(l-naphtalènyloxy)-3-(2-thiophényl)propanamine et de (S)-(+)-N,N-diméthyl-3-(l-naphtalènyloxy)-3-(2-thiophényl)propanamine afin d'éliminer l'isomère R de (S)-(+)-N-méthyl-3-(l-naphtalènyloxy)-3-(2-thiophényl)propanamine et de (S)-(+)-N,N-diméthyl-3-(l-naphtalènyloxy)-3-(2-thiophényl)propanamine évitant l'élimination de l'impureté constituée par l'isomère R sans résolution par formation de sel chiral.
PCT/IN2009/000058 2008-01-23 2009-01-22 Nouveau procédé de préparation de duloxétine et intermédiaires pour l'utiliser WO2009109992A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN162MU2008 2008-01-23
IN162/MUM/2008 2008-01-23

Publications (1)

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WO2009109992A1 true WO2009109992A1 (fr) 2009-09-11

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006099433A1 (fr) * 2005-03-14 2006-09-21 Teva Pharmaceutical Industries Ltd. Hydrochlorure de duloxetine pur
WO2007077580A2 (fr) * 2006-01-06 2007-07-12 Msn Laboratories Limited Procédé amélioré pour la préparation de chlorhydrate de duloxetine pur
WO2007084193A1 (fr) * 2006-01-23 2007-07-26 Teva Pharmaceutical Industries Ltd. Dnt-succinate et procédés de préparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006099433A1 (fr) * 2005-03-14 2006-09-21 Teva Pharmaceutical Industries Ltd. Hydrochlorure de duloxetine pur
WO2007077580A2 (fr) * 2006-01-06 2007-07-12 Msn Laboratories Limited Procédé amélioré pour la préparation de chlorhydrate de duloxetine pur
WO2007084193A1 (fr) * 2006-01-23 2007-07-26 Teva Pharmaceutical Industries Ltd. Dnt-succinate et procédés de préparation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MICHAEL B. SMITH, JERRY MARCH: "March's Advanced Organic Chemistry (Sixth Edition)", 18 May 2006, JOHN WILEY & SONS, INC., ISBN: 9780471720911, XP002540131 *

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