WO2013056809A1 - Procédé de préparation de chlorhydrate de duloxétine hautement pur - Google Patents

Procédé de préparation de chlorhydrate de duloxétine hautement pur Download PDF

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Publication number
WO2013056809A1
WO2013056809A1 PCT/EP2012/004312 EP2012004312W WO2013056809A1 WO 2013056809 A1 WO2013056809 A1 WO 2013056809A1 EP 2012004312 W EP2012004312 W EP 2012004312W WO 2013056809 A1 WO2013056809 A1 WO 2013056809A1
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WO
WIPO (PCT)
Prior art keywords
added
duloxetine hydrochloride
duloxetine
toluene
preparation
Prior art date
Application number
PCT/EP2012/004312
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English (en)
Inventor
V. Theocharis KOFTIS
Theodoros Panagiotidis
Theodoros TSATSAS
Asteria Zitrou
Original Assignee
Pharmathen S.A.
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 Pharmathen S.A. filed Critical Pharmathen S.A.
Priority to CN201280051251.1A priority Critical patent/CN103958494A/zh
Priority to IN1022KON2014 priority patent/IN2014KN01022A/en
Publication of WO2013056809A1 publication Critical patent/WO2013056809A1/fr

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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 Duloxetine and pharmaceutically acceptable salts or derivatives thereof and in particular to a process for the preparation of substantially pure Duloxetine hydrochloride.
  • Duloxetine is a serotonin and norepinephrine re-uptake dual inhibitor and a highly efficient antidepressant agent for treating psychiatric disorders. In some countries, Duloxetine has also been authorized for treatment of diabetic peripheral neuropathic pain and stress urinary incontinence.
  • Duloxetine hydrochloride is chemically designated as (+)-(S)-N-methyl-3-(l-naphthyloxy)-3-(2- thiopenyl)-l-propanamine hydrochloride and is presented by the following chemical structure of Formula 1.
  • EP-B-273 658 discloses a widely used process for the preparation of Duloxetine, or an acid addition salt thereof, which is depicted in Scheme 1.
  • the key intermediate of Formula 4 in the form of oxalate salt is prepared by O-arylation of 3-dimethyl-l-(2-thiophene)-l-propanamine (Formula 2) with 1 -fluoronaphthalene (Formula 3) followed by salt formation.
  • the intermediate of Formula 4 is further subjected to N-demethylation and salt formation to prepare an acid addition salt of Duloxetine, such as Duloxetine oxalate and Duloxetine maleate.
  • dimethylamino alcohol as starting material requires a demethylation step, which is an additional step that may compromise the overall yield of the process.
  • the present invention relates to a process for the preparation of Duloxetine directly through arylation of (S)-(+)-N-methyl-3(l-naphthalenyloxy)-3-(2-thienyl)propanamine (Formula 5) (the monomethyl amino alcohol) with 1-fluoronaphathalene.
  • WO-A-2009/074883 also discloses the same route using Ci -6 alkoxide salt as a base.
  • KOH is disadvantageous because KOH is not soluble in the reaction solvent and therefore the reaction may be carried out in a heterogenous mixture which leads to a decrease of yield.
  • Solvents used in the process are selected from polar solvents such as DMSO, DMF, DMA, l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone, N-methyl-2- pyrrolidone and mixtures thereof or non-polar organic solvents such as pentane, hexane, heptane, toluene, xylene and mixtures thereof.
  • an object of the present invention to provide an improved process for the preparation of Duloxetine or pharmaceutical acceptable salts thereof or its derivatives, which overcomes the deficiencies of the prior art processes and results to a cost effective industrial production without sacrificing the yield and quality of the product.
  • Another object of the present invention is to provide an improved method for the preparation of Duloxetine or salts thereof or its derivatives by optimizing the work-up, so that the purity (both chemical purity and optical purity) and yield of the reaction are increased and racemization is minimized.
  • reaction mixture is heated at 40-60 °C for approximately 30 hours, and subsequently cooled to 20-30 °C, acidified with HC1 in toluene to pH 4.0-5.0 and the separated organic layer is discarded.
  • the aqueous layer is basified with aqueous NaOH in toluene to pH 9.0-9.5.
  • the selected organic layer is washed with NaCl and the solvents are removed by distillation.
  • reaction mass is cooled to about 0-5 °C for 2-3 hours.
  • the precipitated product is filtered under reduced pressure, washed with ethyl acetate and dried in a vacuum oven.
  • the present invention relates to an improved process for the preparation of Duloxetine and pharmaceutically acceptable salts in high enantiomeric and chemical purity, which is characterized in substantially milder and safer reaction conditions, without sacrificing the yield and quality of the product and low cost of reactants and reagents.
  • the reaction mixture is heated at 40-60 °C, preferably 45-50 °C for 30 hours, cooled at 20-30°C and treated with D.M. water and toluene.
  • the reaction mass is acidified with HC1 and the pH is adjusted at 4.0-5.0.
  • the collected aqueous layer is extracted with toluene and the organic layers are discarded.
  • Toluene is added to the aqueous layer and the reaction mass is basified with 50% aqueous NaOH solution to reach pH 9.0-9.5, filtered through Buchner funnel and spray washed with toluene.
  • the layers are separated and the aqueous layer is extracted with toluene.
  • the yield of isolated Duloxetine hydrochloride solid obtained according to the present invention is in the range of 82-97%, the enantiomeric purity is higher than 99.7%, i.e. the presence of the unwanted (R)-enantiomer is less than 0.3% and HPLC purity is higher than 99.9%.
  • NaH is used as base due to its better activity in DMSO, leading to shortened reaction time in lower temperatures.
  • the acidic treatment of the reaction mass in process step (3) removes any excess of the 1- fluoronaphathalene and other non polar impurities while the pH adjustment at 4.0-5.0 assures that no degradation of the formed Duloxetine takes place.
  • Process steps (5) and (6) eliminate the inorganic water soluble impurities by distillation and filtration of the reaction mass.
  • the amount of HC1 addition as in step (7) had to be fine tuned in order to achieve optimum results in terms of quality and yield of the isolated Duloxetine salt.
  • the amount of HC1 added is crucial as the authors of the invention have observed that less molar equivalents lead to lower yield of Duloxetine hydrochloride, for obvious reasons. Excess molar equivalents lead to significantly lower purity, both chemical and chiral.
  • the optimal quantity of HC1 has been found to be 0.85-0.90 molar equivalents of the (S)-3-(methylamino)-l-(thiophen-2-yl) propan-l-ol.
  • Duloxetine obtained according to the process of the present invention may be further purified by conventional means, such as crystallization from solvents, acid base purification, etc. This additional purification step can be applied to achieve higher quality material.
  • the separated aqueous layer is extracted with 0.5 L toluene and the collected organic layers are discarded.
  • To the aqueous layer is added 1 L toluene and the reaction mass is basified with 80 mL 50% aq. sodium hydroxide solution (pH at 9.0-9.5) and is filtered through Buchner funnel and washed with 100 mL toluene.
  • the separated aqueous layer is extracted with 1 L toluene and the combined organic layers are washed with 800 mL 20% w/v sodium chloride solution and the solvents are removed by distillation under reduced pressure until dry.
  • the separated aqueous layer is extracted with 0.5 L toluene and the collected organic layers are discarded.
  • To the aqueous layer is added 1 L toluene and the reaction mass is basified with 100 mL 50% aq. sodium hydroxide solution (pH at 9.0-9.5) and is filtered through Buchner funnel and washed with 100 mL toluene.
  • the separated aqueous layer is extracted with 1 L toluene and the combined organic layers are washed with 1 L 20% w/v sodium chloride solution and the solvents are removed by distillation under reduced pressure until dry.
  • Example 3 Purification of Duloxetine hydrochloride 100.0 g of Duloxetine hydrochloride crude are dissolved in 0.5 L D.M. water and 1.5 L ethyl acetate. The resulting solution is basified with 50 mL 50% aq. sodium hydroxide (pH above 9.0) and is extracted with 1.5 L ethyl acetate at 20-30°C. To the collected aqueous layer is charged 1.5 L ethyl acetate and is further basified at pH above 9.0. The separated organic layers are combined and 12.4 mL (0.5eq) concentrated hydrochloric acid 37% are added and the reaction mass is distilled off under atmospheric pressure until 1 L of solvents are distilled out.
  • the hot reaction mass is filtered through 10 g celite bed, washed with 100 mL hot ethyl acetate and 9.9 mL (0.4eq) cone, hydrochloric acid 37% are added to the filtrate (pH 5.0-6.0).
  • the reaction mass is distilled off under atmospheric pressure until 1.2 L of solvents are distilled out, cooled at 0- 5°C and further stirred for 120-150 minutes at 0-5°C.
  • the present invention describes a large-scale manufacture process for the preparation of Duloxetine hydrochloride in high purity at relative low production cost compared to the available processes for producing similar products, wherein the reaction conditions and the work-up are optimized in order to minimize racemization

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

Abstract

La présente invention concerne un procédé amélioré de préparation de duloxétine et de sels ou dérivés pharmaceutiquement acceptables associés, notamment un procédé de production à grande échelle de chlorhydrate de duloxétine en un rendement élevé et en une pureté énantiomérique et chimique élevée.
PCT/EP2012/004312 2011-10-17 2012-10-16 Procédé de préparation de chlorhydrate de duloxétine hautement pur WO2013056809A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201280051251.1A CN103958494A (zh) 2011-10-17 2012-10-16 高纯度盐酸度洛西汀的制备方法
IN1022KON2014 IN2014KN01022A (fr) 2011-10-17 2012-10-16

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GR20110100599A GR1007725B (el) 2011-10-17 2011-10-17 Μεθοδος δια την παρασκευη υδροχλωρικης ντουλοξετινης υψηλης καθαροτητας
GR20110100599 2011-10-17

Publications (1)

Publication Number Publication Date
WO2013056809A1 true WO2013056809A1 (fr) 2013-04-25

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Application Number Title Priority Date Filing Date
PCT/EP2012/004312 WO2013056809A1 (fr) 2011-10-17 2012-10-16 Procédé de préparation de chlorhydrate de duloxétine hautement pur

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CN (1) CN103958494A (fr)
GR (1) GR1007725B (fr)
IN (1) IN2014KN01022A (fr)
WO (1) WO2013056809A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0273658B1 (fr) 1986-12-22 1990-10-31 Eli Lilly And Company Propanamines 3-aryloxy-3-substituées
EP2060559A1 (fr) * 2007-11-19 2009-05-20 Cadila Pharmaceuticals Limited Procédé pour la préparation de 3-hyxdroxy-3-arylpropylamines énantiomériquement pures et leurs stéréoisomères optiques
US7538232B2 (en) 2006-01-19 2009-05-26 Eli Lilly And Company Process for the asymmetric synthesis of duloxetine
WO2009074883A2 (fr) 2007-11-06 2009-06-18 Medichem, S.A. Procédé amélioré pour la préparation de duloxétine
WO2010003942A2 (fr) * 2008-07-07 2010-01-14 Krka, D.D. Novo Mesto Préparation de la duloxétine et de ses sels pharmaceutiquement acceptables en utilisant le procédé d’hydrogénation asymétrique par transfert

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0273658B1 (fr) 1986-12-22 1990-10-31 Eli Lilly And Company Propanamines 3-aryloxy-3-substituées
US7538232B2 (en) 2006-01-19 2009-05-26 Eli Lilly And Company Process for the asymmetric synthesis of duloxetine
WO2009074883A2 (fr) 2007-11-06 2009-06-18 Medichem, S.A. Procédé amélioré pour la préparation de duloxétine
EP2060559A1 (fr) * 2007-11-19 2009-05-20 Cadila Pharmaceuticals Limited Procédé pour la préparation de 3-hyxdroxy-3-arylpropylamines énantiomériquement pures et leurs stéréoisomères optiques
WO2010003942A2 (fr) * 2008-07-07 2010-01-14 Krka, D.D. Novo Mesto Préparation de la duloxétine et de ses sels pharmaceutiquement acceptables en utilisant le procédé d’hydrogénation asymétrique par transfert

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TETRAHEDRON ASYMMETRY, vol. 16, 2005, pages 1873

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Publication number Publication date
CN103958494A (zh) 2014-07-30
GR1007725B (el) 2012-10-18
IN2014KN01022A (fr) 2015-10-09

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