EP2016066A2 - Procédé de préparation de duloxétine - Google Patents

Procédé de préparation de duloxétine

Info

Publication number
EP2016066A2
EP2016066A2 EP07762094A EP07762094A EP2016066A2 EP 2016066 A2 EP2016066 A2 EP 2016066A2 EP 07762094 A EP07762094 A EP 07762094A EP 07762094 A EP07762094 A EP 07762094A EP 2016066 A2 EP2016066 A2 EP 2016066A2
Authority
EP
European Patent Office
Prior art keywords
duloxetine
salt
reacting
formula
hydrochloride
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.)
Withdrawn
Application number
EP07762094A
Other languages
German (de)
English (en)
Other versions
EP2016066A4 (fr
Inventor
Srinivasalu Gudipati
Srinivas Katkam
Jaya Prakash Pitta
Prasad Ganji
Nageswara Rao Challa
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.)
Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
Original Assignee
Dr Reddys Laboratories Ltd
Dr Reddys Laboratories Inc
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 Dr Reddys Laboratories Ltd, Dr Reddys Laboratories Inc filed Critical Dr Reddys Laboratories Ltd
Publication of EP2016066A2 publication Critical patent/EP2016066A2/fr
Publication of EP2016066A4 publication Critical patent/EP2016066A4/fr
Withdrawn legal-status Critical Current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
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms

Definitions

  • the present invention relates to a process for the preparation of duloxetine and its pharmaceutically acceptable salts.
  • it relates to a process for preparing duloxetine and its pharmaceutically acceptable salts having low concentrations of impurities.
  • Duloxetine hydrochloride is the adopted name for a compound having the chemical name (+)-(S)- ⁇ /-methyl- ⁇ -(1 -naphthyloxy)-2-thiophenepropylamine hydrochloride and structurally represented by Formula I.
  • U.S. Patent No. 5,023,269 describes N-methyl-3-(1 -naphthalenyloxy)-3-(2- thienyl) propaneamine oxalate, its related compounds and processes for their preparation.
  • WO 2006/099433 discloses pharmaceutically acceptable salts of duloxetine containing less than 0.14% of (+)- N-methyl-3-(1 -naphtaleneyloxy)-3-(3-thienyl)propanamine (hereinafter designated as "DLX-ISO-3") impurity, and less than 0.04% of the R-enantiomer of duloxetine.
  • DLX-ISO-3 (+)- N-methyl-3-(1 -naphtaleneyloxy)-3-(3-thienyl)propanamine
  • the ICH Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
  • Enantiomeric purity of pharmaceutical compounds is important because the two isomers may exhibit different potency and certain isomers may actually be deleterious rather than simply inert. Therefore, there is a need to obtain the desired enantiomer of duloxetine hydrochloride which is free of its enantiomeric impurity, and also free of other process related impurities. Therefore there is a need for a process, which is advantageous in preventing racemization, so as to increase the yields of the final product and also to yield an enantiomerically pure form of duloxetine and its pharmaceutically acceptable salts.
  • the present invention relates to a process for the preparation of duloxetine and its pharmaceutically acceptable salts. In an aspect, it relates to a process for the preparation of duloxetine and its pharmaceutically acceptable salts having low concentrations of impurities.
  • One aspect of the present invention provides a process for the preparation of duloxetine hydrochloride.
  • a process for the preparation of duloxetine hydrochloride comprises: a) providing a solution comprising duloxetine; and b) reacting the solution obtained of a) with less than about 1.5 molar equivalents of hydrochloric acid.
  • a process for the preparation of duloxetine comprises: a) reacting racemic duloxetine of Formula VIII or an acid addition salt thereof with (S)-6-methoxy- ⁇ -methyl-2 naphthalene acetic acid of Formula IX (hereinafter referred to as "naproxen”) to give a salt represented by Formula X;
  • Formula X c) reacting the salt of Formula X with a suitable base to get duloxetine.
  • Formula Il Formula III b) condensing N,N-dimethyl-3-hydroxy-3-(2-thienyl) propanamine of Formula IV with 1-fluoronapthalene of Formula V to give N, N-dimethyl-3-(1- naphthalenyloxy)-3-(2-thienyl) propanamine which can be converted to its oxalate salt of Formula Vl;
  • Formula Vl c) reacting N, N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine oxalate of Formula Vl with ethylchloroformate to give N-ethoxycarbonyl-N-methyl- 3-(1-naphthanlenyloxy)-3-(2-thienyl) propanamine of Formula VII; and
  • Still another aspect of the present invention provides substantially pure duloxetine and its pharmaceutically acceptable salts.
  • a further aspect of the present invention provides a process for the preparation of 4-(3-methylamino-1 -thiophen-2-yl-propyl)naphthalene-1 -ol hydrochloride represented by Formula Ib, useful as a reference standard for determining the purity of duloxetine hydrochloride by HPLC.
  • a yet further aspect of the invention provides pharmaceutical compositions comprising substantially pure duloxetine hydrochloride prepared according to the process of the present invention along with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • Fig. 1 is a schematic representation of a process for the preparation of duloxetine according to an embodiment of the present invention.
  • Fig. 2 is an X-ray powder diffraction pattern of duloxetine hydrochloride prepared in Example 8.
  • the present invention relates to a process for the preparation of duloxetine and its pharmaceutically acceptable salts. In an embodiment, it relates to a process for preparing duloxetine and its pharmaceutically acceptable salts having low concentrations of impurities.
  • Step a) involves reacting racemic duloxetine of Formula VIII or an acid addition salt thereof with naproxen to give a salt of duloxetine and naproxen represented by Formula X.
  • Step b) involves condensation of N,N-dimethyl-3-hydroxy-3-(2-thienyl) propanamine of Formula IV with 1-fluoronapthalene of Formula V to give N 1 N- dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine which can be converted to its oxalate salt of Formula Vl.
  • Suitable organic solvents which can be used for the reaction include but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, n- butanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; aprotic polar solvents such as N. N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA) and the like; and mixtures thereof
  • the amount of base that can be used in the reaction can vary depending upon the base used.
  • the molar ratio of base to the starting material compound of Formula Vl can range from about 0.75 to 2, or about 1.
  • ethyl chloroformate can be added to the reaction mixture over a prolonged time, such as about 20 minutes to about 5 hours, or about 1 to 2 hours, at temperatures ranging from about 20 0 C to about 80 0 C, or 40 0 C to about 60 0 C, and can be maintained further until reaction completion, such as for about 2 to 10 hours, or about 4 to 6 hours.
  • the reaction mixture is quenched with water and pH is adjusted to about 7 to 12, or about 8 to 9, by adding a suitable base.
  • the organic layer is separated and may be progressed to further processing directly or it can be concentrated to form a residue.
  • an organic layer containing the free base obtained from previous step or the free base residue dissolved in a suitable solvent can be used for reacting with oxalic acid to form an oxalate salt.
  • Formula IV used in the reaction can range from about 0.75 to 2, or about 1. Suitable temperatures for the formation of the oxalate salt range form about
  • Still another aspect of the present invention provides substantially pure duloxetine.
  • substantially pure duloxetine it is meant that duloxetine or any of the pharmaceutically acceptable salts of duloxetine prepared in accordance with the present invention contains less than about 0.5%, or less than about 0.1 %, by weight of the corresponding impurities like the R-enantiomer of duloxetine, 4- napthol impurity of duloxetine, and DLX-ISO-3 impurities, as characterized by a high performance liquid chromatography (“HPLC”) chromatogram obtained from a mixture comprising the desired compound and one or more of the said impurities.
  • HPLC high performance liquid chromatography
  • R-enantiomeric of duloxetine refers to (-)-(R)- ⁇ /-methyl- ⁇ -(1-naphthyloxy)- 2-thiophenepropylamine of Formula Ia;
  • Formula Ia “4-Naphthol duloxetine” refers to 4-(3-methylamino-1-thiophen-2-yl-propyl)- naphthalen-1-ol hydrochloride compound of Formula Ib;
  • DLX-ISO-3 impurity refers to (+)-N-methyl-3-(1-naphtaleneyloxy)-3-(3- thienyl)propanamine hydrochloride of Formula Ic.
  • Hydrochloric acid used in the process can be in the form of aqueous hydrochloric acid, hydrochloric acid gas, alcoholic hydrochloride, ethyl acetate hydrochloride and the like. Suitable temperatures for preparation of the compound range from about 10 0 C to about 50 0 C.
  • a compound in a relatively pure state can be used as a "reference standard."
  • a reference standard is similar to a reference marker, which not only is used for qualitative analysis, but is also used to quantify the amount of the compound of the reference standard in an unknown mixture, as well.
  • the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.
  • 4-naphthol duloxetine is useful as a reference marker compound in identifying the purity of the duloxetine hydrochloride.
  • Formula Ib A still further aspect of the invention provides a pharmaceutical composition comprising substantially pure duloxetine hydrochloride along with one or more pharmaceutically acceptable excipients.
  • compositions comprising substantially pure duloxetine hydrochloride and their combination with a pharmaceutically acceptable carrier of this invention may be further formulated as solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions.
  • Formulations may be in the form of immediate release, delayed release or modified release.
  • duloxetine is a useful active ingredient in the range of 20 mg to 30 mg, or 30 mg to 60 mg, per dosage unit.
  • the separated compound 3-dimethylamino-1-(2- theinyl)-1-propanone hydrochloride of Formula III was centrifuged and the wet cake was washed with 5 liters of isopropyl alcohol.
  • the above obtained wet solid was dissolved in 60 liters of water and the solution cooled to 1 1 0 C.
  • 2.4 kg of sodium borohydride was added slowly in 3 equal lots at 10 °C over 2 hours, 45 minutes.
  • the reaction mixture was heated to 20 0 C and stirred for 1 hour, 45 minutes at 19-25 0 C. 14.3 liters of 48 % aqueous sodium hydroxide solution was added and the reaction mixture was stirred at 30 0 C for 2 hours.
  • the resultant reaction suspension was stirred for 15 minutes and extracted with ethyl acetate in two lots of 97 liters and 48 liters at 50 0 C.
  • the total organic layer was washed with 38 liters of water in two equal lots at 50 °C.
  • 3.3 kg of oxalic acid was added to the organic layer and the reaction mixture was heated to 58 0 C.
  • the resultant mixture thus obtained was stirred for 40 minutes and then cooled to 35 0 C.
  • the resultant slurry was stirred for 1.5 hours.
  • the solid that separated was centrifuged and the wet cake was washed with 10 liters of ethyl acetate.
  • the solid obtained was dried at 60 0 C under a vacuum of about 550 mm Hg for 9 hours to yield 9.5 kg of crystalline solid.
  • 2-YL-PROPYL1-AMINE NAPROXEN SALT 39 liters of ethyl acetate, 78 liters of water and 7.8 kg of racemic oxalate salt of racemic duloxetine prepared above were taken into a clean and dry reactor.
  • Residual solvent content methanol 41 ppm; acetone not detected, isopropanol 497 ppm; ethyl acetate 73 ppm; toluene 1 11 ppm.
  • Particle size distribution Di 0 17 ⁇ m, D 50 69 ⁇ m, D 90 191 ⁇ m.
  • duloxetine 4 g was dissolved in 40 ml of methyl isobutyl ketone followed by cooling to 0 0 C. pH of the solution was adjusted to 2 by the addition of 1.6 ml of 12 N hydrochloric acid under stirring, and maintained under stirring for 5 hours.
  • the amount of 2-[3-chloro-1-(naphthalenyloxy-propyl] thiophene of Formula Vila in methyl-[3-(naphthalen-1-yloxy)-3-thiophen-2-yl-propyl]-carbamic acid ethyl ester of Formula Vl is determined using HPLC.
  • the HPLC analysis conditions are described in Table 1.
  • the R-duloxetine hydrochloride impurity is determined using HPLC.
  • the HPLC analysis conditions are as described in Table 2. Table 2

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)

Abstract

L'invention concerne un procédé de préparation de duloxétine ou d'un sel de celle-ci.
EP07762094A 2006-05-10 2007-05-10 Procédé de préparation de duloxétine Withdrawn EP2016066A4 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN828CH2006 2006-05-10
US80525406P 2006-06-20 2006-06-20
US82063606P 2006-07-28 2006-07-28
PCT/US2007/068667 WO2007134168A2 (fr) 2006-05-10 2007-05-10 Procédé de préparation de duloxétine

Publications (2)

Publication Number Publication Date
EP2016066A2 true EP2016066A2 (fr) 2009-01-21
EP2016066A4 EP2016066A4 (fr) 2010-11-24

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP07762094A Withdrawn EP2016066A4 (fr) 2006-05-10 2007-05-10 Procédé de préparation de duloxétine

Country Status (2)

Country Link
EP (1) EP2016066A4 (fr)
WO (1) WO2007134168A2 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2107057A1 (fr) 2008-04-04 2009-10-07 Ranbaxy Laboratories Limited Procédé de préparation de duloxetine pur
EP2123626A1 (fr) * 2008-05-21 2009-11-25 Laboratorios del Dr. Esteve S.A. Co-cristaux de duloxétine et générateurs de co-cristaux pour le traitement de la douleur
EP2332930A1 (fr) * 2009-11-23 2011-06-15 Laboratorios Del. Dr. Esteve, S.A. Sels de duloxétine et AINS pour le traitement de la douleur
WO2011077443A1 (fr) * 2009-12-22 2011-06-30 Biocon Limited Procédé amélioré pour la préparation de chlorhydrate de duloxétine
CN114778707A (zh) * 2019-05-13 2022-07-22 南京制药厂有限公司 用液相色谱测定度洛西汀中间体酰胺的方法
CN113429380B (zh) * 2021-07-14 2022-07-01 新发药业有限公司 一种度洛西汀的制备方法

Family Cites Families (9)

* 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
US5910319A (en) * 1997-05-29 1999-06-08 Eli Lilly And Company Fluoxetine enteric pellets and methods for their preparation and use
CA2350531A1 (fr) * 1998-11-13 2000-05-25 Smriti Iyengar Methode de traitement de la douleur
GB0410470D0 (en) * 2004-05-11 2004-06-16 Cipla Ltd Pharmaceutical compound and polymorphs thereof
US7550605B2 (en) * 2004-08-05 2009-06-23 Sun Pharmaceutical Industries Ltd. Process for preparation of an anitdepressant compound
CZ297560B6 (cs) * 2004-10-26 2007-02-07 Zentiva, A. S. Zpusob výroby hydrochloridu (S)-N-methyl-3-(1-naftyloxy)-3-(2-thienyl)propylaminu (duloxetinu)
TWI306858B (en) * 2004-12-23 2009-03-01 Teva Pharma Process for preparing pharmaceutically acceptable salts of duloxetine and intermediates thereof
EP1971593A2 (fr) * 2005-12-12 2008-09-24 Medichem, S.A. Procede perfectionne de synthese et de preparations de sels de duloxetine
HU228458B1 (en) * 2006-03-13 2013-03-28 Egis Gyogyszergyar Nyrt Duloxetine salts for producing pharmaceutical compositions

Also Published As

Publication number Publication date
WO2007134168A3 (fr) 2008-01-24
EP2016066A4 (fr) 2010-11-24
WO2007134168A2 (fr) 2007-11-22

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