WO2009130708A2 - Préparation de duloxétine et de ses sels - Google Patents

Préparation de duloxétine et de ses sels Download PDF

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Publication number
WO2009130708A2
WO2009130708A2 PCT/IN2009/000028 IN2009000028W WO2009130708A2 WO 2009130708 A2 WO2009130708 A2 WO 2009130708A2 IN 2009000028 W IN2009000028 W IN 2009000028W WO 2009130708 A2 WO2009130708 A2 WO 2009130708A2
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WO
WIPO (PCT)
Prior art keywords
formula
duloxetine
thienyl
dimethyl
reacting
Prior art date
Application number
PCT/IN2009/000028
Other languages
English (en)
Other versions
WO2009130708A3 (fr
Inventor
Thota Giridhar
Gudipati Srinivasulu
Kotaru Srinivasa Rao
Original Assignee
Shodhana Laboratories 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 Shodhana Laboratories Limited filed Critical Shodhana Laboratories Limited
Publication of WO2009130708A2 publication Critical patent/WO2009130708A2/fr
Publication of WO2009130708A3 publication Critical patent/WO2009130708A3/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

  • the present patent application relates to a process for the preparation of Duloxetine and its salts.
  • Duloxetine hydrochloride is chemically described as (+)-(S)-N-methyl- ⁇ -(l-na ⁇ hthyloxy)-2-thiophene ⁇ ropylamine hydrochloride and is structurally represented by Formula I.
  • Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor and is useful in the treatment of depression.
  • Pharmaceutical products containing duloxetine hydrochloride salt as the active ingredient are commercially available in the market under the brand name CYMBALTATM as capsules containing an equivalent of 20, 30 and 60 mg of duloxetine for oral administration.
  • U.S. Patent No. 5,023,269 describes (S) -(+)-N-methyl-3-(l -naphtha lenyloxy)-3-(2-thienyl) propanamine oxalate, its related compounds and processes for their preparation.
  • U.S. patent no. 5,362,886 discloses the process for preparation of Duloxetine HCl by that includes reacting (S)-( ⁇ )-N, N-Dimethyl-3-(2-thienyl)- 3-hydroxy propanamine with fluoronapthalene in presence of potassium benzoate and sodium hydride to produce (S)-(+) N, N-Dimethyl-3-(l- naphthalenyloxy)-3-(2-thienyl) propanamine followed by conversion to phosphoric acid salt.
  • the product obtained is further converted to Duloxetine phenylcarbamate by reacting with phenylchloroformate, which is further reacted with sodium hydroxide in dimethylsulfoxide (DMSO) to form Duloxetine followed by reacting with HCl to form Duloxetine HCl.
  • DMSO dimethylsulfoxide
  • DMSO is relatively not a .suitable solvent for use in commercial scale as it is not recoverable, it undergoes decomposition at high temperature in the presence' of a base and moreover it is an expensive solvent.
  • the present patent application provides a process for the preparation of Duloxetine or a pharmaceutically acceptable salt thereof that includes: a) reacting (S) - (+)-N, N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine of Formula II or a salt there of with 1-fluoronapthalene of Formula III in the presence of sodium hydride and potassium 4-methyl benzoate
  • Duloxetine refers to the S-isomer of iV-methyl- ⁇ -(l- naphthyloxy) -2 -thiophenepropylamine and JV-methyl- ⁇ - ( 1 -naphthyloxy) -2 - thiophenepropylamine referred to as the racemic mixture of S and R isomers.
  • Pyridine refers to the potassium salt of 4-methyl benzoic acid which is represented by the following structural formula.
  • the present patent application provides a process for the preparation of Duloxetine or a pharmaceutically acceptable salt thereof that includes: a) reacting (S) - (+)-N, N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine of Formula II or a salt there of with 1-fluoronapthalene of Formula III in the presence of sodium hydride and potassium 4-methyl benzoate
  • Step a) involves reaction of (S) - (+)-N, N-Dimethyl-3-(2-thienyl)-3- hydroxypropanamine of Formula II or a salt there of with 1-fluoronapthalene of Formula III.
  • Suitable solvent that may be used for the reaction of step a) includes polar aprotic solvents such as dimethylformamide(DMF), dimethylacetamide(DMAC), dimethylsulfoxide(DMSO) and the like; aromatic hydrocarbons such as toluene, xylene and the like.
  • polar aprotic solvents such as dimethylformamide(DMF), dimethylacetamide(DMAC), dimethylsulfoxide(DMSO) and the like
  • aromatic hydrocarbons such as toluene, xylene and the like.
  • reaction is carried out in the presence of a strong base such as sodium hydride.
  • Suitable temperature for conducting the reaction can range from about 25°C to about reflux temperature of the solvent used, preferably about 40 0 C to about 80 0 C.
  • the reaction can be conducted till the completion of the reaction.
  • the reaction time varies from about 1 hour to about
  • reaction mixture may be quenched with water and excess base is neutralized with a suitable acid such as acetic acid.
  • a suitable acid such as acetic acid.
  • the product may be extracted into a suitable organic solvent at a suitable pH such as about 7.5 to about 10 being suitable.
  • Organic layer containing the product may be separated, washed with water and proceed to next step directly or it can be distilled to obtain the product as residue.
  • Suitable solvent that may be useful for extracting the product includes esters such as ethyl acetate, n-propylacetate, isopropyl acetate and the like; hydrocarbon solvents such as toluene, xylene and the like.
  • (S)-(+) N, N-Dimethyl-3-(l-naphthalenyloxy)-3-(2- thienyl) propanamine of Formula IV obtained as residue may be purified by using suitable techniques such as isolating as a salt form including phosphate salt.
  • Step b) involves reacting (S)-(+) N, N-Dimethyl-3-(l-naphthalenyloxy)-
  • Suitable solvent that may be used for the reaction of step a) includes aromatic hydrocarbon solvents such as toluene, xylene and the like. If (S)-(+) N, N-Dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine of Formula IV is in the form of an acid addition salt, it may be converted to free base before it is reacted with phenylchloroformate using suitable techniques such as by treating with an aqueous base solution and extracting into an organic solvent followed by distillation. Suitably the reaction is carried out in the presence of acid scavenger such as triethylamine, diisopropylamine, diisopropylethylamine and the like.
  • acid scavenger such as triethylamine, diisopropylamine, diisopropylethylamine and the like.
  • Suitable temperature for conducting the reaction can range from about 25°C to about reflux temperature of the solvent used, preferably about
  • reaction time varies from about 30 minutes to about 10 hours.
  • Step c) involves reacting Duloxetine phenyl carbamate of compound of Formula V with alkali metal hydroxide in C3-C6 alcohol to form Duloxetine;
  • Suitable C3-C6 alcohols that may be used include isopropanol, 2- butanol, tertiary butanol and the like.
  • Alkali metal hydroxide that may be used includes lithium hydroxide, sodium hydroxide, and potassium hydroxide.
  • Alkali metal hydroxide may be used in the form of solid or as a solution obtained by dissolving alkali metal hydroxide in water.
  • Suitable temperature for conducting the reaction can range from about 5O 0 C to about reflux temperature of the solvent used, preferably reflux temperature of the solvent used.
  • the reaction can be conducted till the completion of the reaction.
  • the reaction time varies from about 1 hour to about 20 hours.
  • the molar ratio of compound of Formula V to alkali metal hydroxide can range from about 1: 1 to about 1: 10.
  • reaction mixture may be quenched with ice cold water and excess base is neutralized with a suitable acid such as acetic acid.
  • a suitable acid such as acetic acid.
  • the product may be extracted into a suitable organic solvent at a suitable pH such as about 8 to about 10 being suitable.
  • Organic layer containing the product may be separated, washed with water and proceed to next step directly or it can be distilled to obtain the product as residue.
  • Suitable solvent that may be useful- for extracting the product includes esters such as ethyl acetate, n-propylacetate, isopropyl acetate and the like; hydrocarbon solvents such as toluene, xylene and the like.
  • Step d) involves reacting Duloxetine with a pharmaceutically acceptable acid.
  • Suitable pharmaceutically acceptable acids include hydrobromic acid, hydrochloric acid, and organic acids such as acetic acid, succinic acid, oxalic acid, tartaric acid, formic acid, and maleic acid.
  • Preferable acid is Hydrochloric acid.
  • Suitable organic solvents include, but are not limited to: alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone, and n-butanone; esters such as ethyl acetate, n-propyl acetate, and isopropyl acetate; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, and cyclohexane. Mixtures of any of these solvents are also contemplated or their combinations without limitation.
  • the product obtained may be further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at temperatures of about 35° C to about 70° C with or without vacuum. The drying can be carried out for any desired time periods to achieve the desired product purity, time from about 1 to 20 hours frequently being appropriate.
  • N, N-Dimethyl-3-(2-thienyl)-3- hydroxypropanamine or a salt there of is reacted with 1-fluoro naphthalene in the presence of potassium 4-methyl benzoate and sodium hydride to yield N, N-Dimethyl ⁇ 3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine.
  • iV-methyl- ⁇ -(l-naphthyloxy)-2- thiophenepropylamine is prepared by reacting N, N-Dimethyl-3-(l- naphthalenyloxy)-3-(2-thienyl) propanamine with phenyl chloroforamte in the presence of triethylamine to yield corresponding carbamate intermediate, which is then reacted with alkali metal hydroxide in C3-C6 alcohol.
  • racemic intermediates may then be converted into Duloxetine or a salt there of using processes including those known in the art.
  • reaction mass is quenched into ice cold water (600 ml) and pH was adjusted to about 4 with 140 ml of acetic acid.
  • Reaction mixture was washed with pet ether (3 X 100 ml).
  • Aqueous layer was separated and pH adjusted about 8.5 with caustic soda and extracted with ethyl acetate (2 X 200 ml; 1 X 150 ml).
  • the organic layer was washed with saturated aqueous sodium chloride solution (3x200) and further dried with sodium chloride.
  • the organic layer pH was adjusted to about 2 with phosphoric acid and maintain for 30 minutes.
  • the precipitated phosphate salt was filtered and washed with ethyl acetate to obtain 230 gm of the title compound as wet solid.
  • Example 2 Preparation of Duloxetine phenyl carbamate (Formula V)
  • the organic layer was washed with 5% aqueous HCl solution(2 X 100 ml) followed by with 5% aqueous sodium bicarbonate solution (2 X 100 ml) .
  • the organic layer was washed with 10 % aqueous sodium chloride solution (3 X 100ml) and further dried with sodium chloride.
  • the final organic layer was distilled completely under vacuum to obtain 100 gm of the title compound as residue.
  • reaction solution pH was adjusted to about 2 with 16 % isopropyl alcoholic HCl (45 ml) slowly and stirred for about 1 hour at 0 to 5 °C.
  • the precipitated solid was filtered and washed with ethyl acetate to get(S)-(+)
  • reaction mass is quenched into ice cold water (150 ml) and pH was adjusted to about 4 with 25 ml of acetic acid.
  • Reaction mixture was washed with pet ether (3 X -25 ml).
  • Aqueous layer was separated and pH adjusted about 8.5 with caustic soda and extracted with ethyl acetate (2 X 50 ml).
  • the organic layer was washed with saturated aqueous sodium chloride solution (3X50 ml) and further dried with sodium chloride. The organic layer was distilled completely under vacuum to give 29 gm of title compound as residue.

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

Abstract

La présente invention concerne un procédé de préparation de duloxétine et de ses sels comprenant la réaction de (S)-(+)-N,N-diméthyl-3-(2- thiényl)-3-hydroxypropanamine ou d'un de ses sels avec du 1-fluoronapthalène en présence d'hydrure de sodium et de 4-méthylbenzoate de potassium, la  N-déméthylation par formation de phénylcarbamate pour obtenir la duloxétine, qui peut ensuite être convertie en un sel pharmaceutiquement acceptable.
PCT/IN2009/000028 2008-04-22 2009-01-09 Préparation de duloxétine et de ses sels WO2009130708A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN993/CHE/2008 2008-04-22
IN993CH2008 2008-04-22

Publications (2)

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WO2009130708A2 true WO2009130708A2 (fr) 2009-10-29
WO2009130708A3 WO2009130708A3 (fr) 2012-10-04

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017019727A (ja) * 2015-07-07 2017-01-26 東和薬品株式会社 デュロキセチン塩基及びデュロキセチン塩酸塩の製造方法

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
WO2004056795A1 (fr) * 2002-12-19 2004-07-08 Cipla Ltd Procede de preparation de la duloxetine et intermediaires destines a etre utilises dans ledit procede

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
WO2004056795A1 (fr) * 2002-12-19 2004-07-08 Cipla Ltd Procede de preparation de la duloxetine et intermediaires destines a etre utilises dans ledit procede

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017019727A (ja) * 2015-07-07 2017-01-26 東和薬品株式会社 デュロキセチン塩基及びデュロキセチン塩酸塩の製造方法

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WO2009130708A3 (fr) 2012-10-04

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