WO2006126213A1 - An improved process for the preparation of duloxetine - Google Patents

An improved process for the preparation of duloxetine Download PDF

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Publication number
WO2006126213A1
WO2006126213A1 PCT/IN2006/000174 IN2006000174W WO2006126213A1 WO 2006126213 A1 WO2006126213 A1 WO 2006126213A1 IN 2006000174 W IN2006000174 W IN 2006000174W WO 2006126213 A1 WO2006126213 A1 WO 2006126213A1
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Prior art keywords
dimethyl
thienyl
propanamine
naphthalenyloxy
salt
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PCT/IN2006/000174
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French (fr)
Inventor
Chava Satyanarayana
Gorantla Seeta Ramanjaneyulu
Chavakula Ramdas
Konudula Babu Rao
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Matrix Laboratories Ltd
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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 invention relates to an improved process for the preparation of (S)-(+)-N, N- dimethyl-3- (1-naphthalenyloxy) -3-(2-thienyl) propanamine, a key intermediate for the preparation of Duloxetine or an acid addition salt.
  • Duloxetine [(+)-N-methyl-3- (l-naphthalenyloxy)-3-(2-thienyl) propanamine] has the following structure
  • Duloxetine hydrochloride is the active ingredient of 'CYMBALTA', which inhibits the uptake of both norepinephrine and serotonin.
  • Duloxetine was first disclosed in U.S. Pat. No. 4,956,388 by Robertson, et al., and the synthesis of it was discussed in more detail by Deeter, et al., in Tetrahedron Letters, 31 (49), 7101 -04 ( 1990).
  • PCT publication WO 2004/056795 discloses a process for the preparation of Duloxetine, or an acid addition salt thereof, which process comprises resolving racemic Duloxetine with a chiral acid so as to obtain a salt of the chiral acid and (+) Duloxetine, substantially free of (-) Duloxetine; and also disclosed a process for preparing (+) Duloxetine, or an acid addition salt thereof, comprise an O-alkylation intermediate process step which is carried out in the presence of a base and a phase transfer catalyst.
  • EP 0457559 discloses a process for the preparation of D (+) Duloxetine oxalate as shown in the following scheme-3.
  • the present invention provides a process for preparation of Duloxetine, or an acid addition salt by coupling N, N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with 1- fluoro naphthalene in presence of an alkoxide in an organic polar solvent followed by resolution and demethylation yields Duloxetine or coupling (S)-(-)-N,N-dimethyl-3-(2- thienyl)-3 -hydroxy propanamine with 1-fiuoronaphthalene in presence of an alkoxide in an organic polar solvent followed by demethylation yields Duloxetine and also recycling the unwanted isomer in the preparation of Duloxetine.
  • N, N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with 1- fluoro naphthalene in presence of an alkoxide in an organic polar solvent followed by resolution and demethylation yields Duloxetine
  • a process for the preparation of Duloxetine, or an acid addition salt comprising steps; i. Condensation of N, N-dimethyl-3 ⁇ (2-thienyI)-3-hydroxypropanamine with 1- fluoro naphthalene so as to obtain N,N-dimethyl-3-(l-naphthalenyloxy) -3-(2- thienyl) propanamine (optionally converting it to its oxalate salt), ii.
  • Condensation of N,N-dimethyI-3-(2-thienyl)-3-hydroxy propanamine with 1-fluoro naphthalene is carried out in presence of an alkoxide selected from potassium tert.butoxide, sodium methoxide and sodium ethoxide in an organic polar solvent selected from Dimethyl sulphoxide, N,N-Dimethyl formamide and N,N-Dimethyl acetamide at a temperature ranging from room temperature to 70°C, preferably at 50-60°C.
  • an alkoxide selected from potassium tert.butoxide, sodium methoxide and sodium ethoxide
  • organic polar solvent selected from Dimethyl sulphoxide, N,N-Dimethyl formamide and N,N-Dimethyl acetamide
  • N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine prepared according to the present invention as described above can be isolated as its acid addition salts which includes oxalate salt, phosphate salt, hydrochloride salt, nitrate salt and tartrate salt among which preferable one is the oxalate salt.
  • N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine is achieved with a suitable chiral acid in a suitable solvent.
  • the chiral acids employed in a process according to the present invention are Tartaric acid, Mandelic acid, camphor sulphonic acid, Dibenzyl tartaric acid and Diparatolyl tartaric acid.
  • the solvents employed are alkanols, esters or a mixture of alkanol, ester and water.
  • the present invention further relates to a process for the preparation of Duloxetine, or an acid addition salt comprising steps:
  • the present invention further relates to a process for the preparation of Duloxetine, or an acid addition salt comprising steps:
  • Racemization of the (-)-N,N-dimethyl-3-( 1-naphthalenyloxy) -3-(2 -thienyl) propanamine is carried out in alkanols or polar aprotic solvents in presence of a base selected from alkali metal hydroxides preferably potassium hydroxide and alkoxide of alkali metals to get N,N-dimethyl-3-( 1-naphthalenyloxy) -3 -(2 -thienyl) propanamine.
  • a base selected from alkali metal hydroxides preferably potassium hydroxide and alkoxide of alkali metals to get N,N-dimethyl-3-( 1-naphthalenyloxy) -3 -(2 -thienyl) propanamine.
  • N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine is achieved with a suitable chiral acid in a suitable solvent.
  • the chiral acids employed in a process according to the present invention are Tartaric acid, Mandeiic acid, camphor sulphonic acid, Dibenzyl tartaric acid and Diparatolyl tartaric acid.
  • the solvents employed are alkanols, esters or a mixture of alkanol, ester and water.
  • the invention can be further illustrated by the below non-limiting examples.
  • N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine (25.0gm) is dissolved in DMSO (150ml) at room temperature.
  • Potassium.tertButoxide (15.5gm) is added over a period of 30min at room temperature.
  • the reaction mixture is stirred for 30min at 25-30 C and 4- Fluoronaphthalene (24.45gm) is added slowly over a period of lhour.
  • Reaction mass temperature is slowly raised to 50-55 0 C and maintained for about ⁇ hours at that temperature.
  • After the reaction is completed reaction mass is cooled to room temperature and Acetic acid (10ml) is slowly added over a period of lOmin and quenched in water at 20 0 C.
  • Reaction mass pH is adjusted to about 5.0 with acetic acid and extracted with n-Hexane. Aq layer is separated and pH is adjusted to 11.5 with 5N NaOH and extracted with ethyl acetate. The ethyl acetate layer is washed and concentrated under vacuum. The residue is dissolved in ethyl acetate and treated with activated charcoal. To the clear filtrate Oxalic acid (15.3gm) is added. The reaction mixture is stirred for 2hrs and the precipitated Oxalate salt is filtered. Out put: 44.0gm (81.5 % yield)
  • Duloxetine (27gm) is dissolved in ethyl acetate (90ml) and cooled the mass to 10 0 C. pH is adjusted to below 2.0 with IPA.HC1 over a period of one hour. Stirred the reaction mass for lhour at 10 0 C and lhour at O 0 C. Precipitated hydrochloride salt is filtered, washed with 100ml ethyl acetate and dried the product at 50-55 0 C. Out put: 14.0 gm.
  • Example-4 (+)-N-methyI-3-(l-naphthalenyloxy)-3-(2-thie ⁇ yl) propanamine (Duloxetine)
  • reaction mass After the reaction is completed cooled the reaction mass to 20 0 C and slowly quenched in DM water at 20°C.Reaction mass pH is adjusted to 7.7 with Acetic acid and washed the reaction mass with n-hexane. Aq.layer is separated and pH is adjusted to 10.5 with caustic lye. Extracted with ethyl acetate and ethyl acetate is concentrated under vacuum to get residue. The obtained residue is dissolved in ethyl acetate and treated with activated charcoal. The filtered ethyl acetate layer is concentrated to give Duloxetine. Out put: 26gm (Yield; 95.0 %)
  • Duloxetine (26gm) is dissolved in ethyl acetate (90ml) and cooled the mass to 10 0 C. pH is adjusted to below 2.0 with IPA.HC1 over a period of one hour. Stirred the reaction mass for lhour at 10 0 C and lhour at O 0 C. Precipitated hydrochloride salt is filtered, washed with 100ml ethyl acetate and dried the product at 50-55 0 C. Out put: 13.8gm.

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

Abstract

A process for preparing Duloxetine, or its acid addition salt, which process comprises (i) condensation of (S)-(-)-N, N-dimethyl-3-(2-thienyl)-3-hydroxy propanamine with 1-fluoronaphthalene followed by demethylation or condensation of N, N-dimethyl-3-(2-thienyl)-3-hydroxy propanamine with 1-fluoronaphthalene followed by resolution and demethylation; and (ii) if desired, converting Duloxetine to its acid addition salt.

Description

"An improved process for the preparation of Buloxetine"
The present invention relates to an improved process for the preparation of (S)-(+)-N, N- dimethyl-3- (1-naphthalenyloxy) -3-(2-thienyl) propanamine, a key intermediate for the preparation of Duloxetine or an acid addition salt.
Background of the Invention: Duloxetine, [(+)-N-methyl-3- (l-naphthalenyloxy)-3-(2-thienyl) propanamine] has the following structure
Figure imgf000002_0001
Duloxetine
Duloxetine hydrochloride is the active ingredient of 'CYMBALTA', which inhibits the uptake of both norepinephrine and serotonin. Duloxetine was first disclosed in U.S. Pat. No. 4,956,388 by Robertson, et al., and the synthesis of it was discussed in more detail by Deeter, et al., in Tetrahedron Letters, 31 (49), 7101 -04 ( 1990).
US 5,362,886 discloses a process for the preparation of Duloxetine, or an acid addition salt comprising
i. Condensing (S)~(-)-N, N-dimethyl-3 - (2-thienyl)-3-hydroxypropanamine with 1- fluoronaphthalene in presence of sodium hydride and potassium benzoate in DMSO so as to obtain (S)-(+)-N, N-dimethyl-3- (1-naphthalenyloxy) -3-(2- thienyl) propanamine (optionally converting it to its phosphate salt). iii. If desired, converting Duloxetine to its acid addition salt as appropriate
Figure imgf000003_0001
Scheme- 1
PCT publication WO 2004/056795 discloses a process for the preparation of Duloxetine, or an acid addition salt thereof, which process comprises resolving racemic Duloxetine with a chiral acid so as to obtain a salt of the chiral acid and (+) Duloxetine, substantially free of (-) Duloxetine; and also disclosed a process for preparing (+) Duloxetine, or an acid addition salt thereof, comprise an O-alkylation intermediate process step which is carried out in the presence of a base and a phase transfer catalyst.
Figure imgf000003_0002
Scheme-2
EP 0457559 discloses a process for the preparation of D (+) Duloxetine oxalate as shown in the following scheme-3.
Figure imgf000003_0003
Scheme-3 In the prior art processes coupling of (S)-(+)-N,N-dimethyl-3-(2-thienyl)-3- hydroxypropanamine with 1-fluoronaphthalene is conducted in presence of a strong base, such as sodium hydride, in a protic polar solvent, such as DMSO, the dimesyl anion generated under the prior art reaction conditions, becomes a hazardous reaction due to non-compatibility of DMSO with strong bases(NaH, NaOH etc) and also caused partial or complete racemisatioή of the condensed product.
It has been a long standing need in industry to provide a process for the preparation of Duloxetine which overcomes the problems associated with prior art processes such as usage of sodium hydride in DMSO and the usage of expensive phase transfer catalysts the inventors have developed such a process, which is advantageous in obviating racemisation, so as to yield an enantiomerically pure form of Duloxetine. In particular, our process can be seen to achieve the above described advantage, by carrying out the coupling of (S)-(+)-N, N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with 1- fluoronaphthalene in presence of base which does not effect the chiral purity of the final product or coupling of N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with 1- fiuoronaphthalene in presence of base followed by resolution of the coupled product obtained in the reaction process (thereby obviating the opportunity for racemisation during preceeding intermediate process steps).
Summary of the Invention:
The present invention provides a process for preparation of Duloxetine, or an acid addition salt by coupling N, N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with 1- fluoro naphthalene in presence of an alkoxide in an organic polar solvent followed by resolution and demethylation yields Duloxetine or coupling (S)-(-)-N,N-dimethyl-3-(2- thienyl)-3 -hydroxy propanamine with 1-fiuoronaphthalene in presence of an alkoxide in an organic polar solvent followed by demethylation yields Duloxetine and also recycling the unwanted isomer in the preparation of Duloxetine. Detailed description of the Invention:
In accordance with the present invention there is provided a process for the preparation of Duloxetine, or an acid addition salt comprising steps; i. Condensation of N, N-dimethyl-3~(2-thienyI)-3-hydroxypropanamine with 1- fluoro naphthalene so as to obtain N,N-dimethyl-3-(l-naphthalenyloxy) -3-(2- thienyl) propanamine (optionally converting it to its oxalate salt), ii. Resolving the racemic N,N-dimethyl-3-(l-naphthalenyloxy) -3-(2-thienyl) propanamine with a chiral acid so as to obtain a salt of the chiral acid and N5N- dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine iii. Demethylation of (S)-(+)-N,N-dimethyl-3-(l -naphthalenyloxy) -3-(2-thienyl) propanamine to get Duloxetine iv. If desired, converting Duloxetine to its acid addition salt as appropriate as shown in scheme-4
Condensation of N,N-dimethyI-3-(2-thienyl)-3-hydroxy propanamine with 1-fluoro naphthalene is carried out in presence of an alkoxide selected from potassium tert.butoxide, sodium methoxide and sodium ethoxide in an organic polar solvent selected from Dimethyl sulphoxide, N,N-Dimethyl formamide and N,N-Dimethyl acetamide at a temperature ranging from room temperature to 70°C, preferably at 50-60°C.
N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine prepared according to the present invention as described above can be isolated as its acid addition salts which includes oxalate salt, phosphate salt, hydrochloride salt, nitrate salt and tartrate salt among which preferable one is the oxalate salt.
Resolution of N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine is achieved with a suitable chiral acid in a suitable solvent. Preferably the chiral acids employed in a process according to the present invention are Tartaric acid, Mandelic acid, camphor sulphonic acid, Dibenzyl tartaric acid and Diparatolyl tartaric acid. Suitably, the solvents employed are alkanols, esters or a mixture of alkanol, ester and water. (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine or its acid addition salt is converted to Duloxetine by demethylation in the presence of phenyl chloroformate, which is hydrolyzed to provide Duloxetine, or an acid addition salt thereof.
Pot . cere . Bucoxi.de Oxalic acid
Figure imgf000006_0002
Figure imgf000006_0001
D(-) Tartaric acid
Isopropyl alcohol Ethyl acecate Water
Figure imgf000006_0003
Figure imgf000006_0004
Figure imgf000006_0005
Duloxetine hydrochloride
Scheme-4
The present invention further relates to a process for the preparation of Duloxetine, or an acid addition salt comprising steps:
i. Condensing (S)-(-)-N, N-dimethyl-3 - (2-thienyl)-3-hydroxy propanamine with 1- fluoronaphthalene so as to obtain (S)-(+)-N, N-dimethyl-3 - (1-naphthalenyloxy)- 3-(2-thienyl) propanamine (optionally converting it to its oxalate salt).
ii. Demethylation of (S)-(+)-N, N-dimethyl-3 - ( 1 -naphthalenyloxy)-3 -(2-thienyl) propanamine to get Duloxetine. iii. If desired, converting Duloxetine to its acid addition salt as appropriate.
Condensation of (S)-(-)-N, N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with 1- fluoronaphthalene is carried out in presence of an alkoxide in an organic polar solvent at a temperature ranging from room temperature to 700C, preferably at 50-600C.
(S) - (+) -N, N -dimethyl - 3 - (1 -naphthalenyloxy) - 3 - (2-thienyl)propanamine prepared according to the present invention as described above can be isolated as its acid addition salts which includes oxalate salt, phosphate salt, hydrochloride salt, nitrate salt and tartrate salt among which preferable one is the oxalate salt.
(S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine or its acid addition salt is converted to Duloxetine by demethylation in the presence of phenyl chloroformate, which is hydrolyzed to provide Duloxetine, or an acid addition salt thereof as shown in scheme-5.
Figure imgf000007_0001
Figure imgf000007_0002
Duloxetine hydrochloride Scheme-5
The present invention further relates to a process for the preparation of Duloxetine, or an acid addition salt comprising steps:
a. Racemization of the unwanted isomer of (-)-N,N-dimethyl-3-(l- naphthalenyloxy) -3-(2-thienyl) propanamine b. Resolution of the racemic N,N-dimethyl-3-( 1-naphthalenyloxy) -3-(2-thienyl) propanamine and separating (S)-(+)-N, N-diraethyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propanamine c. Demethylation of the (S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2- thienyl) propanamine to get Duloxetine d. If desired, converting Duloxetine to its acid addition salt as appropriate.
Racemization of the (-)-N,N-dimethyl-3-( 1-naphthalenyloxy) -3-(2 -thienyl) propanamine is carried out in alkanols or polar aprotic solvents in presence of a base selected from alkali metal hydroxides preferably potassium hydroxide and alkoxide of alkali metals to get N,N-dimethyl-3-( 1-naphthalenyloxy) -3 -(2 -thienyl) propanamine.
Resolution of N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine is achieved with a suitable chiral acid in a suitable solvent. Preferably the chiral acids employed in a process according to the present invention are Tartaric acid, Mandeiic acid, camphor sulphonic acid, Dibenzyl tartaric acid and Diparatolyl tartaric acid. Suitably, the solvents employed are alkanols, esters or a mixture of alkanol, ester and water.
(S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2 -thienyl) propanamine or its acid addition salt is converted to (+) Duloxetine by demethylation in the presence of a reagent such as phenyl chloro formate, which is hydrolyzed to provide (+) Duloxetine, or an acid addition salt thereof.
The invention can be further illustrated by the below non-limiting examples.
Example-l:
N, N-dimethyI-3-(l-naphthalenyloxy) -3-(2-thienyl) propanamine oxalate
N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine (25.0gm) is dissolved in DMSO (150ml) at room temperature. Potassium.tertButoxide (15.5gm) is added over a period of 30min at room temperature. The reaction mixture is stirred for 30min at 25-30 C and 4- Fluoronaphthalene (24.45gm) is added slowly over a period of lhour. Reaction mass temperature is slowly raised to 50-550C and maintained for about όhours at that temperature. After the reaction is completed reaction mass is cooled to room temperature and Acetic acid (10ml) is slowly added over a period of lOmin and quenched in water at 200C. Reaction mass pH is adjusted to about 5.0 with acetic acid and extracted with n-Hexane. Aq layer is separated and pH is adjusted to 11.5 with 5N NaOH and extracted with ethyl acetate. The ethyl acetate layer is washed and concentrated under vacuum. The residue is dissolved in ethyl acetate and treated with activated charcoal. To the clear filtrate Oxalic acid (15.3gm) is added. The reaction mixture is stirred for 2hrs and the precipitated Oxalate salt is filtered. Out put: 44.0gm (81.5 % yield)
Example-2:
(S) - (+)-N, N-dimethyl-3- (1-naphthalenyloxy) -3-(2-thienyl) propanamine tartrate hemihydrate;
N, N-dimethyl-3 -(1-naphthalenyloxy) -3-(2-thienyl) propanamine (20gm) is dissolved in ethyl acetate(120ml).Isopropyl alcohol(20ml) is charged to the reaction mass and the temperature is raised to around 400C. To the reaction mixture D (-) tartaric acid (2.4gm dissolved in 6.0ml water) is added over a period of 45min.Reaction mass is maintained for 15 min at 400C. Reaction mass is cooled to about 300C and filtered the product. Washed with 40ml ethyl acetate and dried the product at 30-350C under aerial drying. Out put: 6.4gm (yield: 22.0 %) Moisture content: 8.8% Specific optical rotation (C=I % methanol) : 74.24°
IRAnalysis: cm"' 3323, 3053,2934,2970,1595,1397, 1264, 1236,1095,1067,795,775 and 705
IH NMR (300MHz, DMSO-d6) δ 6.88 (lH,d, Ar-H), 7.26-7.32(1 H,m, Ar-H), 7.42(lH,d, Ar-H), 7.78- 7.81(lH,m, Ar-H), 7.47-7.54(1 H,m, Ar-H), 7.47-7.54(1 H,m, Ar-H), 8.30-8.33(1 H,m, Ar-H), 5.83- 5.85(lH,dd, COCH),2.47-2.64(2H,m,CH2), 3.03(2H,t,CH2N),2.47-2.64(6H,s, N(CH3)2), 3.13(2H,t,CH2), 7.12(lH,d,Ar-H), 6.93-6.96(lH,dd,Ar-H),7.21-7.23(lH,dd, Ar-H),4.42(1H, tartrate)
13C NMR (75MHz, DMSO-d6) δ 152.88,107.15,125.74,120.91, 134.58, 127.55, 125.34,126.35,121.89, 25.97,73.24,34.65,54.84,43.82,143.9425.12,126.78,125.0 and 177.9 ExampIe-3:
(+)-N-methyI-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine (Duloxetine)
(S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine tartrate salt (44.0gm) is suspended in Toluene (350ml) and DM water (350ml).Raised the temperature to 35-400C and aq. ammonia (55ml) is added. Reaction mixture is stirred for 30min and the organic layer is separated and aq.layer is extracted with toluene. Combined the toluene layer, washed with water and concentrated under vacuum to get (S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy) -3-(2-thienyl)propanamine base.
(S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine is dissolved in toluene (140 ml) and the temperature is raised to 40°C.Diisopropylamine (1.76 gm) is added the temperature is raised to 50-55°C.Phenylchloroformate (21.4 gm) is added slowly over a period of 1.5 hours at 50-550C. Reaction mass is maintained at 50-550C for 1.5 hours. After the reaction is completed cool the reaction mass to 40 C and quenched the reaction mass in 1% NaHCO3 (440ml). Organic layer is separated and washed with 0.5N HCl followed by 1% NaHCO3. Toluene is evaporated completely under vacuum and the obtained residue is dissolved in DMSO (480ml) and Caustic lye solution (16.7gm in 105ml water) is added over a period of one hour at 30-400C. Reaction mass is stirred for 12 hrs at 40-450C. After the reaction is completed cooled the reaction mass to 200C and slowly quenched in DM water at 200C. Reaction mass pH is adjusted to 5.7 with Acetic acid and washed the reaction mass with n-hexane. Aq.layer is separated and pH is adjusted to 10.5 with caustic lye. Extracted with ethyl acetate and ethyl acetate is concentrated under vacuum to get residue. The obtained residue is dissolved in ethyl acetate and treated with activated charcoal. The filtered ethyl acetate layer is concentrated to give Duloxetine (27gm. Yield; 95.0 %).
Duloxetine (27gm) is dissolved in ethyl acetate (90ml) and cooled the mass to 100C. pH is adjusted to below 2.0 with IPA.HC1 over a period of one hour. Stirred the reaction mass for lhour at 100C and lhour at O0C. Precipitated hydrochloride salt is filtered, washed with 100ml ethyl acetate and dried the product at 50-550C. Out put: 14.0 gm. Example-4: (+)-N-methyI-3-(l-naphthalenyloxy)-3-(2-thieπyl) propanamine (Duloxetine)
(S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine oxalate salt (37.0gm) is suspended in Toluene (296ml) and DM water (296ml).Raised the temperature to 35-400C and aq.ammonia (42ml) is added. Reaction mixture is stirred for 30min and the organic layer is separated and aq.layer is extracted with toluene. Combined the toluene layer, washed with water and concentrated under vacuum to get (S)-(+)-N, N-dimethyl-3-( 1 -naphthalenyloxy) -3-(2-thienyl)propanamine base.
(S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine is dissolved in toluene (120ml) and the temperature is raised to 400C. Diisopropylamine (1.5gm) is added the temperature is raised to 50-550C. Phenylchloroformate (18.3gm) is added slowly over a period of 1.5 hours at 50-550C. Reaction mass is maintained at 50-550C for 1.5 hours. After the reaction is completed cool the reaction mass to 400C and quenched the reaction mass in 1% NaHCθ3 (370ml). Organic layer is separated and washed with 0.5N HCl followed by 1% NaHCO3 Toluene is evaporated completely under vacuum and the obtained residue is dissolved in DMSO (370ml). Caustic lye solution (14.9gm in 83ml water) over a period of one hour at 30-400C. Reaction mass is stirred for 12 hrs at 40-450C.
After the reaction is completed cooled the reaction mass to 200C and slowly quenched in DM water at 20°C.Reaction mass pH is adjusted to 7.7 with Acetic acid and washed the reaction mass with n-hexane. Aq.layer is separated and pH is adjusted to 10.5 with caustic lye. Extracted with ethyl acetate and ethyl acetate is concentrated under vacuum to get residue. The obtained residue is dissolved in ethyl acetate and treated with activated charcoal. The filtered ethyl acetate layer is concentrated to give Duloxetine. Out put: 26gm (Yield; 95.0 %)
Duloxetine (26gm) is dissolved in ethyl acetate (90ml) and cooled the mass to 100C. pH is adjusted to below 2.0 with IPA.HC1 over a period of one hour. Stirred the reaction mass for lhour at 100C and lhour at O0C. Precipitated hydrochloride salt is filtered, washed with 100ml ethyl acetate and dried the product at 50-550C. Out put: 13.8gm.
ExampIe-5:
Preparation of racemic Duloxetine:
D(-) Duloxetine(84 g) is dissolved in 1260ml of Methanol. To the reaction mass 35.5 g KOH powder is added and the temperature is raised to 70-750C. Reaction mass is maintained for 2hrs at 70-750C. Reaction mass is cooled to room temperature over a period of two hours. Reaction mass is quenched into DM water (1260ml) during 30-45 min. Reaction mixture is extracted with ethyl acetate and evaporated to give the title compound. Out put: 78.0 g SOR: 0.14 (1% MeOH)

Claims

We claim:
1. A process for the preparation of Duloxetine, or an acid addition salt comprising steps:
a. Condensation of N, N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine with 1- fluoro naphthalene so as to obtain N, N-dimethyl-3-(l-naphthalenyloxy) -3-(2- thienyl) propanamine (optionally converting it to its oxalate salt). b. Resolving the racemic N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine with a chiral acid so as to obtain a salt of the chiral acid and N,N- dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine c. Demethylation of (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy) -3-(2-thienyl) propanamine to get Duloxetine d. If desired, converting Duloxetine to its acid addition salt.
2. The process as claimed in claim 1, wherein the condensation is carried out in the presence of an alkoxide selected from potassium tertbutoxide, sodium methoxide and sodium ethoxide.
3. The process as claimed in claim 1, wherein the condensation is carried out in an organic polar solvent selected from Dimethyl sulphoxide, N,N-Dimethyl formamide and N,N-Dimethyl acetamide.
4. The process as claimed in claim 1, wherein the N,N-dimethyl-3-(l-naphthalenyloxy) -
3-(2-thienyl) propanamine is isolated as its acid addition salt which includes oxalate salt, phosphate salt, hydrochloride salt, nitrate salt and tartrate salt.
5. The process as claimed in claim 1, wherein the resolution of N,N-dimethyl-3-(l- naphthalenyloxy) - 3-(2-thienyl) propanamine is carried out with a chiral acid selected from Tartaric acid, Mandelic acid, camphor sulphonic acid, Dibenzyl tartaric acid and Diparatolyl tartaric acid
6. The process as claimed in claim 1, wherein the resolution of N,N-dimethyl-3-(l- naphthalenyloxy) - 3-(2-thienyl) propanamine is carried out in a solvent selected from alkanols, esters or a mixture of alkanol, ester and water.
7. The process as claimed in claim 1, wherein the demethylation takes place in presence of phenyl chloroformate.
8. The process as claimed in claim 1, wherein the preferable addition salt is hydrochloride.
9. A process for the preparation of Duloxetine, or an acid addition salt comprising steps:
a. Condensing (S)-(-)-N, N-dimethyl-3 - (2-thienyl)-3-hydroxy propanamine with 1- fiuoronaphthalene so as to obtain (S)-(+)-N, N-dimethyl-3 - (1-naphthalenyloxy)-
3-(2-thienyl) propanamine (optionally converting it to its oxalate salt). b. Demethylation of (S)-(+)-N, N-dimethyl-3 - (l-naphthalenyloxy)-3-(2-thienyl) propanamine to get Duloxetine. c. If desired, converting Duloxetine to its acid addition salt as appropriate.
10. The process as claimed in claim 9, wherein the condensation is carried out in the presence of an alkoxide selected from potassium tert.butoxide, sodium methoxide and sodium ethoxide
11. The process as claimed in claim 9, wherein the condensation is carried out in an organic polar solvent selected from Dimethyl sulphoxide, N,N-Dimethyl formamide and N,N-Dimethyl acetamide
12. The process as claimed in claim 9, wherein the (S)-(+)-N, N~dimethyl-3 - (1- naphthalenyloxy)-3-(2-thienyl) propanamine is isolated as its acid addition salt which includes oxalate salt, phosphate salt, hydrochloride salt, nitrate salt and tartrate salt
13. The process as claimed in claim 9, wherein the demethylation takes place in presence of phenyl chloro formate
14. The process as claimed in claim 1, wherein the preferable addition salt is hydrochloride.
15. A process for the preparation of Duloxetine, or an acid addition salt comprising steps:
a. Racemization of the (-)-N,N-dimethyl-3-(l-naphthalenyloxy) -3-(2-thienyl) propanamine b. Resolution of the racemic N,N-dimethyl-3-( 1-naphthalenyloxy) -3-(2-thienyl) propanamine and separating (S)-(+)-N, N-dimethyl-3- (1-naphthalenyloxy) -3-(2- thienyl) propanamine c. Demethylation of the (S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine to get Duloxetine d. If desired, converting Duloxetine to its acid addition salt as appropriate.
16. The process as claimed in claim 15, wherein the racemization of the (-)-N,N- dimethy 1-3 -(1-naphthalenyloxy) -3-(2-thienyI) propanamine is carried out in a solvent solvent selected from alkanols or polar aprotic solvents.
17. The process as claimed in claim 15, wherein the employed (-)-N,N-dimethyl-3-(l- naphthalenyloxy) -3-(2-thienyl) propanamine for racemization contains about 1% to 45% (+)-N,N-dimethyl-3-( 1-naphthalenyloxy) -3-(2-thienyl) propanamine.
18. The process as claimed in claim 15, wherein the racemization of the (-)-N,N- dimethyl-3-( 1-naphthalenyloxy) -3-(2-thienyl) propanamine is carried out in presence of a base selected from alkali metal hydroxides preferably potassium hydroxide
19. The process as claimed in claim 15, wherein the resolution of N,N-dimethyl-3-(l- naphthalenyloxy) - 3-(2-thienyl) propanamine is carried out in a solvent selected from alkanols, esters or a mixture of alkanol, ester and water
20. The process as claimed in claim 15, wherein the demethylation takes place in presence of phenyl chloroformate
21. The process as claimed in claim 15, wherein the preferable addition salt is hydrochloride.
PCT/IN2006/000174 2005-05-24 2006-05-23 An improved process for the preparation of duloxetine WO2006126213A1 (en)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007067581A1 (en) * 2005-12-05 2007-06-14 Teva Pharmaceutical Industries Ltd. 2-(n-methyl-propanamine)-3-(2-naphthol) thiophene, an impurity of duloxetine hydrochloride
WO2007076733A2 (en) * 2006-01-04 2007-07-12 Zentiva A.S. A METHOD FOR THE PREPARATION OF (S)-N-METΗYL-3-(l-NAPHTHYLOXY)-3-(2-THIENYL)PROPYLAMINE HYDROCHLORIDE (DULOXETINE)
WO2007095200A2 (en) * 2006-02-13 2007-08-23 Teva Pharmaceutical Industries Ltd. A process for the preparation of (s)-(+)-n,n-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, a duloxetine intermediate
WO2008107911A3 (en) * 2007-03-05 2008-11-20 Lupin Ltd Novel process for preparation of duloxetine hydrochloride
US7534900B2 (en) 2005-03-14 2009-05-19 Teva Pharmaceutical Industries Ltd Process for the purification of duloxetine hydrochloride
WO2009074883A2 (en) * 2007-11-06 2009-06-18 Medichem, S.A. Improved process for preparing duloxetine
US7842717B2 (en) 2005-09-22 2010-11-30 Teva Pharmaceutical Industries Ltd. DNT-maleate and methods of preparation thereof
WO2011033366A3 (en) * 2009-09-16 2011-09-01 Jubilant Life Sciences Limited Process for the preparation of duloxetine hydrochloride and its precursors
JP2011236195A (en) * 2010-05-06 2011-11-24 Sci Pharmatech Inc Process for preparing (s)-(+)-n-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine using optically active methylhydroxylaminopropanol compound as intermediate
CN104163811A (en) * 2013-05-16 2014-11-26 重庆圣华曦药业股份有限公司 New method for preparation of duloxetine hydrochloride
CN114163415A (en) * 2021-12-01 2022-03-11 珠海润都制药股份有限公司 Preparation method of duloxetine hydrochloride intermediate

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
WO2006045255A1 (en) * 2004-10-26 2006-05-04 Zentiva, A.S. Method of manufacturing (s)-n-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride (duloxetine)

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
WO2006045255A1 (en) * 2004-10-26 2006-05-04 Zentiva, A.S. Method of manufacturing (s)-n-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride (duloxetine)

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7534900B2 (en) 2005-03-14 2009-05-19 Teva Pharmaceutical Industries Ltd Process for the purification of duloxetine hydrochloride
US7842717B2 (en) 2005-09-22 2010-11-30 Teva Pharmaceutical Industries Ltd. DNT-maleate and methods of preparation thereof
WO2007067581A1 (en) * 2005-12-05 2007-06-14 Teva Pharmaceutical Industries Ltd. 2-(n-methyl-propanamine)-3-(2-naphthol) thiophene, an impurity of duloxetine hydrochloride
US7759500B2 (en) 2005-12-05 2010-07-20 Teva Pharmaceutical Industries Ltd. 2-(N-methyl-propanamine)-3-(2-naphthol)thiophene, an impurity of duloxetine hydrochloride
US8071791B2 (en) 2006-01-04 2011-12-06 Zentiva K.S. Method for the preparation of (S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride (duloxetine)
EA014559B1 (en) * 2006-01-04 2010-12-30 ЗЕНТИВА, а.с. A method for the preparation of (s)-n-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride (duloxetine)
US8207356B2 (en) 2006-01-04 2012-06-26 Zentiva K.S. Method for the preparation of (S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride (duloxetine)
WO2007076733A2 (en) * 2006-01-04 2007-07-12 Zentiva A.S. A METHOD FOR THE PREPARATION OF (S)-N-METΗYL-3-(l-NAPHTHYLOXY)-3-(2-THIENYL)PROPYLAMINE HYDROCHLORIDE (DULOXETINE)
EP2172464A3 (en) * 2006-01-04 2010-05-12 Zentiva, k.s. A method for the preparation of the hydrochloride salt from the duloxetine base
WO2007076733A3 (en) * 2006-01-04 2007-08-23 Zentiva As A METHOD FOR THE PREPARATION OF (S)-N-METΗYL-3-(l-NAPHTHYLOXY)-3-(2-THIENYL)PROPYLAMINE HYDROCHLORIDE (DULOXETINE)
WO2007095200A3 (en) * 2006-02-13 2008-08-21 Teva Pharma A process for the preparation of (s)-(+)-n,n-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, a duloxetine intermediate
WO2007095200A2 (en) * 2006-02-13 2007-08-23 Teva Pharmaceutical Industries Ltd. A process for the preparation of (s)-(+)-n,n-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, a duloxetine intermediate
US8269023B2 (en) 2007-03-05 2012-09-18 Lupin Ltd. Process for preparation of duloxetine hydrochloride
WO2008107911A3 (en) * 2007-03-05 2008-11-20 Lupin Ltd Novel process for preparation of duloxetine hydrochloride
WO2009074883A3 (en) * 2007-11-06 2009-08-06 Medichem Sa Improved process for preparing duloxetine
WO2009074883A2 (en) * 2007-11-06 2009-06-18 Medichem, S.A. Improved process for preparing duloxetine
WO2011033366A3 (en) * 2009-09-16 2011-09-01 Jubilant Life Sciences Limited Process for the preparation of duloxetine hydrochloride and its precursors
JP2011236195A (en) * 2010-05-06 2011-11-24 Sci Pharmatech Inc Process for preparing (s)-(+)-n-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine using optically active methylhydroxylaminopropanol compound as intermediate
CN104163811A (en) * 2013-05-16 2014-11-26 重庆圣华曦药业股份有限公司 New method for preparation of duloxetine hydrochloride
CN114163415A (en) * 2021-12-01 2022-03-11 珠海润都制药股份有限公司 Preparation method of duloxetine hydrochloride intermediate
CN114163415B (en) * 2021-12-01 2023-03-03 珠海润都制药股份有限公司 Preparation method of duloxetine hydrochloride intermediate

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