[go: up one dir, main page]

WO2008081476A2 - Procédé d'élaboration de chlorhydrate de duloxétine - Google Patents

Procédé d'élaboration de chlorhydrate de duloxétine Download PDF

Info

Publication number
WO2008081476A2
WO2008081476A2 PCT/IN2007/000632 IN2007000632W WO2008081476A2 WO 2008081476 A2 WO2008081476 A2 WO 2008081476A2 IN 2007000632 W IN2007000632 W IN 2007000632W WO 2008081476 A2 WO2008081476 A2 WO 2008081476A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
thiophen
amine
thienyl
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.)
Ceased
Application number
PCT/IN2007/000632
Other languages
English (en)
Other versions
WO2008081476A3 (fr
Inventor
Dhimant Jasubhai Patel
Shriprakash Dhar Dwivedi
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.)
Zydus Lifesciences Ltd
Original Assignee
Cadila Healthcare Ltd
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 Cadila Healthcare Ltd filed Critical Cadila Healthcare Ltd
Publication of WO2008081476A2 publication Critical patent/WO2008081476A2/fr
Publication of WO2008081476A3 publication Critical patent/WO2008081476A3/fr
Anticipated expiration legal-status Critical
Ceased 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
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to improved process for preparing duloxetine hydrochloride of formula (I). More particularly, present invention relates to enantiomerically pure S-(+)-duloxetine hydrochloride with high purity as determined by area percentage of HPLC. The present invention also relates to the novel intermediates for the preparation of S-(+)-duloxetine hydrochloride. Duloxetine is useful for the treatment of depression.
  • Duloxetine HCl is a dual reuptake inhibitor of the neurotransmitter serotonin and norepinephrine. It is used for the treatment of stress urinary incontinence (SUI), depression, and pain management. It is commercially available as CYMBALTA .
  • Duloxetine hydrochloride has the chemical name (S)-(+)-N-methyl-3-(l- naphthalenyloxy)-3-(2-thienyl)propanamine hydrochloride acid salt and represented by the structure of formula (I).
  • Duloxetine and related class of compounds like fluoxetine, tomoxetine etc. are important for treating psychiatric disorders. Fluoxetine is a selective inhibitor of serotonin in serotonergic neurons, tomoxetine and nisoxetine are selective inhibitors of norepinephrine in noradrenergic neurons while duloxetine is a dual inhibitor of serotonin and norepinephrine reuptake and thus have a better pharmacological profile as an antidepressant drug (EP 273658, 1988; Chem. Abstr., 1988, 109, 170224n; Life Sci. 1988, 43, 2049). Duloxetine having one chiral center can exist in two isomeric forms. In view of the different pharmacological activities displayed by individual enantiomers, differences in metabolic behavior and importance to provide enantiomerically pure forms as drugs, the preparation of this drug in enantiomerically pure form is highly desirable.
  • Duloxetine was disclosed in U.S. Pat. Nos. 5,023,269 and 4,956,388 by Robertson, et al. and the synthesis of it was discussed in more detail by Berglund, R. A., Org. Proc. Res. Devei, 1, 328, (1997) and Deeter, et al., in Tetrahedron Letters, 31 (40), 7101-04 (1990) and aspects patented in U.S. Patents No. . 5,362,886 and 5,491,243.
  • WO 2003070720 Al discloses the preparation of N-methyl-3-hydroxy-3-(2- thienyl)propylamine via novel thiophene derivatives containing carbamate groups as intermediates.
  • the below reaction scheme-4 discloses the process for preparation of thiophene derivative, an important intermediate for preparation of duloxetine hydrochloride.
  • WO 2006/071868 A2 discloses the process for preparing pharmaceutically acceptable salts of duloxetine and intermediates thereof.
  • the patent discloses the process for preparing DNT-base, duloxetine alkyl carbamate, duloxetine-base and duloxetine hydrochloride. Also provided, are processes for converting DNT-base, duloxetine carbamate and duloxetine-base into pharmaceutically acceptable salts of duloxetine.
  • WO 2006/099433 Al discloses chemically and/or enantiomerically pure duloxetine HCl and process for preparing chemically and/or enantiomerically pure duloxetine HCI.
  • the present invention encompasses pharmaceutically acceptable salts of duloxetine, containing less than about 0.14 percent area by HPLC of the impurity (+)-jV-methyl-3-(l-napththalenyloxy)-3-(3-thienyl)propanamine (DLX-ISO3) and 0.04 percent area by HPLC of the duloxetine R-enantiomer.
  • WO 2006/081515 A2 discloses the polymorphs of duloxetine hydrochloride.
  • Form A and Form B are the only known polymorphs for duloxetine hydrochloride characterized by XRD, IR and raman spectras.
  • the patent application also encompasses that when duloxetine hydrochloride is prepared according to preparation 2 of U.S. Patent No. 5,362,886, an anhydrous crystalline form of duloxetine is obtained.
  • the term "Form A” referes to the anhydrous crystalline form of duloxetine HCl obtained using preparation 2 of U.S. Patent No. 5,362,886.
  • Duloxetine HCl is available commercially as CYMBALT A ® , which contains Form A as the active ingredient.
  • Ri, R 2 and R 3 are each independently selected from hydrogen, halogen, substituted or unsubstituted alkyl containing 1 to 5 carbon atoms or substituted or unsubstituted aryl;
  • R 4 is selected from hydrogen, hydroxyl protecting group or hydroxyl activating group;
  • R 6 and R 7 are each independently selected from hydrogen, amino protecting group, amido protecting group or substituted or unsubstituted alkyl contains about 1 to 5 carbon atoms, or pharmaceutically acceptable salt, complex or solvate thereof.
  • WO 2007096707 A2 discloses the process for the preparation of (S)-(+)- duloxetine HCl by condensation of (S)-3-(dimethyIamino)- 1 -(2-thienyl)- 1 -propanol and 1 -fluoronaphthalene and at least one alkaline metal hydroxide or alkoxide in DMSO or DMSO-cosolvent mixture, where said process doesn't require the use of phase transfer catalyst. Further reaction proceeds through oxalate salt of condense product characterized by XRD, DSC and IR.
  • WO 2007/093439 A2 discloses the preparation of crystalline duloxetine HCl characterized by XRD and conversion of crystalline Form T to crystalline Form A.
  • WO 2007/139984 A2 claims the crystalline duloxetine hydrochloride solvate of acetone designated as Form C. Also, claims the process for the preparation of crystalline duloxetine hydrochloride Form A characterized by XRD 20 values by drying crystalline solvated Form C.
  • WO 2007/074060 Al discloses the process for the preparation of optically active (S)-3-chloro-l-(2-thienyl)-propane-l-ol by reducing 3-chloro-l-(2-thienyl)- propane-2-one by means of alcohol dehydrogenase from the genus therraoanaerobacter and the product thus formed is isolated in essentially enantiomerically pure form. Therefore, there is a further need to have simple process, that allow for preparation of highly pure duloxetine hydrochloride in a facile manner on an industrial scale which yields enantiomerically pure (S)-(+)-duloxetine hydrochloride with high chemical purity when measured by area percentage of HPLC.
  • Objects of the Invention It is an important object of the present invention is to provide a process for the preparation of Duloxetine and its pharmaceutically acceptable salts.
  • Yet another object of the present invention is to provide novel intermediates for the preparation of Duloxetine and its pharmaceutically acceptable salts.
  • Still another object of the present invention is to provide a process for the preparation of substantially pure Duloxetine and its pharmaceutically acceptable salts
  • the object of the present invention to provide novel intermediate for the preparation of enantiomerically pure (S)-(+)-Duloxetine hydrochloride and their process for preparation.
  • Summary of the Invention In one embodiment, the invention provides a novel intermediate 2-(3-Hydroxy-
  • the invention provides a novel intermediate 2-(3- Hydroxy-3-thiophen-2-yl-propyl)-isoindole-l ,3-dione "compound IV" which is isolated in a crystalline form and characterized by 1 H NMR, 13 C NMR and X-ray powder diffraction pattern.
  • the invention provides a novel intermediate 2-[3- (Naphthalen-l-yloxi)-3-thiophen-2-yl-propyl]-isoindole-l ,3-dione "compound V" for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymorphic Form A.
  • the invention provides a novel intermediate 2-[3- (Naphthalen-l-yloxi)-3-thiophen-2-yl-propyl]-isoindole-l ,3-dione "compound V" which is isolated in a crystalline form and characterized by 1 H NMR, 13 C NMR and X- ray powder diffraction pattern.
  • compound V 2-(3-Hydroxy-3-thiophen-2-yl-propyl)-iso indole- 1, 3 -dione
  • Compound V an intermediate for the preparation of crystalline (S)-(+)-duloxetine hydrochloride of formula (I)
  • the invention provides a novel intermediate 3-(Naphthlen- l -yloxy)-3-thiophen-2-yl-propylamine ("Compound VI") for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymorphic Form A.
  • the invention provides a novel intermediate a 3- (Naphthlen-l-yloxy)-3-thiophen-2-yl-propylamine ("Compound VI") which is isolated in a crystalline form and characterized by 1 H NMR, 13 C NMR and X-ray powder diffraction pattern.
  • the isolated compound VI is racemic.
  • the invention provides a novel intermediate (S)-(+)-3- (Naphthlen-l-yloxy)-3-thiophen-2-yl-propylamine ("Compound VII") for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymorphic Form A.
  • the novel intermediate crystalline (S)-(+)-3-(Naphthlen- l-yloxy)-3-thiophen-2-yl-propylamine (“Compound VII") is characterized by X-ray powder diffraction pattern.
  • invention provides a novel intermediate Di-p-toluyl-L- tartaric acid salt of (S)-(+)-3-(l -naphthyloxy)-3-(2-thienyl)propan-l -amine of formula Vila
  • invention provides a novel intermediate Di-p-toluyl-L- tartaric acid salt of (S)-(+)-3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (Vila) in crystalline form characterized by X-ray powder diffraction pattern.
  • a process for the preparation of crystalline (S)-(+)-duloxetine hydrochloride of formula (I) substantially free from (R)-(-)-duloxetine hydrochloride and characterized by an X- ray powder diffraction with peaks at about 9.6°, 13.9°, 18.1°, 18.9°, 20.9° and 23.4° 2 ⁇ ⁇ 0.2° 2 ⁇ comprising: (a) reducing 3-chloro-l-thiophen-2-yl-propane-l-one of formula (II) to obtain 3- chloro-l-thiophen-2-yl-propane-l-ol of formula (III);
  • the invention provides a novel intermediate 2-(3-oxo-3- thiophen-2-yl-propyl)-isoindole- ! ,3-dione "Compound of formula (Ha)" for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymorphic Form A.
  • the invention provides a novel intermediate 2-(3-oxo-3- thiophen-2-yl-propyl)-isoindole- l ,3-dione "compound Ha” which is isolated in a crystalline form and characterized by 1 H NMR, 13 C NMR and X-ray powder diffraction pattern.
  • the invention provides a novel intermediate 2-(3-oxo-3- thiophen-2-yl-propyl)-isoindole-l,3-dione "Compound of formula (Ha)" for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymorphic Form A.
  • the invention provides a novel intermediate 2-(3-oxo-3- thiophen-2-yl-propyl)-isoindole-l ,3-dione "Compound of formula (Ha)" which is isolated in a crystalline form and characterized by 1 H NMR, 13 C NMR and X-ray powder diffraction pattern.
  • the invention provides a novel intermediate Substituted sulfonic acid 3-(l ,3-dioxo-l ,3-dihydro-isoindol-2-yl)-l -thiophen-2-yl)-propyl ester "Compound IVa" for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymo ⁇ hic Form A.
  • R mesyl or tosyl.
  • the invention provides a novel intermediate methanesulfonic acid 3-( 1 ,3-dioxo- 1 ,3-dihydro-isoindol-2-yl)- 1 -thiophen-2-yl)-propyl ester (Compound IVa')
  • R represent Q-C 4 alkyl, or aryl and X represent halogen selected from Cl
  • FIG.l X-ray diffraction of crystalline (S)-(+)-Duloxetine hydrochloride Form A
  • FIG.2 IR Spectra of crystalline (S)-(+)-Duloxetine hydrochloride Form A
  • FIG.3 DSC of crystalline (S)-(+)-Duloxetine hydrochloride Form A
  • FIG.4 1 H NMR spectrum of compound of formula IV
  • FIG.5 13 C NMR spectrum of compound of formula IV
  • FIG.6 X-ray diffraction of crystalline compound of formula FV
  • FIG.7 1 H NMR spectrum of compound of formula V
  • FIG.8 13 C NMR spectrum of compound of formula V
  • FIG.9 X-ray diffraction of crystalline compound of formula V
  • FIG.10 1 H NMR spectrum of compound of formula VI
  • FIG.ll 13 C NMR spectrum of compound of formula VI
  • FIG.12 X-ray diffraction of crystalline compound of formula VI
  • FIG.13 X-ray diffraction of crystalline compound of formula VII
  • FIG.14 X-ray diffraction of crystalline Di-p-toluyl-L-tartaric acid salt of compound of formula VII.
  • FIG.15 H NMR spectrum of compound of formula Ha
  • FIG.16 13 C NMR spectrum of compound of formula Ha
  • FIG.17 X-ray diffraction of crystalline compound of formula Ha
  • FIG.18 1 H NMR spectrum of compound of formula IVa'
  • FIG.19 13 C NMR spectrum of compound of formula IVa'
  • FIG.20 X-ray diffraction of crystalline compound of formula IVa'
  • the invention provides a novel intermediate 2-(3-Hydroxy- 3-thiophen-2-yl-propyl)-isoindole-l ,3-dione "compound IV" for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymorphic Form A.
  • the invention provides a novel intermediate 2-(3- Hydroxy-3-thiophen-2-yl-propyl)-isoindole-l ,3-dione "compound IV" which is isolated in a crystalline form and characterized by 1 H NMR (300 MHz, DMSO-D6) ⁇ (ppm) :
  • reduction of compound of formula (II) is carried by using reducing agent selected from the group comprising of sodium borohydride, lithium aluminum hydride, n-butyl lithium, lithium diisopropyl amide and the like.
  • reducing agent selected from the group comprising of sodium borohydride, lithium aluminum hydride, n-butyl lithium, lithium diisopropyl amide and the like.
  • sodium borohydride can be used as reducing agent.
  • the reaction is carried out in suitable organic solvent or optionally its presence of water.
  • Preferred organic solvent is methylene dichloride.
  • invention provides process for reacting reduced compound of formula (III) with potassium phthalimide in a suitable organic solvent selected form the group of alcohols like methanol, ethanol, propanol, isopropanol, butanol etc., esters like ethyl acetate, methyl acetate, n-butyl acetate etc., ketones like acetone, methyl ethyl ketone, methyl tertiary butyl ketone, etc., chlorinated solvents like methylene dichloride, ethylene dichlorde, chloroform etc., amides like dimethyl formamide, dimethyl acetamide etc., sulphoxides like dimethyl sulfoxide., sulpholanes like dimethyl sulpholanes etc., preferably dimethyl sulfoxide.
  • the reaction is carried out in presence of catalytic amount of reaction initiator like sodium iodide.
  • the invention provides a novel intermediate 2-[3- (Naphthalen-l-yloxi)-3-thiophen-2-yl-propyl]-isoindole-l,3-dione "compound V".
  • the invention provides a novel intermediate 2- [3- (Naphthalen-l-yloxi)-3-thiophen-2-yl-propyl]-isoindole-l ,3-dione "compound V" which is isolated in a crystalline form and characterized by 1 H NMR (300 MHz, DMSO-D6) ⁇ (ppm) : 8.40 (s, IH), 8.13 (m, 2H), 7.78 (s, 4H), 7.35 (m, 3H), 7.23 (t, I H), 7.05 (d, IH), 6.88 (m, 2H), 5.05 (t, IH), 3.60 (t, 2H), 2.49 (m, 2H); 13 C NMR (75 MHz, DMSO-D6) : ⁇ 167.84, 152.16, 149.36, 134.22, 132.02, 131.68, 129.70, 126.51 , 124.94, 124.25, 124.18, 122
  • reduction of compound of formula (II) is carried by using metal hydride reducing agent selected from the group consisting of sodium borohydride, lithium aluminum hydride, n-butyl lithium, lithium diisopropyl amide and the like. Most Preferably sodium borohydride can be used as reducing agent.
  • the reaction is carried out in suitable organic solvent or optionally its presence of water. Preferred organic solvent is methylene dichloride.
  • invention provides process for reacting reduced compound of formula (III) with potassium phthalimide in a suitable organic solvent selected form the group of alcohols like methanol, ethanol, propanol, isopropanol, butanol etc., esters like ethyl acetate, methyl acetate, n-butyl acetate etc., ketones like acetone, methyl ethyl ketone, methyl tertiary butyl ketone, etc., chlorinated solvents like methylene dichloride, ethylene dichlorde, chloroform etc., amides like dimethyl formamide, dimethyl acetamide etc., sulphoxides like dimethyl sulfoxide., sulpholanes like dimethyl sulpholanes etc., preferably dimethyl sulfoxide.
  • the reaction is carried out in presence of catalytic amount of reaction initiator like sodium iodide.
  • the compound of formula V is condensed with ⁇ -naphthol in presence of acid catalyst selected from organic acid like acetic acid, formic acid, triflouroacetic acid, perchloric acid and the like, inorganic acid like hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and the like, preferably triflouroacetic acid.
  • acid catalyst selected from organic acid like acetic acid, formic acid, triflouroacetic acid, perchloric acid and the like, inorganic acid like hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid and the like, preferably triflouroacetic acid.
  • the condensation is carried out in suitable organic solvent selected form the group of alcohols like methanol, ethanol, propanol, isopropanol, butanol and the like; esters like ethyl acetate, methyl acetate, n-butyl acetate and the like; ketones like acetone, methyl ethyl ketone, methyl tertiary butyl ketone and the like; chlorinated solvents like methylene dichloride, ethylene dichlorde, chloroform and the like; aromatic hydrocarbons like toluene, xylene, ethyl benzene and the like; aliphatic hydrocarbons like n-hexane, n-heptane, cyclohexane and the like; amides like dimethyl formamide, dimethyl acetamide and the like; preferably aromatic hydrocarbons or aliphatic hydrocarbons like toluene or cyclohexane, respectively.
  • the condensation is carried out at a temperature of about reflux temperature of solvent, particularly from about 6O 0 C to 7O 0 C for time sufficient to obtain compound V.
  • the reaction mixture is concentrated under vacuum at 45 0 C to 55 0 C and cooled gradually to 10°C to 15 0 C to isolate crystalline compound V by filtration.
  • the invention provides a novel intermediate 3- (Naphthlen-l-yloxy)-3-thiophen-2-yl-propylamine ("Compound VI") for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymorphic Form A.
  • the invention provides a novel intermediate a 3- (Naphthlen-l -yloxy)-3-thiophen-2-yl-propylamine ("Compound VI") which is isolated in a crystalline form and characterized by 1 H NMR (300 MHz, DMSO-D6) ⁇ (ppm) :
  • the isolated compound VI is racemic.
  • the isolated compound of formula VI was purified to toluene followed by mixture of isopropanol and water and finally in ethyl acetate water mixture to obtain crystalline 3-(l-naphthyloxy)-3-(2-thienyl)propan- 1 -amine of formula in a racemic mixture.
  • the invention provides a novel intermediate (S)-(+)-3- (Naphthlen-l -yloxy)-3-thiophen-2-yl-propylamine ("Compound VII") for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymorphic Form A.
  • the novel intermediate crystalline (S)-(+)-3-(Naphthlen- l-yloxy)-3-thiophen-2-yl-propylamine (“Compound VII") is characterized by X-ray powder diffraction pattern having peaks at about 1 1.7°, 14.0°, 18.6°, 21.7°, 24.4° and 29.3° 2 ⁇ ⁇ 0.2° 20.
  • optically active acid for resolving racemic 3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VII) can be selected from the group consisting of D-lactic acid, D-tartaric acid, D-malic acid, l S-10-camphor sulfonic acid, S-hydratropic acid, (S)-2-methoxy phenyl acetic acid, (R)-2-methoxy-2-trifluoromethyl phenyl acetic acid, D-mandelic acid, Di- p-anisoyl-D-tartaric acid, D-tartaric acid monoparachloro anilide, Dibenzoyl-D-tartaric acid monodimethyl amide
  • the resolution is performed in suitable organic solvent selected from the group consisting of an aliphatic C 1-C4 alcohol, an aliphatic C2-C6 ketone, an aliphatic CI -C4 chlorinated hydrocarbon, nitriles, and/or an aliphatic C2-C6 and mixtures thereof.
  • suitable organic solvent selected from the group consisting of an aliphatic C 1-C4 alcohol, an aliphatic C2-C6 ketone, an aliphatic CI -C4 chlorinated hydrocarbon, nitriles, and/or an aliphatic C2-C6 and mixtures thereof.
  • the isolated salt of formula Vila is treated with base selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metals such sodium carbonate, potassium carbonate, and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; ammonia; and mixture thereof.
  • base selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metals such sodium carbonate, potassium carbonate, and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; ammonia; and mixture thereof.
  • the bases can be used in the form of solids or in the form of aqueous solutions.
  • duloxetine isolating crystalline (S)-(+)-3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (VIl); and (e) converting compound of formula (VII) to duloxetine and its pharmaceutically acceptable salts thereof.
  • the pharmaceutically acceptable salt of duloxetine can be selected from maleate, succinate, benzenesulfonate, tartarate, hydrochloride and the like, preferably hydrochloride.
  • invention provides a novel intermediate Di-p-toluyl-L- tartaric acid salt of (S)-(+)-3-(l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (Vila):
  • invention provides a novel intermediate Di-p-toIuyl-L- tartaric acid salt of (S)-(+)-3-( l-naphthyloxy)-3-(2-thienyl)propan-l -amine of formula (Vila) in crystalline form characterized by X-ray powder diffraction pattern 6.1°, 9.5°, 11.8°, 17.2°, 18.4°, 20.8°, 23.0° and 23.7° 2 ⁇ ⁇ 0.2° 20.
  • the invention provides a novel intermediate 2-(3-oxo-3- thiophen-2-yl-propyl)-isoindole-l,3-dione "compound Ha" for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymorphic Form A.
  • the invention provides a novel intermediate 2-(3-oxo-3- thiophen-2-yl-propyl)-isoindole-l,3-dione "compound Ha" for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymorphic Form A.
  • a reaction in step (b) can be carried out in a suitable organic solvent selected form the group of alcohols like methanol, ethanol, propanol, isopropanol, butanol etc., esters like ethyl acetate, methyl acetate, n-butyl acetate etc., ketones like acetone, methyl ethyl ketone, methyl tertiary butyl ketone, etc., chlorinated solvents like methylene dichloride, ethylene dichloride, chloroform etc., amides like dimethyl formamide, dimethyl acetamide etc., sulphoxide like dimethyl sulphoxide, sulpholanes like dimethyl sulpholanes etc., preferably dimethyl foramide.
  • a suitable organic solvent selected form the group of alcohols like methanol, ethanol, propanol, isopropanol, butanol etc., esters like ethyl acetate, methyl
  • the reaction in step (b) is performed at a suitable temperature from about 50 0 C to about reflux temperature of the solvent, preferably from about 85 0 C to about 15O 0 C, more preferably from about 100 0 C to about 105 0 C.
  • the reaction mixture is further cooled at an ambient temperature below 4O 0 C, more particularly from about 25 0 C to about 35 0 C.
  • the invention provides a novel intermediate Substituted sulfonic acid 3-( l ,3-dioxo- l ,3-dihydro-isoindol-2-yl)-l -thiophen-2-yl)-propyl ester "Compound IVa" for the preparation of crystalline (S)-(+)-duloxetine hydrochloride in polymorphic Form A.
  • R mesyl or tosyl
  • the invention provides a novel intermediate methanesulfonic acid 3-( 1 ,3-dioxo- 1 ,3-dihydro-isoindol-2-yl)- 1 -thiophen-2-yl)-propyl ester (Compound IVa') which is isolated in a crystalline form and characterized by 1 H NMR (300 MHz, DMSO-D6) as disclosed in Fig. 18, 13 C NMR (78 MHz, DMSO) as disclosed in Fig. 19 and X-ray powder diffraction pattern 7.6°, 15.2°, 17.6°, 20.2°, 26.1°, 27.4° and 32.1° 2 ⁇ ⁇ 0.2° 20.
  • (S)-(+)- duloxetine hydrochloride wherein single individual impurity is less than 0.1% and total impurities is less than 0.5%.
  • (S)-(+)-duloxetine hydrochloride is having purity of atleast 99.5% by area percentage of HPLC, preferably
  • substantially free from (R)-(-)-duloxetine hydrochloride means (S)- (+)-duloxetine hydrochloride having chiral purity of atleast about 99.0%, preferably about 99.5%, preferably about 99.75% and more preferably about 99.9%.
  • S-(+)-Duloxetine Hydrochloride wherein S-(+)-Duloxetine hydrochloride is anhydrous crystalline Form A.
  • S-(+)-Duloxetine Hydrochloride is characterized by XRD as shown in Fig-1 , IR as shown in Fig-2 and DSC as shown in Fig-3.
  • the Impurity Profile Determination of Duloxetine hydrochloride comprised testing a sample using HPLC.
  • the HPLC testing parameters included a column of C l 8 monomeric, 100 A, 4.6*250 mm (Grace Vydac or equivalent column) at a temperature of 25°C, Isocratic elution Buffer is 10 mL TEA in 1000 niL water and 5 mL of THF, adjusted to pH 4.0 with H 3 PO 4 .
  • the system equilibrated further for 10 min and a flow rate of 1.0 ml/min.
  • the detector was set for 230 nm.
  • the sample volume was 5 ⁇ L and the diluent was mobile phase.
  • the mobile phase composition and flow rate may be varied in order to achieve the required system suitability.

Landscapes

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

Abstract

La présente invention concerne un chlorhydrate de S-(+)-duloxétine énantiomériquement pure, d'un degré levé de pureté tel que l'atteste le pourcentage de superficie de la chromatographie en phase liquide à haute performance (HPLC). L'invention concerne également une amélioration d'un procédé d'élaboration de chlorhydrate de duloxétine représenté par la formule (I).
PCT/IN2007/000632 2006-12-29 2007-12-28 Procédé d'élaboration de chlorhydrate de duloxétine Ceased WO2008081476A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2168MU2006 2006-12-29
IN2168/MUM/2006 2006-12-29

Publications (2)

Publication Number Publication Date
WO2008081476A2 true WO2008081476A2 (fr) 2008-07-10
WO2008081476A3 WO2008081476A3 (fr) 2008-11-20

Family

ID=39473228

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2007/000632 Ceased WO2008081476A2 (fr) 2006-12-29 2007-12-28 Procédé d'élaboration de chlorhydrate de duloxétine

Country Status (1)

Country Link
WO (1) WO2008081476A2 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105085468A (zh) * 2014-05-15 2015-11-25 重庆常捷医药化工有限公司 一种度洛西汀中间体制备的新方法
WO2017025511A1 (fr) 2015-08-10 2017-02-16 Biogasol Aps Pastilles de biomasse de composition mixte
CN107021949A (zh) * 2017-06-08 2017-08-08 武汉励合生物医药科技有限公司 一种度洛西汀的制备方法
CN107200724A (zh) * 2016-03-18 2017-09-26 江苏恩华药业股份有限公司 盐酸度洛西汀单晶及其制备方法
CN110627766A (zh) * 2018-06-25 2019-12-31 江阴安博生物医药有限公司 一种新的度洛西汀类似物及其制备方法和应用
CN115286613A (zh) * 2022-10-08 2022-11-04 潍坊市海欣药业有限公司 一种盐酸度洛西汀的制备方法

Family Cites Families (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
US7550605B2 (en) * 2004-08-05 2009-06-23 Sun Pharmaceutical Industries Ltd. Process for preparation of an anitdepressant compound

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105085468A (zh) * 2014-05-15 2015-11-25 重庆常捷医药化工有限公司 一种度洛西汀中间体制备的新方法
WO2017025511A1 (fr) 2015-08-10 2017-02-16 Biogasol Aps Pastilles de biomasse de composition mixte
CN107200724A (zh) * 2016-03-18 2017-09-26 江苏恩华药业股份有限公司 盐酸度洛西汀单晶及其制备方法
CN107021949A (zh) * 2017-06-08 2017-08-08 武汉励合生物医药科技有限公司 一种度洛西汀的制备方法
CN110627766A (zh) * 2018-06-25 2019-12-31 江阴安博生物医药有限公司 一种新的度洛西汀类似物及其制备方法和应用
CN110627766B (zh) * 2018-06-25 2023-12-29 北京安博睿达医药科技有限公司 一种新的度洛西汀类似物及其制备方法和应用
CN115286613A (zh) * 2022-10-08 2022-11-04 潍坊市海欣药业有限公司 一种盐酸度洛西汀的制备方法
CN115286613B (zh) * 2022-10-08 2023-01-31 潍坊市海欣药业有限公司 一种盐酸度洛西汀的制备方法

Also Published As

Publication number Publication date
WO2008081476A3 (fr) 2008-11-20

Similar Documents

Publication Publication Date Title
WO2008081476A2 (fr) Procédé d'élaboration de chlorhydrate de duloxétine
CA2341525A1 (fr) Derives d'indoline utilises comme ligands des recepteurs 5-ht2b et/ou 5-ht2c
US20060258871A1 (en) (S)-n,n-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine-di-p-toluoyl-l-tartarate and methods of preparation thereof
EP2114912B1 (fr) Procede de fabrication de la duloxetine et de composes apparentes
EP1008594B1 (fr) Composes derives de thiophene et de benzothiophene, leur utilisation et composition
WO2007096707A2 (fr) Procede ameliore de synthese et preparations de sels de duloxetine
US7550605B2 (en) Process for preparation of an anitdepressant compound
WO2007077580A2 (fr) Procédé amélioré pour la préparation de chlorhydrate de duloxetine pur
CA2477082A1 (fr) Preparation de derives de n-methyl-3-hydroxy- 3-(2-thienyl)propylamine via de nouveaux derives de thiophene contenant des groupes carbamates en tant qu'intermediaires
EP2016066A2 (fr) Procédé de préparation de duloxétine
US4024156A (en) Thiophene ethanolamines
US20070281989A1 (en) Process for preparing duloxetine and intermediates thereof
US8168805B2 (en) Optically active methylhydroxylaminopropanol compound and its use as intermediate for preparation of (S)-(−)-3-methylamino-1-(2-thienyl)propan-1-ol
US20100280093A1 (en) Process for the preparation enantiomerically pure salts of n-methyl-3-(1-naphthaleneoxy)-3-(2-thienyl)propanamine
EP2172464B1 (fr) Procédé de préparation du sel chlorhydrate de Duloxetin
US4105663A (en) Thiophene ethanolamines
US4082772A (en) Thiophene ethanolamines
WO2009019719A2 (fr) Procédé de préparation de 3-aryloxy-3-arylpropanamines
EP1857451B1 (fr) Procédé pour la préparation d'un intermédiare pour la production asymmetirique du (+)Duloxetine
CA1267653A (fr) DERIVES DE SUBSTITUTION SUR LE CYCLE DE .alpha.- (ALCOYLAMINOPROPIONYL)-THIOPHENE
WO2009144263A2 (fr) Procédé d’obtention de 4-hydroxy-6-méthyl-5,6-dihydro-4h-thiéno [2,3-b] thiopyran-7,7-dioxyde et ses énantiomères, et ses applications
WO2009130708A2 (fr) Préparation de duloxétine et de ses sels
WO2008078124A1 (fr) Procédé de préparation de duloxétine et nouveaux intermédiaires clés pour une utilisation dans celui-ci.
WO2009109992A1 (fr) Nouveau procédé de préparation de duloxétine et intermédiaires pour l'utiliser
WO2011029088A2 (fr) Préparation de raloxifène et de ses sels

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07870579

Country of ref document: EP

Kind code of ref document: A2

DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07870579

Country of ref document: EP

Kind code of ref document: A2