US20090093645A1 - Synthesis and preparations of duloxetine salts - Google Patents

Synthesis and preparations of duloxetine salts Download PDF

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US20090093645A1
US20090093645A1 US12/097,251 US9725106A US2009093645A1 US 20090093645 A1 US20090093645 A1 US 20090093645A1 US 9725106 A US9725106 A US 9725106A US 2009093645 A1 US2009093645 A1 US 2009093645A1
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propylamine
dimethyl
naphthyloxy
thien
oxalic acid
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Stephen Benedict David Winter
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Medichem SA
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the invention relates to an improved process for the preparation of duloxetine hydrochloride.
  • Duloxetine hydrochloride (Compound I) is the international commonly accepted name for N-methyl-N-[(3S-(3-(1-naphthyloxy)-3-thien-2-yl)propyl]amine hydrochloride (which is also known as methyl-[(S)-3-(naphthalen-1-yloxy)-3-thiophen-2-yl-propyl]-amine) hydrochloride and has an empirical formula of C 18 H 19 NOS.HCl and a molecular weight of 333.88.
  • Duloxetine hydrochloride is a commercially marketed pharmaceutically active substance known to be useful for the treatment of major depressive disorder.
  • Duloxetine hydrochloride is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration.
  • SSNRI norepinephrine reuptake inhibitor
  • Cymbalta® for the treatment of major depressive disorder and diabetic peripheral neuropathic pain.
  • duloxetine hydrochloride has been approved for the treatment of major depressive disorder and also for the treatment of moderate to severe stress urinary incontinence.
  • Duloxetine and its pharmaceutically acceptable salts are disclosed in U.S. Pat. No. 5,023,269 (“the '269 patent”). No examples related to the preparation of (S)-duloxetine, or one of its pharmaceutically acceptable salts (e.g., the hydrochloride salt), are disclosed.
  • racemic duloxetine was prepared by demethylating the corresponding N,N-dimethylpropanamine derivative using phenyl chloroformate to yield the corresponding carbamate as an intermediate. The carbamate was then hydrolyzed to afford racemic duloxetine as an oil, and was subsequently isolated as the oxalate salt.
  • the process disclosed in the '269 patent for obtaining racemic duloxetine is shown in Scheme 1.
  • (S)-Duloxetine can be obtained using the same strategy outlined in Scheme 1, but starting from (S)-3-dimethylamino-1-(2-thienyl)-1-propanol (Compound S-II), as described in Tetrahedron Letters, 31, (49), 7101-04 (1990) and in U.S. Pat. No. 5,362,886 (“the '886 patent”).
  • the '886 patent also provides a procedure for the preparation of (S)-duloxetine in the form of its hydrochloride salt.
  • duloxetine and its salts there are several other known methods for producing duloxetine and its salts. Generally, these alternative processes include resolution of a key intermediate or a stereoselective synthesis usually involving a stereospecific reduction of a keto group to give the corresponding alcohol. These other processes include those disclosed in: WO 03/070720; WO 04/011452; WO 04/024708; T. Chirality, 12:26-29 (2000); Advanced Synthesis and Catalysis (2003), 345(1+2), 261-274; WO 04/005307; JP 2004123596; WO 04/13123; WO 04/005220; and Tetrahedron: Asymmetry (2003), 14(12), 1631-1636.
  • duloxetine hydrochloride is prepared by using a phase transfer catalyst for the reaction of (S-3-(dimethylamino)-1-(2-thienyl)-1-propanol (Compound S-II) and 1-fluoronaphthalene (Scheme 1, Compound III) with sodium hydroxide in DMSO.
  • the invention relates to an improved process for the preparation of duloxetine hydrochloride.
  • the invention provides an improved process for the preparation of duloxetine hydrochloride as shown, generally, in Scheme 2 (below).
  • FIG. 1 illustrates the X-ray powder diffractogram (XRD) of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine oxalic acid salt, Form A, obtained in Example 10;
  • FIG. 2 illustrates the combined Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) thermogram of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine oxalic acid salt, Form A, obtained in Example 10;
  • DSC Differential Scanning Calorimetry
  • TGA Thermogravimetric Analysis
  • FIG. 3 illustrates the IR spectra of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine oxalic acid salt, Form A, obtained in Example 11;
  • FIG. 4 illustrates the X-ray powder diffractogram (XRD) of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine oxalic acid salt, Form C, obtained in Example 13;
  • FIG. 5 illustrates the IR spectra of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine oxalic acid salt, Form C, obtained in Example 13;
  • FIG. 6 illustrates the X-ray powder diffractogram (XRD) of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine oxalic acid salt, Form B, obtained in Example 14;
  • FIG. 7 illustrates the IR spectra of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine oxalic acid salt, Form B, obtained in Example 14;
  • FIG. 8 illustrates the X-ray powder diffractogram (XRD) of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine oxalic acid salt, Form E, obtained in Example 15; and
  • FIG. 9 illustrates the IR spectra of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine oxalic acid salt, Form E, obtained in Example 15.
  • the invention relates to an improved process for the preparation of duloxetine hydrochloride.
  • one aspect of the invention includes a method for preparing duloxetine and duloxetine intermediates from (S)-3-dimethylamino)1-(2-thienyl)-1-propanol (Compound S-II) and 1-fluoronaphthalene (Compound III) using an alkaline metal hydroxide or alkoxide, in DMSO or DMSO-cosolvent mixtures, in the absence of a phase transfer catalyst and with a low degree of the undesired racemization.
  • This process can that optionally include using potassium carbonate or sodium sulphate.
  • the alkaline metal hydroxide or alkoxide used can be, for example, NaOH, KOH or CsOH.
  • Another aspect of the invention includes the method described above, further characterized by a product in which the enantiomeric purity is >94:6 ratio of enantiomers.
  • Another aspect of the invention includes the method described above further including the step of partially distilling the solvent and thereby removing water from the reaction mixture and increasing the rate of reaction.
  • Another aspect of the invention includes a method for purifying (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)-1-propylamine (Compound IV, which is also known as dimethyl-[(S-3-(naphthalen-1-yloxy)-3-thiophen-2-yl-propyl]-amine), which is a duloxetine intermediate, in which Compound IV is selectively purified from (S)-3-(dimethylamino)-1-(2-thienyl)-1-propanol (Compound S-II) by means of forming a derivative of (S)-3-(dimethylamino)-1-(2-thienyl-1-propanol (Compound S-II) in a solvent.
  • the derivative is an ester derivative including, more preferably, a mineral acid ester derivative.
  • Another aspect of the invention includes the method for purifying (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)-1-propylamine described above further including the use of pyridine sulfur trioxide to form a sulphate derivative of (S)-3-dimethylamino-1-(2-thienyl)-1-propanol; Compound S-II).
  • Another aspect of the invention includes the methods for purifying (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)-1-propylamine described above wherein the solvent used is at least one of a hydrocarbon solvent, an ester solvent, an ether solvent or combinations thereof.
  • a hydrocarbon solvent include heptane and toluene, where toluene is more preferred.
  • Preferred ester solvents include ethyl acetate, isopropyl acetate and isobutyl acetate are preferred, where ethyl acetate or isopropyl acetate are more preferred.
  • Preferred ether solvents include tertbutyl methyl ether and tetrahydrofuran.
  • Another aspect of the invention includes a method for demethylating (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)-1-propylamine (Compound IV) that includes reacting Compound IV with a chloroformate, preferably where the chloroformate is 1-chloroethyl chloroformate, in the presence of an acid scavenger in a solvent.
  • the amount of acid scavenger is preferably from approximately 0.02 to approximately 2 equivalents relative to Compound IV, more preferably from approximately 0.05 to approximately 1 equivalents relative to Compound IV and most preferably approximately 0.1 equivalents relative to Compound IV.
  • Another aspect of the invention includes a method for demethylating (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)-1-propylamine (Compound IV) as described above wherein the acid scavenger is a hindered tertiary amine.
  • Another aspect of the invention includes a method for demethylating (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)-1-propylamine (Compound IV) as described above wherein the acid scavenger is diisopropylethylamine.
  • the solvent used for the demethylation reaction is preferably at least one of an aromatic solvent, an ester solvent, an ether solvent or combinations thereof.
  • Preferred aromatic solvents include toluene and xylene are preferred, where toluene is more preferred.
  • Preferred ester solvents include ethyl acetate, isopropyl acetate and isobutyl acetate, where ethyl acetate or isopropyl acetate are more preferred.
  • Preferred ether solvents include tertbutyl methyl ether and tetrahydrofuran.
  • Another aspect of the invention includes a method for the demethylation of (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)-1-propylamine (Compound IV) as described above further including a treatment step with an alcohol, a ketone, an ether, water or mixtures thereof at a temperature of less than or equal to 50° C., preferably of less than or equal to 40° C.
  • the invention further includes a method for synthesizing (S)-N-methyl-[3-(naphthalen-1-yloxy)-3-thiophen-2-yl-propyl]-carbamic acid 1-chloroethyl ester including reacting (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)-1-propylamine (Compound IV) with 1-chloroethyl chloroformate in the presence of an acid scavenger.
  • Another aspect of the invention includes a method for synthesizing (S)-N-methyl-[3-(naphthalen-1-yloxy)-3-thiophen-2-yl-propyl]-carbamic acid 1-chloroethyl ester as described above wherein the acid scavenger is a hindered tertiary amine.
  • Another aspect of the invention includes a method for synthesizing (S)-N-methyl-[3-(naphthalen-1-yloxy)-3-thiophen-2-yl-propyl]-carbamic acid 1-chloroethyl ester as described above wherein the acid scavenger is diisopropylethylamine.
  • Chromatographic separation was carried out in a Phenomenex Luna C18, 5 ⁇ m, 4.6 ⁇ 150 mm column at room temperature (20-25° C.).
  • the chromatograph was equipped with a 220 nm detector, and the flow rate was 1 mL per minute.
  • Test samples (10 ⁇ L) were prepared by dissolving an appropriate amount of sample in the mobile phase in order to obtain 0.5 mg of sample per mL.
  • the chromatogram was run for at least 30 minutes.
  • the chromatographic separation was carried out in a Daicel CHIRALCEL OD-RH, 5 ⁇ m, 4.6 ⁇ 150 mm column at room temperature (20-25° C.).
  • the chromatograph was equipped with a 216 nm detector and the flow rate was 0.5 mL per minute.
  • Test samples (5 ⁇ L) were prepared by dissolving the appropriate amount of sample in the mobile phase in order to obtain 0.5 mg of sample per mL.
  • the chromatogram was run for at least 25 minutes.
  • the resulting product was slurried in additional ethyl acetate (200 mL), filtered and dried under vacuum to yield 63.3 g of the product as a white solid (0.158 moles, Yield: 59%).
  • the resulting product had a molar ratio of Product:(S)-3-dimethylamino-1-(2-thienyl)-1-propanol: 1-fluoronaphthalene of 99.53:0.46:0.02 and 88% ee.
  • Duloxetine base (99% ee, 0.5 g, 1.68 mmoles) was dissolved in acetone (5 mL) and stirred with cooling in an ice-water bath. Hydrochloric acid in diethyl ether (2M, 0.8 mL) was added, and a precipitate formed within 2 minutes. The mixture was stirred at ambient temperature 16 hours, filtered and the collected solid washed with acetone (0.5 mL). The white solid was then dried under vacuum at ambient temperature to yield duloxetine hydrochloride (0.485 g, 1.45 mmoles, yield: 86%; Chiral HPLC: 99.5% ee).
  • the mixture was then evaporated to a final volume of about 4.5 L, and diisopropylethylamine (37 g, 0.29 moles, 0.1 eq.) was added followed by the addition of 1-chloroethyl chloroformate (456 g, 3.2 moles,1.1 eq.) over 20 minutes at a temperature of between 20 and 30° C.
  • the mixture was heated to 50° C. for 5 hours, cooled to 30° C., and washed with 10% aqueous sodium hydroxide (1 L) followed by water (1 L). Methanol (5 L) was added, and the mixture stirred at 30° C. for 44 hours.
  • Oxalic acid dihydrate (0.38 kg, 3.0 moles, 0.75 eq.) was then added, and the mixture stirred at 15-20° C. for 16 hours.
  • the mixture was then filtered and slurried in acetone (2.5 L) and isopropyl acetate (5 L) for one hour, and then filtered to yield 2.1 kg (wet product) of (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-thien-2-yl)propylamine oxalic acid salt as an off-white solid (Yield: 75%; equivalent to 1.21 kg, (dry product)).
  • the molar ratio of product (Compound IV) to starting alcohol (Compound S-II) was 98.7:1.3 as determined by HPLC.
  • Compound IV oxalate salt was 92% ee as determined by chiral HPLC.
  • the mixture was cooled to 25° C., quenched with water (533 kg) and extracted twice with isopropyl acetate (2 ⁇ 460 kg). The two organic phases were combined, washed with water (400 kg), and added to pyridine sulphur trioxide complex (6.8 kg.). The mixture was then stirred at 20-25° C. for 30 minutes and then a solution made from ammonium chloride (32 kg) in water (533 kg) was added and the mixture stirred for 30 minutes. The aqueous layer was adjusted to pH 6.5-pH 7.0, the mixture stirred for an additional 30 minutes before the aqueous phases were separated.
  • Oxalic acid dihydrate 44 kg was dissolved in methanol (173 kg), and this solution was added over a period of 2 hours to the organic mixture above maintained at 40-45° C. The mixture was placed under vacuum at this temperature and 500 kg of solvent removed by distillation. Iso-propyl acetate (1000 kg) was added and a further 500 kg removed by distillation under vacuum. At this point precipitation occurred, and the mixture was cooled to 0-5° C. and stirred for 2 hours.
  • the aqueous layer was extracted with toluene (547 kg), and the organic phases were combined and washed with deionised water (301 kg).
  • the mixture was heated and distilled to remove 547 kg of solvent and then cooled to 20-25° C.
  • Diisopropylethylamine (4.25 kg) was added over 30 minutes and without allowing the temperature to increase above 30° C., then 56.7 kg of 1-chloroethyl chloroformate was added.
  • the mixture was heated to 50 ⁇ 3° C. and stirred for 2 hours at this temperature. It was then cooled to 20-25° C. and washed first with a mixture made from 85 kg of water and 47.3 kg of 30% aqueous ammonium hydroxide and then water 67 kg.
  • the mixture was cooled to 25° C., quenched with water (533 kg) and extracted twice with isopropyl acetate (2 ⁇ 460 kg). The two organic phases were combined, washed with water (400 kg), and added to pyridine sulphur trioxide complex (6.8 kg.). The mixture was then stirred at 20-25° C. for 30 minutes and then a solution made from ammonium chloride (32 kg) in water (533 kg) was added and the mixture stirred for 30 minutes. The aqueous layer was adjusted to pH 6.5-pH 7.0, the mixture stirred for an additional 30 minutes before the aqueous phases were separated.
  • Oxalic acid dihydrate 44 kg was dissolved in methanol (173 kg.) and this solution was added over a period of 2 hours to the organic mixture above maintained at 40-45° C. The mixture was placed under vacuum at this temperature and 500 kg of solvent removed by distillation. Isopropyl Acetate (1000 kg) was added and a further 500 kg removed by distillation under vacuum. At this point precipitation occurred and the mixture was cooled to 0-5° C. and stirred for 2 hours.

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US81585606P 2006-06-23 2006-06-23
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CN104478849A (zh) * 2014-02-14 2015-04-01 广东东阳光药业有限公司 制备去甲肾上腺素再摄取双重抑制剂的方法
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WO2006099433A1 (en) 2005-03-14 2006-09-21 Teva Pharmaceutical Industries Ltd. Pure duloxetine hydrochloride
WO2007038253A2 (en) 2005-09-22 2007-04-05 Teva Pharmaceutical Industries Ltd. Dnt-maleate and methods of preparation thereof
EP1971592B1 (de) 2005-12-12 2011-04-27 Medichem, S.A. Verbesserte synthese und zubereitungen von duloxetinsalzen
CZ299270B6 (cs) * 2006-01-04 2008-06-04 Zentiva, A. S. Zpusob výroby hydrochloridu (S)-N-methyl-3-(1-naftyloxy)-3-(2-thienyl)propylaminu

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EP1971592B1 (de) 2011-04-27
WO2007096707A3 (en) 2008-01-24
PL1971592T3 (pl) 2011-09-30
IL192116A0 (en) 2009-08-03
CA2634008A1 (en) 2007-10-25
DE602006021628D1 (de) 2011-06-09
WO2007119114A2 (en) 2007-10-25
WO2007119114A3 (en) 2008-01-24
IL192114A0 (en) 2009-08-03
CA2634007A1 (en) 2007-08-30
IL192115A0 (en) 2009-08-03
US20090182156A1 (en) 2009-07-16
AR058321A1 (es) 2008-01-30
US20100286412A1 (en) 2010-11-11
WO2007096707A2 (en) 2007-08-30
WO2007119116A2 (en) 2007-10-25
US8158808B2 (en) 2012-04-17
EP1971592A2 (de) 2008-09-24
EP1971593A2 (de) 2008-09-24
ATE507215T1 (de) 2011-05-15
US20090221668A1 (en) 2009-09-03

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