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US20090221668A1 - Synthesis and preparations of duloxetine salts - Google Patents

Synthesis and preparations of duloxetine salts Download PDF

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Publication number
US20090221668A1
US20090221668A1 US12/097,247 US9724706A US2009221668A1 US 20090221668 A1 US20090221668 A1 US 20090221668A1 US 9724706 A US9724706 A US 9724706A US 2009221668 A1 US2009221668 A1 US 2009221668A1
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United States
Prior art keywords
duloxetine
compound
hydrochloride
salt
salts
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.)
Abandoned
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US12/097,247
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English (en)
Inventor
Stephen Benedict David Winter
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.)
Medichem SA
Original Assignee
Medichem SA
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Filing date
Publication date
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=38437735&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20090221668(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Medichem SA filed Critical Medichem SA
Priority to US12/097,247 priority Critical patent/US20090221668A1/en
Assigned to MEDICHEM S.A. reassignment MEDICHEM S.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WINTER, STEPHEN BENEDICT DAVID
Publication of US20090221668A1 publication Critical patent/US20090221668A1/en
Abandoned legal-status Critical Current

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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
    • 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 preparing duloxetine hydrochloride. More particularly, the invention relates to the preparation of duloxetine hydrochloride by a process that provides a maximum yield of desired product with a minimum amount of undesired by-products.
  • 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.
  • duloxetine and/or its salts are disclosed in various references, including: U.S. Pat. No. 5,362,886; WO 04/056795; WO 03/062219; WO 00/61540; WO 03/070720; WO 04/011452; WO 04/024708; WO 04/005307; JP 2004123596; WO 04/13123; and WO 04/005220.
  • Preparation of duloxetine hydrochloride is specifically described in the following references: U.S. Pat. No. 5,362,886, U.S. Pat. No. 5,491,243; WO 04/056795 ; J. Labelled Compd. Radiopharm., 36, 213 (1995); and Zhongguo Xinyao Zazhi, 14(1), 74-76 (2005).
  • duloxetine base was dissolved in ethyl acetate and treated with HCl/ethyl acetate. After stirring for 1 hour and chilling to ⁇ 20° C. for an additional hour, the mixture was diluted with ether, filtered, washed with fresh ether and dried to yield duloxetine hydrochloride.
  • duloxetine hydrochloride of a high grade and having a minimum amount of impurities present in order to minimize the occurrence of adverse side effects and to facilitate formulation and formulation shelf life.
  • the invention relates to an improved process for preparing duloxetine hydrochloride. More particularly, the invention relates to the preparation of duloxetine hydrochloride by a process that provides a maximum yield of desired product with a minimum amount of undesired by-products.
  • duloxetine degrades upon contact with an acidic medium.
  • Contact with an acidic medium is necessary to form an acid addition salt.
  • careful control of the reaction conditions for the conversion of duloxetine base into an acid addition salt is required.
  • the temperature, the molar ratio of the different reagents, the reaction media and the presence of water may affect the synthesis of duloxetine hydrochloride from duloxetine base.
  • the main degradation impurity when treating duloxetine with acid has here been isolated and identified as 4-(3-methylamino-1-thiophen-2-yl-propyl)-naphthalen-1-ol (Compound II, below) or salts thereof.
  • One aspect of the invention includes the synthesis of Compound II as its hydrochloride salt and its use as a marker for measuring the purity of duloxetine salts.
  • Another aspect of the invention includes a process for monitoring the reaction products obtained during the preparation of duloxetine hydrochloride for the presence of undesirable by-products.
  • the monitoring process includes monitoring the products for the presence of 4-(3-methylamino-1-thiophen-2-yl-propyl)-naphthalen-1-ol (Compound II) or salts thereof (Compound II salt, e.g., Compound II hydrochloride).
  • Another aspect of the invention includes the use of Compound II or salts thereof as a reference marker for the analysis of duloxetine and its pharmaceutically acceptable salts.
  • Another aspect of the invention includes methods for preparing duloxetine hydrochloride having reduced levels of Compound II or salts thereof. These methods provide high quality and purity duloxetine hydrochloride without requiring complicated separation procedures.
  • Another aspect of the invention includes the production of duloxetine hydrochloride having less than approximately 0.1% area by HPLC of Compound II and/or salts thereof.
  • Another aspect of the invention includes the production of duloxetine hydrochloride having less than approximately 0.1% area by HPLC of Compound II and/or salts thereof, wherein the production of duloxetine hydrochloride does not require procedures to separate Compound II and/or salts thereof from the crude duloxetine hydrochloride reaction product.
  • Another aspect of the invention includes formulating duloxetine hydrochloride having less than approximately 0.1% area by HPLC of Compound II and/or salts thereof into readily usable dosage units for the therapeutic treatment of mammals, including humans.
  • Another aspect of the invention includes producing Compound II from 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol (Compound III, below) and/or its salts:
  • Compound III includes the Compound III and salts thereof (Compound III salt, e.g., Compound III hydrochloride).
  • Another aspect of the invention includes the use of Compound III as a reference marker.
  • the invention relates to an improved process for preparing duloxetine hydrochloride. More particularly, the invention relates to the preparation of duloxetine hydrochloride by a process that provides a maximum yield of desired product with a minimum amount of undesired by-products.
  • One aspect of the invention includes a compound obtained during the production of duloxetine hydrochloride named 4-(3-methylamino-1-thiophen-2-yl-propyl)-naphthalen-1-ol (Compound II), characterized as its hydrochloride salt by 1 H and 13 C NMR, mass spectroscopy, IR and elemental analysis.
  • Another aspect of the invention includes a process of using Compound II and/or salts thereof as a marker in the production of duloxetine and its pharmaceutically acceptable salts.
  • Another aspect of the invention includes producing Compound II from 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol (Compound III) and/or its salts.
  • Compound III can be obtained as a degradation impurity when treating the duloxetine intermediate (S)—N,N-dimethyl-(3-(1-naphthyloxy)-3-(thien-2-yl)propylamine with acid.
  • Compound III includes the Compound III and salts thereof (Compound III salt, e.g., Compound III hydrochloride).
  • Another aspect of the invention includes the use of Compound III as a reference marker in the synthesis of (S)—N,N-dimethyl-(3-(1-naphthyloxy)-3-(thien-2-yl)propylamine and salts thereof, and, in particular, the oxalate salt.
  • duloxetine hydrochloride containing less than approximately 0.1% of Compound II and/or salts thereof.
  • Another aspect of the invention includes a method for preparing duloxetine hydrochloride from duloxetine base that includes contacting duloxetine base with ammonium chloride
  • Another aspect of the invention includes a method for preparing duloxetine hydrochloride from (S)—N-methyl-[3-(naphthalen-1-yloxy)-3-thiophen-2-yl-propyl]-carbamic acid 1-chloroethyl ester, wherein the duloxetine hydrochloride has less than approximately 0.1% area by HPLC of Compound II and/or salts thereof.
  • Another aspect of the invention includes a method for preparing duloxetine hydrochloride from duloxetine base, wherein the duloxetine hydrochloride has less than approximately 0.1% area by HPLC of Compound II and/or salts thereof.
  • Another aspect of the invention includes formulating duloxetine hydrochloride having less than approximately 0.1% area by HPLC of Compound II and/or salts thereof into readily usable dosage units for the therapeutic treatment of mammals, including humans.
  • Such formulations are normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • a pharmaceutical composition that includes the compounds of the invention in association with a pharmaceutically acceptable diluent or carrier.
  • formulations of the invention can also include alternative equivalent excipients (i.e., other release control agents, fillers, lubricants and/or binders) having the same and/or similar functions and/or properties may be readily substituted and used in the above illustrative formulation.
  • alternative equivalent excipients i.e., other release control agents, fillers, lubricants and/or binders
  • Additional suitable pharmaceutically-acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
  • inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate
  • granulating and disintegrating agents such as corn starch or algenic acid
  • binding agents such as starch
  • lubricating agents such as magnesium stearate, stearic acid or talc
  • preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
  • the chromatographic separation is 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 the appropriate amount of sample in the mobile phase in order to obtain 0.5 mg 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.
  • Duloxetine base (10 g, 90% ee) was dissolved in acetone (100 mL) and stirred with cooling in an ice-water bath. Hydrogen chloride in diethyl ether (2M, 15.9 mL) was added, and a precipitate formed within 15 minutes. The mixture was then stirred at 0° C. for 165 minutes, filtered and the collected solid washed with acetone (10 mL). The resulting white solid was dried under vacuum at 45° C. to yield 8.16 g of duloxetine hydrochloride (Yield: 77%). The product was analyzed by chiral HPLC and determined to be 97% ee. The level of Compound II was ⁇ 0.05% peak area at 220 nm.
  • Duloxetine base (99% ee, 0.5 g) was dissolved in acetone (5 mL) and stirred with cooling in an ice-water bath. Hydrogen chloride in diethyl ether (2M, 0.8 mL) was added, and a precipitate formed within 2 minutes. The mixture was stirred at ambient temperature for 16 hours, filtered, and the collected solid was washed with acetone (0.5 mL). The resulting white solid was dried under vacuum at ambient temperature to yield 0.485 g of duloxetine hydrochloride (Yield: 91%). The product was analyzed by chiral HPLC and determined to be 99.5% ee. The level of Compound II was ⁇ 0.007% peak area at 220 nm.
  • duloxetine hydrochloride Yield: 29%; 98% ee.
  • the liquors were concentrated and dissolved in acetone (5 mL). After being maintained at 5° C. for 16 hours, a second crop of duloxetine hydrochloride was obtained (0.486 g; Yield: 9%; 94% ee). Analysis of the liquors indicated ⁇ 5% ee.
  • Duloxetine base (0.5 g) was dissolved in acetone (2.5 mL) and water (2.5 mL). The mixture was cooled in ice, and a saturated solution of ammonium chloride (2.5 mL) was added. The mixture was stirred at ambient temperature for 16-24 hours. The acetone was then removed by evaporation under reduced pressure causing precipitation. The resulting suspension was then stirred at ambient temperature for 16-24 hours, filtered, washed with water (0.5 mL) and dried in a vacuum oven at ambient temperature overnight. Analysis: 99.5% ee, >99.2% peak area of duloxetine hydrochloride, ⁇ 0.2% (peak area) of Compound II.
  • Duloxetine hydrochloride (5 g) was heated at reflux temperature in 0.1 N hydrochloric acid (50 mL) for 6 hours. The mixture was then concentrated under reduced pressure and slurried in 2-propanol (20 mL). The mixture was then filtered and dried to yield 4.16 g of a brown solid. A portion of this solid (3.7 g) was heated in 2-propanol to reflux temperature for 30 minutes, cooled, filtered, washed with 2-propanol (10 mL) and dried under vacuum at 40° C. to yield 2.51 g of Compound II as an off-white solid.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
US12/097,247 2005-12-12 2006-12-12 Synthesis and preparations of duloxetine salts Abandoned US20090221668A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/097,247 US20090221668A1 (en) 2005-12-12 2006-12-12 Synthesis and preparations of duloxetine salts

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US74909505P 2005-12-12 2005-12-12
US74909605P 2005-12-12 2005-12-12
US74909705P 2005-12-12 2005-12-12
US81583506P 2006-06-23 2006-06-23
US81585606P 2006-06-23 2006-06-23
US81585406P 2006-06-23 2006-06-23
US12/097,247 US20090221668A1 (en) 2005-12-12 2006-12-12 Synthesis and preparations of duloxetine salts
PCT/IB2006/004252 WO2007119116A2 (en) 2005-12-12 2006-12-12 Improved synthesis and preparations of duloxetine salts

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US20090221668A1 true US20090221668A1 (en) 2009-09-03

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US12/097,251 Abandoned US20090093645A1 (en) 2005-12-12 2006-12-12 Synthesis and preparations of duloxetine salts
US12/097,247 Abandoned US20090221668A1 (en) 2005-12-12 2006-12-12 Synthesis and preparations of duloxetine salts
US12/097,245 Abandoned US20090182156A1 (en) 2005-12-12 2006-12-12 Synthesis and preparations of duloxetine salts
US12/762,131 Expired - Fee Related US8158808B2 (en) 2005-12-12 2010-04-16 Synthesis and preparations of duloxetine salts

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US12/762,131 Expired - Fee Related US8158808B2 (en) 2005-12-12 2010-04-16 Synthesis and preparations of duloxetine salts

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US (4) US20090093645A1 (es)
EP (3) EP1971593A2 (es)
AR (1) AR058321A1 (es)
AT (1) ATE507215T1 (es)
CA (3) CA2634008A1 (es)
DE (1) DE602006021628D1 (es)
IL (3) IL192116A0 (es)
PL (1) PL1971592T3 (es)
WO (3) WO2007119116A2 (es)

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US20250205160A1 (en) * 2022-12-17 2025-06-26 Sun Pharmaceutical Industries Limited Stable pharmaceutical composition of an amine drug

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CA2599475A1 (en) 2005-03-14 2006-09-21 Teva Pharmaceutical Industries Ltd. Pure duloxetine hydrochloride
EP1838692A2 (en) 2005-09-22 2007-10-03 Teva Pharmaceutical Industries Ltd Dnt-maleate and methods of preparation thereof
EP1863782A1 (en) 2005-12-05 2007-12-12 Teva Pharmaceutical Industries Ltd. 2-(n-methyl-propanamine)-3-(2-naphtol) thiophene, an imputity of duloxetine hydrochloride
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CN103524480B (zh) * 2013-10-21 2016-04-20 山东鲁药制药有限公司 一种盐酸度洛西汀的制备方法
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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AR058321A1 (es) 2008-01-30
WO2007096707A2 (en) 2007-08-30
CA2634009A1 (en) 2007-10-25
WO2007096707A3 (en) 2008-01-24
US20090093645A1 (en) 2009-04-09
EP1971592A2 (en) 2008-09-24
CA2634007A1 (en) 2007-08-30
PL1971592T3 (pl) 2011-09-30
WO2007119114A2 (en) 2007-10-25
US20090182156A1 (en) 2009-07-16
EP1971591A2 (en) 2008-09-24
US20100286412A1 (en) 2010-11-11
WO2007119116A2 (en) 2007-10-25
IL192114A0 (en) 2009-08-03
WO2007119114A3 (en) 2008-01-24
EP1971593A2 (en) 2008-09-24
IL192115A0 (en) 2009-08-03
CA2634008A1 (en) 2007-10-25
DE602006021628D1 (de) 2011-06-09
US8158808B2 (en) 2012-04-17
IL192116A0 (en) 2009-08-03
EP1971592B1 (en) 2011-04-27
WO2007119116A3 (en) 2008-01-31
ATE507215T1 (de) 2011-05-15

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