WO2017216805A1 - Intermédiaires et procédés de préparaton de vortioxétine - Google Patents

Intermédiaires et procédés de préparaton de vortioxétine Download PDF

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Publication number
WO2017216805A1
WO2017216805A1 PCT/IN2017/050077 IN2017050077W WO2017216805A1 WO 2017216805 A1 WO2017216805 A1 WO 2017216805A1 IN 2017050077 W IN2017050077 W IN 2017050077W WO 2017216805 A1 WO2017216805 A1 WO 2017216805A1
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WIPO (PCT)
Prior art keywords
compound
vortioxetine
reaction
carried out
solvent
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PCT/IN2017/050077
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English (en)
Inventor
Alaparthi LAKSHMI PRASAD
Ginjupalli SADASIVA RAO
Madala MURALIKRISHNA
Mantri ANAND
Sharma UDAY
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Lakshmi Prasad Alaparthi
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Application filed by Lakshmi Prasad Alaparthi filed Critical Lakshmi Prasad Alaparthi
Publication of WO2017216805A1 publication Critical patent/WO2017216805A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Definitions

  • the present invention relates to new intermediate compounds useful in the preparation of phenyl-piperazine compounds such as Vortioxetine and process for their preparation.
  • the present invention also relates to process for preparing Vortioxetine or its pharmaceutically acceptable salts using said intermediates. Background of the invention
  • MDD Major depressive disorder
  • SSRIs selective serotonin reuptake inhibitors
  • SNRIs serotonin norepinephrine reuptake inhibitors
  • Vortioxetine is chemically known as l-[2-(2,4-dimethylphenyl) sulfanylphenyl]piperazine represented by the below formula,
  • Vortioxetine is an investigational multi-modal antidepressant that is believed to work through a combination of two pharmacological modes of action: serotonin (5- HT) reuptake inhibition and 5-HT receptor activity (du Jardin KG, Jensen JB, Sanchez C, Pehrson AL Eur Neuropsychopharmacol. 2014 Jan; 24(1): 160-71 ; Hussar et al., J. Am. Pharm. Assoc. (2003). 2014 Jan-Feb; 54(l):91 -4).
  • Vortioxetine hydrobromide was approved by the US Food and Drug Administration (FDA) for the once-daily treatment of adults with MDD in the USA (Gibb & Deeks, Drugs.
  • WO2007144005 disclose process for preparation of Vortioxetine by reacting piperazine, 2,4-dimethylthiophenol and 1,2-dihalogenbenzene in toluene in presence of a palladium catalyst and a phosphine ligand to afford Vortioxetine.
  • WO2015079018 describes process for preparation of Vortioxetine which comprises lithiation reaction of piperazine compound having amino protecting group or 2,4- dimethylphenylsulfide moiety followed by substitution or deprotection step.
  • the present inventors have prepared the intermediate compounds which are useful for the preparation of Vortioxetine.
  • the present invention provides process for preparation of these intermediate compounds and also process for preparing Vortioxetine using these intermediate compounds.
  • the present invention relates to novel intermediate compound (5) useful for preparation of Vortioxetine or pharmaceutically acceptable salts thereof.
  • the present invention relates to a process for preparation of intermediate compounds (5) and (6).
  • the present invention relates to a process for preparation of Vortioxetine or pharmaceutically acceptable salts thereof comprising coupling of compound (5) and 2, 4-dimethyl halobenzene in presence of copper catalyst and a base to get compound (6); reacting compound (6) with 1-chloroethylchloro formate in presence of 1,2-dichloroethane to get Vortioxetine and optionally converting Vortioxetine into pharmaceutically acceptable salts.
  • Fig. 3 It represents HPLC profile of Compound (5)
  • Fig. 6 It represents Mass spectra of Vortioxetine hydrobromide
  • Fig. 7 It represents HPLC profile of Vortioxetine hydrobromide Detailed description of the invention
  • the present invention provides an intermediate compound represented by formula (5) which is a useful intermediate in the preparation of Vortioxetine.
  • the compound (5) is characterized by studying IH-NMR spectra, mass spectra, and HPLC profile; the details of which are provided in figures 1, 2 and 3.
  • the gradient is provided under table 2.
  • *A is mobile phase containing 0.1 % orthophosphoric acid acid in Milli Q water and B is acetonitrile.
  • the new intermediate compound (5) elutes at the retention time of around 26 or 27 such as at 26.86.
  • the intermediate compound (6) is characterized as follows:
  • the compound (6) is characterized by studying the mass spectra, the details of which are provided in figure 4.
  • the present invention provides processes for preparation of the intermediate compounds (5) and (6).
  • the process for preparing the compound (5) comprises the steps of; a) reacting piperazine with halo nitro benzene compound (1) in presence of solvent to obtain a compound (2)
  • the halo nitro benzene compound (1) as used in step a) is 1-fluoro -2- nitrobenzene or 1-chloro -2-nitrobenzene.
  • the solvent used in step a) is selected from the group comprising Ci to C 4 alcohol such as methanol, ethanol, n-propanol, isopropanol and n-butanol and the like.
  • the reaction is carried out at temperature in the range of 60 - 100°C for a period of 2 to 4 hours.
  • the benzyl halide used in step b) is benzyl bromide or benzyl chloride.
  • the solvent used in step b) is selected from the group comprising dimethylformamide (DMF), DMA (dimethylacetamide) and N-methylpyrrolidone (NMP).
  • the reaction is carried out at temperature in the range of 50 - 100°C for a period of 2 to 4 hour.
  • the base used in step b) is potassium carbonate.
  • the compound (3) is reduced to compound (4) in step c) in presence of reducing agent such as tin chloride (SnCk) and acid such as hydrochloric acid.
  • the solvent used is alcohol solvent such as methanol and ethanol.
  • the reaction is carried out at temperature in the range of 20-35°C for a period of 2 to 4 hour.
  • the reaction of step d) is carried out by reacting a compound of formula (4) in presence of suitable solvent and suitable acid and sodium nitrite.
  • the solvent used is selected from the group comprising acetonitrile, water, methanol or mixtures thereof.
  • the acid used is selected from hydrochloric acid, HBr, sulphuric acid and p-toluene sulphonic acid.
  • the alkali metal alkyl xanthate compound in step d) is potassium ethyl xanthate.
  • the reaction is carried out at temperature in the range of 0-10°C preferably 5 for a period of 30 minutes to 2 hours.
  • the compound (5) thus obtained is optionally purified by conventional column chromatography .
  • the process for preparing the compound (6) comprises coupling of compound (5) and 2, 4-dimethyl halo benzene using copper based catalyst in presence of base.
  • the compound (5) is coupled with either 2,4-dimethyl bromobenzene or 2,4-dimethyl iodobenzene.
  • the copper based catalyst used is copper acetate.
  • the base used is inorganic base such as potassium hydroxide and sodium hydroxide.
  • the coupling reaction is carried out at temperature in the range of 100-150°C for a period of 10 to 20 hours.
  • the compound (6) thus obtained is optionally purified by conventional chromatography method.
  • the present invention provides a process for preparation of Vortioxetine or its pharmaceutically acceptable salts comprising a) coupling of compound (5) and 2,4-dimethyl halobenzene in presence of copper catalyst and a base to get compound (6)
  • Vortioxetine optionally converting Vortioxetine into pharmaceutically acceptable salts.
  • step a) the copper catalyst used is copper acetate and the base is potassium hydroxide.
  • the reaction of step a) is carried out at temperature in the range of 100- 150°C for a period of 10 to 20 hours.
  • step b) the reaction is carried out at temperature in the range of 50-80°C for a period of 2 to 8 hours.
  • the present invention provides a process preparation of Vortioxetine or its pharmaceutically acceptable salts comprising a) reacting piperazine with compound (1) to obtain the compound (2)
  • Vortioxetine prepared by the processes as described above can be purified with conventional methods to obtain pure Vortioxetine.
  • Vortioxetine prepared by the process as described hereinabove is converted into its pharmaceutically acceptable salts such as Vortioxetine hydrobromide.
  • the process for converting Vortioxetine into its hydrobromide salt comprising (a) dissolving Vortioxetine in suitable solvent such as ethyl acetate to obtain a solution and (b) treating the obtained solution with aqueous HBr to obtain Vortioxetine hydrobromide.
  • the reaction is carried out at temperature 20-35°C.
  • the Vortioxetine hydrobromide thus obtained can be further purified to obtain pure Vortioxetine hydrobromide.
  • reaction mass was brought to room temperature and the mass was diluted with water (100ml).
  • the mixture was extracted with ethyl acetate (2x150ml).
  • the organic layer was separated and washed with water (2x100ml) followed by brine (150ml) and dried over anhydrous sodium sulphate.
  • the solvent was removed under reduced pressure to obtain the crude compound.
  • the crude compound was purified by flash to afford the title compound (6g) as light yellow viscous oil.
  • l-benzyl-4-(2-((2,4- dimethylphenyl)thio)phenyl)piperazine (6g, 15.44mmol) was dissolved in 1,2- dichloroethane (30ml) followed by addition of 4A molecular sieve (5gm, 4AMS).
  • 1-chloroethylchloroformate (5.52g, 38.6mmol) was added drop wise to the reaction mass over a period of 10 minutes. The mixture was heated at 90°C for 3hours after which the solvent was removed under reduced pressure. Methanol (20ml) was added to the reaction mass and the contents were heated at 70°C for 2 hours.

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

Abstract

L'invention concerne de nouveaux composés intermédiaires utiles dans la préparation de composés de phénylpipérazine, tels que la Vortioxétine, ainsi qu'un procédé de préparation associé. L'invention concerne également un procédé de préparation de Vortioxétine ou de ses sels pharmaceutiquement acceptables au moyen desdits intermédiaires.
PCT/IN2017/050077 2016-06-15 2017-03-01 Intermédiaires et procédés de préparaton de vortioxétine WO2017216805A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201621020465 2016-06-15
IN201621020465 2016-06-15

Publications (1)

Publication Number Publication Date
WO2017216805A1 true WO2017216805A1 (fr) 2017-12-21

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114075153A (zh) * 2020-08-11 2022-02-22 成都倍特药业股份有限公司 一种伏硫西汀杂质的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5885999A (en) * 1996-01-29 1999-03-23 Merck Sharp & Dohme Ltd. Serine derivatives and their use as therapeutic agents
US20030220324A1 (en) * 2001-07-25 2003-11-27 Fotsch Christopher H. Substituted piperazines and methods of use
EP2894154A1 (fr) * 2014-01-14 2015-07-15 LEK Pharmaceuticals d.d. Synthèse de vortioxetine via des intermédiaires de (2-(piperazine-1-yl)phényl)aniline
EP3023417A1 (fr) * 2014-11-21 2016-05-25 Dipharma Francis S.r.l. Procédé pour la préparation d'un antidépresseur et ses intermédiaires

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5885999A (en) * 1996-01-29 1999-03-23 Merck Sharp & Dohme Ltd. Serine derivatives and their use as therapeutic agents
US20030220324A1 (en) * 2001-07-25 2003-11-27 Fotsch Christopher H. Substituted piperazines and methods of use
EP2894154A1 (fr) * 2014-01-14 2015-07-15 LEK Pharmaceuticals d.d. Synthèse de vortioxetine via des intermédiaires de (2-(piperazine-1-yl)phényl)aniline
EP3023417A1 (fr) * 2014-11-21 2016-05-25 Dipharma Francis S.r.l. Procédé pour la préparation d'un antidépresseur et ses intermédiaires

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
D. J. C. PRASAD ET AL.: "Cu-Catalyzed One-Pot Synthesis of Unsymmetrical Diaryl Thioethers by Coupling of Aryl Halides Using a Thiol Precursor", ORGANIC LETTERS, vol. 13, no. 5, 27 January 2011 (2011-01-27), pages 1008 - 1011, XP055447925 *
FUKUSHIMA, D. K. ET AL.: "m-Thiocresol", ORGANIC SYNTHESES, vol. 27, 1947, pages 81, XP055447923 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114075153A (zh) * 2020-08-11 2022-02-22 成都倍特药业股份有限公司 一种伏硫西汀杂质的制备方法
CN114075153B (zh) * 2020-08-11 2023-12-08 成都倍特药业股份有限公司 一种伏硫西汀杂质的制备方法

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