WO2014061000A1 - Procédé pour la préparation de vilazodone ou d'un sel pharmaceutiquement acceptable de celle-ci - Google Patents

Procédé pour la préparation de vilazodone ou d'un sel pharmaceutiquement acceptable de celle-ci Download PDF

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Publication number
WO2014061000A1
WO2014061000A1 PCT/IB2013/059457 IB2013059457W WO2014061000A1 WO 2014061000 A1 WO2014061000 A1 WO 2014061000A1 IB 2013059457 W IB2013059457 W IB 2013059457W WO 2014061000 A1 WO2014061000 A1 WO 2014061000A1
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Prior art keywords
formula
compound
process according
solvent
benzofuran
Prior art date
Application number
PCT/IB2013/059457
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English (en)
Inventor
Prasenjit Das
Bindu Srivastava
Sony Joseph
Nitin Maheshwari
Mohan Prasad
Sudershan Kumar Arora
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Ranbaxy Laboratories Limited
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.)
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Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2014061000A1 publication Critical patent/WO2014061000A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2

Definitions

  • the present invention provides a novel intermediate of vilazodone and its process of preparation.
  • the present invention further provides a process for preparing vilazodone or a pharmaceutically acceptable salt thereof using the novel intermediate.
  • Vilazodone hydrochloride is indicated for the treatment of major depressive disorder (MDD). Processes for the preparation of vilazodone free base and its different intermediates are described in U.S. Patent Nos. 5,532,241, 5,723,614, and 5,977, 112 and European Patent No. EP 0 648 767.
  • the present invention provides a novel intermediate of vilazodone and its process of preparation.
  • the present invention further provides a process for preparing vilazodone or a pharmaceutically acceptable salt thereof using the novel intermediate.
  • the invention relates to a novel intermediate compound of Formula III.
  • the invention relates to a process for the preparation of 5-(4-formylpiperazin- 1 -yl)- 1 -benzofuran-2-carboxamide of Formula III,
  • the process includes the steps of:
  • Embodiments of the process may include one or more of the following features.
  • the formylation of the compound of Formula IV or its salt may be carried out in the presence of a formylating agent.
  • the formylating agent may be selected from the group consisting of formamide, chloral, formic acid- dicyclohexylcarbodiimide, formic acid- l -ethyl-3(3- dimethylaminopropyl)carbodiimide (EDC1), formic acid - zinc chloride, formic acid - polyethylene glycol 400, activated formic acid esters, acetic formic anhydride, ammonium formate, 2-chloro-4,6-dimethoxy-l,3,5-triazine (CDMT), or mixtures thereof.
  • the formylating agent is formamide.
  • the formylation of the compound of Formula IV or its salt may be carried out in the presence of a base and a solvent.
  • the base may be sodium methoxide.
  • the solvent may be selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N-methyl pyrrolidone, formamides, ethers, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof.
  • the solvents may be selected from formamide, dichloromethane, methanol, or mixtures thereof.
  • the invention relates to a process for the preparation of vilazodone free base of Formula I
  • Larmaceutically acceptable salts thereof includes the steps of formylating ethyl 5-(piperazin-l-yl)-l-benzofuran-2-carboxylate compound of Formula IV or its salt
  • Embodiments of the process may include one or more of the following features.
  • the formylation of the compound of Formula IV or its salt may be carried out in the presence of a formylating agent.
  • the formylating agent may be selected from the group consisting of formamide, chloral, formic acid- dicyclohexylcarbodiimide, formic acid- l -ethyl-3(3- dimethylaminopropyl)carbodiimide (EDC1), formic acid - zinc chloride, formic acid - polyethylene glycol 400, activated formic acid esters, acetic formic anhydride, ammonium formate, 2-chloro-4,6-dimethoxy-l,3,5-triazine (CDMT), or mixtures thereof.
  • the formylating agent is formamide.
  • the formylation of the compound of Formula IV or its salt may be carried out in the presence of a base and a solvent.
  • the base may be sodium methoxide.
  • the solvent may be selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N-methyl pyrrolidone, formamides, ethers, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof.
  • the solvents may be selected from formamide, dichloromethane, methanol, or mixtures thereof.
  • the compound of Formula III may be converted to the compound of Formula V in step b) in the presence of an acid and a solvent.
  • the acid may be selected from the group consisting of inorganic or organic acids.
  • the solvent may be selected from the group consisting of water, alcohol, esters, nitriles, amides, ketones, ethers, aromatic or aliphatic hydrocarbons, dimethyl sulfoxide, or mixtures thereof. In particular, the solvent may be water.
  • the reaction of the compound of Formula V and the compound of Formula VI in step c) may be carried out in the presence of a base and a solvent.
  • the solvent may be selected from the group consisting of water, organic solvent, or mixtures thereof.
  • the solvent may be water alone or in combination with 2-propanol, 1 -propanol, dimethyl formamide, or toluene.
  • the base may be selected from the group consisting of organic or inorganic bases.
  • reaction mixture of the compound of the Formula V and the compound of Formula VI may be treated with hydrobromic acid before converting to vilazodone free base.
  • the pharmaceutically acceptable salt in step e) may be the hydrochloric acid salt.
  • treating includes adding, dissolving, slurrying, stirring, or combinations thereof.
  • isolation refers to an isolation process by means of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, centrifugation, recrystallization, or combinations thereof.
  • a first aspect of the present invention provides a novel intermediate compound of Formula III.
  • a second aspect of the present invention provides a process for the preparation of 5-(4-formylpiperazin- 1 -yl)- 1 -benzofuran-2-carboxamide of Formula III
  • the compound of Formula IV or its salt may be prepared by methods known in the literature, for example, in U.S. Patent Nos. 5,532,241, and 5,723,614.
  • the preferred salt of the compound of Formula IV is hydrochloride salt.
  • the formylation of the compound of Formula IV or its salt may be carried out in the presence of a formylating agent.
  • the formylating agent is selected from the group consisting of formamide, chloral, formic acid- dicyclohexylcarbodiimide, formic acid- l-ethyl-3(3- dimethylaminopropyl)carbodiimide (EDC1), formic acid - zinc chloride, formic acid - polyethylene glycol 400, activated formic acid esters, acetic formic anhydride, ammonium formate, 2-chloro-4,6-dimethoxy-l,3,5-triazine (CDMT), or mixtures thereof.
  • the preferred formylating agent is formamide.
  • the formylation of the compound of Formula IV or its salt is carried out in the presence of a solvent and a base.
  • the solvent is selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N-methyl pyrrolidone, formamides, ethers, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof.
  • Suitable alcoholic solvents are methanol, 2-propanol, or 1 -propanol.
  • a suitable nitrile solvent is acetonitrile.
  • Suitable ether solvents are diisopropyl ether, methyl t-butyl, or ether.
  • Suitable aromatic and aliphatic hydrocarbons solvents are hexane, heptane, or toluene.
  • a suitable halogenated hydrocarbon solvent is dichloromethane.
  • the preferred solvents are formamide, dichloromethane, methanol, or mixtures thereof.
  • the base is selected from the group consisting of alkali metal alkoxide or organic bases.
  • the organic base is selected from the group consisting of ammonia, triethyl amine, or diisopropyl ethyl amine.
  • the preferred alkali metal alkoxide is sodium methoxide.
  • the formylation of the compound of Formula IV or its salt is carried out at a temperature of about 10°C to about 40°C, preferably at about 20°C to about 30°C.
  • the formylation of the compound of Formula IV or its salt is carried out for about 2 hours to about 8 hours, preferably for about 4 hours to about 6 hours.
  • the compound of Formula III may optionally be isolated by filtration, concentration, precipitation, cooling, centriiugation, decantation, or combinations thereof.
  • a third aspect of the present invention provides a process for the preparation of vilazodone free base of Formula I
  • the compound of Formula IV or its salt may be prepared by methods known in the literature, for example, in U.S. Patent Nos. 5,532,241, and 5,723,614.
  • the preferred salt of the compound of Formula IV is hydrochloride salt.
  • the formylation of the compound of Formula IV or its salt is carried out as described in the second aspect.
  • the compound of Formula III may optionally be isolated by filtration, concentration, precipitation, cooling, centrifugation, decantation, or combinations thereof.
  • the compound of Formula III is converted to the compound of Formula V in the presence of an acid and a solvent.
  • the acid is selected from the group consisting of inorganic or organic acid.
  • the preferred inorganic acid is hydrochloric acid.
  • the solvent is selected from the group consisting of water, alcohols, esters, nitriles, amides, ketones, ethers, aromatic or aliphatic hydrocarbons, dimethyl sulfoxide, or mixtures thereof.
  • Suitable alcoholic solvents are methanol, 2-propanol, or 1 -propanol.
  • a suitable nitrile solvent is acetonitrile.
  • Suitable ester solvents are ethyl acetate or propyl acetate.
  • Suitable ether solvents are diisopropyl ether or methyl t-butyl ether.
  • Suitable aromatic and aliphatic hydrocarbon solvents are hexane, heptane, or toluene.
  • a suitable amide solvent is formamide.
  • the preferred solvent is water.
  • the compound of Formula III is converted to the compound of Formula V at about 10°C to about 70°C, preferably at about 30°C to about 60°C.
  • the conversion of the compound of Formula III to the compound of Formula V is carried out for about 1 hour to about 6 hours, preferably for about 2 hours to about 4 hours.
  • the reaction of the compound of Formula V and the compound of Formula VI is carried out in the presence of a base and a solvent.
  • the solvent is selected from the group consisting of water, organic solvent, or mixtures thereof.
  • the organic solvent is selected from the group consisting of alcohols, ketones, nitriles, amides, aromatic or aliphatic hydrocarbons, dimethyl sulfoxide, or mixtures thereof.
  • Suitable alcoholic solvents are methanol, 2-propanol, or 1 -propanol.
  • a suitable nitrile solvent is acetonitrile.
  • Suitable amide solvents are N-methylpyrrolidone or dimethyl formamide.
  • Suitable ketonic solvents are acetone or methyl isobutyl ketone.
  • a suitable aromatic hydrocarbon solvent is toluene.
  • the preferred solvent is water, either alone or in combination with 2-propanol, 1 -propanol, dimethyl formamide, or toluene.
  • the treatment of compound of Formula V and compound of Formula VI is carried out in the presence of only water without using any other solvent.
  • the base is selected from the group consisting of organic bases or inorganic bases.
  • Suitable organic bases are triethyl amine, diisopropyl amine, diisopropyl ethylamine, 4- dimethylaminopyridine, pyrollidine, or N-methyl morpholine.
  • the preferred organic base is triethylamine.
  • Suitable inorganic bases are hydroxides, or carbonates and bicarbonates of alkali or alkaline metal. Suitable carbonates or bicarbonates of alkali or alkaline metal are sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, or potassium bicarbonate.
  • the preferable inorganic base is potassium carbonate.
  • the treatment of the compound of Formula V and the compound of Formula VI is carried out in the presence of alkali metal halides, for example, sodium iodide.
  • the treatment of the compound of Formula V and the compound of Formula VI is carried out at a temperature of about 20°C to about 140°C, preferably at about 50°C to about 120°C.
  • the treatment of the compound of Formula V and the compound of Formula VI is carried for about 2 hours to about 35 hours, preferably for about 5 hours to about 30 hours.
  • Formula VI is treated with hydrobromic acid before converting to vilazodone free base.
  • the hydrobromic acid may be diluted or concentrated.
  • the hydrobromic acid may be used in a solution form or a gaseous form.
  • the solution of hydrobromic acid may be aqueous or in an organic solvent.
  • the preferred organic solvents are methanol, ethanol, or 2- propanol.
  • the treatment of the reaction mixture of the compound of Formula V and the compound of Formula VI with hydrobromic acid is carried out in the presence of an organic solvent.
  • the organic solvent is selected from the group consisting of alcohols, ketones, esters, formamides, water, halogenated hydrocarbons, N-methyl pyrollidone, or combinations thereof.
  • Suitable alcoholic solvents are methanol, ethanol, 2-propanol, 1- propanol, butanol, or methylated ethanol.
  • Suitable ketonic solvents are acetone or methyl isobutyl ketone.
  • Suitable ester solvents are ethyl acetate or isopropyl acetate.
  • a suitable halogenated hydrocarbon is dichloromethane.
  • the preferred solvents include N-methyl pyrollidone in combination with 2-propanol, methanol, or methylated ethanol.
  • the dissolution of the reaction mixture of the compound of Formula V and the compound of Formula VI with hydrobromic acid is carried out at a temperature of about 10°C to about 40°C, preferably at about 20°C to about 30°C.
  • the dissolution of the reaction mixture of the compound of Formula V and the compound of Formula VI with hydrobromic acid is carried out for about 5 minutes to about 25 hours, preferably for about 7 hours to about 18 hours.
  • the vilazodone hydrobromide salt may optionally be isolated by filtration, decantation, drying, vacuum drying, or combinations thereof.
  • the vilazodone hydrobromide may be converted to vilazodone free base.
  • the conversion of vilazodone hydrobromide to vilazodone free base is carried out in the presence of a base and a solvent.
  • the base is selected from the group consisting of organic or inorganic bases.
  • the inorganic bases are selected from the group consisting of carbonates, bicarbonates, or hydroxides.
  • the preferred base for the conversion of vilazodone hydrobromide to vilazodone free base is sodium bicarbonate.
  • the base for the conversion of vilazodone hydrobromide to vilazodone free base is used as a solid or an aqueous solution.
  • the solvent for the conversion of vilazodone hydrobromide to vilazodone free base is selected from the group consisting of water, an organic solvent, or combinations thereof.
  • the organic solvent is selected from the group consisting of alcohols, esters, halogenated hydrocarbons, ketones, amides, nitriles, or combinations thereof.
  • Suitable alcoholic solvents are methanol, ethanol, methylated ethanol, 2-propanol, 1 -propanol, or butanol.
  • Suitable ester solvents are ethyl acetate, methyl acetate, or isopropyl acetate.
  • a suitable halogenated hydrocarbon is dichloromethane.
  • Suitable ketonic solvents are acetone or methyl isobutyl ketone.
  • Suitable amide solvents are N-methylpyrrolidone, dimethyl acetamide, or dimethyl formamide.
  • a suitable nitrile solvent is acetonitrile.
  • the preferred solvent is water in combination with methanol, ethanol, or 2-propanol.
  • the conversion of vilazodone hydrobromide to vilazodone free base is carried out at a temperature of about 10°C to about 100°C, preferably at about 20°C to about 85°C.
  • the dissolution of vilazodone free base with water and an alcoholic solvent is carried out for about 30 minutes to about 6 hours, preferably for about 1 hour to about 4 hours.
  • the vilazodone free base of Formula I may be isolated by filtration, concentration, precipitation, cooling, centrifugation, decantation, or combinations thereof.
  • the vilazodone free base obtained by the present invention may be converted to its pharmaceutically acceptable salt, for example, hydrochloric acid salt.
  • the vilazodone free base is treated with hydrochloric acid in the presence of water, alcohols, amides, halogenated hydrocarbons, esters, or mixtures thereof.
  • Suitable alcoholic solvents are methanol, ethanol, 2-propanol, 1 -propanol, or butanol.
  • Suitable amide solvents are N-methylpyrrolidone, dimethyl acetamide, or dimethyl formamide.
  • Suitable halogenated hydrocarbon solvents are dichloromethane or chloroform.
  • Suitable ester solvents are ethyl acetate, methyl acetate, or isopropyl acetate.
  • the preferred solvents are 2-propanol, either alone or in combination with N-methylpyrrolidone, or water.
  • the treatment of vilazodone free base with hydrochloric acid is carried out at a temperature of about 50°C to about 100°C, preferably at about 70°C to about 85°C.
  • the treatment of the reaction mixture obtained in step c) with hydrochloric acid is carried out for about 30 minutes to about 2 hours, preferably for about 60 minutes to about 2 hours.
  • the hydrochloric acid may be dilute or concentrated.
  • the hydrochloric acid is used in solution or gaseous form.
  • the solution of hydrochloric acid is aqueous or in an alcoholic solvent.
  • the preferred alcoholic solvent for the preparation of hydrochloric acid solution is 2-propanol.
  • the vilazodone hydrochloride salt may be isolated by filtration, distillation, evaporation, centrifugation, decantation, drying, vacuum drying, or combinations thereof.
  • the vilazodone hydrochloride prepared by the present invention may be characterized using X-ray powder diffraction (XRPD) patterns.
  • Step A Preparation of ethyl- 5-amino-l-benzofuran-2-carboxylate
  • Ethyl-5-nitro- l-benzofuran-2-carboxylate 100 g was added to methanol (500 mL). 2.5% (w/w) Palladium/carbon (10 g in 10 mL water) was added to the hydrogenator. The hydrogen gas was passed at a pressure of 1 to 4 kg/cm 2 for 2 hours to 4 hours at 25°C to 50°C. The reaction mixture was filtered through a Celite® filter. The solvent was recovered under vacuum. A mixture of de-ionized water (500 mL) and dichloromethane (300 mL) was added to the reaction mixture and the layers obtained were separated. The organic layer was recovered under vacuum to obtain the title compound.
  • Step B Preparation of ethyl-5-(piperazine-l-yl)-l-benzofuran-2-carboxylate hydrochloride
  • Ethyl-5-amino-l-benzofuran-2-carboxylate prepared in step A was added to N, N-Bis-2-chloroethylamine hydrochloride (91.14 g) and I, 2-dichlorobenzene (500 mL) at 20°C to 30°C.
  • the temperature of the reaction mixture was increased to 180°C and the reaction mixture was further heated for 2 hours to 4 hours.
  • the reaction mixture was cooled to 20°C to 30°C and filtered. The solid obtained was washed with
  • Ethyl-5-(piperazine- l-yl)-l-benzofuran-2-carboxylate hydrochloride (210 g) prepared in step B was added to dichloromethane (800 mL) and the pH was adjusted to 7 to 8 with 5% sodium bicarbonate solution. The organic layer was separated and dichloromethane was recovered completely under vacuum.
  • Formamide 500 mL was added to the reaction mixture along with 30% methanolic solution of sodium methoxide (76.6 g). The reaction mixture was stirred for 2 hours at 20°C to 30°C.
  • Deionized water (1000 mL) was added to the reaction mixture and the reaction mixture was stirred at 10°C for 1 hour. The solid obtained was filtered and washed with deionized water (200 mL) to obtain the title compound. Yield (Wet): 79 g
  • Example 8 Preparation of vilazodone hydrochloride.

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

Abstract

La présente invention concerne un nouvel intermédiaire de la vilazodone et son procédé de préparation. La présente invention concerne de plus un procédé de préparation de vilazodone ou d'un sel pharmaceutiquement acceptable de celle-ci à l'aide du nouvel intermédiaire.
PCT/IB2013/059457 2012-10-19 2013-10-18 Procédé pour la préparation de vilazodone ou d'un sel pharmaceutiquement acceptable de celle-ci WO2014061000A1 (fr)

Applications Claiming Priority (2)

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IN3247DE2012 2012-10-19
IN3247/DEL/2012 2012-10-19

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WO2014061000A1 true WO2014061000A1 (fr) 2014-04-24

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014199313A1 (fr) * 2013-06-12 2014-12-18 Lupin Limited Chlorhydrate de vilazodone sensiblement pur et son procédé de préparation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0648767A1 (fr) 1993-09-30 1995-04-19 MERCK PATENT GmbH Dérivés de piperidine et piperazine qui puissent agir sur le "CNS"
US5723614A (en) 1995-04-20 1998-03-03 Merck Patent Gesellschaft Mit Beschrankter Haftung Benzofurans

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0648767A1 (fr) 1993-09-30 1995-04-19 MERCK PATENT GmbH Dérivés de piperidine et piperazine qui puissent agir sur le "CNS"
US5532241A (en) 1993-09-30 1996-07-02 Merck Patent Gesellschaft Mit Beschrankter Haftung Piperidines and piperazines
US5723614A (en) 1995-04-20 1998-03-03 Merck Patent Gesellschaft Mit Beschrankter Haftung Benzofurans
US5977112A (en) 1995-04-20 1999-11-02 Merck Patent Gesellschaft Mit Beschrankter Haftung Process of making substituted benzofurans

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SORBERA L A ET AL: "VILAZODONE HYDROCHLORIDE", DRUGS OF THE FUTURE, PROUS SCIENCE, ES, vol. 26, no. 3, 1 January 2001 (2001-01-01), pages 247 - 252, XP009035003, ISSN: 0377-8282, DOI: 10.1358/DOF.2001.026.03.611242 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014199313A1 (fr) * 2013-06-12 2014-12-18 Lupin Limited Chlorhydrate de vilazodone sensiblement pur et son procédé de préparation

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