WO2014061004A2 - Process for the preparation of vilazodone or pharmaceutically acceptable salt thereof - Google Patents

Process for the preparation of vilazodone or pharmaceutically acceptable salt thereof Download PDF

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Publication number
WO2014061004A2
WO2014061004A2 PCT/IB2013/059518 IB2013059518W WO2014061004A2 WO 2014061004 A2 WO2014061004 A2 WO 2014061004A2 IB 2013059518 W IB2013059518 W IB 2013059518W WO 2014061004 A2 WO2014061004 A2 WO 2014061004A2
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formula
benzofuran
compound
carboxamide
solvent
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PCT/IB2013/059518
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French (fr)
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WO2014061004A3 (en
Inventor
Prasenjit Das
Bindu Srivastava
Nitin Maheshwari
Hashim Nizar Poovanathil Nagoor Meeran
Mohan Prasad
Sudershan Kumar Arora
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Ranbaxy Laboratories Limited
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Publication of WO2014061004A3 publication Critical patent/WO2014061004A3/en

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    • 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
    • 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

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 said novel intermediate.
  • Vilazodone hydrochloride is indicated for the treatment of major depressive disorder (MDD).
  • MDD major depressive disorder
  • Processes for the preparation of vilazodone free base and its different intermediates are purportedly described in U.S. Patent Nos. 5,532,241, 5,723,614, and 5,977,112 and European Patent No. 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 said novel intermediate.
  • the invention relates to a novel intermediate compound of Formula III.
  • the invention relates to a process for the preparation of 5-amino-l-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 compound of Formula IV may be converted to the compound of Formula V in step a) in the presence of formamide, a base, and a solvent.
  • the compound of Formula IV may be converted to the compound of Formula V in step a) in the presence of formamide, a base, and a solvent.
  • the solvent may be selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N-alkyl pyrollidone, formamide, ethers, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof.
  • the solvent may be N-methyl pyrollidone.
  • the base may be selected from the group consisting of alkali metal alkoxide or organic bases.
  • the base may be sodium methoxide.
  • the compound of Formula V may be converted to the compound of Formula III in the presence of a reducing agent and a solvent.
  • the reducing agent may be selected from the group consisting of palladium/carbon, platinum/dioxide, or Raney-Nickel in the presence of ammonium formate.
  • the reducing agent may be palladium/carbon in the presence of ammonium formate.
  • the solvent may be selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N-alkyl pyrollidone, formamide, ethers, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof.
  • the invention relates to a process for preparing vilazodone free base of Formula I
  • larmaceutically acceptable salts thereof which comprises: converting ethyl 5-nitro-l-benzofuran-2-carboxylate of Formula IV
  • Embodiments of the process may include one or more of the following features.
  • the compound of Formula IV may be converted to the compound of Formula V in step a) in the presence of formamide, a base, and a solvent.
  • the compound of Formula IV may be converted to the compound of Formula V in step a) in the presence of formamide, a base, and a solvent.
  • the solvent may be selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N-alkyl pyrollidone, formamide, ethers, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof.
  • the solvent may be N-methyl pyrollidone.
  • the base may be selected from the group consisting of alkali metal alkoxide or organic bases.
  • the base may be sodium methoxide.
  • the compound of Formula V may be converted to the compound of Formula III in the presence of a reducing agent and a solvent.
  • the reducing agent may be selected from the group consisting of palladium/carbon, platinum/dioxide, or Raney-Nickel in the presence of ammonium formate.
  • the reducing agent may be palladium/carbon in the presence of ammonium formate.
  • the solvent may be selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N-alkyl pyrollidone, formamide, ethers, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof.
  • the 5-amino-l-benzofuran-2-carboxamide compound of Formula III may be converted to the 5-(piperazin-l-yl)-l-benzofuran-2-carboxamide of Formula VI in step c) by reacting with bis-2-chloroethylamine in the presence of a solvent.
  • the solvent may be selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N- alkyl pyrollidone, ethers, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof.
  • the reaction of the compound of Formula VI and the compound of Formula VII in step d) 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 solvents, or mixtures thereof.
  • Formula VII may be treated with hydrobromic acid before converting to vilazodone free base.
  • the pharmaceutically acceptable salt in step f) may be the hydrochloric acid salt.
  • a first aspect of the present invention provides an intermediate compound of
  • the intermediate compound of Formula III is chemically described as 5-amino-l- benzofuran-2-carboxamide.
  • a second aspect of the present invention provides a process for the preparation of 5-amino-l-benzofuran-2-carboxamide of Formula III
  • the compound of Formula IV may be prepared by methods known in literature, for example, by the process known from U.S. Patent No. 5,532,241.
  • the compound of Formula IV is converted to the compound of Formula V in the presence of formamide, a base, and a solvent.
  • the solvent is selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N-alkyl pyrollidone, formamide, ethers, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof.
  • Suitable alcoholic solvents are methanol, 2-propanol, or 1-propanol.
  • a suitable halogenated hydrocarbon solvent is
  • the preferred solvent is N-methyl pyrollidone.
  • the base is selected from the group consisting of alkali metal alkoxide or organic bases. Suitable alkali metal alkoxides are sodium methoxide or sodium i-butoxide. Suitable organic bases are ethyl amine, tri-n-butyl amine, diisopropyl ethyl amine, or methyl amine. The preferred base is sodium methoxide.
  • the conversion of the compound of Formula IV to the compound of Formula V is carried out at about 10°C to about 60°C, preferably at about 20°C to about 40°C.
  • the conversion of the compound of Formula IV to the compound of Formula V is carried out for about 3 hours to about 9 hours, preferably for about 5 hours to about 7 hours.
  • the compound of Formula V may optionally be isolated by filtration, concentration, precipitation, cooling, centrifugation, decantation, or a combination thereof.
  • the compound of Formula V is reduced to the compound of Formula III in the presence of a reducing agent and a solvent.
  • the reducing agent is selected from the group consisting of palladium/carbon, platinum/dioxide, or Raney-Nickel and is used in the presence of ammonium formate.
  • the preferred reducing agent is palladium/carbon in the presence of ammonium formate.
  • the solvent is selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N-alkyl pyrollidone, formamide, ethers, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof.
  • Suitable alcoholic solvents are methanol, 2-propanol, or 1-propanol.
  • a suitable halogenated hydrocarbon solvent is dichloromethane.
  • the preferred solvent is methanol.
  • the conversion of the compound of Formula V to the compound of Formula III is carried out at about 20°C to about 80°C, preferably at about 30°C to about 70°C.
  • the conversion of the compound of Formula V to the compound of Formula III is carried out for about 2 hours to about 7 hours, preferably for about 3 hours to about 5 hours.
  • the compound of Formula III may be isolated by filtration, concentration, precipitation, cooling, centrifugation, decantation, or a combination 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 may be prepared by methods known in the literature, for example, by the process known from U.S. Patent No. 5,532,241.
  • the compound of Formula IV is converted to the compound of Formula V as described in the second aspect.
  • the compound of Formula V may optionally be isolated by filtration,
  • the compound of Formula V is reduced to the compound of Formula III as described in the second aspect.
  • the compound of Formula III may be isolated by filtration, concentration, precipitation, cooling, centriiugation, decantation, or a combination thereof.
  • the 5-amino-l-benzofuran-2-carboxamide compound of Formula III is converted to 5-(piperazin-l-yl)-l-benzofuran-2-carboxamide of Formula VI by reacting with bis-2- chloroethylamine in the presence of a solvent.
  • the solvent is selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N-alkyl pyrollidone, ethers, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof.
  • Suitable alcoholic solvents are methanol, 2-propanol, or 1-propanol.
  • Suitable halogenated hydrocarbon solvent are dichlorome thane, 1,2-dichlorobenzene, or chlorobenzene.
  • Suitable aromatic hydrocarbon solvents are toluene or xylene.
  • the preferred solvent is N-methyl pyrollidone.
  • the conversion of the compound of Formula III to the compound of Formula VI is carried out in the presence of a base.
  • the base is selected from the group consisting of inorganic bases or organic bases.
  • 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.
  • a preferable inorganic base is potassium carbonate.
  • Suitable organic bases are tributyl amine, ethyl amine, diisopropyl ethyl amine, triethyl amine, or methyl amine.
  • the preferred base is tributyl amine.
  • the conversion of the compound of Formula III to the compound of Formula VI is carried out at about -20°C to about 180°C, preferably at about 0°C to about 160°C.
  • the conversion of the compound of Formula III to the compound of Formula VI is carried out for about 2 hours to about 7 hours, preferably for about 3 hours to about 5 hours.
  • the compound of Formula VI may be isolated by filtration, concentration, precipitation, cooling, centrifugation, decantation, or a combination thereof.
  • the compound of Formula VI is converted to vilazodone free base or its salt by treating with the compound of Formula VII.
  • the treatment of the compound of Formula VI and the compound of Formula VII is carried out in the presence of a base and a solvent.
  • the solvent is selected from the group consisting of water, organic solvents, or mixtures thereof.
  • the organic solvent is selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N-alkyl pyrollidone, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof.
  • a suitable halogenated hydrocarbon solvent is dichloromethane.
  • Suitable alcoholic solvents are methanol, 2-propanol, or 1-propanol.
  • Suitable ketone solvents are acetone or methyl isobutyl ketone.
  • a suitable nitrile solvent is acetonitrile.
  • Suitable amide solvents are N-methyl pyrrolidone or dimethyl formamide.
  • a suitable aromatic hydrocarbon solvent is toluene.
  • the preferred solvent is N-methyl pyrollidone.
  • the base is selected from the group consisting of organic bases or inorganic bases.
  • Suitable organic bases are tributyl amine, triethyl amine, diisopropyl amine, diisopropyl ethylamine, 4-dimethylaminopyridine, pyrollidine, or N-methyl morpholine.
  • the preferred organic base is tributyl amine.
  • Suitable inorganic bases are hydroxides, or carbonates or 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 preferred base is potassium carbonate.
  • the treatment of the compound of Formula VI and the compound of Formula VII is carried out in the presence of alkali metal halides, for example, sodium iodide.
  • the treatment of the compound of Formula VI and the compound of Formula VII is carried out at a temperature of about 5°C to about 130°C, preferably at about 20°C to about 120°C.
  • the treatment of the compound of Formula VI and the compound of Formula VII is carried for about 2 hours to about 35 hours, preferably for about 5 hours to about 30 hours.
  • the reaction mixture of the compound of the Formula VI and the compound of Formula VII is treated with hydrobromic acid before converting to vilazodone free base.
  • the hydrobromic acid may be dilute or concentrated.
  • the hydrobromic acid may be used in a solution or in gaseous form.
  • the solution of hydrobromic acid may be aqueous or in an organic solvent.
  • the organic solvents are selected from the group consisting of methanol, ethanol, or 2-propanol.
  • the treatment of reaction mixture of the compound of Formula VI and the compound of Formula VII with hydrobromic acid is carried out in the presence of an organic solvent.
  • the organic solvent is selected from a 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, or butanol.
  • the preferred solvent is N-methyl pyrollidone in combination with 2-propanol, methanol, or methylated ethanol.
  • the dissolution of the reaction mixture of the compound of Formula VI and the compound of Formula VII with hydrobromic acid is carried out at a temperature of about 10°C to about 40°C, preferably at about 20°C to about 35°C.
  • the dissolution of the reaction mixture of the compound of Formula VI and the compound of Formula VII 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 a combination thereof.
  • the vilazodone hydrobromide is 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 base is 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 used for the conversion of vilazodone hydrobromide to vilazodone free base may be used in the form of 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, organic solvents, or combinations thereof.
  • the organic solvent is selected from the group consisting of alcohols, esters, halogenated hydrocarbons, ketones, amides, esters, or combinations thereof.
  • Suitable alcoholic solvents are methanol, ethanol, methylated ethanol, 2-propanol, 1-propanol, or butanol.
  • Suitable amide solvents are N-methyl pyrrolidone, dimethyl acetamide, or dimethyl formamide.
  • a suitable nitrile solvent is acetonitrile.
  • Suitable ketonic solvents are acetone or methyl isobutyl ketone.
  • a suitable chlorinated solvent is dichloromethane.
  • Suitable ester solvents are ethyl acetate, methyl acetate, or isopropyl acetate.
  • 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 a combination thereof.
  • the vilazodone free base obtained by the present invention can 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, alcohol, amide, halogenated hydrocarbon, esters, or mixtures thereof.
  • Suitable alcoholic solvents are methanol, ethanol, 2-propanol, 1-propanol, or butanol.
  • Suitable amide solvents are N- methyl pyrrolidone, 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 solvent is 2-propanol, either alone or in combination with N-methyl pyrrolidone 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 may be used in solution form or gaseous form.
  • the solution of hydrochloric acid may be aqueous or in an alcoholic solvent.
  • the alcoholic solvent used for the preparation of hydrochloric acid solution is 2-propanol.
  • the vilazodone hydrochloride salt may be isolated by filtration, distillation, evaporation, centriiugation, decantation, drying, vacuum drying, or a combination thereof.
  • the vilazodone hydrochloride prepared by the present invention may be characterized using an X-ray powder diffraction (XRPD) pattern.
  • Ethyl 5-nitro-l-benzofuran-2-carboxylate 100 g was added to N-methyl pyrollidone (250 mL) at 20°C to 25°C.
  • a solution of formamide (57.4 g) in N-methyl pyrollidone (250 mL) was added to the reaction mixture.
  • a solution of 30% sodium methoxide (230 g) was added to the reaction mixture over 1 hour at 20°C to 25°C.
  • the reaction mixture was stirred at 20°C to 25 °C for 1 hour.
  • the temperature of the reaction mixture was increased to 30°C to 35°C.
  • Deionized water (3 L) was added to the reaction mixture at 30°C to 35 °C for 1 hour.
  • the reaction mixture was filtered and washed with deionized water (500 mL x 6) to obtain the title compound.
  • step a) The solid obtained in step a) was added to methanol (1 L). A solution of 2.5% palladium/carbon (20 g) in deionized water (20 mL) was added to the reaction mixture. Ammonium formate (26.8 g x 4) was added to the reaction mixture at 30°C to 45°C. The reaction mixture was stirred at 40°C to 45 °C for 1 hour. The reaction mixture was filtered and washed with methanol (2 x 100 mL). Methanol was recovered under vacuum at 60°C to 65°C. Deionized water (200 mL) was added to the reaction mixture and the mixture stirred for 1 hour. The reaction mixture was filtered and washed with water (200 mL). The solid obtained was dried in air at 50°C to 55 °C to obtain the title compound.
  • 5-Amino-l-benzofuran-2-carboxamide (10 g; prepared according to Example 1) was added to N-methyl pyrollidone (50 mL).
  • Bis-2-chloroethylamine (12.2 g) was added to the reaction mixture.
  • the temperature of the reaction mixture was raised to 150°C to 155°C and the mixture stirred for 2 hours.
  • Tributyl amine (10.5 g) was added to the reaction mixture and stirred at 150°C to 155°C for 6 hours.
  • the reaction mixture was cooled to 25 °C to 30°C.
  • Deionized water 350 mL was added to the reaction mixture and the pH was adjusted to 12 with 20% sodium hydroxide solution (35 mL).
  • the reaction mixture was cooled to 0°C to 5°C and stirred for 2 hours.
  • the reaction mixture was filtered and washed with water (50 mL).
  • Deionized water (50 mL) was added to the reaction mixture and the pH was adjusted to 4.7 with concentrated hydrochloric acid (3.1 mL).
  • Activated carbon (1 g) was added to the reaction mixture and stirred for 45 minutes.
  • the reaction mixture was filtered and washed with deionized water (50 mL).
  • the pH of the filtrate was adjusted to 12.0 with 20% sodium hydroxide solution (4 mL).
  • the reaction mixture was cooled to 0°C to 5°C and stirred for 1 hour.
  • the reaction mixture was filtered and washed with deionized water (2 x 10 mL).
  • the solid obtained was dried in air at 50°C to 55°C to obtain the title compound.
  • Example 2 3-(4-chloro butyl)-lH-indole-5-carbonitrile (5.7 g) were added to N- methyl pyrollidone (25 mL). The temperature of the reaction mixture was increased to 110°C to 120°C and stirred for 2 hours. Tributyl amine (3.77 g) was added to the reaction mixture and stirred at 110°C to 120°C for 4 hours. The reaction mixture was cooled to 20°C to 35°C. Hydrobromic acid (2.5 mL) and 2-propanol (50 mL) were added to the reaction mixture. Vilazodone hydrobromide seed (0.005 g) was added to the reaction mixture and stirred at 0°C to 5°C for 1 hour. The reaction mixture was filtered, and then washed with cooled 2-propanol (25 mL).
  • reaction mixture was added to a mixture of N-methyl pyrollidone (25 mL) and hydrobromic acid (0.5 mL).
  • 2-Propanol (50 mL) was added to the reaction mixture and stirred for 2 hours.
  • the reaction mixture was filtered and washed with 2-propanol (10 mL).
  • the reaction mixture was added to 2-propanol (100 mL) and deionized water (50 mL).
  • the temperature of the reaction mixture was increased to 80°C to 82°C.
  • Activated carbon (1 g) was added to the reaction mixture and stirred for 1 hour.
  • the reaction mixture was filtered and washed with 2-propanol (20 mL) and deionized water (10 mL).
  • the pH of the filtrate was adjusted to 7.2 with 7% sodium bicarbonate solution (9 mL).
  • the reaction mixture was filtered and washed with deionized water (20 mL) and 2- propanol (20 mL).
  • the solid obtained was dried in air at 50°C to 55°C to obtain the title compound.

Abstract

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 said novel intermediate.

Description

PROCESS FOR THE PREPARATION OF VILAZODONE OR
PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
Field of the Invention
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 said novel intermediate.
Background of the Invention
Vilazodone free base is chemically described as 5-{4-[4-(5-cyano-lH-indol-3- yl)butyl]piperazin-l-yl}-l-benzofuran-2-carboxamide of Formula I.
Figure imgf000002_0001
FORMULA I
Vilazodone hydrochloride is chemically described as 5-{4-[4-(5-cyano-lH-indol- 3-yl)butyl]piperazin-l- l}-l-benzofuran-2-carboxamide hydrochloride of Formula II.
Figure imgf000002_0002
FORMULA II
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 purportedly described in U.S. Patent Nos. 5,532,241, 5,723,614, and 5,977,112 and European Patent No. 0 648 767.
Summary of the Invention
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 said novel intermediate.
In one general aspect, the invention relates to a novel intermediate compound of Formula III.
Figure imgf000003_0001
FORMULA III
In another general aspect, the invention relates to a process for the preparation of 5-amino-l-benzofuran-2-carboxamide of Formula III
Figure imgf000003_0002
FORMULA III
The process includes the steps of:
a) converting ethyl 5-nitro-l-benzofuran-2-carboxylate of Formula IV
Figure imgf000003_0003
FORMULA IV
to 5-nitro-l-benzofuran-2-carboxamide of Formula V;
Figure imgf000004_0001
FORMULA V
b) converting 5-nitro-l-benzofuran-2-carboxamide of Formula V to 5-amino- l-benzofuran-2-carboxamide of Formula III; and
c) isolating 5-amino-l-benzofuran-2-carboxamide of Formula III from the reaction mixture thereof.
Embodiments of the process may include one or more of the following features. For example, the compound of Formula IV may be converted to the compound of Formula V in step a) in the presence of formamide, a base, and a solvent.
The compound of Formula IV may be converted to the compound of Formula V in step a) in the presence of formamide, a base, and a solvent. The solvent may be selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N-alkyl pyrollidone, formamide, ethers, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof. The solvent may be N-methyl pyrollidone.
The base may be selected from the group consisting of alkali metal alkoxide or organic bases. The base may be sodium methoxide.
The compound of Formula V may be converted to the compound of Formula III in the presence of a reducing agent and a solvent. The reducing agent may be selected from the group consisting of palladium/carbon, platinum/dioxide, or Raney-Nickel in the presence of ammonium formate. The reducing agent may be palladium/carbon in the presence of ammonium formate. The solvent may be selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N-alkyl pyrollidone, formamide, ethers, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof.
In another general aspect, the invention relates to a process for preparing vilazodone free base of Formula I
Figure imgf000005_0001
FORMULA I
larmaceutically acceptable salts thereof which comprises: converting ethyl 5-nitro-l-benzofuran-2-carboxylate of Formula IV
Figure imgf000005_0002
FORMULA IV
to 5-nitro-l-benzofuran-2-carboxamide of Formula V;
Figure imgf000005_0003
FORMULA V
b) converting 5-nitro-l-benzofuran-2-carboxamide of Formula V to 5- l-benzofuran-2-carboxamide of Formula III;
Figure imgf000005_0004
FORMULA III
c) converting 5-amino- l-benzofuran-2-carboxamide of Formula III to 5 (piperazin-l-yl)-l-benzofuran-2-carboxamide of Formula VI;
Figure imgf000006_0001
FORMULA VI
d) reacting 5-(piperazin- 1 -yl)- 1 -benzofuran-2-carboxamide of Formula VI with 3-(4-chlorobutyl)-lH-indole-5-carbonitrile of Formula VII;
Figure imgf000006_0002
FORMULA VII
e) isolating vilazodone free base of Formula I from the reaction mixture thereof; and
f) optionally converting the compound of Formula I to its pharmaceutically acceptable salts.
Embodiments of the process may include one or more of the following features. For example, the compound of Formula IV may be converted to the compound of Formula V in step a) in the presence of formamide, a base, and a solvent.
The compound of Formula IV may be converted to the compound of Formula V in step a) in the presence of formamide, a base, and a solvent. The solvent may be selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N-alkyl pyrollidone, formamide, ethers, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof. The solvent may be N-methyl pyrollidone.
The base may be selected from the group consisting of alkali metal alkoxide or organic bases. The base may be sodium methoxide.
The compound of Formula V may be converted to the compound of Formula III in the presence of a reducing agent and a solvent. The reducing agent may be selected from the group consisting of palladium/carbon, platinum/dioxide, or Raney-Nickel in the presence of ammonium formate. The reducing agent may be palladium/carbon in the presence of ammonium formate. The solvent may be selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N-alkyl pyrollidone, formamide, ethers, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof.
The 5-amino-l-benzofuran-2-carboxamide compound of Formula III may be converted to the 5-(piperazin-l-yl)-l-benzofuran-2-carboxamide of Formula VI in step c) by reacting with bis-2-chloroethylamine in the presence of a solvent. The solvent may be selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N- alkyl pyrollidone, ethers, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof.
The reaction of the compound of Formula VI and the compound of Formula VII in step d) 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 solvents, or mixtures thereof.
The reaction mixture of the compound of Formula VI and the compound of
Formula VII may be treated with hydrobromic acid before converting to vilazodone free base.
The pharmaceutically acceptable salt in step f) may be the hydrochloric acid salt.
Detailed Description of the Invention
A first aspect of the present invention provides an intermediate compound of
Formula III.
Figure imgf000007_0001
FORMULA III
The intermediate compound of Formula III is chemically described as 5-amino-l- benzofuran-2-carboxamide.
A second aspect of the present invention provides a process for the preparation of 5-amino-l-benzofuran-2-carboxamide of Formula III
Figure imgf000008_0001
FORMULA III
wherein the process comprises:
a) converting ethyl 5-nitro-l-benzofuran-2-carboxylate of Formula IV
Figure imgf000008_0002
FORMULA IV
to 5-nitro-l-benzofuran-2-carboxamide of Formula V;
Figure imgf000008_0003
FORMULA V
b) converting 5-nitro-l-benzofuran-2-carboxamide of Formula V to 5-amino-l- benzofuran-2-carboxamide of Formula III; and
c) isolating 5-amino-l-benzofuran-2-carboxamide of Formula III from the reaction mixture thereof.
The compound of Formula IV may be prepared by methods known in literature, for example, by the process known from U.S. Patent No. 5,532,241. The compound of Formula IV is converted to the compound of Formula V in the presence of formamide, a base, and a solvent. The solvent is selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N-alkyl pyrollidone, formamide, ethers, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof. Suitable alcoholic solvents are methanol, 2-propanol, or 1-propanol. A suitable halogenated hydrocarbon solvent is
dichloromethane. The preferred solvent is N-methyl pyrollidone. The base is selected from the group consisting of alkali metal alkoxide or organic bases. Suitable alkali metal alkoxides are sodium methoxide or sodium i-butoxide. Suitable organic bases are ethyl amine, tri-n-butyl amine, diisopropyl ethyl amine, or methyl amine. The preferred base is sodium methoxide.
The conversion of the compound of Formula IV to the compound of Formula V is carried out at about 10°C to about 60°C, preferably at about 20°C to about 40°C. The conversion of the compound of Formula IV to the compound of Formula V is carried out for about 3 hours to about 9 hours, preferably for about 5 hours to about 7 hours. The compound of Formula V may optionally be isolated by filtration, concentration, precipitation, cooling, centrifugation, decantation, or a combination thereof.
The compound of Formula V is reduced to the compound of Formula III in the presence of a reducing agent and a solvent. The reducing agent is selected from the group consisting of palladium/carbon, platinum/dioxide, or Raney-Nickel and is used in the presence of ammonium formate. The preferred reducing agent is palladium/carbon in the presence of ammonium formate. The solvent is selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N-alkyl pyrollidone, formamide, ethers, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof. Suitable alcoholic solvents are methanol, 2-propanol, or 1-propanol. A suitable halogenated hydrocarbon solvent is dichloromethane. The preferred solvent is methanol.
The conversion of the compound of Formula V to the compound of Formula III is carried out at about 20°C to about 80°C, preferably at about 30°C to about 70°C. The conversion of the compound of Formula V to the compound of Formula III is carried out for about 2 hours to about 7 hours, preferably for about 3 hours to about 5 hours. The compound of Formula III may be isolated by filtration, concentration, precipitation, cooling, centrifugation, decantation, or a combination thereof.
A third aspect of the present invention provides a process for the preparation of vilazodone free base of Formula I
Figure imgf000010_0001
FORMULA I
or pharmaceutically acceptable salts thereof which comprises:
a) converting ethyl 5-nitro-l-benzofuran-2-carboxylate of Formula IV
Figure imgf000010_0002
FORMULA IV
to 5-nitro-l-benzofuran-2-carboxamide of Formula V;
Figure imgf000010_0003
FORMULA V
b) converting 5-nitro-l-benzofuran-2-carboxamide of Formula V to 5-amino-l- benzofuran-2-carboxamide of Formula III;
Figure imgf000010_0004
FORMULA III
c) converting 5-amino-l-benzofuran-2-carboxamide of Formula III to 5- (piperazin-l-yl)-l-benzofuran-2-carboxamide of Formula VI;
Figure imgf000011_0001
FORMULA VI
reacting 5-(piperazin-l-yl)-l-benzofuran-2-carboxamide of Formula VI with 3-(4-chlorobutyl)-lH-indole-5-carbonitrile of Formula VII;
Figure imgf000011_0002
FORMULA VII
e) isolating vilazodone free base of Formula I from the reaction mixture thereof; and
f) optionally converting the compound of Formula I to its pharmaceutically acceptable salts.
The compound of Formula IV may be prepared by methods known in the literature, for example, by the process known from U.S. Patent No. 5,532,241. The compound of Formula IV is converted to the compound of Formula V as described in the second aspect.
The compound of Formula V may optionally be isolated by filtration,
concentration, precipitation, cooling, centriiugation, decantation, or a combination thereof.
The compound of Formula V is reduced to the compound of Formula III as described in the second aspect. The compound of Formula III may be isolated by filtration, concentration, precipitation, cooling, centriiugation, decantation, or a combination thereof.
The 5-amino-l-benzofuran-2-carboxamide compound of Formula III is converted to 5-(piperazin-l-yl)-l-benzofuran-2-carboxamide of Formula VI by reacting with bis-2- chloroethylamine in the presence of a solvent. The solvent is selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N-alkyl pyrollidone, ethers, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof. Suitable alcoholic solvents are methanol, 2-propanol, or 1-propanol. Suitable halogenated hydrocarbon solvent are dichlorome thane, 1,2-dichlorobenzene, or chlorobenzene. Suitable aromatic hydrocarbon solvents are toluene or xylene. The preferred solvent is N-methyl pyrollidone.
The conversion of the compound of Formula III to the compound of Formula VI is carried out in the presence of a base. The base is selected from the group consisting of inorganic bases or organic bases. 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. A preferable inorganic base is potassium carbonate. Suitable organic bases are tributyl amine, ethyl amine, diisopropyl ethyl amine, triethyl amine, or methyl amine. The preferred base is tributyl amine.
The conversion of the compound of Formula III to the compound of Formula VI is carried out at about -20°C to about 180°C, preferably at about 0°C to about 160°C. The conversion of the compound of Formula III to the compound of Formula VI is carried out for about 2 hours to about 7 hours, preferably for about 3 hours to about 5 hours. The compound of Formula VI may be isolated by filtration, concentration, precipitation, cooling, centrifugation, decantation, or a combination thereof.
The compound of Formula VI is converted to vilazodone free base or its salt by treating with the compound of Formula VII. The treatment of the compound of Formula VI and the compound of Formula VII is carried out in the presence of a base and a solvent. The solvent is selected from the group consisting of water, organic solvents, or mixtures thereof. The organic solvent is selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N-alkyl pyrollidone, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof. A suitable halogenated hydrocarbon solvent is dichloromethane. Suitable alcoholic solvents are methanol, 2-propanol, or 1-propanol. Suitable ketone solvents are acetone or methyl isobutyl ketone. A suitable nitrile solvent is acetonitrile. Suitable amide solvents are N-methyl pyrrolidone or dimethyl formamide. A suitable aromatic hydrocarbon solvent is toluene. The preferred solvent is N-methyl pyrollidone. The treatment of the compound of Formula VII and the 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 tributyl amine, triethyl amine, diisopropyl amine, diisopropyl ethylamine, 4-dimethylaminopyridine, pyrollidine, or N-methyl morpholine. The preferred organic base is tributyl amine. Suitable inorganic bases are hydroxides, or carbonates or 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 preferred base is potassium carbonate. The treatment of the compound of Formula VI and the compound of Formula VII is carried out in the presence of alkali metal halides, for example, sodium iodide.
The treatment of the compound of Formula VI and the compound of Formula VII is carried out at a temperature of about 5°C to about 130°C, preferably at about 20°C to about 120°C. The treatment of the compound of Formula VI and the compound of Formula VII is carried for about 2 hours to about 35 hours, preferably for about 5 hours to about 30 hours.
The reaction mixture of the compound of the Formula VI and the compound of Formula VII is treated with hydrobromic acid before converting to vilazodone free base. The hydrobromic acid may be dilute or concentrated. The hydrobromic acid may be used in a solution or in gaseous form. The solution of hydrobromic acid may be aqueous or in an organic solvent. The organic solvents are selected from the group consisting of methanol, ethanol, or 2-propanol. The treatment of reaction mixture of the compound of Formula VI and the compound of Formula VII with hydrobromic acid is carried out in the presence of an organic solvent. The organic solvent is selected from a 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, or butanol. The preferred solvent is N-methyl pyrollidone in combination with 2-propanol, methanol, or methylated ethanol.
The dissolution of the reaction mixture of the compound of Formula VI and the compound of Formula VII with hydrobromic acid is carried out at a temperature of about 10°C to about 40°C, preferably at about 20°C to about 35°C. The dissolution of the reaction mixture of the compound of Formula VI and the compound of Formula VII 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 a combination thereof.
The vilazodone hydrobromide is 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 base is 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 used for the conversion of vilazodone hydrobromide to vilazodone free base may be used in the form of 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, organic solvents, or combinations thereof. The organic solvent is selected from the group consisting of alcohols, esters, halogenated hydrocarbons, ketones, amides, esters, or combinations thereof. Suitable alcoholic solvents are methanol, ethanol, methylated ethanol, 2-propanol, 1-propanol, or butanol. Suitable amide solvents are N-methyl pyrrolidone, dimethyl acetamide, or dimethyl formamide. A suitable nitrile solvent is acetonitrile. Suitable ketonic solvents are acetone or methyl isobutyl ketone. A suitable chlorinated solvent is dichloromethane. Suitable ester solvents are ethyl acetate, methyl acetate, or isopropyl acetate. 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 a combination thereof.
The vilazodone free base obtained by the present invention can 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, alcohol, amide, halogenated hydrocarbon, esters, or mixtures thereof. Suitable alcoholic solvents are methanol, ethanol, 2-propanol, 1-propanol, or butanol. Suitable amide solvents are N- methyl pyrrolidone, 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 solvent is 2-propanol, either alone or in combination with N-methyl pyrrolidone 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 may be used in solution form or gaseous form. The solution of hydrochloric acid may be aqueous or in an alcoholic solvent. The alcoholic solvent used for the preparation of hydrochloric acid solution is 2-propanol.
The vilazodone hydrochloride salt may be isolated by filtration, distillation, evaporation, centriiugation, decantation, drying, vacuum drying, or a combination thereof. The vilazodone hydrochloride prepared by the present invention may be characterized using an X-ray powder diffraction (XRPD) pattern.
In the following section, embodiments are described by way of examples to illustrate the process of the invention. Several variants of these examples would be evident to persons ordinarily skilled in the art.
EXAMPLES
Example 1 : Preparation of 5-amino-l-benzofuran-2-carboxamide
Step a): Preparation of 5-nitro-l-benzofuran-2-carboxamide
Ethyl 5-nitro-l-benzofuran-2-carboxylate (100 g) was added to N-methyl pyrollidone (250 mL) at 20°C to 25°C. A solution of formamide (57.4 g) in N-methyl pyrollidone (250 mL) was added to the reaction mixture. A solution of 30% sodium methoxide (230 g) was added to the reaction mixture over 1 hour at 20°C to 25°C. The reaction mixture was stirred at 20°C to 25 °C for 1 hour. The temperature of the reaction mixture was increased to 30°C to 35°C. Deionized water (3 L) was added to the reaction mixture at 30°C to 35 °C for 1 hour. The reaction mixture was filtered and washed with deionized water (500 mL x 6) to obtain the title compound.
Step b): Preparation of 5-amino-l-benzofuran-2-carboxamide
The solid obtained in step a) was added to methanol (1 L). A solution of 2.5% palladium/carbon (20 g) in deionized water (20 mL) was added to the reaction mixture. Ammonium formate (26.8 g x 4) was added to the reaction mixture at 30°C to 45°C. The reaction mixture was stirred at 40°C to 45 °C for 1 hour. The reaction mixture was filtered and washed with methanol (2 x 100 mL). Methanol was recovered under vacuum at 60°C to 65°C. Deionized water (200 mL) was added to the reaction mixture and the mixture stirred for 1 hour. The reaction mixture was filtered and washed with water (200 mL). The solid obtained was dried in air at 50°C to 55 °C to obtain the title compound.
Yield: 45 g
Mass data (m/e): 177 (M+l).
NMR data (DMSO-d6): 4.99 (s, 2H), 6.74-6.79 (m, 2H), 7.28-7.31 (t, 2H), 7.56 (s, 1H), 7.96 (s, 1H).
Example 2: Preparation of 5-(piperazin-l-yl)-l-benzofuran-2-carboxamide
5-Amino-l-benzofuran-2-carboxamide (10 g; prepared according to Example 1) was added to N-methyl pyrollidone (50 mL). Bis-2-chloroethylamine (12.2 g) was added to the reaction mixture. The temperature of the reaction mixture was raised to 150°C to 155°C and the mixture stirred for 2 hours. Tributyl amine (10.5 g) was added to the reaction mixture and stirred at 150°C to 155°C for 6 hours. The reaction mixture was cooled to 25 °C to 30°C. Deionized water (350 mL) was added to the reaction mixture and the pH was adjusted to 12 with 20% sodium hydroxide solution (35 mL).
The reaction mixture was cooled to 0°C to 5°C and stirred for 2 hours. The reaction mixture was filtered and washed with water (50 mL). Deionized water (50 mL) was added to the reaction mixture and the pH was adjusted to 4.7 with concentrated hydrochloric acid (3.1 mL). Activated carbon (1 g) was added to the reaction mixture and stirred for 45 minutes. The reaction mixture was filtered and washed with deionized water (50 mL). The pH of the filtrate was adjusted to 12.0 with 20% sodium hydroxide solution (4 mL). The reaction mixture was cooled to 0°C to 5°C and stirred for 1 hour. The reaction mixture was filtered and washed with deionized water (2 x 10 mL). The solid obtained was dried in air at 50°C to 55°C to obtain the title compound.
Yield: 5.6 g
Example 3: Preparation of vilazodone free base
5-(Piperazin-l-yl)-l-benzofuran-2-carboxamide (5 g; prepared according to
Example 2) and 3-(4-chloro butyl)-lH-indole-5-carbonitrile (5.7 g) were added to N- methyl pyrollidone (25 mL). The temperature of the reaction mixture was increased to 110°C to 120°C and stirred for 2 hours. Tributyl amine (3.77 g) was added to the reaction mixture and stirred at 110°C to 120°C for 4 hours. The reaction mixture was cooled to 20°C to 35°C. Hydrobromic acid (2.5 mL) and 2-propanol (50 mL) were added to the reaction mixture. Vilazodone hydrobromide seed (0.005 g) was added to the reaction mixture and stirred at 0°C to 5°C for 1 hour. The reaction mixture was filtered, and then washed with cooled 2-propanol (25 mL).
The reaction mixture was added to a mixture of N-methyl pyrollidone (25 mL) and hydrobromic acid (0.5 mL). 2-Propanol (50 mL) was added to the reaction mixture and stirred for 2 hours. The reaction mixture was filtered and washed with 2-propanol (10 mL). The reaction mixture was added to 2-propanol (100 mL) and deionized water (50 mL). The temperature of the reaction mixture was increased to 80°C to 82°C. Activated carbon (1 g) was added to the reaction mixture and stirred for 1 hour. The reaction mixture was filtered and washed with 2-propanol (20 mL) and deionized water (10 mL). The pH of the filtrate was adjusted to 7.2 with 7% sodium bicarbonate solution (9 mL). The reaction mixture was filtered and washed with deionized water (20 mL) and 2- propanol (20 mL). The solid obtained was dried in air at 50°C to 55°C to obtain the title compound.
Yield: 2.8 g
Example 4: Preparation of vilazodone hydrochloride
Vilazodone free base (2 g; prepared according to Example 3) was added to 2- propanol (86 mL). N-methyl pyrollidone (6 mL) and a solution of 20% 2-propanolic hydrochloride solution (0.2 mL) were added to the reaction mixture. The temperature of the reaction mixture was increased to 80°C to 82°C. Activated carbon (0.4 g) was added to the reaction mixture and stirred for 30 minutes. The reaction mixture was filtered and washed with 2-propanol (4 mL). A solution of 0.1 N 2-propanolic hydrochloric acid (20%; 46 mL) was added to the filtrate over 30 minutes at 75°C to 78°C. The reaction mixture was stirred at 55°C to 60°C for 1 hour. The reaction mixture was filtered and washed with 2-propanol (2 x 5 mL). The solid obtained was dried in air at 50°C to 55°C to obtain the title compound.
Yield: 1.63 g
Example 5: Preparation of vilazodone hydrobromide
5-(piperazin-l-yl)-l-benzofuran-2-carboxamide (50 g; prepared according to Example 2) and 3-(4-chlorobutyl)-lH-indole-5-carbonitrile (52.3 g) were added to N- methyl pyrollidone (250 mL) at 30°C. The temperature of the reaction mixture was increased to 120°C and maintained at 115°C to 120°C for 2 hours. Tributylamine (38 g) was added to the reaction mixture at 115°C to 117°C and the temperature was maintained at 115°C to 120°C for 6 hours. The reaction mixture was cooled to 30°C. 2-propanol (500 mL) and concentrated (40% to 48%) hydrobromic acid (37 g) were added to the reaction mixture at 25 °C to 30°C and the mixture was seeded with vilazodone hydrobromide (0.25 g) at 25°C to 30°C. The reaction mixture was stirred at 25°C to 30°C for 6 hours. The reaction mixture was filtered and washed with 2-propanol (50 mL x 4) at 20°C to 30°C to obtain the title compound.
Yield (Wet): 89 g
Example 6: Preparation of vilazodone hydrobromide
Vilazodone hydrobromide (88 g; prepared according to Example 5) was added to N-methyl pyrollidone (250 mL) and concentrated hydrobromic acid (5 mL). The reaction mixture was heated to 55°C. 2-propanol (250 mL) was added to the reaction mixture at 50°C to 55°C and cooled to 30°C. The reaction mixture was stirred for 1 hour at 25°C to 30°C. The reaction mixture was filtered and washed with 2-propanol (50 mL x 2) at 20°C to 30°C to obtain the title compound.
Yield (Wet): 104 g
Example 7: Preparation of vilazodone free base
Vilazodone hydrobromide (102 g; prepared according to Example 6) was added to a mixture of 2-propanol (1000 mL) and deionized water (500 mL). The reaction mixture was heated to 70°C. Activated carbon (10 g) was added to the reaction mixture at 70°C. The reaction mixture was filtered and washed with a mixture of 2-propanol (100 mL) and deionized water (50 mL). The pH of the reaction mixture was adjusted to 7 with sodium bicarbonate solution (150 mL) at 65°C to 70°C. The reaction mixture was cooled to 30°C and stirred for 30 minutes. The reaction mixture was filtered and washed with 2-propanol (50 mL x 2) at 20°C to 30°C. The solid obtained was dried under air oven at 50°C to 55°C for 16 hours to obtain the title compound.
Yield: 42.5 g
Example 8: Preparation of vilazodone hydrochloride
Vilazodone free base (40 g; prepared according to Example 7) was added to 2- propanol (1720 mL) at 20°C to 30°C. The temperature of the reaction mixture was raised to 82°C. Deionized water (80 mL) was added to the reaction mixture at 78°C to 80°C. Activated carbon (2 g) was added at 80°C and maintained for 30 minutes. The reaction mixture was filtered and washed with 2-propanol (200 mL) at 80°C. 0.1 N 2-propanolic hydrochloride (9.4 g concentrated hydrochloric acid in 904 mL 2-propanol) was added to the reaction mixture over 60 minutes at 78°C to 80°C. The reaction mixture was cooled to 55°C. The reaction mixture was filtered and washed with 2-propanol (80 ml) at 55°C. The reaction mixture was dried under vacuum at 50°C to 55°C for 16 hours to obtain the title compound.
Yield: 39.5 g

Claims

We claim:
1. An intermediate compound of Formula III.
Figure imgf000020_0001
FORMULA III
2. A process for the preparation of 5-amino-l -benzofuran-2-carboxamide of Formula III
Figure imgf000020_0002
FORMULA III
wherein the process comprises:
a) converting ethyl 5-nitro-l-benzofuran-2-carboxylate of Formula IV
Figure imgf000020_0003
FORMULA IV
to 5-nitro-l-benzofuran-2-carboxamide of Formula V;
Figure imgf000020_0004
FORMULA V
b) converting 5-nitro-l-benzofuran-2-carboxamide of Formula V to 5-amino-l- benzofuran-2-carboxamide of Formula III; and
c) isolating 5-amino-l-benzofuran-2-carboxamide of Formula III from the reaction mixture thereof. A process for the preparation of vilazodone free base of Formula I
Figure imgf000021_0001
FORMULA I
or pharmaceutically acceptable salts thereof which comprises:
a) converting ethyl 5-nitro-l-benzofuran-2-carboxylate of Formula IV
Figure imgf000021_0002
FORMULA IV
to 5-nitro-l-benzofuran-2-carboxamide of Formula V;
Figure imgf000021_0003
FORMULA V
b) converting 5-nitro-l-benzofuran-2-carboxamide of Formula V to 5-amino-l- benzofuran-2-carboxamide of Formula III;
Figure imgf000021_0004
FORMULA III
c) converting 5-amino-l-benzofuran-2-carboxamide of Formula III to 5- (piperazin-l-yl)-l-benzofuran-2-carboxamide of Formula VI;
Figure imgf000022_0001
FORMULA VI
reacting 5-(piperazin-l-yl)-l-benzofuran-2-carboxamide of Formula VI with 3-(4-chlorobutyl)-lH-indole-5-carbonitrile of Formula VII;
Figure imgf000022_0002
FORMULA VII
e) isolating vilazodone free base of Formula I from the reaction mixture thereof; and
f) optionally converting the compound of Formula I to its pharmaceutically acceptable salts.
4. The process according to claims 2 or 3, wherein the compound of Formula IV is converted to the compound of Formula V in step a) in the presence of formamide, a base, and a solvent.
5. The process according to claim 4, wherein the solvent is selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N-alkyl pyrollidone, formamide, ethers, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof.
6. The process according to claim 5, wherein the solvent is N-methyl pyrollidone.
7. The process according to claim 4, wherein the base is selected from the group consisting of alkali metal alkoxide or organic bases.
8. The process according to claim 7, wherein the base is sodium methoxide.
9. The process according to claims 2 or 3, wherein the compound of Formula V is converted to compound of Formula III in the presence of a reducing agent and a solvent.
10. The process according to claim 9, wherein the reducing agent is selected from the group consisting of palladium/carbon, platinum/dioxide, or Raney-Nickel in the presence of ammonium formate.
11. The process according to claim 10, wherein the reducing agent is palladium/carbon in the presence of ammonium formate.
12. The process according to claim 9, wherein the solvent is selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N-alkyl pyrollidone, formamide, ethers, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof. 13. The process according to claim 3, wherein the 5-amino-l-benzofuran-2- carboxamide compound of Formula III is converted to the 5-(piperazin-l-yl)-l- benzofuran-2-carboxamide of Formula VI in step c) by reacting with bis-2- chloroethylamine in the presence of a solvent.
14. The process according to claim 13, wherein the solvent is selected from the group consisting of halogenated hydrocarbons, alcohols, ketones, N-alkyl pyrollidone, ethers, nitriles, aromatic and aliphatic hydrocarbons, or mixtures thereof.
15. The process according to claim 3, wherein the reaction of the compound of Formula VI and the compound of Formula VII in step d) is carried out in the presence of a base and a solvent.
16. The process according to claim 15, wherein the solvent is selected from the group consisting of water, organic solvents, or mixtures thereof.
17. The process according to claim 3, wherein the reaction mixture of the compound of Formula VI and the compound of Formula VII is treated with hydrobromic acid before converting to vilazodone free base.
18. The process according to claim 3, wherein the pharmaceutically acceptable salt in step f) is hydrochloric acid salt.
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EP0648767A1 (en) 1993-09-30 1995-04-19 MERCK PATENT GmbH Piperdine and piperazine derivatives which affect the C.N.S.
US5723614A (en) 1995-04-20 1998-03-03 Merck Patent Gesellschaft Mit Beschrankter Haftung Benzofurans

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