WO2013175361A1 - Process for the preparation of vilazodone hydrochloride - Google Patents

Process for the preparation of vilazodone hydrochloride Download PDF

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Publication number
WO2013175361A1
WO2013175361A1 PCT/IB2013/054021 IB2013054021W WO2013175361A1 WO 2013175361 A1 WO2013175361 A1 WO 2013175361A1 IB 2013054021 W IB2013054021 W IB 2013054021W WO 2013175361 A1 WO2013175361 A1 WO 2013175361A1
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Prior art keywords
process according
formula
compound
reaction mixture
hydrochloric acid
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PCT/IB2013/054021
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French (fr)
Inventor
Prasenjit Das
Nitin Maheshwari
Hashim Nizar Poovanathil Nagoor Meeran
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Ranbaxy Laboratories Limited
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Publication of WO2013175361A1 publication Critical patent/WO2013175361A1/en

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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

Definitions

  • the present invention relates to a process for the preparation of vilazodone hydrochloride without isolating vilazodone free base.
  • the present inventors have developed a simple and efficient process for the preparation of vilazodone hydrochloride without isolating vilazodone free base.
  • Vilazodone hydrochloride obtained by the present process can be directly isolated from the reaction mixture obtained after reacting 3-(4-chlorobutyl)- lH-indole-5-carbonitrile of Formula II, 5-(piperazin- 1 -yl)- 1 -benzofuran-2-carboxamide of Formula III, and hydrochloric acid.
  • An aspect of the present invention provides a process for the preparation of vilazodone hydrochloride of Formula I,
  • step b) treating the reaction mixture obtained in step a) with hydrochloric acid; and c) isolating vilazodone hydrochloride of Formula I from the reaction mixture thereof.
  • reaction of the compound of Formula II and the compound of Formula III may be carried out in the presence of a base and solvent.
  • the solvent used for the reaction of the compound of Formula II and the compound of Formula III may be selected from the group consisting of water, organic solvent, or a mixture thereof.
  • Suitable organic solvents may be selected from the group consisting of alcohol, ketone, nitrile, amide, aromatic, aliphatic hydrocarbon, or dimethyl sulfoxide.
  • Suitable alcoholic solvents may include methanol, 2-propanol, or 1 -propanol.
  • Suitable nitrile solvents may include acetonitrile.
  • Suitable amide solvents may include N- methylpyrrolidone, dimethylacetamide, and ⁇ , ⁇ -dimethylformamide.
  • Suitable ketone solvents may include acetone or methyl isobutyl ketone.
  • Suitable aromatic hydrocarbon solvents may include toluene.
  • Preferable solvents may include N-methylpyrrolidone or N,N-dimethylformamide.
  • the base used for the reaction of the compound of Formula II and the compound of Formula III may be selected from organic or inorganic bases.
  • Suitable organic bases may include tributylamine, triethylamine, diisopropylamine, diisopropylethylamine, 4- dimethylaminopyridine, pyrollidine, or N-methylmorpholine.
  • a preferable organic base is tributylamine.
  • Suitable inorganic bases may include hydroxides or carbonates and bicarbonates of alkali or alkaline metals. Suitable carbonates or bicarbonates of alkali or alkaline metals may include sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, or potassium bicarbonate.
  • a preferable inorganic base is potassium carbonate.
  • the treatment of the compound of Formula II and the compound of Formula III may be carried out in the presence of alkali metal halides, for example, sodium iodide.
  • the reaction of the compound of Formula II and the compound of Formula III may be carried out at a temperature of about 5°C to about 130°C, preferably at about 10°C to about 120°C.
  • the treatment of the compound of Formula II and the compound of Formula III may be carried out for about 1 hour to about 10 hours, preferably for about 2 hours to about 6 hours. This reaction mixture may be cooled to 30°C.
  • the reaction mixture obtained in step a) may be directly treated with hydrochloric acid without isolating vilazodone free base.
  • the hydrochloric acid may be diluted 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 may preferably be 2- propanol.
  • the treatment of the reaction mixture obtained in step a) with hydrochloric acid may be carried out at a temperature of about 10°C to about 100°C, preferably at about 25°C to about 80°C.
  • the treatment of the reaction mixture obtained in step a) with hydrochloric acid may be carried out for about 2 hours to about 25 hours, preferably for about 3 hours to about 20 hours.
  • the vilazodone hydrochloride of Formula I may be isolated by filtration, concentration, precipitation, cooling, centrifugation, decantation, or a combination thereof.
  • the vilazodone hydrochloride prepared by the present invention may be characterized using X-ray powder diffraction pattern (XRPD).
  • the reaction mixture was decanted and 2-propanol (100 mL) was added to the reaction mixture.
  • the reaction mixture was heated at 80°C for 60 minutes.
  • the reaction mixture was cooled to 30°C and stirred for 16 hours, filtered, and washed with 2-propanol (10 mL).
  • the solid obtained was dried in an air oven at 50°C to 55°C for 8 hours to obtain the title compound.

Abstract

The present invention relates to a process for the preparation of vilazodone hydrochloride without isolating vilazodone free base.

Description

PROCESS FOR THE PREPARATION OF VILAZODONE HYDROCHLORIDE
Field of the Invention
The present invention relates to a process for the preparation of vilazodone hydrochloride without isolating vilazodone free base.
Background of the Invention
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 I.
Figure imgf000002_0001
FORMULA I
Vilazodone hydrochloride is indicated for the treatment of major depressive disorder (MDD).
Processes for the preparation of vilazodone free base or its hydrochloride are described in U.S. Patent Nos. 5,532,241 and 7,834,020 and European Patent Nos. EP 0 648 767 and EP 1 397 357.
Summary of the Invention
The present inventors have developed a simple and efficient process for the preparation of vilazodone hydrochloride without isolating vilazodone free base.
Vilazodone hydrochloride obtained by the present process can be directly isolated from the reaction mixture obtained after reacting 3-(4-chlorobutyl)- lH-indole-5-carbonitrile of Formula II, 5-(piperazin- 1 -yl)- 1 -benzofuran-2-carboxamide of Formula III, and hydrochloric acid.
Detailed Description of the Invention
An aspect of the present invention provides a process for the preparation of vilazodone hydrochloride of Formula I,
Figure imgf000003_0001
FORMULA I
which comprises:
a) reacting 3-(4-chlorobutyl)-lH-indole-5-carbonitrile of Formula II
Figure imgf000003_0002
FORMULA II
with 5-(piperazin-l-yl)-l-benzofuran-2-carboxamide of Formula III;
Figure imgf000003_0003
FORMULA III
b) treating the reaction mixture obtained in step a) with hydrochloric acid; and c) isolating vilazodone hydrochloride of Formula I from the reaction mixture thereof.
The reaction of the compound of Formula II and the compound of Formula III may be carried out in the presence of a base and solvent.
The solvent used for the reaction of the compound of Formula II and the compound of Formula III may be selected from the group consisting of water, organic solvent, or a mixture thereof. Suitable organic solvents may be selected from the group consisting of alcohol, ketone, nitrile, amide, aromatic, aliphatic hydrocarbon, or dimethyl sulfoxide. Suitable alcoholic solvents may include methanol, 2-propanol, or 1 -propanol. Suitable nitrile solvents may include acetonitrile. Suitable amide solvents may include N- methylpyrrolidone, dimethylacetamide, and Ν,Ν-dimethylformamide. Suitable ketone solvents may include acetone or methyl isobutyl ketone. Suitable aromatic hydrocarbon solvents may include toluene. Preferable solvents may include N-methylpyrrolidone or N,N-dimethylformamide.
The base used for the reaction of the compound of Formula II and the compound of Formula III may be selected from organic or inorganic bases. Suitable organic bases may include tributylamine, triethylamine, diisopropylamine, diisopropylethylamine, 4- dimethylaminopyridine, pyrollidine, or N-methylmorpholine. A preferable organic base is tributylamine. Suitable inorganic bases may include hydroxides or carbonates and bicarbonates of alkali or alkaline metals. Suitable carbonates or bicarbonates of alkali or alkaline metals may include sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, or potassium bicarbonate. A preferable inorganic base is potassium carbonate. The treatment of the compound of Formula II and the compound of Formula III may be carried out in the presence of alkali metal halides, for example, sodium iodide.
The reaction of the compound of Formula II and the compound of Formula III may be carried out at a temperature of about 5°C to about 130°C, preferably at about 10°C to about 120°C. The treatment of the compound of Formula II and the compound of Formula III may be carried out for about 1 hour to about 10 hours, preferably for about 2 hours to about 6 hours. This reaction mixture may be cooled to 30°C.
The reaction mixture obtained in step a) may be directly treated with hydrochloric acid without isolating vilazodone free base. The hydrochloric acid may be diluted 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 may preferably be 2- propanol.
The treatment of the reaction mixture obtained in step a) with hydrochloric acid may be carried out at a temperature of about 10°C to about 100°C, preferably at about 25°C to about 80°C. The treatment of the reaction mixture obtained in step a) with hydrochloric acid may be carried out for about 2 hours to about 25 hours, preferably for about 3 hours to about 20 hours.
The vilazodone hydrochloride of Formula I may be isolated by filtration, concentration, precipitation, cooling, centrifugation, decantation, or a combination thereof.
The vilazodone hydrochloride prepared by the present invention may be characterized using X-ray powder diffraction pattern (XRPD).
In the following section, embodiments are described by way of examples to illustrate the process of invention. Several variants of these examples would be evident to persons ordinarily skilled in the art.
Example 1 : Preparation of Vilazodone Hydrochloride
5-(Piperazin-l-yl)-l-benzofuran-2-carboxamide (5 g) and 3-(4-chlorobutyl)-5- cyanoindole (5.22 g) were added to N-methylpyrrolidone (25 mL). The reaction mixture was heated to 1 10°C to 120°C for 2 hours. Tributylamine (3.77 g) was added to the reaction mixture at 1 10°C to 120°C, and the mixture was stirred for 6 hours. The reaction mixture was cooled to 30°C and 2-propanol (50 mL) was added to the reaction mixture. Concentrated hydrochloric acid (3.5 mL) was added to the reaction mixture, and it was stirred at 25°C to 30°C for 3 hours. The solid obtained was filtered, washed with 2- propanol (10 mL), and dried in a vacuum oven at 50°C to 55°C for 12 hours to obtain the title compound.
Yield: 6.1 g
Example 2: Preparation of Vilazodone Hydrochloride
5-(Piperazin-l-yl)-l-benzofuran-2-carboxamide (50 g) and 3-(4-chlorobutyl)-5- cyanoindole (52.3 g) were added to N-methylpyrrolidone (250 mL). The reaction mixture was heated to 80°C to 90°C for 2 hours. Tributylamine (3.77 g) was added to the reaction mixture at 80°C to 90°C and the mixture was stirred for 10 hours. The reaction mixture was cooled to 30°C and 2-propanol (500 mL) was added to the reaction mixture. 2- Propanolic hydrochloric acid (57 mL, 20% to 25% w/w) was added to the reaction mixture, and it was stirred at 25°C to 30°C for 3 hours. The solid obtained was filtered, washed with 2-propanol (50 mL x 4), and dried in an air oven at 50°C to 55°C for 12 hours to obtain the title compound.
Yield: 195 g (wet)
Example 3: Preparation of Vilazodone Hydrochloride
5-(Piperazin-l-yl)-l-benzofuran-2-carboxamide (5 g), 3-(4-chlorobutyl)-5- cyanoindole (5.22 g), and potassium carbonate (2.82 g) were added to N,N- dimethylformamide (25 mL) at 20°C to 30°C. The reaction mixture was heated to 1 10°C and stirred for 6 hours at 1 10°C to 1 12°C. The reaction mixture was cooled to 30°C, and water (100 mL) was added to it. Concentrated hydrochloric acid (4.2 ml) was added to the reaction mixture, and it was stirred at 25°C to 30°C. The reaction mixture was decanted and 2-propanol (100 mL) was added to the reaction mixture. The reaction mixture was heated at 80°C for 60 minutes. The reaction mixture was cooled to 30°C and stirred for 16 hours, filtered, and washed with 2-propanol (10 mL). The solid obtained was dried in an air oven at 50°C to 55°C for 8 hours to obtain the title compound.
Yield: 5.5 g

Claims

We Claim:
1. A process for the reparation of vilazodone hydrochloride of Formula I,
Figure imgf000007_0001
FORMULA I
which comprises:
a) reacting 3-(4-chlorobutyl)-lH-indole-5-carbonitrile of Formula II
Figure imgf000007_0002
FORMULA II
with 5-(piperazin-l-yl)-l-benzofuran-2-carboxamide of Formula III;
Figure imgf000007_0003
FORMULA III
treating the reaction mixture obtained in step a) with hydrochloric acid; and isolating vilazodone hydrochloride of Formula I from the reaction mixture thereof.
2. The process according to claim 1, wherein the reaction of the compound of Formula II and the compound of Formula III is carried out in the presence of a base and a solvent.
3. The process according to claim 2, wherein the solvent is selected from a group consisting of water, organic solvent, or a mixture thereof.
4. The process according to claim 3, wherein the organic solvent is selected from a group consisting of alcohol, ketone, nitrile, amide, aromatic, aliphatic hydrocarbon, or dimethyl sulfoxide.
5. The process according to claim 4, wherein alcoholic solvents are methanol, 2- propanol, or 1-propanol.
6. The process according to claim 4, wherein amide solvents are N- methylpyrrolidone, dimethylacetamide, and N,N-dimethylformamide.
7. The process according to claim 4, wherein ketone solvents are acetone or methyl isobutyl ketone.
8. The process according to claim 4, wherein the aromatic hydrocarbon solvent is toluene.
9. The process according to claim 2, wherein the solvents are N-methylpyrrolidone or N,N-dimethylformamide.
10. The process according to claim 2, wherein the base used for the reaction of the compound of Formula II and the compound of Formula III is selected from organic or inorganic bases.
11. The process according to claim 10, wherein the organic base is tributylamine, triethylamine, diisopropylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyrollidine, or N-methylmorpholine.
12. The process according to claim 10, wherein the inorganic base is hydroxides or carbonates or bicarbonates of alkali or alkaline metal.
13. The process according to claim 12, wherein carbonates or bicarbonates of alkali or alkaline metal are sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, or potassium bicarbonate.
14. The process according to claim 1, wherein the treatment of the compound of Formula II and the compound of Formula III is carried out in the presence of alkali metal halides.
15. The process according to claim 14, wherein the alkali metal halide is sodium iodide.
16. The process according to claim 1, wherein the reaction mixture obtained in step a) is directly treated with hydrochloric acid without isolating vilazodone free base.
17. The process according to claim 1, wherein the hydrochloric acid used in step b) is in an aqueous or alcoholic solvent.
18. The process according to claim 17, wherein the alcoholic solvent used for the preparation of hydrochloric acid solution is 2-propanol.
PCT/IB2013/054021 2012-05-24 2013-05-16 Process for the preparation of vilazodone hydrochloride WO2013175361A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITMI20131598A1 (en) * 2013-09-27 2015-03-28 Dipharma Francis Srl PROCEDURE FOR THE PREPARATION OF AN ACTIVE PHARMACEUTICAL PRINCIPLE IN AMORPHOUS FORM

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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.
EP0738722A1 (en) * 1995-04-20 1996-10-23 MERCK PATENT GmbH 5-Amino-benzofuran-2-carboxylic acid derivatives
EP1397357A2 (en) 2001-06-19 2004-03-17 MERCK PATENT GmbH Polymorphic forms of 1-'4-(5-cyanoindol-3-yl)butyl-4-(2-carbamoylbenzofuran-5-yl)piperazine hydrochloride
WO2006114202A1 (en) * 2005-04-26 2006-11-02 Merck Patent Gmbh Method for the production of 5-(4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl)-benzofuran-2-carboxamide

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Publication number Priority date Publication date Assignee Title
EP0648767A1 (en) 1993-09-30 1995-04-19 MERCK PATENT GmbH Piperdine and piperazine derivatives which affect the C.N.S.
US5532241A (en) 1993-09-30 1996-07-02 Merck Patent Gesellschaft Mit Beschrankter Haftung Piperidines and piperazines
EP0738722A1 (en) * 1995-04-20 1996-10-23 MERCK PATENT GmbH 5-Amino-benzofuran-2-carboxylic acid derivatives
EP1397357A2 (en) 2001-06-19 2004-03-17 MERCK PATENT GmbH Polymorphic forms of 1-'4-(5-cyanoindol-3-yl)butyl-4-(2-carbamoylbenzofuran-5-yl)piperazine hydrochloride
US7834020B2 (en) 2001-06-19 2010-11-16 Merck Patent Gesellschaft Polymorphic forms of 1-′4-(5-cyanoindol-3-yl)butyl-4-(2-carbamoylbenzofuran-5-yl) piperazine hydrochloride
WO2006114202A1 (en) * 2005-04-26 2006-11-02 Merck Patent Gmbh Method for the production of 5-(4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl)-benzofuran-2-carboxamide

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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
ITMI20131598A1 (en) * 2013-09-27 2015-03-28 Dipharma Francis Srl PROCEDURE FOR THE PREPARATION OF AN ACTIVE PHARMACEUTICAL PRINCIPLE IN AMORPHOUS FORM

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