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WO2013054273A2 - Process for the preparation of agomelatine - Google Patents

Process for the preparation of agomelatine Download PDF

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Publication number
WO2013054273A2
WO2013054273A2 PCT/IB2012/055485 IB2012055485W WO2013054273A2 WO 2013054273 A2 WO2013054273 A2 WO 2013054273A2 IB 2012055485 W IB2012055485 W IB 2012055485W WO 2013054273 A2 WO2013054273 A2 WO 2013054273A2
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Prior art keywords
formula
compound
methoxynaphthalen
agomelatine
ethanamine
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PCT/IB2012/055485
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French (fr)
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WO2013054273A9 (en
WO2013054273A3 (en
Inventor
Anu Mittal
Mahavir Singh Khanna
Rajesh Kumar Thaper
Mohan Prasad
Sudershan Kumar Arora
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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Publication of WO2013054273A3 publication Critical patent/WO2013054273A3/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/08—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated
    • C07C247/10—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being unsaturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention provides a process for the preparation of agomelatine and its intermediate compounds.
  • the invention also provides intermediate compounds of agomelatine, represented by Formula IV, Formula V and Formula VIII.
  • Agomelatine is chemically known as N-[2-(7-methoxynaphthalen-l- yl)ethyl]acetamide. It is indicated for the treatment of major depressive episodes in adults and is represented by Formula I.
  • Agomelatine and its preparation are disclosed in U.S. Patent No. 5,225,442.
  • the preparation comprises converting (7-methoxy- l-naphthyl)acetic acid to (7-methoxy- 1 - naphthyl)ethanamine via preparation of (7-methoxy- l-naphthyl)acetamide or (7-methoxy- 1 -naphthyl)acetonitrile intermediate compounds.
  • 2010/0137628 and 2010/0036161 describe a process for the preparation of agomelatine comprising reduction of (7-methoxy- 1 -naphthyl)acetonitrile into (7-methoxy- 1 - naphthyl)ethylamine followed by an acetylation step.
  • U.S. Publication No. 201 1/0130571 describes a process for the preparation of agomelatine comprising reacting 7-methoxy- 1 -naphthyl ethanol with benzenesulfonyl chloride to obtain 7-methoxy- l-naphthylethyl benzene sulfonate and condensing it with potassium phthalimide, followed by sequential hydrolysis and acetylation steps.
  • the present invention provides an alternate process for the preparation of agomelatine and its intermediate compounds.
  • the present invention provides a process for the preparation of agomelatine using 2-(7-methoxynaphthalen- 1 -yl)ethyl 4-nitrobenzene sulfonate (Formula IV), l-[2-(7- methoxynaphthalen-l-yl)ethyl]-2 ⁇ 5 -triaz- l-en-2-yne (Formula V) and the carbon dioxide adduct of 2-(7-methoxynaphthalen- 1 -yl)ethanamine (Formula VIII) as intermediate compounds.
  • the present invention is also directed towards compounds of Formula IV, Formula V and Formula VIII. Brief Description of the Drawing
  • Figure 1 depicts the X-ray powder diffraction pattern of the crystalline adduct of Formula VIII recorded on a PANalytical X'pert Pro instrument. The measurements were done using CuK a radiation at 45kV.
  • organic solvent is meant to comprise polar solvent (for example, dichloromethane, methanol, tetrahydrofuran, dimethylformamide, ethyl acetate, etc.) and/or non-polar solvents (for example, cyclohexane, diethyl ether, toluene, etc.).
  • polar solvent for example, dichloromethane, methanol, tetrahydrofuran, dimethylformamide, ethyl acetate, etc.
  • non-polar solvents for example, cyclohexane, diethyl ether, toluene, etc.
  • organic solvents are dichloromethane, ethyl acetate, butyl acetate, dichloroethane, tetrahydrofuran, acetonitrile, acetone, cyclohexane, toluene, chloroform, 1 ,4-dioxane, dimethylsulfoxide, dimethylformamide, methanol, ethanol, propanol and/or butanol.
  • base is meant to comprise organic bases (for example, pyridine, triethylamine, etc.) and/or inorganic bases (for example, sodium hydride, ammonium hydroxide, sodium carbonate, etc.).
  • organic bases for example, pyridine, triethylamine, etc.
  • inorganic bases for example, sodium hydride, ammonium hydroxide, sodium carbonate, etc.
  • bases are sodium hydroxide, potassium hydroxide, magnesium hydroxide, dipotassium hydrogen orthophosphate, magnesium carbonate, sodium carbonate, potassium carbonate, pyridine, trimethylamine, triethylamine, diisopropylethylamine and/or N-methyl morpholine.
  • a first aspect of the present invention provides a process for the preparation of agomelatine wherein the process comprises converting a carbon dioxide adduct of 2-(7- methoxynaphthalen- 1 -yl)ethanamine (Formula VIII) into agomelatine.
  • the carbon dioxide adduct (Formula VIII) is acetylated to obtain agomelatine.
  • the adduct compound of Formula VIII can be acetylated using acetyl chloride or acetic anhydride.
  • the compound of Formula VIII is acetylated using acetic anhydride in the presence of methanol to obtain agomelatine.
  • a second aspect of the present invention provides a process for the preparation of agomelatine comprising a step of converting l-[2-(7-methoxynaphthalen- l-yl)ethyl] ⁇ 5 - triaz-l-en-2-yne (Formula V)
  • the conversion of the compound of Formula V into the compound of Formula VIII can be performed with or without isolating the 2-(7- methoxynaphthalen- 1 -yl)ethanamine intermediate compound of Formula VII.
  • the conversion of the compound of Formula V into the compound of Formula VIII can be performed without isolating the 2-(7- methoxynaphthalen- 1 -yl)ethanamine intermediate compound of Formula VII.
  • the compound of Formula V is converted to the compound of Formula VIII by reducing the compound of Formula V, followed then treating the reduced product with carbon dioxide.
  • the reduced product is 2-(7- methoxynaphthalen- 1 -yl)ethanamine of Formula VII.
  • the compound of Formula V is reduced and then treated with carbon dioxide to obtain an adduct compound of Formula VIII which is acetylated to get agomelatine.
  • the reduction of the compound of Formula V can be performed using hydrogen gas in the presence of a reduction catalyst.
  • the reduction catalyst can be platinum, palladium, rhodium and/or Raney nickel.
  • the reduction can be carried out at a temperature range of about 10°C to about 70°C.
  • the hydrogen pressure can be in the range of about 1.0 kg/cm 2 to about 3.0 kg/cm 2 .
  • the compound of Formula VII (reduction product), if isolated or in concentrated form (wet), can be dissolved in non-polar solvent and then treated with carbon dioxide to obtain the adduct compound of Formula VIII.
  • the obtained adduct can be converted into agomelatine by following the process described hereinabove in the first aspect of the present invention.
  • a third aspect of the present invention provides a process for the preparation of agomelatine comprising a step of converting 2-(7-methoxynaphthalen- 1 -yl)ethyl 4- nitrobenzene sulfonate of Formula IV
  • the compound of Formula IV is converted to the compound of Formula V by treatment of the compound of Formula IV with an azide salt.
  • the azide salt can be selected from the group comprised of sodium azide, silver azide and phenyl azide.
  • the compound of Formula IV is treated with sodium azide to obtain the compound of Formula V, which is reduced, then treated with carbon dioxide to provide an adduct compound of Formula VIII. This adduct is then acetylated to obtain agomelatine.
  • the compound of Formula V can be converted into the carbon dioxide adduct of Formula VIII by following the process described hereinabove in the second aspect of the present invention.
  • the obtained adduct (Formula VIII) can be converted into agomelatine by following the process described hereinabove in the first aspect of the present invention.
  • a fourth aspect of the present invention provides a process for the preparation of agomelatine comprising the steps of: (a) reacting (7-methoxy- 1 -naphthyl)ethanol of Formula III
  • step (b) converting the compound of Formula IV obtained in step (a) into
  • the compound of Formula III is reacted with 4-nitrobenzene sulfonyl chloride in the presence of a base and an organic solvent.
  • the base used is triethylamine.
  • the organic solvent is dichloromethane.
  • the conversion of the compound of Formula IV into agomelatine can be performed via preparation of l-[2-(7-methoxynaphthalen-l-yl)ethyl]- 2 ⁇ 5 - ⁇ 3 ⁇ - 1 -en-2-yne (Formula V), 2-(7-methoxynaphthalen- 1 -yl)ethanamine (Formula VII), and/or a carbon dioxide adduct of 2-(7-methoxynaphthalen- 1 -yl)ethanamine (Formula VIII) intermediate compounds.
  • the compound of Formula IV can be converted into the compound of Formula V by following the process described hereinabove in the third aspect of the present invention.
  • the compound of Formula V can be converted into the carbon dioxide adduct of Formula VIII by following the process described hereinabove in the second aspect of the present invention.
  • the obtained adduct (Formula VIII) can be converted into agomelatine by following the process described hereinabove in the first aspect of the present invention.
  • a fifth aspect of the present invention provides 2-(7-methoxynaphthalen- 1 -yl)ethyl 4-nitrobenzene sulfonate compound of Formula IV.
  • the compound of Formula IV can be used as an intermediate for the preparation of agomelatine.
  • the compound of Formula IV can be used to prepare agomelatine described hereinabove in the third aspect of the present invention.
  • a sixth aspect of the present invention provides l-[2-(7-methoxynaphthalen-l- yl)ethyl]-2 ⁇ 5 -triaz-l-en-2-yne compound of Formula V.
  • the compound of Formula V can be used as an intermediate for the preparation of agomelatine.
  • the compound of Formula V can be used to prepare agomelatine as described hereinabove in the second aspect of the present invention.
  • a seventh aspect of the present invention provides a carbon dioxide adduct of 2-(7- methoxynaphthalen-l-yl)ethanamine represented by Formula VIII.
  • the compound of Formula VIII can be used as an intermediate for the preparation of agomelatine.
  • the compound of Formula V can be used to prepare agomelatine as described hereinabove in the first aspect of the present invention.
  • compound of Formula VIII can be crystalline.
  • the crystalline adduct of Formula VIII can be any suitable adduct of Formula VIII.
  • the crystalline adduct of Formula VIII can be any suitable adduct of Formula VIII.
  • the starting material (7-methoxy- l-naphthyl)ethanol, as used herein, in this invention can be prepared by treating 7-methoxy- 1 -naphthyl acetic acid represented by Formula II with lithium aluminum hydride in the presence of tetrahydrofuran.
  • the 7-methoxy- l-naphthyl acetic acid of Formula II can be prepared by any method known in the art, for example, by following the process described in U.S. Patent No. 5,225,442.
  • XRPD X-ray powder diffractograms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention provides a process for the preparation of agomelatine and its intermediate compounds. The invention also provides intermediate compounds of agomelatine represented by Formula IV, Formula V and Formula VIII. Formula IV Formula V Formula VIII

Description

PROCESS FOR THE PREPARATION OF AGOMELATINE
Field of the Invention
The present invention provides a process for the preparation of agomelatine and its intermediate compounds. The invention also provides intermediate compounds of agomelatine, represented by Formula IV, Formula V and Formula VIII.
Figure imgf000002_0001
Formula IV
Figure imgf000002_0002
Formula V Formula VIII
Background of the Invention
Agomelatine is chemically known as N-[2-(7-methoxynaphthalen-l- yl)ethyl]acetamide. It is indicated for the treatment of major depressive episodes in adults and is represented by Formula I.
Figure imgf000002_0003
Formula I
Agomelatine and its preparation are disclosed in U.S. Patent No. 5,225,442. The preparation comprises converting (7-methoxy- l-naphthyl)acetic acid to (7-methoxy- 1 - naphthyl)ethanamine via preparation of (7-methoxy- l-naphthyl)acetamide or (7-methoxy- 1 -naphthyl)acetonitrile intermediate compounds. U.S. Patent Nos. 7,476,751 ; 7,479,569; and 7,470,806 and U.S. Publication Nos. 2010/0137628 and 2010/0036161 describe a process for the preparation of agomelatine comprising reduction of (7-methoxy- 1 -naphthyl)acetonitrile into (7-methoxy- 1 - naphthyl)ethylamine followed by an acetylation step.
U.S. Publication No. 201 1/0130571 describes a process for the preparation of agomelatine comprising reacting 7-methoxy- 1 -naphthyl ethanol with benzenesulfonyl chloride to obtain 7-methoxy- l-naphthylethyl benzene sulfonate and condensing it with potassium phthalimide, followed by sequential hydrolysis and acetylation steps.
The present invention provides an alternate process for the preparation of agomelatine and its intermediate compounds.
Summary of the Invention
The present invention provides a process for the preparation of agomelatine using 2-(7-methoxynaphthalen- 1 -yl)ethyl 4-nitrobenzene sulfonate (Formula IV), l-[2-(7- methoxynaphthalen-l-yl)ethyl]-2λ5-triaz- l-en-2-yne (Formula V) and the carbon dioxide adduct of 2-(7-methoxynaphthalen- 1 -yl)ethanamine (Formula VIII) as intermediate compounds.
Figure imgf000003_0001
Formula V Formula VIII
The present invention is also directed towards compounds of Formula IV, Formula V and Formula VIII. Brief Description of the Drawing
Figure 1 depicts the X-ray powder diffraction pattern of the crystalline adduct of Formula VIII recorded on a PANalytical X'pert Pro instrument. The measurements were done using CuKa radiation at 45kV.
Detailed Description of the Invention
The term "organic solvent", as employed herein, is meant to comprise polar solvent (for example, dichloromethane, methanol, tetrahydrofuran, dimethylformamide, ethyl acetate, etc.) and/or non-polar solvents (for example, cyclohexane, diethyl ether, toluene, etc.). Some non- limiting examples of "organic solvents" are dichloromethane, ethyl acetate, butyl acetate, dichloroethane, tetrahydrofuran, acetonitrile, acetone, cyclohexane, toluene, chloroform, 1 ,4-dioxane, dimethylsulfoxide, dimethylformamide, methanol, ethanol, propanol and/or butanol.
The term "base", as employed herein, is meant to comprise organic bases (for example, pyridine, triethylamine, etc.) and/or inorganic bases (for example, sodium hydride, ammonium hydroxide, sodium carbonate, etc.). Some non- limiting examples of "base" are sodium hydroxide, potassium hydroxide, magnesium hydroxide, dipotassium hydrogen orthophosphate, magnesium carbonate, sodium carbonate, potassium carbonate, pyridine, trimethylamine, triethylamine, diisopropylethylamine and/or N-methyl morpholine.
The term "about", as employed herein, when used with values assigned to certain measurements and parameters means a variation of 10% from such values, or in the case of a range of values, means a 10% variation from both the lower and upper limits of such ranges.
The present invention can be explained by way of the following aspects.
A first aspect of the present invention provides a process for the preparation of agomelatine wherein the process comprises converting a carbon dioxide adduct of 2-(7- methoxynaphthalen- 1 -yl)ethanamine (Formula VIII) into agomelatine.
Figure imgf000005_0001
Formula VIII
In an embodiment of this aspect, the carbon dioxide adduct (Formula VIII) is acetylated to obtain agomelatine.
In another embodiment, the adduct compound of Formula VIII can be acetylated using acetyl chloride or acetic anhydride.
Accordingly, the compound of Formula VIII is acetylated using acetic anhydride in the presence of methanol to obtain agomelatine.
A second aspect of the present invention provides a process for the preparation of agomelatine comprising a step of converting l-[2-(7-methoxynaphthalen- l-yl)ethyl]^5- triaz-l-en-2-yne (Formula V)
Figure imgf000005_0002
Formula V
into a carbon dioxide adduct of 2-(7-methoxynaphthalen-l-yl)ethanamine (Formula VIII).
Figure imgf000005_0003
Formula VIII
In an embodiment of this aspect, the conversion of the compound of Formula V into the compound of Formula VIII can be performed with or without isolating the 2-(7- methoxynaphthalen- 1 -yl)ethanamine intermediate compound of Formula VII.
Figure imgf000006_0001
Formula VII
In an another embodiment, the conversion of the compound of Formula V into the compound of Formula VIII can be performed without isolating the 2-(7- methoxynaphthalen- 1 -yl)ethanamine intermediate compound of Formula VII.
In an another embodiment, the compound of Formula V is converted to the compound of Formula VIII by reducing the compound of Formula V, followed then treating the reduced product with carbon dioxide.
In an another embodiment of this aspect, the reduced product is 2-(7- methoxynaphthalen- 1 -yl)ethanamine of Formula VII.
Accordingly, the compound of Formula V is reduced and then treated with carbon dioxide to obtain an adduct compound of Formula VIII which is acetylated to get agomelatine.
The reduction of the compound of Formula V can be performed using hydrogen gas in the presence of a reduction catalyst. The reduction catalyst can be platinum, palladium, rhodium and/or Raney nickel. The reduction can be carried out at a temperature range of about 10°C to about 70°C. The hydrogen pressure can be in the range of about 1.0 kg/cm2 to about 3.0 kg/cm2.
The compound of Formula VII (reduction product), if isolated or in concentrated form (wet), can be dissolved in non-polar solvent and then treated with carbon dioxide to obtain the adduct compound of Formula VIII.
The obtained adduct can be converted into agomelatine by following the process described hereinabove in the first aspect of the present invention.
A third aspect of the present invention provides a process for the preparation of agomelatine comprising a step of converting 2-(7-methoxynaphthalen- 1 -yl)ethyl 4- nitrobenzene sulfonate of Formula IV
Figure imgf000007_0001
Formula IV
into l-[2-(7-methoxyna hthalen-l-yl)ethyl]-2λ5-triaz-l-en-2-yne of Formula V.
Figure imgf000007_0002
Formula V
In an embodiment of this aspect, the compound of Formula IV is converted to the compound of Formula V by treatment of the compound of Formula IV with an azide salt.
In another embodiment of this aspect, the azide salt can be selected from the group comprised of sodium azide, silver azide and phenyl azide.
Accordingly, the compound of Formula IV is treated with sodium azide to obtain the compound of Formula V, which is reduced, then treated with carbon dioxide to provide an adduct compound of Formula VIII. This adduct is then acetylated to obtain agomelatine.
The compound of Formula V can be converted into the carbon dioxide adduct of Formula VIII by following the process described hereinabove in the second aspect of the present invention.
The obtained adduct (Formula VIII) can be converted into agomelatine by following the process described hereinabove in the first aspect of the present invention.
A fourth aspect of the present invention provides a process for the preparation of agomelatine comprising the steps of: (a) reacting (7-methoxy- 1 -naphthyl)ethanol of Formula III
Figure imgf000008_0001
Formula III
with 4-nitrobenzene sulfonyl chloride to obtain 2-(7-methoxynaphthalen- 1 - yl)ethyl 4-nitrobenzene sulfonate of Formula IV; and
Figure imgf000008_0002
Formula IV
(b) converting the compound of Formula IV obtained in step (a) into
agomelatine.
In one embodiment, the compound of Formula III is reacted with 4-nitrobenzene sulfonyl chloride in the presence of a base and an organic solvent.
In another embodiment, the base used is triethylamine.
In another embodiment, the organic solvent is dichloromethane.
In another embodiment, the conversion of the compound of Formula IV into agomelatine can be performed via preparation of l-[2-(7-methoxynaphthalen-l-yl)ethyl]- 2λ5-ίΠ3ζ- 1 -en-2-yne (Formula V), 2-(7-methoxynaphthalen- 1 -yl)ethanamine (Formula VII), and/or a carbon dioxide adduct of 2-(7-methoxynaphthalen- 1 -yl)ethanamine (Formula VIII) intermediate compounds.
Accordingly, (7-methoxy- l-naphthyl)ethanol (Formula III) is reacted with 4- nitrobenzene sulfonyl chloride in the presence of triethylamine and dichloromethane to obtain 2-(7-methoxynaphthalen- 1 -yl)ethyl 4-nitrobenzene sulfonate (Formula IV). This compound is then reacted with sodium azide to get l-[2-(7-methoxynaphthalen-l- yl)ethyl]-2λ5-triaz-l-en-2-yne (Formula V) which, upon sequential reduction and carbon dioxide treatment, gives a carbon dioxide adduct of 2-(7-methoxynaphthalen- l- yl)ethanamine (Formula VIII). This adduct is then acetylated to obtain agomelatine.
The compound of Formula IV can be converted into the compound of Formula V by following the process described hereinabove in the third aspect of the present invention.
The compound of Formula V can be converted into the carbon dioxide adduct of Formula VIII by following the process described hereinabove in the second aspect of the present invention.
The obtained adduct (Formula VIII) can be converted into agomelatine by following the process described hereinabove in the first aspect of the present invention.
A fifth aspect of the present invention provides 2-(7-methoxynaphthalen- 1 -yl)ethyl 4-nitrobenzene sulfonate compound of Formula IV.
Figure imgf000009_0001
Formula IV
embodiment, the compound of Formula IV can be used as an intermediate for the preparation of agomelatine.
Accordingly, the compound of Formula IV can be used to prepare agomelatine described hereinabove in the third aspect of the present invention.
A sixth aspect of the present invention provides l-[2-(7-methoxynaphthalen-l- yl)ethyl]-2λ5-triaz-l-en-2-yne compound of Formula V.
Figure imgf000009_0002
Formula V In an embodiment, the compound of Formula V can be used as an intermediate for the preparation of agomelatine.
Accordingly, the compound of Formula V can be used to prepare agomelatine as described hereinabove in the second aspect of the present invention.
A seventh aspect of the present invention provides a carbon dioxide adduct of 2-(7- methoxynaphthalen-l-yl)ethanamine represented by Formula VIII.
Figure imgf000010_0001
Formula VIII
In one embodiment, the compound of Formula VIII can be used as an intermediate for the preparation of agomelatine.
Accordingly, the compound of Formula V can be used to prepare agomelatine as described hereinabove in the first aspect of the present invention.
In another embodiment, compound of Formula VIII can be crystalline.
In another embodiment, the crystalline adduct of Formula VIII can be
characterized by X-ray powder diffraction peaks (expressed in degrees 2Θ) at about 10.07, 15.14, 16.03, 16.80, 17.36, 19.01, 20.29, 22.06, 22.72, 24.43, 25.89, 26.70, and 26.97 (± 0.2°) 2Θ.
In another embodiment, the crystalline adduct of Formula VIII can be
characterized by the X-ray powder diffraction pattern depicted in Figure 1.
The starting material (7-methoxy- l-naphthyl)ethanol, as used herein, in this invention can be prepared by treating 7-methoxy- 1 -naphthyl acetic acid represented by Formula II with lithium aluminum hydride in the presence of tetrahydrofuran.
Figure imgf000011_0001
Formula II
The 7-methoxy- l-naphthyl acetic acid of Formula II can be prepared by any method known in the art, for example, by following the process described in U.S. Patent No. 5,225,442.
While the present invention has been described in terms of its specific aspects, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be within the scope of the present invention.
In the following section, aspects are described by way of examples to illustrate the processes of the invention. However, these are not intended in any way to limit the scope of the present invention. Several variants of these examples would be evident to persons ordinarily skilled in the art.
EXAMPLES
Example 1 : Preparation of (7-Methoxy- l-Naphthyl)Ethanol
Figure imgf000011_0002
Formula III
To a solution of 7-methoxy- 1 -naphthyl acetic acid (Formula II, 60 g) in tetrahydrofuran (240 mL), a suspension of lithium aluminum hydride (16.8 g) in tetrahydrofuran (1500 mL) was slowly added over a period of 15 minutes to 20 minutes at 0°C. The reaction mixture was stirred for 4 hours at 25°C to 30°C. After completion of the reaction, ethyl acetate (120 mL) was added, followed by the slow addition of 5N hydrochloric acid (100 mL) over a period of 30 minutes at 0°C. The reaction mixture was stirred and the layers were allowed to settle. The organic layer was separated and removed under vacuum (40°C to 45°C, -100 mbar). The residue so obtained was used for the next step.
Example 2: Preparation of 2-(7-Methoxynaphthalen- 1 -Yl)Ethyl 4-Nitrobenzene Sulfonate
Figure imgf000012_0001
Formula IV
To a mixture of (7-methoxy- 1 -naphthyl)ethanol (Formula III, obtained in Example 1), triethyl amine (55 g), dichloromethane (550 mL), and 4-nitrobenzene sulfonyl chloride (72.3 g) were added in small lots at 0°C. The reaction mixture was stirred and heated to 25°C to 30°C. After completion of the reaction, 2.5% sodium hydroxide solution (200 mL) was added at 25°C to 30°C. The reaction mixture was stirred and the product was extracted with the addition of dichloromethane (550 mL). The organic layer was concentrated under vacuum. The residue so obtained was stirred in toluene (165 mL) and then in methanol (165 mL) for 30 minutes. This was filtered and the product obtained was dried under vacuum (5-10 mbar) at 45°C to 50°C.
Yield (w/w): 83%
Example 3: Preparation of l-Γ2- 7-Methoxynaphthalen-l-Yl Ethyl1-2λ5-Triaz-l-En-2-Yne
Figure imgf000012_0002
Formula V
A mixture of 2-(7-methoxynaphthalen-l-yl)ethyl 4-nitrobenzene sulfonate (Formula IV, obtained as per Example 2, 2 g) and sodium azide (0.4 g) were stirred in dimethylformamide (10 mL) at 30°C to 35°C. The reaction was monitored and after its completion, the product was extracted with diethyl ether (20 mL). The solvent was recovered to obtain the title product.
Yield (w/w): 79%
Example 4: Preparation of 2-(7-Methoxynaphthalen- 1 -Yl)Ethanamine Carbon Dioxide Adduct
Figure imgf000013_0001
Formula VIII
A solution of l-[2-(7-methoxynaphthalen-l-yl)ethyl]-2λ5-triaz-l-en-2-yne (Formula V, obtained as per Example 3, 1 g) in methanol (10 mL) was treated with hydrogen gas (2 Kg/cm2) in the presence of Raney nickel (1.0 g) at 40°C. After completion of the reaction, the reaction mixture was filtered through Hyflo®. The filtrate was concentrated under vacuum (50°C to 55°C, 200-210 mbar) and the residue was obtained. A solution of the residue in toluene (15 mL) was purged with carbon dioxide gas (for at least 2 hours) at 10°C to 15°C. The solid so obtained was filtered and dried under vacuum (5-10 mbar) at 30°C over 10 hours to 15 hours.
Yield (w/w): 87%
Example 4(A): Preparation of 2-(7-Methoxynaphthalen- 1 -YDEthanamine Carbon Dioxide Adduct
Figure imgf000013_0002
Formula VIII
A solution of (7-methoxynaphthalen- 1 -yl)acetonitrile (5 g) in methanol (20 mL) and aqueous ammonia (10 mL) was treated with hydrogen gas (2 Kg) in the presence of Raney nickel (2.5 g) at 40°C. After completion of the reaction, the reaction mixture was filtered through Hyflo®. The filtrate was concentrated under vacuum to obtain a residue. The residue was dissolved in toluene (30 mL), and was purged with carbon dioxide gas (for at least 4 hours to 5 hours) at 10°C to 15°C to obtain a solid. The solid was dried under vacuum at 30°C to 35°C for 10 hours to 15 hours.
Yield (w/w): 81%
Mass = 202.4 (M+l)
!H NMR (CDC13): 2.31 (bs, NH2), 3.10-3.13 (m, 2H), 3.17-3.20 (m, 2H), 3.92 (s, 3H), 7.15 (dd, 1H), 7.20-7.32 (m, 3H), 7.65 (d, 1H), 7.75 (d, 1H)
XRD (degrees 2Θ) = 5.00, 10.07, 14.30, 15.14, 16.03, 16.80, 17.36, 18.08, 19.01, 20.29, 22.06, 22.72, 22.99, 24.43, 25.89, 26.70, 26.97, 28.92, 35.83 and 38.37 (± 0.2°) 2Θ
The X-ray powder diffractograms (XRPD) were recorded on a PANalytical X'pert Pro instrument. The measurements were done using CuKa radiation at 45kV.
Example 5: Preparation of Agomelatine
Figure imgf000014_0001
Formula I
To a mixture of 2-(7-methoxynaphthalen-l-yl)ethanamine carbon dioxide adduct (Formula VIII, obtained as per Example 4, 0.6 g) and sodium acetate (0.24 g) in methanol (9 mL), acetic anhydride (0.3 g) was added drop-wise. The reaction mixture was heated to reflux temperature and stirred for 1 to 2 hours. After completion of the reaction, the reaction mixture was cooled to 30°C to 35°C. Ice (18 g) was added to the reaction mixture and stirred for another 2 hours at 10°C to 15°C. The solid product was filtered and dried under vacuum (5-10 mbar) at 45°C to 50°C over a time period of 10 to 15 hours to get the title product.
Yield (w/w): 91%

Claims

Claims:
1. A process for the preparation of agomelatine wherein the process comprises converting a carbon dioxide adduct of 2-(7-methoxynaphthalen- 1 -yl)ethanamine (Formula VIII) into agomelatine.
Figure imgf000015_0001
Formula VIII
2. The process of claim 1, wherein the carbon dioxide adduct is acetylated to obtain agomelatine.
3. The process of claim 2, wherein the carbon dioxide adduct is acetylated using acetyl chloride or acetic anhydride.
4. A process for the preparation of agomelatine comprising a step of converting l-[2- (7-methoxynaphthalen- 1 -yl)ethyl]^5-triaz- 1 -en-2-yne (Formula V)
Figure imgf000015_0002
Formula V
into a carbon dioxide adduct of 2-(7-methoxynaphthalen-l-yl)ethanamine (Formula VIII).
Figure imgf000015_0003
Formula VIII
5. The process of claim 4, wherein the conversion of the compound of Formula V into the compound of Formula VIII can be performed with or without isolating a 2-(7- methoxynaphthalen- 1 -yl)ethanamine intermediate compound of Formula VII.
Figure imgf000016_0001
Formula VII
6. The process of claim 4, wherein the conversion of the compound of Formula V into the compound of Formula VIII can be performed without isolating a 2-(7- methoxynaphthalen- 1 -yl)ethanamine intermediate compound of Formula VII.
7. The process of claim 4, wherein the compound of Formula V is converted to the compound of Formula VIII by reducing the compound of Formula V then treating the reduced product with carbon dioxide.
8. The process of claim 7, wherein the reduced product is 2-(7 -methoxynaphthalen- 1 - yl)ethanamine of Formula VII.
9. The process of claim 7, wherein the compound of Formula VIII is further converted into agomelatine.
10. A process for the preparation of agomelatine comprising a step of converting 2-(7- methoxynaphthalen- 1-yl) ethyl 4-nitrobenzene sulfonate of Formula IV
Figure imgf000016_0002
Formula IV
into l-[2-(7-methoxynaphthalen-l-yl)ethyl]-2λ5-triaz-l-en-2-yne of Formula V.
Figure imgf000016_0003
Formula V
1 1. The process of claim 10, wherein the compound of Formula IV is converted to the compound of Formula V by treatment of the compound of Formula IV with an azide salt.
12. The process of claim 1 1, wherein an azide salt is selected from the group comprised of sodium azide, silver azide and phenyl azide.
13. The process of claim 11, wherein the compound of Formula V is further converted to agomelatine.
14. A process for the preparation of agomelatine comprising the steps of:
a) reacting (7-methoxy- 1 -naphthyl)ethanol (Formula III)
Figure imgf000017_0001
Formula III
with 4-nitrobenzene sulfonyl chloride to obtain 2-(7-methoxynaphthalen- 1 - yl)ethyl 4-nitrobenzene sulfonate of Formula IV; and
Figure imgf000017_0002
Formula IV
b) converting the compound of Formula IV obtained in step a) into agomelatine.
15. The process of claim 14, wherein the compound of Formula III is reacted with 4- nitrobenzene sulfonyl chloride in the presence of a base and an organic solvent.
16. The process of claim 15, wherein the base used is triethylamine.
17. The process of claim 15, wherein the organic solvent is dichloromethane.
18. The process of claim 14, wherein the conversion of the compound of Formula IV into agomelatine can be performed via preparation of 1 -[2-(7-methoxynaphthalen- 1 - yl)ethyl]-2λ5-triaz- l-en-2-yne (Formula V), 2-(7-methoxynaphthalen- l-yl)ethanamine (Formula VII), and/or a carbon dioxide adduct of 2-(7-methoxynaphthalen- l- yl)ethanamine (Formula VIII) intermediate compounds.
19. A compound 2-(7-methoxynaphthalen- 1 -yl)ethyl 4-nitrobenzene sulfonate represented by Formula IV.
Figure imgf000018_0001
Formula IV
20. A compound 1-[2-(7^εί1ιοχ3Τΐ3ρ1ιί1ΐ3ΐ6η-1^1)6^1]-2λ5-ίΠ3ζ-1-6η-2-3Τΐ6 represented by Formula V.
Figure imgf000018_0002
Formula V
21. A compound carbon dioxide adduct of 2-(7-methoxynaphthalen- 1 -yl)ethanamine represented by Formula VIII.
Figure imgf000018_0003
Formula VIII
22. The compound of claim 21 in crystalline form.
23. The compound of claim 22, characterized by having X-ray powder diffraction peaks (expressed in degrees 2Θ) at 10.07, 15.14, 16.03, 16.80, 17.36, 19.01, 20.29, 22.06, 22.72, 24.43, 25.89, 26.70, and 26.97 (± 0.2°) 2Θ.
24. The compound of claim 22, characterized by having an X-ray powder diffraction pattern as depicted in Figure 1.
PCT/IB2012/055485 2011-10-11 2012-10-10 Process for the preparation of agomelatine Ceased WO2013054273A2 (en)

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CN110141935A (en) * 2019-05-13 2019-08-20 华侨大学 A functionalized ionic liquid phase change system for carbon dioxide capture and its application

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US7470806B2 (en) 2004-02-13 2008-12-30 Les Laboratories Servier Process for the synthesis of (7-methoxy-1-naphthyl) acetonitrile and its application in the synthesis of agomelatine
US7476751B2 (en) 2004-02-13 2009-01-13 Les Laboratoires Servier Process for the synthesis of (7-methoxy-1-naphthyl)acetonitrile and its application in the synthesis of agomelatine
US7479569B2 (en) 2004-02-13 2009-01-20 Les Laboratoires Servier Process for the synthesis of (7-methoxy-3,4-dihydro-1-naphthalenyl) acetonitrile and its application in the synthesis of agomelatine
US20100036161A1 (en) 2008-08-05 2010-02-11 Les Laboratoires Servier Process for the synthesis of agomelatine
US20100137628A1 (en) 2007-08-03 2010-06-03 Les Laboratoires Servier Process for the synthesis of (methoxy-1-naphthyl) acetonitrile and application in the synthesis of agomelatine
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US7470806B2 (en) 2004-02-13 2008-12-30 Les Laboratories Servier Process for the synthesis of (7-methoxy-1-naphthyl) acetonitrile and its application in the synthesis of agomelatine
US7476751B2 (en) 2004-02-13 2009-01-13 Les Laboratoires Servier Process for the synthesis of (7-methoxy-1-naphthyl)acetonitrile and its application in the synthesis of agomelatine
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US20100137628A1 (en) 2007-08-03 2010-06-03 Les Laboratoires Servier Process for the synthesis of (methoxy-1-naphthyl) acetonitrile and application in the synthesis of agomelatine
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110141935A (en) * 2019-05-13 2019-08-20 华侨大学 A functionalized ionic liquid phase change system for carbon dioxide capture and its application
CN110141935B (en) * 2019-05-13 2021-06-01 华侨大学 A functionalized ionic liquid phase change system for carbon dioxide capture and its application

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