WO2012127483A1 - Procédés pour la préparation d'intermédiaires de n-[2-(7-méthoxy-1-naphtyl)éthyl]acétamide - Google Patents

Procédés pour la préparation d'intermédiaires de n-[2-(7-méthoxy-1-naphtyl)éthyl]acétamide Download PDF

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Publication number
WO2012127483A1
WO2012127483A1 PCT/IN2011/000203 IN2011000203W WO2012127483A1 WO 2012127483 A1 WO2012127483 A1 WO 2012127483A1 IN 2011000203 W IN2011000203 W IN 2011000203W WO 2012127483 A1 WO2012127483 A1 WO 2012127483A1
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Prior art keywords
formula
compound
solvents
naphthyl
methoxy
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PCT/IN2011/000203
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English (en)
Inventor
Dodda Mohan Rao
Pingili Krishna Reddy
Ambati Anna Reddy
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Symed Labs Ltd
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Symed Labs Ltd
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Priority to PCT/IN2011/000203 priority Critical patent/WO2012127483A1/fr
Priority to ARP110104215A priority patent/AR083841A1/es
Publication of WO2012127483A1 publication Critical patent/WO2012127483A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups

Definitions

  • the present invention relates to processes for the preparation of intermediates of N-[2-(7- methoxy-l-naphthyl) ethyl] acetamide.
  • Agomelatine is an agonist of melatoninergic system receptors and an antagonist of the 5-HT2C receptor. Those properties confer activity in the central nervous system and, more especially, in the treatment of severe depression, seasonal affective disorders, sleep disorders, cardiovascular pathologies, and pathologies of the digestive system, insomnia and fatigue resulting from jetlag, appetite disorders and obesity. Agomelatine is under regulatory review in US and is being approved in EU for the treatment of major depressive disorder. It is marketed under the trade names Valdoxan, Melitor, Thymanax in the form of tablets in dosage strength 25 mg. Agomelatine is chemically described as N-[2-(7-methoxy-l- naphthyl)ethyl]acetamide (herein after referred by generic name agomelatine) and is represented by the structural formula I
  • the processes of present invention are simple, eco-friendly, inexpensive, reproducible, and robust and feasible on an industrial scale.
  • the present invention relates to processes for the preparation of intermediates of N-[2-(7- methoxy-l-naphthyl) ethyl] acetamide (I).
  • the present invention relates to a process for the preparation of intermediate compound of formula II
  • X is halogen atom (F,C1, Br,I)
  • the present invention relates to isolated solid (7-Methoxy-l-naphthyl) ethanamine compound of structural formula VI as free base.
  • Fig. 1 is a schematic representation of the processes of the present invention.
  • the present invention is directed to processes for the preparation of intermediates of N-[2- (7-methoxy-l-naphthyl) ethyl] acetamide (I).
  • X is halogen atom (F,C1, Br,I)
  • the suitable aromatization reagents include but are not limited to quinone derivatives such as compounds of formula IV or V where X is halogen atom like F, CI, Br, and I which include DDQ, p-chloranil, p-bromanil, p-floranil, 2,3-dibromo-5,6-dicyano benzoquinone, 2,3- dicyano-4-chlorobenzoquinone, 2,3-dicyanobenzoquinone and other quinone derivatives such as 1,2-benzoquinones, 1,3-benzoquinones, o-chloranil, o-bromanil, o-floranil and the like or mixtures thereof, preferably DDQ or p-chloranil.
  • quinone derivatives such as compounds of formula IV or V where X is halogen atom like F, CI, Br, and I which include DDQ, p-chloranil, p-bromanil, p-f
  • the molar ratio of aromatization reagent to the compounds of formula (III) can be from about 5 : 1 to about 1 : 1 , preferably 1 : 1.
  • the organic solvents that can be used include but are not limited to halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene and the like; esters such as ethyl acetate, isopropyl acetate, tertiary butyl acetate and the like; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene, o-xylene, p-xylene and the like; ethers such as tetrahydrofuran, 1,4-dioxane, diethyl ether and the like; aprotic polar solvents such as ⁇ , ⁇ -dimethylformamide (DMF), dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA), N-methyl pyrrolidone (NMP), ethylene glycol and the like; or mixtures thereof in various proportions without limitation.
  • the reaction is optionally performed in the absence of organic solvents.
  • the reaction temperature and the time should be suitable to bring the reaction to completion at a minimum time, without the production of unwanted side products. In general, it is convenient to carry out the reaction at a temperature of from about 35°C to about reflux temperatures of the solvents used. Preferably at reflux temperatures of the solvents used.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagent and solvent employed. However, provided that the reaction is effected under the preferred conditions discussed above, a period from about 1 hour to about 15 hours, preferably from about 5 hour to 10 hours.
  • the desired compounds can be obtained from the reaction mixture by conventional means known in the art.
  • the working-up of reaction mixtures, especially in order to isolate desired compounds follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like.
  • the intermediate compounds of formula II obtained by the process of present invention are optionally purified either by converting into respective acid addition salts or by recrystallization using the solvents or mixture of solvents or their aqueous mixtures or by slurry in the customary solvents.
  • the processes of present invention is of particular interest for the following reasons it allows the compound of formula (II), exclusively, to be obtained on an industrial scale.
  • This result is altogether surprising is due to the use of cheaper and simple reagents like DDQ and chloranil unlike palladium -carbon.
  • the rate of conversion of the compound of formula (III) to the compound of formula (II) is very high, exceeding 80%, unlike that which could be observed using palladium carbon, for which the rate does not exceed 75% whereas the use of quinone derivatives like DDQ or chloranil are entirely compatible with industrial requirements in terms of cost and the environment unlike hydrogenation catalyst for the conversion of the compound of formula (III) to the compound of formula (II) currently used.
  • it allows the compound of formula (II), exclusively, in particular free from the corresponding impurities.
  • the processes of present invention provides the compound of formula I from intermediate compound of formula II by using quinone derivatives of formula IV or V like DDQ or chloranil resulted in tremendous improvement in the yields and purities which ultimately lead to the higher yields and purities of final product.
  • the present process is very cost effective, reproducible and more viable on commercial scale.
  • the quinone derivatives described above can be recovered, recycled and reused thus making the process of present invention more economic.
  • the molar ratio of selenium to the compound of formula (III) can be from about 5:1 to about 1: 1, preferably 1 :1.
  • the reaction temperature and time when selenium is being used as reagent can be from about 100°C to about 250°C, preferably at a temperature of from about 215°C to about 220 °C.
  • the time required is from about 1 hour to about 10 hours, preferably from about 3 to 5 hours.
  • the processes of present invention described herein produces the intermediates and the final product in high yields and purities than the processes reported in the literature that too using simple and cost effective industrially applicable processes.
  • the isolated solid (7-Methoxy-l-naphthyI)ethanamine (VI) is pure. Preferably it has about 95% purity by weight with respect to other compounds. Preferably, the (7-Methoxy-l- naphthyl)ethanamine of formula VI is isolated in about 99% purity by weight. Thus, the isolated solid (7-Methoxy-l-naphthyl)ethanamine contains less than about 2%, preferably less than about 1 % by weight of impurities by HPLC.
  • the isolated solid (7-Methoxy-l-naphthyl)ethanamine (VI) of the present invention is prepared and isolated by the process substantially as described in example 9.
  • the solid 7-Methoxy-l-naphthyl)ethanamine (VI) is prepared either from its respective acid addition salt for example hydrochloric acid salt by using an organic or inorganic base in the presence of organic solvents or directly by free base using conventional techniques like crystallization from solvents or their mixtures or their aqueous mixtures thereof or by solvent- antisolvent technique.
  • the solvents that can be used for the isolation of compound of formula VI as solid include but are not limited alcohols such as methanol, ethanol, n-propanol, isopropanol, n- butanol, isobutanol, and tertiary butyl alcohol and the like; halogenated solvents dichloromethane, ethylene dichloride, chloroform and the like; ketonic solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-butanone and the like; nitrile solvents such as acetonitrile, propionitrile and the like; esters such as ethyl acetate, isopropyl acetate and the like; hydrocarbons such as toluene, o-xylene, cyclohexane and the like or mixtures thereof in various proportions without limitation.
  • ethyl acetate ethyl acetate.
  • the antisolvents include, but are not limited to water, hydrocarbon solvents such as n- hexane, n-heptane, cyclohexane, petroleum ether, toluene and the like; ethers such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, and the like or mixtures thereof in various proportions without limitation.
  • hydrocarbon solvents such as n- hexane, n-heptane, cyclohexane, petroleum ether, toluene and the like
  • ethers such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, and the like or mixtures thereof in various proportions without limitation.
  • n-hexane Preferably n-hexane.
  • a solvent is any liquid substance capable of dissolving compound of VI or a salt thereof.
  • antisolvent means a liquid in which a compound is poorly soluble. The addition of an antisolvent to a solvent reduces the solubility of a compound.
  • a mixture of solvents refers to a composition comprising more than one solvent.
  • the isolated solid (7-Methoxy-l-naphthyl)ethanamine (VI) of the present invention is useful as a reference marker for agomelatine (I). As such, it may be used in order to detect the (7-Methoxy-l-naphthyl)ethanamine impurity in a agomelatine sample.
  • the starting intermediate compounds of formula III and the intermediate compound of formula VI can be prepared either by the processes reported in the art or by the process disclosed in our PCT application PCT/IN2011/000003.
  • the intermediate compounds of formula (II) obtained by the processes of present invention can be converted into final active compound agomelatine of formula I by processes described in the art. Illustratively, by the process described in U.S. Patent No. 7,544,839.
  • Exaniple-1 15 g. ( 0.07 mol) of (7-Methoxy-3,4-dihydro-l-naphthyl)acetonitrile, 24 g. (0.09 mol) of Chloranil (2,3,5,6-Tetrachlorocyclohexa-2,5-diene- 1 ,4-dione ) and 600 ml. of O-xylene were charged in a clean and dry 4 neck R.B. Flask and heated to reflux temperature for about 8 hrs. The resultant reaction mixture was cooled to about 30°C and filtered. The filtrate was washed with 3x50 ml of 10% w/v sodium hydroxide solution and 2x50 ml of water. The solvent was distilled completely under vacuum, the solid separated was recrystallized from ethanol and water mixture in 8:2 ratio to afford 13 g. (88%) of the title compound with a chemical purity 99%.
  • Example-2 The process is same as described in above example 1 by using toluene instead of o-xylene to yield 13.5 gr. (91%) of the title compound with a chemical purity 99%.
  • Example-3 5 g. (0.02 mol.) of (7-Methoxy-3,4-dihydro-l-naphthyl)acetonitrile, 7.5 g. (0.03 mol.) of 2,3-Dichloro-5,6-dicyano-benzoquinone (DDQ) and 200 ml. of O-xylene or toluene were charged in a clean and dry 4 neck R.B. Flask and heated to reflux temperature for about 2 hrs. The resultant reaction mixture was cooled to about 30°C and filtered. The filtrate was washed with 3x25 ml. of 10% w/v sodium hydroxide solution and 2x25 ml. of water.
  • DDQ 2,3-Dichloro-5,6-dicyano-benzoquinone
  • Example-4 5 g. (0.02 mol) of N-[2-(7-Methoxy-3,4-dihydro-l-naphthyl)ethyl]acetamide, 6 g. (0.03 mol.) of 2,3-Dichloro-5,6-dicyano-benzoquinone (DDQ) and 200 ml. O-xylene or toluene were charged in a clean and dry 4 neck R.B. Flask and heated to reflux temperature for about 4 hrs. The resultant reaction mixture was cooled to about 30°C and filtered. The filtrate was washed with 3x30 ml. of 10% w/v of sodium hydroxide solution and 2x30 ml. of water.
  • DDQ 2,3-Dichloro-5,6-dicyano-benzoquinone
  • Example-5 15 g. (0.06 mol) of N-[2-(7-Methoxy-3,4-dihydro-l-naphthyl)ethyl]acetamide, 19.5 g. (0.08 mol.) Chloranil (2,3,5,6-Tetrachlorocyclohexa-2,5-diene-l,4-dione ) and 600 ml. of O-xylene were charged in a clean and dry 4 neck R.B.Flask and heated to reflux temperature for about 5 hrs. The reaction mixture was cooled to about 30°C and filtered. The filtrate was washed with 3x50 ml. of 10%w/v sodium hydroxide solution and 3x50 ml.
  • Example-6 The process is same as described in above example 5 but using toluene instead of o-xylene to yield 13 g. (87%) of the title compound with a chemical purity exceeding 99%.
  • Example-7 Preparation of (7-Metboxy-l-naphthyl)acetonitrile using selenium
  • Example-8 Preparation of N-[2-(7-Methoxy-l-naphthyl)ethyl]acetamide using selenium lOg. (0.04mol.) of N-[2-(7-Methoxy-3,4-dihydro-l-naphthyl)ethyI]acetamide and 5 g. (0.06 mol.) of selenium metal powder were charged into a clean and dry 4 neck R.B.Flask and heated to about 220 °C for about 4 hrs. The resultant reaction mixture was allowed to reach about 65°C and extracted with 100 ml. of ethyl acetate.

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Abstract

La présente invention concerne des procédés pour la préparation d'intermédiaires de N-[2-(7-méthoxy-1-naphtyl)éthyl]acétamide. Plus particulièrement, la présente invention concerne des procédés pour la préparation du composé de formule structurelle II. Elle concerne également le composé solide isolé (7-méthoxy-l-naphtyl)éthanamine de formule structurelle VI comme base libre.
PCT/IN2011/000203 2011-03-24 2011-03-24 Procédés pour la préparation d'intermédiaires de n-[2-(7-méthoxy-1-naphtyl)éthyl]acétamide Ceased WO2012127483A1 (fr)

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Application Number Priority Date Filing Date Title
PCT/IN2011/000203 WO2012127483A1 (fr) 2011-03-24 2011-03-24 Procédés pour la préparation d'intermédiaires de n-[2-(7-méthoxy-1-naphtyl)éthyl]acétamide
ARP110104215A AR083841A1 (es) 2011-03-24 2011-11-11 Procesos para la preparacion de intermediarios de n-[2-(7-metoxi-1-naftil)etil]acetamida

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PCT/IN2011/000203 WO2012127483A1 (fr) 2011-03-24 2011-03-24 Procédés pour la préparation d'intermédiaires de n-[2-(7-méthoxy-1-naphtyl)éthyl]acétamide

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103113243A (zh) * 2013-03-08 2013-05-22 山东方明药业集团股份有限公司 一种2-（7-甲氧基-1-萘基）乙胺盐酸盐的合成方法
WO2014072998A1 (fr) * 2012-11-07 2014-05-15 Cadila Healthcare Limited Procédé perfectionné pour la préparation d'agomélatine
CN104130154A (zh) * 2013-05-03 2014-11-05 郭炳华 一种制备高纯度阿戈美拉汀的方法
CN113773221A (zh) * 2021-10-08 2021-12-10 湖北工业大学 一种对苯醌类化合物及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4764635A (en) * 1986-08-14 1988-08-16 Ethyl Corporation Aromatization process
US6020513A (en) * 1996-08-29 2000-02-01 Eli Lilly And Company Dihydronaphthalene and naphthalene compounds, intermediates, formulations, and methods
US20050182276A1 (en) * 2004-02-13 2005-08-18 Jean-Claude Souvie Process for the synthesis and crystalline form of agomelatine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4764635A (en) * 1986-08-14 1988-08-16 Ethyl Corporation Aromatization process
US6020513A (en) * 1996-08-29 2000-02-01 Eli Lilly And Company Dihydronaphthalene and naphthalene compounds, intermediates, formulations, and methods
US20050182276A1 (en) * 2004-02-13 2005-08-18 Jean-Claude Souvie Process for the synthesis and crystalline form of agomelatine

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014072998A1 (fr) * 2012-11-07 2014-05-15 Cadila Healthcare Limited Procédé perfectionné pour la préparation d'agomélatine
CN103113243A (zh) * 2013-03-08 2013-05-22 山东方明药业集团股份有限公司 一种2-（7-甲氧基-1-萘基）乙胺盐酸盐的合成方法
CN104130154A (zh) * 2013-05-03 2014-11-05 郭炳华 一种制备高纯度阿戈美拉汀的方法
CN113773221A (zh) * 2021-10-08 2021-12-10 湖北工业大学 一种对苯醌类化合物及其制备方法
CN113773221B (zh) * 2021-10-08 2023-09-29 湖北工业大学 一种对苯醌类化合物及其制备方法

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