USRE46218E1 - Process for the synthesis of agomelatine - Google Patents

Process for the synthesis of agomelatine Download PDF

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USRE46218E1
USRE46218E1 US14/619,284 US201214619284A USRE46218E US RE46218 E1 USRE46218 E1 US RE46218E1 US 201214619284 A US201214619284 A US 201214619284A US RE46218 E USRE46218 E US RE46218E
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compound
formula
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Samir Zard
Béatrice Sire
Mehdi Boumediene
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Laboratoires Servier SAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/37—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by etherified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/40—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by doubly-bound oxygen atoms
    • C07C2102/10—
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to a new process for the industrial synthesis of agomelatine, or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, of formula (I):
  • Agomelatine or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, has valuable pharmacological properties.
  • Patent specification EP 0 447 285 describes production of agomelatine in eight steps starting from 7-methoxy-1-tetralone.
  • This synthesis route is based on carrying out free radical reactions that are not very commonly used but are nevertheless very effective. Converting these reactions to the industrial scale using continuous-flow reactors is promising as it becomes simpler to control propagation of the chain reaction.
  • agomelatine can accordingly be synthesised in 6 steps in the course of which only two of the intermediates are isolated.
  • the present invention relates to a process for the industrial synthesis of the compound of formula (I):
  • Xa represents a group —S—C(S)—OR in which R represents a linear or branched (C 1 -C 6 )alkyl group,
  • the compound of formula (VII) is then subjected to reduction using hydrogen in the presence of Raney nickel in an ammoniacal ethanol medium and then converted into a salt using hydrochloric acid to yield the compound of formula (VIII):
  • the compound of formula (VII) can be subjected to reduction by hydrogen in the presence of Raney nickel in a medium comprising acetic anhydride in a polar protic medium to yield the compound of formula (I), which is isolated in the form of a solid.
  • Xa represents a group —S—C(S)—OC 2 H 5 .
  • initiation of the free radical reactions is carried out by thermal means.
  • the reaction mixture is heated to a temperature of from 50° C. to 140° C.
  • cyclisation is carried out at a temperature of from 130 to 135° C.
  • Peroxides are free radical initiators that are especially suitable for carrying out the step of addition of the compound of formula (II) to the compound of formula (III), or for performing cyclisation of the compound of formula (IV) to form the compound of formula (V).
  • diisobutyryl peroxide cumyl peroxyneodecanoate, tert-amyl peroxyneodecanoate, di(2-ethylhexyl)peroxydicarbonate, tert-butyl peroxyneodecanoate, dibutyl peroxydicarbonate, dicetyl peroxydicarbonate, dimyristyl peroxydicarbonate, tert-butyl peroxyneoheptanoate, tert-amyl peroxypivalate, didecanoyl peroxide, tert-amyl peroxy-2-ethylhexanoate, tert-butyl peroxyis
  • the reaction is initiated in the presence of dilauroyl peroxide.
  • the amount of dilauroyl peroxide used in the cyclisation is preferably from 1 to 2.5 equivalents.
  • dilauroyl peroxide is added to the medium in stages.
  • the addition and/or cyclisation reactions are carried out in a solvent customarily used in free radical chemistry such as 1,2-dichloroethane, dichloromethane, benzene, toluene, trifluoromethylbenzene, chlorobenzene, hexane, cyclohexane, heptane, octane, ethyl acetate, tert-butyl alcohol, and mixtures thereof.
  • free radical chemistry such as 1,2-dichloroethane, dichloromethane, benzene, toluene, trifluoromethylbenzene, chlorobenzene, hexane, cyclohexane, heptane, octane, ethyl acetate, tert-butyl alcohol, and mixtures thereof.
  • Conversion of the compound of formula (V) into the compound of formula (VI) is advantageously carried out in the presence of a Lewis acid such as aluminium isopropoxide or samarium isopropoxide. This conversion is moreover preferably carried out in an alcohol (primary or secondary), and even more preferably in isopropanol.
  • a Lewis acid such as aluminium isopropoxide or samarium isopropoxide.
  • a catalytic amount of p-toluenesulphonic acid is added to the mixture once all the tetralone (V) has been consumed at the end of conversion of the compound of formula (V) into the compound of formula (VI).
  • Aromatisation of compound (VI) is carried out in the presence of a quinone, preferably in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or tetrachlorobenzoquinone (TCQ). Even more preferably, aromatisation is carried out in the presence of TCQ at the reflux of toluene.
  • DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
  • TCQ tetrachlorobenzoquinone
  • Example 2 corresponds to the same reaction route as that used in Example 1 but with the difference that only (7-methoxy-1,2-dihydro-1-naphthyl)acetonitrile and (7-methoxy-1-naphthyl)acetonitrile were isolated.
  • Step A S-[1-(cyanomethyl)-4-(4-methoxyphenyl)-4-oxobutyl]-O-ethyl dithiocarbonate
  • Step B (7-Methoxy-4-oxo-1,2,3,4-tetrahydro-1-naphthyl)acetonitrile
  • Step A The compound of Step A, used directly without having been purified, is redissolved in chlorobenzene (900 mL) and the solution is refluxed for 15 minutes under a nitrogen atmosphere. Dilauroyl peroxide is then gradually added to the solution under reflux (10 mol % every 10 minutes). When the reaction is complete, the mixture is cooled to ambient temperature and concentrated under reduced pressure. Acetonitrile is then introduced in order to cause a large part of the dilauroyl peroxide compounds to precipitate out. The mixture is then filtered, concentrated under reduced pressure and purified by flash column chromatography (petroleum ether-ethyl acetate: 60-40) to yield the title compound in solid form in a yield of 40%.
  • Aluminium isopropoxide (2.05 g, 10.0 mmol) is added to a solution of the compound obtained in Step B (680 mg, 3.15 mmol) in isopropanol (15 mL) at ambient temperature.
  • the reaction mixture is refluxed.
  • a few crystals of p-toluenesulphonic acid monohydrate are added and a Dean-Stark apparatus is mounted on top of the flask.
  • the mixture is again refluxed for 1 hour, during which the isopropanol is gradually replaced with toluene by means of the Dean-Stark apparatus.
  • a 1N HCl solution is then added and the resulting phases are separated.
  • the aqueous phase is extracted with ethyl acetate, the organic phases being washed with saturated NaHCO 3 solution and with saturated NaCl solution, then dried over MgSO 4 , filtered and concentrated under reduced pressure.
  • the residue is purified by column chromatography (petroleum ether-ethyl acetate: 80-20) to yield the title product in the form of an oil in a yield of 85%.
  • the reaction was carried out on a larger batch in order to optimise the yield obtained: 136 g of Raney nickel, 2.06 L of ethanol and 0.23 L of water are introduced into an 8 L reactor. Whilst stirring at 70° C. and under 30 bars of hydrogen, the compound obtained in Step D (0.8 kg) dissolved in acetic anhydride (2.4 L) is slowly added. At the end of the addition, the reaction mixture is stirred for 1 hour under hydrogen at 30 bar, the reactor is then decompressed and the liquors are filtered. After concentration of the mixture, the residue is crystallised from a mixture of ethanol/water 35/65 to yield the title product in a yield of 89% and with a chemical purity greater than 99%.
  • the crude mixture is redissolved in chlorobenzene (640 mL) and the solution is refluxed for 15 minutes under a nitrogen atmosphere. Dilauroyl peroxide is then gradually added to the solution under reflux (10 mol % every 10 minutes). When the reaction is complete, the mixture is cooled to ambient temperature and concentrated under reduced pressure. Acetonitrile is then introduced in order to cause a large part of the dilauroyl peroxide compounds to precipitate out. The mixture is then filtered and concentrated under reduced pressure. Half the crude oil thereby obtained is redissolved in isopropanol (100 mL) at ambient temperature in the presence of aluminium isopropoxide (13.6 g, 66.6 mmol). The reaction mixture is refluxed.

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US14/619,284 2011-01-05 2012-01-04 Process for the synthesis of agomelatine Active USRE46218E1 (en)

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FR1100024 2011-01-05
FR1100024A FR2970000B1 (fr) 2011-01-05 2011-01-05 Nouveau procede de synthese de l'agomelatine
PCT/FR2012/000005 WO2012113999A1 (fr) 2011-01-05 2012-01-04 Procede et intermediaires de synthese de l ' agomelatine
US14/619,284 USRE46218E1 (en) 2011-01-05 2012-01-04 Process for the synthesis of agomelatine
US13/977,799 US8853449B2 (en) 2011-01-05 2012-01-04 Process for the synthesis of agomelatine

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CN103058879B (zh) * 2012-12-20 2015-09-09 安徽悦康凯悦制药有限公司 阿戈美拉汀的制备方法
CN103804232B (zh) * 2014-01-26 2015-08-19 江西同和药业股份有限公司 一种1-氰基-1-(7-甲氧基-3,4-二氢-1-萘基)甲醇酯类化合物及其制备方法和应用
CN107353229B (zh) * 2017-08-08 2019-04-30 许昌恒生制药有限公司 一种阿戈美拉汀中间体的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0447285A1 (fr) 1990-02-27 1991-09-18 Adir Et Compagnie Nouveaux dérivés à structure naphtalénique, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
EP1564202A1 (fr) 2004-02-13 2005-08-17 Les Laboratoires Servier Nouveau procédé de synthèse et nouvelle forme cristalline de l'agomelatine ainsi que les compositions pharmaceutiques qui la contiennent
US20050182267A1 (en) 2004-02-13 2005-08-18 Jean-Claude Souvie Process for the synthesis of (7-methoxy-1-naphthyl)acetonitrile and its application in the synthesis of agomelatine
CN101486665A (zh) 2009-03-03 2009-07-22 上海医药工业研究院 阿戈美拉汀中间体2-(7-甲氧基-1-萘基)乙酰胺的制备方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0447285A1 (fr) 1990-02-27 1991-09-18 Adir Et Compagnie Nouveaux dérivés à structure naphtalénique, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
US5318994A (en) 1990-02-27 1994-06-07 Adir Et Compagnie N-[2-(7-lower-alkoxynaphth-1-yl)ethyl]benzamides
EP1564202A1 (fr) 2004-02-13 2005-08-17 Les Laboratoires Servier Nouveau procédé de synthèse et nouvelle forme cristalline de l'agomelatine ainsi que les compositions pharmaceutiques qui la contiennent
US20050182267A1 (en) 2004-02-13 2005-08-18 Jean-Claude Souvie Process for the synthesis of (7-methoxy-1-naphthyl)acetonitrile and its application in the synthesis of agomelatine
US7544839B2 (en) 2004-02-13 2009-06-09 Les Laboratoires Servier Process for the synthesis and crystalline form agomelatine
CN101486665A (zh) 2009-03-03 2009-07-22 上海医药工业研究院 阿戈美拉汀中间体2-(7-甲氧基-1-萘基)乙酰胺的制备方法

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International Preliminary Report on Patentability Written Opinion for PCT/FR2012/000005, 2012.
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Kalinin et al., Journal of Organometallic Chemistry 383, 1990, 85-91.
Liard et al., Tetrahedron Letters 38(10), 1997, 1759-1762.

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FR2970000B1 (fr) 2013-01-04
ME02408B (me) 2016-09-20
DK2661422T3 (en) 2016-10-24
CA2823587A1 (fr) 2012-08-30
HUE028471T2 (en) 2016-12-28
CN103313965A (zh) 2013-09-18
MY162977A (en) 2017-07-31
EA201300794A1 (ru) 2014-02-28
RU2013136344A (ru) 2015-02-10
CO6731101A2 (es) 2013-08-15
WO2012113999A8 (fr) 2013-08-01
CU20130092A7 (es) 2013-08-29
JO3200B1 (ar) 2018-03-08
EP2661422A1 (fr) 2013-11-13
US8853449B2 (en) 2014-10-07
TWI438180B (zh) 2014-05-21
KR20130115345A (ko) 2013-10-21
EA022077B1 (ru) 2015-10-30
RU2550812C2 (ru) 2015-05-20
SG191733A1 (en) 2013-08-30
PE20140037A1 (es) 2014-02-01
MX2013007837A (es) 2013-09-06
CA2823587C (fr) 2015-11-24
AP2013007022A0 (en) 2013-07-31
JP5837616B2 (ja) 2015-12-24
AU2012220474A1 (en) 2013-07-11
CL2013001882A1 (es) 2013-12-06
JP2014509309A (ja) 2014-04-17
ES2583682T3 (es) 2016-09-21
CY1117774T1 (el) 2017-05-17
AP3609A (en) 2016-02-26
IL227281A0 (en) 2013-09-30
TW201309623A (zh) 2013-03-01
FR2970000A1 (fr) 2012-07-06
NZ612173A (en) 2015-08-28
CU24289B1 (es) 2017-12-08
EP2661422B9 (fr) 2016-09-07
US20130289307A1 (en) 2013-10-31
HRP20160713T1 (hr) 2016-07-29
IL227281A (en) 2015-06-30
ECSP13012735A (es) 2013-09-30
KR101543432B1 (ko) 2015-08-10
EP2661422B1 (fr) 2016-04-20
GEP20156365B (en) 2015-09-10
ES2583682T9 (es) 2016-10-31
SI2661422T1 (sl) 2016-08-31
NI201300062A (es) 2013-12-11
CR20130301A (es) 2013-08-08
SA112330134B1 (ar) 2014-08-25
AR084780A1 (es) 2013-06-26
WO2012113999A1 (fr) 2012-08-30
ZA201305027B (en) 2014-03-26
PL2661422T3 (pl) 2016-10-31
TN2013000274A1 (fr) 2014-11-10
UA104122C2 (ru) 2013-12-25
RS54753B1 (sr) 2016-10-31
CN103313965B (zh) 2015-08-05
AU2012220474B2 (en) 2015-08-20
BR112013017307A2 (pt) 2016-10-04
RS54753B9 (sr) 2019-09-30
UY33845A (es) 2012-07-31
HK1189571A1 (en) 2014-06-13

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