Classifications

• • 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
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/22—Separation; Purification; Stabilisation; Use of additives
  • C07C231/24—Separation; Purification
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C253/00—Preparation of carboxylic acid nitriles
  • C07C253/20—Preparation of carboxylic acid nitriles by dehydration of carboxylic acid amides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
• • 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
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
  • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
  • C07C69/734—Ethers

Definitions

• the present invention relates to an improved process for the preparation of Agomelatine of formula (I) and also concerns new process for the preparation of crystalline form I of Agomelatine.
• Agomelatine is chemically known as N-[2-(7-methoxy-1 -naphthalenyl] acetamide. It was developed by the French company Servier. The current pharmaceutical product containing this drug is being sold using the trade name Valdoxan® / Thymanax®. The drug is approved by the EU for the treatment of adult depression treatment. Indeed Agomelatine has double feature of being, on the one hand, an agonist of melatoninergic system receptors, on the other hand, an antagonist of 5-HT 2c 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.
• US 5225442 describes a process for the preparation of Agomelatine in eight steps starting from 7-methoxy tetralone giving and average yield of less than 30%. This process involves the action of ethyl bromoacetate, followed by aromatization and saponification to yield the corresponding acid, which is then converted to acetamide and subsequently dehydrated to yield (7-methoxy-1 -naphthyl) acetonitrile, which on reduction to amine and subsequent reaction with acetylene chloride to give Agomelatine of formula I.
• Synthetic Communication, 2001 , 31 (4), 621 -629 describes process of obtaining (7-methoxy-1 -naphthyl) acetonitrile in three steps starting from 7-methoxy-1 -tetralone, by the action of LiCH2CN followed by dehydrogenation with DDQ (2,3-dichloro-5,6- dicyano-1 ,4-benzoquinone) and finally dehydration in acid medium.
• DDQ 2,3-dichloro-5,6- dicyano-1 ,4-benzoquinone
• Tinant and Declercq also disclose the fractional atomic coordinates and equivalent isotropic displacement parameters and selected geometric parameters as well as the hydrogen bonding geometry of this polymorph form. This data is included herein by reference.
• EP 0 447 285 in example 1 also discloses a process for the preparation of Agomelatine.
• Agomelatine is obtained by recrystallization from isopropyl ether. No information on the polymorph form can be found in EP 0 447 285.
• Object of the present application provide safe and simpler process for the preparation of Agomelatine.
• Each step of the process disclosed herein are contemplated both in the context of the multi step sequences described, and individually.
• It is an object of the present invention is to provide an improved process for the preparation of Agomelatine comprising a step of converting compound of formula (la) to the compound of formula (lb).
• Further object of the present invention is to provide a process for the preparation of Agomelatine comprising a step of converting compound of formula (lb) to the compound of formula (Ic).
• Yet another object of the present invention is to provide a process for the preparation of Agomelatine comprising a step of converting a compound of formula (Ic) to compound of formula (Id) by aromatization in suitable solvent.
• Further object of present invention is to provide a process for the preparation of Agomelatine comprising a step of converting compound of formula (Id) to compound of formula (If) by amidation of compound of formula (le)
• Yet another object of present invention to provide a process for the preparation of Agomelatine comprising a step of converting compound of formula (If) to compound of formula (Ig) by dehydration of compound of formula (If).
• Further object of present invention to provide a process for the preparation of Agomelatine comprising reduction of compound of formula (Ig) to obtain compound of formula (Ih).
• Further object of present invention is to provide a process for the preparation of Agomelatine comprising acylation of compound of formula (Ih) to obtain compound of formula (I).
• Further object of the present invention is to provide process for the preparation of stable crystalline form I of Agomelatine, comprising the steps of
• step (i) providing a solution of Agomelatine in organic amine or mixture there of ii) adding solution of organic acid and water to the solution obtain in step (i) iii) optionally seeding crystals of form I
• Fig: 1 depicts a powder X-ray diffractogram (PXRD) of crystalline Form I of Agomelatine
• the present invention provides an improved process for the preparation of Agomelatine comprising a step of converting compound of formula (la) to the compound of formula (Ic) by in situ preparation of compound of formula (lb) in the presence of ethyl
• Suitable base that may be used in the conversion of formula (la) to (lb) may be selected from sodium hydride, potassium tertiary butoxide, butyl lithium and metal hydroxide such as KOH, NaOH and the like.
• the quantity of base used in this step may range from about 1 to about 3 molar equivalents, per mole of compound (la).
• Suitable solvents that used for the reaction is selected form the group consisting of C1 to C5 alcohol such as ethanol, methanol, 1 -propanol, isoprpanol, 1 -butanol, 2- butanol, tert. Butanol, 1 -pantenol, 2-butanol, tert-pantenol and aromatic hydrocarban such as toluene, xylene and like or mixture there of.
• the amount of solvent that preferably used in this step may range from about 1 to 10 volumes to compound of formula (la).
• Suitable temperatures for conversion of compound of formula (la) to compound of formula (lb) may be less than about 150°C, less than about 100°C, less than about 60°C, less than about 25°C, less than bout 0°C or any other suitable temperatures.
• the reaction may be carried out for time periods ranging from about 30 minutes to about 5 hours, or longer.
• the compound of formula (lc) may be optionally be isolated and purified or the reaction mass comprising the compound of formula (lc) may be taken for next step of the process.
• the reaction mass comprising the compound of formula (lc) further be purified by a process involving acidifying and basifying steps, in any order, crystallization and combination thereof, to enhance the purity.
• In another embodiment of the present invention provides a process for the preparation of Agomelatine comprising a step of converting a compound of formula (lc) to compound of formula (Id) by aromatization in suitable solvent.
• the suitable reagent that may be used in the process of converting a compound of formula (lc) include but are not limited to sulphur, raney Ni/H 2 , FeC , Pd/C-Acrylic acid, Raney Ni-methyl acrylate, and the like.
• the suitable aromatization reagent used in the above step is preferably Pd/C acrylic acid in the presence of sodium bicarbonate.
• the amount of acrylic acid that may be used ranges from about 1 to 3 mole eq. to compound (lc).
• the amount of Pd/C that may be used ranges from about 0.01 to about 0.1 mole eq to compound (lc).
• solvents used for aromatization includes but are not limited to water, alcoholic solvent such as methanol, ethanol, isoproanol and the like; The amount of solvent that preferably used in this step may range from about 3 to 10 volumes to compound of (lc).
• Suitable temperatures for reaction may be less than about 125°C, less than about 100°C, less than about 60°C, less than about 25°C, less than about 0°C or any other suitable temperatures.
• the reaction may be carried out for time periods ranging from about 30 minutes to about 15 hours, or longer.
• the compound of formula (Id) may be optionally be isolated and purified or the reaction mass comprising the compound of formula (Id) may be taken for next step of the process.
• the reaction mass comprising the compound of formula (Id) further be purified by a process involving acidifying and basifying steps, in any order, crystallization and combination thereof, to enhance the purity.
• Another embodiment of present invention provides a process for the preparation of Agomelatine comprising a step of converting compound of formula (Id) to compound of formula (If) by preparation of compound of formula (le)
• Source of ammonia is used for the conversion of formula (le) to l(f) selected from ammonia gas, liquid ammonia, aqueous ammonia, ammonium hydroxide, magnesium nitride and formamide with base and the like.
• the suitable source of ammonia that was used in this reaction is preferably ammonia gas.
• Ammonia gas is purged to the reaction mixture till pH is more then 8.
• the temperature on which ammonia gas purged to the reaction mixture is -10 to 20°C, preferably 0-5 °C.
• the product can be isolated from the reaction mass by quenching the reaction mixture in cold water and the separated organic layer was distilled off and recrystallized with methanol solvent to give pure compound of formula (If).
• In another embodiment of the present invention provides a process for the preparation of Agomelatine comprising a step of converting compound of formula (If) to compound of formula (Ig) by dehydration of compound of formula (If) in the presence of POCI 3 or combination of Ethyldichlorophsophate and DBU or P 2 0 5 or mixture there of, preferably in the presence of POCI 3 .
• the quantity of dehydrating agent preferably POCI 3 used may range from about 0.8 to about 2 mol eq. to compound (Id), preferably 0.08 to 1.5 mole eq.
• the reaction relating to dehydration is carried out at 50°C to 120°C preferably at 80°C to 90°C.
• a suitable solvent includes but are not limited to aromatic hydrocarbons such as toluene, xylene, n-hexane, n-heptane and cyclohexane and the like preferably toluene or xylene.
• the amount of solvent that preferably used is 2 to 5 volume to compound of (If).
• the reaction may be carried out for time periods ranging from about 30 minutes to about 3 hours, or longer.
• One of the embodiments of present invention provides reduction of Compound of formula (Ig) with suitable reducing agent in present of solvent, which is converted to its hydrochloride salt by IPA/ HCI to yield the compound of formula (Ih),
• Reducing agents that may be used in this step of this process include but are not limited to Pd on carbon, raney nickel, or Pd(OH) 2 under a hydrogen atmosphere.
• the reduction process of this step may be carried out in a presence of a solvent, including alcohols solvents such as methanol, ethanol, tert-butyl alcohol, or the like.
• the reduction may be carried out a temperature ranging from about 0°C to about 75°C or higher or about 20 to 40, based on the reagents.
• Compound of formula (Ig) is treated with aq. NaOH solution and raney Ni/H 2 . Hydrogen gas is applied up to 7 to 9 kg.
• the amount of raney Ni is preferably used 0.1 to 0.4 times to compound of formula (Ig).
• the amount of solvents that preferably used for the reaction is 8 to 10 times to compound of formula (Ig).
• the reaction is carried out at 50 to 100 °C preferably at 20 to 40 °C.
• One of the embodiments of present invention provides a process for the preparation of Agomelatine comprising a step of converting compound of formula (Ih) to compound of formula (I) by acylation with acetic anhydride or acetyl chloride in the presence sol
• Further embodiment of the present invention is to provide process for the preparation of Agomelatine in pure crystalline form I, comprising the steps of;
• step (i) providing a solution of Agomelatine in organic amine or mixture there of ii) adding solution of organic acid and water to the solution obtain in step (i) iii) optionally seeding crystals of form I
• the crystals of polymorph form I of Agomelatine obtained by the process of the present invention have a specific surface and are therefore less hygroscopic than the crystals of polymorph form I of Agomelatine obtained by other processes.
• Providing a solution in step i) include obtaining a solution of Agomelatine in organic amine or in a mixture of organic amine and water.
• Suitable organic amines that may be used for this step includes but are not limited to primary amine such as t-butyl amine, ammonia, propyl amine, methyl amine; secondary amine such as diethylamine, dimethyamine, methylethylamine, tertiary amine such as triethyl amine, tertiary butyl amine.
• the temperature at which solution of Agomelatine prepared in organic amine is cooled is not particularly restricted, but usually the temperature is in the range of 10°C to -80 °C, preferably 0 °C to -20 °C.
• Step (ii) involves adding solution of organic acid and water to the solution obtains in step (i).
• Suitable organic acids that may be used for this step includes but are not limited to formic acid, acetic acid, propionic acid, butyric acid, lactic acid, preferred organic acid is propionic acid.
• step (ii) may be carried out in the presence of water, and the reaction may be carried out at temperature ranging from about 0°C to about -60°C, or about 0°C to about -20°C.
• the solution obtained in step (iii) may be seeded with form I of Agomelatine crystals and may be cooled to a temperature below 10°C to precipitate the solid. In embodiments, the solution may be cooled to temperatures about 0°C to about 5°C.
• Step (iv) involves isolating the crystals of the polymorphic form I of Agomelatine.
• Drying may be suitable carried out using any equipment at atmospheric pressure or under reduced pressures, at temperatures less than about 70°C, less than about 50°C less than about 30°C and any other suitable temperatures.
• the drying may be carried out at any time periods required for obtaining a desired quality, such as from about 15 minutes to several hours or longer.
• the polymorphic form I of Agomelatine can be reliably obtained by an easy process in excellent reproducibility using process of present invention.
• the obtained polymorph form I of Agomelatine has a chemical purity of preferably 98% or more, more preferably 99% or more, in particular 99.5% or more, such as 99.8% or more.
• the obtained polymorphic form I of Agomelatine is pure crystalline form I, which is not contaminated with other crystalline form.
• the obtained polymorph from I of Agomelatine preferably has a low hygroscopic, and with the process of the invention Agomelatine of polymorph form I is obtained in the form of crystals having a very narrow particle size distribution
• seed crystal means crystals of form I of Agomelatine obtained by the prior art process or by the process of the present invention (Example I). It was also unexpectedly found that a very high reproducibility of the product characteristics can be obtained by seeding of the solution with seeds consisting of Agomelatine in crystalline form I.
• the Agomelatine obtained by the process of the present invention is the polymorph form I of Agomelatine which is known from Acta Cryst. (1994), C50, 907-910. Regarding the details and the definition of the crystal form, it is referred to this document.
• the polymorph form I of Agomelatine can also be characterized by its powder diffraction diagram. An XRPD of form I that has been obtained by the process of the present invention is enclosed as figure I.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Applications Claiming Priority (4)

Publications (1)

Family

ID=49782351

Family Applications (1)

Country Status (1)

Cited By (4)

Citations (3)

• 2013
  • 2013-06-14 WO PCT/IB2013/054867 patent/WO2014001939A1/fr not_active Ceased

Patent Citations (3)

Similar Documents

Legal Events