Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
  • C07C41/01—Preparation of ethers
  • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
  • C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
• • 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
  • C07C231/02—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
  • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
  • C07C41/01—Preparation of ethers
  • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C43/00—Ethers; Compounds having groups, groups or groups
  • C07C43/02—Ethers
  • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
  • C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
• • 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 novel process for the preparation or tetralin and naphthalene derivatives. Such compounds are considered to be interesting either as useful building blocks or due to their biological activity. BACKGROUND OF THE INVENTION
• EP 1831159 tetralin derivatives are prepared, for use in the treatment of CNS diseases and gastrointestinal tract disorders, starting from the fluoro-tetralone shown in the following scheme.
• MeSOoCI According to this process, it takes five steps to obtain the amine from the respective phenylsulphonyl intermediate and, in addition, it uses L1AIH 4 and NaN 3 , which are known to be difficult to handle in industrial scale.
• L1AIH 4 and NaN 3 which are known to be difficult to handle in industrial scale.
• tetralin (and indan) derivatives are prepared according to the following scheme.
• EP 1564202 prepares Agomelatine, a compound used for the treatment of depressive disorder (EP0447285B1), from 7-methoxy-tetralone:
• WO2012046253 A2 prepares Agomelatine according to the above scheme.
• the process needs very low temperatures for the performance of the first step (below -70 °C), conditions difficult to maintain in manufacturing processes.
• the second step which includes reduction of the CN group and elimination towards a formation of a double bond, is a reaction with conflicting reports found in the prior art.
• Agomelatine is prepared through a chloroethylnaphthalene derivative prepared according to following scheme.
• the process continues with two possible routes: i) formation of the respective phthalimide and hydrolysis, ii) formation of the respective nitro-derivative and subsequent catalytic hydrogenation, iii) formation of the respective ⁇ , ⁇ -diformylaminoethyl derivative, followed by hydrolysis.
• the ethylamine intermediate obtained is then acetylated, under known conditions, to Agomelatine.
• the process is also very long and includes the use of dimethylsulphate, which is a known genotoxic substance.
• the present invention discloses a novel process for the preparation of a compound of Formula IV from a compound of Formula I,
• ring A may be an aromatic or heteroaromatic ring, each of which may be optionally substituted and Y may be halogen, preferably a chloro atom, a hydroxy or protected hydroxy group, an amino or substituted amino group, an amido or substituted amido group or a phthalimide group.
• the present invention discloses the preparation of a compound of Formula rv from a compound of Formula I through a novel process comprising an allylic rearrangement step.
• the novel process for the transformation of a compound of Formula I to a compound of Formula IV comprises the following steps:
• the process described above may further comprise step d), wherein Y is converted to an amido group, preferably NHCOCH 3 , when Y is other than an amido group.
• a particular object of the present invention is a previously undisclosed allylic rearrangement of a compound of Formula I that enables the preparation of a compound of Formula II.
• a further object of the present invention is the preparation of a compound of
• steps a) and b) of the process described above may be performed without isolation of any intermediate compound.
• steps a), b) and c) of the process described above may be performed without isolation of any intermediate compound.
• a further object of the present invention is a novel process for the preparation of a compound of Formula IVa from a compound of Formula la.
• the present invention discloses the preparation of a compound of Formula la from a compound of Formula la through a novel process comprising an allylic rearrangement step.
• novel process for the transformation of a compound of Formula la to a compound of Formula IVa comprises the following steps:
• Y is a halogen atom, more preferably a chloro atom.
• the process described above may further comprise step d), wherein Y is converted to an amido group, preferably NHCOCH 3 , when Y is other than an amido group.
• step d) Y is preferably a halogen atom, even more preferably chloro atom.
• steps a) and b) of the process described above may be performed without isolation of any intermediate compound.
• steps a), b) and c) of the process described above may be performed without isolation of any intermediate compound.
• a particular object of the present invention is a previously undisclosed allylic rearrangement of a compound of Formula la that enables the preparation of a compound of Formula Ila.
• a further object of the present invention is the preparation of a compound of Formula Ilia from a compound of Formula la or Ila through an allylic rearrangement step.
• Y is preferably a halogen atom, most preferably a chloro atom.
• a further object of the present invention is a novel process for the preparation of agomelatine (compound of Formula VI) or a salt thereof, from a compound of Formula la.
• the present invention discloses the preparation of agomelatine of formula VI or a salt thereof from a compound of Formula la through a novel process comprising an allylic rearrangement step.
• the process described above may further comprise converting compound of formula IVa to a compound of formula V, which is then converted to compound of formula VI.
• the process described above may further comprise converting compound of formula IVa to a compound of formula VII, as defined below, further converted to compound of formula V and then to compound of formula VI.
• aromatic ring means a C 6-18 aromatic group, formed by one or more rings, which may be substituted with one or more substituents, or unsubstituted.
• the aromatic ring is a C 6- io ring system. Typical examples include phenyl, naphthyl and anthracenyl.
• heterocyclic ring means an aromatic ring, defined as above, which contains one or more heteroatoms. Suitable heteroatoms will be apparent to those skilled in the art and include, for example, nitrogen, oxygen, sulphur, phosphorus and silicon. Preferable heteroatoms are nitrogen, oxygen and sulphur.
• alkyl means a monovalent straight or branched chain group of the formula C m H 2m+ i or a cyclic group of the formula C m H 2m- i, with m being the number of carbon atoms.
• Preferable alkyl groups are C 1-2 o alkyl groups, more preferably C 1-10 alkyl groups, more preferably Ci -8 alkyl groups.
• Particularly preferred alkyl groups include, for example, methyl, ethyl, n-propyl, /so-propyl, w-butyl, sec-butyl, wo-butyl, w-pentyl, n-hexyl, «-heptyl, «-octyl.
• haloalkyl refers to alkyl groups substituted with one or more halogen atoms in one or more positions of the alkyl chain.
• alkenyl means monovalent straight or branched chain moieties containing one or more carbon-carbon double bonds and at least 2 carbon atoms. These moieties conform to the formula C m H( 2m-1 ), with m being the number of carbon atoms present.
• Preferable alkenyl groups are C 2-2 o alkenyl groups, more preferably still a C 2-1 o alkenyl group, more preferably still a C 2-1 o, more preferably still a C 2- 8 alkenyl group.
• alkynyl means monovalent straight or branched chain moieties containing one or more carbon-carbon triple bonds and at least 2 carbon atoms. These moieties conform to the formula C m H( 2m- 3), with m being the number of carbon atoms present.
• Preferable alkynyl groups are C 2-20 alkynyl groups, more preferably still a C 2- ! o alkynyl group, more preferably still a C 2-10 alkynyl, more preferably still a C 2- g alkynyl group.
• aryl refers to an aromatic ring system, as defined above.
• substituted hydroxy means -O-alkyl, -O-aryl, -0-C(0)-alkyl, -O- C(0)-aryl, -0-S0 2 -0-alkyl, -0-S0 2 -0-haloalkyl, -0-SO- 2 -0-aryl.
• Preferable substituted hydroxyl groups are -0-Ci -8 alkyl, -0-C 6-1 o aryl, -0-C(0)-C 1-8 -alkyl, -O- C(O)-C 6-10 -aryl, -0-S0 2 -0-C 1-8 alkyl, -0-S0 2 -0-Ci -8 alkyl substituted with one or more halogen atoms, -0-SO- 2 -0-C 6- io aryl- More preferable substituted hydroxyl groups are -O-methyl, -O-ethyl, 0- «-propyl, O-z ' -propyl, -0- «-butyl, -O-z ' -butyl, -O- sec-butyl, -O-phenyl, -O-p-tolyl, -O-l-naphthyl, - O-2-naphthyl, are -0-C
• More preferable substituted hydroxyl groups are -O-methyl, -O-ethyl, 0- «-propyl, O-z-propyl, -O-phenyl, -O-p-tolyl, -O- S0 2 -methyl, -0-S0 2 - trifluoromethyl, -0-S0 2 -p-tolyl. More preferable substituted hydroxyl groups are -O-methyl, -O-ethyl, O-n-propyl, O-z ' -propyl, -0-S0 2 -methyl, -O- S0 2 - trifluoromethyl, -0-S0 2 -p-tolyl.
• aminoalkyl means an amino group substituted with one or two of the same or different alkyl groups.
• Preferred aminoalkyl groups are -N (Ci -2 o-alkyl) 2 . More preferred aminoalkyl groups are -N (Ci.g-alkyl) 2 .
• alkoxycarbonyl means alkyl-O-C(O)- groups.
• Preferred alkoxycarbonyl groups are (C 1-2 o alkyl)-0-C(0)- groups, more preferably (C 1-8 -alkyl)- O-C(O)- groups.
• protected hydroxyl refers to hydroxyl groups suitably protected with protecting groups. Such groups are known in the art and are exemplified such as in Greene's Protective Groups on Organic Synthesis 4 th Edition, John Wiley & Son, Peter G. M. Wuts, Theodora W. Greene, Print ISBN: 9780471697541.
• Preferred protecting groups are trityl, benzyl, naphthyl, methoxybenzyl, p-nitrobenzyl, benzoyl, a substituted benzoyl, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert- butyldimethylsilyl, tert-butyldiphenylsilyl, thexyldimethylsilyl, allyl, methoxymethyl, (2-methoxyethoxy)methyl, tetrahydropyranyl.
• substituted amino means an amino group substituted with one or two alkyl, alkoxy, alkoxyalkyl, alkylocarbonyl groups, wherein alkoxy is alkyl-O-, alkoxyalkyl is alkyl-O-alkyl-, aminoalkyl is defined as above and wherein each alkyl is preferably as defined above.
• amido means -NHCOX, wherein X is alkyl, alkoxy, alkoxyalkyl, alkylocarbonyl or aminoalkyl, as defined above.
• substituted amido means -N(Z)COX, wherein X is defined above and Z is alkyl.
• phthalimido refers to the radical
• substituents may include one or more of halogen, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, halo, hydroxyl, substituted hydroxy, amino, substituted amino, nitro, cyano, formyl, alkyl carbonyl, alkoxycarbonyl, carboxyl.
• Salts It will be appreciated by the person skilled in the art that, whenever possible, compounds of the formulae II, III, IV, V and VI may also exist in the form of addition salts. Acceptable salts of the compounds prepared herein include suitable acid addition or base salts thereof. A review of suitable pharmaceutical salts may be found in Berge et al, J. Pharm. Sci., 66, 1, 19 (1977). Salts are formed, for example, with strong acids such as mineral acids, e. g. sulphuric acid, phosphoric acid or hydrohalic acids; with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (e.
• strong acids such as mineral acids, e. g. sulphuric acid, phosphoric acid or hydrohalic acids
• strong organic carboxylic acids such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (e.
• halogen such as acetic acid and trifluoroacetic acid
• saturated or unsaturated dicarboxylic acids for example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic
• hydroxycarboxylic acids for example ascorbic, glycolic, lactic, malic, tartaric or citric acid
• aminoacids for example aspartic or glutamic acid
• benzoic acid or with organic sulfonic acids, such as or aryl-sulfonic acids which are substituted or unsubstituted (for example, by a halogen) such as methane- or p-toluene sulfonic acid. Salts which are not pharmaceutically acceptable may still fall within the scope of the invention.
• the invention provides a process for the preparation of compounds of Formula r , where A may be an aromatic or heteroaromatic ring, each of which may be optionally substituted and Y may be a halogen, a hydroxy or protected hydroxy group, an amino or substituted amino group, an amido or substituted amido group or a phthalimide group.
• step d) conversion of a compound of Formula III where A and Y are defined as above, to a compound of Formula IV, which may be optionally isolated as a free compound or a salt.
• the above described process may further comprise step d), wherein Y is converted to an amido group, preferably NHCOCH 3 , when Y is other than an amido group.
• step a) the rearrangement is performed under conditions which can either induce transformation of the OH group of compound of formula I to a good leaving group, or under conditions comprising halogenating reagents, Brownsted-Lowry acids, or Lewis acids.
• the reaction can run in typical organic solvents such as alcohols, for example methanol, ethanol or similar alcohols; ethers, for example diethyl ether; tetrahydrofuran (THF) or similar, or halogenated solvents, for example dichloromethane, chloroform or similar.
• organic solvents such as alcohols, for example methanol, ethanol or similar alcohols; ethers, for example diethyl ether; tetrahydrofuran (THF) or similar, or halogenated solvents, for example dichloromethane, chloroform or similar.
• THF tetrahydrofuran
• halogenated solvents for example dichloromethane, chloroform or similar.
• the temperature of the rearrangement can vary from about -30 °C to the boiling point of the selected solvent.
• Compound of Formula II may be optionally isolated.
• step b) the isomerization takes place in commonly used organic solvents that can efficiently solvate compound of Formula II.
• Compound of Formula III may be optionally isolated.
• step c) the preparation of compound of Formula IV can be achieved by known in the art methods for the dehydrogenation of partially hydrogenated aromatic compounds.
• the dehydrogenation of compound of Formula III can be accomplished using Sg, 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ), p- chloranil or transition metal catalysis in the presence of a hydrogen acceptor.
• DDQ 2,3-dichloro-5,6-dicyano-l,4-benzoquinone
• p- chloranil transition metal catalysis in the presence of a hydrogen acceptor.
• a substitution reaction and an acylation reaction are involved.
• the substitution step may be achieved with a nitrogen source.
• Non limiting examples are ammonia, amines of general type RNH 2 , R 2 NH, dialkyl phosphoramidite compounds of general type H 2 NP(0)(OR) 2 , phthalimide derivatives (e. g. salts thereof, such as potassium phthalimide), azide derivatives (e. g. salts thereof, such as sodium azide) and sulfonamides of general type RS0 3 NH 2 , wherein is R an alkyl or aryl group, defined as above.
• the acylation step may be performed with an alkyl halide or an acyl anhydride in the presence of a base.
• step c) may also be performed with a catalytic amount of DDQ.
• This feature is an important improvement over prior art methods, due to the fact that DDQ is considered genotoxic and moreover leads to laborious workup procedures. Therefore, the significant reduction of the amount used in an industrial process is a major advantage of the present invention.
• DDQ after performing the aromatization reaction may be regenerated by using a suitable catalytic cycle involving one or more co-oxidants.
• Non limiting examples of co-oxidants are Pb0 2 , HC10 4 /H 2 S0 4 , HI0 4 , Mn0 2 , Mn(OAc) 3 , tert-butylnitrite (TBN)/0 2 , NaN0 2 /0 2 , FeCl 3 , Pd(OAc) 3 , HN0 3 .
• the substitution step is performed with aqueous ammonia.
• step a) may be performed under acidic conditions involving Brownsted-Lowry acids.
• Non limiting examples are hydrohalic acids, sulfuric acid, acetic acid or similar.
• the step may also be performed with Lewis acids, such as metal halides, semimetal halides and non metal halides, for example TiHal 4 , LiHal, or halogenating reagents such as thionyl halide, phosphorus halides, oxalyl halide.
• the step may also be performed with compounds that can transform the hydroxyl group into a good leaving group, for example acetyl chloride, p-tosyl halide, trimethylsilyl halide.
• the solvent of the reaction can be selected among commonly used organic solvents such as ethers, for example diethyl ether, THF or similar or halogenated solvents, for example dichloromethane, chloroform or similar.
• the temperature of the rearrangement can vary from about 0 °C to the boiling point of the selected solvent.
• Compound of Formula Ila may be optionally isolated.
• the solvent used in the reaction of step b can be selected among typical organic solvents, preferably but not restricted to halogenated solvents such as dichloromethane, chloroform or 1 ,2-dichloroethane or ethers such as diethyl ether, THF or similar.
• the isomerization occurs at temperatures between about 0 °C and about 100 °C.
• Compound of Formula Ilia may be optionally isolated.
• the dehydrogenation of compound of Formula Ilia takes place by known in the art methods for the dehydrogenation of partially hydrogenated aromatic compounds. In an embodiment of the present invention, the transformation could be efficiently accomplished using DDQ or p-chloranil in commonly used organic solvents and at ambient temperature. The said oxidation is completed in short reaction times, usually in a course of a few hours, but may require longer reaction time depending on the compound.
• the dehydrogenation could be achieved by the action of catalytic amounts of Pd in the presence of a hydrogen acceptor.
• a hydrogen acceptor unsaturated compounds such as 1-dodecene, allyl methacrylate or compounds bearing reducible functional groups such as nitroalkanes or nitroarenes can be utilized.
• the reaction typically requires heating at temperatures above 100 °C for a course of about 12 h or longer.
• a further object of the present invention is a novel method for the preparation of Agomelatine (compound of Formula VI) or a salt thereof, from a compound of Formula la
• compound of Formula la is treated with concentrated aqueous HCl.
• the amount of the acid required is typically between 2 and 3 times the amount by molar of the starting material.
• the rearrangement takes place in common organic solvents such as THF, diethyl ether, tert-butyl methyl ether, preferably in THF.
• the temperature of the reaction ranges from about 0 °C to about 40 °C, typically being between 20-30 °C.
• Compound of formula la is fully consumed usually within 0.5 h to 2 h.
• the reaction mixture is worked up using known methods in the art.
• a solution of compound of formula Ila in common organic solvents typically selected among halogenated ones such as dichloromethane, chloroform, 1,2-dichloroethane or similar is stirred at temperature ranging between 20 and 60 °C, preferably between 20-30 °C.
• the isomerization process usually requires about 12 h to about 24 h to be completed.
• the reaction mixture is worked up using known methods in the art.
• the aromatization of compound of Formula Ilia could be accomplished using DDQ, in 1 to 2 fold molar excess, in any low-polar organic solvent, preferably toluene or dichloromethane (DCM).
• DCM dichloromethane
• the transformation is completed in short reaction times, typically 1-2 hours, at ambient temperature.
• Compound of Formula Ilia can also be dehydrogenated using various palladium sources such as Pd metal or Pd(OH) 2 on activated carbon in the presence of a hydrogen acceptor.
• allyl methacrylate is utilized as the hydrogen acceptor in 3 fold molar excess compared to compound Ilia.
• reaction time varies from about 12 h to about 48 h at a temperature range from 100 °C to 130 °C and the product can be isolated by a simple filtration through a celite pad.
• the aromatization step can be performed with a catalytic amount of DDQ using as a co-oxidant NaN0 2 in the presence of oxygen gas.
• the amount of DDQ required for the completion of the transformation can vary from 0.1 to 0.3 folds the molar amount of the substrate. In a preferred embodiment, this amount can be as low as 0.1 folds the molar amount of the substrate.
• the amount of NaN0 2 can be equal or greater than the amount of DDQ used.
• the amount of co-oxidant NaN0 2 is the same as the molar amount of DDQ, in which case the presence of oxygen gas is required.
• the reaction means can be selected among various medium to high polar aprotic solvents such as ethyl acetate, acetone, acetonitrile.
• the aromatization step is performed in acetonitrile.
• the temperature of the reaction can vary from 30 to 110°C, preferably between 60 and 100°C. More specifically the aromatization takes place by heating between 80-95°C.
• IVa wherein Y is chloro, is converted to agomelatine.
• compound IVa (Y is chloro) is converted to the hydrochloride salt of compound V, using various nitrogen sources.
• the transformation can be achieved directly through a substitution reaction using aqueous ammonia as the nucleophile.
• the substitution is achieved by heating a biphasic system at a temperature range between 80 and 120 °C and typically is completed within a course of a few hours.
• the said transformation can be succeeded through a two-step process comprising conversion of compound of formula IVa, where Y is chloro, to a compound of formula IVa, where Y is phthalimide radical and subsequent hydrolysis to compound of Formula V.
• Compound IVa (Y is phthalimide radical) is prepared using potassium phthalimide as the nitrogen source under heating at about 100 °C in polar solvents such as dimethylformamide. Conversion of phthalimide IVa to compound V is accomplished by hydrazinolysis in protic solvents such as methanol or ethanol.
• acetylation of compound of Formula V or a salt thereof forms compound of Formula VI (Agomelatine).
• the acylation takes place using acetic anhydride as the acylating agent in common protic organic solvents, such as methanol or ethanol, preferably ethanol.
• common protic organic solvents such as methanol or ethanol, preferably ethanol.
• the reaction is completed after heating at the boiling point of the selected solvent for about 1 h.
• the reaction mixture is worked up using known methods in the art.
• the final product, compound of Formula VI is isolated in pharmaceutical acceptable purity after recrystallization from commonly used solvents such as a mixture of water and ethanol.
• Agomelatine is prepared through an allylic rearrangement from compound of formula la, which is prepared from tetralone of formula VII.
• compound of Formula Ilia (1.00 g) is dissolved in toluene and DDQ (1.22 g) is added in one portion at room temperature. The reaction mixture is stirred at the same temperature for 1 h before brine (40 ml) is added. The mixture is extracted with cyclohexane (2 x 40 ml), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to deliver compound of Formula IVa.
• Example 6 Preparation of compound Va (Hydrochloride salt of V)
• Aqueous ammonia 25 % w/w, 1.63 L
• Reaction mixture is cooled down to room temperature and the solvents are removed under vacuum.
• Demineralized water (1.8 L) is added under vigorous stirring followed by addition of 0.63 L dichloromethane.
• the biphasic system is briefly stirred and the organic phase is separated. The organic phase is washed twice with demineralized water (2 x 0.72 L).
• the combined aqueous phases are evaporated to afford a brown wet cake.

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