WO2014009767A1 - Procédé perfectionné pour la préparation de dérivés de 1-aryl-2-aminométhylcyclopropanecarboxamide (z), de leurs isomères et de leurs sels - Google Patents

Procédé perfectionné pour la préparation de dérivés de 1-aryl-2-aminométhylcyclopropanecarboxamide (z), de leurs isomères et de leurs sels Download PDF

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WO2014009767A1
WO2014009767A1 PCT/IB2012/001765 IB2012001765W WO2014009767A1 WO 2014009767 A1 WO2014009767 A1 WO 2014009767A1 IB 2012001765 W IB2012001765 W IB 2012001765W WO 2014009767 A1 WO2014009767 A1 WO 2014009767A1
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compound
formula
azide
group
phenyl
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PCT/IB2012/001765
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English (en)
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Venugopal Reddy GADDAM
Jayakrishna VARADA
Cheluvaraju
Madhusudana Rao Gajula
Pramod Kumar RASTOGI
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Micro Labs Limited
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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
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • 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
    • C07C247/04—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated
    • C07C247/06—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/32—Oxygen atoms
    • C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to an improved process for the preparation of Milnacipran, its stereo specific isomers and its derivatives or a pharmaceutically acceptable salts, hydrate, or solvate thereof. More particularly, the present invention relates to the process for preparation of Milnacipran by in-situ and also using with single solvent to give the high urity and good yield.
  • Milnacipran is chemically known as cyclopropanecarboxamide, 2- (Aminomethyl)-N,N-diethyl-l -phenyl-, cis-( ⁇ )-; ( ⁇ )-[lR(S) ' , 2S(R)]-2-(Aminomethyl)- N,N-diethyl-l-phenylcyclopropanecarboxamide in the form of a base or of a pharmaceutically acceptable salt, and in particular the hydrochloride thereof.
  • Milnacipran is an antidepressant inhibiting recapture of serotonin- noradrenaline recommended in the treatment of depression. It was first approved in France in December 1996. Milnacipran hydrochloride is currently marketed in the form of tablets in Europe, it is available under the brand name Ixel®. It is also available in Japan under the brand name Toledomin® and Mexico under the brand name Dalcipran® for depression. While In January 2009 the U.S. Food and Drug Administration (FDA) approved Milnacipran under the brand name Savella® only for the treatment of fibromyalgia, making it the third medication approved for this purpose in the United States.
  • FDA U.S. Food and Drug Administration
  • Milnacipran hydrochloride is a racemic mixture of two of the four possible stereoisomers; specifically, a 1 :1 mixture of the two Z (cis) isomers and chemical structurally represented as followin :
  • Milnacipran hydrochloride is recrystallized from petroleum ether.
  • the reaction is schematically represented by scheme 1.
  • the process involves multi step and ether as solvent, which is not commercially feasible.
  • the United States Patent No. 5,034,541 discloses a process for the preparation of phthalimide derivative, which involves the l-Phenyl-3-oxabicyclo [3,1,0] hexan-2- one reacted with diethyl amine in presence of lewis acid such as aluminum chloride in dichloroethane as a solvent to get the hydroxyl compound.
  • lewis acid such as aluminum chloride in dichloroethane as a solvent
  • the obtained intermediate of hydroxyl compound is chlorinated by using with thionyl chloride in dichloroethane as solvent and the resulting chloro compound was reacted with potassium phthalimide in dimethyl formamide to get a phthalimide derivative.
  • the reaction is schematically represented. by scheme 2.
  • the United States Patent Application No.US2008/0051604 Al discloses process for preparing Milnacipran, which involves the hydrolysis of (Z)-l -phenyl- 1 diethylaniinocarbonyl-2-phthalimidomethylcyclopropane in the presence of aqueous methylamine solution having concentration of from 1 to 25% by weight to obtain (Z)- 1 -phenyl- l-diethylaminocarbonyl-2-aminoethylcyclopropane.
  • the reaction is schematically represented by scheme 3.
  • the process involves costly key starting material and uses methyl amine, which is irritating to eyes, nose and throat.
  • the United States Patent Application No.US 2010/0145099 Al discloses a process for preparing Milnacipran, which involves the hydrolysis of (Z)- 1 -Phenyl- 1 - diethylaminocarbonyl-2-phthalimidomethylcyclopropane in presence of aqueous hydrazine hydrate in ethanol.
  • the resulting Milnacipran hydrochloride was obtained in a mixture of IPA-HC1 and ethyl acetate.
  • the reaction is schematically represented by scheme 4.
  • the process involves costly key starting material and uses hydrazine hydrate, which is highly explosive.
  • the European Patent No. EP 0200638 Bl discloses a process for preparing Milnacipran hydrochloride, which comprises the reaction of potassium phthalimide with l-Phenyl-3-oxabicyclo [3,1,0] hexan-2-one in presence of high boiling solvent such as dimethyl sulfoxide at 150-200°C to get the intermediate of acid compound.
  • the intermediate of acid compound was treated with thionyl chloride and followed by diethyl amine to resulting phthalimide compound, further it's hydrolyzed in presence of organic base in organic solvent to get the desired compound.
  • the reaction is schematically represented by scheme 5.
  • the PCT Patent Application No. WO2010/086394 Al discloses a process for the preparation of Milnacipran hydrochloride, which comprises the reaction of phenylacetonitrile and (R)-epichlorohydrin in presence of alkaline metal base, followed by basic hydrolysis and acid treatment to obtain the lactone compound.
  • the lactone compound is opened by using diethyl amine in presence of lewis acid such as aluminum chloride in toluene as a solvent and further chlorination with thionyl chloride in dichloroethane as solvent.
  • lewis acid such as aluminum chloride in toluene as a solvent
  • thionyl chloride in dichloroethane as solvent.
  • the resulting chloro compound is reacted with potassium phthalimide in toluene to forms phthalimide intermediate.
  • the main objective of the present invention is to provide a single pot process for the preparation of Milnacipran, derivatives and its stereospecific isomers or acid addition salts.
  • Another object of the present invention is to provide is simple and rapid work up process in a single solvent for the isolation of Milnacipran, derivatives and/or its stereospecific isomers or its pharmaceutically acceptable salts thereof, which employs less time consuming with unproblematic, convenient to carry out.
  • Yet another object of the present invention is to provide Milnacipran hydrochloride and /evo-Milnacipran hydrochloride having purity >99.8%.
  • Yet another object of the present invention is to provide a pharmaceutical composition containing Milnacipran, its stereospecific isomers and its pharmaceutically acceptable salts, prepared according to instant invention.
  • the present invention relates to provide an improved process for preparing a compound of formula (I)
  • Ri and R 2 are independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, and lower-alkylaryl, wherin aryl or alkylaryl group is optionally substituted by a halogen atom.
  • R ⁇ and R 2 are the same as defined above.
  • the present invention relates to a process, which is carried out without isolating any intermediate products (a method described as a one- pot method).
  • the present invention relates to the preparation of stereo specific isomer of Milnacipran by carrying the similar stereo specific isomers of intermediates.
  • the present invention can be carried out in a reaction medium comprising same and single suitable solvent system such as toluene or multiple organic solvents.
  • the present invention relates to a process which affords good quality and yield.
  • the process is simple and cost-effective.
  • the present invention relates to prepare substantially pure crystalline forms of Milnacipran hydrochloride.
  • the present invention relates to prepare substantially pure crystalline forms of /evo-Milnacipran hydrochloride. Further, it is the aim of the invention to provide a process for the preparation of Milnacipran and its pharmaceutically acceptable salts, prepared according to present invention.
  • the present invention provides a process for the preparation of highly pure Milnacipran, derivatives and its stereo specific isomers or a pharmaceutically acceptable salt thereof, with good yield and purity.
  • R ⁇ and R 2 represents independently selected group consisting of hydrogen, lower alkyl, lower aryl, and lower-alkylaryl, wherein aryl or alkylaryl group is optionally substituted by a halogen atom, and, with the adjacent nitrogen atom, a heterocycle of 5 or 6 ring members; comprising the following successive steps: a) reacting l-phenyl-3-oxabicyclo[3.1.0]hexan-2-one, a compound of formula (II)
  • the present invention relates to a method for synthesizing a pharmaceutically acceptable acid addition salt of milnacipran, its stereo specific isomers of the following formula (la):
  • steps (a) to (e) will advantageously be carried out in a reaction medium comprising a same and single solvent such as toluene.
  • the reaction step-a is condensation reaction between l-phenyl-3- oxabicyclo[3.1.0]hexan-2-one compound of formula (II) and amine compound of formula (VI) in the presence of lewis acids or metal alkoxide or metal hydride or organolithium reagents in suitable organic solvents.
  • the reaction step-a is carried out with molar equivalent of amine compound of formula (VI) inhabits 1 to 5 equivalents with respect to the compound of formula II. Preferably about 2 to 3 equivalents are used.
  • the reaction step-a is carried out with the suitable lewis acids which includes, but are not limited to aluminium chloride, aluminium bromide, aluminium triethoxide, aluminium triisopropoxide, boron trifluoride, boron trichloride, iron(III) chloride (ferric chloride), iron(III) bromide (ferric bromide), tin(IV) chloride (stannic chloride), titanium tetrachloride, titanium isopropoxide.
  • the lewis acid is selected from aluminum chloride, aluminum bromide.
  • reaction step-a is carried out with molar equivalent of lewis acid employed is from about an equimolar amount to about 4 times the equimolar amount with respect to the compound of formula II. Preferably about 1 to 1.5 equivalents are used.
  • the reaction also can carried out using the metal alkoxide such as sodium methoxide, potassium ethoxide, potassium tertiary butoxide etc or metal halides such as sodium hydride, lithium hydride, potassium hydride etc or organolithium reagents such as «-butyllithium, hexllithium, lithium di-isopropyl amide (LDA), lithium bis(trimethylsilyl)amide (LilTMDS) etc.
  • metal alkoxide such as sodium methoxide, potassium ethoxide, potassium tertiary butoxide etc or metal halides
  • sodium hydride, lithium hydride, potassium hydride etc or organolithium reagents such as «-butyllithium, hexllithium, lithium di-isopropyl amide (LDA), lithium bis(trimethylsilyl)amide (LilTMDS) etc.
  • the reaction step-a is carried out in a suitable organic solvent preferably selected, but is not limited to aliphatic hydrocarbons such as CI -CIO straight chain or branched hydrocarbons such as n-hexane, «-heptane, cyclohexane, pentane, etc; and aromatic hydrocarbons such as toluene, xylene, etc; ethers such as diethyl ether, , diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, dioxane, etc; and mixtures thereof.
  • aliphatic hydrocarbons such as CI -CIO straight chain or branched hydrocarbons such as n-hexane, «-heptane, cyclohexane, pentane, etc
  • aromatic hydrocarbons such as toluene, xylene, etc
  • ethers such as diethyl ether, , diiso
  • the organic solvent is selected from toluene, diethyl ether; more preferably the solvent is toluene.
  • the reaction step-a is carried out at a temperature of about -10°C to about 80°C.
  • the reaction is carried out at a temperature of about 20°C to about 30 °C.
  • the reaction step-a is carried out for a period of about 30 minutes to about 3 hours. Preferably from about 1 hour to about 2 hours.
  • reaction completion may be monitored by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC).
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • reaction mixture is quenched either into water or into dilute hydrochloric acid.
  • the organic layer may be optionally washed with aqueous sodium chloride solution and the organic layer, containing 1-phenyl-l- diethylaminocarbonyl-2-hydroxymethylcyclopropane, the compound of formula (III), is used for step (b) in the process, just described in above detailed description.
  • the reaction step-b is chlorination reaction between hydroxy compound and chlorinating agent in suitable organic solvents.
  • the reaction step-b is carried out with the suitable chlorinating agents which includes, but is not limited to organic or inorganic chlorinating agents such as thionyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorous oxychloride, etc; preferably the chlorinating agent is thionyl chloride.
  • the reaction step-b is carried out the suitable organic solvent preferably selected, but is not limited to aliphatic hydrocarbons such as CI -CIO straight chain or branched hydrocarbons such as -hexane, «-heptane, cyclohexane, pentane, etc; and aromatic hydrocarbons such as toluene, xylene, etc; haloalkanes such as dichloromethane, chloroform, etc; ethers such as diethyl ether, , diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, dioxane, etc; and mixtures thereof.
  • the organic solvent is selected from dichloromethane, toluene; More preferably the solvent is dichloromethane.
  • the reaction step-b is beautifully carried out at a temperature of about - 10°C to about 160°C.
  • the reaction is carried out at a temperature of about 50°C to about 110°C.
  • the reaction step-b is well carried out for a period of about 15 minutes to about 2 hours. Preferably about 30 minutes to about 45 minutes.
  • reaction completion may be monitored by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC).
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • the reaction mixture is quenched either into water or into partially alkaline solution.
  • the organic layer may be optionally washed with weak base such as alkali metal carbonate, alkali metal bicarbonate agents such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
  • the base is sodium bicarbonate.
  • the organic layer, containing 1-phenyl-l- diethylaminocarbonyl-2-chloromethylcyclopropane, the compound of formula (IV), is used for (c) in the process, just described in above detailed description.
  • the reaction step-c is an azide formation, the reaction between chloro compound and an azide compound in the presence or absence of a phase-transfer catalyst in suitable organic solvents.
  • the reaction step-c is carried out with a suitable azide compound which includes, but is not limited to metal azide such as sodium azide, potassium azide, zinc azide, tributyltin azide, aluminum azide, trialkyl silyl azide etc; preferably the azide compound is sodium azide.
  • metal azide such as sodium azide, potassium azide, zinc azide, tributyltin azide, aluminum azide, trialkyl silyl azide etc; preferably the azide compound is sodium azide.
  • the reaction step-c is carried out the suitable organic solvent preferably selected, but is not limited to aliphatic hydrocarbons such as CI -CIO straight chain or branched hydrocarbons such as tt-hexane, rc-heptane, cyclohexane, pentane, etc; alcoholic solvents such as branched or chain C 1-C4 selected alcohols as methanol, ethanol, isopropyl alcohol, etc; and aromatic hydrocarbons such as toluene, xylene, etc; ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, dioxane, etc; dimethylformaniide, w-methylpyrrolidone, etc; and mixtures thereof.
  • the organic solvent is selected from toluene, diethyl ether; more preferably the solvent is toluene.
  • the reaction step-c is well carried out
  • reaction is carried out at a temperature of about 90°C to about 1 10°C.
  • the reaction step-c is incredibly carried out with the suitable phase transfer catalyst which includes, but is not limited to tetrabutylammonium bromide. triethylbenzylammonium chloride, tricaprylmethylammonium chloride and tetrabutylammonium hydroxide etc; preferably the phase transfer catalyst is tetrabutylammonium bromide.
  • the reaction step-c is carried out in the presence of phase transfer catalyst for a period of about 30 minutes to about 5 hours. Preferably about 1 hour to about 2 hours. In absence of phase transfer catalyst the reaction carried out for a period of about 15 hours to 30 hours. Preferably about 20 hour to about 24 hours.
  • reaction mixture is cooled to 0 to 30°C and proceeds for step-d in the process.
  • reaction mixture is quenched in water and separates the layers; optionally the organic layer washed with water and the resulting organic layer is used for step-d in the process, just described in above detailed description.
  • organic layer washed with water and the resulting organic layer is used for step-d in the process, just described in above detailed description.
  • washed out organic layer distilled the solvent completely under vacuum.
  • the resulting residue compound of formula (V) is used for step-d in the process, just described in above detailed description.
  • the reaction step-d is reduction reaction between an azide compound and reducing agent in suitable organic solvents.
  • the reaction may takes place in an aqueous or non-aqueous medium.
  • the reaction step-d is carried out with a suitable reducing agent which includes, but is not limited to metal or non-metal reducing agents such as iron, zinc, magnesium, palladium, platinum, triphenylphosphine, etc; preferably the reducing agent is tiphenyl phosphine or iron.
  • a suitable reducing agent which includes, but is not limited to metal or non-metal reducing agents such as iron, zinc, magnesium, palladium, platinum, triphenylphosphine, etc; preferably the reducing agent is tiphenyl phosphine or iron.
  • the reaction step-d is carried out in suitable organic solvent preferably selected, but is not limited to aliphatic hydrocarbons such as CI -CIO straight chain or branched hydrocarbons such as w-hexane, rc-heptane, cyclohexane, pentane, etc; alcoholic solvents such as branched or chain C1-C4 selected alcohols as methanol, ethanol, isopropyl alcohol, etc; haloalkanes such as dichloromethane, chloroform, etc; and aromatic hydrocarbons such as toluene, xylene, etc; ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, dioxane, etc; dimethylformamide (DMF), «-methylpyrrolidone, etc; and mixtures thereof. More preferably, the organic solvent selected is toluene.
  • the reaction step-d
  • reaction is carried out at a temperature of about 60°C to about 1 10°C.
  • the reaction step-d is carried out for a period of about 10 minutes to about 5 hours. Preferably about 30 minutes to about 1 hour using triphenyl phosphine as reducing agent. In particularly the reaction will proceeds for a period of about 3 to 4 hrs using iron/ammonium chloride as reducing agent in suitable solvents such as alcohols or chlorinating solvents.
  • reaction may be monitored by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC).
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • the reaction mixture is distilled out completely under vacuum.
  • the resulting residue is quenched either into water or into dilute hydrochloric acid and filtered the reaction mixture.
  • the resulting filtrate was dissolved in suitable organic solvent; adjust the pH 9-12 using with base such as alkali metal hydroxide, alkali metal carbonate, and alkali metal bicarbonate agents such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
  • base is sodium hydroxide.
  • the layers were separated; the organic layer optionally washed with aqueous sodium chloride solution and optionally the organic layer distilled the solvent completely under vacuum.
  • the resulting residue compound of formula is used in step-e in the process, just described in above detailed description.
  • the reaction step-e is salification reaction between the resulting compound of step-d and pharmaceutical acceptable acid salts in suitable organic solvents for the conventional methods.
  • the reaction is carried out with the pharmaceutical acceptable acid salts includes, but is not limited to mineral acids or inorganic acids or organic acids such as 1 -hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2- oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor- 10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid dodecylsulfuric acid
  • the reaction step-e is carried out the suitable organic solvent preferably selected, but is not limited to aliphatic hydrocarbons such as CI -CIO straight chain or branched hydrocarbons such as n-hexane, «-heptane, cyclohexane, pentane, etc; alcoholic solvents such as branched or chain C1-C4 selected alcohols as methanol, ethanol, isopropyl alcohol, etc; and aromatic hydrocarbons such as toluene, xylene, etc; haloalkanes such as dichloromethane, chloroform, etc; ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, tetrahydrofuran, dioxane, etc; and mixtures thereof.
  • the organic solvent is selected from dichloromethane, toluene, and diethyl ether; More preferably the solvent is toluene.
  • the reaction step-e is well carried out at a temperature of about 0°C to about 1 10°C. Preferably, the reaction is carried out at a temperature of about 20°C to about 30°C.
  • the reaction step-e is carried out for a period of about 10 minutes to about 1 hour. Preferably about 20 minutes to about 30 minutes.
  • the reaction step-f is purification reaction for the resulting compound of step- d or step-e in suitable organic solvents for the conventional methods.
  • the present invention provides an additional new aspect i.e. one-pot process in a single solvent, with high yield and purity.
  • the reaction can either be carried out in a reaction medium comprising a same and single suitable solvent such as toluene or multiple solvent systems with different suitable organic solvents.
  • R4 and R 2 are represents independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, and lower-alkylaryl, which aryl or alkylaryl group is optionally substituted by a halogen atom, and, with the adjacent nitrogen atom, a heterocycle of 5 or 6 ring members; comprising the following successive steps: a) reacting l-phenyl-2-hydroxymethylcyclopropane, a compound of formula (III)
  • the reaction is well carried out at a temperature of about 0°C to about 1 10°C. Preferably, the reaction is carried out at a temperature of about 10°C to about 30°C.
  • the reaction is incredibly carried out for a period of about 30 minutes to about 5 hours. Preferably about 1 hour to about 3 hours.
  • the reaction is carried out the suitable organic solvents for preferably selected, the organic solvent is selected from dimethylformamide, dichloromethane, chloroform, toluene, diethyl ether; more preferably the solvent is dimethylformamide, toluene.
  • Ri and R 2 are represented by independently selected from the group consisting of hydrogen, lower alkyl, lower aryl, and lower-alkylaryl, which aryl or alkylaryl group is optionally substituted by a halogen atom, and, with the adjacent nitrogen atom, a heterocycle of 5 or 6 ring members; comprising the following successive steps: a) reacting l -phenyl-2-hydroxymethylcyclopropane, a compound of formula (III)
  • the reaction is well carried out at a temperature of about 0°C to about 1 10°C. Preferably, the reaction is carried out at a temperature of about 10°C to about 30°C.
  • the reaction is carried out for a period of about 30 minutes to about 5 hours. Preferably about 1 hour to about 3 hours.
  • the reaction is carried out the suitable organic solvents for preferably selected, the organic solvent is selected from dimethylformamide, dichloromethane, chloroform, toluene, diethyl ether; more preferably the solvent is dimethylformamide, toluene.
  • milnacipran its stereospecific isomers compound of formula (I) as used herein refers to inclusive all polymorphs forms of milnacipran or its pharmaceutically acceptable salt thereof, for example polymorphs of crystalline form, or hydrates, and solvates thereof.
  • Aluminium chloride 100 g was suspended in (600 ml) toluene and then added diethylamine (109 g) under stirring at below room temperature.
  • diethylamine 109 g was added to the reaction mass for 1 hour.
  • the temperature of the reaction mass was raised at room temperature and stirred for 1 hour.
  • quenched the reaction mass in ice-cooled water 700 ml).
  • the organic layers was collected and washed with water and hydrochloric acid. This was directly taken as such for the next stage.
  • the resulting reaction mass was distilled out completely under vacuum. To the residual mass was added IPA and IPA.HCl and stirred for 30 minutes at room temperature. Distilled out completely under vacuum. The resulting crude compound was suspended in ethyl acetate. The reaction mass was refluxed for 1 hour and cooled to 20 to 30°C and maintained for 30 minutes. The solid was filtered and dried at 50 to 60°C for 4 hours to obtain 135 gm of Milnacipran hydrochloride.
  • Example 2 Preparation of 1 -phenyl- 1 -diethylaminocarbonyl-2- hydroxymethylcyclopropane.
  • Aluminium chloride 100 g was suspended in (600 ml) EDC and then added diethylamine (109 g) under stirring at below room temperature.
  • cis-( ⁇ )-l-phenyl-3- oxabicyclo[3.1.0]hexan-2-one was added to the reaction mass for 1 hour.
  • the temperature of the reaction mass was raised at room temperature and stirred for 1 hour.
  • the layers were separated and the aqueous layer was discarded.
  • the resulting organic layer was distilled out completely under vacuum.
  • the residue was dissolved in (400 ml) diisopropyl ether and stirred for 1 hour at 0°C to 30°C, filtered the precipitated desired compound (135 g).
  • Example 3 Preparation of l-phenyl-l-diethylaminocarbonyl-2- chloromethylcyclopropane.
  • 1 -Phenyl- l-diethylaminocarbonyl-2-hydroxymethylcyclopropane (100 g) was dissolved in (1000 ml) MDC at room temperature and cooled to 0-10°C followed by added thionyl chloride (80 g) at to 0-10°C for about 1 hour.
  • the reaction mass was stirred for 2 hour at reflux temperature. After completion of the reaction, quenched the reaction mass in water (600 ml).
  • the layers were separated and the aqueous layer was discarded, collected the MDC layer and wash with water and sodium bicarbonate solution.
  • the resulting organic layer was distilled out completely under vacuum.
  • the desired compound residue was obtained (100 g).
  • Example 4 Preparation of l-phenyl-l-diethylaminocarbonyl-2- azidoromethylcyclopropane.
  • l-Phenyl-l-diethylaminocarbonyl-2-chloromethylcyclopropane (100 g) was dissolved in DMF (200 ml) at room temperature and followed by addition of .sodium azide (24 g).
  • the reaction mass was stirred for 1 to 2 hours at 50-60°C. After completion of the reaction, quenched the reaction mass in water (400 ml) followed by ethyl acetate (500 ml).
  • the layers were separated and the aqueous layer was discarded, collected the ethyl acetate layer and wash with water.
  • the resulting organic layer was distilled out completely under vacuum.
  • the desired compound residue was obtained (100 g).
  • Example 5 Preparation of l-phenyl-l-diethylaminocarbonyl-2- chloromethylcyclopropane.
  • l-Phenyl-l-diethylaminocarbonyl-2-azidoromethylcyclopropane 100 g was dissolved in toluene (300 ml) at room temperature and triphenylphosphine (100 g) and toluene (200 ml) was added to the reaction mass for 30 minutes and stirred for 1 hour. After completion of the reduction, distilled out completely under vacuum. Water (400 ml) was added to the reaction mass and adjust the pH of the reaction mass to 1-2 with con. HCl and stirred for 1 hour at room temperature.
  • Milnacipran (80 g) was dissolved in IPA (150 ml), IPA.HC1 (100 ml) and stirred for 30 minutes at room temperature. Distilled out completely under vacuum. The resulting crude compound was suspended in ethyl acetate. The reaction mass was stir for refluxed for 1 hour and cooled to 20 to 30°C and maintained for 30 minutes. The separated solid was filtered, washed with ethyl acetate (200 ml) and dried at 50 to 60°C for 4 hours to obtain 82 gm of Milnacipran hydrochloride.
  • Example 7 Preparation of cis-( ⁇ )-l-phenyl-l-diethylaminocarbonyl-2-azidomethyl cyclopropane Sodium azide (37 g) and tetrabutyl ammonium bromide (10 g) was added to a toluene layer obtained from step-ii in Example 1 at below room temperature. The reaction mass was stirred for 4 to 5 hour at reflux. After completion of the reaction, quenched the reaction mass in water (300 ml). The layers were separated and the aqueous layer was discarded. The residue of title compound (120 g) was isolated by concentrating the toluene layer.
  • Example 8 Preparation of cis-( ⁇ )-l-phenyl-l-diethylaminocarbonyl-2-azidomethyl cyclopropane l-Phenyl-l-diethylaminocarbonyl-2-chloromethylcyclopropane (140 g) was dissolved in DMF (500 ml) at room temperature and followed by addition of .sodium azide (37 g) and tetrabutyl ammonium bromide (10 g) at room temperature. The reaction mass was stirred for 1 to 2 hour at 50 to 60oC. After completion of the reaction, quenched the reaction mass in water (300 ml).
  • Example- 1 A residue obtained from Example- 1 (600 ml) was dissolved in water (200 ml). Iron (38 g) and ammonium chloride (1 10 g) was added to the reaction mass. The reaction mass was re fluxed for 4 to 5 hours at room temperature. After completion of the reduction, cooled the reaction mass and filtered through hyflo bed. Concentrating the filtrate and extract the compound from filtrate with dichloromethane. The solvent of resulting reaction mass was distilled out completely under vacuum. To the residual mass was added ethyl acetate, IPA.HC1 and stirred for 30 minutes at room temperature. The reaction mass was cooled to 10 to 15°C and maintained for 1 hour 30 minutes. The separated solid was filtered and dried at 50 to 60°C for 4 hours to obtain milnacipran hydrochloride (125 gm).
  • Aluminium chloride 100 g was suspended in (600 ml) toluene and then added diethylamine (109 g) under stirring at below room temperature.
  • diethylamine 109 g was added to the reaction mass for 1 hour at below room temperature.
  • the temperature of the reaction mass was raised at room temperature and stirred for 1 hour.
  • quenched the reaction mass in ice-cooled water 700 ml).
  • the organic layers was collected and washed with water and hydrochloric acid. This was directly taken as such for the next stage.
  • the resulting reaction mass was distilled out completely under vacuum. To the residual mass was added IPA and IPA.HCl and stirred for 30 minutes at room temperature. Distilled out completely under vacuum. The resulting crude compound was suspended in ethyl acetate. The reaction mass was refluxed for 1 hour and cooled to 20 to 30°C and maintained for 30 minutes. The solid was filtered and dried at 50 to 60°C for 4 hours to obtain 135 gm of Levomilnacipran hydrochloride.
  • Example 11 Preparation of (IS, 2 R)-l -phenyl- 1-diethylamino carbonyl-2- hydroxymethyl cyclopropane.
  • Aluminium chloride 100 g was suspended in (600 ml) EDC and then added diethylamine (109 g) under stirring at below room temperature.
  • cis-(+)-l-phenyl-3- oxabicyclo[3.1.0]hexan-2-one was added to the reaction mass for 1 hour.
  • the temperature of the reaction mass was raised at room temperature and stirred for at least 1 hour.
  • the layers were separated and the aqueous layer was discarded.
  • the resulting organic layer was distilled out completely under vacuum.
  • the residue was dissolved in (400 ml) diisopropyl ether and stirred for 1 hour at 0°C to 30°C, filtered the precipitated desired compound (135 g).
  • Example 12 Preparation of (IS, 2R)-l-phenyl-l-diethylaminocarbonyl-2-chloromethyl cyclopropane. (IS, 2R)- 1 -Phenyl- 1 -diethylaminocarbonyl-2-hydroxymethylcyclopropane
  • Example 13 Preparation of (IS, 2R)-l-phenyl-l-diethylaminocarbonyl-2- azidoromethyl cyclopropane.
  • (I S, 2R)-l-Phenyl-l-diethylaminocarbonyl-2-chloromethylcyclopropane (100 g) was dissolved in DMF (200 ml) at room temperature and followed by added Sodium azide. The reaction mass was stirred for 1 to 2 hours at 50-60°C. After completion of the reaction, quenched the reaction mass in water (400 ml) followed by ethyl acetate (500 ml). The layers were separated and the aqueous layer was discarded, collected the ethyl acetate layer and washed with water. The resulting organic layer was distilled out completely under vacuum. The desired compound residue was obtained (100 g).
  • Example 14 Preparation of (IS, 2R)-l-phenyl-l-diethylaminocarbonyl-2-chloromethyl cyclopropane (Levomilnacipran) crude.
  • Levomilnacipran crude 80 g was dissolved in IPA (150 ml), IPA.HC1 (100 ml) and stirred for 30 minutes at room temperature. Distilled out completely under vacuum. The resulting crude compound was suspended in ethyl acetate. The reaction mass was stir for refluxed for 1 hour and cooled to 20 to 30°C and maintained for 30 minutes. The separated solid was filtered, washed with ethyl acetate (200 ml) and dried at 50 to 60°C for 4 hours to obtain 82 gm of Levomilnacipran hydrochloride.
  • Example 16 Preparation of (IS, 2R)-l-phenyl-l-diethylaminocarbonyl-2- azidoromethyl cyclopropane Sodium azide (37 g) and tetrabutyl ammonium bromide (10 g) was added to a toluene layer obtained from step-ii in Example 10 at below room temperature. The reaction mass was stirred for 4 to 5 hour at reflux. After completion of the reaction, quenched the reaction mass in water (300 ml). The layers were separated and the aqueous layer was discarded. The residue of title compound (120 g) was isolated by concentrating the toluene layer.
  • Example- 10 A residue obtained from Example- 10 (600 ml) was dissolved in water (200 ml). Iron (38 g) and ammonium chloride (1 10 g) was added to the reaction mass. The reaction mass was reflex for 4 to 5 hour at room temperature. After completion of the reduction, cooled the reaction mass and filtered through hyflo bed. Concentrating the filtrate and extract the compound from filtrate with dichloromethane. The resulting reaction mass was distilled out completely under vacuum. To the residual mass was added ethyl acetate, isopropyl alcohol in HC1 and stirred for 30 minutes at room temperature. The reaction mass was cooled to 10 to 15°C and maintained for 1 hour 30 minutes. The separated solid was filtered and dried at 50 to 60°C for 4 hours to obtain levomilnacipran hydrochloride (125 gm).
  • Example 19 Preparation of cis-(+)-l-phenyl-3-oxabicyclo[3.1.0]hexan-2-one or (IS, 5R) -1- Phenyl-3-oxabicyclo (3, 1, 0) hexane -2-one [(S)-Lactone] : Sodium amide (20 g) was suspended in toluene (100 ml) and added phenyl acetonitrile (20 g) at below room temperature. The reaction mass was stirred for 1 hour at 0°C. Added the (R)-epichlorohydrin (15 g) to the reaction mass and stirred for 2 hours at room temperature. After completion of the reaction, quenched the reaction mass in ice-cooled water (400 ml). The layers were separated and the aqueous layer was discarded, collected the residue compound (20 g) by concentrating the toluene layer.
  • IPA.HC1 Isopropyl alcohol, hydrochloride
  • LiHMDS Lithium bis(trimethylsilyl)amide

Abstract

La présente invention porte sur un procédé monotope perfectionné pour la préparation de dérivés de 1-aryl-2-aminométhylcyclopropanecarboxamide (Z), de leurs isomères de formule (I) ou de leurs sels pharmaceutiquement acceptables, dans laquelle formule R1 et R2 représentent chacun indépendamment un groupe choisi parmi l'atome d'hydrogène, un groupe alkyle inférieur, un groupe aryle inférieur et un groupe alkylaryle inférieur, lequel groupe aryle ou alkylaryle est éventuellement substitué par un atome d'halogène.
PCT/IB2012/001765 2012-07-07 2012-09-12 Procédé perfectionné pour la préparation de dérivés de 1-aryl-2-aminométhylcyclopropanecarboxamide (z), de leurs isomères et de leurs sels WO2014009767A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
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CN104058992A (zh) * 2014-06-13 2014-09-24 上海现代制药股份有限公司 左旋米那普仑盐酸盐的晶型
WO2016071303A1 (fr) 2014-11-04 2016-05-12 Quimica Sintetica, S.A. Procédé pour la préparation de (1s,2r)-milnacipran
WO2019097539A1 (fr) * 2017-11-14 2019-05-23 Metrochem Api Pvt Ltd. Procédé amélioré pour la préparation de lévomilnacipran

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* Cited by examiner, † Cited by third party
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CN104058992A (zh) * 2014-06-13 2014-09-24 上海现代制药股份有限公司 左旋米那普仑盐酸盐的晶型
WO2016071303A1 (fr) 2014-11-04 2016-05-12 Quimica Sintetica, S.A. Procédé pour la préparation de (1s,2r)-milnacipran
US10131624B2 (en) 2014-11-04 2018-11-20 Quimica Sintetica, S.A. Process for the preparation of (1S,2R)-Milnacipran
WO2019097539A1 (fr) * 2017-11-14 2019-05-23 Metrochem Api Pvt Ltd. Procédé amélioré pour la préparation de lévomilnacipran

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