WO2008072257A2 - Process for the preparation of indole derivatives - Google Patents

Process for the preparation of indole derivatives Download PDF

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Publication number
WO2008072257A2
WO2008072257A2 PCT/IN2007/000571 IN2007000571W WO2008072257A2 WO 2008072257 A2 WO2008072257 A2 WO 2008072257A2 IN 2007000571 W IN2007000571 W IN 2007000571W WO 2008072257 A2 WO2008072257 A2 WO 2008072257A2
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Prior art keywords
formula
acid
ethyl
methylsulfamoyl
compound
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PCT/IN2007/000571
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French (fr)
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WO2008072257A3 (en
Inventor
Ashvin Kumar Aggarwal
Gurdeep Singh Sarin
Chidambaram Venkateswaran Srinivasan
Lalit Wadhwa
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Ind-Swift Laboratories Limited
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Publication of WO2008072257A3 publication Critical patent/WO2008072257A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/31—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms
    • C07C311/35—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atoms of the sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel process for the preparation of indole derivatives.
  • present invention relates to a process for preparing naratriptan of formula I, and its salts using novel intermediates. 3
  • This invention also relates to novel synthetic intermediates useful in the processes of the present invention.
  • Naratriptan of formula I is being sold as hydrochloride salt in pharmaceutical products using the trademark AMERGE, for treating migraine and is chemically known as N-methyl-3-(l - methyl-4-piperidinyl)-l-H-indole-5-ethanesulphon- amide.
  • naratriptan is prepared by the reduction of N-mcthyl-3- (l -methyl-pyridin-4-yl)-lH-indole-5-ethenesulphonarnide in the presence of hydrogen and a noble metal catalyst same as described above.
  • the corresponding 5-ethenesulphonamide is prepared by ⁇ eck reaction in the presence of tri-o-tolylphosphine, palladium catalyst and base like triethyl amine.
  • patent 5,659,040 discloses a process for preparing naratriptan hydrochloride by reducing the diene intermediate, N-methyl-2-[3-(l,2,3,6-tetrahydro- l-methyl-4-pyridinyl)-l H-indol-5- yl]ethenesulphonamide in the presence of hydrogen and a noble metal catalyst like palladium, palladium oxide, Raney nickel, platinum, platinum oxide or rhodium and homogenous catalyst like tris(triphenylphosphine)rhodium chloride.
  • the synthesis of diene intermediate also involves ⁇ eck reaction.
  • PCT application WO 2006/010079 discloses a process for preparing naratriptan by reacting a diazotized derivative of N-methyl-2-(4-amino-phenyl)ethane sulphonamide with a compound selected from
  • the present invention meets the need in the art for a novel, efficient and improved process for providing naratriptan, unique with respect to its simplicity, cost effectiveness and scalability.
  • the present invention relates to a novel and efficient process for the preparation of naratriptan of formula I,
  • novel intermediates of formulae II, III and IV further forms the part of the invention.
  • the present invention provides a novel process for the preparation of compound of formula II, which comprises reacting 2-(4-hydrazino-phenyl)cthanesuIphonic acid methylamide of formula V or an acid addition salt thereof,
  • the present invention further provides a novel process for the preparation of compound of formula II, which comprises reacting the diazotized derivative of 2- (4-amino-phenyl)-ethanesulphonic acid methylamide of formula VI,
  • the present invention provides a novel and efficient process for the preparation of naratriptan of formula I and pharmaceutically acceptable salt thereof which comprises:
  • Figures 1 and 2 illustrate X-ray diffraction pattern and DSC for naratriptan respectively
  • Figures 3 and 4 illustrate X-ray, diffraction pattern and DSC for naratriptan hydrochloride respectively.
  • the process of the present invention is a high throughput, novel, efficient and industrially viable process for the preparation of naratriptan of formula I,
  • Novel intermediates prepared using process of the present invention also forms the part of the present invention and may be characterized by at least one of the mass spectra (MS), infra-red (IR) spectroscopy, 1 H or 13 C nuclear magnetic resonance (NMR) spectroscopy or differential scanning calorimetry (DSC).
  • MS mass spectra
  • IR infra-red
  • NMR nuclear magnetic resonance
  • DSC differential scanning calorimetry
  • X-ray diffraction of naratriptan and its hydrochloride salt were measured on a PANalytical X' Pert Pro diffractometer with Cu radiation and expressed in terms of two-thcta, d-spacings and relative intensities.
  • PANalytical X' Pert Pro diffractometer with Cu radiation and expressed in terms of two-thcta, d-spacings and relative intensities.
  • DSC analysis was performed using a Mettler Toledo DSC 823 e .
  • the weight of the samples was about 5-10 mg; the samples were scanned at a rate of 10°C/min. from 80 0 C to 280 0 C.
  • Mass spectrometry was performed using an ionization method i.e. atmospheric pressure chemical ionization (APCI) at atmospheric pressure using micromass Q-Tof micro LCMS/MS.
  • APCI atmospheric pressure chemical ionization
  • 1 H or 13 C NMR was performed using BRUKER AVANCE II 400 NMR Spectrometer.
  • the reaction involves adding ethyl pyruvate and a mild organic acid to the mixture of 2-(4-hydrazino-phenyl)-ethanesulphonic acid methylamide acid addition salt particularly its hydrochloride salt in a suitable solvent, while maintaining the temperature of the reaction at about 20-80 0 C, preferably at 20-40 0 C for a period of about 1 to 6 hours.
  • the mild organic acid can be selected from, but not limited to acetic acid, formic acid and the like.
  • the solvent can be selected from, but not limited to C M alcohols; ethers such as diethyl ether; halogenated solvent like methylene dichloride; water, the like and mixtures thereof.
  • the present invention provides an alternate process for preparing the novel intermediate, 2- ⁇ [4- (2-methylsulfamoyl-ethyl)-phenyI]-hydrazono ⁇ -propionic acid ethyl ester of formula II under Japp-Klingemann coupling conditions.
  • 2- ⁇ [4-(2-methylsulfamoyl-ethyl)-phenyl]-hydrazino ⁇ -propionic acid ethyl ester of formula II can be prepared by reacting the diazotized derivative of 2-(4-amino-phenyl)- ethanesulphonic acid methylamide of formula VI,
  • Diazotization of 2-(4-amino-phenyl)-ethanesulphonic acid methylamide of formula VI can be conveniently carried out by conventional methods using reagents like sodium nitrite, amyl nitrite and the like in the presence of water and a suitable mineral acid preferably hydrochloric acid.
  • the diazotization reaction may be carried at a temperature of about -20 to 30 0 C, preferably at about -15 to 25°C until the reaction is complete.
  • the diazonium salt is further reacted with ethyl-2-methyIacetoacetatc in the presence of a suitable solvent under basic conditions.
  • bases like metal hydroxides selected from sodium hydroxide, potassium hydroxide, barium hydroxide; alcohlates like sodium methoxidc, sodium ethoxide and the like can be employed, it is preferable to use alkali metal or alkaline earth metal acetate selected from sodium acetate, potassium acetate or barium acetate due to milder conditions, providing a reaction wherein the formation of impurities is remarkably reduced.
  • Suitable solvent can be selected from C M alcohols, tetrahydrofuran, 1,4-dimethoxy tetrahydrofuran, 1,2-diethoxy ethane, 1,2-dimethoxy ethane, the like and mixtures thereof.
  • the temperature of the reaction is usually maintained at about 0 0 C to 50 0 C, preferably till reaction ' completion, such as for a period of about 1 to 10 hours with stirring.
  • the reaction mass is diluted with suitable solvent like ethyl acetate followed by separation of the layers.
  • the organic layer is concentrated under vacuum to obtain 2- ⁇ [4-(2-methylsulfamoyl-ethyl)-phcnyl
  • the starting material of formula V or formula VI can be procured from the commercial source or can be prepared by the methods well known in prior art.
  • the compound of formula II is further made to cyclize to form 5-(2-methylsulfamoyl-cthyl)- lH-indole-2-carboxylic acid ethyl ester of formula III, salt or solvate thereof under Fisher indole reaction conditions.
  • Useful acids include inorganic Bronsted acids like poly-phosphoric acid, phosphoric acid, phosphorous acid, hydrochloric acid, sulfuric'acid; organic acids like para-toluenesulphonic acid; Lewis acids like boron trifluoride, boron' tribromide, titanium tetrachloride, aluminium trichloride, iron chloride and the like.
  • polyphosphoric acid is employed.
  • the solvent can be selected from dichloromethane, chloroform, ethyl acetate, the like, or mixtures thereof with alcohols like methanol, ethanol, propanol, isopropanol.
  • The, reaction is preferably conducted at a temperature of about 60-200 0 C, preferably at 70- 150 0 C, more preferably at 80-130 0 C for a period of about 1 -6 hours, preferably till completion of the reaction.
  • demineralized water is added to the reaction mass with stirring.
  • the immiscible layers are separated and the organic layer is washed with aqueous sodium carbonate solution followed by concentration under vacuum to isolate 5-(2- methylsulfamoyl-ethyl)-lH-indole-2-carboxylic acid ethyl ester of formula III.
  • the product can be isolated by the methods well known in art particularly filtration, extraction and a combination of these procedures can be employed.
  • Formula IV that further represents an important and novel intermediate for the preparation of naratriptan and represents an inventive step of the present invention.
  • the reaction is preferably conducted under suitable acidic or basic conditions.
  • the basic hydrolysis of compound of formula III can be carried out in the presence of a suitable base like metal hydroxides like sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like.
  • the acidic hydrolysis employs the use of suitable inorganic acids like hydrochloric acid, sulphuric acid and the like.
  • the 5-(2-methylsulfamoyl-ethyl)-] /7- indole-2-carboxylic acid ethyl ester is added to suitable base in the presence of a suitable solvent like Ci -4 alcohols, esters like ethyl acetate, halogenated solvents like methylene dichloride, aromatic hydrocarbons like toluene, water and the like or mixture thereof optionally in the presence of phase transfer catalysts such as quaternary ammonium salts at a temperature of about 15-140 0 C.
  • phase transfer catalysts such as quaternary ammonium salts
  • reaction mass is optionally concentrated under vacuum or acidified directly with a mineral acid like hydrochloric acid in the presence of water to obtain 5-(2-methylsulfamoyl-ethyl)-lH- indole-2-carboxylic acid of formula IV.
  • the compound of formula IV can be isolated by the methods well known in art particularly filtration, extraction and a combination of these procedures can be employed.
  • the compound is isolated by extraction with a suitable organic solvent like ester such as ethyl acetate; halogenated solvent such as methylene chloride and* the separated organic layer is washed with suitable solvent like water, dried over anhydrous sodium sulphate and concentrated under vacuum to give 5-(2-methylsulfamoyl-ethyl)-l /V- indole-2-carboxylic acid of formula IV in high yield and purity.
  • Compound of formula IV can be isolated as its salt with alkali metals, alkaline earth metals, quaternary ammonium salts like ammonium or phosphonium that further represents an inventive part of the present invention.
  • Decarboxylation reaction can be performed in the presence of suitable solvent with or without catalyst under inert reaction conditions.
  • suitable solvent can be selected from quinolinc, dimethylsulphoxide, dimethylformamide, dimethylacetamide, diphenylether, dimethyl aniline, pyridine and the like.
  • the reaction can be employed in the presence of transition metal catalyst such as copper oxides, copper chromite, copper and. its salts.
  • the reaction is preferably conducted at a temperature of about 150-300 0 C, preferably at 200-230 0 C, preferably till reaction completion.
  • 5-(2-Methylsulfamoyl-ethyl)-lH-indole of formula VII can optionally be crystallized from a suitable solvent selected form amongst aliphatic C 5 -9 alkanes like hexane, heptane; C5.9 cycloalkanes like cyclohexane, cycloheptane; alkyl ethers like isopropyl ether, methyl tcrt. % butyl ether; aromatic solvents like, toluene, xylene and the like to yield highly pure 5-(2- methylsulfamoyl-ethyl)-lH-indole of formula VII.
  • a suitable solvent selected form amongst aliphatic C 5 -9 alkanes like hexane, heptane; C5.9 cycloalkanes like cyclohexane, cycloheptane; alkyl ethers like is
  • 5-(2-Methylsulfamoyl-ethyl)-lH-indole of formula VII can further be converted to naratriptan of formula I by the methods well known in prior art.
  • the condensation reaction may be performed in the presence of an acid or a base in a suitable solvent, at a temperature of 25°C to reflux temperature of the solvent.
  • Useful acids include organic or inorganic acids such as sulphonic acids, carboxylic acids, polyphosphoric acid, sulphuric acid, hydrochloric acid and the like.
  • Useful bases include alkali metal hydroxides, alkali metal alkoxides, alkali metal hydrides, and alkali metal amides, preferably selected from potassium hydroxide, sodium methoxide, potassium methoxidc, sodium ethoxide, sodium t- butoxide, sodium hydride, sodamide and the like.
  • Suitable solvents for the reaction include methanol, ethanol, tetrahydrofuran, dioxanc, dimethylsulphoxidc and the like.
  • the condensed product can further be washed with suitable solvent like acetone or isopropyl ether.
  • 2-[3-(l -Methyl- 1, 2,3, 6-tetrahydro-pyridin-4-yl)-lH-indol-5-yl]ethanesulphonic acid methylamide of formula VIIl is further subjected to catalytic reduction to afford naratriptan.
  • the reduction process can preferably be carried out in the presence of hydrogen and a noble metal catalyst, such as palladium, Raney nickel, platinum, platinum oxide or rhodium which may be supported, for example, on charcoal.
  • the reduction is preferably performed in the presence of a suitable solvent such as methanol or ethanol, dioxane, tetrahydrofuran, 1 ,4- dimethoxy tetrahydrofuran, din ⁇ ethylacetamide, dimethylformamide or ethyl acetate and the like, at a temperature of from 10 0 C to 50 0 C preferably at 25-35 0 C.
  • a suitable solvent such as methanol or ethanol, dioxane, tetrahydrofuran, 1 ,4- dimethoxy tetrahydrofuran, din ⁇ ethylacetamide, dimethylformamide or ethyl acetate and the like.
  • the reduction is preferably performed at a hydrogen gas pressure of 1-20 kg/cm 2 , preferably at a hydrogen gas pressure of 1-10 kg/cm 2 .
  • naratriptan so formed can further be purified by using conventional methods like recrystallization from a suitable solvent selected from ester like ethyl acetate: alcohol like ethanol; ketone like acetone.
  • intermediates and naratriptan can be washed with suitable solvent selected from ether such as isopropyl ether, tetrahydrofuran; alcohol such as methanol, ethanol, isopropanol; ketone such as acetone; ester such as ethyl acetate; water or mixtures thereof to improve colour and quality of the material.
  • suitable solvent selected from ether such as isopropyl ether, tetrahydrofuran; alcohol such as methanol, ethanol, isopropanol; ketone such as acetone; ester such as ethyl acetate; water or mixtures thereof to improve colour and quality of the material.
  • naratriptan can be isolated as its free base but it is usually more convenient to isolate it as its pharmaceutically acceptable salt.
  • Suitable pharmaceutically acceptable salt of the naratriptan include acid addition salt formed with organic or inorganic acid, for example, hydrochloride, hydrobromide, sulphate, fumarate and maleate.
  • naratriptan is-isolated as its hydrochloride salt.
  • Naratriptan can be converted to pharmaceutically acceptable acid addition salt thereof by the methods well known in art.
  • pharmaceutically acceptable salts can be prepared by dissolving the free base of naratriptan in a suitable solvent, containing the appropriate acid and isolating the salt therefrom.
  • naratriptan can be converted to its hydrochloride salt by adjusting the pH of the reaction mixture to 1 to 4 using suitable hydrochloric acid selected from alcoholic hydrogen chloride preferably methanolic hydrogen chloride, isopropanolic hydrogen chloride, in a suitable solvent like alcohol or ester, preferably methanol, ethanol, ethyl acetate and the like.
  • the reaction is usually performed at ambient temperature under inert atmosphere followed by cooling to a temperature of below 20 0 C, preferably at 10 0 C and isolating naratriptan hydrochloride by conventional means like filtration in high yield and purity greater than 99.5% by HPLC.
  • naratriptan free base can be converted to its hydrochloride salt by refluxing a mixture of naratriptan free base and ammonium chloride in alcoholic solvent like methanol for a time sufficient to convert to its hydrochloride salt.
  • naratriptan hydrochloride produced by the process of the present invention is pharmaceutically pure and does not require further purification.
  • the product can further be purified by using conventional methods like crystallization from a suitable solvent selected from water, Cj -4 alcohol, ketone like acetone, ester like ethyl acetate, amide like N,N-dimethyl acetamidc, NN-dimethyl formamide; ester like ethyl acetate, the like and mixtures thereof.
  • Naratriptan hydrochloride can also be purified by base acid treatment such as neutralizing naratriptan hydrochloride with a base to form naratriptan followed by treatment with an acid such as hydrochloric acid to form highly pure naratriptan hydrochloride
  • Suitable base that can used for conversion of naratriptan hydrochloride to its free base include but are not limited to: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; ammonia; and mixtures thereof. These bases can be used in the form of solids or in the form of aqueous solutions in any suitable concentration.
  • the reaction is optionally performed in the presence of biphasic solvent system such as water/ethyl acetate, water/dichloromethane.
  • the naratriptan so formed can be converted back to naratriptan hydrochloride by the methods known per se or as described in the present invention.
  • Example 1 To a stirred suspension of 2-(4-hydrazino-phenyl)-ethanesu!phonic acid methylamide hydrochloride (100 g, 0.38 mol) in ethanol (300 ml), was slowly added acetic acid (50ml) and ethyl pyruvate (46g, 0.39 mol) at 25-35°C. After stirring for 60 minutes, the solid was filtered, washed with ethanol and dried to obtain 120 g of the title compound as a yellow crystalline solid (yield 97.5%) having purity of 97% by HPLC.
  • Example 2 To a stirred suspension of 2-(4-hydrazino-phenyI)ethanesulphonic acid methylamide hydrochloride (4.0kg, 15.0 mol) in ethanol (16 It.), was slowly added acetic acid (2 It.) and ethyl pyruvate (2.2kg, 18 mol) at 25-35°C and progress of the reaction was monitored by thin layer chromatography. After stirring for 60 minutes, the solid was filtered, washed with hexane and dried to obtain 4.4 kg of title compound as a solid (yield 89%) having purity of 96.7% by HPLC.
  • Example 3 Ethyl-2-methylacetoacetate (25 g, 0.17 mol) and sodium acetate (82.5g) were added to methanol (250ml) at 25-35°C and reaction mass was stirred for 2 hours at 25-35°C.
  • 2-(4-aminophenyl)ethanesulphonic acid methylamide (25g, 0.125 mol) in water (400ml) was treated with cone, hydrochloric acid (14.5ml) and aqueous solution of sodium nitrite (23.5 g in 100ml of demineralized water) at 0-5°C.
  • the reaction mass was further stirred for 1 hour at 0-5°C to afford the corresponding diazonium salt.
  • the diazonium salt was slowly added to the above mixture of ethyl-2-methylacetoacetate and sodium acetate (82.5g) at 0°C and the reaction mass was stirred for 3 hours at 25-35 0 C. After completion of reaction, the reaction mass was diluted with ethyl acetate and the layers were separated. The organic layer was washed with water, brine solution and concentrated under vacuum to obtain 38.5g of the title compound.
  • Example 2 2- ⁇ [4-(2-Methylsulfamoyl-ethyl)-phenyl]-hydrazono ⁇ -propionic acid ethyl ester (2.2kg, 6.72 mol) was added to pre-heated poly-phosphoric acid (2.2kg) at 80°C and the suspension was diluted with ethanol (44 It.). The reaction mass was stirred for 60 minutes and after completion of reaction, the reaction mass was cooled to 10-15°C and basificd with aqueous sodium hydroxide solution to a pH of 8.0-8.5. The reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed subsequently with demineralized water and brine solution, followed by concentration under vacuum to give a solid which was filtered using isopropyl ether to obtain 1.85 kg of the title compound.
  • Example 1 To a stirred ethanolic solution of potassium hydroxide (1 13.8g in 1260ml of ethanol), was added 5-(2-methylsulfamoyl-ethyl)-l ⁇ -indole-2-carboxylic acid ethyl ester (21Og, 0.67mol) at 25-35°C and the reaction mixture was refluxed for 5-6 hours. The progress of the reaction was monitored by thin layer chromatography and after completion of the " reaction, the reaction mass was concentrated under vacuum to give a solid, which was dissolved in water and acidified with cone, hydrochloric acid at 15°C.
  • reaction mixture was extracted with ethyl acetate and the separated organic layer was washed with water, brine and dried over anhydrous sodium sulphate. The organic layer was concentrated under vacuum to obtain 166.2g of the title compound as a yellowish crystalline solid (yield 86.9%).
  • Example 2 To a stirred ethanolic solution of potassium hydroxide (812g potassium hydroxide in 9 It. of ethanol), was added 5-(2-methylsulfamoyl-ethyl)-lH-indole-2-carboxylic acid ethyl ester (1.5kg,4.8mol) at 25-35°C and the reaction mixture was refluxed for 5-6 hours when the thin layer chromatography indicated the reaction to be complete. The reaction mass was concentrated under vacuum to give a solid which was dissolved in water and cooled to 15°C, acidified with cone, hydrochloric acid and the precipitated solid was filtered to obtain 1.1 kg of the title compound as a yellowish brown crystalline solid (yield 80.5%).
  • Example 1 5-(2-Methylsulfamoylethyl)-lH-indoIe-2-carboxylic acid (1.1 kg, 3.9mol) and copper chromite (303g, 0.975mol) were added into quinoline (5.5 It.) at 215-225°C. The reaction mass was further cooled to 25-30°C and diluted with ethyl acetate (22 It.) and hydrochloric acid (3.3 It.). The layers were separated. The organic layer was washed with hydrochloric acid (3.3 It. ⁇ 2), aqueous brine solution and concentrated under vacuum to yield an oil which was crystallized with cyclohexane to give 0.61 kg of the title compound (yield 65.0%).
  • Example 2 5-(2-Methylsulfamoyl-ethyl)-l ⁇ -indole-2-carboxylic acid (155g, 0.54mo! and copper chromite (42.7g, 0.137mol) were added to quinoline (775ml) at 215-225 0 C.
  • the reaction mass was further cooled to 25-30°C and diluted with ethyl acetate (3.11t.) and hydrochloric acid (2375ml).
  • the organic layer was washed with hydrochloric acid (2375ml ⁇ 2), aqueous brine and concentrated under vacuum to yield an oil which was crystallized with cyclohexane to obtain 87.Og of the title compound (yield 66.8%).
  • Example 3 5-(2-Methylsulfamoyl-ethyl)-l H-indole-2-carboxylic acid (66g, 0.23 mol) and copper chromite (18.2g) were added to diphenyl ether (528ml) at 25-35°C under nitrogen atmosphere. After completion of the reaction at 220-225 °C, the reaction mass was cooled to 25- 30°C and diluted with cyclohexane to give a residue which was taken up in ethyl acetate. The organic layer was concentrated under vacuum to yield an oil which was crystallized with cyclohexane to obtain 36g of the title compound as off white to light brown solid ( yield 64%).
  • Example 1 5-(2-methylsulfamoyl-ethyl)-lH-indole (75g, 0.32mol) was added to a stirred solution of potassium hydroxide (105.8g) in methanol (450ml) at 25-35 0 C. After stirring for 10 minutes, N-methyl-4-piperidone (85.4g) was added at 25-35 0 C and the mixture was rcfluxcd for 24 hours. After completion of reaction, the reaction mixture was cooled to 30°C and diluted with water. The solid was filtered, washed with cold water, ethyl acetate and acetone to obtain 77.5g of the title compound as off white solid ( yield 73.8%) having purity of 99.1 % by HPLC.
  • Example 2 5-(2-methylsulfamoyl-ethyl)-lH-indole (41Og, 1.72mol) was added to a stirred solution of potassium hydroxide (58Og) in methanol (2.51t.) at 25-35°C. After stirring for 10 minutes, N-methyl-4-piperidone (470 g) was added at 25-35°C and the mixture was refluxed for 24 hours. After completion of reaction, the reaction mixture was cooled to 30°C and diluted with water. The solid was filtered, washed with cold water, ethyl acetate and acetone to obtain 44Og of the title compound as off white solid ( yield 76.6%) having purity of 99.22% by ⁇ PLC.
  • Example 1 2-[3-(l-Methyl-l,2,3,6-tetrahydro-pyridin-4-yl)-l ⁇ -indol-5-yl]ethanesulphonic acid methylamide (75.Og, 0.22 mol) was taken in ethanol (1.125 It.). The reaction mixture was subjected to hydrogen gas pressure of 3.0 kg/cm 2 at 25-35°C in the presence of 10% palladium on carbon (37.5g). After, completion of the reaction, the reaction mass was filtered, concentrated and dissolved in ethyl acetate.
  • Example 2 2-[3-(l -Methyl-l ,2,3,6-tetrahydro-pyridin-4-yl)-lH-indol-5-yl]ethanesulphonic acid methylamide (0.44kg, 1.32mol) was dissolved in ethanol (6.6It). and dimethylformamide (3ml). The reaction mixture was subjected to hydrogen gas pressure of 3.0 kg/cm 2 for 2 hours at 25-35°C in presence of 10% palladium on carbon (0.22kg). After completion of the reaction, the reaction mass was filtered and concentrated under vacuum to give an oil which was dissolved in ethyl acetate.
  • Example 1 Naratriptan (50g, 0.14mol) was dissolved in ethanol (500ml).The clear solution was acidified with ethanolic-hydrochloride to a p ⁇ of 1.0-1.5 at 25-30°C under nitrogen atmosphere. The reaction mass was further stirred for 60 minutes at 0-5°C, filtered, washed with ethanol and dried to obtain 52.5g of naratriptan hydrochloride ( yield 95.4%) having purity of 99.77% by ⁇ PLC.
  • Example 2 Naratriptan (36g, O. lOmol) was dissolved in ethanol (360ml). The clear solution was acidified with ethanolic-hydrochloride to a pH of 1.0-1.5 at 25-30°C under nitrogen atmosphere. The reaction mass was further stirred for 60 minutes at 0-5 °C, filtered, washed with ethanol and dried to obtain 37.Og of naratriptan hydrochloride ( yield 93.4%) having purity of 99.70% by HPLC.

Abstract

The present invention relates to a novel process for the preparation of indole derivatives. In particular, present invention relates to the process for preparing naratriptan of formula (I), and its salts using novel intermediates. The present invention also relates to novel synthetic intermediates useful in the preparation of naratriptan hydrochloride.

Description

PROCESS FOR THE PREPARATION OF INDOLE DERIVATIVES
FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of indole derivatives. In particular, present invention relates to a process for preparing naratriptan of formula I, and its salts using novel intermediates. 3
Formula I
Figure imgf000002_0001
This invention also relates to novel synthetic intermediates useful in the processes of the present invention.
BACKGROUND OF THE INVENTION
Naratriptan of formula I, is being sold as hydrochloride salt in pharmaceutical products using the trademark AMERGE, for treating migraine and is chemically known as N-methyl-3-(l - methyl-4-piperidinyl)-l-H-indole-5-ethanesulphon- amide.
US patents 4,997,841 and 5,066,660 disclose naratriptan and its pharmaceutical acceptable salts, as well as its related compounds useful in the treatment of migraine. The above patents disclose several processes for synthesizing naratriptan and related compounds. According to one process, the condensation of substituted 4-piperidone derivative with an appropriately substituted indole derivative in the presence of an acidic or basic medium give N-mcthyl-3- (l ,2,3,6-tetrahydro-l-methyl-pyridin-4-yl)-lH-indole-5-ethanesulphonamide which is reduced in the presence of hydrogen and a noble metal catalyst such as palladium, Raney nickel, platinum, rhodium or homogenous catalyst such as tris (triphenylphosphine)rhodium chloride to yield naratriptan. In yet another process, naratriptan is prepared by the reduction of N-mcthyl-3- (l -methyl-pyridin-4-yl)-lH-indole-5-ethenesulphonarnide in the presence of hydrogen and a noble metal catalyst same as described above. The corresponding 5-ethenesulphonamide is prepared by Ηeck reaction in the presence of tri-o-tolylphosphine, palladium catalyst and base like triethyl amine. U.S. patent 5,659,040 discloses a process for preparing naratriptan hydrochloride by reducing the diene intermediate, N-methyl-2-[3-(l,2,3,6-tetrahydro- l-methyl-4-pyridinyl)-l H-indol-5- yl]ethenesulphonamide in the presence of hydrogen and a noble metal catalyst like palladium, palladium oxide, Raney nickel, platinum, platinum oxide or rhodium and homogenous catalyst like tris(triphenylphosphine)rhodium chloride. The synthesis of diene intermediate also involves Ηeck reaction.
These processes comprise cumbersome operations like Ηeck reaction that are not useful at commercial scale as these involve the use of Pd (II) salt or complex which is reduced in situ to an active palladium (0) species under homogeneous conditions. The Pd (II) species that is subsequently regenerated in the reaction is very difficult to separate and reuse for the reaction directly without further processing, that make these processes difficult to reproduce in larger scale. Further, these processes involve purification of naratriptan and intermediates using chromatographic technique which is again unpractical on commercial scale.
PCT application WO 2006/010079 discloses a process for preparing naratriptan by reacting a diazotized derivative of N-methyl-2-(4-amino-phenyl)ethane sulphonamide with a compound selected from
Figure imgf000003_0001
to form an intermediate of following formula through several steps,
Figure imgf000003_0002
which upon saponification and decarboxylation elaborates to naratriptan.
Most of the processes described above use expensive reagents and reactants. Additionally, some intermediates are not commercially available and are difficult to prepare which makes the processes unattractive from commercial point of view.
In view of the above, there still remains a need to develop an industrially viable and improved method for synthesizing naratriptan and pharmaceutically acceptable salts thereof. Thus, the present invention meets the need in the art for a novel, efficient and improved process for providing naratriptan, unique with respect to its simplicity, cost effectiveness and scalability.
SUMMARY OF THE INVENTION
The present invention relates to a novel and efficient process for the preparation of naratriptan of formula I,
Formula I
Figure imgf000004_0001
and pharmaceutically acceptable salts thereof.
In another embodiment, the novel intermediates of formulae II, III and IV further forms the part of the invention.
Formula II
Formula III
Formula IV
Figure imgf000004_0002
In one another embodiment, the present invention provides a novel process for the preparation of compound of formula II, which comprises reacting 2-(4-hydrazino-phenyl)cthanesuIphonic acid methylamide of formula V or an acid addition salt thereof,
Formula V
Figure imgf000004_0003
with ethyl pyruvate under mild reaction conditions. In one another embodiment, the present invention further provides a novel process for the preparation of compound of formula II, which comprises reacting the diazotized derivative of 2- (4-amino-phenyl)-ethanesulphonic acid methylamide of formula VI,
Formula VI
Figure imgf000005_0001
with ethyl-2-methylacetoacetate under mild reaction conditions.
In yet one another embodiment, the present invention provides a novel and efficient process for the preparation of naratriptan of formula I and pharmaceutically acceptable salt thereof which comprises:
(a) cyclizing 2-{[4-(2-methylsulfamoyl-ethyl)-phenyl]-hydrazono}-propionic acid ethyl ester of formula II;
Formula II
Figure imgf000005_0002
to form 5-(2-methylsulfarnoyl-ethyl)-lH-indole-2-carboxylic acid ethyl ester of formula III;
Formula III
Figure imgf000005_0003
(b) hydrolyzing compound of formula III to form 5-(2-methylsulfamoyl-cthyl)- l /7-indole-2- carboxylic acid of formula IV;
Formula IV
Figure imgf000005_0004
(c) decarboxylating compound of formula IV to form 5-(2-methylsulfamoyl-ethyl)-lH-indole of formula VII;
Formula VIl
Figure imgf000005_0005
(d) condensing compound of formula VIl with N-methyl-4-piperidone to form 2-[3-(l -methyl- l,2,3,6-tetrahydro-pyridin-4-yl)-lH-indol-5-yl]ethanesulfonic acid methylamide of formula VIII; and
Formula VTII
Figure imgf000006_0001
(e) reducing the compound of formula VIII to form naratriptan of formula I and pharmaceutically acceptable salt thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
Figures 1 and 2 illustrate X-ray diffraction pattern and DSC for naratriptan respectively
Figures 3 and 4 illustrate X-ray, diffraction pattern and DSC for naratriptan hydrochloride respectively.
DETAILED DESCRIPTION OF THE INVENTION
The process of the present invention is a high throughput, novel, efficient and industrially viable process for the preparation of naratriptan of formula I,
Formula I
Figure imgf000006_0002
and pharmaceutically acceptable salts thereof using novel intermediates.
Novel intermediates prepared using process of the present invention also forms the part of the present invention and may be characterized by at least one of the mass spectra (MS), infra-red (IR) spectroscopy, 1H or 13C nuclear magnetic resonance (NMR) spectroscopy or differential scanning calorimetry (DSC).
X-ray diffraction of naratriptan and its hydrochloride salt were measured on a PANalytical X' Pert Pro diffractometer with Cu radiation and expressed in terms of two-thcta, d-spacings and relative intensities. One of the ordinary skilled in art understands that experimental differences may arise due to differences in instrumentation, sample preparation or other factors.
All infrared measurements were made using Perkin Elmer Spectrum 100 FT-IR spectrometer using KBr pellets having the characteristic absorption bands expressed irreciprocal centimeter.
DSC analysis was performed using a Mettler Toledo DSC 823e. The weight of the samples was about 5-10 mg; the samples were scanned at a rate of 10°C/min. from 800C to 2800C.
Mass spectrometry was performed using an ionization method i.e. atmospheric pressure chemical ionization (APCI) at atmospheric pressure using micromass Q-Tof micro LCMS/MS. 1H or 13C NMR was performed using BRUKER AVANCE II 400 NMR Spectrometer.
It is thus the basic object of the present invention to provide an improved and efficient process for preparing naratriptan of formula I starting from 2-{[4-(2-methylsulfamoyl-ethyl)-phenyl|- hydrazono}-propionic acid ethyl ester of formula II, a pharmaceutically acceptable salt, or solvate inclusive of isomers thereof.
Formula II
Figure imgf000007_0001
In another aspect of the present invention there is provided a method for preparation of 2-{[4- (2-methylsulfamoyl-ethyl)-phenyl]-hydrazono}-propionic acid ethyl ester of formula II which comprises reacting 2-(4-hydrazino-phenyl)ethanesulphonic acid methylamide of formula V or an acid addition salt thereof,
Formula V
Figure imgf000007_0002
with ethyl pyruvate under mild reaction conditions.
Typically, the reaction involves adding ethyl pyruvate and a mild organic acid to the mixture of 2-(4-hydrazino-phenyl)-ethanesulphonic acid methylamide acid addition salt particularly its hydrochloride salt in a suitable solvent, while maintaining the temperature of the reaction at about 20-800C, preferably at 20-400C for a period of about 1 to 6 hours. The mild organic acid can be selected from, but not limited to acetic acid, formic acid and the like. The solvent can be selected from, but not limited to CM alcohols; ethers such as diethyl ether; halogenated solvent like methylene dichloride; water, the like and mixtures thereof. The solid so formed is filtered, washed with suitable solvent like isopropyl ether or cyclohexane and dried to obtain 2-{[4-(2- methylsulfamoyl-ethyl)-phenyl]-hydrazono}-propionic acid ethyl ester of formula II in high yield and purity.
The present invention provides an alternate process for preparing the novel intermediate, 2-{[4- (2-methylsulfamoyl-ethyl)-phenyI]-hydrazono}-propionic acid ethyl ester of formula II under Japp-Klingemann coupling conditions.
Specifically, 2-{[4-(2-methylsulfamoyl-ethyl)-phenyl]-hydrazino}-propionic acid ethyl ester of formula II can be prepared by reacting the diazotized derivative of 2-(4-amino-phenyl)- ethanesulphonic acid methylamide of formula VI,
Formula VI
Figure imgf000008_0001
with ethyI-2-methylacetoacetate under mild reaction conditions.
Diazotization of 2-(4-amino-phenyl)-ethanesulphonic acid methylamide of formula VI can be conveniently carried out by conventional methods using reagents like sodium nitrite, amyl nitrite and the like in the presence of water and a suitable mineral acid preferably hydrochloric acid. The diazotization reaction may be carried at a temperature of about -20 to 300C, preferably at about -15 to 25°C until the reaction is complete.
The diazonium salt is further reacted with ethyl-2-methyIacetoacetatc in the presence of a suitable solvent under basic conditions. Although bases like metal hydroxides selected from sodium hydroxide, potassium hydroxide, barium hydroxide; alcohlates like sodium methoxidc, sodium ethoxide and the like can be employed, it is preferable to use alkali metal or alkaline earth metal acetate selected from sodium acetate, potassium acetate or barium acetate due to milder conditions, providing a reaction wherein the formation of impurities is remarkably reduced. Suitable solvent can be selected from CM alcohols, tetrahydrofuran, 1,4-dimethoxy tetrahydrofuran, 1,2-diethoxy ethane, 1,2-dimethoxy ethane, the like and mixtures thereof. The temperature of the reaction is usually maintained at about 00C to 500C, preferably till reaction ' completion, such as for a period of about 1 to 10 hours with stirring. The reaction mass is diluted with suitable solvent like ethyl acetate followed by separation of the layers. The organic layer is concentrated under vacuum to obtain 2-{[4-(2-methylsulfamoyl-ethyl)-phcnyl|- hydrazono}-propionic acid ethyl ester of formula II.
The starting material of formula V or formula VI can be procured from the commercial source or can be prepared by the methods well known in prior art. The compound of formula II is further made to cyclize to form 5-(2-methylsulfamoyl-cthyl)- lH-indole-2-carboxylic acid ethyl ester of formula III, salt or solvate thereof under Fisher indole reaction conditions.
Formula III
Figure imgf000009_0001
Compounds of formulae II and III further represent important and novel intermediates for the preparation of naratriptan and represent an inventive step of the present invention. 2-{[4-(2- Methylsulfarnoyl-ethyl)-phenyl]-hydrazono}-propionic acid ethyl ester of formula II can preferably be cyclized under acidic conditions in a suitable solvent. Useful acids include inorganic Bronsted acids like poly-phosphoric acid, phosphoric acid, phosphorous acid, hydrochloric acid, sulfuric'acid; organic acids like para-toluenesulphonic acid; Lewis acids like boron trifluoride, boron' tribromide, titanium tetrachloride, aluminium trichloride, iron chloride and the like. Preferably polyphosphoric acid is employed. The solvent can be selected from dichloromethane, chloroform, ethyl acetate, the like, or mixtures thereof with alcohols like methanol, ethanol, propanol, isopropanol.
The, reaction is preferably conducted at a temperature of about 60-2000C, preferably at 70- 1500C, more preferably at 80-1300C for a period of about 1 -6 hours, preferably till completion of the reaction. After completion of the reaction, demineralized water is added to the reaction mass with stirring. The immiscible layers are separated and the organic layer is washed with aqueous sodium carbonate solution followed by concentration under vacuum to isolate 5-(2- methylsulfamoyl-ethyl)-lH-indole-2-carboxylic acid ethyl ester of formula III. The product can be isolated by the methods well known in art particularly filtration, extraction and a combination of these procedures can be employed.
In another aspect of the present invention there is provided a method for hydrolysis of 5-(2- methylsulfamoyl-ethyl)-lH-indole-2-carboxylic acid ethyl ester of formula III, so formed by the process of the present invention, to form 5-(2-methylsulfamoyl-cthyl)-l H-indolc-2- carboxylic acid of formula IV, or salt and solvate thereof,
Formula IV
Figure imgf000009_0002
that further represents an important and novel intermediate for the preparation of naratriptan and represents an inventive step of the present invention. The reaction is preferably conducted under suitable acidic or basic conditions. Generically, the basic hydrolysis of compound of formula III can be carried out in the presence of a suitable base like metal hydroxides like sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like. The acidic hydrolysis employs the use of suitable inorganic acids like hydrochloric acid, sulphuric acid and the like.
In the preferred embodiment of the present invention, the 5-(2-methylsulfamoyl-ethyl)-] /7- indole-2-carboxylic acid ethyl ester is added to suitable base in the presence of a suitable solvent like Ci-4 alcohols, esters like ethyl acetate, halogenated solvents like methylene dichloride, aromatic hydrocarbons like toluene, water and the like or mixture thereof optionally in the presence of phase transfer catalysts such as quaternary ammonium salts at a temperature of about 15-1400C. The reaction mixture is further refluxed for a period of about 1 -9 hours preferably 4-7 hours. Progress of the reaction can be monitored by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC) for the absence of starting material. The reaction mass is optionally concentrated under vacuum or acidified directly with a mineral acid like hydrochloric acid in the presence of water to obtain 5-(2-methylsulfamoyl-ethyl)-lH- indole-2-carboxylic acid of formula IV. The compound of formula IV can be isolated by the methods well known in art particularly filtration, extraction and a combination of these procedures can be employed. Preferably the compound is isolated by extraction with a suitable organic solvent like ester such as ethyl acetate; halogenated solvent such as methylene chloride and* the separated organic layer is washed with suitable solvent like water, dried over anhydrous sodium sulphate and concentrated under vacuum to give 5-(2-methylsulfamoyl-ethyl)-l /V- indole-2-carboxylic acid of formula IV in high yield and purity. Compound of formula IV can be isolated as its salt with alkali metals, alkaline earth metals, quaternary ammonium salts like ammonium or phosphonium that further represents an inventive part of the present invention.
In another aspect of the present invention there is provided a method for decarboxylation of 5- (2-methylsulfamoyl-ethyl)-lH-indole-2-carboxylic acid of formula IV or salt thereof to form the key intermediate, 5-(2-methylsulfamoyl-ethyl)-lH-indole of formula VII,
Formula VII
Figure imgf000010_0001
Decarboxylation reaction can be performed in the presence of suitable solvent with or without catalyst under inert reaction conditions. The suitable solvent can be selected from quinolinc, dimethylsulphoxide, dimethylformamide, dimethylacetamide, diphenylether, dimethyl aniline, pyridine and the like. The reaction can be employed in the presence of transition metal catalyst such as copper oxides, copper chromite, copper and. its salts. The reaction is preferably conducted at a temperature of about 150-3000C, preferably at 200-2300C, preferably till reaction completion. This is followed by cooling the reaction mass to a temperature of about 20-80°C and dilution with a suitable organic solvent like cyclohexane, ethyl acetate optionally in addition with a mineral acid like hydrochloric acid. The layer is washed with hydrochloric acid and concentrated under vacuum to yield 5-(2-methylsulfamoyl-ethyl)-lH-indole of formula VII.
5-(2-Methylsulfamoyl-ethyl)-lH-indole of formula VII can optionally be crystallized from a suitable solvent selected form amongst aliphatic C5-9 alkanes like hexane, heptane; C5.9 cycloalkanes like cyclohexane, cycloheptane; alkyl ethers like isopropyl ether, methyl tcrt.% butyl ether; aromatic solvents like, toluene, xylene and the like to yield highly pure 5-(2- methylsulfamoyl-ethyl)-lH-indole of formula VII.
5-(2-Methylsulfamoyl-ethyl)-lH-indole of formula VII can further be converted to naratriptan of formula I by the methods well known in prior art.
Specifically, 5-(2-methylsulfamoyl-ethyl)-lH-indole of formula VII is condensed with N- methyl-4-piperidone to afford 2-[3-(l -methyl-l ,2,3,6-tetrahydro-pyridin-4-yl)-lH-indol-5- yljethanesulphonic acid methylamide of formula VIII
Formula VIII
Figure imgf000011_0001
Typically;- the condensation reaction may be performed in the presence of an acid or a base in a suitable solvent, at a temperature of 25°C to reflux temperature of the solvent.
Useful acids include organic or inorganic acids such as sulphonic acids, carboxylic acids, polyphosphoric acid, sulphuric acid, hydrochloric acid and the like. Useful bases include alkali metal hydroxides, alkali metal alkoxides, alkali metal hydrides, and alkali metal amides, preferably selected from potassium hydroxide, sodium methoxide, potassium methoxidc, sodium ethoxide, sodium t- butoxide, sodium hydride, sodamide and the like. Suitable solvents for the reaction include methanol, ethanol, tetrahydrofuran, dioxanc, dimethylsulphoxidc and the like. The condensed product can further be washed with suitable solvent like acetone or isopropyl ether. 2-[3-(l -Methyl- 1, 2,3, 6-tetrahydro-pyridin-4-yl)-lH-indol-5-yl]ethanesulphonic acid methylamide of formula VIIl is further subjected to catalytic reduction to afford naratriptan. The reduction process can preferably be carried out in the presence of hydrogen and a noble metal catalyst, such as palladium, Raney nickel, platinum, platinum oxide or rhodium which may be supported, for example, on charcoal. The reduction is preferably performed in the presence of a suitable solvent such as methanol or ethanol, dioxane, tetrahydrofuran, 1 ,4- dimethoxy tetrahydrofuran, dinϊethylacetamide, dimethylformamide or ethyl acetate and the like, at a temperature of from 100C to 500C preferably at 25-350C. The reduction is preferably performed at a hydrogen gas pressure of 1-20 kg/cm2, preferably at a hydrogen gas pressure of 1-10 kg/cm2.
However naratriptan so formed can further be purified by using conventional methods like recrystallization from a suitable solvent selected from ester like ethyl acetate: alcohol like ethanol; ketone like acetone.
Wherever required, intermediates and naratriptan can be washed with suitable solvent selected from ether such as isopropyl ether, tetrahydrofuran; alcohol such as methanol, ethanol, isopropanol; ketone such as acetone; ester such as ethyl acetate; water or mixtures thereof to improve colour and quality of the material.
Although naratriptan can be isolated as its free base but it is usually more convenient to isolate it as its pharmaceutically acceptable salt. Suitable pharmaceutically acceptable salt of the naratriptan include acid addition salt formed with organic or inorganic acid, for example, hydrochloride, hydrobromide, sulphate, fumarate and maleate. Preferably naratriptan is-isolated as its hydrochloride salt.
Naratriptan can be converted to pharmaceutically acceptable acid addition salt thereof by the methods well known in art. Generically, pharmaceutically acceptable salts can be prepared by dissolving the free base of naratriptan in a suitable solvent, containing the appropriate acid and isolating the salt therefrom. Preferably, naratriptan can be converted to its hydrochloride salt by adjusting the pH of the reaction mixture to 1 to 4 using suitable hydrochloric acid selected from alcoholic hydrogen chloride preferably methanolic hydrogen chloride, isopropanolic hydrogen chloride, in a suitable solvent like alcohol or ester, preferably methanol, ethanol, ethyl acetate and the like. The reaction, is usually performed at ambient temperature under inert atmosphere followed by cooling to a temperature of below 200C, preferably at 100C and isolating naratriptan hydrochloride by conventional means like filtration in high yield and purity greater than 99.5% by HPLC.
I l In yet another embodiment, naratriptan free base can be converted to its hydrochloride salt by refluxing a mixture of naratriptan free base and ammonium chloride in alcoholic solvent like methanol for a time sufficient to convert to its hydrochloride salt.
One of the most significant advantage of the present invention is that naratriptan hydrochloride produced by the process of the present invention is pharmaceutically pure and does not require further purification. However, the product can further be purified by using conventional methods like crystallization from a suitable solvent selected from water, Cj-4 alcohol, ketone like acetone, ester like ethyl acetate, amide like N,N-dimethyl acetamidc, NN-dimethyl formamide; ester like ethyl acetate, the like and mixtures thereof. Naratriptan hydrochloride can also be purified by base acid treatment such as neutralizing naratriptan hydrochloride with a base to form naratriptan followed by treatment with an acid such as hydrochloric acid to form highly pure naratriptan hydrochloride
Suitable base that can used for conversion of naratriptan hydrochloride to its free base include but are not limited to: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; ammonia; and mixtures thereof. These bases can be used in the form of solids or in the form of aqueous solutions in any suitable concentration. The reaction is optionally performed in the presence of biphasic solvent system such as water/ethyl acetate, water/dichloromethane. The naratriptan so formed can be converted back to naratriptan hydrochloride by the methods known per se or as described in the present invention.
Major advantages realized in the present invention are cost effectiveness since expensive reactants/reagents are not employed and use of novel intermediates prepared by using simple and economical processes. Further process is efficient and can be easily scalable at industrial scale.
The manner in which the specific compounds can be prepared is illustrated in the following examples, which are illustrative only and should not be construed so as to limit the scope of the claimed invention in any manner.
EXAMPLES
Preparation of 2-{[4-(2-methylsulfamoyl-ethyl)-phenyl]-hydrazono}-propionic acid ethyl ester
Example 1: To a stirred suspension of 2-(4-hydrazino-phenyl)-ethanesu!phonic acid methylamide hydrochloride (100 g, 0.38 mol) in ethanol (300 ml), was slowly added acetic acid (50ml) and ethyl pyruvate (46g, 0.39 mol) at 25-35°C. After stirring for 60 minutes, the solid was filtered, washed with ethanol and dried to obtain 120 g of the title compound as a yellow crystalline solid (yield 97.5%) having purity of 97% by HPLC.
IR (KBr) (υmax, cm"1): 3309, 3286, 1888, 1693, 1615, 1598, 1566, 1309, 1245
'H NMR(DMSO-d63 (δppm): 1.33 -1.37 (3H, t); 2.1 1 (3H, s); 2.69 -2.70 (3H, d); 2.97-3.01 (2H, m); 3.17 - 3.21 (2H, m); 4.23 - 4.28 (2H, q); 6.54 -6.57 (I H, q ); 7.10 -7.12 (2H, d); 7.24 -7.26 (2H, d); 9.26(l H, s);
APCI-MS: = 328.22 [M+l]
Example 2: To a stirred suspension of 2-(4-hydrazino-phenyI)ethanesulphonic acid methylamide hydrochloride (4.0kg, 15.0 mol) in ethanol (16 It.), was slowly added acetic acid (2 It.) and ethyl pyruvate (2.2kg, 18 mol) at 25-35°C and progress of the reaction was monitored by thin layer chromatography. After stirring for 60 minutes, the solid was filtered, washed with hexane and dried to obtain 4.4 kg of title compound as a solid (yield 89%) having purity of 96.7% by HPLC.
Example 3: Ethyl-2-methylacetoacetate (25 g, 0.17 mol) and sodium acetate (82.5g) were added to methanol (250ml) at 25-35°C and reaction mass was stirred for 2 hours at 25-35°C. In a separate pot, 2-(4-aminophenyl)ethanesulphonic acid methylamide (25g, 0.125 mol) in water (400ml) was treated with cone, hydrochloric acid (14.5ml) and aqueous solution of sodium nitrite (23.5 g in 100ml of demineralized water) at 0-5°C. The reaction mass was further stirred for 1 hour at 0-5°C to afford the corresponding diazonium salt. The diazonium salt was slowly added to the above mixture of ethyl-2-methylacetoacetate and sodium acetate (82.5g) at 0°C and the reaction mass was stirred for 3 hours at 25-350C. After completion of reaction, the reaction mass was diluted with ethyl acetate and the layers were separated. The organic layer was washed with water, brine solution and concentrated under vacuum to obtain 38.5g of the title compound.
Preparation of 5-(2-methylsulfamoylethyl)-lH-indole-2-carboxyIic acid ethyl ester t Example 1: 2-{[4-(2-Methylsulfamoyl-ethyl)-phenyl]-hydrazono}-propionic acid ethyl ester
(270 g, 0.82mol) was added to pre-heated poly-phosphoric acid (27Og) at 60°C and the suspension was diluted with ethyl acetate (2.7 It.). The reaction mass was stirred under reflux for 60 minutes. After completion of the reaction, demineralized water was added to the reaction mass. The reaction mass was stirred and the immiscible layers were separated. The organic layer was washed 'with 20% aqueous sodium carbonate solution and 20% brine solution followed by concentration under vacuum to obtain a solid which was filtered using isopropyl ether to obtain 213.6g of the title compound as solid (83.4% yield).
IR(KBr) (υmax, cm'1): 3326, 2956, 1700, 1532, 1487, 1342, 1304
1H NMR(DMSOd6) (δppm): 1.39-1.42 (3H, t); 2.68-2.71 (3H, d); 3.10-3.15 (2H, m); 3.24-3.28 (2H, m), 4.35-4.40 (2H, q), 6.51 -6.55 (IH, q),' 7.08-7.09 (I H, d), 7.10-7.13 (I H, d), 7.43-7.45 (I H, d), 7.48 (I H, s), 1 1.22 (IH, s)
APCI-MS: = 31 1.04 [M+1]
Example 2: 2-{[4-(2-Methylsulfamoyl-ethyl)-phenyl]-hydrazono}-propionic acid ethyl ester (2.2kg, 6.72 mol) was added to pre-heated poly-phosphoric acid (2.2kg) at 80°C and the suspension was diluted with ethanol (44 It.). The reaction mass was stirred for 60 minutes and after completion of reaction, the reaction mass was cooled to 10-15°C and basificd with aqueous sodium hydroxide solution to a pH of 8.0-8.5. The reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed subsequently with demineralized water and brine solution, followed by concentration under vacuum to give a solid which was filtered using isopropyl ether to obtain 1.85 kg of the title compound.
Preparation of 5-(2-methylsulfamoyI-ethyl)-lH-indole-2-carboxylic acid
Example 1: To a stirred ethanolic solution of potassium hydroxide (1 13.8g in 1260ml of ethanol), was added 5-(2-methylsulfamoyl-ethyl)-l Η-indole-2-carboxylic acid ethyl ester (21Og, 0.67mol) at 25-35°C and the reaction mixture was refluxed for 5-6 hours. The progress of the reaction was monitored by thin layer chromatography and after completion of the" reaction, the reaction mass was concentrated under vacuum to give a solid, which was dissolved in water and acidified with cone, hydrochloric acid at 15°C. The reaction mixture was extracted with ethyl acetate and the separated organic layer was washed with water, brine and dried over anhydrous sodium sulphate. The organic layer was concentrated under vacuum to obtain 166.2g of the title compound as a yellowish crystalline solid (yield 86.9%).
IR (KBr) (υmax, cm"1) : 3381 , 3291, 2930, 2585, 1674, 1579, 1543, 1337.
1H NMR(DMSOd6): (δppm) 2.67-2.69 (3H, d); 3.08 -3.12 (2H, m); 3.23 -3.28 (2H, m); 6.72 - 6.76 (I H, q); 7.05(1 H, d); 7.09-7.1 1(1 H, dd); 7.42-7.44 (I H, d); 7.47(1 H, s); 1 1.37( 1 H, s)
APCI-MS: =280.82[M-l]
Example 2: To a stirred ethanolic solution of potassium hydroxide (812g potassium hydroxide in 9 It. of ethanol), was added 5-(2-methylsulfamoyl-ethyl)-lH-indole-2-carboxylic acid ethyl ester (1.5kg,4.8mol) at 25-35°C and the reaction mixture was refluxed for 5-6 hours when the thin layer chromatography indicated the reaction to be complete. The reaction mass was concentrated under vacuum to give a solid which was dissolved in water and cooled to 15°C, acidified with cone, hydrochloric acid and the precipitated solid was filtered to obtain 1.1 kg of the title compound as a yellowish brown crystalline solid (yield 80.5%).
Preparation of 5-(2-methylsulfamoyl-ethyl)-lH-indole
Example 1: 5-(2-Methylsulfamoylethyl)-lH-indoIe-2-carboxylic acid (1.1 kg, 3.9mol) and copper chromite (303g, 0.975mol) were added into quinoline (5.5 It.) at 215-225°C. The reaction mass was further cooled to 25-30°C and diluted with ethyl acetate (22 It.) and hydrochloric acid (3.3 It.). The layers were separated. The organic layer was washed with hydrochloric acid (3.3 It. χ2), aqueous brine solution and concentrated under vacuum to yield an oil which was crystallized with cyclohexane to give 0.61 kg of the title compound (yield 65.0%).
Example 2: 5-(2-Methylsulfamoyl-ethyl)-lΗ-indole-2-carboxylic acid (155g, 0.54mo!) and copper chromite (42.7g, 0.137mol) were added to quinoline (775ml) at 215-2250C. The reaction mass was further cooled to 25-30°C and diluted with ethyl acetate (3.11t.) and hydrochloric acid (2375ml). The organic layer was washed with hydrochloric acid (2375mlχ2), aqueous brine and concentrated under vacuum to yield an oil which was crystallized with cyclohexane to obtain 87.Og of the title compound (yield 66.8%).
IR(KBr) (υmax, cm"1): 3415, 3289, 3050, 1603, 1556, 1517, 1400.
1 H (DMSO-d6) : (δppm)2.67-2.69 (3H, d); 3.10-3.14 (2H, m); 3.23 -3.27 (2H, m); 6.38 -6.39 (I H, d), 6.45-6.48 (I H, q); 6.95 -6.97 (I H, dd); 7.18 -7.19 (I H, t); 7.33-7.35( I H, d ); 7.40 (I H, s); 10.37 (I H, s)
APCI-MS: = 239.09[M+l]
Example 3: 5-(2-Methylsulfamoyl-ethyl)-l H-indole-2-carboxylic acid (66g, 0.23 mol) and copper chromite (18.2g) were added to diphenyl ether (528ml) at 25-35°C under nitrogen atmosphere. After completion of the reaction at 220-225 °C, the reaction mass was cooled to 25- 30°C and diluted with cyclohexane to give a residue which was taken up in ethyl acetate. The organic layer was concentrated under vacuum to yield an oil which was crystallized with cyclohexane to obtain 36g of the title compound as off white to light brown solid ( yield 64%).
Preparation of 2-[3-(l-methyl-l,2,3,6-tetrahydro-pyridin-4-yl)-l//-indol-5-yl|- ethanesulphonic acid methylamide
Example 1: 5-(2-methylsulfamoyl-ethyl)-lH-indole (75g, 0.32mol) was added to a stirred solution of potassium hydroxide (105.8g) in methanol (450ml) at 25-350C. After stirring for 10 minutes, N-methyl-4-piperidone (85.4g) was added at 25-350C and the mixture was rcfluxcd for 24 hours. After completion of reaction, the reaction mixture was cooled to 30°C and diluted with water. The solid was filtered, washed with cold water, ethyl acetate and acetone to obtain 77.5g of the title compound as off white solid ( yield 73.8%) having purity of 99.1 % by HPLC.
Example 2: 5-(2-methylsulfamoyl-ethyl)-lH-indole (41Og, 1.72mol) was added to a stirred solution of potassium hydroxide (58Og) in methanol (2.51t.) at 25-35°C. After stirring for 10 minutes, N-methyl-4-piperidone (470 g) was added at 25-35°C and the mixture was refluxed for 24 hours. After completion of reaction, the reaction mixture was cooled to 30°C and diluted with water. The solid was filtered, washed with cold water, ethyl acetate and acetone to obtain 44Og of the title compound as off white solid ( yield 76.6%) having purity of 99.22% by ΗPLC.
Preparation of naratriptan
Example 1: 2-[3-(l-Methyl-l,2,3,6-tetrahydro-pyridin-4-yl)-l Η-indol-5-yl]ethanesulphonic acid methylamide (75.Og, 0.22 mol) was taken in ethanol (1.125 It.). The reaction mixture was subjected to hydrogen gas pressure of 3.0 kg/cm2 at 25-35°C in the presence of 10% palladium on carbon (37.5g). After, completion of the reaction, the reaction mass was filtered, concentrated and dissolved in ethyl acetate. The ethyl acetate layer was washed with water, dried over sodium sulfate and concentrated under vacuum to give a solid which was treated with isopropyl ether/acetone to obtain 55.Og of the title compound as off white solid (yield 73.3%) having purity of 99.7% by HPLC.
Example 2: 2-[3-(l -Methyl-l ,2,3,6-tetrahydro-pyridin-4-yl)-lH-indol-5-yl]ethanesulphonic acid methylamide (0.44kg, 1.32mol) was dissolved in ethanol (6.6It). and dimethylformamide (3ml). The reaction mixture was subjected to hydrogen gas pressure of 3.0 kg/cm2 for 2 hours at 25-35°C in presence of 10% palladium on carbon (0.22kg). After completion of the reaction, the reaction mass was filtered and concentrated under vacuum to give an oil which was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, dried over sodium sulphate and concentrated under vacuum to give a solid which was treated with isopropyl ether/acetone to give 0.32kg of the title compound (yield 72.7%) as off white solid having purity of 99.2% by ΗPLC.
Preparation of naratriptan hydrochloride
Example 1: Naratriptan (50g, 0.14mol) was dissolved in ethanol (500ml).The clear solution was acidified with ethanolic-hydrochloride to a pΗ of 1.0-1.5 at 25-30°C under nitrogen atmosphere. The reaction mass was further stirred for 60 minutes at 0-5°C, filtered, washed with ethanol and dried to obtain 52.5g of naratriptan hydrochloride ( yield 95.4%) having purity of 99.77% by ΗPLC. Example 2: Naratriptan (36g, O. lOmol) was dissolved in ethanol (360ml). The clear solution was acidified with ethanolic-hydrochloride to a pH of 1.0-1.5 at 25-30°C under nitrogen atmosphere. The reaction mass was further stirred for 60 minutes at 0-5 °C, filtered, washed with ethanol and dried to obtain 37.Og of naratriptan hydrochloride ( yield 93.4%) having purity of 99.70% by HPLC.

Claims

WE CLAIM:
1. A process for the preparation of indole derivative, particularly naratriptan of formula I and pharmaceutically acceptable salt thereof,
Formula I
Figure imgf000019_0001
comprises:
(a) cyclizing 2-{[4-(2-methylsulfamoyl-ethyl)-phenyl]-hydrazono}-propionic acid ethyl ester of formula II;
Formula II
Figure imgf000019_0002
to form 5-(2-methylsulfamoyl-ethyl)-lH-indole-2-carboxylic acid ethyl ester of formula III ;
Formula III
Figure imgf000019_0003
b) hydrolyzing compound of formula III to form 5-(2-methylsulfamoyl-ethyl)- l H-indole- 2-carboxylic acid of formula IV;
Formula IV
Figure imgf000019_0004
c) decarboxylating compound of formula IV to form 5-(2-methylsulfamoyl-ethyl)-lH- indole of formula VII;
Formula VII
Figure imgf000019_0005
d) condensing compound of formula VII with N-methyl-4-piperidone to form 2-f3-(l - methyl-l ,2,3,6-tetrahydro-pyridin-4-yl)-lH-indol-5-yl]ethane sulphonic acid methylamide of formula VIII;
Formula VIII
Figure imgf000020_0001
e) reducing compound of formula VIII to form naratriptan, f) optionally converting naratriptan to pharmaceutically acceptable salts thereof.
2. The process according to claim 1, wherein in step a) cyclization is performed in the presence of acid selected from inorganic acids like poly-phosphoric acid, phosphoric acid, phosphorous acid, hydrochloric acid, sulfuric acid; organic acids like para-toluenesulphonic acid; Lewis acids like boron trifluoride, boron tribromide, titanium tetrachloride, aluminium trichloride, iron chloride and the like.
3. The process according to claim 1, wherein in step b) hydrolysis is performed using acid selected from inorganic acid like hydrochloric acid, sulfuric acid and the like; or base selected from metal hydroxide like sodium hydroxide, potassium hydroxide; lithium hydroxide and the like.
4. The process according to claim 1, wherein in step c) decarboxylation is performed in the presence of suitable solvent selected from quinoline, dimcthylsulphoxidc, dimethylformamide, dimethylacetamide, diphenylether, dimethyl aniline, pyridine and the like; optionally in the presence of catalyst such as copper oxides, copper chromite, copper and its salts.
5. The process according to claim 1 , wherein in step d) reduction is performed catalytically, in the presence of hydrogen and a noble metal catalyst, such as palladium on carbon, Rancy nickel, platinum on carbon, platinum oxide.
6. A process for the preparation of 2-{[4-(2-methylsulfamoyl-ethyl)-phenyl|-hydrazono}- propionic acid ethyl ester of formula II, Formula II
Figure imgf000021_0001
which comprises reacting 2-(4-hydrazino-phenyl)ethanesulphonic acid methylamide of formula V or acid addition salt thereof,
Formula V
Figure imgf000021_0002
with ethyl pyruvate in the presence of mild organic acid and a suitable solvent at a temperature of about 20-400C for a time sufficient to convert to compound of formula II.
7. The process according to claim 6, wherein organic acid is selected from acetic acid, formic acid and the like and solvent is selected from C]-4 alcohols; ethers such as diethyl ether; halogenated solvent like methylene dichloride; water, or the like and mixtures thereof.
8. A process for the preparation of 2-{[4-(2-methylsulfamoyl-ethyl)-phenyl]-hydrazono}- propionic acid ethyl ester of formula II, which comprises reacting the diazotized derivative of 2-(4-amino-phenyl)-ethanesulphonic acid methylamide of formula VI,
Formula VI
Figure imgf000021_0003
with ethyl-2-methylacetoacetate in the presence of suitable solvent and base at a temperature of 00C to 5O0C for a time sufficient to convert to compound of formula II.
9. The process according to claim 8, wherein base is selected from alkali metal or alkaline earth metal acetate like sodium acetate, potassium acetate or barium acetate; metal hydroxides like sodium hydroxide, potassium hydroxide, barium hydroxide; alcoholates like sodium methoxide, sodium ethoxide; and solvent is selected from Ci-4 alcohols, tetrahydrofuran, 1,4-dimethoxy tetrahydrofuran, 1 ,2-diethoxy ethane, 1 ,2-dimethoxy ethane, the like and mixtures thereof
10. A process for the preparation of 5-(2-methylsulfamoyl-ethyl)-lH-indole of formula VII;
Formula VII
Figure imgf000021_0004
which comprises: a) cyclizing 2-{[4-(2-methylsulfamoyl-ethyl)-phenyl]-hydrazono}-propionic acid ethyl ester of formula II;
Formula II
Figure imgf000022_0001
to form 5-(2-methylsulfamoyl-ethyl)-lH-indole-2-carboxyIic acid ethyl ester of formula III;
Formula III
Figure imgf000022_0002
b) hydrolyzing compound of formula III to form 5-(2-methylsulfarnoyl-ethyl)-lH-indo!e- _.2-carboxylic acid of formula IV, c) decarboxylating compound of formula IV to form 5-(2-methylsulfamoyl-cthyl)-l H- indole of formula VII and ' d) further converting compound of formula VII to naratriptan and pharmaceutically acceptable salt thereof.
11. A compound of formula II, a pharmaceutically acceptable salt or solvate thereof, inclusive of isomers thereof.
Formula II
Figure imgf000022_0003
i compound of formula III, solvate thereof.
Formula III
Figure imgf000022_0004
13. A compound of formula IV; a pharmaceutically acceptable salt and solvate thereof.
Formula IV
Figure imgf000022_0005
PCT/IN2007/000571 2006-12-12 2007-12-10 Process for the preparation of indole derivatives WO2008072257A2 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009118753A2 (en) * 2008-03-07 2009-10-01 Usv Limited Process for preparation of naratriptan hydrochloride
WO2011021000A2 (en) 2009-08-20 2011-02-24 Cipla Limited A process for the synthesis of naratriptan
CN103408491A (en) * 2013-08-22 2013-11-27 通化茂祥制药有限公司 Chloroxoquinoline preparation method

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4997841A (en) * 1987-08-13 1991-03-05 Glaxo Group Limited Indole derivatives
US5066660A (en) * 1987-08-13 1991-11-19 Glaxo Group Limited Indole derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4997841A (en) * 1987-08-13 1991-03-05 Glaxo Group Limited Indole derivatives
US5066660A (en) * 1987-08-13 1991-11-19 Glaxo Group Limited Indole derivatives

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009118753A2 (en) * 2008-03-07 2009-10-01 Usv Limited Process for preparation of naratriptan hydrochloride
WO2009118753A3 (en) * 2008-03-07 2010-01-28 Usv Limited Process for preparation of naratriptan hydrochloride
WO2011021000A2 (en) 2009-08-20 2011-02-24 Cipla Limited A process for the synthesis of naratriptan
WO2011021000A3 (en) * 2009-08-20 2011-09-15 Cipla Limited A process for the synthesis of naratriptan
US8735589B2 (en) 2009-08-20 2014-05-27 Cipla Limited Process for the synthesis of naratriptan
CN103408491A (en) * 2013-08-22 2013-11-27 通化茂祥制药有限公司 Chloroxoquinoline preparation method

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