WO2019058271A1 - Procédé de préparation d'eluxadoline - Google Patents

Procédé de préparation d'eluxadoline Download PDF

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Publication number
WO2019058271A1
WO2019058271A1 PCT/IB2018/057207 IB2018057207W WO2019058271A1 WO 2019058271 A1 WO2019058271 A1 WO 2019058271A1 IB 2018057207 W IB2018057207 W IB 2018057207W WO 2019058271 A1 WO2019058271 A1 WO 2019058271A1
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Prior art keywords
formula
compound
acid
eluxadoline
iva
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PCT/IB2018/057207
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English (en)
Inventor
Vishal Sukhadeo MAWALE
Kumodini Kashinath Mahakal
Dabeer Rauf Karnalkar
Pravin Raghunath Mahajan
Purna Chandra Ray
Girij Pal Singh
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Lupin Limited
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Publication of WO2019058271A1 publication Critical patent/WO2019058271A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine

Definitions

  • the present invention relates to a process for the preparation of Eluxadoline or pharmaceutically acceptable salts thereof and its intermediates.
  • the present invention also relates to a process for the preparation of crystalline form a of Eluxadoline.
  • Diarrhea-predominant irritable bowel syndrome is a chronic disorder that affects about 28 million patients.
  • Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. Opioid ligands can be usefully employed to normalize altered visceral sensitivity in IBS patients.
  • Mu ( ⁇ ), kappa ( ⁇ ), and delta ( ⁇ ) opioid receptors represent the originally classified receptor subtypes, with opioid receptor like- 1 (ORL1) being the least characterized.
  • Eluxadoline (designated as VIBERZI ® ) chemically represented as 5-[[[(2S)-2- amino-3 -[4-(aminocarbonyl)-2, 6-dimethylphenyl] - 1 -oxopropyl] [(1S)-1 -(4-phenyl- 1H- imidazol-2-yl) ethyl]amino]methyl]-2-methoxy benzoic acid is a mu-opioid receptor agonist, indicated in adults for the treatment of irritable bowel syndrome with diarrhea (IBS-D). Its chemical
  • WO 2005/090315 discloses Eluxadoline and pharmaceutically acceptable enantiomers, diastereomers, racemates, and salts thereof, methods for its preparation, pharmaceutical composition and their use in the treatment of disorders that may be ameliorated or treated by the modulation of opioid receptors.
  • WO 2009/009480 describes process for making the zwitterion of Eluxadoline and two novel crystals of this zwitterion, namely crystalline form a and ⁇ of Eluxadoline and process for their preparation.
  • Example 2 of WO '480 describes the process for the preparation of crystalline form a of Eluxadoline by storing the zwitterion of Eluxadoline at 0-25% relative humidity for 3 days.
  • WO 2017/015606, WO 2017/153471 and WO 2017/191650 describe processes for preparation of Eluxadoline.
  • the method for the preparation of crystalline form a (alpha) of Eluxadoline described in the literature is difficult to operate at large scale and thus rendering them unsuitable for commercial scale. Therefore, there remains a need for the environmental friendly, highly pure, cost effective and industrially applicable process for the preparation of crystalline form a of Eluxadoline.
  • Eluxadoline The processes for preparation of Eluxadoline described in the literature involves the reaction of the suitable amine with the suitable carboxylic acid under standard peptide coupling conditions with a carbodiimide coupling agent such as N-(3- Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDCI) and an additive such as hydroxybenzotriazole (HOBt) to prevent racemization for introduction of the carboxamide moiety in Eluxadoline.
  • a carbodiimide coupling agent such as N-(3- Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDCI) and an additive such as hydroxybenzotriazole (HOBt) to prevent racemization for introduction of the carboxamide moiety in Eluxadoline.
  • EDCI N-(3- Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride
  • WO 2017153471 describes use of 2-chloro-4, 6-dimethoxy-l, 3, 5-triazine (CDMT) for introducing the carboxamide function in Eluxadoline.
  • the present inventors have surprisingly found that introduction of the carboxamide moiety in Eluxadoline is better achieved by using quinoline based coupling agent, l-ethoxycarbonyl-2-ethoxy-l, 2-dihydroquinoline (EEDQ) and isobutyl 1, 2- dihydro-2-isobutoxy-l-quinolinecarboxylate (IIDQ).
  • quinoline based coupling reagent involves direct coupling as the mixed carbonic anhydride intermediate is consumed very rapidly by the amino-component as soon as it is formed. This minimizes racemization during product formation, minimizes side reactions and workup is simple.
  • IIDQ is an improved version of EEDQ. Both reagents are easily prepared, easily stored, and not prone to side reactions or racemization. No additives to prevent racemization and tertiary amine bases are needed for these reactions.
  • the present invention provides a process for the preparation of Eluxadoline of formula (I) or pharmaceutically acceptable salts thereof and its intermediates.
  • the present invention also provides a process for the preparation of crystalline form a of Eluxadoline.
  • the present invention provides a process for preparation of Eluxadoline of formula (I) comprising of reacting compound of formula (IV) with compound of formula (V) to provide compound of formula (VI) in the presence of a coupling agent such as 1- ethoxycarbonyl-2-ethoxy-l, 2-dihydroquinoline (EEDQ), wherein no additives to prevent racemization and tertiary amine bases are required.
  • a coupling agent such as 1- ethoxycarbonyl-2-ethoxy-l, 2-dihydroquinoline (EEDQ), wherein no additives to prevent racemization and tertiary amine bases are required.
  • Figure 1 depicts the a - crystalline form of Eluxadoline
  • room temperature refers to a temperature in the range of about 25°C to about 30°C.
  • alkyl group means a straight or branched saturated monovalent hydrocarbon chain having 1 to 12 carbon atoms.
  • the suitable alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4, 4- dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, and various branched chain isomers thereof. Further, the alkyl group may optionally be substituted.
  • arylalkyl refer to alkyl groups as described above having an aryl substituent.
  • aryl group means a monocyclic or bicyclic monovalent aromatic hydrocarbon group having 6 to 10 carbon atoms. Suitable arylalkyl group include - CH2C6H5 and -C2H4C6H5. Further, the arylalkyl group may optionally be substituted.
  • nitrogen protecting group shall mean a group which is attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction.
  • a suitable nitrogen protecting group is selected from tert-butoxy carbonyl (BOC), benzyloxy carbonyl (CBz), acetyl (Ac), triflouoroacetyl (TFA), benzyl (Bn), dibenzyl, phthalimido, tosyl (Ts), p- methoxybenzylcarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), carbamate, p- methoxybenzyl (PMB), p-methoxyphenyl (PMP), tosyl (Ts), phenyl sulfonyl, trimethylsilylethoxymethyl (SEM) and benzoyl (Bz).
  • the present invention provides a process for the preparation of crystalline form a of Eluxadoline; comprising the steps of:
  • Providing of Eluxadoline in step (a) includes:
  • reaction mixture containing Eluxadoline that is obtained during its synthesis
  • Eluxadoline that may be used as the input for the process of the present invention may be obtained by any process including the process described in the art (for e.g., WO 2005/090315 Al and WO2018/020450 A2) or by process of the present invention.
  • the ketone solvent of step (a) may be selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone or mixtures thereof in any suitable proportion. More preferably acetone may be used in any suitable proportion.
  • the reaction mixture obtained in step (a) may be heated at reflux temperature of the solvent for a period of about 10 minutes to about 40 hours.
  • the solution obtained above may be filtered to remove any insoluble particles.
  • the insoluble particles may be removed suitably by filtration, centrifugation, decantation or any other suitable techniques.
  • the solution may optionally be treated with carbon, hyflow or any other suitable material to remove colour and/or to clarify the solution.
  • the reaction mixture obtained in step (b) may be cooled to a temperature from about 0°C to about room temperature, preferably to room temperature.
  • the stirring may be carried for a period of about 10 minutes to about 30 hours.
  • the resultant mixture may be further seeded with previously prepared crystals of a form of Eluxadoline.
  • the obtained precipitate may be isolated using conventional techniques known in the art.
  • One skilled in the art may appreciate that there are many ways to separate a solid from the mixture, for example it may be separated by using any techniques such as filtration, centrifugation, decantation and the like. After separation, the solid may optionally be washed with a suitable solvent.
  • the obtained crystalline form a of Eluxadoline may optionally be further dried.
  • Drying may be suitably carried out in equipment such as tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like.
  • the drying may be carried out at a temperature about 35°C to about 70°C, optionally under reduced pressure.
  • the drying may be carried out for any time periods necessary for obtaining a product with desired purity such as from about 1 hour to about 25 hours or longer.
  • the present invention provides a process for the preparation of crystalline form a of Eluxadoline; comprising the steps of:
  • Eluxadoline that may be used as the input for the process of the present invention may be obtained by any process including the process described in the art (for e.g., WO 2005/090315 Al and WO2018/020450 A2) or by the process of the present invention.
  • the suspension obtained in step (a) may be heated at a reflux temperature, preferably at a temperature about 50°C to about 60°C for a period about 10 minutes to about 40 hours.
  • the resultant mixture may be further seeded with previously prepared crystals of a form of Eluxadoline.
  • the reaction mixture obtained in step (b) may be cooled to room temperature followed by stirring for a period about 10 minutes to about 30 hours, preferably about 1 hour to about 3 hours.
  • the obtained precipitate may be isolated using conventional techniques known in the art.
  • One skilled in the art may appreciate that there are many ways to separate a solid from the mixture, for example it may be separated by using any techniques such as filtration, centrifugation, decantation and the like.
  • the solid may optionally be washed with a suitable solvent.
  • the obtained crystalline form a of Eluxadoline may optionally be further dried. Drying may be suitably carried out in equipment such as tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperature about 35°C to about 70°C, optionally under reduced pressure.
  • the drying may be carried out for any time periods necessary for obtaining a product with desired purity such as from about 1 hour to about 25 hours or longer.
  • the present invention provides a process for the preparation of crystalline form a of Eluxadoline; comprising the steps of:
  • Eluxadoline that may be used as the input for the process of the present invention may be obtained by any process including the process described in the art (for e.g., WO 2005/090315 Al and WO2018/020450 A2) or by the process of the present invention.
  • the reaction mixture obtained in step (a) may be heated at a reflux temperature, preferably at a temperature of about 50°C to about 60°C, more preferably at a temperature of about 30°C to 40°C for a period about 10 minutes to about 40 hours.
  • the reaction mixture of step (a) may be seeded with previously prepared crystals of a form of Eluxadoline.
  • the solution obtained in step (b) may be cooled to room temperature followed by stirring for a period about 10 minutes to about 30 hours, preferably about 1 hour to about 3 hours.
  • the obtained precipitate may be isolated using conventional techniques known in the art.
  • One skilled in the art may appreciate that there are many ways to separate a solid from the mixture, for example it may be separated by using any techniques such as filtration, centrifugation, decantation and the like. After separation, the solid may optionally be washed with a suitable solvent.
  • the obtained crystalline form a of Eluxadoline may optionally be further dried. Drying may be suitably carried out in equipment such as tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperature about 35°C to about 70°C, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a product with desired purity such as from about 1 hour to about 25 hours or longer.
  • crystalline form a of Eluxadoline prepared according to the processes of the present invention can be substantially pure having a chemical purity greater than about 99% by weight as determined using high performance liquid chromatography.
  • the present invention provides pharmaceutical composition comprising crystalline form a of Eluxadoline prepared according to process of present invention with one or more pharmaceutically acceptable excipients and their use in the treatment of disorders that may be ameliorated or treated by the modulation of opioid receptors.
  • pharmaceutically acceptable excipients used in the pharmaceutical composition of invention comprise but are not limited to diluents, binders, pH stabilizing agents, disintegrants, surfactants, glidants and lubricants known in the art.
  • the present invention provides a process for the preparation of Eluxadoline of formula (I) or pharmaceutically acceptable salts thereof; comprising the steps of:
  • the hydride source of step (a) includes metal hydride or hydrogen in the presence of a catalyst.
  • a catalyst is a transition metal catalyst optionally in the form of a complex.
  • metal hydride is used as a hydride source.
  • the metal hydride is selected from sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride, lithium cyanoborohydride, potassium borohydride, lithium borohydride, zinc borohydride, calcium borohydride, magnesium borohydride and zirconium borohydride.
  • the suitable solvent of step (a) is selected from the group of alcohol, ester, ether, formamide, hydrocarbon, sulfoxide, nitrile, water or mixtures thereof in a suitable proportion.
  • the preferred alcohol is methanol, ethanol, isopropanol, 2-propanol, 1- butanol, t-butyl alcohol, 1-pentanol, 2-pentanol and amyl alcohol;
  • the preferred ester is ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate and isobutyl acetate;
  • the preferred ether is methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, dimethyl ether, isopropyl ether, dibutyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether,
  • the acid is selected from inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid and organic acid such as citric acid, malic acid, succinic acid, p-toluene sulfonic acid, ethane sulfonic acid, methane sulfonic acid and the like in a suitable solvent.
  • inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid
  • organic acid such as citric acid, malic acid, succinic acid, p-toluene sulfonic acid, ethane sulfonic acid, methane sulfonic acid and the like in a suitable solvent.
  • the compound of formula (IV.acid) is compound (S)-2-methoxy-5-(((l- (4-phenyl-lH-imidazol-2-yl) ethyl)amino)methyl)benzoate citric acid salt of formula:
  • the suitable solvent of step (b) is selected from the group of alcohol, ester and chlorinated hydrocarbon.
  • the preferred alcohol is methanol, ethanol and isopropanol;
  • the preferred ester is ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate and isobutyl acetate;
  • the preferred chlorinated hydrocarbon is dichloromethane and ethylene dichloride
  • the base of step (c) is selected from hydroxides of alkali and alkaline earth metals such as sodium hydroxide, potassium hydroxide calcium hydroxide, ammonium hydroxide and the like; carbonates of alkali and alkaline metals such as sodium carbonate, potassium carbonate and the like; and bicarbonates of alkali and alkaline metals such as sodium bicarbonate, potassium bicarbonate and the like.
  • the suitable solvent of step (c) is selected from the group of alcohol, ester and chlorinated hydrocarbon and mixtures thereof.
  • the compound of formula (IV) is optionally subjecting it to process steps (b) and (c) and may be used directly for the next step (d) as present in the reaction mixture,without isolation.
  • a compound of formula (VI) is prepared in step (d) by contacting compound of formula (IV) or compound of formula (IV. Pure) with a compound of formula (V) in the presence of a suitable coupling agent; in the absence of an additive; in a suitable solvent.
  • the reaction of step (d) is carried out at a temperature of about 5°C to about 70°C, preferably at about 25°C to 40°C.
  • the suitable coupling agent of step (d) is quinoline based coupling reagent such as l-ethoxycarbonyl-2-ethoxy-l, 2-dihydroquinoline (EEDQ) and isobutyl 1, 2-dihydro-2- isobutoxy- 1 -quinolinecarboxylate (IIDQ) .
  • step (d) is carried out in a suitable solvent selected from the group of alcohols, amides, sulphoxides, pyrrolidones, esters, hydrocarbons, ketones, ethers, nitriles or mixtures thereof in a suitable proportion.
  • a suitable solvent selected from the group of alcohols, amides, sulphoxides, pyrrolidones, esters, hydrocarbons, ketones, ethers, nitriles or mixtures thereof in a suitable proportion.
  • the preferred alcohol is methanol, ethanol, isopropanol, butanol and iso-butanol; the preferred ester is ethyl acetate, methyl acetate, tertiarybutyl acetate and iso-propyl acetate; the preferred ketone is acetone, methylisobutyl ketone, methylethyl ketone, diethyl ketone and dimethyl ketone; the preferred hydrocarbon is toluene; the preferred ether is ethyl ether, methyl ether, diisopropylether, methyltertbutyl ether, dioxane and tetrahydrofuran the preferred amide is N,N-dimethylformamide, N-methyl acetamide and N,N-dimethylacetamide; the preferred sulfoxide is dimethylsulphoxide; the preferred pyrrolidone is N- methylpyrrolidone; the preferred hydrocarbon is 1, 1-
  • step (e) the compound of formula (VI) is converted to compound of formula (VII) by conventional processes such as reduction, acid treatment and the like.
  • Acid treatment is done by contacting the compound of formula (VI) with organic or inorganic acids.
  • the organic acid is selected form the group of carboxylic acid or sulphonic acid such as trifluoroacetic acid, trifluoromethane sulphonic acid, methane sulphonic acid, formic acid, tartaric acid and p-toluenesulphonic acid and the like.
  • the inorganic acid is selected from the group of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and sodium hydrogen phosphate and the like.
  • the said reaction is carried out at a temperature of about 50°C to 70°C, preferably at about 25°C to 50°C.
  • step (e) is optionally carried out in the presence of an organic solvent.
  • the organic solvent of step (e) is selected from the group of alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof.
  • suitable solvent includes but not limited to methanol, ethanol, isopropanol, butanol, iso-butanol, ethyl acetate, methyl acetate, tertiary butyl acetate, isopropyl acetate, acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, dimethyl ketone, methyl isobutyl ketone, toluene, ethyl ether, methyl ether, diisopropylether, methyltertbutylether, cyclopentyl methyl ether, dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methyl acetamide, N,N-dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone 1, 1-dichloroethane, dichloromethane, chloroform, carbon tetrach
  • the compound of formula (I) is prepared in step (f) by contacting the compound of formula (VII) with an aqueous base in a suitable solvent.
  • the said reaction is carried out at a temperature of about -10°C to 70°C, preferably at about 0°C to 45 °C.
  • the base used in step (f) is selected from the group of hydroxides of alkali and alkaline earth metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide calcium hydroxide, ammonium hydroxide, cesium hydroxide and the like; carbonates of alkali and alkaline metals such as sodium carbonate, potassium carbonate and the like; and bicarbonates of alkali and alkaline metals such as sodium bicarbonate, potassium bicarbonate and the like.
  • the suitable solvent of step (f) is selected from the group of alcohol such as methanol, ethanol, isopropanol and water or mixtures thereof.
  • the preferred alcohol of step (e) is methanol.
  • the invention provides a process for the preparation of Eluxadoline of formula (I) or pharmaceutically acceptable salts thereof; comprising the steps of: (a) contacting a compound of formula (II) with a compound of formula (Ilia) in the presence of metal hydride and a catalytic amount of acetic acid, to obtain the compound
  • step (g) optionally, providing Eluxadoline of formula(I) in a ketone solvent and isolating crystalline form a of Eluxadoline.
  • step (a) the compound of formula (II) is reacted with a compound of formula
  • step (Ilia) in the presence of a metal hydride and catalytic amount of acetic acid, in a suitable solvent; to obtain the compound of formula (IVa).
  • the step (a) is carried out at a temperature of about 20°C to about 50°C, preferably at about 25°C to 45°C.
  • the metal hydride of step (a) is selected from sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride, lithium cyanoborohydride, potassium borohydride, lithium borohydride, zinc borohydride, calcium borohydride, magnesium borohydride and zirconium borohydride.
  • the preferred hydride of step (a) is sodium borohydride.
  • the suitable solvent of step (a) is selected from the group of alcohol, ester, ether, formamide, hydrocarbon, sulfoxide, nitrile, water or mixtures thereof in a suitable proportion.
  • the preferred alcohol is methanol, ethanol, isopropanol, 2-propanol, 1- butanol, t-butyl alcohol, 1-pentanol, 2-pentanol and amyl alcohol;
  • the preferred ester is ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate and isobutyl acetate;
  • the preferred ether is methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, dimethyl ether, isopropyl ether, dibutyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether,
  • the acid is selected from inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid and organic acid such as citric acid, malic acid, succinic acid, p-toluene sulfonic acid, ethane sulfonic acid, methane sulfonic acid and the like in a suitable solvent.
  • inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid
  • organic acid such as citric acid, malic acid, succinic acid, p-toluene sulfonic acid, ethane sulfonic acid, methane sulfonic acid and the like in a suitable solvent.
  • the suitable solvent of step (b) is selected from the group of alcohol, ester and chlorinated hydrocarbon.
  • the preferred alcohol is methanol, ethanol and isopropanol;
  • the preferred ester is ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate and isobutyl acetate;
  • the preferred chlorinated hydrocarbon is dichloromethane and ethylene dichloride
  • the base of step (c) is selected from hydroxides of alkali and alkaline earth metals such as sodium hydroxide, potassium hydroxide calcium hydroxide, ammonium hydroxide and the like; carbonates of alkali and alkaline metals such as sodium carbonate, potassium carbonate and the like; and bicarbonates of alkali and alkaline metals such as sodium bicarbonate, potassium bicarbonate and the like.
  • the suitable solvent of step (c) is selected from the group of alcohol, ester and chlorinated hydrocarbon and mixtures thereof.
  • the compound of formula (IVa) is optionally subjecting it to process steps (b) and
  • a compound of formula (Via) is prepared in step (d) by contacting a compound of formula (IVa) or compound of formula (IVa.Pure) with a compound of formula (Va) in the presence of a suitable coupling agent; in the absence of an additive; in a suitable solvent.
  • the reaction step (d) is done at a temperature of about 5°C to about 70°C, preferably at about 25°C to 40°C.
  • the suitable coupling agent of step (d) is quinoline based coupling reagent such as l-ethoxycarbonyl-2-ethoxy-l, 2-dihydroquinoline (EEDQ) and isobutyl 1, 2-dihydro-2- isobutoxy- 1 -quinolinecarboxylate (IIDQ) .
  • EEDQ 2-dihydroquinoline
  • IIDQ isobutoxy- 1 -quinolinecarboxylate
  • the suitable solvent of step (d) is selected from the group of alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof in any suitable proportion.
  • suitable solvent includes but are not limited to methanol, ethanol, isopropanol, butanol, iso-butanol, ethyl acetate, methyl acetate, tertiarybutyl acetate, iso-propyl acetate, acetone, methylisobutyl ketone, methylethyl ketone, diethyl ketone, dimethyl ketone, toluene, ethyl ether, methyl ether, diisopropylether, methyltertbutyl ether, dioxane, tetrahydrofuran, N,N- dimethylformamide, N-methyl acetamide, ⁇ , ⁇ -dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone 1, 1-dichloroethane, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, benzene, xylene or
  • step (e) the compound of formula (Via) is contacted with an acid.
  • the said reaction is carried out at a temperature of about 5°C to 70°C, preferably at about 25°C to 50°C.
  • the reaction of step (e) is optionally carried out in the presence of an organic solvent.
  • the organic solvent of step (e) is selected from the group of alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof.
  • suitable solvent includes but not limited to methanol, ethanol, isopropanol, butanol, iso-butanol, ethyl acetate, methyl acetate, tertiary butyl acetate, isopropyl acetate, acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, dimethyl ketone, methyl isobutyl ketone, toluene, ethyl ether, methyl ether, diisopropylether, methyltertbutylether, cyclopentyl methyl ether, dioxane, tetrahydroiuran, N,N-dimethylform
  • the acid of step (e) is selected from organic and inorganic acid.
  • the organic acid is selected form carboxylic acid or sulphonic acid such as trifluoroacetic acid, trifluoromethane sulphonic acid, methane sulphonic acid, formic acid, tartaric acid and p- toluene sulphonic acid.
  • the inorganic acid is selected from hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and sodium hydrogen phosphate.
  • the preferred acid of step (e) is hydrochloric acid.
  • the compound of formula (I) is prepared in step (f) by contacting the compound of formula (Vila) with an aqueous base in a suitable solvent.
  • the said reaction is carried out at temperature of about -10°C to 70°C, preferably at about 0°C to 45 °C.
  • the base used in step (f) is selected from the group of hydroxides of alkali and alkaline metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide calcium hydroxide, ammonium hydroxide, cesium hydroxide and the like; carbonates of alkali and alkaline metals such as sodium carbonate, potassium carbonate and the like; and bicarbonates of alkali and alkaline metals such as sodium bicarbonate, potassium bicarbonate and the like.
  • sodium hydroxide may be used as base.
  • Suitable solvents that can be used in the step (f) include but are not limited to alcoholic solvents such as methanol, ethanol, isopropanol preferably methanol and the like; water and mixtures thereof.
  • the invention provides a process for the preparation of
  • Eluxadoline of formula (I) or pharmaceutically acceptable salts thereof; comprising the steps of:
  • the suitable acid is selected from inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid and organic acid such as citric acid, malic acid, succinic acid, p-toluene sulfonic acid, ethane sulfonic acid, methane sulfonic acid and the like in a suitable solvent.
  • inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid
  • organic acid such as citric acid, malic acid, succinic acid, p-toluene sulfonic acid, ethane sulfonic acid, methane sulfonic acid and the like in a suitable solvent.
  • the suitable solvent of step (a) is selected from the group of alcohol, ester and chlorinated hydrocarbon.
  • the preferred alcohol is methanol, ethanol and isopropanol;
  • the preferred ester is ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate and isobutyl acetate;
  • the preferred chlorinated hydrocarbon is dichloromethane and ethylene dichloride.
  • the base of step (b) is selected from hydroxides of alkali and alkaline earth metals such as sodium hydroxide, potassium hydroxide calcium hydroxide, ammonium hydroxide and the like; carbonates of alkali and alkaline metals such as sodium carbonate, potassium carbonate and the like; and bicarbonates of alkali and alkaline metals such as sodium bicarbonate, potassium bicarbonate and the like.
  • the suitable solvent of step (b) is selected from the group of alcohol, ester and chlorinated hydrocarbon and mixtures thereof.
  • the compound of formula (IV) may be used as such; optionally subjecting it to process steps (a) and (b).
  • the compound of formula (IV. Pure) is contacted with the compound of formula (VI) in step (c) in the presence of a suitable coupling agent; in the absence of additive; in a suitable solvent as described hereinabove.
  • the compound of formula (VIII) is prepared in step (d) by treating the compound of formula (VI) with an aqueous base in a suitable solvent.
  • the said reaction is carried out at a temperature of about -10°C to 70°C, preferably at a temperature of about 0°C to 50°C.
  • the base used in step (d) is selected from the group of hydroxides of alkali and alkaline metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide calcium hydroxide, ammonium hydroxide, rubidium hydroxide, cesium hydroxide and the like; carbonates of alkali and alkaline metals such as sodium carbonate, potassium carbonate and the like; and bicarbonates of alkali and alkaline metals such as sodium bicarbonate, potassium bicarbonate and the like.
  • hydroxides of alkali and alkaline metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide calcium hydroxide, ammonium hydroxide, rubidium hydroxide, cesium hydroxide and the like
  • carbonates of alkali and alkaline metals such as sodium carbonate, potassium carbonate and the like
  • bicarbonates of alkali and alkaline metals such as sodium bicarbonate, potassium bicarbonate and the like.
  • the suitable solvents of step (d) includes but is not limited to alcoholic solvents such as methanol, ethanol, isopropanol preferably methanol and the like; water and mixtures thereof.
  • the compound of formula (I) is prepared in step (e) by subjecting compound of formula (VIII) to conventional processes such as reduction, acid treatment and like. Acid treatment is carried out by treating the compound of formula (VIII) with organic or inorganic acids.
  • the organic acid is selected form carboxylic acid or sulphonic acid such as trifluoroacetic acid, trifluoromethane sulphonic acid, methane sulphonic acid, formic acid, tartaric acid, p-toluenesulphonic acid and the like.
  • the inorganic acid is selected from hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, sodium hydrogen phosphate and the like.
  • the said reaction is carried out at a temperature of about 50°C to 70°C, preferably at about 25°C to 50°C.
  • the reaction of step (e) is carried out in the absence or presence of a suitable organic solvent which is selected from the group of alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof.
  • suitable solvent includes but not limited to methanol, ethanol, isopropanol, butanol, iso-butanol, ethyl acetate, methyl acetate, tertiary butyl acetate, isopropyl acetate, acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, dimethyl ketone, methyl isobutyl ketone, toluene, ethyl ether, methyl ether, diisopropylether, methyltertbutylether, cyclopentyl methyl ether, dioxane, tetrahydrofuran, N,N- dimethylformamide, N-methyl acetamide, ⁇ , ⁇ -dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone 1, 1-dichloroethane, dichloromethane, chloroform, carbon tetrach
  • the compound of formula (I) prepared in step (e) is isolated at a pH range of about 5 to 11, more preferably at a pH range of about 6 to 7.
  • the pH is adjusted using organic or inorganic acids.
  • the organic acid is selected form the group of carboxylic acid such as citric acid, tartaric acid, malic acid and the like.
  • the inorganic acid is selected from the group of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and sodium hydrogen phosphate and the like.
  • the said pH adjustment is carried out at a temperature of about 10°C to 50°C, preferably at about 20°C to 40°C.
  • the present invention provides process for preparation of intermediate of Eluxadoline, compound of formula (VI) comprising reacting compound of formula (IV) or compound of formula (IV. Pure) with a compound of formula (V) in the presence of a suitable coupling agent; in the absence of an additive; in a suitable solvent.
  • the suitable coupling agent is quinoline based coupling reagent such as quinoline based coupling agent, l-ethoxycarbonyl-2-ethoxy-l, 2-dihydroquinoline (EEDQ) and isobutyl 1, 2-dihydro-2-isobutoxy-l-quinolinecarboxylate (IIDQ).
  • quinoline based coupling agent such as quinoline based coupling agent, l-ethoxycarbonyl-2-ethoxy-l, 2-dihydroquinoline (EEDQ) and isobutyl 1, 2-dihydro-2-isobutoxy-l-quinolinecarboxylate (IIDQ).
  • the invention provides a process for the preparation of Eluxadoline of formula (I) or pharmaceutically acceptable salts thereof; comprising the steps of:
  • step (a) the compound of formula (II) is reacted with a compound of formula (Ilia) in the presence of a metal hydride and catalytic amount of acetic acid, in a suitable solvent; to obtain the compound of formula (IVa).
  • the step (a) is carried out at a temperature of about 20°C to about 50°C, preferably at about 25°C to 45°C.
  • the metal hydride of step (a) is selected from sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride, lithium cyanoborohydride, potassium borohydride, lithium borohydride, zinc borohydride, calcium borohydride, magnesium borohydride and zirconium borohydride.
  • the preferred hydride of step (a) is sodium borohydride.
  • the suitable solvent of step (a) is selected from the group of alcohol, ester, ether, formamide, hydrocarbon, sulfoxide, nitrile, water or mixtures thereof in a suitable proportion.
  • the preferred alcohol is methanol, ethanol, isopropanol, 2-propanol, 1- butanol, t-butyl alcohol, 1-pentanol, 2-pentanol and amyl alcohol;
  • the preferred ester is ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate and isobutyl acetate;
  • the preferred ether is methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, dimethyl ether, isopropyl ether, dibutyl ether, tert-butyl methyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether,
  • step (b) The preferred alcohol of step (a) is methanol.
  • the acid is selected from inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid and organic acid such as citric acid, malic acid, succinic acid, p-toluene sulfonic acid, ethane sulfonic acid, methane sulfonic acid and the like in a suitable solvent.
  • the suitable solvent of step (b) is selected from the group of alcohol, ester and chlorinated hydrocarbon.
  • the preferred alcohol is methanol, ethanol and isopropanol;
  • the preferred ester is ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate and isobutyl acetate;
  • the preferred chlorinated hydrocarbon is dichloromethane and ethylene dichloride.
  • the base of step (c) is selected from hydroxides of alkali and alkaline earth metals such as sodium hydroxide, potassium hydroxide calcium hydroxide, ammonium hydroxide and the like; carbonates of alkali and alkaline metals such as sodium carbonate, potassium carbonate and the like; and bicarbonates of alkali and alkaline metals such as sodium bicarbonate, potassium bicarbonate and the like.
  • the suitable solvent of step (c) is selected from the group of alcohol, ester and chlorinated hydrocarbon and mixtures thereof.
  • the compound of formula (IVa) may be used as such without isolation in step (d) and optionally subjecting it to process steps (b) and (c).
  • a compound of formula (Via) is prepared in step (d) by contacting a compound of formula (IVa) or compound of formula (IVa.Pure) with a compound of formula (Va) in the presence of a suitable coupling agent; in the absence of an additive; in a suitable solvent.
  • the reaction step (d) is done at a temperature of about 5°C to about 70°C, preferably at about 25°C to 40°C.
  • the suitable coupling agent of step (d) is quinoline based coupling reagent such as l-ethoxycarbonyl-2-ethoxy-l, 2-dihydroquinoline (EEDQ) and isobutyl 1, 2-dihydro-2- isobutoxy- 1 -quinolinecarboxylate (IIDQ) .
  • the suitable solvent of step (d) is selected from the group of alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof in any suitable proportion.
  • suitable solvent includes but are not limited to methanol, ethanol, isopropanol, butanol, iso-butanol, ethyl acetate, methyl acetate, tertiarybutyl acetate, iso-propyl acetate, acetone, methylisobutyl ketone, methylethyl ketone, diethyl ketone, dimethyl ketone, toluene, ethyl ether, methyl ether, diisopropylether, methyltertbutyl ether, dioxane, tetrahydrofuran, N,N- dimethylformamide, N-methyl acetamide, ⁇ , ⁇ -dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone 1,1-dichloroethane, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, benzene, xylene
  • the compound of formula (VIII) is prepared in step (e) by treating the compound of formula (Via) with an aqueous base in a suitable solvent.
  • the said reaction is carried out at a temperature of about -10°C to 70°C, preferably at a temperature of about 0°C to 50°C.
  • the base used in step (e) is selected from the group of hydroxides of alkali and alkaline metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide calcium hydroxide, ammonium hydroxide, rubidium hydroxide, cesium hydroxide and the like; carbonates of alkali and alkaline metals such as sodium carbonate, potassium carbonate and the like; and bicarbonates of alkali and alkaline metals such as sodium bicarbonate, potassium bicarbonate and the like.
  • the suitable solvents of step (e) includes but is not limited to alcoholic solvents such as methanol, ethanol, isopropanol preferably methanol and the like; water and mixtures thereof.
  • the compound of formula (I) is prepared in step (f) by subjecting compound of formula (VIII) to conventional processes such as reduction, acid treatment and like.
  • Acid treatment is carried out by treating the compound of formula (VIII) with organic or inorganic acids.
  • the organic acid is selected form carboxylic acid or sulphonic acid such as trifluoroacetic acid, trifluoromethane sulphonic acid, methane sulphonic acid, formic acid, tartaric acid, p-toluenesulphonic acid and the like.
  • the inorganic acid is selected from hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, sodium hydrogen phosphate and the like.
  • the said reaction is carried out at a temperature of about 50°C to 70°C, preferably at about 25°C to 50°C.
  • step (f) is carried out in the absence or presence of a suitable organic solvent which is selected from the group of alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof.
  • a suitable organic solvent which is selected from the group of alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof.
  • Suitable solvent includes but not limited to methanol, ethanol, isopropanol, butanol, iso-butanol, ethyl acetate, methyl acetate, tertiary butyl acetate, isopropyl acetate, acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, dimethyl ketone, methyl isobutyl ketone, toluene, ethyl ether, methyl ether, diisopropylether, methyltertbutylether, cyclopentyl methyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, N,N-dimethylformamide, N-methyl acetamide, N,N-dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone 1, 1-dichloroethane, dichloromethane
  • the compound of formula (I) prepared in step (e) is isolated at a pH range of about 5 to 1 1, more preferably at a pH range of about 6 to 7.
  • the pH is adjusted using organic or inorganic acids and/or inorganic bases.
  • the organic acid is selected form the group of carboxylic acid such as citric acid, tartaric acid, malic acid and the like.
  • the inorganic acid is selected from the group of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and sodium hydrogen phosphate and the like.
  • the inorganic base is selected from the group of hydroxides of alkali and alkaline metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide calcium hydroxide, ammonium hydroxide, rubidium hydroxide, cesium hydroxide and the like; carbonates of alkali and alkaline metals such as sodium carbonate, potassium carbonate and the like; and bicarbonates of alkali and alkaline metals such as sodium bicarbonate, potassium bicarbonate and the like.
  • hydroxides of alkali and alkaline metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide calcium hydroxide, ammonium hydroxide, rubidium hydroxide, cesium hydroxide and the like
  • carbonates of alkali and alkaline metals such as sodium carbonate, potassium carbonate and the like
  • bicarbonates of alkali and alkaline metals such as sodium bicarbonate, potassium bicarbonate and the like.
  • the said pH adjustment is carried out at a temperature of about 10°C to 50°C, preferably at about 20°C to 40°C.
  • the present invention provides pharmaceutical composition comprising of Eluxadoline and crystalline form a of Eluxadoline prepared by the processes of the present invention with one or more pharmaceutically acceptable excipients and their use in the treatment of disorders that may be ameliorated or treated by the modulation of opioid receptors.
  • Step 1- Preparation of 5-( ⁇ [2-tert-butoxycarbonylmethyl-3-(4-carbamoyl-2,6-dimethyl- phenyl)-propionyl] - [ 1 -(4-phenyl- lH-imidazol-2-yl)-ethyl] -amino ⁇ -methyl)-2-methoxy- benzoic acid methyl ester
  • DIPEA Diisopropylethylamine
  • Step 2 Preparation of 5-( ⁇ [2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl- phenyl)-propionyl] - [ 1 -(4-phenyl- 1 W-imidazol-2-yl)-ethyl] -amino ⁇ -methyl)-2-methoxy- benzoic acid.
  • Step 3 Preparation of Eluxadoline 5-( ⁇ [2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)- propionyl]-[l-(4-phenyl-lH-imidazol-2-yl)-emyl]-amino ⁇ -methyl)-2-methoxy-benzoic acid (Step-2 product, 100 gm) was added into ice cooled solution of IPA.HC1 (650 ml). The reaction mixture was stirred at room temperature for 24 hours. After completion of reaction, the resultant residue was added into water. The pH (6-7) was adjusted using IN NaOH solution and the precipitated was filtered, washed with water and dried to obtain titled compound, (yield: 75 gm).
  • Eluxadoline 100 gm was suspended in acetone (950 ml) and resultant reaction mixture was heated at 50 to 55 °C and further seeded with crystalline form a of Eluxadoline. The mixture was stirred at same temperature for 26 hours. The mixture was cooled to room temperature and solid precipitate was filtered, washed with acetone and further dried to obtain 75 gm of crystalline form a of Eluxadoline.
  • Step 1 Preparation of methyl (S)-2-methoxy-5-(((l-(4-phenyl-lH-imidazol-2-yl) ethyl) amino)methyl)benzoate
  • Step 2 Preparation of (S)-2-methoxy-5-(((l -(4-phenyl- lH-imidazol -2- citric acid salt
  • Step 3 Preparation of 5-( ⁇ [2-tert-butoxycarbonylmethyl-3-(4-carbamoyl-2,6-dimethyl- phenyl)-propionyl] - [ 1 -(4-phenyl- lH-imidazol-2-yl)-ethyl] -amino ⁇ -methyl)-2-methoxy- benzoic acid methyl ester
  • the reaction mixture was stirred for 4hrs at 0-5°C, then the temperature was raised to 15-18 °C and stirring was continued for 20 hrs. Thereafter dichloromethane (500 ml) and water (500 ml) were added to the reaction mixture and stirred and settled. The phases were separated. The organic layer was washed with 5% aqueous sodium hydroxide (500 ml), cooled to 0-5°C and added dil. hydrochloric acid (1000 ml) gradually and stirred the reaction mixture for 3 hrs., filtered and dried under vacuum to afford 256.89 gm of the title compound.
  • Step 4 Preparation of methyl 5-((2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)-N-(l-(4- phenyl- anamido)methyl)-2-methoxybenzoate
  • Step 1 Preparation of 5-( ⁇ [2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl- phenyl)-propionyl] - [ 1 -(4-phenyl- lH-imidazol-2-yl)-ethyl] -amino ⁇ -methyl)-2-methoxy- benzoic acid
  • Example-8 Preparation of 5-( ⁇ [2-tert-butoxycarbonylmethyl-3-(4-carbamoyl-2,6- dimethyl-phenyl)-propionyl]-[l-(4-phenyl-lH-imidazol-2-yl)-ethyl]-amino ⁇ -methyl)- ester
  • the reaction mixture was stirred for 4hrs at 0-5°C, then the temperature was raised to 15-18 °C and stirring was continued for 20 hrs. Thereafter dichloromethane (500 ml) and water (500 ml) were added to the reaction mixture and stirred and settled. The phases were separated. The organic layer was washed with 2% aqueous sodium hydroxide (500 ml), cooled to 0- 5°C and added dil. hydrochloric acid ( 1000 ml) gradually and stirred the reaction mixture for 3 hrs., filtered and dried under vacuum to afford 284.9 gm of the title compound.
  • Step-1 Preparation of 5-( ⁇ [2-tert-butoxycarbonylmethyl-3-(4-carbamoyl-2,6-dimethyl- phenyl)-propionyl] - [ 1 -(4-phenyl- lH-imidazol-2-yl)-ethyl] -amino ⁇ -methyl)-2-methoxy- benzoic acid methyl ester
  • the dichloromethane layer ( ⁇ 600 ml) containing (S)-2-methoxy-5-(((l- (4-phenyl-lH-imidazol-2-yl)ethyl)amino)methyl)benzoate was distilled to reduce volume to 2 to 2.5 volumes of the input batch size and diluted with dimethylformamide (100ml).
  • reaction mixture was quenched into dilute hydrochloric acid solution (2000 ml) at 25-30 °C.
  • the quenched reaction mixture was cooled to 10-15 °C and stirred for 1 to 2 hrs, filtered and washed with dichloromethane followed by water.
  • the solid obtained was purified by dissolving in methanol and precipitating with ethylacetate and dried under vacuum to afford 250 gm of title compound.
  • Step-2 Preparation of 5-( ⁇ [2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl- phenyl)-propionyl] - [ 1 -(4-phenyl- lH-imidazol-2-yl)-ethyl] -amino ⁇ -methyl)-2-methoxy- benzoic acid
  • reaction mixture was diluted with water (300 ml) and the pH of the reaction mixture was adjusted to 7.5 to 8 with 20% aqueous citric acid solution. Reduced the volume of reaction mixture till -8-10 volume of reaction mixture is left with respect to input. Thereafter water (450 ml) is added gradually at 45-50°C and stirred for 1 hr followed by stirring for 1 hr at 25-30°C, filtered washed with water and dried the solid to afford 85 gm of title compound.
  • the wet cake was added to water (900 ml), stirred and filtered through micron filter.
  • the resultant filtrate was gradually added to a cooled solution of IN sodium hydroxide (380 ml) at 10-15°C maintaining the pH at 6.5 to 7 (adjusted using IN NaOH or IN HC1). Raised the temperature to 25-30°C and stirred for 2-3 hrs, filtered, washed with water (500 ml) followed by cyclohexane (200 ml).
  • the wet cake was slurried with water and dried under vacuum to afford 65 gm of title compound.

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Abstract

La présente invention concerne un procédé de préparation d'éluxadoline ou de sels pharmaceutiquement acceptables de celle-ci, ainsi que ses produits intermédiaires. La présente invention concerne également un procédé de préparation d'une forme cristalline α d'éluxadoline. (I)
PCT/IB2018/057207 2017-09-19 2018-09-19 Procédé de préparation d'eluxadoline WO2019058271A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114630828A (zh) * 2019-10-30 2022-06-14 杨森科学爱尔兰无限公司 3-({5-氯-1-[3-(甲基磺酰基)丙基]-1H-吲哚-2-基}甲基)-1-(2,2,2-三氟乙基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮的合成
WO2022184606A1 (fr) * 2021-03-01 2022-09-09 Janssen Sciences Ireland Unlimited Company Synthèse de rilématovir

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017153471A1 (fr) * 2016-03-11 2017-09-14 Euticals S.P.A. Nouvelles formes cristallines de solvate stables d'eluxadoline

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017153471A1 (fr) * 2016-03-11 2017-09-14 Euticals S.P.A. Nouvelles formes cristallines de solvate stables d'eluxadoline

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114630828A (zh) * 2019-10-30 2022-06-14 杨森科学爱尔兰无限公司 3-({5-氯-1-[3-(甲基磺酰基)丙基]-1H-吲哚-2-基}甲基)-1-(2,2,2-三氟乙基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮的合成
CN114630828B (zh) * 2019-10-30 2023-10-31 杨森科学爱尔兰无限公司 一种rsv抑制化合物的合成
WO2022184606A1 (fr) * 2021-03-01 2022-09-09 Janssen Sciences Ireland Unlimited Company Synthèse de rilématovir

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