WO2018020450A2 - Process for the preparation of eluxadoline - Google Patents

Process for the preparation of eluxadoline Download PDF

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WO2018020450A2
WO2018020450A2 PCT/IB2017/054561 IB2017054561W WO2018020450A2 WO 2018020450 A2 WO2018020450 A2 WO 2018020450A2 IB 2017054561 W IB2017054561 W IB 2017054561W WO 2018020450 A2 WO2018020450 A2 WO 2018020450A2
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eluxadoline
selected
formula
acid
compound
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PCT/IB2017/054561
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French (fr)
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WO2018020450A3 (en )
Inventor
Vishal Sukhadeo MAWALE
Kumodini Kashinath Mahakal
Pravin Raghunath Mahajan
Gurvinder Pal Singh
Purna Chandra Ray
Girij Pal Singh
Lalitkumar Dilipsing RAJPUT
Radhakrishna Bhikaji SHIVDAVKAR
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Lupin Limited
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic 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
    • C07D233/64Heterocyclic 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

Abstract

The present invention provides a process for the preparation of eluxadoline. The present invention also provides a process for the preparation of amorphous form of eluxadoline. The present invention further provides Form L of eluxadoline and process for its preparation.

Description

PROCESS FOR THE PREPARATION OF ELUXADOLINE

FIELD OF THE INVENTION

The present disclosure relates to a process for the preparation of eluxadoline. The disclosure also provides a process for the preparation of amorphous form of eluxadoline. The present disclosure further provides Form L of eluxadoline and process for its preparation.

BACKGROUND OF THE INVENTION

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 (μ), kappa (κ), and delta (δ) 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- 1 H- 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 structure is represented by Formula (I).

Figure imgf000003_0001

Formula (I)

WO 2005/090315 discloses eluxadoline and it's pharmaceutically acceptable salt, 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 2009009480 discloses crystalline zwitterion of eluxadoline and process for its preparation. WO2017015606 Al covers Form I, Form II, Form III and Form IV of the eluxadoline and process for it's preparation.

In the pharmaceutical industry, the discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. In view of the above, it is also desirable to provide new polymorphic form of eluxadoline which is suitable for pharmaceutical preparation.

While developing the process of making eluxadoline, the inventor come across the environmental friendly, cost effective and industrially applicable process for the preparation of eluxadoline.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of eluxadoline. The present invention also provides a process for the preparation of amorphous form of eluxadoline. The present invention also provides Form L of eluxadoline, 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. BRIEF DESCRIPTION OF THE FIGURE

Fig. 1 : depicts the X-ray powder diffraction pattern of the amorphous form of eluxadoline obtained according to the procedure of Example 1.

Fig. 2: depicts the infra-red (IR) spectrum of the amorphous form of eluxadoline obtained according to the procedure of Example 1.

Fig. 3 : depicts the thermogravimetric analysis (TGA) thermogram of the amorphous form of eluxadoline obtained according to the procedure of Example 1. Fig. 4: depicts the X-ray powder diffraction pattern of the Form L of eluxadoline obtained according to the procedure of Example 6.

DETAILED DESCRIPTION OF THE INVENTION

The term "alkyl group" means a straight or branched saturated monovalent hydrocarbon chain having 1 to 12 carbon atoms. Suitable alkyl groups selected from 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 substituted.

The terms "arylalkyl" refer to alkyl groups as described above having an aryl substituent. The term "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 substituted.

As used herein, unless otherwise noted, the term "nitrogen protecting group" shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction. Suitable nitrogen protecting group selected from the group consisting of 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). Other suitable nitrogen protecting groups may be found in texts such as T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

The term 'slurrying' as used herein means a process wherein the eluxadoline is treated with suitable solvent, which includes mixing, agitating, leaching, triturating and stirring. Analytical Methods:

1) Powder X-ray Diffraction:

Powder X-ray diffraction can be obtained under following conditions: XRPD pattern is made using Cu K-al radiation at a voltage 40 mA & 45 kV. XRPD pattern was observed at 25°C and scanned from 3.5 to 40 two theta values.

2) Thermogravimetric analysis:

Thermogravimetric analysis was performed using a Pyris 1 TGA PERKIN ELMER measurement unit. 2-5 mg samples were placed in open Platinum pans and heated from 25 °C to 300 °C in a dry nitrogen atmosphere at a heating rate of 10 °C/min.

3) Infra-red (IR) spectrum:

IR spectroscopy was performed using a Spectrum 400 using a neat liquid sample or dispersion of solid sample material in KBr.

The process according to this invention are described in detail. The reaction conditions such as reagents, catalysts, solvents and temperature given are meant to provide preferred ranges and examples for the respective transformation that can be principally applied but are not supposed to restrict them to the selection given.

In one aspect, the present invention provides a process for the preparation of eluxadoline of formula (I) or pharmaceutically acceptable salts thereof;

comprising the step of:

(a) reductive amination of a compound of formula (II) with a compound of formula (III), wherein R1 is lower alkyl or aryl alkyl; in presence of hydride source to obtain the corresponding compound of formula (IV);

Figure imgf000006_0001
(b) condensing the compound of formula (IV) with a compound of formula (V) using suitable coupling agent, to obtain the corresponding compound of formula (VI); wherein 'Prof is a nitrogen protecting group;

Figure imgf000007_0001

(c) deprotecting the compound of formula (VI) to the corresponding compound of formula (VII);

Figure imgf000007_0002
(d) treating the compound of formula (VII) with base in suitable solvent to obtain the corresponding compound of formula (I);

Figure imgf000007_0003
Reductive amination of a compound of formula (II) with a compound of formula

(III), in presence of hydride source; in suitable solvent to obtain the corresponding compound of formula (IV).

Hydride source that may be used in step (a) include metal hydride or hydrogen in the presence of catalyst (transition metal optionally in the form of complex). Preferably, metal hydride may be used as a hydride source. Metal hydride is selected from the group consisting of sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride, lithium cyanoborohydride, potassium borohydride, lithium borohydride, zinc borohydride, calcium borohydride, magnesium borohydride and zirconium borohydride. Acetic acid may optionally be used as a catalyst in reductive amination step.

Suitable solvents that may be used in step (a) include but are not limited alcohol, ester, ether, formamide, hydrocarbon, sulfoxide, water, nitrile or mixtures thereof in any suitable proportion. Particularly preferred solvents includes methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, 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, THF, diglyme, dimethylformamide, dichloromethane, ethylene dichloride, cyclohexane, dimethoxyethane, toluene, xylene, dioxane, dimethyl sulfoxide, acetonitrile, water or mixtures thereof in any suitable proportion. Preferably methanol may be used as suitable solvent. Reductive amination step may be carried out at any suitable temperature for e.g., at a temperature of about 20°C to about 50°C, preferably about 25°C to 45°C.

A compound of formula (VI) can be prepared in step (b) by condensing a compound of formula (IV) with a compound of formula (V) under standard peptide coupling conditions using suitable coupling agent and additive in suitable solvent. This condensation reaction may optionally be carried out in presence of base at a temperature of about 5°C to about 70°C, preferably about 25°C to 40°C.

The coupling agent may be selected from the group consisting of alkyl or aryl chloroformate (for e.g., methyl chloroformate, isobutyl chloroformate, pivolyl chloride, phenyl chloroformate or nitrophenyl chloroformate); (benzotriazol- 1 -yloxy)tris (dimethylamino)phosphonium hexafluorophosphate (i.e., BOP); azoles (for e.g., NN- dicyclohexylcarbodiimide); imides [for e.g., l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (i.e., EDC), 1, 1-carbonyldiimidazole] and the like or mixtures thereof. Preferably l -ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride may be used as coupling agent.

2-hydroxypyridine-N-oxide (HOPO), N-hydroxysuccinimide (HOSu), N-hydroxy- 5-norbornene-2,3-dicarboximide (HONB), 1-hydroxybenzotriazole (HOBt), 6-chloro- l- hydroxybenzotriazole (6-Cl-HOBt), 1 -hydroxy-7-azabenzotriazole (HOAt), 3-hydroxy-4- oxo-3,4-dihydro- l,2,3-benzotriazine (HODhbt) and its aza derivative (HODhat) may be used as the additive in the coupling reactions. Preferably, HOBt may be used as additive.

The base used in step (b) can be any organic base. The suitable base is selected from the group consisting of triethyl amine, diisopropylethyl amine, diethyl amine, isopropyl amine, morpholine, N-methyl morpholine, pyridine, ammonia, 1,8- diazabicyclo[5.4.0] undec-7-ene, l,4-diazabicyclo[2.2.2] octane, and the like or mixtures thereof.

The condensation reaction of step (b) is carried out in suitable solvent selected from the group consisting of alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof in any suitable proportion. Examples of suitable solvent includes but 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, Ν,Ν-dimethylformamide, N-methyl acetamide, N,N- dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone 1, 1-dichloroethane, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, benzene, xylene or mixtures thereof in any suitable proportion. A compound of formula (VII) can be prepared in step (c) by deprotecting the amine protection of compound of formula (VI) by conventional processes such as reduction, acid treatment and like. Acid treatment can be carried out by treating the compound of formula (VI) with organic or inorganic acids. The organic acid may be selected form the group consisting of carboxylic acid or sulphonic acid such as trifluoroacetic acid, trifluoromethane sulphonic acid, methane sulphonic acid, formic acid, tartaric acid and p-touenesulphonic acid. The inorganic acid may be selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and sodium hydrogen phosphate. The said reaction is carried out at a temperature from about 05°C to 70°C, preferably about 25°C to 50°C.

The reaction of step (c) is carried out in absence or presence of suitable organic solvent which is selected from the group consisting of alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof. Examples of 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, Ν,Ν-dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone 1 , 1 -dichloroethane, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, benzene, xylene, monoglyme, diglyme, diethoxy methane or mixtures thereof.

A compound of formula (I) can be prepared in step (d) by treating the compound of formula (VII) with aqueous base in suitable solvent. The said reaction is carried out at a temperature from about -10°C to 70°C, preferably about 0°C to 45°C.

Base used in step (d) is selected from the group consisting 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. Suitable solvents that can be used in the step (d) include but are not limited to alcoholic solvents such as methanol, ethanol, isopropanol preferably methanol and the like; water and mixtures thereof. In one embodiment, the invention provides a process for the preparation of eluxadoline of formula (I) or pharmaceutically acceptable salts thereof;

comprising the step of:

(a) reductive amination of a compound of formula (II) with a compound of formula (Ilia) in the presence of metal hydride and catalytic amount of acetic acid, to obtain

Figure imgf000011_0001

(b) condensing the compound of formula (IVa) with a compound of formula (Va) in the presence of suitable coupling agent and additive; to obtain the corresponding compo

Figure imgf000011_0002

(c) deprotecting the compound of formula (Via) with acid to obtain the corresponding compound of formula (Vila);

Figure imgf000011_0003
(d) treating the compound of formula (Vila) with aqueous solution of base; to

Figure imgf000012_0001

A compound of formula (II) may be reacted with a compound of formula (Ilia) in the presence of metal hydride and catalytic amount of acetic acid, in suitable solvent; to obtain the corresponding compound of formula (IVa). Reductive amination step may be carried out at any suitable temperature for e.g., at a temperature of about 20°C to about 50°C, preferably about 25°C to 45°C.

Metal hydride is selected from the group consisting of sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride, lithium cyanoborohydride, potassium borohydride, lithium borohydride, zinc borohydride, calcium borohydride, magnesium borohydride and zirconium borohydride. Preferably sodium hydride may be used.

Suitable solvents that may be used in step (a) include but are not limited alcohol, ester, ether, formamide, hydrocarbon, sulfoxide, water, nitrile or mixtures thereof in any suitable proportion. Particularly preferred solvents includes methanol, ethanol, isopropanol, 2-propanol, 1 -butanol, t-butyl alcohol, 1-pentanol, 2-pentanol, amyl alcohol, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, 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, THF, diglyme, dimethylformamide, dichloromethane, ethylene dichloride, cyclohexane, dimethoxyethane, toluene, xylene, dioxane, dimethyl sulfoxide, acetonitrile, water or mixtures thereof in any suitable proportion. Preferably methanol may be used as suitable solvent.

A compound of formula (Via) can be prepared in step (b) by condensing a compound of formula (IVa) with a compound of formula (Va) under standard peptide coupling conditions using suitable coupling agent and additive in suitable solvent. This condensation reaction may optionally be carried out in presence of base at a temperature of about 5°C to about 70°C, preferably about 25°C to 40°C. The coupling agent may be selected from the group consisting of alkyl or aryl chloroformate (for e.g., methyl chloroformate, isobutyl chloroformate, pivolyl chloride, phenyl chloroformate or nitrophenyl chloroformate); (benzotriazol- 1 -yloxy)tris (dimethylamino)phosphonium hexafluorophosphate (i.e., BOP); azoles (for e.g., NN- dicyclohexylcarbodiimide); imides [for e.g., l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (i.e., EDC), 1, 1-carbonyldiimidazole] and the like or mixtures thereof. Preferably l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride may be used as coupling agent.

2-hydroxypyridine-N-oxide (HOPO), N-hydroxysuccinimide (HOSu), N-hydroxy- 5-norbornene-2,3-dicarboximide (HONB), 1-hydroxybenzotriazole (HOBt), 6-chloro- l- hydroxybenzotriazole (6-Cl-HOBt), 1 -hydroxy-7-azabenzotriazole (HOAt), 3-hydroxy-4- oxo-3,4-dihydro-l,2,3-benzotriazine (HODhbt) and its aza derivative (HODhat) can be used as the additive in the condensation reactions. Preferably, HOBt may be used as additive.

The base used in step (b) can be any organic base. The suitable base is selected from the group consisting of triethyl amine, diisopropylethyl amine, diethyl amine, isopropyl amine, morpholine, N-methyl morpholine, pyridine, ammonia, 1,8- diazabicyclo[5.4.0] undec-7-ene, l,4-diazabicyclo[2.2.2] octane, and the like or mixtures thereof. The condensation reaction of step (b) is carried out in suitable solvent selected from the group consisting of alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof in any suitable proportion. Examples of suitable solvent includes but 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, Ν,Ν-dimethylformamide, N-methyl acetamide, N,N- dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone 1, 1-dichloroethane, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, benzene, xylene or mixtures thereof in any suitable proportion. Preferably dichloromethane, dimethylformamide or mixtures thereof may be used as suitable solvent.

A compound of formula (Vila) can be prepared in step (c) by deprotecting the amine protection of compound of formula (Via) with organic or inorganic acid. The said reaction is carried out at a temperature from about 05°C to 70°C, preferably about 25°C to 50°C.

The organic acid may be selected form carboxylic acid or sulphonic acid such as trifluoroacetic acid, trifluoromethane sulphonic acid, methane sulphonic acid, formic acid, tartaric acid and p-touenesulphonic acid. The inorganic acid may be selected from hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and sodium hydrogen phosphate. Preferably hydrochloric acid may be used for deprotection. The reaction of step (c) is carried out in absence or presence of suitable organic solvent which is selected from the group consisting of alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof. Examples of 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, Ν,Ν-dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone 1 , 1 -dichloroethane, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, benzene, xylene, monoglyme, diglyme, diethoxy methane or mixtures thereof. Preferably THF may be used as suitable solvent.

A compound of formula (I) can be prepared in step (d) by treating the compound of formula (Vila) with aqueous base in suitable solvent. The said reaction is carried out at temperature from about -10°C to 70°C, preferably at about 0°C to 45°C. Base used in step (d) is selected from the group consisting 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. Preferably sodium hydroxide may be used as base.

Suitable solvents that can be used in the step (d) include but are not limited to alcoholic solvents such as methanol, ethanol, isopropanol preferably methanol and the like; water and their mixtures.

In yet another aspect, the invention provides a process for the preparation of eluxadoline of formula (I); comprising the steps of:

(a) reacting the compound of formula (VI), wherein R1 is lower alkyl or aryl alkyl and 'Prof is a nitrogen protecting group; with aqueous solution of base to obtain the corresponding compound of formula (VIII);

Figure imgf000015_0001
(b) deprotecting the compound of formula (VIII) to the corresponding compound of

Figure imgf000016_0001

A compound of formula (VIII) can be prepared in step (a) by treating the compound of formula (VI) with aqueous base in suitable solvent. The said reaction is carried out at a temperature from about -10°C to 70°C, preferably about 0°C to 50°C.

Base used in step (a) is selected from the group consisting 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.

Suitable solvents that can be used in the step (a) include but are not limited to alcoholic solvents such as methanol, ethanol, isopropanol preferably methanol and the like; water and their mixtures. A compound of formula (I) can be prepared in step (b) by deprotecting the amine protection of compound of formula (VIII) by conventional processes such as reduction, acid treatment and like. Acid treatment can be carried out by treating the compound of formula (VIII) with organic or inorganic acids. The organic acid may be selected form carboxylic acid or sulphonic acid such as trifluoroacetic acid, trifluoromethane sulphonic acid, methane sulphonic acid, formic acid, tartaric acid and p-touenesulphonic acid. The inorganic acid may be selected from hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and sodium hydrogen phosphate. The said reaction is carried out at a temperature from about 05°C to 70°C, preferably about 25°C to 50°C.

The reaction of step (b) is carried out in absence or presence of suitable organic solvent which is selected from the group consisting of alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof. Examples of 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, Ν,Ν-dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone 1 , 1 -dichloroethane, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, benzene, xylene, monoglyme, diglyme, diethoxy methane or mixtures thereof.

In yet another aspect, the present invention provides amorphous form of eluxadoline. In yet another aspect, the invention provides a process for the preparation of amorphous form of eluxadoline.

In yet another aspect, the present invention provides pharmaceutical composition comprising amorphous form of eluxadoline 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.

In yet another aspect, the invention provides a process for the preparation of amorphous form of eluxadoline comprising the steps of:

(a) providing solution of eluxadoline in suitable solvent or mixtures thereof;

(b) treating the solution of step (a) with an antisolvent; (c) isolating an amorphous form of eluxadoline from the reaction mixture.

Providing solution of eluxadoline in step (a) includes:

(i) direct use of reaction mixture containing eluxadoline that is obtained during its synthesis; or

(ii) dissolving eluxadoline in suitable solvent or mixtures thereof.

Eluxadoline that may be used as the input for the process of the invention may be obtained by any process including the process described in the art.

Suitable solvents that may be used in step (a) comprises of alcohol, polar aprotic solvents such as amide and sulfoxide or mixtures thereof in any suitable proportion. Particularly preferred solvents selected from methanol, ethanol, isopropanol, 2-propanol, t-butyl alcohol, 1 -pentanol, 2-pentanol, amyl alcohol, dimethylformamide (DMF), N- methyl pyrrolidone (NMP), dimethylacetamide (DMAc), formamide, acetamide, propanamide, dimethyl sulfoxide (DMSO) or mixtures thereof in any suitable proportion. More preferably methanol may be used in any suitable proportion.

The dissolution temperature may range from about 10°C to about reflux temperature of the solvent. Optionally, 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 anti-solvent for step (b) comprises of water, alkane, ketone, acetate, ether, hydrocarbon or mixtures thereof in any suitable proportion. Particularly preferred solvents selected from n-pentane, n-hexane, n-heptane, cyclohexane, methylcyclohexane, acetone, butanone, 2-pentanone, 3-pentanone, methylbutyl ketone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, diisopropyl ether, water, toluene or mixtures thereof in any suitable proportion. More preferably acetone or water may be used as anti-solvent.

The treatment with the antisolvent may be carried out, for example, by adding the antisolvent into the solution of eluxadoline or vice versa at temperature about -10°C to refluxing temperature, preferably at 25°C to 30°C. The treatment with antisolvent may be followed by stirring the mixture.

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 amorphous 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 suitable temperature, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a product with desired purity.

In yet another aspect, the invention provides a process for the preparation of amorphous form of eluxadoline comprising the steps of:

(a) providing solution of eluxadoline;

(b) removing solvent from the solution obtained in step (a); and

(c) isolating the amorphous form of eluxadoline from the reaction mixture thereof.

Providing solution of eluxadoline in step (a) includes:

(i) direct use of reaction mixture containing eluxadoline that is obtained during its synthesis; or

(ii) dissolving eluxadoline in suitable solvent or mixtures thereof. Eluxadoline that may be used as the input for the process of the invention may be obtained by any process including the process described in the art.

Suitable solvents that may be used in step (a) comprises of alcohol, polar aprotic solvent such as amide and sulfoxide or mixtures thereof in any suitable proportion. Particularly preferred solvents selected from methanol, ethanol, isopropanol, 2-propanol, t-butyl alcohol, 1 -pentanol, 2-pentanol, amyl alcohol, dimethylformamide (DMF), N- methyl pyrrolidone (NMP), dimethylacetamide (DMAc), formamide, acetamide, propanamide, dimethyl sulfoxide (DMSO) or mixtures thereof in any suitable proportion. More preferably methanol may be used in any suitable proportion.

The dissolution temperature may range from about 10°C to about reflux temperature of the solvent. Optionally, 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.

Step b) involves the removal of solvents from the solution obtained from step a). Suitable techniques which may be used for the removal of the solvent comprises distillation, distillation under vacuum, spray drying, agitated thin film drying (ATFD), freeze drying (lyophilization), flash evaporation, Hot- Melt Extrusion (HME) and the like.

Step c) involves isolation of an amorphous form of eluxadoline from the solution of step b). The compound obtained from step b) may be collected using techniques such as by scraping, or by shaking the container, or adding solvent to make slurry followed by filtration, or other techniques.

The amorphous 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 suitable temperature, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a product with desired purity.

In yet another embodiment, the present invention provides amorphous form of eluxadoline characterized by powder X-ray diffraction pattern as depicted in Figure 1. The amorphous form of eluxadoline obtained by the process of the present invention further characterized by thermogravimetric analysis (TGA) thermogram, and infra-red (IR) spectrum. In yet another aspect, the invention provides Form L of eluxadoline.

In yet another aspect, the present invention provides Form L of eluxadoline characterized by X-ray powder diffraction pattern as depicted in Figure 4; In yet another aspect, the present invention provides pharmaceutical composition comprising Form L of eluxadoline together with one or more pharmaceutically acceptable excipients for use in in the treatment of disorders that may be ameliorated or treated by the modulation of opioid receptors. The pharmaceuticals can be safely administered orally or non-orally. Routes of administration include, but are not limited to, oral, topical, mucosal, nasal, parenteral, gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic, transdermal, rectal, buccal, epidural and sublingual. The pharmaceutical composition can be formulated as solid oral dosage forms such as, but are not limited to, powders, granules, pellets, tablets (single layered tablets, multilayered tablets, mini tablets, bioadhesive tablets, caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, immediate release tablets, sustained release tablet, extended release tablet, modified release tablets, pulsatile release tablets, and timed release tablets), beads, granules, sustained release formulations, capsules, microcapsules, tablets in capsules, microspheres, matrix formulations, microencapsulation, or capsules; liquid oral dosage forms such as, but are not limited to, syrups, suspensions, dispersions, or emulsions; or injectable preparations such as, but not limited to, solutions, dispersions, or freeze dried compositions.

The term "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.

In yet another aspect, the invention provides a process for the preparation of Form L of eluxadoline;

comprising the steps of:

(i) slurrying eluxadoline in suitable solvent selected from the group consisting of ester, alcohol and nitrile or mixtures thereof in any suitable proportion; and

(ii) isolating the Form L of eluxadoline from the reaction mixture. Eluxadoline that may be used as the input for the process of the invention may be obtained by any process including the process described in the art.

The preferred temperature for the process of slurrying is about room temperature to about 80°C; preferably at about 40°C to about 70°C; more preferably, at about 45°C to about 55°C. 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.

After separation, the solid may optionally be washed with a suitable solvent. The obtained 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 suitable temperature, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a product with desired purity. One skilled in the art will recognize that additional starting compounds and/or reagents are commercially available or may be easily prepared according to conventional methods well known to these skilled in the art.

EXAMPLES

Example 1

Preparation of Eluxadoline

Step 1- Preparation of 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[l- (4-phenyl- lH-imidazol-2-yl)-ethyl]-amino} -methyl)-2-methoxy-benzoic acid

Figure imgf000023_0001

To a stirred solution of 1 -(4-phenyl- lH-imidazole-2-yl)-ethyl amine (20 gm) and 5-formyl-2-methoxy-benzoic acid methyl ester (20 gm) in methanol was added catalytic amount of acetic acid (3 ml). The reaction mixture was cooled at 5°C-10°C and sodium borohydride (4 gm) was added. The reaction mixture was further stirred for 2-3 hours at room temperature. The resultant mixture was diluted with water and then partially concentrated. To this mixture was added 2N HCl solution followed by addition of dichloromethane. The phases were separated and the pH (9-1 1) of aqueous layer was adjusted using 2N NaOH solution; which was further extracted with dichloromethane. The combined organic layers were concentrated under vacuum to afford titled compound as oil (yield: 40 gm).

Step 2- Preparation of 5-({[2-tert-butoxycarbonylmethyl-3-(4-carbamoyl-2,6-dimethyl- phenyl)-propionyl] - [ 1 -(4-phenyl- 1 H-imidazol-2-yl)-ethyl] -amino} -methyl)-2-methoxy- benzoic acid methyl ester

Figure imgf000023_0002
To a stirring mixture of 2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6- dimethyl-phenyl-propionic acid (100 gm), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (159.4 gm) and 1- hydroxybenzotriazole (45.4 gm) in dimethylformamide (80 ml) & dichloromethane (1920 ml) was added 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[l-(4- phenyl-lH-imidazol-2-yl)-ethyl] -amino }-methyl)-2-methoxy-benzoic acid (step 1 product, 146.6 gm). The resulting mixture was stirred at room temperature for overnight and further diluted with water. The separated organic phase was washed sequentially with aqueous Na2C03 solution, IN HCl solution, water and brine. After concentration, the residue was further dissolved in DCM. The resultant solution was washed sequentially with water & IN HCl solution and then concentrated under vacuum to afford titled compound (yield: 145 gm).

Step 3- Preparation of methyl 5-((2-amino-3-(4-carbamoyl-2,6-dimethylphenyl)-N-(l-(4- phenyl- 1 H-imidazol-2-yl)ethyl) enzoate

Figure imgf000024_0001

To a stirred solution of 5-({[2-tert-butoxycarbonylmethyl-3-(4-carbamoyl-2,6- dimethyl-phenyl)-propionyl] - [ 1 -(4-phenyl- 1 H-imidazol-2-yl)-ethyl] -amino } -methyl)-2- methoxy-benzoic acid methyl ester (step -2 product, 20 gm) in THF (80 ml) was added Cone. HCl solution (30 ml). The reaction mixture was heated at 40°C-45°C. After completion of reaction, the mixture was concentrated and resultant residue was diluted with water. The pH (9-10) was adjusted using 3N NaOH solution; and resultant stick mass was dissolved in methanol. The resultant solution was concentrated under vacuum to afford titled compound (yield: 18.1 gm).

Step 4- Preparation of Eluxadoline

Figure imgf000025_0001

Into an ice cooled solution of methyl 5-((2-amino-3-(4-carbamoyl-2,6- dimethylphenyl)-N-( 1 -(4-phenyl- 1 H-imidazol-2-yl)ethyl)propanamido)methyl)-2- methoxybenzoate (step 3 product, 15 gm) in methanol was added an aqueous lithium hydroxide (3.23 gm in 30 ml water) and resultant mixture was heated at 40°C-45°C. After completion of reaction, mixture was concentrated and further diluted with water. The pH (6-7) was adjusted using 2N citric acid and resultant residue was dissolved in methanol. The resultant solution was added slowly to the acetone and stirring was continued for overnight. The solid precipitated was filtered, washed with acetone and dried to obtain an amorphous form of titled compound (Yield: 3.50 gm).

Example 2

Preparation of Eluxadoline

Step 1 : 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

Figure imgf000025_0002

Into an ice cooled solution of 5-({[2-tert-butoxycarbonylmethyl-3-(4-carbamoyl- 2,6-dimethyl-phenyl)-propionyl] - [ 1 -(4-phenyl- 1 H-imidazol-2-yl)-ethyl] -amino } -methyl)- 2-methoxy-benzoic acid methyl ester (160 gm) in methanol (800 ml) was added an aqueous solution of lithium hydroxide (29.46 gm in 350 ml water) and resultant mixture was stirred at room temperature for overnight. After completion of reaction, mixture was partially concentrated and further diluted with water. The pH (4-5) was adjusted using 2N citric acid and further stirred for 60 min. The solid precipitated was filtered, washed with water and dried to obtain titled compound (yield: 140 gm). Step 2: Preparation of Eluxadoline

To a stirred solution of 5-( {[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6- dimethyl-phenyl)-propionyl] - [ 1 -(4-phenyl- 1 H-imidazol-2-yl)-ethyl] -amino } -methyl)-2- methoxy-benzoic acid (step-1 product, 100 gm) in acetone (1200 ml) was added Cone. HC1 solution (50 ml). The reaction mixture was heated at 40°C-45°C. After completion of reaction, the supernatant solution was decanted; resultant residue was rinsed with acetone and further dissolved in water. The pH (6-7) was adjusted using IN NaOH solution and the precipitated was filtered, washed with water and dried to obtain an amorphous form of eluxadoline (yield: 72 gm).

Example 3

Preparation of Eluxadoline

To a stirred solution of 5-( {[2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6- dimethyl-phenyl)-propionyl] - [ 1 -(4-phenyl- 1 -imidazol-2-yl)-ethyl] -amino } -methyl)-2- methoxy-benzoic acid (50 gm) in dichloromethane (250 ml) were added solution of Cone. HC1 (50 ml) and water (50 ml). The reaction mixture was heated at 35°C-40°C and further stirred for 10-20 minutes. Tetrahydrofuran (50 ml) & Cone. HC1 (20 ml) were added to the sticky mass and reaction mixture was heated at 40°C for 2 hours. After completion of reaction, the mixture was diluted with water. The pH (6-7) was adjusted using 4N NaOH solution and the obtained sticky mass was dissolved in methanol. The resultant solution was concentrated under vacuum to afford eluxadoline (yield: 16 gm).

Example 4

Preparation of amorphous form of eluxadoline Eluxadoline (1 gm) was dissolved in methanol (20 ml) at 25-30°C. Water (60 ml) was added to the resultant solution and stirred for 15-20 minutes. The resultant slurry was filtered, washed with water and further dried to obtain amorphous form of eluxadoline (Yield: 0.80 gm).

Example 5

Preparation of amorphous form of eluxadoline

Eluxadoline (1 gm) was dissolved in methanol (20 ml) at 25-30°C. Acetone (80 ml) was added to the resultant solution and stirred for 15-20 minutes. The resultant slurry was filtered, washed with acetone and further dried to obtain amorphous form of eluxadoline (Yield: 0.80 gm).

Example 6

Preparation of Form L of eluxadoline

Eluxadoline (1 gm) was charged into flask containing acetonitrile (60 ml) and slurried for 24 hours to 25 hours at 50°C. The resultant solid was filtered, and dried to obtain titled compound (Yield: 0.80 gm).

Example 7

Preparation of Form L of eluxadoline

Eluxadoline (1 gm) was charged into flask containing ethyl acetate (50 ml) and slurried for 6 to 7 hours at 50°C. The resultant solid was filtered, and dried to obtain titled compound (Yield: 0.80 gm). Example 8

Preparation of Form L of eluxadoline

Eluxadoline (1 gm) was charged into flask containing n-butanol (40 ml) and slurried for 17 hours to 18 hours at 50°C. The resultant solid was filtered, and dried to obtain titled compound (Yield: 0.60 gm).

Example 9

Preparation of Form L of eluxadoline

Eluxadoline (1 gm) was charged into flask containing acetonitrile (15 ml) and slurried for 24 hours at 50°C. The resultant mixture was cooled at room temperature, filtered, further washed with acetonitrile and dried to obtain titled compound (Yield: 0.76 gm).

Example 10

Preparation of Form L of eluxadoline

Eluxadoline (3 gm) was charged into flask containing ethyl acetate (30 ml) and slurried for 24 hours at 50°C. The resultant mixture was cooled at room temperature, filtered, further washed with ethyl acetate and dried to obtain titled compound (Yield: 0.73 gm).

Example 1 1

Preparation of Form L of eluxadoline

Eluxadoline (2 gm) was charged into flask containing ethyl acetate (90 ml) and slurried for 7 hours at 50°C. The resultant mixture was cooled at room temperature, filtered, further washed with ethyl acetate and dried to obtain titled compound (Yield: 0.54 gm).

Claims

27 CLAIMS
1. A process for the preparation of amorphous form of eluxadoline comprising the steps of:
(a) providing solution of eluxadoline in suitable solvent or mixtures thereof;
(b) treating the solution of step (a) with an antisolvent;
(c) isolating an amorphous form of eluxadoline from the reaction mixture.
2. The process according to claim 1, wherein the solvent comprises of alcohols selected from ethanol, methanol, isopropanol, 2-propanol, t-butyl alcohol, 1 -pentanol, 2-pentanol and amyl alcohol; polar aprotic solvents selected from dimethylformamide, N-methyl pyrrolidone, dimethylacetamide, formamide, acetamide, propanamide and dimethyl sulfoxide or mixtures thereof. 3. The process according to claim 1 , wherein the anti-solvent for step (b) comprises of water; alkanes selected from n-pentane, n-hexane, n-heptane, cyclohexane, methylcyclohexane; ketones selected from acetone, butanone, 2-pentanone,
3-pentanone, methylbutyl ketone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone; esters selected from ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate; ethers selected from methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, diisopropyl ether; and hydrocarbons selected from toluene or mixtures thereof.
4. A process for the preparation of amorphous form of eluxadoline comprising the steps of:
(a) providing solution of eluxadoline in suitable solvent or mixtures thereof;
(b) removing solvent from the solution obtained in step (a); and
(c) isolating the amorphous form of eluxadoline from the reaction mixture.
5. The process according to claim 4, wherein the solvent comprises of alcohols selected from ethanol, methanol, isopropanol, 2-propanol, t-butyl alcohol, 1 -pentanol, 2-pentanol and amyl alcohol; polar aprotic solvents selected from dimethylformamide, N-methyl 28
pyrrolidone, dimethylacetamide, formamide, acetamide, propanamide and dimethyl sulfoxide or mixtures thereof.
6. The process according to claim 4, wherein the removal of solvents comprises distillation, distillation under vacuum, spray drying, agitated thin film drying (ATFD), freeze drying (lyophilization), flash evaporation, and Hot-Melt Extrusion (HME).
7. Form L of Eluxadoline characterized by X-ray powder diffraction pattern as depicted in Figure 4.
8. A process for the preparation of Form L of Eluxadoline;
comprising the steps of:
(a) slurrying eluxadoline in suitable solvent selected from the group consisting of ester, alcohol and nitrile or mixtures thereof; and
(b) isolating the Form L of eluxadoline from the reaction mixture.
9. The process according to claim 8, wherein suitable solvent used in step (a) is selected from the group consisting of ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, n-butanol, and acetonitrile or mixtures thereof.
10. The process according to claim 8, wherein slurrying is carried out at a temperature of about 40°C to about 70°C.
1 1. The process according to claim 8, wherein Form L of Eluxadoline is isolated by filtration.
12. A process for the preparation of eluxadoline of formula (I) or pharmaceutically acceptable salts thereof comprising the step of:
(a) reductive amination of a compound of formula (II) with a compound of formula (III), wherein R1 is lower alkyl or aryl alkyl; in presence of hydride source to obtain the corresponding compound of formula (IV); 29
Figure imgf000031_0001
(IV)
(b) condensing the compound of formula (IV) with a compound of formula (V) using suitable coupling agent, to obtain the corresponding compound of formula (VI); wherein 'Prof is a nitrogen protecting group;
Figure imgf000031_0002
(IV)
(vi)
(c) deprotecting the compound of formula (VI) to the corresponding compound of formula (VII);
Figure imgf000031_0003
(d) treating the compound of formula (VII) with base in suitable solvent to obtain the corresponding compound of formula (I); 30
13. The process according to claim 12, wherein the hydride source is metal hydride selected from the group consisting of sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride, lithium cyanoborohydride, potassium borohydride, lithium borohydride, zinc borohydride, calcium borohydride, magnesium borohydride and zirconium borohydride.
14. The process according to claim 12, wherein coupling agent is selected from the group consisting of methyl chloroformate, isobutyl chloroformate, pivolyl chloride, phenyl chloroformate, nitrophenyl chloroformate, (benzotriazol- 1 -yloxy)tris(dimethylamino) phosphonium hexafluoro phosphate, NN'-dicyclohexylcarbodiimide), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride, and 1, 1-carbonyldiimidazole in presence of additives selected form the group consisting of 2-hydroxypyridine-N-oxide, N-hydroxysuccinimide, N-hydroxy-5-norbornene-2,3-dicarboximide, 1 - hydroxybenzotriazole, 6-chloro- 1 -hydroxybenzotriazole, 1 -hydroxy-7-azabenzotriazole, 3-hydroxy-4-oxo-3,4-dihydro-l,2,3-benzotriazine and HODhat.
15. The process according to claim 12, wherein protecting group is selected from the group consisting of tert-butoxy carbonyl, benzyloxy carbonyl, acetyl, triflouoroacetyl, benzyl, dibenzyl, phthalimido, tosyl, p-methoxybenzylcarbonyl, 9- fluorenylmethyloxycarbonyl, carbamate, p-methoxybenzyl, p-methoxyphenyl, tosyl, phenyl sulfonyl, trimethylsilylethoxymethyl and benzoyl.
16. The process according to claim 12, wherein deprotection is carried out using organic or inorganic acids selected from the group consisting of trifluoroacetic acid, trifluoromethane sulphonic acid, methane sulphonic acid, formic acid, tartaric acid, p- touenesulphonic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and sodium hydrogen phosphate.
17. The process according to claim 12, wherein base used in step (d) is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, rubidium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. 31
18. The process according to claim 12, wherein solvent used in step (d) is selected from the group consisting of methanol, ethanol, isopropanol and water or mixtures thereof.
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Citations (3)

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WO2005090315A1 (en) 2004-03-15 2005-09-29 Janssen Pharmaceutica, N. V. Novel compounds as opioid receptor modulators
WO2009009480A2 (en) 2007-07-09 2009-01-15 Janssen Pharmaceutica N.V. Novel crystals and process of making 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy- benzoic acid
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WO2017114446A1 (en) * 2015-12-31 2017-07-06 苏州晶云药物科技有限公司 New crystal form of eluxadoline and preparation method thereof
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WO2005090315A1 (en) 2004-03-15 2005-09-29 Janssen Pharmaceutica, N. V. Novel compounds as opioid receptor modulators
WO2009009480A2 (en) 2007-07-09 2009-01-15 Janssen Pharmaceutica N.V. Novel crystals and process of making 5-({[2-amino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionyl]-[1-(4-phenyl-1h-imidazol-2-yl)-ethyl]-amino}-methyl)-2-methoxy- benzoic acid
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