WO2023131969A1 - Procédé amélioré pour la préparation de luliconazole - Google Patents

Procédé amélioré pour la préparation de luliconazole Download PDF

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Publication number
WO2023131969A1
WO2023131969A1 PCT/IN2023/050001 IN2023050001W WO2023131969A1 WO 2023131969 A1 WO2023131969 A1 WO 2023131969A1 IN 2023050001 W IN2023050001 W IN 2023050001W WO 2023131969 A1 WO2023131969 A1 WO 2023131969A1
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Prior art keywords
formula
acid
cyanomethylimidazole
luliconazole
process according
Prior art date
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PCT/IN2023/050001
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English (en)
Inventor
Ramnik Sharma
Mahesh RAJPUT
Manish CHOUBEY
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Kimia Biosciences Limited
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Publication of WO2023131969A1 publication Critical patent/WO2023131969A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D233/56—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/61—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms

Definitions

  • the present invention relates to an improved process for the preparation of Luliconazole.
  • the present invention also provides a novel intermediate 1- cyanomethylimidazole methanesulphonate of Formula (V), process for its preparation and its use for the preparation of Luliconazole.
  • Luliconazole is chemically known as (2E)-2-
  • Luliconazole is an antifungal azole indicated for the topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by the organisms Trichophyton rubrum and Epidermophyton floccosum, in patients 18 years of age and older.
  • Luliconazole was first disclosed in U.S. Patent No. 5,900,488 by Nihon Nohyaku Co., Ltd.
  • U.S. ‘488 discloses a process for the preparation of Luliconazole of Formula (I) by reacting (>S')-2-chloro-l-(2,4-dichlorophenyl)ethyl methanesulfonate of Formula (II) with 1 -cyanomethylimidazole of Formula (III). The process is depicted in the scheme given below:
  • PCT Publication No. 2017/108972 discloses a use of 1-cyanomethylimidazole hydrochloride in the preparation of Luliconazole.
  • preparation of 1- cyanomethylimidazole hydrochloride involves use of hydrogen chloride gas which is costly and highly corrosive in nature.
  • 1-cyanomethylimidazole hydrochloride is highly hygroscopic due to which it is susceptible to convert to 2-( I H-imidazol- 1 -yl (acetamide of Formula (IV) as an impurity.
  • 1-cyanomethylimidazole hydrochloride is not suitable for commercial purposes.
  • the present invention relates to an improved process for the preparation of Luliconazole.
  • the present invention also provides a novel intermediate 1- cyanomethylimidazole methanesulphonate of Formula (V), process for its preparation and its use for the preparation of Luliconazole.
  • the present invention provides cost-effective, environmental friendly and industrially advantageous process for the preparation of Luliconazole in high yield using 1- cyanomethylimidazole methanesulphonate of Formula (V) as a novel intermediate.
  • Figure 1 High Performance Liquid Chromatography (HPLC) chromatogram of purity of 1-cyanomethylimidazole hydrochloride, obtained as per Reference Example.
  • Figure 2 HPLC chromatogram of purity of 1-cyanomethylimidazole methane sulphonate of compound of Formula (V), obtained as per Example 2 of present invention.
  • room temperature refers to a temperature in the range of 25°C to 35°C.
  • acid addition salt refers to inorganic salt or organic salt.
  • inorganic salt include hydrochloric, hydrobromic, hydroiodic, nitric, phosphoric, sulfuric, and trifluoroacetic.
  • organic salt include acetic, formic, citric, tartaric, benzoic, lactic, malic, fumaric, succinic, methanesulfonic, p- toluenesuphonic, and benzene sulfonic.
  • a first aspect of the present invention provides a process for the preparation of Luliconazole of Formula (I),
  • Formula I comprising a) reacting imidazole with chloroacetonitrile to obtain 1 -cyanomethylimidazole of Formula (III);
  • Formula V c) reacting 1 -cyanomethylimidazole methanesulphonate of Formula (V) with carbon disulfide in the presence of a base and a solvent to form an intermediate of Formula (VI);
  • Formula VI d) reacting the compound of Formula (VI) in-situ with 2,4-dichloro-l-[(l>S')-l,2- dichloroethyl]benzene of Formula (VII) to obtain Luliconazole of Formula (I);
  • a second aspect of the present invention provides a process for the preparation of 1- cyanomethylimidazole methanesulphonate of Formula (V),
  • Formula V comprising a) reacting imidazole with chloroacetonitrile to obtain 1 -cyanomethylimidazole of
  • a third aspect of the present invention provides 1 -cyanomethylimidazole methane sulphonate of Formula (V).
  • the compound of Formula (VII) may be prepared by any method known in the art, for example, the method as described in U.S. Patent No. 5,900,488.
  • the reaction of imidazole with chloroacetonitrile to obtain 1 -cyanomethylimidazole of Formula (III) is carried out in the presence of a base in a solvent.
  • the base is selected from the group consisting of inorganic base or an organic base.
  • inorganic base include sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate.
  • examples of organic base include triethylamine, N, N’ -diisopropylethyl amine, and l,8-diazabicyclo[5.4.0]undec-7- ene.
  • the solvent is selected from the group consisiting of esters, ethers, alcohols, nitriles, halogenated hydrocarbons, aromatic hydrocarbons, ketones, water, and mixtures thereof.
  • esters include ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, and butyl acetate.
  • ethers include tetrahydrofuran, ethyl methyl ether, diethyl ether, diisopropyl ether, and methyl tert-butyl ether.
  • alcohols include methanol, ethanol, propanol, iso-propanol, n-butanol, and iso-butanol.
  • Example of nitrile is acetonitrile.
  • halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
  • aromatic hydrocarbons include toluene and xylene.
  • ketones include acetone, methyl ethyl ketone, and methyl isobutyl ketone.
  • the reaction of imidazole with chloroacetonitrile is carried out for about 20 hours to about 30 hours. In an embodiment, the reaction of imidazole with chloroacetonitrile is carried out for about 22 hours to about 28 hours. In another embodiment, the reaction of imidazole with chloroacetonitrile is carried out for about 22 hours to about 24 hours.
  • reaction of imidazole with chloroacetonitrile is carried out at room temperature to the boiling point of the solvent.
  • reaction mixture containing 1 -cyanomethylimidazole of Formula (III) may be used as such or isolated.
  • 1 -Cyanomethylimidazole of Formula (III) may optionally be isolated using conventional techniques, for example, fdtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
  • 1 -Cyanomethylimidazole of Formula (III) may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin fdm drying.
  • the solvent is selected from the group consisiting of esters, ethers, alcohols, nitriles, halogenated hydrocarbons, aromatic hydrocarbons, ketones, water, and mixtures thereof.
  • esters include ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, and butyl acetate.
  • ethers include tetrahydrofuran, ethyl methyl ether, diethyl ether, diisopropyl ether, and methyl tert-butyl ether.
  • alcohols include methanol, ethanol, propanol, iso-propanol, n-butanol, and iso-butanol.
  • Example of nitrile is acetonitrile.
  • halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
  • aromatic hydrocarbons include toluene and xylene.
  • ketones include acetone, methyl ethyl ketone, and methyl isobutyl ketone.
  • reaction of 1 -cyanomethylimidazole of Formula (III) with methanesulphonic acid is carried out at about 0°C to about 15°C.
  • reaction of 1- cyanomethylimidazole of Formula (III) with methanesulphonic acid is carried out at about 2°C to about 12°C.
  • reaction of 1 -cyanomethylimidazole of Formula (III) with methanesulphonic acid is carried out at about 5°C to about I0°C.
  • reaction of 1 -cyanomethylimidazole of Formula (III) with methanesulphonic acid is carried out for about one hour to about 5 hours. In an embodiment, the reaction of 1 -cyanomethylimidazole of Formula (III) with methanesulphonic acid is carried out for about one hour to about 4 hours. In another embodiment, the reaction of 1- cyanomethylimidazole of Formula (III) with methanesulphonic acid is carried out for about 2 hours to about 3 hours.
  • 1 -Cyanomethylimidazole methane sulphonate of Formula (V) may optionally be isolated using conventional techniques, for example, filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
  • 1 -Cyanomethylimidazole methanesulphonate of Formula V may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.
  • reaction of 1 -cyanomethylimidazole methane sulphonate of Formula (V) with carbon disulphide to obtain the compound of Formula (VI) is carried out in the presence of a base in a solvent.
  • the base is selected from the group consisting of inorganic base or an organic base.
  • inorganic base include sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate.
  • organic base include triethylamine, N, N’ -diisopropylethyl amine, and I,8-diazabicyclo[5.4.0]undec-7- ene.
  • the base may be added to the reaction mixture either in solid form or in solution form.
  • the solvent is selected from the group consisiting of polar aprotic solvent.
  • polar aprotic solvent include dimethyl sulfoxide, dimethylformamide, dimethylacetamide, acetonitrile, or mixture thereof.
  • reaction of 1 -cyanomethylimidazole methane sulphonate of Formula (V) with carbon disulphide is carried out at about -10°C to about 10°C. In an embodiment, the reaction of 1 -cyanomethylimidazole methane sulphonate of Formula (V) with carbon disulphide is carried out at about -7°C to about -3°C. In another embodiment, the reaction of 1 -cyanomethylimidazole methanesulphonate of Formula (V) with carbon disulphide is carried out at about 2°C to about 7°C.
  • reaction of 1 -cyanomethylimidazole methane sulphonate of Formula (V) with carbon disulphide is carried out for about 2 hours to about 10 hours. In an embodiment, the reaction of 1 -cyanomethylimidazole methane sulphonate of Formula (V) with carbon disulphide is carried out for about 3 hours to 8 hours. In another embodiment, the reaction of 1 -cyanomethylimidazole methanesulphonate acid of Formula (V) with carbon disulphide is carried out for about 4 hours to about 6 hours.
  • reaction mixture containing the compound of Formula (VI) is used as such or without isolation.
  • reaction of the compound of Formula (VI) with 2,4-dichloro-l-[(l>S')-l,2- dichloroethyl] benzene of Formula (VII) is carried out at about -10°C to about room temperature.
  • reaction of the compound of Formula (VI) with 2,4-dichloro-l-[(l>S')-l,2- dichloroethyl] benzene of Formula (VII) is carried out for about 2 hours to about 10 hours.
  • reaction ofthe compound of Formula (VI) with 2,4-dichloro-l-[(l>S')- l,2-dichloroethyl]benzene of Formula (VII) is carried out for about 4 hours to about 8 hours.
  • bcnzcnc of Formula (VII) is carried out for about 5 hours to about 7 hours.
  • the reaction mass containing Luliconazole of Formula (I) is quenched with water followed by extraction with a suitable organic solvent.
  • the organic solvent is selected from the group consisting of halogenated hydrocarbons, esters, hydrocarbons, and mixtures thereof.
  • halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
  • esters include ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, and butyl acetate.
  • hydrocarbons include toluene, xylene, and cyclohexane.
  • the organic layer is acidified with the addition of suitable acid to obtain an acid addition salt of Luliconazole.
  • the acid is selected from the group consisting of inorganic acid or organic acid.
  • inorganic acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid, and trifluoroacetic acid.
  • organic acid include acetic acid, formic acid, citric acid, tartaric acid, benzoic acid, lactic acid, malic acid, fumaric acid, succinic acid, methanesulfonic acid, and benzenesulfonic acid.
  • the acid addition salt of Luliconazole may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
  • the acid addition salt of Luliconazole may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.
  • the conversion of the acid addition salt of Luliconazole to Luliconazole of Formula (I) is carried out using a base in a solvent.
  • the base is selected from the group consisting of organic base or inorganic base.
  • organic base include aqueous ammonia solution, ammonia gas, triethylamine, and ammonium hydroxide.
  • inorganic base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate.
  • the solvent is selected from the group consisiting of esters, ethers, alcohols, nitriles, halogenated hydrocarbons, aromatic hydrocarbons, ketones, water, and mixtures thereof.
  • esters include ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, and butyl acetate.
  • ethers include tetrahydrofuran, ethyl methyl ether, diethyl ether, diisopropyl ether, and methyl tert-butyl ether.
  • alcohols include methanol, ethanol, propanol, iso-propanol, n-butanol, and iso-butanol.
  • Example of nitrile is acetonitrile.
  • halogenated hydrocarbons include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
  • aromatic hydrocarbons include toluene and xylene.
  • ketones include acetone, methyl ethyl ketone, and methyl isobutyl ketone.
  • the pH of the reaction mixture is maintained in the range of about 8.0 to about 12.0. In an embodiment, the pH is maintained in the range of about 9.0 to about 11.0. In another embodiment, the pH is maintained in the range of about 9.5 to about 10.5.
  • Luliconazole of Formula (I) may optionally be isolated by fdtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. Luliconazole of Formula (I) may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.
  • the present invention provides a novel intermediate 1 -cyanomethylimidazole methane sulphonate of Formula (V).
  • 1 -Cyanomethylimidazole methanesulphonate of Formula (V) is characterized by H- NMR, 13 C-NMR, IR, and Mass (m/z).
  • 1 -cyanomethylimidazole methane sulphonate of Formula (V) is less hygroscopic, easy to handle, can be stored at room temperature, and less susceptible to conversion to 2-( l/7-imidazol- l -yl)acctamidc of Formula (IV) as an impurity.
  • HPLC chromatogram ( Figure 1) of 1 -cyanomethylimidazole hydrochloride shows the presence of about 12.9% of 2-(lf/-imidazol-l-yl)acetamide of Formula (IV) as an impurity.
  • HPLC chromatogram ( Figure 2) of 1 -cyanomethylimidazole methane sulphonate of Formula (V) shows the presence of 0.04% of 2-( l/7-imidazol- l - yl)acetamide of Formula (IV) as an impurity.
  • the filtrate was distilled under vacuum at 40°C to 45°C (680-720 mmHg) to obtain a residue.
  • Acetone 500 mL was added to the residue and cooled to 0°C to 5 °C.
  • Hydrogen chloride gas was slowly purged into the mixture until the pH was 1.0.
  • the reaction mixture was stirred for 30 minutes at 0°C to 5°C.
  • Excess hydrogen chloride and acetone were recovered at 40°C to 45°C.
  • Acetone (300 mL) was again added to the reaction mixture and then cooled to 0°C to 5°C and stirred for 60 minutes to obtain a solid.
  • the solid was filtered and washed with chilled acetone (200 mL) at 0°C to 5°C.
  • the solid was dried to obtain 1- cyanomethylimidazole hydrochloride.
  • Acetone 750 mL was added to the residue (as obtained in Example 1) under nitrogen atmosphere and then cooled to 5°C to 10°C.
  • Methanesulphonic acid 100 g was added drop wise over a period of 45 minutes to 60 minutes under nitrogen atmosphere and then stirred for 2 hours to 3 hours to obtain a solid.
  • the solid was filtered and washed with chilled acetone (200 mL) under nitrogen atmosphere to obtain a residue.
  • the residue was dried under nitrogen atmosphere and then under vacuum at 40°C to 45°C till moisture content is not more than 2%.
  • DMSO Dimethylsulfoxide
  • dimethylformamide 50 mL
  • 1 -Cyanomethylimidazole methanesulphonate (as obtained in Example 2; 52.5 g; Formula V) was added to the reaction mixture and stirred for 10 minutes.
  • Carbon disulfide (39 g) was then added and flushed with DMSO (14 mL).
  • the reaction mixture was cooled to 2°C to 7°C and an aqueous solution of potassium hydroxide (60 g of potassium hydroxide and 60 mL of DM water) was slowly added over a period of 90 minutes to 120 minutes.
  • reaction mixture was stirred for 2 hours at room temperature and then cooled to -7°C to -3°C to obtain a thick reaction mass.
  • a solution of 2,4-dichloro-l-[(l>S')-l,2-dichloroethyl]benzene (Formula VII; 100 g) in DMSO (100 mL) was added to the reaction mass over a period of 90 minutes to 120 minutes at -7°C to -3°C.
  • the reaction mass was stirred for 5 hours to 6 hours at 0°C to 5°C.
  • Dichloromethane (750 mL) and DM water (800 mL) precooled to 5°C to 10°C were added to the reaction mixture and stirred at room temperature for 30 minutes.
  • Ethanol 400 mL was added to Luliconazole (as obtained in Example 4) and heated at 70°C to 75°C for 30 minutes to obtain a clear solution.
  • Carbon (10 g) was added to the solution and stirred for 30 minutes.
  • the hot solution was filtered through Hyflo bed and washed with hot ethanol (200 mL).
  • the filtrate was heated to 50°C and then slowly cooled to room temperature over a period of 60 minutes to 90 minutes.
  • the solution was stirred for 120 minutes at room temperature and then further cooled to 0°C to 5°C over a period of 90 minutes to 120 minutes.
  • the solution was stirred for 60 minutes and then fdtered and washed with chilled ethanol (100 mL) to obtain a solid.
  • the solid was dried under vacuum at 45°C to 50°C to obtain Luliconazole.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un procédé amélioré de préparation de luliconazole. La présente invention concerne également un nouveau 1-cyanométhylimidazole méthanesulphonate intermédiaire de formule (V), son procédé de préparation et son utilisation pour la préparation de luliconazole.
PCT/IN2023/050001 2022-01-09 2023-01-02 Procédé amélioré pour la préparation de luliconazole WO2023131969A1 (fr)

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IN202211001169 2022-01-09
IN202211001169 2022-01-09

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5900488A (en) * 1995-07-08 1999-05-04 Nihon Nohyaku Co., Ltd. Method for treating mycosis using imidazolylacetonitrile derivatives
US20170362212A1 (en) * 2014-12-12 2017-12-21 Glenmark Pharmaceuticals Limited Process for preparation of luliconazole
WO2019150383A1 (fr) * 2018-02-05 2019-08-08 Nalla Surya Prakash Rao Procédé de préparation de luliconazole

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5900488A (en) * 1995-07-08 1999-05-04 Nihon Nohyaku Co., Ltd. Method for treating mycosis using imidazolylacetonitrile derivatives
US20170362212A1 (en) * 2014-12-12 2017-12-21 Glenmark Pharmaceuticals Limited Process for preparation of luliconazole
WO2019150383A1 (fr) * 2018-02-05 2019-08-08 Nalla Surya Prakash Rao Procédé de préparation de luliconazole

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