WO2017108972A1

WO2017108972A1 - Compounds of r-(-)-(e)-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-1 -imidazolylacetonitrile-ha (luliconazole-ha) as antifungals

Info

Publication number: WO2017108972A1
Application number: PCT/EP2016/082210
Authority: WO
Inventors: Sergio RODRÍGUEZ ROPERO; Pere Dalmases Barjoan; Juan Huguet Clotet
Original assignee: Laboratorios Lesvi, S.L.
Priority date: 2015-12-21
Filing date: 2016-12-21
Publication date: 2017-06-29

Abstract

The present invention refers to compound R-(-)-(E)-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolylacetonitrile HA, wherein HA is an acid; and to a process for their preparation. The present invention also refers to the use of compound R-(-)-(E)-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolylacetonitrile HA for the manufacturing of luliconazole and pharmaceutically acceptable salts or co-crystals thereof in high yield and purity. The present invention further is directed to this compound R-(-)-(E)-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolylacetonitrile HA in the treatment of fungal infections.

Description

COMPOUNDS OF R-(-)-(E)-[4-(2,4-DICHLOROPHENYL)-1 ,3-DITHIOLAN-2-YLIDENE]-1 -

IMIDAZOLYLACETONITRILE HA

FIELD OF THE INVENTION

The present invention refers to compound R-(-)-(E)-[4-(2,4-dichlorophenyl)-1 ,3-dithiolan-2- ylidene]-1 -imidazolylacetonitrile HA, wherein HA is an acid ; and to a process for its preparation. The present invention also refers to the use of compound R-(-)-(E)-[4-(2,4-dichlorophenyl)-1 ,3- dithiolan-2-ylidene]-1 -imidazolylacetonitrile HA for the manufacturing of iconazole or pharmaceutically acceptable salts or co-crystals thereof in high yield and purity. The present invention is further directed to the use of this compound R-(-)-(E)-[4-(2,4-dichlorophenyl)-1 ,3- dithiolan-2-ylidene]-1 -imidazolylacetonitrile HA in the treatment of fungal infections. BACKGROUND OF THE INVENTION

Compound R-(-)-[4-(2,4-dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1 -imidazolylacetonitrile can be found as the geometrical isomers E and Z (also known as trans isomer and cis isomer, respectively), as depicted below in formula (1 ).

(1 )

The E-isomer of compound of formula (1 ), also known as Miconazole, possesses antifungal activity and is marketed under the tradename of Lulicon®/Luzu®, for the topical treatment of interdigital tinea pedis, tinea cruris and tinea corporis caused by the organisms Trichophyton rubrum and Epidermophyton floccosum. Additionally, as disclosed in non-patent publication "In vitro antifungal activities of Miconazole, a new topical imidazole", Medical Mycology, 2009, No. 47, 640-647, Miconazole is one of the most potent and broad-spectrum topical prescription antifungal agents known against the dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes, which cause 90 % of onychomycosis, a fungal infection considered as the most common disease of the nails that affects 10 % to 12 % of the world's adult population .

Luliconazole was first disclosed by WO97/02821 to Nihon Nohyaku, which describes a synthetic approach to the preparation of luliconazole and pharmaceutical compositions containing it. The process described in the aforementioned patent provides R-(-)-[4-(2,4-dichlorophenyl)-1 ,3- dithiolan-2-ylidene]-1 -imidazolyl acetonitrile, which is shown to have antifungal activities several times that of the racemic mixtures thereof against trichophyton spp such as Trichophyton rubrum and Trichophyton mentagrophytes . This patent also discloses that the resulting compound R-(-)-[4-(2,4-dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1 -imidazolyl acetonitrile is obtained as a mixture of the geometrical isomers E and Z. The inventors of the present invention have reproduced the process described in said patent and have observed that the mixture obtained contains a high amount of the Z-isomer to the E-isomer (about 55 % of Z- isomer). This patent also discloses that the desired E-isomer can be isolated and purified by e.g. , silica gel column chromatography or fractional crystallization. These processes have the disadvantage that they are not feasible methods for industrial scale applications.

Chinese patent CN 104151305 describes a method of converting the Z-isomer, which is inevitably produced as a by-product in the synthesis of Miconazole in a content of not less than 30 %, in the E-isomer responsible of its antifungal activity. The conversion method described in this patent comprises dissolving the Z-isomer in DMF, DMSO, dioxane, ethyl acetate, methylene chloride, chloroform, methanol, ethanol, isopropanol, etc or strong polar solvents; under acidic conditions. This method provides E-isomer in yield of about 35 %. However, the inventors of the present application have reproduced the method described in said patent, and they have observed that only Z-isomer is detected, and that conversion to the E-isomer does not take place.

In accordance with health registration requirements of the U.S. and international health registration authorities, e.g. the FDA's Good Guidance Practices ("GGPs") requirements, geometric isomers are both chemically distinct and pharmacologically different and should be treated as separate drugs and developed accordingly. As a result, in the development of physiologically active pharmaceutical ingredients such as Miconazole, it is necessary to selectively produce the E-isomer responsible for its antifungal activity.

Thus, the development of Miconazole or pharmaceutical acceptable salts or co-crystals thereof, in high yield and having good solubility, stability and high chemical and stereoisomeric purity (i.e. , pure (R)-E-isomer), still remains highly desirable. As already explained, to date the prior art only provides expensive methods to obtain pure E-isomer of Miconazole, which are time- consuming and unfeasible at industrial scale. These facts increase the cost and the material balance of the final Miconazole as well as the pharmaceutical compositions containing it, which results in expensive medications.

Thus, in view of the pharmaceutical value of Miconazole for the treatment of fungal infections such as onychomycosis, it is important to develop an industrially feasible and safe process for the preparation of the E-isomer of Miconazole or pharmaceutically acceptable salts or co- crystals thereof, which avoids the racemization and can provide the E-isomer in high yield and high purity. BRIEF DESCRIPTION OF THE INVENTION

According to a first aspect, a compound of formula (2):

(2)

is disclosed, wherein HA is an acid. This compound of formula (2) has good solubility, stability and high chemical and stereoisomeric purity and is suitable for the manufacture of pharmaceutical formulations containing it.

Furthermore, a second aspect of the invention is directed to a mixture of geometrical isomers E and Z of compound of formula (2'):

(2'),

which contains E-isomer in an amount higher than 50 % (w/w) and lower than 100 % (w/w), preferably in an amount equal or higher than 60 % (w/w) and lower than 100 % (w/w), more preferably in an amount equal or higher than 70 % (w/w) and lower than 100 % (w/w).

In a further third aspect, the present invention provides a mixture of geometrical isomers E and Z of compound of formula (1 ):

(1 ),

According to a fourth aspect, the invention is directed to a process for preparing the compound of formula (2) of the first aspect, comprising at least the following steps:

a) treating the mixture of geometrical isomers E and Z of compound of formula (1 ) according to the third aspect of the present invention, with an acid HA in the presence of an organic solvent to obtain the a mixture of geometrical isomers E and Z of compound of formula

(2') according to the second aspect of the present invention, and

b) isolating the compound of formula (2) from the mixture of geometrical isomers E and Z of compound of formula (2') obtained in step a) by means of conventional isolation techniques.

In a fifth aspect, the invention is directed to the use of compound of formula (2) of the first aspect, the mixture of geometrical isomers E and Z of compound of formula (2') of the second aspect, and/or the mixture of geometrical isomers E and Z of compound of formula (1 ) of the third aspect, for preparing Miconazole or a pharmaceutically acceptable salt or co-crystal thereof.

In a still further (and sixth) aspect, the invention is directed to the use of a mixture of geometrical isomers E and Z of compound of formula (2') according to the second aspect and/or the mixture of geometrical isomers E and Z of compound of formula (1 ) according to the third aspect for preparing compound of formula (2).

A seventh aspect of the present invention provides a process for preparing Miconazole or a pharmaceutically acceptable salt or co-crystal thereof, wherein the process comprises at least the following steps:

i) providing a mixture of the compound of formula (2) according to the first aspect of the present invention with an organic solvent;

ii) treating the mixture obtained in step i) with a base to yield Miconazole;

iii) optionally converting Miconazole obtained in step ii) into a pharmaceutically acceptable salt or co-crystal thereof, and

iv) isolating the Miconazole or a pharmaceutically acceptable salt or co-crystal thereof obtained in step ii) or iii) by means of conventional isolation techniques.

In an eighth aspect, the present invention provides a process for preparing Miconazole or a pharmaceutically acceptable salt thereof, wherein the process comprises at least the following steps:

i) treating the mixture of geometrical isomers E and Z of compound of formula (1 ) according to the third aspect with an acid HA in the presence of an organic solvent to obtain the mixture of geometrical isomers E and Z of compound of formula (2') according to the second aspect,

ii) isolating the compound of formula (2) from mixture of geometrical isomers E and Z of compound of formula (2') obtained in step i) by means of conventional isolation techniques, preferably by filtration ; thereby obtaining a compound of formula (2) according to the first aspect;

iii) providing a mixture of compound of formula (2) as obtained in step ii) with an organic solvent, iv) treating the mixture obtained in step iii) with a base to yield luliconazole, v) optionally converting luliconazole obtained in step iv) into a pharmaceutically acceptable salt or co-crystal thereof,

vi) isolating the luliconazole or a pharmaceutically acceptable salt or co-crystal thereof obtained in step iv) or v), and

vii) optionally purifying the luliconazole or a pharmaceutically acceptable salt or co-crystal thereof obtained in step vi).

In a ninth aspect, the invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of compound of formula (2) according to the first aspect of the present invention or luliconazole or a pharmaceutically acceptable salt co-crystal thereof obtained by the process according to the seventh or eighth aspect of the present invention, together with an appropriate amount of pharmaceutically acceptable excipients or carriers. A tenth aspect of the present invention relates to the use of the pharmaceutical composition according to the ninth aspect for the treatment of a fungal infection.

DEFINITIONS

As used herein, "mixture of geometrical isomers E and Z of compound of formula (1 )" refers to a mixture of isomers E and Z of R-(-)-[4-(2,4-dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1- imidazolylacetonitrile, as depicted below:

(1 )

As used herein, "mixture of geometrical isomers E and Z of compound of formula (2')" refers to mixture of isomers E and Z of R-(-)-[4-(2,4-dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1- imidazolylacetonitrile-HA, as depicted below:

(2')

wherein HA is an acid. The term "acid" as used herein refers to a substance that tends to donate protons or hydrogen ions and/or to accept electrons. It comprises inorganic as well as organic acids. The term "inorganic acid" refers to an acid that does not contain any organic moiety. Non-limiting examples of suitable inorganic acids that may be used for the present invention include hydrochloric acid, perchloric acid, hypochloric acid, chloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid (also known as ortho phosphoric acid), fluoroboric acid and mixtures thereof. The term "organic acid" refers to an acid that contains an organic moiety. Non-limiting examples of suitable organic acids that may be used for the present invention include oxalic acid, malonic acid, fumaric acid, citric acid, including citric acid monohydrate, maleic acid, tartaric acid, acetic acid, formic acid, trifluoroacetic acid, gluconic acid, lactic acid, malic acid , succinic acid, acetyl salicylic acid, adipic acid, pivalic acid, benzoic acid , phenylacetic acid, p- methoxybenzoic acid, 4-pyridylcarboxylic acid, oleic acid, organosulfur compounds, embonic acid, gentisic acid, glucuronic acid, pyroglutamic acid , glycolic acid, mandelic acid, aspartic acid, hippuric acid, glutaric acid, pimelic acid, palmitic acid and mixtures thereof. The acid can be in solid form or as a solution in a solvent.

The term "base" as used herein refers to a substance that tends to accept protons and/or to donate electrons or hydroxide ions. The base may be an "inorganic base", which refers to a base that contains a metal cation and does not contain any organic moiety; or an "organic base", which is a substance that contains an organic moiety. Non-limiting examples of "inorganic bases" include metal hydroxides, such as alkali and alkaline earth metal hydroxides (e.g. sodium hydroxide, calcium hydroxide, potassium hydroxide and lithium hydroxide); metal carbonates, such as carbonates and bicarbonates of calcium, sodium or potassium; and mixtures thereof. Suitable "organic bases" include, but are not limited to: alkoxides, including linear or branched metal alkoxides (e.g. sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, sodium butoxide, sodium isobutoxide, sodium sec-butoxide, sodium tert- butoxide, lithium methoxide, lithium ethoxide, lithium tert-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, potassium butoxide, potassium isobutoxide, potassium sec-butoxide, and potassium tert-butoxide, calcium methoxide, calcium ethoxide, magnesium methoxide, magnesium ethoxide, barium methoxide, barium ethoxide, aluminum methoxide, aluminum ethoxide, titanium methoxide, titanium ethoxide, zirconium methoxide, zirconium ethoxide), ammonium alkoxides (e.g. ammonium methoxide, ammonium ethoxide), boron alkoxides (e.g. boron methoxide, boron ethoxide) and silicon alkoxides (e.g. silicon methoxide, silicon ethoxide); metal amides (e.g. lithium diisopropyl amide (LDA), potassium amide, sodium amide, lithium bis(trimethylsilyl)amide (LiHMDS)); amines (e.g. methylamine, ethanolamine, dimethylamine, methylethanolamine, trimethylamine, triethylamine, dicyclohexylamine, N-methylpiperidine, Ν,Ν-diisopropylethylamine); metal acetates, such as sodium acetate and potassium acetate; ammonia and ammonia derivatives such as methanolic ammonia and heterocyclic bases such as pyridine; and mixtures thereof. The base can be in solid form or as a solution in a solvent.

The term "solvent" as used herein refers to a substance capable of at least partially dissolving another substance (i.e. , the solute). Solvents may be liquids at room temperature.

As used herein the term "organic solvent" refers to a solvent containing carbon. Organic solvents may be liquids at room temperature. Examples of organic solvents that may be used in the present invention generally include solvents which are based on cyclic or linear carbon- based solvents. Usual organic solvents as contemplated herein may comprise about 1 -20, preferably about 1 -12 carbon atoms. They may contain additional elements such as O, N, S, P, CI, F, or Br. They may include, but are not limited to: hydrocarbons (e.g. , n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, mineral oil, crude oils, etc.) which also includes aromatic hydrocarbons (e.g. , benzene, toluene, o-xylene, m-xylene, and p-xylene), halogenated hydrocarbons (e.g. , carbon tetrachloride, 1 ,2- dichloroethane, dichloromethane, chloroform , etc.), esters (e.g. , ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, ethyl malonate, etc.), ketones (e.g., acetone, methyl ethyl ketone, cyclohexanone, cyclopentanone, etc.), ethers (e.g., diethyl ether, dipropyl ether, diphenyl ether, tetrahydrofuran (THF), dioxane, etc.), amines (e.g. , propyl amine, diethylamine, triethylamine, aniline, pyridine), alcohols (e.g. , methanol, ethanol, 1 -propanol , 1 -butanol, 1 - octanol, benzyl alcohol, phenol, trifluoroethanol , glycerol, ethylene glycol, propylene glycol, m- cresol, etc.), carbon disulfide, nitrobenzene, dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone, acetonitrile, and mixtures thereof. Alternatively, the solvents may be Si-based i.e. silicone solvents (e.g. , silicone oils, polysiloxanes, cyclosilicones). In some embodiments, the organic solvent may be formed by the combination of two or more organic solvents.

The term "hydrocarbons" as used herein refers to an organic compound consisting entirely of hydrogen and carbon. Non-limiting examples of hydrocarbons that may be used in the present invention include aliphatic, alicyclic or aromatic solvents. If aliphatic, they may comprise 1 -20 carbon atoms; if alicyclic, about 3-20 and if aromatic, about 6-20 carbon atoms. Specific examples of hydrocarbons may be found above.

The term "esters" as used herein means chemical compounds derived from an acid (organic or inorganic) in which at least one -OH (hydroxyl) group is replaced by an -O-alkyl (alkoxy) group. Usually, organic esters are derived from a carboxylic acid and an alcohol. They may contain from 2-40 or more C atoms. Non-limiting examples of organic esters that may be used for the present invention include ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, ethyl malonate, and mixtures thereof. Inorganic esters are derived from an inorganic acid and an alcohol. The inorganic acids may be selected from e.g. phosphoric acid, sulfuric acid , nitric acid and boric acid.

The term "polar solvent" as used herein means a solvent that tends to interact with other compounds or itself through acid-base interactions, hydrogen bonding, dipole-dipole interactions, or by dipole-induced dipole interactions. Non-limiting examples of suitable polar solvents include ketones such as acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK); ethers such as tetrahydrofuran (THF), 2-methyl tetrahydrofuran , dioxane, diisopropyl ether or methyl tert-butyl ether (MTBE); dimethylformamide (DMF); dimethylacetamide (DMA), dimethyl sulfoxide (DMSO); acetonitrile; ethyl acetate; N-methyl-2-pyrrolidone, alcohols such as methanol, ethanol, isopropanol, n-propanol , n-butanol , isobutanol, sec-butanol or tert-butanol; water and mixtures thereof.

The term "non-polar solvent" as used herein means a solvent that is not a polar solvent. Non- polar solvents interact with other compounds or themselves predominantly through dispersion forces. Non-polar solvents interact with polar solvents mainly through dipole-induced dipole interactions or through dispersion forces. Non-limiting examples of these solvents include dichloromethane, toluene, xylene, n-heptane, octane, isooctane, cyclohexane, pentane and dioxane, and mixtures thereof.

The term "sulfonyloxy group" as used herein is understood as a substituted or unsubstituted alkyl or aryl sulfonyloxy group. Examples of a substituted or unsubstituted alkyl or aryl sulfonyloxy groups that may be used in this invention are mesylate (methanesulfonate), tresylate (2,2,2-trifluoroethanesulfonate), tosylate (4-toluensulfonate), benzenesulfonate, 4- methylbenzenesulfonate, brosylate (p-bromobenzenesulfonate), nosylate (4- nitrobenzenesulfonate), triflate (trifluoromethanesulfonate), nonaflate

(nonafluorobutanesulfonate), tridecafluoroheptanesulfonate, heptadecafluorooctanesulfonate, fluorosulfonate and mixtures thereof. The term "room temperature" as used herein means that the temperature is between 15-30 °C, preferably 20-30 °C.

The term "one-pot reaction" as used herein means two or more reactions that take place without isolating intermediate compounds, wherein all the reactants are added at the beginning of the first reaction or adding all reactants sequentially during the course of the reaction.

As used herein , the term "consisting essentially of" means that the entity or process may comprise further features, but those features do not materially cause any surprising technical effect. It in particular has to be understood such that additional components or elements could be present in such amounts and to such an extent that the essential characteristics of the invention are not materially affected.

The term "solvate" refers to a molecular complex comprising luliconazole or a pharmaceutically acceptable salt or co-crystal thereof, and a stoichiometric or non-stoichiometric amount of one or more solvent molecules (e.g. acetone). The term "hydrate" refers to a solvate wherein the solvent is water.

The term "isolation" refers to a process wherein an isolated compound can be obtained. Isolation can be carried out at industrial scale by "conventional isolation techniques", such as solvent extraction, filtration, distillation, slurring, washing, phase separation , evaporation, centrifugation or crystallization.

As used herein, the term, "solvent extraction" refers to the process of separating components of a mixture by using a solvent which possesses greater affinity for one component, and may therefore separate said one component from at least a second component which is less miscible than said one component with said solvent.

The term "filtration" refers to the act of removing solid particles greater than a predetermined size from a feed comprising a mixture of solid particles and liquid. The expression "filtrate" refers to the mixture less the solid particles removed by the filtration process. It will be appreciated that this mixture may contain solid particles smaller than the predetermined particle size. The expression "filter cake" refers to residual solid material remaining on a feed side of a filtration element.

The term "distillation" refers to the act of separating the component substances from a liquid mixture by selective evaporation and condensation. It may result in essentially complete separation (nearly pure components), or it may be a partial separation that increases the concentration of selected components of the mixture. In either case the process exploits differences in the volatility of mixture's components.

As used herein, the term "slurrying" refers to any process which employs a solvent to wash, suspend or disperse a crude solid product. As used herein, the term "washing" refers to the process of purifying a solid mass (e.g., crystals) by passing a liquid over and/or through the solid mass, as to remove undesirable soluble matter. The process includes passing a solvent, such as distilled water, over and/or through a precipitate obtained from filtering, decanting, or a combination thereof. For example, in one embodiment of the invention, washing includes contacting solids with solvent or solvent mixture, vigorously stirring (e.g. , for two hours), and filtering . The solvent can be water, can be an aqueous solvent system, or can be an organic solvent system. Additionally, the washing can be carried out with the solvent having any suitable temperature. For example, the washing step can be carried out with a solvent having a temperature between about 0 °C and about 100 °C. The term "phase separation" refers to a solution or mixture having at least two physically distinct regions.

The term "evaporation" refers to the change in state of solvent from liquid to gas and removal of that gas from the reactor. Various solvents may be evaporated during the synthetic route disclosed herein. As known to those of skill in the art, each solvent may have a different evaporation time and/or temperature.

The term "crystallization" refers to any method known to a person skilled in the art wherein products are obtained in crystal form such as crystallization from single solvent or combination of solvents by dissolving the compound optionally at elevated temperature and precipitating the compound by cooling the solution or removing solvent from the solution or both. It further includes methods such as solvent/antisolvent crystallization .

The term "purification" as used herein refers to a process wherein a purified drug substance can be obtained . The term "industrial purification" refers to conventional purification techniques which can be carried out on an industrial scale such as solvent extraction, filtration, distillation, slurring, washing, phase separation, evaporation, centrifugation or crystallization.

The term "substantially pure" as used herein refers to a drug substance containing less than about 5 % of undesired related substances, preferably less than about 2 % of undesired related substances, and more preferably less than about 1 % of undesired related substances; wherein "undesired related substances" refers to undesired chemical and/or stereoisomeric impurities.

The term "stereoisomers" as used herein denotes all isomers that differ only in the orientation of the atoms in space. Stereoisomers include the mirror image enantiomers ((R) or (S)), the geometric (cis/trans also called E/Z) isomers and diastereoisomers (isomers of drugs with more than one chiral center that are not m irror images of one another).

BRIEF DESCRIPTION OF THE DRAWINGS

Examples of the present invention are illustrated with the following drawings:

Figure 1 shows the PXRD analysis of compound of formula (2), wherein HA is hydrochloric acid. Figure 2 shows the IR spectra of compound of formula (2), wherein HA is hydrochloric acid . Figure 3 shows the PXRD analysis of Miconazole. DETAILED DESCRIPTION OF THE INVENTION

According to a first aspect, compound of formula (2)

(2)

is disclosed, wherein HA is an acid. This compound of formula (2) is characterized to have good solubility, stability and high chemical and stereoisomeric purity and to be suitable for the manufacture of pharmaceutical formulations containing it.

HA may be an inorganic or an organic acid. Should HA be an inorganic acid, it is preferably selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid. Preferably, the inorganic acid is hydrochloric acid or hydrobromic acid, most preferably the inorganic acid is hydrochloric acid.

The inventors have found that the yield of reaction for producing the compound of formula (2) increases when the HA is generated in situ. Preferably the HA is HCI generated in situ by reaction of methanol with acetyl chloride. In a further embodiment, HA is an organic acid selected from oxalic acid, fumaric acid, citric acid, tartaric acid, acetic acid, formic acid, trifluoroacetic acid, gluconic acid, lactic acid, malic acid or succinic acid.

The compound of formula (2) of the present invention may exist as a solid form, which can be a crystalline form, a non-crystalline form or a mixture thereof. For the compounds of the invention that are in crystalline form, the person skilled in the art will appreciate that pharmaceutical acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve non-aqueous solvents such as ethyl acetate, isopropyl acetate, acetone, dichloromethane (DCM), tetrahydrofuran (THF), acetonitrile, dimethylsulfoxide, dimethyl-formamide, toluene or ethanol; or they may involve water. Solvates wherein water is the solvate that is incorporated into the crystal lattice are typically referred as to hydrates. The crystalline solid forms of compound of formula (2) may also exist as an anhydrous material. It is also understood by the person skilled in the art that the term anhydrous when used in reference to solid forms of compound of formula (2) describes solid forms of compound of formula (2) which are substantially free of water. In a preferred embodiment, the solid form of compound of formula (2) of the present invention is in crystalline form. Most preferably, the compound of formula (2), wherein HA is hydrochloric acid is in crystalline form. More preferably, the present invention provides a crystalline compound of formula (2), wherein HA is hydrochloric acid, which is characterized by at least one of the following:

(i) a powder X-ray diffraction (PXRD) pattern having characteristic peaks at approximately 14.7, 22.4, 24.4, 25.2 29.5 and 31.1 ± 0.2. degrees two theta (i.e. Bragg's angle); or

(ii) an IR spectrum substantially in accordance to Figure 2.

In a particular embodiment, the compound of formula (2), wherein HA is hydrochloric acid, having a powder X-ray diffraction (PXRD) pattern with characteristic peaks at approximately 14.7, 22.4, 24.4, 25.2 29.5 and 31.1 ± 0.2. degrees two theta contains less than about 2%, preferably less than 1 % of the Z isomer, and/or does not comprise a peak at about 8.0 ± 0.2 degrees 2-theta. In this embodiment, the compound of formula (2) preferably is in crystalline form.

In a particular embodiment, the crystalline compound of formula (2), wherein HA is hydrochloric acid, is further characterized in that the PXRD pattern further comprises the following peaks at approximately: 17.8, 21.7, 22.2, 23.8, 26.2 and 30.6 ± 0.2 degrees two theta.

The term "approximately" as used herein means in the context of powder X-ray diffraction measurements that there is an uncertainty in the measurements of the degrees 2-theta of ± 0.2 (expressed in degrees 2-theta).

In a further embodiment, the invention provides the crystalline compound of formula (2), wherein HA is hydrochloric acid, characterized in that it provides a PXRD pattern substantially in accordance to Figure 1.

In a still further embodiment, the invention provides the crystalline compound of formula (2), wherein HA is hydrochloric acid, characterized in that it provides a PXRD pattern, which is characterized by the interplanar distance values, shown below in Table 1 :

22.4 3.96

23.8 3.73

24.4 3.64

25.2 3.54

26.2 3.40

29.5 3.03

30.6 2.92

31.1 2.87

Table 1

The inventors found that the compound of formula (2), particularly wherein HA is hydrochloric acid, have the following unexpected advantages: they show a good solubility in water (as high as 500 fold the solubility of iconazole), good stability (stable in atmospheric conditions (25 °C, 60 % RH) for at least 1 month), high chemical purity and high stereoisomeric purity (i.e., pure (R)-E-isomer). Additionally, the compound of formula (2) can be used as intermediate for the preparation of stable iconazole or pharmaceutical salts or co-crystals thereof in high yield and high chemical and stereoisomeric purity (i.e., pure (R)-E-isomer, containing less than 5 % of R- (-)-(Z)-[4-(2,4-dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1-imidazolylacetonitrile, preferably less than about 2 % of R-(-)-(Z)-[4-(2,4-dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1- imidazolylacetonitrile, and more preferably less than about 1 % of R-(-)-(Z)-[4-(2,4- dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1-imidazolylacetonitrile).

A second aspect of the invention is directed to a mixture of geometrical isomers E and Z of compound of formula (2'):

which contains E-isomer in an amount higher than 50 % (w/w) and lower than 100 % (w/w).

In a preferred embodiment, the mixture of geometrical isomers E and Z of compound of formula (2') contains E-isomer in an amount equal or higher than 60 % (w/w) and lower than 100 % (w/w), more preferably in an amount equal or higher than 70 % (w/w) and lower than 100 % (w/w). In other words, the mixture of geometrical isomers E and Z of compound of formula (2') may contain the Z-isomer in an amount lower than 50 % (w/w), preferably in an amount lower 40 % (w/w), more preferably in an amount lower than 30 % (w/w).

The mixture of geometrical isomers E and Z of compound of formula (2') is useful in the preparation of compound of formula (2) according to the first aspect of the present invention.

(1 ),

In a preferred embodiment, the mixture of geometrical isomers E and Z of compound of formula (1 ) contains E-isomer in an amount equal or higher than 60 % (w/w) and lower than 100 % (w/w), preferably in an amount equal or higher than 70 % (w/w) and lower than 100 % (w/w).

In other words, the mixture of geometrical isomers E and Z of compound of formula (1 ) may contain the Z-isomer in an amount lower than 50 % (w/w), preferably in an amount lower than 40 % (w/w), more preferably in an amount lower than 30 % (w/w).

The mixture of geometrical isomers E and Z of compound of formula (1 ) is useful in the preparation of compound of formula (2) according to the first aspect of the present invention.

According to a fourth aspect, the invention is directed to a process for preparing a compound of formula (2) of the first aspect, comprising at least the following steps:

a) treating the mixture of geometrical isomers E and Z of compound of formula (1 ) according to the third aspect of the present invention, with an acid HA in the presence of an organic solvent to obtain the mixture of geometrical isomers E and Z of compound of formula (2') according to the second aspect of the present invention, and

The inventors have observed that the yield of the process is improved when the mixture of geometrical isomers E and Z of compound of formula (1 ) has an E/Z isomeric mixture that contains higher amounts of the E isomer to the Z isomer. The acid used in step a) is not specifically restricted and can be selected from an inorganic or an organic acid .

In a preferred embodiment, the acid used in step a) is an inorganic acid and is selected from hydrochloric acid, hydrobromic acid , sulfuric acid, nitric acid or phosphoric acid. Among these, hydrochloric acid or hydrobromic acids are more preferred, and hydrochloric acid is the most preferred. As noted above, the yield of reaction for producing the compound of formula (2) increases when used HA generated in situ. Preferably the HA is HCI generated in situ by reaction of methanol with acetyl chloride.

Should HA be selected from an organic acid it might be oxalic acid, fumaric acid, citric acid, tartaric acid, acetic acid , formic acid, trifluoroacetic acid, gluconic acid, lactic acid, malic acid or succinic acid . In a particular embodiment, the ratio of the acid HA to the mixture of geometrical isomers E and Z of compound of formula (1 ) may be from 1 : 1 (mol/mol) to 10: 1 (mol/mol), i.e. 1 mol of acid per 1 mol of the mixture of geometrical isomers E and Z of com pound of formula (1 ) to 10 mols of acid per mol of the mixture of geometrical isomers E and Z of compound of formula (1 ); or in other words, the ratio of HA to the mixture of geometrical isomers E and Z of compound of formula (1 ) generally may be in the range of equimolar (1 : 1 ) to a 10 fold molar excess of the acid to the mixture of geometrical isomers E and Z of compound of formula (1 ) (10: 1 ). Preferably, the ratio of the acid HA to the mixture of geometrical isomers E and Z of compound of formula (1 ) is from 1 .1 : 1 (mol/mol) to 8: 1 (mol/mol), more preferably from 1 .5: 1 to 3: 1 (mol/mol).

The organic solvent used in step a) of the present process may be selected from tetrahydrofuran (THF), 2-methyl tetrahydrofuran, acetonitrile, acetone, ethyl acetate, isopropyl acetate, toluene, dichloromethane, methylcyclohexane, methyl ethyl ketone (MEK) methyl isobutyl ketone (M IBK), methanol , ethanol, isopropanol and mixtures thereof; preferably the organic solvent is selected from tetrahydrofuran (THF), 2-methyl tetrahydrofuran, toluene, ethyl acetate, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), and mixtures thereof; more preferably from the group of tetrahydrofuran (THF), 2-methyl tetrahydrofuran, ethyl acetate or methyl ethyl ketone (MEK) and mixtures thereof. Most preferably, the organic solvent is selected from tetrahydrofuran (THF), 2-methyl tetrahydrofuran, acetonitrile, dichloromethane, methylcyclohexane, or mixtures thereof.

In the process according to the fourth aspect, the ratio of organic solvent to the mixture of geometrical isomers E and Z of compound of formula (1 ) may be from 50: 1 (v/w) to 1 : 1 (v/w), 50 volumes of solvent per gram of mixture of the geometrical isomers E and Z of compound of formula (1 ) to 1 volumes of solvent per gram of the mixture of geometrical isomers E and Z of compound of formula (1 ). Preferably, the ratio is from 20: 1 (v/w) to 1 : 1 (v/w). More preferably, the ratio is from 15: 1 to 10: 1 (v/w).

Step a) of the process may be carried out at a temperature between -10 °C and the reflux temperature of the solvent; preferably the temperature is between -10 °C and 75 °C. More preferably, between 0 °C and 65 °C, even more preferably 15 °C and 40 °C, and most preferably at a temperature between 20 °C and 30 °C (room temperature).

Advantageously, the process for obtaining the compound of formula (2) according to the first aspect provides said compound of formula (2) in excellent yields and purity (showing high chemical purity and high stereoisomeric purity, i.e. , pure (R)-E-isomer, containing less than 5 % of R-(-)-(Z)-[4-(2,4-dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1 -imidazolylacetonitrile HA, preferably less than about 2 % of R-(-)-(Z)-[4-(2,4-dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1 - imidazolylacetonitrile- HA, and more preferably less than about 1 % of R-(-)-(Z)-[4-(2,4- dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1 -imidazolylacetonitrile HA, wherein HA is an acid), even if the reaction is carried out at room temperature.

The mixture of geometrical isomers E and Z of compound of formula (2') obtained in step a) can also be stirred to ease the formation of the compound of formula (2) as a precipitate. Afterwards, the obtained compound of formula (2) is isolated by means of conventional isolation techniques. Preferably, the compound of formula (2) is isolated by filtration. Optionally, the compound of formula (2) obtained is purified or dried or both. Preferably, compound of formula (2) is purified by washings with an organic solvent. Preferably, the organic solvent used for washing is the same as that used in step a) of the process, or, alternatively, may be freely selected from the list of organic solvents described above for use in this step.

In a further preferred embodiment, the process according to the fourth aspect of the invention further comprises a previous step of treating the mixture of geometrical isomers E and Z of compound of formula (1 ) with an organic solvent, selected from toluene, THF, methyl THF, methyl ethyl ketone, isopropyl acetate, ethyl acetate and mixtures thereof; preferably the organic solvent is toluene, THF, methyl THF; more preferably the organic solvent is toluene.

In a preferred embodiment, in the process according to the fourth aspect, the acid HA is hydrochloric acid and the organic solvent is selected from tetrahydrofuran (THF), 2-methyl tetrahydrofuran, acetonitrile, dichloromethane, methylcyclohexane, or mixtures thereof.

The ratio of organic solvent to the mixture of geometrical isomers E and Z of compound of formula (1 ) may be from 100: 1 (v/w) to 1 : 1 (v/w), 100 volumes of solvent per gram of the mixture of geometrical isomers E and Z of compound of formula (1 ) to 1 volumes of solvent per gram of the mixture of geometrical isomers E and Z of compound of formula (1 ) . Preferably, the ratio is from 50: 1 (v/w) to 10: 1 (v/w). More preferably the ratio is from 20: 1 (v/w) to 3: 1 (v/w). The slurry obtained by treating the mixture of geometrical isomers E and Z of compound of formula (1 ) with the organic solvent may be stirred and filtered to separate part of the Z-isomer as a precipitate. Optionally, the organic solvent may be concentrated to facilitate the precipitation of Z-isomer. Optionally, a seeding with the Z-isomer may be also performed to facilitate the precipitation of Z-isomer. The filtrate obtained is a mixture of geometrical isomers E and Z of compound of formula (1 ) rich in E-isomer.

This preferred embodiment is included to describe a way of enriching the mixture of geometrical isomers E and Z of compound of formula (1 ) in E-isomer. By pre-treatment with an organic solvent, in particular by toluene, the Z-isomer is precipitated and may be removed at least partially from the mixture E/Z. By using this treatment, the molar ratio of E:Z isomers can be advantageously shifted from about 1 : 1 .2-1 .5 to about 1 .2-1 .5: 1 ; or in other words, the mixture E/Z can be shifted from about 45 %-40 % of E-isomer/ 55 %-60 % of Z-isomer to about 55 %-60 % of E-isomer/ 45 %- 40 % of Z-isomer. After performing the further process steps a) and b) according to the fourth aspect of the invention, even higher yields of the desired form of E- isomer according to compound of formula (2) may be achieved.

Therefore, the present invention is also directed to the compound of formula (2) obtained or obtainable by the process according to the fourth aspect of the invention .

Preferred embodiments of the above process according to the invention can be summarized as follows: In an embodiment, the process to prepare the compound of formula (2) of the first aspect comprises at least the following steps:

a) treating the mixture of geometrical isomers E and Z of compound of formula (1 ) according to the third aspect of the present invention, with hydrochloric acid in a ratio acid HA to the mixture of geometrical isomers E and Z of compound of formula (1 ) of about 2: 1 (mol/mol) in the presence of THF as organic solvent, used in a ratio of organic solvent to the mixture of geometrical isomers E and Z of compound of formula (1 ) of about 10: 1 (v/w), and at a temperature between -10 °C and 75 °C, to obtain the mixture of geometrical isomers E and Z of compound of formula (2') according to the second aspect of the present invention, and

b) isolating the compound of formula (2) from the mixture of geometrical isomers E and Z of compound of formula (2') obtained in step a) by filtration.

In an embodiment, the process to prepare the compound of formula (2) of the first aspect comprises at least the following steps: a) treating the mixture of geometrical isomers E and Z of compound of formula (1 ) according to the third aspect of the present invention, with hydrochloric acid in a ratio acid HA to the mixture of geometrical isomers E and Z of compound of formula (1 ) of about 2: 1 (mol/mol) in the presence of THF as organic solvent, used in a ratio of organic solvent to the mixture of geometrical isomers E and Z of compound of formula (1 ) of about 10: 1 (v/w), and at a temperature between 15 °C and 40 °C, to obtain the mixture of geometrical isomers E and Z of compound of formula (2') according to the second aspect of the present invention, and

In an embodiment, the process to prepare the compound of formula (2) of the first aspect comprises at least the following steps:

a) treating the mixture of geometrical isomers E and Z of compound of formula (1 ) according to the third aspect of the present invention, with hydrochloric acid in a ratio acid HA to the mixture of geometrical isomers E and Z of compound of formula (1 ) of about 2: 1 (mol/mol) in the presence of ethyl acetate as organic solvent, used in a ratio of organic solvent to the mixture of geometrical isomers E and Z of compound of formula (1 ) of about 10: 1 (v/w), and at a temperature between 0 °C and 65 °C, to obtain the mixture of geometrical isomers E and Z of compound of formula (2') according to the second aspect of the present invention, and

b) isolating the compound of formula (2) from the mixture of geometrical isomers E and Z of compound of formula (2') obtained in step a) by filtration. In an embodiment, the process to prepare the compound of formula (2) of the first aspect comprises at least the following steps:

a) treating the mixture of geometrical isomers E and Z of compound of formula (1 ) according to the third aspect of the present invention, with hydrochloric acid in a ratio acid HA to the mixture of geometrical isomers E and Z of compound of formula (1 ) of about 2: 1 (mol/mol) in the presence of ethyl acetate as organic solvent, used in a ratio of organic solvent to the mixture of geometrical isomers E and Z of compound of formula (1 ) of about 10: 1 (v/w), and at a temperature between 15 °C and 40 °C, to obtain the mixture of geometrical isomers E and Z of compound of formula (2') according to the second aspect of the present invention, and

The aforementioned exemplary embodiments may optionally include a pre-treatment step with toluene, where the ratio of toluene: mixture of geometrical isomers E and Z of compound of formula (1 ) is about 20: 1 (v/w), preferably 10: 1 (v/w), more preferably 3: 1 (v/w). The advantages of the process for preparing the compound of formula (2) according to the first aspect are among others:

- It is easily reproducible at an industrial scale with low energy consumption and costs.

- The compound of formula (2) is obtained in high yields and high chemical and stereoisomeric purity (pure (R)-E-isomer). Thus, the compound of formula (2) obtained, contains less than 5 % of R-(-)-(Z)-[4-(2,4-dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1 -imidazolylacetonitrile HA, preferably less than about 2 % of R-(-)-(Z)-[4-(2,4-dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1 - imidazolylacetonitrile- HA, and more preferably less than about 1 % of R-(-)-(Z)-[4-(2,4- dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1 -imidazolylacetonitrile HA, wherein HA is an acid.

In a fifth aspect, the invention is directed to the use of compound of formula (2) of the first aspect, the mixture of geometrical isomers E and Z of compound of formula (2') of the second aspect, and/or the mixture of geometrical isomers E and Z of compound of formula (1 ) of the third aspect, for preparing luliconazole or a pharmaceutically acceptable salt or co-crystal thereof.

In a still further (and sixth) aspect, the invention is directed to the use of the mixture of geometrical isomers E and Z of compound of formula (2') according to the second aspect and/or the use of mixture of geometrical isomers E and Z of compound of formula (1 ) according to the third aspect for preparing compound of formula (2).

As the compound of formula (2) according to the first aspect is obtained in high purity and yields, the inventors have found that this compound of formula (2) can be also used as intermediates for the preparation of luliconazole or a pharmaceutically acceptable salt or co- crystal thereof in high purity and yields. The luliconazole obtained from the compound of formula (2) has a high chemical and stereoisomeric purity (pure (R)-E-isomer). Thus, the luliconazole or a pharmaceutically acceptable salt or co-crystal thereof obtained, has purity not less than 95 % (w/w), preferably not less than 98 % (w/w), more preferably not less than 99 % (w/w).

Additionally, luliconazole obtained from the compound of formula (2) is stable in atmospheric conditions (25 °C, 60 % RH) for at least 1 month. A seventh aspect of the present invention provides a process for preparing luliconazole or a pharmaceutically acceptable salt or co-crystal thereof from the compound of formula (2) of the first aspect. That is to say, the intermediate compound of formula (2) is converted into the base form of luliconazole, which then may be used as an active pharmaceutical ingredient. The process for preparing Miconazole or a pharmaceutically acceptable salt or co-crystal thereof comprises at least the following steps:

i) providing a mixture of compound of formula (2) according to the first aspect of the invention with an organic solvent;

ii) treating the mixture obtained in step i) with a base to yield Miconazole;

iii) optionally converting Miconazole obtained in step ii) into a pharmaceutically acceptable salt or co-crystal thereof;

iv) isolating the Miconazole or a pharmaceutically acceptable salt or co-crystal thereof obtained in step ii) or iii); and

v) optionally purifying the Miconazole or a pharmaceutically acceptable salt or co-crystal thereof obtained in step iv).

In a preferred embodiment, the compound of formula (2) of the step i) is prepared accordingly to the fourth aspect of the present invention.

Preferably, the mixture of compound of formula (2) with the organic solvent of step i) is a suspension of the compound of formula (2) in the organic solvent.

The organic solvent of step i) is preferably selected from tetrahydrofuran (THF), 2-methyl tetrahydrofuran, acetonitrile, acetone, ethyl acetate, isopropyl acetate, toluene, dichloromethane, methylcyclohexane, methyl ethyl ketone (MEK) methyl isobutyl ketone (MIBK), and mixtures thereof; preferably tetrahydrofuran (THF), 2-methyl tetrahydrofuran , toluene, dichloromethane, ethyl acetate, isopropyl acetate, methyl ethyl ketone (MEK) or methyl isobutyl ketone (MIBK), and mixtures thereof; more preferably, ethyl acetate, isopropyl acetate, dichloromethane and mixtures thereof.

The ratio of the organic solvent to the compound of formula (2) in step i) may be from 100: 1 (v/w) to 1 : 1 (v/w), 100 volumes of solvent per gram of compound of formula (2) to 1 volumes of solvent per gram of compound of formula (2). Preferably, the ratio is from 50: 1 (v/w) to 10: 1 (v/w). More preferably, the ratio is from 20: 1 (v/w) to 5 : 1 (v/w).

The base of step ii) can be an inorganic base or an organic base.

In a preferred embodiment, the base of step ii) can be an inorganic base selected from metal hydroxides, metal carbonates and mixtures thereof; preferably, the inorganic base is an alkali or alkaline earth metal hydroxide such as sodium hydroxide, calcium hydroxide, potassium hydroxide and lithium hydroxide; or an alkali or alkaline earth metal carbonate such as sodium carbonate, sodium bicarbonate or potassium bicarbonate; or mixtures thereof. More preferably, the inorganic base is sodium hydroxide, sodium carbonate, or sodium bicarbonate. Said inorganic base is preferably present as an aqueous solution. Alternatively, the base of step ii) can be an organic base selected from amines (e.g. methylamine, ethanolamine, dimethylamine, methylethanolamine, trimethylamine , triethylamine, dicyclohexylamine, N-methylpiperidine, Ν,Ν-diisopropylethylamine); metal acetates, such as sodium acetate and potassium acetate; ammonia and ammonia derivatives such as methanolic ammonia and heterocyclic bases such as pyridine; and mixtures thereof.

In an embodiment of the invention, the ratio of the base to compound of formula (2) may be from 1 : 1 (mol/mol) to 10: 1 (mol/mol), 1 mol of base per 1 mol of compound of formula (2) to 10 mol of base per 1 mol of compound of formula (2). Preferably, the ratio is from 1 .1 : 1 (mol/mol) to 5: 1 (mol/mol). More preferably, the ratio is about 1 .5: 1 (mol/mol).

The purification of step v) may be done by means of conventional purification techniques; preferably it may be purified by crystallization. The crystallization process may be carried out from a single solvent or combination of solvents selected from hydrocarbons, esters and mixtures thereof. Alternatively, also the use of alcoholic solvents (also in admixture with water) is contemplated. Possible alcohols to be used are of formula R-OH, where R is C1 -C10. Also liquid C2-C 10 diols and triols can be used as solvents. Preferably, the crystallization solvent is selected from C4-C10 alkanes, C5-C10 substituted cycloalkanes, C1 -C5 alkyl acetates and mixtures thereof. More preferably, the crystallization solvent is selected from heptane, n-hexane, methylcyclohexane, methyl acetate, ethyl acetate and mixtures thereof. Most preferably, the crystallization solvent is a mixture of methylcyclohexane and ethyl acetate.

In a particular embodiment, the crystallization solvent is a mixture of hydrocarbon and ester (for example heptane to ethyl acetate) in a molar ratio from 1 : 1 to 1 : 10 (mol/mol), preferably from 1 : 1 to 1 :5 (mol/mol). Preferred embodiments of the above process according to the invention can be summarized as follows:

In an embodiment, the process to prepare iconazole or a pharmaceutically acceptable salt or co-crystal thereof according to the seventh aspect comprises at least the following steps:

ii) treating the mixture obtained in step i) with an aqueous inorganic base to yield Miconazole;

iii) optionally converting Miconazole obtained in step ii) into a pharmaceutically acceptable salt or co-crystal thereof; iv) isolating the luliconazole or a pharmaceutically acceptable salt or co-crystal thereof obtained in step ii) or iii); and

v) optionally purifying the luliconazole or a pharmaceutically acceptable salt or co-crystal thereof obtained in step iv).

In an embodiment, the process to prepare luliconazole or a pharmaceutically acceptable salt or co-crystal thereof according to the seventh aspect comprises at least the following steps:

i) providing a mixture of compound of formula (2) according to the first aspect of the invention with an organic solvent, wherein HA is hydrochloric acid;

ii) treating the mixture obtained in step i) with an aqueous inorganic base to yield luliconazole;

iii) optionally converting luliconazole obtained in step ii) into a pharmaceutically acceptable salt or co-crystal thereof;

iv) isolating the luliconazole or a pharmaceutically acceptable salt or co-crystal thereof obtained in step ii) or iii); and

i) providing a mixture of compound of formula (2) according to the first aspect of the invention with THF as the organic solvent;

ii) treating the mixture obtained in step i) with aqueous sodium hydroxide to yield luliconazole;

ii) treating the mixture obtained in step i) with aqueous sodium bicarbonate to yield luliconazole;

iii) optionally converting luliconazole obtained in step ii) into a pharmaceutically acceptable salt or co-crystal thereof; iv) isolating the luliconazole or a pharmaceutically acceptable salt or co-crystal thereof obtained in step ii) or iii); and

i) providing a mixture of compound of formula (2) according to the first aspect of the invention with dichloromethane as the organic solvent;

Preferably, the luliconazole or the pharmaceutically acceptable salt or co-crystal thereof obtained in steps ii), iii), iv) or v) comprises less than 5 % (w/w) of the Z-isomer, preferably less than 2 % (w/w) of the Z-isomer, more preferably less than 1 % (w/w) of the Z-isomer. In other words, the luliconazole or the pharmaceutically acceptable salt or co-crystal thereof obtained in steps ii), iii), iv) or v) comprises more than 95 % (w/w) of the E-isomer, preferably more than 98 % (w/w) of the E-isomer, more preferably more than 99 % (w/w) of the E-isomer.

The luliconazole or the pharmaceutically acceptable salt or co-crystal thereof prepared by the process according to this seventh aspect of the present invention may be obtained in crystalline form . Thus, the crystalline form of Miconazole prepared according to the present invention may be a particular polymorphic form , which is characterized by a powder X-ray diffraction (PXRD) pattern according to Figure 3. According to the eighth aspect of present invention, a process for preparing Miconazole or a pharmaceutically acceptable salt thereof is provided, wherein the process comprises at least the following steps:

ii) isolating the compound of formula (2) from mixture of geometrical isomers E and Z of compound of formula (2') obtained in step i) by means of conventional isolation techniques, preferably by filtration; thereby obtaining a compound of formula (2) according to the first aspect;

iii) providing a mixture of compound of formula (2) as obtained in step ii) with an organic solvent,

iv) treating the mixture obtained in step iii) with a base to yield Miconazole,

v) optionally converting Miconazole obtained in step iv) into a pharmaceutically acceptable salt or co-crystal thereof,

vi) isolating the Miconazole or a pharmaceutically acceptable salt or co-crystal thereof obtained in step iv) or v), and

vii) optionally purifying the Miconazole or a pharmaceutically acceptable salt or co-crystal thereof obtained in step vi). In a preferred embodiment, the organic solvent in step i) is selected from tetrahydrofuran (THF), 2-methyl tetrahydrofuran, acetonitrile, dichloromethane, methylcyclohexane, or mixtures thereof and wherein the acid HA in step i) is hydrochloric acid.

Steps i)-ii) of the process of the eighth aspect correspond to steps a)-b) of the process of the fourth aspect. The embodiments described above in relation to steps a)-b) of the fourth aspect thus are also applicable to steps i)-ii) of the eighth aspect.

Steps iii)-vii) of the process of the eighth aspect correspond to steps i)-v) of the process of the seventh aspect. The embodiments described above in relation to steps i)-v) of the seventh aspect thus are also applicable to steps iii)-vii) of the eighth aspect.

According to the present invention, the mixture of geometrical isomers E and Z of compound of formula (1 ) according to the third aspect may be prepared by a process comprising the following steps: i') reacting 2-(1 H-imidazole-1-yl) acetonitrile (also known as 1-cyanomethylimidazole) or an acid addition salt thereof with carbon disulfide and a base in the presence of a polar solvent to yield a dithiolate salt represented by formula (4)

(4)

wherein R1 represents an alkali metal atom, preferably selected from sodium; ii') reacting the dithiolate salt of formula (4) obtained in step i') with a compound of formula (3)

(3)

wherein R2 and R3 are the same or different and each represents an halogen atom or a sulfonyloxy group, wherein R2 preferably is a sulfonyloxy group and/or R3 preferably is bromine, in the presence of a polar solvent to yield a mixture of geometrical isomers E and Z of compound of formula (1 );

iii') optionally treating the mixture of geometrical isomers E and Z of compound of formula (1 ) of step ii') with an organic solvent and filtering to obtain a filtrate comprising a mixture of geometrical isomers E and Z of compound of formula (1 ) rich in E-isomer; and iv') isolating the mixture of geometrical isomers E and Z of compound of formula (1 ) obtained in step ii') or iii').

In a more preferred embodiment, an acid addition salt of 1-cyanomethylimidazole is used in step i'), preferably, the hydrochloride salt.

In another preferred embodiment, the base used in step i') is an inorganic base selected from metal hydroxides, such as sodium hydroxide, calcium hydroxide, potassium hydroxide and lithium hydroxide; metal carbonates, such as carbonates and bicarbonates of calcium, sodium or potassium; and mixtures thereof. Preferably, the inorganic base is selected from sodium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and mixtures thereof. More preferably, the inorganic base is sodium hydroxide, calcium hydroxide or potassium hydroxide. Most preferably, the inorganic base is sodium hydroxide. The base can be in solid form or as a solution in the polar solvent.

In a particularly preferred embodiment, the base used in step i') is an organic base selected from linear or branched metal alkoxides (e.g. sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, sodium butoxide, sodium isobutoxide, sodium sec-butoxide, sodium tert-butoxide, lithium methoxide, lithium ethoxide, lithium tert-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, potassium butoxide, potassium isobutoxide, potassium sec-butoxide, and potassium tert-butoxide, calcium methoxide, calcium ethoxide, magnesium methoxide, magnesium ethoxide, barium methoxide, barium ethoxide, aluminum methoxide, aluminum ethoxide, titanium methoxide, titanium ethoxide, zirconium methoxide, zirconium ethoxide), ammonium alkoxides (e.g. ammonium methoxide, ammonium ethoxide), boron alkoxides (e.g. boron methoxide, boron ethoxide) and silicon alkoxides (e.g. silicon methoxide, silicon ethoxide); metal amides (e.g. lithium diisopropyl amide (LDA), potassium amide, sodium amide, lithium bis(trimethylsilyl)amide (LiHMDS)); amines (e.g. methylamine, ethanolamine, dimethylamine, methylethanolamine, trimethylamine, triethylamine, dicyclohexylamine, N-methylpiperidine, Ν,Ν-diisopropylethylamine); metal acetates, such as sodium acetate and potassium acetate; ammonia derivatives such as methanolic ammonia and heterocyclic bases such as pyridine; and mixtures thereof. Preferably, the organic base is selected from a metal alkoxide such as sodium tert-butoxide, lithium tert- butoxide and potasium tert-butoxide; lithium bis(trimethylsilyl)amide (LiHMDS), and mixtures thereof. More preferably, the organic base is lithium tert-butoxide. The base can be in solid form or as a solution in the polar solvent. It surprisingly turned out that the use of an organic base might have unexpected advantages over the use of an inorganic base. The inventors found that a mixture of geometrical isomers E and Z of compound of formula (1 ) rich in Z is obtained when an inorganic base such as NaOH is used (E/Z with a weight ratio 1 : 1 .2 (mol/mol)). However, when using an organic base such as tBuOLi, a mixture of geometrical isomers E and Z of compound of formula (1 ) rich in E is obtained (E/Z with a weight ratio 1 .5: 1 (mol/mol) could be achieved).

In another more preferred embodiment, the polar solvent used in step i') and ii') is the same or different and is selected from ketones such as acetone, methyl ethyl ketone (MEK) or methyl isobutyl ketone (MIBK); ethers such as tetrahydrofuran (THF), 2-methyl tetrahydrofuran , dioxane, diisopropyl ether or methyl tert-butyl ether (MTBE); dimethylformamide (DMF); dimethylacetamide (DMA); dimethyl sulfoxide (DMSO); acetonitrile; ethyl acetate; N-methyl-2- pyrrolidone; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol , sec-butanol or tert-butanol; water and mixtures thereof. Preferably the polar solvent of steps i') and ii') is the same and selected from THF, 2-methyl tetrahydrofuran, DMSO, ethyl acetate, water and mixtures thereof. More preferably, the polar solvent of steps i') and ii') is the same and selected from THF, DMSO, water and mixtures thereof.

In a preferred embodiment, R1 represents Na, K, or Ca; preferably R1 is Na or K; more preferably R1 is Na. In a preferred embodiment, R2 and R3 are different and each represents a halogen atom or a sulfonyloxy group. Preferably, R2 is a sulfonyloxy group and R3 is a halogen atom . More preferably, R2 is selected from mesylate (methanesulfonate), tosylate (4-toluensulfonate) or benzenesulfonate groups and R3 is selected from CI, Br, F and I. More preferably, R2 is mesylate or tosylate and R3 is selected from CI, Br and I . Most preferably, R2 is mesylate and R3 is selected from CI and Br. In a particularly preferred embodiment, R3 is bromine.

In a particular embodiment the compound of formula (4) is selected from (S)-2-bromo-1 -(2,4- dichlorophenyl)ethyl methanesulfonate, (S)-2-bromo-1 -(2,4-dichlorophenyl)ethyl 4- toluensufonate, (S)-2-bromo-1 -(2,4-dichlorophenyl)ethyl 4-methylbenzenesulfonate, and (S)-2- bromo-1 -(2,4-dichlorophenyl)ethyl benzenesulfonate.

In another more preferred embodiment, the steps i'), ii') and the optional step iii') may be carried out in one-pot.

In a more preferred embodiment, the dithiolate salt of formula (4) is not isolated . Therefore, the solution obtained by means of the step i'), which contains the dithiolate salt of formula (4) is added to a suspension of the compound of formula (3) in a polar solvent. The solution containing the dithiolate salt of formula (4) is preferably added dropwise to the suspension of the compound of formula (3) in order to avoid racemization of the mixture of geometrical isomers E and Z of R-(-)-[4-(2,4-dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1 -imidazolylacetonitrile (mixture of geometrical isomers E and Z of compound of formula (1 )) obtained. Advantageously, the mixture of geometrical isomers E and Z of compound of formula (1 ) is obtained in a high enantiomeric purity, containing higher than 99 % of (R) enantiomer.

In a preferred embodiment, the ratio of the 1 -cyanomethylimidazole or acid addition salt thereof to base to carbon disulfide may be from 1 :2: 1 (mol/mol) to 1 :3:4 (mol/mol), 1 mol of 1 - cyanomethylimidazole or acid addition salt thereof per 2 mols of base and 1 mol of carbon disulfide to 1 mol of 1 -cyanomethylimidazole or acid addition salt thereof per 3 mols of base and 4 mol of carbon disulfide, preferably from 1 :3: 1 (mol/mol) to 1 :3:3 (mol/mol).

Preferably, the ratio of polar solvent to 1 -cyanomethylimidazole or acid addition salt thereof may be from 100: 1 (v/w) to 1 : 1 (v/w), 100 volumes of solvent per gram of 1 -cyanomethylimidazole or acid addition salt thereof to 1 volumes of solvent per gram of 1 -cyanomethylimidazole or acid addition salt thereof. Preferably, the ratio is from 50 : 1 (v/w) to 10: 1 (v/w). More preferably the ratio is from 20: 1 (v/w) to 5: 1 (v/w).

In a particular embodiment, the step iii') may be done previous to the isolation performed in step iv'), in order to enrich the mixture of geometrical isomers E and Z of compound of formula (1 ) obtained in step ii') in E-isomer. The step iii') comprises the treating of the mixture of geometrical isomers E and Z of compound of formula (1 ) of step ii') with an organic solvent, optionally stirring, and filtering; obtaining a mixture of geometrical isomers E and Z of compound of formula (1 ) rich in E-isomer as a filtrate. The organic solvent used in this step iii') is preferably selected from toluene, THF, 2-methyl tetrahydrofuran, methyl ethyl ketone, isopropyl acetate, ethyl acetate and mixtures thereof; more preferably the organic solvent is toluene, THF or 2- methyl tetrahydrofuran; most preferably the organic solvent is toluene. The ratio of organic solvent to the mixture of geometrical isomers E and Z of compound of formula ( 1 ) may be from 100: 1 (v/w) to 1 :1 (v/w), 100 volumes of solvent per gram of the mixture of geometrical isomers E and Z of compound of formula (1 ) to 1 volumes of solvent per gram of the mixture of geometrical isomers E and Z of compound of formula (1 ). Preferably, the ratio is from 50:1 (v/w) to 10: 1 (v/w). More preferably the ratio is from 20:1 (v/w) to 3:1 (v/w). Optionally, the organic solvent may be concentrated to facilitate the precipitation of Z-isomer. Optionally, a seeding with the Z-isomer may be also performed to facilitate the precipitation of Z-isomer.

In a preferred embodiment, the isolation of step iv') is preferably carried out by distillation.

The process may be carried out at a temperature between -10 °C and 100 °C, preferably the temperature is from 0 °C to 50 °C, more preferably the temperature is from 0 °C to room temperature.

Preferred embodiments of the above process according to the invention can be summarized as follows:

1 ) In an embodiment, the process to prepare the mixture of geometrical isomers E and Z of compound of formula (1 ) according to the third aspect comprises at least the following steps: i') reacting 2-(1 H-imidazole-1-yl) acetonitrile (also known as 1-cyanomethylimidazole) or an acid addition salt thereof with carbon disulfide and an inorganic base in the presence of a polar solvent to yield a dithiolate salt represented by formula (4)

(4)

wherein R1 represents an alkali metal atom; ii') reacting the dithiolate salt of formula (4) obtained in step i') with a compound of formula (3a)

(3a)

in the presence of a polar solvent to yield a mixture of geometrical isomers E and Z of compound of formula (1 );

iii') treating the mixture of geometrical isomers E and Z of compound of formula (1 ) of step ii') with toluene and filtering to obtain a filtrate comprising a mixture of geometrical isomers E and Z of compound of formula (1 ) rich in E-isomer; and

iv') isolating the mixture of geometrical isomers E and Z of compound of formula (1 ) obtained in step iii').

2) In an embodiment, the process to prepare the mixture of geometrical isomers E and Z of compound of formula (1 ) according to the third aspect comprises at least the following steps: i') reacting 2-(1 H-imidazole-1-yl) acetonitrile (also known as 1-cyanomethylimidazole) or an acid addition salt thereof with carbon disulfide and a metal carbonate in the presence of a polar solvent selected from THF, DMSO, water of mixtures thereof, to yield a dithiolate salt represented by formula (4)

(4)

(3a)

in the presence of a polar solvent selected from THF, DMSO, water of mixtures thereof, to yield a mixture of geometrical isomers E and Z of compound of formula (1 );

3) In an embodiment, the process to prepare the mixture of geometrical isomers E and Z of compound of formula (1 ) according to the third aspect comprises at least the following steps: i') reacting 2-(1 H-imidazole-1-yl) acetonitrile (also known as 1-cyanomethylimidazole) or an acid addition salt thereof with carbon disulfide and a metal hydroxide in the presence of a polar solvent, selected from THF, DMSO, water of mixtures thereof, to yield a dithiolate salt represented by formula (4)

(4)

wherein R1 represents an alkali metal atom ; ii') reacting the dithiolate salt of formula (4) obtained in step i') with a compound of formula (3a)

(3a)

4) In an embodiment, the process to prepare the mixture of geometrical isomers E and Z of compound of formula (1 ) according to the third aspect comprises at least the following steps: i') reacting 2-(1 H-imidazole-1 -yl) acetonitrile (also known as 1 -cyanomethylimidazole) or an acid addition salt thereof with carbon disulfide and a metal hydroxide in the presence of a polar solvent, selected from DMSO, water of mixtures thereof, to yield a dithiolate salt represented by formula (4)

(4)

wherein R1 represents an alkali metal atom; ii') reacting the dithiolate salt of formula (4) obtained in step i') with a compound of formula (3b)

in the presence of a polar solvent selected from DMSO, water of mixtures thereof, to yield a mixture of geometrical isomers E and Z of compound of formula (1 );

5) In an embodiment, the process to prepare the mixture of geometrical isomers E and Z of compound of formula (1 ) according to the third aspect comprises at least the following steps: i') reacting 2-(1 H-imidazole-1-yl) acetonitrile (also known as 1-cyanomethylimidazole) or an acid addition salt thereof with carbon disulfide and an organic base in the presence of a polar solvent to yield a dithiolate salt represented by formula (4)

(4)

(3a)

iv') isolating the mixture of geometrical isomers E and Z of compound of formula (1 ) obtained in step ii').

6) In an embodiment, the process to prepare the mixture of geometrical isomers E and Z of compound of formula (1 ) according to the third aspect comprises at least the following steps: i') reacting 2-(1 H-imidazole-1-yl) acetonitrile (also known as 1-cyanomethylimidazole) or an acid addition salt thereof with carbon disulfide and a metal alkoxide in the presence of a polar solvent, selected from THF, DMSO, water of mixtures thereof, to yield a dithiolate salt represented by formula (4)

(3a)

in the presence of a polar solvent, selected from THF, DMSO, water of mixtures thereof, to yield a mixture of geometrical isomers E and Z of compound of formula (1 );

7) In an embodiment, the process to prepare the mixture of geometrical isomers E and Z of compound of formula (1 ) according to the third aspect comprises at least the following steps: i') reacting 2-(1 H-imidazole-1-yl) acetonitrile (also known as 1-cyanomethylimidazole) or an acid addition salt thereof with carbon disulfide and a metal tert-butoxide in the presence of THF to yield a dithiolate salt represented by formula (4)

(4)

(3a) in the presence of THF to yield a mixture of geometrical isomers E and Z of compound of formula (1 );

8) In an embodiment, the process to prepare the mixture of geometrical isomers E and Z of compound of formula (1 ) according to the third aspect comprises at least the following steps: i') reacting 2-(1 H-imidazole-1-yl) acetonitrile (also known as 1-cyanomethylimidazole) or an acid addition salt thereof with carbon disulfide and a metal tert-butoxide in the presence of THF to yield a dithiolate salt represented by formula (4)

(4)

in the presence of THF to yield a mixture of geometrical isomers E and Z of compound of formula (1 );

Notably, in processes 5)-8), wherein an organic base is used in step i'), a very high ratio of the E isomer in mixture of geometrical isomers E and Z of compound of formula (1 ) could be obtained in step ii') (mixtures E/Z of 1.2-1.5: 1 ). Therefore, in contrast to processes 1 )-4), it was not necessary to perform the optional step iii") in order to obtained a mixture of geometrical isomers E and Z of compound of formula (1 ) rich in E-isomer.

An exemplary way of producing the starting compound of formula (3), where R2 is mesylate and R3 is Br (compound of formula (3a)) is outlined in the following reaction scheme (1 ):

Reaction Scheme (1 ) The first reaction step to achieve compound I I is described in Example 1 . To a solution of (S)- (-)-1 -Methyl-3,3-diphenyl-tetrahydro-pyrrolo[1 ,2c][1 ,3,2]oxazaborole in THF, borane N,N- diethylaniline complex is added . Then, a solution of compound I in THF is added and, after stirring, the reaction mixture is quenched by addition of methanol. The solvent is concentrated under vacuum and the resulting crude partitioned between isopropyl acetate and an aqueous solution of H₂S0₄. The aqueous phase is reextracted with more isopropyl acetate and the combined organic phases were washed with water. The solvent is distilled under vacuum and the resulting solid purified by recrystallization with methylcyclohexane affording compound I I.

The second reaction step to yield compound (3a) can be performed as follows (see also Example 2): To a solution of compound II in toluene triethylamine is added. To the resulting solution methane sulfonyl chloride is dropwise added under ice cooling. After stirring, the reaction mixture is washed with an aqueous solution of NaHC0₃ and the aqueous phase is reextracted with toluene and the combined organic phases were washed with hydrochloric acid and water. The solvent is concentrated under vacuum and the resulting crude containing compound (3a) can be used in the next reaction without any further purification.

The advantages of the process according to the seventh aspect of the invention are, among others: - the luliconazole is obtained in high yields and high chemical purity and stereoisomeric purity (pure (R)-E-isomer). Thus, the luliconazole obtained contains less than 5 % of R-(-)-(Z)-[4-(2,4- dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1 -imidazolylacetonitrile, preferably less than about 2 % of R-(-)-(Z)-[4-(2,4-dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1 -imidazolylacetonitrile, and more preferably less than about 1 % of R-(-)-(Z)-[4-(2,4-dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1 - imidazolylacetonitrile.

In an ninth aspect, the invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of compound of formula (2) according to the first aspect of the present invention , or luliconazole or a pharmaceutically acceptable salt or co-crystal thereof obtained by the process according to the seventh aspect of the present invention , together with an appropriate amount of pharmaceutically acceptable excipients or carriers. For example, it is formed into preparations suitable for oral or non-oral (such as topical) administration, such as liquid formulation, tablet, solution, emulsion, ointment, cream, lotion, and poultice.

The amount administered can be any convenient amount according to age, body weight, and administration form, but is normally at least 0.05 mg, preferably from 0.5 to 50 mg, per 1 kg of body weight and per one day for general treatment of adults and the agent can be administered at one time or several times in parts in one day.

In the case of local treatment, for example, in the form of topical application, the concentration of the active ingredient is preferably at least 0.001 %, more preferably from 0.1 to 10 % by weight. The amount of treatment is preferably from 30 to 100 mg per cm².

The antifungal agent of the present invention may be used in admixture with other antifungal agents or antibacterial agents such as amphotericin B, trichomycin, varitotin, ciclopiroxolamine, terbinafine, amorolfine, miconazole, ketoconazole, neticonazole, and/or clotrimazole.

The pharmaceutical composition of the invention finds application in the treatment of a fungal infection, in particular infections caused by the dermatophytes species, such as Trichophyton rubrum and Trichophyton mentagrophytes.

In the following, the present invention is further illustrated by examples. They should in no case be interpreted as a limitation of the scope of the invention as defined in the claims. Unless indicated otherwise, all indications of percentage are by weight and temperatures are in degrees Celsius.

EXAMPLES General methods Powder X-Ray Diffraction (PXRD) were acquired on a D8 Advance Series 2Theta/Theta powder diffraction system using CuKal -radiation (1.54056 A) in transmission geometry. The system is equipped with a VANTEC-1 single photon counting PSD, a Germanium monochromator, a ninety positions auto changer sample stage, fixed divergence slits and radial soller. Programs used: Data collection with DIFFRAC plus XRD Commander V.2.5.1 and evaluation with EVA V.14.0.0.0 (Bruker-AXS 1996-2007). In order to acquire a powder diffraction pattern of the obtained solid, approximately 15 mg of the non-manipulated samples were prepared in standard sample holders using two foils of polyacetate. Each sample was measured in a 1 hour scan in a range from 4° to 40° in 2Θ. Infrared spectrometry analyses were recorded in a Perkin Elmer FTIR Spectrum One appliance using a Perkin Elmer ATR accessory.

Example 1 : Preparation of (S)-2-bromo-1-(2,4-dichlorophenyl)ethan-1-ol (II).

To a solution of (S)-(-)-1 -Methyl-3,3-diphenyl-tetrahydro-pyrrolo[1 ,2c][1 ,3,2]oxazaborole (44.0 mL, 0.044 mol of 1 M solution in toluene) in 470 mL of dry tetrahydrofuran was added 100g (0.61 mol) of borane Ν,Ν-diethylaniline complex. Then, a solution of 2-bromo-1 -(2,4- dichlorophenyl)ethan-1 -one (I) (235 g, 0.87 mol) in dry tetrahydrofuran (705 mL) was added maintaining the temperature below 30 °C. One hour after stirring at room temperature, the reaction mixture was quenched by addition of 470 mL of methanol under cooling. The solvent was concentrated under vacuum and the resulting crude was partitioned between isopropyl acetate and a 10 % w/w aqueous solution of H₂S0₄. The aqueous phase was reextracted with more isopropyl acetate and the combined organic phases were washed with water. The solvent was distilled under vacuum and the resulting solid was purified by recrystallization with methylcyclohexane affording 170 g of (S)-2-bromo-1 -(2,4-dichlorophenyl)ethan-1 -ol (compound II)

Yield: 72 %.

Purity (HPLC) > 99.0 %

Enantiomeric purity by quiral HPLC > 99.9 % of the S isomer H-RMN (200 MHz, CDCI₃): 2.63 (sa, 1 H); 3.40 (dd, J-i = 10 Hz, J₂ = 8 Hz, 1 H); 3.76 (dd, J-i = 10 Hz, J₂ = 4 Hz, 1 H); 5.24 (dd, J-i = 10 Hz, J₂ = 4 Hz, 1 H); 7.30 (dd, J-, = 8 Hz, J₂ = 2 Hz, 1 H); 7.36 (d, J = 2 Hz, 1 H); 7.57 (d, J = 8 Hz, 1 H) ppm.

Example 2: Preparation of (S)-2-bromo-1-(2,4-dichlorophenyl)ethyl methanesulfonate (3a).

To a solution of (S)-2-bromo-1 -(2,4-dichlorophenyl)ethan-1 -ol (I I) (100g , 0.37 mol) in toluene (500 mL) was added triethylamine (60.6 mL, 0.44 mol). To the resulting solution was added dropwise methanesulfonyl chloride (34.5 mL, 0.44 mol) under ice cooling. One hour after stirring at room temperature, the reaction mixture was washed with a 7.5 % w/w aqueous solution of NaHC0₃. The aqueous phase was reextracted with toluene and the combined organic phases were washed with 1 M hydrochloric acid and water. The solvent was concentrated under vacuum and the resulting crude containing (S)-2-bromo-1 -(2,4-dichlorophenyl)ethyl methanesulfonate (3a) was used in the next reaction without any further purification. H-RMN (200 MHz, CDCI₃): 3.09 (s, 3H); 3.63 (dd, J-i = 8.0 Hz, J₂ = 12.0 Hz, 1 H); 3.72 (dd, J-i = 4.0 Hz, J₂ = 12.0 Hz, 1 H); 6.06 (dd, J-i = 4.0 Hz, J₂ = 8.0 Hz, 1 H); 7.35 (dd, J-i = 4.0 Hz, J₂ = 8.0 Hz, 1 H); 7.36 (d, J = 2.0 Hz, 1 H); 7.52 (d , J = 8.0 Hz, 1 H) ppm .

Example 3: Preparation of R-(-)-(E)-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-1- imidazolylacetonitrile hydrochloride (2a).

To a solution of 2-(1 H-imidazol-1 -yl)acetonitrile hydrochloride (24.8 g, 0.17 mol) in dimethyl sulfoxide (16 OmL) was added sodium hydroxide (20.6 g, 0.51 mol). The mixture was stirred at room temperature for 15 min. and then a solution of carbon disulfide (10.4 mL, 0.17 mol) in 40 mL of dimethyl sulfoxide was added dropwise maintaining the internal temperature below 35°C. The resulting brown solution was stirred at room temperature for 2 h. Then the resulting sodium 2-cyano-2-(1 H-imidazol-1 -yl)ethene-1 , 1 -bis(thiolate) solution was added dropwise to a solution of (S)-2-bromo-1 -(2,4-dichlorophenyl)ethyl methanesulfonate (3a) (40.0 g, 0.1 1 mol) in dimethyl sulfoxide (200 mL) maintaining the internal temperature below 30°C. One hour after stirring at room temperature, toluene (200 mL) and water (200 mL) were added. The aqueous phase was reextracted with toluene and the combined organic phases were washed with water. The solvent was partially concentrated under vacuum and seeded with R-(-)-(Z)-[4-(2,4- dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1 -imidazolylacetonitrile. The slurry was stirred at room temperature and filtered. The solid thus obtained contained practically pure Z isomer of R-(-)-[4- (2,4-dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1 -imidazolylacetonitrile, which is discarded. The mother liquors were distilled under vacuum and the obtained crude was dissolved in 400mL of tetrahydrofuran. To this solution, 28.7 mL of a 4M solution of anhydrous hydrogen chloride in ethyl acetate were added and the resulting slurry was heated to reflux, cooled to room temperature, stirred for 6 h .filtered and washed with tetrahydrofuran to providing 20.2 g of R-(-)- (E)-[4-(2,4-dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1 -imidazolylacetonitrile hydrochloride (2a).

Yield: 45 %.

Purity (HPLC) > 98.0 %, containing less than 2 % of Z-isomer

PXRD peaks (2Θ values, (CuK_a1 1 .54056 A)): 14.7, 17.8, 21 .7, 22.2, 22.4, 23.8, 24.4, 25.2, 26.2,

29.5, 30.6 and 31 .1 (±0.2).

PXRD peaks correspond to Figure 1

IR spectra corresponds to Figure 2. H-RMN (200 MHz, d₆DMSO): 4.12 (dd, J-i = 6.0 Hz, J₂ = 14.0 Hz, 1 H); 4.22 (dd, J-i = 6.0 Hz, J₂ = 14.0 Hz, 1 H); 5.86 (dd, ^ = J₂ = 4.0 Hz, 1 H); 7.51 (dd, J-i = 1 .0 Hz, J₂ = 10.0 Hz, 1 H); 7.77 (d, J = 2.0 Hz, 1 H); 7.78 (d, J = 6.0 Hz, 1 H); 7.83 (dd, J ₁ = J₂ = 2 Hz, 1 H); 8.01 (dd, J-, = J₂ = 2 Hz, 1 H); 9.46 (dd, J-, = J₂ = 2 Hz, 1 H) ppm. Example 4: Preparation of R-(-)-(E)-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-1- imidazolylacetonitrile (luliconazole). 20.0 g (0.051 mol) of R-(-)-(E)-[4-(2,4-dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1 - imidazolylacetonitrile hydrochloride (2a) is suspended in ethyl acetate and treated with a 7.5 % w/w aqueous solution of NaHC0₃ to recover luliconazole as a free base form . Final luliconazole was obtained by refluxing the former solid in a mixture of ethyl acetate-methylcyclohexane (3: 1 ), filtering and oven drying. 14.5 g of pure luliconazole were achieved.

Yield: 80 %.

Purity (HPLC) > 99.7 %

Stereoisomeric purity by quiral HPLO 99.85 % of the R isomer and < 0.15 % of Z-isomer PXRD peaks (2Θ values, (CuK_a1 1 .54056 A)): 16.3, 18.2, 21 .3, 21 .8, 23.3, 24.4 and 25.7 ± 0.2. degrees two theta.

PXRD peaks correspond to Figure 3

Example 5: Preparation of R-(-)-(E)-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-1- imidazolylacetonitrile (luliconazole).

To a solution of 2-(1 H-imidazol-1 -yl)acetonitrile hydrochloride (80.0 g, 0.56 mol) in dimethyl sulfoxide (400 mL) was added sodium hydroxide (66.7 g, 1 .7 mol). The mixture was stirred at room temperature for 15 min. and then a solution of carbon disulfide (67 mL, 1 .7 mol) in 100 mL of dimethyl sulfoxide was added dropwise maintaining the internal temperature below 35°C. The resulting brown solution was stirred at room temperature for 2 h. Then the resulting sodium 2- cyano-2-(1 H-imidazol-1 -yl)ethene-1 , 1 -bis(thiolate) solution was added dropwise to a solution of (S)-2-bromo-1 -(2,4-dichlorophenyl)ethyl methanesulfonate (3a) in dimethyl sulfoxide (500 mL) maintaining the internal temperature below 30°C. One hour after stirring at room temperature, toluene (500 mL) and water (500 mL) were added. The aqueous phase was reextracted with toluene and the combined organic phases were washed with water. The solvent was partially concentrated under vacuum and seeded with R-(-)-(Z)-[4-(2,4-dichlorophenyl)-1 ,3-dithiolan-2- ylidene]-1 -imidazolylacetonitrile. The slurry was stirred at room temperature and filtered. The solid thus obtained contained practically pure Z isomer of R-(-)-[4-(2,4-dichlorophenyl)-1 ,3- dithiolan-2-ylidene]-1 -imidazolylacetonitrile, which is discarded . The mother liquors were distilled under vacuum and the obtained crude was dissolved in 1000 mL of tetrahydrofuran. To this solution, 70.0 mL of a 4M solution of anhydrous hydrogen chloride in ethyl acetate were added and the resulting slurry, containing a mixture of geometrical isomers E and Z of R-(-)-[4-(2,4- dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1 -imidazolylacetonitrile hydrochloride (2'a), was heated to reflux, cooled to room temperature, stirred for 6 h and filtered washing with tetrahydrofuran to providing R-(-)-(E)-[4-(2,4-dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1-imidazolylacetonitrile hydrochloride (2a).

Purity (HPLC) > 95 %.

R-(-)-(E)-[4-(2,4-dichlorophenyl)-1 ,3-dithiolan-2-ylidene]-1-imidazolylacetonitrile hydrochloride (2a) is suspended in ethyl acetate and treated with a 7.5 % w/w aqueous solution of NaHC0₃ to recover Miconazole as a free base form. Final iconazole was obtained by refluxing the former solid in a mixture of ethyl acetate-methylcyclohexane (3: 1 ), filtering and oven drying. 39.3 g of pure Miconazole were achieved.

Yield: 30 %.

Purity (HPLC) > 99.7 %

Stereoisomeric purity by quiral HPLO 99.85 % of the R isomer and < 0.15 % of Z-isomer. PXRD peaks (2Θ values, (CuK_a1 1 .54056 A)): 16.3, 18.2, 21 .3, 21.8, 23.3, 24.4 and 25.7 ± 0.2. degrees two theta.

PXRD peaks correspond to Figure 3. H-RMN (200 MHz, d₆DMSO): 4.01 (dd, J-i = 4.0 Hz, J₂ = 12.0 Hz, 1 H); 4.12 (dd, J-i = 6.0 Hz, J₂ = 12.0 Hz, 1 H); 5.78 (dd, J-, = J₂ = 4.0 Hz, 1 H); 7.08 (dd, J-, = J₂ = 2 Hz, 1 H); 7.39 (dd, J-, = J₂ = 2 Hz, 1 H); 7.51 (dd, J-i = 2.0 Hz, J₂ = 8.0 Hz, 1 H); 7.74 (d, J = 4.0 Hz, 1 H); 7.76 (d, J = 2.0 Hz, 1 H); 7.88 (dd, J-i = J₂ = 2 Hz, 1 H) ppm.

Example 6: Preparation of a mixture of E and Z isomers of R-(-)-[4-(2,4-dichlorophenyl)- 1,3-dithiolan-2-ylidene]-1-imidazolylacetonitrile (mixture of geometrical isomers E and Z of compound of formula (1)).

1.5 5g, (10.8 mmol) of 2-(1 H-imidazol-1-yl)acetonitrile hydrochloride were dissolved under nitrogen stream in 12.5ml_ of dry tetrahydrofuran. To the resulting solution, 0.975 mL (16.2 mmol) of carbon disulfide was added and the resulting solution was cool down to 0-5°C. Then 32.3 mL (32.3 mmol) of a 1 M solution of lithium tert-butoxyde in tetrahydrofuran was added dropwise and the reaction was stirred at room temperature for 90min. The resulting lithium 2- cyano-2-(1 H-imidazol-1-yl)ethene-1 , 1-bis(thiolate) solution was added dropwise to a solution of (S)-2-bromo-1-(2,4-dichlorophenyl)ethyl methanesulfonate (3a) (2.5 g, 7.2 mmol) in tetrahydrofuran (12.5 mL) maintaining the internal temperature below 30°C. One hour after stirring at room temperature water was added. The solvent was concentrated under vacuum and toluene was added. The aqueous phase was reextracted with toluene and the combined organic phases were washed water. The solvent was concentrated under vacuum and the resulting crude affording 1.05 g of Miconazole (41 % yield) and 0.72 g of the Z isomer (28 % yield).

Purity (HPLC) > 99.7 %

Enantiomeric purity by quiral HPLC> 99.85 % of the R isomer

Claims

A compound of formula (2):

(2)

wherein HA is an acid.

2. The compound of formula (2) according to the preceding claim, wherein HA is an inorganic acid or an organic acid.

3. The compound of formula (2) according to the preceding claim, wherein HA is an inorganic acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid.

4. The compound of formula (2) according to claim 2, wherein HA is an organic acid selected from oxalic acid, fumaric acid, citric acid, tartaric acid, acetic acid, formic acid, trifluoroacetic acid, gluconic acid, lactic acid, malic acid or succinic acid.

5. The compound of formula (2) according to any of the preceding claims in solid form.

6. The compound of formula (2) according to the preceding claim which is in crystalline form.

7. The compound of formula (2) according to the any of the preceding claims 3 and/or 6, wherein HA is hydrochloric acid.

8. The compound of formula (2) according to the preceding claim characterised by having a powder X-ray diffraction pattern comprising the following main peaks at 2-theta values: 14.7, 22.4, 24.4, 25.2, 29.5 and 31.1 ± 0.2,

9. The compound of formula (2) according to the preceding claim containing less than about 2%, preferably less than 1 % of the Z isomer, and/or not comprising a peak at about 8.0 ± 0.2 degrees 2-theta.

10. The compound of formula (2) according to the preceding claim which is in crystalline form.

1 1 . The compound of formula (2) according to any of the two preceding claims characterised by having a powder X-ray diffraction pattern further comprising the following peaks at 2-theta values: 17.8, 21 .7, 22.2, 23.8, 26.2 and 30.6 ± 0.2 ,

12. The compound of formula (2) according to any of the three preceding claims having a powder X-ray diffraction pattern in accordance with Figure 1 .

13. A mixture of geometrical isomers E and Z of compound of formula (2'):

14. A mixture of geometrical isomers E and Z of compound of formula (1 ):

(1 ) which contains E-isomer in an amount higher than 50 % (w/w) and lower than 100 % (w/w), preferably in an amount equal or higher than 60 % (w/w) and lower than 100 % (w/w), more preferably in an amount equal or higher than 70 % (w/w) and lower than 100 % (w/w).

15. A process for preparing a compound of formula (2) according to any of claims 1 to 12, which comprises at least the following steps: a) treating the mixture of geometrical isomers E and Z of compound of formula (1 ) according to claim 14, with an acid HA in the presence of an organic solvent to obtain the mixture of geometrical isomers E and Z of compound of formula (2') according to claim 1 3, and b) isolating the compound of formula (2) from mixture of geometrical isomers E and Z of compound of formula (2') obtained in step a) by means of conventional isolation techniques, preferably by filtration.

16. The process according to the preceding claim, wherein the acid HA used in step a) is an inorganic acid or an organic acid.

17. The process according to the preceding claim, wherein the acid HA used in step a) is an inorganic acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; preferably the inorganic acid is hydrochloric acid.

18. The process according to claim 16, wherein the acid HA used in step a) is an organic acid selected from oxalic acid, fumaric acid, citric acid, tartaric acid, acetic acid, formic acid, trifluoroacetic acid, gluconic acid, lactic acid, malic acid and succinic acid.

19. The process according to any of claims 15 to 18, wherein the organic solvent of step a) is selected from tetrahydrofuran (THF), 2-methyl tetrahydrofuran, acetonitrile, acetone, ethyl acetate, isopropyl acetate, toluene, dichloromethane, methylcyclohexane, methyl ethyl ketone (MEK) methyl isobutyl ketone (MIBK), and mixtures thereof; preferably the organic solvent is tetrahydrofuran (THF), 2-methyl tetrahydrofuran, toluene, ethyl acetate, methyl ethyl ketone (MEK) or methyl isobutyl ketone (MIBK); more preferably is tetrahydrofuran (THF), 2-methyl tetrahydrofuran, ethyl acetate or methyl ethyl ketone (MEK), most preferably is selected from tetrahydrofuran (THF), 2-methyl tetrahydrofuran, acetonitrile, dichloromethane, methylcyclohexane, or mixtures thereof.

20. The process according to any of claims 15 to 19, wherein step a) is carried out at a temperature between -10 °C and the reflux temperature of the solvent, preferably the temperature is between -10 °C and 75 °C; more preferably between 0 °C and 75 °C; even more preferably between 15 °C and 40 °C; and most preferably at a temperature between 20 °C and 30 °C.

21. The process according to any of claims 15 to 20, wherein the mixture of geometrical isomers E and Z of compound of formula (1 ) of step a) is previously treated with an organic solvent and filtered to obtain a filtrate comprising a mixture of geometrical isomers E and Z of compound of formula (1 ) rich in E-isomer.

22. The process according to the preceding claim, wherein the organic solvent is selected from toluene, THF, methyl THF, methyl ethyl ketone, isopropyl acetate, ethyl acetate and mixtures thereof; preferably toluene, THF, methyl THF; more preferably toluene.

23. The process according to any of claims 15-22, wherein the acid HA is hydrochloric acid and the organic solvent is selected from tetrahydrofuran (THF), 2-methyl tetrahydrofuran, acetonitrile, dichloromethane, methylcyclohexane, or mixtures thereof.

24. A process for preparing Miconazole or a pharmaceutically acceptable salt thereof, wherein the process comprises at least the following steps:

i) providing a mixture of compound of formula (2) as defined in any of claims 1 to 1 2 with an organic solvent;

ii) treating the mixture obtained in step i) with a base to yield Miconazole;

iii) optionally converting Miconazole obtained in step ii) into a pharmaceutically acceptable salt or co-crystal thereof

iv) isolating the Miconazole or a pharmaceutically acceptable salt or co-crystal thereof obtained in step ii) or iii), and

25. The process according to the preceding claim, wherein the compound of formula (2) is prepared as defined in any of claims 15 to 23.

26. The process according to any of the two preceding claims, wherein the organic solvent of step i) is selected from tetrahydrofuran (THF), 2-methyl tetrahydrofuran, dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone, acetonitrile, acetone, ethyl acetate, isopropyl acetate, toluene, dichloromethane, methylcyclohexane, methyl ethyl ketone (MEK) methyl isobutyl ketone (MIBK), and mixtures thereof; preferably tetrahydrofuran (THF), 2-methyl tetrahydrofuran , toluene, dichloromethane, ethyl acetate, isopropyl acetate, methyl ethyl ketone (MEK) or methyl isobutyl ketone (MIBK); more preferably, ethyl acetate, isopropyl acetate and dichloromethane.

27. The process according to any of claims 24 to 26, wherein the base of step ii) is an inorganic base selected from metal hydroxides, metal carbonates and mixtures thereof; preferably, the inorganic base is an alkali or alkaline earth metal hydroxide or carbonate; more preferably, the inorganic base is sodium hydroxide, sodium carbonate, or sodium bicarbonate.

28. The process according to the preceding claim, wherein the inorganic base is present as an aqueous solution.

29. The process according to any of claims 24 to 28, wherein the purification of step v) is carried out by crystallization in a solvent selected from hydrocarbons, esters and mixtures thereof; preferably the solvent is selected from heptane, n-hexane, methylcyclohexane, ethyl acetate and mixtures thereof; more preferably the solvent is a mixture of methylcyclohexane and ethyl acetate.

30. The process according to the preceding claim, wherein the solvent is selected from mixtures of hydrocarbons and esters in a ratio of hydrocarbon to ester from 1 : 1 to 1 : 10, preferably from 1 : 1 to 1 :5.

31 . The process according to any of claims 24 to 30 wherein the luliconazole or the pharmaceutically acceptable salt or co-crystal thereof is obtained in crystalline form.

32. The process according to any of claims 24 to 31 , wherein the luliconazole or the pharmaceutically acceptable salt or co-crystal thereof obtained in steps ii), iii), iv) or v) comprises less than 5 % (w/w) of the Z-isomer, preferably less than 2 % (w/w) of the Z- isomer, more preferably less than 1 % (w/w) of the Z-isomer.

33. The process according to any of claims 24 to 31 , wherein the luliconazole or the pharmaceutically acceptable salt or co-crystal thereof obtained in steps ii), iii), iv) or v) comprises equal or more than 95 % (w/w) of the E-isomer, preferably more than 98 % (w/w) of the E-isomer, more preferably more than 99 % (w/w) of the E-isomer.

34. A process for preparing luliconazole or a pharmaceutically acceptable salt thereof, wherein the process comprises at least the following steps:

i) treating the mixture of geometrical isomers E and Z of compound of formula (1 ) according to claim 14, with an acid HA in the presence of an organic solvent to obtain the mixture of geometrical isomers E and Z of compound of formula (2') according to claim 1 3,

ii) isolating the compound of formula (2) from mixture of geometrical isomers E and Z of compound of formula (2') obtained in step i) by means of conventional isolation techniques, preferably by filtration; thereby obtaining a compound of formula (2) according to any of claims 1 to 12;

iv) treating the mixture obtained in step iii) with a base to yield luliconazole,

v) optionally converting luliconazole obtained in step iv) into a pharmaceutically acceptable salt or co-crystal thereof,

35. The process according to the preceding claim, wherein the organic solvent in step i) is selected from tetrahydrofuran (THF), 2-methyl tetrahydrofuran, acetonitrile, dichloromethane, methylcyclohexane, or mixtures thereof and wherein the acid HA in step i) is hydrochloric acid.

36. Luliconazole or a pharmaceutically acceptable salt co-crystal thereof obtained or obtainable by the process according to any of claims 24 to 35.

37. A process for preparing a mixture of geometrical isomers E and Z of compound of formula (1 ) according to claim 14, comprising the steps of: i') reacting 2-(1 H-imidazole-1-yl) acetonitrile or an acid addition salt thereof with carbon disulfide and a base in the presence of a polar solvent to yield a dithiolate salt represented by formula (4)

(4)

wherein R1 represents an alkali metal atom, preferably selected from sodium;

ii') reacting the dithiolate salt of formula (4) obtained in step i') with a compound of formula (3)

(3)

38. The process according to claim 37, wherein the base of step i') is NaOH.

39. The process according to claim 37, wherein the base of step i') is selected from an organic base, for example from tBuOLi, and wherein the weight ratio of E:Z isomers in the mixture of geometrical isomers E and Z of compound of formula (1 ) obtained in step ii') is about 1 .5 : 1.

40. A pharmaceutical composition comprising a therapeutically effective amount of compound of formula (2) according to any of claims 1 to 12 or luliconazole or a pharmaceutically acceptable salt co-crystal thereof according to claim 36, together with an appropriate amount of pharmaceutically acceptable excipients or carriers.

41 . The pharmaceutical composition according to the preceding claim, further comprising one or more additional pharmacologically active ingredients.

42. The pharmaceutical composition according to the two preceding claims for use in the treatment of a fungal infection.

43. A method of treating a fungal infection comprising the administration, to a subject in need of such treatment, of a pharmaceutical composition according to any of claims 40-41 .

44. Use of the compound of formula (2) according to any of claims 1 to 12 for the preparation of Miconazole or a pharmaceutically acceptable salt or co-crystal thereof.

45. Use of the mixture of geometrical isomers E and Z of compound of formula ( 1 ) according to claim 14, for the preparation of the compound of formula (2) according to any of claims 1 to 12.

46. Use of the mixture of geometrical isomers E and Z of compound of formula (2') according to claim 13 for the preparation of the compound of formula (2) according to any of claims 1 to 12.

47. Use of the mixture of geometrical isomers E and Z of compound of formula ( 1 ) according to claim 14 for the preparation of Miconazole or a pharmaceutically acceptable salt or co- crystal thereof.

48. Use of the mixture of geometrical isomers E and Z of compound of formula (2') according to claim 13 for the preparation of Miconazole or a pharmaceutically acceptable salt or co- crystal thereof.

49. Use of the mixture of geometrical isomers E and Z of compound of formula ( 1 ) according to claim 14 for the preparation of the mixture of geometrical isomers E and Z of compound of formula (2') according to claim 13.