WO2018202537A1

WO2018202537A1 - Process for the preparation of an azolic derivative

Info

Publication number: WO2018202537A1
Application number: PCT/EP2018/060713
Authority: WO
Inventors: Graziano Castaldi; Marco Baratella; Mauro Gaboardi; Alessandro BARUTO
Original assignee: Seegpharm SA
Current assignee: Seegpharm SA
Priority date: 2017-05-04
Filing date: 2018-04-26
Publication date: 2018-11-08
Anticipated expiration: 2019-11-04
Also published as: IT201700048270A1

Abstract

The present invention refers to a process for the preparation of an azolic derivative used in the treatment of onychomycosis. Said process comprises the reaction between (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane and 4-methylenepiperidine or a salt thereof, in the presence of a zinc derivative in an alcoholic solvent.

Description

"Process for the preparation of an azotic derivative"

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DESCRIPTION

The present invention refers to a process for the preparation of an azolic derivative and, more in particular, refers to a process for the preparation of efinaconazole or pharmaceutically acceptable salts thereof.

Efinaconazole, chemical name (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene-1- piperidinyl)-1-(1 H-1 ,2,4-triazol-1- -2-butanol, is a triazolic antimycotic of formula (I)

disclosed for the first time in the International patent application WO 94/26734 and marketed under the name JUBLIA^®.

Efinaconazole is employed in the treatment of onychomycosis, in particular of distal subungual onychomycosis. It is a selective inhibitor of fungal lanosterol 14a- demethylase which causes lack of conversion of lanosterol to ergosterol, an essential component of fungal cell membrane. The inhibition of ergosterol synthesis leads to an accumulation of C-14 methylated sterols unable to duly interact with membrane phospholipids. Fungal membrane integrity is thereby compromised and the permeability is altered with consequent cellular disorganization and fungus death.

The structural formula of efinaconazole (I) is characterized by the presence of a β- amino alcoholic moiety. Methods known in the art for the synthesis of said β-amino alcoholic moiety include, among others, the ring-opening reaction of an epoxide by the addition of an amine, usually employed in large excess.

WO 94/26734 discloses a process for the preparation of efinaconazole providing for the reaction of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1 H-1 ,2,4-triazol-1- yl)methyl]oxirane (hereinafter also referred to as epoxytriazole) with a large excess of 4-methylenepiperidine (hereinafter also referred to as 4-MP) in ethanol and water. After HPLC purification, the product is obtained in 54% yield.

EP 2 612 859 discloses a process for the preparation of efinaconazole which provides for the reaction of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1 H-1 ,2,4- triazol-1 -yl)methyl]oxirane with an acid addition salt of 4-methylenepiperidine in the presence of a hydroxide of an alkali metal or an alkaline earth metal selected among lithium and calcium. EP 2 612 859 teaches also that different metallic catalysts affect the course of said reaction (i.e. epoxide ring-opening reaction of the epoxytriazole by addition of 4-MP) with high variability.

WO 16/181306 discloses a process for the synthesis of efinaconazole which provides for the reaction of (2R,3S)-2-(2_!4-difluorophenyl)-3-methyl-2-[(1 H-1 _!2,4- triazol-1 -yl)methyl]oxirane with 4-methylenepiperidine or a salt thereof, in the presence of an alkali or an alkaline earth metal halide.

EP 2 612 859 and WO 16/181306 do not require the use of a large excess of 4- methylenepiperidine, but provide for the use of very dangerous reaction solvents such as, for example, acetonitrile. Acetonitrile is a highly volatile solvent that, when inhaled, is metabolised by the organism to hydrogen cyanide, extremely toxic.

The processes for the synthesis of efinaconazole known in the art has numerous drawbacks among which: use of a large excess of 4-methylenepiperidine and very toxic reagents and/or solvents, formation of a high number of impurities and/or reaction by-products, challenging purification and/or poor optical purity of the final product.

Therefore, the need of an alternative process for the synthesis of efinaconazole which overcomes, at the same time, all the drawbacks of the processes known in the art remains. In particular, there is the need of an improved process for the synthesis of efinaconazole which allows to obtain the compound with good yields and high optical purity without, however, using a large excess of 4- methylenepiperidine or very toxic reagents and/or solvents and which does not cause the formation of a high number of impurities and/or reaction by-products, difficult to remove.

The inventors of the present invention have now surprisingly found that, when the epoxidic ring-opening reaction of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1 H- 1 ,2,4-triazol-1 -yl)methyl]oxirane by the addition of 4-methylenepiperidine or a derivative thereof is carried out in the presence of a zinc derivative, the process of the present invention allows to obtain efinaconazole (I) with good yields and high optical purity without the use of a large excess of 4-methylenepiperidine or very toxic reagent/solvents. Moreover, said process does not lead to the formation of impurities and/or reaction by-products difficult to remove. Therefore, an object of the present invention is a process for the synthesis of efinaconazole (I) or pharmaceutically acceptable salt thereof comprising the reaction between 4-methylenepiperidine of formula (II) or an acid salt thereof

and (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1 H-1 ,2,4-triazoM -yl)methyl]oxirane of formula (III)

in the presence of a zinc derivative, in a suitable reaction solvent.

In an embodiment according to the present invention, said zinc derivative can be a zinc salt.

Therefore, a first aspect of the present invention is a process for the synthesis of efinaconazole (I) or a pharmaceutically acceptable salt thereof comprising the reaction between 4-methylenepiperidine di formula (II)

in the presence of a zinc salt, in a suitable reaction solvent. Said zinc salt, according to the present invention, is selected among zinc bromide, zinc chloride, zinc iodide, zinc acetate, zinc methanesulfonate and zinc trifluoroacetate and is preferably zinc bromide.

In particular, the molar ratio zinc salt:epoxytriazole (III) is comprised between about 0.5:1 and about 2:1 and is preferably 1 .5:1.

The zinc salts of the present invention have shown to be particularly useful and effective in the epoxide ring-opening reaction of the epoxytriazole (III) by addition of 4-MP (II) or a derivative thereof providing the desired β-amino alcoholic moiety with high yield and excellent chemo, stereo and regioselectivity.

A further advantage of the process object of the present invention is the fact that said zinc salt can be generated directly in the reaction environment.

In fact, in an alternative embodiment according to the present invention, said zinc derivative can be a basic zinc derivative.

Therefore, a further aspect of the present invention is a process for the synthesis of efinaconazole (I) or a pharmaceutically acceptable salt thereof comprising the reaction between an acid salt of 4-methylenepiperidine of formula (Ila)

wherein HX is an organic or inorganic acid,

and (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1 H-1 ,2,4-triazol-1 -yl)methyl] of formula (III)

in the presence of a basic zinc derivative, in a suitable reaction solvent.

In particular, HX means the (organic or inorganic) acid of the acid salt of 4- methylenepiperidine. The acid salt of 4-methylenepiperidine used in the process of the present invention can be any pharmaceutically acceptable acid salt and is preferably selected among 4-methylenepiperidine hydrochloride, 4-methylenepiperidine hydrobromide and 4- methylenepiperidine trifluoroacetate. In a preferred embodiment 4- methylenepiperidine hydrochloride is used.

The basic zinc derivative used in the process of the present invention is selected among zinc oxide and basic zinc carbonate and is preferably zinc oxide.

The molar ratio basic zinc derivative:acid salt of 4-methylenepiperidine is comprised between about 1 :1 and about 2:1 , and is preferably 1 :1 .

According to this last aspect of the process object of the present invention, the zinc salt can be generated directly in the reaction environment. In fact, in the reaction environment, the acid salt of 4-methylenepiperidine of formula (I la) (e.g., 4- methylenepiperidine hydrochloride) dissociates to give 4-MP free base and acid (in this case HCI). The acid reacts with the basic zinc derivative (e.g., ZnO) resulting in the corresponding zinc salt (in this case ZnC ). Therefore, the reaction proceeds according to the process of the present invention, based on which the resultant zinc salt catalyses the reaction between 4-methylenepiperidine of formula (II) and (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1 H-1 ,2,4-triazoM -yl)methyl]oxirane of formula (III) to give efinaconazole of formula (I).

In summary, using zinc salts as catalysts in the process object of the present invention allows to obtain efinaconazole (I) with very high optical purity, practically without the formation of the enantiomer and/or by-products. In addition, the catalyst (i.e. the zinc salt) can be easily removed from the reaction environment, for example, by filtration on coal/celite filter.

As a consequence, the process of the present invention does not require any further purification phase such as, for example, column chromatography and/or crystallization.

With the process of the present invention, efinaconazole is obtained with optical purity equal to that of the starting epoxytriazole (III) and there are no evidences of the formation of the undesired diastereoisomer (2R,3S)-2-(2,4-difluorophenyl)-3-(4- methylene-1-piperidinyl)-1 -(1 H-1 ,2,4-triazol-1-yl)-2-butanol. In an embodiment according to the present invention, the optical purity of the resultant product is equal to 99.0% or higher. The process object of the present invention allows to obtain efinaconazole with an enantiomeric excess yield (e.e.%) equal to 98.0% or higher.

The process object of the present invention avoids also the use of a large excess of 4-methylenepiperidine, thus preventing the need to remove large amounts of unreacted amine, the formation of undesired reaction by-products and laborious removal phases thereof. In particular, the molar ratio epoxytriazole:4- methylenepiperidine or derivative thereof is preferably comprised between about 1 :1 and about 1 :2. In a preferred embodiment, the molar ratio epoxytriazole:4- methylenepiperidine or derivative thereof is 1 :1.5.

The reaction solvent of the present invention is an alcoholic solvent preferably selected among alcohols having a boiling point higher than 80°C. More in particular, said alcoholic solvent is a tertiary alcohol preferably selected among ie f-amyl alcohol, ie f-butanol and 1 -methoxy-2-propanol. In a preferred embodiment, the solvent is ie f-amyl alcohol. Tertiary alcohols of the present invention have the advantage to be stable to oxidation (i.e. they are not metabolized to aldehydes or to carboxylic acid, metabolites that often can be toxic), little reactive and non-volatile. The process object of the present invention is carried out at a temperature between about 80°C and about 130°C, preferably between about 100°C and about 120°C. If desired, the product of formula (I), obtained according to the process disclosed in the present invention, can be converted in a pharmaceutically acceptable salt thereof.

All the terms used in the present application, unless otherwise indicated, should be understand in their common meaning as known in the art. The term "about" comprises the experimental error which can occur in a measurement.

Although the present invention has been described in its characterising features, modification and equivalents evident to a man skilled in the art are encompassed in the present invention. Below, the present invention will be illustrated by means of some examples which have illustrative purposes only and are not meant to limit the scope of the invention.

EXAMPLES

The melting point of efinaconazole (I) obtained according to the process of the present invention was experimentally determined by differential scanning calorimeter DSC 3500 S/^'r/^'us^® model from NETZSCH to give a range of 86-89°C. Optical power was determined by JASCO P-1010 polarimeter and provided a [O]D - 87° (c = 1 ,0, chloroform) value, where "c" is the concentration expressed in g/100 ml and chloroform is the solvent where the measurement was performed.

EXAMPLE 1

In a reaction flask (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1 H-1 ,2,4-triazol-1- yl)methyl]oxirane (1.0 g, 3.94 mmol), 4-methylenepiperidine (0.58 g, 5.91 mmol), fe/f-amyl alcohol (10 mL) and zinc chloride (0.81 g, 5.91 mmol) were loaded.

The reaction mixture was brought to the reflux temperature of the solvent and maintained under these conditions for twenty-four hours.

Once the reaction was completed, the solvent was removed by vacuum distillation, ethyl acetate (10 mL) was added and the organic phase was washed with water (2 x 10 mL). The reunited organic phases were filtered on a coal/celite filter and reduced till residue by vacuum distillation to give 1 .0 g of efinaconazole.

EXAMPLE 2

In a reaction flask (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1 H-1 ,2,4-triazol-1- yl)methyl]oxirane (1.0 g, 3.94 mmol), 4-methylenepiperidine (0.58 g, 5.91 mmol), ie f-amyl alcohol (10 mL) and zinc bromide (1.33 g, 5.91 mmol) were loaded.

Once the reaction was completed, the solvent was removed by vacuum distillation, ethyl acetate (10 mL) was added and the organic phase was washed with water (2 x 10 mL). The reunited organic phases were filtered on a coal/celite filter and reduced till residue by vacuum distillation to give 1 .1 g of efinaconazole.

EXAMPLE 3

In a reaction flask (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1 H-1 ,2,4-triazol-1- yl)methyl]oxirane (1.0 g, 3.94 mmol), 4-methylenepiperidine (0.58 g, 5.91 mmol), ie f-amyl alcohol (10 mL) and zinc trifluoroacetate (1.72 g, 5.91 mmol) were loaded. The reaction mixture was brought to the reflux temperature of the solvent and maintained under these conditions for twenty-four hours.

Once the reaction was completed, the solvent was removed by vacuum distillation, ethyl acetate (10 mL) was added and the organic phase was washed with water (2 x 10 mL). The reunited organic phases were filtered on a coal/celite filter and reduced till residue by vacuum distillation to give 1 .1 g of efinaconazole. EXAMPLE 4

In a reaction flask (2R_!3S)-2-(2_!4-difluorophenyl)-3-methyl-2-[(1 H-1 _!2,4-triazol-1- yl)methyl]oxirane (1.0 g, 3.94 mmol), 4-methylenepiperidine (0.78 g, 5.91 mmol), ie f-amyl alcohol (10 mL) and zinc oxide (0.48 g, 5.91 mmol) were loaded.

Once the reaction was completed, the solvent was removed by vacuum distillation, ethyl acetate (10 mL) was added and the organic phase was washed with water (2 x 10 mL). The reunited organic phases were filtered on a coal/celite filter and reduced till residue by vacuum distillation to give 0.9 g of efinaconazole.

EXAMPLE 5

In a reaction flask (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1 H-1 ,2,4-triazol-1- yl)methyl]oxirane (1.0 g, 3.94 mmol), 4-methylenepiperidine bromide (0.96 g, 5.91 mmol), ie f-amyl alcohol (10 mL) and zinc oxide (0.48 g, 5.91 mmol) were loaded. The reaction mixture was brought to the reflux temperature of the solvent and maintained under these conditions for twenty-four hours.

EXAMPLE 6

In a reaction flask (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1 H-1 ,2,4-triazol-1- yl)methyl]oxirane (1 .0 g, 3.94 mmol), 4-methylenepiperidine trifluoacetate (0.96 g, 5.91 mmol), ie/f-amyl alcohol (10 mL) and zinc oxide (0.48 g, 5.91 mmol) were loaded.

Claims

1 ) A process for the preparation of efinaconazole of formula (I)

or a pharmaceutically acceptable salt thereof comprising the reaction between 4-methylenepiperidine of formula (II) or an acid salt thereof

and (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1 H-1 ,2,4-triazol-1- yl)methyl]oxirane of formula (III)

in the presence of a zinc derivative, in a suitable reaction solvent.

2) The process according to claim 1 , comprising the reaction between 4- methylenepiperidine of formula (II) and epoxytriazole of formula (III) in the presence of a zinc salt.

3) The process according to claim 2, wherein said zinc salt is selected among zinc chloride, zinc bromide, zinc iodide, zinc acetate, zinc methanesulfonate and zinc trifluoroacetate and is preferably zinc bromide.

4) The process according to claims 1 -3 wherein the molar ratio zinc salt:epoxytriazole (III) is between 0.5:1 and 2:1 and is preferably 1 .5:1.

5) The process according to claim 1 comprising the reaction between an acid salt of 4-methylenepiperidine of formula (I la)

wherein HX is an organic or inorganic acid,

and epoxytriazole of formula (III) in the presence of a basic zinc derivative.

6) The process according to claim 5, wherein said acid salt of 4- methylenepiperidine is selected among 4-methylenepiperidine hydrochloride, 4-methylenepiperidine hydrobromide and 4-methylenepiperidine trifluoroacetate, and is preferably 4-methylenepiperidine hydrochloride.

7) The process according to claim 5, wherein said basic zinc derivative is selected among zinc oxide and basic zinc carbonate, and is preferably zinc oxide.

8) The process according to claims 5-7, wherein the molar ratio basic zinc derivative:acid salt of 4-methylenepiperidine is between 1 :1 and 2:1 , and is preferably 1 :1.

9) The process according to any one of the previous claims, wherein the reaction solvent is an alcoholic solvent having a boiling point higher than 80°C.

10) The process according to claim 9, wherein said alcoholic solvent is a tertiary alcohol selected among ie f-amyl alcohol, ie f-butanol and 1-methoxy-2- propanol, and is preferably fe/t-amyl alcohol.