WO2011003455A1

WO2011003455A1 - Method for producing 4-(alkyl)-1-(2-methyl-3-(2,6-dimethylmorpholine)propyl) benzol compounds

Info

Publication number: WO2011003455A1
Application number: PCT/EP2009/058780
Authority: WO
Inventors: Uwe Albrecht; Stefanie Ackermann; Marcin Sawicki; Ulrich Weigl
Original assignee: Cilag Ag
Priority date: 2009-07-09
Filing date: 2009-07-09
Publication date: 2011-01-13

Abstract

The invention relates to a method for producing 4-(alkyl)-1-(2-methyl-3-(2,6-dimethylmorpholine)propyl) benzol, in particular for producing 4-(1,1-dimethylpropyl)-1-(2-methyl-3-(2,6-dimethylmorpholine)propyl) benzol (amorolfine), by selectively reducing the corresponding alpha benzyl keto compound using hydrogen in that the corresponding 4-(alkyl)-1-(2-methyl-1-oxo-3-(2,6-dimethylmorpholine)propyl)benzol compound is provided as a salt of a strong acid in a suitable inert solvent and said salt is hydrated using hydrogen in the presence of a suitable catalyst.

Description

Process for the preparation of 4- (alkyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene compounds

The present invention relates to a process for the preparation of 4- (alkyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene, preferably of 4- (1, 1-dimethylpropyl) - 1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene (amorolfine), by selective reduction of the corresponding 4- (alkyl) -1- (2-methyl-1-oxo-3- (2, 6-dimethylmorpholine) propyl) benzene with

Hydrogen.

State of the art

The preferred compound amorolfine is referred to chemically as 4- (1,1-dimethylpropyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene and has the chemical formula:

A m o ro lfm base

Amorolfin is a per se known pharmaceutical active substance and is used as an antifungal agent for the treatment of fungal infections, preferably in the form of the hydrochloride salt.

According to ES 549250, amorolfine is prepared by hydrogenating 4- (1,1-dimethylpropyl) -1- (2-methyl-1-oxo-3- (2,6-dimethylmorpholine) propyl) benzene in glacial acetic acid with hydrogen. Laboratory tests showed, however, that with this method, the keto group in the 1-position is hydrogenated only to the hydroxyl group. There is no Amorolfin in technically useful

Amounts . Description of the invention

It has now been found that the keto group of 4- (alkyl) -1- (2-methyl-1-oxo-3- (2,6-dimethylmorpholine) propyl) benzene (hereinafter also referred to as "alpha-Benzylketoverbindung" ), and preferably the keto group of 4- (1, 1-dimethylpropyl) -1- (2-methyl-1-oxo-3- (2,6-dimethylmorpholine) propyl) benzene, directly reduced to the methylene group, if the hydrogenation presents the alpha-benzyl ketone compound as the salt of a strong acid and hydrogenates this salt with hydrogen in the presence of a suitable catalyst

Hydrogen under elevated pressure, for example in the presence of palladium on activated carbon in a polar inert solvent, and hydrogenated at elevated temperature, for example at about 70 ⁰ C. Preferably, hydrogenation in the presence of a strong acid, such as hydrochloric acid or sulfuric acid. Thus, the hydrogenated compound is obtained as a crude product in high yield and high purity. In this case, the salt of the hydrogenated compound can be isolated directly from the reaction mixture. By alkaline work-up of the reaction mixture can win the crude product as the free base, which can be converted with acid into a salt. For example, amorolfine can be isolated as free base and with hydrochloric acid in amorolfine. Convert HCl to a purity higher than 99%. The total yield in the range is usually 75-80%. In this sense, the inventive hydrogenation of the salt of the alpha-benzyl ketone compound can be formulated as follows:

anion

Keto compound salt Amorpholfin salt The present invention is defined in the claims. The present invention relates to a process for the preparation of 4- (alkyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene by selective reduction of the corresponding alpha-benzyl ketone compound with hydrogen characterized in that the corresponding 4- (alkyl) -1- (2-methyl-1-oxo-3- (2,6-dimethylmorpholine) propyl) benzene compound as the salt of a strong acid in a suitable inert

Submitted solvent and hydrogenated this salt in the presence of a suitable catalyst with hydrogen.

Preference is given to the process for preparing 4- (1,1-dimethylpropyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene (amorolfine) by selective reduction of the corresponding alpha-benzyl ketone compound with hydrogen, characterized in that 4- (1, 1-dimethylpropyl) -1- (2-methyl-l-oxo-3- (2, 6-dimethylmorpholine) propyl) benzene as the salt of a strong acid and presents this salt hydrogenated in the presence of a suitable catalyst with hydrogen.

The invention also relates to the compounds thus prepared. The invention also relates to the use of Amorolfins, or Amorolfinsalzes prepared according to the invention, as an antifungal agent for the treatment of fungal infections. The invention also relates to the use of Amorolfins, or Amorolfinsalzes prepared according to the invention, for the preparation of a remedy for the treatment of fungal infections.

Preferably, the preparation of 4- (Ci-β-alkyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene compounds, in particular of corresponding (Ci_ ₅ ) alkyl compounds and in particular of (1, 1-dimethylpropyl) compound, that is 4- (1,1-dimethyl-propyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene. Analogously, in each case for the corresponding alpha-benzyl ketone compound as starting compound, it is true that this is a (Ci_ ₈ ) Alkyl compound, in particular a (Ci_ ₅ ) alkyl compound. In particular, 4- (1, 1-dimethylpropyl) -1- (2-methyl-1-oxo-3- (2,6-dimethylmorpholine) propyl) benzene is preferred as the starting compound.

The term "strong acid salt" is understood as meaning the salt of the alpha-benzyl ketone compound with a strong organic or inorganic acid, for example, hydrochloric, hydrobromic, sulfuric, perchloric, trichloroacetic, trifluoroacetic, methylsulfonic, benzenesulfonic or para-hydroxy acids. Particular preference is given to hydrochloric acid and sulfuric acid.A strong acid is an acid having a pKa value in the range of pKs <0 to 4. In particular, acids are preferred which are dissolved in aqueous solution at a concentration of 0.1 to 1 mol / 1 give an acid value (pH) of less than 2 (pH <2) and preferably less than 1 (pH <1).

Preferably, the salt of the alpha-benzyl ketone compound is hydrogenated in a suitable inert solvent and in the presence of a strong acid. Suitable inert solvents for the hydrogenation are polar protic and aprotic solvents. Preference is given to protic, water-miscible solvents which are inert under the reaction conditions of the hydrogenation according to the invention. Aliphatic alcohols, preferably aliphatic (C 1 -C 8) -alcohols, are preferred

Methanol, ethanol, propanol or butanol, or a mixture of these compounds. Preference is given to methanol or ethanol or a mixture of these compounds.

Aprotic solvents are, for example, dimethylformamide (DMF), dimethylacetamide (DMA) or N-methylpyrrolidone (NMP) and related compounds. However, these solvents have the Disadvantage that the workup of the compounds produced is technically more difficult.

Preferably, the inert solvent contains during the

Hydrogenation reaction at most 10 wt .-% water, preferably at most 5 wt .-% water, preferably at most 2 wt .-% water, or is substantially anhydrous.

The hydrogenation of the salt of the alpha-Benzylketoverbindung is preferably carried out in acidic medium, d.i. in the presence of a strong acid, as these strong acids are defined in advance. The addition of a strong acid to the solvent produces a low acid value (pH). Preferably, this is in the range of zero to 2, preferably less than 1 (pH <1). In this case, the acid is added to the reaction mixture until the desired acid value (pH) is reached.

The strong acid may be added to the solvent as anhydrous acid, gaseous (e.g., hydrogen chloride or hydrogen bromide) or as a concentrated aqueous solution. If the alpha-benzyl ketone compound is added as the base in the solvent and the strong acid is added to the solvent, the corresponding salt of the alpha-benzyl ketone compound is formed in situ. The same is the case when the solvent already contains the strong acid and then the solvent is added to the alpha-benzyl ketone compound.

It is likewise possible to add to the solvent a salt of the alpha-benzyl ketone compound, for example the hydrochloride or the sulfate. If a strong acid is added in advance or subsequently to the solvent, an equilibrium of the salt of the alpha-benzyl ketone compound is formed in situ if this acid is different from the already present salt-forming acid. The hydrogenation according to the invention is carried out in the presence of at least one catalytically active metal of group VIII of the Periodic system performed. Preferred metals of Group VIII of the Periodic Table are nickel, ruthenium, rhodium, iridium, platinum or palladium, preferably palladium, ruthenium, platinum or rhodium, preferably palladium or platinum, or mixed catalysts which are more than one of these

Contain metals. Preference is given to palladium, optionally in combination with a further metal or with further metals of group VIII of the Periodic Table, preferably in

Combination with platinum, these metals are preferably present in pure form.

The catalytically active metal or catalytically active metals used are preferably used together with a support material, preferably applied to activated charcoal as a support material, in known and known amounts for hydrogenation reactions.

The hydrogenation reaction is carried out preferably at elevated temperature, preferably in the range of about 40 ⁰ C to 90 ⁰ C, preferably at about 60 ⁰ C to 80 ⁰ C. The higher the temperature, the faster the hydrogenation reaction proceeds. The optimum temperature to use depends on the boiling point of the solvent and the applied pressure and can be readily determined by one skilled in the art.

In this sense, the present invention relates to a process for preparing 4- (alkyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene, preferably 4- (1, 1-dimethylpropyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene, by selective reduction of the corresponding alpha-benzyl ketone compound with hydrogen, characterized in that

(i) introducing the corresponding 4- (alkyl) -1- (2-methyl-1-oxo-3- (2,6-dimethylmorpholine) propyl) benzene compound as the salt of a strong acid in a suitable inert solvent and this salt hydrogenated in the presence of a noble metal catalyst with hydrogen, wherein (ii) hydrogenation in acidic medium at an acid value (pH) of less than 2 (pH <2), and

(iii) in the presence of at least one catalytically active

Metal of Group VIII of the Periodic Table as a noble metal catalyst.

The present invention makes it possible to isolate the hydrogenated compound in salt form or as a free base. For example, when the hydrogenation reaction is carried out in the presence of additional hydrogen chloride, the hydrogenated compound is obtained in the form of the hydrochloride, which can be crystallized from the reaction mixture, preferably after removal of the hydrogenation catalyst. Thus, in this embodiment, amorolfine hydrochloride can be isolated directly from the reaction mixture as a crude product.

However, it is also possible to isolate 4- (alkyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene as free base if the reaction mixture obtained in the hydrogenation is removed, preferably after removal of the hydrogenation catalyst, mixed with a base, so that an alkaline acid value (pH> 7) is formed in the reaction mixture. Thus, the hydrogenated compound formed can be used as the free base, optionally after prior extraction with a suitable organic water-insoluble compound, e.g. Ethyl acetate, obtained directly and the isolated oil e.g. be further purified by distillation.

Thus, the present invention further relates to a process for the preparation of 4- (alkyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene, preferably 4- (1, 1-dimethyl) propyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene, in salt form or as the free base, by means of selective reduction of the corresponding alpha-benzyl ketone compound by hydrogen, characterized in that

(i) the corresponding 4- (alkyl) -1- (2-methyl-1-oxo-3- (2,6-dimethylmorpholine) propyl) benzene compound as the salt of a strong Acid in a suitable inert solvent and hydrogenating this salt in the presence of a suitable catalyst with hydrogen, and either

(ii) crystallizing the hydrogenated compound in salt form, preferably after removal of the hydrogenation catalyst, from the reaction mixture; or

(Iii) the resulting reaction mixture, preferably after removal of the hydrogenation catalyst, to produce an alkaline acid value with a base, and then 4- (alkyl) - 1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene as free

Base, preferably isolated by extraction as an oil. The free base can optionally be further purified by distillation and converted into a salt. For use as a base for making an alkaline

Acid value are hydroxides, such as alkali metal hydroxides, preferably, in particular sodium hydroxide or potassium hydroxide, preferably sodium hydroxide. When adding the base, a basic acid value (pH) is preferably generated, preferably a pH in the range of 9 to 14, preferably in the range of 10 to 12, and preferably about 11.5.

The following examples illustrate the invention without limiting it.

Examples - General procedure

4- (1,1-Dimethylpropyl) -1- (2-methyl-1-oxo-3- (2,6-dimethylmorpholine) propyl) benzene or a salt of this compound, such as the hydrochloride, are added together with hydrochloric acid or sulfuric acid dissolved in an alcohol. Thereafter, the catalyst, for example palladium on activated carbon, is added and heated under a hydrogen atmosphere for 20-40 hours at elevated pressure and elevated temperature. To gain the

Amorolfinbase is filtered off after completion of the reaction of the catalyst, the reaction mixture made alkaline by the addition of alkali and the solvent, eg methanol, distilled off profiled. Amorolfin is by means of an organic, immiscible with water, solvent, preferably with a

Ester compound such as ethyl acetate, extracted from the alkaline aqueous phase. By drying the organic phase and adding aqueous hydrochloric acid Amorolfin hydrochloride can be crystallized out. Thereafter, amorolfine hydrochloride is recrystallized from a mixture of water and alcohol.

It is also possible, after completion of the reaction, preferably after removal of the hydrogenation catalyst, amorolfine in

Salt form directly from the reaction mixture, optionally after removing a portion of the solvent to crystallize.

example 1

15 g of 4- (1,1-dimethylpropyl) -1- (2-methyl-1-oxo-3- (2,6-dimethyl-morpholine) -propyl) benzene as the base or as the hydrochloride are dissolved in a mixture of 300 grams (g ) Methanol and 3.5g aqueous conc. Sulfuric acid and 3 g of palladium on carbon (with 5 percent by weight of palladium) at room temperature. Thereafter, an overpressure of 3 to 4 bar is set with hydrogen. It is heated to 62 ⁰ C and hydrogenated for 20 hours. After completion of the reaction, the catalyst is filtered off. The methanolic solution is treated with 8 g of aqueous 30% sodium hydroxide solution, whereupon the methanol is distilled off under vacuum. To the residue are added 75 g of an aqueous 10% sodium bicarbonate solution and 105 g of ethyl acetate. The mixture is stirred and the aqueous phase separated. The ethyl acetate phase is dried over 15 g of anhydrous sodium sulfate, the sodium sulfate is filtered off and washed with 60 g of ethyl acetate. The combined phase is added dropwise 3.5 g of aqueous 37% hydrochloric acid, after which the mixture is briefly heated. Upon cooling, the desired product precipitates. 10.5 g of amorolfine hydrochloride are obtained crude, in a purity of more than 99% (> 99%). The crude product is dissolved in a mixture of 40 g of ethanol and 10 g of water at a temperature of about 60 ⁰ C. Upon cooling, the pure product crystallizes out. you receives 9.6g amorolfin hydrochloride with a purity greater than 99.8% (> 99.8%).

Example 2

15 g of 4- (1,1-dimethylpropyl) -1- (2-methyl-1-oxo-3- (2,6-dimethyl-morpholine) propyl) benzene as base or as hydrochloride are dissolved in a mixture of 300 g of ethanol and 3.5 g conc. aqueous sulfuric acid and 3 g of palladium on carbon (with 5 weight percent of palladium) at room temperature. Thereafter, an overpressure of 3 to 4 bar is set with hydrogen. It is heated to 80 ⁰ C and hydrogenated for 30 hours. After completion of the reaction, the catalyst is filtered off. The ethanolic solution is treated with 8 g of aqueous 30% sodium hydroxide solution, whereupon the ethanol is distilled off under vacuum. The residue is treated with 75 g of an aqueous 10% sodium bicarbonate solution and 105 g of ethyl acetate. The mixture is stirred and the aqueous phase separated. The ethyl acetate phase is dried over 15 g of anhydrous sodium sulfate, the sodium sulfate is filtered off and washed with 60 g of ethyl acetate. The combined organic phases are with 3.5g 37%

Hydrochloric acid is added, after which the mixture is briefly heated. Upon cooling, the desired product precipitates. This gives 10.0 g of amorolfine hydrochloride crude with a purity of greater than 99% (> 99%). The crude product is dissolved in a mixture of 40 g of ethanol and 10 g of water at a temperature of about 60 ⁰ C. Upon cooling, the pure product crystallizes out. This gives 9.0 g of amorolfine hydrochloride with a purity of more than 99.8% (> 99.8%). Example 3

15 g of 4- (1,1-dimethylpropyl) -1- (2-methyl-1-oxo-3- (2,6-dimethyl-morpholine) propyl) benzene as base or as hydrochloride are dissolved in a mixture of 300 g of ethanol and 3.2 g of aqueous 37% hydrochloric acid and 3 g of palladium on carbon (with 5 percent by weight of palladium) at room temperature. After that is with

Hydrogen an overpressure of 3 to 4 bar set. It will heated to 80 ⁰ C and hydrogenated for 30-40 hours. After completion of the reaction, the catalyst is filtered off. The ethanolic solution is treated with 8 g of aqueous 30% sodium hydroxide solution, whereupon the ethanol is distilled off under vacuum. The residue is mixed with 75 g of an aqueous 10% sodium bicarbonate solution and with 105 g of ethyl acetate. The mixture is stirred and the aqueous phase separated. The ethyl acetate phase is dried over 15 g of anhydrous sodium sulfate, the sodium sulfate is filtered off and washed with 60 g of ethyl acetate. 3.5 g of aqueous 37% hydrochloric acid are added dropwise to the combined organic phase and the mixture is briefly heated. Upon cooling, the desired product precipitates. This gives 9.5 g amorolfine hydrochloride crude with a purity of greater than 99% (> 99%). The crude product is dissolved in a mixture of 36 g ethanol and 9 g water in the heat. Upon cooling, the pure product crystallizes out. 8.7 g of amorolfin hydrochloride are obtained with a purity of greater than 99.8% (> 99.8%).

Example 4

15 g of 4- (1,1-dimethylpropyl) -1- (2-methyl-1-oxo-3- (2,6-dimethyl-morpholine) propyl) benzene as the base of the hydrochloride are dissolved in a mixture of 300 g of methanol and 3.2 g of aqueous 37% hydrochloric acid and 3 g of palladium on carbon (with 5 wt .-% of palladium) initially charged at room temperature. Thereafter, an overpressure of 3 to 4 bar is set with hydrogen. It is heated to 62 ⁰ C and hydrogenated for 30 hours. After completion of the reaction, the catalyst is filtered off. The methanolic solution is treated with 8 g of aqueous 30% sodium hydroxide solution, whereupon the methanol is distilled off under vacuum. The residue is treated with 75 g of an aqueous 10% sodium bicarbonate solution and 105 g of ethyl acetate. The mixture is stirred and the aqueous phase separated. The ethyl acetate phase is dried over 15 g of anhydrous sodium sulfate, the sodium sulfate is filtered off and washed with 60 g of ethyl acetate. 3.5 g of aqueous 37% strength hydrochloric acid are added dropwise to the combined phase and the mixture is briefly heated. When it cools down that desired product. 10.5 g of amorolfine hydrochloride are obtained crude with a purity of more than 99% (> 99%). The crude product is dissolved in a mixture of 40 g of ethanol and 10 g of water in the heat. Upon cooling, the pure product crystallizes out. 9.6 g of amorolfine hydrochloride having a purity of greater than 99.8% (> 99.8%) are obtained.

Example 5

15 g of 4- (1,1-dimethylpropyl) -1- (2-methyl-1-oxo-3- (2,6-dimethyl-morpholine) propyl) benzene as the base or as the hydrochloride are dissolved in a mixture of 300 g of methanol and 3.2 g of aqueous 37% hydrochloric acid and 3 g of palladium on carbon (with 5 wt .-% of palladium) initially charged at room temperature. Thereafter, an overpressure of 3 to 4 bar is set with hydrogen. It is heated to 62 ° C and hydrogenated for 30 hours. After completion of the reaction, the catalyst is filtered off and the solvent is concentrated. By adding water, amorpholfin .HCl is directly crystallized, which can be recrystallized from ethanol / water. This gives 10.2 g of amorolfine .HCl crude with a purity greater than 98.8% (> 98.8%).

Analogously, also in Examples 1 to 3, after the hydrogenation reaction and the removal of the catalyst, the corresponding salt of amorolfine can be crystallized out.

Claims

claims

1. A process for the preparation of 4- (alkyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene by means of selective

Reduction of the corresponding alpha-Benzylketoverbindung with

Hydrogen, characterized in that the corresponding 4- (alkyl) -1- (2-methyl-l-oxo-3- (2,6-dimethylmorpholine) propyl) benzene compound as the salt of a strong acid in a suitable inert Submitted solvent and hydrogenated this salt in the presence of a suitable catalyst with hydrogen.

2. The method according to claim 1, characterized in that as appropriate 4- (alkyl) -1- (2-methyl-l-oxo-3- (2, 6-dimethylmorpholine) propyl) benzene compound, a corresponding (Ci_ ₈ ) -Alkyl compound, preferably a corresponding (Ci_ ₅ ) - alkyl compound, as a salt of a strong acid in one

suitable inert solvent and hydrogenated this salt in the presence of a suitable catalyst with hydrogen.

3. The method according to claim 1, characterized in that 4- (1, 1-dimethylpropyl) -1- (2-methyl-l-oxo-3- (2,6-dimethylmorpholine) propyl) benzene as the salt of a strong acid and hydrogenated this salt in the presence of a suitable catalyst with hydrogen to 4- (1, 1-dimethylpropyl) -1- (2-methyl-3- (2, 6-dimethylmorpholine) propyl) benzene (amorolfine).

4. The method according to any one of claims 1-3, characterized in that the salt of the alpha-Benzylketoverbindung with a strong organic or inorganic acid as a salt with hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, trichloroacetic acid, trifluoroacetic acid, methylsulfonic acid, benzenesulfonic acid or submits para-toluenesulfonic acid,

preferably as a salt with hydrochloric acid, hydrobromic acid or Sulfuric acid, and preferably as a salt with hydrochloric acid or sulfuric acid.

5. Process according to one of claims 1-4, characterized in that an inert polar protic and / or aprotic solvent is used for the hydrogenation.

6. The method according to claim 5, characterized in that one uses for the hydrogenation a protic water-miscible solvent selected from the group of alifatic alcohols, preferably selected from the group of aliphatic (Ci-Cs) -alcohols, preferably methanol , Ethanol, propanol or butanol, or a mixture of these compounds, preferably methanol or ethanol, or a mixture of these compounds.

7. The method according to claim 5, characterized in that one uses for the hydrogenation aprotic solvent, preferably dimethylformamide (DMF), dimethylacetamide (DMA) or N-methylpyrrolidone (NMP) and related compounds or a mixture of these compounds.

8. The method according to any one of claims 1-7, characterized in that the solvent during the hydrogenation reaction at most 10 wt .-% water, preferably at most 5 wt .-%

Water, preferably at most 2 wt .-% water or substantially free of water.

9. The method according to any one of claims 1-8, characterized in that the hydrogenation of the salt of the alpha-benzylketo compound is carried out in an acidic medium, in the presence of a strong organic or inorganic acid, preferably in the presence of hydrochloric acid, hydrobromic acid, Sulfuric acid, perchloric acid, trichloroacetic acid, trifluoroacetic acid, methylsulfonic acid, benzenesulfonic acid or para-toluenesulfonic acid, preferably in the presence of hydrochloric acid, bromine acid or sulfuric acid, preferably at an acid value (pH) in the range of zero to 2, preferably at an acid value (pH) of less than 1 (pH <l).

10. The method according to any one of claims 1-9, characterized in that the catalyst for the hydrogenation is a catalytically effective metal of Group VIII of the Periodic Table and is preferably selected from the group comprising nickel, ruthenium, rhodium, iridium, platinum or palladium, preferably palladium, ruthenium, platinum or rhodium, preferably palladium or platinum, or mixed catalysts containing more than one of these metals.

11. The method according to claim 10, characterized in that the catalyst for the hydrogenation palladium, optionally in

Combination with another metal or with other metals of Group VIII of the Periodic Table, preferably in combination with platinum, these metals preferably being present in pure form.

12. The method according to any one of claims 1-11, characterized in that one carries out the hydrogenation reaction at elevated temperature, preferably in the range of about 40 ⁰ C to 90 ⁰ C, preferably at about 60 ⁰ C to 80 ⁰ C.

13. The method according to any one of claims 1-12, characterized in that one

(i) introducing the corresponding 4- (alkyl) -1- (2-methyl-1-oxo-3- (2,6-dimethylmorpholine) propyl) benzene compound as the salt of a strong acid in a suitable inert solvent and this salt hydrogenated in the presence of a noble metal catalyst with hydrogen, wherein

(ii) hydrogenation in acidic medium at an acid value (pH) of less than 2 (pH <2), and (iii) in the presence of at least one catalytically active

Group VIII metal of the Periodic Table as a noble metal catalyst.

14. The method according to any one of claims 1-12, characterized in that one

(i) introducing the corresponding 4- (alkyl) -1- (2-methyl-1-oxo-3- (2,6-dimethylmorpholine) propyl) benzene compound as the salt of a strong acid in a suitable inert solvent and this salt in the presence of a suitable

Hydrogenated catalyst with hydrogen, and either

(ii) the hydrogenated compound in salt form, preferably after

Removing the hydrogenation catalyst crystallized from the reaction mixture; or

(iü) adding to the resulting reaction mixture, preferably after removal of the hydrogenation catalyst, an alkaline acid value with base, followed by 4- (alkyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene as the free base, preferably isolated by extraction as an oil.

15. Use of the compounds prepared according to any one of claims 1-14, preferably of 4- (1, 1-dimethylpropyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene (amorolfine) or a Amorolfine salt, as an antifungal agent for the treatment of fungal infections.

16. Use of the compounds prepared according to any one of claims 1-14, preferably of 4- (1, 1-dimethylpropyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene (amorolfine) or a Amorolfine salt for the preparation of a remedy for the treatment of fungal infections.