Description:“NOVEL PROCESS FOR THE PREAPARATION OF AMOROLFINE HYDROCHLORIDE”

FIELD OF THE INVENTION

The present invention relates to a novel process for the preparation of Amorolfine hydrochloride (I). Furthermore, the invention pertains to novel compounds of formulae (IV) and (V), which are used in the preparation of Amorolfine hydrochloride (I) with high purity and yield.
and

BACKGROUND OF THE INVENTION
Amorolfine hydrochloride is a morpholine antifungal drug that inhibits Δ14-sterol reductase and cholestenol Δ-isomerase, resulting in the depletion of ergosterol and accumulation of ignosterol in fungal cytoplasmic cell membranes. Marketed under the names Curanail, Loceryl, Locetar, and Odenil, Amorolfine is commonly available in the form of a nail lacquer, containing 5% amorolfine hydrochloride as the active ingredient. It is used to treat onychomycosis, a fungal infection of the toenails and fingernails. The product is approved for over-the-counter sale in Australia, Brazil, Russia, Germany, and the UK, and requires a prescription in other countries for the treatment of toenail fungus. Amorolfine hydrochloride is chemically known as (2R,6S)-2,6-dimethyl-4-{2-methyl-3-[4-(tert-pentyl) phenyl] propyl} morpholine hydrochloride, and its chemical structure is represented by formula I.

Amorolfine hydrochloride was first reported in US4202894 by Hoffmann LA. The patent describes a process for the preparation of Amorolfine by reacting the compound of formula (VI) with cis-2,6-dimethylmorpholine in the presence of toluene, 5% Pd/C catalyst, and hydrogen gas. The resulting Amorolfine hydrochloride is further isolated using high vacuum distillation at 134°C and 0.036 torr to obtain the final product. The process can be represented schematically as follows:

The major disadvantages of the aforementioned prior art process are the unavailability of the aldehyde compound and the isolation of Amorolfine base via high vacuum distillation at 0.036 torr, which is an expensive process.

US4384116 discloses a process for the preparation of Amorolfine hydrochloride. The process involves reacting the compound of formula (VIII) with 2-chloro-2-methylbutane in the presence of FeCl3 to obtain a crude product. The Amorolfine free base is then isolated using high vacuum distillation at 0.1 to 0.4 mbar vacuum and at temperatures ranging from 140 to 180 degrees Celsius. Subsequently, the isolated Amorolfine free base is reacted with hydrochloric acid in the presence of ethanol to obtain Amorolfine hydrochloride. The schematic representation of the above process is as follows:

The major disadvantage of the aforementioned prior art process is that the unavailability of tert-amyl chloride, isolation of Amorolfine base via high vacuum distillation at 0.036 torr vacuum.

EP1842848 discloses a process for the preparation of Amorolfine hydrochloride. The process involves reacting the compound of formula (IX) with the compound of formula (X) in the presence of palladium acetate (Heck reaction) to obtain the compound of formula (VI). Subsequently, the compound of formula (VI) is reacted with 2,6-dimethylmorpholine in the presence of Pd/C. After that, it is further reacted with hydrochloric acid in the presence of ethanol to obtain Amorolfine hydrochloride. The schematic representation of the above process is as follows

The major disadvantages of the aforementioned prior art process are the unavailability of 1-iodo-4-(tert-pentyl) benzene (IX) and 2-methylprop-2-en-1-ol (X), as well as the usage of highly expensive palladium acetate and palladium carbon.

The known processes for the preparation of Amorolfine hydrochloride suffer from several disadvantages. These include the use of expensive reagents and the requirement of high vacuum distillation, which can be difficult to handle.

The present invention provides process of Amorolfine hydrochloride (I) with high yield from step-a, b and c by using novel compounds of formulae (IV) and (V), which is efficient, cost-effective process and consistent reproducibility in producing Amorolfine and its hydrochloride.

The present invention to provides a commercially available method capable of improving the productivity of a Amorolfine hydrochloride (I) from compounds of the formulae (IV) and (V), which are useful in large scale.

SUMMARY OF THE INVENTION

The present invention relates to a novel process for the preparation of Amorolfine hydrochloride (I). Furthermore, the invention pertains to novel compounds of formulae (IV) and (V), which are used in the preparation of Amorolfine hydrochloride (I) with high purity and yield.

In one aspect of the present invention provides, novel process for the preparation of Amorolfine hydrochloride (I) comprises the steps of:

a) reacting compound of the formula (II) with a brominating agent, paraformaldehyde /formaldehyde in presence of phase transfer catalyst (PTC) and a solvent to obtain compound of formula (III);

b) reacting the compound of the formula (III) with diethylmethylmalonate in the presence of base and a solvent to obtain the compound of the formula (IV);

c) hydrolyzing the compound of the formula IV in the presence of a base to obtain the compound of formula (V);

d) decarboxylating the compound of formula (V) in the presence of a solvent to obtain the compound of formula (VI);

e) condensing the compound of formula (VI) with cis-2,6-dimethylmorpholine in the presence of an acid chloride, a base, and a solvent to obtain the compound of formula (VII), and

f) reducing the compound of formula (VII), followed by salt formation using aqueous/anhydrous HCl, to obtain Amorolfine hydrochloride (I).

In another aspect, the present invention provides novel compounds of the formulae (IV) and (V).
and

In another aspect, the present invention provides novel compounds of the formulae (IV) and (V) that are used for the preparation of Amorolfine hydrochloride (I).

DETAILED DESCRIPTION

The present invention relates to the novel and improved process for the preparation of Amorolfine hydrochloride (I) and the present invention further relates to a novel compounds of formula (IV) and (V) is used in the preparation of Amorolfine hydrochloride (I) with high purity and yield.

In one aspect of the present invention provides, novel process for the preparation of Amorolfine hydrochloride (I) comprises the steps of:

a) reacting compound of the formula (II) with a brominating agent, paraformaldehyde /formaldehyde in presence of phase transfer catalyst (PTC) and a solvent to obtain compound of formula (III);

b) reacting the compound of the formula (III) with diethylmethylmalonate in the presence of base and a solvent to obtain the compound of the formula (IV);

c) hydrolyzing the compound of the formula IV in the presence of a base to obtain the compound of formula (V);

d) decarboxylating the compound of formula (V) in the presence of a solvent to obtain the compound of formula (VI);

e) condensing the compound of formula (VI) with cis-2,6-dimethylmorpholine in the presence of an acid chloride, a base, and a solvent to obtain the compound of formula (VII), and

f) reducing the compound of formula (VII), followed by salt formation using aqueous/anhydrous HCl, to obtain Amorolfine hydrochloride (I).

In one embodiment, the present invention provides a process for the preparation of Amorolfine hydrochloride (I). The process begins by reacting the compound of formula (II) with a brominating reagent in the presence of paraformaldehyde, solvent, and phase transfer catalyst (PTC). The reaction mixture is carried out at 90-110°C, followed by cooling to 15-45°C, resulting in the compound of formula (III). Further, the compound of formula (III) is reacted with diethylmethylmalonate in the presence of a base and solvent. The reaction is carried out at 15-40°C for 2-3 hours, yielding the compound of formula (IV) and then undergoes base hydrolysis at 65-90°C for 2-5 hours, followed by cooling to 15-40°C, resulting in the compound of formula (V).
The compound (V) is decarboxylated in the presence of a solvent, with the temperature raised to 110-135°C and maintained for 1-3 hours before cooling to 0-25°C to get the compound of formula (VI), Subsequently, the compound (VI) is condensed with cis-2,6-dimethylmorpholine in the presence of an acid chloride, solvent, and base. The reaction mixture is initially kept below 15°C, then raised to 15-40°C and maintained for 3-6 hours, leading to the compound of formula (VII), and then subjected to reduction in the presence of a base and solvent, followed by reaction with hydrochloric acid in the presence of solvent. The reaction mixture is carried out at 0-15°C for 15-40 minutes, raised to 40-65°C, and maintained for an additional 5-40 minutes, resulting in crude Amorolfine hydrochloride (I). Crude Amorolfine hydrochloride dissolved in in presence of solvent at 25-30oC. The reaction temperature was then raised to 70-75oC, followed by cooling to 25-30oC, and further cooled to 0-5oC. The product was filtered at 0-5oC, washed with solvent and then dried to yield pure Amorolfine hydrochloride with a purity greater than 99.80%.

According to an embodiment of the present invention. wherein the solvent is selected sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutanol, tert-butanol; nitriles such as acetonitrile and propionitrile; ether solvent such as tetrahydrofuran, diisopropylether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, 1,4-dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and aromatic hydrocarbons such as toluene, anisole, heptane and xylene; esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone; halogenated hydrocarbons such as chloroform, dichloromethane; water; cyclohexane and N-methyl-2-pyrrolidone and or mixtures thereof.

According to an embodiment of the present invention, wherein the base is selected from inorganic base and organic base, wherein the inorganic base is selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like, tri potassium phosphate, ammonia; organic base is selected from triethylamine (TEA), triethanolamine, diisopropylethylamine, di-n-propylamine or mixtures thereof.

According to an embodiment of the present invention, wherein the brominating agent is selected from bromine, hydrobromic acid, N-bromosuccinic acid (NBS), Dibromoisocyanuric acid (DBI), phosphorus tribromide and bromotrichloromethane.

According to an embodiment of the present invention, wherein the phase transfer catalyst (PTC) is selected from tetrabutylphosphonium bromide, tetrabutylammonium bromide (TBAB), Tetrabutylammonium fluoride (TBAF), tetrabutylammonium hydroxide (TBAH), and triethylbenzyl ammonium chloride (TEBA).

According to an embodiment of the present invention, wherein the acid chloride is selected from acetyl chloride, thionyl chloride, propanoyl chloride, butanoyl chloride and benzoyl chloride.

According to an embodiment of the present invention, wherein the reducing agent is selected from sodium boro hydride, raney Nickel, lithium aluminium hydride, sodium bis(2-methoxy ethoxy)aluminium hydride (vitride) and zinc amalgam.

Another embodiment of the present invention provides a novel compounds of the formulae (IV) and (V).

and

In another embodiment of the present invention, novel compounds of the formula (IV) and (V) are used for the preparation of Amorolfine hydrochloride (I).

The advantages of the present invention:

• The present invention relates to novel compounds of the formula (IV) and (V).
• The present invention provides an improved and commercially viable process for the preparation of Amorolfine hydrochloride using the novel compounds of the formula (IV) and (V).
• The present invention's process for Amorolfine hydrochloride provides a simple, cost-effective, environmentally friendly, and industrially applicable method with high purity and good yield.

The process details of the invention are provided in the examples given below, which are provided by way of illustration only. Therefore, they should not be construed to limit the scope of the invention.

EXAMPLES
Example-1: Preparation of 1-(bromomethyl)-4-(tert-pentyl) benzene

Tert-amylbenzene (100.0g) and paraformaldehyde (30.0g) were added to a mixture of acetic acid (151 ml), 48% HBr (569 ml), and tetrabutylammonium bromide in a reaction flask. The temperature was raised to 100-110°C and then cooled to 25-35°C, after which the layers were separated. The aqueous layer was extracted with MDC (methylene dichloride). The resulting organic layer was washed with water and then with a sodium bicarbonate solution. It was then filtered, dried over sodium sulfate, and the solvent was evaporated under vacuum to obtain 1-(bromomethyl)-4-(tert-pentyl)benzene.

Example-2: Preparation of 1-(bromomethyl)-4-(tert-pentyl) benzene

Tert-amylbenzene (100.0g) and formaldehyde (30.0g) were added to a mixture of acetic acid (151 ml), 48% HBr (569 ml), and tetrabutylammonium bromide in a reaction flask. The temperature was raised to 100-110°C and then cooled to 25-35°C, after which the layers were separated. The aqueous layer was extracted with MDC (methylene dichloride). The resulting organic layer was washed with water and then with a sodium bicarbonate solution. It was then filtered, dried over sodium sulfate, and the solvent was evaporated under vacuum to obtain 1-(bromomethyl)-4-(tert-pentyl)benzene

Example-3: Preparation of 2-methyl-2-(4-(tert-pentyl) benzyl) malonic acid

Sodium methoxide (101 gm) and ethanol (580.0 ml) were added to a reaction flask at a temperature below 45oC. Diethyl-2-methylmalonate was then added to the reaction mixture and maintained at 25-30oC for 2 hrs. Subsequently, 1-(bromomethyl)-4-(tert-pentyl) benzene (155.0 g) was added to the obtained reaction mixture over a period of 30-60 minutes at 25-30oC and kept for 3 hrs. The solvent was distilled off under vacuum upon completion of the reaction conversion.
The resulting reaction mixture was cooled to 25-30oC, and sodium hydroxide solution was added to the mixture at a temperature below 25oC. The reaction temperature was then raised to 75-80oC and maintained for 3-4 hrs before cooling again to 25-30oC. The obtained reaction mixture was washed with toluene, cooled to 5-10oC, and the pH was adjusted to 1.0-2.0 with Conc. HCl. It was then extracted with ethyl acetate and washed with water. The solvent was distilled off under vacuum to yield the crude product of 2-methyl-2-(4-(tert-pentyl) benzyl) malonic acid as a viscous liquid.

Example-4: Preparation of 2-methyl-3-(4-(tert-pentyl) phenyl) propanoic acid

In a reaction flask, 2-Methyl-2-(4-(tert-pentyl) benzyl) malonic acid and N,N-dimethylformamide (200.0 ml) were combined, and the temperature was raised to 120-125oC. The mixture was maintained at this temperature for 2 hrs and then cooled to 10-15oC. Water (435 ml) was subsequently added to the reaction mixture at a temperature below 30oC. The resulting mixture was then extracted with ethyl acetate, washed with water, and followed by a 10% sodium chloride solution. The solvent was then distilled off under vacuum to obtain 2-methyl-3-(4-(tert-pentyl) phenyl) propanoic acid.

Example-5: Preparation of 1-((2S,6R)-2,6-dimethylmorpholino)-2-methyl-3-(4-(tert-pentyl) phenyl) propan-1-one.

Thionyl chloride (80.0g), dichloromethane (500.0ml), 2-methyl-3-(4-(tert-pentyl) phenyl) propanoic acid (100.0g), and N,N-dimethylformamide (10.0 ml) were added to a reaction flask at a temperature below 20oC. The reaction temperature was raised to 25-30oC and maintained for 2-3 hrs. Toluene was then added to the reaction mixture, and the solvent was distilled off under vacuum at below 70oC.
Cis-2,6-dimethylmorpholine (58.90g), triethylamine (75.0g), and dichloromethane were added to the reaction mixture at a temperature below 5oC. The temperature was then raised to 25-30oC and maintained for 4-5 hrs. Purified water (400.0ml) was added to the mixture, stirred for 10 min, and allowed to settle for 10 min. Two layers were formed, and the organic layer was separated. It was then extracted with dichloromethane and washed successively with dilute HCl solution, sodium bicarbonate solution, and sodium chloride solution. The mixture was filtered, dried with sodium sulfate, and the solvent was distilled off under vacuum at below 40oC to yield 1-((2S,6R)-2,6-dimethylmorpholino)-2-methyl-3-(4-(tert-pentyl) phenyl)propan-1-one.

Example-6: Preparation of Amorolfine hydrochloride

Vitride solution, 1-((2S,6R)-2,6-dimethylmorpholino)-2-methyl-3-(4-(tert-pentyl) phenyl)propan-1-one (1 , and toluene were added to a reaction flask at a temperature below 15oC. The temperature was then raised to 35-40oC and maintained for 3-4 hrs. Sodium hydroxide solution was added to the reaction mixture at a temperature below 30oC, resulting in the formation of two layers. The aqueous layer was separated and washed with sodium hydroxide solution, the obtained organic phase, and the solvent was distilled off under vacuum at below 70oC.
The mixture was then cooled to 40-45oC, and acetone (50.0 ml) was added. The mixture was further cooled to 0-5oC, and aqueous HCl (40.0ml) was added to the reaction mixture at 0-5oC. The mixture was maintained at this temperature for 15-30 min, after which the temperature was raised to 50-55oC and maintained for another 15-30 min. Subsequently, it was cooled to 0-5oC and kept at this temperature for 15-30 min. The mixture was then filtered and dried at 40-45o C to yield crude Amorolfine hydrochloride.

Example-7: Purification of crude Amorolfine hydrochloride
Crude Amorolfine hydrochloride (100.0g) and ethanol (125.0 ml) were added to the reaction flask at 25-30oC. The reaction temperature was then raised to 70-75oC, followed by cooling to 25-30oC, and further cooled to 0-5oC, the mixture was maintained at this temperature for 2-3 hrs. The product was filtered at 0-5oC, washed with ethanol (15.0ml) and then dried at 45-50oC for 7-8 hrs to yield pure Amorolfine hydrochloride (100.0g) with a purity greater than 99.80%
, Claims:WE CLAIMS:

1. A process for the preparation of Amorolfine hydrochloride (I), comprises the steps of:

a) reacting compound of the formula (II) with a brominating agent, paraformaldehyde /formaldehyde in presence of phase transfer catalyst (PTC) and a solvent to obtain compound of formula (III);

b) reacting the compound of the formula (III) with diethylmethylmalonate in the presence of base and a solvent to obtain the compound of the formula (IV);

c) hydrolyzing the compound of the formula IV in the presence of a base to obtain the compound of formula (V);

d) decarboxylating the compound of formula (V) in the presence of a solvent to obtain the compound of formula (VI);

e) condensing the compound of formula (VI) with cis-2,6-dimethylmorpholine in the presence of an acid chloride, a base, and a solvent to obtain the compound of formula (VII), and

f) reducing the compound of formula (VII), followed by salt formation using aqueous/anhydrous HCl, to obtain Amorolfine hydrochloride (I).

2. The process as claimed in claim 1, wherein the solvent is selected sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutanol, tert-butanol; nitriles such as acetonitrile and propionitrile; ether solvent such as tetrahydrofuran, diisopropylether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, 1,4-dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and aromatic hydrocarbons such as toluene, anisole, heptane and xylene; esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone; halogenated hydrocarbons such as chloroform, dichloromethane; water; cyclohexane and N-methyl-2-pyrrolidone and or mixtures thereof.

3. The process as claimed in claim 1, wherein the brominating agent is selected from bromine, hydrobromic acid, N-bromosuccinic acid (NBS), Dibromoisocyanuric acid (DBI), phosphorus tribromide and bromotrichloromethane.

4. The process as claimed in claim 1, wherein the phase transfer catalyst (PTC) is selected from tetrabutylphosphonium bromide, tetrabutylammonium bromide (TBAB), Tetrabutylammonium fluoride (TBAF), tetrabutylammonium hydroxide (TBAH), and triethylbenzyl ammonium chloride (TEBA).

5. The process as claimed in claim 1, wherein the base is selected from inorganic base and organic base, wherein the inorganic base is selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like, tri potassium phosphate, ammonia; organic base is selected from triethylamine (TEA), triethanolamine, diisopropylethylamine, di-n-propylamine or mixtures thereof.

6. The process as claimed in claim 1, wherein the acid chloride is selected from acetyl chloride, thionyl chloride, propanoyl chloride, butanoyl chloride and benzoyl chloride.

7. The process as claimed in claim 1, wherein the reducing agent is selected from sodium boro hydride, raney Ni, lithium aluminium hydride, sodium bis(2-methoxy ethoxy)aluminium hydride (vitride) and zinc amalgam.

8. Novel compounds of the formulae (IV) and (V).

and

9. The process as claimed in claim 8, novel compounds of the formula (IV) and (V) are used for the preparation of Amorolfine hydrochloride (I).