Description:“AN IMPROVED PROCESS FOR THE PREAPARATION OF AMOROLFINE HYDROCHLORIDE”

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Amorolfine hydrochloride (I). Furthermore, the invention pertains to novel compounds of formulae (VIa), which is used in the preparation of Amorolfine hydrochloride (I) with high purity and yield.

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, which 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 is that 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 is that 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 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 an improved process for the preparation of Amorolfine hydrochloride (I). Furthermore, the invention pertains to novel compounds of formulae (VIa), which is used in the preparation of Amorolfine hydrochloride (I) with high purity and yield

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

a) reacting the compound of the formula (VI) with pivaloyl chloride in the presence of base and solvent to obtain the compound of the formula (VIa);

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

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

In another aspect, the present invention provides novel compound of the formula (IVa).

In another aspect, the present invention provides novel compound of the formula (VIa), which is used for the preparation of Amorolfine hydrochloride (I).

DETAILED DESCRIPTION

The present invention relates to an improved process for the preparation of Amorolfine hydrochloride (I). Furthermore, the invention pertains to novel compounds of formulae (VIa), which is used in the preparation of Amorolfine hydrochloride (I) with high purity and yield.

In one embodiment of the present invention provides, an improved process for the preparation of Amorolfine hydrochloride (I) comprises the steps of:

a) reacting the compound of the formula (VI) with pivaloyl chloride in the presence of base and solvent to obtain the compound of the formula (VIa);

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

c) reducing the compound of formula (VII) and 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), which comprises reacting the compound of formula (VI) with pivaloyl chloride in presence of solvent and base to obtain the compound of formula (VIa). Subsequently, the compound (VIa) is condensed with cis-2,6-dimethylmorpholine in presence of 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 base and solvent, followed by reaction with hydrochloric acid in presence of solvent. The reaction mixture is carried out at 0-15°C for 15-40 minutes, raised to 40-65°C, resulting in crude Amorolfine hydrochloride (I). Crude Amorolfine hydrochloride dissolved in in presence of solvent at 25-30oC, raised the reaction temperature to 70-75oC, cooled to 25-30oC. The product was filtered at 0-5oC, washed with solvent and then dried to yield pure Amorolfine hydrochloride.

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 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 (VIa).

In another embodiment of the present invention, novel compounds of the formula (VIa) 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 (VIa).
• The present invention provides an improved and commercially viable process for the preparation of Amorolfine hydrochloride using the novel compounds of the formula (VIa).
• 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-((2S,6R)-2,6-dimethylmorpholino)-2-methyl-3-(4-(tert-pentyl) phenyl) propan-1-one.

Pivaloyl chloride (56.30g), dichloromethane (500.0ml), 2-methyl-3-(4-(tert-pentyl) phenyl) propanoic acid (100.0g) and triethylamine (65.0g) were added into a reaction flask at below 5oC under nitrogen atmosphere, maintain the reaction mass for 60-90 min. This was followed by addition of cis-2,6-dimethylmorpholine (54.0g) to the reaction mixture at below 5oC, maintain at below 5oC for 90-120 min. Further, purified water (400.0ml) was added to the mixture, stirred for 10 min and allowed to settled for 10 min. Two layers were separated, take organic layer, extracted with dichloromethane, followed by washed with dilute HCl solution, sodium bicarbonate solution and sodium chloride solution. The obtained reaction 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-2: 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 into a reaction flask at below 15oC, raised the reaction temperature to 35-40oC and maintained for 3-4 hrs. Sodium hydroxide solution was added to the reaction mixture at below 30oC, resulting in the formation of two layers. Take aqueous layer and washed with sodium hydroxide solution, the obtained organic phase and the solvent was distilled off under vacuum at below 70oC.

The obtained reaction mixture was cooled to 40-45oC, acetone (50.0 ml) was added. The mixture was further cooled to 0-5oC, aqueous HCl (40.0ml) was added to the reaction mixture at 0-5oC, maintained for 15-30 min, raised the reaction temperature to 50-55oC and maintained for 15-30 min. Subsequently, it was cooled to 0-5oC maintained for 15-30 min. The mixture was then filtered and dried at 40-45o C to yield crude Amorolfine hydrochloride.

Example-3: Purification of crude Amorolfine hydrochloride
Crude Amorolfine hydrochloride (100.0g) and ethanol (125.0 ml) were added into the reaction flask at 25-30oC, raised the reaction temperature to 70-75oC, cooled to 25-30oC, further cooled to 0-5oC and maintained for 2-3 hrs. The obtained reaction mixture 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 the compound of the formula (VI) with pivaloyl chloride in the presence of base and a solvent to obtain the compound of the formula (VIa);

b) condensing the compound of formula (VIa) 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

c) 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 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.

4. 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.

5. 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.

6. Novel compounds of the formulae (VIa).

7. The process as claimed in claim 8, novel compounds of the formula (VIa)are used for the preparation of Amorolfine hydrochloride (I).