FORM 2

THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10; rule 13)

1. Title of the invention – Process for the preparation of Mexiletine Hydrochloride

2. Applicant(s)

(a) NAME : ALEMBIC LIMITED

(b) NATIONALITY: An Indian Company.

(c) ADDRESS: Alembic Campus, Alembic Road,
Vadodara-390, 003, Gujarat, India

3. PREAMBLE TO THE DESCRIPTION

The following specification particularly describes the invention and the manner in which it is to be performed:

Description

Field of the invention

The present invention relates to an improved process for the preparation of Mexiletine Hydrochloride of formula (I).

Background of Invention

Mexiletine hydrochloride of the formula (I) is chemically known as [2- (2, 6- dimethylphenoxy) -1- methylethyl] ethylamine hydrochloride. Mexiletine hydrochloride is a sodium channel blocker, and thus exhibits useful pharmacological properties, especially utility for the alleviation of neuropathic pain.

Neuropathic pain can be described as pain associated with damage or permanent alteration of the peripheral or central nervous system. Clinical manifestations of neuropathic pain include a sensation of burning or electric shock, feelings of bodily distortion, allodynia and hyperpathia.

Sodium channel-blocking agents have been reported to be effective in the treatment of various disease states. They are in particular useful as local anesthetics, and in the treatment of arrhythmia. It has also been reported for many years that sodium channel-blocking agents may be useful in the treatment of pain, including neuropathic pain; see, for example, Tanelian et al., Pain Forum. , 4(2), 75-80, (1995). There is evidence that sodium channel-blocking agents selectively suppress ectopic neural firing in injured nerves, and it is via this mechanism that they are believed to be useful for relieving pain.

US3,954,872 is product patent of Mexiletine hydrochloride. It discloses method for the preparation of compounds of formula (a)

Formula (a)
by reacting compound of formula (b) with 1-halo-2-oxo alkane of corresponding carbon length to obtain 1-(2’,6’-dimethyl-phenoxy)-2-oxo-alkane which is reacted with ammonia, hydroxyl amine or hydrazine to obtain compound of formula (c). Compound of formula (c) is reduced with catalytically activated hydrogen or complex metal hydride.

Formula (b)
wherein M is hydrogen or a metal cation

Formula (c)

IN 177147 discloses process for the manufacturing of Mexiletine via condensation of 2’, 6’-dimethylphenoxy with chloroacetone in methanol and a base such as sodium hydroxide to give the corresponding oxime, which is hydrogenated to give Mexiletine base. This patent also provides process for the preparation of the hydrochloride salt of Mexiletine.

The above processes suffer one or more drawbacks such as use of costly, hazardous reagents. Some process reports low yield whereas other reports low purity. The above processes have large number of steps which increases the overall cost of the production. Therefore, above processes are industrially not suitable.

Consequently, there is a long-felt need for a process for the preparation Mexiletine which not only overcomes the problems in the Prior art processes as mentioned above, but is also safe, cost effective, and industrially feasible.

Thus, an alternative process for the preparation of Mexiletine Hydrochloride of formula (I), which is more direct, higher yield, environmental friendly and applicable to industrial scale production is desirable.

The present invention provides a process for preparing Mexiletine hydrochloride of formula (I) i.e. 1-(2’,6’-dimethylphenoxy)-2-amino-propane hydrochloride and preparation of 1-(2’,6’-dimethylphenoxy)-2-propane oxime of formula (IV). Unexpectedly, the process of present invention overcomes the above mentioned problems and results in good yield and purity of Mexiletine hydrochloride of formula (I).

Object of the invention

Therefore, it is an object of the invention to provide an improved process preparing Mexiletine hydrochloride of formula (I)

Yet another aspect of the present invention provides a process for preparation of compound of formula (III)

Summary of the invention

An aspect of the present invention provides a process for the preparation of Mexiletine hydrochloride of formula (I), comprising the steps of

a) acylating 2,6-dimethylphenol of formula (II) with chloroacetone in the presence of polar aprotic solvent and base to obtain 1-(2,6-dimethylphenoxy)propan-2-one of formula (III);

b) reacting 1-(2,6-dimethylphenoxy)propan-2-one of formula (III) with hydroxylamine hydrochloride in the presence of suitable solvent and base to obtain 1-(2’,6’-dimethylphenoxy)-2-propane oxime of formula (IV);

c) reducing compound of formula (IV) in the presence of reducing agent in alcohol to obtain 1-(2’,6’-dimethylphenoxy)-2-amino-propane (Mexiletine base);

d) treating compound of formula (I)-base in alcoholic hydrochloric acid to obtain compound of formula (I).

Another aspect of the present invention provides a process for the preparation of Mexiletine Hydrochloride of formula (I) comprising a step of acylating 2,6-dimethylphenol of formula (II) with chloroacetone in the presence of polar aprotic solvent, base and hydroxylamine hydrochloride to obtain 1-(2’,6’-dimethylphenoxy)-2-propane oxime of formula (IV).

Yet another aspect of the present invention provides a process for preparation of compound of formula (III) comprising acylating 2,6-dimethylphenol of formula (II) with chloroacetone in the presence of polar aprotic solvent and a base to obtain 1-(2,6-dimethylphenoxy)propan-2-one of formula (III).

Brief description of the drawings

FIG. 1 shows the X-ray powder diffraction pattern of Mexiletine Hydrochloride prepared by the present invention.

Detailed description of the invention

The present invention relates to an improved process of the preparation of 1-(2’, 6’-dimethylphenoxy)-2-amino-propane (Mexiletine) of formula (I).

The term ‘polar aprotic solvent’ as used hereinabove is meant to include but not limited to acetone, ethyl-acetate, acetonitrile, and the like or mixtures thereof. The preferable polar aprotic solvent is acetone.

The term ‘base’ as used hereinabove is meant to include but not limited to potassium hydrogen carbonate, potassium carbonate, sodium carbonate, ammonium carbonate, potassium hydroxide and aluminum hydroxide and the like or mixture thereof. The preferable base is potassium carbonate and sodium carbonate.

The meaning of the term “suitable solvent” as used hereinabove include but not limited to substituted or unsubstituted alcoholic solvent, ketones solvent, halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ester solvent, ether solvent, cyclic ether solvent, nitrile solvent and aqueous solvent or mixture thereof. It also includes polar or nonpolar protic solvent, polar or nonpolar aprotic solvent or mixture thereof.

Suitable solvents include lower alcohols such as methanol, ethanol, isopropanol, propanol, and the like, or mixtures thereof ; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone or mixtures thereof; nitriles such as acetonitrile, benzonitrile or mixtures thereof; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, ethylene dichloride or mixtures thereof; aromatic hydrocarbon solvent such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl toluene, xylene, cumene (isopropylbenzene), pseudo cumene (1,2,4-trimethylbenzene); polar aprotic solvents such as dimethylsulphoxide, dimethylacetamide, dimethylformamide or mixtures thereof; esters such as ethyl acetate, ethyl formate, methyl formate, methyl acetate, n-propyl acetate, isopropyl acetate or mixtures thereof; cyclic ethers such as dioxane, tetrahydrofuran or mixtures thereof. The preferable suitable solvent is toluene.

The meaning of the term “alcohol” as used hereinabove include but not limited to such as methanol, ethanol, isopropanol and the like or mixtures thereof. The preferable alcohol is methanol.

The term “alcoholic hydrochloride” used hereinabove is meant to include but not limited to a solution of Hydrochloride with alcohol which is selected from group of methanol, ethanol, isopropanol and the like or mixtures thereof. The preferable alcohol is methanol.

The term “reducing agent” for the reducing step is preferably a metal catalyst, and is most preferably selected from the group comprising of metal catalysts for example Raney nickel, copper, iron, cobalt, ruthenium, rhodium, palladium, osmium, iridium and platinum or mixtures thereof, wherein catalysts with a catalytically active amount raney nickel is particularly preferred

According to the present invention process for preparation of Mexiletine hydrochloride of formula (I), comprising the steps of

comprising steps of:
a) acylating 2,6-dimethylphenol of formula (II) with chloroacetone in the presence of polar aprotic solvent and base to obtain 1-(2,6-dimethylphenoxy)propan-2-one of formula (III);

b) reacting 1-(2,6-dimethylphenoxy)propan-2-one of formula (III) with hydroxylamine hydrochloride in the presence of suitable solvent and base to obtain 1-(2’,6’-dimethylphenoxy)-2-propane oxime of formula (IV);

c) reducing compound of formula (IV) in the presence of reducing agent in alcohol to obtain 1-(2’,6’-dimethylphenoxy)-2-amino-propane (Mexiletine base);

d) treating compound of formula (I)-base in alcoholic hydrochloric acid to obtain compound of formula (I).

Another aspect of the present invention provides a process for the preparation of Mexiletine Hydrochloride of formula (I) comprising a step of acylating 2,6-dimethylphenol of formula (II) with chloroacetone in the presence of polar aprotic solvent, base and hydroxylamine hydrochloride to obtain 1-(2’,6’-dimethylphenoxy)-2-propane oxime of formula (IV).

Yet another aspect of the present invention provides a process for preparation of compound of formula (III) comprising acylating 2,6-dimethylphenol of formula (II) with chloroacetone in the presence of polar aprotic solvent and a base to obtain 1-(2,6-dimethylphenoxy)propan-2-one of formula (III).

A preferred embodiment of the present invention is shown in the scheme-I

2,6-dimethylphenol of formula (II) was acylated with chloroacetone in the presence of polar aprotic solvent and base; wherein polar aprotic solvent was selected from group comprising of acetone, ethyl-acetate, acetonitrile, or mixtures thereof, preferably acetone. Base was selected from group comprising of potassium hydrogen carbonate, potassium carbonate, sodium carbonate, ammonium carbonate, potassium hydroxide and aluminum hydroxide, and or mixtures thereof, preferably sodium carbonate. The reaction was carried out at a temperature of about 20° to about 40°C, preferably at about 25° to 30°C. 1-(2,6-dimethylphenoxy)propan-2-one of formula (III) solid residue was isolated and washed with acetone. Toluene was charged to reaction mass and than distilled out from reaction mass under vacuum at about 50-55°C.

Residues of 1-(2,6-dimethylphenoxy)propan-2-one of formula (III) was reacted with hydroxylamine hydrochloride at temperature of about 15-30°C in the presences of suitable solvent and a base to obtain 1-(2’,6’-dimethylphenoxy)-2-propane oxime of formula (IV). The suitable solvent was selected from group comprising of substituted or unsubstituted alcoholic solvent, halogenated hydrocarbon solvent, aromatic hydrocarbon solvent, ester solvent, ether solvent, cyclic ether solvent, nitrile solvent and aqueous solvent or mixtures thereof. It also includes polar or nonpolar protic solvent, or mixture thereof. Preferable suitable solvent is toluene; Base was selected from group comprising of potassium hydrogen carbonate, potassium carbonate, sodium carbonate, ammonium carbonate, potassium hydroxide and aluminum hydroxide, and or mixtures thereof, preferably sodium carbonate. 1-(2’,6’-dimethylphenoxy)-2-propane oxime of formula (IV) was than filtered and washed with toluene, and than toluene was distilled out at about 50-55°C.

1-(2’,6’-dimethylphenoxy)-2-amino-propane (Mexiletine base) was obtained by reducing 1-(2’,6’-dimethylphenoxy)-2-propane oxime of formula (IV) in the presence of reducing agent comprising of metal catalysts for example raney nickel, copper, iron, cobalt, ruthenium, rhodium, palladium, osmium, iridium and platinum or mixtures thereof, wherein catalysts with a catalytically active amount in alcohol; raney nickel was particularly preferred in alcohol wherein alcohol was selected form methanol, ethanol, isopropanol and the like or mixtures thereof, preferably methanol.

Mexiletine base was acidified with alcoholic hydrochloride. Wherein alcoholic hydrochloride is a solution of hydrochloride with alcohol wherein alcohol selected from group of methanol, ethanol, isopropanol or mixtures thereof, preferably methanol. Methanol was distilled out form reaction mass at reflux temperature; acetone was added to the reaction mass. Acetone was distilled out at the reflux temperature. Reaction mass was cooled to about 0-5°C. Solid was filtered at about 0-5°C and washed with chilled acetone. Mexiletine Hydrochloride was dried under vacuum at about 60- 70 °C.

Mexiletine Hydrochloride exhibits an X-ray powder diffraction pattern substantially according to the pattern of FIG. 1 with characteristic peaks expressed in d-values (A°) and in 2θ angles as given in the following Table 1:

Table 1
2θ Angle (degrees) d-spacing (A°)
5.1 17.41
6.4 13.84
9.0 9.81
10.3 8.62
11.8 7.52
12.7 7.00
14.5 6.10
15.1 5.87
15.8 5.62
16.6 5.30
17.5 5.06
18.0 4.92
19.4 4.57
19.9 4.46
20.8 4.27
21.6 4.12
22.2 4.00
22.9 3.89
23.7 3.75
25.1 3.55
25.5 3.49
25.8 3.45
26.4 3.38
27.0 3.30
27.5 3.24
28.3 3.15
28.7 3.12
29.4 3.04
30.3 2.95

The following examples illustrate the invention further. It should be understood however, that the invention is not confined to the specific limitations set forth in the individual example but rather to the scope of the appended claims.

Example 1
Preparation of 1-(2’,6’-dimethylphenoxy)-2-propane oxime

2,6-dimethyl phenol (100g) is dissolved in acetone (500 ml) at 25°-30°C and potassium carbonate(226.2 g) and charge potassium iodide (13.5 g), stir the reaction mass for 15 minutes at 25°-30°C. Add chloroacetone (84.0 g) drop wise in the reaction mass within 1 hour, at 25-30°C. Raise the temperature to 55-65°C and stir the reaction mass at 55-65°C and reflux for 1.5-2.5 hrs. Filter the solid after cooling the reaction mass to 25-30°C. Wash the solid residue with acetone (200ml), distilled out acetone atmospherically and finally under vacuum from filtrate at 45-50°C.

Toluene (200 ml) is charged to reaction mass and than distilled out from reaction mass under vacuum at 50-55°C. Residues are dissolved in toluene (350ml) and 2.5% sodium hydroxide solution (500ml) is added to the solution with stirring. Separate aqueous layer and organic layer. Charge sodium carbonate (130.1 gm) to organic layer and cool reaction mass to 15-20 °C. Add hydroxylamine hydrochloride (56.8 gm) 15-30°C and stir the reaction mass at 25-30°C for 1.5-2.5 hrs. Filter the solid at 15-30°C, wash with toluene, distilled out toluene at 50-55°C.
Yield : 150gm

Example 2
Preparation of Mexiletine base

Dissolve 1-(2’,6’-dimethylphenoxy)-2-propane oxime(100g) in methanol and Raney Ni (10 g) at 25°-30°C. Cool the reaction to 25°-30°C and filter the Raney Ni and wash with methanol (200ml) distil out Methanol form the reaction mass. Wash the product with toluene and than with dichloromethane. Distill out Mexiletine base from reaction mass temperature below 190°C (vapor temperature 120-145°C) under high vacuum (25 mbar).
Yield : 67.5gm

Example 3
Preparation of Mexiletine Hydrochloride

Dissolve Mexiletine base (100g) in methanol, add 15% methanolic Hydrochloride (163 gm) in reaction mass in 30-60 min at 10-20°C. Filter reaction mass through hyflo. Distill out methanol form reaction mass at reflux temperature, cool reaction mass to 45-55°C. Add acetone to reaction mass and distill out acetone at reflux temperature. Cool reaction mass to 0-5°C. Maintain reaction mass at 0-5°C. Filter the solid at 0-5°C Wash solid with chill acetone. Dry solid Mexiletine Hydrochloride under vacuum at 60- 70 °C.
Yield : 92.5gm

We Claim,

1. A process for the preparation of Mexiletine Hydrochloride of formula (I) comprising a step of acylating 2,6-dimethylphenol of formula (II) with chloroacetone in the presence of polar aprotic solvent, base and hydroxylamine hydrochloride to obtain 1-(2’,6’-dimethylphenoxy)-2-propane oxime of formula (IV).

2. A process for the preparation of compound of formula (III) comprising acylating 2,6-dimethylphenol of formula (II) with chloroacetone in the presence of polar aprotic solvent and a base to obtain 1-(2,6-dimethylphenoxy)propan-2-one of formula (III).

3. A process according to claim 1 & 2 wherein said the polar aprotic solvent is selected form group comprising of acetone, ethyl-acetate, acetonitrile or mixtures thereof.

4. A process according to claim 4, wherein said polar aprotic solvent is acetone.

5. A process according to claim 1, 2 & 3, wherein said base is selected form group comprising of potassium hydrogen carbonate, potassium carbonate, sodium carbonate, ammonium carbonate, potassium hydroxide and aluminum hydroxide or mixtures thereof.

6. A process according to claim 6, wherein said base is potassium carbonate, sodium carbonate or mixtures thereof.