AN IMPROVED PROCESS FOR THE PREPARATION OF BETAHISTINE HYDROCHLORIDE
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of N-methyl-2-pyridineethanamine of Formula I
Formula I
BACKGROUND OF THE INVENTION
N-Methyl-2-pyridineethanamine is generically known as Betahistine. It is a histamine agonist, which improves the microcirculation of the labyrinth resulting in reduced endolymphatic pressure. Betahistine is indicated for the treatment of vertigo and Menieres diseases.
Ber. 37, (1904), 161, reported a process for the preparation of Betahistine, by reacting 2-(2-pyridyl)ethyl bromide with methylamine. The process is as shown in Scheme-I below:
Scheme I:

Journal Of American Chemical Society, 77(1955), 5434 reported a process for the preparation Betahistine by reacting 2-vinylpyridine with methylamine hydrochloride in a molar ratio of 1:1 under reflux conditions. The process is as shown in Scheme-II below:

Scheme II:

2-Vinylpyridine
Further, similar processes have been reported in Journal Of Organic Chemistry, 26(1961), 3257 and US 3,410,861. In Journal Of Organic Chemistry, 26(1961), 3257, the above reaction is carried out using an aqueous solution of methylamine hydrochloride in a molar ratio of 1:2, whereas in US 3,410,861, reaction is carried out in presence of isopropanol.
In the above prior-art processes, methylamine hydrochloride is used as the starting material and is reacted with vinyl pyridine while heating under reflux conditions. The above processes are carried out at atmospheric pressure, the temperature of reaction is limited and accordingly, a longer period of time is required for completion of reaction.
To overcome this problem, GB 1 403 476 discloses a different process, which involves reaction of 2-vinylpyridine with methylamine in presence of carboxylic acid and aqueous medium to produce Betahistine. The main disadvantage with the above process is the usage of 2-vinylpyridine, which tends to undergo polymerization in more acidic and basic medium and needs to be stored in cold conditions.
In the instant invention, it has been found that the reaction of 2-pyridineethanol methanesulfonate or p-toluenesulfonate of Formula II with methylamine in presence of solvent requires less reaction time and controls the formation of undesired degradation by-products in Betahistine.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a simple, effective and industrially feasible process for the preparation of Betahistine hydrochloride with high purity and good yields on a commercial scale.
SUMMARY OF THE INVENTION
Accordingly, the present invention relates to an improved process for the preparation of N-methyl-2-pyridineethanamine (Betahistine) of Formula I,
Formula I
which comprises :
(i) reacting the 2-pyridineethanol of Formula II;
Formula II
with a sulfonyl chloride in presence of base in an organic solvent to produce 2-pyridineethanol sulfonate of Formula III,
Formula III wherein R is methyl or p-toluoyl;
(ii) condensing 2-pyridineethanol sulfonate (III) with methylamine to produce N-methyl-2-pyridineethanamine (Betahistine) of Formula I;
(iii) converting Betahistine (I) to Betahistine hydrochloride.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of N-methyl-2-pyridineethanamine (Betahistine) (I).
2-Pyridinneethanol is reacted with sulfonyl chloride selected from methane sulfonyl chloride or p-toluenesulfonyl chloride in presence of base selected from organic amine such as triethylamine in an organic solvent selected from chlorinated hydrocarbons such as dichloromethane. The reagent addition is at a temperature of about 0-10°C, and the further reaction is carried out at a temperature of about 20-30°C for about 1-4 hrs, preferably 2 hrs. After completion of reaction, as ascertained by the known detection methods such as TLC, the reaction mass is filtered to remove organic amine salts, the filtrate obtained is washed with aqueous basic solution selected from dilute sodium bicarbonate solution and the organic layer is separated and distilled to produce 2-pyridineethanol sulfonate (III) as an oily liquid.
2-Pyridineethanol sulfonate (III) is condensed with methylamine in an aqueous medium at a temperature of about 20-30°C for about 2-4 hrs. After completion of reaction, as ascertained by the known detection methods such as TLC, the reaction mass is saturated with sodium chloride solution and extracted with an organic solvent selected from dichloromethane, which is further distilled out to produce N-methyl-2-pyridineethanamine (Betahistine) (I).
N-Methyl-2-pyridineethanamine (I) is converted to its hydrochloride salt in presence of hydrogen chloride in an alcoholic solvent selected from methanol, ethanol or isopropanol.
The following examples to prepare Betahistine hydrochloride illustrate the nature of the invention and are provided for illustrative purpose only and should not be construed to limit the scope of the invention

Example 1
Preparation of N-methyl-2-pyridineethanamine dihydrochloride
2-Pyridineethanol (25 g, 0.20 mol) was dissolved in dichloromethane (75 ml) and triethylamine (24.63 g, 0.24 moles) was added. The reaction mixture was cooled to 0-5°C and methanesulfonyl chloride (25.6 g, 0.22 mol) was added dropwise. The reaction mixture was gradually warmed to 20-25°C and stirred for 2 h. the solid triethylamine hydrochloride was filtered off and the filtrate was washed with saturated sodium bicarbonate solution (50 ml) and dichloromethane layer was concentrated to produce 2-pyridineethanol methane sulfonate ester as an oily liquid.
2-Pyridineethanol methane sulfonate ester obtained by the above method was added to the previously cooled aqueous solution of methylamine (-36%) (262.5 g, 3 mol) in 45 minutes at 0-5°C. The reaction mixture was allowed to attain 20-25°C and stirred for 4 h, which was then saturated with sodium chloride (50 g) and extracted with dichloromethane (4x 75 ml). The combined dichloromethane layer was concentrated and the resultant crude product was purified by distillation at 60-65 °C /l mm Hg to produce N-methyl-2-pyridineethanamine as a pale yellow oil. N-Methyl-2-pyridineethanamine was further treated with hydrogen chloride gas in ethanol at 0-5°C to produce N-methyl-2-pyridineethanamine dihydrochloride (24.6 g, HPLC purity >99.7%).
Example 2
Preparation of N-methyl-2-pyridineethanamine dihydrochloride
2-pyridineethanol (l0g, 0.08 mol) was dissolved in dichloromethane (50 ml) at 25-30°C followed by the addition of triethylamine (9 g, 0.09 mol). The solution was cooled to 0-5°C and p-toluenesulfonyl chloride (17 g, 0.09mol) was added in portions at the 0-5°C in about 30 min. The reaction mixture was stirred for 7hrs, washed with saturated sodium bicarbonate solution (20 ml) and the organic layer was concentrated and added to a solution of-36% aqueous methylamine solution (105 g, 1.22 mol) at 5-10°C in 10 min. After completion of reaction, sodium hydroxide (3.6 g) and sodium chloride (20 g) were added and stirred. The reaction mixture was extracted with dichloromethane (4

x 30 ml) and the organic layer was concentrated. The crude liquid was distilled at 52-54°C / 0.6 mm Hg to obtained Betahistine (4 g). It was dissolved in ethanol and converted into hydrochloride with hydrogen chloride gas to produce N-methyl-2-pyridineethanamine dihydrochloride as a white solid (3.3 g).

WE CLAIM:
1. A process for the preparation of N-methyl-2-pyridineethanamine (Betahistine) of Formula I,
Formula I which comprises :
(i) reacting the 2-pyridineethanol of Formula II;
Formula II
with a sulfonyl chloride in presence of base in an organic solvent to produce 2-pyridineethanol sulfonate of Formula III,
Formula HI wherein R is methyl or p-toluoyl;
(ii) condensing 2-pyridineethanol sulfonate (III) with methylamine to produce N-methyl-2-pyridineethanamine (Betahistine) of Formula I;
(iii) converting Betahistine (I) to Betahistine hydrochloride.
2. The process according to claim 1, wherein sulfonyl chloride is methanesulfonyl chloride or p-toluenesulfonyl chloride.
3. The process according to claim 1, wherein base is organic amine.
4. The process according to claim 3, wherein organic amine is triethylamine.

5. The process according to claim 1, wherein organic solvent is selected from chlorinated hydrocarbon.
6. The process according to claim 5, wherein chlorinated hydrocarbon is dichloromethane.
7. The process according to claim 1, wherein conversion of Betahistine to betahistine hydrochloride is performed in presence of hydrochloride in ethanol or methanol.