Claims:WE CLAIM:

1. An improved process for the preparation of Betahistine of Formula I

Formula I
which comprises:
(i) reacting the 2-(Pyridin-2-yl)ethanol of Formula II;

Formula II

with methane sulfonyl chloride in presence of organic base in non-polar solvent to produce 2-(Pyridin-2-yl)ethyl methanesulfonate of Formula III,

Formula III

(ii) condensing 2-(Pyridin-2-yl)ethyl methanesulfonate (III) with methylamine to produce Betahistine(N-Methyl-2-(pyrididin-2-yl)ethanamine),

(iii) optionally, converting Betahistine to its pharmaceutically acceptable salt.

2. The process according to claim 1, wherein organic base is selected from the group of triethylamine, trimethylamine, pyridine, morpholine and piperazine.
3. The process according to claim 1, wherein the non-polar solvent is selected from the group of toluene, benzene, xylene.

4. The process according to claim 1, wherein the alcoholic solvent is selected from the group of methanol, ethanol, isopropanol, n-propanol, butanol or a mixture thereof.

5. The process according to claim1, wherein the pharmaceutically acceptable salts can be selected from the group of HCl. HBr, CH3SO3H.
, Description:FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Betahistine and its pharmaceutically acceptable salts of Formula I

Formula I

BACKGROUND OF THE INVENTION

Betahistine 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, it is chemically known as N-Methyl-2-(pyrididin-2-yl)ethanamine or N-Methyl-2-pyridineethanamine.

Betahistine was first reported in the Journal of Berichte Der Deutschen Chemischen Gesellschaft, 1904, Volume 37, Issue 1, 161–174. This journal also discloses a process for the preparation of Betahistine, by reacting 2-(2-pyridyl)ethylbromide with methylamine.

Journal of American Chemical Society, Volume 77, 1955, pp – 5434, has reported a process for the preparation of Betahistine by reacting 2-vinylpyridine with methylamine hydrochloride in a molar ratio of 1:1 under reflux conditions.

Preparation of Betahistine by reacting 2-vinylpyridine with methylamine hydrochloride is also reported in Journal of Organic Chemistry, Volume 26, (1961), 3257 and US 3,410,861.

In Journal of Organic Chemistry, Volume 26, (1961), 3257, the reaction is carried out by reacting 2-vinylpyridine with an aqueous solution of methylamine hydrochloride in a molar ratio of 1:2.

US 3,410,861 assigned to Unimed Inc, discloses a process for preparing Betahistine, by reacting 2-vinylpyridine with methylamine hydrochloride in presence of aqueous solution and further extracting the reaction mixture, separating the aqueous phase, and recovering the Betahistine from the separated aqueous phase. Schematically shown in Scheme - 1

Scheme – 1

GB 1 403 476 assigned to Ohta Seiyaku KK, 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.

CN 105175319 A assigned to Jiangsu Baozhong Baoda Pharmaceutical Co., Ltd, discloses a process for preparing Betahistine HCl, by dehydrating 2-hydroxyethylpyridine to prepare 2-vinylpyridine, wherein the dehydrating agent is hydroxide Sodium and anhydrous magnesium sulfate in which sodium hydroxide accounts for 60% by weight of the dehydrating agent and anhydrous magnesium sulfate accounts for 40%; which is further reacted with Monomethylamine in presence of toluene and hydrochloric acid and aqueous solution two-phase reaction system. Schematically shown in Scheme - 2

Scheme – 2

In the above prior-art processes, 2-vinyl pyridine is used as the starting material and is carried out at atmospheric pressure, the temperature of reaction is limited and accordingly, a longer period of time is required for completion of reaction.

IN 1195/CHE/2005 assigned to Aurobindo Pharma, discloses a process for preparing Betahistine, comprise reacting the 2-(Pyridin-2-yl)ethanolwith a sulfonyl chloride in presence of base in an organic solvent to produce 2-pyridineethanol sulfonate, which is further condensed with methylamine to produce Betahistine, which is converted to Betahistine hydrochloride. Schematically shown in Scheme – 3

Scheme – 3
However, this process holds few disadvantages like isolation of mesylate derivative of Formula - III as vinyl pyridine is observed during the distillation. Isolation of Formula I also involves extraction using high volumes of chlorinated solvents.

Hence, it is observed that the prior art process is not suitable from industrial point of view, in required purity and requires purification techniques to remove the unwanted impurities generate. Therefore, there is an urgent need to develop a simple, industrially suitable and cost-effective process for the preparation of Betahistine with high yields and high purity levels.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a simple, economic, effective and industrially feasible process for the preparation of Betahistine and its pharmaceutically acceptable salts with high purity and high yields on a Industrial scale.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of Betahistine of Formula I

Formula I
which comprises:
(i) reacting 2-(Pyridin-2-yl)ethanol of Formula II;

Formula II

with methanesulfonyl chloride in presence of organic base in non-polar solvent to produce 2-(Pyridin-2-yl)ethyl methanesulfonate of Formula III,

Formula III

(ii) condensing 2-(Pyridin-2-yl)ethylmethanesulfonate (III) with methylamine to produce Betahistine (N-Methyl-2-(pyrididin-2-yl)ethanamine),

(iii) optionally, converting Betahistine to its pharmaceutically acceptable salts.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of Betahistine of Formula I

Formula I

2-(Pyridin-2-yl)ethanol is dissolved in the non-polar solvent and an organic base at room temperature and the reaction mixture is cooled to 0-10°C. To this reaction mixture, methane sulfonyl chloride is added dropwise for about 1-4 hr. After completion of reaction, water was added to the reaction mixture and stirred, the organic layer is separated to produce 2-(Pyridin-2-yl)ethyl methanesulfonate (III), which is directly condensed with methylamine in an aqueous medium at a temperature of about 20-35°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 hydroxide flakes and separated the layers to produce Betahistine (I).
Optionally, Betahistine is converted to its pharmaceutically acceptable salts in presence of an alcoholic solvents selected from methanol, ethanol or isopropanol.

The process is schematically represented as follows:

According to the first embodiment of the present invention, the organic base is selected from the group of triethylamine, trimethylamine, pyridine, morpholine and piperazine.

According to the second embodiment of the present invention, the non-polar solvent is selected from the group of toluene, benzene, xylene.

According to the other embodiment of the present invention, the alcoholic solvent is selected from the group of methanol, ethanol, isopropanol, n-propanol, butanol or a mixture thereof.

According to another embodiment of the present invention, the pharmaceutically acceptable salts can be selected from the group of HCl, HBr and CH3SO3H.

This improved process hold few advantages over the prior art like 2-(Pyridin-2-yl)ethyl methanesulfonate (III) in toluene is not distilled and carried to the next stage. And this step will avoid the formation of vinyl pyridine an impurity which, effects the yield of the product. And the Betahistine is isolated using sodium hydroxide flakes, hence no need of extraction stage, which makes this process cost effective and industrially feasible due less usage of the operational capacity.

And Betahistine is isolated and used directly (without purification by high vacuum distillation) for the process of Betahistine dihydrochloride (Example 2).
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

The present invention can be illustrated in one of its embodiment by the following non- limiting examples.

EXAMPLE 1
Preparation of N-Methyl-2-(pyrididin-2-yl)ethanamine dihydrochloride:

240.0 g of 2-(Pyridin-2-yl)ethanol (1.95 mol) was dissolved in 635 mL of toluene and 240 g of triethylamine (2.37 mol) at 24-30oC. Then the reaction mixture was cooled to 0-5oC and 250 g of methanesulfonyl chloride (2.18 mol) was added dropwise under N2 atmosphere at below 12oC for 2 h. The reaction mixture was left to 24-30oC. After completion of the reaction, 240 mL of DM water was charged and stirred for 15 min. The toluene layer was then separated and extracted from the aqueous layer with toluene (2 X 240 mL). The toluene layers was washed with DM water (2 X 60 mL). The obtained toluene layer was carried to the next step without any isolation.
The toluene layer obtained from the previous step was added to the pre-cooled aqueous layer of 985 g methylamine at 0-5oC. Then the reaction mixture was stirred at 24-32oC for 3 h. After completion of the reaction, the toluene aqueous layer was separated. To the aqueous layer 400 g of sodium hydroxide was charged at 33-43oC under vacuum and the layers were settled in 30 min. The product layer was separated from aqueous layer. To the aqueous layer 400 g of sodium hydroxide was charged at room temperature under vacuum and the layers were settled in 30 min. The obtained N-Methyl-2-(pyrididin-2-yl)ethanamine layers from 2 lots were mixed. The crude product was purified using high vacuum distillation at 95-100oC to get N-Methyl-2-(pyridin-2-yl)ethanamine as light yellow to colourless liquid.
N-Methyl-2-(pyridin-2-yl)ethanamine (170.0 g, 1.25 mol) was charged to isopropyl alcohol (588 mL) and decolorized with active carbon and the solution was filtered to obtain a colourless solution. The pH of this colourless solution was adjusted to 1-2 with 464 g of 20% isopropyl alcohol hydrochloride (IPA. HCl,) and stirred under nitrogen atmosphere 3 h. The obtained solid was filtered and washed with isopropyl alcohol. The solid (Betahistine dihydrochloride technical grade) was further purified in methanol/Isopropyl alcohol and dried at 55oC to get 230 g Betahistine dihydrochloride as a white solid in high purity of 99%.

EXAMPLE 2
Preparation of N-Methyl-2-(pyrididin-2-yl)ethanamine dihydrochloride:

240.0 g of 2-(Pyridin-2-yl)ethanol (1.95 mol) was dissolved in 635 mL of toluene and 240 g of triethylamine (2.37 mol) was charged at 24-30oC. Then the reaction mixture was cooled to 0-5oC and 250 g of methanesulfonyl chloride (2.18 mol) was added dropwise under N2 atmosphere at below 12oC for 1.5 h. The reaction mixture was left at 24-30oC. After completion of the reaction, 240 mL of DM water was charged and stirred for 15 min. The toluene layer was then separated and extracted from the aqueous layer with toluene (2 X 240 mL). The toluene layers was washed with DM water (2 X 60 mL). The obtained toluene layer was carried to the next step without any isolation.
The toluene layer obtained from the previous stage was added to the pre-cooled aqueous layer of 960 g methylamine at 0-5oC. Then the reaction mixture was stirred at 24-32oC for 3 h. After completion of the reaction, the toluene aqueous layer was separated. To the aqueous layer 400 g of sodium hydroxide was charged at 33-43oC under vacuum and the layers were settled in 30 min. The product layer was separated from aqueous layer. To the aqueous layer 400 g of sodium hydroxide was charged at room temperature under vacuum and the layers were settled in 30 min. The obtained N-Methyl-2-(pyrididin-2-yl)ethanamine layers from 2 lots were mixed. The crude product was purified using high vacuum distillation at 95-100oC to get N-Methyl-2-(pyridin-2-yl)ethanamine as light yellow to colourless liquid.
N-Methyl-2-(pyridin-2-yl)ethanamine (170.0 g, 1.25 mol) was charged to isopropyl alcohol (588 mL) and decolorized with active carbon and the solution was filtered to obtain a colourless solution. The pH of this colourless solution was adjusted to 1-2 with 460 g of 20% isopropyl alcohol hydrochloride (IPA. HCl,) and stirred under nitrogen atmosphere 3 h. The obtained solid was filtered and washed with isopropyl alcohol. The solid (Betahistine dihydrochloride technical grade) was further purified in DM water/Isopropyl alcohol and dried at 65oC to get 228 g Betahistine dihydrochloride as a white solid in high purity of 99.5%.

EXAMPLE 3
Preparation of N-Methyl-2-(pyrididin-2-yl)ethanamine dihydrochloride

100.0 g of 2-(Pyridin-2-yl)ethanol (0.81 mol) was dissolved in 450 mL methylene dichloride and 100 g of triethylamine (0.98 mol) was charged at 24-30oC. Then the reaction mixture was cooled to 0-5oC and 105 g of methanesulfonyl chloride (0.92 mol) was added dropwise under N2 atmosphere at below 5oC for 2 h. The reaction mixture was left at 24-30oC. After completion of the reaction, 300 mL of DM water was charged and stirred for 10 min. The methylene dichloride layer was separated and extracted from the aqueous layer with methylene dichloride (2 X 50 mL). The methylene dichloride layer was washed with DM water (2 X 50 mL). The obtained methylene dichloride layer was used for next step without isolation.
The methylene dichloride (MDC) layer obtained from the previous stage was added to the pre-cooled aqueous layer of 885 g of methylamine at 0oC. Then the reaction mixture was stirred at 24-32oC for 9 h. After completion of the reaction, MDC was distilled under vacuum below 40oC for 4 h. To the aqueous layer 170 g of sodium hydroxide was charged at 33-43oC under vacuum and the layers were settled in 30 min. The product layer was separated from aqueous layer. To the aqueous layer 150 g of sodium hydroxide was charged at room temperature under vacuum and the layers were settled in 30 min. The obtained N-Methyl-2-(pyrididin-2-yl)ethanamine layers from 2 lots were mixed. The crude product was purified using high vacuum distillation at 95-100oC to get N-Methyl-2-(pyridin-2-yl)ethanamine as light yellow to colourless liquid.
N-Methyl-2-(pyridin-2-yl)ethanamine (70.0 g, 0.52 mol) was charged to isopropyl alcohol (250 mL) and decolorized with active carbon and the solution filtered. The pH of this colourless solution was adjusted to 1-2 with 226 g of 20% isopropyl alcohol hydrochloride (IPA. HCl,) and stirred under nitrogen atmosphere 3 h. The obtained solid was filtered and washed with isopropyl alcohol. The solid (betahistine dihydrochloride technical grade material) was further purified in methanol/Isopropyl alcohol or DM water/Isopropl alcohol mixture, dried at 60-55oC to 70 g Betahistine dihydrochloride white solid in high purity of 90%.

EXAMPLE 4
Preparation of N-Methyl-2-(pyrididin-2-yl)ethanamine Mesylate

170.0 g of N-Methyl-2-(pyridin-2-yl)ethanamine (1.25 mol) from the example 3 was mixed with 910 litres of isopropyl alcohol and decolorized with activated charcoal at 25-35°C and filtered through leaf. The clear solution was charged with 255 g of methane sulphonic acid (2.65 mol) at 25-30oC under stirring. The obtained solid was filtered under nitrogen atmosphere and washed with isopropyl alcohol. The obtained solid was again dissolved in 1450 mL of Isopropyl alcohol at 75-85oC, cooled to 25-35oC, maintained for 2 h and centrifuged. The filtered solid was dried at 60-65oC to get Betahistine mesylate as a white solid.