Claims:1. A process for preparation of highly pure Betahistine comprising:
a) reacting 2-(pyridin-2-yl)ethanol with a chlorinating agent in a suitable organic solvent to obtain 2-(2-chloroethyl)pyridine;
b) reacting 2-(2-chloroethyl)pyridine with aq. Methylamine in presence of acetic acid at pH 6.8-6.9 to obtain Betahistine base;
c) extracting the Betahistine base into toluene by adjusting the pH with a base in the range of 12.5-13.0 and
d) optionally converting the Betahistine base into Betahistine dihydrochloride using IPA/HCl.
2. The process as claimed in claim 1, wherein, the chlorinating agent is selected from thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, sulfuryl chloride.
3. The process as claimed in claim 1, wherein, the chlorinating agent is thionyl chloride.
4. The process as claimed in claim 1, wherein, the suitable organic solvent in step a) is selected from hydrocarbon solvents including but not limited to toluene, xylene or chlorinated hydrocarbon solvents including but not limited to methylene dichloride, ethylene dichloride, chloroform.
5. The process as claimed in claim 1, wherein, the chlorination reaction in step a) is carried out at ambient temperature and the reaction of step b) is carried out at temperature of 50 to 90°C.
6. The process as claimed in claim 1, wherein, the molar ratio of (2-(2-chloroethyl) pyridine) to aq. Methylamine is 1:1.5 to 1:2.
7. The process as claimed in claim 1, wherein weight ratio of (2-(2-chloroethyl)pyridine) to acetic acid required to adjust the pH in range of 6.8-6.9 is 1:1.5 to 1:3.
8. The process as claimed in claim 1, wherein, the base in step c) is an alkali and alkaline earth metal hydroxides or carbonates selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate or calcium carbonate.
9. The process as claimed in claim 1, wherein, the highly pure Betahistine is obtained by the following steps;
a) reacting 2-(pyridin-2-yl)ethanol with thionyl chloride in a suitable solvent to obtain 2-(2-chloroethyl)pyridine;
b) reacting 2-(2-chloroethyl)pyridine with aq. Methylamine in presence of acetic acid at pH 6.8-6.9 to obtain Betahistine base;
c) extracting the Betahistine base using toluene by adjusting the pH with a base in the range of 12.5-13.0; and
d) optionally converting the Betahistine base into Betahistine dihydrochloride using IPA/HCl.
10. The process as claimed in claim 9, wherein, the suitable solvent in step a) is methylene dichloride and the base in step c) is sodium hydroxide.
, Description:Technical filed:
The present invention relates to an improved process for preparation of Betahistine. More particularly, the present invention relates to an efficient industrial process for the preparation of highly pure Betahistine that eliminates the use of 2-vinylpyridine and 2-ethynylpyridine, as starting materials.

Background and Prior art:
Betahistine is an anti-vertigo medication. It is commonly prescribed for balance disorders or to alleviate vertigo symptoms associated with Ménière's disease.
Chemically, Betahistine is known as N-methyl-2-(pyridin-2-yl)ethanamine of formula (I).

A number of processes are known in the literature for preparing Betahistine and its salts. Preparation of Bestahistine from 2-Vinylpyridine and methylamine hydrochloride has been described in J. Am. Chem. Soc. 1955, 77, 5434-6and Journal of Organic Chemistry 1961, 26, 3257-60.US3410861A describes similar process in the presence of isopropyl alcohol (IPA) (Scheme-I).

Scheme-I
All these processes suffer from the drawback that 2-vinylpyridine is extremely susceptible to polymerization under acidic or basic conditions thereby decreasesoverall yield and purity of the final product.
To prevent the polymerization of 2-vinylpyridine and to achieve a higher yield of Betahistine, GB1403476A suggests use of lower carboxylic acids such as acetic and propionic acid with methylamine. However, the process requires reaction at superatomic pressure in an autoclave and a very high temperature above 100oC, which makes it industrially less feasible.
All the above processes involve use of 2-Vinylpyridine which polymerizes during storage even after the addition of polymerization inhibitor as well as under acidic/basic conditions, which is a major drawback.

Preparation of Betahistine from 2-ethynylpyridine and methylamine hydrochloride in presence of sodium cyanoborohydride is described in Chemical & Pharmaceutical Bulletin 1984, 32(12), 4866-72. Sodium cyanoborohydride is costly and hazardous. Further, preparation of 2-ethynylpyridine is tedious and requires use of costly trimethylsilylacetylene as a reagent (Scheme-II).

Scheme-II

Use of NiCuFeO catalyst for preparing Betahistine from 2-(pyridin-2-yl)ethanamine has been described in Chemistry-A European Journal, 2013, 19(11), 3665-3675. The process is not industrially viable (Scheme-III) due to longer reaction time of 24 hrs.

Scheme-III
CN105175319A discloses a method for preparation of Betahistine employing 2-methylpyridine, as a starting material. This method involves multistep synthesis viz., an addition reaction of 2-methylpyridine with formaldehyde in an autoclave at 120-125° C to obtain 2-hydroxyethyl pyridine followed by dehydration of the 2-hydroxyethyl pyridine in presence of NaOH/MgSO4 to obtain 2-vinyl pyridine, a condensation reaction of 2-vinyl pyridine with methylamine hydrochloride to obtain Betahistine(Scheme IV).

Scheme IV
The synthesis disclosed in Scheme IVagain involves high temperature reaction and hence is not energy efficient; lower yields due to polymerization of 2-vinyl pyridine and hence industrially not applicable.

Another modified method for obtaining Betahistine hydrochloride is disclosed in Journal of Serbian Chemical Society 62(6):455. The synthesis involves four steps; condensation of paraformaldehyde and 2-methylpyridine at 130-135°C to obtain 2-(2-pyridyl)ethanol; dehydration of 2-(2-pyridyl)ethanol with acetic anhydride under refluxto obtain 2-vinylpyridine followed by condensation with methyl amine to give Betahistine. Betahistine thus obtained is finally converted into Betahistine hydrochloride by reacting with gaseous hydrochloride in absolute ethanol(Scheme V).

The synthesis disclosed in scheme V also involves high temperature reaction and hence is not suitable for industrial scale up and further lower yields due to polymerization of 2-vinyl pyridine under acidic reaction conditions.

Scheme V

A further method is reported by Ivano, I. C. et al in Archiv der Pharmazie 322 (1989) 181-182. This article reports one-pot synthesis of Betahistine from 2-pyridineethanol and methylamine hydrochloride. This reaction involves in-situ preparation of 2-vinylpyridine from 2-pyridineethanol to minimize the polymerization of 2-vinylpyridine. However, this method also yields Betahistine, with moderate yields of about 60%(Scheme VI).

Scheme VI

A cursory review of the above literature reveals that there are many disadvantages involved in adopting the methods known in the art viz.,
(i) 2-vinylpyridine and 2-ethynylpyridine raw materials are not readily available.
(ii) 2-vinylpyridine undergoes polymerization during storage and under acidic and basic reaction conditions and thus results in Betahistine with poor quality.
(iii) Use of costly and hazardous reagents such as trimethylsilylacetylene, sodium cyanoborohydride, etc.
(iv) Requirement of higher pressure and temperature which is difficult to maintain for the production on industrial scale.
(v) Lengthy and tedious process steps and hence is notsuitable for industrial point of view.
(vi) Lower yields and lower purity due to polymerization of 2-vinylpyridine and other side reactions because of lack of optimization of the reaction conditions reported.

In view of the above, there is a need in the art to provide an efficient and cost-effective process for preparation of Betahistine with good yields and high purity. Therefore, the objective of the instant invention is to provide an efficient and economic process for preparation of highly pure Betahistine which is simple, economic, involves use of readily accessible raw materials and devoid of expensive hazardous reagents that can be industrially scalable.

Summary of the invention:
In line with the above, the present invention provides a simple, economic and industrial process for preparation of Betahistine that involves use of readily accessible raw materials and devoid of expensive hazardous reagents.
Accordingly, in one aspect, the invention provides a process for preparation of highly pure Betahistine which comprises;
a) Chlorinating 2-(pyridin-2-yl)ethanol with a chlorinating agent to obtain 2-(2-chloroethyl)pyridine;
b) reacting 2-(2-chloroethyl)pyridine with aq. Methylamine in presence of acetic acid at pH 6.8-6.9 to obtain Betahistine base;
c) extracting the Betahistine base into an organic solvent by adjusting the pH with a base at 12.5-13.0; and
d) optionally converting the Betahistine base to Betahistine dihydrochloride using IPA/HCl.

In an aspect, the chlorinating agent may be selected from the group consisting of thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, sulfuryl chloride. In one preferred embodiment, the chlorinating agent is thionyl chloride. The chlorination reaction may be conveniently conducted at ambient temperature for 2 to 5 hrs. Theambient temperature may be construed for the purpose of invention as a temperature range of 20 to 30°C.

In an aspect, the condensation reaction of 2-(2-chloroethyl)pyridinewith aq. Methylaminein presence of acetic acid may be conveniently conducted at temperature of 50 to 90°C for 5 to 10hrs. The Betahistine thus obtained is extracted into an organic solvent by adjusting the pH in the range of 12.5-13.0 using a base selected from alkali and alkaline earth metal hydroxides or carbonates. The alkali and alkaline earthmetal hydroxides or carbonates are selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate.

The Betahistine thus obtained may be converted into its dihydrochloride salt.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the appended examples and claims.

Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The present invention provides a simple, economic and industrial process for preparation of highly pure Betahistine which process comprises;
a) Chlorinating 2-(pyridin-2-yl)ethanol with a chlorinating agent to obtain 2-(2-chloroethyl)pyridine;
b) reacting 2-(2-chloroethyl)pyridine with aq. Methylamine in presence of acetic acid at pH 6.8-6.9 to obtain Betahistine base;
c) extracting the Betahistine base using an organic solvent by adjusting the pH with a base at 12.5-13.0; and
d) optionally converting the Betahistine base to Betahistine dihydrochloride using IPA/HCl.
The synthetic method according to the present invention is shown in reaction scheme VII.

Scheme VII
The chlorination of 2-(pyridin-2-yl)ethanol is conducted using suitable chlorinating agent in an organic solvent for a period of 2 to 5 hrs at a temperature of 20-30°C. The addition of chlorinating agent may be performed over a period of 2 to 3 hrs under constant stirring for uniform mixing of the mass. After the completion of addition, the reaction mass is further stirred for an additional 2 to 3 hrs at 25-30°C. After the completion of the reaction(monitored by TLC), the organic solvent is distilled under reduced pressure to obtain 2-(2-chloroethyl)pyridine as an oily mass.
The chlorinating agent for the chlorination of 2-(pyridin-2-yl)ethanol can be selected from the group consisting of thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, sulfuryl chloride.

In one preferred embodiment, the chlorinating agent is thionyl chloride.
The chlorination reaction may be conveniently conducted at ambient temperature for 2 to 6 hrs.

The oily mass (2-(2-chloroethyl)pyridine) is washed with aq. base and further taken up for subsequent condensation reaction with aq. methylamine solution in presence of acetic acid.

In an embodiment, the molar ratio of (2-(2-chloroethyl)pyridine) to aq. Methylamine is 1:1.5 to 1:2. In a preferred embodiment, the ratio of (2-(2-chloroethyl)pyridine) to aq. Methylamine is 1:1.7. Similarly in another embodiment, weight ratio of (2-(2-chloroethyl)pyridine) to acetic acid required to adjust the pH in range of 6.8-6.9 is 1:1.5 to 1:3.

The condensation reaction is preferably carried out at near neutral pH in range of 6.8-6.9 at 50 to 90°C for 5 to 10 hours.The pH of 6.8-6.9 is critical for the completion of the reactionas well as for minimization of side-reaction/impurities’formation and the extraction of the Betahistine using an organic solvent at a pH range of 12.5-13.0 is also critical to reduce the Betahistine dimer impurity C in the final product.

This feature was surprisingly found by the present inventors that the reaction of 2-(2-chloroethyl)pyridine with aq. methylamine in presence of acetic acid at pH 6.8-6.9 followed by extraction with suitable organic solvent in the pH range of 12.5-13.0 minimizes the formation of Betahistine dimer impurity (C) drastically and provides Betahistine in excellent yields.

Accordingly, in an aspect, the Betahistine is extracted into suitable organic solvent by adjusting the pH in the range of 12.5-13.0 using a base selected from alkali and alkaline earth metal hydroxides or carbonates. The alkali and alkaline earth metal hydroxides or carbonates may be selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate or calcium carbonate. In one preferred embodiment, the base is sodium hydroxide.

Although, any suitable organic solvent that can be used for the extraction of Betahistine in the pH range of 12.5-13.0, however, Toluene was found to be best suitable for extraction over other non-polar solvents viz. Chloroform, Methylene dichloride (MDC) etc. The extraction of Betahistine oily base with solvents such as MDC or Chloroform is observed to pose a problem in organic layer separation while isolating the oily base. Further, the purity of the product is alsodependent on pHduring extraction and at pH lower or higher than the preferred range of 12.5-13.0, the layer separation as well as isolation becomes difficult and purity also decreases.

A comparative account of effect of different acids, pH for the condensation process of step b) and different solvents for extraction of Betahistine of step c) on formation of impurity C content is provided in table 1.
Table 1:
Acid pH (step-b) Solvent for Extraction Impurity C
HCl 7.2 Toluene 15.9%
HCl 5.5 Chloroform 17.2%
HCl 7.5 MDC 16.4%
HCl 6.8 Toluene 14.3%
H2SO4 7.1 MDC 26.7%
H2SO4 6.9 Toluene 24.5%
CH3COOH 6.8 Toluene 2.33%
CH3COOH 7.2 Toluene 5.05%
CH3COOH 7.1 MDC 7.31%

In yet another aspect, the Betahistine thus obtained may be converted into its pharmaceutical salt such as dihydrochloride. According to this aspect, Betahistine is taken in isopropyl alcohol and treated with IPA/HCl. The pH of the reaction mass is adjusted to 2.0-2.5 under inert atmosphere at a temperature of 50-70°C under constant stirring to obtain Betahistine dihydrochloride, which is centrifuged under nitrogen and further washed with IPA.

Thus the present invention successfully achieved Betahistine in higher yields of upto 95% and above which the prior art methods fail to provide. Moreover, the process of the present invention achieves Betahistine with high purity and with lower amount of Betahistine dimer (Impurity C). Further, the process is totally devoid of readily unavailablematerials such as 2-vinylpyridine and 2-ethynylpyridine; costly and hazardous reagents such as trimethylsilylacetylene, sodium cyanoborohydride, etc. and hence is cost effectiveso that easier to scale up for industrial production.

Additionally, the process is energy efficient as there is no requirement for high temperature reactions in the entire process steps of Betahistine provided in the present invention.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Example-1:
Preparation of Betahistine Base:
To a 500 mL round bottomed flask equipped with mechanical stirrer, 2-(pyridin-2-yl)ethanol (38 g) and Methylene dichloride (45 mL) were charged and cooled. To this flask, thionyl chloride (48 g) was added slowly with stirring during the period of 2-3 hours at 20-30°C and the resulting mass was stirred for 2 hours at 25-30°C. After the reaction was complete, Methylene dichloride was distilled out at 35-40°C under vacuum. The resulting oily mass was washed with aq. Na2CO3 solution. The oily mass (42.2 g) and aq. Monomethylamine solution (20%, 78.6 g) were charged in a clean assembly. Acetic acid was added to this mixture till the pH 6.8-6.9 (65 g was required) and the reaction mass was heated at 70°C for 7 hours. The resulting mass was cooled. Toluene and sodium hydroxide flakes were added till the pH 12.5-13.0. The resulting mass was stirred for 1 hr. and organic layer was separated. Toluene was distilled to get the Betahistine base as an oil.
Yield: 95%
Purity by HPLC: 96%
Betahistine dimer impurity: 2.33%

Example 2:
The preparation of Betahistine was performed by reacting 2-(2-chloroethyl)pyridine with aq. Methylamine in presence of HCl, H2SO4 acids at various pH range of 5.5.-7.5 to obtain Betahistine base and further extraction of Betahistine was conducted using different organic solvents such as chloroform and MDC to assess the formation of Betahistine dimer impurity C. The results are provided in table 1.

Example-3:
Preparation of BetahistineDiydrochloride:
To a 500 mL round bottomed flask equipped with mechanical stirrer, Isopropyl alcohol (56 mL) under nitrogen purging and Betahistine base (42 g) were added at ambient temperature. Further, IPA.HCl was added and pH of reaction mass was adjusted to 2.0-2.5. The resulting mass was heated at 60-65°C with stirring, centrifuged under nitrogen and washed with IPA to get Betahistinedihydrochloride.
Yield: 92%
Purity by HPLC: 99%
Thus the present invention provides a simple and economic process for preparation of Betahistine using readily available raw materials with excellent yield and purity.
Industrial Advantages:
(i) Use of readily available raw material.
(ii) Elimination of use of 2-vinylpyridine and 2-ethynylpyridine.
(iii) Devoid of costly and hazardous reagents such as trimethylsilylacetylene, sodium cyanoborohydride, etc.
(iv) No Requirement of higher pressure, temperature and special equipment.
(v) Simple process steps and easier work-up.
(vi) Higher yields and higher purity.