DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

A PROCESS FOR THE PREPARATION OF MEBEVERINE

Vasudha Pharma Chem Limited
An Indian company having its registered office at
78/A, Vengalrao Nagar,
Hyderabad – 500038,
Telangana
India

The following specification particularly describes the nature of this invention and the manner in which it is to be performed:
A PROCESS FOR THE PREPARATION OF MEBEVERINE
FIELD OF THE INVENTION
The present application relates to a process for the preparation of Mebeverine.
BACKGROUND OF THE INVENTION
Mebeverine is a drug used to alleviate some of the symptoms of irritable bowel syndrome. It works by relaxing the muscles in and around the gut. Mebeverine is chemically described as 4-[ethyl-[1-(4-methoxyphenyl)propan-2-yl]amino]butyl 3,4-dimethoxybenzoate and is structurally represented by Formula I:

Formula I
Various processes for the preparation of Mebeverine and its intermediates have been reported in the patent publications GB893088A, GB1009082 and US3254112.
Major processes to obtain Mebeverine are as follows:
(1) Process where an iodo intermediate is used:

(2) Process where a bromo intermediate is used:

According to the above-mentioned processes the condensation of bromo or iodo intermediate with amine intermediate takes place in the presence of organic solvent. The reaction time is more than 30 hours, a large amount of by-products are generated and provides very low yield with low purity.
The process of the present invention has advantages of simple, easy handling and increased productivity which afford a significantly greater yield and takes less time. The process is also industrially scalable, cost effective which makes it highly suitable for industrial scale.

SUMMARY OF THE INVENTION
In the first embodiment the present application provides a process for the preparation of Mebeverine, comprising:
reacting a compound of formula II with a compound of formula III in water optionally in the presence of phase transfer catalyst and a base

wherein X is a halogen selected from the group consisting of chloro, bromo and iodo.
In the second embodiment the present application provides a process for the preparation of Mebeverine, by reacting 4-chlorobutyl-3,4-dimethoxybenzoate compound of formula II’ with a compound of formula III in water optionally in the presence of a phase transfer catalyst and a base:

In the third embodiment the present application provides a process for the preparation of Mebeverine, by reacting 4-bromobutyl-3,4-dimethoxybenzoate compound of formula II’’ with a compound of formula III in water optionally in the presence of a phase transfer catalyst and a base:

DETAILED DESCRIPTION OF THE INVENTION
In the aspects of the first embodiment, the present application provides a process for the preparation of Mebeverine, comprising:
reacting a compound of formula II with a compound of formula III in water optionally in the presence of phase transfer catalyst and a base

Wherein X is a halogen selected from the group consisting of chloro, bromo and iodo.
The reaction between compound of formula II and compound of formula III may be carried out for about 30 minutes to about 15 hours at about 0 °C to about boiling point of water which is used as a solvent. Specifically, the reaction may be carried out for about 4 hour to about 10 hours at about 90 °C to about 95 °C. The resulting compound of formula I may be isolated from the reaction mass by any method known in the art.
In the aspects, the phase transfer catalysts includes but not limited to tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltriethylammonium chloride, benzyltriethylammonium chloride, benzyltributylammonium chloride, dodecyltrimethylammonium bromide, methyltributylammonium chloride and the like and the mixtures thereof. Specifically, the phase transfer catalyst may be tetrabutylammonium bromide.
The base includes but not limited to organic base such as triethylamine, diisopropyl ethylamine and the like; inorganic base such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and the like. Specifically, the base may be an inorganic base. More specifically, the base may be sodium carbonate.
In the aspects of the second embodiment, the present application provides a process for the preparation of Mebeverine, by reacting 4-chlorobutyl-3,4-dimethoxybenzoate compound of formula II’ with a compound of formula III in water optionally in the presence of a phase transfer catalyst and a base:
The reaction between compound of formula II’ and compound of formula III may be carried out for about 30 minutes to about 15 hours at about 0 °C to about boiling point of water which is used as a solvent. Specifically, the reaction may be carried out for about 4 hour to about 10 hours at about 90 °C to about 95 °C. The resulting compound of formula I may be isolated from the reaction mass by any method known in the art.
In the aspects, the phase transfer catalysts includes but not limited to tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltriethylammonium chloride, benzyltriethylammonium chloride, benzyltributylammonium chloride, dodecyltrimethylammonium bromide, methyltributylammonium chloride and the like and the mixtures thereof. Specifically, the phase transfer catalyst may be tetrabutylammonium bromide.
The base includes but not limited to organic base such as triethylamine, diisopropyl ethylamine and the like; inorganic base such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and the like. Specifically, the base may be an inorganic base. More specifically, the base may be sodium carbonate.
In the aspects of the third embodiment, the present application provides a process for the preparation of Mebeverine, by reacting 4-bromobutyl-3,4-dimethoxybenzoate compound of formula II’’ with a compound of formula III in water optionally in the presence of a phase transfer catalyst and a base:

The reaction between compound of formula II’’ and compound of formula III may be carried out for about 30 minutes to about 15 hours at about 0 °C to about boiling point of water which is used as a solvent. Specifically, the reaction may be carried out for about 4 hours to about 10 hours at about 90 °C to about 95 °C. The resulting compound of formula I may be isolated from the reaction mass by any method known in the art.
In the aspects, the phase transfer catalysts include but not limited to tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltriethylammonium chloride, benzyltriethylammonium chloride, benzyltributylammonium chloride, dodecyltrimethylammonium bromide, methyltributylammonium chloride and the like and the mixtures thereof. Specifically, the phase transfer catalyst may be tetrabutylammonium bromide.
The base includes but not limited to organic base such as triethylamine, diisopropyl ethylamine and the like; inorganic base such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and the like. Specifically, the base may be an inorganic base. More specifically, the base may be sodium carbonate.
Optionally, Mebeverine may easily be converted into its acid-addition salts by reacting it with a pharmaceutically acceptable acid. Examples of such salt include acid addition salts with a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid; and those with an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid or glutamic acid.
In another general aspect, there is provided pharmaceutical composition comprising therapeutically effective amount of Mebeverine or its salts and one or more pharmaceutically acceptable carriers, excipients or diluents.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The terms "about," "general, "generally," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25 °C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms "comprising" and "comprises" mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
The term "optional" or "optionally" is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
Room temperature as used herein refers to ‘the temperatures of the thing close to or same as that of the space, e.g., the room or fume hood, in which the thing is located’. Typically, room temperature can be from about 20 °C to about 30 °C, or about 22 °C to about 27 °C, or about 25 °C.
The reaction time should be sufficient to complete the reaction which depends on scale and mixing procedures, as is commonly known to one skilled in the art. Typically, the reaction time can vary from about few minutes to several hours.
The reactions of the processes described herein can be carried out in air or under an inert atmosphere. Typically, reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the person skilled in art.
The isolation may be affected by methods such as, removal of solvent, crash cooling, flash evaporation, rotational drying, spray drying, thin-film drying, agitated nutsche filter drying, freeze drying, or any other suitable fast evaporation technique.
Suitable temperatures for isolation may be less than about 120 °C, less than about 80 °C, less than about 60 °C, less than about 40 °C, less than about 30 °C, less than about 20 °C, less than about 10 °C, less than about 0 °C, less than about -10 °C, less than about -40 °C or any other suitable temperatures.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only and should not be construed as limiting the scope of the present application in any manner.

EXAMPLES
Example 1: Preparation of Mebeverine Hydrochloride
In a round bottom flask charge N-ethyl-1-(4-methoxyphenyl)propan-2-amine (117g), 4-bromobutyl-3,4-dimethoxybenzoate (220g), sodium carbonate (256g), potassium iodide (1.5g) and water (585ml) at room temperature. Raise the reaction mixture to 90-95°C and stir for 10 hours. After completion of reaction cool the reaction mixture to room temperature and charge toluene (351ml) and adjust pH 5.5-6.5 with acetic acid (3.5ml) and separate the layers and again pH was adjusted to 1.0 to 2.0 with Con. HCl (45ml) and extract the product methylenedichloride (585ml). Distilled the solvent and the titled product was isolated in ethyl acetate (702ml).
Example 2: Preparation of Mebeverine Hydrochloride
In a round bottom flask charge N-ethyl-1-(4-methoxyphenyl)propan-2-amine hydrochloride (110g), 4-bromobutyl-3,4-dimethoxybenzoate (152g), sodium carbonate (203g), potassium iodide (1.2g) and water (550ml) at room temperature. Raise the reaction mixture to 90-95°C and stir for 10 hours. After completion of reaction cool the reaction mixture to room temperature and charge toluene (330ml) and adjust pH 5.5-6.5 with acetic acid (5.5ml) and separate the layers and again pH was adjusted to 1.0 to 2.0 with Con. HCl (70ml) and extract the product methylenedichloride (550ml). Distilled the solvent and the titled product was isolated in ethyl acetate (660ml).
Example 3: Preparation of Mebeverine Hydrochloride
In a round bottom flask charge N-ethyl-1-(4-methoxyphenyl)propan-2-amine (10g), 4-chlorobutyl-3,4-dimethoxybenzoate (14.8g), sodium carbonate (22g), potassium iodide (130mg) and water (50ml) at room temperature. Raise the reaction mixture to 90-95°C and stir for 10 hours. After completion of reaction cool the reaction mixture to room temperature and charge toluene (30ml) and adjust pH 5.5-6.5 with acetic acid (2ml) and separate the layers and again pH was adjusted to 1.0 to 2.0 with Con. HCl (5ml) and extract the product methylenedichloride (50ml). Distilled the solvent and the titled product was isolated in ethyl acetate (60ml).
Example 4: Preparation of 4-chlorobutyl-3,4-dimethoxybenzoate
In a round bottom flask charge 1,4-dichlorobutane (450 ml), veratric acid (100g), benzyltriethylammoniumchloride (2g) and sodium carbonate (100g) at room temperature. Raise the temperature to 80 oC and maintain for 2-3 hours and then add water (1000ml) and separate the product layer and washed with 10% sodium hydroxide solution (20ml) and further washed with water (200ml). Distilled the solvent from the product layer completely under vacuum to obtain 4-chlorobutyl 3,4-dimethoxybenzoate.

Dated this on 13th day of June, 2023

Signature: ___________________
Name: Dr. Phani Kumar Balsu
Vasudha Pharma Chem Limited
,CLAIMS:We Claim:
1) A process for the preparation of Mebeverine, comprising:
reacting a compound of formula II with a compound of formula III in water optionally in the presence of phase transfer catalyst and a base

wherein X is a halogen selected from the group consisting of chloro, bromo and iodo.

2) The process according to claim 1, wherein the phase transfer catalysts selected from the group comprising tetrabutylammonium bromide, tetrabutylammonium chloride, benzyltriethylammonium chloride, benzyltriethylammonium chloride, benzyltributylammonium chloride, dodecyltrimethylammonium bromide, methyltributylammonium chloride and mixtures thereof.

3) The process according to claim 1, wherein the base is selected from the group comprising organic bases triethylamine, diisopropyl ethylamine and the like; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate.

4) A process for the preparation of Mebeverine, by reacting 4-chlorobutyl-3,4-dimethoxybenzoate compound of formula II’ with a compound of formula III in water optionally in the presence of a phase transfer catalyst and a base:

5) A process for the preparation of Mebeverine, by reacting 4-bromobutyl-3,4-dimethoxybenzoate compound of formula II’’ with a compound of formula III in water optionally in the presence of a phase transfer catalyst and a base:

Dated this on 13th day of June, 2023

Signature: ___________________
Name: Dr. Phani Kumar Balsu
Vasudha Pharma Chem Limited