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 INTERMEDIATES

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 INTERMEDIATES
FIELD OF THE INVENTION
The present application relates to a process for the preparation of one of the intermediates of Mebeverine.
BACKGROUND OF THE INVENTION
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:

4-bromobutyl-3,4-dimethoxybenzoate, 4-chlorobutyl-3,4-dimethoxybenzoate and 4-iodobutyl-3,4-dimethoxybenzoate are very important intermediates in the preparation of Mebeverine. The above mentioned processes has a disadvantage in that, due to low yield, low purity, a large amount of by-products is generated and the reaction time is 90 hours
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 compound of formula A, comprising:
reacting a compound of formula II with tetrahydrofuran in the presence of a Lewis acid and halogenation reagent

wherein X is halogen.
In the second embodiment the present application provides a process for the preparation of, 4-chlorobutyl-3,4-dimethoxybenzoate compound of formula III, comprising:
reacting a compound of formula II with tetrahydrofuran in the presence of Fe / Zn powder and thionyl chloride

DETAILED DESCRIPTION OF THE INVENTION
In the aspects, the present application provides a process for the preparation of compound of formula A, comprising:
reacting a compound of formula II with tetrahydrofuran in the presence of a Lewis acid and halogenation reagent

wherein X is halogen.
In aspects, the reaction of compound of formula II with tetrahydrofuran may be performed in a suitable solvent. The solvents includes but not limited to water, ether solvent such as, diethyl ether and the like; aromatic hydrocarbon solvent such as benzene, toluene and the like; aliphatic hydrocarbon solvent such as heptane, hexane and the like; chlorinated hydrocarbon solvent such as dichloromethane and the like and the mixtures thereof. Specifically, the solvent may be dichloromethane.
In aspects, the Lewis acid is selected from but not limited to AlCl3, BF3, BCl3, FeCl3, SnCl4, SbCl5, AsF5, AsF3, TiCl4, Al(C2H5)3, Al(C2H5)2Cl and Al(C2H5)Cl2. The halogenation reagent is selected from but not limited to thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, N-chlorosuccinimide, bromotrichloromethane, carbon tetrabromide, N-bromosuccinimide, boron tribromide, hydriodic acid, N-iodosuccinimide and carbon tetraiodide.
The reaction between compound of formula II and tetrahydrofuran may be carried out for about 30 minutes to about 24 hours at about 0 °C to about boiling point of the solvent. Specifically, the reaction may be carried out for about 1 hour to about 4 hours
at about 60 °C to about 75 °C. The resulting compound of formula A may be isolated from the reaction mass by any method known in the art. Specifically, the compound of formula A may be isolated from the reaction mass by filtration.
In aspects, the present application provides a process for the preparation of, 4-chlorobutyl-3,4-dimethoxybenzoate compound of formula III, comprising:
reacting a compound of formula II with tetrahydrofuran in the presence of Fe / Zn powder and thionyl chloride

In aspects, the reaction of compound of formula II with tetrahydrofuran may be performed in a suitable solvent. The solvents includes but not limited to water, ether solvent such as, diethyl ether and the like; aromatic hydrocarbon solvent such as benzene, toluene and the like; aliphatic hydrocarbon solvent such as heptane, hexane and the like; chlorinated hydrocarbon solvent such as dichloromethane and the like and the mixtures thereof. Specifically, the solvent may be dichloromethane.
The reaction between compound of formula III and tetrahydrofuran may be carried out for about 30 minutes to about 24 hours at about 0 °C to about boiling point of the solvent. Specifically, the reaction may be carried out for about 1 hour to about 4 hours at about 60 °C to about 75 °C. The resulting compound of formula A may be isolated from the reaction mass by any method known in the art. Specifically, the compound of formula III may be isolated from the reaction mass by filtration.
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. For example the reaction time can be from about 10 minutes to about 24 hours, or any other suitable time period.
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 effected 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 4-chlorobutyl-3,4-dimethoxybenzoate
In a round bottom flask charge toluene (750 ml), veratric acid (250 gm), dimethylformamide (7.5 ml) and thionyl chloride (125 ml) at room temperature and stir for 10 minutes. Raise the temperature to 55 oC and maintain for 2-3 hours and then distil the solvent completely. Cool the reaction mass to 35 oC and dichloromethane (500 ml) and stirred for 5 minutes.

In another flask dichloromethane (250 ml), tetrahydrofuran (167.5 ml) and Fe powder (15.32 gm) were added and stirred for 10 minutes. To this the reaction mass from first flask was added and maintained for 14-15 hours. The reaction mass was cooled to room temperature and filtered and washed with dichloromethane (250 ml) to give titled compound.

Example 2: Preparation of 4-chlorobutyl-3,4-dimethoxybenzoate
In a round bottom flask charge toluene (75 ml), veratric acid (25 gm), dimethylformamide (0.75 ml) and thionyl chloride (12.5 ml) at room temperature and stir for 10 minutes. Raise the temperature to 55 oC and maintain for 2-3 hours and then distil the solvent completely. Cool the reaction mass to 35 oC and dichloromethane (500 ml) and stirred for 5 minutes.
In another flask dichloromethane (25 ml), tetrahydrofuran (17 ml) and Zn powder (1.5 gm) were added and stirred for 10 minutes. To this the reaction mass from first flask was added and maintained for 14-15 hours. The reaction mass was cooled to room temperature and filtered and washed with dichloromethane (25 ml) to give titled compound. ,CLAIMS:We Claim:
1) A process for the preparation of compound of formula A, comprising:
reacting a compound of formula II with tetrahydrofuran in the presence of a Lewis acid and halogenation reagent

wherein X is halogen.

2) The process according to claim 1, wherein the Lewis acid is selected from the group comprising AlCl3, BF3, BCl3, FeCl3, SnCl4, SbCl5, AsF5, AsF3, TiCl4, Al(C2H5)3, Al(C2H5)2Cl and Al(C2H5)Cl2.

3) The process according to claim 1, wherein the halogenation reagent is selected from the group comprising thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, N-chlorosuccinimide, bromotrichloro methane, carbon tetrabromide, N-bromosuccinimide, boron tribromide, hydriodic acid, N-iodosuccinimide and carbon tetraiodide.

4) A process for the preparation of, 4-chlorobutyl-3,4-dimethoxybenzoate compound of formula III, comprising:
reacting a compound of formula II with tetrahydrofuran in the presence of Fe / Zn powder and thionyl chloride.