Claims:I/We Claims:
1. A process for the preparation of Mebeverine of formula-1 or its pharmaceutically acceptable salts thereof comprising:
reacting 4-bromobutyl 3,4-dimethoxybenzoate of formula-3a

Formula-3a
with N-ethyl-1-(4-methoxy phenyl) propan-2-amine of formula-4

Formula-4
to provide Mebeverine of formula-1 or its pharmaceutically acceptable salts

Formula-1
wherein the reaction is carried out in presence of a base, metal iodide and phase transfer catalyst.
2. The process as claimed in claim 1, base selected from metal carbonates or metal bicarbonates; metal iodide selected from copper iodide, nickel iodide, zinc iodide, lithium iodide, potassium iodide or sodium iodide; phase transfer catalyst used is quaternary ammonium salts selected from tetramethyl ammonium salt, tetraethyl ammonium salt, benzyl triethyl ammonium salt, benzyl trimethyl ammonium salt, benzyl tributyl ammonium salt, tetrabutyl ammonium salt such as tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), tetrabutylammonium iodide (TBAI); bromidetetraphenylphosphonium bromide (TPPB) or tetrabutylphosphonium bromide (TBPB).
3. A process for the preparation of Mebeverine of formula-1 or its pharmaceutically acceptable salts thereof comprising:
a) reacting 1,4-dibromobutane with veratric acid compound of formula-2

Formula-2
in presence of an organic base to provide 4-bromobutyl 3,4-dimethoxy benzoate compound of formula-3a

Formula-3a,
b) converting 4-bromobutyl 3,4-dimethoxybenzoate compound of formula-3a
to Mebeverine of formula-1 or its pharmaceutically acceptable salts.

4. The process as claimed in claim 3, wherein, organic base used in step-a) is selected from triethylamine, tribenzylamine or diisopropylethylamine.

5. A process for the preparation of Mebeverine hydrochloride of formula-1a comprising:
a) reacting 1,4-dibromobutane with veratric acid compound of formula-2

Formula-2
in presence of triethylamine to provide 4-bromobutyl 3,4-dimethoxybenzoate of formula-3a

Formula-3a,

b) reacting 4-bromobutyl 3,4-dimethoxybenzoate of formula-3a with N-ethyl
1-(4-methoxy phenyl) propan-2-amine of formula-4

Formula-4
in presence of sodium carbonate, sodium iodide and tetrabutylammonium bromide to provide Mebeverine of formula-1,
c) treating Mebeverine of formula-1 obtained in step-b) with hydrochloric
acid source to provide Mebeverine hydrochloride of formula-1a

Formula-1a.

6. The process as claimed in claim 5, wherein, The hydrochloric acid source in step-c) selected from hydrochloric acid (HCl), HCl gas, aqueous HCl, dry HCl, ethyl acetate-HCl, isopropyl acetate-HCl, isopropanol-HCl (IPA-HCl), ethanol-HCl, methanol-HCl or dioxane-HCl. , Description:Field of the invention:
The present invention relates to an improved process for the preparation of Mebeverine of formula-1 or its pharmaceutically acceptable salts.

Formula-1
Background of the invention:
Mebeverine of formula-1 is chemically known as 4-[ethyl-[1-(4-methoxyphenyl)propan-2-yl]amino]butyl 3,4-dimethoxybenzoate. Mebeverine is an Anti-spasmodic drug used to relieve the symptoms of irritable bowel syndrome. The drug marketed as Mebeverine hydrochloride salt under various trade names includes Colofac, Duspatalin, Duspatal …ect.,

US3254112 patent discloses the process for the preparation of Mebeverine and its hydrochloride salt.
Process described in US’112 patent is shown in following scheme

The above said process has some disadvantages i.e., benzene is used as a reaction solvent and it is a carcinogenic in nature, usage in large scale is not viable also the reaction time in stage 2 is taking longer hours with lower yields. This process is not commercial preferable in large scale industry.
BE609490 patent discloses the process for the preparation of Mebeverine of formula-1 and its hydrochloride salt by reacting 4-iodobutyl-3,4-dimethoxybenzoate with N-ethyl-p-methoxy phenylisopropylamine.
Process described in BE’490 patent is shown in following scheme

The above said process has some disadvantages i.e., involves sodium metal in the reaction, which is hazardous in nature and also lengthy process. And involved huge workup process for manufacture formula-1. By considering all the above parameters, this process is not viable in commercial scale.

IN646/MUM/2015 patent describes the process for the preparation of Mebeverine by reacting 4-(ethyl (1-(4-methoxyphenyl)propan-2-yl)amino)butan-1-ol with 3,4-dimethoxy benzoyl chloride in presence of triethylamine in toluene.

IN201841023171 patent describes the process for the preparation of Mebeverine and its hydrochloride salt by reacting 4-(N-ethyl (N-(4-methoxyphenyl)propan-2-yl)amino) butan-1-ol with 3,4-dimethoxy benzoyl chloride presence of p-toluenesulfonic acid in toluene.

The prior art processes has some disadvantages including, low product yield, use of hazardous, toxic, expensive reagents and solvent like benzene in the reaction, multiple step processes, longer hours reactions. These disadvantages make the processes not suitable in large scale production.
Thus, there remains a need to develop an improved process for the preparation of Mebeverine and its hydrochloride salt, which is simple, economic and industrially viable process with excellent yields and good quality.
The present inventors have developed an improved industrially viable process which does not involve the usage of any toxic and/or costly solvents or reagents and critical workup procedures. Accordingly, the present invention provides a process for the preparation of Mebeverine and its pharmaceutically acceptable salts, which is simple, efficient, cost effective, environmentally friendly and commercially scalable for large scale operations with excellent yields and good quality.

Summary of the invention
The first embodiment of the present invention provides a process for the preparation of Mebeverine of formula-1 or its pharmaceutically acceptable salts thereof.
The second embodiment of the present invention provides a process for the preparation of Mebeverine of formula-1 or its pharmaceutically acceptable salts thereof.
The third embodiment of the present invention provides a process for the preparation of Mebeverine of formula-1 or its pharmaceutically acceptable salts thereof.

Brief description of the drawings
Figure 1: Illustrates powder X-ray power diffraction (PXRD) pattern of crystalline form of Mebeverine hydrochloride obtained according to Example-5.

Detailed description of the invention
The term “pharmaceutically acceptable salts” or ”salts” described in hereinbefore are obtained by reacting Mebeverine of formula-1 with acid selected from but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; and organic acids such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, salicylic acid, 2-chloromandelate, para toluene sulfonic acid, ethane-1,2-disulfonic acid, camphor sulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid or aspartic acid and thereof.
The term "solvent" used in the present invention refers to "non polar solvents like “hydrocarbon solvents" selected from n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene or mixtures thereof; "ether solvents" selected from dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane or mixtures thereof; "ester solvents" selected from methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixtures thereof; "polar-aprotic solvents selected from dimethylacetamide, dimethylformamide, dimethylsulfoxide, Nmethylpyrrolidone or mixtures thereof; "chloro solvents" selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixtures thereof; "ketone solvents" selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and thereof; "nitrile solvents" selected form acetonitrile, propionitrile, isobutyronitrile or mixtures thereof; "alcoholic solvents" selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol or mixtures thereof; "polar solvents" selected from water or mixtures thereof.
The term “hydrochloric acid source” used in the present invention is selected from but not limited to hydrochloric acid (HCl), aqueous HCl, dry HCl, ethyl acetate-HCl, isopropyl acetate-HCl, isopropanol-HCl (IPA-HCl), ethanol-HCl, methanol-HCl or dioxane-HCl and the like.

The first embodiment of the present invention provides a process for the preparation of Mebeverine of formula-1 or its pharmaceutically acceptable salts thereof comprising:
reacting 4-bromobutyl 3,4-dimethoxybenzoate of formula-3a

Formula-3a
with N-ethyl-1-(4-methoxy phenyl) propan-2-amine of formula-4

Formula-4
to provide Mebeverine of formula-1 or its pharmaceutically acceptable salts

Formula-1
and optionally purifying the compound to provide substantially pure Mebeverine of formula-1 or its pharmaceutically acceptable salts.

In first aspect of first embodiment, wherein the reaction is carried out in presence of a base, metal iodide and phase transfer catalyst.
Wherein base selected from inorganic bases, preferably metal carbonates or metal bicarbonates, more preferably sodium carbonate; metal iodide selected from but not limited to copper iodide, nickel iodide, zinc iodide, lithium iodide, potassium iodide or sodium iodide (NaI), preferably sodium iodide; phase transfer catalyst used is quaternary ammonium salts selected from but not limited to tetramethyl ammonium salt, tetraethyl ammonium salt, benzyl triethyl ammonium salt, benzyl trimethyl ammonium salt, benzyl tributyl ammonium salt, tetrabutyl ammonium salt such as tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), tetrabutylammonium iodide (TBAI); bromidetetraphenylphosphonium bromide (TPPB) or tetrabutylphosphonium bromide (TBPB), preferably tetrabutylammonium bromide (TBAB).
In second aspect of first embodiment, wherein the reaction is carried out in presence of a solvent selected from hydrocarbon solvent, ketone solvents or polar solvents or mixtures thereof, preferably ketone solvents more preferably methyl isobutyl ketone (MIBK).
In third aspect of first embodiment converting Mebeverine of formula-1 to its pharmaceutically acceptable salts can be done by treating Mebeverine of formula-1 with an acid optionally in presence of a solvent.
Wherein acid used in third aspect is selected from but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; and organic acids such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, salicylic acid, 2-chloromandelate, para toluene sulfonic acid, ethane-1,2-disulfonic acid, camphor sulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid or aspartic acid and thereof; solvent is selected from solvents as described in the second aspect or hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents or any of the mixtures thereof.
In fourth aspect of first embodiment of the present invention provides a process for the preparation of Mebeverine hydrochloride of formula-1a, comprising:
a) reacting 4-bromobutyl 3,4-dimethoxybenzoate of formula-3a with N-ethyl-1-(4-methoxy phenyl) propan-2-amine of formula-4 in presence of sodium carbonate, sodium iodide and tetrabutylammonium bromide to provide Mebeverine of formula-1,
b) treating Mebeverine of formula-1 obtained in step-a) with hydrochloric acid source to provide Mebeverine hydrochloride of formula-1a.
Wherein, hydrochloric acid source in step-b) of fourth aspect selected from hydrochloric acid (HCl), aqueous HCl, dry HCl, ethyl acetate-HCl, isopropyl acetate-HCl, isopropanol-HCl (IPA-HCl), ethanol-HCl, methanol-HCl or dioxane-HCl, preferably IPA-HCl.
Further aspect, in step-b), in-situ or isolated Mebeverine of formula-1 obtained from step-a) is treated with IPA-HCl to produce Mebeverine hydrochloride of Formula-1a.
Another aspect of present invention, compound of formula-1a obtained by the above process is crystalline in nature and is characterized by its PXRD pattern as illustrated in figure-1.

The second embodiment of the present invention provides a process for the preparation of Mebeverine of formula-1 or its pharmaceutically acceptable salts thereof, comprising:
a) reacting 1,4-dihalobutane with veratric acid compound of formula-2 in presence of an organic base to provide 4-halobutyl 3,4-dimethoxybenzoate of formula-3,
b) reacting 4-halobutyl 3,4-dimethoxybenzoate of formula-3 with N-ethyl-1-(4-methoxy phenyl) propan-2-amine of formula-4 to provide Mebeverine of formula-1 or its pharmaceutically acceptable salts and optionally purifying the compound to provide substantially pure compound.

In first aspect of second embodiment, organic base used in step-a) selected from tertiary amines, preferably triethylamine, tribenzylamine or diisopropylethylamine thereof, more preferably triethylamine; 1,4-dihalobutane selected from 1,4-chlorobutane or 1,4-dibromobutane; the reaction temperature in step-a) range from about from 15-65°C.
In second aspect of second embodiment, 4-halobutyl 3,4-dimethoxy benzoate of formula-3 may be used in the next reaction directly or optionally after further purification with suitable solvent as described in above.
In third aspect of second embodiment, wherein step-b) is carried out in presence of a base, metal iodide and phase transfer catalyst.
Wherein base selected from inorganic bases, preferably metal carbonates or metal bicarbonates, more preferably sodium carbonate; metal iodide selected from but not limited to copper iodide, nickel iodide, zinc iodide, lithium iodide, potassium iodide or sodium iodide, preferably sodium iodide; phase transfer catalyst used is quaternary ammonium salts selected from but not limited to tetramethyl ammonium salt, tetraethyl ammonium salt, benzyl triethyl ammonium salt, benzyl trimethyl ammonium salt, benzyl tributyl ammonium salt, tetrabutyl ammonium salt such as tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), tetrabutylammonium iodide (TBAI); bromidetetraphenylphosphonium bromide (TPPB) or tetrabutylphosphonium bromide (TBPB), preferably tetrabutylammonium bromide (TBAB).
In fourth aspect of second embodiment, wherein step-b) is carried out in presence of a solvent selected from hydrocarbon solvent, ketone solvents or polar solvents or mixtures thereof, preferably ketone solvents more preferably methyl isobutyl ketone (MIBK).
In fifth aspect of second embodiment converting Mebeverine of formula-1 to its pharmaceutically acceptable salts can be done by treating Mebeverine of formula-1 with an acid optionally in presence of a solvent.
Wherein acid used in fifth aspect is selected from but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; and organic acids such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, salicylic acid, 2-chloromandelate, para toluene sulfonic acid, ethane-1,2-disulfonic acid, camphor sulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid or aspartic acid and thereof; solvent is selected from but not limited to hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents or any of the mixtures thereof.
In sixth aspect of second embodiment of the present invention provides a process for the preparation of Mebeverine hydrochloride of formula-1a, comprising:
a) reacting 1,4-dibromobutane with veratric acid compound of formula-2

Formula-2
in presence of triethylamine to provide 4-bromobutyl 3,4-dimethoxy benzoate of formula-3a

Formula-3a,
b) reacting 4-bromobutyl 3,4-dimethoxybenzoate of formula-3a with N-ethyl
1-(4-methoxy phenyl) propan-2-amine of formula-4

Formula-4
in presence of sodium carbonate, sodium iodide and tetrabutylammonium bromide to provide Mebeverine of formula-1

Formula-1,
c) treating Mebeverine of formula-1 obtained in step-b) with hydrochloric
acid source to provide Mebeverine hydrochloride of formula-1a.

Wherein, hydrochloric acid source in step-c) of sixth aspect selected from hydrochloric acid (HCl), aqueous HCl, dry HCl, ethyl acetate-HCl, isopropyl acetate-HCl, isopropanol-HCl (IPA-HCl), ethanol-HCl, methanol-HCl or dioxane-HCl, preferably IPA-HCl.
Further aspect, in step-c), in-situ or isolated Mebeverine of formula-1 obtained from step-b) is treated with IPA-HCl to produce Mebeverine hydrochloride of Formula-1a.
In seventh aspect of second embodiment of the present invention, the above sequential process for the preparation of compound of formula-1 or formula-1a can be carried out as a single-pot process. i.e., the above process can be carried out in a sequential manner without isolating any of the process intermediate from the reaction mixture.

The third embodiment of the present invention provides a process for the preparation of Mebeverine of formula-1 or its pharmaceutically acceptable salts thereof, comprising:
a) reacting 1,4-dihalobutane with veratric acid compound of formula-2 in
presence of an organic base to provide 4-halobutyl 3,4-dimethoxybenzoate of formula-3,
b) converting 4-halobutyl 3,4-dimethoxybenzoate of formula-3 to Mebeverine of formula-1or its pharmaceutically acceptable salts.

In first aspect of third embodiment, wherein organic base used in step-a) selected from tertiary amines, preferably triethylamine, tribenzylamine or diisopropylethylamine thereof, more preferably triethylamine; 1,4-dihalobutane selected from 1,4-chlorobutane, 1,4-dibromobutane; the reaction temperature in step a) range from about from 15-65°C.
In second aspect of third embodiment, 4-halobutyl 3,4-dimethoxybenzoate of formula-3 may be used in the next reaction directly or optionally after further purification.
In third aspect of third embodiment 4-halobutyl 3,4-dimethoxybenzoate of formula-3 can be converted to Mebeverine of formula-1 or its pharmaceutically acceptable salts by process according to the present invention or by other similar processes known in the art.
In fourth aspect of third embodiment of the present invention provides a process for the preparation of Mebeverine of formula 1 or its pharmaceutically acceptable salts thereof comprising:
a) reacting 1,4-dibromobutane with veratric acid compound of formula-2

Formula-2
in presence of an organic base to provide 4-bromobutyl 3,4-dimethoxy benzoate compound of formula-3a

Formula-3a,
b) converting 4-bromobutyl 3,4-dimethoxybenzoate compound of formula-3a
to Mebeverine of formula-1 or its pharmaceutically acceptable salts.
Further aspect, wherein organic base used in step-a) of fourth aspect
selected from tertiary amines, preferably triethylamine, tribenzylamine or diisopropylethylamine thereof, more preferably triethylamine.

Advantages of the present invention:
• The process described in the present invention is simple, safe, economic, eco-friendly and suitable for the production of Mebeverine of formula-1 and its salts on commercial scale with a high reproducibility.
• Use of single solvent system in the process for preparation of Mebeverine is highly recommended in large scale production.
• Usage of sodium iodide (catalytic amount) and phase transfer catalyst in stage-2, reduce the reaction time and provide fast completion of reaction with good yield.
• The present invention controlled the formation of critical dimer impurity in the process for preparation of 4-bromobutyl 3,4-dimethoxybenzoate reaction.
• Use of commercially available and cheaper reagents and solvent provides cost-effective process.
• Solvents used in the present invention are recycled and reused in the process.

The inventors of the present invention have carried out the process for the preparation of Mebeverine through 4-chlorobutyl 3,4-dimethoxybenzoate intermediate. The said reaction is very slow, takes more time for the completion of reaction and yield of the reaction of is also low compare to the process involves the usage of 4-bromobutyl 3,4-dimethoxybenzoate intermediate.
The inventors of the present invention have observed by in-process reaction monitoring that the quantity of the 1,4-dibromobutane affect the formation and purity of 4-bromobutyl 3,4-dimethoxybenzoate. For instance, the conversion of the reactants to 4-bromobutyl 3,4-dimethoxybenzoate was experimented using 1,4-dibromobutane at different molar concentrations. The following Table-A, refers to the results obtained by the use of 1,4-dibromobutane at different molar ratio, wherein the higher % of 4-bromobutyl 3,4-dimethoxybenzoate formation 16 kg (91.89%) (about 98% purity by GC) was observed with decrease in dimer impurity % (about 1.9% purity by GC) formation in total impurities using 7.6 mole equivalents of 1,4-dibromobutane with Veratric acid.
Table-A
Example 1,4-dibromobutane quantity Observation
1 4.5 mole equivalent In-process product
formation 14.96 kg (85.92 %)
Purity: 93% (purity by GC). Dimer impurity 6.9% (purity by GC)
2 6.1 mole equivalent In-process product
formation 15.45 kg (88.73%)
Purity: 96% (purity by GC). Dimer impurity 3.8% (purity by GC)
3 7.6 mole equivalent In-process product
formation 16 kg (91.89%)
Purity: 98% (purity by GC). Dimer impurity 1.9% (purity by GC)

Structure of above discussed dimer impurity:

The other embodiment of the present invention provides a method of treating a patients suffering from irritable bowel syndrome comprising administering to the patients with a therapeutically effective amount of Mebeverine of formula-1 or its pharmaceutically acceptable salts obtained by the process of the present invention.
In another embodiment of the present invention provides pharmaceutical composition/ formulation comprising Mebeverine of formula-1 or its pharmaceutically acceptable salts and pharmaceutically acceptable excipients wherein, the pharmaceutical acceptable excipients include (but are not limited to) binders, diluents, disintegrants, surfactants and lubricants. Suitable binders that can be include (but are not limited to) polyvinylpyrolidone, copovidone, starches such as pregelatinized starch, cellulose derivatives such as hydroxypropylmethyl cellulose, ethylcellulose, hydroxylpropyl cellulose and carboxymethyl cellulose and their salts, gelatine, acacia, agar, alginic acid, carbomer, chitosan, dextrates, cyclodextrin, dextrin, glycerol dibehenate, guargum, hypromellose, maltodextrin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, sodium alginate, sucrose, mixtures thereof and the like; suitable diluents that can be include (but are not limited to) anhydrous lactose, lactose monohydrate, modified lactose, dibasic calcium phosphate, tribasic calcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, maize starch, pregelatinized starch, calcium carbonate, sucrose, glucose, dextrates, dextrins, dextrose, fructose, lactitol, mannitol, sorbitol starch, calcium lactate or mixtures of diluents; suitable disintegrants that can be include (but are not limited to) magnesium aluminometa silicate (or magnesium aluminum silicate), starch, pregelatinized starch, sodium starch glycolate, crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, alginic acid, carboxy methyl cellulose sodium, sodium alginate, calcium alginate and chitosan; suitable lubricants that can be include (but are not limited to) magnesium stearate, stearic acid, palmitic acid, talc, and aerosil. Suitable surfactants that can be include (but are not limited to) polysorbate 80, polyoxyethylene sorbitan, polyoxyethylene-polyoxy-propylene copolymer and sodium lauryl sulphate.
Various modes of administration of the pharmaceutical composition/ formulation of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
Starting materials utilized in the present invention are commercially available in the market (or) they can be prepared according to the any of the processes known in the prior art.

Powder X-ray power diffraction (PXRD) method of analysis:
PXRD analysis of the crystalline form of Mebeverine hydrochloride is carried out by using Bruker D8 advance X-ray powder diffractometer using Cu-Ka radiation of wavelength 1.54060A° and at continuous scan speed of 0.033°/min.

The First, second and third embodiments of the present invention are schematically represented as follows:

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are for illustrative purposes only and in no way limit the scope of the present invention.

Examples:
Example-1: Preparation of 4-bromobutyl 3,4-dimethoxybenzoate
Triethylamine (11.5 L, 1.5 mole equivalent) is added to the mixture of 1,4-dibromobutane (30 L, 4.5 mole equivalent) and Veratric acid (10 kg, 1.0 mole equivalent) at 15-20°C and stirred the reaction mixture at same temperature for 12 hours. After completion of the reaction, reaction mixture was quenched with water. Layers separated. Organic layer is washed with 5% aqueous sodium bicarbonate solution and distilled off the solvent completely to get the title compound.
Yield: 14.96 kg (85.92 %). Purity by GC: 93%, Dimer impurity: 6.9%.
Example-2: Preparation of 4-bromobutyl 3,4-dimethoxybenzoate
Triethylamine (11.5 L, 1.5 mole equivalent) is added to the mixture of 1,4-dibromobutane (40 L, 6.1 mole equivalent) and Veratric acid (10 kg, 1.0 mole equivalent) at 15-20°C and stirred the reaction mixture at same temperature for 12 hours. After completion of the reaction, reaction mixture was quenched with water. Layers separated. Organic layer is washed with 5% aqueous sodium bicarbonate solution and distilled off the solvent completely to get the title compound.
Yield: 15.45 kg (88.73%). Purity by GC: 96%, Dimer impurity: 3.8%.
Example-3: Preparation of 4-bromobutyl 3,4-dimethoxybenzoate
Triethylamine (11.5 L, 1.5 mole equivalent) is added to the mixture of 1,4-dibromobutane (50 L, 7.6 mole equivalent) and Veratric acid (10 kg, 1.0 equivalent) at 15-20°C and stirred the reaction mixture at same temperature for 12 hours. After completion of the reaction, reaction mixture was quenched with water. Layers separated. Organic layer is washed with 5% aqueous sodium bicarbonate solution and distilled off the solvent completely to get the title compound.
Yield: 16 kg (91.89%). Purity by GC: 98%, Dimer impurity: 1.9%.
Example-4: Preparation of 4-chlorobutyl 3,4-dimethoxybenzoate
Triethylamine (2.3 L, 1.5 mole equivalent) is added to the mixture of 1,4-dichlorobutane (10 L, 8.3 mole equivalent) and Veratric acid (2 kg, 1.0 mole equivalent) at 15-20°C and stirred the reaction mixture at same temperature for 16 hours. After completion of the reaction, reaction mixture was quenched with water. Layers separated. Organic layer is washed with 5% aqueous sodium bicarbonate solution and distilled off the solvent completely to get the title compound.
Yield: 2.6 kg (86.95%). Purity by GC: 98.7%, Dimer impurity: 1.3%.
Example-5: Preparation of Mebeverine hydrochloride of formula-1a
Sodium carbonate (7 kg, 1.27 mole equivalent), catalytic amount of sodium iodide (50 g, 0.007 mole equivalent) and tetrabutylammonium bromide (50 g, 0.003 mole equivalent) were added to the mixture of methyl isobutyl ketone (30 L), 4-bromobutyl 3,4-dimethoxybenzoate (14 kg, 1.2 mole equivalent) and N-Ethyl-1-(4-methoxyphenyl)propan-2-amine of formula-4 (10 kg, 1.0 mole equivalent) at 25-30°C. Heated the reaction mixture to 85-90 °C and stirred at same temperature for 12 hours. Further the reaction mixture was quenched with water. Layers separated. Aqueous layer is washed with methyl isobutyl ketone. Adjust reaction mass pH 1-2 by using 25% IPA.HCl and stirred for 4 hours at same temperature. Filtered the precipitated solid and dried at 75-80 deg for 8h to get the title compound.
Yield: 18 kg (75%). Assay:100.2%.
PXRD pattern of the above compound is illustrated in figure-1.
Example-6: Preparation of Mebeverine hydrochloride of formula-1a
Sodium carbonate (7 kg, 1.27 mole equivalent), catalytic amount of sodium iodide (50 g, 0.007 mole equivalent) and tetrabutylammonium bromide (50 g, 0.003 mole equivalent) were added to the mixture of toluene (50 L), 4-bromobutyl 3,4-dimethoxybenzoate (14 kg, 1.2 mole equivalent) and N-Ethyl-1-(4-methoxyphenyl) propan-2-amine of formula-4 (10 kg, 1.0 mole equivalent) at 25-30°C. Heated the reaction mixture to 115-118 °C and stirred at same temperature for 12 hours. Further the reaction mixture was quenched with water. Layers separated. Aqueous layer is washed with toluene. Adjust reaction mass pH 1-2 by using 25% IPA.HCl and stirred for 4 hours at same temperature. Filtered the precipitated solid and dried to get the title compound.
Yield: 16.5 kg (68.7%). Assay: 99.4%.
Example-7: Preparation of Mebeverine hydrochloride of formula-1a
Sodium carbonate (7 kg, 1.27 mole equivalent), catalytic amount of sodium iodide (50 g, 0.007 mole equivalent) and tetrabutylammonium bromide (50 g, 0.003 mole equivalent) were added to the mixture of acetone (40 L), 4-bromobutyl 3,4-dimethoxybenzoate (14 kg, 1.2 mole equivalent) and N-Ethyl-1-(4-methoxyphenyl) propan-2-amine of formula-4 (10 kg, 1.0 mole equivalent) at 25-30°C. Heated the reaction mixture to 55-58 °C and stirred at same temperature for 18 hours. Distilled out acetone from reaction and then added water and toluene to the reaction mixture. Layers separated. Aqueous layer is washed with toluene. Adjust reaction mass pH 1-2 by using 25% IPA.HCl and stirred for 4 hours at same temperature. Filtered the precipitated solid and dried to get the title compound.
Yield: 17.1 kg (71.25%). Assay: 100.5%.
Example-8: Preparation of Mebeverine hydrochloride of formula-1a
Sodium carbonate (7 kg, 1.27 mole equivalent), catalytic amount of sodium iodide (50 g, 0.007 mole equivalent) and tetrabutylammonium bromide (50 g, 0.003 mole equivalent) were added to the mixture of water (40 L), 4-bromobutyl 3,4-dimethoxybenzoate (14 kg, 1.2 mole equivalent) and N-Ethyl-1-(4-methoxyphenyl) propan-2-amine of formula-4 (10 kg, 1.0 mole equivalent) at 25-30°C. Heated the reaction mixture to 50-55 °C and stirred at same temperature for 12 hours. Toluene was added to above reaction mixture. Layers separated. Aqueous layer is washed with toluene. Adjust reaction mass pH 1-2 by using 25% IPA.HCl and stirred for 4 hours at same temperature. Filtered the precipitated solid and dried to get the title compound.
Yield: 15.4 kg (64.16%). Assay: 100.1%.