FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 4-(ethyl(l-(4-methoxyphenyl)propan-2-yl)amino)butan-l-ol (hereafter referred to as the compound (VI)), which is useful as a key intermediate for the synthesis of Mebeverine (I) which is chemically known as 4-(ethyl(I-(4-methoxyphenyl)propan-2-yl)amino)butyl 3,4-dimethoxybenzoate. The process of the present invention further involves transformation of the said alcohol (the compound (VI)) into Mebeverine (referred to as the compound-I) and/or pharmaceutically acceptable salts thereof.
BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated, Unless clearly indicated to the contrary, however, reference to any prior art in this specification should not be construed as an express or implied admission that such art is widely known or forms part of common general knowledge in the field.
Mebeverine, chemically known as 4-(ethyl(l-(4-methOxyphenyl)propan-2-yl)amino)butyl 3,4-dimethoxybenzoate is structurally represented by compound of formula (I):
Mebeverine is an anti-spasmodic agent used to relieve the symptoms of irritable bowel syndrome, which includes abdominal pain, cramps, bowel spasm, diarrhoea and flatulence. The drug provides relief by relaxing muscles of the gut. The drug is marketed as hydrochloride salt under various trade names such as Colofac, Duspatal, Colospa retard, Duspatal retard, Duspatalin and Duspatalin retard by Abbott Laboratories.
United States Patent No. 3,254,112 (US '112) discloses a process for the preparation of Mebeverine and hydrochloride salt thereof.
Belgium Patent No. 609490 (BE '490) also discloses a process for the preparation of Mebeverine and hydrochloride salt thereof.

Mebeverine can be obtained by a process as shown in the following scheme described in US'112.
There are significant drawbacks of the process shown above, which adversely affects yield of the product, cost of manufacture of the product, safety of the personnel and the environment. For example, in the above process, the preparation of intermediate 3 involves use of toxic benzene. The final product, Mebeverine of formula (I) comprises of chlorine, about 7.7%.
In view of these drawbacks, there is a need to develop an industrially viable commercial process for the preparation of mebeverine and its intermediates; which is a simple, efficient and cost-effective process and provides the desired compounds in improved yield and purity.
The inventors of the present invention have developed an improved process that addresses the problems associated with the processes reported in the prior art. The process of the present invention does not involve use of any toxic and/or costly solvents. Particularly, the process of the instant invention does not involve use of toxic benzene. The genotoxic intermediate (4-bromobutyl 3,4-dimethoxyenzoate) is also not used in the instant process. Accordingly, the present invention provides a process for the preparation of mebeverine and its intermediates, which is simple, efficient, cost effective, environment friendly and industrially feasible for large scale operations.

SUMMARY OF THE INVENTION
In one aspect, the present invention relates to an improved process for the preparation of 4-(ethyl(l-(4-methoxyphenyl)propan-2-yl)amino)butyl acetate, compound (V), comprising reacting compound (III) with compound (IV).
In another aspect, the present invention relates to an improved process for the preparation of 4-(ethyI(l-(4-methoxyphenyl)propan-2-yl)amino)butan-l-ol, compound (VI), comprising in situ hydrolysis of compound (V).
In another aspect, the present invention relates to a use of compound (VI), obtained from compound (V) for the preparation of 4-(ethyl(l-(4-methOxyphenyl)propan-2-yl)amino)butyl 3,4-dimethoxybenzoate, a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention relates to an improved process for the preparation of compound of formula (VI) wherein the said compound has impurities not more than 8%.
In a general aspect, the present invention relates to an improved process for the preparation of
Mebeverine (I) or a pharmaceutically acceptable salt thereof comprising,
(x) reacting compound (IV) with compound (Ilia) to obtain 4-(ethyl(l-(4-
methoxyphenyl)propan-2-yl)amino)butyl acetate (V);
(y) in situ hydrolysis of compound (V) of step (x) to obtain 4-(ethyl(I-(4-methoxyphenyl)
propan-2-yl)amino)butan-l-ol (VI);
(z) reacting compound (VI) of step (y) with compound (Villa).
DETAILED DESCRIPTION OF THE INVENTION
The term "ratio" as used herein with respect to any element e.g. solvent; it is intended to mean that the subject element consists of v/v (volume/volume) ratio ranging from 1:1 to 10:10 of the organic solvent to water. All the possible permutation and combination alternatives of v/v ratio are intended to be within the scope of the present invention.
The term "about" as used herein along with the numerical values with respect to certain measurements or parameters means a variation of upto +10 % from such values or when used

with respect to range of values, it means a variation of upto + 10% from both the upper and lower limits of such ranges.
The term 'room temperature' as used herein refers to the temperature in the range from 25 °C to 35 °C.
In one aspect of the present invention, there is provided a process for the preparation of 4-(ethyl(l-(4-methoxyphenyl)propan-2-yl)amino)butyl acetate, an intermediate of formula (V)
comprising the step of reacting compound of formula (III) with compound of formula (IV)
in presence of a base and solvent.
The compound (III) may be prepared by the processes known in the literature, such as those described in The Journal of Organic Chemistry, 1975, 40, 3571 or by the processes described herein.
In another aspect of the present invention, there is provided a process for the preparation of 4-(ethyl(l-(4-methoxyphenyl)propan-2-yl)amino)butan-l-ol, an intermediate of formula (VI)
wherein the process comprises hydrolysis of compound (V) to a compound (VI)

in presence of a base and solvent.
In another aspect of the present invention, there is provided use of compound (VI) obtained from the methods described above, in preparation of mebeverine of formula (I).
In another aspect of the present invention, there is provided a process for the preparation of mebeverin of formula (I) or a pharmaceutically acceptable salt thereof, wherein the process comprises the steps of: (i) reacting veratric acid of formula (VII) with a chlorinating agent
v ' —J
to obtain veratroyl chloride of formula (VIII)
(ii) reacting veratroyl chloride of formula (VIII) with compound (VI) in presence of a base to obtain mebeverine, a compound of formula (I)
(vii) optionally converting mebeverine to a pharmaceutically acceptable salt.
In an embodiment, the compound of formula (III) is reacted with compound of formula (IV) in presence of a base selected from the group consisting of sodium carbonate, potassium

carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, potassium phosphate, triethylamine and pyridine.
In another embodiment, the compound of formula (III) is reacted with compound of formula (IV) in presence of an inorganic base.
In another embodiment, the compound of formula (III) is reacted with compound of formula (IV) in presence of potassium carbonate.
In another embodiment, the compound of formula (III) is reacted with compound of formula (IV) in a solvent selected from the group consisting of N,N-dimethyIformamide (DMF), N, N- dimethylacetamide (DMA), dimethylsulfoxide (DMSO), l-methyl-2-pyrrolidinone, pyridine, acetic anhydride or a mixture thereof.
In another embodiment, the reaction of compound of formula (III) with compound of formula (IV) is carried out in dimethylsulfoxide (DMSO).
In another embodiment, the compound of formula (III) is reacted with compound of formula (IV) at about 55°C to about 65 °C.
In another embodiment, the compound of formula (III) is reacted with compound of formula (IV) from about 20 hours to about 30 hours.
In another embodiment, the compound of formula (V) is converted to compound (VI) in presence of a base selected from the group consisting of sodium hydroxide, potassium hydroxide and lithium hydroxide.
In another embodiment, the compound of formula (V) is reacted with compound of formula (VI) in presence of sodium hydroxide.
In another embodiment, the compound of formula (V) is converted to compound (VI) in a polar protic solvent selected from the group consisting of water, methanol, ethanol, isopropanol, n-propanol and isobutanol, or a mixture thereof.
In another embodiment, the reaction of compound of formula (V) with compound of formula (VI) is carried out in a mixture of solvents.

In another embodiment, the reaction of compound of formula (V) with compound of formula (VI) is carried out in a mixture of water and an organic solvent selected from aromatic hydrocarbon, a halogenated hydrocarbon, an alcohol, an ester, an ether, a ketone, a nitrile, an amide, a sulfoxide or a lactam.
In another embodiment, the reaction of compound of formula (V) with compound of formula (VI) is carried out in a mixture of water and an alcoholic solvent.
In another embodiment, the reaction of compound of formula (V) with compound of formula (VI) is carried out in a mixture of water and methanol.
In another embodiment, the mixture of solvents comprises alcohol and water in the range of 1:1 to 10:10as v/v (volume/volume). Preferably, the ratio of alcohol to water ranges from 1:1 to 10:5 as v/v (volume/volume).
In another embodiment, the mixture of polar protic solvents comprises an alcohol and water (alcohol: water) in the ratio of 2: 1 (v/v).
In another embodiment, the mixture of polar protic solvents comprises methanol (MeOH) and water (MeOH: water) in the ratio of 2: 1 (v/v).
In another embodiment, the reaction of compound of formula (V) with compound of formula (VI) is carried out in situ.
In another embodiment, there is provided a method for the purification of compound (VI), the process comprising treating compound (VI) with a suitable solvent and isolating pure compound (VI).
The process of the present invention as per the specific embodiment described above is illustrated in the following Scheme-I,

In a further embodiment, there is provided a specific process for the preparation of 4-(emyl(l-(4-methoxyphenyl)propan-2-yl)amino)butyl acetate, an intermediate of formula (V), comprising the steps of:
(1) dissolving compound (III) and a base in a solvent;
(2) adding the compound (IV) to the reaction mixture of step (1);
(3) the reaction mixture is cooled to about 25 °C to about 30 °C; to obtain compound (V)
In a further embodiment, there is provided a specific process for the preparation of 4-(ethyl(l-(4-methoxyphenyl)propan-2-yl)amino)butan-l-ol, an intermediate of formula (VI), comprising the steps of:
(4) adding an alcohol, a base and water to the slurry of step (3) described above in situ;
(5) stirring the reaction mixture of step (4) at a temperature of about 25 °C to about 30 °C for about 4 to about 5 hours;
(6) isolating and purifying compound (VI).
The process as described above further comprises optionally, converting the pure compound-VI into mebeverine free base or a pharmaceutically acceptable salt thereof.
In one embodiment, in step (1) compound (III) and a base are dissolved in suitable solvent and stirred for about 10 to 15 minutes at about 25 °C to about 28 °C.

In one embodiment, the base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, potassium phosphate, triethylamine and pyridine.
In an embodiment, the base is an inorganic base.
In an embodiment, the base is potassium carbonate.
In another embodiment, in step (2) compound (IV) dissolved in a suitable solvent is added to the solution of (1) and stirred at about 100 to 120 rpm, at about 60 °C to 62 °C for about 25 to about 30 hours.
The suitable solvent is selected from the group consisting of N,N-dimethyIformamide (DMF), N, N- dimethylacetamide (DMA), dimethylsulfoxide (DMSO), l-methyl-2-pyrrolidinone, pyridine, acetic anhydride and mixtures thereof.
In another embodiment, the suitable solvent is dimethylsulfoxide (DMSO).
In another embodiment, in step (3) the compound (V) is obtained as pale yellow slurry by cooling the reaction temperature to about 25 °C to about 30 °C.
In another embodiment, in step (4), polar protic solvent or mixture thereof and a base are added to compound (V).
In another embodiment, the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium phosphate, triethylamine and pyridine.
In a further embodiment, the base is sodium hydroxide.
In an embodiment, the polar protic solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, n-propanol and isobutanol, or a mixture thereof.
In another embodiment, the solvent used is a mixture of polar protic solvents.
In another embodiment, the mixture of polar protic solvents is a mixture of water and an alcoholic solvent.

In another embodiment, the mixture of polar protic solvents is a mixture of methanol and water.
In another embodiment, ratio of the alcohol to water in the mixture of polar protic solvents ranges from 1:1 to 10:10 as v/v (volume/volume). Preferably, the ratio of the alcohol to the water ranges from 1:1 to 10:5 as v/v (volume/volume).
In another embodiment, the ratio of alcohol to water (alcohol: water) is 2: 1 (v/v).
In another embodiment, the mixture of polar protic solvents comprises methanol (MeOH) and water (MeOH: water) in the ratio of 2: 1 (v/v).
In another embodiment, there is provided a method for the purification of compound (VI), the process comprising treating compound (VI) with a suitable solvent and isolating pure compound (VI).
In a general aspect, the present invention relates to an improved process for the preparation of
Mebeverine (I) or a pharmaceutically acceptable salt thereof comprising,
(x) reacting compound (IV) with compound (Ilia) to obtain 4-(ethyl(l-(4-
methoxyphenyl)propan-2-yl)amino)butyl acetate (V);
(y) in situ hydrolysis of compound (V) of step (x) to obtain 4-(ethyl(l-(4-methoxyphenyl)
propan-2-yl)amino)butan-l-ol (VI);
(z) reacting compound (VI) of step (y) with compound (Villa).
The process of the present invention as per the general aspect described above is illustrated in the following Scheme-II,

In an embodiment, the Leaving group 'L' at compound (Villa) is selected from halogen, alkyl or aryl sulfonyloxy, alkyl or aryl sulfate, or alkoxy. More preferably, 'L' is chloro, bromo, iodo, benzenesulfonyloxy, p-toluenesulfonyloxy, methanesulfonyloxy, or t-butoxy.
In a further embodiment, there is provided a process for the purification of compound (VI). The process comprises of
(a) removing the alcoholic solvent preferably by distillation and adding water and suitable solvent to the reaction mass;
(b) stirring the reaction mass for about 15 to 20 minutes;
(c) separation of the organic and aqueous layers;
(d) adding suitable solvent to the aqueous layer, stirring for about 15 to 20 minutes; and separating the organic and aqueous layers;
(e) combining the organic layers of step (c) and step (d) and adding water;
(f) adding acid to the solvent mixture of step (e) at about 10 to about 15 °C;
(g) stirring the solvent mixture of step (f) at about 25 to about 30 °C for about 15 to 20
minutes and separating the organic and aqueous layers;
(h) adding suitable solvent to the aqueous layer, stirring the solvent mixture for about 15 to 20 minutes and separating the organic and aqueous layers;

(i) adding suitable solvent to the aqueous layer and cooling the reaction mixture to about 10 to about 15 °C;
(j) adding a base to the biphasic solution of step (i), and stirring the solvent mixture for about 10 to 15 minutes at about 10 to about 15 °C;
(k) stirring the solvent mixture of step (j) at about 25 to about 30 °C for about 15 to 20 minutes and separating the organic and aqueous layers;
(1) adding suitable solvent to the aqueous layer of step (k) and stirring the solvent mixture for about 15 to 20 minutes and separating the organic and aqueous layers; (m) combining organic layers of step (k) and step (1) and washing with a brine solution; (n) removal of the organic layer, preferably by distillation at about 55 °C to about 60 °C under vacuum for about 1 hour; (o) isolation of the compound (VI) as pale yellow to brown oil.
A suitable solvent is selected from the group consisting of ketones such as acetone, 2-butanone, 2-propanone; esters such as methyl acetate, ethyl acetate, propyl acetate; ethers such as tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, terf-butanol; hydrocarbons such as toluene, benzene, xylene, cyclohexane; water or mixtures thereof. Preferably, the solvent is a hydrocarbon. Preferably the solvent is toluene.
In another aspect, the present invention relates to an improved process for the preparation of compound of formula (VI) wherein the said compound has impurities not more than 8%.
In a further embodiment, there is provided an improved process for the preparation of compound (VI) (4-(ethyl(l-(4-methoxyphenyl)propan-2-yl)amino)butan-l-ol), wherein the compound (VI) contains total amount of un-reacted compound (IV) as impurities in a quantity less than 3.5 %.
In a further embodiment, there is provided an improved process for the preparation of compound (VI) (4-(ethyl(l-(4-methoxyphenyl)propan-2-yl)amino)butan-l-ol), wherein the compound (VI) contains total amount of un-reacted compound (V) as impurities in a quantity less than 0.5 %.
In a further embodiment, purity of the compound (VI) is about > 96%.

The pure product, 4-(ethyl(l-(4-methoxyphenyl)propan-2-yl)amino)butan-l-ol (compound (VI)) was further converted to mebeverine free base or pharmaceutically acceptable salt thereof by a process known in the art, for instance, the process described in US patent No. 3,254,112; wherein 4-(ethyl(l-(4-methoxyphenyl)propan-2-yl)amino)butan-l-ol (compound (VI)) is reacted with 3,4-dimethoxy benzoylchloride.
The processes reported in the prior art for the synthesis of compound (VI) involves use of toxic solvents, such as benzene; and use of genotoxic intermediates. The volumes of the solvent used in the instant process are very low, hence the batch size of each step can be increased to reduce the overall cycle time, providing high yields of compound (VI). The hydrocarbon solvent, namely toluene was recovered at each stage, thus demonstrating an environmental friendly process. The overall effluent load is very low.
Advantageously, the above identified elements of the process of the instant invention effectively contribute to the reduction of overall cost of the process.
The invention is further illustrated by the following examples which are provided to be exemplary of the invention, and do not limit the scope of the invention. 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.
EXAMPLES
Example-1: Preparation of 44-(ethyl(l-(4-methoxyphenyl)propan-2-yl)amino)butan-l-ol
(the compound VI)
In a jacketed glass reactor with anchor stirrer, air condenser and thermometer, was charged 171.54 g of 4-bromobutyl acetate (compound (III)), 25 mL of dimethyl sulfoxide (DMSO) and 78.64 g of anhydrous potassium carbonate powder followed by addition of a solution of N-ethyl-l-(4-methoxyphenyl)propan-2-amine (100 g) (compound (IV)) in 25 mL of DMSO. The reaction mixture was heated at a temperature of 60 °C to 62 °C for 25 hours to 30 hours and stirred at 100 rpm to 120 rpm. The reaction mixture was cooled to room temperature and charged with 200 mL of methanol, 100 mL of demineralized water (DM water) and 162 mL of aqueous sodium hydroxide (62 g in 100 mL demineralized water). The organic solvent was evaporated under vacuum at 55-55 °C to obtain a thick pale yellow slurry. The reaction mass

was cooled to room temperature, and was stirred in 200 mL DM water and 150 mL of toluene. The impurities were removed by extraction and washing with toluene and DM water. The organic layer was separated and subjected to distillation to obtain compound (VI) as pale yellow to brown oil. Yield: 91%
Example-2: Preparation of Mebeverine free base
100.0 mL of toluene, 75.5 g of the Veratric acid, 67.25 g of thionyl chloride and 0.5 ml of N,N-dimethylforrnarnide (DMF) were charged in a flask under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was heated at 55 to 60°C for 3 hours to 4 hours. After the completion of the reaction, thionyl chloride and toluene were removed by distillation to obtain a thick oil. 350 mL of toluene was added to the thick oil and one volume (about 100 mL) was distilled out under vacuum. To this reaction mixture was added 100 g of compound (VI) dissolved in 50 mL toluene, and 38.5 g of triethylamine under nitrogen atmosphere at 10 °C to 20 °C. The reaction mixture was stirred for 3 hours to 5 hours. A brown oil solution was obtained. The solution was washed with 1% aqueous sodium hydroxide, 5% brine solution and DM water. The organic layer was subjected to distillation to obtain Mebeverine as a free base.
We claim
A process for the preparation of Mebeverine (I) or a pharmaceutically acceptable salt thereof, of the following formula;
comprising the steps;
(x) reacting N-ethyl-l-(4-methoxyphenyl)propan-2-amine (IV) of following formula
with compound (Ilia) of following formula,

in the presence of a base to obtain 4-(ethyl(l-(4-methoxyphenyi)propan-2-yl)amino)butyl acetate (V) of following formula;
(y) 'in situ' hydrolysis of compound (V) of step (x) to obtain 4-(ethyl(l-(4-methoxyphenyl) propan-2-yl)amino)butan-l-ol (VI) of following formula;
in the presence of a base and a solvent mixture, and
(z) reacting compound (VI) of step (y) with compound (Villa) of following formula,
in the presence of a base.
The process according to claim 1, wherein the base used in step (x) and step (z) is
selected from the group consisting of sodium carbonate, potassium carbonate, cesium
carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium
hydroxide, potassium phosphate, triethylamine and pyridine.
The process according to claim 1, wherein the base used in step (y) for hydrolysis is

selected from sodium hydroxide, potassium hydroxide or lithium hydroxide.
4. The process according to claim 1, wherein the solvent mixture used in step (y) is a
mixture of water and an organic solvent selected from aromatic hydrocarbon, a
halogenated hydrocarbon, an alcohol, an ester, an ether, a ketone, a nitrile, an amide, a
sulfoxide or a lactam.
5. The process according to claim 1, wherein the solvent mixture at step (y) is a mixture
of water and alcoholic solvent.
6. The process according to claim 1, wherein the Leaving group 'L' in compound (Villa) is selected from halogen, alkyl or aryl sulfonyloxy, alkyl or aryl sulfate or alkoxy.
7. A process for the preparation of 4-(ethyl(l-(4-methoxyphenyl) propan-2-yl)amino)butan-l-ol (VI) of following formula,
comprising the steps;
(A) reacting N-ethyl-l-(4-methoxyphenyl)propan-2-amine (IV) of following formula
with compound (III) of following formula,
in the presence of potassium carbonate in DMSO to obtain 4-(ethyl(l-(4-methoxyphenyl)propan-2-yl)amino)butyl acetate (V) of following formula;

(B) 'z'« situ' hydrolysis of compound (V) of step (A) in the presence of sodium
hydroxide and a solvent mixture comprising water and methanol.
The process according to claim 1 or claim 7, wherein the 4-(ethyl(l-(4-
methoxyphenyl)propan-2-yl)amino)butan-l-ol (VI) has a purity of about > 96%
(HPLC).