DESC:A PROCESS FOR THE PREPARATION OF MEBEVERINE
FIELD OF THE INVENTION
The present application relates to a process for the preparation of Mebeverine and its salts.
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:

The process of the present invention has advantages of improved yield and increased productivity which affords a significantly greater weight of Mebeverine and its pharmaceutically acceptable salts. The process is also industrially scalable, and cost effective.
SUMMARY OF THE INVENTION
In the first embodiment the present application provides a process for the preparation of compound of formula I, comprising:
a) reacting a compound of formula II with a compound of formula III to give a compound of formula IV;
wherein R is a lower alkyl group and X a leaving group,
b) hydrolysing the compound of formula IV obtained in step a) to give a compound of formula V;

wherein R is as defined above,
c) condensing the compound of formula V obtained in step b) with a compound of formula VI to give Mebeverine;
wherein X is leaving group;
d) optionally, converting Mebeverine obtained in step c) to its pharmaceutically acceptable salts.
In the second embodiment the present application provides a process for the preparation of compound of formula I, comprising:
a) hydrolysing a compound of formula IV to give a compound of formula V;

wherein R is a lower alkyl group;
b) condensing the compound of formula V obtained in step a) with a compound of formula VI to give Mebeverine;
wherein X is leaving group;
c) optionally, converting Mebeverine obtained in step b) to its pharmaceutically acceptable salts.
In the third embodiment the present application provides a process for the preparation of compound of formula I, comprising, condensing the compound of formula V with a compound of formula VI to give Mebeverine;
wherein X is leaving group;
b) optionally, converting Mebeverine obtained in step a) to its pharmaceutically acceptable salts.
In the fourth embodiment the present application provides a process for the preparation of compound of formula IV, comprising:
a) reacting a compound of formula II with a compound of formula III to give a compound of formula IV;
wherein R is a lower alkyl group and X a leaving group.
In the fifth embodiment the present application provides a process for the preparation of compound of formula V, comprising, hydrolysing the compound of formula IV to give a compound of formula V;

wherein R is as defined above.
In the sixth embodiment the present application provides a process for the preparation of compound of formula V, comprising:
a) reacting a compound of formula II with a compound of formula III to give a compound of formula IV;
wherein R is a lower alkyl group and X a leaving group.
b) hydrolysing the compound of formula IV obtained in step a) to give a compound of formula V;

wherein R is as defined above.
In the seventh embodiment of the present application provides a pharmaceutical composition comprising Mebeverine or its pharmaceutically acceptable salts prepared by the process of the present application, and one or more pharmaceutically acceptable excipients.
DETAILED DESCRIPTION OF THE INVENTION
In the aspects, the present application provides a process for the preparation of compound of formula I, comprising:
a) reacting a compound of formula II with a compound of formula III to give a compound of formula IV;
wherein R is a lower alkyl group and X a leaving group;
b) hydrolysing the compound of formula IV obtained in step a to give a compound of formula V;

wherein R is as defined above;
c) condensing the compound of formula V obtained in step b) with a compound of formula VI to give Mebeverine;
wherein X is leaving group;
d) optionally, converting Mebeverine obtained in step c) to its pharmaceutically acceptable salts.
In aspects, the reaction of compound of formula II with compound of formula III may be performed in a suitable solvent in presence of a base and optionally in the presence of phase transfer catalyst. The solvents includes but not limited to water, ether solvent such as tetrahydrofuran, 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 is a mixture of an aromatic solvent and water. More specifically, the solvent may be a mixture of toluene and water. The base includes but not limited to organic base such as triethylamine, diisopropyl ethylamine and the like; inorganic base such as sodium hydroxide, potassium carbonate and the like. Specifically, the base may be an inorganic base. More specifically, the base may be potassium carbonate. 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 reaction between compound of formula II and the compound of formula III 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 between compound of formula II and the compound of formula III 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 IV may be carried forward to the next step without isolation from the reaction mass or the compound of formula IV may be isolated from the reaction mass by any method known in the art. Specifically, the compound of formula IV may be isolated from the reaction mass by filtration.
In aspects, the compound of formula IV may be hydrolysed in a suitable solvent in presence of a suitable base to provide compound of formula V. The suitable solvent may include but not limited to alcohol solvent such as methanol, ethanol, 2-propanol, n-butanol and the like; ketone solvent such as acetone, methyl ethyl ketone and the like; ether solvent such as tetrahydrofuran, diethyl ether and the like. Specifically, the solvent may be an alcohol solvent. More specifically, the solvent may be methanol. The base includes but not limited to organic base such as triethylamine, diisopropyl ethylamine and the like; inorganic base such as sodium hydroxide, potassium carbonate and the like. Specifically, the base may be an inorganic base. More specifically, the base may be sodium hydroxide. The resulting compound of formula V may be carried forward to the next step without isolation from the reaction mass or the compound of formula V may be isolated from the reaction mass by any method known in the art. Specifically, the compound of formula V may be isolated from the reaction mass by filtration.
In aspects, the condensation of compound of formula V with compound of formula VI may be performed in a suitable solvent optionally in the presence of a suitable catalyst to provide Mebeverine. The solvents includes but not limited to water, ether solvent such as tetrahydrofuran, 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 is an aromatic solvent. More specifically, the solvent may be toluene. The catalyst includes but not limited to sulphuric acid, hydrochloric acid, p-toluene sulfonic acid, thionylchloride and phosphorous oxychloride and the like. Specifically, the catalyst may be p-toluene sulfonic acid. The resulting Mebeverine may be carried forward to the next step without isolation from the reaction mass or it may be isolated from the reaction mass by any method known in the art. Specifically Mebeverine may be isolated from the reaction mass by filtration.
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.
The compound of formula II, III and VI used as starting materials may be prepared by methods known in the literature or by methods as described in the present application.
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.
Unless otherwise specified, the term “lower alkyl group” as used in the definition of the general formulae III and IV in this specification means a linear or branched carbon chain having 1 to 6 carbon atoms. Accordingly, the “lower alkyl group” means linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl groups. Among these groups, alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl and butyl groups are preferred, and a methyl group is more preferred.
The leaving group X embraces, for example, a halogen atom, a hydroxyl group, a lower alkoxy group, a phenoxy group and an imidazolyl group.
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.
The term "pharmaceutical composition" is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.
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 N-ethyl-1-(4-methoxyphenyl)propan-2-amine
To a solution of 4-methoxyphenylacetone (200.0 gm) in methanol(1200 ml) was added acetic acid (7.2 gm) at room temperature, then reaction mass cooled to -5 to 0 0C. After stirring for 10min. 70% aqueous ethylamine (500 ml) was added and stirred for 1 hour. To this reaction mixture sodium borohydride (33.83 gm) was added in 5 lots, further stirred for 2 hours. The reaction was monitored by TLC (Thin layer chromatography). The reaction mass was then evaporated under reduced pressure, thus obtained crude was acidified with concentrated hydrochloric acid (1.25 ml). The above aqueous solution was washed with toluene (200 ml). Then the pH of aqueous solution was adjusted to basic using sodium hydroxide solution (200 ml). The above solution was extracted with toluene (600 ml) and dried over sodium sulphate and concentrated under reduced pressure to give titled compound.
Yield: 233.2 gm
Example: 2: Preparation of 4-(N-ethyl-N-(1-(4-methoxyphenyl) propan-2-yl) amino) butyl acetate
To a solution of N-ethyl-1-(4-methoxyphenyl) propan-2-amine (117.0 gm) in toluene (300 ml) was added potassium carbonate (250.0 gm), 4-bromobutylacetate (236.0 gm), tetra butyl ammonium bromide (2.34 gm) and water (234 ml) at room temperature. The reaction mixture was stirred at about 95-100 0C for about 35-36 hours. After completion of the reaction, water (234 ml) was added and separated toluene layer, again washed with water (117 ml). The pH of the reaction medium was acidified with concentrated hydrochloric acid (68 ml). The aqueous layer was washed with toluene (117 ml). The pH of the aqueous solution basified with aqueous sodium hydroxide (50 ml). The above solution was extracted with toluene (234 ml), dried over sodium sulphate and concentrated under reduced pressure to give the titled compound.
Yield: 176.0 gm
Example: 3: Preparation of 4-(N-ethyl-N-(1-(4-methoxyphenyl) propan-2-yl) amino) butan-1-ol
To a solution of methanol (245 ml) and water (245 ml), 4-(N-ethyl-N-(1-(4-methoxyphenyl) propan-2-yl) amino) butyl acetate (245.0 gm), sodium hydroxide (245 ml) were added and reaction mass cooled to 10 0C. The reaction mass was stirred for 2 hours at room temperature. On completion of reaction water (1000 ml) and toluene (490 ml) were added to reaction mixture and stirred for 20 min. Toluene layer was separated, further aqueous layer extracted with toluene (245 ml). All the organic layers were combined and washed with water (490 ml). The toluene layer was evaporated under reduced pressure to give the titled compound.
Yield: 212.0 gm
Example: 4: Preparation of Mebeverine
To a stirred solution of 4-(N-ethyl-N-(1-(4-methoxyphenyl) propan-2-yl) amino) butan-1-ol (148.0 gm) in toluene (964 ml), 3,4-dimethoxybenzoic acid (121.0 gm) and p-tolunesulfonic acid (190.72 gm) were added at room temperature, slowly the temperature of the reaction mass was increased to 110 0C and maintained for 20-26 hours. After the completion of reaction, reaction mass was cooled to room temperature, water (1480 ml) was added to reaction mixture and stirred for 10 min. The pH of the reaction mixture was adjusted to 8.5 - 9.5 by adding aqueous sodium hydroxide solution (71.04 ml) and stirred for 15-20 min. Both the layers were separated, toluene layer dried over sodium sulphate and evaporated under vacuum to give Mebeverine.
Yield: 212.0 gm
Example-5: Preparation of Mebeverine Hydrochloride
To a solution of Mebeverine (212.0 gm) in methanol (740 ml) at 0-5 0C, was slowly added methanolic hydrochloride solution (120.5 ml) and stirred for 10-20 min. Reaction mass slowly brought to room temperature and stirred for 40- 60 min. Then the reaction mass was distilled under vacuum to get crude compound and co-distilled with ethylacetate (148 ml). To this crude product ethylacetate (742 ml) was added and stirred for 2-3 hours (white solid precipitation was observed). The obtained solid was filtered, washed with ethylacetate (74 ml) and dried under vacuum to give the titled compound as a white solid.
Yield: 188.0 gm
Example-6: Purification of Mebeverine Hydrochloride
To a 10% solution of isopropyl alcohol (104 ml) and ethyl acetate (936 ml), Mebeverine Hydrochloride (130.0 gm) was added at room temperature and reaction mass was heated to 80-85 0C for 30 min. To the clear solution activated charcoal (6.5 gm) was added in hot condition and heating continued for 30 min. After 30min., reaction mass was filtered in hot condition over hyflow bed. Further hyflow bed washed with 10% isopropyl alcohol (6.5 ml) and ethylacetate (58.5 ml) mixture. Filtrates were allowed to stir for 2-3 hours at 0-5 0C, thus formed white solid, filtered and dried in hot air oven at 60 0C, to give pure Mebeverine Hydrochloride.
Yield: 108.0 gm
Example-7: Preparation of 4-bromobutyl acetate
To a cooled solution of Tetrahydrofuran (450.0 gm) at 0-5 0C, was slowly added 33% HBr in acetic acid (1000 ml) and reaction continued for 2-3 hours at same temperature. After completion of the reaction, solvent was evaporated and diluted with water (450 ml), extracted with dichloromethane (600 ml) and followed by 10% sodium bicarbonate solution (150.0 ml) washing. The dichloromethane layer was dried over sodium sulphate and concentrated under vacuum to give titled compound.
Yield: 673.0 gm ,CLAIMS:1) A process for the preparation of Mebeverine or its pharmaceutically acceptable salts, comprising:
a) reacting a compound of formula II with a compound of formula III to give a compound of formula IV;
b) hydrolysing the compound of formula IV obtained in step a) to give a compound of formula V;

c) condensing the compound of formula V obtained in step b) with a compound of formula VI to give Mebeverine;
d) optionally, converting Mebeverine obtained in step c) to its pharmaceutically acceptable salts,
wherein R is a lower alkyl group and X a leaving group.

2) A process for the preparation of Mebeverine or its pharmaceutically acceptable salts, comprising:
a) hydrolysing a compound of formula IV to give a compound of formula V;

b) condensing the compound of formula V obtained in step a) with a compound of formula VI to give Mebeverine;
c) optionally, converting Mebeverine obtained in step b) to its pharmaceutically acceptable salts,
wherein R is a lower alkyl group and X a leaving group.

3) A process for the preparation of Mebeverine or its pharmaceutically acceptable salts, comprising:
a) condensing the compound of formula V with a compound of formula VI to give Mebeverine;
wherein X is leaving group;
b) optionally, converting Mebeverine obtained in step a) to its pharmaceutically acceptable salts.

4) The process according to claim 1, step (a), wherein the reaction of compound of Formula II with the compound of Formula III is carried out in the presence of (a) a phase transfer catalyst and (b) a base.

5) The process according to claim 4, wherein the phase transfer catalyst is tetrabutyl ammonium bromide and the base is potassium carbonate.

6) The process according to claims 1 and 2, wherein hydrolysis of compound of formula IV is carried out in the presence of a base.

7) The process according to claim 6, wherein the base is sodium hydroxide.

8) The process according to claims 1, 2 and 3, wherein the condensation of compound of Formula V with the compound of Formula VI is carried out in the presence of catalyst.

9) The process according to claim 8, wherein the catalyst is selected from sulphuric acid, hydrochloric acid, p-toluene sulfonic acid, thionylchloride and phosphorous oxychloride.

10) A pharmaceutical composition comprising Mebeverine obtained in claims 1, 2 or 3 as an active ingredient together with pharmaceutically acceptable carriers and/or excipients.