DESC:CROSS REFERENCE TO RELATED APPLICATION

This patent application claims the benefit of priority to Indian Provisional Patent Application No. 202041010209, filed on March 10, 2020, which is incorporated herein by reference in their entirety.

FIELD OF THE INVENTION
The present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of Otilonium bromide in high yield and purity.
BACKGROUND OF THE INVENTION
U.S. Patent No. 3,536,723 (hereinafter referred to as the US‘723 patent) discloses p-(2-alkyloxy-benzoyl)-aminobenzoates of N-alkylamino-alkyl, the quarternary ammonium salts thereof and their preparation. These compounds have antispastic-spasmolytic activities and coronary-dilatory properties. Among them, Otilonium bromide, chemically named as N,N-Diethyl-N-methyl-2-[[4-[[2-(octyloxy)benzoyl]amino]benzoyl]oxy]ethanaminium bromide, is a selective anti-spastic-spasmolytic agent used to relieve spasmodic pain of the gut, especially in irritable bowel syndrome. Otilonium bromide is represented by the following structural formula I:

Otilonium bromide was approved by Central Drugs Standard Control Organization (CDSCO) for use in the treatment of irritable bowel syndrome, painful spastic condition of distal enteric tract and is sold under the brand name Colirid. Colirid is available in the market as 40 mg tablets.
Various processes for the preparation of Otilonium bromide are apparently described in U.S. Patent No. US 3,536,723; Chinese Patent Application Publication Nos. CN 103030572 A and CN 105037193 A, and Journal of Medicinal Chemistry (1973), 16(9), 1063-1065.
U.S. Patent No. 3,536,723 describes several general synthetic routes for the preparation of Otilonium bromide. One of the synthetic routes described in US’723 patent is depicted in scheme 1:

The other synthetic routes described in US’723 patent are depicted below in schemes 2-5:

Chinese Patent Application Publication No. CN 103030572 A (hereinafter referred to as the CN’572 publication) discloses a synthetic process for the preparation of Otilonium bromide. The said synthetic route is depicted in scheme-6:

Chinese Patent Application Publication No. CN 105037193 A (hereinafter referred to as the CN’193 publication) discloses a synthetic process for the preparation of Otilonium bromide. The said synthetic route is depicted in scheme-7:

The processes for the preparation of Otilonium bromide as described in the aforementioned prior art suffers from several disadvantages and shortcomings such as (i) the process involves the use of expensive chemicals such as 2-diethylamino ethanol, 2-diethylamino ethyl chloride; (ii) the process involves the use of highly reactive, pyrophoric and difficult to handle reagents such as sodium metal; (iii) the process involves the use of highly flammable and/or toxic solvents such as hexane and pyridine; and (iv) the process involves multiple recrystallizations and column chromatographic purifications.
A need still remains for simple, cost effective, consistently reproducible and environmentally friendly processes for preparing Otilonium bromide with high yield and purity.

SUMMARY OF THE INVENTION
Provided herein is a novel, commercially viable and industrially advantageous process for the preparation of Otilonium bromide in high yield and with high purity.
In one aspect of the present invention, Otilonium bromide is prepared by a process comprising the following steps: (a) 2-hydroxybenzoic acid is reacted with methanol in presence of a suitable activating agent to produce 2-hydroxy benzoic acid methyl ester; (b) 2-hydroxy benzoic acid methyl ester is reacted with 1-chlorooctane to produce 2-(octyloxy)benzoic acid methyl ester; (c) 2-(octyloxy)benzoic acid methyl ester is hydrolyzed with sodium hydroxide in presence of dilute hydrochloric acid to produce 2-(octyloxy)-benzoic acid; (d) 2-(octyloxy)benzoic acid is reacted with 4-aminobenzoic acid in presence of triethylamine to produce 4-[2-(octyloxy)-benzoylamino]-benzoic acid; (e) 4-[2-(octyloxy)-benzoylamino]-benzoic acid is further reacted with ethylenedichloride and diethylamine in presence of sodium carbonate to produce N,N-diethyl-2-[4-(2-octyloxy)benzoylamino)benzoyloxy]ethylamine; and (f) N,N-diethyl-2-[4-(2-octyloxy)benzoylamino)benzoyloxy]ethylamine is finally reacted with methylbromide in acetonitrile to produce Otilonium bromide.
The novel process for the preparation of Otilonium bromide disclosed in the present invention may be represented by a schematic diagram as depicted in scheme-8:

The process for the preparation of Otilonium bromide described herein has the following advantages over the processes described in the prior art:
i) the process involves the use of cheaper raw materials such as ethylene dichloride and diethyl amine;
ii) the process avoids the use of a expensive chemicals such as 2-diethylaminoethanol and 2-diethylamino ethyl chloride;
iii) the process avoids the use of highly reactive, pyrophoric and difficult to handle reagent such as sodium metal;
iv) the process avoids the use of highly flammable and highly toxic solvents such as hexane and pyridine.

DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, there is provided a process for the preparation of Otilonium bromide of formula I:

which comprises:
a) reacting 2-hydroxybenzoic acid of formula VII:

with methanol in presence of an activating agent to produce 2-hydroxybenzoic acid methyl ester of formula VI:

b) reacting the compound of formula VI with 1-chlorooctane in presence of a suitable base in a suitable solvent to produce 2-(n-octyloxy)benzoic acid of formula V:

c) reacting the compound of formula V with 4-aminobenzoic acid of formula (IV):

or a salt thereof, in the presence of an alkyl or aryl chloroformate and a suitable base in a suitable solvent to produce 4-[2-(n-octyloxy)-benzoylamino]-benzoic acid of formula III:

d) reacting the compound of formula III with ethylene dichloride and diethylamine in the presence of a suitable base using a suitable solvent to produce N,N-diethyl-2-[4-(2-(n-octyloxy)-benzoylamino)benzoyloxy]ethylamine of formula II:

e) reacting the compound of formula II with methyl bromide in a suitable solvent to produce Otilonium bromide of formula I, and optionally purifying and/or recrystallizing the resulting compound of formula I with a suitable solvent or a mixture of suitable solvents to produce highly pure compound of formula I.
Unless otherwise specified, the term ‘base’ as used herein includes, but is not limited to, organic bases and inorganic bases.
In one embodiment, the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, sodium amide, potassium amide, lithium amide, ammonia, and mixtures thereof.
In one embodiment, the organic base is selected from the group consisting of dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di n-butylamine, diisobutylamine, triethylamine, tributylamine, tert-butyl amine, and mixtures thereof.
Unless otherwise specified, the solvent used for isolating, purifying and/or recrystallizing the compounds obtained by the processes described in the present invention is selected from the group consisting of water, an alcohol, a ketone, an ether, an ester, a hydrocarbon, a halogenated hydrocarbon, and mixtures thereof. Specifically, the solvent is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, butyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.
Unless otherwise specified, the carbon treatment is carried out by methods known in the art, for example, by stirring the reaction mass/solution with finely powdered carbon at a temperature of about 40°C to the reflux temperature for at least 5 minutes, specifically at the reflux temperature; and filtering the resulting mixture through charcoal bed to obtain a filtrate containing compound by removing charcoal. Specifically, finely powdered carbon is a special carbon or an active carbon.
Unless otherwise specified, the term ‘salt’ as used herein may include acid addition salts and base addition salts.
Acid addition salts may be derived from organic and inorganic acids. For example, the acid addition salts are derived from a therapeutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, phosphoric acid, succinic acid, maleic acid, fumaric acid, citric acid, glutaric acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid, malic acid, ascorbic acid, and the like.
Exemplary acid addition salts include, but are not limited to, hydrochloride, hydrobromide, sulphate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, tartrate, and the like. A most specific acid addition salt is hydrochloride salt.
Base addition salts may be derived from an organic or an inorganic base. For example, the base addition salts are derived from alkali or alkaline earth metals such as sodium, calcium, potassium and magnesium, ammonium salt and the like.
As used herein, the term “reflux temperature” means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
As used herein, the term “room temperature” refers to a temperature of about 20°C to about 35°C. For example, “room temperature” can refer to a temperature of about 25°C to about 30°C.
In one embodiment, the activating agent used in step-(a) is an acid or an acid chloride. Specifically, the activating agent used in step-(a) is sulfuric acid or thionyl chloride.
In another embodiment, the reaction in step-(a) is carried out at a temperature of about 20°C to the reflux temperature of the solvent used, and most specifically at the reflux temperature of the solvent used. The reaction time may vary between about 30 minutes to about 15 hours, specifically about 2 hours to about 10 hours, and more specifically about 7 to 8 hours.
The reaction mass containing the 2-hydroxybenzoic acid methyl ester of formula VI obtained in step-(a) may be subjected to usual work up methods such as a washing, a quenching, a distillation, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula V, or the compound of formula VI may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula VI may be isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The solvent used for work up, isolation and/or recrystallization of the compound of formula VI obtained by the process described herein is selected from the group as described hereinabove.
In one embodiment, the base used in step-(b) is an organic base or an inorganic base selected from the group as described hereinabove. Specifically, the base used in step-(b) is an inorganic base selected from the group as described hereinabove. A most specific base used in step-(b) is sodium carbonate or potassium carbonate.
In one embodiment, the solvent used in step-(b) include, but are not limited to, a hydrocarbon solvent, an ester, an ether, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof.
Specifically, the solvent used in step-(b) is selected from the group consisting of n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, tetrahydrofuran, 2-methyl-tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, and mixtures thereof. A most specific solvent is N,N-dimethylformamide.
In one embodiment, the reaction in step-(b) is carried out at a temperature of about 10°C to about 120°C, specifically at a temperature of about 50°C to about 110°C. The reaction time may vary between about 5 hours to about 30 hours, specifically about 15 hours to about 22 hours.
The reaction mass containing the 2-(n-octyloxy)benzoic acid of formula V obtained in step-(b) may be subjected to usual work up methods such as a washing, a quenching, a distillation, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula III, or the compound of formula V may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula V may be isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The solvent used for work up, isolation and/or recrystallization of the compound of formula V obtained by the process described herein is selected from the group as described hereinabove.
In one embodiment, the base used in step-(c) is an organic base or an inorganic base selected from the group as described hereinabove. Specifically, the base used in step-(c) is an organic base. A most specific base used in step-(c) is triethylamine.
In one embodiment, the alkyl or aryl chloroformate used in step-(c) is selected from the group consisting of methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, tert-butyl chloroformate, phenyl chloroformate, benzyl chloroformate, p-nitrobenzyl chloroformate, and the like. A most specific chloroformate used in step-(c) is methyl chloroformate or ethyl chloroformate.
In one embodiment, the solvent used in step-(c) include, but are not limited to
a hydrocarbon solvent, a chlorinated hydrocarbon solvent, and mixtures thereof.
Specifically, the solvent used in step-(c) is selected from the group consisting of toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof; and a most specific solvent is dichloromethane.
In one embodiment, the reaction in step-(c) is carried out at a temperature of about -5°C to about 50°C, specifically at a temperature of about 0°C to about 35°C. The reaction time may vary from about 10 minutes to about 20 hours, specifically about 1 hour to about 18 hours.
The reaction mass containing the 4-[2-(n-octyloxy)-benzoylamino]-benzoic acid of formula III obtained in step-(c) may be subjected to usual work up methods such as a washing, a quenching, a distillation, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula II, or the compound of formula III may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula III may be isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The solvent used for work up, isolation and/or recrystallization of the compound of formula III obtained by the process described herein is selected from the group as described hereinabove.
In one embodiment, the base used in step-(d) is an organic base or an inorganic base selected from the group as described hereinabove. Specifically, the base used in step-(d) is an inorganic base. A most specific base used in step-(d) is sodium carbonate or potassium carbonate.
In another embodiment, the ethylene dichloride is used as a solvent and reactant.
In one embodiment, the reaction in step-(d) is carried out at a temperature of about 20°C to about the reflux temperature of the solvent used, specifically at a temperature of about 25°C about 50°C. The reaction time may vary from about 1 hour to about 10 hours, specification about 7 hours to about 8 hours.
The reaction mass containing the N,N-diethyl-2-[4-(2-(n-octyloxy)-benzoylamino)benzoyloxy]ethylamine of formula II obtained in step-(d) may be subjected to usual work up methods such as a washing, a quenching, a distillation, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula I, or the compound of formula II may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula II may be isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The solvent used for work up, isolation and/or recrystallization of the compound of formula II obtained by the process described herein is selected from the group as described hereinabove.
The reaction in step-(e) is carried out in a suitable solvent. Exemplary solvents used in step-(e) includes, but are not limited to, an alcohol, a ketone, a halogenated hydrocarbon, an ether, an ester, a hydrocarbon, and mixtures thereof.
Specifically, the solvent used in step-(e) is selected from the group consisting of methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof. A most specific solvent is ethanol.
In one embodiment, the methyl bromide is used in step-(e) is 2.5M solution of methyl bromide in acetonitrile.
In one embodiment, the reaction in step-(e) is carried out at a temperature of about -5°C to about 45°C, specifically at a temperature of about 0°C to about 35°C. The reaction time may vary from about 1 hour to about 20 hours, specifically about 15 hours to about 18 hours.
The reaction mass containing the Otilonium bromide of formula I obtained in step-(e) may be subjected to usual work up methods such as a washing, a quenching, a distillation, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof.
In one embodiment, the Otilonium bromide of formula I may be isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The solvent used for work up, isolation and/or recrystallization of the compound of formula I obtained by the process described herein is selected from the group as described hereinabove.
The pure Otilonium bromide of formula I obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.
The compounds of formula II, III, V and VI or a salt thereof obtained by the process disclosed herein have a purity of greater than about 90%, specifically greater than about 95%, more specifically greater than about 98%, and most specifically greater than about 99% as measured by HPLC.
The pure Otilonium bromide of formula I obtained by the processes disclosed herein has chemical purity of greater than about 99.5%, specifically greater than about 99.7%, and most specifically greater than about 99.9% as measured by HPLC.
According to another aspect, there is provided a process for the preparation of Otilonium bromide of formula I:

which comprises:
a) reacting 2-(n-octyloxy)benzoic acid of formula V:

with 4-aminobenzoic acid of formula (IV):

or a salt thereof, in the presence of an alkyl or aryl chloroformate and a suitable base in a suitable solvent to produce 4-[2-(n-octyloxy)-benzoylamino]-benzoic acid of formula III:

b) reacting the compound of formula III with ethylene dichloride and diethylamine in the presence of a suitable base using a suitable solvent to produce N,N-diethyl-2-[4-(2-(n-octyloxy)-benzoylamino)benzoyloxy]ethylamine of formula II:

c) reacting the compound of formula II with methyl bromide in a suitable solvent to produce Otilonium bromide of formula I, and optionally purifying and/or recrystallizing the resulting compound of formula I with a suitable solvent or a mixture of suitable solvents to produce highly pure compound of formula I.
The preparation of the Otilonium bromide of formula I as described in the above process can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove.
The solvent used for work up, isolation and/or recrystallization of the compound of formula I obtained by the process described herein is selected from the group as described hereinabove.
According to another aspect, there is provided a process for the preparation of N,N-diethyl-2-[4-(2-(n-octyloxy)-benzoylamino)benzoyloxy]ethylamine of formula II:

which comprises:
a) reacting 2-hydroxybenzoic acid of formula VII:

with methanol in presence of an activating agent to produce 2-hydroxybenzoic acid methyl ester of formula VI:

b) reacting the compound of formula VI with 1-chlorooctane in presence of a suitable base in a suitable solvent to produce 2-(n-octyloxy)benzoic acid of formula V:

c) reacting the compound of formula V with 4-aminobenzoic acid of formula (IV):

or a salt thereof, in the presence of an alkyl or aryl chloroformate and a suitable base in a suitable solvent to produce 4-[2-(n-octyloxy)-benzoylamino]-benzoic acid of formula III:

d) reacting the compound of formula III with ethylene dichloride and diethylamine in the presence of a suitable base using a suitable solvent to produce N,N-diethyl-2-[4-(2-(n-octyloxy)-benzoylamino)benzoyloxy]ethylamine of formula II.

The preparation of the N,N-diethyl-2-[4-(2-(n-octyloxy)-benzoylamino)benzoyloxy]ethylamine of formula II as described in the above process can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove.
The following examples are given only to illustrate the present invention. However, they should not be considered as limitation on the scope or spirit of the invention.

EXAMPLES
Example 1
Preparation of 2-Hydroxybenzoic acid methyl ester
2-Hydroxybenzoic acid (400 g) and methanol (1000 ml) were taken into a reaction flask at room temperature (25-30°C) and the resulting mixture was stirred for 5-10 minutes at the same temperature to obtain a clear solution. The resulting solution was heated to reflux temperature. Thionyl chloride (700 g) was added slowly to the resulting mass at reflux temperature and then stirred for 7-8 hours at the same temperature. The resulting mass was cooled to 10-15°C. The pH of the reaction mass was adjusted to 7 with ammonia solution (156-160 ml). The solvent was distilled off under vacuum to obtain the residue weight of 580-600g. Water (840 ml) was added to the resulting residue at room temperature and the resulting mass was extracted with dichloromethane (420 ml x 1 time and 210 ml x 2 times). The organic layers were combined and washed with saturated sodium bicarbonate solution (165 ml x 2 times). The resulting organic layer was washed with water (165 ml x 2 times). Carbon powder (20 g) was added to the organic layer and stirred for 10 minutes. The resulting mass was filtered and the carbon bed was washed with dichloromethane (200 ml). The solvent was distilled off completely and finally dried under vacuum at 65-75°C to produce 340 g of 2-Hydroxybenzoic acid methyl ester as a residue [Purity by HPLC: 99%].

Example 2
Preparation of 2-(n-Octyloxy)benzoic acid
Dimethylformamide (62.5 ml), 2-hydroxybenzoic acid methyl ester (25 g), potassium carbonate (34 g) and 1-chlorooctane (49 g) were taken into a reaction flask at room temperature. The resulting mass was heated to 100°C and maintained for 21 hours at the same temperature. The resulting mass was cooled to room temperature followed by the addition of water (625 ml) at the same temperature. The resulting mass was cooled to 10-20°C. The pH of the resulting mass was adjusted to 2 with dilute hydrochloric acid solution (1:1). The layers were separated and 30 g of organic layer was collected. Sodium hydroxide solution (13.4 g in 320 ml water) was taken into a reaction flask and the organic layer (30 g) was added. The resulting mass was heated to reflux temperature and then stirred for 6-8 hours at the same temperature. After completion of the reaction, the resulting mass was cooled to room temperature followed by 20-25°C. The pH of the resulting mass was adjusted to 1-2 with conc. Hydrochloric acid solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane (70 ml x 2 times). The organic layers were combined and washed with water (70 ml x 2 times). Carbon (4.34 g) was added to the organic layer and stirred for 10 minutes. The resulting mass was filtered and the carbon bed was washed with dichloromethane (50 ml). The solvent was distilled off completely under reduced pressure to produce 41 g of 2-(n-Octyloxy)benzoic acid (Purity by HPLC: 97.5%).

Example 3
Preparation of 4-[2-(n-Octyloxy)-benzoylamino]-benzoic acid
Dichloromethane (615.2 ml) and 2-(n-Octyloxy)benzoic acid (153.8 g) were taken into a reaction flask at room temperature. The resulting mass was stirred for 5 minutes at room temperature, followed by the addition of triethylamine (63.5 g) at the same temperature. The resulting mass was cooled to 0-5°C followed by drop-wise addition of ethyl chloroformate (60.5 g) at the same temperature. The reaction mass was stirred for 1 hour at 0-5°C followed by the addition of 4-aminobenzoic acid (84 g) and stirred for 5 minutes at the same temperature. Dichloromethane (615 ml) was added to the resulting mass at 0-5°C and stirred for 1 hour at the same temperature. The resulting mass was allowed to room temperature and stirred for 17 hours at the same temperature. The solvent was distilled off completely under vacuum to produce 350 g of solid. Water (3065 ml) was added to the obtained solid and stirred for 10-20 minutes. The pH of the resulting mass was adjusted to 1-2 with conc. hydrochloric acid solution (51 ml). Solid formation was observed. The resulting mass was stirred for 30 minutes at room temperature. The solid obtained was filtered and washed with hydrochloric acid solution (1:1, 769 ml x 2 times) and then washed with water (769 ml x 2 times) to produce 210 g of crude 4-[2-(n-Octyloxy)-benzoylamino]-benzoic acid [Purity by HPLC: 94%].
First Purification:
Crude 4-[2-(n-Octyloxy)-benzoylamino]-benzoic acid (108 g) and ethyl acetate (2376 ml) were taken into a reaction flask at room temperature and stirred for 5 minutes at the same temperature. The resulting mass was heated to reflux temperature and then stirred for 15 minutes at the same temperature. Clear solution was not observed. The undissolved particles were filtered and washed with hot ethyl acetate (25 ml x 2 times). The filtrate was cooled to 0-5°C and stirred for 30 minutes at the same temperature. The solid obtained was filtered and washed with cold ethyl acetate (100 ml x 2 times) to produce 91 g of 4-[2-(n-Octyloxy)-benzoylamino]-benzoic acid, which was further purified using ethyl acetate (2275 g) [Purity by HPLC: 98%] .
Second Purification:
The Pure 4-[2-(n-Octyloxy)-benzoylamino]-benzoic acid (91 g) and ethyl acetate (2875 ml) were taken into a reaction flask at room temperature and stirred for 5 minutes at the same temperature. The resulting mass was heated to reflux temperature and stirred for 15 minutes at the same temperature. Clear solution was observed. Carbon (9.1 g) was added to the resulting solution at reflux temperature and stirred for 5 minutes at the same temperature. The resulting mass was filtered and the carbon bed was washed with hot ethyl acetate (50 ml x 2 times). The filtrate was cooled to room temperature and further cooled to 0-5°C and stirred for 30 minutes at the same temperature. The solid obtained was filtered and washed with cold ethyl acetate (50 ml x 2 times) to produce 75.4 g of pure 4-[2-(n-Octyloxy)-benzoylamino]-benzoic acid [Purity by HPLC: 99%].

Example 4
Preparation of N,N-Diethyl-2-[4-(2-(n-octyloxy)-benzoylamino)benzoyloxy] ethylamine
Ethylene dichloride (177.84 g), 4-[2-(Octyloxy)-benzoylamino]-benzoic acid (30 g), diethyl amine (12.348 g) and sodium carbonate (14.8 g) were taken into a reaction flask at room temperature and the contents were stirred for 5 minutes. The resulting mass was heated to reflux temperature and maintained for 7 hours at the same temperature. The resulting mass was cooled to room temperature followed by the addition of water (125 ml) and ethyl acetate (160 ml) at the same temperature. The resulting mass was stirred for 5 minutes at room temperature. The organic layer was separated. The aqueous layer was extracted with ethyl acetate (160 ml x 2 times). Carbon (1.6 g) was added to the organic layer, stirred for 5 minutes and the carbon bed was washed with water (50 ml x 2 times). The solvent was distilled completely under vacuum to produce 32.5 g of N,N-Diethyl-2-[4-(2-(n-octyloxy)-benzoylamino)benzoyloxy]ethylamine as a residue [Purity by HPLC: 90%].

Example 5
Preparation of Otilonium bromide
N,N-Diethyl-2-[4-(2-(n-octyloxy)-benzoylamino)benzoyloxy]ethylamine (24 g) and ethanol (237 ml) were taken into a reaction flask at room temperature and the contents were stirred for 10 minutes at the same temperature. The resulting mass was cooled to 0-5°C followed by the slow addition of 2.5M methyl bromide in acetonitrile (69 ml) at the same temperature. The resulting mass was stirred for 2 hours at 0-5°C, followed by stirring for 17 hours at room temperature. Carbon (1.1 g) was added to the reaction mass at room temperature and stirred for 10 minutes at the same temperature. The carbon was filtered and the bed was washed with ethanol (50 ml). The solvent was distilled completely under reduced pressure. The resulting mass was cooled to room temperature followed by the addition of acetone (152 ml) at the same temperature. The resulting mass was heated to reflux temperature and stirred for 30 minutes at the same temperature. The resulting mass was cooled to room temperature. The solid obtained was filtered, washed with acetone (24 ml x 2 times) and dried at 60-70°C for 2 hours. The material was unloaded and packed in nitrogen gas seal pack to produce 17 g of crude Otilonium bromide [Purity by HPLC: 99.3%].
Recrystallization:
A mixture of crude Otilonium bromide (40 g) in acetone (200 ml) was taken into a reaction flask at room temperature. The resulting mass was heated to reflux temperature and stirred for 30 minutes at the same temperature. The resulting mass was cooled to room temperature and stirred for 1 hour at the same temperature. The solid obtained was filtered, washed with acetone (40 ml x 2 times) and then dried at 60-70°C for 2 hours. The material was unloaded and packed in nitrogen gas seal pack to produce 32 g of pure Otilonium bromide [Purity by HPLC: 99.7%].

The examples and embodiments are provided only for the purpose of understanding and none of them shall limit the scope of the invention. All variants and modifications as will be envisaged by skilled person are within the spirit and scope of the invention.

The applicant relies upon the provisional specification filed in this application and shall be considered as part and parcel of complete specification
,CLAIMS:We Claim:
1. A process for the preparation of Otilonium bromide of formula I:

which comprises:
a) reacting 2-hydroxybenzoic acid of formula VII:

with methanol in presence of an activating agent to produce 2-hydroxybenzoic acid methyl ester of formula VI:

b) reacting the compound of formula VI with 1-chlorooctane in presence of a suitable base in a suitable solvent to produce 2-(n-octyloxy)benzoic acid of formula V:

c) reacting the compound of formula V with 4-aminobenzoic acid of formula (IV):

or a salt thereof, in the presence of an alkyl or aryl chloroformate and a suitable base in a suitable solvent to produce 4-[2-(n-octyloxy)-benzoylamino]-benzoic acid of formula III:

d) reacting the compound of formula III with ethylene dichloride and diethylamine in the presence of a suitable base using a suitable solvent to produce N,N-diethyl-2-[4-(2-(n-octyloxy)-benzoylamino)benzoyloxy] ethylamine of formula II:

e) reacting the compound of formula II with methyl bromide in a suitable solvent to produce Otilonium bromide of formula I, and optionally purifying and/or recrystallizing the resulting compound of formula I with a suitable solvent or a mixture of suitable solvents to produce highly pure compound of formula I.

2. The process as claimed in claim 1, wherein the activating agent used in step-(a) is an acid or an acid chloride; wherein the base used in step-(b) is an organic base or an inorganic base, wherein the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert. butoxide, potassium tert. butoxide, sodium amide, potassium amide, lithium amide, ammonia, and mixtures thereof; wherein the solvent used in step-(b) is selected from the group consisting of n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, tetrahydrofuran, 2-methyl-tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, and mixtures thereof; wherein the base used in step-(c) is an organic base or an inorganic base, wherein the organic base is selected from the group consisting of dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di n-butylamine, diisobutylamine, triethylamine, tributylamine, tert-butyl amine, and mixtures thereof; wherein the alkyl or aryl chloroformate used in step-(c) is selected from the group consisting of methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, tert-butyl chloroformate, phenyl chloroformate, benzyl chloroformate and p-nitrobenzyl chloroformate; wherein the solvent used in step-(c) is selected from the group consisting of toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof; wherein the base used in step-(d) is an organic base or an inorganic base, wherein inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert. butoxide, potassium tert. butoxide, sodium amide, potassium amide, lithium amide, ammonia, and mixtures thereof; wherein the solvent and reagent used in step-(d) is ethylene dichloride; and wherein the solvent used in step-(e) is selected from the group consisting of methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.
3. The process as claimed in claim 2, wherein the activating agent used in step-(a) is sulphuric acid or thionyl chloride; wherein the inorganic base used in step-(b) is sodium carbonate or potassium carbonate; wherein the solvent used in step-(b) is N,N-dimethylformamide; wherein the organic base used in step-(c) is triethylamine; wherein the alkyl or aryl chloroformate used in step-(c) is methyl chloroformate or ethyl chloroformate; wherein the solvent used in step-(c) is dichloromethane; wherein the inorganic base used in step-(d) is sodium carbonate or potassium carbonate; and wherein the solvent used in step-(e) is ethanol.
4. A process for the preparation of Otilonium bromide of formula I:

which comprises:
a) reacting 2-(n-octyloxy)benzoic acid of formula V:

with 4-aminobenzoic acid of formula (IV):

or a salt thereof, in the presence of an alkyl or aryl chloroformate and a suitable base in a suitable solvent to produce 4-[2-(n-octyloxy)-benzoylamino]-benzoic acid of formula III:

b) reacting the compound of formula III with ethylene dichloride and diethylamine in the presence of a suitable base using a suitable solvent to produce N,N-diethyl-2-[4-(2-(n-octyloxy)-benzoylamino)benzoyloxy]
ethylamine of formula II:

c) reacting the compound of formula II with methyl bromide in a suitable solvent to produce Otilonium bromide of formula I, and optionally purifying and/or recrystallizing the resulting compound of formula I with a suitable solvent or a mixture of suitable solvents to produce highly pure compound of formula I.

5. The process as claimed in claim 4, wherein the base used in step-(a) is an organic base or an inorganic base, wherein the organic base is selected from the group consisting of dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di n-butylamine, diisobutylamine, triethylamine, tributylamine, tert-butyl amine, and mixtures thereof; wherein the alkyl or aryl chloroformate used in step-(a) is selected from the group consisting of methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, tert-butyl chloroformate, phenyl chloroformate, benzyl chloroformate and p-nitrobenzyl chloroformate; wherein the solvent used in step-(a) is selected from the group consisting of toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof; wherein the base used in step-(b) is an organic base or an inorganic base, wherein inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert. butoxide, potassium tert. butoxide, sodium amide, potassium amide, lithium amide, ammonia, and mixtures thereof; wherein the solvent and reagent used in step-(b) is ethylene dichloride; and wherein the solvent used in step-(c) is selected from the group consisting of methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.
6. The process as claimed in claim 5, wherein the organic base used in step-(a) is triethylamine; wherein the alkyl or aryl chloroformate used in step-(a) is methyl chloroformate or ethyl chloroformate; wherein the solvent used in step-(a) is dichloromethane; wherein the inorganic base used in step-(b) is sodium carbonate or potassium carbonate; and wherein the solvent used in step-(c) is ethanol.
7. A process for the preparation of N,N-diethyl-2-[4-(2-(n-octyloxy)-benzoylamino)benzoyloxy]ethylamine of formula II:

which comprises:
a) reacting 2-hydroxybenzoic acid of formula VII:

with methanol in presence of an activating agent to produce 2-hydroxybenzoic acid methyl ester of formula VI:

b) reacting the compound of formula VI with 1-chlorooctane in presence of a suitable base in a suitable solvent to produce 2-(n-octyloxy)benzoic acid of formula V:

c) reacting the compound of formula V with 4-aminobenzoic acid of formula (IV):

or a salt thereof, in the presence of an alkyl or aryl chloroformate and a suitable base in a suitable solvent to produce 4-[2-(n-octyloxy)-benzoylamino]-benzoic acid of formula III:

d) reacting the compound of formula III with ethylene dichloride and diethylamine in the presence of a suitable base using a suitable solvent to produce N,N-diethyl-2-[4-(2-(n-octyloxy)-benzoylamino)benzoyloxy]
ethylamine of formula II.

8. The process as claimed in claim 7, wherein the activating agent used in step-(a) is an acid or an acid chloride; wherein the base used in step-(b) is an organic base or an inorganic base, wherein the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert. butoxide, potassium tert. butoxide, sodium amide, potassium amide, lithium amide, ammonia, and mixtures thereof; wherein the solvent used in step-(b) is selected from the group consisting of n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, tetrahydrofuran, 2-methyl-tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, and mixtures thereof; wherein the base used in step-(c) is an organic base or an inorganic base, wherein the organic base is selected from the group consisting of dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di n-butylamine, diisobutylamine, triethylamine, tributylamine, tert-butyl amine, and mixtures thereof; wherein the alkyl or aryl chloroformate used in step-(c) is selected from the group consisting of methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, tert-butyl chloroformate, phenyl chloroformate, benzyl chloroformate and p-nitrobenzyl chloroformate; wherein the solvent used in step-(c) is selected from the group consisting of toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof; wherein the base used in step-(d) is an organic base or an inorganic base, wherein inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert. butoxide, potassium tert. butoxide, sodium amide, potassium amide, lithium amide, ammonia, and mixtures thereof; and wherein the solvent and reagent used in step-(d) is ethylene dichloride.
9. The process as claimed in claim 8, wherein the activating agent used in step-(a) is sulphuric acid or thionyl chloride; wherein the inorganic base used in step-(b) is sodium carbonate or potassium carbonate; wherein the solvent used in step-(b) is N,N-dimethylformamide; wherein the organic base used in step-(c) is triethylamine; wherein the alkyl or aryl chloroformate used in step-(c) is methyl chloroformate or ethyl chloroformate; wherein the solvent used in step-(c) is dichloromethane; and wherein the inorganic base used in step-(d) is sodium carbonate or potassium carbonate.