DESC:RELATED PATENT APPLICATION(S):

This application claims the priority to and benefit of Indian Patent Application No. 202141027639 filed on June 21, 2021; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION:

The present invention relates to a novel process for the preparation of tranexamic acid. More specifically the present invention relates to a novel process for the preparation of tranexamic acid from 1,4-cyclohexanedimethanol and intermediates thereof.

BACKGROUND OF THE INVENTION:

Tranexamic acid is chemically known as trans-4-(aminomethyl)cyclohexanecarboxylic acid and it is a very well-known drug used as an antifibrinolytic medication to treat or prevent excessive blood loss from major trauma, postpartum bleeding, dental procedures, surgeries, and heavy menstruation. The structure of tranexamic acid is shown in formula I.

Formula I
This compound and its process for preparation are first disclosed in the patents US 3,499,925 and US 3,950,405 respectively. The Patent US 3,950,405 discloses the preparation of tranexamic acid involving the steps of catalytic reducing 4-cyanobenzoic acid in presence of platinum catalyst to cyanocyclohexane-1-carboxylic acid; reducing cyanocyclohexane-1-carboxylic acid to a mixture of cis and trans-4-(aminomethyl)cyclohexanecarboxylic acid; and then heating this mixture in presence of an alkylating agents at a temperature of 160º to 250 ºC to produce exclusively, trans-4-(aminomethyl)cyclohexanecarboxylic acid.

The patent US 3,449,411 discloses the process for the preparation of tranexamic acid from acetamidomethylbenzoic acid, as described in the below scheme, on heating over metal catalyst about 160-180ºC under a pressure of hydrogen, followed by hydrolysis with alkali metal hydroxide at about 180-250 ºC produces tranexamic acid.

The patent US RE30149 discloses the below mentioned process for the preparation of tranexamic acid starting from dimethyl cyclohexane-1,4-dicarboxylate.

The publication Organic. Process Res. Development. 2015, 19, 444-448 discloses the process for the preparation of tranexamic acid, from dimethyl terephthalate as described in the below scheme, where tranexamic acid is prepared from multiple steps.

The use of p-aminomethyl benzoic acid or its derivatives as starting material for the preparation of tranexamic acid is done through catalytic hydrogenation. Generally, the catalysts are noble metals such as Pd, Pt, Rh, Ru and are relatively costlier.

The patent JP 3,763,598 assigned to Asahi Denka Kogyo discloses the preparation of tranexamic acid from 1,4-cyclohexanedimethanol as mentioned below, where the metal azide has been used followed by the metal catalyst for reduction of azide group. Further, this process discloses the need for the highly pure trans-1,4-cyclohexanedimethanol, which greatly affects the purity of tranexamic acid.

The patent application IN 3367/CHE/2010 assigned to Bal Pharma discloses the process for the preparation of tranexamic acid, involved the following steps as shown in the below scheme (i) bromination of 1,4-cyclohexanedimethanol in the presence of sodium bromide and sulfuric acid at about 85° C for 24 hours in water (ii) oxidation of 4-(bromomethyl)cyclohexanemethanol using catalytic TEMPO in sodium hypochlorite at 35° C for 2.5 hours in sodium phosphate buffer in aqueous acetonitrile (iii) ammonolysis of 4-(bromomethyl)cyclohexane-1-carboxylic acid using aqueous ammonia.

The formation of 1,4-(dibromomethyl)cyclohexane during the bromination of 1,4-cyclohexanedimethanol and fractional distillation to reduce this impurity, lowers the yield of 4-(bromomethyl)cyclohexanemethanol. Further, the poor overall yield of tranexamic acid (i.e.) ~12% makes this process dearer to operate on large scale.

The patent application CN 110156620 assigned to CECEP Valiant discloses the preparation of tranexamic acid from 1,4-cyclohexanedimethanol as described below:

All the reported procedures either involve harsh conditions such as high pressure and temperature or produce poor overall yield. Besides the availability of process for the preparation of tranexamic acid in state of the art, there is a need for a novel process for the preparation of pure tranexamic acid that is economically significant and surpass the manufacturing challenges.

OBJECTS OF THE INVENTION:

The primary object of the present invention is to provide an efficient, industry viable and economically significant process for the preparation of tranexamic acid.

Yet another object of the invention is to provide a novel process for the preparation of intermediates which are used during the process for the preparation of tranexamic acid.

SUMMARY OF THE INVENTION:

Accordingly, the present invention discloses and describes a novel process for the preparation of tranexamic acid from 1,4-cyclohexanedimethanol which is economically significant. The present invention also discloses a novel process for the preparation of intermediates which are used during the process for the preparation of tranexamic acid.

The main aspect of the present invention is to provide a process for the preparation of tranexamic acid of formula-I,

Formula I
comprising the steps of:
(i) treating 1,4-cyclohexanedimethanol of formula-V,

with aqueous hydrobromic acid in an organic solvent to obtain 4-(bromomethyl)cyclohexane-1-methanol of formula-IV;

(ii) treating 4-(bromomethyl)cyclohexane-1-methanol of formula-IV with oxidizing agent in the presence of sodium phosphate buffer to obtain 4-bromomethyl cyclohexane-1-carboxylic acid of formula III;

(iii) reacting 4-bromomethyl cyclohexane-1-carboxylic acid of formula-III with benzylamine in presence of a base to obtain a compound of formula-II; and

(iv) converting the compound of formula-II to obtain the tranexamic acid of formula-I.

The step (i) of the present process is carried out at a temperature ranging between 50 °C to reflux temperature of the solvent.

The organic solvent in step (i) is selected from the group comprising of aromatic hydrocarbons such as toluene, xylene, and benzene; aliphatic hydrocarbons such as hexane, heptane, and cyclohexane; or mixtures thereof.

The oxidizing agent in step (ii) is 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) or its derivatives.

The step (ii) of the present process is carried out at a temperature of 30°C to 40°C.

The solvent in step (ii) is selected from a group comprising of aliphatic hydrocarbons such as hexane, heptane, and cyclohexane; aromatic hydrocarbons such as toluene, xylene, and benzene; polar organic solvents such as, methanol, ethanol, propanol, butanol, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide; or mixtures thereof.

The step (ii) of the said process involves addition of sodium hypochlorite and sodium chloride solution to obtain compound of formula III.

The base employed in step (iii) is selected from a group comprising of the alkali metals such as sodium, potassium, lithium; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate or alkali metal hydroxides such as sodium hydroxide, calcium hydroxide, potassium hydroxide.

The step (iii) of the said process is carried out at a temperature of 20 °C to 40 °C.

The solvent in step (iii) is selected from a group comprising of ester such as n-butyl acetate, isobutyl acetate, methyl acetate, ethyl acetate and isopropyl acetate; ethers such as cyclopentyl methyl ether, tetrahydrofuran, tetrahydropyran; ketones such as acetone, methyl isobutyl ketone and N-methyl-2-pyrrolidone; halogenated solvents such as chloroform, dichloromethane, 1,1,1-trichloroethane trichlorethylene, or mixture thereof.

The step (iv) of the said process is carried out at the temperature ranging from 20 ºC to 45 ºC.

The solvent in step (iv) is selected from methanol, ethanol, propanol, butanol, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, water, or mixtures thereof.
Another aspect of the present invention is to provide a process for the preparation of compound of formula-II, an intermediate useful for the preparation of tranexamic acid comprising the step of: treating 4-bromomethyl cyclohexane-1-carboxylic acid of formula-III

with benzylamine to obtain a compound of formula-II.

Another aspect of the present invention is to provide a process for preparation of tranexamic acid of formula-I from a compound of formula-II comprising the step of: converting the compound of formula-II

to tranexamic acid of formula-I.

Formula I

Still another aspect of the present invention is to provide a process for the preparation of tranexamic acid of formula-I,

Formula I
comprising the steps of:
(i) reacting 4-bromomethyl cyclohexane-1-carboxylic acid of formula-III

with substituted benzylamine of formula VI in presence of a base to obtain a compound of formula-IIa; and

Formula VI
wherein, R1 to R5 each independently selected from the group consisting of: hydrogen, hydroxyl, alkyl hydroxyl, alkoxy, substituted or unsubstituted C1 to C20 alkyl, substituted or unsubstituted C2 to C20 alkenyl, substituted or unsubstituted C2 to C20 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted carbonyl, aldehyde, substituted or unsubstituted carboxylate, substituted or unsubstituted ester, substituted or unsubstituted C1 to C20 alkoxy, substituted or unsubstituted carboxamide, substituted or unsubstituted imine,

(ii) converting the compound of formula-IIa to obtain the tranexamic acid of formula-I.

The step (i) of the above process is carried out at a temperature of 25 ºC to 30 ºC and stirred at 95 ºC to 100 °C.

The base employed in step (i) is selected from a group comprising of the alkali metals such as sodium, potassium, lithium; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate or alkali metal hydroxides such as sodium hydroxide, calcium hydroxide, potassium hydroxide.

The solvent in step (i) is selected from a group comprising of ester such as n-butyl acetate, isobutyl acetate, methyl acetate, ethyl acetate and isopropyl acetate; ethers such as cyclopentyl methyl ether, tetrahydrofuran, tetrahydropyran; ketones such as acetone, methyl isobutyl ketone and N-methyl-2-pyrrolidone; or halogenated solvents such as chloroform, 1,1,1-trichloroethane trichlorethylene.

The step (ii) of the said process is carried out at a temperature of 25 ºC to 30 ºC.

The step (ii) is carried out in the presence of palladium on carbon catalyst, and wherein the reaction mixture is pressurized in the range of 5 Kg/cm2 at 70 °C.

The solvent in step (ii) is selected from a group comprising of methanol, ethanol, propanol, butanol, isopropyl alcohol, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, or mixtures thereof.

Yet another aspect of the present invention is to provide a process for the preparation of tranexamic acid of formula-I from a compound of formula-IIa comprising the step of: converting the compound of formula IIa

to obtain the tranexamic acid of formula-I.

Formula I

DETAILED DESCRIPTION OF THE INVENTION:

Accordingly, in one aspect the present invention discloses and describes a novel process for the preparation of tranexamic acid from 1,4-cyclohexanedimethanol which is economically significant. In another aspect the present invention discloses a novel process for the preparation of intermediates which are used during the process for the preparation of tranexamic acid.

First embodiment of the present invention is to provide a novel process for the preparation of tranexamic acid of formula-I,

Formula I
comprising the steps of:
(i) treating 1,4-cyclohexanedimethanol of formula-V,

with aqueous hydrobromic acid in a suitable organic solvent to obtain 4-(bromomethyl)cyclohexane-1-methanol of formula-IV;

(ii) treating 4-(bromomethyl)cyclohexane-1-methanol of formula-IV with oxidizing agent to obtain 4-bromomethyl cyclohexane-1-carboxylic acid of formula III;

(iii) reacting 4-bromomethyl cyclohexane-1-carboxylic acid of formula-III with benzylamine in presence of a base to obtain a compound of formula-II; and

(iv) converting the compound of formula-II to obtain the tranexamic acid of formula-I.

The treating 1,4-cyclohexanedimethanol of formula-V with aqueous hydrobromic acid in a suitable organic solvent to obtain 4-(bromomethyl)cyclohexane-1-methanol of formula-IV according to the step (i) is carried out at temperature ranging from 50 °C to reflux temperature of the suitable solvent.

The suitable solvent for treating 1,4-cyclohexanedimethanol of formula-V with aqueous hydrobromic acid according to the step (i) is selected from the group comprising of aromatic hydrocarbons such as toluene, xylene, and benzene; aliphatic hydrocarbons such as hexane, heptane, cyclohexane; or mixtures thereof, preferably toluene and xylene.

Preferably oxidizing the compound of formula-IV with an appropriate oxidizing agent to obtain a compound of formula-III according to step (ii) is carried out in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) or its derivatives.

The step of treating 4-(bromomethyl)cyclohexane-1-methanol of formula-IV with oxidizing agent according to step (ii) is carried out at temperature ranging from 30°C to 40°C, preferably at 35°C.

The suitable solvent for treating 4-(bromomethyl)cyclohexane-1-methanol of formula-IV with oxidizing agent according to step (ii) is selected from the group comprising of aliphatic hydrocarbons such as hexane, heptane, cyclohexane; aromatic hydrocarbons such as toluene, xylene and benzene; polar organic solvents such as methanol, ethanol, propanol, butanol, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide; or mixtures thereof. In a preferred embodiment the solvent employed in step (ii) is combination of acetonitrile, water, and cyclohexane.

Preferably the step of treating 4-(bromomethyl)cyclohexane-1-methanol of formula-IV with 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) according to step (ii) is carried out in presence of sodium phosphate buffer, followed by addition of sodium hypochlorite and sodium chloride solution to obtain compound of formula III.

The step of reacting 4-bromomethyl cyclohexane-1-carboxylic acid of formula-III with benzylamine to obtain a compound of formula-II according to step (iii) is carried out at temperature ranging from at 20-40 ºC, preferably at 25-30 ºC.

The suitable solvent for treating 4-bromomethyl cyclohexane-1-carboxylic acid of formula-III with benzylamine to obtain 4-((benzylamino)methyl)cyclohexane-1-carbarboxylic acid formula-II according to step (iii) is selected from a group comprising of ester such as n-butyl acetate, isobutyl acetate, methyl acetate, ethyl acetate and isopropyl acetate; ethers such as cyclopentyl methyl ether, tetrahydrofuran, tetrahydropyran; ketones such as acetone, methyl isobutyl ketone and N-methyl-2-pyrrolidone; halogenated solvents such as chloroform, 1,1,1-trichloroethane trichlorethylene, or its mixture thereof, preferably dichloromethane.

The base employed in step (iii) may be selected from a group comprising of the alkali metals such as sodium, potassium, lithium; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate; or alkali metal hydroxides such as sodium hydroxide, calcium hydroxide, potassium hydroxide. In a preferred embodiment, the alkali base employed in step (iii) is sodium hydroxide.

Converting compound of formula-II to tranexamic acid of formula-I according to step (iv) is carried out at the temperature ranging from 20-45 ºC. In a preferred embodiment, the temperature is 25-30 ºC.

Converting compound of formula-II to tranexamic acid of formula-I according to step (iv) is carried out in suitable solvents or a combination of solvents comprising of methanol, ethanol, propanol, butanol, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, water or mixtures thereof. In a preferred embodiment the solvent employed in step (iv) is combinations of methanol and water thereof.

Second embodiment of the present invention is to provide a process for the preparation of compound of formula-II, an intermediate useful for the preparation of tranexamic acid comprising the steps of: reacting 4-bromomethyl cyclohexane-1-carboxylic acid of formula-III,

with benzylamine in a suitable solvent to obtain a compound of formula-II.

The reacting 4-bromomethyl cyclohexane-1-carboxylic acid of formula-III with benzylamine in presence of base according to the second embodiment is carried out at temperature ranging from 25-30 ºC and stirred at 95-100 °C.

The suitable solvent for reacting 4-bromomethyl cyclohexane-1-carboxylic acid of formula-III with benzylamine according to second embodiment is selected from a group comprising of ester such as n-butyl acetate, isobutyl acetate, methyl acetate, ethyl acetate and isopropyl acetate; ethers such as cyclopentyl methyl ether, tetrahydrofuran, tetrahydropyran; ketones such as acetone, methyl isobutyl ketone and N-methyl-2-pyrrolidone; halogenated solvents such as chloroform, 1,1,1-trichloroethane trichlorethylene, or its mixture thereof, preferably dichloromethane.

The base employed in second embodiment is selected from the group comprising of the alkali metals such as sodium, potassium, lithium; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate; or alkali metal hydroxides such as sodium hydroxide, calcium hydroxide, potassium hydroxide. In a preferred embodiment, the alkali base employed in step (iii) is sodium hydroxide.

Third embodiment of the present invention is to provide a process for preparation of tranexamic acid of formula-I from a compound of formula-II comprising the step of: converting the compound of formula-II

to tranexamic acid of formula-I.

Formula I

Converting compound of formula-II to tranexamic acid of formula-I according to third embodiment is carried out at the temperature ranging from 20-45 ºC. In a preferred embodiment, the temperature is 25-30 ºC.

Converting compound of formula-II to tranexamic acid of formula-I according to third embodiment is carried out in suitable solvents or a combination of solvents comprising of methanol, ethanol, propanol, butanol, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, water or mixtures thereof. In a preferred embodiment the solvent is combinations of methanol and water thereof.

Fourth embodiment of the present invention is to provide a process for the preparation of tranexamic acid of formula-I from a compound of formula-IIa, an intermediate useful for the preparation of tranexamic acid of formula-I,

Formula I
comprising the steps of:
(i) reacting 4-bromomethyl cyclohexane-1-carboxylic acid of formula-III,

with substituted benzylamine of formula VI in presence of base to obtain a compound of formula-IIa; and

Formula VI
wherein, R1 to R5 each independently selected from the group consisting of: hydrogen, hydroxyl, alkyl hydroxyl, alkoxy, substituted or unsubstituted C1 to C20 alkyl, substituted or unsubstituted C2 to C20 alkenyl, substituted or unsubstituted C2 to C20 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted carbonyl, aldehyde, substituted or unsubstituted carboxylate, substituted or unsubstituted ester, substituted or unsubstituted C1 to C20 alkoxy, substituted or unsubstituted carboxamide, substituted or unsubstituted imine,

(ii) converting the compound of formula-IIa to obtain the tranexamic acid of formula-I.

The reacting 4-bromomethyl cyclohexane-1-carboxylic acid of formula-III with substituted benzylamine of formula-VI in presence of base according to the fourth embodiment is carried out at temperature ranging from 25-30 ºC and stirred at 95-100 °C.

The suitable solvent for reacting 4-bromomethyl cyclohexane-1-carboxylic acid of formula-III with substituted benzylamine of formula-VI according to fourth embodiment is selected from a group comprising of ester such as n-butyl acetate, isobutyl acetate, methyl acetate, ethyl acetate and isopropyl acetate; ethers such as cyclopentyl methyl ether, tetrahydrofuran, tetrahydropyran; ketones such as acetone, methyl isobutyl ketone and N-methyl-2-pyrrolidone; halogenated solvents such as chloroform, 1,1,1-trichloroethane trichlorethylene, or its mixture thereof, preferably dichloromethane.

The base employed for reacting 4-bromomethyl cyclohexane-1-carboxylic acid of formula-III with substituted benzylamine of formula-VI according to fourth embodiment is selected from the group comprising of the alkali metals such as sodium, potassium, lithium; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate; or alkali metal hydroxides such as sodium hydroxide, calcium hydroxide, potassium hydroxide. In a preferred embodiment, the alkali base is sodium hydroxide.

Converting the compound of formula-IIa to form tranexamic acid of formula-I according to fourth embodiment is carried out at the temperature ranging from 25-30 ºC.

Converting the compound of formula-IIa to form tranexamic acid of formula-I according to fourth embodiment is carried out in the presence of palladium on carbon catalyst, wherein the reaction mixture is pressurized in the range of 5 Kg/cm2 at 70 °C. Further, tranexamic acid is extracted from the reaction mixture by treating it with suitable solvents such as methanol, ethanol, propanol, butanol, isopropyl alcohol, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, water, or its mixtures thereof. In a preferred embodiment the solvent employed is combinations of methanol and water thereof.

Fifth embodiment of the present invention is to provide a novel process for the preparation of tranexamic acid from a compound of formula-IIa comprising the step of: converting the compound of formula IIa;

to obtain the tranexamic acid of formula-I.

Formula I
Converting the compound of formula-IIa to form tranexamic acid of formula-I according to fifth embodiment is carried out at the temperature ranging from 25-30 ºC.

Converting the compound of formula-IIa to form tranexamic acid of formula-I according to fifth embodiment is carried out in the presence of palladium on carbon catalyst, wherein the reaction mixture is pressurized in the range of 5 Kg/cm2 at 70 °C. Further, tranexamic acid is extracted from the reaction mixture by treating it with suitable solvents such as methanol, ethanol, propanol, butanol, isopropyl alcohol, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, water or its mixtures thereof. In a preferred embodiment the solvent is combinations of methanol and water thereof.

The present invention is explained in detail with reference to the following examples described below, which are given for the purpose of illustration only and are not intended to limit the scope of invention.

EXAMPLES:

Example-1: Preparation of 4-(bromomethyl)cyclohexane carboxylic acid of formula-III:
Step (a) - Preparation of 4-(bromomethyl)cyclohexanemethanol of formula IV: To a solution of 1,4-cyclohexanedimethanol (500.0 g) in toluene (5 l), an aqueous 48% hydrobromic acid (876.6 g, 5.20 mol) was added at 25-30 ºC and stirred at reflux temperature for 7-8 hours. The progress of the reaction was monitored by gas chromatography. After completion of reaction, the reaction mass was cooled to 25-30ºC and mixed with water (1.5 l) to form a biphasic mixture. The formed biphasic mixture was stirred for 30 minutes and allowed to settle. The organic layer from the biphasic mixture was separated, washed with 3% w/w aqueous solution of sodium bicarbonate (1.5 l) followed by the washing with water (1.5 l). The organic layer containing compound 4-(bromomethyl)cyclohexanemethanol of formula IV was collected and proceeded for the next stage.

Step (b) - Preparation of 4-(bromomethyl)cyclohexane carboxylic acid of formula-III: To the organic layer (500 g of 4-(bromomethyl) cyclohexanemethanol in toluene) obtained in step (a) of (500 g), acetonitrile (500 ml) was added followed by the addition of water (1.2 l) at 30 °C. The reaction mixture was cooled to 10-15°C. To the cooled reaction mixture, 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) (3.8 g, 0.024 mol) was added at 10-15°C, followed by the addition of 12% of sodium hypochlorite solution (600 ml) and stirred for 2 hours at 10-15°C. To the stirred reaction mixture, sodium dihydrogen phosphate solution (205.5 g of sodium dihydrogen phosphate in 1.2 l of water) was added, followed by the addition of sodium chloride solution (269.5 g of sodium chloride in 1.2 l of water), and stirred for 3-4 hours at 10-15°C. The progress of the reaction was monitored by TLC. After completion of the reaction, the pH of the reaction mass was adjusted to 10-11 using 25% of sodium hydroxide solution followed by the addition of sodium sulphite solution (50 g of sodium sulphite in 500 ml of water). The reaction mass was then warmed to 25-30 °C, stirred for 30 minutes. The organic layer was removed from the reaction mass. To the aqueous layer, cyclohexane (4 l) was added to form a biphasic mixture. The pH of the aqueous layer of the biphasic mixture was adjusted to 3.5 to 4.5 using concentrated hydrochloric acid and stirred for 30 minutes at 25-30 °C. The organic layer was then separated from the biphasic mixture and concentrated at 50°C and cooled to 25-30 °C. The cooled contents were stirred for 12-15 hours at 25-30 °C. The resultant solid was filtered, and dried. Yield: 232 g.

Example-2: Preparation of 4-((benzylamino)methyl)cyclohexane-1-carboxylic acid of formula-II:
To a mixture of sodium hydroxide solution (36.2 g of sodium hydroxide in 700 mL of water) and 4-(bromomethyl) cyclohexane-1-carboxylic acid (100 g), benzylamine (97 g) was added at 25-30 ºC and stirred at 95-100 °C for 15 hours. The progress of reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mass was cooled at 25-30 °C and washed with dichloromethane (500 ml). The pH of the aqueous layer was adjusted to 7.0 to 7.50 using 1:1 aqueous hydrochloric acid and stirred at 25-30 ºC for 1 hour. The resultant solid was filtered, washed with water (200 ml) followed by washing with acetone (200 ml) and dried. Yield: 46%

Example-3: Preparation of 4-((benzylamino)methyl)cyclohexane-1-carboxylic acid of formula-II:
To benzylamine (600 ml) was added 4-(bromomethyl) cyclohexane-1-carboxylic acid (400 g) in 4 lots at 85-90ºC for 1 hour and stirred at 95-100°C for 1-2 hours. The progress of reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mass was cooled at 25-30 °C. To the cooled reaction mass, water (2000 ml) was added, and the resulting aqueous solution was washed with dichloromethane (2000 ml). The pH of the washed aqueous solution was adjusted to 7.0 to 7.50 using 1:1 aqueous hydrochloric acid and stirred at 25-30ºC for 1 hour. The resultant solid was filtered; washed with water (200 ml); slurried in tetrahydrofuran (3000 ml) at 25-30°C; then filtered, washed with tetrahydrofuran (400 ml) and dried. Yield: 63%

Example-4: Preparation of tranexamic acid of formula I:
To a mixture of 4-((benzylamino)methyl))cyclohexane-1-carboxylic acid (50 g), water (300 ml) and methanol (200 ml), 10% of palladium on carbon catalyst (5 g) with 50 % moisture was added and hydrogenated under a pressure 5 Kg/cm2 at 70 °C for 5-6 hours. The progress of reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mass was cooled at 25-30 °C and the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure to obtain a residue. The obtained residue was dissolved in water (360 ml) and treated with activated carbon. The treated contents were filtered, and the filtrate was concentrated at 60-70 °C to obtain a residue. The residue was mixed with methanol (150 ml) at 60 °C. The contents were then cooled at 25-30°C and stirred for 15 hours at 25-30 °C. The resultant solid was filtered, washed with methanol (100 ml) and dried. Yield: 66%.
,CLAIMS:1. A process for the preparation of tranexamic acid of formula-I,

Formula I
comprising the steps of:
(i) treating 1,4-cyclohexanedimethanol of formula-V;

with aqueous hydrobromic acid in an organic solvent to obtain 4-(bromomethyl)cyclohexane-1-methanol of formula-IV;

(ii) treating 4-(bromomethyl)cyclohexane-1-methanol of formula-IV with oxidizing agent in the presence of sodium phosphate buffer to obtain 4-bromomethyl cyclohexane-1-carboxylic acid of formula III;

(iii) treating 4-bromomethyl cyclohexane-1-carboxylic acid of formula-III with benzylamine in presence of a base to obtain a compound of formula-II; and

(iv) converting the compound of formula-II to obtain the tranexamic acid of formula-I.

2. The process as claimed in claim 1, wherein step (i) is carried out at a temperature ranging between 50 °C to reflux temperature of the solvent.

3. The process as claimed in claim 1, wherein the organic solvent in step (i) is selected from the group comprising of aromatic hydrocarbons such as toluene, xylene and benzene; aliphatic hydrocarbons such as hexane, heptane, and cyclohexane; or mixtures thereof.

4. The process as claimed in claim 1, wherein the oxidizing agent in step (ii) is 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) or its derivatives.

5. The process as claimed in claim 1, wherein the step (ii) is carried out at a temperature of 30°C to 40°C.

6. The process as claimed in claim 1, wherein the solvent in step (ii) is selected from group comprising of aliphatic hydrocarbons such as hexane, heptane, and cyclohexane; aromatic hydrocarbons such as toluene, xylene and benzene; polar organic solvents such as methanol, ethanol, propanol, butanol, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide; or mixtures thereof.

7. The process as claimed in claim 1, wherein step (ii) involves addition of sodium hypochlorite and sodium chloride solution to obtain compound of formula III.

8. The process as claimed in claim 1, wherein the base in step (iii) is selected from a group comprising of the alkali metals such as sodium, potassium, lithium; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate or alkali metal hydroxides such as sodium hydroxide, calcium hydroxide, potassium hydroxide.

9. The process as claimed in claim 1, wherein the step (iii) is carried out at a temperature of 20 °C to 40 °C.

10. The process as claimed in claim 1, wherein the solvent in step (iii) is selected from a group comprising of ester such as n-butyl acetate, isobutyl acetate, methyl acetate, ethyl acetate and isopropyl acetate; ethers such as cyclopentyl methyl ether, tetrahydrofuran, tetrahydropyran; ketones such as acetone, methyl isobutyl ketone and N-methyl-2-pyrrolidone; halogenated solvents such as chloroform, dichloromethane, 1,1,1-trichloroethane trichlorethylene, or mixture thereof.

11. The process as claimed in claim 1, wherein the step (iv) is carried out at the temperature ranging from 20 ºC to 45 ºC.

12. The process as claimed in claim 1, wherein the solvent in step (iv) is selected from methanol, ethanol, propanol, butanol, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, water or mixtures thereof.

13. A process for the preparation of tranexamic acid formula-I,

Formula I
comprising the steps of:
(i) reacting 4-bromomethyl cyclohexane-1-carboxylic acid of formula-III;

with substituted benzylamine of formula VI;

Formula VI
in presence of a base to obtain a compound of formula-IIa; and

wherein, R1 to R5 each independently selected from the group consisting of: hydrogen, hydroxyl, alkyl hydroxyl, alkoxy, substituted or unsubstituted C1 to C20 alkyl, substituted or unsubstituted C2 to C20 alkenyl, substituted or unsubstituted C2 to C20 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted carbonyl, aldehyde, substituted or unsubstituted carboxylate, substituted or unsubstituted ester, substituted or unsubstituted C1 to C20 alkoxy, substituted or unsubstituted carboxamide, substituted or unsubstituted imine,
(ii) converting the compound of formula-IIa to obtain the tranexamic acid of formula-I.

14. The process as claimed in claim 13, wherein the step (i) is carried out at a temperature of 25 ºC to 30ºC and stirred at 95 ºC to 100 °C.

15. The process as claimed in claim 13, wherein the base in step (i) is selected from a group comprising of the alkali metals such as sodium, potassium, lithium; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate or alkali metal hydroxides such as sodium hydroxide, calcium hydroxide, potassium hydroxide.

16. The process as claimed in claim 13, wherein the solvent in step (i) is selected from a group comprising of ester such as n-butyl acetate, isobutyl acetate, methyl acetate, ethyl acetate and isopropyl acetate; ethers such as cyclopentyl methyl ether, tetrahydrofuran, tetrahydropyran; ketones such as acetone, methyl isobutyl ketone and N-methyl-2-pyrrolidone; or halogenated solvents such as chloroform, 1,1,1-trichloroethane trichlorethylene.

17. The process as claimed in claim 13, wherein the step (ii) is carried out at a temperature of 25 ºC to 30 ºC.

18. The process as claimed in claim 13, wherein the step (ii) is carried out in the presence of palladium on carbon catalyst, and wherein the reaction mixture is pressurized in the range of 5 Kg/cm2 at 70 °C.

19. The process as claimed in claim 13, wherein the solvent in step (ii) is selected from a group comprising of methanol, ethanol, propanol, butanol, isopropyl alcohol, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, or mixtures thereof.