DESC:RELATED PATENT APPLICATION(S):

This application claims the priority to and benefit of Indian Patent Application No. 202141000843 filed on January 08, 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 to treat or prevent excessive blood loss from major trauma, postpartum bleeding, surgery and heavy menstruation. The structure of tranexamic acid is shown in 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.

Another object of the invention is to provide an improved process for the preparation of tranexamic acid from 1,4-cyclohexanedimethanol with high purity.

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 having less impurities and is economically significant.

The main aspect of the present invention is to provide a novel process for the preparation of tranexamic acid of 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)cyclohexanemethanol of formula-IV;

(ii) reacting 4-(bromomethyl)cyclohexanemethanol of formula-IV with alkali metal salt of phthalimide in a solvent to obtain a compound of formula-III, wherein M is alkali metal;

(iii) oxidizing the compound of formula-III with an oxidizing agent to obtain a compound of formula-II; and

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

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

The solvent in step (i) of the said process 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.

The step (ii) of the said process is carried out at the temperature ranging from 50ºC to 150°C.
In step (ii) of the said process the solvent is selected from the group comprising of ester such as n-butyl acetate, ethyl acetate, isobutyl acetate, methyl acetate and isopropyl acetate; ethers such as cyclopentyl methyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, tetrahydropyran, 1,4-dioxane and dimethoxyethane; amides such as dimethylacetamide and dimethylformamide; alcohols such as isopropyl alcohol, ethanol and methanol; aromatic hydrocarbons such as toluene, xylene and benzene; ketones such as methyl isobutyl ketone and N-methyl-2-pyrrolidone; or mixtures thereof.

The oxidization in step (iii) of the present process is carried out in the presence of TEMPO in the presence of sodium hypochlorite.

The step (iv) of the said process is carried out at the temperature ranging from 25°C to 150°C.

In step (iv) of the said process the solvent is selected from a group comprising of ethers such as cyclopentyl methyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, tetrahydropyran, 1,4-dioxane and dimethoxyethane; amides such as dimethylacetamide and dimethylformamide; alcohols such as isopropyl alcohol, ethanol and methanol; ketones such as acetone, methyl isobutyl ketone and N-methyl-2-pyrrolidone; water; or mixtures thereof.

The base employed in step (iv) of the present process is selected from a group comprising of organic amines such as ethylenediamine, monoethanolamine, methylamine, butylamine and hydroxylamine; hydrazines; or inorganic bases such as sodium hydroxide, potassium hydroxide and calcium hydroxide.

Another aspect of the present invention is to provide an improved process for the preparation of 4-(bromomethyl)cyclohexanemethanol of formula-IV, an intermediate useful for the preparation of tranexamic acid comprising the steps of: treating 1,4-cyclohexanedimethanol of formula-V with aqueous hydrobromic acid in an organic solvent to obtain 4-(bromomethyl)cyclohexanemethanol of formula-IV.

Another aspect of the present invention is to provide a novel process for the preparation of compound of formula-III, an intermediate useful for the preparation of tranexamic acid comprising the steps of: reacting 4-bromocyclohexane-1-methanol of formula-IV with alkali metal salt of phthalimide in a solvent to obtain a compound of formula-III, wherein M is an alkali metal salt.

Another aspect of the present invention is to provide a novel process for the preparation of compound of formula-II from a compound of formula-III comprising the steps of: oxidizing a compound of formula-III with an oxidizing agent to obtain a compound of formula-II;

Still another aspect of the present invention is to provide a novel process for the preparation of tranexamic acid from a compound of formula-II comprising the step of hydrolysis of the compound of formula-II to obtain the tranexamic acid of formula-I.

Yet another aspect of the present invention is to provide a novel intermediate of formula-IIIa for the preparation of tranexamic acid having the structure mentioned below

Wherein R is selected from the group of
;
;

Wherein X is C or N; Y is C or N; and Z is C or N independently.

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 having less impurities and 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 comprising the steps of:
(i) treating 1,4-cyclohexanedimethanol of formula-V with hydrobromic acid in a suitable organic solvent to obtain 4-(bromomethyl)cyclohexanemethanol of formula-IV;

(ii) reacting 4-(bromomethyl)cyclohexanemethanol of formula-IV with alkali metal salt of phthalimide in a suitable solvent to obtain a compound of formula-III, wherein M is alkali metal;

(iii) oxidizing the compound of formula-III with an appropriate oxidizing agent to obtain a compound of formula-II; and

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

The treating 1,4-cyclohexanedimethanol of formula-V with hydrobromic acid in a suitable organic solvent to obtain 4-(bromomethyl)cyclohexanemethanol 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; and aliphatic hydrocarbons such as hexane, heptane, cyclohexane, preferably toluene and xylene.

The step of reacting 4-(bromomethyl)cyclohexanemethanol of formula-IV with alkali metal salt of phthalimide according to the step (ii) is carried out at temperature ranging from 50ºC to 150°C.

The suitable solvent for reacting 4-(bromomethyl)cyclohexanemethanol of formula-IV with alkali metal salt of phthalimide according to the step (ii) is selected from the group comprising of ester such as n-butyl acetate, ethyl acetate, isobutyl acetate, methyl acetate and isopropyl acetate; ethers such as cyclopentyl methyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, tetrahydropyran, 1,4-dioxane and dimethoxyethane; amides such as dimethylacetamide and dimethylformamide; alcohols such as isopropyl alcohol, ethanol and methanol; aromatic hydrocarbons such as toluene, xylene and benzene; ketones such as methyl isobutyl ketone and N-methyl-2-pyrrolidone, or its mixtures thereof, preferably dimethylformamide.

Preferably oxidizing the compound of formula-III with an appropriate oxidizing agent to obtain a compound of formula-II according to step (iii) is carried out in the presence of TEMPO in the presence of sodium hypochlorite.

The hydrolysis of the compound of formula-II to obtain the tranexamic acid of formula-I according to the step (iv) is carried in the temperature ranging from 25°C to 150°C.

The hydrolysis of the compound of formula-II to obtain the tranexamic acid of formula-I according to the step (iv) is carried out in the suitable solvent selected from a group comprising of ethers such as cyclopentyl methyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, tetrahydropyran, 1,4-dioxane and dimethoxyethane; amides such as dimethylacetamide and dimethylformamide; alcohols such as isopropyl alcohol, ethanol and methanol; ketones such as acetone, methyl isobutyl ketone and N-methyl-2-pyrrolidone; water and its mixtures thereof, preferably acetonitrile.

The base employed in step (iv) may be selected from a group comprising of organic amines such as ethylenediamine, monoethanolamine, methylamine, butylamine and hydroxylamine; hydrazines; inorganic bases such as sodium hydroxide, potassium hydroxide and calcium hydroxide.

Surprisingly the inventors of the present invention observed that the use of suitable organic solvents selected from the group comprising of aromatic hydrocarbons such as toluene, xylene and benzene; and aliphatic hydrocarbons such as hexane, heptane, cyclohexane during the preparation of 4-(bromomethyl)cyclohexanemethanol of formula-IV from 1,4-cyclohexanedimethanol of formula-V by the treatment with aqueous hydrobromic acid in organic solvent reduced the formation of undesired 1,4-(dibromomethyl)cyclohexane and also decreases the time of the reaction.

Unexpectedly the novel process for the tranexamic acid of the present invention involving the formation of novel intermediate of formula of formula-III enhances the formation of trans-derivative of the intermediates and avoids the formation of cis-derivative. The unreacted cis-derivatives are then easily removed from the reaction mixture, thus the process avoids the conversion of cis-4-(aminomethyl)cyclohexanecarboxylic acid to trans-4-(aminomethyl)-cyclohexanecarboxylic acid at higher temperatures.

Second embodiment of the present invention is to provide an improved process for the preparation of 4-(bromomethyl)cyclohexanemethanol of formula-IV, an intermediate useful for the preparation of tranexamic acid comprising the steps of: treating 1,4-cyclohexanedimethanol of formula-V with aqueous hydrobromic acid in a suitable organic solvent to obtain 4-(bromomethyl)cyclohexanemethanol of formula-IV.

The treating 1,4-cyclohexanedimethanol of formula-V with aqueous hydrobromic acid in a suitable organic solvent to obtain 4-(bromomethyl)cyclohexanemethanol of formula-IV according to the second embodiment is carried out at the 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 second embodiment is selected from the group comprising of aromatic hydrocarbons such as toluene, xylene and benzene; aliphatic hydrocarbons such as hexane, heptane, cyclohexane; ether such as diethyl ether and tetrahydrofuran; and its mixtures thereof.

Third embodiment of the present invention is to provide a novel process for the preparation of compound of formula-III, an intermediate useful for the preparation of tranexamic acid comprising the steps of: reacting 4-(bromomethyl)cyclohexanemethanol of formula-IV with alkali metal salt of phthalimide in a suitable solvent to obtain a compound of formula-III, wherein M is alkali metal salt.

The reaction of 4-(bromomethyl)cyclohexanemethanol of formula-IV with alkali metal salt of phthalimide according to the third embodiment is carried out at the temperature ranging from 50°C to 150°C.

The suitable solvent for reacting 4-(bromomethyl)cyclohexanemethanol of formula-IV with alkali metal salt of phthalimide according to the third embodiment is selected from the group comprising of ester such as n-butyl acetate, ethyl acetate, isobutyl acetate, methyl acetate and isopropyl acetate; ethers such as cyclopentyl methyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, tetrahydropyran, 1,4-dioxane and dimethoxyethane; amides such as dimethylacetamide and dimethylformamide; alcohols such as isopropyl alcohol, ethanol and methanol; ketones such as methyl isobutyl ketone and N-methyl-2-pyrrolidone, and its mixtures thereof.

Fourth embodiment of the present invention is to provide a novel process for the preparation of compound of formula-II from a compound of formula-III comprising the steps of: oxidizing a compound of formula-III with an appropriate oxidizing agent to obtain a compound of formula-II.

Preferably oxidizing the compound of formula-III with an appropriate oxidizing agent to obtain a compound of formula-II according to the fourth embodiment is carried out in the presence of TEMPO in the presence of sodium hypochlorite.

Fifth embodiment of the present invention is to provide a novel process for the preparation of tranexamic acid from a compound of formula-II comprising the step of hydrolysis of the compound of formula-II to obtain the tranexamic acid of formula-I.

The hydrolysis of the compound of formula-II to obtain the tranexamic acid of formula-I according to the fifth embodiment is carried out at the temperature ranging from 25°C to 150°C.

The hydrolysis of the compound of formula-II to obtain the tranexamic acid of formula-I according to the fifth embodiment is carried out in the suitable solvent selected from a group comprising of ethers such as cyclopentyl methyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, tetrahydropyran, 1,4-dioxane and dimethoxyethane; amides such as dimethylacetamide and dimethylformamide; alcohols such as isopropyl alcohol, ethanol and methanol; ketones such as acetone, methyl isobutyl ketone and N-methyl-2-pyrrolidone; water and its mixtures thereof.

Sixth embodiment of the present invention is to provide a novel intermediate of formula-IIIa for the preparation of tranexamic acid having the structure mentioned below.

Wherein R is selected from the group of
;
;

Wherein X is C or N; Y is C or N; and Z is C or N independently.

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 the invention.

EXAMPLES:

Example-1: Preparation of 4-(Bromomethyl)cyclohexanemethanol of formula-IV
To a solution of 1,4-cyclohexanedimethanol (500.0 g, 3.47 mol) in toluene (5 L), an aqueous 48% hydrobromic acid (876.6 g, 5.20 mol) was added at 25-30 ºC and stirred the reaction mass at reflux for 7-8 hours, while removing the water azeotropically. The progress of the reaction was monitored by GC. After completion of reaction, the reaction mass was cooled to 25-30 ºC and mixed with water (1.5 L) to form a biphasic mixture. The biphasic mixture was stirred for 30 minutes and separated the organic layer. The organic layer was washed with 3% w/w aqueous solution of sodium bicarbonate (1.5 L) and water (1.5 L) and concentrated under reduced pressure at 50-55 ºC to obtain 4-(bromomethyl)cyclohexanemethanol as an oily liquid (587.5 g). %Yield: 81.7%

Example-2: Preparation of 4-(Bromomethyl)cyclohexanemethanol of formula-IV
To a solution of 1,4-cyclohexanedimethanol (100.0 g, 0.69 mol) in toluene (1 L), an aqueous 48% hydrobromic acid (175.3 g, 1.03 mol) was added at 25-30 ºC and stirred the reaction mass at reflux for ~20 hours. The progress of the reaction was monitored by GC. After completion of reaction, the reaction mass was cooled to 25-30 ºC and separated the aqueous layer. The organic layer was washed with water (300 mL) and with 3% w/w aqueous solution of sodium bicarbonate (300 mL). Finally the organic layer was concentrated under reduced pressure at 50-55 ºC to obtain 4-(bromomethyl)cyclohexanemethanol as an oily liquid (104.0 g). %Yield: 72.2%

Example-3: Preparation of trans-4-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl] cyclohexane-methanol of formula-III
To a solution of 4-(bromomethyl)cyclohexanemethanol (235.0 g, 1.13 mol) in dimethylformamide (705 mL), potassium phthalimide (217.6 g, 1.17 mol) was added at 25-30 ºC and stirred the reaction mass at 90-95ºC for 4-5 hours. The progress of the reaction was monitored by HPLC. After completion of reaction, the reaction mass was filtered. To the filtrate, water (1645 mL) was added at 25-30 ºC and stirred at 25-30 ºC for 2 hours. The resultant solid was filtered, washed with water (470 mL) and dried under reduced pressure at 50-55 ºC. %Yield: 74.0%

Example-4: Preparation of trans-4-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-methyl] cyclohexane-carboxylic acid of formula-II
To a suspension of trans-4-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-methyl]cyclohexane methanol (230.0 g, 0.84 mol) in acetonitrile (690 mL), water (920 mL) was added at 25-30 ºC and cooled to 10ºC. Further, TEMPO (1.18 g, 0.008 mol) was added to the reaction mixture, followed by an aqueous solution of 12% sodium hypochlorite (276 mL) at 10-20 ºC. The reaction mass was stirred at 10-20 ºC for 2 hours and then an aqueous solution of sodium dihydrogen phosphate (460 mL, 0.36 mol) was added followed by the addition of a solution of sodium chlorite (460 mL, 0.72 mol) at 10-20 ºC. The resulting reaction mixture was stirred for 12-14 hours at 25-30 ºC. The progress of the reaction was monitored by HPLC. After completion of reaction, the reaction mass was quenched with an aqueous solution of 10% sodium sulfite (230 mL) at 25-30 ºC and stirred for 30 minutes. The resultant solid was filtered, washed with water (400 mL) and dried under reduced pressure at 50-55 ºC. %Yield: 73.6%

Example-5: Preparation of trans-4-(aminomethyl)cyclohexanecarboxylic acid of formula-I
To a suspension of trans-4-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl]cyclohexane-carboxylic acid (30.0 g, 0.104 mol) in isopropyl alcohol (300 mL), aqueous solution of 40% monomethyl amine (56.4 g, 0.73 mol) was added at 25-30 ºC and stirred at reflux for 3-4 hours. The progress of the reaction was monitored by HPLC. After completion of reaction, the reaction mass was concentrated under reduced pressure at 50-55 ºC. To the concentrated residue, isopropyl alcohol (300 mL) was added and stirred for 30 minutes at 25-30 ºC. The resulting solid was filtered, washed with isopropyl alcohol (180 mL) and dried under reduced pressure at 50-55 ºC. %Yield: 66.6%

Example-6: Purification of trans-4-(aminomethyl)cyclohexanecarboxylic acid of formula-I:
To a solution of trans-4-(aminomethyl)cyclohexanecarboxylic acid (5.0 g) in water (30 mL), acetone (60 mL) was added at 25-30 ºC and stirred for 3hours at 25-30 ºC. The resultant solid was filtered, washed with acetone (5 mL) and dried under reduced pressure at 45-50 ºC. %Yield: 80.0%
,CLAIMS:1. A process for the preparation of tranexamic acid of 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)cyclohexanemethanol of formula-IV;

(ii) reacting 4-(bromomethyl)cyclohexanemethanol of formula-IV with alkali metal salt of phthalimide in a solvent to obtain a compound of formula-III, wherein M is alkali metal;

(iii) oxidizing the compound of formula-III with an oxidizing agent to obtain a compound of formula-II; and

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

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

3. The process as claimed in claim 1, wherein the 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, cyclohexane; or mixtures thereof.

4. The process as claimed in claim 1, wherein the step (ii) is carried out at the temperature ranging from 50ºC to 150°C.

5. The process as claimed in claim 1, wherein the solvent in step (ii) is selected from the group comprising of ester such as n-butyl acetate, ethyl acetate, isobutyl acetate, methyl acetate and isopropyl acetate; ethers such as cyclopentyl methyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, tetrahydropyran, 1,4-dioxane and dimethoxyethane; amides such as dimethylacetamide and dimethylformamide; alcohols such as isopropyl alcohol, ethanol and methanol; aromatic hydrocarbons such as toluene, xylene and benzene; ketones such as methyl isobutyl ketone and N-methyl-2-pyrrolidone; or mixtures thereof.

6. The process as claimed in claim 1, wherein the oxidization in step (iii) is carried out in the presence of TEMPO in the presence of sodium hypochlorite.

7. The process as claimed in claim 1, wherein the step (iv) is carried out at the temperature ranging from 25°C to 150°C.

8. The process as claimed in claim 1, wherein the solvent in step (iv) is selected from a group comprising of ethers such as cyclopentyl methyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, tetrahydropyran, 1,4-dioxane and dimethoxyethane; amides such as dimethylacetamide and dimethylformamide; alcohols such as isopropyl alcohol, ethanol and methanol; ketones such as acetone, methyl isobutyl ketone and N-methyl-2-pyrrolidone; water; or mixtures thereof.

9. The process as claimed in claim 1, wherein the base employed in step (iv) is selected from a group comprising of organic amines such as ethylenediamine, monoethanolamine, methylamine, butylamine and hydroxylamine; hydrazines; or inorganic bases such as sodium hydroxide, potassium hydroxide and calcium hydroxide.

10. An intermediate compound of formula-IIIa for the preparation of tranexamic acid,
Wherein R is selected from the group of
;
;

Wherein X is C or N; Y is C or N; and Z is C or N independently.