DESC:Related Patent Application
This application claims the priority to and benefit of Indian Provisional Patent Application No. 202141055279 filed on November 29, 2021; the disclosure of which are incorporated herein by reference.

Field of the Invention
The present invention relates to an improved process for the preparation of Tranexamic acid or its pharmaceutically acceptable salts 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.

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 a process for the preparation of tranexamic acid and the process comprises the steps of reducing a mixture of cis and trans form of cyanocyclohexane-1-carboxylic acid ester to a mixture of cis and trans-4-(aminomethyl)cyclohexanecarboxylic acid; and hydrolyzing the mixture in the presence of sodium hydroxide as mentioned below.

The crude tranexamic acid as obtained in the process could be purified by passing through ion-exchange resin column and then crystallized in a mixture of acetone and water. Tranexamic acid is soluble in water and insoluble in methanol, whereas the hydrochloric acid salt of cis-isomer is soluble in methanol.

The Patent JP 56044061 assigned to Daiichi Seiyaku discloses a process for the preparation of highly pure tranexamic acid from trans-4-cyanocyclohexane carboxylic acid as mentioned below.

The crude tranexamic acid as obtained in the process is passed over Amberlite IRC-50 to eliminate Nickel ion and passed over Amberlite IR-45 to provide pure tranexamic acid.

The patent US RE30149 discloses the below mentioned process for the preparation of tranexamic acid starting from 4-cyno-cyclohexane-1-carboxylate as mentioned below.

The aforementioned process involves the reduction of free 4-cyano-cyclohexane carbocyclic acid is carried out in a sufficient water-soluble alkaline agent suitable for catalytic reduction and feeding in hydrogen gas in the presence of Raney nickel catalyst. The tranexamic acid obtained in the process has a purity 95% or better.

The patent US 3449411 discloses a process for the preparation of tranexamic acid from acetamidomethylbenzoic acid, as described in the below scheme, on heating over metal catalyst at a temperature between 160º C-180º C under a pressure of hydrogen, followed by hydrolysis with alkali metal hydroxide at a temperature between 180º C-250º C to produce tranexamic acid.

The publication of Organic Process Research & Development, 19(3). 2015, 444-448 discloses a process for the preparation of tranexamic acid, from dimethyl terephthalate involving 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 3763598 assigned to Asahi Denka Kogyo discloses a process for the preparation of tranexamic acid from 1,4-cyclohexanedimethanol as mentioned below, where the metal azide have 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 a temperature of 85° C for 24 hours in water (ii) oxidation of 4-(bromomethyl)cyclohexanemethanol using catalytic TEMPO in sodium hypochlorite at a temperature of 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 may be removed by fractional distillation. The formation of this impurity during the preparation lowers the yield of 4-(bromomethyl)cyclohexanemethanol. Further, the overall yield of tranexamic acid by this process is too low that is below 12%, making this process not suitable for commercial scale.

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

Controlling the formation of the cis-isomer (Impurity-B) and other impurities such as Impurity A, Impurity C, Impurity E and Impurity F during the process for preparing tranexamic acid is essential to increase the yield and quality of the product. Further, the removal of impurities Impurity A, Impurity C, Impurity E, and Impurity F formed during the process are difficult to remove by purification methods. Structures of Impurity A, Impurity C, Impurity E and Impurity F are mentioned below.

Besides the availability of process for the preparation of tranexamic acid in state of the art, there is a need for a process for the preparation of pure tranexamic acid, which is simple and has economically significant and surpassing challenges in the preparation of tranexamic acid.

Summary of the Invention
The main objective of the present invention is to provide a process for preparing tranexamic acid of formula-I or its pharmaceutically acceptable salts, comprising the steps of:

(i) preparing compound of formula-II,

wherein R is selected from substituted or unsubstituted C1 to C8 alkyl; and
(ii) treating the compound of formula-II with Raney nickel catalyst in the presence of alkali metal hydroxide in a suitable organic solvent to obtain tranexamic acid of formula-I.

In one embodiment, the compound of formula-II is prepared by a method comprising the steps of: converting a cis and trans mixture of 1,4-dimethyl-cyclohexane dicarboxylate to a mixture containing predominantly trans-isomer; reacting the mixture containing predominantly trans-isomer of 1,4-dimethyl-cyclohexane dicarboxylate with alkali metal hydroxide in a solvent to corresponding mono-ester; treating the corresponding mono-ester with thionyl chloride in a solvent to obtain corresponding acid halide of the mono-ester; reacting the corresponding acid halide of the mono-ester with ammonia to obtain corresponding half ester of amide; and converting the corresponding half ester of amide into the compound of formula II.

Accordingly in one embodiment of the present invention, the alkali metal hydroxide used in step (ii) is selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, and cesium hydroxide. In a preferable embodiment, the alkali metal hydroxide used in step (ii) is sodium hydroxide.

Accordingly in one embodiment of the present invention, the organic solvent used in step (ii) is selected from the group comprising: alcohols, ether, esters, ketones, aromatic hydrocarbons, aliphatic hydrocarbons, nitriles, amides, dimethyl sulfoxide, sulfolane, chlorinating solvents, and mixtures thereof. In a preferable embodiment, the organic solvent used in step (ii) is a mixture of methanol and toluene.

In another aspect of the present invention, a process for preparing tranexamic acid of formula-I or its pharmaceutically acceptable salts, comprising the steps of:

(i). preparing the compound of formula-IIa as mentioned below,

(ii). treating the compound of formula-IIa with Raney nickel catalyst in the presence of alkali metal hydroxide in a organic solvent to obtain a tranexamic acid of formula-I.

Detailed Description of the Invention
One embodiment of the present invention is to provide a process for preparing tranexamic acid of formula-I or its pharmaceutically acceptable salts, comprising the steps of:

(i) preparing compound of formula-II,

wherein R is selected from substituted or unsubstituted C1 to C8 alkyl; and
(ii) treating the compound of formula-II with Raney nickel catalyst in the presence of alkali metal hydroxide in a suitable organic solvent to obtain tranexamic acid of formula-I.

The compound of formula II is prepared by methods known in the state of art. In one embodiment of the present invention, the compound of formula II is prepared from 1,4-dimethyl-cyclohexane dicarboxylate involving the steps of: converting a cis and trans mixture of 1,4-dimethyl-cyclohexane dicarboxylate to a mixture containing predominantly trans-isomer; reacting the mixture containing predominantly trans-isomer of 1,4-dimethyl-cyclohexane dicarboxylate with alkali metal hydroxide in a suitable solvent to corresponding mono-ester; treating the corresponding mono-ester with thionyl chloride in a suitable solvent to obtain corresponding acid halide of the mono-ester; reacting the corresponding acid halide of the mono-ester with ammonia to obtain corresponding half ester of amide; and converting the corresponding half ester of amide into the compound of formula II.

In one embodiment of the present invention, the step (ii) of treating the compound of formula II with Raney nickel catalyst in the presence of alkali metal hydroxides in a suitable organic solvent is carried out in the temperature between 30? to 150?.Preferably, the step (ii) is carried out in the temperature between 50? to 100?.

In one embodiment, hydrogen gas is applied during the step (ii) of treating the compound of formula II with Raney nickel catalyst in the presence of alkali metal hydroxides in a suitable organic solvent according to the present invention. Preferably, the hydrogen gas is applied at pressure of 20 Kg/cm2 at a pressure of 20 Kg/cm2 during the step (ii).

In one embodiment, the alkali metal hydroxides are selected from the group comprising of sodium hydroxides, potassium hydroxides, lithium hydroxides, and cesium hydroxides. Preferably, the alkali metal hydroxides are sodium hydroxides.

In one embodiment of the present invention, the suitable organic solvent used in step (ii) is selected from group comprising: alcohols such as methanol, ethanol, 1-propanol and 2-propanol; ether such as tetrahydrofuran, dioxane, diethyl ether, methyl t-butyl ether, diisopropyl ether, butyl ether, diphenyl ether and methylphenyl ether; esters such as ethyl acetate and isopropyl acetate; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; aromatic hydrocarbons such as toluene, benzene and xylenes; aliphatic hydrocarbons such as hexane and heptane; nitriles such as acetonitrile, propionitrile, butyronitrile and benzonitrile; amide such as dimethylformamide, dimethylacetamide; N-methyl-2-pyrrolidinone; dimethyl sulfoxide; sulfolane; chlorinating solvents such as chloroform, dichloromethane and dichloroethane or mixtures thereof. Preferably, the suitable organic solvent used in step (ii) is a mixture of toluene and methanol.

Unexpectedly, the present inventors found that the use of alkali metal hydroxide in the treatment of the compound of formula-II with Raney nickel results in tranexamic acid having better yield and purity than tranexamic acid resulted in the below mentioned prior art processes.
Process-I:

Process-II:

Further, tranexamic acid resulting in the process of treating the compound of formula-II with Raney nickel in the presence of alkali metal hydroxide could be purified easily to obtain pure tranexamic acid than the tranexamic acid resulted in the prior art processes such as Process-I and Process-II.

Further, the process disclosed in the Patent US 3574721 involves the hydrolysis after reduction of the cyanide group in cyclohexane moiety in the presence of Raney nickel and the process disclosed in the Patent US RE30149 involves the hydrolysis before reduction of the cyanide group in cyclohexane moiety in the presence of Raney nickel. The process of the present invention does not involve a separate hydrolysis step during the preparation of tranexamic acid from the cyanide group in cyclohexane moiety.

The present invention achieved and developed an improved process for preparing tranexamic acid in a high degree of purity than the prior art processes using ammonia.

Preferred embodiment of the present invention is to provide a process for preparing tranexamic acid of formula-I or its pharmaceutically acceptable salts comprising the steps of:

(i) preparing compound of formula-IIa as mentioned below,

; and

(ii) treating the compound of formula-IIa with Raney nickel catalyst in the presence of alkali metal hydroxide in a suitable organic solvent to obtain a tranexamic acid of formula-I.

Certain specific aspects and embodiments of the present invention will be better understood in connection with the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.

Table-1: Comparative table on the Content of Impurities in Tranexamic acid from the process of the present invention with prior art process using ammonia
Tranexamic acid process Content of Impurities in Tranexamic acid directly resulted in the Process
Content of Impurity A (%w/w) Content of Impurity B (% w/w) Content of Impurity C (% w/w) Content of total impurities (% w/w)
Process of the present invention: Tranexamic acid resulted from the process as mentioned below

ND 0.95 0.001 1.14
Tranexamic acid resulted from the process as mentioned below

0.48 0.57 0.02 5.82

Further tranexamic acid resulting in the process of present invention could be purified easily to obtain pure tranexamic acid than the tranexamic acid resulted in the prior art process using ammonia.

Table-2: Comparative table on the Content of Impurities in Tranexamic acid from the process of the present invention after purification with prior art process using ammonia
Tranexamic acid process Content of Impurities in Tranexamic acid resulted in the Process after Purification
Content of Impurity A (%w/w) Content of Impurity B (% w/w) Content of Impurity C (% w/w) Content of total impurities (% w/w)
Process of the present invention: Tranexamic acid resulted from the process as mentioned below

ND 0.12 0.001 0.12
Tranexamic acid resulted from the process as mentioned below
0.22 Not Detected 0.01 1.31

The tranexamic acid obtained by the process of the present invention exhibit a purity of 95 % by High-performance liquid chromatography (HPLC).

The purified tranexamic acid from the tranexamic acid obtained by the process of the present invention has the corresponding cis-isomer impurity not more than 0.2 % by HPLC.

Further, the tranexamic acid obtained by the process of the present invention has the impurity A not more than 0.1 % by HPLC; the impurity C not more than 0.1 % by HPLC; impurity E not more than 0.1 % by HPLC; and impurity F not more than 0.1 % by HPLC.

Examples
Example 1: Conversion of mixture of trans & cis-dimethyl 1,4-cyclohexane dicarboxylate to its trans isomer (Epimerization)

A mixture of dimethyl 1,4-cyclohexane dicarboxylate (500 g) and potassium acetate (2.5 g) was added into an autoclave pressure reactor at a temperature between 30°C-35 °C and stirred for 10-15 minutes at a temperature between 30°C-35°C. Nitrogen gas was applied at a pressure of 5-6 Kg/cm2 at a temperature between 30°C-35°C to the reaction mixture in the autoclave. The reaction mixture in the autoclave was heated to a temperature between 240°C-250°C and stirred for 24 hours at the same temperature. The progress of the reaction was monitored by HPLC chromatography. After completion of reaction, the reaction mass was then cooled to a temperature between 70°C-80 °C and transferred to round bottom flask at a temperature between 50°C-60°C then the reaction mass was cooled to a temperature between 35°C-40°C and stirred for 5 hours at the same temperature. n-Heptane (500 mL) was added to the stirred reaction mass at a temperature between 35°C-40°C and stirred at for 2 hours at the same temperature. The contents were than cooled to a temperature between 22°C-25°C and stirred for 2-3 hours at the same temperature till precipitation. The resultant solid was filtered, washed with chilled n-heptane (150 ml, less than 10?) and dried. % Yield: 49%.

Example-2: Preparation of trans-4-(methoxycarbonyl)-cyclohexane-1-carboxylic acid from trans-isomer of 1,-4-dimethyl-cyclohexane dicarboxylate

A mixture of dichloromethane (200 ml), methanol (100 ml), sodium hydroxide (20 g) and the trans-dimethyl 1,4-cyclohexane dicarboxylate obtained from Example-1 (100 g) were stirred for 6 hours at a temperature of 30?± 5?. The progress of the reaction was monitored by HPLC. After completion of the reaction, water (100 ml) was added to the reaction mass to form a biphasic mixture. Aqueous layer was separated from the biphasic mixture. Water (300 ml) was added to the separated aqueous layer and the pH was adjusted to 5.0 to 5.5 using hydrochloric acid at a temperature of 30?. The pH adjusted layer was heated to a temperature of 45?±5? and stirred for 2 hours at the same temperature. The contents were cooled to a temperature of 30±5? and stirred for 1 hour at the same temperature. The contents were further cooled to a temperature of 12.5?±2.5? and stirred for 2 hours at the same temperature till precipitation. The resultant solid was filtered, washed with prechilled water (50 ml, less than 10?) and dried. % Yield: 59%.

Example-3: Preparation of trans-methyl-4-carbamoyl-cyclohexane-1-carboxylate
Step (i): Preparation of trans-methyl-4-(chlorocarbonyl)-cyclohexane-1-carboxylate from trans-4-(methoxycarbonyl)-cyclohexane-1-carboxylic acid

To a mixture of trans-4-(methoxycarbonyl)-cyclohexane-1-carboxylic acid obtained from the example-2 (100 g) and toluene (300 ml), thionyl chloride (65.4 g) was slowly added at a temperature of 30?± 5? and stirred for 15 minutes at the same temperature. Dimethylformamide (0.5 ml) was added to the reaction mixture at a temperature of 30?± 5?; heated to a temperature of 50?± 5?; and the reaction mixture was stirred for 3 hours at a temperature of 50?± 5?. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was concentrated under vacuum to obtain a residue.

Step (ii): Preparation of trans-methyl-4-carbamoyl-cyclohexane-1-carboxylate from trans-methyl-4-(chlorocarbonyl)-cyclohexane-1-carboxylate

The residue obtained in step (i) was mixed with ethyl acetate (50 ml) and cooled to a temperature of 30?± 5? under nitrogen atmosphere. Cooled aqueous ammonia solution (100 ml of Aqueous ammonia in 350 ml of water at a temperature of 7.5 ± 2.5?) was added to the reaction mixture at a temperature of 10?± 5? and stirred for 3 hours at the same temperature. The resultant solid was filtered, washed with prechilled water (100 ml, 10?) and dried. % Yield: 71%.

Example-4: Preparation of tranexamic acid formula-I
Step-(a) Preparation of trans methyl-4-cyano cyclohexane-1-carboxylate of formula-IIa from trans-methyl-4-carbamoyl-cyclohexane-1-carboxylate

To a reaction mixture of trans methyl-4-carbamoyl yclohexane-1-carboxylate obtained from example-3 (100 g) and toluene (500 mL), thionyl chloride (78.33 g) was added at a temperature between 30°C-35°C and then heated to a temperature between 70°C-75°C. The reaction mixture was stirred for 8 hours at a temperature between 70°C-75°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mas was cooled at a temperature between 20°C-25°C and then mixed with (500 ml) water to form a biphasic mixture. The formed biphasic mixture was stirred for a temperature between 30°C-35°C. The organic layer from the biphasic mixture was separated. Water (300 ml) was added to the organic layer to form a biphasic mixture. The pH of the biphasic mixture was adjusted to 6 to 7 using sodium hydroxide solution and stirred for 30 minutes. The organic layer was separated from the biphasic layer was separated and proceeded for the next stage.
Step (b) – Preparation of tranexamic acid of formula-I from Trans methyl-4-cyano cyclohexane-1-carboxylate of formula-IIa

To the organic layer obtained in step (a), toluene (250 mL), methanol (250 mL), Raney nickel (20 g) and sodium hydroxide pellets (21.6 g) were added at a temperature between 30°C-35 °C. 20 Kg/cm2 of hydrogen pressure was applied to the reaction mixture at a temperature between 30°C-35 °C and heated to a temperature between 60-65°C. The reaction mixture was then maintained at a temperature between 60°C-65°C for 3 to 4 hours. The progress of reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled at a temperature between 30°C-35°C. The catalyst from the reaction mass was removed by filtration through hyflo bed. To the filtrate, acetic acid (32.4 g) was added and stirred for 1 hour at a temperature between 30°C-35°C. The contents were then stirred for 2 hours at a temperature between 30°C-35°C. The resultant solid was filtered and washed with methanol (100 ml) to obtain a wet solid. Purity: 98.85% W/W; Content of cis-isomer by HPLC:0.95% w/w; Content of Impurity-A by HPLC: Not detected; Content of Impurity-C: 0.001% w/w.

Step (c): Purification of tranexamic acid of formula-I
The wet solid obtained in step (b) was dissolved in water (500 ml) at a temperature between 30?-35°C. To this solution, activated charcoal (5 g, black powder having pH not more than 9) was added and stirred for 1 hour at a temperature between 30?-35°C. The contents were filtered through hyflo and then filtered through 0.45 µ membrane. The filtrate was concentrated under vacuum. To the concentrated solution, methanol (350 ml) was added. The contents were heated to a temperature of 55?±5? and stirred for 1 hour at a temperature of 55±5?. The contents were then cooled to a temperature of 30?±5? and stirred for 1 hour at a temperature of 30±5?. The contents were further cooled to a temperature of 22.5?±2.5? and stirred for 2 hours at a temperature of 22.5?±2.5?. The resultant solid was filtered, washed with methanol (100 ml) and dried. % Yield: 54%; Purity by HPLC: 99.8% W/W; Content of cis-isomer by HPLC: Not detected; Content of Impurity-A by HPLC: Not detected; Content of Impurity-C by HPLC: Not detected.

Example-5: Purification of Tranexamic acid
To a mixture of tranexamic acid (200 g) and water (1200 ml), activated carbon (6 g, Grade 51AL (7-12 pH)) was added at a temperature of 30?±5? and stirred for 1 hour at the same temperature. The resultant mass was filtered. The filtrate was heated to a temperature of 70?±5? and concentrated under vacuum at a temperature of 60?. To the concentrated mass, methanol (700 ml) was added at a temperature of 60?; stirred for 1 hour at the same temperature; then stirred for 1 hour at a temperature of 30?; stirred for 2 hours at a temperature of 22.5?. The resultant solid was filtered, washed with methanol (200 ml); dried for 2 hours at a temperature of 30?; then dried for 8 hours at a temperature of 55?. % Yield: 80%.
,CLAIMS:1. A process for preparing tranexamic acid of formula-I or its pharmaceutically acceptable salts, comprising the steps of:

(i) preparing compound of formula-II,

wherein R is selected from substituted or unsubstituted C1 to C8 alkyl; and
(ii) treating the compound of formula-II with Raney nickel catalyst in the presence of alkali metal hydroxide in an organic solvent to obtain tranexamic acid of formula-I.

2. The process as claimed in claim 1, wherein the compound of formula-II is prepared by a method comprising the steps of:
converting a cis and trans mixture of 1,4-dimethyl-cyclohexane dicarboxylate to a mixture containing predominantly trans-isomer;
reacting the mixture containing predominantly trans-isomer of 1,4-dimethyl-cyclohexane dicarboxylate with alkali metal hydroxide in a solvent to corresponding mono-ester;
treating the corresponding mono-ester with thionyl chloride in a solvent to obtain corresponding acid halide of the mono-ester;
reacting the corresponding acid halide of the mono-ester with ammonia to obtain corresponding half ester of amide; and
converting the corresponding half ester of amide into the compound of formula II.

3. The process as claimed in claim 1, wherein the alkali metal hydroxide used in step (ii) is selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, and cesium hydroxide.

4. The process as claimed in claim 1, wherein the alkali metal hydroxide used in step (ii) is sodium hydroxide.

5. The process as claimed in claim 1, wherein the organic solvent used in step (ii) is selected from the group comprising: alcohols, ether, esters, ketones, aromatic hydrocarbons, aliphatic hydrocarbons, nitriles, amides, dimethyl sulfoxide, sulfolane, chlorinating solvents, and mixtures thereof.

6. The process as claimed in claim 1, wherein the organic solvent used in step (ii) is a mixture of methanol and toluene.

7. A process for preparing tranexamic acid of formula-I or its pharmaceutically acceptable salts, comprising the steps of:

(i). preparing the compound of formula-IIa as mentioned below,

(ii). treating the compound of formula-IIa with Raney nickel catalyst in the presence of alkali metal hydroxide in a organic solvent to obtain a tranexamic acid of formula-I.

8. The process as claimed in claim 7, wherein the alkali metal hydroxide used in step (ii) is selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, and cesium hydroxide.

9. The process as claimed in claim 7, wherein the alkali metal hydroxide used in step (ii) is sodium hydroxide.

10. The process as claimed in claim 7, wherein the organic solvent used in step (ii) is selected from the group comprising: alcohols, ether, esters, ketones, aromatic hydrocarbons, aliphatic hydrocarbons, nitriles, amides, dimethyl sulfoxide, sulfolane, chlorinating solvents, and mixtures thereof.

11. The process as claimed in claim 7, wherein the organic solvent used in step (ii) is a mixture of methanol and toluene.