FIELD OF INVENTION

[0001] The present invention relates to a process for the preparation of Tranexamic acid, and more particularly to the preparation of pure Tranexamic acid.

BACKGROUND OF INVENTION

[0002] Tranexamic acid, also known as trans-4-(aminomethyl)cyclohexanecarboxylic acid, is a synthetic lysine derivative which acts as an antifibrinolytic agent. It competitively inhibits the activation of plasminogen by binding to the lysine binding sites on plasminogen. Tranexamic acid blocks the lysine binding site and prevents the activation of plasminogen by lysine.

[0003] Plasminogen on activation converts to plasmin which degrades fibrin. Fibrin is very essential in clot formation as it polymerizes to form a mesh which forms a clot or plug and prevents blood loss at a wound site.

[0004] Tranexamic acid is used for treatment of excessive menstrual bleeding. It is also used in the field of surgery to reduce pre and post operative blood loss. Tranexamic acid tablets are prescribed for excessive bleeding and are being marketed under various brand names. Many processes for the preparation of Tranexamic acid have earlier been developed.

[0005] CN1524847A (hereinafter referred to as ‘847) provides a process for the production of Tranexamic acid from p-aminomethyl benzoic acid. The process provides that p-aminomethyl benzoic acid on catalytic hydrogenation and transformation crystallization leads to the formation of Tranexamic acid.

[0006] US3950405 provides a process for the preparation of trans-4 (aminomethyl)cyclohexanecarboxylic acid by reducing trans-4-cyanocyclohexane-1-carboxylic acid in a solvent in the presence of a hydrogenating catalyst such as platinum oxide, palladium charcoal, palladium black, Raney cobalt and Raney nickel.

[0007] Further, JP240611 and JP242664 provide a process for the preparation of trans-4-cyanocyclohexane-1-carboxylic acid by reducing 4-cyanobenzoic acid or 4-aminomethylbenzoic acid with platinum oxide as catalyst.

[0008] The present invention provides a process for the preparation of Tranexamic acid with high purity. The process is a four step procedure which involves treating cyclohexane-1,4-dimethanol with sodium bromide to yield an intermediate which is further oxidized and then treated with ammonia to yield Tranexamic acid. The Tranexamic acid obtained is then purified to yield Tranexamic acid of high purity.

OBJECT OF INVENTION

[0009] The primary object of the invention is to provide a process for the preparation of Tranexamic acid.

[0010] Another object of the invention is to provide a process for the preparation of Tranexamic acid of high purity.

STATEMENT OF INVENTION

[0011] Accordingly the invention provides a process for the preparation of Tranexamic acid.

[0012] There is also provided a process for the preparation of Tranexamic acid of high purity.

[0013] An aspect of the invention provides a process for the preparation of Tranexamic acid, wherein 1,4-cyclohexane dimethanol is reacted with sodium bromide in the presence of sulphuric acid to yield 4-(bromomethyl)1-cyclohexane methanol (bromo alcohol). The bromo alcohol obtained is reacted with 2,2,6,6-tetramethyl-1-piperidinyloxyl free radical in the presence of sodium hypochlorite and sodium chlorite to yield 4-Bromomethyl cylohexane-1-carboxylic acid, which is further treated with aqueous ammonia to yield crude Tranexamic acid. Crude Tranexamic acid is further purified to obtain pure Tranexamic acid.

DETAILED DESCRIPTION OF INVENTION

[0014] The embodiments herein and the various features and advantageous details thereof are explained in greater depth with reference to the non-limiting embodiments that are detailed in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.

[0015] In an embodiment of the invention, the process for the preparation of Tranexamic acid comprises of reacting cyclohexane-1,4-dimethanol with sodium bromide in the presence of sulphuric acid to yield 4-bromomethyl cyclohexane-1-methanol. The reaction takes place at a temperature in the range of 80oC to 90oC, preferably at 85oC. The 4-bromomethyl cyclohexane-1-methanol obtained is further reacted with 2,2,6,6-tetramethyl-1-piperidinyloxyl free radical (TEMPO) or its derivatives in the presence of acetonitrile and sodium phosphate buffer of pH 6.7, followed by the slow addition of sodium hypochlorite and sodium chlorite solution to yield 4-Bromomethyl cylohexane-1-carboxylic acid. The reaction takes place at a temperature in the range of 30oC to 40oC, preferably at 35oC. The 4-Bromomethyl cylohexane-1-carboxylic acid obtained is then treated with aqueous ammonia to yield crude Tranexamic acid.

[0016] In another embodiment of the invention, the process for the preparation of pure Tranexamic acid comprises of hydrogenation of crude Tranexamic acid in the presence of palladium on carbon catalyst, wherein the reaction mixture is pressurized in the range of 2-6 Kg/cm2, preferably at 4 Kg/cm². Further, tranexamic acid in its pure form is extracted from the reaction mixture by treating it with solvents or a combination of solvents such as Isopropyl alcohol (IPA), water and methanol.

[0017] The invention is further illustrated by the following example, which should not be construed to limit the scope of the invention in anyway. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

[0018] EXAMPLE

[0019] Stage 1: Preparation of 4-bromomethyl cyclohexane-1-methanol.
Representation of the reaction at Stage 1 is as follows:

[0020] Procedure: 2.86 kg of sodium bromide (27.78 mol) is added in a thin stream, to avoid formation of lumps, to a mechanically stirred slurry of cyclohexane-1,4-dimethanol (1. CHDM, 4.0 kg, 27.78 mol) in water (1.75L, 97.3 mol). The mixture is then cooled to around 0°C-5°C and 1.75 L sulphuric acid (98%, d=1.84, 1.75 L, 32.22 mol) is slowly added, maintaining the temperature of the reaction between 20°C -25°C. The mixture is then heated to 85°C and is maintained at this temperature for about 24 hrs. The reaction mixture is further cooled to room temperature and poured into 10L of ice-water. The mixture is then extracted with Dichloromethane (DCM) (3 x 1.5L). The combined organic extract is then washed successively with water (4 x 1.5 L), 10% aqueous sodium bicarbonate solution (2 x 105 L) and water (1 x 2 L). The DCM layer is dried on sodium sulphate and concentrated. The residue (syrupy liquid) obtained is distilled under reduced pressure. (Crude yield: 3.32 Kg (43.65%); Purity (GC Area %): 75-80% of 4 bromomethyl cyclohexane-1-methanol, 15-20% of 1,4-di(bromomethyl) cyclohexane (3))

[0021] The purity and yield of various fractions obtained on distillation of crude product (an amount of 3.32 Kg of crude product) is as follows:

Wherein,

Compound 1 is cyclohexane-1,4-dimethanol
Compound 2 is 4-bromomethyl cyclohexane-1-methanol
Compound 3 is 1,4-Di-(bromomethyl)cyclohexane

[0022] Stage 2: Preparation of 4-Bromomethyl cylohexane-1-carboxylic acid.
Representation of the reaction at Stage 1 is as follows:

[0023] Procedure: A mechanically stirred mixture of 2.5 Kg of 4-bromomethyl cyclohexane-1-methanol (2, 70.67%, 8.53 mol), 29 g of 2,2,6,6-tetramethyl-1-piperidinyloxyl free radical (TEMPO, 0.186 mol), 10 L of acetonitrile and sodium phosphate buffer (prepared from 2.1 Kg sodium dihydrogen phosphate dihydrate and 20 L water and adjust pH to 4 using 25 ml acetic acid) is heated to 35°C. Further, a dilute solution of sodium hypochlorite (prepared from 5 L water and 130 ml of 12% sodium hydrochlorite solution) and sodium chlorite solution (prepared from 1.39 Kg of sodium chlorite and 5 L water) is added (drop wise) while maintaining the temperature of the reaction at 35°C for around 2 to2.5 hrs. The mixture is stirred at 35°C for 2 hrs. After cooling the reaction mixture to room temperature, a 20% sodium hydroxide solution is added to the reaction mixture till the pH becomes 8-9. The reaction mixture is then poured to pre cooled (~5°C) solution of sodium sulphite (prepared from 1.475 Kg of sodium sulphite in 5 L water). The mixture is washed with DCM (2 x 4 L). The alkaline layer is acidified with 6N hydrochloric acid to pH 3-4 and the acidic layer is extracted by DCM (2 x 5 L). The organic layer is washed with water (3 L), saturated sodium chloride solution (3 L) and dried (over sodium sulphate). DCM is then removed to get the product 4-bromomethyl cylohexane-1-carboxylic acid (4, 1.76 Kg, 93.25%, a mixture of cis and trans isomers). The crude product (4, 1.76 Kg) is stirred with 1.76 L of hexane for 15 min at room temperature and filtered to get trans isomer enriched product (yield 1.40 kg, 74.18%, 95.8% trans, 1.6% cis).

[0024] Stage 3: Preparation of crude Tranexamic acid.

[0025] Procedure: 4-Bromomethyl cylohexane-1-carboxylic acid (4, a trans enriched product, 120 g, 0.52 mol) is dissolved in 1.2 L of ~30-35% aqueous ammonia and kept sealed in an air tight container for 3.5-4 days. Ammonia is removed by passing air slowly into the reaction mixture. The mixture is then concentrated to about 500 ml under reduced pressure. Further, Acetone (300ml) is added and stirred for 15-20 min. The upper layer is decanted and fresh acetone is later added. The mixture is then stirred for 15-10 min. This operation is repeated for 4-5 times to get the white solid. The white solid is stirred in methanol (500 ml) for 30 min and filtered to get the crude product of tranexamic acid. (5, 53.0 g, 64.9%, 90% pure by HPLC).

[0026] Stage 4: Purification of pure Tranexamic acid from crude Tranexamic acid

[0027] Procedure: 53 g of Crude product of tranexamic acid is dissolved in 350ml of water followed by the addition of 1.0 g of 10% palladium on carbon catalyst with 50% moisture. The mixture is then hydrogenated at 4 Kg/cm² pressure at room temperature for 3 hrs. The reaction mixture is further filtered and the filtrate is concentrated under reduced pressure to get a white solid (46 g, 97.8% pure by HPLC). The white solid is then suspended in 230 ml of IPA and heated under reflux. 368ml of Water is then added in portions and the mixture is refluxed for 15 min and filtered hot. Further the filtrate is stirred and cooled to 0°C for 5-7 hrs and the white solid is separated by filtration, washed with methanol and dried to get pure tranexamic acid (32g, 31.9%, HPLC purity 99.8%).

[0028] The purity of tranexamic acid obtained was analysed by High pressure liquid chromatograph (HPLC). HPLC was performed on a Shimadzu LC solutions – Prominence 20 series instrument equipped with UV spectrophotometer detector. The purity of tranexamic acid by related substances as per EP was performed using a C-18 column (250 mm x 4.6 mm, 5 ? pores size), with column pressure of 72 kgf. The programme and other parameters are given below:

Column oven temperature: ambient

Mobile phase: 11.0g of sodium dihydrogen phosphate was dissolved in 500ml water, 5ml of triethylamine and 1.4g of sodium laurilsulfate was then added. The pH was adjusted to 2.5 with dilute phosphoric acid and the solution was diluted to 600ml with water. Further, 400ml of methanol was added to the solution and mixed.

Diluent: Mobile phase
Injection volume: 20mL
Detector: UV lamp 220nm
Flow rate: 0.9ml/min
Run time: 35 min

PDA Ch1 220nm 4nm

[0029] The foregoing description of the specific embodiments will very well reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and adapt for various applications such specific embodiments without departing from the generic concept and therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the appended claims.

STATEMENT OF CLAIMS

We Claim:

1. A process for the preparation of Tranexamic acid comprising:

(a) reacting cyclohexane-1,4-dimethanol with sodium bromide in the presence of sulphuric acid to yield 4-bromomethyl cyclohexane-1-methanol,

(b) reacting 4-bromomethyl cyclohexane-1-methanol with 2,2,6,6-tetramethyl-1-piperidinyloxyl free radical (TEMPO) or its derivatives in the presence of acetonitrile and sodium phosphate buffer to yield 4-Bromomethyl cylohexane-1-carboxylic acid,

(c) treating 4-Bromomethyl cylohexane-1-carboxylic acid with aqueous ammonia to yield crude Tranexamic acid.

2. The process for the preparation of Tranexamic acid as claimed in claim 1, wherein the reaction of step (a) is carried out at a temperature in the range of 80oC to 90oC, preferably 85oC.

3. The process for the preparation of Tranexamic acid as claimed in claim 1, wherein the reaction of step (b) takes place at a temperature in the range of 30oC-40oC, preferably 35oC.

4. The process for the preparation of Tranexamic acid as claimed in claim 1, wherein sodium phosphate buffer of step (b) has a pH of 6.7.

5. The process for the preparation of Tranexamic acid as claimed in claim 1, further comprising purifying Tranexamic acid from crude Tranexamic acid wherein the process comprises:

(a) hydrogenating crude Tranexamic acid in the presence of palladium on carbon catalyst;

(b) extracting pure Tranexamic acid with extracting solvents selected from a group consisting of isopropyl alcohol, water, methanol and combinations thereof.

6. The process for the preparation of Tranexamic acid as claimed in claim 5, wherein said hydrogenation of step (a) takes place at a pressure in the range of 2-6 Kg/cm².

7. The process for the preparation of Tranexamic acid as claimed in claim 6, wherein said pressure is 4 Kg/cm².

Dated this 10th November 2010