Claims:We Claim:
1. A process for synthesis of Tranexamic acid using continuous flow chemistry (as illustrated in Figure 1), the said process comprising the steps of:
i) Pump A is primed with 4-halomethyl cyclohexane carboxylic acid and its esters (1equivalent) in polar solvents and is fed into a flow reactor at a rate of 1 to 15 ml/minute to get 5 to 25 minutes residence time;
wherein the flow reactor is connected to two or more 10ml plug flow reactor coils (Reactors), the outlet of Reactor 1 (R.01 in Fig.1) is connected to Reactor 2 (R.02 in Fig.1), the outlet of Reactor 2 is connected to Reactor 3 (R.03 in Fig.1), and so on; the outlet of the end reactor in the flow reactor is connected to a 70 to 130 psi back pressure regulator and then directed to a stirred collection flask (F.01 in Fig.1); and the temperature set for the reactors and the process ranges from 300C to 1500C;
ii) Pump B is primed with ammonia source reagent and connected with a tee fitting to the inlet of Reactor 1 (R.01 in Fig.1), wherein the ammonia source reagent feeding rate is kept at 5ml to 30 ml per minute;
iii) Pumping is continued until all solutions are consumed and the reaction mixture is later flushed with solvents to get complete reaction stream and collecting it into continuous stirred tank reactor (CSTR) (F.01 in Fig.1);
iv) A base is added to the reactor to adjust the pH to 10 to 13 and stirring of the reaction mixture is continued for 1 to 10 hours;
v) The reaction mixture is then neutralized to pH 7 and the desired crude tranexamic acid is isolated;
vi) The crude product is crystallized in a mixture of various solvents (both polar and non-polar), at a temperature between 30 to 1000C to get pure tranexamic acid.
2. The process as claimed in Claim 1, wherein the flow reactor is connected to two to three 10ml of plug flow reactor coils (reactors) and the outlet of Reactor 1 is connected to Reactor 2, and the outlet of Reactor 2 is connected to Reactor 3; the outlet of Reactor 2 in the two coil flow reactor or the outlet of Reactor 3 in the three coil flow reactor is connected to a 70 to 130 psi back pressure regulator and then directed to a stirred collection flask; 4-halomethyl cyclohexane carboxylic acid and its esters (1equivalent) in polar solvents is fed into a flow reactor at a rate of 1 to 10 ml/minute to get 10 to 15 minutes residence time and the ammonium source reagent feeding rate is kept at 5ml to 15 ml per minute; the Reactor 1 temperature is set to be between 1000C to 1500C, Reactor 2 temperature is set to 750C to 1300C, and Reactor 3 temperature is set to 500C to 750C; and the solvents used to crystallize the crude tranexamic acid in Step (vi) are water (1 to 5ml), ammonia ( 1 to 5ml) and alcohol (3 to 10 volume) and its mixture.
3. The process as claimed in Claims 1 and 2, wherein the 4-halomethyl cyclohexane carboxylic acid is selected from the group comprising of 4-chloromethyl cyclohexane carboxylic acid, 4-bromomethyl cyclohexane carboxylic acid, 4-chloromethyl cyclohexane methyl carboxylate , 4-chloromethyl cyclohexane ethyl carboxylate , 4-bromomethyl cyclohexane methyl carboxylate, 4-bromomethyl cyclohexane ethyl carboxylate, 4-bromomethyl cyclohexane isopropyl carboxylate, 4-chloromethyl cyclohexane isopropyl carboxylate, 4-Iodomethyl cyclohexane carboxylic acid , 4-Iodomethyl cyclohexane carboxylate .
4. The process as claimed in Claims 1 and 2, wherein the Ammonia source reagent used for the reaction is selected from the group comprising of 25 to 30% aqueous ammonia, 14 M of methanolic ammonia, 14 M of ammonia in 1,4 dioxane and Ammonia gas.
5. The process as claimed in Claims 1 and 2, wherein the solvents used in step (iii) are selected from the group comprising of methanol, ethanol, isopropanol, Tetrahydrofuran, 2- methyl Tetrahydrofuran, Dimethylformamide, Acetonitrile, water, Methyl tertiary butyl ether, 1,4 dioxan, toluene, 2-chlorobenzene, ammonia, and other non-polar solvents.
6. The process as claimed in Claims 1 and 2, wherein the base is selected from the group comprising of Potassium hydroxide, Sodium hydroxide, Potassium carbonate, Calcium hydroxide, Sodium carbonate, Triethyl amine, di isopropyl ethyl amine (DIPEA), Sodium amide, pyridine, ammonia and other organic bases.
7. The process as claimed in Claims 1 and 2, wherein the mixture of solvents used for crystallization in step (vi) is water and alcohol mixture (1:10 ratio).
8. The process as claimed in Claims 1 and 2, wherein the back pressure applied in the process ranges from 50 psi to 170psi.
9. The process as claimed in Claims 1 and 2, wherein the acids used for the neutralization are selected from a group comprising of concentrated HCl, Acetic acid, p-para toluene sulphonic acid, dilute sulphuric acid and carbon dioxide.
Date this, the 6th Day of September 2021.

------Digitally Signed--------
Bandita Panda
IN/PA-1880
Agent for the Applicant
To
The Controller of Patents
The Patent Office at Chennai , Description:F O R M 2
THE PATENTS ACT, 1970
(39 of 1970)

COMPLETE SPECIFICATION
(See section 10 and rule 13)

Title of the Invention:
COST EFFECTIVE, SCALABLE PROCESS FOR SYNTHESIS OF TRANEXAMIC ACID USING CONTINOUS FLOW REACTOR.

Name of the Applicant & Address:
Negha Green Lab LLP.,
Women’s Biotech Park, Siruseri
Chennai.

Nationality:
INDIAN

Preamble to the description:
The following specification particularly describes the invention and the manner in which it is to be performed.

Title:
COST EFFECTIVE, SCALABLE PROCESS FOR SYNTHESIS OF TRANEXAMIC ACID USING CONTINOUS FLOW- REACTOR.

FIELD OF INVENTION
The present disclosure relates to the process of manufacture of Tranexamic acid or trans-4-aminomethyl cyclohexane carboxylic acid; more particularly relates to a novel cost effective, highly efficient, and greener process of synthesis of pure Tranexamic acid using continuous flow technologies to make it commercially viable, with high yield and quality.
BACKGROUND OF THE INVENTION
Nitrogen containing compounds are essential for the pharmaceuticals, agrochemicals, and food additive industries. Consequently, numerous methods have been investigated over the years to form carbon-nitrogen bonds. Among them, displacement reactions with nitrogen nucleophiles are versatile transformations allowing the synthesis of a large variety of amine products.
Tranexamic acid is an antifibrinolytic agent and is used in the prevention of hemorrhage due to dental procedures in hemophilic, cyclic heavy menstrual bleeding, hereditary angioedema and during surgery. There are many commercially known processes for synthesis of Tranexamic acid. Most of these are batch processes for the synthesis, which either lead to formation of crude tranexamic acid that requires further purification or yields undesired poly alkylated by-products. Also, in hydrogenation process used high cost catalyst and reaction conducted over high temperature and pressure as safety concern. To overcome these problems, azides and phthalimides have been used in the synthesis of Tranexamic acid. However, these compounds are hazardous and not environment friendly. Handling of sodium azide and formation of Azide reaction on large scale have more challenges and safety concerns, especially handling during bulk production at high temperature. Also, in these cases an additional step is necessary to reveal the amine moiety. In traditional batch processes dimer impurities are produced and it is difficult to control the reaction kinetics. The purification of the target compounds become more difficult and too much attempt in purification process will result in loss of product in mother liquor. The cost is also high because of these multi-step processes. Alternatively special techniques were addressed such as microwave irradiation to promote the amination of alkyl halides using 7M ammonia solution in methanol at 1300C for 0.25 to 2.5h. However, the scale up of such techniques are often limited. The known processes of synthesis of tranexamic acid involve vigorous reaction conditions, employ complex reagents which are hazardous, are expensive and lead to undesirable byproducts. Furthermore, an amination process using commercially available cheap aqueous ammonia (and methanolic ammonia) is highly desirable. Therefore, there is a need in the state of art for a simple, cost effective and green process which can produce high yield of pure tranexamic acid.
SUMMARY:
To overcome the problems in the existing art described above in the manufacture of tranexamic acid, a novel, green, economical and commercially feasible process of synthesis of tranexamic acid is provided in the present disclosure. The said process of the present disclosure uses continuous flow technologies enabled rapid reactions, with excellent heat transfer, facilitating the manipulation of gas and its addition rate, decreasing the formation of by-products, and leading to formation of tranexamic acid product with increased yield of 75% with 99.8% purity with 99.0% Assay. Also, the production time cycle comparatively decreased to one third time compared to batch process by minimizing the number of steps by adopting simplest protocol. Evaluation of all parameters (Cheapest chemicals, minimize number of steps, control of impurities, simplified workup, minimize production time cycle and most important highly safe on scale handling) in the process parameters of present disclosure has provided high yield with EP monograph qualified product. Overall, this improved flow process leads to highly cost-effective process on scale.
Accordingly, in one of the embodiments of the present disclosure a process of synthesis of Tranexamic acid using continuous flow chemistry (as illustrated in Figures 1) is provided, the said process comprising the steps of:
i) Pump A is primed with 4-halomethyl cyclohexane carboxylic acid or its esters (1 equivalent) in polar solvents and is fed into a flow reactor at a rate of 1 to 15 ml/minute to get 5 to 25 minutes residence time; wherein the flow reactor is connected to two or more 10ml plug flow reactor coils (Reactors), the outlet of Reactor 1 (R.01 in Fig.1) is connected to Reactor 2 (R.02 in Fig.1), the outlet of Reactor 2 (R.02 in Fig.1) is connected to Reactor 3 (R.03 in Fig.1), and so on; the outlet of the end reactor in the flow reactor is connected to a 70 to 130 psi back pressure regulator and then directed to a stirred collection flask; and the temperature set for the reactors and the process ranges from 300C to 1500C.
ii) Pump B is primed with ammonia source reagent and connected with a tee fitting to the inlet of Reactor 1 (R.01 in Fig.1), wherein the ammonium source reagent feeding rate is kept at 5ml to 30 ml per minute.
iii) Pumping is continued until all solutions are consumed and the reaction mixture is later flushed with solvents to get complete reaction stream and collecting it into continuous stirred tank reactor (CSTR) (F.01 in Fig.1).
iv) A base is added to the reactor to adjust the pH to 10 to 13 and stirring of the reaction mixture is continued for 1 to 10 hours.
v) The reaction mixture is then neutralized to pH 7 and isolated the desired crude tranexamic acid.
vi) The crude product is further crystallized in a mixture of various solvents (both polar and non-polar), at a temperature between 30 to 1000C to get pure tranexamic acid.
In a preferred embodiment a process of synthesis of Tranexamic acid using continuous flow chemistry (as illustrated in Figures 1) as described above is provided, wherein the flow reactor is connected to two to three 10ml of plug flow reactor coils (reactors) and the outlet of Reactor 1 (R.01 in Fig.1) is connected to Reactor 2 (R.02 in Fig.1), and the outlet of Reactor 2 is connected to Reactor 3 (R.03 in Fig.1); the outlet of Reactor 2 in the two coiled flow reactor or the outlet of Reactor 3 in the three coiled flow reactor is connected to a 70 to 130 psi back pressure regulator and then directed to a stirred collection flask (F.01 in Fig.1); 4-halomethyl cyclohexane carboxylic acid and its esters (1equivalent) in polar solvents is fed into the flow reactor at a rate of 1 to 10 ml/minute to get 10 to 15 minutes residence time and the ammonium source reagent feeding rate is kept at 5ml to 15 ml per minute; the Reactor 1 temperature is set to be between 1000C to 1500C, Reactor 2 temperature is set to 750C to 1300C, and Reactor 3 temperature is set to 500C to 750C; and the solvents used to crystallize the crude tranexamic acid are water (1 to 5ml), ammonia ( 1 to 5ml) and alcohol (3 to 10 volume) and its mixture.
In yet another preferred embodiment a process of synthesis of Tranexamic acid using continuous flow chemistry (as illustrated in Figure 1) as described above is provided, wherein the 4-halomethyl cyclohexane carboxylic acid is selected from the group comprising of 4-chloromethyl cyclohexane carboxylic acid, 4-bromomethyl cyclohexane carboxylic acid, 4-chloromethyl cyclohexane methyl carboxylate, 4-chloromethyl cyclohexane ethyl carboxylate , 4-bromomethyl cyclohexane methyl carboxylate, 4-bromomethyl cyclohexane ethyl carboxylate, 4-bromomethyl cyclohexane isopropyl carboxylate, 4-chloromethyl cyclohexane isopropyl carboxylate. 4-Iodomethyl cyclohexane carboxylic acid, 4-Iodomethyl cyclohexane methyl carboxylate.
In yet another preferred embodiment a process of synthesis of Tranexamic acid using continuous flow chemistry (as illustrated in Figures 1) as described above is provided, wherein the Ammonia source reagent used for the reaction is selected from the group comprising of 25 to 30% aqueous ammonia, 14 M of methanolic ammonia, 14 M of ammonia in 1,4 dioxane and Ammonia gas.
In yet another preferred embodiment a process of synthesis of Tranexamic acid using continuous flow chemistry (as illustrated in Figure 1) as described above is provided, wherein the solvents used in step (iii) are selected from the group comprising of methanol, ethanol, isopropanol, THF, 2- methyl THF, DMF, Acetonitrile, water, MTBE, 1,4 dioxan, toluene, 2-chlorobenzene, and other non-polar solvents.
In yet another preferred embodiment a process of synthesis of Tranexamic acid using continuous flow chemistry (as illustrated in Figure 1) as described above is provided, wherein the base is selected from the group comprising of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, calcium hydroxide, Triethyl amine, di isopropyl ethyl amine (DIPEA), pyridine, ammonia and other organic bases.
In yet another preferred embodiment a process of synthesis of Tranexamic acid using continuous flow chemistry (as illustrated in Figure 1) as described above is provided, wherein the mixture of solvents used for crystallization in step (vi) is Acetonitrile, ammonia, water and alcohol and its mixture.
In yet another preferred embodiment a process of synthesis of Tranexamic acid using continuous flow chemistry (as illustrated in Figure 1) as described above is provided, wherein the back pressure applied in the process ranges from 50 psi to 170psi.
In yet another preferred embodiment a process of synthesis of Tranexamic acid using continuous flow chemistry (as illustrated in Figure 1) as described above is provided, wherein the acids used for the neutralization are selected from a group comprising of concentrated hydrochloric acid, acetic acid, dilute sulphuric acid, carbon dioxide and para toluene sulphonic acid.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGURE 1: FIG.1 is a schematic illustration of the continuous flow process for synthesis of Tranexamic Acid, wherein R.01 is Reactor 1, R.02 is Reactor 2, R.03 is Reactor 3, F.01 is the collection flask and W.01 is the waste generated in the process.
FIGURE 2: FIG.2 is a HPLC chromatograph, based on the said process a purity of 99.8% product Tranexamic acid is obtained based on High Performance liquid chromatography with the individual impurity qualified as per the pharmacopeia acceptance level criteria.
FIGURE 3: FIG.3 is a 13CNMR spectrum, based on the Carbon 13 NMR values it is found that this spectrum matches and desired peaks matches with standard Tranexamic acid.
FIGURE 4: FIG.4 is a spectrum, based on the proton NMR values, it is found that this spectrum confirms/matches with the standard values of Tranexamic acid.
FIGURE 5: FIG.5 is an Ultraviolet spectrum in which the wavelength at 210nm of the Isolated Tranexamic acid by the above process matches with the standard compound.
DETAILED DESCRIPTION
Throughout this specification, the use of the word "comprises" and “include” and variations such as "comprises "comprising", “includes”, and “including” implies the inclusion of an element or elements not specifically recited.
All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice of the disclosure, the preferred methods, and materials are now described.
In the process described in the present disclosure selective amination of para substituted 4-halomethyl cyclohexane carboxylic acid and its ester with methanolic ammonia /aqueous ammonia was achieved in flow chemistry to produce primary ammonium salts in high yields. An inline work up was designed to isolate the corresponding Tranexamic acid (4-Aminomethyl cyclohexane carboxylic acid).
Continuous flow technologies used in the process of present disclosure enable rapid reactions with excellent heat transfer, facilitating the manipulation of gas and decreasing the formation of by-products in the synthesis of Tranexamic acid and helps in getting clean product profile. The process controls formation of by-products like di-substitution product and other impurity formation especially control of impurity A, D and E which can meet EP monograph. In the process of the present disclosure, a general amination procedure in flow is done, applicable to alkyl halides with both methanolic ammonia and ammonium hydroxide solution (25–30%) along with ammonia gas. Follow up was done with in line process to simplify the workup and to get desired target tranexamic acid product with increased yield of 75% and 99.8% purity with 99.0% Assay. To improve the mixing, various flow rates were tested using a mixer; the same yield was obtained with a residence time of 2 to 30 mins at 800C to 1600C.
In the process of the present disclosure a flow reactor connected with two or more 10ml of plug flow reactor coils (reactors) (as illustrated in Fig.1) is used for the process of synthesis of Tranexamic acid. In the flow reactor the outlet of Reactor 1 (R.01 in Fig.1) is connected to Reactor 2 (R.02 in Fig.1), and the outlet of Reactor 2 is connected to Reactor 3 (R.03 in Fig.1) and so on. The outlet of Reactor 2/Reactor 3 is connected to 70 to 130 psi back pressure regulator and then directed to stirred collection flask (F.01 in Fig.1). The temperature set for the reactors and the process ranges from 300C to 1500C. More particularly, The Reactor 1 temperature is set to be between 1000C to 1500C, Reactor 2 temperature is set to 750C to 1300C, and Reactor 3 temperature is set to 500C to 750C.
In one of the main embodiments of the present disclosure, the general process of synthesis of Tranexamic acid through Flow chemistry (as illustrated in Figure 1) comprises of the steps described below:
1. Pump A is primed with 4-halomethyl cyclohexane carboxylic acid and its esters (1equivalent) in polar solvents is fed into the reactor at the rate of 1 to 15 ml/minute to get 5 to 25 minutes residence time.
2. Pump B is primed with Ammonia source reagent and connected with a tee fitting to the inlet of Reactor 1 (R.01 in Fig.1). Ammonium source reagent feeding rate is kept at 5ml to 30 ml per minute.
3. In the flow reactor the outlet of Reactor 1 (R.01 in Fig.1) is connected to Reactor 2 (R.02 in Fig.1), and the outlet of Reactor 2 is connected to Reactor 3 (R.03 in Fig.1) and so on. The outlet of Reactor 2/Reactor 3 is connected to 70 to 130 psi back pressure regulator and then directed to stirred collection flask (F.01 in Fig.1). The temperature set for the reactors and the process ranges from 300C to 1500C. More particularly, The Reactor 1 temperature is set to be between 1000C to 1500C, Reactor 2 temperature is set to 750C to 1300C, and Reactor 3 temperature is set to 500C to 750C. Pumping is continued until all solutions are consumed.
4. The reaction mixture is later flushed with solvents to get complete reaction stream and collecting it into continuous stirred tank reactor (CSTR (F.01 in Fig.1)).
5. A base is added to the reactor to adjust the pH to 10 to 13. Stirring of the reaction mixture is continued for 1 to 10 hours, it is neutralized to the pH 7 and the desired free tranexamic acid is isolated.
6. The crude product is further crystallized in a mixture of various solvents (both polar and non-polar), mainly water (1 to 5ml), ammonia (1 to 5ml) and alcohol (3 to 10 volume) and its mixture, at a temperature between 300C to 1000C to get 75% yield of Pure Tranexamic acid product with 99.8% HPLC purity and 99% QNMR assay.
General reaction scheme of the present disclosure:

Wherein, the X is Cl or Br or I and Y is independently selected from a group consisting of H, CH3, C2H5, i-Pr., and other ester protecting group.
In one of the embodiment of the present disclosure, a process of synthesis of Tranexamic acid using continuous flow chemistry (as illustrated in Figures 1 ) as described above is provided, wherein the flow reactor is connected to two to three 10ml of plug flow reactor coils (reactors) and the outlet of Reactor 1 (R.01 in Fig.1) is connected to Reactor 2 (R.02 in Fig.1), and the outlet of Reactor 2 is connected to Reactor 3 (R.03 in Fig.1); the outlet of Reactor 2 in the two coiled flow reactor or the outlet of Reactor 3 in the three coiled flow reactor is connected to a 70 to 130 psi back pressure regulator and then directed to a stirred collection flask (F.01 in Fig.1); 4-halomethyl cyclohexane carboxylic acid and its esters (1equivalent) in polar solvents is fed into the flow reactor at a rate of 1 to 10 ml/minute to get 10 to 15 minutes residence time and the ammonium source reagent feeding rate is kept at 5ml to 15 ml per minute; the Reactor 1 temperature is set to be between 1000C to 1500C, Reactor 2 temperature is set to 750C to 1300C, and Reactor 3 temperature is set to 500C to 750C; and the solvents used to crystallize the crude tranexamic acid are water (1 to 5ml), ammonia ( 1 to 5ml) and alcohol (3 to 10 volume) and its mixture.
In one of the embodiment of the present disclosure, the 4-halomethyl cyclohexane carboxylic acid used as the starting material in the process of synthesis of Tranexamic acid described in step 1 above is selected from the group comprising of 4-chloromethyl cyclohexane carboxylic acid, 4-bromomethyl cyclohexane carboxylic acid, 4-chloromethyl cyclohexane methyl carboxylate , 4-chloromethyl cyclohexane ethyl carboxylate , 4-bromomethyl cyclohexane methyl carboxylate, 4-bromomethyl cyclohexane ethyl carboxylate, 4-bromomethyl cyclohexane isopropyl carboxylate, 4-chloromethyl cyclohexane isopropyl carboxylate, 4-Iodomethyl cyclohexane carboxylic acid, 4-Iodomethyl cyclohexane methyl carboxylate.
In one of the embodiments of the present disclosure, the Ammonia source reagent used for the reactions for synthesis of Tranexamic acid and its esters described in step 2 above is selected from the group comprising of 25 to 30% aqueous ammonia, 14 M of methanolic ammonia, 14 M of ammonia in 1,4 dioxane and Ammonia gas.
In one of the embodiments of the present disclosure, the solvents used for the reaction described above in step 3 of the process of synthesis of Tranexamic acid and its esters are selected from the group comprising of methanol, ethanol, isopropanol, Tetrahydrofuran, 2- methyl Tetrahydrofuran, Dimethylformamide, Acetonitrile, water, Methyl tertiary butyl ether, 1,4 dioxan, toluene, 2-chlorobenzene, Ammonia, and other non-polar solvents.
In one of the embodiments of the present disclosure, the base used for the reaction described above in step 4 of the process of synthesis of Tranexamic acid and its esters is selected from the group comprising of Potassium hydroxide, Sodium hydroxide, Potassium carbonate, Sodium carbonate, calcium hydroxide, Triethyl amine, di isopropyl ethyl amine (DIPEA), pyridine, ammonia and other organic bases.
In one of the embodiments of the present disclosure, the temperature used for the reaction according to the process of synthesis of Tranexamic Acid and its esters described above ranges from 30oC to 150oC.
In one of the embodiments of the present disclosure, the back pressure applied in the process of synthesis of Tranexamic acid and its esters described above ranges from 50 psi to 170psi.
In one of the embodiments of the present disclosure, acids used for the neutralization are concentrated hydrochloric acid, dilute sulphuric acid, acetic acid, carbon dioxide and p-toluene sulphonic acid.
WORKING EXAMPLES:
The process of the present disclosure will now be illustrated with working examples, which is intended to illustrate the best mode for working of the disclosed process and not intended to take restrictively to imply any limitations on the scope of the present disclosure.
Example 1:
Synthetic process for the preparation of tranexamic acid using 4-(bromomethyl) cyclohexane-1-carboxylic acid:

A flow reactor connected with the three 10ml of plug flow reactor coils made in SS tubing with 1mm internal diameter was used for the reaction. Pump A was primed with 4-Bromo methyl cyclohexane carboxylic acid (25g) in 150ml ethanol solvent and fed into the reactor. Pump B was primed with methanolic ammonium solution (NH3.MeOH) (14M) 250ml and connected with a tee fitting to the inlet of Reactor 1. Reactor 1 outlet was connected to Reactor 2 followed by connecting to Reactor 3. The outlet of Reactor 3 was connected to 70psi back pressure regulator and then directed to the stirred collection flask. The Reactor 1 temperature was set to 1300C, Reactor 2 temperature was set to 1100C, and Reactor 3 temperature was set to 750C.
The starting material 4-Bromo methyl cyclohexane carboxylic acid (25g) in 250ml ethanol solvent was fed into the Reactor 1 at 5 ml/minute to get 20 minutes residence time. Methanolic Ammonia feeding rate was kept at 10ml per minute. Pumping was continued until all solutions were consumed. Then later flushed the reactor with 100ml of ethanol and 100ml of water to get complete reaction stream and collecting it in CSTR. Then to the reactor added 7g of potassium hydroxide in 40ml of water to adjust the pH to 10 and continued stirring the reaction mixture for 10 hours. The reaction mixture was then neutralized to pH 7 using hydrochloric acid and crystallized the mixture after removal of 90% water. Isopropyl alcohol (IPA) was added to crystallize the solid to get 24g crude product (tranexamic acid and esters). The crude product (24g) was then dissolved in a mixture of water (60ml) and Isopropyl Alcohol (240ml), then heated to 60oC, maintained at 60oC for 60 minutes and cooled to room temperature. Continued stirring for 30 minutes, then filtered and washed with IPA (20ml), and dried at 600C for 4hrs to get 13.4g pure product. Overall, 75% yield of the product (tranexamic acid) was obtained with 99.8% HPLC purity and 99% QNMR assay.
Example 2
Synthetic process for the preparation of tranexamic acid using 4-(chloromethyl) cyclohexane-1-carboxylic acid:

A flow reactor connected with the three 10ml of plug flow reactor coils made in SS tubing with 1mm internal diameter was used for this process. Pump A was primed with 4-chloromethyl cyclohexane carboxylic acid (20g) in 250ml Methanol as solvent and fed into the reactor. Pump B was primed with ammonia in methanolic solution (14M) 250ml and connected with a tee fitting to the inlet of Reactor 1. Reactor 1 outlet was connected to Reactor 2 followed by connecting to Reactor 3. The outlet of Reactor 3 was connected to 70psi back pressure regulator and then directed to stirred collection flask. The Reactor 1 temperature was set to 1100C, Reactor 2 temperature was set to 1000C and Reactor 3 temperature was set to 750C.
The starting material 4-chloromethyl cyclohexane carboxylic acid (20g) in 250ml Methanol was fed into the reactor at 3 ml/minute to get 15 minutes residence time. Ammonia solution feeding rate was kept at 7 ml per minute. Pumping was continued until all solutions were consumed. Then later flushed the reactor with 100ml of ethanol and 100ml of water to get complete reaction stream and collecting it in CSTR. Then to the reactor added the 6g of potassium hydroxide in 40ml of water to adjust the pH to 9 and continued stirring the reaction mixture for 6 hours. Neutralized the reaction mixture to pH 7 using acetic acid and crystallized the mixture after removal of 90% water. 60ml IPA was added to crystallize and get 18g of the crude product (tranexamic acid).
The crude product (18g) was dissolved in water (60ml) and methanol (200ml), heated to 60oC, maintained for 60 minutes, and cooled to Room Temperature. Continued stirring for 30 minutes, then filtered and washed with IPA (20ml), and dried at 600C for 4 hours to get 12.8g of pure product. Overall, 71% yield of product (tranexamic acid) was obtained with 99.6% HPLC purity and 99.0% QNMR assay
Example 3
Synthetic process for the preparation of tranexamic acid using 4-(chloromethyl) cyclohexane-1-carboxylic acid using aqueous ammonia solution:

A flow reactor connected with the three 10ml of plug flow reactor coils made in SS tubing with 1mm internal diameter was used for this process. Pump A was primed with 4-chloromethyl cyclohexane carboxylic acid (20g) in 250ml Methanol as solvent and into the reactor. Pump B was primed with aqueous ammonia solution (28%) 300ml and connected with a tee fitting to the inlet of Reactor 1. Reactor 1 outlet was connected to Reactor 2 followed by connecting to Reactor 3. The outlet of Reactor 3 was connected to 70psi back pressure regulator and then directed to stirred collection flask. The Reactor 1 temperature set to 1150C, Reactor 2 temperature set to 1050C and Reactor 3 set to 650C.
The starting material was fed into the Reactor at 3 ml/minute to get 15 minutes residence time. Ammonia solution feeding rate was kept at 7 ml per minute. Pumping was continued until all solutions were consumed. Then later flushed with 100ml of ethanol and 100ml of water to get complete reaction stream and collecting in CSTR. Then to the reactor added the 6g of potassium hydroxide in 40ml of water to adjust the pH to 9 and continued stirring for 6 hours. Neutralized the reaction mixture to pH 7 by using acetic acid and crystallized the mixture after removal of 90% water. 60ml IPA was added to crystallize and get 20.1g of crude product (tranexamic acid).
Crude product (20g) was crystallized by dissolving in a mixture of water(60ml) and methanol (200ml), heated to 60oC and maintained for 60 minutes. Cooled it to Room Temperature, continued stirring for 30 min and then filtered and washed with IPA (20ml). It was then dried at 600C for 4hrs to get 12.8g of pure product. Overall, 71% yield of product (tranexamic acid) was obtained with 99.6% HPLC purity and 99.0% QNMR assay.
Example 4
Synthetic process for the preparation of tranexamic acid using 4-(bromomethyl) cyclohexane-1-carboxylic acid using aqueous ammonia:

A flow reactor connected with the three 10ml of plug flow reactor coils made in SS tubing with 1mm internal diameter was used for this process. Pump A was primed with 4-bromomethyl cyclohexane carboxylic acid (25g) in 150ml Isopropanol as solvent and fed into the reactor. Pump B was primed with aqueous Ammonia solution (28%) 350ml and connected with a tee fitting to the inlet of Reactor 1. Reactor 1 outlet connected to Reactor 2 followed by connecting to Reactor 3. The outlet of Reactor 3 was connected to 70psi back pressure regulator and then directed to stirred collection flask. The Reactor 1 temperature was set to 1100C, Reactor 2 temperature set to 1000C and Reactor 3 temperature set to 750C.
The starting material 4-bromomethyl cyclohexane carboxylic acid (25g) in 250ml Isopropanol was fed into the reactor at 3 ml/minute to get 15 minutes residence time. Aqueous Ammonia solution feeding rate was kept at 5 ml per minute. Pumping was continued until all solutions were consumed. Then later flushed the reactor with a mixture of 100ml of ethanol and 100ml of water to get complete reaction stream and collecting it in CSTR. Then to the reactor added 9g of potassium hydroxide in 55ml of water to adjust the pH to 9 and continued stirring for 6 hours. Neutralized the reaction mixture to pH 7 using acetic acid and crystallized the mixture after removal of 90% water. 60ml IPA was added to crystallize the crude solid to get 19.5g of crude product (tranexamic acid).
Crude product (19.5g) was dissolved in water(60ml) and methanol (200ml) mixture, heated to 60oC and maintained for 60 minutes. Cooled it to Room Temperature and continued stirring for 30 minutes. Then filtered and washed with IPA (20ml) and dried at 600C for 4 hours to get 13.6g of pure product (tranexamic acid). Overall, 70% yield was obtained of product (tranexamic acid) with 99.5% HPLC purity and 99.2% QNMR assay.
Example 5
Synthetic process for the preparation of tranexamic acid using methyl 4-(bromomethyl) cyclohexane-1-carboxylate:

A flow reactor connected with the two 10ml of plug flow reactor coils made in SS tubing with 0.8 mm internal diameter was used for this process. Pump A was primed with methyl 4-bromomethyl cyclohexane carboxylate (23g) in 300ml of methanol as solvent and fed into the reactor. Pump B was primed with ammonia in methanol solution 450ml and connected with a tee fitting to the inlet of Reactor 1. Reactor 1 outlet was connected to Reactor 2. The outlet of Reactor 2 was connected to 50psi back pressure regulator and then directed to stirred collection flask. The Reactor 1 temperature set to 500C, and Reactor 2 temperature was set to 600C.
The starting material 4-bromomethyl cyclohexane carboxylate (23g) in 300ml of methanol was fed into the reactor at 6 ml/minute to get 10 minutes residence time. Methanolic ammonia solution feeding rate was kept at 6 ml per minute. Pumping was continued until all solutions were consumed. Then later the reactor was flushed with a mixture of 100ml of ethanol and 100ml of water to get complete reaction stream and collecting it in CSTR. Then to the CSTR added 25g of Lithium hydroxide in 80ml of water, continued heating it to 80OC for 6 hours after saponification reaction, then adjusted the pH to 7 using acetic acid. Crystallized the mixture after removal of 80% water and added 80ml IPA to crystallize the crude solid at Room Temperature to get 17.5g of crude product.
Crude product (17.5g) was crystallized by dissolving it in aqueous ammonia, water (30ml) and IPA (200ml), heated to 60oC and maintain for 60 minutes. Cooled it to Room Temperature and continued stirring for 30 minutes, then filtered and washed with IPA (20ml). Dried at 600C for 4hrs to get 8.5g of pure product (tranexamic acid). Over all 66% yield of the product (tranexamic acid) was obtained with 99.0% HPLC purity and 98.5% QNMR assay.
Example 6
Synthetic process for the preparation of tranexamic acid using methyl 4-(chloromethyl) cyclohexane-1-carboxylate:

A flow reactor connected with the two 10ml of plug flow reactor coils made in SS tubing with 1mm internal diameter was used for this process. Pump A was primed with methyl 4-Chloromethyl cyclohexane carboxylate (20g) in 300ml of 1,4-dioxane as solvent and fed into the reactor. Pump B was primed with ammonium hydroxide solution (28%) 430ml and connected with a tee fitting to the inlet of Reactor 1. Reactor 1 outlet was connected to Reactor 2. The outlet of Reactor 2 was connected to 50psi back pressure regulator and then directed to stirred collection flask. The Reactor 1 temperature was set to 700C, Reactor 2 temperature was set to 1000C.
The starting material methyl 4-Chloromethyl cyclohexane carboxylate (20g) in 300ml of 1,4-dioxane was fed into the reactor at 5 ml/minute to get 12 minutes residence time. Ammonium hydroxide feeding rate was kept at 6 ml per minute. Pumping was continued until all solutions were consumed. Then later the reactor was flushed with a mixture of 100ml of 1,4-dioxane and 80ml of water to get complete reaction stream and collecting it in CSTR. Then to the CSTR added 15g of potassium hydroxide in 80ml of water, continued heating for 80OC for 5hrs after saponification reaction then adjust the pH to 7 using hydrochloric acid. Crystallized the mixture after removal of 80% water and added IPA 80ml to get the crude solid at Room Temperature to get 15.0g crude product.
Crude product (15g) was crystallized by dissolving in water(40ml) and IPA (200ml), heated to 60oC, maintained for 60 minutes and cooled to Room Temperature. Continued stirring for 30 min then filtered and washed with IPA (20ml). Dried it at 600C for 4 hours to get 8.6g of pure product. Over all 55% yield of the product (tranexamic acid) was obtained with 99.0% HPLC purity and 98.5% QNMR assay.
Example 7
Synthetic process for the preparation of tranexamic acid using propoan-2-yl 4-(bromomethyl) cyclohexane-1-carboxylate:

A flow reactor connected with the two 10ml of plug flow reactor coils made in SS tubing with 1mm internal diameter was used for this process. Pump A was primed with isopropyl 4-bromomethyl cyclohexane carboxylate (23g) in 400ml of 1,4-dioxane as solvent and fed into the reactor. Pump B was primed with ammonium solution (28%) 450ml and connected with a tee fitting to the inlet of Reactor 1. Reactor 1 outlet was connected to Reactor 2. The outlet of Reactor 2 connected to 50psi back pressure regulator and then directed to stirred collection flask. The Reactor 1 temperature was set to 800C, and Reactor 2 temperature was set to 1000C
The starting material isopropyl 4-bromomethyl cyclohexane carboxylate (23g) in 400ml of 1,4-dioxane was fed into the reactor at 4 ml/minute to get 13 minutes residence time. Ammonia solution feeding rate was kept at 6 ml per minute. Pumping was continued until all solutions were consumed. Then later the reactor was flushed with 100ml of 1,4-dioxane and 80ml of water to get complete reaction stream and collecting it in CSTR. Then to the CSTR added 20g of potassium hydroxide in 100ml of water, continued heating for 80OC for 6 hours after saponification reaction then adjusted the pH to 7 using hydrochloric acid. Crystallize the mixture after removal of 80% water and added IPA 100ml to isolate the crude solid at Room Temperature to get 14.0g of crude product.
Crude product (14g) was crystallized by dissolving in water(40ml) and IPA (200ml), heated to 60oC, maintained for 60 minutes and cooled to Room Temperature. Continued stirring for 30 minutes, then filtered and washed with IPA (20ml) and dried at 600C for 4 hours to get 8.4g of pure product. Over all 57% yield of the product (tranexamic acid) was obtained with 99.2% HPLC purity and 98.0% QNMR assay.
It will be apparent to a person skilled in the art that the above description is for illustrative purposes only and should not be considered as limiting. Various modifications, additions, alterations, and improvements without deviating from the spirit and the scope of the disclosure may be made by a person skilled in the art. Such modifications, additions, alterations, and improvements should be construed as being within the scope of this disclosure.
Advantages of the present invention
The process of the present disclosure provides continuous flow technologies enabled rapid reactions with excellent heat transfer, facilitates the manipulation of gas and has reduced formation of by-products.
The processes known in the art use hazardous chemicals like sodium azide and other chemicals, which may have harmful effect on the environment. By avoiding use of hazardous chemicals that cause pollution, the process of present disclosure is ecofriendly and provides safe handling of commercial production of Tranexamic acid and derivatives. Also, high cost catalyst usage has been avoided to reduce cost of manufacturing, and high pressure and temperature reaction conditions which have potential safety issues on handling in scale have been controlled in the process of present disclosure.
The process of present disclosure provides a green way of synthesizing Tranexamic acid and derivatives through Flow reactor, which cuts the number of steps and its chemical usage, thereby reducing major cost of production due to the continuous production process and provides efficient management of temperature and pressure. Therefore, manufacturing using methodology of present disclosure is more safe on large scale production, and is cheaper than the batch processes known for synthesis of Tranexamic acid.
Possible future enhancements:
Innovative combination of catalyst is being studied to work on this flow chemistry to attain high purity API intermediates in manufacture of pharmaceutical drugs.
To evaluate further the optimal conditions like temperature, increase in the number of coils, residence time, flow rate and solvent volume to achieve higher yields to enhance the productivity and still reduce the cost.
Date this, the 06th Day of September 2021.

--------Digitally signed-------
Bandita Panda
IN/PA-1880
Agent for the Applicant
To
The Controller of Patents
The Patent Office at Chennai