Description:FIELD OF THE INVENTION:
The present invention relates to a process for the preparation of cetyl tranexamate hydrochloride of Formula I.
The present invention also relates to a crystalline form of cetyl tranexamate hydrochloride of Formula I.
BACKGROUND OF THE INVENTION:
Cetyl tranexamate hydrochloride (TXC™) is a whitening substance that can act and be absorbed into the skin. TXC™ was developed by Chanel Keshohin Gijutsu Kaihatsu Kenkyusho KK and is considered a Quasi-drug according to FDA Japan.
Cetyl tranexamate hydrochloride is structurally represented by Formula I,

[Formula I]
In the recent past, tranexamic acid is proved to have whitening effects especially for ultraviolet-induced hyperpigmentation, such as melasma and other skin related ailments. This triggered the further studies of exploring tranexamic acid in the cosmetics products such as creams, lotions, emulsion serums, lightening, brightening and antiaging preparations.
Researchers have also found that salts of tranexamic acid, such as cetyl tranexamate mesylate, cetyl tranexamate hydrochloride are promising candidates in cosmetic preparations as a replacement to tranexamic acid due to their unique molecular structure.
As per the recent market studies, the global skin care products market size was valued at USD 130.50 billion in 2021 and is expected to expand at a rate of around 4% to 5% in the next 10 years. In view of the rising demands, there is a need to scale up the manufacturing capacity of salts of tranexamic acid.
One such attempt has been made in WO2021101508, hereafter referred to as WO’508. This patent publication discloses the various salts of tranexamic acid ester compounds and their preparation methods. WO’508 further discloses the compositions comprising the said salts of tranexamic acid esters. The esters are prepared by reacting tranexamic acid with saturated or unsaturated, substituted, or unsubstituted aliphatic fatty alcohol or polyol with hydrocarbon chain of C1 to C20 and having counter-ion having a sulfonic acid moiety. Some of the salts disclosed in WO’508 include lauryl tranexamate mesylate, lauryl tranexamate esylate, lauryl tranexamate besylate, lauryl tranexamate tosylate, myristyl tranexamate mesylate, myristyl tranexamate esylate, myristyl tranexamate besylate, myristyl tranexamate tosylate, cetyl tranexamate mesylate. Preferred salt disclosed in WO’508 is cetyl tranexamate mesylate. The process as disclosed in WO’508 to prepare cetyl tranexamate mesylate includes adding cetyl alcohol and tranexamic acid at a molar ratio of 1.1: 1, heating to 80°C, followed by addition of methanesulfonic acid. Finally, the mixture was heated to 140°C to get the mesylate salt of tranexamic acid ester.
WO’508 process does not disclose the process for the preparation of cetyl tranexamate hydrochloride. Further, cetyl tranexamate hydrochloride is not stable at 140°C as it degrades.
US patent numbers US9833401 and US8647650 discloses the use of cetyl tranexamate hydrochloride for the preparation of composition for external use as a cosmetic for inhibiting hyperpigmentation of and/or whitening the skin, for reducing aging spots or pigmentation spots. However, the process for the preparation of cetyl tranexamate hydrochloride is not disclosed in these patents.
In view of the foregoing, it is evident that many of the prior art documents suggest the use of cetyl tranexamate hydrochloride in various skin care compositions. However, prior art documents neither describes crystalline cetyl tranexamate hydrochloride nor the method of preparing cetyl tranexamate hydrochloride. Therefore, there is a need to develop a crystalline cetyl tranexamate hydrochloride and a process for the preparation of cetyl tranexamate hydrochloride which can be used commercially to meet the future requirements of skin compositions which uses cetyl tranexamate hydrochloride.
The present inventors have developed a novel, economic and industrially viable process, which provides highly pure cetyl tranexamate hydrochloride.
OBJECTS OF THE INVENTION:
The main object of the present invention is to provide an efficient and industrially advantageous process for the preparation of a highly pure cetyl tranexamate hydrochloride of Formula I,

[Formula I]
Another object of the present invention is to provide a process for the purification of cetyl tranexamate hydrochloride of Formula I.
Yet another object of the present invention is to provide a crystalline form of cetyl tranexamate hydrochloride of Formula I.
SUMMARY OF INVENTION:
First aspect of the present invention is to provide a process for the preparation of cetyl tranexamate hydrochloride of Formula I,

[Formula I]
comprising the steps of:
(a) chlorinating tranexamic acid of Formula II,

[Formula II]
using chlorinating agent to obtain trans-4-(aminomethyl) cyclohexanecarbonyl chloride hydrochloride of the Formula III,

[Formula III]
(b) reacting trans-4-(aminomethyl)cyclohexanecarbonyl chloride hydrochloride of Formula III with cetyl alcohol of Formula IV,

[Formula IV]
to obtain cetyl tranexamate hydrochloride of Formula I.
Second aspect of the present invention is to provide a process for the purification of cetyl tranexamate hydrochloride of Formula I,

[Formula I]
comprising, treating cetyl tranexamate hydrochloride of Formula I with C1 to C4 alcohol to obtain highly pure cetyl tranexamate hydrochloride of Formula I.

Third aspect of the present invention is to provide a crystalline form of cetyl tranexamate hydrochloride of Formula I,

[Formula I].
BRIEF DESCRIPTION OF DRAWINGS:
Figure 1: Illustrates the X-ray powder diffractogram (XRPD) of crystalline form of cetyl tranexamate hydrochloride obtained according to Example 2.
Figure 2: Illustrates the differential scanning calorimetry (DSC) of crystalline form of cetyl tranexamate hydrochloride according to Example 2.
DETAILED DESCRIPTION OF INVENTION:
In order to provide a clear and consistent understanding of the terms used in the present specification, a number of definitions are provided below. Moreover, unless defined otherwise, all technical and scientific terms as used herein have the same meaning as understood by the person skilled in the art.
The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may not only mean “one”, but also encompasses the meaning of “one or more”, “at least one”, and “one or more than one”. Similarly, the word “another” may mean at least a second or more.
As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “consisting” (and any form of consisting, such as “consists”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.
The invention will now be described in detail in connection with certain preferred embodiments, so that various aspects thereof may be fully understood and appreciated.
Accordingly, in a first embodiment, the present invention provides a process for the preparation of cetyl tranexamate hydrochloride of the Formula I,

(Formula I)

comprising the steps of:
(a) chlorinating tranexamic acid of Formula II,

[Formula II]
using chlorinating agent to obtain trans-4- (aminomethyl) cyclohexanecarbonyl chloride hydrochloride of the Formula III,

[Formula III]
(b) reacting trans-4-(aminomethyl) cyclohexanecarbonyl chloride hydrochloride of Formula III with cetyl alcohol of Formula IV,

[Formula IV]
to obtain cetyl tranexamate hydrochloride of Formula I.

Tranexamic acid of Formula II and cetyl alcohol of Formula IV used as starting material for the preparation of cetyl tranexamate hydrochloride of Formula I can be prepared by processes known in the prior-art.
In accordance with the first embodiment, chlorination of tranexamic acid in step (a) can be carried out by using chlorinating agent selected from the group consisting of thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and phosphorus oxychloride. Preferably, the chlorinating agent is thionyl chloride.
In accordance with the first embodiment, chlorinating agent can be used in the proportion of 1.0 to 1.5 molar equivalents with respect to tranexamic acid of Formula II, preferably 1.1 to 1.2 equivalents.
In accordance with the first embodiment, the chlorination reaction can be carried out in presence of catalyst N,N-dimethylformamide.
In accordance with the first embodiment, catalyst N,N-dimethylformamide can be used in the proportion of 0.02 to 0.05 molar equivalent with respect to tranexamic acid of Formula II, preferably 0.02 to 0.03 equivalent.
In accordance with the first embodiment, the chlorination reaction can be carried out in presence of solvent selected from the group consisting of toluene, xylene, dichloromethane, chloroform or mixture thereof, preferably the solvent is toluene.
The volume of the solvent used during the chlorination reaction can be in the range of 3.0 volume to 8.0 volume, preferably 4.0 volume to 5.0 volume.
In accordance with the first embodiment, the chlorination reaction can be carried out at temperature of about 40? to 65?, preferably at 45? to 55?.
In accordance with the first embodiment, the chlorination reaction can be carried out for 2 hours to 7 hours, preferably for 2 hours to 5 hours.
After completion of chlorination reaction, resulting reaction mixture containing trans-4-(aminomethyl) cyclohexanecarbonyl chloride hydrochloride of Formula III can be carried forward as such for the next stage.
Alternatively, trans-4-(aminomethyl) cyclohexanecarbonyl chloride hydrochloride of Formula III can be isolated.
In accordance with the step (b) of the first embodiment, trans-4-(aminomethyl) cyclohexanecarbonyl chloride hydrochloride of Formula III can be reacted with cetyl alcohol of Formula IV.
In accordance with the step (b) of the first embodiment, the reaction of trans-4-(aminomethyl) cyclohexanecarbonyl chloride hydrochloride of Formula III with cetyl alcohol of Formula IV can be carried out in presence of solvent selected from the group consisting of toluene, xylene, dichloromethane, chloroform, or mixture thereof; preferably the solvent is toluene.
In accordance with the step (b) of the first embodiment, cetyl alcohol can be used in the proportion of 1.0 to 1.2 molar equivalents with respect to trans-4-(aminomethyl) cyclohexanecarbonyl chloride hydrochloride of Formula III, preferably 1.0 to 1.1 equivalents.
In accordance with the step (b) of the first embodiment, cetyl alcohol can be added slowly to the solution of trans-4-(aminomethyl) cyclohexanecarbonyl chloride hydrochloride over a period of 4 hours to 8 hours, preferably for 6 hours to 7 hours.
In accordance with the step (b) of the first embodiment, the reaction of trans-4-(aminomethyl) cyclohexanecarbonyl chloride hydrochloride of Formula III with cetyl alcohol of Formula IV can be carried out at temperature of 40? to 65?, preferably at 50? to 60?.
After completion of reaction of trans-4-(aminomethyl) cyclohexanecarbonyl chloride hydrochloride of Formula III with cetyl alcohol of Formula IV, reaction mixture can be cooled to 25? to 35? and can be further stirred for 1 hour to 2 hours at the same temperature. Resulting mixture can be filtered, washed with solvent used during the reaction to obtain a cetyl tranexamate hydrochloride of Formula I.
The resulting cetyl tranexamate hydrochloride of Formula I may have purity greater than 99% by gas chromatography (GC), preferably greater than 99.4% by GC.
The resulting cetyl tranexamate hydrochloride of Formula I may have yield greater than 85%, preferably greater than 90%.
In second embodiment, cetyl tranexamate hydrochloride of Formula I is treated with C1 to C4 alcohol to obtain highly pure cetyl tranexamate hydrochloride of Formula I,

[Formula I].
In accordance with the second embodiment, C1 to C4 alcohol used for the treatment of cetyl tranexamate hydrochloride can be selected from the group consisting of methanol, ethanol n-propanol, isopropanol, n-butanol, isobutanol, tert-butyl alcohol, or mixture thereof. Preferably the solvent is methanol.
The volume of the solvent used during the purification can be in the range of 2.0 volume to 8.0 volume, preferably 2.0 to 5.5 volumes.
In accordance with the second embodiment, cetyl tranexamate hydrochloride of Formula I can be added in the solvent so as to make a slurry at 20°C to 35°C. Resulting slurry can be stirred at same temperature for 1 hour to 2 hours. Cetyl tranexamate hydrochloride of Formula I can be isolated by removing the solvent.
In accordance with the second embodiment, the pure cetyl tranexamate hydrochloride of Formula I can be isolated by removing the solvent by the known methods such as filtration, distillation, decantation; preferably the solvent is removed by filtration.
The resulting cetyl tranexamate hydrochloride of Formula I may have purity greater than 99.4% by GC, preferably greater than 99.8% by GC.
The resulting cetyl tranexamate hydrochloride of Formula I may have yield greater than 85%, preferably greater than 90%.
The resulting cetyl tranexamate hydrochloride of Formula I is crystalline having the X-ray powder diffractogram (XRPD) as depicted in Figure 1 and DSC as depicted in Figure 2.
In third embodiment of the present invention, the cetyl tranexamate hydrochloride of Formula I is in the crystalline form, having X-ray powder diffraction (XRPD) pattern as described in Figure 1.
In accordance with the third embodiment, cetyl tranexamate hydrochloride of Formula I is in the crystalline form, wherein X-ray powder diffraction (XRPD) of said crystalline form shows characteristic peak at 2-theta values of 4.04, 8.01, 10.00, 11.99, 15.98, 24.03, 24.93, 26.07 and 28.11 ± 0.2 degrees 2?.
Table 1 summarizes the d-spacing values in Angstrom (Ao) and the corresponding 2? values of the crystalline form of cetyl tranexamate hydrochloride of Formula I.
Table 1: XRPD peaks of a crystalline form of cetyl tranexamate hydrochloride

Position [2?] d-Spacing [Ao] Relative intensity [%]
4.0490 21.80 100.00
6.0313 14.64 8.44
8.0181 11.01 34.77
10.0081 8.83 35.43
11.9989 7.36 13.37
15.0118 5.89 0.85
15.9886 5.53 33.30
19.0652 4.65 0.65
20.0063 4.43 8.21
20.3536 4.35 1.71
21.0539 4.21 6.22
22.0200 4.03 3.84
22.5363 3.94 2.16
23.3006 3.81 4.63
24.0395 3.69 50.65
24.9319 3.56 13.04
26.0752 3.41 29.42
27.4215 3.24 3.01
28.1149 3.17 30.56
29.1498 3.06 0.66
30.1685 2.95 4.05
31.4591 2.84 1.11
32.2181 2.77 5.40
34.2810 2.61 3.87
36.3727 2.46 9.48
37.5069 2.39 1.44
38.4452 2.33 2.43
39.1713 2.29 1.96
40.3968 2.23 1.20
42.3400 2.13 2.65
42.6698 2.11 2.92
43.5351 2.07 1.10
44.3530 2.04 1.74
45.3706 1.99 1.55
47.4355 1.91 1.16
49.5205 1.83 0.63

In third embodiment of the present invention, the cetyl tranexamate hydrochloride of Formula I is in the crystalline form, having DSC curve of crystalline form is substantially as depicted in Figure 2.
In accordance with the third embodiment, cetyl tranexamate hydrochloride of Formula I is in a crystalline form, having DSC endotherm peak at around 133.89°C.
A crystalline cetyl tranexamate hydrochloride of Formula I according to present invention is stable at 40?/ 75% Relative Humidity (RH).
EXAMPLES
Following examples are given by way of illustration. It may be understood for the person skilled in the art that these examples are only typical embodiments of the invention and are not therefore considered to be limiting the scope of the present invention.
Example 1: Preparation of Cetyl tranexamate hydrochloride Formula I
To a stirred solution of toluene (300 mL) and tranexamic acid (100.0 g, N,N-dimethylformamide (1.0 mL) was added at 25°C to 35°C. Resulting mixture was heated to 45°C to 55°C.
Meanwhile, solution of thionyl chloride (83 g) in toluene (175 mL) was prepared and added slowly to a previously prepared solution of tranexamic acid at 45°C to 55°C and stirred for 3 hours at 45°C to 55°C. After completion of reaction, resulting mixture of trans-4-(aminomethyl) cyclohexanecarbonyl chloride hydrochloride was taken as such for next step.
A solution of cetyl alcohol (162 g) and toluene (275 mL) was added slowly to the above obtained mixture of trans-4-(aminomethyl) cyclohexanecarbonyl chloride hydrochloride over a period of 6 hours at a temperature of 50? to 60?. Resulting mixture was stirred for 2 hours at the same temperature. After completion of reaction, reaction mixture was cooled to 25°C to 35°C and further stirred for 2 hours. Resulting mixture was then filtered, washed with toluene (2 x 200 mL) and dried to obtain title compound (250 g) having purity of 99.48% by GC.
Example 2: Purification of cetyl tranexamate hydrochloride of Formula I
Cetyl tranexamate hydrochloride of Formula I obtained in example 1 was taken in methanol (500 mL) to make a slurry at 25°C to 35°C. Resulting slurry was further cooled to 20°C to 30°C and stirred for 2 hours. Resulting slurry was filtered, washed with methanol (50 mL) to obtain a wet cake. The obtained wet cake was dried at 50°C to 60°C for 8 hours to obtain highly pure crystalline cetyl tranexamate hydrochloride of Formula I (232 g) having purity of 99.87% by GC.
Advantages of the present invention:
1. Process provides highly pure cetyl tranexamate hydrochloride.
2. Minimum work up required to isolate the cetyl tranexamate hydrochloride.
3. Cetyl tranexamate hydrochloride obtained with higher yield.
4. The crystalline cetyl tranexamate hydrochloride is stable, which makes it more suitable for preparing stable cosmetic compositions.
, Claims:I / We Claim:
1. A process for the preparation of cetyl tranexamate hydrochloride of Formula I,

[Formula I]
comprising the steps of:

(a) chlorinating tranexamic acid of Formula II,

[Formula II]
using a chlorinating agent to obtain trans-4-(aminomethyl) cyclohexanecarbonyl chloride hydrochloride of the Formula III,

[Formula III]
(b) reacting trans-4-(aminomethyl) cyclohexanecarbonyl chloride hydrochloride of Formula III with cetyl alcohol of Formula IV,

[Formula IV]
to obtain cetyl tranexamate hydrochloride of Formula I.
2. The process as claimed in claim 1; wherein the chlorinating agent is selected from the group consisting of thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and phosphorus oxychloride.
3. The process as claimed in claim 1; wherein solvent in step (a) and step (b) reaction is selected from the group consisting of toluene, xylene, dichloromethane, chloroform or mixture(s) thereof.
4. The process as claimed in claim 1; wherein step (a) is carried out at temperature of 40? to 65?.
5. The process as claimed in claim 1; wherein step (b) is carried out at temperature of 40? to 65?.
6. A process for the purification of cetyl tranexamate hydrochloride of Formula I,

[Formula I]
comprising treating cetyl tranexamate hydrochloride of Formula I with C1 to C4 alcohol to obtain highly pure cetyl tranexamate hydrochloride of Formula I.
7. The process as claimed in claim 6; wherein C1 to C4 alcohol is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butyl alcohol, or mixture(s) thereof.
8. A crystalline form of cetyl tranexamate hydrochloride of Formula I,

[Formula I]
9. The crystalline form of cetyl tranexamate hydrochloride of Formula I as claimed in claim 8, further characterized by an X-ray powder diffractogram pattern having peaks at values of 4.04, 8.01, 10.00, 11.99, 15.98, 24.03, 24.93, 26.07 and 28.11 ± 0.2 degrees 2?.

10. The crystalline form of cetyl tranexamate hydrochloride of Formula I as claimed in claim 8, further characterized by a differential scanning calorimetry thermogram having endotherms at around 133.89°C.

Dated this 16th day of November 2022

Dr. Virendra Thakrar,
Sr. Vice- President R&D,
Ami Lifesciences Pvt. Ltd.