DESC:

FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See Section 10)

AN IMPROVED PROCESS FOR THE PREPARATION OF
TAFAMIDIS FORM 1
Morepen Laboratories Limited,
Morepen Village, Malkumajra, Baddi
Distt. –Solan,
Himachal Pradesh (HP), INDIA

The following application particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to an improved and industrially advantageous process for the preparation of tafamidis form 1. In particular, the present invention provides an efficient process for the preparation of tafamidis form 1 which is free from other polymorphic forms.

BACKGROUD OF INVENTION
Tafamidis (2-(3,5-Dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid) is having the following chemical structure (Formula I)

Formula – I
Tafamidis and its meglumine salts are both approved under the brand names Vyndamax and Vyndaquel respectively by the USFDA to Foldrx Pharmaceuticals Inc.
Vyndaquel and Vyndamax both indicated for the treatment of the cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization.
Tafamidis and its pharmaceutically acceptable salts thereof have been disclosed first time in US 7,214,695. The patent also discloses the process for the preparation of tafamidis which involves reaction of 4-amino-3-hydroxybenzoic acid with 3,5-dichlorobenzoyl chloride in presence of tetrahydrofuran and pyridine to provide 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid followed by the reaction with p-toluenesulfonic acid monohydrate in presence of xylene and reflux to provide crude tafamidis. The obtained compound is dissolved in methanol-benzene and reacted with trimethylsilyl diazomethane to provide methyl ester which is further hydrolyzed to provide tafamidis. In the said patent final compound is purified by using thin layer chromatography which is a very tedious and cumbersome process and is not advisable from industrial point of view. On the contrary, the patent is silent about any polymorphic form of the tafamidis.
US 9,249,112 discloses crystalline form, liquid crystal form and amorphous form of tafamidis meglumine.
US 9,770,441 discloses crystalline form 1, form 2, form 4 and form 6 of tafamidis. Form 1 is used for the pharmaceutical formulation as it is more stable than other forms of the tafamidis. The patent further discloses the method for the preparation of crystalline tafamidis form 1 as exemplified in example 1 wherein 4-amino-3-hydroxybenzoic acid is reacted with 3,5-dichlorobenzoyl chloride in presence of aqueous tetrahydrofuran and triethylamine to provide a reaction mixture. From this mixture, solvent is partially displaced with ethanol by constant level distillation to obtain the slurry. The slurry is filtered and then dried under vacuum to obtain pure 4-(3,5- dichlorobenzamido)-3-hydroxybenzoic acid. The obtained compound is further dissolved in THF followed by addition of triethylamine and water to obtain a reaction mixture. The mixture is then filtered, and methanesulfonic acid is added to it with subsequent displacement of THF/water with toluene to obtain tafamidis. The crude tafamidis is dissolved in 2-propanol and granulated for at least 1 hour, then filtered and washed with 2-propanol and dried under vacuum at 60-70 ? to obtain tafamidis form 1.
In above said patent, form 2 is obtained by evaporating tetrahydrofuran (THF) solution of form 1 at ambient condition.
Another crystalline form 4 is obtained by suspending form 1 in tetrahydrofuran (THF) and heated at 75? then attained solution is hot filtered followed by cooling to acquire form 4 of tafamidis.
In addition to other crystalline forms, form 6 is obtained by suspending form 1 in tetrahydrofuran (THF), heated, and stirred at 60 ? followed by addition of dimethylacetamide (DMAc) and then the resulting solution is hot filtered followed by cooling to get solid which is subjected for isolation by vacuum filtration and dried at ambient temperature.
Above all these forms, forms 4/6 are unstable and form 2 is a tetrahydrofuran solvate, thus unacceptable for drug development.
Even though the patent provides tafamidis form 1 with an enhanced yield, however the process involves multiple downstream operations such as isolation, solvent displacement through distillation for the purification of intermediates and tafamidis.
Another patent US 11,208,391 unveils another crystalline form of tafamidis which is prepared by dissolving tafamidis acetic adduct in a mixture of solvent ethyl acetate and water. The medium is heated to reflux until the slurry is disappeared and allowed to cool to room temperature. Further, the solution is filtered by vacuum and dried under hood to get crystalline form of tafamidis. As, said process involves multiple steps and excess use of solvents which makes the process tedious and cumbersome at large scale production.
A PCT publication WO 2021/152623 discloses different processes for the preparation of form-T1, form-T2, form-T3 and form-T4 of tafamidis, by mixing tafamidis with solvents selected from 2-methoxyethanol, N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMAC), dimethyl sulfoxide (DMSO) respectively followed by stirring for 5-24 hours then finally filtering to obtain desired polymorph of tafamidis.
In above process, crystallization is performed in single solvent wherein isolation of tafamidis from single solvent does not provide desired quality of final crystals as single solvent system is inefficient to remove undesired impurities which are intact with the crystal lattice.
Several other patent applications IN201941026908, IN202041028537 and IN202041038234 disclose different crystalline forms of tafamidis. However, the crystalline form obtained in above said applications are generally a mixture of different polymorphs. The quality of drug substance is particularly important from a regulatory vantage point, since drugs are approved by regulatory agencies only if they meet exacting purity and characterization standards. Indeed, the mixture of polymorphs exhibits different dissolution rates and may be converted to some other form while change in physiological factors like temperature, humidity and others which critically effects the solubility and bioavailability of pharmaceutical preparations.
So, it is evident from the prior art that the process involves in the preparation of tafamidis form 1 either requires multiple operations such as isolation, displacement of solvents or the process leads to a mixture of polymorphs. Most of preceding methods are poorly reproducible, necessitating the optimization of experimental conditions along with that of the selection of solvent. Since tafamidis form 1 is the marketed product so there is an urgent need to develop an industrially friendly process for the manufacture of pure tafamidis form 1 in consistent manner, without allowing other forms to coexist, and unique with respect to simplicity and cost effectiveness. The present invention aims to develop an efficient process which can give form 1 in consistence manner and is free from other polymorphic forms.

OBJECT OF THE INVENTION
The principal object of the present invention is to provide an efficient and industrial advantageous process for the preparation of tafamidis form 1.
Another object of the present invention is to provide an efficient and industrial advantageous process for the preparation of tafamidis form 1 which is free from the contamination of the other polymorphic forms.
One another object of the present invention is to provide tafamidis form 1 with acceptable level of impurities and residual solvents.

SUMMARY OF INVENTION
The present invention provides an improved process for preparation of tafamidis form 1 which is free from other polymorphic forms of tafamidis.
According to an embodiment, the present invention provides an improved process for the preparation of tafamidis form 1 of Formula I,

Formula I
which comprises steps of:
i. dissolving tafamidis in a suitable organic solvent,
ii. heating the solution at a temperature range of 40?-95? to obtain a clear solution,
iii. adding an antisolvent to the clear solution,
iv. cooling the reaction mass to ambient temperature,
v. isolating highly pure tafamidis form 1.

BRIEF DESCRIPTION OF THE DRAWINGS
1. Figure 1- represents PXRD pattern of tafamidis form 1.

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides an efficient process for the preparation of tafamidis form 1 which is free from other polymorphic forms of tafamidis. The process eradicates the problems of the prior art and is convenient to operate for commercial production.
As used herein, the term ‘ambient temperature’ represents a temperature 25?± 5?.
As used herein, the term ‘highly pure’ represents a compound having purity greater than 99.0 w/w by HPLC, preferably greater than 99.0% w/w by HPLC, more preferably greater than 99.5% w/w by HPLC and any individual impurity present in an amount of less than 0.3% more preferably less than 0.15% w/w by HPLC and total impurities present in an amount less than 0.5% w/w by HPLC.
The present invention relates to an efficient process for the preparation of tafamidis by using solvent antisolvent technique. The basic idea of the invention is to specifically develop an improved process to prepare tafamidis form 1 which is free from the contamination of other polymorphic forms.
The process comprises of the step of dissolving tafamidis, namely, 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid in a suitable organic solvent system. The dissolution of tafamidis in a suitable organic solvent may be achieved by heating the reaction mixture at a temperature range of 40?- 95?. The suitable solvent system used in the reaction can be selected from any suitable organic solvent which is selected from the group consisting of C1-C4 amides such as dimethylformamide (DMF), dimethylacetamide (DMAc), and the like; C2-C3 sulfoxides such as dimethyl sulfoxide (DMSO) and the like; C2-C5 ethers such as dioxane, tetrahydrofuran (THF) and the like; C5-C6 pyrrolidones such as N-methyl-2-pyrrolidone and the like; C3-C10 ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone, diisobutyl ketone or mixture thereof.
In general, organic solvents used herein includes but not limited to dimethylformamide (DMF), tetrahydrofuran (THF) and acetone. After obtaining the clear solution, an antisolvent is added to the above reaction mass.
The antisolvent is chosen in such manner where tafamidis is slightly soluble. The antisolvent can be selected from the group consisting of ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and mixture thereof, and water. The antisolvent used herein is preferably ethyl acetate or water.
According to the invention it was also unexpectedly found that a good reproducibility of the tafamidis form 1 can be obtained by using a preferable solvent/antisolvent ratio in the process. Preferably the solvent/antisolvent ratio may be 1 to 15: 1 to 3, preferably 1 to 12 :1 to 2.
Then, the resulting reaction mixture can be cooled to an ambient temperature of 25?± 5? with stirring for complete crystallization. Optionally, the reaction mass can be further cooled at -5°C to 10°C. The resulting solid can be isolated by any method known in the art such as filtration. Thereafter the solid obtained can be dried at a temperature range of 35-65? under vacuum to obtain tafamidis form 1.
The tafamidis form 1 obtained by the process of the present invention is highly pure, free from other polymorphic forms.
The process of the present invention provides tafamidis form 1 wherein the level of individual specified, and unspecified impurities is controlled at a level of equal to or less than 0.15% and 0.1% respectively and total impurities at a level of less than 0.5% as per regulatory guidelines. The tafamidis form 1 obtained by the process of the present invention is thermodynamically stable, the crystal morphology and flow properties remaining essentially unchanged over a period of time. Moreover, the process for the preparation of tafamidis form 1 is simple and easy to adopt on a commercial scale.
The crude tafamidis can be prepared by the methods reported in prior art or by the process as given in the present specification. The process involves reaction of 4-amino-3-hydroxybenzoic acid with 3,5-dichlorobenzoyl chloride in presence of tetrahydrofuran and pyridine to provide 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid followed by the reaction with p-toluenesulfonic acid monohydrate in presence of xylene and reflux to provide crude tafamidis. The obtained compound is dissolved in methanol-benzene and reacted with trimethylsilyl diazomethane to provide methyl ester which is further hydrolyzed to provide crude tafamidis.
X-Ray Powder Diffraction:
X-ray powder diffraction analyses were carried out on a PANalytical X'Pert Pro diffractometer using Cu K alpha radiation. The instrument was equipped with a line focus X-ray tube, and the voltage and amperage were set to 45kV and 40mA respectively. The scanning rate was set as 10 second per step and the step size is set as 0.01º. The diffractometer was equipped with X’celerator detector and rotating sample stage. X-ray diffractometer was used to record diffractogram from 4º to 50º (2-theta).
Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples.
EXAMPLES:
Example 1: Process for the preparation of tafamidis form 1
Tafamidis (10g) was dissolved in 80 mL of N’N- dimethylformamide (DMF) and heated at 80-90?. The reaction mass was stirred until a clear solution was obtained. To the solution, 80 mL water was added at 80-90?. The solution was cooled to an ambient temperature with stirring till complete crystallization. Thereafter, the reaction mass was filtered to obtain the desired product. The resulting product was dried at 50-60°C under vacuum to obtain tafamidis form 1.
XRD of resulting product matches with XRD reported for tafamidis form 1.
Example 2: Process for the preparation of tafamidis form 1
Tafamidis (10g) was taken in 220 mL of tetrahydrofuran (THF) and heated at 60-70?. The reaction mass was stirred until a clear solution was obtained. To the solution, 50 mL water was added at 60-70?. The reaction mass was cooled to an ambient temperature with continuous stirring. After complete crystallization, the reaction mass further cooled at 0-10°C and filtered to obtain the product as wet cake. The wet cake was dried at 50-60°C under vacuum to obtain tafamidis form 1.
XRD of resulting product matches with XRD reported for tafamidis form 1.
Example 3: Process for the preparation of tafamidis form 1
Tafamidis (10g) was dissolved in 200 mL of acetone and heated at 55-65?. The reaction mixture was stirred until a clear solution was obtained. To the reaction mixture, 20 mL water was added at 60-70?. The reaction mixture was cooled to an ambient temperature with continuous stirring. After complete crystallization, the reaction mass was filtered to obtain wet cake as product. The product was dried at 50-60°C under vacuum to obtain tafamidis form 1.
XRD of resulting product matches with XRD reported for tafamidis form 1.
Example 4: Process for the preparation of tafamidis form 1
Tafamidis (100 g) was dissolved in tetrahydrofuran (2200 ml) at 20-30°C and heated at 60-70°C followed by stirring for dissolution. The reaction mass was cooled to 20-30°C and ethyl acetate (500 ml) was then added followed by cooling at -5 to +5°C and stirring for 1.5 hours. The recrystallized reaction mass was then filtered and washed with ethyl acetate (25 ml). The wet cake thus obtained was dried for 22 hours at 50-60°C to obtain tafamidis form 1 having purity 100% w/w by HPLC.
XRD of resulting product matches with XRD reported for tafamidis form 1.
Example 5: Process for the preparation of tafamidis form 1
Tafamidis (100 g) was dissolved in tetrahydrofuran (2200 ml) at 20-30°C and heated at 60-70°C followed by stirring for dissolution. The reaction mass was cooled to 20-30°C and stirred. Ethyl acetate (500 ml) was then added followed by cooling at -5 to +5°C and stirring for 1.5 hours. The reaction mass was then filtered and washed with ethyl acetate (25 ml). Thereafter, the wet cake was suspended in water (1000 ml) at 20-30°C, heated to 80-90°C, stirred for 22 hours and filtered. The resulting solid, thus obtained, was dried for 22 hours at 50-60°C to obtain tafamidis form.
XRD of resulting product matches with XRD reported for tafamidis form 1.

Example 6: Process for the preparation of tafamidis form 1
Tafamidis (100 g) was dissolved in tetrahydrofuran (2200 ml) at 20-30°C and heated at 60-70°C followed by stirring for dissolution. The reaction mass was cooled to 20-30°C and ethyl acetate (500 ml) was then added followed by cooling at -5 to +5°C and stirring for 1.5 hours. The reaction mass was then filtered and washed with ethyl acetate (25 ml). Thereafter, the wet cake was suspended in water (1000 ml) at 20-30°C. The reaction mixture was heated to 80-90°C and stirred for 22 hours. The reaction mass was filtered, washed with water (25 ml) and the wet cake thus obtained was dried for 22 hours at 50-60°C to obtain tafamidis form 1 having purity 100% w/w by HPLC.
XRD of resulting product matches with XRD reported for tafamidis form 1

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.

,CLAIMS:WE CLAIM:
1. A process for the preparation of tafamidis form 1 of Formula I,

Formula I
which comprises steps of:
i. dissolving tafamidis in a suitable organic solvent,
ii. heating the solution at a temperature range of 40?-95? to obtain a clear solution,
iii. adding an antisolvent to the clear solution,
iv. cooling the reaction mass to ambient temperature,
v. isolating highly pure tafamidis form 1.

2. The process as claimed in claim 1, wherein in step i), the suitable organic solvent is selected form the group consisting of C1-C4 amides such as dimethylformamide (DMF), dimethylacetamide (DMAc), C2-C3 sulfoxides such as dimethyl sulfoxide (DMSO); C2-C5 ethers such as dioxane, tetrahydrofuran (THF); C5-C6 pyrrolidones such as N-methyl-2-pyrrolidone; C3-C10 ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone, diisobutyl ketone or mixture thereof.
3. The process as claimed in claim 1, wherein in step iii), antisolvent is selected from the group consisting of ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and mixture thereof, and water.
4. The process as claimed in claim 1, wherein solvent and antisolvent ratio in the process is in the range to 1 to 15: 1 to 3.
5. The process as claimed in claim 4, wherein solvent and antisolvent ratio in the process is in the range to 1 to 12: 1 to 2.

Dated this 29th day of July, 2022