Description:FIELD OF THE INVENTION:
The present invention relates to pharmaceutical solid-state chemistry. More particularly, the
invention relates to a crystalline polymorphic form of 2-(3,5-dichlorophenyl)benzo[d]oxazole-
6-carboxylic acid, also known as Tafamidis, and to an industrially viable and reproducible
process for its preparation.
10 BACKGROUND OF THE INVENTION:
Tafamidis is a benzoxazole derivative known for its therapeutic activity as a selective stabilizer
of transthyretin and is used in the management of transthyretin amyloidosis. The compound
and some of its salts have been previously disclosed, along with various crystalline and amorphous
forms. Numerous patent publications have reported polymorphic forms of Tafamidis
15 and Tafamidis meglumine, reflecting the polymorphic richness of the molecule.
The inventors of the present disclosure have developed a reproducible, scalable, and efficient
method for obtaining Form 4, utilizing tetrahydrofuran and water as solvents and water as an
anti-solvent under controlled conditions. The resulting product is pure, crystalline Form 4, exhibiting
defined thermal and spectral characteristics.
20
Formula I a
VYNDAQEL (tafamidis meglumine) and VYNDAMAX (tafamidis) contain tafamidis as the
active moiety, which is a selective stabilizer of transthyretin. The chemical name of tafamidis
meglumine is 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid mono (1-deoxy-1-
25 methylamino-D-glucitol). The molecular formula is C14H7Cl2NO3 C7H17NO5, and the molecular
weight is 503.33 g/mol. The structural formula is:
Formula I
3
Tafamidis and its pharmaceutically acceptable salts were first disclosed in US Patent No. 5 7,214,695, which describes a process involving the reaction of 4-amino-3-hydroxybenzoic acid with 3,5-dichlorobenzoyl chloride in the presence of tetrahydrofuran and pyridine to yield 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid. This intermediate is subsequently cyclized using p-toluenesulfonic acid monohydrate in xylene under reflux to obtain crude Tafamidis. The final product is methylated using trimethylsilyl diazomethane, followed by hydrolysis to 10 yield Tafamidis. The compound is then purified using thin-layer chromatography (TLC), a method unsuitable for industrial-scale manufacturing due to its complexity and inefficiency. Moreover, this patent does not disclose or address any polymorphic forms of Tafamidis.
The solid states of Tafamidis are described in U.S. patent Nos. 9770441 name as crystalline forms 1, form 2, form 3 and form 4 and methods of making carboxy-2-phenyl-benzoxazoles, 15 as well as pharmaceutical compositions comprising the same, are also described therein.not advisable from industrial point of view. On the contrary, the patent is silent about any poly-morphic form of tafamidis. The appearance of the characteristic peaks of Form 1 might be due to the use of IPA as the solvent in the process for preparing the Tafamidis free acid.
US 9,249,112 discloses crystalline form, liquid crystal form and amorphous form of tafamidis 20 meglumine.
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.
PCT publication WO 2021/152623 teaches different processes for the preparation of form-T1, T2, T3 and T4 of tafamidis, by mixing tafamidis with solvents selected from 2-methoxyethanol, 25 N-methyl-2-pyrrolidone (NMP), dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO) followed by stirring for 5-24 hours then finally filtering to obtain desired polymorph of ta-famidis
IN 201941026908 discloses crystalline form R and teaches the processes to prepare form S and N of tafamidis. Form R is prepared by dissolving tafamidis in DMSO (dimethyl sulfoxide) at 30 70- 75℃ followed by addition of water.
IN 202041051430 teaches the processes to prepare form N1 and N2 of tafamidis.
4
PCT Publication No. WO2020/232325A1 (Applicant: Teva, hereinafter referred to as the 5 WO’325 publication) discloses Tafamidis crystalline Forms I to V, processes for their prepa-ration, and characterizes the crystalline forms by X-ray powder diffraction (XRPD) patterns.
Patent Application Publication No. US2021/0363116A1; PCT Publication Nos. WO2020/232325A1, 10 WO2021/232619A1, WO2022/084790A1; and Indian Patent Appli-cation Nos. IN202041038234A, IN202041028537A, IN202041051430A and 10 IN202041049413A. Several other patent applications IN 202041028537, IN 202041038234, IN 202211047452, IN 202241005427 A, IN 202327070775 disclose different crystalline forms of tafamidis.
Although significant steps have been made in the development of polymorphic form of Ta-famidis still there is a need in the art to develop stable and commercially viable polymorphic 15 forms.
Existing disclosures describe multiple polymorphic forms obtained using high-boiling polar aprotic solvents, extended ageing, or solvent-intensive crystallization techniques, which are often associated with scale-up limitations, solvent residue concerns, and polymorphic incon-sistency. 20
Accordingly, there remains an unmet need for a controlled, low-temperature crystallization process that reliably yields tafamidis in a single crystalline polymorphic form with high purity and batch-to-batch consistency, while avoiding hazardous solvents and complex operational steps.
25
OBJECTIVE OF THE INVENTION:
The primary objective of the present invention is to provide a crystalline polymorphic form of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) having high purity and well-defined solid-state characteristics.
Another objective of the present invention is to provide a crystalline polymorphic form of Ta-30 famidis characterized by distinct X-ray powder diffraction (XRPD) peaks, thereby enabling its clear identification and differentiation from known forms.
5
A further objective of the present invention is to provide an improved, industrially viable, and 5 reproducible process for the preparation of said crystalline polymorphic form, ensuring high polymorphic purity and batch-to-batch consistency.
Yet another objective of the present invention is to provide an improved upstream synthetic route for Tafamidis, which offers enhanced impurity control, improved safety, and operational efficiency. 10
A further objective of the present invention is to provide a safe and scalable crystallization process, particularly a low-temperature, anti-solvent-based crystallization method employing water and/or toluene, suitable for large-scale manufacturing.
In another embodiment, the present invention provides a crystalline polymorphic form of Ta-famidis, wherein said crystalline form is characterized by powder X-ray diffraction (XRPD) 15 peaks at diffraction angles (2θ) of:
11.7 ± 0.2, 12.5 ± 0.2, 13.3 ± 0.2, 13.7 ± 0.2, 17.0 ± 0.2, 19.4 ± 0.2, 24.2 ± 0.2, 24.8 ± 0.2, and 27.4 ± 0.2 degrees.
The primary objective of the invention is to provide:
1.
A novel crystalline form of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid 20 characterized by unique XRPD peaks.
2.
An improved industrial process for producing novel crystalline Form with high poly-morphic purity and reproducibility.
3.
To offer an improved upstream synthesis route featuring better impurity control and safer operating parameters. 25
4.
A safe, scalable crystallization method, to establish a low‑temperature, anti‑sol-vent‑based crystallization method employing water and/or toluene.
SUMMARY OF THE INVENTION:
The present invention provides a simple, efficient, and multi-step process for the preparation 30 of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis) from 4-(3,5-dichlo-robenzamido)-3-hydroxybenzoic acid.
In one aspect, the process comprises:
6
•
employing precise molar equivalents of triethylamine and methanesulfonic acid for cy-5 clization;
•
conducting azeotropic dehydration under reflux conditions for about 18–20 hours;
•
carrying out purification using toluene and tetrahydrofuran (THF) in the presence of activated carbon;
•
performing low-temperature anti-solvent crystallization using water maintained at a 10 temperature of ≤10°C; and
•
subjecting the product to controlled drying under vacuum to obtain a stable crystalline form.
In another aspect, the present invention provides a crystalline polymorphic form of Tafamidis 15 obtained by the above process, characterized by one or more of the following physicochemical properties:
•
X-ray powder diffraction (XRPD) peaks at diffraction angles (2θ) of 13.7°, 17.0°, 24.2°, and 27.4° ± 0.2°;
•
Differential scanning calorimetry (DSC) showing an endothermic peak at approxi-20 mately 287.60°C, with an onset at about 285.77°C;
•
Thermogravimetric analysis (TGA) indicating no significant weight loss up to 450°C, and a loss on drying (LOD) of approximately 0.466% at 105°C; and
•
Fourier-transform infrared spectroscopy (FT-IR) peaks at 1694, 1546, 1438, and 860 cm⁻¹. 25
In a further aspect, the invention provides an improved and integrated process for the prepara-tion of Tafamidis, comprising the steps of:
a) reacting 4-amino-3-hydroxybenzoic acid with in-situ generated 3,5-dichlorobenzoyl chlo-ride in a mixed solvent system comprising acetone and water to obtain an amide intermediate;
b) isolating the intermediate 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid, followed by 30 cyclization in the presence of a base and an acid, preferably triethylamine and methanesulfonic acid, in an organic solvent such as toluene;
c) subjecting the reaction mixture to azeotropic reflux conditions to facilitate intramolecular cyclization and ring closure, thereby forming the benzo[d]oxazole core; and
d) dissolving the heterogeneous reaction mass in a suitable organic solvent, preferably tetrahy-35 drofuran, followed by anti-solvent crystallization using water to obtain the desired crystalline polymorphic form.
7
The process of the present invention is integrated, robust, and suitable for industrial-scale pro-5 duction, providing improved overall yield, reduced impurity formation, and enhanced process control. Advantageously, the process avoids solvent distillation and solvent switching steps, thereby simplifying operations and improving safety and scalability.
ADVANTAGES OF THE INVENTION: 10
The process and crystalline form of the present invention provide several advantages over prior art, including:
•
elimination of hazardous isolation steps through in-situ generation and consumption of reactive intermediates;
•
high chemical purity, thermal stability, and polymorphic consistency of the final prod-15 uct;
•
improved industrial scalability due to reproducible and controlled process parameters;
•
enhanced solvent compatibility, enabling seamless integration of reaction and crystal-lization steps;
•
reduced solvent usage and waste generation, with water serving as a benign anti-sol-20 vent;
•
improved impurity control through an integrated upstream synthesis approach;
•
operational simplicity by avoiding solvent distillation and solvent switching; and
•
cost-effectiveness and environmental friendliness due to minimized byproducts and simplified workup procedures. 25
DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to an improved, industrially feasible, and scalable process for the preparation of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis), a phar-maceutically important compound. The process employs readily available starting materials 30 and is carried out under mild and controlled conditions to afford the desired product in high purity, good yield and distinct polymorph.
The invention further provides an integrated synthetic and crystallization process that mini-mizes intermediate handling, reduces impurity formation, and enhances process efficiency, making it suitable for commercial-scale manufacturing. 35
The process of the present invention is described below in sequential stages:
8
5
Scheme – 1
Step 1: In-situ Preparation of 3,5-Dichlorobenzoyl Chloride
3,5-Dichlorobenzoic acid is dissolved in an organic solvent, preferably toluene. To this solu10
tion, a catalytic amount of dimethylformamide (DMF) is added, followed by the controlled
addition of thionyl chloride as a chlorinating agent.
The reaction mixture is heated to a temperature in the range of 65-75°C to facilitate the in-situ
formation of 3,5-dichlorobenzoyl chloride. During the reaction, gaseous byproducts such as
sulfur dioxide (SO₂) and hydrogen chloride (HCl) are evolved and are suitably vented or ab15
sorbed using standard scrubbing systems.
The acid chloride thus formed is not isolated and is directly utilized in the subsequent step,
thereby improving process safety and efficiency.
Step 2: Amidation with 4-Amino-3-hydroxybenzoic Acid
The in-situ generated 3,5-dichlorobenzoyl chloride is added, preferably in a controlled manner,
20 to a solution containing 4-amino-3-hydroxybenzoic acid.
9
The amidation reaction is carried out in a mixed solvent system comprising water, acetone, 5 methanol, and aqueous ammonia, which enhances solubility and provides mildly basic condi-tions conducive for amide bond formation.
The reaction mixture is stirred until completion of the amidation, as monitored by analytical techniques such as HPLC or TLC, to afford the intermediate 4-(3,5-dichlorobenzamido)-3-hy-droxybenzoic acid. 10
The intermediate may be isolated, if desired, or directly carried forward to the next step without isolation.
Step 3: Cyclization to Form the Benzoxazole Ring followed by crystalline form
The above amide intermediate is subjected to intramolecular cyclization to form the benzo[d]oxazole ring system. The cyclization is carried out in an organic solvent, preferably 15 toluene, in the presence of: a base, preferably triethylamine, and an acid catalyst, preferably methanesulfonic acid (MSA).
The reaction mixture is heated under reflux conditions, typically at a temperature ranging from 90–110°C, to facilitate ring closure and formation of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid under azeotropic dehydration. 20
The cyclization is generally completed within 18-20 hours, depending on the reaction scale, and is monitored using suitable analytical techniques.
Crystallization of the Desired Polymorphic Form
Upon completion of cyclization, the reaction mass is subjected to a controlled crystallization process to obtain the desired crystalline polymorphic form. 25
The crystallization process comprises:
• dissolving the reaction mass in an organic solvent, preferably tetrahydrofuran (THF);
• treating the solution with activated carbon to remove colored impurities.
• filtering to obtain a clear solution;
• slowly adding the solution into water maintained at a temperature of ≤10°C to induce 30 anti-solvent crystallization; and
10
• isolating the crystalline product followed by controlled drying under vacuum. 5
The crystalline polymorphic form thus obtained exhibits high chemical purity, defined solid-state characteristics, and excellent reproducibility. crystalline polymorphic form, designated as Form J, of 2‑(3,5‑dichlorophenyl)benzo[d]oxazole‑6‑carboxylic acid (Tafamidis), and a pro-cess for its preparation.
10
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: XRPD pattern of the crystalline form of Tafamidis according to the present inven-tion.
Figure 2: DSC pattern of the crystalline form of Tafamidis according to the present invention.
Figure 3: TGA pattern of the crystalline form of Tafamidis according to the present invention. 15
EXAMPLES
Example 1: Preparation of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid
Part A: In-situ Preparation of 3,5-Dichlorobenzoyl Chloride 20
To a clean and dry reaction vessel equipped with a mechanical stirrer, thermometer, reflux condenser, and maintained under a nitrogen atmosphere, 185 g of 3,5-dichlorobenzoic acid was charged. To this, 740 mL of toluene and 7.5 mL of N,N-dimethylformamide (DMF) were added, and the mixture was stirred at 25-30°C.
290 g of thionyl chloride was added dropwise over a period of 30-45 minutes, maintaining the 25 internal temperature at 25-30°C. After completion of the addition, the reaction mixture was heated to 65-75°C and maintained at this temperature for 3-4 hours to achieve complete con-version to 3,5-dichlorobenzoyl chloride (in situ).
Upon completion, volatile components were removed by distillation under reduced pressure. Subsequently, 92.5 mL of toluene was added and again distilled under reduced pressure to 30
11
remove residual impurities. The reaction mixture was cooled to 25-30°C, and 55 mL of tetra-5 hydrofuran (THF) was added.
The resulting solution containing in-situ generated acid chloride was used directly in the next step without isolation.
Part B: Preparation of 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid
In a separate reaction vessel, 100 g of 4-amino-3-hydroxybenzoic acid was suspended in a 10 mixture of 1000 mL of acetone and 100 mL of water.
The reaction mass from Part A was added slowly over 2-4 hours, maintaining the temperature at 25-30°C. After complete addition, the mixture was stirred for an additional 3-4 hours, and completion of the reaction was confirmed by HPLC or TLC.
The solvent was then removed by distillation. Subsequently, 300 mL of water followed by 500 15 mL of methanol were added, and the suspension was stirred for 1-2 hours.
The solid was filtered and washed with a mixture of 100 mL water and 100 mL methanol. The wet solid was then suspended in 1000 mL of water, and the pH was adjusted to 6.0-7.0 using aqueous ammonia. After stirring for 1-2 hours, the solid was filtered and washed with 100 mL water and 100 mL methanol. 20
The product was dried under vacuum at 60–70°C to afford 4-(3,5-dichlorobenzamido)-3-hy-droxybenzoic acid in 89% yield.
Example 2: Preparation of Tafamidis crystalline polymorphic form.
To a clean and dry reaction vessel equipped with a mechanical stirrer, thermometer, and reflux 25 condenser, 100 g of 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid was charged. To this, 1000 mL of toluene was added, and the suspension was stirred at 20-30°C for 20-30 minutes.
60 mL of triethylamine was added dropwise over 15-20 minutes, maintaining the temperature at 20-30°C, followed by stirring for 30-40 minutes. Thereafter, 65 g of methanesulfonic acid was added slowly at the same temperature, and the mixture was stirred for an additional 30-40 30 minutes.
The reaction setup was then configured for azeotropic reflux, and the reaction mass was heated to approximately 110°C. The mixture was maintained under reflux for 18-20 hours to complete
12
cyclization, as confirmed by HPLC. After completion, the reaction mixture was cooled to room 5 temperature, and 2300 mL of tetrahydrofuran (THF) was added. The mixture was heated to 50-60°C and stirred for 30-40 minutes until a clear solution was obtained.
Activated carbon was added, and the mixture was stirred for 10-15 minutes at 50-60°C, fol-lowed by filtration through a bed of Hy-Flow. The Hy-Flow bed was washed with 200 mL of THF to ensure complete transfer. 10
In a separate vessel, 5000 mL of water was charged and cooled to 0-10°C. The hot filtered solution was slowly transferred into the pre-cooled water while maintaining the temperature below 10°C.
The resulting mixture was stirred at 0-10°C for 2-3 hours to induce crystallization. The solid product was collected by filtration and washed with 200 mL of water, followed by suction 15 drying.
The wet cake was dried under vacuum at 60-65°C temperature, cooled to 25-35°C, and col-lected. The final product was obtained in 71% yield, and the obtained PXRD pattern depicted in Figure-1. HPLC: 99.83%
20
Example 3: Preparation of Tafamidis crystalline polymorphic form.
To a clean and dry reaction vessel equipped with a mechanical stirrer, thermometer, and reflux condenser, 25 g of 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid was charged. To this, 250 mL of toluene was added, and the suspension was stirred at 20-30°C for 20-30 minutes.
15 mL of triethylamine was added dropwise over 15-20 minutes, maintaining the temperature 25 at 20-30°C, followed by stirring for 30-40 minutes. Thereafter, 16.25 g of methanesulfonic acid was added slowly at the same temperature, and the mixture was stirred for an additional 30-40 minutes.
The reaction setup was then configured for azeotropic reflux, and the reaction mass was heated to approximately 110°C. The mixture was maintained under reflux for 18-20 hours to complete 30 cyclization, as confirmed by HPLC. After completion, the reaction mixture was cooled to room temperature, and 575 mL of tetrahydrofuran (THF) was added. The mixture was heated to 50-60°C and stirred for 30-40 minutes until a clear solution was obtained.
13
Activated carbon was added, and the mixture was stirred for 10-15 minutes at 50-60°C, fol-5 lowed by filtration through a bed of Hy-Flow. The Hy-Flow bed was washed with 50 mL of THF to ensure complete transfer.
In a separate vessel, 1250 mL of water was charged and cooled to 0-10°C. The hot filtered solution was slowly transferred into the pre-cooled water while maintaining the temperature below 10°C. 10
The resulting mixture was stirred at 0-10°C for 2-3 hours to induce crystallization. The solid product was collected by filtration and washed with 50 mL of water, followed by suction dry-ing.
The wet cake was dried under vacuum at 40-50°C temperature, cooled to 25-35°C, and col-lected. The final product was obtained in 69% yield, and the obtained PXRD pattern depicted 15 in Figure-1. HPLC: 99.76%
Example 4: Process for the preparation of crystalline form of tafamidis.
The procedure described in Example 3 was repeated, except that toluene was used as the anti-solvent in place of water during the crystallization step. 20
Upon completion of the cyclization reaction and subsequent dissolution in tetrahydrofuran (THF) and treatment with activated carbon, the clarified solution was introduced into toluene maintained under controlled temperature conditions to induce crystallization of the desired product.
The resulting suspension was stirred for a suitable duration to ensure complete crystallization. 25 The solid product was then isolated by filtration and subjected to suction drying.
The wet cake was further dried under vacuum, cooled to 25-35°C, and collected to obtain the crystalline polymorphic form of Tafamidis with 60% yield and the obtained PXRD pattern depicted in Figure-2. HPLC: 99.79%.
30
35 , Claims:5 I/WE CLAIMS
1. A crystalline polymorphic form of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic
acid, characterized by X-ray powder diffraction (XRPD) peaks at 2θ values of 13.7 ±
0.2, 17.0 ± 0.2, 24.2 ± 0.2, 24.8 ± 0.2, and 27.4 ± 0.2 degrees.
2. The crystalline polymorphic form as claimed in claim 1, wherein said form exhibits a
10 differential scanning calorimetry (DSC) showing an endothermic peak at approximately
287.60°C, with an onset at about 285.77°C;
3. The crystalline polymorphic form as claimed in claim 1, wherein said form shows thermogravimetric
analysis (TGA) shows with no significant weight loss up to 450°C; with
LOD ≤ 0.466% at 105°C.
15 4. The crystalline polymorphic form as claimed in claim 1, wherein said form shows IR
spectrum showing peaks at 1694, 1546, 1438, and 860 cm⁻¹.
5. A process for the preparation of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic
acid, comprising:
(a) in-situ generation of 3,5-dichlorobenzoyl chloride from 3,5-dichlorobenzoic acid
20 using a chlorinating agent;
(b) reacting the in-situ generated acid chloride with 4-amino-3-hydroxybenzoic acid
to obtain an amide intermediate;
(c) cyclizing the intermediate in the presence of a base and an acid catalyst in an organic
solvent under reflux conditions; and
25 (d) crystallizing the product using an anti-solvent to obtain a crystalline polymorphic
form.
6. The process as claimed in claim 5, wherein the base is triethylamine and the acid catalyst
is methanesulfonic acid.
7. The process as claimed in claim 5, wherein the organic solvent used for cyclization is
30 toluene, and the crystallization solvent is tetrahydrofuran (THF).
8. The process as claimed in claim 5, wherein the anti-solvent is water/Toluene, optionally
maintained at a temperature of ≤10°C.
9. A crystalline polymorphic form of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic
acid obtained by the process as claimed in claims 5 to 8.