DESC:FIELD OF THE INVENTION
The present invention relates to simple, commercially viable, economical and environment friendly process for preparing Tafamidis and its salts, in high yield and purity. Specifically, present invention relates to process for preparation of Tafamidis and/or its salts involving coupling of 4-amino-3-hydroxybenzoic acid or its alkyl ester with 3,5-dichlorobenzoic acid.
BACKGROUND OF THE INVENTION
Tafamidis is chemically known as 2-(3,5-dichlorophenyl)-l,3- benzoxazole-6-carboxylic acid. The molecular formula is C14H7CI2NO3 and the molecular weight is 308.11 g/mol. Tafamidis meglumine is an organoammonium salt obtained by combining Tafamidis with one molar equivalent of 1-deoxy-1-(methylamino)-D-glucitol. The structure of Tafamidis meglumine is shown below (Formula I).

(I)
Tafamidis free acid (VYNDAMAX®) and Tafamidis meglumine (VYNDAQEL) are indicated for the treatment of the cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization. The recommended dosage is either VYNDAQEL 80 mg (four 20 mg Tafamidis meglumine capsules) orally once daily or VYNDAMAX 61 mg (one 61-mg Tafamidis capsule) orally once daily.
Several processes of preparation for Tafamidis and Tafamidis meglumine have been reported in the literature. For example, US Patent No. 7214695 disclosed a synthetic route in which 3-hydroxyanthranilic acid is condensed with 3,5-dichlorobenzoyl chloride in presence of pyridine in THF as solvent. Ring closure of the resulting compound is done using p-TSA in xylene. The resulting benzoxazole carboxylic acid is converted to its methyl ester using TMSCHN2 as the methylating agent. Tafamidis free acid is generated in the next step by hydrolysis of the methyl ester with LiOH.H2O. The route is depicted in Scheme 1 below.

Scheme 1

US Patent application 20200399234 discloses a process for preparation of Tafamidis acetic acid adduct by cyclization of 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid in the presence of acetic acid and a sulfonic acid. Further, said application provides the process of production of crystalline and amorphous Tafamidis meglumine using said acetic acid adduct (Scheme 2).

Scheme 2

PCT application WO2021019448A1 discloses a process for preparation of Tafamidis meglumine by cyclization of 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid with acid or acid anhydrides, wherein the said process is carried out without isolating the free acid. Acid or acid anhydride is selected from the group comprising of Methane sulfonic acid, Ethane sulfonic acid, p-Toluene sulfonic acid, Benzene sulfonic acid, Camphor sulfonic acid, D- Camphor sulfonic acid, L-Camphor sulfonic acid, pyridine sulfonic acid, polyphosphoric acid, acetic anhydride, triflic anhydride Said patent publication also discloses Tafamidis alkali, alkaline earth metal salts, amine salts or process for preparation thereof (Scheme 3).

Scheme 3

PCT application WO2021001858A1 provides a process for the preparation of Tafamidis or its pharmaceutically acceptable salts, comprising: a) reacting 3,5-dichlorobenzoyl chloride with 4-amino-3-hydroxybenzoic acid to provide 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid, b) converting 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid to Tafamidis. The synthetic route is shown in Scheme 4.

Scheme 4
PCT application WO2020207753A1 discloses a method of synthesis for Tafamidis meglumine, which involves reaction of methyl 4-amino-3-hydroxybenzoate with 3,5-dichlorobenzoyl chloride to obtain methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate. Benzoxazole formation/ring closure is carried out using p-TSA in toluene, reflux for 16 hrs and followed by purification using acetone and water mixture. The resultant methyl 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylate was dissolve in THF and treated with aq. KOH at 50-55°C. After neutralization with 6M HCl and separation of the phases, meglumine was added to organic phase, solvent removed by vacuum distillation, purification of crude using ethanol: water (Scheme 5).

Scheme 5

PCT application WO2021124158A1 discloses a process of preparation of Tafamidis, which involves reaction of 4-amino-3-hydroxybenzoic acid compound of Formula III with a 3,5-dichlorophenyl ortho ester compound of formula II (Scheme 6).

Scheme 6

This process disclosed in US Patent 7214695 has several drawbacks. Reaction of 3-hydroxyanthranilic acid with 3,5-dichlorobenzoyl chloride is done in presence of pyridine in THF as solvent. Pyridine is not friendly solvent due to its smell and toxic properties. Moreover, benzoxazole formation is carried out in presence of pTSA and xylene followed by esterification of carboxylic acid using trimethylsilyldiazomethane (TMSCHN2). TMSCHN2 is toxic, shock sensitive and pyrophoric liquid. Hydrolysis of methyl ester is carried out with LiOH.H2O. Lithium hydroxide is expensive and is not commercially viable and Lithium is a toxic metal with the PDE of 560µg/day.
Most of the prior art processes disclose use of triethyl amine in the condensation reaction. Triethyl amine is direct source of secondary amines which in presence of nitrites result in formation of genotoxic nitrosamine impurities, which are cohort of concern. Further, the prior art processes disclose use of methane sulfonic acid for the formation of benzoxazole ring. It can lead to formation of methyl and ethyl esters of methane sulfonic acid which are genotoxic.
Thus, there is a need to develop an improved process for preparation of Tafamidis which is simple, cost-effective, eco-friendly and overcome the drawbacks associated with the prior art processes.

OBJECTS OF THE INVENTION
The primary object of the invention is to provide an improved process of preparation of Tafamidis and/or its salts thereof.
It is another object of the present invention is to overcome or alleviate at least one of the deficiencies of prior art and provide a useful alternative for the preparation of Tafamidis and/or its salts thereof, suitable for human consumption.
It is another object of the present invention is to provide process for preparation of Tafamidis and/or its salts thereof, which involves coupling of 3,5-dichlorobenzoic with 4-amino-3-hydroxybenzoic acid.
It is yet another object of the present invention is to provide process for preparation of Tafamidis and/or its salts thereof, which involves coupling of 3,5-dichlorobenzoic with 4-amino-3-hydroxybenzoic acid in presence of boric acid.
It is yet another object of the present invention is to provide process for preparation of Tafamidis and/or its salts, which involves coupling of 3,5-dichlorobenzoic with 4-amino-3-hydroxybenzoic acid in presence of boric acid, with or without isolation of any intermediate compound.
It is yet another object of the present invention is to provide one pot process for preparation of Tafamidis and/or its salts starting from 3,5-dichlorobenzoic acid and 4-amino-3-hydroxybenzoic acid.
It is another object of the present invention is to provide one pot process for preparation of Tafamidis and/or its salts, which involves coupling of 3,5-dichlorobenzoic with 4-amino-3-hydroxybenzoic acid in presence of boric acid.
It is yet another object of the present invention is to provide one pot process for preparation of Tafamidis and/or its salts thereof, which involves coupling of 3,5-dichlorobenzoic with 4-amino-3-hydroxybenzoic acid in presence of boric acid and an aromatic hydrocarbon solvent.
In an another object of the present invention is to provides one pot synthesis of Tafamidis and/or its salts from 3,5-dichlorobenzoic and 4-amino-3-hydroxybenzoic acid in presence of boric acid and xylene or toluene.
In yet another object the present invention is to provides the use of inexpensive and commercially available 3-hydroxy-4-nitrobenzoic acid by catalytic reduction using Raney Nickel in methanol as solvent to obtain 4-amino-3-hydroxybenzoic acid in quantitative yield which is then coupled with 3,5-dichlorobenzoyl chloride in presence of base.
In yet another object of the present invention is to provides process of preparation of Tafamidis meglumine in which benzoxazole ring formation is achieved by reacting methyl 4-amino-3-hydroxybenzoate with 3,5-dichlorobenzoic acid in presence of 10-20 mol% of Boric acid in presence of hydrocarbon solvent at ambient to reflux temperature.
In yet another object the present invention is to provides process of preparation of Tafamidis and its salts thereof in high yield and purity, which devoid of below mentioned impurities.

SUMMARY OF THE INVENTION
According to one aspect of the present invention there is provided an efficient and cost effective process for the preparation of Tafamidis and/or its pharmaceutically acceptable salts thereof, which involves coupling of 3,5-dichlorobenzoic with 4-amino-3-hydroxybenzoic acid.
In an embodiment, the present invention relates to a process for the preparation of Tafamidis and/or its salts thereof comprising the steps of:
i) reacting 4-amino-3-hydroxybenzoic acid or its alkyl ester (III) and 3,5-dichlorobenzoic acid (IV) to obtain compound of Formula V;
ii) cyclization of compound of formula V to obtain compound of formula VI;
iii) hydrolysis of compound of formula VI, if R is an alkyl group, to obtain compound of formula VII; and
iv) optionally, converting compound of formula VII to its salts thereof
wherein reaction proceed with or without isolation of compound of formula V; R is H or an alkyl group having C1-C6 carbon atoms.
In an another embodiment, the present invention relates to a process for the preparation of Tafamidis and/or its salts thereof comprising the steps of:
i) reacting 4-amino-3-hydroxybenzoic acid or its alkyl ester (III) and 3,5-dichlorobenzoic acid (IV) to obtain compound of Formula VI;
ii) hydrolysis of compound of formula VI, if R is an alkyl group, to obtain compound of formula VII; and
iii) optionally, converting compound of formula VII to its salts thereof
wherein R is H or an alkyl group having C1-C6 carbon atoms.

According to yet another embodiment the present invention provides a process for the preparation of Tafamidis and/or its salts thereof comprising the steps of:
i) reacting 4-amino-3-hydroxybenzoic acid or its alkyl ester (III) and 3,5-dichlorobenzoic acid (IV) in presence of boric acid to obtain compound of Formula VI;
ii) hydrolysis of compound of formula VI, if R is an alkyl group, to obtain compound of Formula VII; and
iii) optionally, converting compound of formula VII to its salts thereof

wherein R is H or an alkyl group having C1-C6 carbon atoms.

In yet another embodiment, the present invention relates to a process for the preparation of Tafamidis or salts thereof comprising the steps of:
i) reacting 4-amino-3-hydroxybenzoic acid or its alkyl ester (III) and 3,5-dichlorobenzoic acid (IV) in presence solvent and coupling agent to obtain compound of Formula V;
ii) cyclization of compound of formula V to obtain compound of formula VI;
iii) hydrolysis of compound of formula VI, if R is an alkyl group, to obtain compound of formula VII; and
iv) optionally, converting compound of formula VII to its salts thereof
wherein reaction proceed with or without isolation of compound of formula V; R is H or an alkyl group having C1-C6 carbon atoms.

According to yet another embodiment the present invention provides a process for the preparation of Tafamidis or salts thereof comprising the steps of:
(i) reacting 4-nitro-3-hydroxybenzoic acid or its ester compound of formula VIII with 3,5-dichlorobenzoyl chloride compound of Formula IX in presence of base to obtain 3-(3,5-dichlorobenzoyloxy)-4-nitrobenzoic acid or its ester compound of Formula X;
(ii) catalytic hydrogenation of 3-(3,5-dichlorobenzoyloxy)-4-nitrobenzoic acid methyl ester; followed by cyclization under acidic conditions to obtain compound of Formula VI;
(iii) hydrolysis of compound of formula VI, if R is an alkyl group, to obtain compound of formula VII; and
(iv) optionally converting compound of formula VII to its salts thereof
wherein R is H or an alkyl group having C1-C6 carbon atoms.

In yet another object the present invention is to provides process of preparation of Tafamidis and its salts thereof in high yield and purity, which devoid of below mentioned impurities.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process of preparation of Tafamidis and/or its salts thereof, which is simple, cost effective, uses readily available inexpensive starting material and does not generate nitrosamine impurities.
In an embodiment, the present invention relates to a process for the preparation of Tafamidis or salts thereof (Scheme 7) comprising the steps of:
i) reacting 4-amino-3-hydroxybenzoic acid or its alkyl ester (III) and 3,5-dichlorobenzoic acid (IV) in presence of solvent and in presence or absence of coupling agent to obtain compound of Formula V;
ii) cyclization of compound of formula V to obtain compound of formula VI;
iii) hydrolysis of compound of formula VI, if R is an alkyl group, to obtain compound of formula VII; and
iv) optionally converting compound of formula VII to its salts thereof
wherein reaction proceed with or without isolation of compound of formula V; R is H or an alkyl group having C1-C6 carbon atoms.

Scheme 7

In an another embodiment, the present invention relates to a process for the preparation of Tafamidis or salts thereof comprising the steps of:
i) reacting 4-amino-3-hydroxybenzoic acid or its alkyl ester (III) and 3,5-dichlorobenzoic acid (IV) in presence of a solvent to obtain compound of Formula VI;
ii) hydrolysis of compound of formula VI, if R is an alkyl group, to obtain compound of formula VII; and
iii) optionally converting compound of formula VII to its salts thereof
wherein R is H or an alkyl group having C1-C6 carbon atoms.

According to yet another embodiment the present invention provides a process for the preparation of Tafamidis or salts thereof comprising the steps of:
i) reacting 4-amino-3-hydroxybenzoic acid or its alkyl ester (III) and 3,5-dichlorobenzoic acid (IV) in presence of solvent and boric acid to obtain compound of Formula VI;
ii) hydrolysis of compound of formula VI, if R is an alkyl group, to obtain compound of formula VII; and
iii) optionally, converting compound of formula VII to its salts thereof

wherein R is H or an alkyl group having C1-C6 carbon atoms.

In yet another embodiment, the present invention relates to a process for the preparation of Tafamidis or salts thereof comprising the steps of:
i) reacting 4-amino-3-hydroxybenzoic acid or its alkyl ester (III) and 3,5-dichlorobenzoic acid (IV) in presence of solvent and coupling agent to obtain compound of Formula V;
ii) cyclization of compound of formula V to obtain compound of formula VI;
iii) hydrolysis of compound of formula VI, if R is an alkyl group, to obtain compound of formula VII; and
iv) optionally, converting compound of formula VII to its salts thereof
wherein reaction proceed with or without isolation of compound of formula V; R is H or an alkyl group having C1-C6 carbon atoms.

In yet another embodiment, the present invention relates to a process for the preparation of Tafamidis or salts thereof comprising the steps of:
i) reacting 4-amino-3-hydroxybenzoic acid or its alkyl ester (III) and 3,5-dichlorobenzoic acid (IV) in presence of solvent and coupling agent to obtain compound of Formula V;
ii) cyclization of compound of formula V in presence of boric acid to obtain compound of formula VI;
iii) hydrolysis of compound of formula VI, if R is an alkyl group, to obtain compound of formula VII; and
iv) optionally converting compound of formula VII to its salts thereof
wherein reaction proceed with or without isolation of compound of formula V; R is H or an alkyl group having C1-C6 carbon atoms.

During the reaction of 4-amino-3-hydroxybenzoic acid or its alkyl ester (III) with 3,5-dichlorobenzoic acid (IV), solvent is selected from the group comprising of water, organic solvent and mixture thereof; preferably the solvent is hydrocarbon solvent such as toluene, xylene etc.

Hydrolysis is performed with an alkali, which is selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and magnesium hydroxide. Alkali is preferably sodium hydroxide or potassium hydroxide. Hydrolysis of Formula VI (Tafamidis methyl ester) is carried out in presence of solvent selected from group comprising of water, organic solvent and mixture thereof; preferably hydrocarbon solvent such as tetrohydrofuran, Methyl tetrohydrofuran and the like.

Coupling agent is selected from the group comprising of 1,1'-carbonyl diimidazole (CDI), N,N'-diisopropyl carbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide HC1 (EDC.HC1), (benzotriazol-l-yloxy) tris(dimethylamino)phosphonium hexafluoro phosphate (BOP), benzotriazol-l-yl-oxy tripyrrolidinophosphonium hexafluorophosphate (PyBOP), N,N'-dicyclohexylcarbodiimide (DCC), l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo [4,5-b]pyridinium3-oxide hexafluoro phosphate (HATU), 2-(1H-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluoro phosphate (HBTU), HCTU, TATU, TBTU alkyl/aryl haloformates selected from but not limited to ethyl chloroformate, benzylchloroformate; diphenylphosphoroazidate (DPPA), oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4-methyl-2-oxopentanoyl chloride (iBuCOCOCl), methane sulfonyl chloride, p-toluenesulfonyl chloride and mixture thereof and the like.
In one of the aspect the invention provides a process for preparation of Tafamidis and/or salts thereof wherein benzoxazole ring formation is achieved by reacting Methyl 4-amino-3-hydroxybenzoate with 3,5-dichlorobenzoic acid in presence of 10-20 mol% of Boric acid in toluene or xylene at ambient to reflux temperature.
Use of boric acid as per the process of the current invention is advantageous as it is inexpensive, readily available and non-toxic.
In yet another embodiment, the present invention relates to a process for the preparation of Tafamidis or salts thereof comprising the steps of:
(i) conversion of 3-hydroxy-4-nitrobenzoic acid compound of Formula I to 4-amino-3-hydroxybenzoic acid compound of Formula II;

(ii) reaction of 4-amino-3-hydroxybenzoic acid compound of Formula II with thionyl chloride in presence of methanol to obtain methy-4-amino-3-hydroxybenzoate compound of Formula III;

(iii) reacting methy-4-amino-3-hydroxybenzoate compound of Formula III with 3,5-Dichlorobenzoic acid compound of Formula IV in presence of coupling agent to obtain compound of Formula V;

(iv) ring closure of compound of Formula V in presence of sulfonic acid and a solvent to obtain compound of Formula VI;

(v) hydrolysis of Formula VI in presence of aqueous alkali to obtain compound of Formula VII; and

(vi) optionally, conversion of compound of Formula VII to its acid addition salts thereof.

According to yet another embodiment the present invention provides a process for the preparation of Tafamidis or salts thereof comprising the steps of:
(i) reacting 4-nitro-3-hydroxybenzoic acid or its ester compound of formula VIII with 3,5-dichlorobenzoyl chloride compound of Formula IX in presence of base to obtain 3-(3,5-dichlorobenzoyloxy)-4-nitrobenzoic acid or its ester compound of Formula X;
(ii) catalytic hydrogenation of 3-(3,5-dichlorobenzoyloxy)-4-nitrobenzoic acid methyl ester; followed by cyclization under acidic conditions to obtain compound of Formula VI;
(iii) hydrolysis of compound of formula VI, if R is an alkyl group, to obtain compound of formula VII; and
(iv) optionally converting compound of formula VII to its salts thereof
wherein R is H or an alkyl group having C1-C6 carbon atoms.

During the reaction of 4-amino-3-hydroxybenzoic acid or its alkyl ester (III) with 3,5-dichlorobenzoic acid (IV), solvent is selected from the group comprising of water, organic solvent and mixture thereof; preferably the solvent is hydrocarbon solvent such as toluene, xylene etc.

Conversion of 3-hydroxy-4-nitrobenzoic acid compound of Formula I to 4-amino-3-hydroxybenzoic acid compound of Formula II may be carried out in presence of any suitable reducing agent, which is able to convert nitro group to amino group such as catalytic hydrogenation in presence of Raney Nickel.

Hydrolysis is performed with an alkali, which is selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and magnesium hydroxide. Alkali is preferably sodium hydroxide or potassium hydroxide.

Coupling agent is selected from the group comprising of l,1'-carbonyl diimidazole (CDI), N,N'-diisopropyl carbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide HC1 (EDC.HC1), (benzotriazol-l-yloxy) tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazol-l-yl-oxy tripyrrolidinophosphonium hexafluorophosphate (PyBOP), N,N'-dicyclohexylcarbodiimide (DCC), l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo [4,5-b]pyridinium3-oxide hexafluoro phosphate (HATU), 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluoro phosphate (HBTU), HCTU, TATU, TBTU alkyl/aryl haloformates selected from but not limited to ethyl chloroformate, benzylchloroformate; diphenylphosphoroazidate (DPPA), oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4-methyl-2-oxopentanoyl chloride (iBuCOCOCl), methane sulfonyl chloride, p-toluenesulfonyl chloride and mixture thereof and the like.
Ring closure reaction carried out in presence of suitable cyclization reagent selected from the group comprising of sulfonic acid like 5-Sulfosalicylic acid dihydrate, p-Toluene sulfonic acid, Methane sulfonic acid, PEG-6000, Dowex50W (Hydrogen form, strongly acidic) or heating with propionic acid to reflux temperature.
The solvent is selected from group comprising of water, sulfoxides, alcohols, halogenated hydrocarbons, ethers, esters, amides, hydrocarbons such as dimethyl sulfoxide (DMSO), methanol, ethanol, n-propanol, isopropanol, n-butanol, dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene, diethyl ether, methyl tert-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, dioxane, methyl acetate, ethyl acetate, butyl acetate, isopropyl acetate, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylformamide, N-methylpyrrolidone, pentane, hexane, heptane, octane, cyclohexane, cyclopentane, toluene, xylene or the like and mixture thereof.
In yet another aspect the salt of Tafamidis is preferable meglumine salt. The process for preparation of said meglumine salt involves a process comprising the steps of reacting compound of Formula VII (Tafamidis free acid) with N-methylglucamine or meglumine in solvent selected from the group comprising organic solvent, water and mixture thereof; preferably alcohol or its mixture with water such as 2-propanol/water and the like.
In an another embodiment, the present invention relates to a process for the preparation of Tafamidis or Tafamidis meglumine comprising the steps of:
(i) reacting 4-amino-3-hydroxybenzoic acid with 3,5-dichlorobenzoic acid in presence of boric acid and solvent to obtain Tafamidis; and/or
(ii) converting Tafamidis to Tafamidis meglumine.

In an another embodiment, the present invention relates to a process for the preparation of Tafamidis or Tafamidis meglumine comprising the steps of:
(i) conversion of 3-hydroxy-4-nitrobenzoic acid compound of Formula I to 4-amino-3-hydroxybenzoic acid compound of Formula II;

(ii) reacting 4-amino-3-hydroxybenzoic acid with 3,5-dichlorobenzoic acid in presence of boric acid and solvent to obtain Tafamidis; and/or
(iii) converting Tafamidis to Tafamidis meglumine.

EXAMPLES:
Example 1: Preparation of 4-Amino-3-hydroxy benzoic acid methyl ester:
To a stirred solution of 4-amino-3-hydroxybenzoic acid (40g,0.2611mole) in methanol (400ml) added dropwise Thionyl chloride (62.12g, 0.522mole) at 0-5°C. Allowed the reaction mass to attained at room temperature and stirred it at 25-30°C for 16-18 h. After completion of the reaction), solvent was distilled out under vacuum at 40-45°C. The residue was diluted with Ethyl Acetate (800ml) the pH was adjusted to 8.0 with saturated aqueous sodium bicarbonate solution at 25-30°C. Layers were separated and aqueous layer was extracted with Ethyl acetate (100ml). Combined organic layers was distilled out under vacuum at 40-45°C and Cyclohexane (240ml) is added to the residue at RT. Stirred reaction mass for 1h at RT, filtered the solid and washed with cyclohexane (80ml). Dried the material under vacuum at 40-45°C. for 8-10 h to yield the ester (39.7g) as brown solid. Yield; 91%
Data: 1H-NMR (400 MHz, DMSO-d6) d 3.715(s, 3H, CH3), 5.377(s, 2H, NH2), 6.567-6.588(d, 1H, Ar), 7.225-7.245(m, 2H, Ar), 9.439 (br. s,1H, OH),
HRMS in ESI (+ve) calcd. for C8H11NO3 [M+H]+ is 168.066 and found 168.0658.

Example 2: Preparation of methyl 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylate (Tafamidis methyl ester):
A mixture of methyl 4-amino-3-hydroxybenzoate (3g, 0.0180 mole), 3.5-dichlorobenzoic acid (4.12g, 0.0215mole) and boric acid (1.1g, 0.0180 mole) in o-xylene (50 mL) was refluxed with stirring with azeotropically removal of water for 22-24 h. After completion of reaction solvent was distilled out under vacuum at 75-80°C and the residual mass was stirred with water (30ml) at 40-45°C for 30 min. Cooled the reaction mass to 25-30°C and the precipitated solid was filtered, washed with DM water (10 mL) and suck dried solid under vacuum for 30min to obtain crude title compound (wet wt. 7.11g). The wet solid was purified by crystallization using isopropyl alcohol (30ml) to yield title compound (5.2g,) as brownish solid. Yield 90%.
1H-NMR (400 MHz, DMSO-d6) d 3.977 (s, 3H, CH3), 7.538-7.547 (t, 1H, Ar), 7.788-7.809 (d,1H, Ar), 8.104-8.153(m,3H, Ar), 8.271-8.273(d,1H, Ar),
HRMS value in ESI (+ve) calculated. for C15H11Cl2NO3 [M+H]+ 322.0038 and found 322.00.

Example 3: Preparation of 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylic acid (Tafamidis):
To a stirred suspension of methyl 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylate (1g, 0.0031 mole) in tetrahydrofuran (20 mL), an aqueous solution of sodium hydroxide (0.150g, 0.00375mole) in DM Water (3ml) was added at RT. Reaction mixture stirred at 55-60°C for 6-8 h. After completion, reaction mass was cooled to room temperature and pH was adjusted to 5-6 with 6 M aqueous HCl solution. The residual mass after removal of solvent under vacuum at 40-45°C was stirred in water (5 mL) and methanol (20 mL) for 30 min at 25-30°C. The precipitated solid was filtered, washed with Methanol (3ml) and finally dried solid under vacuum at 40-45°c for 8-10 h to produce Tafamidis (0.91g) as light brown solid.
Yield: 96%.
1H-NMR (400 MHz, DMSO-d6) d 7.874-7.906 (m, 2H, Ar), 8.002-8.023(d,1H, Ar), 8.071-8.099 (d, 2H, Ar), 8.238 (s,1H, Ar), 13.245(br. s, COOH).
HRMS value in ESI (-ve) calculated for C14H7Cl2NO3 [M-H]- is 306.9803 and found 305.97

Example 4: Preparation of Tafamidis meglumine:
To a stirred slurry of Tafamidis (1 g, 0.0032 mole) in Isopropyl alcohol (12 mL) and DM Water (5 mL) was added N-Methyl-D-glucamine (0.665g, 0.0034mole) at RT and the resulting suspension was heated at 65-70°C for 30 min. Then the reaction mass was gradually cooled to room temperature and was stirred for 6 h. The resulting precipitated solid was filtered, washed with a mixture of IPA/water and dried to furnish Tafamidis meglumine (1.30g) as white solid. Yield: 80%

Example 5: Preparation of 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylic acid (Tafamidis):

A stirred mixture of 4-amino-3-hydroxybenzoic acid (0.5g,0.00032mole), 3.5-dichlorobenzoic acid (0.74g,0.00039mole) and boric acid (0.20g,0.00032mole) in o-xylene (50ml) was refluxed for 22-24 h with continuous removal of water using Dean-Stark apparatus. After reaction completion, distilled out solvent under vacuum at 75-80°C. The residue was triturated with DM water (30ml) at 40-45°C for 30min. The reaction mass was cooled to 25-30°C, filtered the solid product and washed with DM water (10ml) at RT. Suck dried solid under vacuum at RT for 30 min. Resulting wet solid (7.11g) was refluxed in Isopropyl alcohol (30ml) for 30min., then cooled to 10-15°C and stirred for 1h. Filtered the solid, washed with chilled Isopropyl alcohol (3ml) and finally dried under vacuum at 40-45°c for 8-10h to produce the desired Tafamidis (0.40 g) Yield = 80%.
Data: 1H-NMR (400 MHz, DMSO-d6) d 7.874-7.906(m,2H, Ar), 8.002-8.023(d,1H, Ar), 8.071-8.099(d,2H, Ar), 8.238(s, 1H, Ar), 13.245(br. s, COOH),
HRMS value in ESI (-ve) calculated for C14H7Cl2NO3 [M-H]- is 306.9803 and found 305.97

Example 6: Preparation of Tafamidis meglumine:
To a stirred slurry of Tafamidis (1g,0.0032 mole) in Isopropyl alcohol (12ml) and DM Water (5ml) was added N-Methyl-D-glucamine (0.665g, 0.0034mole) at RT and the resulting suspension was heated at 65-70°C for 30min. Then the reaction mass was gradually cooled to room temperature and was stirred for 6h. The resulting precipitated solid was filtered, washed with a mixture of IPA/water and dried in to furnish Tafamidis meglumine (1.30g) as white solid. Yield-80%

Example 7: Preparation of methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate
To a stirred suspension of 3,5-dichlorobenzoic acid (1.51g, 0.0079mole) in ethyl acetate,1,1’-Carbonyldiimidazole (CDI) (1.28g, 0.0079mole) was added at room temperature and then stirred at 35-40°C for 3-4h followed by addition of methyl 4-amino-3-hydroxybenzoate (1.1g, 0.0066 mole) in it & stirred at 40-50°C for 4h. After reaction completion, solvent was distilled out under vacuum at 40-45°C and the residual mass was stirred with a mixture of acetone (5 mL) and DM Water (5 mL) at 25-30°C for 1h The reaction mass was further cooled to 5-10°C and stirred for 1h. The precipitated solid was filtered, washed with acetone/water mixture and finally dried the material under vacuum at 40-45°C. for 8-10 h to produce the corresponding amide (2.01 g) as solid. Yield: 90%
1H-NMR (400 MHz, DMSO-d6) d 3.356 (s, 3H, CH3), 7.446-7.472 (dd,1H, Ar), 7.519-7.524 (d,2H, Ar), 7.852-7.872 (m,2H, Ar), 7.969-7.972 (d,2H, Ar), 9.983(br. s, 2H, OH&CONH), HRMS in ESI (+ve) calcd. For C15H12Cl2NO4 (M+H) is 339.01; found 340.0137.

Example 8: Preparation of methyl 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylate (Tafamidis methyl ester):
A mixture of methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (2.0 g, 0.0059 mole) and p-Toluenesulfonic acid (0.1125g, 0.00059mole) in toluene was stirred at reflux with azeotropically removal of water using Deans-Stark apparatus for 16 h. After reaction completion the reaction mass was cooled to RT and filtered. The filtrate was distilled out under vacuum at 40-45°C and the residual mass was treated with acetone (16ml) and DM Water (2ml) at 25-30°C, stirred for 1h at RT. The precipitated solid was filtered, washed with acetone/water mixture and finally dried the material under vacuum at 40-45°C. for 8-10h to obtain the title compound (1.7g) as light brown solid. Yield: 90%
1H-NMR (400 MHz, DMSO-d6) d 3.977(s,3H, CH3), 7.538-7.547(t,1H, Ar), 7.788-7.809(d,1H, Ar), 8.104-8.153(m,3H, Ar), 8.271-8.273(d,1H, Ar),
HRMS value in ESI (+ve) calculated. for C15H11Cl2NO3 [M+H]+ 322.0038 and found 322.00.

Example 9: Preparation of methyl 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylate (Tafamidis methyl ester):
A suspension of methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (2.0g, 0.0059mole) and 5-sulfosalicylic acid dihydrate (2.0g,0.0079 mole) in o-Xylene (50ml) was refluxed with continuous removal of water using Deans-Stark apparatus. After reaction completion (~16 h) (monitored by TLC), the reaction mass was cooled to 75-80°C and the solvents was removed under vacuum. The residue was triturated using a mixture of acetone (16ml) and DM Water (2ml) to furnish Title compound (1.8g,) as light brown solid. Yield = 95.23%
1H-NMR (400 MHz, DMSO-d6) d 3.977(s,3H, CH3), 7.538-7.547(t,1H, Ar), 7.788-7.809(d,1H, Ar), 8.104-8.153(m,3H, Ar), 8.271-8.273(d,1H, Ar).
HRMS value in ESI (+ve) calculated. for C15H11Cl2NO3 [M+H]+ is 322.0038 and found 322.00.

CLAIMS:

We claim:
1. A process for the preparation of Tafamidis and/or salts thereof comprising the steps of:
(i) reacting 4-amino-3-hydroxybenzoic acid or its alkyl ester (III) and 3,5-dichlorobenzoic acid (IV) in presence of solvent and in presence or absence of coupling agent to obtain compound of Formula V;

(ii) cyclization of compound of formula V to obtain compound of formula VI;

(iii) hydrolysis of compound of formula VI, if R is an alkyl group, to obtain compound of formula VII; and

(iv) optionally, converting compound of formula VII to its salts thereof
wherein reaction proceed with or without isolation of compound of formula V; R is H or an alkyl group having C1-C6 carbon atoms.

2. The process as claimed in claim 1, wherein coupling agent is selected from the group comprising of 1,1'-carbonyl diimidazole (CDI), N,N'-diisopropyl carbodiimide (DIC), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide HC1 (EDC.HC1), (benzotriazol-l-yloxy) tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazol-l-yl-oxy tripyrrolidinophosphonium hexafluorophosphate (PyBOP), N,N'-dicyclohexylcarbodiimide (DCC), l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo [4,5-b]pyridinium3-oxide hexafluoro phosphate (HATU), 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluoro phosphate (HBTU), HCTU, TATU, TBTU.

3. The process as claimed in claim 1, wherein hydrolysis is performed with an alkali, which is selected from the group comprising of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and magnesium hydroxide.

4. The process as claimed in claim 1, wherein cyclization reaction carried out in presence of cyclization reagent selected from the group comprising of sulfonic acid, 5-sulfosalicylic acid dihydrate, p-toluene sulfonic acid, methane sulfonic acid, PEG-6000, Dowex50W (Hydrogen form, strongly acidic) or heating with propionic acid.

5. The process for the preparation of Tafamidis and/or its salts thereof comprising the steps of:
(i) reacting 4-amino-3-hydroxybenzoic acid or its alkyl ester (III) and 3,5-dichlorobenzoic acid (IV) in presence of boric acid and solvent to obtain compound of Formula VI;
(ii) hydrolysis of compound of formula VI, when R is an alkyl group, to obtain compound of formula VII; and
(iii) optionally, converting compound of formula VII to its salts thereof
wherein R is H or an alkyl group having C1-C6 carbon atoms.

6. A process for the preparation of Tafamidis and/or salts thereof comprising the steps of:
i) reacting 4-amino-3-hydroxybenzoic acid or its alkyl ester (III) and 3,5-dichlorobenzoic acid (IV) in presence of solvent and coupling agent to obtain compound of Formula V;
ii) cyclization of compound of formula V in presence of boric acid to obtain compound of formula VI;
iii) hydrolysis of compound of formula VI, when R is an alkyl group, to obtain compound of formula VII; and
iv) optionally, converting compound of formula VII to its salts thereof
wherein reaction proceed with or without isolation of compound of formula V; R is H or an alkyl group having C1-C6 carbon atoms.

7. A process for the preparation of Tafamidis and/or salts thereof comprising the steps of:
(i) conversion of 3-hydroxy-4-nitrobenzoic acid compound of Formula I to 4-amino-3-hydroxybenzoic acid compound of Formula II;

(ii) reaction of 4-amino-3-hydroxybenzoic acid compound of Formula II with thionyl chloride in presence of methanol to obtain methy-4-amino-3-hydroxybenzoate compound of Formula III;

(iii) reacting methy-4-amino-3-hydroxybenzoate compound of Formula III with 3,5-Dichlorobenzoic acid compound of Formula IV in presence of coupling agent to obtain compound of Formula V;

(iv) ring closure of compound of Formula V in presence of sulfonic acid and a solvent to obtain compound of Formula VI;

(v) hydrolysis of Formula VI in presence of aqueous alkali to obtain compound of Formula VII; and

(vi) optionally, conversion of compound of Formula VII to its acid addition salts thereof.

8. A process for the preparation of Tafamidis and/or salts thereof comprising the steps of:
(i) reacting 4-nitro-3-hydroxybenzoic acid or its ester compound of formula VIII with 3,5-dichlorobenzoyl chloride compound of Formula IX in presence of base to obtain 3-(3,5-dichlorobenzoyloxy)-4-nitrobenzoic acid or its ester compound of Formula X;
(ii) catalytic hydrogenation of 3-(3,5-dichlorobenzoyloxy)-4-nitrobenzoic acid methyl ester; followed by cyclization under acidic conditions to obtain compound of Formula VI;
(iii) hydrolysis of compound of formula VI, if R is an alkyl group, to obtain compound of formula VII; and
(iv) optionally, converting compound of formula VII to its salts thereof
wherein R is H or an alkyl group having C1-C6 carbon atoms.

9. The process for the preparation of Tafamidis or Tafamidis meglumine comprising the steps of:
(i) reacting 4-amino-3-hydroxybenzoic acid with 3,5-dichlorobenzoic acid in presence of boric acid and solvent to obtain Tafamidis; and/or
(ii) converting Tafamidis to Tafamidis meglumine.

10. Tafamidis or its meglumine salt comprising one or more impurities selected from the below mentioned impurities

wherein content of each impurity is less than 0.10%.