DESC:The present invention relates to an improved process for the preparation of Tafamidis meglumine of formulae I.

The present invention also relates to an improved process for the preparation of Tafamidis of formula Ia.

The present invention also relates to novel compound of formula 4.

The present invention also relates to process for the preparation of compound of formula 4 and it is used in the preparation of Tafamidis meglumine of formula I and Tafamidis of formula Ia.

The present invention also relates to process for the preparation of Tafamidis meglumine of formula I from compound of formula 5 without isolating Tafamidis of formula Ia.

Background of the Invention
Tafamidis meglumine (VYNDAQEL®) is chemically known as 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid mono (1-deoxy-1-methylamino-D-glucitol). The molecular formula is C14H7Cl2NO3.C7H17NO5, and the molecular weight is 503.33 g/mol. The structural formula is:

Tafamidis (VYNDAMAX®) is chemically known as 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid. The molecular formula is C14H7Cl2NO3 and the molecular weight is 308.11 g g/mol. The structural formula is:

Tafamidis meglumine (VYNDAQEL®) and Tafamidis (VYNDAMAX®) 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 20mg Tafamidis meglumine capsules) orally once daily or VYNDAMAX 61 mg (one 61mg Tafamidis capsule) orally once daily. VYNDAMAX and VYNDAQEL are not substitutable on a per mg basis.

US 7,214,695 B2 discloses Tafamidis and its pharmaceutically acceptable salts. The patent also discloses the process for the preparation of Tafamidis using TLC which is not industrially feasible.

In view of all these disadvantages, there is a significant need for simple, eco-friendly, convenient, inexpensive and commercially viable process for the synthesis of Tafamidis meglumine and Tafamidis.

Summary of the Invention

The present invention provides a cost effective, novel and an efficient process for the preparation of Tafamidis meglumine of formula I and Tafamidis of formula Ia with higher yields and purity.

In one aspect, the present invention provides an improved process for the preparation of Tafamidis meglumine having the structural formula I, which comprises:

i) reacting of substituted aniline compound of formula 1

with SOCl2 in the presence of solvent to give compound formula 2;

ii) reaction of substituted aniline compound of formula 2 with 3,5-dichloro benzoyl compound of formula 3

with base in the presence of solvent to give substituted benzamide derivative of formula 4
;

iii) cyclization of the compound of formula 4

in the present reagents to give benzoxazole derivative of compound of formula 5
;
iv) hydrolysis of compounds of formula 5 in the presence of base and solvent to give Tafamidis free base of formula Ia in a solution; and
v) adding N-methyl-D-glucamine to the solution obtained in step (iv), and isolating Tafamidis meglumine of formula I.

In another aspect, the present invention provides an improved process for the preparation of Tafamidis having the structural formula Ia, which comprises:

i) reacting of substituted aniline compound of formula 1

with SOCl2 in the presence of solvent to give compound formula 2;

ii) reaction of substituted aniline compound of formula 2 with 3,5-dichloro benzoyl compound of formula 3

with base in the presence of solvent to give substituted benzamide derivative of formula 4
;
iii) cyclization of the compound of formula 4 in the presence of reagents to give benzoxazole derivative of compound of formula 5

iv) hydrolysis of compounds of formula 5 in the presence of base and solvent to give Tafamidis free base of formula Ia.

In yet another aspect, the present invention provides a novel process for the preparation compounds of formulae 4, which comprises:

i) reacting of substituted aniline compound of formula 1

with SOCl2 in the presence of solvent to give compound formula 2;

ii) reaction of substituted aniline compound of formula 2 with 3,5-dichloro benzoyl compound of formula 3

with base in the presence of solvent to give substituted benzamide derivative of formula 4

In yet another aspect, the present invention provides novel compound of formula 4.

In yet another aspect, the present invention provides an improved process for the preparation of Tafamidis meglumine by treating of Tafamidis of formula Ia with N-methyl-D-glucamine.

In yet another aspect, the present invention provides an improved process for the preparation of Tafamidis meglumine of formula I without isolating Tafamidis free base of formula Ia.

Detailed Description of the Invention
Accordingly, the present invention provides an improved process for the preparation of Taafamidis meglumine having the structural formula I.

The main embodiment of the present invention provides an improved process for the preparation of Tafamidis meglumine having the structural formula as shown in the Scheme-I given below.

Scheme-I
In step-i), reacting of substituted aniline compound of formula 1 with SOCl2 in the presence of solvent to give wet compound formula 2;

Solvent used in this reaction is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using alcoholic solvent. More preferably Methanol.

The reaction temperature may range from -5 to 10 °C and preferably at a temperature in the range from 0 to 5 °C.

In step-ii), substituted aniline wet compound of formula 2 is reacted with 3,5-dichloro benzoyl compound of formula 3 in the presence of base, solvent, purified water to give compound of formula 4.

Solvent used in this reaction is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using Ether solvent. More preferably Tetrahydrofuran.

Base used in this reaction is selected from the group consisting of Pyridine, N,N-Diisopropylethylamine or Triethylamine.

The reaction temperature may range from 10 to 30 °C and preferably at a temperature in the range from 15 to 20 °C.

In step-iii), cyclization of compound of formula 4 in the presence of reagents to give benzoxazole derivative of compound of formula 5.

Reagents used in cyclization reaction is selected from the group consisting of P-Toluenesulfonic acid, Benzene sulfonic acid, Methanesulfonic acid, Acetic acid or PCl3.

Solvent used in this reaction is selected from the group consisting of Xylene or Toluene. Preferably Toluene.

In step-iv), hydrolysis of compound of formula 5 in the presence of base and solvent to give compound of formula Ia in a solution.

Solvent used in this reaction is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using THF and Methanol.

Base used in the reaction is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide or cesium hydroxide and the like. Preferably lithium hydroxide.

The reaction temperature may range from 20 to 40 °C and preferably at a temperature in the range from 25 to 35 °C. The duration of the reaction may range from 3-5 hours; preferably for a period of 4 hours.

In step-v), adding N-methyl-D-glucamine to the solution obtained in step (iv); and isolating Tafamidis meglumine of formula I.

Solvent used for the meglumine salt formation is selected from alcoholic solvents, ether solvents, ester solvents, nitrile solvents, ketone solvents, chloro solvents and its mixture thereof. Preferably using alcoholic solvent. More preferably Isopropanol.

The reaction temperature may range in meglumine salt formation from 70-85 °C and preferably at a temperature in the range from 75-80 °C. The duration of the reaction may range from 3-5 hours; preferably for a period of 4 hours.

In yet another embodiment the present invention provides an improved process for the preparation of Taafamidis having the structural formula as shown in the Scheme-II given below.

Scheme-II
In step-i), reacting of substituted aniline compound of formula 1 with SOCl2 in the presence of solvent to give wet compound formula 2;

Solvent used in this reaction is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using alcoholic solvent. More preferably Methanol.

The reaction temperature may range from -5 to 10 °C and preferably at a temperature in the range from 0 to 5 °C.

In step-ii), substituted aniline wet compound of formula 2 is reacted with 3,5-dichloro benzoyl compound of formula 3 in the presence of solvent and purified water to give compound of formula 4.

Solvent used in this reaction is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using Ether solvent. More preferably Tetrahydrofuran.

Base used in this reaction is selected from the group consisting of Pyridine, N,N-Diisopropylethylamine, Triethylamine.

The reaction temperature may range from 10 to 30 °C and preferably at a temperature in the range from 15 to 20 °C.

In step-iii), cyclization of compound of formula 4 in the presence of reagents to give benzoxazole derivative of compound of formula 5.

Reagents used in cyclization reaction is selected from the group consisting of P-Toluenesulfonic acid, Benzene sulfonic acid, Methanesulfonic acid, Acetic acid or PCl3.

Solvent used in this reaction is selected from the group consisting of Xylene or Tolune. Preferably Toluene.

In step-iv), hydrolysis of compound of formula 5 in the presence of base and solvent to give compound of formula Ia.

Solvent used in this reaction is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using THF and Methanol.

Base used in the reaction is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide and the like. Preferably lithium hydroxide.

The reaction temperature may range from 20 to 40 °C and preferably at a temperature in the range from 25 to 35 °C. The duration of the reaction may range from 3-5 hours; preferably for a period of 4 hours.

In yet another embodiment the present invention provides an improved process for the preparation compound of formula 5 as shown in scheme-III given below:

Scheme-III
In step-i), reacting of substituted aniline compound of formula 1 with SOCl2 in the presence of solvent to give wet compound formula 2;

Solvent used in this reaction is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using alcoholic solvent. More preferably Methanol.

The reaction temperature may range from -5 to 10 °C and preferably at a temperature in the range from 0 to 5 °C.

In step-ii), substituted aniline wet compound of formula 2 is reacted with 3,5-dichloro benzoyl compound of formula 3 in the presence of solvent and purified water to give compound of formula 4.

Solvent used in this reaction is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using Ether solvent. More preferably Tetrahydrofuran.

Base used in this reaction is selected from the group consisting of Pyridine, N,N-Diisopropylethylamine or Triethylamine.

The reaction temperature may range from 10 to 30 °C and preferably at a temperature in the range from 15 to 20 °C.

In step-iii), cyclization of compound of formula 4 in the presence of reagents to give benzoxazole derivative of compound of formula 5.

Reagents used in cyclization reaction is selected from the group consisting of P-Toluenesulfonic acid, Benzene sulfonic acid, Methanesulfonic acid, Acetic acid or PCl3.

Solvent used in this reaction is selected from the group consisting of Xylene or Tolune. Preferably Toluene.

In yet another embodiment the present invention provides an improved process for the preparation of Tafamidis meglumine of formula (I).

which comprises:
i) cyclization of the compound of formula 4 in the presence of reagents

to give benzoxazole derivative of compound of formula 5
;
ii) hydrolysis of compound of formula 5 in the presence of a base and solvent to give Tafamidis free base of formula Ia, in solution;
iii) adding N-methyl-D-glucamine to the solution obtained in step (ii) in the presence of solvent; and, isolating Tafamidis meglumine of formula (I).

In step-i), Reagents used in cyclization reaction is selected from the group consisting of P-Toluenesulfonic acid, Benzene sulfonic acid, Methanesulfonic acid, Acetic acid or PCl3.

Solvent used in this reaction is selected from the group consisting of Xylene or Tolune. Preferably Toluene.

In step-ii), Solvent used in this reaction is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using THF and Methanol.

Base used in the reaction is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide or cesium hydroxide and the like. Preferably lithium hydroxide.

In step-iii), Solvent used in this reaction is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using isopropanol.

In yet another embodiment, the present invention provides a process for the preparation of Tafamidis meglumine of formula (I)

which comprises:
i) hydrolysis of compound of formula 5

in the presence of a base and solvent to give Tafamidis free base of formula Ia in a solution;
ii) adding N-methyl-D-glucamine to the solution obtained in step (i) in the presence of solvent; and isolating Tafamidis meglumine of formula (I).

In step-i), Solvent used in this reaction is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using THF and Methanol.

Base used in the reaction is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide or cesium hydroxide and the like. Preferably lithium hydroxide.

In step-ii), Solvent used in this reaction is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using isopropanol.

In yet another embodiment, the present invention provides an improved process for the preparation of Tafamidis meglumine of formula I, which comprises:

i) dissolving Tafamidis of compound of formula Ia

in a solvent mixture and adding N-methyl-D-glucamine of compound of formula 6 to this solution and isolating Tafamidis meglumine of formula I.

Solvent used in this reaction is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using isopropanol.

In a preferred embodiment, the present invention provides a novel compound of formulae 4.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.

In yet another embodiment the term "isolating" means isolating by way of solvent crystallization method, partial removal of the solvent from the solution, sonication, solvent/antisolvent method, slurry, cooling, seeding, filtration, filtration under vacuum, centrifugation, decantation, distillation, evaporation, evaporation under reduced pressure. The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.

EXPERIMENTAL PORTION:
The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.
EXAMPLES:
Preparation-1: Process for the preparation of 4-amino-3-hydroxy-benzoic acid methyl ester compound of formula 2.
A stirred solution of 4-amino-3-hydroxy benzoic acid (1.0 eq), thionyl chloride (1.0 eq) and methanol (5.0 vol) were stirred at 0-5 °C. After completion of the reaction, the reaction mass was cooled to room temperature and continue the stirring till complies the reaction. After completion of reaction concentrate the mass and resulted residue was dissolved in purified water (5 vol). Reaction mass pH adjust to 7.5-8 with 10% aqueous sodium bi carbonate solution and stir for 30 minutes. The resulting precipitate filter and wash with Purified water to obtain the wet title compound.

Example-1: Process for the preparation of Tafamidis meglumine I.
Step-1: Process for the preparation of substituted benzamide compound of formula 4.
To a mixture of 4-amino-3-hydroxy-benzoic acid methyl ester 2 (obtained in preparation 1), THF (19 vol) and purified water (1.5 vol) were added and cool the reaction mass to 15-20 °C. A solution of 3,5- dichloro benzoyl chloride (1.3 eq) was add at 15-20 °C and stir the reaction mass till reaction complies. Adjust the reaction mass pH to 7.5-8.0 with triethylamine stir for 90 min and distil off solvent under vacuum at below 50°C. Hexane (5 vol) was added to residue and stir for 30 minutes at 5-10 °C. After completion of the reaction filter the solid and dry in Vacuum oven at 50-55 °C to give the title compound (Yield: 70%).

Step-2: Process for the preparation of substituted 2-(3,5-dichlorophenyl)benzo[d]oxazole 5.
To a mixture of the substituted benzamide compound of formula 4 (obtained in step-1) (1.0 eq), Thionyl chloride (0.2 eq), xylene (15 vol) were added and refluxed till the reaction complete. The reaction mass was then allowed to cool to room temperature and wash the organic layer with 5% Sodium bicarbonate solution and aqueous layer extracted with Ethyl acetate and distil off the organic layer under vacuum at below 60 °C to give the residue compound. Hexane (5 vol) was added to residue compound and stir for 30 minutes at 5-10 °C. Filter the solid and wash with Hexane (2 vol) and dried the solid under vacuum at 50-55 °C to give the title compound (Yield: 70%).

Step-3: Process for the preparation of 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid meglumine compound of formula I.
A stirred solution of substituted 2-(3,5-dichlorophenyl)benzo[d]oxazole 5 (obtained in step-2), Lithium hydroxide monohydrate (4.0 eq), methanol (5 vol) and THF (20 vol) and purifie water was stirred at 25-35 °C. After completion of the reaction, the reaction mass pH adjusted to 1.5-2.0 with 2N HCl solution and stirred for 2 hours, compound extracted with ethyl acetate (50 vol), ethyl acetate was evaporation. the resulted residual was dissolved in Isopropanol (19.6.0 vol) and water (3.52 vol) were added and heated to 70-75 °C. N-methyl-D-glucamine (1.0 eq) in water (2 vol) was added to residual at same temperature. heat the reaction mass to 75-80 °C. The solution was filtered through a hyflo bed and collect the filtrate, then cooled to 5-10 °C over 2 hours and stirred for 1 hour at same temperature. The resulting solids were collected by filtration, washing with IPA (2 vol). Dry the solid through vacuum at below 60 °C, title product was obtained (Yield: 60%).

1H-NMR (300MHz, DMSO-d6, ppm): d values: 8.16-8.19 (m, 3H), 8.01-8.04 (m, 1H), 7.92-7.93 (m, 1H), 7.76-7.79 (m, 1H), 3.89-3.94 (m, 1H), 3.58-3.63 (m, 1H), 3.39-3.55 (m, 5H), 2.87-3.04 (m, 2H), 2.53-2.55 (m, 3H).

13C-NMR (75MHz, DMSO-d6, ppm): d values: 169.05, 160.69, 150.11, 142.48, 136.59, 135.09, 131.19, 129.63, 126.46, 125.63, 118.74, 111.42, 71.33, 70.57, 70.34, 68.80, 63.43, 51.47, 33.32.

Example 2: Process for the preparation of Tafamidis Ia.
Step-1: Process for the preparation of substituted benzamide compound of formula 4.
To a mixture of 4-amino-3-hydroxy-benzoic acid methyl ester 2 (obtained in preparation 1), THF (19 vol) and purified water (1.5 vol) were added and cool the reaction mass to 15-20°C. A solution of 3,5- dichloro benzoyl chloride (1.3 eq) was add at 15-20 °C and stir the reaction mass till reaction complies. Adjust the reaction mass pH to 7.5-8.0 with triethylamine, stir for 90 minutes and distil off solvent under vacuum at below 50°C. Hexane (5 vol) was added to residue and stir for 30 minutes at 5-10 °C. After completion of the reaction filter the solid and dry in Vacuum oven at 50-55 °C to give the title compound (Yield: 70%).

Step-2: Process for the preparation of substituted 2-(3,5-dichlorophenyl)benzo[d]oxazole 5.
To a mixture of the substituted benzamide compound of formula 4 (obtained in step-1) (1.0 eq), Thionyl chloride (0.2 eq), xylene (15 vol) were added and refluxed till the reaction complete. The reaction mass was then allowed to cool to room temperature and wash the organic layer with 5% Sodium bicarbonate solution and aqueous layer extracted with ethyl acetate and distil off the organic layer under vacuum at below 60 °C to give the residue compound. Hexane (5 vol) was added to residue compound and stir for 30 minutes at 5-10 °C. Filter the solid and wash with Hexane (2 vol) and dried the solid under vacuum at 50-55 °C to give the title compound (Yield: 70%).

Step-3: Process for the preparation of substituted 2-(3,5-dichlorophenyl)benzo[d]oxazole Ia.
A stirred solution of substituted 2-(3,5-dichlorophenyl)benzo[d]oxazole 5 (obtained in step-2), Lithium hydroxide monohydrate (4.0 eq), methanol (5 vol) and THF (20 vol) and purifie water was stirred at 25-35 °C. After completion of the reaction, the reaction mass pH adjusted to 1.5-2.0 with 2N HCl solution). Cool the reaction mass. The reaction mass was stirred for 1 hour at 5-10 °C and filter the solid and washed with purified water to give the title compound (Yield: 70%).
,CLAIMS:1. A process for the preparation of Tafamidis meglumine having the structural formula I.

which comprises:
i) reacting of substituted aniline compound of formula 1

with SOCl2 in the presence of solvent to give compound formula 2;

ii) reaction of substituted aniline compound of formula 2 with 3,5-dichloro benzoyl compound of formula 3

in a solvent in the presence of base to give substituted benzamide derivative of formula 4
;
iii) cyclization of the compound of formula 4

in the presence of reagents to give benzoxazole derivative of compound of formula 5;
;
iv) hydrolysis of compounds of formula 5 in the presence of base and solvent to give Tafamidis free base of compound of formula Ia in a solution;

v) adding N-methyl-D-glucamine to the solution obtained in step (iv), and isolating Tafamidis meglumine of formula I.

2. A process for the preparation of Tafamidis having the structural formula I.

which comprises:
i) reacting of substituted aniline compound of formula 1

with SOCl2 in the presence of solvent to give compound formula 2;

ii) reaction of substituted aniline compound of formula 2 with 3,5-dichloro benzoyl compound of formula 3

with base in the presence of solvent to give substituted benzamide derivative of formula 4
;
iii) cyclization of the compound of formula 4

in the presence of reagents to give benzoxazole derivative of compound of formula 5;
; and
iv) hydrolysis of compounds of formula 5 in the presence of base and solvent to give compound of formula Ia.

3. A process for the preparation of Tafamidis novel intermediate having the structural formula 5.

which comprises:
i) reacting of substituted aniline compound of formula 1

with SOCl2 in the presence of solvent to give compound formula 2;

ii) reaction of substituted aniline compound of formula 2 with 3,5-dichloro benzoyl compound of formula 3

with base in the presence of solvent to give substituted benzamide derivative of formula 4
; and
iii) cyclization of the compound of formula 4 in the presence of reagents to give benzoxazole derivative of compound of formula 5.

4. A process for the preparation of Tafamidis meglumine of formula I without isolating Tafamidis of formula Ia.

5. A novel compound of formulae 4.