Process for preparation of tafamidis and salts thereof

1 . A process for the preparation of crystalline Form 4 of tafamidis, the process comprising:

(a) providing a solution of tafamidis in a solvent selected from the group consisting of C 1 -C 4 amides, C 2 -C 3 sulfoxides, C 5 -C 6 pyrrolidones, and mixtures thereof; and

(b) obtaining a crystalline Form 4 of tafamidis from the solution of step (a) by:

(i) combining the solution of step (a) with an anti-solvent selected from the group consisting of C 1 -C 8 alcohols, C 3 -C 10 ketones, C 1 -C 3 nitriles, water and mixtures thereof; or

(ii) removing the solvent from the solution of step (a),

wherein the crystalline Form 4 of tafamidis is characterized by an X-ray powder diffraction (XRPD) pattern as illustrated in FIG. 1 .

2 . The process of claim 1 , wherein the step (a) of providing the solution of tafamidis comprises reacting 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid with a coupling agent in the solvent to obtain tafamidis, wherein the coupling agent is methanesulfonic acid.

3 . The process of claim 1 , wherein the step (a) of providing the solution of tafamidis comprises reacting a salt of tafamidis with an acid to obtain tafamidis.

4 . The process of claim 2 , wherein the solvent comprises an amide solvent selected from C 1 -C 4 amides.

5 . The process of claim 4 , wherein the amide solvent is one or more of dimethylacetamide and dimethylformamide.

6 . The process of claim 3 , wherein the salt of tafamidis is a morpholine salt of tafamidis.

7 . The process of claim 1 , wherein the crystalline Form 4 of tafamidis obtained in step (b) contains less than about 0.5% w/w of crystalline Form 1 of tafamidis.

8 . A process for the preparation of a salt of tafamidis, the process comprising:

(a) reacting tafamidis with an inorganic base or an organic base to form a reaction mixture comprising the tafamidis salt; and

(b) separating the tafamidis salt from the reaction mixture of the step (a),

wherein the tafamidis of step (a) is obtained by reacting 4-(3,5-dichlorobenzamido)-3-hydroxybenzoic acid with methanesulfonic acid in an amide solvent.

9 . The process of claim 8 , further comprising the step of converting the obtained tafamidis salt to tafamidis comprising:

(a) treating the tafamidis salt with an acid to obtain a reaction mixture; and

(b) separating and isolating the tafamidis obtained in step (a),

wherein the tafamidis obtained is amorphous or crystalline.

10 . The process of claim 8 , wherein the amide solvent is selected from C 1 -C 4 amides.

11 . The process of claim 8 , wherein the tafamidis obtained is not isolated from the reaction mixture and is reacted with the inorganic base or the organic base to form the tafamidis salt.

12 . The process of claim 11 , wherein the organic base is morpholine.

13 . The process of claim 8 , wherein the tafamidis obtained from the reaction mixture is crystalline Form 4 of tafamidis by any one of the following:

(i) combining the reaction mixture with an alcohol, water or mixture thereof; or

(ii) removing the amide solvent from the reaction mixture.