DESC:FORM 2

THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION

PROCESS FOR THE PREPARATION OF 6-CARBOXY-2-(3, 5-DICHLOROPHENYL)-BENZOXAZOLE AND PHARMACEUTICALLY ACCEPTABLE SALTS

Nuray Chemicals Private Limited
Plot No. 111, SIDCO Industrial Estate,
Kakkalur, Thiruvallur District,
Tamil Nadu, India 602003

The following specification describes the nature of the invention and manner in which it has been performed.
Field of the Invention
The present invention relates to a process for the preparation of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of Formula-I and its pharmaceutically acceptable salts, polymorphs and hydrates thereof.

Background of the Invention
The 6-Carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (I) and 6-Carboxy-2-(3,5-dichlorophenyl)-benzoxazole 1-deoxy-1-methylamino-D-glucitol or meglumine salt of Formula-IA are indicated for the treatment of transthyretin-related hereditary amyloidosis. Transthyretin is a homotetrameric protein present in serum and cerebral spinal fluid and the main function is the transport of L-thyroxine and the holo-retinol-binding- protein.

US patent 7,214,695 described a process for the preparation of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole as given below scheme

The main drawback of this patent is use of hazardous and highly toxic reagent such as pyridine and trimethylsilyldiazomethane for the preparation of compound of formula-I and the methylating agent trimethylsilyldiazomethane is very expensive; hence this process is not safe and cost effective. In this process, the final compound is isolated by using thin layer chromatography which is not viable in commercial scale process.

US patent 8,168,663 described the pharmaceutically acceptable salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (I) more specifically meglumine salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of Formula-IA.

US patent 9,770,441 disclosed various crystalline forms of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of compound of formula I and process for the preparation of compound of formula I as given below scheme.

Even though this patent provides good yield and quality and this patent process involves tedious workup procedures, the compounds obtained in the reaction mass are coloured and it required multiple purifications and isolation of the compounds are very difficult from the reaction mass. Hence this process is only viable for small scale production and it is not useful for commercial process

US patent publication 20190119226 A1 described the polymorphic form Form-E of Tafamidis meglumine and process for its preparation.

WO2019175263A1 described the various polymorphs of Tafamidis meglumine and Tafamidis free acid.

WO2020207753A1 described the process for the preparation of Tafamidis meglumine without isolation of Tafamidis free acid by cyclising ester of compound of Formula (VII) and hydrolysing ester with sodium or potassium hydroxide and followed by extraction of Tafamidis in tetrahydrofuran and addition of meglumine in tetrahydrofuran solution. In this process, the ester compound of Formula (VII) is prepared by esterifying 4-amino-3-hydroxy-benzoic acid of compound of Formula IV followed by coupling of ester with 3, 5-dichloro-benzoyl chloride of Formula-III as given below scheme.

This patent publication is not disclosed process for the preparation of the ester compound of Formula (IV). In conventional methods, the ester compound was prepared by using acid or acid chlorides such as sulfuric acid or hydrochloric acid or acetyl chloride. If the hydrochloric acid was used for esterification, the reaction mass needs be cooled to 0 °C and the reaction will take atleast 48 hours to complete for 5 g scale followed by workup procedures. This process requires high conventional cost and it is not a commercial viable process. The sulfuric acid process requires reflux temperature which is not user friendly for commercial scale due to its hazardous in nature.

Hence there is a need for a simple, industrially feasible and commercially viable process for the preparation of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of compound of formula (I) and its pharmaceutically acceptable salts. The present inventors surprisingly found a simple process for the preparation of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole of compound of formula (I) and its pharmaceutically acceptable salts.

Objectives of the Invention
The main objective of the present invention is to provide a simple and cost effective process for the preparation of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole of Formula (I).
In an another objective of the present invention is to provide a process for the preparation of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole which is suitable for large scale preparation and economically viable.
In yet another objective of the present invention is to provide novel polymorphic forms of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole of formula (I) and its pharmaceutically acceptable salts.

Summary of the Invention
The present invention relates to a process for the preparation 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole of formula (I) which comprising steps of:
i. esterifying 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid of formula (V) to obtain 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid alkyl ester of formula (VII);
ii. cyclizing 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid alkyl ester to obtain 2-(3,5-dichlorophenyl)-benzoxazole-6-carboxylic acid alkyl ester of Formula (VIII);
iii. hydrolysing 2-(3,5-dichlorophenyl)-benzoxazole-6-carboxylic acid alkyl ester of Formula (VIII) to obtain 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole of formula (I);
iv. optionally converting 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole of formula (I) to its Base salt of formula (II);
v. hydrolysing 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole Base salt of formula (II) to obtain 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole formula (I); and
vi. optionally converting 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole of formula (I) obtained from step-iii) or step-v) to its pharmaceutically acceptable salt.
The present invention is represented by following scheme

In another embodiment of the present invention relates to a process for the preparation of novel salts of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (II)

wherein the “HB?” is basic salts which comprising steps of:
a) providing 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (I) or its ester of compound of formula (III) in a solvent;
b) optionally hydrolysing ester of compound of formula (III);
c) adding base to the reaction mass;
d) optionally heating the reaction mass; and
e) isolating novel salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (II).

Brief Description of Drawing
FIG-1 shows an X-ray powder diffraction pattern of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole diethanolamine salt
FIG-2 shows an X-ray powder diffraction pattern of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole pyridine salt
FIG-3 shows an X-ray powder diffraction pattern of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole dicyclohexylamine
FIG-4 shows an X-ray powder diffraction pattern of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole t-butylamine
FIG-5 shows an X-ray powder diffraction pattern of crystalline Form-L of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole.
FIG-6 shows an X-ray powder diffraction pattern of crystalline Form P of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole.
FIG-7 shows an X-ray powder diffraction pattern of crystalline Form-M of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine.
FIG-8 shows an X-ray powder diffraction pattern of Hydrate Form of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine.

Detailed Description of the Invention

In an embodiment of the present invention, the esterification reaction is carried out by activating acid to obtain acid halide followed by esterification by using respective alcohols. The preferred acid activation reaction product is acid chloride and it is prepared by the reaction of acid of Formula (V) with thionyl chloride or oxalyl chloride. The alkanol used in step (i) is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, 1-pentanol and 2-pentanol preferably methanol.

In another embodiment of the present invention, the cyclization reaction is carried out in presence of acid selected from the group consisting of para toluenesulfonic acid, methane-sulfonic acid, ethanesulfonic acid, phenylmethanesulfonic acid, camphor-10-sulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid and sulfuric acid, fumaric acid, methanesulfonic acid, camphor sulfonic acid, phosphoric acid and polyphosphoric acid or a combination thereof.

In another embodiment of the present invention, the cyclization reaction is carried out in presence of solvent selected from ethyl acetate, methyl acetate, toluene, hexane, heptane, acetonitrile, acetone, methylethyl ketone, methyl isobutyl ketone, isopropyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran, methanol, ethanol, isopropyl alcohol, isobutyl alcohol, butanol, isobutanol and pentanol or combination thereof.

In another embodiment of the present invention, the ester hydrolysis is carried out by using base selected from group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, caesium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, caesium carbonate, sodium bicarbonate, potassium bicarbonate and caesium bicarbonate or combination thereof.

In another embodiment of the present invention, the base used in step-iv) for formation Base salt of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole of formula (I) is including but not limited to alkylamines selected from ethylamine, mono-, di- or triethanolamine, mono- and dipropanolamine, methyldiethanolamine, dipropanolamine, butyldiethanolamine, diethyl ethanolamine, isopropylamine, diisopropylamine, diisopropylethylamine, butylamine, t-butylamine, piperazine, piperidine, morpholine, cyclopentylamine, cyclohexylamine, dicyclohexylamine, aniline, benzylamine, diphenylamine, dibenzylamino, N-methylbenzylamine, naphthylethylamine, N-methylpiperazine, pyridine, phenetidine, lutidines, piperidine, 2-methyl piperidine, 5-dimethylaminopyridine and quinoline. These amine salts are increasing the solubility of formula (I) and it is very useful to purify the compound of formula (I).

In still another embodiment of the present invention, the base salt of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole of formula (I) is neutralised with acid such as hydrochloric acid, sulfuric acid, acetic acid and trifluoroacetic acid preferably hydrochloric acid to obtain 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole of formula (I) which is further converted into pharmaceutically acceptable salt of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole of formula (I) wherein the neutralisation and salt formation steps are carried out without isolation of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole of formula (I).

In still another embodiment of the present invention, the ester hydrolysis, salt formation and pharmaceutically acceptable salt preparation steps are carried out without isolating intermediate compounds.

Still another embodiment of the present invention, the novel Base salts of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (I) disclosed herein are identified by several analytical parameters, alone or combination such as, but not limited to NMR, powder X-ray diffraction pattern (PXRD), differential scanning calorimetry and Infrared spectra.

One aspect of the present invention provides crystalline diethanolamine salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (I). The diethanolamine salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (I) has a PXRD pattern comprising peaks at 8.91, 16.7, 19.9 and 22.8 ± 2?. In another embodiment of the present invention, the diethanolamine salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (I) has PXRD pattern at 8.91, 9.28, 11.34, 12.96, 13.82, 16.76, 17.76, 19.9, 22.79, 23.25, 27.55 and 29.00 ± 2?. Still one more aspect of the present invention the diethanolamine salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole was characterised by PXRD pattern as shown by Fig-1.

One aspect of the present invention provides novel pyridine salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole. The pyridine salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole has a PXRD pattern comprising peaks at 8.24, 9.99, 13.3, 17.33, 26.14 and 27.16 ± 2?. Still one more aspect of the present invention the pyridine salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole was characterised by PXRD pattern as shown by Fig-2.

One aspect of the present invention provides novel dicyclohexylamine salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole. The dicyclohexylamine salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole has a PXRD pattern comprising peaks at 8.00, 10.63, 15.68, 21.52 and 28.99 ± 2?. In another embodiment of the present invention, the dicyclohexylamine salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole has PXRD pattern at 6.80, 7.17, 8.00, 10.63, 13.82, 15.68, 19.17, 20.63, 21.52, 22.32, 23.95 and 28.99 ± 2?. Still one more aspect of the present invention the dicyclohexylamine salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole was characterised by PXRD pattern as shown by Fig-3.

Another aspect of the present invention provides novel t-butylamine salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole. The t-butylamine salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole has a PXRD pattern comprising peaks at 9.65, 14.52, 19.41 and 24.68 ± 2?. In another embodiment of the present invention, the t-butylamine salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole has PXRD pattern at 9.65, 11.72, 14.52, 16.35, 19.41, 20.82, 22.78, 24.68, 25.26 and 34.31 ± 0.2 °2?. Still one more aspect of the present invention the t-butylamine salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole was characterised by PXRD pattern as shown by Fig-4.

Still one more embodiment of the present invention, crystalline Base salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (II) can be converted in to other solid forms of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (I) and the solid forms of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine salt of Formula (IA)

Still one more embodiment of the present invention provides a process for the preparation of Form-4 by cyclising compound of formula (VI) using acid selected form methane-sulfonic acid, ethanesulfonic acid, phenylmethanesulfonic acid, camphor-10-sulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid and sulfuric acid, fumaric acid or combinations thereof and in presence or absence of solvent. In one more embodiment of the reaction the cyclisation reaction is carried out at temperature in the range of about 80 °C to about 130 °C. The present inventors surprisingly found that the cyclising compound of formula (VI) using methanesulfonic acid in absence of solvent results Form-4. The present inventors also observed that stirring the 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole with fumaric acid in presence of solvent or solvent combination at temperature in the range of 50 to 90 °C resulting the Form-4 of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole. The PXRD of wet material and the final compound obtained from the reaction is matching with Form-4.

Still one more embodiment of the present invention provides polymorphic Form-L of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (I) has a PXRD pattern comprising peaks at 6.4, 13.0, 22.0 and 27.2 ± 0.2 ° 2?. In another embodiment of the present invention, the novel polymorph of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (I) has PXRD pattern at 9.52, 10.9, 16.7, 19.7, 23.8 and 44.6 ± 2?. Still one more aspect of the present invention the novel polymorph of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (I) was characterised by PXRD pattern as shown by Fig-5.

Still one more embodiment of the present invention provides polymorph Form-P of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (I) has a PXRD pattern comprising peaks at 6.6, 12.5, and 22.8 ± 2?. In another embodiment of the present invention, the novel polymorph of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (I) has PXRD pattern at 7.5, 10.7, 16.5, 18.4, 19.6, 25.0 and 44.6 ± 0.2 °2?. Still one more aspect of the present invention the novel polymorph of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (I) was characterised by PXRD pattern as shown by Fig-7.

The polymorphic forms Form-4 or new forms such as Form-L and Form-P obtained from present invention can be converted in to other solid forms of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (I) and the solid forms of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine salt

Still one more embodiment of the present invention, the pharmaceutically acceptable salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (I) is meglumine salt of Formula-IA. The 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine salt of Formula-IA is prepared by adding meglumine to the reaction mass as a solid or it is dissolved in solvent and then added.

Still one more embodiment of the present invention provides process for the preparation of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine salt by adding 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (I) with suitable solvent selected from water, ethyl acetate, methyl acetate, toluene, hexane, heptane, acetonitrile, acetone, methyl isobutyl ketone, isopropyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran, methanol, ethanol, isopropyl alcohol, isobutyl alcohol, butanol, isobutanol and pentanol or combination thereof, adding meglumine to the reaction mass, stirring the reaction mass at temperature in the range of 25 °C to 70 °C and filtering the stable polymorph of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine of Formula-IA..

Still one more embodiment of the present invention provides process for the preparation of meglumine salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of Formula-IA with/without isolating 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (I). If the 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (I) is isolated from the reaction mass, the PXRD of solid obtained from the reaction mass is matching with Form-4 as described in US patent 9,770,441.

Still one more embodiment of the present invention provides hydrate form of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine of formula (IA) having characterised PXRD pattern comprising peaks at 3.85, 6.62, 7.63, 10.01, 11.44, 13.75, 16.63, 21.28, 22.95 and 24.43 ± 2° 2 theta.

Still one more embodiment of the present invention provides a hydrate form of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine salt of Formula-IA having a PXRD pattern comprising peaks at 3.85, 6.62, 7.63, 10.09, 11.44, 13.75, 16.63, 22.65 ± 0.2 °2?. The hydrate form of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine of Formula-IA according to the present invention having moisture content in the range of about 3.5% to about 9 % preferably about 5 to 7%. The hydrate form of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine salt of Formula-IA having moisture up to 15 to 20 % but the only 5 to 7 % water is present in crystal lattice and the excess water molecule is present in surface of the Tafamidis meglumine crystal. The present inventors are tried to remove the water present in the hydrate form of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine salt of Formula-IA having moisture content about 6.64% but the water content is not considerably reduced even after drying at 55 °C temperature for 24 hours. The hydrate form of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine salt of Formula-IA having moisture content about 6.64% and moisture content about 15% are resulting the same PXRD diffractogram as shown in Fig-8 and Fig-9. This confirms the water molecules up to moisture content about 6% is present in crystal lattice and the excess water is present in surface of the crystal.

The starting material 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid of formula (V) of the present invention is prepared by conventional methods.

The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of this invention.

Example 1: Preparation of 4-(3, 5-dichloro-benzoylamino)-3-hydroxy-benzoic acid.
To the stirred solution of 3, 5-dichlorobenzoic acid in tetrahydrofuran, oxalyl chloride was added and stirred. To the reaction mass dimethylformamide was slowly added and stirred for 2-3 hrs. After completion of the reaction, the solvent from reaction mass was distilled completely. The obtained reaction mass was dissolved in tetrahydrofuran and 4-amino-3-hydroxy-benzoic acid was added at 25-35°C and stirred for 3 hrs. The reaction mass was quenched with water followed by triethylamine. The obtained wet solid was slurred in aq. isopropanol solution. The obtained wet solid was slurred in dichloromethane, filtered, suck dried and dried under vacuum to obtain 4-(3, 5-dichloro-benzoylamino)-3-hydroxy-benzoic acid.
Yield: 88%.
Example 2: 2-(3, 5-Dichlorophenyl)-benzoxazole-6-carboxylic acid methyl ester of Formula (VIII)
To the stirred solution of 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid in tetrahydrofuran at 30±5°C thionyl chloride was slowly added followed by methanol. The reaction was heated to 50°C and stirred. After completion of the reaction, the reaction mass was distilled, the residue obtained was slurred in methanol and filtered and tried to obtain 4-(3, 5-dichloro-benzoylamino)-3-hydroxy-benzoic acid methyl ester of formula (VII).
To the stirred solution of 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid methyl ester of formula (VII) in toluene at 30 °C p-toluene sulfonic acid was charged, the reaction mass was heated to azeotropic reflux temperature under stirring. After completion of the reaction, the solvent was distilled and the obtained solid was slurred in methanol and filtered and dried to obtain 2-(3,5-dichlorophenyl)-benzoxazole-6-carboxylic acid methyl ester of Formula (VIII).

Example 3: In-situ Process for the preparation of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine (Form M)
To the stirred solution of aq. lithium hydroxide (52.5 g in 500 L water), 2.2 Kg of tetrahydrofuran and 100 g of 2-(3, 5-dichlorophenyl)-benzoxazole-6-carboxylic acid methyl ester of Formula (VIII) was added. The reaction mass was stirred at 30±5°C for 15 hrs. After completion of the reaction, the pH of the reaction mass was adjusted to acidic at 30±5°C with dil. hydrochloric acid and separated the layers, Aq. layer back extracted with tetrahydrofuran, combined organic layers washed with brine solution and separated the layers, charcoal treatment given to organic layer and filtered. To the filtrate 48 g of meglumine was added at 30±5°C and stirred at 30±5°C for 6 hr. After completion of the reaction, obtained solid was filtered, washed with tetrahydrofuran and dried to obtain Form M of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine.

Example 4: Preparation of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole Diethanolamine salt
To a solution of toluene in 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid of formula (V), p-toluenesulfonic acid was added and stirred. The reaction was heated to 110-140 °C and stirred for 40 hours. After completion of the reaction, the mass was stirred with aq. tetrahydrofuran and filtered. A solution of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole was stirred at 25-35 °C. The reaction mass was warmed and cooled to room temperature. To the reaction mass diethanolamine was added and stirred for 4 hours. The obtained solid was filtered and washed with tetrahydrofuran to obtain 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole diethanolamine salt.

Example 5: Preparation of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole pyridine salt
To a solution of toluene in 4-(3, 5-dichloro-benzoylamino)-3-hydroxy-benzoic acid of formula (V), p-toluenesulfonic acid was added and stirred. The reaction was heated to 110-140 °C and stirred for 40 hours. After completion of the reaction, the mass was stirred with aq. tetrahydrofuran and filtered. A solution of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole was stirred at 25-35 °C. The reaction mass was warmed and cooled to room temperature. To the reaction mass pyridine was added and stirred for 4 hours. The obtained solid was filtered and washed with tetrahydrofuran to obtain 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole pyridine salt.

Example 6: Preparation of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole dicyclohexylamine salt
To a solution of toluene in 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid of formula (V), p-toluenesulfonic acid was added and stirred. The reaction was heated to 110-140 °C and stirred for 40 hours. After completion of the reaction, the mass was stirred with aq. tetrahydrofuran and filtered. A solution of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole was stirred at 25-35 °C. The reaction mass was warmed and cooled to room temperature. To the reaction mass dicyclohexylamine was added and stirred for 4 hours. The obtained solid was filtered and washed with tetrahydrofuran to obtain 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole dicyclohexylamine salt

Example 7: Preparation of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole t-butylamine salt
To a solution of toluene in 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid of formula (V), p-toluenesulfonic acid was added and stirred. The reaction mass was heated to 110-140 °C and stirred for 40 hours. After completion of the reaction, the mass was stirred with aq. tetrahydrofuran and filtered. A solution of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole was stirred at 25-35 °C. To the reaction mass t-butylamine was added and stirred for 4 hours. The obtained solid was filtered and washed with tetrahydrofuran to obtain 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole t-butylamine salt.

Example 8: General process for the preparation of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine from 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole Base salt.
To a solution of toluene in 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid of formula (V), p-toluenesulfonic acid was added and stirred. The reaction was heated to 110-140 °C and stirred for 40 hours. After completion of the reaction the reaction, the mass was stirred with aqueous tetrahydrofuran and filtered. To the filtrate containing 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole, corresponding Base was added, stirred for 4 hours and filtered to obtain Base salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole. To the wet solid aqueous tetrahydrofuran was added and the pH was adjusted with hydrochloric acid. To the reaction mass water was added and layers were separated. To the organic layer meglumine was added, heated to 50 to 60 °C and stirred for 24 hours. The obtained solid is filtered and washed with acetone and dried to obtain stable crystalline Form-M of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine of Formula-IA.

Example 9:
To a 20 g of 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid, 200 mL methane sulfonic acid was added and stirred. The reaction mass was heated to 80-120 °C and stirred for 24 hours. The reaction mass was cooled to room temperature. To the solution 1000 mL n-butanol was added lot wise (200 mLX5) and stirred for 2hr. The obtained solid was filtered and dried.
PXRD: Form L Fig-5

Example 10:
To a 20 g of 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid, 200 mL methane sulfonic acid was added and stirred. The reaction mass was heated to 80-120 °C and stirred for 24 hours. The reaction mass was cooled to room temperature. To the solution 800 mL of n-butanol was added and stirred for 1hr. The obtained solid was filtered and dried.
PXRD: Form P: Fig-6

Example 11: Process for the preparation of Form-4
To a 2 g of 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid, 20 mL methane sulfonic acid was added and stirred. The reaction mass heated to 80-120 °C and stirred for 24 hours. The reaction mass was cooled to room temperature. To the solution 80 mL of isopropanol was added and stirred for 1hr. The obtained solid was filtered and dried.
PXRD: Form-4

Example 12: Process for the preparation of Form-4
To a 2 g of 4-(3, 5-dichloro-benzoylamino)-3-hydroxy-benzoic acid, 20 mL methane sulfonic acid was added and stirred. The reaction mass was heated to 80-120 °C and stirred for 24 hours. The reaction mass was cooled to room temperature. To the solution 80 mL methanol was added and stirred for 1hr. The obtained solid was filtered and dried.
PXRD: Form-4

Example 13: Process for the preparation of Form-4
To a 2 g of 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid, 20 mL methane sulfonic acid was added and stirred. The reaction mass heated to 80-120 °C and stirred for 24 hours. The reaction mass was cooled to room temperature. To the solution 80 mL acetone was added and stirred for 1hr. The obtained solid was filtered and dried.
PXRD: Form-4

Example 14: Process for the preparation of Form-4
To a 3 g of 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid, 30 mL methane sulfonic acid was added and stirred. The reaction mass heated to 80-120 °C and stirred for 24 hours. The reaction mass was cooled to room temperature. To the solution 120 mL dioxane was added and stirred for 1hr. The obtained solid was filtered and dried.
PXRD: Form-4

Example 15: Process for the preparation of Form-4
To a 10 g of 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid, 100 mL methane sulfonic acid was added and stirred. The reaction mass heated to 80-120 °C and stirred for 24 hours. The reaction mass was cooled to room temperature. To the solution 400 mL of methyl tertiarybutyl ether was added and stirred for 1hr. The obtained solid was filtered and dried.
PXRD: Form-4

Example 16: Process for the preparation of Form-4
To a 10 g of 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid, 100 mL methane sulfonic acid was added and stirred. The reaction mass heated to 80-120 °C and stirred for 24 hours. The reaction mass was cooled to room temperature. To the solution 400 mL of diisopropylether was added and stirred for 1hr. The obtained solid was filtered and dried.
PXRD: Form-4

Example 17: Process for the preparation of Form-4
To a 2 g of 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid, 20 mL methane sulfonic acid was added and stirred. The reaction mass heated to 80-120 °C and stirred for 24 hours. The reaction mass was cooled to room temperature. To the solution 80 mL of acetonitrile was added and stirred for 1hr. The obtained solid was filtered and dried.
PXRD: Form-4

Example 18: Process for the preparation of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine (Form M)
To a 60 mL of acetone 2 g of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole Form 4 was added. The reaction mass was heated to 55-65 °C, 1.28 g of meglumine was added to the reaction mass and stirred for 2 hrs. The reaction mass was cooled to 25-35 °C and the obtained solid was washed with acetone, filtered and dried to obtain stable crystalline Form-M of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine of Formula-IA.
Dry weight 3.2 g

Example 19: Process for the preparation of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine of Formula-IA
To a 60 mL of acetone 2 g of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole Form L or Form P was added. The reaction mass was heated to 55-65 °C, 1.28 g of meglumine was added to the reaction mass and stirred for 2 hrs. The reaction mass was cooled to 25-35 °C and the obtained solid was washed with acetone, filtered and dried to obtain stable crystalline Form-M of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine of Formula-IA.
Dry weight 3.04 g

Example 20: Process for the preparation of Hydrate form of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine of Formula-IA
To the stirred solution of aq. lithium hydroxide (52.5 g in 500 L water), 2.2 Kg of tetrahydrofuran and 100 g of 2-(3, 5-dichlorophenyl)-benzoxazole-6-carboxylic acid methyl ester of Formula (VIII) was added. The reaction mass was stirred at 30±5°C for 15 hrs. After completion of the reaction, the reaction mass pH was adjusted to acidic at 30±5°C with dil. hydrochloric acid. The reaction mas treated with carbon filtered and washed the bed with tetrahydrofuran. To the filtrate 48 g of meglumine was added at 30±5°C and stirred at 30±5°C for 6 hr. After completion of the reaction, the obtained solid was filtered, washed with tetrahydrofuran and dried to obtain Hydrate of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine.

Dated this 25th day of June 2021
for Nuray Chemicals Private Limited

Dr. K. Ravi
Technical Director and Unit Head
,CLAIMS:We Claim:

1. A process for the preparation 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole of formula (I)

and its pharmaceutically acceptable salt comprising steps of;
i. esterifying 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid of formula (V)

to obtain 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid alkyl ester of formula (VII);

ii. cyclizing 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid alkyl ester to obtain 2-(3,5-dichlorophenyl)-benzoxazole-6-carboxylic acid methyl ester of Formula (VIII);

iii. hydrolysing 2-(3,5-dichlorophenyl)-benzoxazole-6-carboxylic acid alkyl ester of Formula (VIII) to obtain 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole of formula (I);
iv. optionally converting 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole of formula (I) to its Base salt of formula (II); and
v. converting 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole Base salt of formula (II) to 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole of formula (I) and its pharmaceutically acceptable salt.
2. The process according to the claim 1, wherein the esterification is carried out in presence of activating agent and alkanol wherein the activating agent is selected from thionyl chloride or oxalyl chloride and the alkanol is selected from methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, 1-pentanol and 2-pentanol.
3. The process according to the claim 1, wherein the cyclization of step ii) is carried out in presence of acid selected from p-toluenesulphonic acid, methane-sulfonic acid, ethanesulfonic acid, phenylmethanesulfonic acid, camphor-10-sulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid and sulfuric acid.
4. The process according to the claim 1, wherein the pharmaceutically acceptable salts of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole of formula (I) prepared by without isolation of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole of formula (I).
5. A process for the preparation of Form-4 of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (I) which comprising steps of:
a. cyclizing 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid presence of methanesulfonic acid to obtain 2-(3,5-dichlorophenyl)-benzoxazole-6-carboxylic acid of Formula (I); and

b. isolating Form-4 of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole of formula (I).
6. The process for the preparation of Form-4 according to the claim 5, wherein the Form-4 of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole formula (I) is converted in to other solid forms of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole formula (I) or solid forms of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine salt of Formula (IA).
7. Base salt of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole of formula (II)

wherein the HB? is basic addition salt.
8. The process according to the claim 7, wherein the base salt is selected from sodium, potassium, calcium, magnesium, diethanolamine, pyridine, dicyclohexylamine, phenylethylamine, isopropylamine, diisopropylethylamine, triethylamine and t-butylamine.
9. The base salt of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole of formula (II) according claim 6 wherein
a) diethanolamine salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole has a PXRD pattern comprising peaks at 8.91, 16.7, 19.9 and 22.8 ± 0.2° 2?;
b) Pyridine salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole has a PXRD pattern comprising peaks at 8.24, 9.99, 13.3, 17.33, 26.14 and 27.16 ± 0.2° 2?;
c) Dicyclohexylamine salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole has a PXRD pattern comprising peaks at 8.00, 10.63, 15.68, 21.52 and 28.99 ± 0.2° 2?; and
d) t-Butylamine salt of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole of formula (I) has a PXRD pattern comprising peaks at 9.65, 14.52, 19.41 and 24.68 ± 2?.
10. Crystalline Form-L of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole is characterised by PXRD peaks at 6.4, 13.0, 22.0 and 27.2 ± 0.2 ° 2?.
11. Crystalline Form P of 6-Carboxy-2-(3, 5-dichlorophenyl)-benzoxazole characterised by powder X-ray diffraction pattern comprising peaks at 6.6, 12.5, and 22.8 ± 0.2° 2?.
12. Hydrate of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine having water content about 3% to about 20%.

Dated this 25th day of June 2021
for Nuray Chemicals Private Limited

Dr. K. Ravi
Technical Director and Unit Head