Field of the Invention
The present invention relates to a novel process for the preparation of stable crystalline form of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine.
Background of the Invention
6-Carboxy-2-(3, 5-dichlorophenyl)-benzoxazole and its meglumine sat 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 disclosed the process for the preparation of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole.
US patent 8,168,663 described the pharmaceutical^ acceptable salt of the compound 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole more specifically meglumine salt.
Organic small drug molecules have a tendency to self-assemble into various polymorphic forms by altering the conditions like heating, rate of cooling, ratios of solvents and other solvent effects.
Identifying most stable polymorphic form in each condition is the
interest and the processes that lead to changes in the polymorphic form is
crucial to the design of the drug manufacturing process in order to ensure
iT 0 RKatTtfieF final HrircMihLtAiS in i'ts^pfeferrerJ ^p'o^mbrpnic1 form? Different

polymorphic forms of an active pharmaceutical ingredient (API) can lead to changes in the drug's solubility, dissolution rate, pharmacokinetics and ultimately its bioavailability and efficacy in patients.
US patent 9,770,441 disclosed various crystalline forms of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazoIe.
US patent 9,249,112 described crystalline and amorphous forms of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine. This patent is using isopropanol and water for the preparation of said crystalline form. The isolation of above salt is difficult from water medium and hence it is not a viable for industrial scale.
US patent publication 20190119226 Al disclosed a process for the preparation of Form E of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine. As per this patent process the salt formation is not completed and the residue of free acid and meglumine salt has been present in the reaction mixture which will affect the quality of the final product and it leads poor yield. Hence this process is not feasible for the commercial scale process.
Hence there is a need for a simple, industrially feasible and commercially viable process for the preparation of crystalline 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine. The present inventors surprisingly found a simple process for the preparation of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine.

Objectives of the Invention
The main objective of the present invention is to provide a new simple and cost effective process for the preparation of stable crystalline forms of 6-carboxy-2-(355-dichlorophenyl)-benzoxazole meglumine by using single solvent system.
In yet another objective of the present invention is to provide a process for the preparation of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine which is suitable for large scale preparation and economically viable.
Summary of the Invention
The present invention relates to a novel process for the preparation stable crystalline forms of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine which comprises;
a) providing 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole in suitable solvent;
b) adding meglumine;
c) optionally heating the reaction mass;
d) cooling the reaction mass; and
e) isolating the stable crystalline form of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine salt.
Still another embodiment of the present invention relates to a novel process for the preparation stable crystalline Form M of 6-carboxy-2-(3,5-~j fdichlorciphenyi-)-:benz©x-a2oIe meglumine which' compriieS;' '
4

i. providing 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole
meglumine in suitable solvent; ii. heating the reaction mass; iii. cooling the reaction mass; and
iv. isolating the stable crystalline form M of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine salt.
Brief Description of Drawing
FIG-1 shows an X-ray powder diffraction pattern of crystalline Form-M of
the present invention
FIG-2 shows an X-ray powder diffraction pattern of crystalline form E
Detailed Description of the Invention
In an embodiment of the present invention, a suitable solvent in step a) is selected from aliphatic or aromatic hydrocarbon solvent selected from ethyl acetate, methyl acetate, toluene, hexane, heptane and acetonitrile, ketone solvent selected from acetone and methyl isobutyl ketone, ether solvent selected from isopropyl ether, methyl tertiary butyl ether, dioxane and tetrahydrofuran and alcohol solvent selected from methanol, ethanol, isopropyl alcohol, isobutyl alcohol, butanol, isobutanol and pentanol.
In another embodiment of the present invention, the meglumine was added to the reaction mass as a solid or it is dissolved in solvent and then added.
In another embodiment of rthe .present invention, the reaction mass
4 T OFFTf.F r.HFWNAI 1 S / r i <" 7 I-M n t > - < X

was heated to reflux temperature of solvent used in the reaction of step a) and b), preferably 40 ° to 120 °C more preferably 50 °C to 80 °C.
In another embodiment of the present invention, the reaction mass was completely dissolved in a solvent or the reaction mass is in heterogeneous mixture.
In still another embodiment of the present invention, after crystallization reaction, the reaction mass was cooled to 0-40 °C, preferably 20- 35 °C.
In still another embodiment of the present invention. 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine of step-i is treated with suitable solvent which is selected from aliphatic or aromatic hydrocarbon solvent selected from ethyl acetate, methyl acetate, toluene, hexane, heptane and acetonitrile, ketone solvent selected from acetone and methyl isobutyl ketone, ether solvent selected from isopropyl ether, methyl tertiary butyl ether, dioxane and tetrahydrofuran and alcohol solvent selected from methanol, ethanol, isopropyl alcohol, isobutyl alcohol, butanol, isobutanol and pentanol
In another embodiment of the present invention, heating temperature of step-ii is reflux temperature of solvent used in the reaction preferably 40 ° to 100 °C more preferably 50 °C to 70 °C.
In still another embodiment of the present invention, after crystallization reaction, the reaction mass was cooled to 0-40 °C, preferably 20- 35 °C.

In still another embodiment of the present invention, crystalline form of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine salt is more stable, highly pure, suitable for pharmaceutical preparations and it is isolated easily from the reaction mass.
The starting material 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole used in the present invention is prepared by conventional methods.
In still another embodiment of the present invention, 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole is prepared by the reaction of 3, 5-dichlorobenzoyl chloride with 4-amino-3-hydroxy-benzoic acid without using any base at temperature in the range of 25-70 °C. The prior art conventional process for amide coupling reaction requires more number of purification to get pure compound which leads the less than 60% yield. The present inventors surprisingly found that the avoiding the usage of base in amide coupling reaction eliminates the more number of purifications and the current process enhances the yield up to about 90%.
In still another embodiment of the present invention, the crystalline forms prepared by the present invention having more that 99 % polymorphic purity preferably 100% and it is free from other polymorphic forms.
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 solid wet solid slurred in dichloromethane and filtered and suck dried and dried under vacuum to obtain 4-(3,5-dichloro-benzoylamino)-3-hydroxy-benzoic acid Yield: 88%.
Example 2: Preparation of 4-(3, 5-dichloro-benzoylamino)-3-hydroxybenzoic acid
To a stirred solution of 4-(3, 5-dichloro-benzoylamino)-3-hydroxybenzoic acid in toluene para-toluenesulfonic acid monohydrate was added and stirred for 30 hours. After completion of the reaction, the obtained solid was filtered and washed with toluene. Obtained crude solid slurred in water two times. Then the solid dissolved in tetrahydrofuran at room temperature and treated with carbon. The obtained resulting wet solid, slurry in acetone and dried.
Example 3: Preparation of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine
To a stirred solution of 4-(3, 5-dichloro-benzoylamino)-3-hydroxybenzoic
0 F F T f F f.HF N NAT 1 S / 1 1 / 7 A 1 $ 1 S = 7 ft

acid in toluene, para-toluenesulfonic acid monohydrate was added, heated to reflux temperature and stirred for 30 hours. After completion of the reaction, the obtained solid was filtered and washed with toluene. Obtained crude solid slurred in water two times. Then the solid dissolved in tetrahydrofuran at room temperature and treated with carbon. The reaction mass was filtered, to the filtrate meglumine was added under stirring. The reaction mass was distilled partially at 35-50°C and stirred the reaction mass for 5hrs at room temp. The obtained solid was filtered and dried to obtain 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine.
Example 4: Preparation of Crystalline Fortn-M of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine
a) To a 100 mL of ethylacetate 10 g of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine was added. The reaction mass was heated to 60-75 °C and stirred for 1-2 hours. The reaction mass was cooled to 25-35 °C under stirring, filtered and dried to obtain stable crystalline Form-M of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine.
b) To a 100 mL of acetone 10 g of -carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine was added. The reaction mass was heated to reflux temperature and stirred for 5 hours. The reaction mass was cooled to 25-35 °C under stirring, filtered and dried to obtain stable crystalline Form-M of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine.
c) To a 200 mL of toluene 10 g of -carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine was added. The reaction mass was heated to 60-70 C and stirred for 1-2 hours. The reaction mass was cooled to 25-

35 °C under stirring, filtered and dried to obtain stable crystalline Form-M of 6-carboxy-2-(335-dichlorophenyl)-benzoxazole meglumine.
Example 5: Alternative process for the preparation of 6-carboxy-2-(3, 5-dichlorophenyI)-benzoxazole meglumine
To a 60 mL of acetone 2 g of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole 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 , Dry weight 3.14 g
The above process (Example-5) was repeated by using various solvents and results are tabulated as given below table.

We Claim:
1. A novel process for the preparation stable crystalline forms of 6-
carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine which
comprises;
a) providing 6-carboxy-2-(355-dichlorophenyl)-benzoxazole in suitable solvent;
b) adding meglumine;
c) optionally heating the reaction mass;
d) cooling the reaction mass; and
e) isolating the stable crystalline form of 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole meglumine salt.

2. The process according to the claim 1, the solvent used in step a) is aliphatic or aromatic hydrocarbon, ketone, ether and alcohol.
3. The process according to the claim 1, the solvent used in step a) is 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.
4. The process according to the claim 1, the reaction of mass is heated to 35 °C to reflux temperature of solvent used in the reaction of step a).
5. The process according to the claim 1, the reaction mass in step d) is
_ ^ ,_ T ,. cooled to_2fl ?C,tQ35 °C. _ , . „ „ _ , ,. ...

6. A novel process for the preparation stable crystalline Form M of 6-
carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine which
comprises;
i. providing 6-carboxy-2-(3, 5-dichlorophenyl)-benzoxazole
meglumine in suitable solvent; ii. heating the reaction mass; iii. cooling the reaction mass; and iv. isolating the stable crystalline forms of 6-carboxy-2-(3. 5-
dich!orophenyl)-benzoxazole meglumine salt.
7. The process according to the claim 1, the solvent used in step a) is aliphatic or aromatic hydrocarbon, ketone, ether and alcohol.
8. The process according to the claim 6, the solvent used in step a) is selected from the group consisting of 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, isobutano! and pentanol.
9. The process according to the claim 6, the reaction of mass is heated to 35 °C to reflux temperature of solvent used in the reaction of step a).

10. The process according to the claim 9, the reaction mass in step d) is cooled to 20. °C to 35 °C.