DESC: “IMPROVED PROCESSES FOR THE PREPARATION OF TAFAMIDIS”

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Tafamidis. And also the present invention relates to a simple, cost effective, commercially viable and industrially applicable process of Tafamidis with high yield.

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/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.
Tafamidis was first disclosed in US 7,214,695, describes a process for the preparation of Tafamidis (I), which comprises the compound of formula (II) is reacted with the compound of formula (III) in presence of in presence of pyridine / THF to yield the compound of formula (IV), which is undergoes cyclisation in presence of TsOH.H2O, Xylenes TMSCHN2, and followed by reacted with MeOH to yield methyl ester of Tafamidis (V). The compound of formula (V) converts into Tafamidis.
The scheme representation is shown in Scheme.

The patent has been used hazardous reagent such as pyridine and trimethylsilyldiazomethane for the preparation of Tafamidis and the trimethylsilyldiazomethane is very expensive reagent; hence this process is not safe and expensive. In this process, the final compound was isolated by TLC which is not industrially feasible.

The process for the preparation of Tafamidis Meglumine (I), described in IN 202041020352, involves a series of steps. First, the compound of formula (II) reacted with SOCl2 / MeOH in presence of NaHCO3 to yield the compound of formula (IIA). Further, reacted with the compound of formula (III) in presence of TEA/ THF to yield the compound of formula (IV), which is undergoes cyclisation in presence of SOCl2 / xylene / NaHCO3 to yield the compound of formula (V). The compound of formula (V) converts into Tafamidis in presence of LiOH.H2O and followed by treating with N-methyl-D-glucamine in presence of IPA to get Tafamidis meglumine. The scheme representation is shown in Scheme.

In the prior art the compound of formula (IIA) is reacted with the compound of formula (III) in presence of organic base (triethylamine) to get the compound of formula (IV) with low yield.

WO 2020207753 describes process of or the preparation of Tafamidis Meglumine, which comprises the compound of formula (III) is reacted with the compound of formula (V) in presence of dry THF / NaHCO3 to yield the compound of formula (VI), which is undergoes cyclisation in presence of p-TSA. H2O to yield the compound of formula (V). Further, compound of formula (V) converts into Tafamidis in presence of KOH in water / THF / HCl followed by treating with meglumine to yield Tafamidis Meglumine. The scheme representation is shown in Scheme.

In the prior art the compound of formula (IIA) is reacted with the compound of formula (III) in presence of inorganic base (NaHCO3) to get the compound of formula (IV). Usage of inorganic base reaction time is increased, which is not industrially feasible.

The advantage of the present invention comprising by the coupling of compound of formula (IIA) with the compound of formula (III) in presence of mixture of organic and inorganic base to get the compound of formula (IV). Usage of mixture of organic and inorganic base in the reaction reduce the reaction time and yield of the product is high. which was not disclosed in the literature well known to those skilled in the art. Therefore, there is always a need in the preparation of pharmaceutical compounds to develop a process which is advantageous than the existing process in order to increase the yields, most commercially suitable, industrially applicable and cost effective process. The present invention is providing Tafamidis with good yield and purity.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of Tafamidis. And also the present invention relates to a simple, cost effective, commercially viable and industrially applicable process of Tafamidis with high yield.

One aspect of the present invention provides, a process for the preparation of Tafamidis, which comprises the steps of:

a) reacting the compound of formula (I) with chlorinating agent in presence of solvent and followed by reacted with methyl 4-amino-3-hydroxy benzoate (IIA) in presence of mixture of organic base and inorganic base to obtain the methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (IV);

b) treating the compound of formula (IV) with cyclizing agent in presence of solvent to obtain the methyl 2-(3,5-dichlorophenyl) benzo [d]oxazole-6-carboxylate (V); and

c) hydrolyzing the compound of formula (V) in presence of base to obtain Tafamidis.

Another aspect of the present invention provides, a process for the preparation of methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (IV), which comprises reacting the compound of formula (I) with chlorinating agent in presence of solvent and followed by reacted with methyl 4-amino-3-hydroxy benzoate (IIA) in presence of mixture of organic base and inorganic base to obtain the methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (IV).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of Tafamidis. And also the present invention relates to a simple, cost effective, commercially viable and industrially applicable process of Tafamidis with high yield.

One embodiment of the present invention provides, a process for the preparation of Tafamidis, which comprises the steps of:
a) reacting the compound of formula (I) with chlorinating agent in presence of solvent and followed by reacted with methyl 4-amino-3-hydroxy benzoate (IIA) in presence of mixture of organic base and inorganic base to obtain the methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (IV);

b) treating the compound of formula (IV) with cyclizing agent in presence of solvent to obtain the methyl 2-(3,5-dichlorophenyl) benzo [d]oxazole-6-carboxylate (V); and

c) hydrolyzing the compound of formula (V) in presence of base to obtain Tafamidis.

In an embodiment of the present invention provides, a process for the preparation of Tafamidis, which comprises compound of the formula (I) is reacted with chlorinating agent in presence of solvent at 40-60?, followed by reacted with compound of the formula (IIA) in presence of mixture of organic base and inorganic base / solvent at room temperature stir for 5-6 hrs to get crude compound. which is purified with methanol to get pure compound of the formula (IV). Further, compound of the formula (IV) undergoes cyclization in presence of cyclising agent / solvent heated at reflux temperature stir for 3-6 hrs to get crude compound. Followed by purification with purified water to get pure compound of the formula (V), which is undergoes hydrolysis in presence of base and solvent at 40-60? for 3-6 hrs to get wet solid, take the wet solid in IPA and purified with water at 80-85?. Filter the mass through hyflo and washed with IPA, cool the clear solution to room temperature and adjust pH to 3.0-4.0 with acetic acid and filter the solid to get Tafamidis.

Another embodiment of the present invention provides, a process for the preparation of methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (IV), which comprises reacting the compound of formula (I) with chlorinating agent in presence of solvent and followed by reacted with methyl 4-amino-3-hydroxy benzoate (IIA) in presence of mixture of organic base and inorganic base to obtain the methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (IV).

According to an embodiment of the present invention, wherein the chlorinating agent is selected from thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, chlorine, carbon tetrachloride, sulfuryl chloride, ferric chloride and aluminium chloride.

According to an embodiment of the present invention mixture of organic and inorganic base; organic base is selected from pyridine, triethylamine, methylamine, ethylamine, diethylamine, diisopropylethylamine, triethylenediamine (DABCO), 1,8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[ 4.3.0]-5-nonene (DBN), tetramethylethylenediamine, 4-dimethylaminopyridine, pyridine, N-methylmorpholine; inorganic base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, carbonic acid Lithium, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium methoxide, sodium methoxide, lithium ethoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide.
sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, lithium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide.

According to an embodiment of the present invention, wherein the cyclizing agent is selected from the group consisting of hydrochloric acid, acetic acid, trifluoroacetic acid or methane sulfonic acid.

According to an embodiment of the present invention, wherein the hydrolysing agent (Base) is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide and cesium hydroxide.

According to an embodiment of the present invention, wherein the solvent is selected from alcohols such as methanol, ethanol, propanol, butanol, n-propyl alcohol, isopropyl alcohol, and t-butyl alcohol; nitriles such as acetonitrile and propionitrile; amides such as N,N-dimethylformamide, tetrahydrofuran and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; and aromatic hydrocarbons such as toluene, heptane and xylene; esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methylisobutyl ketone,pentanone, ethylmethylketone, diethylketone; halogenated hydrocarbons such as chloroform, dichloromethane; ethers such as diethyl ether, tetrahydrofuran, dioxane or water and or mixtures thereof.

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES
Example 1:
Step-a: Preparation of Methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate:
To a suspension of 3,5-dichlorobenzoic acid (131 gm; 0.6894) and thionyl chloride (177.8 gm; 1.5138) in toluene (5 vol) were added in to reaction flask and the reaction mixture was heated to 50-55°C, distilled the solvent under reduce pressure to obtain residue. Methyl 4-amino-3-hydroxybenzoate (100 gm; 0.5982) and mixture sodium bicarbonate (57.9 g 1.2 mol) and Triethylamine (69.8g ;0.69 mol) in tetrahydrofuran (5 vol) added to the residue at room temperature and maintain the reaction mass for 5-6 hrs at room temperature. Further, distilled the solvent and added purified water (5 vol), filtered to obtained crude material. The crude material was purified in methanol (5 vol) and then dried the material at 60°C for 8-10 hours to get dry weight of about 182.7 g. Yield: 90.0 % (theoretical amount: 203 g). HPLC purity 99.55. % for pure Methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate.

Yield: 85-90 %.

Step-b: Preparation of Methyl 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylate: -
Take methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (100 gm; 0.2939 moles), p-toluene sulphonic acid (28.0 gm; 0.1471) in toluene (5.0 vol). The reaction mixture was heated to reflux temperature 100-110°C and stirred for 4-5. Distilled the solvent and added methanol (5.0 vol) to the mixture, filtered to obtained crude material. The crude material was purified in water (5.0 vol) and then dried the material at 60°C for 8-10 hours to get dry weight of about 78.6 g. Yield: 83.0% (theoretical amount: 94.7 g). HPLC purity 99.12. % of Methyl 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylate.

Yield: 80-85%.

Step-c: Preparation of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid (Tafamidis):
Take methyl 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylate (100.0 gm; 0.3104) and lithium hydroxide monohydrate (26.0 gm; 0.4655) in tetrahydrofuran (4.0 vol). The reaction mixture was heated to 45-50°C and maintain for 4-5 hours. Distilled the solvent, added purified water and filtered the wet solid. The wet solid was dissolved in 20 vol of (1:1) isopropyl alcohol and purified water and heated to 80-85°C to get the clear solution, which is filtered through hyflo and washed with isopropyl alcohol. The obtained reaction mas was cooled to room temperature and acidify the reaction mass with acetic acid (pH to 3.0-4.0), The obtained reaction mass was filtered and dried the material at 65°C for 8-10 hours to give dry weight of about 71.7 g. Yield: 75.0% (theoretical amount: 95.6 g). HPLC purity 99.85. % of pure 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid.

Yield: 75- 80 %

Example 2:
Step-a: Preparation of Methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate:
To a suspension of methyl 3,5-dichlorobenzoate (122.06 gm; 0.5982), 4-Amino-3-hydroxybenzoic acid (100 gm; 0.5982) in xylene (500 ml) and DMAP (0.05 moles). The reaction mixture was heated to reflux temperature and maintain for 20-24 hrs. Distilled the solvent and added purified water (5.0 vol) to obtained crude material. The crude material was purified in methanol (5.0 vol) and then dried the material at 60°C for 8-10 hours to get about 70.70 g. Yield: 74 % (theoretical amount: 95.6 g). HPLC purity 99.52. % Methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate.

Yield: 74-80 %

Step-b: Preparation of Methyl 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylate:
Take methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (100 gm; 0.2939 moles), p-Toluene sulphonic acid (28.0 gm; 0.1471) in toluene (5.0 vol). The reaction mixture was heated to reflux temperature 100-110°C and stirred for 4-5 hours. Distilled the solvent, added methanol (5.0 vol) to the mixture and filtered to obtained crude material. Crude material was purified in purified water (5.0 vol) and then dried the material at 60°C for 8-10 hours to give about 80.2 g. Yield: 83.89 % (theoretical amount: 95.6 g). HPLC purity 99.62. % of Methyl 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylate.
Yield: 80-85%

Step-c: Preparation of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid (Tafamidis):
Take methyl 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylate (100.0 gm; 0.3104) and lithium hydroxide monohydrate (26.0 gm; 0.4655) in tetrahydrofuran (4.0 vol). The reaction mixture was heated to 45-50°C and maintain for 4-5 hours. Distilled the solvent, added water and filtered the wet solid. The wet solid dissolved in 20 vol of (1:1) isopropyl alcohol and purified water, heated to 80-85°C to get clear solution and filtered the reaction mass through hyflo and washed with isopropyl alcohol. Further, the reaction mass was cooled to room temperature and acidify with acetic acid (pH to 3.0-4.0), filtered the solid and then dried the material at 65°C for 8-10 hours to get pure dry weight of about 69.7 g. Yield: 0.73 % (theoretical amount: 95.6 g). HPLC purity 99.85. % of 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid.

Yield: 70-75 %
,CLAIMS:WE CLAIMS:

1. A process for the preparation of Tafamidis, which comprises the steps of:
a) reacting the compound of formula (I) with chlorinating agent in presence of solvent and followed by reacted with methyl 4-amino-3-hydroxy benzoate (IIA) in presence of mixture of organic base and inorganic base to obtain the methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (IV);

b) treating the compound of formula (IV) with cyclizing agent in presence of solvent to obtain the methyl 2-(3,5-dichlorophenyl) benzo [d]oxazole-6-carboxylate (V); and

c) hydrolyzing the compound of formula (V) in presence of base to obtain Tafamidis.

2. The process as claimed in claim 1, wherein the chlorinating agent is selected from thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, chlorine, carbon tetrachloride, sulfuryl chloride, ferric chloride and aluminium chloride.

3. The process as claimed in claim 1, wherein the organic and inorganic base; organic base is selected from pyridine, triethylamine, methylamine, ethylamine, diethylamine, diisopropylethylamine, triethylenediamine (DABCO), 1,8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[ 4.3.0]-5-nonene (DBN), tetramethylethylenediamine, 4-dimethylaminopyridine, pyridine, N-methylmorpholine; inorganic base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, carbonic acid Lithium, sodium carbonate, potassium carbonate, cesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, lithium methoxide, sodium methoxide, lithium ethoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide. sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, lithium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide.

4. The process as claimed in claim 1, wherein the cyclizing agent is selected from the group consisting of hydrochloric acid, acetic acid, trifluoroacetic acid or methane sulfonic acid.

5. The process as claimed in claim 1, wherein the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide and cesium hydroxide.

6. The process as claimed in claim 1, wherein the solvent is selected from alcohols such as methanol, ethanol, propanol, butanol, n-propyl alcohol, isopropyl alcohol, and t-butyl alcohol; nitriles such as acetonitrile and propionitrile; amides such as N,N-dimethylformamide, tetrahydrofuran and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; and aromatic hydrocarbons such as toluene, heptane and xylene; esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methylisobutyl ketone,pentanone, ethylmethylketone, diethylketone; halogenated hydrocarbons such as chloroform, dichloromethane; ethers such as diethyl ether, tetrahydrofuran, dioxane or water and or mixtures thereof.

7. A process for the preparation of methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (IV), which comprises reacting the compound of formula (I) with chlorinating agent in presence of solvent and followed by reacted with methyl 4-amino-3-hydroxy benzoate (IIA) in presence of mixture of organic base and inorganic base to obtain the methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (IV).

8. The process as claimed in claim 7, wherein the chlorinating agent is selected from thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, chlorine, carbon tetrachloride, sulfuryl chloride, ferric chloride and aluminium chloride.

9. The process as claimed in claim 7, wherein the organic and inorganic base; organic base is selected from pyridine, triethylamine, methylamine, ethylamine, diethylamine, diisopropylethylamine, triethylenediamine (DABCO), 1,8-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[ 4.3.0]-5-nonene (DBN), tetramethylethylenediamine, 4-dimethylaminopyridine, pyridine, N-methylmorpholine; inorganic base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, caesium hydroxide, carbonic acid Lithium, sodium carbonate, potassium carbonate, caesium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, caesium bicarbonate, lithium methoxide, sodium methoxide, lithium ethoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide. sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, lithium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide.

10. The process as claimed in claim 7, wherein the coupling reaction carried out at room temperature and stirred for 5-6 hrs.