DESC:“IMPROVED PROCESS FOR TAFAMIDIS”

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of Tafamidis. The present invention is also relating to an improved and commercially viable process of Tafamidis with high yield.

BACKGROUND OF THE INVENTION

Tafamidis as active moiety chemically known as 2-(3,5-dichlorophenyl)-l,3-benzoxazole-6-carboxylic acid, and structurally represented as below.

Tafamidis is a transthyretin stabilizers indicated for the treatment of the cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization. In USA Tafamidis has been approved in different compositions using Tafamidis and Tafamidis Meglumine salt, whereas in Europe it’s approved using Tafamidis Meglumine salt and are marketed under the trade name VYNDAMAX™ and VYNDAQEL®. Tafamidis and its salts are approved. The recommended dosage is either VYNDAQEL 80 mg (four 20-mg Tafamidis Meglumine capsules) orally once daily, or VYNDAMAX 61 mg (one 61 -mg Tafamidis capsule) orally once daily.

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 obtain the compound of formula (IV). The compound of formula (IV) undergoes cyclisation in presence of TsOH.H2O, Xylenes TMSCHN2, Benzene and followed by reacted with MeOH to obtain methyl ester of Tafamidis (V). The compound of formula (V) converts into Tafamidis in presence of LiOH, THF MeOH and H2O.

The scheme representation is shown in Scheme-I.

The process described in the aforementioned patent US 7,214,695 provides Tafamidis in low yields of 8% - 27% over four steps. Additionally, toxic reagents and solvents such as pyridine and benzene and also dangerous reagents such as the diazomethane derivative TMSCHN2 are used. Purities are not disclosed.

WO 2020207753 describes a process for the preparation of Tafamidis (I), which comprises methyl 4-amino-3-hydroxy benzoate (VI) is reacted with 3,5-dichlorobenzoyl chloride (III) in presence of dry THF / NaHCO3 / acetone and water to obtain methyl 4-(3,5-dichloro benzamido) -3-hydroxybenzoate (VII). The compound of formula (VII) undergoes cyclisation in presence of pTsOH.H2O / toluene / acetone and water to obtain methyl 2-(3,5-dichloro phenyl) benzo [d]oxazole-6-carboxylate (V). The compound of formula (V) converts into Tafamidis (I) in presence of THF / KOH in water and HCl.

The scheme representation is shown in scheme-II:

The main drawback of the prior art is process for the preparation of Tafamidis with low yield and it is a time consuming process.
The advantage of the present invention is process for the preparation of Tafamidis with high yield, high purity, less impurity, less time cycle and no aqueous effluent.

In view of the foregoing, the present inventors have result of extensive studies, process for the preparation of methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (VII) from methyl 4-amino-3-hydroxy benzoate (VI) reacted with 3,5-dichlorobenzoyl chloride (III) in presence of organic base, further converts into Tafamidis (I).

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of Tafamidis. The present invention is also relating to an improved and commercially viable process of Tafamidis with high yield.

In one aspect of the present invention provides an improved process for the preparation of Tafamidis (I), comprising the steps of;

a) 3,5-dichlorobenzoic acid (VIII) is reacted with chlorinating agent in presence of organic solvent to obtain in-situ 3,5-dichlorobenzoyl chloride (III), which is reacted with methyl 4-amino-3-hydroxy benzoate (VI) in presence of organic base and organic solvent to obtain methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (VII).

b) The compound of (VII) undergoes cyclisation in presence of acid to obtain methyl 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylate (V).

c) The compound of formula (V) undergoes base hydrolysis in presence of inorganic base and organic solvent to obtain Tafamidis (I).

In another aspect of the present invention provides, Process for the preparation of Tafamidis (I), comprising the steps of;

a) 3,5-dichlorobenzoyl chloride (III) is reacted with methyl 4-amino-3-hydroxy benzoate (VI) in presence of Dimethylaminopyridine to obtain methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (VII).

b) The compound of (VII) undergoes cyclisation in presence of acid to obtain methyl 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylate (V).

c) The compound of formula (V) undergoes base hydrolysis in presence of inorganic base and organic solvent to obtain Tafamidis (I).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of Tafamidis. The present invention is also relating to an improved and commercially viable process of Tafamidis with high yield.

In one embodiment of the present invention provides an improved process for the preparation of Tafamidis (I), comprising the steps of;

a) 3,5-dichlorobenzoic acid (VIII) is reacted with chlorinating agent in presence of organic solvent to obtain in-situ 3,5-dichlorobenzoyl chloride (III), which is reacted with methyl 4-amino-3-hydroxy benzoate (VI) in presence of organic base and organic solvent to obtain methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (VII).

b) The compound of (VII) undergoes cyclisation in presence of acid to obtain methyl 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylate (V).

c) The compound of formula (V) undergoes base hydrolysis in presence of inorganic base and organic solvent to obtain Tafamidis (I).

According to embodiment of the present invention provides, which comprises 3,5-dichloro benzoic acid (VIII) is reacted with chlorinating agent in presence of organic solvent and the reaction is carried out at 50-55°C to obtain in-situ 3,5-dichlorobenzoyl chloride (III), which is reacted with methyl 4-amino-3-hydroxy benzoate (VI) in presence of organic base and organic solvent and the reaction is carried out at RT, the crude compound purified with methanol to obtain methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (VII). The compound of (VII) undergoes cyclisation in presence of acid, reaction is carried out at reflux temperature and the crude compound purified with water to obtain methyl 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylate (V). The compound of formula (V) undergoes base hydrolysis in presence of inorganic base and organic solvent, reaction is carried out at 40-45°C maintain for 4-5 hours and acidify the reaction mass pH to 3.0-4.0 with acetic acid to obtain Tafamidis (I).

In another embodiment of the present invention provides, Process for the preparation of Tafamidis (I), comprising the steps of;

a) 3,5-dichlorobenzoyl chloride (III) is reacted with methyl 4-amino-3-hydroxy benzoate (VI) in presence of Dimethylaminopyridine to obtain methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (VII).

b) The compound of (VII) undergoes cyclisation in presence of acid to obtain methyl 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylate (V).

c) The compound of formula (V) undergoes base hydrolysis in presence of inorganic base and organic solvent to obtain Tafamidis (I).

According to embodiment of the present invention provides, which comprises 3,5-dichlorobenzoyl chloride (III) is reacted with methyl 4-amino-3-hydroxy benzoate (VI) in presence of Dimethylaminopyridine and the reaction is carried out at RT to obtain methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (VII). The compound of (VII) undergoes cyclisation in presence of acid, reaction is carried out at reflux temperature and the crude compound purified with water to obtain methyl 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylate (V). The compound of formula (V) undergoes base hydrolysis in presence of inorganic base and organic solvent, reaction is carried out at 40-45°C maintain for 4-5 hours and acidify the reaction mass pH to 3.0-4.0 with acetic acid to obtain Tafamidis (I).

According to an embodiment of the present invention, wherein the chlorinating agent is selected from thionyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorus oxychloride, carbon tetrachloride and N-chlorosuccinimide.

According to an embodiment of the present invention, wherein the organic base is selected from triethylamine (TEA), diisopropylethylamine (DIPEA), trimethylamine, diethylamine, tertiary butyl amine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), dimethylaminopyridine (DMAP), 5-diazabicyclo [4.3.0] non-5-ene (DBN), pyridine,

According to an embodiment of the present invention, wherein the acid is selected from hydrochloric acid, sulphuric acid, methane sulphonic acid, p-toluene sulphonic acid, acetic acid and trifluoro acetic acid.

According to an embodiment of the present invention, wherein the inorganic base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, Lithium carbonate, potassium bicarbonate and sodium bicarbonate.

According to an embodiment of the present invention, wherein the organic solvent is selected from acetone, acetonitrile, ethyl acetate, water, isopropyl alcohol, methanol, ethanol, toluene, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dichloromethane (MDC), isopropyl acetate and n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, and water 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: Preparation of Methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate:

Charge 3,5-dichlorobenzoic acid (131 gm; 0.6894), Thionyl chloride (177.8 gm; 1.5138) and toluene (5 vol) into RB flask. The resultant reaction mass was heated to 50-55°C and stir for 2-3 hours. After completion of the reaction by TLC, distil out the solvent completely from the reaction mixture under reduce pressure to get 3,5-dichloro benzoyl chloride., Charge with 4-amino-3-hydroxy benzoic acid (100 gm; 0.5982), Triethylamine (90.6 gm;08970), tetrahydrofuran (5 vol) in another RB flask at room temperature and its allow to cool at 0-5°C. Add 3,5-dichloro benzoyl chloride into the reaction mixture and heat the reaction mixture to 50-55°C and stir for 1-2 hours. After completion of the reaction, distil out the solvent and purified water (5 vol) was added to the reaction mixture and filtered. The resultant crude product is purified in methanol (5 vol) and then dried the material at 60°C for to get titled compound.
Yield: 82%
Purity: 96%

Example-2: Preparation of Methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate

To a mixture of 4-amino-3-hydroxy-benzoic acid methyl ester (100 gm), xylene and purified water were added and cool the reaction mass to 25-30°C. A solution of 3,5-dichloro benzoyl chloride (100 gm )was add at room temperature and stir the reaction mass till reaction complies. Add Dim ethylaminopyridine stir for 30-60 min and distil off solvent under vacuum at below 50°C. purified water 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: 93%
Purity: 96%

Example-2: Preparation of Methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate:

Charge methyl 3,5-dichlorobenzoate (122.06 gm; 0.5982), 4-amino-3-hydroxy benzoic acid (100 gm; 0.5982), xylene (500 ml) and DMAP (0.05 moles) into RB flask at reflux temperature and its allow to cool at 0-5°C. The resultant reaction mass was heated to reflux temperature and stir for 2-3 hours. After completion of the reaction, distil out the solvent and purified water (5.0 vol) was added to the reaction mixture and filtered. The resultant crude product is purified in methanol (5.0 vol) and then dried the material at 60°C to get titled compound.
Yield: 70%
Purity: 91%

Example-3: Preparation of Methyl 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylate:

Charge methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (100 gm; 0.2939 moles), p-Toluene sulphonic acid (28.0 gm; 0.1471) and toluene (5.0 vol) into RB flask at reflux temperature 100-110°C and stir for 4-5 hours. After completion of the reaction, distil out the solvent and charge methanol (5.0 vol) to the reaction mixture, which allows to cool at 0-5°C and filtered the solid. The resultant crude product is purified in water (5.0 vol) and then dried at 60°C to get titled compound.
Yield: 84%)
Purity: 98%

Example-4: Preparation of Methyl 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylate:

Charge methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (100 gm; 0.2939 moles), p-toluene sulphonic acid (28.0 gm; 0.1471), toluene (5.0 vol) into RB flask at reflux temperature 100-110°C and stir for 4-5 hours. After completion of the reaction, distil out the solvent and charge methanol (5.0 vol) to the reaction mixture, which allows to cool at 0-5°C and filtered the solid. The resultant crude product is purified in purified water (5.0 vol) and then dried at 60°C to get titled product.
Yield: 86%
Purity: 97%

Example-5: Preparation of Tafamidis:

Charge methyl 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylate (100.0 gm; 0.3104), Lithium hydroxide monohydrate (26.0 gm; 0.4655), tetrahydrofuran (4.0 vol) into RB flask. The obtained reaction mixture heated to 45-50°C and stir for 4-5 hours. After completion of the reaction, distil out the solvent, charge water to the reaction mixture, filtered the solid. Take wet solid into the flask add 20 vol of (1:1) isopropyl alcohol and purified water. The obtained reaction mixture was heated to 80-85°C and stir for 2-3 hours, to get a clear solution. Filtered the mass through hyflo and wash with isopropyl alcohol, which allows to cool at room temperature and acidify the reaction mass pH to 3.0-4.0 with acetic acid and filter the solid. The resultant material dried at 65°C to get titled compound.
Yield: 80%
Purity: 99.7%

Example-6: Preparation of Tafamidis:

Charge methyl 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylate (100.0 gm; 0.3104), Lithium hydroxide monohydrate (26.0 gm; 0.4655), tetrahydrofuran (4.0 vol) into RB flask. The obtained reaction mixture heated to 45-50°C and stir for 4-5 hours. After completion of the reaction, distil out the solvent, charge water to the reaction mixture, filtered the solid. Take wet solid into the flask add 20 vol of (1:1) isopropyl alcohol and purified water. The obtained reaction mixture was heated to 80-85°C and stir for 2-3 hours to get a clear solution. Filtered the mass through hyflo and wash with isopropyl alcohol, which allows to cool at room temperature and acidify the reaction mass pH to 3.0-4.0 with acetic acid and filter the solid. The resultant material dried at 65°C to get titled compound.
Yield: 85%
Purity: 99.6%
,CLAIMS:We Claim:

1. An improved process for the preparation of Tafamidis (I), comprising the steps of;

a) 3,5-dichlorobenzoic acid (VIII) is reacted with chlorinating agent in presence of organic solvent to obtain in-situ 3,5-dichlorobenzoyl chloride (III), which is reacted with methyl 4-amino-3-hydroxy benzoate (VI) in presence of organic base and organic solvent to obtain methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (VII).

b) The compound of (VII) undergoes cyclisation in presence of acid to obtain methyl 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylate (V).

c) The compound of formula (V) undergoes base hydrolysis in presence of inorganic base and organic solvent to obtain Tafamidis (I).

2. Process for the preparation of Tafamidis (I), comprising the steps of;

a) 3,5-dichlorobenzoyl chloride (III) is reacted with methyl 4-amino-3-hydroxy benzoate (VI) in presence of Dimethylaminopyridine to obtain methyl 4-(3,5-dichlorobenzamido)-3-hydroxybenzoate (VII).

b) The compound of (VII) undergoes cyclisation in presence of acid to obtain methyl 2-(3,5-dichlorophenyl) benzo[d]oxazole-6-carboxylate (V).

c) The compound of formula (V) undergoes base hydrolysis in presence of inorganic base and organic solvent to obtain Tafamidis (I).

3. The process as claimed in claim 1, wherein the chlorinating agent is selected from thionyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorus oxychloride, carbon tetrachloride and N-chlorosuccinimide.

4. The process as claimed in claim 1, wherein the organic base is selected from triethylamine (TEA), diisopropylethylamine (DIPEA), trimethylamine, diethylamine, tertiary butyl amine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), dimethylaminopyridine (DMAP), 5-diazabicyclo [4.3.0] non-5-ene (DBN), pyridine.

5. The process as claimed in claim 1 and 2, wherein the acid is selected from hydrochloric acid, sulphuric acid, methane sulphonic acid, p-toluene sulphonic acid, acetic acid and trifluoro acetic acid.

6. The process as claimed in claim 1 and 2, wherein the inorganic base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, Lithium carbonate, potassium bicarbonate and sodium bicarbonate.

7. The process as claimed in claim 1 and 2, wherein the organic solvent is selected from acetone, acetonitrile, ethyl acetate, water, isopropyl alcohol, methanol, ethanol, toluene, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dichloromethane (MDC), isopropyl acetate and n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, and water or mixtures thereof.