Claims:We Claim:
1. A process for the preparation of Triclabendazole (I),

Formula I

which comprises,

i. acetylation of compound (IX) or salt thereof;

Formula IX

wherein, X is F, Cl, Br, I

with acetylating agent in absence of solvent to obtain compound (IVa);

Formula IVa
wherein, X is defined as above,

ii. nitration of compound (IVa) using nitration mixture in presence of high boiling point solvent to obtain compound (Va);

Formula Va

wherein, X is defined as above,

iii. compound (Va) is condensed with 2,3-dichlorophenol (VII),

Formula VII

in presence of suitable solvent and suitable base to obtain
4-chloro-5-(2,3-dichlorophenoxy)-2-nitroaniline (VIII);

Formula VIII
iv. reduction of 4-chloro-5-(2,3-dichlorophenoxy)-2-nitroaniline (VIII) in presence of suitable reducing agent and suitable solvent to obtain 4-chloro-5-(2,3-dichlorophenoxy)benzene-l,2-diamine (II);

Formula II

v. cyclization of 4-chloro-5-(2,3-dichlorophenoxy)benzene-l,2-diamine (II) in presence of carbondisulfide to obtain 6-chloro-5-(2,3-dichlorophenoxy)-lH-benzimidazole-2-thiol (III);

Formula III

vi. methylation of 6-chloro-5-(2,3-dichlorophenoxy)-lH-benzimidazole-2-thiol (III) using suitable methylating agent in presence of suitable solvent to obtain Triclabendazole (I).

2. The process as claimed in claim 1, wherein acetylating agent used in step-i comprises acetic anhydride, acetyl chloride and/or acetic acid.

3. The process as claimed in claim 1, wherein nitration mixture used in step-ii comprises nitric acid or alkali metal salt of nitric acid in combination with sulfuric acid, acetic acid, acetic anhydride, phosphoric acid or mixtures thereof.

4. The process as claimed in claim 1, wherein high boiling point solvent used in step-ii comprises ethylene dichloride (EDC), benzene, toluene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, dimethylformamide, dimethyl sulfoxide, water and/or mixture thereof.

5. The process as claimed in claim 1, wherein solvent used in step-iii, step-iv and step-vi comprises water, methanol, ethanol, propanol, isopropanol, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, methylene chloride, chloroform, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof.

6. The process as claimed in claim 1, wherein base used in step-iii comprises an inorganic base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or an organic base selected from triethylamine, pyridine, methyl amine, diisopropyl ethyl amine, DBU, DABCo and 2,6-Lutidine or mixtures thereof.

7. The process as claimed in claim 1, wherein reducing agent used in step-iv comprises raney nickel, palladium on carbon, platinum on carbon in presence of hydrogen gas or zinc dust and formic acid or ammonium formate, sodiumborohydride, lithium aluminum hydride, sodium triacetoxyborohydride (NaBH(OAc)3), stannous chloride (SnCl2), diborane, borane-THF complex and hydrazine hydrate.

8. The process as claimed in claim 1, wherein methylating agent used in step-vi comprises dimethyl sulfate, methyl chloride, methyl bromide, methyl iodide or dimethyl carbonate.

9. A process for the preparation of compound IVa,

Formula IVa
wherein, X is F, Cl, Br, I

which comprises,
acetylation of compound (IX) or salt thereof;

Formula IX

wherein, X is defined as above

with acetylating agent in absence of solvent. , Description:FIELD OF INVENTION

The present invention relates to a process for the preparation of Triclabendazole (I).

Formula I
BACKGROUND OF THE INVENTION

Triclabendazole (I) is chemically known as 6-chloro-5-(2, 3-dichlorophenoxy)-2-(methylthio)-1Hbenzimidazole. Triclabendazole (I) is an anthelmintic drug used for the treatment of fascioliasis in patients 6 years of age and older. Triclabendazole (I) is also used for the treatment of fascioliasis in domestic animals such as cattle, sheep, pigs, goats, dogs and poultry.

Triclabendazole (I) is disclosed in US 4197307.

US 4197307 discloses a process for the preparation of Triclabendazole (I), wherein 4-chloro-5-(2,3-dichlorophenoxy)-l,2-benzenediamine (II) is reacted with carbondisulfide to give 4-chloro-5-(2,3-dichloro phenoxy)-1H-benzimidazole-2-thiol (III), which is further subjected to alkylation reaction with dimethyl sulfate to give Triclabendazole (I).

The process is as shown in scheme-I below:

CN 101555231 describes a process for the preparation of Triclabendazole (I), wherein, 3,4-dichloro acetanilide (IV) undergoes nitration reaction in presence of H2SO4/HNO3 followed by addition of water to obtain 4,5-dichloro-2-nitro acetanilide (V), which undergoes hydrolysis to obtain 4,5-dichloro-2-nitroaniline (VI) and condensing it with 2,3-dichlorophenol (VII) in presence of a phase transfer catalyst to obtain 4-chloro-5-(2,3-dichlorophenoxy)-2-nitroaniline (VIII), which is further reduced in presence of Iron to obtain 4-chloro-5-(2,3-dichlorophenoxy)benzene-l,2-diamine (II). The obtained diamine (II) is cyclized in presence of carbondisulfide to obtain 6-chloro-5-(2,3-dichlorophenoxy)-lH-benzimidazole-2-thiol (III), which is methylated using dimethyl sulphate to obtain Triclabendazole (I).

The process is as shown in scheme-II below:

The main disadvantages of the above process are, nitration reaction on 3,4-dichloro acetanilide (IV) using H2SO4/HNO3 followed by addition of water results in formation of undesired isomer of the product in nitration step and leads to get low yield. Hydrolysis of 4,5-dichloro-2-nitro acetanilide (V) is carried out before condensation with 2,3-dichlorophenol (VII), which is labile to formation of impurities and moreover the condensation is carried out in the presence of a phase transfer catalyst. Further, Iron is used as a catalyst for reduction of 4-chloro-5-(2,3-dichlorophenoxy)-2-nitroaniline (VIII) which is not environment friendly and involves tedious work-up.

IN 326040 describes a process for the preparation of Triclabendazole (I), wherein, 4,5-dichloro-2-nitro acetanilide (V) is condensed with 2,3-dichlorophenol (VII) followed by hydrolysis to obtain 4-chloro-5-(2,3-dichlorophenoxy)-2-nitroaniline (VIII), which is further reduced with raney cobalt and hydrazine hydrate in presence of toluene and methanol to obtain 4-chloro-5-(2,3-dichlorophenoxy)benzene-l,2-diamine (II). The obtained diamine (II) is cyclized in presence of carbondisulfide to obtain 6-chloro-5-(2,3-dichlorophenoxy)-lH-benzimidazole-2-thiol (III), which is methylated using dimethyl sulphate to obtain Triclabendazole (I).
The process is as shown in scheme-III below:

The main disadvantages of the above process are, use of cobalt catalyst will ultimately makes the process expensive and poor availability in the market. The quantity of the catalyst is very high due to its poor selectivity of the reaction. Ultimately, the consumption of the hydrogen gas requires high to maintain the high pressure (3 Kg). Further, hydrazine hydrate is a combustible liquid and corrosive material. It is toxic if swallowed, contacted with skin. It causes severe skin burns and eye damage. It may cause respiratory irritation, allergic skin reaction, cancer. It is reported to be fatal if inhaled.

The aforementioned prior-art processes are not suitable for commercial scale as they are high in cost, operational difficulties and not environment friendly for the preparation of Triclabendazole (I).

However, there is always a need for an alternate process, which for example, involves use of reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, provide higher yield of product, have smaller and/or more eco-friendly waste products, and/or provide a product with higher purity.

The present invention involves use of less expensive reagents, less toxic, easier to handle, results in high yield and purity of the product, thus the process is economical and industrially viable.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a simple, industrially feasible and cost effective process for the preparation of Triclabendazole (I) with high purity and good yield on commercial scale.
SUMMARY OF THE INVENTION

The main embodiment of the present invention is to provide a process for the preparation of Triclabendazole (I),

Formula I

which comprises,

i. acetylation of compound (IX) or salt thereof;

Formula IX

wherein, X is F, Cl, Br, I

with acetylating agent in absence of solvent to obtain compound (IVa);

Formula IVa
wherein, X is defined as above,

ii. nitration of compound (IVa) using nitration mixture in presence of high boiling point solvent to obtain compound (Va);

Formula Va

wherein, X is defined as above,

iii. compound (Va) is condensed with 2,3-dichlorophenol (VII),

Formula VII

in presence of suitable solvent and suitable base to obtain 4-chloro-5-(2,3-dichlorophenoxy)-2-nitroaniline (VIII);

Formula VIII
iv. reduction of 4-chloro-5-(2,3-dichlorophenoxy)-2-nitroaniline (VIII) in presence of suitable reducing agent and suitable solvent to obtain 4-chloro-5-(2,3-dichlorophenoxy)benzene-l,2-diamine (II);

Formula II

v. cyclization of 4-chloro-5-(2,3-dichlorophenoxy)benzene-l,2-diamine (II) in presence of carbondisulfide to obtain 6-chloro-5-(2,3-dichlorophenoxy)-lH-benzimidazole-2-thiol (III);

Formula III

vi. methylation of 6-chloro-5-(2,3-dichlorophenoxy)-lH-benzimidazole-2-thiol (III) using suitable methylating agent in presence of suitable solvent to obtain Triclabendazole (I).
DETAILED DESCRIPTION OF THE INVENTION
The main advantages of the present invention are neat reaction, which made the process economical not only economical but also eco-friendly as reaction takes place in neat i.e. without use of external solvent thereby making it safe and eco-friendly. Use of high boiling solvents during nitration reaction on compound (IVa), which takes place at high temperatures i.e 70oC – 90oC. The main advantage of selecting the high boiling solvent for nitration reaction is to make the process easier and compound IVa will get solidify at below 60°C. Hence, use of high boiling solvent protects compound IVa from solidification. Once the nitration reaction is completed, organic solvent is distilled-out using water by azeotropic distillation to get high yields.
The present invention is related to a process for the preparation of Triclabendazole (I).

The process comprises, 3,4-dichloroaniline (IXa) is reacted with acetylating agent in absence of solvent to obtain 3,4-dichloro acetanilide (IV).

Acetylating agent used in above reaction comprises acetic anhydride, acetyl chloride and/or acetic acid.

3,4-Dichloro acetanilide (IV) is isolated as solid or as such used in next step. Optionally, 3,4-dichloro acetanilide (IV) is subjected to purification either by column chromatography or by crystallization by dissolving in a solvent or by adding an anti-solvent.

3,4-Dichloro acetanilide (IV) is reacted with nitration mixture to obtain 4,5-dichloro-2-nitro acetanilide (V).

Nitration mixture used in the above reaction comprises nitric acid or alkali metal salt of nitric acid in combination with sulfuric acid, acetic acid, acetic anhydride, phosphoric acid or mixtures thereof.

The above reaction is carried out in the presence/absence of a solvent or mixture of solvents thereof. The solvent comprises ethylene dichloride (EDC), benzene, toluene, o-xylene, m-xylene, p-xylene, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, acetone, acetonitrile, ethyl acetate, dimethylformamide, dimethyl sulfoxide, water and/or mixture thereof.

4,5-Dichloro-2-nitro acetanilide (V) is isolated as solid or as such used in next step. Optionally, 4,5-dichloro-2-nitro acetanilide (V) is subjected to purification either by column chromatography or by crystallization by dissolving in a solvent or by adding an anti-solvent.

4,5-Dichloro-2-nitro acetanilide (V) is condensed with 2,3-dichlorophenol (VII) followed by hydrolysis to obtain 4-chloro-5-(2,3-dichlorophenoxy)-2-nitroaniline (VIII).

The above reaction is carried out in presence of a base and in the presence/absence of a solvent or mixture of solvents thereof. The base comprises an organic base selected from triethylamine, pyridine, methyl amine, diisopropyl ethyl amine, DBU, DABCo and 2,6-Lutidine or an inorganic base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or mixtures thereof. The solvent comprises water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, methylene chloride, chloroform, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof.

4-Chloro-5-(2,3-dichlorophenoxy)-2-nitroaniline (VIII) is isolated as solid or as such used in next step. Optionally, 4-chloro-5-(2,3-dichlorophenoxy)-2-nitroaniline (VIII) is subjected to purification either by column chromatography or by crystallization by dissolving in a solvent or by adding an anti-solvent.

Reduction of 4-chloro-5-(2,3-dichlorophenoxy)-2-nitroaniline (VIII) in presence of reducing agent to obtain 4-chloro-5-(2,3-dichlorophenoxy)benzene-l,2-diamine (II).

Reducing agent used in above reaction comprises raney nickel, palladium on carbon, platinum on carbon in presence of hydrogen gas or zinc dust and formic acid or ammonium formate, sodiumborohydride, lithium aluminum hydride, sodium triacetoxyborohydride (NaBH(OAc)3), stannous chloride (SnCl2), diborane, borane-THF complex and hydrazine hydrate.
The above reduction reaction is carried out in presence/absence of a base and in the presence of a solvent or mixture of solvents thereof. The base comprises an organic base selected from triethylamine, pyridine, methyl amine, diisopropyl ethyl amine, DBU, DABCo and 2,6-Lutidine or an inorganic base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or mixtures thereof. The solvent comprises water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, methylene chloride, chloroform, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof.

4-chloro-5-(2,3-dichlorophenoxy)benzene-l,2-diamine (II) is isolated as solid or as such used in next step. Optionally, the compound (II) is subjected to purification either by column chromatography or by crystallization by dissolving in a solvent or by adding an anti-solvent.

4-chloro-5-(2,3-dichlorophenoxy)benzene-l,2-diamine (II) undergoes cyclization in presence of carbon disulfide (CS2) to obtain 6-chloro-5-(2,3-dichlorophenoxy)-lH-benzimidazole-2-thiol (III).

The above cyclization reaction is carried in presence of a base and in the presence/absence of a solvent or mixture of solvents thereof followed by treated with acid. The base comprises an organic base selected from triethylamine, pyridine, methyl amine, diisopropyl ethyl amine, DBU, DABCo and 2,6-Lutidine or an inorganic base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or mixtures thereof. The solvent comprises water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, methylene chloride, chloroform, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof. The acid comprises formic acid, acetic acid, propionic acid, HCl, sulphuric acid, nitric acid, phosphoric acid or mixtures thereof.

6-Chloro-5-(2,3-dichlorophenoxy)-lH-benzimidazole-2-thiol (III) is isolated as solid or as such used in next step. Optionally, the compound (III) is subjected to purification either by column chromatography or by crystallization by dissolving in a solvent or by adding an anti-solvent.

6-Chloro-5-(2,3-dichlorophenoxy)-lH-benzimidazole-2-thiol (III) is reacted with methylating agent to obtain Triclabendazole (I) or salt thereof.

Methylating agent used in the above reaction comprises dimethyl sulfate, methyl chloride, methyl bromide, methyl iodide or dimethyl carbonate.

The above reaction is carried out in presence of solvent comprises water, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, methylene chloride, chloroform, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof.

Triclabendazole (I) salt formed in the above reaction selected from but not limited to methosulfate salt or methane sulfonate salt.

Triclabendazole (I) salt is isolated as solid or as such used in next step. Optionally, Triclabendazole (I) salt is subjected to purification either by column chromatography or by crystallization by dissolving in a solvent or by adding an anti-solvent.

Triclabendazole (I) salt is treated with base in presence of solvent to obtain Triclabendazole (I).

The base used in the above reaction comprises ammonia, triethylamine, pyridine, monomethyl amine, dimethyl amine, trimethyl amine, ethyl amine, diethyl amine, diisopropyl ethyl amine, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or mixtures thereof. The solvent comprises water, methanol, ethanol, propanol, isopropanol, toluene, benzene, o-xylene, m-xylene, p-xylene, acetone, acetonitrile, ethyl acetate, methylene chloride, chloroform, dioxane, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methyl tert-butyl ether, diethyl ether, hexane, cyclohexane, heptanes or mixture thereof.

The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be constructed to limit the scope of the invention.

Examples:

Example-1:

a) Preparation of 4,5-dichloro-2-nitroacetanilide (V):
Charged 3,4-dichloroaniline (IXa) (0.617 mol) into the reactor and heated to 75-90°C. Slowly added acetic anhydride (0.637 mol) at 75-90°C. Maintained the reaction mass for 1 h and distilled-out acetic acid at below 90°C under reduced pressure (NLT 500 mmHg). Charged ethylene dichloride at 80°C and cooled the reaction mass to 20-30°C. Charged sulfuric acid (1.86 mol) and further cooled the reaction mass to 15-20°C. Slowly added nitric acid (0.93 mol) and maintained for 3 hrs. Reaction mass was quenched with mixture of ethylene dichloride (6.0 V) and DM water (10.0 V) and organic layer was separated. Organic layer was washed with 10% sodium bicarbonate solution (0.5 V) to maintain the pH: 6.5-7.0. Organic layer was separated and distilled-out solvent at below 95°C under atmospheric pressure. DM water (0.2 V) was added to strip-out the organic solvent. 10% aqueous methanol (7.0 V) was added and cooled the reaction mixture followed by filtered and dried the material at 50-60°C for 10 h.
Yield: 75%

b) Preparation of 4-chloro-5-(2,3-dichlorophenoxy)-2-nitroaniline (VIII):
Charged 4,5-dichloro-2-nitroacetanilide (V) (0.40 mol) into reactor then added dimethylformamide (1.0 V), 2,3-dichlorophenol (VII) (0.40 mol), potassium carbonate (0.49 mol) and heated to 90-95°C and maintained the mass for 10 hr. After completion of reaction, cooled the reaction mass to ambient temperature and charged methanol (1.32 V) and 40% sodium hydroxide solution (0.5 mol). Maintained the reaction mass at 50-55°C for 4 h. Charged DM water (2.62 V) to the reaction mass followed by filtration and washed with DM water (2. 0 V), 30% aqueous methanol (1.0 V) and chilled toluene (0.5 V) and dried the material.
Yield: 93%
Purity: Min. 98%
c) Preparation of 5-chloro-6-(2,3-dichlorophenoxy)-1H-benzimidazole-2-thiol (III):
Charged 4-chloro-5-(2,3-dichlorophenoxy)-2-nitroaniline (VIII) (0.299 mol) into pressure reactor and then added methanol (3.5 V), sodium hydroxide (0.008 mol), Raney Ni (2% w/w) and flushed the reactor with nitrogen and purged hydrogen with pressure 1.5 kg at 50-55°C. Maintained the mass for 2 hr. After completion of the reaction, reaction mass was cooled to ambient temperature and released hydrogen and flushed with nitrogen. Filtered the reaction mass and washed with methanol (0.63 V). Filtrate was transferred to another reactor and added sodium hydroxide (0.515 mol), carbondisulfide (0.472 mol). Reaction mass was heated to reflux temperature and maintained for 6 h. After completion of the reaction, charged EDTA (0.4% w/w), hydrose (0.4% w/w) and DM water (6.0 V) into the reactor. pH of the reaction mass was adjusted to neutral with acetic acid. Methanol was distilled out at 90°C under atmospheric pressure. DM water was charged (6.35 V) and heated to 90°C and filtered the material. Washed with DM water (2.0 V) and dried the material at 100°C.
Yield: 95%
Purity: 98%
d) Preparation of Triclabendazole methosulfate salt:
5-Chloro-6-(2,3-dichlorophenoxy)-1H-benzimidazole-2-thiol (III) (0.289 mol) was dissolved in methanol (2.0 V). Dimethylsulfate was added (0.643 mol) in 2 h at below 60°C. Maintained the reaction mass for 3-5 h at below 60°C. Cooled the reaction mass to 5-10°C and maintained for 1.5 h. Filtered the reaction mass and washed with methanol (0.33 V).
Yield: 92%
Purity: Min. 98%
e) Preparation of Triclabendazole (I):
Triclabendazole methosulfate salt (0.212 mol) was dissolved in methanol (4.67 V) and heated to 40-45°C. pH of the reaction mass was adjusted to 8.0-8.5 with ammonia gas (0.98 mol). Reaction mass was further heated to 60-65°C and treated with activated carbon (5% w/w) and EDTA (3.3% w/w) twice. Maintained the mass for 1 h and filtered. Filtrate was charged into another reactor and added DM water (2.0 V) and refluxed for 1 hr and cooled the mass to 25-35°C to precipitate the material and further cooled the mass to 10-15°C and maintained for 1 h at 10-15°C. Filtered the mass and washed with pre-chilled methanol (0.33 V) and dried the material under vacuum at 70-80°C for 7-8 h.
Yield: 98%
Purity: 99.8%