Claims:1. A process for the preparation of Albendazole (I),

Formula I
which comprises,

i. reacting 2-nitro-4-thiocyanoaniline (VI)

Formula VI

with n-propyl bromide in presence of suitable base and suitable solvent to obtain 4-propylthio-2-nitroaniline (VII);

Formula VII

ii. reduction of 4-propylthio-2-nitroaniline (VII) in presence of iron (Fe) and acid in suitable solvent to obtain 4-propylthio-o-phenylenediamine (IVa) or a salt thereof;

Formula IVa

Wherein, X is 1 or 2

iii. condensing 4-propylthio-o-phenylenediamine (IVa) or a salt with sodium isocyano(methoxycarbonyl)amide in presence of suitable base and suitable solvent to obtain Albendazole (I).

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

3. The process as claimed in claim 1, wherein suitable solvent used in step-i, step-ii and step-iii comprises water, methanol, ethanol, n-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, heptane or mixture thereof.

4. The process as claimed in claim 1, wherein acid used in step-ii comprises HCl, HBr, HI, H2SO4, HNO3, H3PO4 or acetic acid. Preferably HCl.

5. A process for the preparation of 4-propylthio-o-phenylenediamine (IVa) or a salt,

Formula IVa

wherein, X is 1 or 2

which comprises,
reduction of 4-propylthio-2-nitroaniline (VII) in presence of iron (Fe) and acid in suitable solvent;

Formula VII

, Description:FIELD OF INVENTION

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

Formula I

BACKGROUND OF THE INVENTION

Albendazole (I) is chemically known as methyl 5-(propylthio)-2-benzimidazolecarbamate. It is a member of the benzimidazole compounds used as a drug indicated for the treatment of a variety of worm infestations. Albendazole was first discovered at- the SmithKline Animal Health Laboratories in 1972. It is a broad spectrum anthelmintic, effective against roundworms, tapeworms, and flukes of domestic animals and humans. It is efficient antiparasitic agent that has good result of treatment not only to pinworm, ascarid, hookworm and whipworm in the animal bodies such as pig, ox, sheep, but it is also suitable for the treatment to prop up testis trematode, cestode, Echinococcus hydatid cyst, trichina, cysticercus worm etc.

It is marketed as Albenza in United States. Albendazole (I) is first disclosed in US 3915986.

US 3915986 disclosed a three step process for the preparation of Albendazole (I). In first step of the process, 3-chloro-6-nitroacetanilide (II) was reacted with propylmercaptan in presence of sodium hydroxide in water at reflux temperature for overnight to obtain 2-nitro-5-propylthioaniline (III). In second step, 2-nitro-5-propylthioaniline (III) was subjected to hydrogenation in presence of conc. hydrochloric acid and 5% palladium on charcoal in ethanol to obtain 4-propylthio-o-phenylene diamine hydrochloride (IV). In last step, to a mixture of cyanamide, methyl chloroformate, sodium hydroxide, water and acetone was added 4-propylthio-o-phenylene diamine hydrochloride (IV) in ethanol and said mixture was heated to 85oC to obtain Albendazole (I).

The process is as shown in scheme-I below:

The main disadvantage of the above process is use of Palladium in hydrogenation step is expensive and thereby make process uneconomical on industrial scale results in higher cost of the production of API. This process also involves use of pressure reaction, handling of these pressure reactions are not suitable for the large scale process.

US 4152522 disclosed a process in which 2-nitroaniline (V) is thiocyanated to obtain 2-nitro-4-thiocyanoaniline (VI), then alkylated with with n-propyl bromide in presence of n-propanol and methyl tributyl ammonium chloride or the tetrabutyl ammonium bromide as the phase-transfer catalyst and an alkali metal cyanide or alkaline metal cyanide to obtain 4-propylthio-2-nitroaniline (VII). 4-Propylthio-2-nitroaniline (VII) is reduced by sodium sulphide monohydrate in presence of water to obtain 4-propylthio-o-phenylenediamine (IVa). This diamine is further reacted with sodium salt of methyl-N-cyano carbamate to obtain the Albendazole (I).

The process is as shown in scheme-II below:

The main disadvantage of the above process is use of phase transfer catalyst as well as an alkali metal cyanide or alkaline metal cyanide for condensation of 2-nitro-4-thiocyanoaniline (VI) with n-propyl bromide, which adds to the cost of production, increases the organic material content in effluent and may facilitate the formation of impurity and uses toxic cyanide compound. The reduction of 4-propylthio-2-nitroaniline (VII) is done using sodium sulphide monohydrate in presence of water, sodium sulphide is corrosive and toxic to the environment. It is a strong base and can cause severe burns on the mucous membrane and hydrolysis by gastric fluids releases toxic hydrogen sulfide. Use of water as a solvent which makes the reaction sluggish.

Journal of the Mexican Chemical Society, 49(4), 353-358, 2005 disclosed reduction of 4-propylthio-2-nitroaniline (VII) using SnCl2.2H2O in presence of ethanol to obtain 4-propylthio-o-phenylenediamine (IVa). Use of SnCl2.2H2O is expensive and thereby make process uneconomical on industrial scale results in higher cost of the production of API. Also, SnCl2.2H2O can cause headache, nausea, vomiting, fatigue and repeated high exposure may cause anemia (low blood count).

CN101270091B disclosed reduction of 4-propylthio-2-nitroaniline (VII) using FeCl3/hydrazine hydrate in presence of methanol to obtain 4-propylthio-o-phenylenediamine (IVa). The main disadvantage of the process is use of hydrazine hydrate, which 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. Also, hydrazine hydrate is economically not viable for commercial scale.

IN 3539/CHE/2010 disclosed 4-propylthio-2-nitroaniline (VII) is hydrogenated using Raney Nickel in presence of methanol to obtain4-propylthio-o-phenylenediamine (IVa). The main disadvantage of the process is use of expensive Raney Nickel catalyst, which makes the process uneconomical on industrial scale results in higher cost of the production of API. This process also involves use of pressure reaction, handling of these pressure reactions are not suitable for the large scale process.

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 Albendazole (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, thus the process is economical and industrially viable.

The inventors of the present invention have been surprisingly found that reduction of 4-propylthio-2-nitroaniline (VII) using Iron (Fe) and acid in presence of solvent to obtain 4-propylthio-o-phenylenediamine (IVa). Iron (Fe) is less expensive reagent, less toxic, easier to handle, 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 Albendazole (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 Albendazole (I),

Formula I
which comprises,

i. reacting 2-nitro-4-thiocyanoaniline (VI)

Formula VI

with n-propyl bromide in presence of suitable base and suitable solvent to obtain 4-propylthio-2-nitroaniline (VII);

Formula VII

ii. reduction of 4-propylthio-2-nitroaniline (VII) in presence of iron (Fe) and acid in suitable solvent to obtain 4-propylthio-o-phenylenediamine (IVa) or a salt thereof;

Formula IVa

Wherein, X is 1 or 2

iii. condensing 4-propylthio-o-phenylenediamine (IVa) or a salt (IV) with sodium isocyano(methoxycarbonyl)amide in presence of suitable base and suitable solvent to obtain Albendazole (I).

Another embodiment of the present invention relates to a crystalline Form of Albendazole (I) having PXRD pattern having characteristic peaks expressed in degrees 2θ at 6.8, 11.2 and 17.9 (±0.2º).

Yet another embodiment of the present invention relates to a crystalline Form of Albendazole (I) having PXRD pattern as depicted in figure-1.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS

FIG. 1 discloses the x-ray diffractogram (XRD) of the crystalline Form of Albendazole (I).

FIG. 2 discloses DSC thermogram of crystalline Form of Albendazole (I).

FIG. 3 discloses TGA of crystalline Form of Albendazole (I).
DETAILED DESCRIPTION OF THE INVENTION

In an embodiment of the present invention, there is provided an improved process for the preparation of Albendazole (I), as depicted below in scheme-III.

In an embodiment of the invention, 2-nitro-4-thiocyanoaniline (VI) is reacted with n-propyl bromide in presence of base and solvent to obtain 4-propylthio-2-nitroaniline (VII).

The above reaction is carried out in the presence of solvent system include but is not limited to water, alcohols, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers, ketones and/or mixtures thereof. The alcohols include, but are not limited to C1-6 alcohols selected from methanol, ethanol, n-propanol, isopropanol, butanol, and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; hydrocarbons include, but are not limited to hexane, cyclohexane, toluene, xylene and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; esters include, but are not limited to ethyl acetate and butyl acetate and the like; ethers include, but are not limited to diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran and the like; ketones include, but are not limited to acetone, methyl ethyl ketone, methyl isopropyl ketone and the like and mixtures thereof.

The base used in above reaction includes an inorganic and organic bases. Inorganic base is selected from but not restricted to alkaline or alkaline earth metal hydroxide includes sodium hydroxide or potassium hydroxide, lithium hydroxide or like; alkaline or alkaline earth metal carbonate includes sodium carbonate, potassium carbonate, lithium carbonate or like; alkaline or alkaline earth metal bicarbonate includes sodium bicarbonate or potassium bicarbonates, lithium bicarbonate or mixtures thereof and organic base selected from but not restricted to triethylamine, pyridine, monomethyl amine, dimethyl amine, trimethyl amine, ethyl amine, diethyl amine, diisopropyl ethyl amine, DBU, DABCo, 2,6-Lutidine or mixtures thereof.

The reaction is typically carried out at a temperature in the range of from about 0°C to reflux temperature of the solvent used. Preferably, the reaction is carried out at a temperature in the range of from about 25°C to about 65°C.

The reaction is carried out preferably for about 8 hour to about 12 hours.

The compound 4-propylthio-2-nitroaniline (VII) obtained by the process of the present invention is then reduced by treating with iron and acid in presence of solvent to obtain 4-propylthio-o-phenylenediamine (IVa) or a salt (IV) thereof.

Acid used in the above reaction selected from but not restricted to HCl, HBr, HI, H2SO4, HNO3, H3PO4 or acetic acid. More preferably HCl

The above reaction is carried out in the presence of solvent system include but is not limited to alcohols, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers, ketones, water and/or mixtures thereof. The alcohols include, but are not limited to C1-6 alcohols selected from methanol, ethanol, n-propanol, isopropanol, butanol, and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; hydrocarbons include, but are not limited to hexane, cyclohexane, toluene, xylene and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; esters include, but are not limited to ethyl acetate and butyl acetate and the like; ethers include, but are not limited to diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran and the like; ketones include, but are not limited to acetone, methyl ethyl ketone, methyl isopropyl ketone and the like and mixtures thereof.

The reaction is typically carried out at a temperature in the range of from about 0° C to about 40°C. Preferably, the reaction is carried out at a temperature in the range of from about 10°C to about 35°C.

The reaction is carried out for about 3 hours to about 7 hours, preferably for about 4 hours to about 5 hour.

4-Propylthio-o-phenylenediamine (IVa) or salt is reacted with sodium isocyano(methoxycarbonyl)amide in presence of suitable base and suitable solvent to obtain Albendazole (I).

The above reaction is carried out in the presence of solvent system include but is not limited to water, ketones, alcohols, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers and/or mixtures thereof. The ketones include, but are not limited to acetone, methyl ethyl ketone, methyl isopropyl ketone and the like; alcohols include, but are not limited to C1-6 alcohols selected from methanol, ethanol, n-propanol, isopropanol, butanol, and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; hydrocarbons include, but are not limited to hexane, cyclohexane, toluene, xylene and the like; amides include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; esters include, but are not limited to ethyl acetate and butyl acetate and the like; ethers include, but are not limited to diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran and the like mixtures thereof.

The base used in above reaction includes an inorganic and organic bases. Inorganic base is selected from but not restricted to alkaline or alkaline earth metal hydroxide includes sodium hydroxide or potassium hydroxide, lithium hydroxide or like; alkaline or alkaline earth metal carbonate includes sodium carbonate, potassium carbonate, lithium carbonate or like; alkaline or alkaline earth metal bicarbonate includes sodium bicarbonate or potassium bicarbonates, lithium bicarbonate or mixtures thereof and organic base selected from but not restricted to triethylamine, pyridine, monomethyl amine, dimethyl amine, trimethyl amine, ethyl amine, diethyl amine, diisopropyl ethyl amine, DBU, DABCo, 2,6-Lutidine or mixtures thereof.

The reaction is typically carried out at a temperature in the range of from about -70°C to reflux temperature of the solvent used. Preferably, the reaction is carried out at a temperature in the range of from about 50°C to about 90°C.

The reaction is carried out for about 2 hours to about 5 hours, preferably for about 1 hours to about 3 hours.

The reaction may carried out under inert atmosphere, such as nitrogen or argon.

In another embodiment of the present invention is relates to a crystalline Form of Albendazole (I) having PXRD pattern having characteristic peaks expressed in degrees 2θ at 6.8, 11.2 and 17.9 (±0.2º).

Crystalline Form of Albendazole (I) further characterized by PXRD pattern having characteristic peaks expressed in degrees 2θ at 13.7, 19.4, 20.6, 24.6 and 27.1(±0.2º).

Yet another embodiment of the present invention relates to a crystalline Form of Albendazole (I) having PXRD pattern as depicted in figure-1.
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: Preparation of 4-propylthio-2-nitroaniline (VII):
Charged 250 g of 2-nitro-4-thiocyanoaniline (VI) (1.281 mol) into four neck round bottom flask at 25-35°C. Charged 750 mL of n-propanol (3 V), 415 mL of DM water (1.66 V) and stirred for 15 min. Slowly added pre-prepared solution of sodium hydroxide (114 g of flakes dissolves in 114 mL of DM water) into the reaction mass in about 2 hrs at ambient temperature. Continued the stirring for 15 min and heated the mass to 45°C. Added 140 g of n-propylbromide (1.138 mol) in 2 hrs at 45°C. After addition, heated the reaction mass to 65°C and maintained for 6 hrs. After completion of reaction, distilled-off the solvent atmospherically to obtain the residue, which on washed with 500 mL of DM water to obtain 270 g of 4-propylthio-2-nitroaniline (VII).

Example-2: Preparation of 4-propylthio-o-phenylenediamine (IVa):
Charged 926 mL of ethanol (9.26 V) to four neck round bottom flask at 25-35°C. Charged 100 g of 4-propylthio-2-nitroaniline (VII) (0.471 mol) and cooled the mass to 10°C. Added 65 mL of conc. hydrochloric acid (0.65 V) and stirred the mass for 15 min. Heated the reaction mass temperature to ambient temperature and slowly started addition of 156 g of iron powder. Stirred the reaction mass for 1 hr and heated the reaction mass to reflux temperature and maintained at reflux for 3 hrs. Cooled the reaction mass to room temperature and charged 1000 mL of DM water (10 V). Further, cooled the reaction mass to 10°C and adjusted the pH to 9.0-9.5 with 50% sodium hydroxide solution. Extracted the reaction mass with 1000 mL of ethylacetate (10 V) and separated the layers. Organic layer was dried over anhydrous sodium sulfate and distilled the solvent to obtain 85 g of crude 4-propylthio-o-phenylenediamine (IVa). Crude 4-propylthio-o-phenylenediamine (IVa) on fractional distillation to get 75 g of pure 4-propylthio-o-phenylenediamine (IVa).
Example-3: Preparation of Albendazole (I):
Charged 50 mL of acetone and 50 g of 4-propylthio-o-phenylenediamine (IVa) (0.274 mol) into the four neck round bottom flask at 25-35°C. Charged 53 mL of conc. hydrochloric acid (1.06 V) to the reaction mass. Heated the reaction mass to 45°C and maintained for 1 hr. Charged 50 g of sodium isocyano(methoxycarbonyl)amide (0.41 mol) to the reaction mass and further heated to 80°C to obtain solid. Solid product was filtered and washed with 500 mL of pre-heated DM water (10 V) and 500 ml of methanol and finally with 150 mL of acetone to obtain Albendazole (I).