Field of the invention:

The present invention relates to an improved process for the preparation of 4-[5-[Bis(2-chloroethyl)amino]-l-methylbenzimidazol-2-yl]butanoic acid hydrochloride or 1H-Benzimidazole-2-butanoic acid, 5-[bis(2-chloroethyl)amino]-l-methyl-, monohydrochloride commonly known as "Bendamustine HC1" represented by the structural formula-1, Bendamustine is nitrogen mustard used in the treatment of Chronic Lymphocytic Leukemia (CLL) and lymphomas. It belongs to the family of drugs called alkylating agents. It was initially synthesized in 1963 in the German Democratic Republic (GDR) and was available from 1971 to 1992 for the public use under the tradename Cytostasan. Since 1992, it has been marketed in the Germany under the tradename Ribomustin®. In Mar 2010, FDA approved bendamustine HC1 for Chronic Lymphocytic Leukemia (CLL) and Indolent B-cell Non-Hodgkin's Lymphoma (NHL) and it is available in the United States under the tradename TREANDA®. It is supplied as a lypholized cake dissolved in a pharmaceutically acceptable diluent, preferably sodium chloride for injection.

Background of the Invention:

Bendamustine HC1 and its process for the preparation was first disclosed in DD34727 and J.Prakt.Chem 1963, 20, 178-186. The disclosed process involves the catalytic hydrogenation of 4-(5-nitro-l-methylbenzimidazol-2-yl)butanoic acid ethyl ester by using Raney-Ni in methanol provides 4-(5-amino-l-methylbenzimidazol-2-yl)butanoic acid ethyl ester which is then reacts with ethyleneoxide in water provides 4-[5-[Bis(2-hydroxyethyl)amino]-l-methylbenzimidazol-2-yl] butanoic acid ethyl ester . The obtained bis(hydroxyethyl) compound was reacted with thionyl chloride in chloroform provides the 4-[5-[Bis(2-chloroefhyl)amino]-l-methylbenzimidazol-2-yl] butanoic acid ethyl ester which on ester hydrolysis provides bendamustine hydrochloride. It also disclosed a process for the recrystallization of bendamustine hydrochloride from water and the product obtained is a monohydrate with a melting point of 148°-151°C.

DD159877 disclosed the improved process for the preparation of bendamustine HC1 involves the reaction of 4-[5-[Bis(2-hydroxyethyl)amino]-l-methylbenzimidazol-2-yl]butanoic acid ethyl ester (other esters include methyl, propyl or butyl) with thionyl chloride in chloroform at 0°C, and followed by destruction of excess SOCI2 with aq. HC1 and saponification of the resulting ester provides the bendamustine HC1 in 75-80% yield and with better purity.

R.Gust et al., in Monatshefte fur Chemie (1997), 128, 291-299 disclosed the known process for the preparation of bendamustine, which was performed by an eleven step sequence starting from 2,4-dinitrochlorobenzene, and the crucial conversions consisting of chlorination of 4-[5-[Bis(2-hydroxyethyl)amino]-l-methylbenzimidazol-2-yl]butanoic acid ethyl ester with SOCI2, affording 4-[5-[Bis(2-chloroethyl)amino]-l-methylbenzimidazol-2-yl]butanoic acid ethyl ester and subsequent ester hydrolysis with hydrochloric acid to obtain bendamustine hydrochloride. Under the reaction conditions employed, bendamustine hydrolyzes in small amounts to form the monohydroxy monochloro impurity (HP1) and dihydroxy impurity (HP2).

The above mentioned processes involve the usage of ethylene oxide in the preparation of bendamustine HC1, which is often not suitable for industrial scale due to the difficulty in handling ethylene oxide due to its highly toxic nature. Further, ethylene oxide is known to cause several health hazards as it is toxic by inhalation with an LD50 of 330mg/kg and is classified as potentially carcinogenic to humans by International Agency for Research on Cancer (IARC).
IP.COM journal 2009, 9(7B), 21 disclosed a process for the preparation of 4-[5-[Bis(2-hydroxyethyl)amino]-l-methylbenzimidazol-2-yl]butanoic acid ethyl ester, wherein 4-(5-amino-
l-methylbenzimidazol-2-yl)butanoic acid ethyl ester is reacted with 2-haloethanol in the presence of an inorganic base selected from the group consisting of potassium carbonate, potassium bicarbonate, sodium bicarbonate and sodium carbonate.

WO2011/079193 disclosed a process for the preparation of 4-[5-[Bis(2-hydroxyethyl) amino]-l-methylbenzimidazol-2-yl]butanoic acid isopropyl ester, wherein 4-(5-amino-1-methyl benzimidazol-2-yl)butanoic acid isopropyl ester is reacted with 2-haloethanol in the presence of an organic base selected from the group consisting of triethylamine, diisopropylamine, diisopropyl ethylamine(DIPEA), DABCO, pyridine, lutidine, 4-dimethylaminopyridine (DMAP) or N-methylmorpholine.
The above two processes disclosed i.e. IP.COM journal and WO2011/079193 and other known processes involve the multi-stage reactions for the synthesis of bendamustine hydrochloride.
WO2010/042568 and Org.Process.Res.Dev 201 J, 15, 1063-72 disclosed an improved process for the preparation of bendamustine HC1, wherein the process comprising of reductive alkylation of 4-(5-amino-l-methylbenzimidazol-2-yl)butanoic acid methyl ester hydrochloride with chloroacetic acid or chloroacetaldehyde in THF followed by the addition of reducing agents like borane-THF, sodiumcyanoborohydride, sodiumtriacetoxyborohydride or sodiumborohydride provides 4-[5-[Bis(2-chloroethyl)amino]-l-methylbenzimidazol-2-yl]butanoic acid methyl ester, which is then treated with conc.HCl to provide bendamustine HC1.

The above processes disclosed in WO2010/042568 and Org.Process.Res.Dev 2011, 15, 1063-72 involves the usage of highly explosive reducing agents like Borane-THF and metal hydrides are used which are unable to handle at commercial levels.

Therefore, there remains a need for improved process for the preparation of bendamustine hydrochloride, producing high yield and purity, and well-suited for use on an industrial scale.

Brief Description of the Invention:

The first aspect of the present invention relates to an improved process for the preparation of bendamustine hydrochloride comprising;

a) Reacting the 4-(5-Amino-l-methylbenzimidazol-2-yl)butanoic acid alkyl ester or its salts compound of formula-2,

wherein, 'R' is a C1-C4 straight or branched chain alkyl group, with 1,2-dichloroethane in presence of a base and in presence or absence of a catalyst to give compound of formula-3 or its salts,

b) hydrolyzing the compound of formula-3 in presence of hydrochloric acid to give
bendamustine hydrochloride.

The second aspect of the present invention relates to an improved process for the preparation of 4-[5-[Bis(2-chloroethyl)amino]-l-methylbenzimidazol-2-yl]butanoic acid alkyl ester or its salts compound of general formula-3 comprising of, reacting 4-(5-amino-l-methyl benzimidazol-2-yl)butanoic acid alkyl ester or its salts compound of formula-2 with 1,2-dichloroethane in presence of a base and in presence or absence of a catalyst to provide the 4-[5-[Bis(2-chloroethyl)amino]-l-methylbenzimidazol-2-yl] butanoic acid alkyl ester compound of general formula-3 or its salts.

Third aspect of the present invention is to provide a process for the preparation of bendamustine hydrochloride having purity of 99.98% and less than about 0.05% of the bendamustine related compounds HP1,HP2, Impurity-1 and Impurity-2 which comprising of:

a) Combining bendamustine hydrochloride, aqueous hydrochloric acid and acetone,
b) heating the reaction mixture,
c) cooling the reaction mixture,
d) optionally, repeating the steps (a) to (c), and
e) filtering the solid to get pure bendamustine hydrochloride.

Brief description of the drawings:

Figure-1 : Represents the powder X-ray diffractogram of bendamustine hydrochloride according to the present invention.

Figure-2 : Represents the differential scanning calorimetry of bendamustine hydrochloride according to the present invention.

Detailed description of the invention:

As used herein, the present invention, the term "suitable solvent" refers to the solvent selected from "polar solvents" such as water; "polar aprotic solvents" such as dimethylsulfoxide, dimethylacetamide, dimethyl formamide and the like; "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like; "ether solvents" such as di-tert-butylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane; "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t- butanol and the like; "chloro solvents" such as methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, chloro benzene and the like; "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane; "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like; "esters solvents" such as ethyl acetate, methyl acetate, n-butylacetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; and their mixtures thereof.

As used herein the present invention, the term "base" refers to inorganic or organic base. An "inorganic base" is an inorganic compound, which acts as a base.Examples of such bases include, but are not limited to, hydrides, hydroxides, carbonates, bicarbonates, oxides, carboxylates, and alkoxides of alkali or alkaline earth metals, such as lithium hydride, sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, calcium oxide, and barium oxide or ammonium hydroxide. Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof;

An "organic base" is an organic compound, which acts as a base. Examples of such bases
include, but are not limited to, triethylamine, diisopropylamine, Hunig's base, DABCO,
triethanol amine, tributyl amine, pyridine, lutidine, 4-dimethylaminopyridine (DMAP),
diethanolamine, 4-methylmorpholine, dimethylethanolamine, tetramethyl guanidine, tetramethyl
ammonium hydroxide, tetraethylammonium hydroxide, N-methyl-1,5,9-
triazabicyclo[4.4.0]decene, 1 ,8- diazabicyclo[5.4.0]undec-7-ene, dicyclohexyl amine, and picoline.
The first aspect of the present invention provides an improved process for the preparation of bendamustine HO compound of formula-1 which comprises ot;

a) Reacting the 4-(5 -Amino- l-methylbenzimidazol-2-yl)butanoic acid alkyl ester or its salts compound of formula-2;
wherein R is a C1-C4 straight or branched chain alkyl group, with 1,2-dichloroethane in presence of a base and in presence or absence of a catalyst to give a compound of formula-3 or its salts ;
b) hydrolyzing the compound of formula-3 or its salts in presence of hydrochloric acid to give bendamustine hydrochloride.

Wherein, in step a) involves reacting a compound of formula-2 or its salts with 1,2-dichloroethane in presence of a base to give a compound of formula-3 or its salts. The starting compound of formula-2 may be obtained by known processes including the process disclosed in DD34727 and Org. Process Res. Dev. 2011, 15, 1063-1062, Huaxue Shiji (2010), 32(8), 753-755, Chinese Journal of New Drugs, vol. 16, (23), pp. 1960-1961,1970, 2007. Typical amounts of 1,2-dichloroethane that are used in step a) ranges from about 2 to 40 molar equivalents or preferably 10 to 25 molar equivalents, per molar equivalent of the compound of formula-2 or its salts.

Wherein, in step-(a) the bases that are used may be selected from inorganic bases such as alkaline metal hydroxides, metal carbonates, metal bicarbonates, alkaline earth metal hydroxides, metal alkoxides and metal hydrides or the like may be used in step a). Organic bases such as triethylamine, diisopropylamine, diisopropylethylamine, DABCO, Pyridine, Lutidine, 4-Dimethylaminopyridine,4-Methylmorpholine or the like may be used as the base in step a). In particular embodiments, triethylamine, diisopropyl amine, diisopropylethylamine is used as the base in step a). Wherein, step a) is optionally carried out in presence of a potassium iodide catalyst.

The reaction may be carried out at temperatures ranging from about 25°C to about 110°C or from about 70°C to about 100°C. After completion of the reaction, the compound of general formula-3 or its salts thereof may be isolated and optionally purified. In an embodiment, the reaction mixture was extracted with suitable solvent and concentrated under reduced pressure to a minimum volume. The reaction mixture thus obtained was added to the suitable solvent and heated to 50-55°C for 1 hr and filtered the reaction mixture and concentrated the reaction mixture and cooled the reaction mixture to 15°C and filtered the solid and washed with suitable solvent and dried to get the pure compound of general formula-3 having purity greater than 98% by HPLC with not detected levels of 4-[5-(2-chloroethyl)amino]-l-methylbenzimidazol-2-yl]butanoic acid methyl ester (Impurity I) and 4-(5-Amino-l-methylbenzimidazol-2-yl)butanoic acid methyl ester (amine impurity).

The Step-(b) involves hydrolyzing the compound of general formula-3 or its salts thereof to provide bendamustine hydrochloride. The hydrolysis of the compound of general formula-3 can be carried out using hydrochloric acid to provide bendamustine hydrochloride compound of formula-1. The reaction may be carried out at temperatures ranging from about 0°C to about 100°C. After completion of the reaction bendamustine HC1 can be isolated according to the known processes.
The preferred embodiment of the present invention provides an improved process for the preparation of bendamustine HC1 compound of formula-1 comprises of the following steps, a) Reacting the hydrochloride salt of 4-(5-amino-l-methylbenzimidazol-2-yl)butanoic acid methyl ester compound of formula-2a, with 1,2-dichloroethane in presence of diisopropylethylamine (DIPEA) and a catalyst preferably potassium iodide to provide the 4-[5-[Bis(2-chloroethyl)amino]-l-methylbenz imidazol-2-yl]butanoic acid methyl ester compound of formula-3 a,
b) hydrolyzing the 4-[5-[Bis(2-chloroethyl)amino]-l-methylbenzimidazol-2-yl]butanoic acid methyl ester compound of formula-3a with conc.HCl to provide bendamustine hydrochloride compound of formula-1.

The second aspect of the present invention provides an improved process for the preparation of 4-[5-[Bis(2-chloroethyl)amino]-l-methylbenzimidazol-2-yl]butanoic acid alkyl ester compound of general formula-3 comprising of, reacting the 4-(5-amino-l-methylbenzimidazol-2-yl)butanoic acid alkyl ester compound of general formula-2 or its salts, wherein 'R' is C1-C4 straight or branched alkyl group; with 1,2-Dichloroethane in the presence of a base and in presence or absence of a catalyst to provide 4-[5-[Bis(2-chloroethyl)amino]-l-methylbenzimidazol-2-yl]butanoic acid alkyl ester compound of general formula-3 or its salts.

The preferred embodiment of the present invention is to provide an improved process for the preparation of 4-[5-[Bis(2-chloroethyl)amino]-l-methylbenzimidazol-2-yl]butanoic acid methyl ester compound of formula-3a comprising of, reacting the 4-(5-amino-l-methyl benzimidazol-2-yl)butanoic acid methyl ester hydrochloride compound of formula-2a, with 1,2-dichloroethane in presence of diisopropylethylamine (DIPEA) and a catalyst preferably potassium iodide to provide the 4-[5-[Bis(2-chloroethyl)amino]-l-methylbenzimidazol-2-yl]butanoic acid methyl ester compound of formula-3a.
Third aspect of the present invention is to provide a process for the preparation of bendamustine hydrochloride having the purity 99.8% and less than about 0.05% of the bendamustine related compounds mono chloro mono hydroxy impurity (HP1), dihydroxy impurity (HP2), mono substituted impurity(Impurity-l) and methyl ester impurity (Impurity-2) having the structures shown below:

which comprises of:

a) Combining bendamustine hydrochloride , aqueous hydrochloride, and acetone,
b) heating the reaction mixture,
c) cooling the reaction mixture,
d) optionally repeating the steps (a) to (c), and
e) filtering the solid to get the pure bendamustine hydrochloride.

In another aspect, the present invention provides bendamustine hydrochloride which is substantially free from 1,2-dichloroethane.

In another aspect, the present invention provides bendamustine hydrochloride characterized by powder X-ray diffraction pattern substantially as depicted in figure-1.

In another aspect, the present invention provides bendamustine hydrochloride characterized by differential scanning calorimetry pattern substantially as depicted in figure-2.

The purity of bendamustine hydrochloride and its related substances or impurities may be analyzed by various methods. A representative useful HPLC method is described as follows:


In another aspect, the residual solvents and 1,2-dichloroethane present in the bendamustine hydrochloride are analyzed by the useful GC method, in which the chromatographic conditions are as follows:


The present invention schematically represented as follows:

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples

Example-1: Preparation of 4-(2,4-Dinitrophenylcarbamoyl)butyric acid methyl ester.
311.5 gm of glutaric anhydride was added to 775 ml of methanol under N2 atmosphere at 25-35°C and stirred the reaction mixture for 10 min at same temperature. 2.95 gms of sodium methoxide was added to the reaction mixture at 25-35°C under N2 atmosphere and stirred the reaction mixture for 5 hrs. After completion of the reaction, distilled of the reaction mixture completely under reduced pressure and 250 ml of toluene was added to the reaction mixture and cooled the reaction mixture to 20-25°C. 389 ml of thionyl chloride was slowly added to the reaction mixture at 20-25°C under N2 atmosphere for 45 minutes and stirred the reaction mixture for 3 hrs at same temperature and distilled off the reaction mixture completely under reduced pressure to obtain the residue. The obtained residue was slowly added to the reaction mixture containing 2500 ml of toluene and 250 gms of 2,4-Dinitroaniline at 20-25°C over a period of 30 min and heated the reaction mixture to reflux temperature and maintained for 4 hrs. After completion of the reaction cooled the reaction mixture to 40-50°C and water was added to it. Distilled off the reaction mixture under reduced pressure to become minimum volume and cooled the reaction mixture to 20-25°C and stirred for 30 min. Filtered the solid obtained and washed with water. Dried the compound at 40-50°C for 10 hrs. to provide the title compound. Yield: 405 gm.

Example-2: Preparation of 4-[(2,4-Dinitrophenyl)methylcarbamoyl]butyric acid methyl ester.
600 ml of acetonitrile was added to 300 gm of 4-(2,4-Dinitrophenylcarbamoyl)butyric acid methyl ester at 30-35°C under N2 atmosphere. 266 gms of potassium carbonate was added to the reaction mixture at 30-35°C and stirred for 10 min, 138.2 gms of dimethyl sulfate was added to the reaction mixture at same temperature and stirred the reaction mixture for at 30-35°C for 5 hrs. After completion of the reaction, filtered the reaction mixture . The obtained filtrate was slowly added to 5100 ml of water at 25-30°C over a period of 90 min and stirred the reaction mixture at same temperature for 90 min. Filtered the solid obtained and washed with water. The above obtained solid and methanol were charged to the round bottom flask and heated the reaction mixture to reflux temperature and stirred for 20 min. Cooled the reaction mixture to 10-15°C and stirred for 1 hr at same temperature. Filtered the solid obtained and washed with methanol and dried the solid obtained at 35-40°C for 5 hrs to get the title compound. Yield : 290gms.

Example-3: Preparation of 4-(5-Amino-l-methylbenzimidazol-2-yI)butanoic acid methyl ester hydrochloride.

To a clean and dry autoclave with N2 atmosphere was charged with 100 gms of 4-[(2,4-Dinitrophenyl)methylcarbamoyl]butyric acid methyl ester, 1000 ml of methanol and 40 gms 5% Pd/C (50% wet). The reaction mixture was heated to 40-50°C and the resulting reaction mixture was subjected to hydrogenation with 4.5 kg of hydrogen gas at 40-50°C for 6 hrs. After completion of the reaction, filtered the reaction mixture through hi-flow bed . 30 ml of conc.HCl was added to the filtrate and heated the reaction mixture to reflux and stirred for 3 hrs at reflux temperature. After completion of the reaction, the reaction mixture was cooled to 45-50°C and activated carbon was added to the reaction mixture at 45-50°C and stirred the reaction mixture for 30 min and filtered the reaction mixture through hi-flow bed. Distilled off the filtrate under reduced pressure to get the residue and methanol was added to the obtained residue at 20-30°C and stirred the reaction mixture for 20 min. Tetrahydrofuran was slowly added to the reaction mixture at 25-30°C over a period of 60 min and cooled the reaction mixture to 10-15°C and stirred for 90 min. Filtered the solid obtaine and washed with tetrahydrofuran and dried the obtained solid at 35-45°C for 6 hrs to provide the title compound. Yield: 80 gms.

Example-4: Preparation of 4-[5-[Bis(2-chloroethyl)amino]-l-methylbcnzimidazol-2-yl] butanoic acid methyl ester compound of formula-3a.

100 gms of 4-(5-Amino-l-methylbenzimidazol-2-yl)butanoic acid methyl ester. HC1 and 555 ml of 1,2-Dichloroethane are charged into the round bottom flask at 25-35°C. 136 gms of Diisopropyl ethylamine and 2.3 gms of potassium iodide are added to the above reaction mixture and heated the reaction mixture to 90-100°C and maintain the temperature of the reaction mixture at same temperature for 50 hrs. After completion of the reaction, the reaction mixture was cooled to 20-30°C and dichloromethane was added to the reaction mixture. Sodium bicarbonate solution was added to the reaction mixture and stirred for 10 min and both the organic and aqueous layers were separated. The organic layer was washed with 10% sodium thiosulfate solution. Organic layer was dried with sodium sulfate and distilled off the organic layer completely under reduced pressure to get the residue. 100 ml of Dichloromethane and 500 ml of methyl tert-butyl ether were added to the above residue and heated the reaction mixture to 50-60°C and stirred for 60 min. Filtered the reaction mixture through hi-flow bed and washed the hi-flow bed with hot methyl tert-butyl ether. Distilled off the filtrate completely under the reduced pressure to get the residue. 60 ml of methyl tert-butyl ether was added to the residue and cooled to 0-5°C and stirred the reaction mixture at 0-5°C for 60 min and filtered the solid obtained and washed with n-heptane. The obtained solid and 600 ml of methyl tert-butyl ether was added to round bottom flask and heated for 50-60°C for 80 min. Activated carbon was added to the reaction mixture and stirred for 20 min at same temperature. Filtered the reaction mixture through hi-flow bed and distillled off the filtrate completley under reduced pressure. 50 ml of Methyl tert-butyl ether was added to the obtained residue at 25-35°C and 50 ml of n-heptane was slowly added to the reaction mixture for 30 min and cooled the reaction mass to 0-5°C and stirred for 2 hrs. Filtered the reaction mixture and washed the solid obtained with n-heptane. Dried the solid obtained at 30°C for 3 hrs. Yield : 25 g ; amine impurity : Not detected, Impurity-I: 0.01%

Example-5: Preparation of Bendamustine hydrochloride hydrate.

16.5 gms of 4-[5-[Bis(2-chloroethyl)amino]-l-methylbenzimidazol-2-yl] butanoic acid methyl ester and 66 ml of conc.HCl was added to the round bottom flask and heated the reaction mixture to 90-100°C and stirred the reaction mixture for 6 hrs at same temperature. After completion of the reaction, cooled the reaction mixture to 50-60°C and activated carbon was added to the reaction mixture and stirred for 15 min. Filtered the reaction mixture through hi-flow bed and distilled off the filtrate to half of the volume and 99 ml of water was added to the reaction mixture. Cooled the reaction mixture to 0-5°C and stirred for 30 min and filtered the solid and washed with acetone. Dried the solid compound obtained at 35-45°C for 4 hrs. Yield: 14.32 g ; water content: 5.70 %, Impurity-I: 0.02%, Impurity-II: 0.01 %

Example-6: Preparation of crystalline Bendamustine hydrochloride monohydrate.

110 ml of acetone and 11 ml of Dil.HCl was charged into the round bottom flask and heated the reaction mixture to 40 - 45°C. 11 g of Bendamustine hydrochloride hydrate was added to the reaction mixture at 40 - 45°C and stirred the reaction mixture at same temperature for 15 min and cooled the reaction mixture to 0-5°C and maintained for 20 min at the same temeprature. Filtered the solid and washed with acetone. To the obtained wet material 99 ml of acetone and 9 ml of dil.HCl was added and heated the reaction mixture to 40 - 45°C and stirred for 15 min. The reaction mixture was cooled to 0-5°C and stirred for 20 min at 0-5°C and filtered the solid and washed with acetone. Dried the obtained solid for 30-40°C for 4 hrs to provide bendamustine hydrochloride monohydrate in crystalline form.

Yield : 10.2g , Purity by HPLC : 99.80%, water content : 4.20 %, HP1 : Not detected, HP2 : 0.01%, Impurity-1: Not detected, Impurity-2 : Not detected, 1,2-dichloroethane : not detected,
Example-7: Preparation of 4-[5-[Bis(2-chloroethyl)amino]-l-methylbenzimidazol-2-yl] butanoic acid methyl ester compound of formu!a-3a.

4-(5-amino-l-methylbenzimidazol-2-yl) butanoic acid methyl ester (4.0 g), 1,2-dichloro ethane (35 ml), diisopropyl ethylamine (5.46 gm) and potassium iodide (0.12 gm) were charged into a round bottom flask and stirred. The reaction mixture was heated to about 95-100°C for 30 hrs. After completion of the reaction, the reaction mixture was cooled to 20° to 30°C. Dichloromethane (20 ml) was added to the reaction mixture followed by the addition of water (20 ml). Stirred the reaction mixture for 10 min and both aqueous and organic layers were separated. Extracted the aqueous layer with dichloromethane (20 ml) and organic layers were combined and concentrated under reduced pressure. Methyl tertiary butyl ether (15 ml) was added to the obtained residue and heated to 55°C and stirred for 30 min. The reaction mixture was filtered through high flow bed and the filtrate was concentrated up to 50% of the volume. Cooled the reaction mixture to 10 to 15°C and filtered the precipitated solid. The obtained solid was washed with methyl tertiary butyl ether and dried to get the title compound. Yield: 3.0 grams

Example-8: Preparation of Bendamustine hydrochloride

4-[5-[Bis(2-chloroethyl)amino]-l-methylbenzimidazol-2-yl] butanoic acid methyl ester (2 g) was charged into a round bottom flask and hydrochloric acid solution (10 ml) was slowly added. The mixture is slowly heated to reflux temperature and stirred for 3 hrs. The reaction mixture was concentrated under reduced pressure at about 60°C. Water (10 ml) was added to the obtained reaction mixture and stirred for about 1 hr. Filtered the precipitated solid and washed with water. Dried the obtained solid to get the bendamustine hydrochloride. Yield: 1.5 grams

We Claim:

1. A process for the preparation of bendamustine hydrochloride comprising of:

a) Reacting the 4-(5-Amino-l-methylbenzimidazol-2-yl)butanoic acid alkyl ester
compound of formula-2 or its salts, wherein 'R' is a C1-C4 straight or branched chain alkyl group,
with 1,2-dichloroefhane in presence of a base and in presence or absence of a catalyst to provide 4-[5-[Bis(2-chloroethyl)amino]-l-methylbenzimidazoI-2-yl]butanoic acid alkyl ester compound of formula-3 or its salts,

b) hydrolyzing the compound of formula-3 or its salts in presence of hydrochloric acid
to give bendamustine hydrochloride formula-1.

2. The process according to claim 1, wherein the base is selected from organic bases such as pyridine, diisopropyl amine, diisopropylethyl amine, triethylamine, lutidine, dimethylaminopyridine, 4-mefhyl morpholine, l,4-diazabicyclo[2.2.2]octane (DABCO) and l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU).

3. The process according to claim 1, wherein the base is inorganic base selected from hydrides, hydroxides, carbonates and alkoxides of alkali or alkaline earth metals such as sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, calcium carbonate, cesium carbonate, sodium methoxide and potassium tert-butoxide.

4. The process according to claim 1, wherein, the step-(a) is optionally carried out in presence of potassium iodide catalyst.

5. The process according to claim 1, wherein, the amount of 1,2-dichloroethane used in step-(a) ranges from about 10 to 25 molar equivalents per molar equivalent of the compound of formula-2 or its salts.

6. A process for the preparation of bendamustine hydrochloride comprising of:

a) Reacting the hydrochloride salt of 4-(5-Amino-l-methylbenzimidazol-2-yl)butanoic
acid methyl ester compound of formula-2a Formula-2a with 1,2-dichloroethane in presence of diisopropyl ethylamine and potassium iodide to provide 4-[5-[Bis(2-chloroethyl)amino]-l-methylbenzimidazol-2-yl] butanoic acid methyl ester compound of formula-3a,

b) hydrolyzing the compound of formula-3a in presence of hydrochloric acid to give
bendamustine hydrochloride.

7. A process for the preparation of compound of formula-3 or its salts wherein 'R' is a CrC4 straight or branched chain alkyl group; which comprises of, reacting the compound of formula-2 or its salts with 1,2-dichloroethane in presence of a suitable base and in presence or absence of a catalyst to provide the compound of formula-3 or its salts.

8. A process for the preparation of bendamustine hydrochloride having purity 99.8% and less than about 0.05% of each bendamustine related compounds HP1,HP2, Impurity-I and Impurity-II, comprising of:

a) Combining bendamustine hydrochloride, aqueous hydrochloric acid and acetone,
b) heating the reaction mixture,
c) cooling the reaction mixture,
d) optionally, repeating the steps-(a) to step-(c), and
e) filtering the solid to get pure bendamustine hydrochloride.

9. The Bendamustine hydrochloride obtained from the preceding claims is substantially free from 1,2-dichloroethane.

10. Bendamustine hydrocholoride obtained from the preceding claims is characterized by powder X-ray diffraction pattern as depicted in figure-1 and also characterized by differential scanning calorimetry as depicted in figure-2.