Highly pure bendamustine hydrochloride monohydrate

Bendamustine hydrochloride monohydrate crystalline Form-SM characterized by X-ray powder diffraction pattern consisting of peaks selected from the XRPD 2 theta degrees peaks at 7.42, 10.60, 11.17, 16.43, 17.94, 22.89, 26.33, 28.77, 30.28, 31.92 and 40.89±0.1 2θ° having a purity of greater than 99.5% (by HPLC) prepared by a process comprising the steps of—

• a) reacting the crude Bendamustine or its pharmaceutically acceptable salts and their hydrates thereof obtained from any source with diluted aqueous hydrochloric acid solution;
• b) heating the contents up to a temperature ranging between 40 to 65° C.;
• c) maintaining the reaction mass at heated temperature of step b) till desired acceptable purity profile is attained;
• d) cooling the mass to ambient temperature and stirring for time between 1 to 4 hours;
• e) isolating the product as substantially pure crystalline Form-SM;
• f) optionally repeating the steps b) to e).

A process of preparation of crystalline Bendamustine hydrochloride monohydrate crystalline Form-SM having a purity of greater than 99.5% (by HPLC) of formula (I),

• comprising the steps of—
• a) reacting 2,4-dinitrochlorobenzene (VIII) with aqueous methyl amine solution in alcohol solvent to isolate N-methyl-2,4-dinitroaniline (VII);
• b) selectively reducing N-methyl-2,4-dinitroaniline (VII) to isolate N1-methyl-4-Nitrobenzene-1,2-diamine (VI);
• c) reacting N1-methyl-4-Nitrobenzene-1,2-diamine (VI) with Dihydro-2H-pyran-2,6(3H)-dione in isopropyl alcohol to isolate Isopropyl 4-(1-methyl-5-nitro-1/H-benzo[d]imidazol-2-yl) butanoate (V);
• d) selectively reducing the Isopropyl 4-(1-methyl-5-nitro-1/H-benzo[d]imidazol-2-yl) butanoate (V) with metal reducing agent to isolate Isopropyl 4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl) butanoate (IV);
• e) hydroxyethylating the Isopropyl 4-(5-amino-1-methyl-1H-benzo[d]imidazol-2-yl) butanoate (IV) in presence of Diisopropylethylamine (DIPEA) and haloethanol to get Isopropyl 4-(5-bis(2-hydroxyethyl)amino-1-methyl-1H-benzo[d]imidazol-2-yl)butanoate (III);
• and
• f) chlorinating the Isopropyl 4-(5-bis(2-hydroxyethyl)amino-1-methyl-1H-benzo[d]imidazol-2-yl)butanoate (III) with a chlorinating agent and de-esterifying, followed by hydrochlorinating to isolate the Bendamustine HCl monohydrate of formula-I;
• wherein hydrochlorinating in diluted aqueous hydrochloric acid solutions comprising addition of diluted aqueous hydrochloric acid solutions—
• i. the reaction mass is heated up to a temperature ranging between 40 to 65° C.;
• ii. maintaining the reaction mass at heated temperature till desired acceptable purity profile is attained;
• iii. cooling the mass to ambient temperature and stirring for time between 1 to 4 hours;
• and
• iv. isolating the crystalline Bendamustine hydrochloride monohydrate in Form-SM.