97832-05-8

Usage

Uses

Used in Pharmaceutical Industry:
Bendamustine is used as an intermediate in the synthesis of Bendamustine 3-Hydroxyprop-2-yl Ester (B132550), which is an impurity of the anticancer drug Bendamustine Hydrochloride (B132500). This impurity is important for the development and manufacturing of Bendamustine Hydrochloride, a medication used to treat various types of cancer, including non-Hodgkin's lymphoma and chronic lymphocytic leukemia.
Bendamustine is used as an anticancer agent for its ability to cross-link DNA strands, leading to cell cycle arrest and apoptosis in cancer cells. This makes it a valuable component in the development of cancer treatments, particularly for patients with non-Hodgkin's lymphoma and chronic lymphocytic leukemia.

Enzyme inhibitor

This nitrogen mustard and anticancer drug (FWfree-acid = 358.26 g/mol; CAS 16506-27-7), also known by its code name SDX-105, its trade names Treanda?, Treakisym?, Ribomustin?, and Levact?, as well as by its systematic name 4-[5-[bis (2-chloroethyl) amino]-1-methylbenzimidazol-2- yl]butanoic acid, is a relatively nonspecific DNA alkylating agent that causes intra- and inter-strand cross-links. Bendamustine is used in the treatment of chronic lymphocytic leukemia (CLL), Hodgkin’s disease, non- Hodgkin’s lymphoma, multiple myeloma and lung cancer. Pharmacokinetics: After intravenous infusion, >95% of the drug becomes protein-bound, mainly to albumin; however, only free bendamustine is active. Bendamustine is metabolized by liver cytochrome p450, and elimination (renal) is biphasic, with an initial half-life of 6–10 minutes and a terminal half-life of approximately 30 minutes.

InChI:InChI=1/C16H21Cl2N3O2.ClH/c1-20-14-6-5-12(21(9-7-17)10-8-18)11-13(14)19-15(20)3-2-4-16(22)23;/h5-6,11H,2-4,7-10H2,1H3,(H,22,23);1H

Upstream product

• 109882-31-7 4-{5-[bis-(2-hydroxyethyl)amino]-1-methyl-1H-benzoimidazol-2-yl}-butanoic acid methyl ester 
• 1313020-24-4 isopropyl 4-(5-bis(2-hydroxyethyl)amino-1-methyl-1H-benzo[d]imidazol-2-yl)butanoate 
• 1313020-25-5 bendamustine isopropyl ester 
• 3543-74-6 4-{5-[bis-(2-hydroxyl-ethyl)-amino]-1-methyl-1H-benzoimidazol-2yl}-butyric acid ethyl ester 
• 109882-25-9 4-{5-[bis-(2-chloro-ethyl)amino]-1-methyl-1H-benzoimidazol-2-yl}butyric acid methyl ester 

Downstream Products

• 109882-26-0 4-(6-((2-chloroethyl)(2-hydroxyethyl)amino)-3-methylbenzimidazolyl(2))butyric acid hydrochloride 
• 109882-25-9 4-{5-[bis-(2-chloro-ethyl)amino]-1-methyl-1H-benzoimidazol-2-yl}butyric acid methyl ester 
• 1609623-12-2 4-{5-[bis-(2-chloro-ethyl)amino]-1-methyl-1H-benzoimidazol-2-yl}butyric acid cyclohexyl ester 
• 109882-30-6 4-<1-Methyl-5-benzimidazolyl-(2)>butansaeure 
• 109882-29-3 4-<1-Methyl-5-benzimidazolyl-(2)>butansaeure-hydrochlorid 

Relevant academic research and scientific papers

Discovery of a novel, efficient, and scalable route to bendamustine hydrochloride: The API in Treanda

Process Research and Development activities leading to a new and efficient route to bendamustine hydrochloride, 1, the active ingredient in Treanda, a treatment for blood cancers, are disclosed. Two key features of this new process include a one-pot hydrogenation/dehydration sequence to construct the benzimidazole moiety and a novel reductive alkylation using chloroacetic acid and borane to install the bischloroethyl side chain. The number of synthetic steps has been significantly reduced to five from the eight in the current commercial process. The overall yield has been improved from 12% to 45%. Additionally, this new route eliminates chloroform, ethylene oxide, and sodium sulfide. Scale-up of the new route has been successfully demonstrated to prepare kilogram quantities of bendamustine hydrochloride.

Bendamustine hydrochloride preparation method suitable for industrial production

The invention provides a synthetic method of bendamustine hydrochloride. According to the synthetic method, residual thionyl chloride in a chlorination reaction is removed by using a proper solvent, and water is added for crystallization after part of reaction liquid is evaporated after a hydrolysis reaction is finished, so that the generation of impurities can be obviously reduced, the product purity is improved, and the product color is improved. By adopting the method disclosed by the invention, the pure white bendamustine hydrochloride product with the purity of 99.6% or above and the single impurity content of 0.3% or below can be prepared on a laboratory scale and a production scale without refining steps and decoloration operation, the purity of the product after re-crystallization and refining can reach 99.8% or below, the single impurity content is 0.1% or below, the quality requirements of national chemical bulk drugs are met, and qualified bulk drugs can be provided for research and production of bendamustine hydrochloride for injection. The method is mild in reaction condition, safe, simple and convenient to operate and suitable for industrial large-scale production.

Purification method of bendamustine hydrochloride

The invention relates to a purification method for bendamustine hydrochloride. The purification method comprises the following steps: (1) adding an aqueous hydrochloric acid solution to a crude bendamustine hydrochloride product, carrying out stirring for dissolving, and adding active carbon for decolorization; (2) adding an inorganic alkali solution into a solution obtained in the step (1) to adjust the pH value of the solution to 1 to 4, and then carrying out cooling, recrystallizing and filtering to obtain a filter cake; and (3) leaching the filter cake obtained in the step (2), and carrying out drying to obtain bendamustine hydrochloride. By adopting the purification method, high-purity bendamustine hydrochloride can be obtained from the crude bendamustine hydrochloride product at lowtemperature and normal temperature, new impurities are prevented from being generated at high temperature, product purity is 99.8% or above, and the content of each single impurity is lower than 0.10%; and the method has the advantages of simple process, short period, refining yield of 90% or above, good product quality, capacity of meeting preparation requirements and suitability for industrial production.

Solid Forms Of Bendamustine Hydrochlorid

Solid forms of bendamustine hydrochloride are described. The invention relates to a composition containing bendamustine, a pharmaceutical composition containing the bendamustine, methods for their repeat preparation, and pharmaceutical uses thereof.

Novel Solid Forms Of Bendamustine Hydrochloride

Novel solid forms of bendamustine hydrochloride are described, as well as methods of their preparation and use.

Process for preparation of Bendamustine

The present invention relates to a method for preparation of alkyl 4-[5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazol-2-yl]butanoate (7) from 2-fluoro-5-nitroaniline, comprising the steps of: a) conversion of 2-fluoro-5-nitroaniline to 5-(2-fluoro-5-nitroanilino)-5-oxopentanoic acid (1) using glutaric anhydride, conversion of compound (1) to methylammonium 5-[2-(methylamino)-5-nitroanilino]-5-oxopentanoate (2) using methylamine; conversion of compound (2) to 5-[2-(methylamino)-5-nitroanilino]-5-oxopentanoic acid (3) and condensation of compound (3) to 4-(1-methyl-5-nitro-1H-benzimidazol-2-yl)butanoic acid (4), b) esterification of the product (4) of step a) to alkyl 4-(1-methyl-5-nitro1H-benzimidazol-2-yl)butanoate (5), c) reduction of the product of step b) to alkyl 4-(5-amino-1-methyl-1H-benzimidazol-2-yl)butanoate (6), and d) conversion of the product of step c) to alkyl 4-[5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazol-2-yl]butanoate (7).

PROCESS FOR THE PREPARATION OF BENDAMUSTINE

The present invention relates to a method for preparation of alkyl 4-[5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazol-2-yl]butanoate (7) from 2-fluoro-5-nitroaniline, comprising the steps of: (a) conversion of 2-fluoro-5-nitroaniline to 5-(2-fluoro-5-nitroanilino)-5-oxopentanoic acid (1) using glutaric anhydride, conversion of compound (1) to methylammonium 5-[2-(methylamino)-5-nitroanilino]-5-oxopentanoate (2) using methylamine; conversion of compound (2) to 5-[2-(methylamino)-5-nitroanilino]-5-oxopentanoic acid (3) and condensation of compound (3) to 4-(1-methyl-5-nitro-1H-benzimidazol-2-yl)butanoic acid (4); (b) esterification of the product (4) of step a) to alkyl 4-(1-methyl-5-nitro1H-benzimidazol-2-yl)butanoate (5); (c) reduction of the product of step b) to alkyl 4-(5-amino-1-methyl-1H-benzimidazol-2-yl)butanoate (6), and (d) conversion of the product of step c) to alkyl 4-[5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazol-2-yl]butanoate (7)

PROCESS FOR BENDAMUSTINE HYDROCHLORIDE

The present invention provides a process for the preparation of 1H-benzimidazol-1-methyl-5-N,N-di(2-hydroxyethyl)-2-butanoic acid ethyl ester. The present invention also provides a process for the preparation of bendamustine hydrochloride. The present invention further provides a process for the purification of bendamustine hydrochloride.

Process for the preparation of bendamustine hydrochloride and related compounds

The present invention relates to a process for preparing bendamustine hydrochloride, derivatives and related compounds thereof.

PROCESS FOR PREPARING BENDAMUS TINE HYDROCHLORIDE MONOHYDRATE

The present invention provide processes for the preparation of Bendamustine hydrochloride monohydrate of formula (I) The present application also provides a process of purification of Bendamustine hydrochloride or monohydrate to get substantially pure Bendamustine hydrochloride monohydrate crystalline Form-SM. The said Bendamustine hydrochloride monohydrate crystalline Form-SM is characterized by X-ray powder diffraction pattern comprising at least 5 characteristic 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, 40.89±0.1 2θ°. The present application also provides a process for the preparation of Bendamustine hydrochloride monohydrate crystalline Form-SM useful in making pharmaceutical composition for the treatment of cancer or similar proliferative disorders.