- Bendamustine hydrochloride preparation method suitable for industrial production
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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.
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- Purification method of bendamustine hydrochloride
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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.
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Paragraph 0043-0046
(2020/11/23)
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- Solid Forms Of Bendamustine Hydrochlorid
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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.
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Paragraph 0135; 0136; 0137; 0138; 0139; 0140; 0141
(2017/01/12)
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- Novel Solid Forms Of Bendamustine Hydrochloride
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Novel solid forms of bendamustine hydrochloride are described, as well as methods of their preparation and use.
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Paragraph 0099; 0100; 0101; 0102
(2016/07/05)
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- Process for preparation of Bendamustine
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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).
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- PROCESS FOR THE PREPARATION OF BENDAMUSTINE
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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)
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- PROCESS FOR BENDAMUSTINE HYDROCHLORIDE
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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.
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Paragraph 0042
(2014/05/08)
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- Process for Preparation of Intermediates of Bendamustine
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The present invention relates to a process for the preparation of 4-{5-{Bis-(2-hydroxyl-ethyl)-amino}-1-methyl-1H-Benzoimidazol-2yl}-butyric acid alkyl ester of formula IV, a key intermediate in the process for the preparation of Bendamustine HCl (I)
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- Process for the preparation of bendamustine hydrochloride and related compounds
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The present invention relates to a process for preparing bendamustine hydrochloride, derivatives and related compounds thereof.
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- PROCESS FOR PREPARING BENDAMUS TINE HYDROCHLORIDE MONOHYDRATE
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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.
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- PROCESS FOR THE PRODUCTION OF BENDAMUSTINE ALKYL ESTER, BENDAMUSTINE, AND DERIVATIVES THEREOF
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Methods are provided for the production of bendamustine alkyl ester, bendamustine, as well as derivatives thereof. With the methods the production of these compounds is possible in reproducibly high yields. To this end, hydroxyl-group-containing esters are used as the starting material, whose hydroxyl groups are substituted in a simple way by halogen groups. This substitution is possible in the presence of (i) oxalyl chloride and (ii) dialkylformamide, dialkyl acetamide or dimethyl sulfoxide. In a subsequent reaction, the resulting esters can be hydrolyzed to form the acid.
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Page/Page column 7
(2012/07/13)
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- PROCESS FOR PREPARING BENDAMUS TINE HYDROCHLORIDE MONOHYDRATE
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A process for preparing Bendamustine hydrochloride monohydrate is provided. A process for purifying said monohydrate to get substantially purne Bendamustine hydrochloride monohydrate crystalline form is also provided.
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- METHODS FOR THE PREPARATION OF BENDAMUSTINE
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Improved methods for the preparation and purification of bendamustine hydrochloride are described; such as method of preparing bendamustine hydrochloride comprising contacting a compound of formula HB1: with thionyl chloride
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Page/Page column 11
(2012/08/27)
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- PROCESS FOR BENDAMUSTINE HYDROCHLORIDE
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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.
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Page/Page column 5-6
(2013/02/28)
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- Discovery of a novel, efficient, and scalable route to bendamustine hydrochloride: The API in Treanda
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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.
- Chen, Jian,Przyuski, Katrin,Roemmele, Renee,Bakale, Roger P.
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p. 1063 - 1072
(2012/01/04)
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- PREPARATION OF BENDAMUSTINE AND ITS SALTS
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The present application relate to processes for the preparation of bendamustine and its pharmaceutically acceptable salts.
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Page/Page column 20
(2011/07/09)
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- POLYMORPHS OF BENDAMUSTINE HCL AND PROCESSES FOR PREPARATION THEREOF
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Novel polymorphs of Bendamustine HC1 have been prepared and characterized. These polymorphs and pharmaceutical compositions containing them are useful, for example, in treating patients with various cancers.
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Page/Page column 20
(2010/12/29)
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- PROCESSES FOR THE PREPARATION OF BENDAMUSTINE
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New methods for the preparation of bendamustine, and the pharmaceutical salts thereof, are described. Novel compounds useful for the preparation of bendamustine are also described.
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Page/Page column 20-21
(2010/04/28)
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