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Bendamustine hydrochloride preparation method suitable for industrial production

A bendamustine hydrochloride compound technology, applied in the field of preparation of bendamustine hydrochloride raw materials, can solve the problems of unqualified products, long heating and concentration time, and many dimer impurities

Active Publication Date: 2021-04-09
深圳万乐药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The dimer impurity b has poor water solubility, and when bendamustine hydrochloride is crystallized with water, it is precipitated at the same time and is difficult to remove, resulting in unqualified products
Especially in the large-scale production, the heating and concentration time is longer, and the generated dimer impurities are more, so it is difficult to obtain qualified products after the large-scale production
[0016] Therefore prior art is not suitable for being enlarged to workshop production, needs to further optimize reaction process condition, obtains the bendamustine hydrochloride crude drug that can be prepared in scale-up production and obtains purity and impurity all reaching quality standard and color qualified, to further prepare To ensure the safe use of bendamustine hydrochloride products for patients

Method used

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  • Bendamustine hydrochloride preparation method suitable for industrial production
  • Bendamustine hydrochloride preparation method suitable for industrial production
  • Bendamustine hydrochloride preparation method suitable for industrial production

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Preparation and refining (60g scale) of embodiment 1 bendamustine hydrochloride

[0042] 1) Preparation of ethyl 4-{5-[bis-(2-hydroxyethyl)amino]-1-methyl-2-benzimidazole}butyrate

[0043] Stir and dissolve ethyl 5-amino-1-methyl-1H-2-benzimidazole butyrate (60g, 0.23mol), 600mL of water, and 300mL of glacial acetic acid in a 2L reaction flask, cool to -5~0°C, Add 120mL ethylene oxide, and control the temperature until the reaction is complete. The potassium carbonate solution adjusted the pH to 7.0-7.3, extracted with 300 mL×3 dichloromethane, combined the organic phases, washed with 200 mL×3 purified water, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown solid. Then add 1200mL ethyl acetate and heat to 70-80°C to dissolve, cool to room temperature to crystallize, filter and dry to obtain 63g of light brown solid with a purity of 99.3%. Yield 78.5%.

[0044] 2) Preparation of ethyl 4-{5-[bis-(2-chloroethyl)amino]-1-methyl-2-benzi...

Embodiment 2

[0050] The preparation of embodiment 2 bendamustine hydrochloride (60g scale)

[0051] 1) Preparation of ethyl 4-{5-[bis-(2-chloroethyl)amino]-1-methyl-2-benzimidazole}butyrate

[0052] 4-{5-[bis-(2-hydroxyethyl)amino]-1-methyl-2-benzimidazole} ethyl butyrate (60g, 0.17mol) prepared according to the method of Example 1 step (1) ) with 600mL of dichloromethane dissolved in a 2L reaction flask, cooled to -5 ~ 0°C, 30mL of thionyl chloride was added dropwise, and reacted at room temperature for 2 hours after the dropwise reaction was complete. Add 300 mL of dichloromethane to the yellow oil, stir to precipitate a solid, and dry in vacuo to obtain 61 g of a light gray solid. Yield 92%.

[0053] 2) preparation of bendamustine hydrochloride

[0054] Add 60g of the solid obtained in the previous step and 600mL of concentrated hydrochloric acid to the reaction flask equipped with tail gas absorption, and heat to reflux for 4 hours. After the reaction is completed, cool to room temp...

Embodiment 3

[0055] The preparation of embodiment 3 bendamustine hydrochloride (60g scale)

[0056] 1) Preparation of ethyl 4-{5-[bis-(2-chloroethyl)amino]-1-methyl-2-benzimidazole}butyrate

[0057] 4-{5-[bis-(2-hydroxyethyl)amino]-1-methyl-2-benzimidazole} ethyl butyrate (60g, 0.17mol) prepared according to the method of Example 1 step (1) ) with 600mL of dichloromethane dissolved in a 2L reaction flask, cooled to -5 ~ 0°C, 30mL of thionyl chloride was added dropwise, and reacted at room temperature for 2 hours after the dropwise reaction was complete. Add 360 mL of acetone to the yellow oil, stir to precipitate a solid, and dry in vacuo to obtain 59 g of a light gray solid. Yield 89.5%.

[0058] 2) preparation of bendamustine hydrochloride

[0059] In the reaction bottle equipped with tail gas absorption, add 59g of the solid obtained in the previous step, 600mL of concentrated hydrochloric acid, and heat to reflux for 4h. After the reaction is completed, cool to room temperature and ...

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Abstract

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.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of a bendamustine hydrochloride crude drug. Background technique [0002] Bendamustine hydrochloride is a bifunctional alkylating agent with a new mechanism of action, which has antitumor and cytocidal effects. It was first developed in the early 1960s by Ozegowski and colleagues at the Microbiological Experimental Association of the University of Jena, Germany. The main mechanism is that DNA single strands and double strands are cross-linked by alkylation, which disrupts the function of DNA and DNA synthesis, and also causes cross-links between DNA and proteins, as well as between proteins and proteins, thereby exerting anti-tumor effects . Bendamustine hydrochloride injection is used alone or in combination with other antineoplastic drugs to treat diseases such as Hodgkin's disease, non-Hodgkin's lymphoma, plasmacytoma (multiple myeloma), chronic lympho...

Claims

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Application Information

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IPC IPC(8): C07D235/16
CPCC07D235/16
Inventor 罗名汉侯常林王长平阳怡林卓秋琪于玉根
Owner 深圳万乐药业有限公司
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