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Preparation method of impurity HP1 in bendamustine hydrochloride

A technology of bendamustine hydrochloride and impurities, applied in the field of medicinal chemistry, to achieve the effect of high product purity and simple preparation method

Inactive Publication Date: 2013-10-16
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

) reported the use of in situ hydrolysis of bendamustine hydrochloride to detect, separate and analyze the method of HP1, there is no public information reported the synthesis method of impurity HP1

Method used

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  • Preparation method of impurity HP1 in bendamustine hydrochloride
  • Preparation method of impurity HP1 in bendamustine hydrochloride
  • Preparation method of impurity HP1 in bendamustine hydrochloride

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preparation example Construction

[0028] The preparation method of bendamustine hydrochloride impurity HP1 comprises the following steps:

[0029] In the first step, [1-methyl-2-(4'-butyric acid ethyl)-5-amino]-1H-benzimidazole is used as the starting material, and the organic acid aqueous solution of C1~C4 is used as the solvent, React with ethylene oxide, adjust the pH after the reaction, extract the organic phase, wash, dry, and separate to obtain [1-methyl-2-(4'-butyric acid ethyl)-5-N-(2'-hydroxy Ethyl)]-1H-benzimidazole:

[0030]

[0031] Wherein, the molar ratio of [1-methyl-2-(4'-butanoic acid ethyl)-5-amino]-1H-benzimidazole to ethylene oxide is 1:1-2, preferably 1:1 ; The organic acid of C1~C4 is selected from one of formic acid, acetic acid, propionic acid, oxalic acid or n-butyric acid, preferably acetic acid; the solvent is preferably an aqueous solution of acetic acid with a volume ratio of 1:1; the reaction temperature is -10°C-5°C , preferably 0°C-5°C; the reaction time is 1h-6h.

[0032]...

Embodiment 1

[0041] Step 1: Preparation of [1-methyl-2-(4'-butyric acid ethyl)-5-N-(2'-hydroxyethyl)]-1H-benzimidazole

[0042] Add 10.0 g of [1-methyl-2-(4'-butanoic acid ethyl)-5-amino]-1H-benzimidazole, 50 mL of water, and 50 mL of acetic acid into a 200 mL single-necked bottle, and stir for 30 minutes, then add 4.0 mL of ethylene oxide, react in an ice-water bath for 4 hours, stop the reaction, adjust the pH to 7-8 with ammonia water, extract the reaction solution with dichloromethane (100 mL×2), and combine the organic phases. The organic phase was washed with saturated sodium chloride solution (80 mL×2), and dried over anhydrous sodium sulfate. Column chromatography (eluent: dichloromethane:methanol=100:2) separated to obtain 2.2g of the product (yellow oily liquid).

[0043] ESI-MS m / z:306.1[M+H + ] + .

[0044] The second step: preparation of [1-methyl-2-(4'-butyric acid ethyl)-5-N-(2'-chloroethyl)]-1H-benzimidazole

[0045]Add 2.2 g of [1-methyl-2-(4'-butyric acid ethyl)-5-N-...

Embodiment 2

[0054] Step 1: Preparation of [1-methyl-2-(4'-butyric acid ethyl)-5-N-(2'-hydroxyethyl)]-1H-benzimidazole

[0055] Add 10.0 g of [1-methyl-2-(4'-butanoic acid ethyl)-5-amino]-1H-benzimidazole, 50 mL of water, and 50 mL of formic acid in sequence into a 200 mL single-necked bottle, and stir at -10°C After 30 minutes, add 4.0 mL of ethylene oxide, react at -10°C for 1 hour, stop the reaction, adjust the pH to 7-8 with ammonia water, extract the reaction solution with dichloromethane (100 mL×2), and combine the organic phases. The organic phase was washed with saturated sodium chloride solution (80 mL×2), and dried over anhydrous sodium sulfate. The product (yellow oily liquid) was separated by column chromatography (eluent: dichloromethane:methanol=100:2).

[0056] The second step: preparation of [1-methyl-2-(4'-butyric acid ethyl)-5-N-(2'-chloroethyl)]-1H-benzimidazole

[0057] Add 2.2 g of [1-methyl-2-(4'-butyric acid ethyl)-5-N-(2'-hydroxyethyl)]-1H-benzimidazole and 100 mL...

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Abstract

The invention discloses a preparation method of an impurity HP1 in bendamustine hydrochloride. The preparation method comprises the step of using [1-methyl-2-(4'-ethyl carbethoxy)-5-amino]-1H-benzimidazole as a starting raw material to prepare [1-methyl-2-(4'-acidyl)-5-N-(2'-hydroxy-ethyl)-N'-(2'-chloro-ethyl)]-1H-benzo imidazole, namely the HP1. The preparation method of the impurity HP1 in the bendamustine hydrochloride is simple, the prepared product has the advantage of high purity, and a qualified reference is provided for the quality control of the bendamustine hydrochloride.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of bendamustine hydrochloride impurity HP1. Background technique [0002] Bendamustine hydrochloride (bendamustine hydrochloride) is an alkylating antineoplastic drug developed by Merckle Company, which was launched in Germany in October 2003 under the trade name Ribomustin. Salmedix has been authorized to develop in the United States and Canada, the trade name is Treanda (SDX2105), and it is currently in Phase III clinical trials. [0003] Impurity HP1 (formula I) is one of the common impurities in bendamustine hydrochloride. Except for the literature (Monatshefte für Chemie, 1997, 128, 291-299.) which reported the method of using in situ hydrolysis of bendamustine hydrochloride to detect, separate and analyze HP1, there is no published material reporting the synthesis method of impurity HP1. Quality analysis of bendamustine hydrochloride mus...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/16
Inventor 诸海滨
Owner SOUTHEAST UNIV
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