Preparation method for bendamustine hydrochloride crude product

Abstract

The invention discloses a preparation method for a bendamustine hydrochlorichloride crude product. The preparation method comprises the steps of dissolving methyl 4-{5-[bis-(2-chloro-ethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}butyrate or ethyl 4-{5-[bis-(2-chloro-ethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}butyrate in concentrated hydrochloric acid, adding activated carbon, carrying out a reaction, performing cooling to 15-30 DEG C, and performing filtering; and adding purified water or a solution of alkali metal salts containing chloride ions to the obtained filtrate, performing cooling under stirring to -5 DEG C to 5 DEG C, continuing performing stirring for 0.5-2h, performing filtering, separately washing the obtained filtrate cake with icy purified water and icy acetone once, and performing vacuum drying at 40-50 DEG C to obtain the bendamustine hydrochlorichloride crude product. The crude product obtained by the preparation method of the invention has a purity of 99.2% or above and a yield of 75% or above. In addition, the preparation method has mild conditions, low pollution, and high yield and product purity, and is more suitable for industrial production.

Description

technical field

[0001] The invention relates to the technical field of medicine, in particular to a method for preparing crude bendamustine hydrochloride. Background technique

[0002] Bendamustine Hydrochloride. Its structural formula is as follows:

[0003]

[0004] It was originally synthesized in Germany in 1963 by Ozegowski and colleagues and was marketed under the trade name Cytostasan from 1971 to 1992. Since 1993, Ribosepharm GmbH has marketed it in Germany under the trade name Ribomustin. Bendamustine hydrochloride is currently available in the United States under the tradename Treanda (Cephalon, Inc., Frazer, PA). Bendamustine hydrochloride is an alkylating agent that has been shown to be useful in the treatment of various diseases such as chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, and breast cancer. It has therapeutic applicability in diseases.

[0005] At present, the method for preparing the crude product o...

Examples

Embodiment 1

[0027] Add 10 g of 4-{5-[bis-(2-chloro-ethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}-butyric acid methyl ester to 100 g of 36% concentrated hydrochloric acid After stirring and dissolving, add 0.5g of activated carbon, stir and raise the temperature to 95±5°C for 4 hours, lower to 15-30°C, filter, add 450g of purified water to the filtrate, continue to cool down to 2°C, stir for 1.5h, then filter, The filter cake was rinsed once with 10 g of ice-purified water and 10 g of ice-based acetone, and the filter cake was vacuum-dried at 40-50° C. for 12 hours to obtain 7.8 g of a white solid with a yield of 76.3%. The HPLC chromatographic purity of the sample was 99.43%. The content of {5-[bis-(2-chloro-ethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}-butyric acid methyl ester is 0.18%, and the maximum other impurities are 0.10%.

[0028] HPLC purity detection method

[0029] Take about 20mg of this product, put it into a 25ml volumetric flask, add a small amount of methanol to dissolve ...

Embodiment 2

[0033] Add 10 g of 4-{5-[bis-(2-chloro-ethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}-butyric acid methyl ester to 100 g of 36% concentrated hydrochloric acid After stirring and dissolving, add 0.5g of activated carbon, stir and raise the temperature to 95±5°C for 4 hours, lower to 15-30°C, filter, add 400g of saturated sodium chloride solution to the filtrate, continue to cool down to 3°C, and stir for 1.5h , filtered, the filter cake was rinsed once with 10 g of ice-purified water and 10 g of ice-based acetone, and the filter cake was vacuum-dried at 40-50 ° C for 12 hours to obtain 8.3 g of a white solid, with a yield of 81.2%, and a sample chromatographic purity of 99.24%. 4-{5-[bis-(2-chloro-ethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}-butyric acid methyl ester content 0.39%, formula III compound content 0.05% , the content of the compound of formula IV is 0.07%, the maximum other impurities are 0.14%, and the total impurities are 0.76%. HPLC purity detection condition is ...

Embodiment 3

[0035]Add 10 g of 4-{5-[bis-(2-chloro-ethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}-butyric acid methyl ester to 100 g of 36% concentrated hydrochloric acid Add 0.5g of activated carbon after stirring and dissolving, stir and heat up to 95±5°C for 4h, lower to 15-30°C, filter, add 420g of saturated potassium chloride solution to the filtrate, continue to cool down to -5°C, and stir for 1.5h After filtering, the filter cake was rinsed once with 10 g of ice purified water and 10 g of ice acetone respectively, and the filter cake was vacuum-dried at 40-50 °C for 12 hours to obtain 8.0 g of white solid, yield 78.3%, sample chromatographic purity 99.20% , 4-{5-[bis-(2-chloro-ethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}-butyric acid methyl ester content 0.48%, other maximum single hetero 0.11 %. HPLC purity detection condition is the same as embodiment 1

technical field

[0001] The invention relates to the technical field of medicine, in particular to a method for preparing crude bendamustine hydrochloride. Background technique

[0002] Bendamustine Hydrochloride. Its structural formula is as follows:

[0003]

[0004] It was originally synthesized in Germany in 1963 by Ozegowski and colleagues and was marketed under the trade name Cytostasan from 1971 to 1992. Since 1993, Ribosepharm GmbH has marketed it in Germany under the trade name Ribomustin. Bendamustine hydrochloride is currently available in the United States under the tradename Treanda (Cephalon, Inc., Frazer, PA). Bendamustine hydrochloride is an alkylating agent that has been shown to be useful in the treatment of various diseases such as chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, and breast cancer. It has therapeutic applicability in diseases.

[0005] At present, the method for preparing the crude product o...

Examples

Embodiment 1

[0027] Add 10 g of 4-{5-[bis-(2-chloro-ethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}-butyric acid methyl ester to 100 g of 36% concentrated hydrochloric acid After stirring and dissolving, add 0.5g of activated carbon, stir and raise the temperature to 95±5°C for 4 hours, lower to 15-30°C, filter, add 450g of purified water to the filtrate, continue to cool down to 2°C, stir for 1.5h, then filter, The filter cake was rinsed once with 10 g of ice-purified water and 10 g of ice-based acetone, and the filter cake was vacuum-dried at 40-50° C. for 12 hours to obtain 7.8 g of a white solid with a yield of 76.3%. The HPLC chromatographic purity of the sample was 99.43%. The content of {5-[bis-(2-chloro-ethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}-butyric acid methyl ester is 0.18%, and the maximum other impurities are 0.10%.

[0028] HPLC purity detection method

[0029] Take about 20mg of this product, put it into a 25ml volumetric flask, add a small amount of methanol to dissolve ...

Embodiment 2

[0033] Add 10 g of 4-{5-[bis-(2-chloro-ethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}-butyric acid methyl ester to 100 g of 36% concentrated hydrochloric acid After stirring and dissolving, add 0.5g of activated carbon, stir and raise the temperature to 95±5°C for 4 hours, lower to 15-30°C, filter, add 400g of saturated sodium chloride solution to the filtrate, continue to cool down to 3°C, and stir for 1.5h , filtered, the filter cake was rinsed once with 10 g of ice-purified water and 10 g of ice-based acetone, and the filter cake was vacuum-dried at 40-50 ° C for 12 hours to obtain 8.3 g of a white solid, with a yield of 81.2%, and a sample chromatographic purity of 99.24%. 4-{5-[bis-(2-chloro-ethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}-butyric acid methyl ester content 0.39%, formula III compound content 0.05% , the content of the compound of formula IV is 0.07%, the maximum other impurities are 0.14%, and the total impurities are 0.76%. HPLC purity detection condition is ...

Embodiment 3

[0035]Add 10 g of 4-{5-[bis-(2-chloro-ethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}-butyric acid methyl ester to 100 g of 36% concentrated hydrochloric acid Add 0.5g of activated carbon after stirring and dissolving, stir and heat up to 95±5°C for 4h, lower to 15-30°C, filter, add 420g of saturated potassium chloride solution to the filtrate, continue to cool down to -5°C, and stir for 1.5h After filtering, the filter cake was rinsed once with 10 g of ice purified water and 10 g of ice acetone respectively, and the filter cake was vacuum-dried at 40-50 °C for 12 hours to obtain 8.0 g of white solid, yield 78.3%, sample chromatographic purity 99.20% , 4-{5-[bis-(2-chloro-ethyl)-amino]-1-methyl-1H-benzimidazol-2-yl}-butyric acid methyl ester content 0.48%, other maximum single hetero 0.11 %. HPLC purity detection condition is the same as embodiment 1

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