Method for synthesizing highly-pure bendamustine hydrochloride

Abstract

The invention discloses a method for synthesizing highly-pure bendamustine hydrochloride, which comprises the following steps: taking [1-methy-2(4'-ethyl butyrate)-5-amino]-1H-benzimidazole as a raw material; and orderly reacting the [1-methy-2(4'-ethyl butyrate)-5-amino]-1H-benzimidazole with ethylene oxide and phosphorus oxychloride through the four steps of substitution, hydrolysis, salification and refinement so as to produce the bendamustine hydrochloride. The method in the invention is mild in condition, simple in operation, short in synthesis period and suitable for scaled-up industrial production; and the purity of the synthesized bendamustine hydrochloride is over 99.5 percent, while monomeric impurity is below 0.1 percent, which meet the quality standards of raw material medicament.

Description

technical field

[0001] The invention relates to a synthesis method of a chemical raw material medicine, in particular to a synthesis method of high-purity bendamustine hydrochloride. Background technique

[0002] Bendamustine hydrochloride (bendamustine hydrochloride) is a bifunctional alkylating agent, which can cause DNA single-strand and double-strand cross-linking through alkylation, disrupt the function of DNA and DNA synthesis, and make the relationship between DNA and protein Between, and cross-linking between proteins, thus exerting anti-tumor effect. From 1971 to 1992, bendamustine hydrochloride was produced by Jenapharm under the trade name Cytostasan. After 1993, it was marketed in Germany under the trade name Ribomustine by Ribosepharm for the treatment of breast cancer and chronic lymphocytic leukemia. On March 20, 2008, bendamustine hydrochloride developed by Cephalon was approved by the US FDA for the treatment of chronic lymphocytic leukemia (CLL), with the...

Examples

Embodiment 1

[0018] 1) Synthesis of [1-methyl-2(4'-butyric acid ethyl)-5-N,N-bis(2'-hydroxyethyl)]-1H-benzimidazole

[0019] Stir and dissolve [1-methyl-2(4'-butanoic acid ethyl)-5-amino]-1H-benzimidazole (150g, 0.58mol), water 1500mL, and glacial acetic acid 750mL in a 3L reaction flask, Cool to -5~0°C, add 300mL ethylene oxide, and control the temperature until the reaction is complete. Adjust the pH to 7.1-7.3 with saturated potassium carbonate solution, extract with 800 mL×3 dichloromethane, combine the organic phases, wash with saturated brine 600 mL×3, and dry over anhydrous magnesium sulfate. Suction filtration and concentration gave a brown oily solid.

[0020] 2) Chlorination reaction to synthesize [1-methyl-2(4'-butyric acid ethyl)-5-N,N-bis(2'-chloroethyl)]-1H-benzimidazole

[0021] [1-Methyl-2(4'-butanoic acid ethyl)-5-N,N-bis(2'-hydroxyethyl)]-1H-benzimidazole (200g, 0.56mol), xylene 800mL, phosphorus oxychloride 500mL mixed, heated to reflux for 8h. Allow to cool, and con...

Embodiment 2

[0029] 1) Synthesis of [1-methyl-2(4'-butyric acid ethyl)-5-N,N-bis(2'-hydroxyethyl)]-1H-benzimidazole

[0030] Stir and dissolve [1-methyl-2(4'-butanoic acid ethyl)-5-amino]-1H-benzimidazole (150g, 0.58mol), water 1500mL, and glacial acetic acid 750mL in a 3L reaction flask, Cool to -5~0°C, add 250mL ethylene oxide, and control the temperature until the reaction is complete. Adjust the pH to 7.1-7.3 with saturated potassium carbonate solution, extract with 800 mL×3 dichloromethane, combine the organic phases, wash with saturated brine 600 mL×3, and dry over anhydrous magnesium sulfate. Suction filtration and concentration gave a brown oily solid.

[0031] 2) Chlorination reaction to synthesize [1-methyl-2(4'-butyric acid ethyl)-5-N,N-bis(2'-chloroethyl)]-1H-benzimidazole

[0032] [1-Methyl-2(4'-butanoic acid ethyl)-5-N,N-bis(2'-hydroxyethyl)]-1H-benzimidazole (200g, 0.56mol), toluene 1000mL , phosphorus oxychloride 800mL mixed, heated to reflux for 3h. Allow to cool, and ...

Embodiment 3

[0038] 1) Synthesis of [1-methyl-2(4'-butyric acid ethyl)-5-N,N-bis(2'-hydroxyethyl)]-1H-benzimidazole

[0039] Stir and dissolve [1-methyl-2(4'-butanoic acid ethyl)-5-amino]-1H-benzimidazole (150g, 0.58mol), water 1500mL, and glacial acetic acid 750mL in a 3L reaction flask, Cool to -5~0°C, add 400mL ethylene oxide, and control the temperature until the reaction is complete. Adjust the pH to 7.1-7.3 with saturated potassium carbonate solution, extract with 800 mL×3 dichloromethane, combine the organic phases, wash with saturated brine 600 mL×3, and dry over anhydrous magnesium sulfate. Suction filtration and concentration gave a brown oily solid.

[0040] 2) Chlorination reaction to synthesize [1-methyl-2(4'-butyric acid ethyl)-5-N,N-bis(2'-chloroethyl)]-1H-benzimidazole

[0041] [1-Methyl-2(4'-butanoic acid ethyl)-5-N,N-bis(2'-hydroxyethyl)]-1H-benzimidazole (200g, 0.56mol), xylene 800mL, phosphorus oxychloride 1000mL mixed, heated to reflux for 5h. Allow to cool, and co...

technical field

[0001] The invention relates to a synthesis method of a chemical raw material medicine, in particular to a synthesis method of high-purity bendamustine hydrochloride. Background technique

[0002] Bendamustine hydrochloride (bendamustine hydrochloride) is a bifunctional alkylating agent, which can cause DNA single-strand and double-strand cross-linking through alkylation, disrupt the function of DNA and DNA synthesis, and make the relationship between DNA and protein Between, and cross-linking between proteins, thus exerting anti-tumor effect. From 1971 to 1992, bendamustine hydrochloride was produced by Jenapharm under the trade name Cytostasan. After 1993, it was marketed in Germany under the trade name Ribomustine by Ribosepharm for the treatment of breast cancer and chronic lymphocytic leukemia. On March 20, 2008, bendamustine hydrochloride developed by Cephalon was approved by the US FDA for the treatment of chronic lymphocytic leukemia (CLL), with the...

Examples

Embodiment 1

[0018] 1) Synthesis of [1-methyl-2(4'-butyric acid ethyl)-5-N,N-bis(2'-hydroxyethyl)]-1H-benzimidazole

[0019] Stir and dissolve [1-methyl-2(4'-butanoic acid ethyl)-5-amino]-1H-benzimidazole (150g, 0.58mol), water 1500mL, and glacial acetic acid 750mL in a 3L reaction flask, Cool to -5~0°C, add 300mL ethylene oxide, and control the temperature until the reaction is complete. Adjust the pH to 7.1-7.3 with saturated potassium carbonate solution, extract with 800 mL×3 dichloromethane, combine the organic phases, wash with saturated brine 600 mL×3, and dry over anhydrous magnesium sulfate. Suction filtration and concentration gave a brown oily solid.

[0020] 2) Chlorination reaction to synthesize [1-methyl-2(4'-butyric acid ethyl)-5-N,N-bis(2'-chloroethyl)]-1H-benzimidazole

[0021] [1-Methyl-2(4'-butanoic acid ethyl)-5-N,N-bis(2'-hydroxyethyl)]-1H-benzimidazole (200g, 0.56mol), xylene 800mL, phosphorus oxychloride 500mL mixed, heated to reflux for 8h. Allow to cool, and con...

Embodiment 2

[0029] 1) Synthesis of [1-methyl-2(4'-butyric acid ethyl)-5-N,N-bis(2'-hydroxyethyl)]-1H-benzimidazole

[0030] Stir and dissolve [1-methyl-2(4'-butanoic acid ethyl)-5-amino]-1H-benzimidazole (150g, 0.58mol), water 1500mL, and glacial acetic acid 750mL in a 3L reaction flask, Cool to -5~0°C, add 250mL ethylene oxide, and control the temperature until the reaction is complete. Adjust the pH to 7.1-7.3 with saturated potassium carbonate solution, extract with 800 mL×3 dichloromethane, combine the organic phases, wash with saturated brine 600 mL×3, and dry over anhydrous magnesium sulfate. Suction filtration and concentration gave a brown oily solid.

[0031] 2) Chlorination reaction to synthesize [1-methyl-2(4'-butyric acid ethyl)-5-N,N-bis(2'-chloroethyl)]-1H-benzimidazole

[0032] [1-Methyl-2(4'-butanoic acid ethyl)-5-N,N-bis(2'-hydroxyethyl)]-1H-benzimidazole (200g, 0.56mol), toluene 1000mL , phosphorus oxychloride 800mL mixed, heated to reflux for 3h. Allow to cool, and ...

Embodiment 3

[0038] 1) Synthesis of [1-methyl-2(4'-butyric acid ethyl)-5-N,N-bis(2'-hydroxyethyl)]-1H-benzimidazole

[0039] Stir and dissolve [1-methyl-2(4'-butanoic acid ethyl)-5-amino]-1H-benzimidazole (150g, 0.58mol), water 1500mL, and glacial acetic acid 750mL in a 3L reaction flask, Cool to -5~0°C, add 400mL ethylene oxide, and control the temperature until the reaction is complete. Adjust the pH to 7.1-7.3 with saturated potassium carbonate solution, extract with 800 mL×3 dichloromethane, combine the organic phases, wash with saturated brine 600 mL×3, and dry over anhydrous magnesium sulfate. Suction filtration and concentration gave a brown oily solid.

[0040] 2) Chlorination reaction to synthesize [1-methyl-2(4'-butyric acid ethyl)-5-N,N-bis(2'-chloroethyl)]-1H-benzimidazole

[0041] [1-Methyl-2(4'-butanoic acid ethyl)-5-N,N-bis(2'-hydroxyethyl)]-1H-benzimidazole (200g, 0.56mol), xylene 800mL, phosphorus oxychloride 1000mL mixed, heated to reflux for 5h. Allow to cool, and co...

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