Preparation method of highly pure bendamustine hydrochloride

A technology of bendamustine hydrochloride and high purity is applied in the field of preparation of bendamustine hydrochloride to achieve the effects of simple method, low adverse reaction and few impurities

Inactive Publication Date: 2015-06-10
SICHUAN HUIYU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the finished product of bendamustine hydrochloride with almost no impuritie

Method used

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  • Preparation method of highly pure bendamustine hydrochloride
  • Preparation method of highly pure bendamustine hydrochloride
  • Preparation method of highly pure bendamustine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Put 5 grams of crude bendamustine hydrochloride in a 250ml three-necked flask, add 10g of dimethyl sulfoxide to dissolve at about 25°C, add 50ml of purified water, recrystallize at about 5°C, and filter to obtain a filter cake. The filter cake is a solid wet material. Add 3 times the volume of acetone to the filter cake to make a slurry, filter to obtain the undried product of bendamustine hydrochloride, and dry it at 30°C under vacuum -0.09MPa for 24 hours to obtain high-purity bendamustine hydrochloride Ting finished product 3.7g, HPLC (high performance liquid chromatography) content: 99.97%, the map is as follows figure 1 As shown, impurity I: 0.02%, other impurities 0.01%, moisture 4.66%.

[0037] 1 H-NMR(DMSO-d6,400MHz): δ12.23(bs,1H), δ7.72(d,1H),δ7.11(dd,1H),δ6.69(d,1H),δ3.89 (s,3H),δ3.81(m,4H),δ3.76(m,4H),δ3.14(t,2H),δ2.40(t,2H),δ2.00(m,2H) .

[0038] Adopt Carlo Erba 1106 elemental analyzer, elemental analysis result: C 16 h 21 Cl 2 N 3 o 2 .HCl.H 2 ...

Embodiment 2

[0040] Put 5 grams of bendamustine hydrochloride crude product in a 250ml three-necked flask, add 9g of dimethyl sulfoxide and 1g of a mixed solvent with a mass fraction of 36% concentrated hydrochloric acid and dissolve it at about 25°C, add 50ml of purified Water, recrystallize at about 10°C, filter to obtain a filter cake, the filter cake is a solid wet material, add 3 times the volume of tetrahydrofuran to the filter cake to make a slurry, filter to obtain the undried product of bendamustine hydrochloride, vacuum -0.09 at 40°C Dry at MPa for 24 hours to obtain 3.5 g of high-purity bendamustine hydrochloride finished product, HPLC (high performance liquid chromatography) content: 99.99%, and the spectrum is as follows figure 2 As shown, impurity I: less than 0.01%, other impurities less than 0.01%, moisture 4.81%.

Embodiment 3

[0042]Put 5 grams of crude bendamustine hydrochloride in a 250ml three-neck flask, add 10g of dimethyl sulfoxide to dissolve at about 40°C, add 50ml of acetone, recrystallize at about 20°C, filter to obtain a filter cake, filter The cake is a solid wet material. Add 5 times the volume of acetonitrile to the filter cake to make a slurry, filter to obtain the undried product of bendamustine hydrochloride, and dry it under vacuum at -0.09MPa at 60°C for 18 hours to obtain a high-purity bendamustine hydrochloride product 4.3g, HPLC (high performance liquid chromatography) content: 99.92%, the map is as follows image 3 As shown, impurity I: 0.05%, other impurities 0.03%, moisture 4.51%.

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Abstract

The invention discloses a purification method in the organic chemistry field, and especially relates to a preparation method of highly pure bendamustine hydrochloride. The preparation method comprises the following steps: 1, dissolving: dissolving crude bendamustine hydrochloride in a solvent at -20-60DEG C to obtain a crude bendamustine hydrochloride solution; 2, re-crystallizing: adding the crude bendamustine hydrochloride solution into a bendamustine hydrochloride-semisoluble-to-insoluble solvent, re-crystallizing at -20-60DEG C, filtering to obtain a bendamustine hydrochloride wet solid, adding the bendamustine hydrochloride-semisoluble-to-insoluble solvent to the wet solid, beating, and filtering to obtain an undried bendamustine hydrochloride product; and 3, drying. The preparation method has a high purification efficiency, the highest purity of a purified product reaches 99.99%, and the method has the advantages of simplicity, mild condition, repetition rate reaching 100%, and easy industrial production.

Description

technical field [0001] The invention relates to a purification method in the field of organic chemistry, in particular to a preparation method of high-purity bendamustine hydrochloride. Background technique [0002] Bendamustine hydrochloride, the chemical name is 4-[5-[bis-(2-chloroethyl)amino]-1-methyl-2-benzimidazole]butyric acid hydrochloride, and its structural formula is: [0003] [0004] Bendamustine hydrochloride was first developed in the early 1960s by Ozegowski and colleagues at the Institute for Microbiological Experiments in Jena, Germany. The purpose of the synthesis is to link an alkylated nitrogen mustard (a non-functional alkylating agent) to a purine and an amino acid. The major advantage of the newly synthesized compound over chlorambucil is its water solubility. Anger et al. published initial clinical results of the successful use of bendamustine in patients with plasmacytoma. Bendamustine was produced under the trade name Cytostasan by the pharmac...

Claims

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Application Information

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IPC IPC(8): C07D235/16
CPCC07D235/16
Inventor 吴成剑丁兆孙朝国
Owner SICHUAN HUIYU PHARMA
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