阅读说明：本技术 一种盐酸苯达莫司汀多取代杂质化合物的合成方法及应用 (Synthesis method and application of bendamustine hydrochloride polysubstituted impurity compound ) 是由 李红强 于 2020-06-24 设计创作，主要内容包括：本发明公开了一种盐酸苯达莫司汀多取代杂质化合物的合成方法及应用,所要制备的多取代杂质为4-(5-((2-(2-氯乙氧基)乙基)(2-氯乙氧基)胺基)-1-甲基-1H-苯[d]咪唑-2-基)丁酸盐酸盐,该制备方法是以4-(5-氨基-1-甲基苯并咪唑-2-基)丁酸乙酯为原料,经两步取代反应、一步氯代反应、一步水解反应,得到目标产物盐酸苯达莫司汀多取代杂质。盐酸苯达莫司汀多取代杂质化合物可作为盐酸苯达莫司汀有关物质检测用对照品,用于盐酸苯达莫司汀原料药和制剂纯度控制。(The invention discloses a synthesis method and application of a bendamustine hydrochloride polysubstituted impurity compound, wherein the polysubstituted impurity to be prepared is 4- (5- ((2- (2-chloroethoxy) ethyl) (2-chloroethoxy) amino) -1-methyl-1H-benzene [ d ] imidazole-2-yl) butyric acid hydrochloride, and the preparation method takes 4- (5-amino-1-methylbenzimidazole-2-yl) ethyl butyrate as a raw material and obtains the target product bendamustine hydrochloride polysubstituted impurity through two-step substitution reaction, one-step chlorination reaction and one-step hydrolysis reaction. The bendamustine hydrochloride polysubstituted impurity compound can be used as a reference substance for detecting related substances of the bendamustine hydrochloride, and is used for controlling the purity of bendamustine hydrochloride bulk drugs and preparations.)

1. A synthetic method of bendamustine hydrochloride multi-substituted impurity compound is characterized in that the structural formula of the bendamustine hydrochloride multi-substituted impurity compound is shown as a formula I, and the synthetic method comprises the following steps:

(1) reacting the compound shown in the formula IV with a nucleophilic reagent A in an organic solvent under the action of a deacidification agent to obtain a compound shown in the formula III;

(2) reacting the compound shown in the formula III obtained in the step (1) with a nucleophilic reagent B to obtain a compound shown in a formula II;

(3) and (3) reacting the compound shown in the formula II obtained in the step (2) with a chlorinated reagent, and hydrolyzing in hydrochloric acid to obtain the bendamustine hydrochloride polysubstituted impurity compound shown in the formula I.

2. According to claim 1The preparation method is characterized in that the structural formula of the nucleophilic reagent A in the step (1) is shown as a formula AWherein X is one of-Br, -Cl, -I, -methanesulfonate, -p-toluenesulfonate, -p-nitrobenzenesulfonate, -trifluoromethanesulfonate and-p-chlorobenzoate.

3. The method according to claim 1, wherein the organic solvent in step (1) is one or more selected from the group consisting of dimethylformamide, dimethylacetamide, dimethylsulfoxide, ethanol, isopropanol, methanol, butanol, and acetonitrile.

4. The preparation method according to claim 1, wherein the acid-forming agent in step (1) is one or more of sodium hydroxide, potassium carbonate, sodium ethoxide and sodium methoxide.

5. The preparation method according to claim 1, wherein the nucleophile B in step (2) is one or more of 2-bromoethanol, ethylene oxide and 2-chloroethanol.

6. The preparation method of claim 1, wherein the chlorinating reagent in step (3) is one or more of thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride and phosphorus pentachloride.

7. The process according to claim 1, wherein the reaction temperature of the compound of formula II with the chlorinating agent in step (3) is 35 to 50 ℃.

8. A composition comprising bendamustine hydrochloride, wherein the composition is comprised of bendamustine hydrochloride and a compound having a structural formula as shown in formula I.

9. Use of the composition of claim 8 in the preparation of a bendamustine hydrochloride impurity control agent.

10. The use of bendamustine hydrochloride polysubstituted impurity compound of claim 1 in the preparation of a bendamustine hydrochloride impurity control agent.

Technical Field

The invention relates to the field of medicines, in particular to a synthesis method and application of bendamustine hydrochloride polysubstituted impurity compounds.

Background

Bendamustine hydrochloride is a bifunctional nitrogen mustard derivative containing a nitrogen mustard group and a benzimidazole ring, and the pharmacological action of the bendamustine hydrochloride is to cross-link single strands and double strands of DNA through alkylation so as to interfere the synthesis and the function of the DNA, thereby playing an anti-tumor role. Indications are chronic lymphocytic leukemia and for the treatment of relapsed refractory B-cell non-hodgkin's lymphoma that is ineffective with rituximab.

Bendamustine hydrochloride has the chemical structural formula shown in the following figure, and has the chemical name of 4- (5- (bis (2-chloroethyl) amino) -1-methylbenzimidazole-2-yl) butyric acid hydrochloride, and the structural formula is shown in the following figure:

the most common synthetic method is to take 2, 4-dinitrochlorobenzene as a starting material, and obtain the bendamustine hydrochloride through 8 steps of methylamine amination, reduction, amidation with glutaric anhydride, ring closing to form a benzimidazole ring, reduction, substitution with ethylene oxide, chlorination, hydrolysis, salification and the like. The route is as follows:

the synthesis route shows that the intermediate generated in the reaction process of the step 6 can further react with ethylene oxide to generate a byproduct, and the byproduct can be converted into bendamustine hydrochloride polysubstituted impurities through chlorination, hydrolysis and salification and introduced into bendamustine hydrochloride bulk drugs. The content of bendamustine hydrochloride polysubstituted impurities in bendamustine hydrochloride bulk drugs and preparations has important influence on the safety and the effectiveness of the drugs, and the control of the content of the impurities by an impurity comparison method in the prior art is the most effective method.

At present, no relevant literature reports a method for synthesizing bendamustine hydrochloride multi-substituted impurities, so that a method for synthesizing the bendamustine hydrochloride multi-substituted impurities is urgently needed, and the multi-substituted impurities are used as a bendamustine hydrochloride related substance detection reference substance and are used for purity control of bendamustine hydrochloride raw material medicaments and preparations.

Disclosure of Invention

In order to solve the problems, the invention provides a synthetic method and application of a bendamustine hydrochloride polysubstituted impurity compound, the synthetic method is simple to operate, the purity of the obtained impurity reference substance is high, and the compound can be used as a reference substance for detecting bendamustine hydrochloride related substances and is used for controlling the purity of bendamustine hydrochloride raw material medicaments and preparations.

One of the objectives of the present invention is to provide a method for synthesizing bendamustine hydrochloride polysubstituted impurity compound, specifically, the structural formula of the bendamustine hydrochloride polysubstituted impurity compound is shown in formula I, and the synthesis method comprises the following steps:

(1) reacting the compound shown in the formula IV with a nucleophilic reagent A in an organic solvent under the action of a deacidification agent to obtain a compound shown in the formula III;

(2) reacting the compound shown in the formula III obtained in the step (1) with a nucleophilic reagent B to obtain a compound shown in a formula II;

(3) and (3) reacting the compound shown in the formula II obtained in the step (2) with a chlorinated reagent, and hydrolyzing in hydrochloric acid to obtain the bendamustine hydrochloride polysubstituted impurity compound shown in the formula I.

Further, the structural formula of the nucleophilic reagent A in the step (1) is shown as a formula A

Wherein X is one of-Br, -Cl, -I, -methanesulfonate, -p-toluenesulfonate, -p-nitrobenzenesulfonate, -trifluoromethanesulfonate and-p-chlorobenzoate.

Further, the organic solvent in the step (1) is one or more of dimethylformamide, dimethylacetamide, dimethylsulfoxide, ethanol, isopropanol, methanol, butanol and acetonitrile.

Further, the acid-removing agent in the step (1) is one or more of sodium hydroxide, potassium carbonate, sodium ethoxide and sodium methoxide.

Further, the nucleophilic reagent B in the step (2) is one or more of 2-bromoethanol, ethylene oxide and 2-chloroethanol.

Further, the chlorinating reagent in the step (3) is one or more of thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride and phosphorus pentachloride.

Further, the reaction temperature of the compound shown in the formula II in the step (3) and the chlorinated reagent is 35-50 ℃.

The invention also aims to provide a composition, and particularly the composition consists of bendamustine hydrochloride and a compound with a structural formula shown in a formula I.

The invention also aims to provide application of a composition consisting of bendamustine hydrochloride and a compound shown in a structural formula I in preparation of a bendamustine hydrochloride impurity contrast agent.

The invention also aims to provide an application of the bendamustine hydrochloride polysubstituted impurity compound in preparing a bendamustine hydrochloride impurity contrast agent.

The invention has the advantages that: the invention controls the introduction sequence of chloroethyl oxyethyl and chloroethyl, well controls the generation of byproducts in the reaction process, can synthesize the bendamustine hydrochloride polysubstituted impurities with high purity and simple operation, and the compound can be used as a reference substance for detecting related substances of the bendamustine hydrochloride and is used for controlling the purity of the bendamustine hydrochloride raw material medicine and the preparation.

Drawings

Fig. 1 is a process scheme for the synthesis of bendamustine hydrochloride polysubstituted impurity compounds of the present invention.

Detailed Description

The present invention will be described in further detail with reference to the following examples and drawings, it being understood that the present invention is not limited to the particular examples described herein, but is capable of modification in various forms and details, and can be modified within the spirit and scope of the invention.