Preparation method of lidocaine hydrochloride

Abstract

The invention relates to a preparation method of lidocaine hydrochloride, which comprises the following steps: carrying out acylation reaction by using 2, 6-dimethylaniline and chloroacetyl chloride as raw materials, directly adding diethylamine into the system to carry out amination reaction after the reaction is finished, filtering the product, and adding hydrochloric acid into the filtrate to carry out salification reaction. The preparation method of lidocaine hydrochloride provided by the invention is a one-pot method, avoids repeated purification of an intermediate product in a traditional process, and is simple in process, mild in condition, easy to control, high in product yield and high in purity.

Description

technical field [0001] 本发明涉及制药工程技术领域,具体涉及一种盐酸利多卡因的制备方法。 Background technique [0002] 盐酸利多卡因作为一种常见的酰胺类局麻药,被多国药典收载。作为一种较安全的麻醉老药,盐酸利多卡因在临床上已使用多年。1934年由Lofgren首先合成,并用作局部麻醉剂;50年代开始用于治疗手术过程中出现的室性心律失常。由于此药具有安全有效、作用快、消失快等优点,目前已广泛用于治疗各种原因所引起的室性心律失常。 [0003] 目前国内外对利多卡因的研究主要集中在制剂方面,如盐酸利多卡因注射液、复方利多卡因乳膏、利多卡因凝胶等。但是,盐酸利多卡因的合成方法却仍然延续着传统工艺方法:首先,采用间二甲苯为原料,经混酸硝化,通过精馏得到2,6-二甲基硝基苯;然后经还原制得中间体2,6-二甲基苯胺;在缚酸剂作用下,将2,6-二甲基苯胺与氯乙酰氯反应,从而制得中间体氯乙酰-2,6-二甲基苯胺,然后,中间体氯乙酰-2,6-二甲基苯胺与二乙胺回流反应,得到利多卡因;最后与氯化氢或盐酸成盐得盐酸利多卡因。 [0004] 中国专利CN102070483A公开了一种以上述路线制备利多卡因的方法,该方法操作繁琐,产品收率不高,生产成本不具备竞争优势,且工艺中使用了石油醚,为终产品原料药残留溶剂的控制带来了困难。 [0005] 中国专利CN105294477A公开了一种以2,6-二甲酚为原料制备2,6-二甲基苯胺、再与N,N-二乙胺基乙酸甲酯反应生成利多卡因、最后与氯化氢成盐制备盐酸利多卡因的方法。该方法使用的物料N,N-二乙胺基乙酸甲酯价格较高,且市场上供应商较少,不易获得。且工艺中使用了二氯乙烷,该溶剂毒性大,属于已明确的致癌物,ICH指导原则Q3C将其列入一类溶剂,在药品生产中应限制使用。 Contents of the invention [0006] 本发明的目的在于针对现有技术的不足,提供一种“一锅法”制备盐酸利多卡因的方法,该制备方法操作简便、生产成本较低,产物纯度较高,适合工业化大规模生产。 [0007] 本发明所述盐酸利多卡因的结构式为: [0008] [0009] 具体而言,本发明提供的制备盐酸利多卡因的方法,包括如下步骤:以2,6-二甲...

AI Technical Summary

Problems solved by technology

However, the synthetic method of lidocaine hydrochloride still continues the traditional process method: first, adopt m-xylene as raw material, nitrate with mixed acid, obtain 2,6-dimethylnitrobenzene by rectification; then obtain 2,6-dimethylnitrobenzene through reduction; Intermediate 2,6-dimethylaniline; under the action of an acid-binding agent, react 2,6-dimethylaniline with chloroacetyl chloride to obtain the intermediate chloroacetyl-2,6-dimethylaniline, Then, the intermediate chloroacetyl-2,6-dimethylaniline reacts with diethylamine under reflux to obtain lidocaine; finally, it is salified with hydrogen chloride or hydrochloric acid to obtain lidocaine hydrochloride

[0004] Chinese patent CN102070483A discloses a method for preparing lidocaine by the above-mentioned route. The method is cumbersome to operate, the product yield is not high, the production cost does not have a competitive advantage, and petroleum ether is used in the process, which is the residual solvent of the final product raw material drug the control of the

The material N that this method uses, the price of methyl N-diethylaminoacetate is higher, and the supplier is less on the market, is difficult for obtaining

In addition, dichloroethane is used in the process. This solvent is highly toxic and is a known carcinogen. ICH guideline Q3C lists it as a first-class solvent, and its use should be restricted in pharmaceutical production.

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