阅读说明：本技术 1-[2-(((2-巯基乙氧基)乙氧基)乙氧基)乙基]哌嗪盐酸盐的一种新的制备方法 (Novel preparation method of 1- [2- (((2-mercaptoethoxy) ethoxy) ethyl ] piperazine hydrochloride ) 是由 彭海燕 于 2018-08-13 设计创作，主要内容包括：1-[2-(((2-巯基乙氧基)乙氧基)乙氧基)乙基]哌嗪盐酸盐的一种新的制备方法本发明提供了一种经济实用的制备喹硫平关键中间体1-[2-(((2-巯基乙氧基)乙氧基)乙氧基)乙基]哌嗪盐酸盐的新方法。(The invention provides an economical and practical novel method for preparing quetiapine key intermediate 1- [2- (((2-mercaptoethoxy) ethoxy) ethyl ] piperazine hydrochloride.)

1. An economical and practical novel method for preparing quetiapine key intermediate 1- [2- (((2-mercaptoethoxy) ethoxy) ethyl ] piperazine hydrochloride.

2. Under the condition of a proper solvent or no solvent, piperazine hydrochloride and 2- (2-chloroethoxy ethoxy) ethanethiol are stirred at the temperature of 100 ℃ and 150 ℃ to react; 1- [2- (((2-mercaptoethoxy) ethoxy) ethyl ] piperazine hydrochloride is obtained directly in high yield without the need to protect one of the amino groups of piperazine.

Technical Field

The invention provides an economical and practical novel method for preparing a quetiapine key intermediate 1- [2- (((2-mercaptoethoxy) ethoxy) ethyl ] piperazine hydrochloride.

Background

Piperazine is an important component of many drugs, is a six-membered heterocyclic ring containing two nitrogen atoms in a molecule, is an ideal structural unit of a nitrogen-rich heterocyclic compound, and has the characteristics of high enthalpy of formation, good thermal stability and the like. In recent years, the application of piperazine compounds in organic synthesis and medicine has attracted extensive attention from the organic and pharmaceutical communities, and piperazine rings have a symmetrical structure with better nitrogen balance than traditional organic drugs. The piperazine ring is introduced in the drug synthesis and can be used as a drug synergistic group, thereby improving the pharmacokinetic property of the drug and improving the biological activity of the drug; the compounds containing piperazine ring can be further synthesized into a plurality of types of organic compounds, most of the compounds have high-efficiency pharmacological activity, and some of the compounds have been developed into clinical medicines. Among the popular drugs published in 2012, which are globally ranked within 100, we found the corresponding piperazine moieties in about 10 popular drugs, such as Quetiapine (the top ranking), Aripiprazole (Aripiprazole), Clozapine (Clozapine) and Olanzapine (Olanzapine), all for psychiatric treatment, others such as Levofloxacin (Levofloxacin) for anti-inflammatory and Cetirizine hydrochloride (Cetirizine hydrochloride) for anti-allergy.

The traditional process of mono-substituted piperazine comprises the steps of firstly protecting amino at one end by Boc/Cbz/Ac and the like, then reacting with halide to carry out substitution reaction at the other end, and finally removing a protecting group to obtain a final mono-substituted product. The traditional process has long route, time consumption, low total yield and great defects in industrial production and is difficult to adopt.

Disclosure of Invention

The technical problem to be solved by the invention is to overcome the defects in the prior art and provide a practical and simple method for preparing monosubstituted piperazine.

The traditional process of mono-substituted piperazine comprises the steps of firstly protecting amino at one end by Boc/Cbz/Ac and the like, then reacting with halide to carry out substitution reaction at the other end, and finally removing a protecting group to obtain a final mono-substituted product. The traditional process has long route, time consumption, low total yield and great defects in industrial production and is difficult to adopt. One aspect of the present invention is the development of a novel process for the preparation of highly pure 1- [2- (((2-mercaptoethoxy) ethoxy) ethyl ] piperazine hydrochloride: under the condition of a proper solvent or no solvent, piperazine hydrochloride and 2- (2-chloroethoxy ethoxy) ethanethiol are stirred at the temperature of 100 ℃ and 150 ℃ to react; 1- [2- (((2-mercaptoethoxy) ethoxy) ethyl ] piperazine hydrochloride is obtained directly in high yield without the need to protect one of the amino groups of piperazine.

The solvent used may be a high boiling point nonpolar solvent such as toluene, xylene or the like, and is preferably a solvent-free system. The reaction temperature can be between 100 ℃ and 150 ℃, and the best temperature range is between 120 ℃ and 140 ℃. The reaction substrate may be anhydrous piperazine or a combination of piperazine and piperazine hydrochloride, preferably a mixture of piperazine and piperazine hydrochloride. The final purification of the product can obtain a free alkali form by high-temperature reduced pressure distillation, or form a hydrochloride to recrystallize at low temperature to obtain a hydrochloride form of the product, the optimal high-purity product can purify the hydrochloride by recrystallization to obtain a high-purity product with the content of more than 99.5 percent, piperazine impurities generated in the high-temperature distillation purification process are avoided, and the rigorous reaction equipment requirement and high cost and high energy consumption required by high-temperature reduced pressure distillation are also avoided.

The process conditions of the present invention can be carried out within a wide range, and the reaction conditions exemplified in the present invention such as solvent/temperature/reaction ratio/substrate selection and the like are not limitative and correspond only to the preferred conclusion of the present invention.