Novel preparation method of 1-[2-((2-hydroxyethoxy) ethoxy) ethyl] piperazine hydrochloride

Abstract

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

Description

TECHNICAL FIELD

[0001] The present application provides a new method for preparing the key intermediate of Quetiapine, 1-[2-((2-hydroxyethoxy)ethoxy)ethyl]piperazine hydrochloride. BACKGROUND

[0002] Piperazine is an important component of many drugs, a six-membered heterocyclic ring containing two nitrogen atoms, is a ideal structural unit of nitrogen-rich heterocyclic compounds, with high enthalpy of formation, good thermal stability and other characteristics. In recent years, piperazine compounds have attracted widespread attention in the field of organic chemistry and pharmaceutical industry in the application of organic synthesis and medicine, piperazine ring and the traditional organic drugs compared to a better nitrogen balance of symmetrical structure. In drug synthesis, the introduction of piperazine ring, as a drug synergistic group, can improve the pharmacokinetic properties of drugs, improve the biological activity of drugs; piperazine ring containing compounds can be further synthesized into many types of organic compounds, most of these compounds have high pharmacological activity, some have been developed into clinical drugs. In 2012, the global ranking of 100 best-selling drugs, we found about 10 best-selling drugs corresponding piperazine components, such as the ranking of Quetiapine (Quetiapine), Aripiprazole (Aripiprazole), Clozapine (Clozapine) and Olanzapine (Olanzapine) are used for the treatment of mental illness, others such as Levofloxacin (Levofloxacin) for anti-inflammatory and bactericidal, Cetirizine hydrochloride (Cetirizine hydrochloride) for anti-allergic.

[0003] The traditional process of monosubstituted piperazine is to protect the amino group first, that is, to protect the amino group of one end first, then to react with halide to substitute the other end, and finally to remove the protecting group to obtain the final monosubstituted product. These traditional process routes are long, time-consuming, and have low total yield, which has great defects in industrial production and is difficult to adopt. SUMMARY

[0004] The technical problem to be solved by the present application is to overcome the defects of the above-mentioned technology, and to provide a practical and simple method for preparing monosubstituted piperazine.

[0005] The traditional process of monosubstituted piperazine is to protect the amino group first, then to react with halide to substitute the other end, and finally to remove the protecting group to obtain the final monosubstituted product. These traditional process routes are long, time-consuming, and have low total yield, which has great defects in industrial production and is difficult to be adopted. One aspect of the present application is to develop a new method for preparing high-purity 1-[2-((2-hydroxyethoxy)ethoxy)ethyl]piperazine hydrochloride: under suitable solvent or solvent-free conditions, piperazine hydrochloride and 2-((2-chloroethoxy)ethoxy)ethanol are stirred to react at 100-150 degrees Celsius; without protecting one amino group of piperazine, 1-[2-((2-hydroxyethoxy)ethoxy)ethyl]piperazine hydrochloride is directly obtained in high yield.

[0006] The solvent used can be high-boiling nonpolar solvents such as toluene and xylene, and the preferred is a solvent-free system. The reaction temperature can be 100-150 degrees Celsius, and the best temperature range is 120-140 degrees Celsius. The reaction substrate can be anhydrous piperazine or the combined action of piperazine and piperazine hydrochloride, and the preferred is a mixture of piperazine and piperazine hydrochloride. The final purification of the product can be high-temperature vacuum distillation to obtain the free base form, or low-temperature recrystallization to form the hydrochloride salt to obtain the hydrochloride salt form of the product. The best high-purity product can be purified by recrystallization of the hydrochloride salt to obtain high-purity product with a content of more than 99.5%, avoiding the generation of piperazine impurities in the high-temperature distillation purification process, and avoiding the harsh requirements of reaction equipment and high cost and high energy consumption of high-temperature vacuum distillation.

[0007] The process conditions of the present application can be carried out within a wide range, and the reaction conditions listed in the present application such as solvent / temperature / reaction ratio / substrate selection are not limiting, and only correspond to the preferred conclusions of the present application.

[0008] The method of the present application will be illustrated by specific examples below. DETAILED DESCRIPTION

[0009] The present application will be further illustrated by the following examples. The synthesis process described in the examples of the present application is only used to illustrate the present application, and is not a limitation of the present application. Simple improvements to the process of the present application in the process route of the present application also belong to the content claimed by the present application.

[0010] Example 1:

[0011] 100 g (1.2 mol) of anhydrous piperazine and 240 g (1.5 mol) of piperazine dihydrochloride were heated to 120 °C, and 170 g (1.2 mol) of 2-((2-chloroethoxy)ethoxy)ethanol was added dropwise. After the addition was complete, heating and stirring continued, and the temperature was raised to 136-140 °C and maintained for 1 hour. Heating was stopped after TLC showed that the reaction was complete. When the temperature dropped to 80 °C, 500 mL of 95% ethanol was added, and the mixture was cooled in a refrigerator overnight. The next day, piperazine dihydrochloride was recovered by filtration. The filter cake was thoroughly washed with a small amount of ethanol, and the filtrates were combined. 200 g of 30% sodium hydroxide solution was added for alkalization, and the insoluble inorganic salts were filtered off. After concentration and removal of solvent, the residue was extracted with ethyl acetate, and dry hydrogen chloride gas was passed through. After filtration and drying, a white solid 1-[2-((2-hydroxyethoxy)ethoxy)ethyl]piperazine hydrochloride was obtained; the solid content was over 98%. Recrystallization once with 90% ethanol aqueous solution yields 220 grams of white crystals, with a yield of 75% and a purity of over 99.5%.

Claims

1. A novel, economical, and practical method for preparing the pharmaceutical intermediate 1-[2-((2-hydroxyethoxy)ethoxy)ethyl]piperazine hydrochloride. Under suitable solvent or solvent-free conditions, piperazine hydrochloride and 2-((2-chloroethoxy)ethoxy)ethanol react with stirring at 100-150°C; 1-[2-((2-hydroxyethoxy)ethoxy)ethyl]piperazine hydrochloride is obtained directly in high yield without the need to protect one amino group of the piperazine.