Novel technology for trans-2,6-lupetazin

Abstract

The invention relates to a novel technology for trans-2,6-lupetazin. Chirality substances of S-configuration alanine or R-configuration alanine are adopted, carbonyl imidazole is taken as a condensing agent for preparing dipeptide, walden inversion occurs through a mitsunobu reaction in cyclization so as to obtain a trans-form chirality structure, and then the final product 2S, 6S-lupetazin or 2R, 6R-lupetazin is obtained through reducing by using a reducing agent. Reactions in each step need purification treatment, so that the purity achieves over 98%, and a chemical intermediate of trans 2S, 6S-lupetazin or trans 2R, 6R-lupetazina has pharmaceutical activity and is high in yield.

Description

technical field [0001] The invention relates to the field of pharmaceutical intermediates, more specifically, to a new process of trans-2,6-dimethylpiperazine. Background technique [0002] 2,6-Dimethylpiperazine is an important drug intermediate, and a variety of drugs contain this molecular fragment, such as the psychotropic drug lincazole, the floxacin drugs sparfloxacin and orbifloxacin. It is also widely used in the design of new drugs. For example, the new product JJC-1-059 of Arena Pharmaceutical Company and the new product SU-11925 of SU Biopharmaceutical Company in the Netherlands all introduce this molecular fragment. [0003] Chinese patent CN101463016A discloses a 1,2-propanediamine as a starting material, and the reaction conditions are copper nitrate, iron nitrate, aluminum oxide, and the high temperature in the water system reaches 300-320 degrees Celsius, and an atmospheric pressure Hydrogen to obtain the product racemate 2,6-dimethylpiperazine, and then sep...

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Problems solved by technology

[0003] Chinese patent CN101463016A discloses a 1,2-propanediamine as a starting material, and the reaction conditions are copper nitrate, iron nitrate, aluminum oxide, and the high temperature in the water system reaches 300-320 degrees Celsius, and an atmospheric pressure Hydrogen to obtain the product racemate 2,6-dimethylpiperazine, and then separate the cis and trans configurations through a chromatographic column. However, this reaction system has too many inorganic salts, which is not conducive to amplifying the number of reactions; temperature Too high, there is a safety hazard; water as a solvent is not conducive to subsequent processing; only two trans-structure racemates can be obtained, but two absolute configurations of 2S, 6S- and 2R, 6R- cannot be obtained

[0004] Chinese patent CN1634896A discloses that a kind of 3-[(2-aminopropyl)amino]propan-1-o1 is used raw material, and reaction condition is two aluminum oxides, two chromium oxides, iron oxide, copper, ether make solvent and in 260 Celsius, the air pressure is 2MPa, but the raw materials used in this reaction system are uncommon, which is not conducive to industrial production; the reaction system has too many inorganic salts, which is not conducive to scale-up production and subsequent processing; the reaction temperature is too high, and ether is used as a solvent at the same time. There is a great safety hazard; only the racemate of trans-2,6-dimethylpiperazine can be obtained, and the two absolute configurations of 2R, 6R- and 2S, 6S- cannot be obtained

[0005] Xibei Daxue Xuebao, Ziran Kexueban, 40(3), 460-463; 2010 (Natural Science Edition, Journal of Northwest University, 40(3), 460-463; 2010) discloses a method using 1,2-propanediamine as The raw material, the reaction condition is Al2O3, and reacts at 300-340 degrees Celsius in the water system to obtain the product 2,6-dimethylpiperazine racemate and the by-product 2,5-dimethylpiperazine. However, this reaction There are too many inorganic salts in the system, and water is used as a solvent, which is not conducive to scale-up production and subsequent treatment; the temperature is too high, and the safety hazard is great; a large number of by-products are obtained, and the yield is too low; only trans-2,6-dimethylpiperazine can be obtained The racemate, the absolute configuration cannot be obtained

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