Hantzsch 반응을 통한 1,4-Dihydropyridine계 화합물의 PEG-Promoted One-Pot 합성

Abstract

1,4-Dihydropyridines (1,4-DHPs) are well known as Ca channel blockers, and have emerged as one of the most important classes of drugs for the treatment of cardiovascular diseases. Dihydropyridines have been classically synthesized using the Hantzsch synthesis described in 1882, which is one-pot condensation of aldehydes with ethyl acetoacetate, and ammonia in acetic acid or in refluxing alcohol. However, this method involves long reaction time, harsh reaction conditions, the use of a large quantity of volatile organic solvents and generally gives low yields. Therefore, it is necessary to develop an efficient and versatile method for the preparation of 1,4DHPs and there were several efficient methods developed for the synthesis of 1,4-dihydropyridines, comprising the use of microwave, ionic liquid, solvent-free, TMSClNaI, solar energy, and so on. Green chemistry is a major issue of modern chemistry currently. The use of environmentally benign solvent instead of traditional organic solvents is the important and efficient strategy in green chemistry. Water is a promising green solvent for use in chemistry because it is cheap, readily available, and nontoxic. There is increasing recognition that organic reactions carried out in water may offer advantages over those in organic solvents. However, the poor solubility of reactants in water is the main obstacle to the use of water as reaction solvent. In previous studies, many additives, such as ionic liquid (ILs), poly(ethylene glycol) (PEG), and sodium dodecyl sulfate(SDS) have been successfully applied in cross-coupling reaction of arylboronic acid with carboxylic derivative as useful promoters. As a part of our program aiming at developing selective and environmental friendly methodologies for the preparation of fine chemicals and in continuation of our interest in PEG or ionic liquid promoted organic reactions, in this paper, we report on the evaluation of Hantzsch’s dihydropyridine synthesis in the H2O-PEG system. The method is straightforward and the 1,4-dihydropyridines can be synthesized under mild reaction conditions in high yields in short reaction times.