Indolizine derivative and preparation method thereof

Abstract

The invention discloses an indolizine derivative and a preparation method thereof. A cheap copper compound is taken as a catalyst, a pyridine derivative, an olefinic derivative and a heavy nitrogen derivative are taken as reactants, and the catalyst and the reactants are subjected to cyclization reaction in a mixed solvent to obtain a product indolizine. The catalyst prepared with the method disclosed by the invention is cheap, can be easily obtained, is high in reaction activity, is moderate in reaction conditions, only needs to be carried out in the air, has a wide primer applicable range and is convenient in aftertreatment, and a final product can be obtained through simple column chromatography after reaction is finished. A target product has the advantages of high yield, simple preparation process, environment protection and wide raw material resource. The indolizine derivative conforms to the requirement and the direction of modern green chemistry development and has a potential industrial application value.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and relates to an indolizine derivative and a preparation method thereof. Background technique [0002] Indolizine is a very important structural unit, which widely exists in natural products and drug molecules with physiological drug activity, and is also a common class of synthetic intermediates. At present, the method for preparing indolizine has the use of noble metals, and the synthesis route has the disadvantages of complex synthesis of raw materials, harsh reaction conditions, cumbersome operations, and low selectivity. For example: [0003] Xihe Bi et al. used 2-pyridyl alkynol derivatives and isocyanides under the action of silver acetate to activate alkynes with noble metals and undergo allene intermediate states to obtain 2,3-disubstituted indolizines in good yields V. Gevorgyan etc. use triazoles and alkynes under the catalysis of precious metal rhodium and can only obtain...

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Problems solved by technology

[0003] Xihe Bi et al. used 2-pyridyl alkynol derivatives and isocyanides under the action of silver acetate to activate alkynes with noble metals and undergo allene intermediate states to obtain 2,3-disubstituted indolizines in good yields V. Gevorgyan etc. use triazoles and alkynes under the catalysis of precious metal rhodium and can only obtain the indolizine compound with a lower yield. The shortcoming of this reaction is the use of precious metal rhodium, and can only limit the 8-position chlorine Substituted triazoles; although metal copper can be used as a catalyst to obtain indolizine smoothly, it needs to be reacted at a high temperature of 130 °C; Miguel Toma´s et al. used pyridine and alkenyl diazonium compounds with a low catalytic amount Under the catalysis of cuprous bromide, 2,3-disubstituted indolizine compounds were directly synthesized; Yuhong Zhang et al. used 2-alkylpyridine and unsaturated carboxylic acid compounds with copper as catalyst and nickel powder as reduction Lithium acetate is used as the base to obtain 2,3-disubstituted indolizine compounds; however, the reaction temperature of this synthesis method is 140 °C and the time is long; Aiwen Lei et al. found that methyl acetoacetate, alkenes or alkynes Using iodine as catalyst and oxidant, in the presence of base, indolizine compounds were synthesized through a series of free radical addition and cyclization processes (see: Meng, X.; Liao, P.; Liu, J.; Bi , X. Chem. Commun. 2014, 50 , 11837−11839; Chernyak, D.; Chuprakov, S.; Hwang, F. W.; Gevorgyan, V. Angew. Chem., Int. Ed. 2007, 46 , 4757−4759; Helan, V.; Gulevich, A. V.; Gevorgyan, V. Chem. Sci. 2015, 6 , 1928−1931;Barluenga, J.; Lonzi, G.; Riesgo, L.; Lopez, L. A.; Tomas, M. J. Am. Chem. Soc. 2010, 132 , 13200−13202)

[0004] In addition, the existing methods commonly used to prepare indolizine first need to prepare pyridinium salts, and then need to add a large amount of alkali to make pyridine ylides, and most of these reactions can only be reacted in polar solvents, which greatly limits Its application in industrialization

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