1,2,3-trisubstituted indolizine derivative and preparation method thereof

Abstract

The present invention relates to an indolizine derivative, and specifically discloses a 1,2,3-trisubstituted indolizine derivative and a preparation method thereof, wherein the chemical structure formula of the indolizine derivative is I as shown in the specification. The 1,2,3-trisubstituted indolizine derivative has benzoyl groups at both 1 and 3 positions, and an ester group at 2-position, namely, the 1,2,3-trisubstituted indolizine derivative has substituents containing carbonyl groups, benzene rings and the ester group, and further modification and processing of the product structure arefacilitated by the chemical nature of the benzoyl groups and the ester group, and more possibilities are provided for the construction of more complex indolizine derivatives. Moreover, the preparationmethod of the 1,2,3-trisubstituted indolizine derivative does not require addition of a metal catalyst, does not require inert gas protection, and has the advantages of easy-to-obtain reaction raw materials, high reaction yield, and mild reaction conditions.

Description

technical field [0001] The invention relates to indolizine compounds, in particular to a 1,2,3-trisubstituted indolizine derivative and a preparation method thereof. Background technique [0002] Indolizine compounds are a class of very useful compounds that are widely used in the fields of medicine, organic light-emitting materials and organic synthesis. Indolizine is a heterocyclic compound consisting of a five-membered and six-membered fused ring and a bridgehead nitrogen atom. It exhibits excellent properties in many biological activities and can be used as various inhibitors and antiviral, antibacterial, antibacterial, and antibacterial agents. Drugs such as tumors; in addition, indolizine derivatives are key intermediates for the synthesis of a class of alkaloids with physiological activity, and complex molecules containing indolizine skeletons can also be found in natural product molecules isolated and extracted from some plants and marine organisms . In addition, i...

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Problems solved by technology

[0003] The methods of the multi-substituted indolizines and derivatives thereof reported in the literature include: (1) Scholtz reaction, utilizing 2-substituted pyridine and acid anhydride to cyclize at 200-220° C. to obtain acyl-substituted indolizine compounds, and then Obtain indolizine derivatives by hydrolysis reaction, although this reaction has a wide range of sources of raw materials, the reaction yield is low and the conditions are harsh; (2) Tschitschibabin reaction, utilizing 2-alkyl substituted pyridine halocarbonyl compounds as substrates, first forming Pyridinium quaternary ammonium salts are then subjected to intramolecular condensation to obtain indolizine skeletons, but this method can only obtain indolizine skeletons with alkyl or aryl substitutions at the 2-position

Like the Scholtz reaction, the Tschitschibabin reaction also has the disadvantages of harsh reaction conditions (240-260°C) and low reaction yield; (3) cycloaddition reaction, which synthesizes the middle nitrogen band by 1,3-dipolar cycloaddition reaction Skeleton compounds are mainly generated from N-ylides and electron-deficient alkenes, alkynes and their derivatives as substrates. The source of substrates is limited. The obtained indolizine structure only contains electron-withdrawing groups, and the positions of substituents have Larger limitations; and 1,5-dipolar cycloaddition reactions often require multiple steps to obtain the indolizine structure, which also results in low overall yields

(4) Photodecomposition reaction, compared with the chemical reaction in the traditional sense, the energy source of the photoreaction is light with higher energy, so the photoreaction rate is faster, but the photoreaction also has the disadvantage of complex reaction and difficult control

[0005] The above defects about indolizine and its derived synthetic method mainly contain the following points: (1) the synthetic method is harsh, as in the above-mentioned method 1 and method 2, a higher temperature of reaction is needed, which does not meet the requirements of green compounds Require and need to consume too much energy; (2) synthetic yield is low, as above-mentioned method 1, method 2 and method 4, all have the generation of pyridinium quaternary ammonium salt intermediate in synthetic method 1 and method 2, next step occurs subsequently Reaction increases the complexity of the reaction, which is the main reason for the low yield; the reaction process of the photoreaction in method 4 is difficult to control, the forward and reverse reaction speed is fast, and the reaction controllability is low, which is also the main reason for the low yield; ( 3) The source of the substrate is limited. For example, both method 1 and method 2 require 2-substituted pyridine as a raw material, and the source of raw material is single; in method 3, only electron-deficient alkenes, alkynes and their derivatives can be used as substrates. (4) The structure of the product is single, such as method 1 and method 2, which are often only enough to obtain indolizine and its derivatives substituted at certain positions, and cannot obtain indolizines with diverse structures. Indene core structure

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