CN-121974840-A - Nitration method of indole derivative

Abstract

The invention belongs to the field of medicine synthesis, and particularly relates to a nitration method of indole derivatives. According to the invention, acetonitrile is used as a solvent, indole or substituted indole is used as a substrate, copper nitrate trihydrate is used as a nitrifying reagent, and p-toluenesulfonyl chloride is used as an accelerator, so that a series of 3-nitroindole derivatives are obtained in a simple and convenient manner under mild conditions at a high yield. The synthesis method has the characteristics of easily available raw materials, wide substrate application range, short reaction time, simple operation, easy amplification and the like.

Inventors

• HE XIN
• SHAO QI
• JIN YUANFENG
• DONG SHUHAN
• Yin Canyu
• CHEN HUIRU
• DU HAORAN
• SONG WEIJIE
• LIU SHIRONG

Assignees

• 常州工程职业技术学院

Dates

Publication Date

20260505

Application Date

20260317

Claims (7)

1. 1. A nitration method of indole derivatives is characterized in that in the presence of a reaction solvent and an accelerator, a compound 1 reacts with copper nitrate trihydrate to obtain 3-nitroindole derivatives 2, wherein the reaction formula is as follows: , Wherein R is H, C-C6 straight-chain or branched-chain alkyl, C3-C6 cycloalkyl, R 1 is H, C-C6 straight-chain or branched-chain alkyl, C3-C6 cycloalkyl, nitro, cyano, alkoxy, halogen, carboxyl, ester group or trifluoromethyl substituted at any position on the benzene ring, and R 2 is H, C-C6 alkyl, C3-C6 cycloalkyl, ester group, nitro or cyano.
2. 2. The method for nitrifying an indole derivative according to claim 1, wherein R is H, C.about.C4 alkyl, R 1 is H, nitro, cyano, methoxy, fluoro, chloro, bromo, iodo, carboxyl, ester and trifluoromethyl, and R 2 is H, methyl, ester and cyano.
3. 3. The method for nitrifying an indole derivative according to claim 1, wherein the accelerator is one of benzoyl chloride, p-toluenesulfonyl chloride or N-fluoro bis-benzenesulfonimide.
4. 4. The method for nitrifying an indole derivative according to claim 1, wherein the reaction solvent is selected from the group consisting of acetonitrile, ethylene glycol dimethyl ether, tetrahydrofuran, ethyl acetate, 1,4' -dioxane, and a combination of one or more solvents of N, N-dimethylformamide.
5. 5. The nitrifying method of an indole derivative according to claim 1, wherein the feeding molar ratio of the compound 1 to copper nitrate trihydrate to the accelerator is 1:0.5-2.0:1.0-2.0.
6. 6. The method for nitrifying an indole derivative according to claim 1, wherein the reaction temperature is 50 ℃ to 130 ℃.
7. 7. The method for nitrifying an indole derivative according to claim 1, wherein the method further comprises a separation and purification operation after the completion of the reaction.

Description

Nitration method of indole derivative Technical Field The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a nitration method of indole derivatives. Background The compound with indole nucleus is an important skeleton of a large number of natural products and medicines, and the medicines taking indole as the nucleus are mainly used for resisting rheumatism, inflammation, depression and the like, and particularly have wide biological activity in the field of resisting tumors. The 3-nitroindole is used as a multipurpose reaction substrate, has the characteristic of strong plasticity of functional groups, and can be further derivatized to modify drug molecules so as to optimize pharmacological activity and pharmacokinetic properties. The method comprises the steps of introducing nitro into indole ring, reducing and converting the indole ring into intermediate groups such as nitroso, hydroxylamine and amino, removing reduction reaction, activating nitro ortho-position hydrogen atom by electron withdrawing effect of the nitro, carrying out nucleophilic substitution, finally realizing substitution or functionalization of indole ring nitro, and carrying out structural modification on drug molecules. Although indoles themselves have high reactivity, the introduction of nitro groups into the indole ring presents challenges. Since the indole ring is an electron-rich aromatic ring, the nitro group is typically electrophilically substituted into the C3 position. The literature reports that the C3-nitration method of indole mainly comprises the following six steps: (1) The C3 nitration of indole is realized by 6 steps of reaction of indole substrate and tetramethyl ammonium nitrate; (2) The C3 nitration of indole is realized by a phosphine catalysis, benzoyl chloride/iodine simple substance and noble metal silver nitrate system, and the yield is 61%; (3) The system of trichloroisocyanuric acid and sodium nitrite is used for realizing the nitrification of indole C3 by two-step reaction under the action of oxidizing agents such as potassium persulfate and the like, and the yield is 72%; (4) Copper acetate catalysis and tert-butyl nitrate are used as nitrifying agents, and C3 nitrifying is realized through two-step reaction; (5) The N-bromosuccinimide and silver nitrate system is used for realizing the nitrification of indole C3, and the yield is 24%; (6) In an acetic acid system, indole and copper nitrate are nitrified under the microwave condition at a high temperature. In the method, dangerous or strong oxidizing reagents are required to be used, or multi-step reactions are adopted, so that the reaction efficiency and the yield are low, or noble metal nitrifying reagent silver nitrate is adopted, the cost is high, or severe reaction conditions, strong acid conditions, microwaves and high temperature are used, so that the industrialized application of the methods is greatly limited. In view of the important application value of 3-nitroindole and the lack of a reliable preparation method at present, the development of a mild, efficient and industrialized indole nitration method is a technical problem to be solved by the invention. Disclosure of Invention The invention aims to provide an indole C3-position nitration method which is mild in condition, low in cost, simple in post-treatment and convenient and easily available in raw materials. The invention provides a C3-position nitration method of indole derivatives, which has the following reaction formula: In the presence of a reaction solvent, the compound 1 and copper nitrate trihydrate are used for synthesizing the 3-nitroindole derivative 2 under the action of an accelerator. Wherein R is H, C-C6 straight-chain or branched-chain alkyl, C3-C6 cycloalkyl, R 1 is H, C-C6 straight-chain or branched-chain alkyl, C3-C6 cycloalkyl, nitro, cyano, alkoxy, halogen, carboxyl, ester group and trifluoromethyl which are substituted at any position on a benzene ring, and R 2 is H, C-C6 alkyl, C3-C6 cycloalkyl, ester group, nitro or cyano. Preferably, R is H, C-C4 alkyl, R 1 is H, nitro, cyano, methoxy, fluoro, chloro, bromo, iodo, carboxyl, ester group and trifluoromethyl, and R 2 is H, methyl, ester group and cyano. The reaction solvent is selected from one or more solvents selected from toluene, chlorobenzene, N ' -dimethylformamide, tetrahydrofuran, 1,4' -dioxane, water, ethylene glycol dimethyl ether, acetonitrile and acetic acid, preferably acetonitrile, ethylene glycol dimethyl ether, tetrahydrofuran, ethyl acetate, 1,4' -dioxane and N, N-dimethylformamide, and more preferably acetonitrile. The feeding molar ratio of the compound 1 to the copper nitrate trihydrate to the accelerator is 1:0.5-2.0:1.0-2.0, preferably 1:0.5-1.0:1.0-2.0, and more preferably 1:0.5-0.75:1.0-1.5. The reaction temperature is 50-130 ℃, and the reaction temperature is preferably 50-100 ℃; The accelerator used is one of benzoyl chloride, p-toluenesulfonyl chloride a