A Green Synthesis Method of Pharmaceutical Intermediate 5-Bromoindole

Abstract

The present invention relates to a kind of green synthesis method of pharmaceutical intermediate 5-bromoindole, comprising the following steps: 1. under the action of metal catalyst, indoline is obtained by hydrogenation of indole in liquid phase at low temperature and low pressure; 2. indoline and acetyl N-acetyl indoline can be generated through the action of chemical reagents; ③N-acetyl-indoline can be cleanly brominated to generate N-acetyl-5-bromoindoline; ④N-acetyl-5-bromoindoline 5-Bromoindoline is obtained by deacylation under acidic conditions; ⑤ 5-Bromoindoline is prepared through oxidative dehydrogenation to prepare the key pharmaceutical intermediate 5-Bromoindole. Compared with the prior art, the beneficial effects of the present invention are: 1) develop a new green synthetic process, compared with the original process, effectively control the brominated isomer of 5-bromoindole products, and ensure that the safety of medical products is higher; 2) Compared with the original acetic anhydride and bromine bromination process, the reaction conditions are mild, the environmental pollution is small, and the cost is low. 3) The equipment investment is small, the process is simple, and the equipment is easy to operate. The corrosion is small, and the process is more suitable for industrial production.

Description

technical field

[0001] The invention relates to a synthesis technology of 5-bromoindole, in particular to a synthesis method for preparing 5-bromoindole from indole through hydrogenation, acylation, bromination, deacylation and oxidative dehydrogenation. Background technique

[0002] 5-Bromoindole, English name 5-Bromoindole, molecular formula C 8 h 6 BrN, with a molecular weight of 196.05, is an important pharmaceutical and chemical intermediate.

[0003] Indole compounds widely exist in nature, and many indoles with substituents on the benzene ring have physiological activity. 5-substituted indole compounds are important intermediates and have important applications in the synthesis of medicines and dyes. Melatonin (melatonin, N-acetyl-5-methoxyyuyptamine), also known as melatonin, is mainly produced from 5-methoxyindole, it acts directly on the hypothalamus, and has the functions of promoting sleep, regulating endocrine, enhancing immunity, etc. Various physiological ...

Examples

example 1

[0092] A green synthesis method for the pharmaceutical intermediate 5-bromoindole, the adopted technical scheme: ① Indoline is obtained from indole through low-temperature and low-pressure liquid-phase hydrogenation; ② Indoline is reacted with an acylating reagent to synthesize N-acetyl Indoline; ③N-acetyl indoline is cleanly brominated to obtain N-acetyl-5-bromoindoline; ④N-acetyl-5-bromoindoline is deacylated under the action of concentrated hydrochloric acid to obtain 5- Bromoindoline; ⑤5-bromoindoline is oxidatively dehydrogenated to obtain the key pharmaceutical intermediate 5-bromoindoline. The specific operation is as follows:

[0093] (1) Synthesis of indoline

[0094] a) Add 100 g (0.85 mol) of indole, 5 g (10% w.t) of palladium carbon catalyst, and 200 g of xylene into an autoclave and stir evenly to obtain a reaction solution A;

[0095] b) After the autoclave is replaced 8 times with nitrogen and 4 times with hydrogen, the reaction solution A is reacted at 2Mpa o...

example 2

[0119] A green synthesis method for the pharmaceutical intermediate 5-bromoindole, the adopted technical scheme: ① Indoline is obtained from indole through low-temperature and low-pressure liquid-phase hydrogenation; ② Indoline is reacted with an acylating reagent to synthesize N-acetyl Indoline; ③N-acetyl indoline is cleanly brominated to obtain N-acetyl-5-bromoindoline; ④N-acetyl-5-bromoindoline is deacylated under the action of concentrated hydrochloric acid to obtain 5- Bromoindoline; ⑤5-bromoindoline is oxidatively dehydrogenated to obtain the key pharmaceutical intermediate 5-bromoindoline. The specific operation is as follows:

[0120] (1) Synthesis of indoline

[0121] a) 100 g (0.85 mol) of indole, 12 g (10% w.t) of palladium carbon catalyst, and 180 g of toluene were put into an autoclave and stirred evenly to obtain a reaction solution A;

[0122] b) After the autoclave has been replaced by nitrogen 8 times and hydrogen 4 times, the reaction solution A is reacted ...

example 3

[0146] A green synthesis method for the pharmaceutical intermediate 5-bromoindole, the adopted technical scheme: ① Indoline is obtained from indole through low-temperature and low-pressure liquid-phase hydrogenation; ② Indoline is reacted with an acylating reagent to synthesize N-acetyl Indoline; ③N-acetyl indoline is cleanly brominated to obtain N-acetyl-5-bromoindoline; ④N-acetyl-5-bromoindoline is deacylated under the action of concentrated hydrochloric acid to obtain 5- Bromoindoline; ⑤5-bromoindoline is oxidatively dehydrogenated to obtain the key pharmaceutical intermediate 5-bromoindoline. The specific operation is as follows:

[0147] (1) Synthesis of indoline

[0148] a) Add 100 g (0.85 mol) of indole, 10 g (10% w.t) of palladium carbon catalyst, and 150 g of xylene into the autoclave and stir evenly to obtain reaction solution A;

[0149] b) After the autoclave has been replaced by nitrogen 8 times and hydrogen 4 times, the reaction solution A is reacted in hydroge...

technical field

[0001] The invention relates to a synthesis technology of 5-bromoindole, in particular to a synthesis method for preparing 5-bromoindole from indole through hydrogenation, acylation, bromination, deacylation and oxidative dehydrogenation. Background technique

[0002] 5-Bromoindole, English name 5-Bromoindole, molecular formula C 8 h 6 BrN, with a molecular weight of 196.05, is an important pharmaceutical and chemical intermediate.

[0003] Indole compounds widely exist in nature, and many indoles with substituents on the benzene ring have physiological activity. 5-substituted indole compounds are important intermediates and have important applications in the synthesis of medicines and dyes. Melatonin (melatonin, N-acetyl-5-methoxyyuyptamine), also known as melatonin, is mainly produced from 5-methoxyindole, it acts directly on the hypothalamus, and has the functions of promoting sleep, regulating endocrine, enhancing immunity, etc. Various physiological ...

Examples

example 1

[0092] A green synthesis method for the pharmaceutical intermediate 5-bromoindole, the adopted technical scheme: ① Indoline is obtained from indole through low-temperature and low-pressure liquid-phase hydrogenation; ② Indoline is reacted with an acylating reagent to synthesize N-acetyl Indoline; ③N-acetyl indoline is cleanly brominated to obtain N-acetyl-5-bromoindoline; ④N-acetyl-5-bromoindoline is deacylated under the action of concentrated hydrochloric acid to obtain 5- Bromoindoline; ⑤5-bromoindoline is oxidatively dehydrogenated to obtain the key pharmaceutical intermediate 5-bromoindoline. The specific operation is as follows:

[0093] (1) Synthesis of indoline

[0094] a) Add 100 g (0.85 mol) of indole, 5 g (10% w.t) of palladium carbon catalyst, and 200 g of xylene into an autoclave and stir evenly to obtain a reaction solution A;

[0095] b) After the autoclave is replaced 8 times with nitrogen and 4 times with hydrogen, the reaction solution A is reacted at 2Mpa o...

example 2

[0119] A green synthesis method for the pharmaceutical intermediate 5-bromoindole, the adopted technical scheme: ① Indoline is obtained from indole through low-temperature and low-pressure liquid-phase hydrogenation; ② Indoline is reacted with an acylating reagent to synthesize N-acetyl Indoline; ③N-acetyl indoline is cleanly brominated to obtain N-acetyl-5-bromoindoline; ④N-acetyl-5-bromoindoline is deacylated under the action of concentrated hydrochloric acid to obtain 5- Bromoindoline; ⑤5-bromoindoline is oxidatively dehydrogenated to obtain the key pharmaceutical intermediate 5-bromoindoline. The specific operation is as follows:

[0120] (1) Synthesis of indoline

[0121] a) 100 g (0.85 mol) of indole, 12 g (10% w.t) of palladium carbon catalyst, and 180 g of toluene were put into an autoclave and stirred evenly to obtain a reaction solution A;

[0122] b) After the autoclave has been replaced by nitrogen 8 times and hydrogen 4 times, the reaction solution A is reacted ...

example 3

[0146] A green synthesis method for the pharmaceutical intermediate 5-bromoindole, the adopted technical scheme: ① Indoline is obtained from indole through low-temperature and low-pressure liquid-phase hydrogenation; ② Indoline is reacted with an acylating reagent to synthesize N-acetyl Indoline; ③N-acetyl indoline is cleanly brominated to obtain N-acetyl-5-bromoindoline; ④N-acetyl-5-bromoindoline is deacylated under the action of concentrated hydrochloric acid to obtain 5- Bromoindoline; ⑤5-bromoindoline is oxidatively dehydrogenated to obtain the key pharmaceutical intermediate 5-bromoindoline. The specific operation is as follows:

[0147] (1) Synthesis of indoline

[0148] a) Add 100 g (0.85 mol) of indole, 10 g (10% w.t) of palladium carbon catalyst, and 150 g of xylene into the autoclave and stir evenly to obtain reaction solution A;

[0149] b) After the autoclave has been replaced by nitrogen 8 times and hydrogen 4 times, the reaction solution A is reacted in hydroge...

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