Method for synthesizing 2-thiophene ethylamine

Abstract

The invention relates to a method for synthesizing 2-thiophene ethylamine, which is characterized in that thiophene is taken as a raw material, intermediate 2-thiophene ethanol is firstly prepared, and then the 2-thiophene ethylamine is obtained through pressurization and ammonolysis. The method mainly comprises the following steps: bromizing thiofuran at low temperature to obtain 2-bromo thiophene; carrying out Grignard reaction on the 2-bromo thiophene and magnesiumchips and reacting with ethylene oxide to generate the 2-thiophene ethanol; and preparing 2-thiophene ethylamine from the 2-thiophene ethanol through the two steps of esterification and ammonolysis. The invention takes cheap and easily obtained thiophene as the raw material which is subjected to the fives reactions of bromination, Grignard, addition, esterification and ammonolysis, greatly reduces the production cost, has mild reaction condition, simple process and small pollution, facilities the realization of the industrialized production, does not use the reducing agent and avoids the utilization of expensive or toxic materials.

Description

technical field

[0001] The invention relates to a preparation method of 2-thienylethylamine, which belongs to the technical fields of medicine and chemical industry. Background technique

[0002] 2-Thienylethylamine is an intermediate of biologically active drugs such as blood lipid-lowering drugs, platelet aggregation inhibitors, cardiovascular relaxants, 5-lipoxygenase inhibitors and various antibacterial drugs, and is mainly used in the synthesis of cardiovascular and cerebrovascular diseases. The important drugs are ticlopidine hydrochloride and clopidogrel bisulfate. With the continuous development of downstream drugs, 2-thienylethylamine has become a fine chemical intermediate that has attracted much attention.

[0003] There are many synthetic routes of 2-thiopheneethylamine reported publicly, among which there are mainly three routes for industrialization or industrial application prospects: nitromethane method, isopropyl chloroacetate method and 2-thiophenecetonitr...

Examples

Embodiment 1

[0037] Example 1. A kind of synthetic method of 2-thienylethylamine, its step is as follows:

[0038] (1) Preparation of 2-bromothiophene: In the presence of an organic solvent, add a brominating agent dropwise to thiophene, control the reaction temperature at -10°C, keep the temperature for 2 hours after the dropwise addition, separate layers, remove the solvent, and then decompress The product is collected by distillation at 45°C / 1.73Kpa; the organic solvent is glacial acetic acid or carbon tetrachloride; the brominating agent is N-succinimide, pyridine hydrobromide, bromine or hydrogen bromide One of the acids; the molar ratio of the substance is: thiophene:brominating agent=1:2;

[0039] (2) Preparation of 2-thiophene ethanol: take 2-bromothiophene and magnesium chips to undergo Grignard reaction in anhydrous solvent, add ethylene oxide to the reaction solution at 0°C, acidify with dilute sulfuric acid to pH< 1. After layering, add an appropriate amount of antioxidant, p...

Embodiment 2

[0041] Example 2. A kind of synthetic method of 2-thienylethylamine, its step is as follows:

[0042] (1) Preparation of 2-bromothiophene: In the presence of an organic solvent, add a brominating agent dropwise to thiophene, control the reaction temperature at 10°C, keep the temperature for 6 hours after the dropwise addition, separate layers, remove the solvent, and then distill under reduced pressure Collect the 47°C / 1.73Kpa fraction to obtain the product; the organic solvent is dichloroethane or toluene; the brominating agent is N-succinimide, pyridine hydrobromide, bromine or hydrobromic acid Two kinds of; The molar ratio of substance is: thiophene: brominating agent=1: 3.0;

[0043] (2) Preparation of 2-thiophene ethanol: take 2-bromothiophene and magnesium chips to undergo Grignard reaction in anhydrous solvent, add ethylene oxide to the reaction solution at 20°C, acidify with dilute sulfuric acid to pH< 1. After layering, add an appropriate amount of antioxidant, remove...

Embodiment 3

[0045] Example 3. A kind of synthetic method of 2-thienylethylamine, its step is as follows:

[0046] (1) Preparation of 2-bromothiophene: in the presence of an organic solvent, add a brominating agent dropwise to thiophene, control the reaction temperature to 0°C, keep the reaction for 4 hours after the dropwise addition, separate layers, remove the solvent, and then distill under reduced pressure Collect 46 ℃ / 1.73Kpa fraction to obtain product; Described organic solvent is acetonitrile; Described brominating agent is the mixture of bromine and hydrobromic acid, and the molar ratio of the two is 1: 1; The molar ratio of substance is: Thiophene:brominating agent=1:2.5;

[0047] (2) Preparation of 2-thiophene ethanol: take 2-bromothiophene and magnesium chips to undergo Grignard reaction in anhydrous solvent, add ethylene oxide to the reaction solution at 9°C, acidify with dilute sulfuric acid to pH< 1. After layering, add an appropriate amount of antioxidant, remove the solv...

technical field

[0001] The invention relates to a preparation method of 2-thienylethylamine, which belongs to the technical fields of medicine and chemical industry. Background technique

[0002] 2-Thienylethylamine is an intermediate of biologically active drugs such as blood lipid-lowering drugs, platelet aggregation inhibitors, cardiovascular relaxants, 5-lipoxygenase inhibitors and various antibacterial drugs, and is mainly used in the synthesis of cardiovascular and cerebrovascular diseases. The important drugs are ticlopidine hydrochloride and clopidogrel bisulfate. With the continuous development of downstream drugs, 2-thienylethylamine has become a fine chemical intermediate that has attracted much attention.

[0003] There are many synthetic routes of 2-thiopheneethylamine reported publicly, among which there are mainly three routes for industrialization or industrial application prospects: nitromethane method, isopropyl chloroacetate method and 2-thiophenecetonitr...

Examples

Embodiment 1

[0037] Example 1. A kind of synthetic method of 2-thienylethylamine, its step is as follows:

[0038] (1) Preparation of 2-bromothiophene: In the presence of an organic solvent, add a brominating agent dropwise to thiophene, control the reaction temperature at -10°C, keep the temperature for 2 hours after the dropwise addition, separate layers, remove the solvent, and then decompress The product is collected by distillation at 45°C / 1.73Kpa; the organic solvent is glacial acetic acid or carbon tetrachloride; the brominating agent is N-succinimide, pyridine hydrobromide, bromine or hydrogen bromide One of the acids; the molar ratio of the substance is: thiophene:brominating agent=1:2;

[0039] (2) Preparation of 2-thiophene ethanol: take 2-bromothiophene and magnesium chips to undergo Grignard reaction in anhydrous solvent, add ethylene oxide to the reaction solution at 0°C, acidify with dilute sulfuric acid to pH< 1. After layering, add an appropriate amount of antioxidant, p...

Embodiment 2

[0041] Example 2. A kind of synthetic method of 2-thienylethylamine, its step is as follows:

[0042] (1) Preparation of 2-bromothiophene: In the presence of an organic solvent, add a brominating agent dropwise to thiophene, control the reaction temperature at 10°C, keep the temperature for 6 hours after the dropwise addition, separate layers, remove the solvent, and then distill under reduced pressure Collect the 47°C / 1.73Kpa fraction to obtain the product; the organic solvent is dichloroethane or toluene; the brominating agent is N-succinimide, pyridine hydrobromide, bromine or hydrobromic acid Two kinds of; The molar ratio of substance is: thiophene: brominating agent=1: 3.0;

[0043] (2) Preparation of 2-thiophene ethanol: take 2-bromothiophene and magnesium chips to undergo Grignard reaction in anhydrous solvent, add ethylene oxide to the reaction solution at 20°C, acidify with dilute sulfuric acid to pH< 1. After layering, add an appropriate amount of antioxidant, remove...

Embodiment 3

[0045] Example 3. A kind of synthetic method of 2-thienylethylamine, its step is as follows:

[0046] (1) Preparation of 2-bromothiophene: in the presence of an organic solvent, add a brominating agent dropwise to thiophene, control the reaction temperature to 0°C, keep the reaction for 4 hours after the dropwise addition, separate layers, remove the solvent, and then distill under reduced pressure Collect 46 ℃ / 1.73Kpa fraction to obtain product; Described organic solvent is acetonitrile; Described brominating agent is the mixture of bromine and hydrobromic acid, and the molar ratio of the two is 1: 1; The molar ratio of substance is: Thiophene:brominating agent=1:2.5;

[0047] (2) Preparation of 2-thiophene ethanol: take 2-bromothiophene and magnesium chips to undergo Grignard reaction in anhydrous solvent, add ethylene oxide to the reaction solution at 9°C, acidify with dilute sulfuric acid to pH< 1. After layering, add an appropriate amount of antioxidant, remove the solv...

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