Synthesis method of 2-thiopheneethylamine

Abstract

The invention discloses a synthesis method of 2-thiopheneethylamine, which comprises the following steps: Friedel-Crafts alkylation reaction: reacting thiophene with 1-bromo-2-chloroethane in a first organic solvent under the catalysis of Lewis acid to obtain 2-(2-bromoethyl) thiophene; and ammonolysis reaction: reacting the 2-(2-bromoethyl) thiophene with an ammonolysis reagent to obtain the 2-thiopheneethylamine. The 2-thiopheneethylamine is obtained through Friedel-Crafts alkylation reaction and ammoniation reaction in a non-aqueous medium by taking thiophene as an initial raw material, and in the whole synthesis process, the atom economy is high, an expensive catalyst is not needed, the reaction condition is mild, the yield is high, aftertreatment is simple, used chemicals can be recycled and reused, pollution is small, and the method is suitable for industrial production; meanwhile, the method avoids using a large amount of strong acid and strong alkali, is less in wastewater discharge and environment-friendly, and obviously reduces the production cost.

Description

Technical Field

[0001] The present invention relates to the technical fields of medicine and chemical synthesis, and particularly relates to a method for synthesizing 2-thiopheneethylamine. Background Art

[0002] 2-Thiopheneethylamine is an amino-substituted thiophene derivative, which has certain basicity and strong nucleophilicity, and is easily oxidized and deteriorated by strong oxidants. It is commonly used as a pharmaceutical chemical intermediate and is mostly used in the synthesis of drug molecules and bioactive molecules. For example, it can be used in the preparation of the drug molecule clopidogrel. Clopidogrel is a drug that inhibits platelet aggregation and can be used for the prevention and treatment of cardiovascular, cerebrovascular and other arterial circulation disorders caused by high platelet aggregation, such as recently occurred stroke, myocardial infarction and diagnosed peripheral arterial disease.

[0003] There are many synthetic routes for 2-thiopheneethylamine. Currently, there are 4 mainstream or promising synthetic routes:

[0004] (1) Thiophene undergoes an electrophilic reaction with DMF in the presence of phosphorus oxychloride to obtain 2-thiophenecarboxaldehyde, and then 2-(nitro)thiophene ethylene is prepared from 2-thiophenecarboxaldehyde and nitromethane in the presence of sodium hydroxide. Finally, using diborane generated from potassium borohydride and boron trifluoride ether solution as a reducing agent, 2-(nitro)thiophene ethylene is reduced to 2-thiopheneethylamine. The yield of this method in three steps is 52.3%. The reaction conditions are harsh, a large amount of dangerous reagents are used, and the amount of wastewater is very large, resulting in high costs.

[0005]

[0006] (2) It is obtained by ammonolysis after sulfonylation of 2-thiopheneethanol with p-toluenesulfonyl chloride.

[0007] (3) Thiophene reacts with HCHO and HCl to obtain 2-chloromethylthiophene, which is obtained by cyanide substitution with NaCN and then reduction with LiAlH4. The total yield of this method is 68.6%. The reaction requires highly toxic NaCN and reducing agent LiAlH4, the reaction conditions are dangerous, and the post-treatment is complex.

[0008]

[0009] (4) Using 2-halothiophene as the starting material, after a Grignard reaction, it reacts with N-protected cyclopropidine, and its protecting group is p-toluenesulfonic acid, and then the protecting group is removed to obtain 2-thiopheneethylamine. The total yield of this method is 70.3%. The reaction conditions are dangerous, unstable Grignard reagents are used, and a large amount of acid is used, which does not conform to the principle of green chemistry.

[0010]

[0011] The above synthesis reaction conditions are harsh, requiring the use of toxic substances and reducing agents, which cause environmental pollution and the overall yield is also relatively low. Summary of the Invention

[0012] The purpose of the present invention is to overcome the above technical deficiencies and propose a synthesis method of 2-thiopheneethylamine to solve the technical problems of harsh synthesis reaction conditions and low yield of 2-thiopheneethylamine in the prior art.

[0013] The present invention provides a synthesis method of 2-thiopheneethylamine, including the following steps:

[0014] Friedel-Crafts alkylation reaction: Thiophene reacts with 1-bromo-2-chloroethane in the presence of a Lewis acid catalyst in a first organic solvent to obtain 2-(2-bromoethyl)thiophene;

[0015] Amination reaction: 2-(2-bromoethyl)thiophene reacts with an amination reagent to obtain 2-thiopheneethylamine.

[0016] Compared with the prior art, the beneficial effects of the present invention include:

[0017] The present invention uses thiophene as the starting material, and in a non-aqueous medium, 2-thiopheneethylamine is obtained through Friedel-Crafts alkylation reaction and amination reaction. During the entire synthesis process, the atom economy is high, no expensive catalyst is required, the reaction conditions are mild, the process is simple, the yield is high, the post-treatment is simple, the chemicals used can be recycled and reused, the pollution is small, and it is suitable for industrial production; at the same time, the present invention avoids the use of a large amount of strong acids and bases, has less wastewater discharge, is environmentally friendly, and significantly reduces the production cost. Detailed Embodiments

[0018] In order to make the purpose, technical solutions and advantages of the present invention clearer, the following further describes the present invention in detail with reference to embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0019] The present invention provides a synthesis method of 2-thiopheneethylamine, including the following steps:

[0020] S1. Friedel-Crafts alkylation reaction: Thiophene reacts with 1-bromo-2-chloroethane in the presence of a Lewis acid catalyst in a first organic solvent to obtain 2-(2-bromoethyl)thiophene;

[0021] S2. Amination reaction: 2-(2-bromoethyl)thiophene reacts with an amination reagent to obtain 2-thiopheneethylamine. The specific reaction formula is as follows:

[0022]

[0023] In this embodiment, the Lewis acid is at least one of aluminum trichloride, titanium tetrachloride, lithium chloride, gallium chloride, indium trichloride, boron trifluoride, or trimethylaluminum.

[0024] In this embodiment, the first organic solvent is at least one of dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, N,N-dimethylformamide, or methyl tert-butyl ether.

[0025] In this embodiment, the molar ratio of thiophene to the Lewis acid and 1-bromo-2-chloroethane is 1:(1.5 - 3):(1 - 2), and further 1:(1.8 - 2.5):(1 - 1.2).

[0026] In this embodiment, the dosage ratio of thiophene to the first organic solvent is 0.1 - 5 mol:1 L, and further 0.5 - 1 mol:1 L.

[0027] In this embodiment, the temperature of the Friedel-Crafts alkylation reaction is 30°C - 80°C, and the time of the Friedel-Crafts alkylation reaction is 5 - 10 hours.

[0028] In some specific embodiments of the present invention, the steps of the above Friedel-Crafts alkylation reaction include: at -5°C - 0°C, add 1-bromo-2-chloroethane and the Lewis acid to the first organic solvent, keep warm for 0.5 - 5 hours, then control the temperature to -15°C to -5°C, add thiophene, and after the addition of thiophene is complete, raise the temperature to 30°C - 80°C and react for 5 - 10 hours; after the reaction is completed, cool, add dilute hydrochloric acid until the solution is clear, extract and concentrate, and perform vacuum distillation to collect the fraction at 93 - 96°C / 2.2 Kpa to obtain 2-(2-bromoethyl)thiophene. Among them, the extractant is dichloromethane.

[0029] In this embodiment, the ammoniating reagent is ammonia or potassium phthalimide.

[0030] In this embodiment, the ammoniating reagent is ammonia, and the molar ratio of 2-(2-bromoethyl)thiophene to the ammoniating reagent is 1:(5 - 10).

[0031] In the embodiment of the present invention, the ammoniating reagent is ammonia, and the ammoniation reaction is carried out under a second organic solvent.

[0032] Among them, the second organic solvent is at least one of water, methanol, ethanol, dioxane, or tetrahydrofuran.

[0033] Among them, the dosage ratio of 2-(2-bromoethyl)thiophene to the second organic solvent is 1 g:(1 - 10) mL, and further 1 g:(2 - 8) mL.

[0034] In this embodiment, the ammoniating reagent is ammonia, the temperature of the ammoniation reaction is 80 - 120°C, and the time of the ammoniation reaction is 4 - 10 h.

[0035] In some more specific embodiments of the present invention, the ammoniating reagent is ammonia. The steps of the above ammoniation reaction include: adding 2-(2-bromoethyl)thiophene, the ammoniating reagent, and optionally a second organic solvent into a pressure-resistant reaction vessel, reacting at a temperature of 80 - 120°C for 4 - 10 hours, cooling after the reaction is completed, filtering, and subjecting to vacuum rectification to collect the fraction at 95 - 99°C / 2.2 KPa to obtain 2-thiopheneethylamine.

[0036] In this embodiment, the ammoniating reagent is potassium phthalimide, and the molar ratio of 2-(2-bromoethyl)thiophene to the ammoniating reagent is 1:(1.01 - 1.5).

[0037] In some specific embodiments of the present invention, the ammoniating reagent is potassium phthalimide. The steps of the above ammoniation reaction include:

[0038] Dissolve 2-(2-bromoethyl)thiophene and potassium phthalimide in a third organic solvent, then raise the temperature to 120°C - 160°C and react for 1 - 5 hours. After the reaction is completed, add water, cool to 0 - 5°C and stir for 0.5 - 2 hours, then filter and dry to obtain an intermediate product; wherein, the third organic solvent is N,N-dimethylformamide (DMF); the dosage ratio of 2-(2-bromoethyl)thiophene to the third organic solvent is 1 g:(5 - 10) mL; the dosage ratio of 2-(2-bromoethyl)thiophene to water is 1 g:(1 - 3) mL;

[0039] Dissolve the intermediate product in a fourth organic solvent, then raise the temperature to 90°C - 110°C, and then dropwise add a hydrazine hydrate solution, keep stirring for 2 - 6 hours while maintaining the temperature, cool and then filter, wash the filter residue with a fifth organic solvent, concentrate the filtrate, and subject to vacuum rectification to collect the fraction at 95 - 99°C / 2.2 KPa to obtain 2-thiopheneethylamine; wherein, the concentration of the hydrazine hydrate solution is 60 - 80%; the molar ratio of the intermediate product to hydrazine hydrate is 1:(2 - 3); the fourth organic solvent and the fifth organic solvent are each selected from at least one of methanol or ethanol; the dosage ratio of the intermediate product to the fourth organic solvent is 1 g:(5 - 15) mL.

[0040] Example 1

[0041] (1) At 0 °C, add 26.6 g (0.2 mol) of aluminum trichloride and 150 mL of dichloromethane to a 250 mL single-necked flask. Then slowly add dropwise 15.7 g (0.11 mol) of 1-bromo-2-chloroethane. After maintaining the temperature for one hour, cool down to -10 °C, and slowly add dropwise 8.4 g (0.1 mol) of thiophene. After the addition is complete, slowly heat up to 80 °C and react for 8 hours. After the reaction is completed, cool it down, add dropwise dilute hydrochloric acid until the solution becomes clear, extract and concentrate with dichloromethane, and perform vacuum distillation to collect the fraction at 93 - 96 °C / 2.2 Kpa to obtain 2-(2-bromoethyl)thiophene (16.2 g), with a yield of 85% and a GC purity of 98%.

[0042] (2) At room temperature, add 47.7 g (0.25 mol) of 2-(2-bromoethyl)thiophene and 170 mL of an ethanol solution of ammonia (22 - 25%) to a 250 mL pressure-resistant flask. Slowly heat up to 100 °C and maintain the temperature for 4 hours. After the reaction is completed, cool it down to room temperature, filter, and perform vacuum rectification to collect the fraction at 95 - 99 °C / 2.2 Kpa to obtain 2-thiopheneethylamine (26.0 g), with a yield of 82% and a GC purity of 97.4%.

[0043] Example 2

[0044] (1) At -5 °C, add 44.2 g (0.2 mol) of indium trichloride and 150 mL of dichloromethane to a 250 mL single-necked flask. Then slowly add dropwise 15.7 g (0.11 mol) of 1-bromo-2-chloroethane. After maintaining the temperature for one hour, cool down to -10 °C, and slowly add dropwise 8.4 g (0.1 mol) of thiophene. After the addition is complete, slowly heat up to 80 °C and react for 8 hours. After the reaction is completed, cool it down, add dropwise dilute hydrochloric acid until the solution becomes clear, extract and concentrate with dichloromethane, and perform vacuum distillation to collect the fraction at 93 - 96 °C / 2.2 Kpa to obtain 2-(2-bromoethyl)thiophene (17.2 g), with a yield of 90% and a GC purity of 98.1%.

[0045] (2) At room temperature, add 47.7 g (0.25 mol) of 2-(2-bromoethyl)thiophene and 280 mL of a methanol solution of ammonia (7M) to a 250 mL pressure-resistant flask. Slowly heat up to 100 °C and maintain the temperature for 6 hours. After the reaction is completed, cool it down to room temperature, filter, and perform vacuum rectification to collect the fraction at 95 - 99 °C / 2.2 KPa to obtain 2-thiopheneethylamine (27.6 g), with a yield of 87% and a GC purity of 97.1%.

[0046] Example 3

[0047] (1) At -5°C, add 37.9 g (0.2 mol) of titanium tetrachloride and 150 mL of dichloromethane to a 250 mL single-necked flask. Then slowly add dropwise 15.7 g (0.11 mol) of 1-bromo-2-chloroethane. After keeping the temperature at -5°C for one hour, cool the mixture to -10°C and slowly add dropwise 8.4 g (0.1 mol) of thiophene. After the addition is complete, slowly heat the mixture to 80°C and react for 8 hours. After the reaction is completed, cool the mixture, add dilute hydrochloric acid dropwise until the solution becomes clear, extract and concentrate with dichloromethane, and perform vacuum distillation to collect the fraction at 93 - 96°C / 2.2 Kpa to obtain 2-(2-bromoethyl)thiophene (16.6 g), with a yield of 87% and a GC purity of 98%.

[0048] (2) At room temperature, dissolve 47.7 g (0.25 mol) of 2-(2-bromoethyl)thiophene and 50.8 g (0.275 mol) of potassium phthalimide in 300 mL of DMF. Heat the mixture to 140°C and react for 2 hours. Add 100 mL of water, cool the mixture to 0°C and stir for 1 hour, filter and dry to obtain 61 g of a yellow solid (MW = 257), with a yield of 95%. Dissolve 51.4 g (0.2 mol) of the yellow solid obtained in the previous step in 500 mL of ethanol, heat the mixture to 100°C and then add dropwise 25 g (0.4 mol) of hydrazine hydrate (80%). Keep the temperature and stir for 4 hours, cool and filter, wash the filter residue with ethanol, concentrate the filtrate, and perform vacuum rectification to collect the fraction at 95 - 99°C / 2.2 Kpa to obtain 2-thiopheneethylamine (23.6 g), with a yield of 93% and a GC purity of 97.2%.

[0049] The specific embodiments of the present invention described above do not constitute a limitation to the protection scope of the present invention. Any other corresponding changes and deformations made according to the technical concept of the present invention shall be included within the protection scope of the claims of the present invention.

Claims

1. A method for synthesizing 2-thiopheneethylamine, characterized in that, It includes the following steps: Friedel-Crafts alkylation reaction: Thiophene reacts with 1-bromo-2-chloroethane in the presence of a Lewis acid catalyst in a first organic solvent to obtain 2-(2-bromoethyl)thiophene; Amination reaction: The 2-(2-bromoethyl)thiophene reacts with an amination reagent to obtain 2-thiopheneethylamine.

2. The synthetic method of 2-thiopheneethylamine according to claim 1, characterized in that, The molar ratio of the thiophene, the Lewis acid, and 1-bromo-2-chloroethane is 1:(1.5 - 3):(1 - 2); the temperature of the Friedel-Crafts alkylation reaction is 30°C - 80°C, and the time of the Friedel-Crafts alkylation reaction is 5 - 10 hours.

3. The synthesis method of 2-thiopheneethylamine according to claim 1, characterized in that, The Lewis acid is at least one of aluminum trichloride, titanium tetrachloride, lithium chloride, gallium chloride, indium trichloride, boron trifluoride, or trimethylaluminum; the first organic solvent is at least one of dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, N,N-dimethylformamide, or methyl tert-butyl ether; the dosage ratio of the thiophene to the first organic solvent is 0.1 - 5 mol:1 L.

4. The synthesis method of 2-thiopheneethylamine according to claim 1, wherein, The steps of the Friedel-Crafts alkylation reaction include: at -5°C - 0°C, add 1-bromo-2-chloroethane and the Lewis acid to the first organic solvent, keep warm for 0.5 - 5 hours, then control the temperature to -15°C to -5°C, add thiophene, and after the thiophene is added dropwise, raise the temperature to 30°C - 80°C and react for 5 - 10 hours; after the reaction is completed, cool, add dilute hydrochloric acid until the solution is clear, extract and concentrate, and perform vacuum distillation to collect the fraction at 93 - 96°C / 2.2 Kpa to obtain 2-(2-bromoethyl)thiophene.

5. The synthesis method of 2-thiopheneethylamine according to claim 1, wherein, The amination reagent is ammonia, and the molar ratio of the 2-(2-bromoethyl)thiophene to the amination reagent is 1:(5 - 10); the temperature of the amination reaction is 80 - 120°C, and the time of the amination reaction is 4 - 10 hours.

6. The synthesis method of 2-thiopheneethylamine according to claim 5, characterized in that, The amination reaction is carried out in a second organic solvent; the second organic solvent is at least one of water, methanol, ethanol, dioxane, or tetrahydrofuran; the dosage ratio of the 2-(2-bromoethyl)thiophene to the second organic solvent is 1 g:(1 - 10) mL.

7. The synthesis method of 2-thiopheneethylamine according to claim 5, wherein The amination reagent is ammonia, and the steps of the amination reaction include: add 2-(2-bromoethyl)thiophene, the amination reagent, and optionally the second organic solvent to a pressure-resistant reaction vessel, react at a temperature of 80 - 120°C, keep warm for 4 - 10 hours, cool after the reaction is completed, filter, perform vacuum distillation, and collect the fraction at 95 - 99°C / 2.2 KPa to obtain 2-thiopheneethylamine.

8. The synthetic method of 2-thiopheneethylamine according to claim 1, characterized in that, The amination reagent is potassium phthalimide, and the molar ratio of the 2-(2-bromoethyl)thiophene to the amination reagent is 1:(1.01 - 1.5).

9. The synthesis method of 2-thiopheneethylamine according to claim 8, wherein The amination reagent is potassium phthalimide, and the steps of the amination reaction include: Dissolve 2-(2-bromoethyl)thiophene and potassium phthalimide in a third organic solvent, then raise the temperature to 120°C - 160°C and react for 1 - 5 hours. After the reaction is completed, add water, cool to 0 - 5°C and stir for 0.5 - 2 hours, and then filter and dry to obtain an intermediate product; Dissolve the intermediate product in a fourth organic solvent, then heat it to 90°C - 110°C, and then dropwise add a hydrazine hydrate solution. Keep stirring for 2 - 6 hours, filter after cooling, wash the filter residue with a fifth organic solvent, concentrate the filtrate, and perform vacuum rectification to collect the fraction at 95 - 99°C / 2.2 Kpa to obtain 2-thiopheneethylamine.

10. The synthetic method of 2-thiopheneethylamine according to claim 9, characterized in that, The third organic solvent is N,N-dimethylformamide; the dosage ratio of 2-(2-bromoethyl)thiophene to the third organic solvent is 1 g : (5 - 10) mL; the dosage ratio of 2-(2-bromoethyl)thiophene to water is 1 g : (1 - 3) mL; the concentration of the hydrazine hydrate solution is 60 - 80%; the molar ratio of the intermediate product to hydrazine hydrate is 1 : (2 - 3); the fourth organic solvent and the fifth organic solvent are each selected from at least one of methanol or ethanol; the dosage ratio of the intermediate product to the fourth organic solvent is 1 g : (5 - 15) mL.

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