A process for the preparation of 1-(2-aminoethyl)pyrrolidine

Abstract

The application discloses a method for preparing 1-(2-aminoethyl) pyrrolidine and belongs to the field of chemical synthesis. The method comprises the following steps: taking tetrahydropyrrole as raw material, adding chloroacetonitrile under a certain temperature for reaction in the presence of an alkali solution as an acid-binding agent, and then performing static layer separation and liquid separation on the reaction solution after the reaction is completed; 1-pyrrolidine acetonitrile is obtained by performing reduced pressure distillation on the organic phase; and then, 1-(2-aminoethyl) pyrrolidine is obtained by performing hydrogenation reduction reaction on 1-pyrrolidine acetonitrile under the action of a catalyst Ni(0)-Fe(0) / rGO and by performing filtration and reduced pressure distillation after the reaction is completed. The method has the advantages of simple operation process, green synthesis process, convenient product purification and high product purity.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, and specifically to a method for preparing 1-(2-aminoethyl)pyrrolidine. Background Technology

[0002] 1-(2-aminoethyl)pyrrolidine, with the molecular formula C6H 14 N2, CAS No.: 7154-73-6, Molecular weight: 114.189, Density: 0.901 g / cm³ 3 With a boiling point of 66-70℃ (23 mmHg), it is a transparent, colorless liquid with important biological activity. It is a key intermediate for cephalosporin antibiotics such as cefdinir. Its chemical structural formula is as follows:

[0003]

[0004] The literature (European Journal of Medicinal Chemistry, 166, 2019, 304-317) describes the reaction of N-(2-bromoethyl)phthalimide and pyrrolidine in DMF to produce 2-(2-(pyrrolidine-1-yl)ethyl)isoindoline-1,3-dione, followed by hydrazolysis with hydrazine hydrate to produce 1-(2-aminoethyl)pyrrolidine. While the N-(2-bromoethyl)phthalimide used in this reaction can be easily prepared by reacting potassium phthalimide with 1,2-dibromoethane, the process is complex. DMF is difficult to remove, requiring the use of an oil pump, and hydrazine hydrate is a highly toxic and easily explosive chemical, making post-processing difficult and failing to meet the requirements of green production.

[0005]

[0006] Patent CN101613246B describes the preparation of 1-(2-aminoethyl)pyrrolidine by Michael addition, followed by hydrazolysis, and finally Curtius rearrangement of pyrrolidine. While the reaction is simple, the raw material ethyl acrylate is an irritating liquid that can harm human health, and the final purification requires column chromatography, making the process complex and unsuitable for large-scale production.

[0007]

[0008] Patent CN118530196A describes a reaction using aminoacetaldehyde diol as a raw material. By adding an acid catalyst to the reaction system, aminoacetaldehyde is generated in situ, further reacting with pyrrolidine to form an enamine. This enamine is then continuously hydrogenated and reduced in a microreactor to obtain 1-(2-aminoethyl)pyrrolidine. This reaction has the advantages of low raw material cost and short reaction time, but the palladium catalyst used is expensive, making it uneconomical for industrial scale-up.

[0009]

[0010] In summary, the existing synthesis processes for 1-(2-aminoethyl)pyrrolidine all have shortcomings, and there is a need to develop more economical, efficient, and safer synthesis technologies. Summary of the Invention

[0011] The method for synthesizing 1-(2-aminoethyl)pyrrolidine provided by this invention uses tetrahydropyrrole as a raw material, adds an alkaline solution as an acid-binding agent, and then heats to a certain temperature before adding chloroacetonitrile to carry out the reaction. After the reaction is completed, the reaction solution is allowed to stand and separate into layers. The organic phase is then distilled under reduced pressure to obtain 1-pyrrolidineacetonitrile. Using ethanol as a solvent, 1-pyrrolidineacetonitrile is added, hydrogen gas is introduced, and the reaction system is adjusted to a set pressure. Under the action of the catalyst Ni(O)-Fe(O) / rGO, the reaction is heated to carry out a catalytic hydrogenation reaction. After the reaction is completed, the catalyst is separated by filtration, and 1-(2-aminoethyl)pyrrolidine is obtained by reduced pressure distillation.

[0012] Specifically, the technical solution of the present invention is as follows:

[0013]

[0014] (1) Using tetrahydropyrrole as raw material, an alkaline solution was added as an acid-binding agent. Then, after heating to a certain temperature, chloroacetonitrile was added to carry out the reaction. After the reaction was completed, the reaction solution was allowed to stand and separate into layers. The organic phase was then distilled under reduced pressure to obtain 1-pyrrole acetonitrile.

[0015] (2) Using ethanol as a solvent, 1-pyrrolidine acetonitrile was added. Under the action of the catalyst Ni(0)-Fe(0) / rGO, hydrogen gas was introduced and the reaction system was adjusted to a set pressure. The reaction was then heated to carry out a catalytic hydrogenation reaction. After the reaction was completed, the catalyst was separated by filtration, and 1-(2-aminoethyl)pyrrolidine was obtained by vacuum distillation.

[0016] More preferably, in step (1) of the above preparation method, the alkaline solution used is one of sodium hydroxide solution, sodium carbonate solution, potassium hydroxide solution, potassium carbonate solution, and cesium carbonate solution, with sodium hydroxide solution being preferred.

[0017] More preferably, in step (1) of the above preparation method, the molar concentration of the alkaline solution used is 6 to 8 mol / L, preferably 7.2 to 7.5 mol / L.

[0018] More preferably, in step (1) of the above preparation method, the reaction temperature is 20℃~40℃, and more preferably 30~35℃.

[0019] More preferably, in step (1) of the above preparation method, the molar ratio of tetrahydropyrrole to chloroacetonitrile is 1:1 to 1.8, the molar ratio of tetrahydropyrrole to base is 1:0.8 to 1.5, the preferred molar ratio of tetrahydropyrrole to chloroacetonitrile is 1:1.3 to 1.4, and the preferred molar ratio of tetrahydropyrrole to base is 1:1.3 to 1.4.

[0020] More preferably, in step (2) of the above preparation method, the molar ratio of 1-pyrrolidine acetonitrile to ethanol is 1:2 to 3, and more preferably the molar ratio is 1:2.1 to 2.5.

[0021] More preferably, in step (2) of the above preparation method, the amount of the catalyst Ni(0)-Fe(0) / rGO added is 0.2% to 0.5% of the mass of 1-pyrrolidine acetonitrile, preferably 0.4%.

[0022] In a further preferred embodiment, in step (2) of the above preparation method, the catalyst Ni(0)-Fe(0) / rGO is prepared by mixing a graphene oxide solution with a solution of hydrated nickel chloride and hydrated ferric chloride. The mass ratio of graphene oxide to hydrated nickel chloride is 1:0.5 to 1:0, and the mass ratio of graphene oxide to hydrated ferric chloride is 1:0.2 to 1. After ultrasonic dispersion, urea and sodium hydroxide aqueous solution are added, and then hydrazine hydrate is slowly added dropwise. The mass ratio of graphene oxide to hydrazine hydrate is 1:3 to 5. After the addition is complete, the mixture is transferred to a hydrothermal reactor and reacted at 190°C for 5 hours. After the system is cooled to room temperature, it is washed three times with anhydrous ethanol and deionized water, and then vacuum dried to obtain the catalyst Ni(0)-Fe(0) / rGO.

[0023] More preferably, in step (2) of the above preparation method, the mass ratio of 1-pyrrolidine acetonitrile to ethanol is 1:1 to 3, and the molar ratio is preferably 1.2 to 2.2.

[0024] More preferably, in step (2) of the above preparation method, the hydrogen pressure is controlled at 0.3 to 0.8 MPa, and the preferred hydrogen pressure is 0.4 to 0.6 MPa.

[0025] More preferably, in step (2) of the above preparation method, the reaction temperature is 50℃~80℃, and more preferably 60~65℃.

[0026] The beneficial effects of this invention are:

[0027] (1) The raw materials used in this method are readily available, the reaction operation is simple, the reaction process meets the requirements of green chemistry, and it has the potential for industrial scale-up.

[0028] (2) The present invention can improve the atomic utilization rate, reduce the waste of raw materials, and reduce production costs while reducing the emissions of waste gas, wastewater, and solid waste.

[0029] (3) The product obtained by this reaction has a high yield and high purity (the yield is above 95% and the purity is above 99%), which enhances the quality and applicability of the product. Detailed Implementation

[0030] Preparation of catalyst Ni(0)-Fe(0) / rGO)

[0031] Weigh 1g of graphene oxide (GO) and add it to a round-bottom flask containing 60mL of ethylene glycol. Sonicate for 15min. Then, add 20mL of ethylene glycol solution of NiCl2·6H2O (2.7g) and FeCl3·6H2O (2.7g) directly to the resulting suspension. Then add 5g of urea and 5mL of sodium hydroxide aqueous solution (6mol / L) and stir for 10min. Then, add 8mL of hydrazine hydrate dropwise to the above solution using a syringe and stir for 10min. Transfer the mixture to a hydrothermal reactor (100mL) and react at 190℃ for 5h. After the system cools to room temperature, wash three times with anhydrous ethanol and deionized water, and vacuum dry (60℃, 3h) to obtain the Ni(0)-Fe(0) / rGO catalyst.

[0032] Example 1:

[0033] Tetrahydropyrrole (10 g, 1 eq) was added to a 100 mL three-necked flask, and NaOH solution (25.2 mL, 7.2 mol / L) was slowly added dropwise. After the addition was completed, the mixture was heated to 30 °C and stirred for 40 min. Chloroacetonitrile (13.74 g, 1.3 eq) was slowly added dropwise. After the addition was completed, the reaction was continued for 4 h. After the reaction was completed, the mixture was separated, and the upper organic phase was retained. After drying with anhydrous sodium sulfate, 1-pyrrolidine acetonitrile (15.17 g) was obtained by vacuum distillation, with a yield of 98.1% and a gas phase purity of 99.4%.

[0034] 15.17 g of 1-pyrrolidine acetonitrile, 20 g of ethanol, and 0.06 g of Ni(0)-Fe(0) / rGO catalyst were added to the hydrogenation reactor. The reactor was stirred and purged with nitrogen three times, followed by hydrogen purging three times. Hydrogen gas was then introduced and the hydrogen pressure was controlled at 0.4 MPa. The reactor was reacted at 60 °C for 5 h. After the reaction was completed, the reactor was allowed to cool naturally to room temperature. The reaction solution was filtered after depressurization and then distilled under reduced pressure to obtain 1-(2-aminoethyl)pyrrolidine (15.03 g), with a yield of 97.2% and a purity of 99.3%.

[0035] Example 2:

[0036] Tetrahydropyrrole (10 g, 1 eq) was added to a 100 mL three-necked flask, and NaOH solution (25.2 mL, 7.2 mol / L) was slowly added dropwise. After the addition was completed, the mixture was heated to 35 °C and stirred for 40 min. Chloroacetonitrile (13.74 g, 1.3 eq) was slowly added dropwise. After the addition was completed, the reaction was continued for 4 h. After the reaction was completed, the mixture was separated, and the upper organic phase was retained. After drying with anhydrous sodium sulfate, 1-pyrrolidine acetonitrile (14.74 g) was obtained by vacuum distillation, with a yield of 96.5% and a gas phase purity of 99.3%.

[0037] 14.74 g of 1-pyrrolidine acetonitrile, 20 g of ethanol, and 0.06 g of Ni(0)-Fe(0) / rGO catalyst were added to the hydrogenation reactor. The reactor was stirred, purged with nitrogen three times, then with hydrogen three times. Hydrogen gas was introduced and the hydrogen pressure was controlled at 0.5 MPa. The reaction was carried out at 60 °C for 5 h. After the reaction was completed, the reactor was allowed to cool naturally to room temperature. After depressurization, the reaction solution was filtered and then distilled under reduced pressure to obtain 1-(2-aminoethyl)pyrrolidine (14.64 g), with a yield of 96.2% and a purity of 99.5%.

[0038] Example 3:

[0039] Add 10 g (1 eq) of tetrahydropyrrole to a 100 mL three-necked flask, and slowly add 25.2 mL (7.5 mol / L) of NaOH solution. After the addition is complete, heat to 30 °C and stir for 40 min. Then slowly add 13.74 g (1.3 eq) of chloroacetonitrile. After the addition is complete, continue the reaction for 4 h. After the reaction is complete, separate the liquid and retain the upper organic phase. After drying with anhydrous sodium sulfate, distill under reduced pressure to obtain 1-pyrrolidine acetonitrile with a yield of 95.8% and a gas phase purity of 99%.

[0040] 14.95 g of 1-pyrrolidine acetonitrile, 20 g of ethanol, and 0.06 g of Ni(0)-Fe(0) / rGO catalyst were added to the hydrogenation reactor. The reactor was stirred, purged with nitrogen three times, then with hydrogen three times. Hydrogen gas was introduced and the hydrogen pressure was controlled at 0.6 MPa. The reactor was reacted at 60 °C for 5 h. After the reaction was completed, the reactor was allowed to cool naturally to room temperature. The reaction solution was filtered after depressurization and then distilled under reduced pressure to obtain 1-(2-aminoethyl)pyrrolidine (14.68 g), with a yield of 97.1% and a purity of 99.5%.

[0041] Comparative Example 1:

[0042] Tetrahydropyrrole (10 g, 1 eq) was added to a 100 mL three-necked flask, and NaOH solution (25.2 mL, 2 mol / L) was slowly added dropwise. After the addition was completed, the mixture was heated to 40 °C and stirred for 40 min. Chloroacetonitrile (13.74 g, 1.3 eq) was slowly added dropwise. After the addition was completed, the reaction was continued for 4 h. After the reaction was completed, the mixture was separated, and the upper organic phase was retained. After drying with anhydrous sodium sulfate, 1-pyrrolidine acetonitrile (9.44 g) was obtained by vacuum distillation, with a yield of 60.5% and a gas phase purity of 98.4%.

[0043] 9.44 g of 1-pyrrolidine acetonitrile, 15 g of ethanol, and 0.036 g of Ni(0)-Fe(0) / rGO catalyst were added to the hydrogenation reactor. Stirring was started, and the reactor was purged with nitrogen three times, followed by hydrogen purging three times. Hydrogen gas was then introduced, and the hydrogen pressure was controlled at 0.2 MPa. The hydrogenation catalytic reaction was carried out at 60°C for 5 hours. After the reaction was completed, the reactor was allowed to cool naturally to room temperature. After depressurization, the reaction solution was filtered, and 1-(2-aminoethyl)pyrrolidine (7.18 g) was obtained by vacuum distillation, with a yield of 75.2% and a gas phase purity of 97.3%.

[0044] Comparative Example 2:

[0045] Add 10 g (1 eq) of tetrahydropyrrole to a 100 mL three-necked flask, and slowly add 25.2 mL (7.2 mol / L) of NaOH solution. After the addition is complete, cool to 20 °C and stir for 40 min. Then slowly add 13.74 g (1.3 eq) of chloroacetonitrile. After the addition is complete, continue the reaction for 4 h. After the reaction is complete, separate the liquid and retain the upper organic phase. After drying with anhydrous sodium sulfate, distill under reduced pressure to obtain 7.18 g of 1-pyrrolidine acetonitrile, with a yield of 45.5% and a gas phase purity of 98.4%.

[0046] 7.18 g of 1-pyrrolidine acetonitrile, 15 g of ethanol, and 0.028 g of Ni(0)-Fe(0) / rGO catalyst were added to a hydrogenation reactor. Stirring was started, and the reactor was purged with nitrogen three times, followed by hydrogen purging three times. Hydrogen gas was then introduced, and the hydrogen pressure was controlled at 2.0 MPa. The hydrogenation catalytic reaction was carried out at 60°C for 5 hours. After the reaction was completed, the reactor was allowed to cool naturally to room temperature. After depressurization, the reaction solution was filtered, and 1-(2-aminoethyl)pyrrolidine (7.18 g) was obtained by vacuum distillation. The yield was 95.2%, and the gas phase purity was 97.3%.

[0047] Comparative Example 3:

[0048] (1) Add water (60 ml), FeCl3·6H2O (0.97 g, 0.1 eq), and tetrahydropyrrole (4.3 g, 1 eq) to a 150 ml three-necked flask in sequence, and slowly add ethyl acrylate (7.7 ml, 1.2 eq). Stir and react at 30 °C for 15 h. Separate the intermediate (I) (9.2 g) by column chromatography.

[0049] (2) Add 80% hydrazine hydrate (7.5 ml, 3 eq) and ethanol (30 ml) to a 150 ml three-necked flask in sequence. Slowly add a mixture of ethanol (10 ml) and intermediate (I) (9.2 g, 1 eq) dropwise. Keep the temperature below 40 °C. Stir the reaction for about 30 min and then heat to reflux for 8 h. Separate intermediate (II) (6.2 g) by column chromatography.

[0050] (3) Add intermediate (II) (6.2 g, 1 eq), water (30 ml), and concentrated hydrochloric acid (10 ml, 3 eq) to a 150 ml three-necked flask. Place the flask on an ice bath and slowly add a 20 ml solution of water containing NaNO2 (3.32 g, 1.6 eq). After reacting for 0.5 h, heat to 90 °C and react for 7 h. Cool to room temperature, adjust the pH to 9-10 with NaOH, evaporate the solvent, place the flask on an ice bath, wash with methanol, and filter to obtain a yellow filtrate. Separate the filtrate by column chromatography to obtain 1-(2-aminoethyl)pyrrolidine (3.2 g), with a yield of 47.1% and a gas phase purity of 97.3%.

[0051] While the specific embodiments of the present invention have been described above, they are not intended to limit the scope of protection of the present invention. Those skilled in the art should understand that various modifications or variations that can be made by those skilled in the art without creative effort based on the technical solutions of the present invention are still within the scope of protection of the present invention.

Claims

1. A method for preparing 1-(2-aminoethyl)pyrrolidine, characterized in that, The preparation method includes: ； (1) Using tetrahydropyrrole as raw material, an alkaline solution was added as an acid-binding agent. After heating to a certain temperature, chloroacetonitrile was added to carry out the reaction. After the reaction was completed, the reaction solution was allowed to stand and separate into layers. The organic phase was distilled under reduced pressure to obtain 1-pyrrolidinyl acetonitrile. (2) Using ethanol as a solvent, 1-pyrrolidine acetonitrile was added. Under the action of the catalyst Ni(0)-Fe(0) / rGO, hydrogen gas was introduced and the reaction system was adjusted to the set pressure. The reaction was heated to carry out catalytic hydrogenation. After the reaction was completed, the catalyst was separated by filtration and 1-(2-aminoethyl)pyrrolidine was obtained by vacuum distillation. The catalyst Ni(0)-Fe(0) / rGO was prepared by mixing graphene oxide solution with solutions of hydrated nickel chloride and hydrated ferric chloride. The mass ratio of graphene oxide to hydrated nickel chloride was 1:0.5~1:0, and the mass ratio of graphene oxide to hydrated ferric chloride was 1:0.2~1. After ultrasonic dispersion, urea and sodium hydroxide aqueous solution were added, and then hydrazine hydrate was slowly added dropwise. The mass ratio of graphene oxide to hydrazine hydrate was 1:3~5. After the addition was completed, the mixture was transferred to a hydrothermal reactor and reacted at 190℃ for 5 minutes. h, after the system was cooled to room temperature, it was washed three times with anhydrous ethanol and deionized water, and then dried under vacuum to obtain the catalyst Ni(0)-Fe(0) / rGO.

2. The method for preparing 1-(2-aminoethyl)pyrrolidine according to claim 1, characterized in that, In step (1), the molar ratio of tetrahydropyrrole to chloroacetonitrile is 1:1.2~1.5, the molar ratio of tetrahydropyrrole to base is 1:1.2~1.5, and the reaction temperature is 20℃~40℃.

3. The method for preparing 1-(2-aminoethyl)pyrrolidine according to claim 1, characterized in that, The alkaline solution used in step (1) is one of sodium hydroxide aqueous solution, sodium carbonate aqueous solution, potassium hydroxide aqueous solution, potassium carbonate aqueous solution, or cesium carbonate aqueous solution, and the molar concentration of the alkaline solution used is 6~8 mol / L.

4. The method for preparing 1-(2-aminoethyl)pyrrolidine according to claim 1, characterized in that, The amount of catalyst added in step (2) is 0.2% to 0.5% of the mass of 1-pyrrolidine acetonitrile.

5. The method for preparing 1-(2-aminoethyl)pyrrolidine according to claim 1, characterized in that, In step (2), the mass ratio of 1-pyrrolidine acetonitrile to ethanol is 1:1~3.

6. The method for preparing 1-(2-aminoethyl)pyrrolidine according to claim 1, characterized in that, In step (2), the hydrogen pressure is controlled at 0.3~0.8 MPa and the reaction temperature is 50~80℃.

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