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

Abstract

The application discloses a preparation method of 1-(2-aminoethyl) pyrrolidine and belongs to the field of chemical synthesis. The application provides a novel synthesis method of 1-(2-aminoethyl) pyrrolidine, which is prepared from 1,2-dichloroethane and pyrrolidine as raw materials, addition of a solvent and alkali, heating reaction, extraction, acidification and reduced-pressure distillation after the reaction is finished to obtain N-(2-chloroethyl) pyrrolidine solution; N-(2-chloroethyl) pyrrolidine and ammonia water are used as raw materials, high-pressure heating reaction is carried out, extraction and reduced-pressure distillation are carried out after the reaction is finished to generate 1-(2-aminoethyl) pyrrolidine. The application has the advantages of simple operation process, green process synthesis, convenient product purification and high product purity.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, 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 It has a boiling point of 66-70℃ (23 mmHg) and is a transparent, colorless liquid. It can be used in the synthesis of various drugs.

[0003] The literature *European Journal of Medicinal Chemistry*, 166, 2019, 304-317 describes a 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 generate 1-(2-aminoethyl)pyrrolidine. While the N-(2-bromoethyl)phthalimide used in this reaction can be readily prepared by reacting potassium phthalimide with 1,2-dibromoethane, the process is complex. DMF removal is difficult and requires pumping, and hydrazine hydrate is a highly toxic and easily explosive chemical, making post-processing challenging and inconsistent with green production practices.

[0004]

[0005] The literature Tetrahedron Letters, 21(31), 1990, 2991-2994 describes the synthesis of 1-(2-aminoethyl)pyrrolidine from tetrahydrofuran and ethylenediamine catalyzed by a heterogeneous titanium dioxide catalyst. This reaction is simple to operate and uses inexpensive and readily available raw materials, but it yields a low yield and produces a 1,2-bis(pyrrolidine)-ethane byproduct.

[0006]

[0007] Patent CN101613246B describes a reaction in which water, FeCl3·6H2O, and pyrrolidine are added sequentially to a three-necked flask, followed by the slow addition of ethyl acrylate. The reaction is carried out at 30°C for 15 hours, and the resulting pale yellow liquid compound is obtained by column chromatography. This reaction uses ethyl acrylate, an irritating liquid that is harmful to human health. Furthermore, the final purification requires column chromatography, making the process complex and unsuitable for large-scale production.

[0008] Summary of the Invention

[0009] This invention addresses the shortcomings of existing technologies by providing a method for obtaining N-(2-chloroethyl)pyrrolidine from 1,2-dichloroethane and pyrrolidine as raw materials, toluene as solvent, the addition of an alkaline auxiliary agent, heating the reaction, cooling to room temperature after the reaction is complete, and then extracting, acidifying, and distilling under reduced pressure; or from N-(2-chloroethyl)pyrrolidine and ammonia as raw materials, heating the reaction under high pressure, cooling to room temperature after the reaction is complete, and then extracting and distilling under reduced pressure to obtain 1-(2-aminoethyl)pyrrolidine.

[0010] Specifically, the technical solution of the present invention is as follows:

[0011]

[0012] (1) Using 1,2-dichloroethane and pyrrolidine as raw materials, a solvent and an alkaline auxiliary agent were added, and the reaction was heated. After the reaction was completed, the mixture was cooled to room temperature, and N-(2-chloroethyl)pyrrolidine solution was obtained by extraction, acidification and vacuum distillation. (2) Using N-(2-chloroethyl)pyrrolidine and ammonia as raw materials, the mixture was heated under high pressure. After the reaction was completed, the mixture was cooled to room temperature, and 1-(2-aminoethyl)pyrrolidine was obtained by extraction and vacuum distillation.

[0013] More preferably, in step (1) of the above preparation method, the solvent used is one of toluene, isopropanol, and N,N-dimethylformamide, with toluene being the preferred solvent.

[0014] More preferably, in step (1) of the above preparation method, the molar ratio of 1,2-dichloroethane to pyrrolidine is 2.5 to 3.5:1, the molar ratio of pyrrolidine to base is 1:0.8 to 1.5, the preferred molar ratio of 1,2-dichloroethane to pyrrolidine is 1:3, and the preferred molar ratio of pyrrolidine to base is 1:1.

[0015] More preferably, in step (1) of the above preparation method, the alkali used is one of sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, DMAP, and tetrabutylammonium iodide, with DMAP being the preferred alkali.

[0016] More preferably, in step (1) of the above preparation method, the reaction time is 4 to 6 hours, and the preferred reaction time is 4 hours.

[0017] More preferably, in step (1) of the above preparation method, the reaction temperature is 50-60°C, and more preferably 55°C.

[0018] More preferably, the reaction pressure of the high-pressure heating reaction in step (2) of the above preparation method is 0.2 to 0.3 MPa, and more preferably 0.2 MPa.

[0019] More preferably, in step (2) of the above preparation method, the molar ratio of N-(2-chloroethyl)pyrrolidine to ammonia is 1:7 to 10, preferably 1:7.

[0020] More preferably, the reaction time of step (2) of the above preparation method is 2 to 4 hours, and the preferred reaction time is 3 hours.

[0021] The beneficial effects of this invention are:

[0022] In reactions using N-(2-bromoethyl)phthalimide and pyrrolidine as raw materials, the procedures are complex, solvent removal is difficult, and the hydrazine hydrate used is a highly toxic explosive, making post-processing challenging. The method for synthesizing 1-(2-aminoethyl)pyrrolidine from tetrahydrofuran and ethylenediamine generates numerous byproducts and has a low yield. The reaction using pyrrolidine and ethyl acrylate as raw materials uses ethyl acrylate, an irritating liquid that harms human health, and requires column chromatography for post-processing, making large-scale production difficult. In contrast, the raw materials used in this invention are inexpensive and non-toxic, the reaction is simple, and the resulting product has high yield and high purity, showing great potential for scale-up. Detailed Implementation

[0023] To further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, and not for limiting the scope of the claims of the present invention.

[0024] Example 1

[0025] Take a 100ml three-necked flask, add 41.6g (3eq) of 1,2-dichloroethane and 40ml of toluene, and then add DMAP (17.15g, 1eq). Heat to 55℃, and slowly add pyrrolidine (10g, 1eq) dropwise. After the addition is complete, continue the reaction for 4 hours. After the reaction is complete, add 30ml of water, adjust the pH to 9 with hydrochloric acid, separate the layers, and retain the organic phase. After drying with anhydrous sodium sulfate, distill under reduced pressure to obtain N-(2-chloroethyl)pyrrolidine. The gas phase purity is 99.2%, and the yield is 91.6%.

[0026] Example 2

[0027] Take a 100ml three-necked flask and add 34.80g (2.5eq) of 1,2-dichloroethane and 40ml of toluene, followed by DMAP (17.15g, 1eq). Heat to 55℃ and slowly add pyrrolidine (10g, 1eq) dropwise. After the addition is complete, continue the reaction for 4 hours. After the reaction is complete, add 30ml of water and adjust the pH to 9 with hydrochloric acid. Separate the mixture, retaining the organic phase. After drying with anhydrous sodium sulfate, distill under reduced pressure to obtain N-(2-chloroethyl)pyrrolidine. The gas phase purity was 98.1%, and the yield was 87.5%.

[0028] Example 3

[0029] Take a 100ml three-necked flask and add 1,2-dichloroethane (48.72g, 3.5eq) and toluene (40ml), then add DMAP (17.15g, 1eq). Heat to 55℃ and slowly add pyrrolidine (10g, 1eq). After the addition is complete, continue the reaction for 4 hours. After the reaction is complete, add 30ml of water, adjust the pH to 9 with hydrochloric acid, separate the layers, and retain the organic phase. After drying with anhydrous sodium sulfate, distill under reduced pressure to obtain N-(2-chloroethyl)pyrrolidine. The gas phase purity is 98.8%, and the yield is 88.6%.

[0030] Example 4

[0031] Take a 100ml three-necked flask and add 41.6g (3eq) of 1,2-dichloroethane and 40ml of toluene, followed by DMAP (13.66g, 0.8eq). Heat to 55℃ and slowly add pyrrolidine (10g, 1eq). After the addition is complete, continue the reaction for 4 hours. After the reaction is complete, add 30ml of water, adjust the pH to 9 with hydrochloric acid, separate the layers, and retain the organic phase. After drying with anhydrous sodium sulfate, distill under reduced pressure to obtain N-(2-chloroethyl)pyrrolidine. The gas phase purity is 98.1%, and the yield is 88.2%.

[0032] Example 5

[0033] Take a 100ml three-necked flask and add 41.6g (3eq) of 1,2-dichloroethane and 40ml of toluene, followed by DMAP (25.62g, 1.5eq). Heat to 55℃ and slowly add pyrrolidine (10g, 1eq). After the addition is complete, continue the reaction for 4 hours. After the reaction is complete, add 30ml of water, adjust the pH to 9 with hydrochloric acid, separate the layers, and retain the organic phase. Dry the mixture with anhydrous sodium sulfate, and then distill under reduced pressure to obtain N-(2-chloroethyl)pyrrolidine. The gas phase purity is 98.2%, and the yield is 87.9%.

[0034] Example 6

[0035] Take a 100ml three-necked flask, add 41.6g (3eq) of 1,2-dichloroethane and 40ml of toluene, and add DMAP (17.15g, 1eq). Heat to 55℃, and slowly add pyrrolidine (10g, 1eq). After the addition is complete, continue the reaction for 6 hours. After the reaction is complete, add 30ml of water, adjust the pH to 9 with hydrochloric acid, separate the layers, and retain the organic phase. After drying with anhydrous sodium sulfate, distill under reduced pressure to obtain N-(2-chloroethyl)pyrrolidine. The gas phase purity is 98.0%, and the yield is 86.9%.

[0036] Example 7

[0037] Take a 100ml three-necked flask, add 41.6g (3eq) of 1,2-dichloroethane and 40ml of toluene, and add DMAP (17.15g, 1eq). Heat to 50℃, and slowly add pyrrolidine (10g, 1eq). After the addition is complete, continue the reaction for 4 hours. After the reaction is complete, add 30ml of water, adjust the pH to 9 with hydrochloric acid, separate the layers, and retain the organic phase. After drying with anhydrous sodium sulfate, distill under reduced pressure to obtain N-(2-chloroethyl)pyrrolidine. The gas phase purity is 98.4%, and the yield is 87.5%.

[0038] Example 8

[0039] Take a 100ml three-necked flask, add 41.6g (3eq) of 1,2-dichloroethane and 40ml of toluene, and then add DMAP (17.15g, 1eq). Heat to 60℃, and slowly add pyrrolidine (10g, 1eq) dropwise. After the addition is complete, continue the reaction for 4 hours. After the reaction is complete, add 30ml of water, adjust the pH to 9 with hydrochloric acid, separate the layers, and retain the organic phase. After drying with anhydrous sodium sulfate, distill under reduced pressure to obtain N-(2-chloroethyl)pyrrolidine. The gas phase purity is 98.3%, and the yield is 88.1%.

[0040] Example 9

[0041] Take a 100ml three-necked flask, add 41.6g (3eq) of 1,2-dichloroethane and 40ml of toluene, and then add 5.62g (1eq) of NaOH. Heat to 55℃, and slowly add pyrrolidine (10g (1eq) dropwise. After the addition is complete, continue the reaction for 4 hours. After the reaction is complete, add 30ml of water, adjust the pH to 9 with hydrochloric acid, separate the layers, and retain the organic phase. After drying with anhydrous sodium sulfate, distill under reduced pressure to obtain N-(2-chloroethyl)pyrrolidine. The gas phase purity is 98.7%, and the yield is 87.2%.

[0042] Example 10

[0043] Take a 100 mL reaction vessel, add N-(2-chloroethyl)pyrrolidine (8 g, 1 eq) and ammonia water (52.63 g, 7 eq), heat to 60 °C, and the pressure of the reaction vessel is 0.2 MPa. React for 3 h. After the reaction is completed, add 90 mL of dichloromethane for extraction three times. After drying the organic phase with anhydrous sodium sulfate, distill under reduced pressure to obtain the product 1-(2-aminoethyl)pyrrolidine. The gas phase purity is 98.2% and the yield is 86.5%.

[0044] Example 11

[0045] Take a 100 mL reaction vessel, add N-(2-chloroethyl)pyrrolidine (8 g, 1 eq) and ammonia water (75.19 g, 10 eq), heat to 60 °C, and the pressure of the reaction vessel is 0.2 MPa. React for 3 h. After the reaction is completed, add 90 mL of dichloromethane for extraction three times. After drying the organic phase with anhydrous sodium sulfate, distill under reduced pressure to obtain the product 1-(2-aminoethyl)pyrrolidine. The gas phase purity is 98.2% and the yield is 87.9%.

[0046] Example 12

[0047] Take a 100 mL reaction vessel, add N-(2-chloroethyl)pyrrolidine (8 g, 1 eq) and ammonia water (52.63 g, 7 eq), heat to 60 °C, and the pressure of the reaction vessel is 0.3 MPa. React for 3 h. After the reaction is completed, add 90 mL of dichloromethane for extraction three times. After drying the organic phase with anhydrous sodium sulfate, distill under reduced pressure to obtain the product 1-(2-aminoethyl)pyrrolidine. The gas phase purity is 97.9% and the yield is 86.4%.

[0048] Example 13

[0049] Take a 100 mL reaction vessel, add N-(2-chloroethyl)pyrrolidine (8 g, 1 eq) and ammonia water (52.63 g, 7 eq), heat to 60 °C, and the pressure of the reaction vessel is 0.2 MPa. React for 4 h. After the reaction is completed, add 90 mL of dichloromethane for extraction three times. After drying the organic phase with anhydrous sodium sulfate, distill under reduced pressure to obtain the product 1-(2-aminoethyl)pyrrolidine. The gas phase purity is 97.7% and the yield is 86.6%.

[0050] Example 14

[0051] Take a 100 mL reaction vessel, add N-(2-chloroethyl)pyrrolidine (8 g, 1 eq) and ammonia water (52.63 g, 7 eq), heat to 60 °C, and the pressure of the reaction vessel is 0.2 MPa. React for 2 h. After the reaction is completed, add 90 mL of dichloromethane for extraction three times. After drying the organic phase with anhydrous sodium sulfate, distill under reduced pressure to obtain the product 1-(2-aminoethyl)pyrrolidine. The gas phase purity is 97.8% and the yield is 86.5%.

[0052] Comparative Example 1

[0053] Take a 100ml three-necked flask and add 41.6g (3eq) of 1,2-dichloroethane and 40ml of toluene. Heat to 55℃ and slowly add pyrrolidine (10g, 1eq). After the addition is complete, continue the reaction for 4 hours. After the reaction is complete, add 30ml of water, adjust the pH to 9 with hydrochloric acid, separate the layers, and retain the organic phase. After drying with anhydrous sodium sulfate, distill under reduced pressure to obtain N-(2-chloroethyl)pyrrolidine. The gas phase purity is 84.2%, and the yield is 50.4%.

[0054] Comparative Example 2

[0055] Take a 100ml three-necked flask, add 1,2-dichloroethane (13.92g, 1eq) and toluene (40ml), then add DMAP (17.15g, 1eq). Heat to 55℃, and slowly add pyrrolidine (10g, 1eq). After the addition is complete, continue the reaction for 4 hours. After the reaction is complete, add 30ml of water, adjust the pH to 9 with hydrochloric acid, separate the layers, and retain the organic phase. After drying with anhydrous sodium sulfate, distill under reduced pressure to obtain N-(2-chloroethyl)pyrrolidine. The gas phase purity is 72.4%, and the yield is 60.4%.

[0056] Comparative Example 3

[0057] Take a 100ml three-necked flask and add 41.6g (3eq) of 1,2-dichloroethane and 40ml of toluene, followed by DMAP (17.15g, 1eq). Heat to 80℃ and slowly add pyrrolidine (10g, 1eq) dropwise. After the addition is complete, continue the reaction for 4 hours. After the reaction is complete, add 30ml of water, adjust the pH to 9 with hydrochloric acid, separate the layers, and retain the organic phase. Dry the mixture with anhydrous sodium sulfate, and then distill under reduced pressure to obtain N-(2-chloroethyl)pyrrolidine. The gas phase purity is 81.6%, and the yield is 69.7%.

[0058] Comparative Example 4

[0059] Take a 100 mL three-necked flask, add N-(2-chloroethyl)pyrrolidine (8 g, 1 eq) and ammonia water (52.63 g, 7 eq), heat to 60 °C and react at atmospheric pressure for 3 h; after the reaction is complete, add 90 mL of dichloromethane for extraction three times, dry the organic phase with anhydrous sodium sulfate, and then distill under reduced pressure to obtain the product 1-(2-aminoethyl)pyrrolidine, the gas phase purity is 41.2, and the yield is 35.8%.

[0060] Comparative Example 5

[0061] Take a 100 mL reaction vessel, add N-(2-chloroethyl)pyrrolidine (8 g, 1 eq) and ammonia water (37.52 g, 5 eq), heat to 60 °C, and the pressure of the reaction vessel is 0.2 MPa. React for 3 h. After the reaction is completed, add 90 mL of dichloromethane for extraction three times. After drying the organic phase with anhydrous sodium sulfate, distill under reduced pressure to obtain the product 1-(2-aminoethyl)pyrrolidine. The gas phase purity is 80.1% and the yield is 72.5%.

[0062] While the specific embodiments of the present invention have been described above in conjunction with examples, they are not intended to limit the implementation of the present invention. For those skilled in the art, various modifications or variations that can be made without creative effort based on the technical solutions of the present invention are still within the protection scope of the present invention.

Claims

1. A method for preparing 1-(2-aminoethyl)pyrrolidine, characterized in that, The reaction equation is as follows: ， The specific preparation method is as follows: (1) Using 1,2-dichloroethane and pyrrolidine as raw materials, a solvent and alkali are added and the mixture is heated to react. After the reaction is completed, the mixture is extracted, acidified, and distilled under reduced pressure to produce an N-(2-chloroethyl)pyrrolidine solution. The molar ratio of 1,2-dichloroethane to pyrrolidine is 2.5-3.5:1, the molar ratio of pyrrolidine to alkali is 1:0.8-1.5, and the reaction temperature is 50-60 °C. (2) Using N-(2-chloroethyl)pyrrolidine and ammonia as raw materials, the reaction is heated. After the reaction is completed, 1-(2-aminoethyl)pyrrolidine is obtained by extraction and vacuum distillation. The reaction pressure is 0.2-0.3 MPa and the molar ratio of N-(2-chloroethyl)pyrrolidine to ammonia is 1:7-10.

2. The method for preparing 1-(2-aminoethyl)pyrrolidine as described in claim 1, characterized in that, The solvent used in step (1) is one of toluene, isopropanol, and N,N-dimethylformamide.

3. The method for preparing 1-(2-aminoethyl)pyrrolidine as described in claim 1, characterized in that, The alkali used in step (1) is one of sodium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, DMAP, and tetrabutylammonium iodide.

4. The method for preparing 1-(2-aminoethyl)pyrrolidine as described in claim 1, characterized in that, The reaction time for step (1) is 4-6 h.

5. The method for preparing 1-(2-aminoethyl)pyrrolidine as described in claim 1, characterized in that, The reaction time is 2-4 hours.

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