A process for the preparation of N-ethyl-2-(N-methylpyrrolyl)pyrrole

Abstract

The application belongs to the technical field of organic synthesis, and discloses a preparation method of N-ethyl-2-(N-methyl pyrrolyl) pyrrole, which comprises the following steps: dissolving 1-furfuryl pyrrole, ethylamine and ethanol in water, adding hydrochloric acid into the water, heating and reacting, the reaction temperature is 150-180 DEG C, and the reaction time is 15-35 h; and the target product is obtained. The 1-furfuryl pyrrole is prepared by condensation reaction of 2-furfurylamine and 2,5-dimethoxy tetrahydrofuran, and then the target product N-ethyl-2-(N-methyl pyrrolyl) pyrrole is prepared by reaction of the 1-furfuryl pyrrole and ethylamine, and the raw materials are relatively cheap and have high industrial value.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing N-ethyl-2-(N-methylpyrrole)pyrrole. Background Technology

[0002] The statements herein provide only background information in relation to this invention and do not necessarily constitute prior art.

[0003] N-Ethyl-2-(N-methylpyrrolidinyl)pyrrole is an organic compound containing a bipyrrole ring structure. Its molecule includes N-ethyl and N-methyl-substituted pyrrole groups, classifying it as a pyrrole derivative, and it is commonly used in the food and cosmetic industries. When applied in the food industry, N-ethyl-2-(N-methylpyrrolidinyl)pyrrole acts as a flavor enhancer, imparting a richer, fuller, and more layered roasted flavor profile, thus enhancing its aromatic characteristics. When used in cosmetics, it can provide an elegant and long-lasting fragrance, enhancing the sensory experience of the product.

[0004] Currently, the synthesis methods for N-ethyl-2-(N-methylpyrrolidinyl)pyrrole generally involve using pyrrole or pyrrole-like compounds as raw materials to prepare N-ethylpyrrole and N-hydroxymethylpyrrole, respectively, and then substituting them in the presence of triphenylphosphine to obtain the target product. However, the raw material pyrrole is expensive, and the substitution process easily produces 3-position and iso-substitution byproducts. The resulting product has a mixed configuration, which is difficult to separate and purify. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing N-ethyl-2-(N-methylpyrrolidinyl)pyrrole. This method uses cheaper furan derivatives to replace pyrrole raw materials, obtaining a target product with a single configuration ratio. This route uses readily available raw materials, has controllable costs, and is more feasible for industrialization.

[0006] To achieve the above objectives, the present invention is implemented through the following technical solution:

[0007] A method for preparing N-ethyl-2-(N-methylpyrrolidinyl)pyrrole includes the following steps:

[0008] Dissolve 1-furfurylpyrrole, ethylamine, and ethanol in water, add hydrochloric acid, and heat the mixture to react at 150-180℃ for 15-25 hours; the product is then obtained.

[0009] The beneficial effects achieved by one or more embodiments of the present invention described above are as follows:

[0010] Adding hydrochloric acid to the reaction system generates ethylamine hydrochloride, which can have a significant catalytic effect and effectively shorten the reaction time.

[0011] 1-Furfurylpyrrole was prepared by condensation reaction of 2-furanmethylamine and 2,5-dimethoxytetrahydrofuran, and then the target product N-ethyl-2-(N-methylpyrrol)pyrrole was prepared by reaction of 1-furylpyrrole with ethylamine. The raw materials used are relatively inexpensive and have high industrial value. Attached Figure Description

[0012] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0013] Figure 1 This is the 1H NMR spectrum of N-ethyl-2-(N-methylpyrrolidinyl)pyrrole, the product prepared in Example 1. Detailed Implementation

[0014] It should be noted that the following detailed description is illustrative and intended to provide further explanation of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0015] To address the problems of high raw material costs, easy generation of byproducts, and difficulty in separation and purification in the preparation of N-ethyl-2-(N-methylpyrrolidinyl)pyrrole in existing technologies, this invention provides a method for preparing N-ethyl-2-(N-methylpyrrolidinyl)pyrrole, comprising the following steps:

[0016] Dissolve 1-furfurylpyrrole, ethylamine, and ethanol in water, add hydrochloric acid, and heat the mixture to react at 150-180℃ for 15-35 hours; the product is then obtained.

[0017] The specific reaction route is as follows:

[0018] .

[0019] In existing technologies using pyrrole as a raw material, the 2 and 3 positions of the pyrrole ring are active sites, making them prone to 3-position substitution or isosubstitution side reactions, resulting in products with mixed configurations. This invention uses 1-furfurylpyrrole (a furan derivative), whose steric hindrance and electronic effects within the furan ring prevent the formation of multi-substitution byproducts, thereby achieving the directed synthesis of a single-configuration product and improving purity from the source.

[0020] Hydrochloric acid reacts with ethylamine to form ethylamine hydrochloride, which acts as a protic acid catalyst with strong catalytic activity. It can significantly reduce the activation energy of the reaction and shorten the reaction time. High temperature (150-180℃) further promotes molecular motion and the forward shift of the reaction equilibrium, enabling the raw materials to be fully converted and improving the yield of the target product.

[0021] Ethanol-water mixed solvent can effectively dissolve raw materials such as 1-furfurylpyrrole and ethylamine, ensuring uniform reaction and reducing side reactions caused by excessively high local concentrations.

[0022] In some embodiments, the mass ratio of 1-furfurylpyrrole, ethylamine, ethanol and water is 1:0.5-0.8:3-5:1.5-2.5.

[0023] In some embodiments, the added hydrochloric acid accounts for 0.3-1% of the total mass of the reaction system, and the concentration of the hydrochloric acid is 30-35%, where % is a mass percentage.

[0024] In some embodiments, the reaction temperature is 155-165°C and the reaction time is 18-22 hours.

[0025] In some embodiments, 1-furfurylpyrrole is prepared by condensation of 2-furanmethylamine and 2,5-dimethoxytetrahydrofuran.

[0026] In some embodiments, the method further includes a step of separating and purifying the prepared N-ethyl-2-(N-methylpyrrole)pyrrole.

[0027] Preferably, the separation and purification method is as follows: after the reaction is completed, the system is cooled and depressurized, ethanol is removed, the reaction solution is extracted with methyl tert-butyl ether, and after concentration, crude N-ethyl-2-(N-methylpyrrol)pyrrole is obtained.

[0028] The crude N-ethyl-2-(N-methylpyrrolidinyl)pyrrole was purified by silica gel column chromatography. The eluent was a mixed solvent of cyclohexane and ethyl acetate, with a volume ratio of cyclohexane to ethyl acetate of 85-92:8-15.

[0029] More preferably, in the mixed solvent, the volume ratio of cyclohexane to ethyl acetate is 88-92:8-12.

[0030] In this eluent system, cyclohexane, as a weakly polar solvent, dominates the separation, while ethyl acetate adjusts the polarity to achieve effective distribution of the target product and impurities. It is suitable for separating moderately polar pyrrole derivatives.

[0031] The present invention will be further described below with reference to the embodiments.

[0032] Example 1

[0033] A method for preparing N-ethyl-2-(N-methylpyrrolidinyl)pyrrole includes the following steps:

[0034] 1) The preparation method of 1-furfurylpyrrole is as follows: 100g of 2-furanmethylamine and 149.7g of 2,5-dimethoxytetrahydrofuran are mixed, and 5.5g of hydrated ferric chloride is added as a catalyst to carry out a condensation reaction. The condensation reaction temperature is 60℃ and the condensation reaction time is 5h to prepare 1-furfurylpyrrole.

[0035] 2) In a 500ml pressure vessel, add 43.7g (2eq) of 70% (% is mass percentage) ethylamine aqueous solution, 50g (1eq) of 1-furfurylpyrrole, 200g of ethanol, 100g of water, and dropwise add 1.9g (0.05eq) of hydrochloric acid (hydrochloric acid concentration is 32%). Secure the pressure vessel, heat to 160℃, maintain the temperature for 20h, cool to room temperature, release pressure, remove ethanol, extract twice with MTBE, and concentrate to obtain 51.3g of crude N-ethyl-2-(N-methylpyrrole)pyrrole.

[0036] The synthesis route is as follows:

[0037] .

[0038] The crude N-ethyl-2-(N-methylpyrrolidinyl)pyrrole was purified by silica gel column chromatography. The specific method is as follows:

[0039] The crude N-ethyl-2-(N-methylpyrrolidinyl)pyrrole prepared above was dissolved in an appropriate amount of eluent (cyclohexane: ethyl acetate = 90:10) and then loaded onto a silica gel chromatography column pre-equilibrated with eluent.

[0040] Elution was performed using a mixed solvent of cyclohexane and ethyl acetate (90:10) as the mobile phase. The elution process was monitored by thin-layer chromatography (TLC), and the eluent containing the target product was collected.

[0041] After merging the target components, the solution was concentrated under reduced pressure to remove the solvent, yielding 43.6 g of a pale yellow oily liquid, with a yield of 73% and a purity of 98.8%. Figure 1 As shown, 1 HNMR (400MHz, CDCl3) δ6.90-6.98(m,3H),6.24(d,1H),6.12(d,2H),5.91-6.11(m,1H),5.02(s,2H),3.58-3.61(m,2H),1.35(t,3H).

[0042] Example 2

[0043] Example 2 is compared with Example 1 in that: in step 2), the addition of hydrochloric acid is omitted, and everything else is the same as in Example 1. The yield of N-ethyl-2-(N-methylpyrrole)pyrrole decreases and the reaction time is prolonged.

[0044] A method for preparing N-ethyl-2-(N-methylpyrrolidinyl)pyrrole includes the following steps:

[0045] 1) The preparation method of 1-furfurylpyrrole is as follows: 100g of 2-furanmethylamine and 149.7g of 2,5-dimethoxytetrahydrofuran are mixed, and 5.5g of hydrated ferric chloride is added as a catalyst to carry out a condensation reaction. The condensation reaction temperature is 60℃ and the condensation reaction time is 5h to prepare 1-furfurylpyrrole.

[0046] 2) In a 500ml pressure vessel, add 43.7g (2eq) of 70% (% is mass percentage) ethylamine aqueous solution, 50g (1eq) of 1-furfurylpyrrole, 170g of ethanol, and 90g of water. Secure the pressure vessel, heat to 160℃, maintain the temperature for 25h, cool to room temperature, release the pressure, remove the ethanol, extract twice with MTBE, and concentrate to obtain crude N-ethyl-2-(N-methylpyrrole)pyrrole.

[0047] The crude N-ethyl-2-(N-methylpyrrolidinyl)pyrrole was purified by silica gel column chromatography. The specific method is as follows:

[0048] The crude N-ethyl-2-(N-methylpyrrolidinyl)pyrrole prepared above was dissolved in an appropriate amount of eluent (cyclohexane: ethyl acetate = 90:10) and then loaded onto a silica gel chromatography column pre-equilibrated with eluent.

[0049] Elution was performed using a mixed solvent of cyclohexane and ethyl acetate (90:10) as the mobile phase. The elution process was monitored by thin-layer chromatography (TLC), and the eluent containing the target product was collected.

[0050] After merging the target components, the solution was concentrated under reduced pressure to remove the solvent, yielding a pale yellow oily liquid with a yield of 35.9% and a purity of 97.9%.

[0051] Example 3

[0052] Compared with Example 1, Example 3 changed the amount of ethylamine added from 2 eq to 1.5 eq, resulting in a decrease in yield.

[0053] A method for preparing N-ethyl-2-(N-methylpyrrolidinyl)pyrrole includes the following steps:

[0054] 1) The preparation method of 1-furfurylpyrrole is as follows: 100g of 2-furanmethylamine and 149.7g of 2,5-dimethoxytetrahydrofuran are mixed, and 5.5g of hydrated ferric chloride is added as a catalyst to carry out a condensation reaction. The condensation reaction temperature is 60℃ and the condensation reaction time is 5h to prepare 1-furfurylpyrrole.

[0055] 2) In a 500ml pressure vessel, add 32.8g (1.5eq) of 70% (% is mass percentage) ethylamine aqueous solution, 50g (1eq) of 1-furfurylpyrrole, 200g of ethanol, 100g of water, and dropwise add 1.9g (0.05eq) of hydrochloric acid (hydrochloric acid concentration is 32%). Secure the pressure vessel, heat to 160℃, maintain the temperature for 20h, cool to room temperature, release pressure, remove ethanol, extract twice with MTBE, and concentrate to obtain 43.5g of crude N-ethyl-2-(N-methylpyrrole)pyrrole.

[0056] The crude N-ethyl-2-(N-methylpyrrolidinyl)pyrrole was purified by silica gel column chromatography. The specific method is as follows:

[0057] The crude N-ethyl-2-(N-methylpyrrolidinyl)pyrrole prepared above was dissolved in an appropriate amount of eluent (cyclohexane: ethyl acetate = 90:10) and then loaded onto a silica gel chromatography column pre-equilibrated with eluent.

[0058] Elution was performed using a mixed solvent of cyclohexane and ethyl acetate (90:10) as the mobile phase. The elution process was monitored by thin-layer chromatography (TLC), and the eluent containing the target product was collected.

[0059] After merging the target components, the solution was concentrated under reduced pressure to remove the solvent, yielding a pale yellow oily liquid with a yield of 58.8% and a purity of 98.3%.

[0060] Example 4

[0061] Compared with Example 1, Example 4 increased the amount of ethylamine aqueous solution from 2.0 eq to 2.5 eq, but the yield did not improve significantly.

[0062] A method for preparing N-ethyl-2-(N-methylpyrrolidinyl)pyrrole includes the following steps:

[0063] 1) The preparation method of 1-furfurylpyrrole is as follows: 100g of 2-furanmethylamine and 149.7g of 2,5-dimethoxytetrahydrofuran are mixed, and 5.5g of hydrated ferric chloride is added as a catalyst to carry out a condensation reaction. The condensation reaction temperature is 60℃ and the condensation reaction time is 5h to prepare 1-furfurylpyrrole.

[0064] 2) In a 500ml pressure vessel, add 54.6g (2.5eq) of 70% (% is mass percentage) ethylamine aqueous solution, 50g (1eq) of 1-furfurylpyrrole, 200g of ethanol, 100g of water, and dropwise add 1.9g (0.05eq) of hydrochloric acid (hydrochloric acid concentration is 32%). Secure the pressure vessel, heat to 160℃, maintain the temperature for 20h, cool to room temperature, release pressure, remove ethanol, extract twice with MTBE, and concentrate to obtain 49.2g of crude N-ethyl-2-(N-methylpyrrole)pyrrole.

[0065] The crude N-ethyl-2-(N-methylpyrrolidinyl)pyrrole was purified by silica gel column chromatography. The specific method is as follows:

[0066] The crude N-ethyl-2-(N-methylpyrrolidinyl)pyrrole prepared above was dissolved in an appropriate amount of eluent (cyclohexane: ethyl acetate = 90:10) and then loaded onto a silica gel chromatography column pre-equilibrated with eluent.

[0067] Elution was performed using a mixed solvent of cyclohexane and ethyl acetate (90:10) as the mobile phase. The elution process was monitored by thin-layer chromatography (TLC), and the eluent containing the target product was collected.

[0068] After merging the target components, the solution was concentrated under reduced pressure to remove the solvent, yielding a pale yellow oily liquid with a yield of 72.3% and a purity of 98.5%.

[0069] Example 5

[0070] Compared with Example 1, Example 5 reduced the reaction temperature to 150°C and extended the reaction time to 30 hours, but the reaction was still incomplete and the yield was low.

[0071] A method for preparing N-ethyl-2-(N-methylpyrrolidinyl)pyrrole includes the following steps:

[0072] Step 1) Same as in Example 1;

[0073] 2) In a 500ml pressure vessel, add 43.7g (2eq) of 70% (% is mass percentage) ethylamine aqueous solution, 50g (1eq) of 1-furfurylpyrrole, 200g of ethanol, 100g of water, and dropwise add 1.9g (0.05eq) of hydrochloric acid (hydrochloric acid concentration is 32%). Secure the pressure vessel, heat to 150℃, maintain the temperature for 30h, cool to room temperature, release pressure, remove ethanol, extract twice with MTBE, and concentrate to obtain 44.8g of crude N-ethyl-2-(N-methylpyrrole)pyrrole.

[0074] The crude N-ethyl-2-(N-methylpyrrolidinyl)pyrrole was purified by silica gel column chromatography. The specific method is as follows:

[0075] The crude N-ethyl-2-(N-methylpyrrolidinyl)pyrrole prepared above was dissolved in an appropriate amount of eluent (cyclohexane: ethyl acetate = 90:10) and then loaded onto a silica gel chromatography column pre-equilibrated with eluent.

[0076] Elution was performed using a mixed solvent of cyclohexane and ethyl acetate (90:10) as the mobile phase. The elution process was monitored by thin-layer chromatography (TLC), and the eluent containing the target product was collected.

[0077] After merging the target components, the solution was concentrated under reduced pressure to remove the solvent, yielding a pale yellow oily liquid with a yield of 59.9% and a purity of 98.1%.

[0078] Example 6

[0079] Compared with Example 1, Example 6 showed a significant increase in impurities and a decrease in yield when the reaction temperature was changed from 160℃ to 180℃.

[0080] A method for preparing N-ethyl-2-(N-methylpyrrolidinyl)pyrrole includes the following steps:

[0081] Step 1) Same as in Example 1;

[0082] 2) In a 500ml pressure vessel, add 43.7g (2eq) of 70% (% is mass percentage) ethylamine aqueous solution, 50g (1eq) of 1-furfurylpyrrole, 200g of ethanol, 100g of water, and dropwise add 1.9g (0.05eq) of hydrochloric acid (hydrochloric acid concentration is 32%). Secure the pressure vessel, heat to 180℃, maintain the temperature for 20h, cool to room temperature, depressurize, remove ethanol, extract twice with MTBE, and concentrate to obtain 48.6g of crude N-ethyl-2-(N-methylpyrrole)pyrrole.

[0083] The crude N-ethyl-2-(N-methylpyrrolidinyl)pyrrole was purified by silica gel column chromatography. The specific method is as follows:

[0084] The crude N-ethyl-2-(N-methylpyrrolidinyl)pyrrole prepared above was dissolved in an appropriate amount of eluent (cyclohexane: ethyl acetate = 90:10) and then loaded onto a silica gel chromatography column pre-equilibrated with eluent.

[0085] Elution was performed using a mixed solvent of cyclohexane and ethyl acetate (90:10) as the mobile phase. The elution process was monitored by thin-layer chromatography (TLC), and the eluent containing the target product was collected.

[0086] After merging the target components, the solution was concentrated under reduced pressure to remove the solvent, yielding a pale yellow oily liquid with a yield of 65.6% and a purity of 97.5%.

[0087] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A process for the preparation of N-ethyl-2-(N-methylpyrrolyl)pyrrole, characterized in that: The method comprises the following steps: 1-furfuryl pyrrole, ethylamine and ethanol are dissolved in water, hydrochloric acid is added, the reaction is heated, the reaction temperature is 150-180℃, and the reaction time is 15-35h; and 1-ethyl-2-(N-methyl pyrrolyl) pyrrole is obtained; The mass ratio of 1-furfuryl pyrrole, ethylamine, ethanol and water is 1:0.5-0.8:3-5:1.5-2.5; The mass percentage of added hydrochloric acid in the whole reaction system is 0.3-1%, and the concentration of hydrochloric acid is 30-35%, which is the mass percentage.

2. Process for the preparation of N-ethyl-2-(N-methylpyrrolyl)pyrrole according to claim 1, characterized in that: The reaction temperature is 155-165℃, and the reaction time is 18-22h.

3. Process for the preparation of N-ethyl-2-(N-methylpyrrolyl)pyrrole according to claim 2, characterized in that: The reaction temperature is 157-162℃, and the reaction time is 19-21h.

4. The process for the preparation of N-ethyl-2-(N-methylpyrrolyl)pyrrole according to claim 1, characterized in that: The preparation method of 1-furfuryl pyrrole is that 2-furfurylamine is condensed with 2,5-dimethoxytetrahydrofuran to prepare 1-furfuryl pyrrole.

5. The process for the preparation of N-ethyl-2-(N-methylpyrrolyl)pyrrole according to claim 1, characterized in that: The method further comprises the step of separating and purifying the prepared N-ethyl-2-(N-methyl pyrrolyl) pyrrole.

6. The process for the preparation of N-ethyl-2-(N-methylpyrrolyl)pyrrole according to claim 5, characterized in that: The separation and purification method is that after the reaction system is cooled and depressurized, ethanol is removed, methyl tert-butyl ether is used to extract the reaction liquid, and N-ethyl-2-(N-methyl pyrrolyl) pyrrole crude product is obtained after concentration. The N-ethyl-2-(N-methyl pyrrolyl) pyrrole crude product is purified by using a silica gel column, the eluent is a mixed solvent of cyclohexane and ethyl acetate, and the volume ratio of cyclohexane to ethyl acetate is 85-92:8-15.

7. The process for the preparation of N-ethyl-2-(N-methylpyrrolyl)pyrrole according to claim 6, characterized in that: In the mixed solvent, the volume ratio of cyclohexane to ethyl acetate is 88-92:8-12.

8. The process for the preparation of N-ethyl-2-(N-methylpyrrolyl)pyrrole according to claim 7, characterized in that: In the mixed solvent, the volume ratio of cyclohexane to ethyl acetate is 90:10.

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