Preparation method of N-ethyl-2-(N-methyl pyrrolyl) pyrrole

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a preparation method of N-ethyl-2-(N-methylpyrrolyl) pyrrole, which comprises the following steps: dissolving 1-furfuryl pyrrole, ethylamine and ethanol in water, adding hydrochloric acid into the solution, and carrying out heating reaction at 150-180 DEG C for 15-35 hours; obtaining a finished product. According to the preparation method, 2-furfurylamine and 2, 5-dimethoxytetrahydrofuran are subjected to a condensation reaction to prepare 1-furfuryl pyrrole, then the 1-furfuryl pyrrole and ethylamine are subjected to a reaction, the target product N-ethyl-2-(N-methylpyrrolyl) pyrrole is prepared, the used raw materials are cheap, and the industrial value is high.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of N-ethyl-2-(N-methyl pyrrolyl) pyrrole. BACKGROUND

[0002] The statements herein are provided only to enhance understanding of the present application and are not necessarily intended to constitute the prior art.

[0003] N-ethyl-2-(N-methyl pyrrolyl) pyrrole is an organic compound containing a double pyrrole ring structure, which contains N-ethyl and N-methyl substituted pyrrole groups in the molecule, belongs to pyrrole derivatives, and is generally used in the fields of food and cosmetics. When applied to the field of food, N-ethyl-2-(N-methyl pyrrolyl) pyrrole can impart a more rich, mellow and layered roasting sensation as a flavor enhancer, and enhance the aroma flavor characteristics. When used for preparing cosmetics, it can provide elegant and long-lasting fragrance and enhance the sensory experience of the product.

[0004] At present, the synthesis method of N-ethyl-2-(N-methyl pyrrolyl) pyrrole generally uses pyrrole or pyrrole compounds as raw materials to prepare N-ethyl pyrrole and N-hydroxymethyl pyrrole, respectively, and then substitution is carried out in the presence of triphenylphosphine to obtain the target product. The raw material pyrrole used is relatively expensive, and 3-position and isosubstitution byproducts are easily produced during substitution. The obtained product is a mixed configuration, which is difficult to separate and purify. SUMMARY

[0005] In view of the deficiencies of the prior art, the present application provides a preparation method of N-ethyl-2-(N-methyl pyrrolyl) pyrrole. The preparation method uses cheaper furan derivatives to replace pyrrole raw materials to obtain a single configuration ratio of the target product. The raw materials are easy to obtain, the cost is controllable, and the industrialization feasibility is higher.

[0006] In order to achieve the above-mentioned purpose, the present application is realized by the following technical scheme: A preparation method of N-ethyl-2-(N-methyl pyrrolyl) pyrrole, comprising the following steps: 1-furfuryl pyrrole, ethylamine and ethanol are dissolved in water, hydrochloric acid is added, heated and reacted, the reaction temperature is 150-180 DEG C, and the reaction time is 15-25 h.

[0007] The beneficial effects obtained by one or more embodiments of the present application are as follows: By adding hydrochloric acid to the reaction system, ethylamine hydrochloride is generated, which can play a significant catalytic role and effectively shorten the reaction time.

[0008] The 2-furfurylamine is condensed with 2,5-dimethoxytetrahydrofuran to prepare 1-furfurylpyrrole, and then the 1-furfurylpyrrole is reacted with ethylamine to prepare the target product N-ethyl-2-(N-methylpyrrolyl)pyrrole, and the raw materials used are relatively cheap and have high industrial value. BRIEF DESCRIPTION OF DRAWINGS

[0009] The accompanying drawings, which form a part of this specification, are included to provide a further understanding of the application and are incorporated in and constitute a part of this specification. The embodiments of the application, and their

[0010] Figure 1 The figure is the nuclear magnetic hydrogen spectrum of the product N-ethyl-2-(N-methylpyrrolyl)pyrrole prepared in Example 1. DETAILED DESCRIPTION

[0011] It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the application. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0012] In order to solve the problems of high price of raw materials, easy generation of by-products and difficult separation and purification in the preparation of N-ethyl-2-(N-methylpyrrolyl)pyrrole in the prior art, the application provides a preparation method of N-ethyl-2-(N-methylpyrrolyl)pyrrole, which comprises the following steps: The 1-furfurylpyrrole, ethylamine and ethanol are dissolved in water, hydrochloric acid is added, and the reaction is heated, and the reaction temperature is 150-180 DEG C, and the reaction time is 15-35 h.

[0013] The specific reaction route is as follows: .

[0014] When pyrrole is used as the raw material in the prior art, the 2-position and the 3-position of the pyrrole ring are active sites, and the 3-position substitution or hetero-substitution side reaction is easy to occur, so that the product is a mixed configuration. The 1-furfurylpyrrole (furan derivative) is used in the application, and the space steric hindrance and electronic effect of the furan ring in the molecule can avoid the generation of multiple substitution by-products, so that the directional synthesis of a single configuration product is realized, and the purity is improved from the source.

[0015] The reaction of hydrochloric acid and ethylamine generates ethylamine hydrochloride, which is used as a protonic acid catalyst and has strong catalytic effect, can significantly reduce the reaction activation energy, and shorten the reaction time; high temperature (150-180 DEG C) further promotes the molecular movement and the forward movement of the reaction equilibrium, so that the raw materials are fully converted, and the yield of the target product is improved.

[0016] The ethanol-water mixed solvent can effectively dissolve 1-furfuryl pyrrole, ethylamine and other raw materials, ensure uniform reaction, and reduce side reactions caused by local high concentration.

[0017] In some embodiments, the mass ratio of 1-furfuryl pyrrole, ethylamine, ethanol and water is 1:0.5-0.8:3-5:1.5-2.5.

[0018] In some embodiments, the mass percentage of added hydrochloric acid in the entire reaction system is 0.3-1%, and the concentration of the hydrochloric acid is 30-35%, which is a mass percentage.

[0019] In some embodiments, the reaction temperature is 155-165℃, and the reaction time is 18-22h.

[0020] In some embodiments, the preparation method of 1-furfuryl pyrrole is to prepare 2-furfurylamine and 2,5-dimethoxy tetrahydrofuran by condensation.

[0021] In some embodiments, the method further comprises the step of separating and purifying the prepared N-ethyl-2-(N-methyl pyrrolyl) pyrrole.

[0022] Preferably, the separation and purification method is as follows: after the reaction is completed, the 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 silica gel column, and 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.

[0023] Further preferably, in the mixed solvent, the volume ratio of cyclohexane to ethyl acetate is 88-92:8-12.

[0024] In this eluent system, cyclohexane acts as a weak polar solvent to dominate separation, and ethyl acetate adjusts polarity to realize effective distribution of target product and impurities, which is suitable for separating pyrrole derivatives with medium polarity.

[0025] The application will be further described below with reference to the examples.

[0026] Example 1 A preparation method of N-ethyl-2-(N-methyl pyrrolyl) pyrrole comprises the following steps: 1) The preparation method of 1-furfuryl pyrrole is as follows: 100g of 2-furfurylamine and 149.7g of 2,5-dimethoxy tetrahydrofuran are mixed, 5.5g of hydrated ferric chloride is added as a catalyst, and condensation reaction is carried out at a temperature of 60℃ for 5h to prepare 1-furfuryl pyrrole.

[0027] 2) In a 500ml autoclave, 43.7g (2eq) of 70% (mass percentage) aqueous ethylamine solution, 50g (1eq) of 1-furfurylpyrrole, 200g of ethanol, 100g of water, 1.9g (0.05eq) of hydrochloric acid (hydrochloric acid concentration is 32%) were added dropwise, the autoclave was fastened, the temperature was raised to 160°C, and the reaction was kept for 20h, then the temperature was lowered to room temperature, the pressure was released, ethanol was removed, and extraction was performed twice with MTBE, and N-ethyl-2-(N-methylpyrrolyl)pyrrole crude product 51.3g was obtained by concentration.

[0028] The synthesis route is as follows: .

[0029] The N-ethyl-2-(N-methylpyrrolyl)pyrrole crude product was purified by silica gel column, and the specific method was as follows: The N-ethyl-2-(N-methylpyrrolyl)pyrrole crude product prepared above was dissolved with an appropriate amount of eluent (cyclohexane: ethyl acetate = 90:10), and then was loaded into a silica gel chromatography column pre-equilibrated with the eluent; Elution was performed with a mixture of cyclohexane: ethyl acetate = 90:10 as the mobile phase, and the elution process was monitored by thin layer chromatography (TLC), and the eluent containing the target product was collected; After the target components were combined, they were concentrated under reduced pressure to remove the solvent, and 43.6g of yellowish oil was obtained, with a yield of 73% and a purity of 98.8%, as shown in Figure 1 . 1 HNMR (400MHz, CDCl3) δ 6.90-6.98 (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). Example 2 Example 2 is different from Example 1 in that in step 2), the addition of hydrochloric acid is omitted, and the other conditions are the same as in Example 1. The yield of N-ethyl-2-(N-methylpyrrolyl)pyrrole decreases, and the reaction time is prolonged.

[0030] A method for preparing N-ethyl-2-(N-methylpyrrolyl)pyrrole, comprising the following steps: 1) The method for preparing 1-furfurylpyrrole is as follows: 100g of 2-furfurylamine and 149.7g of 2,5-dimethoxytetrahydrofuran were mixed, 5.5g of ferric chloride hydrate was added as a catalyst, and condensation reaction was carried out at a temperature of 60°C for 5h to prepare 1-furfurylpyrrole.

[0031] 2) In a 500ml pressure vessel, add 43.7g (2eq) 70% (mass percentage) aqueous ethylamine solution, 50g (1eq) 1-furfuryl pyrrole, 170g ethanol, 90g water, tighten the pressure vessel, heat to 160°C, keep the temperature for 25h, cool to room temperature, release the pressure, remove ethanol, extract twice with MTBE, concentrate to obtain N-ethyl-2-(N-methyl pyrrolyl) pyrrole crude product.

[0032] The N-ethyl-2-(N-methyl pyrrolyl) pyrrole crude product is purified by silica gel column, and the specific method is as follows: The N-ethyl-2-(N-methyl pyrrolyl) pyrrole crude product prepared above is dissolved with an appropriate amount of eluent (cyclohexane: ethyl acetate = 90:10), and then loaded onto a silica gel chromatography column pre-equilibrated with the eluent; Elution is carried out with a mixture of cyclohexane: ethyl acetate = 90:10 as the mobile phase, and the elution process is monitored by thin layer chromatography (TLC), and the eluent containing the target product is collected; After the target components are combined, they are concentrated under reduced pressure to remove the solvent to obtain a light yellow oily liquid, with a yield of 35.9% and a purity of 97.9%.

[0033] Example 3 Example 3 changes the amount of ethylamine added from 2eq to 1.5eq, resulting in a decrease in yield.

[0034] A method for preparing N-ethyl-2-(N-methyl pyrrolyl) pyrrole, comprising the following steps: 1) The method for preparing 1-furfuryl pyrrole is as follows: mix 100g 2-furfurylamine and 149.7g 2,5-dimethoxytetrahydrofuran, add 5.5g ferric chloride hydrate as catalyst, and perform condensation reaction at a temperature of 60°C for 5h to prepare 1-furfuryl pyrrole.

[0035] 2) In a 500ml pressure vessel, add 32.8g (1.5eq) 70% (mass percentage) aqueous ethylamine solution, 50g (1eq) 1-furfuryl pyrrole, 200g ethanol, 100g water, and drop 1.9g (0.05eq) hydrochloric acid (hydrochloric acid concentration is 32%), tighten the pressure vessel, heat to 160°C, keep the temperature for 20h, cool to room temperature, release the pressure, remove ethanol, extract twice with MTBE, concentrate to obtain N-ethyl-2-(N-methyl pyrrolyl) pyrrole crude product 43.5g.

[0036] The N-ethyl-2-(N-methyl pyrrolyl) pyrrole crude product is purified by silica gel column, and the specific method is as follows: The N-ethyl-2-(N-methyl pyrrolyl) pyrrole crude product prepared above was dissolved with an appropriate amount of eluent (cyclohexane: ethyl acetate = 90:10) and then loaded into a silica gel chromatographic column pre-equilibrated with the eluent; The elution was performed with a mixed solvent of cyclohexane: ethyl acetate = 90:10 as the mobile phase, and the elution process was monitored by thin layer chromatography (TLC), and the eluent containing the target product was collected; After the target components were combined, they were concentrated under reduced pressure, and the solvent was removed to obtain a light yellow oily liquid, with a yield of 58.8% and a purity of 98.3%.

[0037] Example 4 Example 4 compared with Example 1, the amount of aqueous ethylamine solution was increased from 2.0 eq to 2.5 eq, and the yield was not significantly improved.

[0038] A method for preparing N-ethyl-2-(N-methyl pyrrolyl) pyrrole, comprising the following steps: 1) The method for preparing 1-furfuryl pyrrole is as follows: 100 g of 2-furfurylamine and 149.7 g of 2,5-dimethoxytetrahydrofuran were mixed, 5.5 g of ferric chloride hydrate was added as a catalyst, and a condensation reaction was performed at a temperature of 60°C for 5 h to prepare 1-furfuryl pyrrole.

[0039] 2) In a 500 ml pressure kettle, 54.6 g (2.5 eq) of 70% (mass percentage) aqueous ethylamine solution, 50 g (1 eq) of 1-furfuryl pyrrole, 200 g of ethanol, and 100 g of water were added, 1.9 g (0.05 eq) of hydrochloric acid (hydrochloric acid concentration of 32%) was added dropwise, the pressure kettle was tightly fastened, the temperature was raised to 160°C, and the reaction was kept for 20 h, then the temperature was lowered to room temperature, the pressure was released, ethanol was removed, and extraction was performed twice with MTBE, and then concentrated to obtain N-ethyl-2-(N-methyl pyrrolyl) pyrrole crude product 49.2 g.

[0040] The N-ethyl-2-(N-methyl pyrrolyl) pyrrole crude product was purified by a silica gel column, and the specific method was as follows: The N-ethyl-2-(N-methyl pyrrolyl) pyrrole crude product prepared above was dissolved with an appropriate amount of eluent (cyclohexane: ethyl acetate = 90:10) and then loaded into a silica gel chromatographic column pre-equilibrated with the eluent; The elution was performed with a mixed solvent of cyclohexane: ethyl acetate = 90:10 as the mobile phase, and the elution process was monitored by thin layer chromatography (TLC), and the eluent containing the target product was collected; After the target components were combined, they were concentrated under reduced pressure, and the solvent was removed to obtain a light yellow oily liquid, with a yield of 58.8% and a purity of 98.3%.

[0041] Example 5 Example 5 The reaction temperature is lowered to 150°C and the reaction time is extended to 30 h, but the reaction is still not complete and the yield is low.

[0042] A method for preparing N-ethyl-2-(N-methylpyrrolyl)pyrrole, comprising the following steps: Step 1) same as Example 1; 2) In a 500 ml pressure kettle, 43.7 g (2 eq) of 70% (mass percentage) aqueous ethylamine solution, 50 g (1 eq) of 1-furfurylpyrrole, 200 g of ethanol, 100 g of water, 1.9 g (0.05 eq) of hydrochloric acid (hydrochloric acid concentration is 32%) are added dropwise, the pressure kettle is fastened, the temperature is raised to 150°C, and the reaction is kept for 30 h. After the temperature is lowered to room temperature, the pressure is released, ethanol is removed, and MTBE is used for extraction twice. N-ethyl-2-(N-methylpyrrolyl)pyrrole crude product 44.8 g is obtained after concentration.

[0043] The N-ethyl-2-(N-methylpyrrolyl)pyrrole crude product is purified by silica gel column, and the specific method is as follows: The N-ethyl-2-(N-methylpyrrolyl)pyrrole crude product prepared above is dissolved with an appropriate amount of eluent (cyclohexane: ethyl acetate = 90:10), and then loaded into a silica gel chromatography column pre-equilibrated with the eluent; The mixed solvent of cyclohexane: ethyl acetate = 90:10 is used as the mobile phase for elution, and the elution process is monitored by thin layer chromatography (TLC), and the eluent containing the target product is collected; After the target components are combined, they are concentrated under reduced pressure to remove the solvent, and a light yellow oily liquid is obtained, with a yield of 59.9% and a purity of 98.1%.

[0044] Example 6 Example 6 Compared with Example 1, the reaction temperature is changed from 160°C to 180°C, and the reaction impurities increase significantly, resulting in a decrease in yield.

[0045] A method for preparing N-ethyl-2-(N-methylpyrrolyl)pyrrole, comprising the following steps: Step 1) same as Example 1; 2) In a 500 ml pressure kettle, 43.7 g (2 eq) of 70% (mass percentage) aqueous ethylamine solution, 50 g (1 eq) of 1-furfurylpyrrole, 200 g of ethanol, 100 g of water, 1.9 g (0.05 eq) of hydrochloric acid (hydrochloric acid concentration is 32%) are added dropwise, the pressure kettle is fastened, the temperature is raised to 150°C, and the reaction is kept for 30 h. After the temperature is lowered to room temperature, the pressure is released, ethanol is removed, and MTBE is used for extraction twice. N-ethyl-2-(N-methylpyrrolyl)pyrrole crude product 44.8 g is obtained after concentration.

[0046] The crude N-ethyl-2-(N-methyl pyrrolyl)pyrrole was purified by silica gel column, and the specific method was as follows: The crude N-ethyl-2-(N-methyl pyrrolyl)pyrrole prepared above was dissolved with an appropriate amount of eluent (cyclohexane: ethyl acetate = 90:10) and then was loaded into a silica gel chromatographic column pre-equilibrated with the eluent; Elution was performed with a mixed solvent of cyclohexane: ethyl acetate = 90:10 as the mobile phase, and the elution process was monitored by thin layer chromatography (TLC), and the eluate containing the target product was collected; After the target components were combined, they were concentrated under reduced pressure, and the solvent was removed to obtain a light yellow oily liquid, with a yield of 65.6% and a purity of 97.5%.

[0047] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing N-ethyl-2-(N-methylpyrrole)pyrrole, characterized in that: Includes the following steps: 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.

2. The method for preparing N-ethyl-2-(N-methylpyrrole)pyrrole according to claim 1, characterized in that: The mass ratio of 1-furfurylpyrrole, ethylamine, ethanol and water is 1:0.5-0.8:3-5:1.5-2.

5.

3. The method for preparing N-ethyl-2-(N-methylpyrrole)pyrrole according to claim 1, characterized in that: The added hydrochloric acid accounts for 0.3-1% of the total mass of the reaction system, and the concentration of hydrochloric acid is 30-35%, where % is the mass percentage.

4. The method for preparing N-ethyl-2-(N-methylpyrrole)pyrrole according to claim 1, characterized in that: The reaction temperature is 155-165℃, and the reaction time is 18-22h.

5. The method for preparing N-ethyl-2-(N-methylpyrrole)pyrrole according to claim 4, characterized in that: The reaction temperature is 157-162℃, and the reaction time is 19-21h.

6. The method for preparing N-ethyl-2-(N-methylpyrrole)pyrrole according to claim 1, characterized in that: 1-Furfurylpyrrole is prepared by condensation of 2-furanmethylamine and 2,5-dimethoxytetrahydrofuran.

7. The method for preparing N-ethyl-2-(N-methylpyrrole)pyrrole according to claim 1, characterized in that: It also includes the step of separating and purifying the prepared N-ethyl-2-(N-methylpyrrole)pyrrole.

8. The method for preparing N-ethyl-2-(N-methylpyrrole)pyrrole according to claim 7, characterized in that: The separation and purification method is as follows: after the reaction is completed, the system is cooled and depressurized, ethanol is removed, and the reaction solution is extracted with methyl tert-butyl ether. After concentration, crude N-ethyl-2-(N-methylpyrrol)pyrrole is obtained. 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.

9. The method for preparing N-ethyl-2-(N-methylpyrrole)pyrrole according to claim 8, characterized in that: In the mixed solvent, the volume ratio of cyclohexane to ethyl acetate is 88-92:8-12.

10. The method for preparing N-ethyl-2-(N-methylpyrrole)pyrrole according to claim 9, characterized in that: In the mixed solvent, the volume ratio of cyclohexane to ethyl acetate is 90:10.

Images