Synthesis method of 2, 4-diphenyl pyrrole

Abstract

The invention discloses a synthesis method of 2, 4-diphenylpyrrole, which comprises the following steps: (a) mixing 1, 3-dithiane and a metal reagent n-butyllithium at-78 DEG C, heating to-20 DEG C, reacting for 2 hours, cooling to-20 to-80 DEG C, dropwise adding chalcone, carrying out addition reaction for 8 hours, slowly heating to room temperature, quenching, extracting, concentrating, and carrying out column chromatography separation to obtain 1, 3-dithiane; a first intermediate A-1 obtained by 1, 2-addition; (b) hydrolyzing the first intermediate A-1 through a calcium carbonate / methyl iodide system or a bis (trifluoroacetoxy) iodobenzene system to obtain a second intermediate A-2; and (c) carrying out cyclization on the second intermediate A-2, ammonium acetate and acetic acid under a heating condition, quenching the reaction liquid with water, and washing the precipitated solid with methanol to obtain 2, 4-diphenyl pyrrole. The method is mild in reaction condition, safe and high in yield, and the highest total yield of three steps is 76% and is obviously higher than that of an existing synthesis method.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical synthesis, and in particular to a method for synthesizing 2,4-diphenylpyrrole. Background Art

[0002] Pyrrole is a biologically active nitrogen-containing five-membered heterocyclic compound that is widely present in natural products and bioactive molecules and is the parent core structure of many drug molecules. In addition, its unique chemical properties make it play an important role in optoelectronic functional materials. 2,4-Diphenylpyrrole is one of the important organic synthesis intermediates. It can be used to construct various complex functional organic molecules through derivatization and has a wide range of applications in materials and medicine. Therefore, the development of a synthetic method for 2,4-diphenylpyrrole has a high application value.

[0003]

[0004] At present, the main synthesis method of 2,4-diphenylpyrrole is as follows:

[0005] (1) In 2016, the literature Synlett 2016, 27, 1738–1742 reported that chalcone was used as the starting material, which first reacted with nitromethane in a 1,2-addition reaction, and then reacted with ammonium acetate at 80°C under the promotion of morpholine and sulfur to obtain the target product. The synthetic route is as follows:

[0006]

[0007] The reaction raw materials involved in this route, such as nitromethane and elemental sulfur, are difficult to obtain, and the use of morpholine as a solvent is expensive, so it is not easy to industrialize production.

[0008] (2) In 2023, WO 2023 / 199670Al reported that chalcone was used as a raw material to undergo a 1,2-addition reaction with methyl (methylthio) methyl sulfone, which was further hydrolyzed under the action of methanol and concentrated hydrochloric acid to obtain methylal, which was then co-thermally cyclized with ammonium acetate and acetic acid to obtain the target product 2,4-diphenylpyrrole. The total yield of the three steps was 44%. The synthetic route is as follows:

[0009]

[0010] In this scheme, methyl (methylthio) methyl sulfone is used for 1,2-addition reaction, but the reaction selectivity is not high, resulting in a low total yield. In addition, methyl (methylthio) methyl sulfone is expensive, and the hydrolysis of methylthio and methyl sulfoxide requires heating under the action of concentrated hydrochloric acid, and the reaction conditions are relatively harsh, which is not conducive to production and preparation.

[0011] Other preparation methods of 2,4-diphenylpyrrole include B.Chem.Soc.Jpn, 1967, 40, 2936-2938.

[0012] Tetrahedron, 2014, 70, 4395.; CN 108218758A; CN 106083686A. The starting materials required for use are difficult to synthesize and difficult to commercialize and directly purchase, so their universality and economy are not high.

[0013] We have discovered a novel and efficient method for synthesizing 2,4-diarylpyrroles. The reaction has the advantages of readily available raw materials, short reaction time, mild reaction conditions, and simple post-treatment, and has good prospects for industrial production. Summary of the invention

[0014] 1. Technical problems to be solved: The existing technical solutions have the problems of difficult to obtain raw materials, harsh reaction conditions, low yield and are not suitable for industrial production.

[0015] In view of the above technical problems, the present invention provides a method for synthesizing 2,4-diphenylpyrrole.

[0016] 2. Technical solution:

[0017] A method for synthesizing 2,4-diphenylpyrrole, the synthetic route of the method is as follows:

[0018]

[0019] The following steps are involved:

[0020] (a) 1,3-dithiane and the metal reagent n-butyl lithium are mixed at -78°C, heated to -20°C for reaction for 2h, then cooled to -20--80°C and dropwise added with a chalcone solution for addition reaction for 8h, slowly heated to room temperature, quenched, extracted, concentrated, and then separated by column chromatography to obtain the 1,2-added first intermediate A-1;

[0021] (b) the first intermediate A-1 is hydrolyzed by a calcium carbonate / methyl iodide system or a di(trifluoroacetoxy)iodobenzene system to obtain a second intermediate A-2;

[0022] (c) The second intermediate A-2, ammonium acetate and acetic acid are subjected to ring closure under heating conditions, the reaction solution is quenched with water, and the precipitated solid is washed with methanol to obtain 2,4-diphenylpyrrole.

[0023] Preferably, the molar ratio of chalcone, 1,3-dithiane and n-butyl lithium in step (a) is 1.0:(1.0-1.5):(1.2-1.5). This preferred ratio can effectively reduce the product cost while ensuring the purity and yield.

[0024] Preferably, when the calcium carbonate / methyl iodide system is used for hydrolysis in step (b), the molar ratio of the first intermediate A-1, calcium carbonate and methyl iodide is 1.0:(3.0-6.0):(8.0-12.0).

[0025] Preferably, when the di(trifluoroacetoxy)iodobenzene system is used for hydrolysis in step (b), the molar ratio of the first intermediate A-1 to di(trifluoroacetoxy)iodobenzene is 1.0:(1.5-3.0).

[0026] Preferably, in step (c), the molar ratio of the second intermediate A-2 to ammonium acetate is 1.0:(3.0-6.0).

[0027] Preferably, the reaction temperature of step (c) is between 100-130°C.

[0028] 3. Beneficial effects:

[0029] (1) This route uses cheap and readily available chalcone and 1,3-dithiane as starting materials, and avoids the use of controlled reagents such as concentrated hydrochloric acid and nitromethane during the reaction.

[0030] (2) The method of the present invention has mild reaction conditions, is safe, and has a high yield. The highest total yield of three steps is 76%, which is significantly higher than the existing synthesis method. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of intermediate A-1 in Example 1 of the present invention;

[0032] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of the final product of Example 1 of the present invention. DETAILED DESCRIPTION

[0033] The present invention will be described in detail below with reference to the accompanying drawings.

[0034] As attached Figure 1 To Attachment Figure 2 ,

[0035] Example 1

[0036] a) Synthesis of intermediate A-1:

[0037] Tetrahydrofuran (200 mL) was added to the reaction kettle and cooled at -78°C. n-BuLi (48 mL; 0.12 mol) was added and stirred for 30 min. 1,3-dithiane (12 g; 0.1 mol) was slowly added dropwise to the reaction bottle. After the addition was completed, the temperature was raised to -20°C and stirred for 2 h. The temperature was then cooled to -78°C again. Chalcone (20.8 g; 0.1 mol) was dissolved in tetrahydrofuran (100 mL) and added dropwise to the reaction bottle. The temperature was maintained for 8 h. After slowly rising to room temperature, a saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate and separated by column chromatography (ethyl acetate: petroleum ether = 5%) to obtain 26.9 g of 1,2-addition intermediate A-1 with a yield of 82%. The hydrogen nuclear magnetic resonance spectrum of intermediate A-1 is shown as follows: Figure 1 shown.

[0038] 1H NMR (400MHz, CDCl3) δ8.00–7.87(m,2H),7.61–7.51(m,1H),7.45–7.41(m,2H),7.34–7.27(m,5H),7.27–7.22(m,1H),4. 37(d,J=6.9Hz,1H),3.97–3.78(m,2H),3.53–3.47(m,1H),2.87–2.75(m,4H),2.11–1.98(m,1H),1.90–1.76(m,1H)ppm.

[0039] b) Synthesis of intermediate A-2:

[0040] The intermediate A-1 (26.9 g; 80 mmol) was dissolved in a mixed solvent of 800 ml acetonitrile and 100 ml water, and then calcium carbonate (40 g; 0.4 mol) and iodomethane (50 mL; 0.8 mol) were added to the reaction system in sequence. The mixture was stirred at room temperature for 24 h. After the reaction was completed by TLC, the solvent was removed, saturated brine was added, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After concentration, 18.6 g of a light yellow oily liquid was obtained, which could be directly used in subsequent reactions without further treatment.

[0041] c) Synthesis of 2,4-diphenylpyrrole:

[0042] The above compound A-2 (18.6 g; 8.4 mmol) was dissolved in acetic acid (100 mL) in a nitrogen atmosphere, and ammonium acetate (32 g) was added, followed by stirring at 120° C. for 2 hours and cooling to room temperature. The reaction solution was quenched with water (200 mL), and the precipitated solid was washed with methanol. Without further treatment, 16.6 g of the product was obtained with a purity of 97.3%. The total yield of steps b) and c) was 92.44%. The H NMR spectrum of the product was as follows: Figure 2 shown.

[0043] 1H NMR(400MHz, CDCl3)δ8.47(s,1H),7.61–7.55(m,2H),7.55–7.49(m,2H),7.4 4–7.33(m,4H),7.25–7.18(m,2H),7.15–7.14(m,1H),6.84–6.83(m,1H)ppm.

[0044] Example 2

[0045] a) Synthesis of intermediate A-1:

[0046] Tetrahydrofuran (200 mL) was added to the reaction kettle and cooled at -78°C. n-BuLi (48 mL; 0.12 mol) was added and stirred for 30 min. 1,3-dithiane (12 g; 0.1 mol) was slowly added dropwise to the reaction bottle. After the addition was completed, the temperature was raised to -20°C and stirred for 2 h. The temperature was then cooled to -78°C again. Chalcone (20.8 g; 0.1 mol) was dissolved in tetrahydrofuran (100 mL) and added dropwise to the reaction bottle. The temperature was maintained for 8 h. After slowly rising to room temperature, a saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate and separated by column chromatography (ethyl acetate: petroleum ether = 5%) to obtain 26.9 g of 1,2-addition intermediate with a yield of 82%.

[0047] b) Synthesis of intermediate A-2:

[0048] A solution of bis(trifluoroacetoxy)iodobenzene (68.8 g; 160 mmol) in dichloromethane / acetonitrile / water (volume ratio 5:5:1, 500 mL) was added dropwise to a mixed solution of intermediate A-1 (26.9 g; 80 mmol) in 300 mL of dichloromethane / acetonitrile / water, and stirred at room temperature for 10 minutes after the addition was complete. The mixture was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain 17 g of intermediate A-2 as a light yellow oily liquid.

[0049] c) Synthesis of 2,4-diphenylpyrrole:

[0050] The intermediate A-2 (17 g, 71 mmol) was dissolved in acetic acid (80 mL) in a nitrogen atmosphere, and ammonium acetate (27 g) was added, followed by stirring at 120° C. for 2 hours and cooling to room temperature. The reaction solution was quenched with water (180 mL), and the precipitated solid was washed with methanol. Without further treatment, 15.1 g of the product was obtained with a purity of 98.6%, and the total yield of steps b) and c) was 84.09%.

[0051] Embodiment 3-5

[0052] The synthesis method of Examples 3-5 is the same as that of Example 1, except that the tetrahydrofuran solution of chalcone is added dropwise during the synthesis of intermediate A-1 in step a) and the reaction temperature is different.

[0053] Example temperature Yield of intermediate A-1 Example 3 -20℃ 64％ Example 4 -30℃ 57％ Example 5 -60℃ 76％

[0054] Compared with Example 1, the yield of intermediate A-1 was significantly reduced by dropping the tetrahydrofuran solution of chalcone and increasing the temperature during the reaction.

[0055] Although the present invention has been disclosed as above in terms of preferred embodiments, they are not intended to limit the present invention. Anyone skilled in the art can make various changes or modifications without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection defined by the claims of this application.

Claims

1. A method for synthesizing 2,4-diphenylpyrrole, characterized in that: The synthetic route of the method is as follows: The following steps are involved: (a) 1,3-dithiane and the metal reagent n-butyl lithium are mixed at -78°C, heated to -20°C for reaction for 2h, then cooled to -20--80°C and dropwise added with a chalcone solution for addition reaction for 8h, slowly heated to room temperature, quenched, extracted, concentrated, and then separated by column chromatography to obtain the 1,2-added first intermediate A-1; (b) the first intermediate A-1 is hydrolyzed by a calcium carbonate / methyl iodide system or a di(trifluoroacetoxy)iodobenzene system to obtain a second intermediate A-2; (c) The second intermediate A-2, ammonium acetate and acetic acid are subjected to ring closure under heating conditions, the reaction solution is quenched with water, and the precipitated solid is washed with methanol to obtain 2,4-diphenylpyrrole.

2. A method for synthesizing 2,4-diphenylpyrrole according to claim 1, characterized in that: The molar ratio of chalcone, 1,3-dithiane and n-butyl lithium in step (a) is 1.0:(1.0-1.5):(1.2-1.5).

3. A method for synthesizing 2,4-diphenylpyrrole according to claim 1, characterized in that: When the calcium carbonate / methyl iodide system is used for hydrolysis in step (b), the molar ratio of the first intermediate A-1, calcium carbonate and methyl iodide is 1.0:(3.0-6.0):(8.0-12.0).

4. A method for synthesizing 2,4-diphenylpyrrole according to claim 1, characterized in that: When the di(trifluoroacetoxy)iodobenzene system is used for hydrolysis in step (b), the molar ratio of the first intermediate A-1 to di(trifluoroacetoxy)iodobenzene is 1.0:(1.5-3.0).

5. A method for synthesizing 2,4-diphenylpyrrole according to claim 3 or 4, characterized in that: The molar ratio of the second intermediate A-2 to ammonium acetate in step (c) is 1.0:(3.0-6.0).

6. A method for synthesizing 2,4-diphenylpyrrole according to claim 5, characterized in that: The reaction temperature of step (c) is between 100-130°C.

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