A method for synthesizing a polysubstituted pyrrole compound

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of a polysubstituted pyrrole compound. The application is reasonable in design, takes metal palladium as a catalyst, takes a phosphorus ligand as a ligand, reacts with electron-deficient alkyne and di-tert-butyl diazepinone, and obtains the polysubstituted pyrrole compound. The synthesis method is simple in steps, convenient to operate, general in synthesis conditions, and high in synthesis efficiency.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, and in particular to a method for synthesizing polysubstituted pyrrole compounds. Background Technology

[0002] Polysubstituted pyrroles are an important class of five-membered heterocycles, with structures shown in the figure below. They are found in many natural products and bioactive molecules. For example, in 1997, Fenical's group isolated Ningalins A from *Didemnum* species collected near Ningalo Reef in Western Australia. Bhimamycin D was isolated from a terrestrial *Streptomyces*. Lycogarbin C and Lycogalic acid A were independently isolated from *Lycogala* by Steglich's and Asajawal's groups in 1994, respectively, and showed anti-HSV-I virus activity. The carbonyl group in all these molecules is a key component closely related to their bioactivity. Therefore, the synthesis and application of polysubstituted pyrroles are receiving increasing attention.

[0003] Summary of the Invention

[0004] The technical problem to be solved by this invention is to overcome the shortcomings of the prior art and provide a method for synthesizing polysubstituted pyrrole compounds. This invention uses di-tert-butyldiaziridinone as a nitrogen source, and under the conditions of palladium compound as catalyst and phosphorus ligand as ligand, a series of polysubstituted pyrrole compounds can be obtained by reacting alkynes with di-tert-butyldiaziridinone.

[0005] The technical solution adopted by this invention to solve its technical problem is: A method for synthesizing a polysubstituted pyrrole compound involves adding an electron-deficient alkyne 1 (as shown in formula (1)), di-tert-butyldiazide pyridone 2, a palladium compound, and a ligand to an organic solvent under an inert gas atmosphere. The reaction is carried out under heating conditions, and the target product, the polysubstituted pyrrole compound 3, is then separated after the reaction is complete. The synthesis is shown below: .

[0006] Furthermore, the electron-deficient alkyne 1 is an electron-deficient alkyne with the same ester groups at both ends; R is selected from one of methyl, ethyl, n-propyl, isopropyl, cyclobutyl, benzyl, 2-fluoroethyl, 2-methoxyethyl, allyl, and 2-(thiophen-2-yl)ethyl.

[0007] Furthermore, the molar ratio between the electron-deficient alkyne 1, di-tert-butyldiazide ketone 2, palladium compound, and ligand is 1:(1-3):(0.025-0.2):(0.05-0.2).

[0008] Furthermore, the organic solvent is selected from one or more of dimethyl sulfoxide (DMSO), acetonitrile, N,N-dimethylformamide (DMF), and tetrahydrofuran, with dimethyl sulfoxide (DMSO) being preferred.

[0009] Furthermore, the palladium compound is selected from one or more of tris(dibenzylacetone)dipalladium-chloroform adduct, palladium trifluoroacetate, palladium chloride, and palladium iodide, preferably tris(dibenzylacetone)dipalladium-chloroform adduct.

[0010] Furthermore, the ligand is a phosphine ligand.

[0011] Furthermore, the phosphine ligand is selected from PPh3 (triphenylphosphine), ( p -Me-Ph)3P (triphenylphosphine), ( p -Cl-Ph)3P (tris(4-chlorophenyl)phosphine), ( p One or more of the following: -CF3-Ph)3P (tris(4-trifluorotolyl)phosphine), (mF-Ph)3P (tris(3-fluorophenyl)phosphine), PPh2Cy (diphenylcyclohexylphosphine), PPhCy2 (phenyl dicyclohexylphosphine), dppm (bis(diphenylphosphinemethane), dppb (1,4-bis(diphenylphosphine)butane), dppf (1,1'-bis(diphenylphosphine)ferrocene), tris(pentafluorophenyl)phosphine, X-phos (2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl), and DPE-phos (bis(2-diphenylphosphine) ether).

[0012] The preferred phosphine ligand is tris(pentafluorophenyl)phosphine, the structural formula of which is shown below: .

[0013] Furthermore, the reaction temperature is 40–130°C.

[0014] The beneficial effects of this invention are as follows: This invention is reasonably designed, using palladium compounds as catalysts and phosphorus ligands as ligands to react electron-deficient alkynes with di-tert-butyldiazidionone to obtain polysubstituted pyrrole compounds. The synthesis method is simple, easy to operate, has conventional synthesis conditions, and has high synthesis efficiency. Attached Figure Description To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0015] Figure 1 The 1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylic acid tetramethyl ester (structural formula 3a) synthesized in Example 1 1 H NMR spectrum; Figure 2 The 1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylic acid tetramethyl ester (structural formula 3a) synthesized in Example 1 13 C NMR spectrum; Figure 3 This is the tetraethyl 1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylic acid (structural formula 3b) synthesized in Example 2. 1 H NMR spectrum; Figure 4 This is the tetraethyl 1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylic acid (structural formula 3b) synthesized in Example 2. 13 C NMR spectrum; Figure 5 This refers to the 1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylic acid tetrapropyl ester (structural formula 3c) synthesized in Example 3. 1 H NMR spectrum; Figure 6 This refers to the 1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylic acid tetrapropyl ester (structural formula 3c) synthesized in Example 3. 13 C NMR spectrum; Figure 7 This refers to the 1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylic acid tetraisopropyl ester (structural formula 3d) synthesized in Example 4. 1 H NMR spectrum; Figure 8 This refers to the 1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylic acid tetraisopropyl ester (structural formula 3d) synthesized in Example 4. 13 C NMR spectrum; Figure 9 This refers to the 1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylic acid tetracyclobutyl ester (structural formula 3e) synthesized in Example 5. 1 H NMR spectrum; Figure 10This refers to the 1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylic acid tetracyclobutyl ester (structural formula 3e) synthesized in Example 5. 13 C NMR spectrum; Figure 11 The 1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylic acid tetrabenzyl ester (structural formula 3f) synthesized in Example 6 1 H NMR spectrum; Figure 12 The 1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylic acid tetrabenzyl ester (structural formula 3f) synthesized in Example 6 13 C NMR spectrum; Figure 13 The tetra(2-fluoroethyl)-1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylate (structural formula 3g) synthesized in Example 7 1 H NMR spectrum; Figure 14 The tetra(2-fluoroethyl)-1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylate (structural formula 3g) synthesized in Example 7 13 C NMR spectrum; Figure 15 This is the tetra(2-methoxyethyl)-1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylate (structural formula 3h) synthesized in Example 8. 1 H NMR spectrum; Figure 16 This is the tetra(2-methoxyethyl)-1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylate (structural formula 3h) synthesized in Example 8. 13 C NMR spectrum; Figure 17 The tetra(but-3-en-1-yl)-1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylate (structural formula 3i) synthesized in Example 9 1 H NMR spectrum; Figure 18 The tetra(but-3-en-1-yl)-1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylate (structural formula 3i) synthesized in Example 9 13 C NMR spectrum; Figure 19 The tetra(2-(thiophen-2-yl)ethyl)-1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylate (structural formula 3j) synthesized in Example 10 1 H NMR spectrum; Figure 20The tetra(2-(thiophen-2-yl)ethyl)-1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylate (structural formula 3j) synthesized in Example 10 13 C10 NMR spectrum. Detailed Implementation

[0016] It should be noted that the following detailed descriptions are illustrative and intended to provide further explanation of this application. Unless otherwise specified, 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 pertains.

[0017] It should be noted that the terminology used herein is for the purpose of describing particular implementations only and is not intended to limit the exemplary implementations according to this application. As used herein, the singular form includes the plural form unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this description, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0018] The technical solutions of the present invention will now be clearly and completely described in conjunction with the embodiments and accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0019] Example 1: Synthesis of tetramethyl 1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylic acid (structural formula 3a)

[0020] Under argon protection, Pd2(dba)3·CHCl3 (0.0155 g, 0.015 mmol), tris(pentafluorophenyl)phosphine (L1) (0.0639 g, 0.12 mmol), an alkyne with structural formula 1a (0.0853 g, 0.6 mmol), 3.0 mL DMSO, and di-tert-butyldiazidimidine 2 (0.2554 g, 1.5 mmol) were added sequentially to the reactor. The container was sealed, and the heating plate temperature was adjusted to 90 °C. Heating was stopped after 2 hours, and the mixture was cooled to room temperature. The solution was diluted with 5 mL of water. The mixture was then extracted three times with EA (8 mL). The extracted organic phase was dried, concentrated, and subjected to column chromatography under the following conditions: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 3:1, yielding a yellow solid (0.0853 g, 74% yield) mp. 61.5–71.7. o C; The structural verification results are as follows: 1H NMR (400 MHz, CDCl3) δ 3.87 (s, 6H), 3.79 (s, 6H), 1.69 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 163.8, 163.3, 129.4, 118.3, 63.3,53.2, 52.4, 30.8;HRMS (ESI) calcd for C 16 H 22 NO8(M+H) + : 356.1340; found:356.1339.

[0021] In addition to the above examples, tetramethyl 1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylic acid (structural formula 3a) can also be synthesized using different palladium compounds, different phosphine ligands, and different organic solvents, as shown in Table 1.

[0022] Table 1

[0023] Example 2: Synthesis of tetraethyl 1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylic acid (structural formula 3b)

[0024] Under argon protection, Pd2(dba)3·CHCl3 (0.0155 g, 0.015 mmol), tris(pentafluorophenyl)phosphine (L1) (0.0639 g, 0.12 mmol), an alkyne with structural formula 1a (0.1021 g, 0.6 mmol), 3.0 mL DMSO, and di-tert-butyldiazidimidine 2 (0.2554 g, 1.5 mmol) were added sequentially to the reactor. The bottle was sealed with the cap, and the heating plate temperature was adjusted to 90 °C. Heating was stopped after 2 hours, and the mixture was cooled to room temperature. It was diluted with 5 mL of water. Then it was extracted three times with EA (8 mL). The extracted organic phase was dried, concentrated, and subjected to column chromatography under the following conditions: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 5:1, to obtain a colorless oil (0.0996 g, 81% yield). The structural verification results are as follows: 1 H NMR (400 MHz, CDCl3) δ 4.32 (q, J = 7.2 Hz, 4H), 4.26 (q, J = 7.2 Hz, 4H), 1.71 (s, 9H), 1.35 (t, J=7.2 Hz, 6H), 1.30 (t, J =7.2 Hz, 6H); 13 C NMR (100 MHz, CDCl3) δ 163.6, 162.9, 129.4, 118.5, 63.2, 62.4,61.2, 30.9, 14.3, 13.9;HRMS (ESI) calcd for C 20 H 30 NO8(M+H) + : 412.1966; found:412.1967.

[0025] Example 3: Synthesis of tetrapropyl 1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylic acid (structural formula 3c)

[0026] Under argon protection, Pd2(dba)3·CHCl3 (0.0155 g, 0.015 mmol), tris(pentafluorophenyl)phosphine (L1) (0.0639 g, 0.12 mmol), an alkyne with structural formula 1a (0.1189 g, 0.6 mmol), 3.0 mL DMSO, and di-tert-butyldiazidimidine 2 (0.2554 g, 1.5 mmol) were added sequentially to the reactor. The bottle was sealed with the cap, and the heating plate temperature was adjusted to 90 °C. Heating was stopped after 2 hours, and the mixture was cooled to room temperature. It was diluted with 5 mL of water. Then it was extracted three times with EA (8 mL). The extracted organic phase was dried, concentrated, and subjected to column chromatography under the following conditions: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 8:1, yielding a yellow oil (0.0997 g, 71% yield). The structural verification results are as follows: 1 H NMR (400 MHz, CDCl3) δ 4.18 (t, J = 6.8 Hz, 4H), 4.12 (t, J = 6.8 Hz, 4H), 1.76-1.60 (m, 8H), 1.68 (s, 9H), 0.95 (t, J = 7.6 Hz, 6H), 0.92 (t, J = 7.6 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 163.6, 163.0, 129.4,118.3, 68.1, 66.9, 63.1, 30.9, 22.1, 21.7, 10.61, 10.59;HRMS (ESI) calcd forC 24 H 38 NO8(M+H) + :468.2592; found: 468.2588.

[0027] Example 4: Synthesis of tetraisopropyl 1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylic acid (structural formula 3d)

[0028] Under argon protection, Pd2(dba)3·CHCl3 (0.0155 g, 0.015 mmol), tris(pentafluorophenyl)phosphine (L1) (0.0639 g, 0.12 mmol), an alkyne with structural formula 1a (0.1189 g, 0.6 mmol), 3.0 mL DMSO, and di-tert-butyldiazidimidine 2 (0.2554 g, 1.5 mmol) were added sequentially to the reactor. The bottle was sealed, and the heating plate temperature was adjusted to 90 °C. Heating was stopped after 2 hours, and the mixture was cooled to room temperature. The solution was diluted with 5 mL of water. The mixture was then extracted three times with EA (8 mL). The extracted organic phase was dried, concentrated, and subjected to column chromatography under the following conditions: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 10:1, yielding a yellow solid (0.0967 g, 69% yield) mp. 42.7–46.4. o C; The structural verification results are as follows: 1 H NMR (400 MHz, CDCl3) δ 5.25-5.04 (m, 4H), 1.69 (s,9H), 1.34 (d, J = 6.4, 12H), 1.29 (d, J = 6.0 Hz, 12H); 13 C NMR (100 MHz, CDCl3) δ163.1, 162.5, 129.5, 118.2, 70.5, 68.9, 62.9, 31.1, 22.0, 21.6; HRMS (ESI) m / zcalcd for C 24 H 38 NO8 + (M+H) +468.2592, found 468.2592.

[0029] Example 5: Synthesis of 1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylic acid tetracyclobutyl ester (structural formula 3e)

[0030] Under argon protection, Pd2(dba)3·CHCl3 (0.0155 g, 0.015 mmol), tris(pentafluorophenyl)phosphine (L1) (0.0639 g, 0.12 mmol), an alkyne with structural formula 1a (0.1333 g, 0.6 mmol), 3.0 mL DMSO, and di-tert-butyldiazidimidine 2 (0.2554 g, 1.5 mmol) were added sequentially to the reactor. The bottle was sealed with the cap, and the heating plate temperature was adjusted to 90 °C. Heating was stopped after 2 hours, and the mixture was cooled to room temperature. It was diluted with 5 mL of water. Then it was extracted three times with EA (8 mL). The extracted organic phase was dried, concentrated, and subjected to column chromatography under the following conditions: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 8:1, yielding a yellow oil (0.0793 g, 51% yield). The structural verification results are as follows: 1 H NMR (400 MHz, CDCl3) δ 5.16-5.06 (m, 4H), 2.44-2.30 (m, 8H), 2.24-2.05 (m, 8H), 1.88-1.72 (m, 4H), 1.68 (s, 9H), 1.67-1.56(m, 4H); 13 C NMR (100 MHz, CDCl3) δ 162.7, 162.1, 129.3, 118.3, 70.7, 69.4,63.1, 30.9, 30.3, 29.9, 13.8, 13.7;HRMS (ESI) calcd for C 28 H 38 NO8(M+H) + :516.2592; found: 516.2590.

[0031] Example 6: Synthesis of 1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylic acid tetrabenzyl ester (structural formula 3f)

[0032] Under argon protection, Pd2(dba)3·CHCl3 (0.0155 g, 0.015 mmol), tris(pentafluorophenyl)phosphine (L1) (0.0639 g, 0.12 mmol), an alkyne with structural formula 1a (0.1966 g, 0.6 mmol), 3.0 mL DMSO, and di-tert-butyldiazidimidine 2 (0.2554 g, 1.5 mmol) were added sequentially to the reactor. The bottle was sealed with the cap, and the heating plate temperature was adjusted to 90 °C. Heating was stopped after 2 hours, and the mixture was cooled to room temperature. It was diluted with 5 mL of water. Then it was extracted three times with EA (8 mL). The extracted organic phase was dried, concentrated, and subjected to column chromatography under the following conditions: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 8:1, yielding a yellow oil (0.1588 g, 80% yield). The structural verification results are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.35-7.29 (m, 10H), 7.29-7.24 (M, 6H), 7.22-7.16 (m, 4H), 5.08 (s, 4H), 4.92 (s, 4H), 1.60 (s, 9H); 13 CNMR (100 MHz, CDCl3) δ 163.2, 162.4, 135.6, 134.6, 129.4, 128.9, 128.7,128.62, 128.60, 128.4, 118.5, 67.1, 63.5, 30.9;HRMS (ESI) calcd for C 40 H 38 NO8(M+H) + : 660.2592; found: 660.2591.

[0033] Example 7: Synthesis of tetra(2-fluoroethyl)-1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylate (structural formula 3g)

[0034] Under argon protection, Pd2(dba)3·CHCl3 (0.0155 g, 0.015 mmol), tris(pentafluorophenyl)phosphine (L1) (0.0639 g, 0.12 mmol), an alkyne with structural formula 1a (0.1236 g, 0.6 mmol), 3.0 mL DMSO, and di-tert-butyldiazidimidine 2 (0.2554 g, 1.5 mmol) were added sequentially to the reactor. The bottle was sealed with the cap, and the heating plate temperature was adjusted to 90 °C. Heating was stopped after 2 hours, and the mixture was cooled to room temperature. It was diluted with 5 mL of water. Then it was extracted three times with EA (8 mL). The extracted organic phase was dried, concentrated, and subjected to column chromatography under the following conditions: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 3:1, yielding a pale yellow oil (0.0799 g, 55% yield). The structural verification results are as follows: 1 H NMR (400 MHz, CDCl3) δ 4.74-4.70 (m, 2H), 4.69-4.65 (m, 2H), 4.62-4.58 (m, 2H), 4.57-4.51 (m, 4H), 4.49-4.44 (m, 4H), 4.41-4.37 (m, 2H), 1.72 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 162.9, 162.2, 129.2,118.3, 81.9 (CF, 1 J C-F =53.0 Hz), 80.2 (CF, 1 J C-F = 53.8 Hz), 65.3 (CF, 2 J C-F =19.9Hz), 64.3 (CF, 2 J C-F = 19.9 Hz), 63.8, 30.8;HRMS (ESI) Calcd for C 20 H 26 F4NO8(M+H) + : 484.1595; found: 484.1591.

[0035] Example 8: Synthesis of tetra(2-methoxyethyl)-1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylate (structural formula 3h)

[0036] Under argon protection, Pd2(dba)3·CHCl3 (0.0155 g, 0.015 mmol), tris(pentafluorophenyl)phosphine (L1) (0.0639 g, 0.12 mmol), an alkyne with structural formula 1a (0.1381 g, 0.6 mmol), 3.0 mL DMSO, and di-tert-butyldiazidimidine 2 (0.2554 g, 1.5 mmol) were added sequentially to the reactor. The bottle was sealed with the cap, and the heating plate temperature was adjusted to 90 °C. After 2 hours, heating was stopped, and the mixture was cooled to room temperature. It was diluted with 5 mL of water. Then, it was extracted three times with EA (8 mL). The extracted organic phase was dried, concentrated, and subjected to column chromatography under the following conditions: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 1:1, yielding a yellow oil (0.1228 g, 80% yield). The structural verification results are as follows: 1 H NMR (400 MHz, CDCl3) δ 4.34 (t, J = 4.8 Hz, 4H), 4.27 (t, J = 4.8 Hz, 4H), 3.59 (t, J = 4.8 Hz, 4H), 3.55 (t, J = 4.8 Hz, 4H), 3.30 (s, 6H), 3.28 (s, 6H), 1.65 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 163.1,162.5, 129.2, 118.2, 70.1, 69.8, 65.2, 64.1, 63.2, 58.83, 58.78, 30.7;HRMS(ESI) calcd for C 24 H 38 NO 12 (M+H) + : 532.2389; found: 532.2390.

[0037] Example 9: Synthesis of tetra(but-3-en-1-yl)-1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylate (structural formula 3i)

[0038] Under argon protection, Pd2(dba)3·CHCl3 (0.0155 g, 0.015 mmol), tris(pentafluorophenyl)phosphine (L1) (0.0639 g, 0.12 mmol), an alkyne with structural formula 1a (0.1333 g, 0.6 mmol), 3.0 mL DMSO, and di-tert-butyldiazidimidine 2 (0.2554 g, 1.5 mmol) were added sequentially to the reactor. The bottle was sealed with the cap, and the heating plate temperature was adjusted to 90 °C. Heating was stopped after 2 hours, and the mixture was cooled to room temperature. It was diluted with 5 mL of water. Then it was extracted three times with EA (8 mL). The extracted organic phase was dried, concentrated, and subjected to column chromatography under the following conditions: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 8:1, yielding a pale yellow oil (0.0744 g, 48% yield). The structural verification results are as follows: 1 H NMR (400 MHz, CDCl3) δ 5.84-5.70 (m, 4H), 5.15-5.00 (m, 8H), 4.28 (t, J = 6.8 Hz, 4H), 4.22 (t, J = 6.8 Hz, 4H), 2.50-2.35 (t, J = 8.0 Hz, 8H), 1.68 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 163.3, 162.8, 133.9,133.6, 129.3, 118.2, 117.8, 117.5, 65.6, 64.6, 63.2, 33.0, 32.6, 30.9;HRMS(ESI) calcd for C 28 H 38 NO8(M+H) + : 516.2592; found: 516.2597.

[0039] Example 10: Synthesis of tetrakis(2-(thiophen-2-yl)ethyl)-1-(tert-butyl)-1H-pyrrole-2,3,4,5-tetracarboxylate (Structural Formula 3j)

[0040] Under argon protection, Pd2(dba)3·CHCl3 (0.0155 g, 0.015 mmol), tris(pentafluorophenyl)phosphine (L1) (0.0639 g, 0.12 mmol), an alkyne with structural formula 1a (0.2006 g, 0.6 mmol), 3.0 mL DMSO, and di-tert-butyldiazide 2 (0.2554 g, 1.5 mmol) were added sequentially to the reactor. The bottle was sealed with the cap, and the heating plate temperature was adjusted to 90 °C. After 2 hours, heating was stopped, and the mixture was cooled to room temperature. It was diluted with 5 mL of water. Then, it was extracted three times with EA (8 mL). The extracted organic phase was dried, concentrated, and subjected to column chromatography under the following conditions: the column was packed with petroleum ether, and the eluent was petroleum ether:ethyl acetate at a ratio of 8:1, yielding a yellow oil (0.1745 g, 79% yield). The structural verification results are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.15 (td, J = 5.2, 1.2 Hz, 4H), 6.94 (dd, J = 5.2, 3.2 Hz, 4H), 6.90-6.84 (m, 4H), 4.42 (t, J = 5.6Hz, 4H), 4.32 (t, J = 7.2Hz, 4H), 3.20 (t, J = 6.8 Hz, 4H), 3.12 (t, J = 6.8 Hz, 4H), 1.62 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 163.2, 162.6, 139.7, 139.4,129.4, 127.2, 127.1, 126.0, 125.8, 124.3, 124.1, 118.1, 66.7, 65.7, 63.4,30.8, 29.2, 28.9;HRMS (ESI) calcd for C 36 H 38 NO8S4(M+H) + : 740.1475; found740.1475.

[0041] In summary, the present invention is reasonably designed. Using palladium compounds as catalysts and phosphorus ligands as ligands, electron-deficient alkynes are reacted with di-tert-butyldiaziridinone to obtain polysubstituted pyrrole compounds. The synthetic method is simple, easy to operate, has conventional synthetic conditions, and has high synthetic efficiency.

[0042] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing a polysubstituted pyrrole compound, characterized in that: Under the protection of an inert gas, electron-deficient alkyne 1, di-tert-butyldiazide ketone 2, palladium compound and ligand as shown in formula (1) were added to an organic solvent and reacted under heating conditions. After the reaction was completed, the target product polysubstituted pyrrole compound 3 was separated. The synthesis is shown below: ； Wherein, the electron-deficient alkyne 1 is an electron-deficient alkyne with the same ester groups at both ends; R is selected from one of methyl, ethyl, n-propyl, isopropyl, cyclobutyl, benzyl, 2-fluoroethyl, 2-methoxyethyl, allyl, and 2-(thiophen-2-yl)ethyl; The organic solvent is selected from one or more of dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, and tetrahydrofuran; The palladium compound is selected from one or more of tris(dibenzylacetone)dipalladium-chloroform adduct, palladium trifluoroacetate, palladium chloride, and palladium iodide. The ligands are selected from PPh3, ( p -Me-Ph)3P、( p -Cl-Ph)3P, ( p One or more of the following: -CF3-Ph)3P, (mF-Ph)3P, PPh2Cy, PPhCy2, dppm, dppb, dppf, tris(pentafluorophenyl)phosphine, X-phos, and DPE-phos.

2. The method for synthesizing a polysubstituted pyrrole compound according to claim 1, characterized in that: The molar ratio between the electron-deficient alkyne 1, di-tert-butyldiazididine ketone 2, palladium compound, and ligand is 1:(1-3):(0.025-0.2):(0.05-0.2).

3. The method for synthesizing a polysubstituted pyrrole compound according to claim 1, characterized in that: The reaction temperature is 40–130°C.

4. The method for synthesizing a polysubstituted pyrrole compound according to claim 1, characterized in that: The separation method is column chromatography.

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