A method for preparing 2,3,4,5-tetrasubstituted pyrrole compounds

Abstract

The application discloses a preparation method of a 2,3,4,5-tetrasubstituted pyrrole compound, which comprises the following steps: adding inorganic base, allene ketone and p-methyl benzene sulfonyl methyl isonitrile into an organic solvent, and carrying out reaction at 80 DEG C; and after the reaction is completed, post-treatment is carried out to obtain the 2,3,4,5-tetrasubstituted pyrrole compound. The preparation method adopts one-pot reaction, and is convenient to operate.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to a preparation method of a 2,3,4,5-tetrasubstituted pyrrole compound. BACKGROUND

[0002] As an important five-membered nitrogen-containing heterocycle, tetrasubstituted pyrrole compounds are widely present in various natural products, such as Polycitone A (Biochem. J. 1999, 344, 85-92.) extracted from sea-squirts, Chlorfenapyr extracted from a Streptomyces fumanus (International Conference on Integrated Fruit Production. 1998, 525, 257-276.) having insect repellent function. The polysubstituted pyrrole skeleton also has pharmacological activity, and is one of important pharmacophores in medicinal chemistry. For example, Sunitinib (J. Med. Chem. 2010, 53, 5929-5941.) can be used for inhibiting receptor tyrosine kinase, and Atorvastatin can be used for preventing and treating cardiovascular diseases (American Journal of Kidney Diseases, 2009, 54, 810-819.). Therefore, it is of important practical significance to efficiently synthesize polysubstituted pyrrole derivatives.

[0003]

[0004] The main methods for synthesizing 2,3,4,5-tetrasubstituted pyrrole compounds reported in the literature are as follows: the Knorr synthesis method in which the corresponding oxime is first subjected to Neber rearrangement to generate an α-aminoketone in situ, and then subjected to reaction with a 1,4-dicarbonyl compound containing an electron-withdrawing group in the presence of zinc and glacial acetic acid; the Hantzsch reaction in which an α-halomethyl ketone, a β-keto ester and ammonia are condensed to obtain a pyrrole; and the like.

[0005]

[0006] However, these methods have common limitations, such as harsh reaction conditions, and often need to be carried out under conditions of high temperature, strong acid, strong base and the like, thereby being not suitable for substrates containing sensitive functional groups.

[0007] In addition to the above pyrrole synthesis methods, the reaction of TosMIC with a Michael addition acceptor (such as an α,β-unsaturated ester, ketone or nitrile) under alkaline conditions, elimination of p-toluenesulfinic acid to obtain a 3-substituted pyrrole is referred to as the Van Leusen pyrrole synthesis method.

[0008]

[0009] This method is mainly limited to electron-deficient olefins, and the obtained pyrrole substituent is less, which cannot meet the synthesis of highly functionalized pyrrole. The present application firstly uses TosMIC to react with allene ketone to synthesize fully substituted pyrrole derivatives, which expands the method of pyrrole synthesis. SUMMARY

[0010] The present application provides a preparation method of 2,3,4,5-tetra-substituted pyrrole compound, which has simple steps, easy-to-prepared raw materials, and is completed by one-pot method, and is easy to operate.

[0011] A preparation method of 2,3,4,5-tetra-substituted pyrrole compound, comprising the following steps: adding inorganic base, allene ketone and p-methyl benzene sulfonyl methyl isonitrile into organic solvent, heating and reacting, after the reaction is completed, post-treatment to obtain the 2,3,4,5-tetra-substituted pyrrole compound;

[0012] The structure of the allene ketone is shown as formula (II):

[0013]

[0014] The structure of the p-methyl benzene sulfonyl methyl isonitrile is shown as formula (III):

[0015]

[0016] The structure of the 2,3,4,5-tetra-substituted pyrrole compound is shown as formula (I):

[0017]

[0018] In formula (I)-(III), R 1 is phenyl-substituted C 1～4 alkyl, substituted or unsubstituted phenyl, naphthyl, five-membered heterocyclic group, benzene five-membered heterocyclic group, C 2～10 long chain alkenyl or C 1～6 alkyl, wherein the substituent on the phenyl is selected from C 1～4 alkyl, C 1～4 alkoxy or halogen;

[0019] R 2 is substituted or unsubstituted phenyl, naphthyl or alkyl group, wherein the substituent on the phenyl is selected from C 1～4 alkyl, C 1～4 alkoxy or polyfluorinated C 1～4 alkyl.

[0020] The reaction formula is as follows:

[0021]

[0022] In the reaction, p-methylbenzenesulfonylmethylisocyanate may form a carbocation intermediate under the promotion of an inorganic base. This intermediate then undergoes a 1,4-Michael addition reaction with an allenone, followed by cyclization to generate a trisubstituted nitrogen-containing five-membered ring intermediate. Cyclopropanization of the intermediate leads to carbon-carbon bond cleavage, resulting in carbonyl group migration, and ultimately, efficient synthesis of 2,3,4,5-tetrasubstituted pyrrole compounds via hydrogen transfer.

[0023] In this invention, the optional post-processing steps include: extraction with ethyl acetate, drying with anhydrous sodium sulfate, and purification by column chromatography after rotary drying to obtain the corresponding 2,3,4,5-tetrasubstituted pyrrole compounds. Column chromatography purification is a commonly used technique in this field.

[0024] As a preferred option, R 1 The allenone can be phenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-methoxyphenyl, benzotetrahydrofuranyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, α-naphthyl, furanyl, thiophene, 3,7-dimethyl-6-octenyl, or n-butyl. In this case, the allenone is readily available, and the reaction yield is high.

[0025] As a preferred option, R 2 The methylbenzenesulfonylmethylisocyanate is phenyl, 4-methylphenyl, 2-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, β-naphthyl, or n-butyl. In this case, the p-methylbenzenesulfonylmethylisocyanate is readily available, and the reaction yield is high.

[0026] Because allenone is prone to undergoing its own two-molecule polymerization, it is used in excess relative to the amount of p-toluenesulfonylmethylisocyanate. Preferably, the molar ratio of allenone: p-toluenesulfonylmethylisocyanate: inorganic base is 1-2:1:2; more preferably, the molar ratio of allenone: p-toluenesulfonylmethylisocyanate: inorganic base is 2:1:2.

[0027] Preferably, the reaction time is 30 minutes. A reaction time that is too long increases the reaction cost, while a reaction that is too long makes it difficult to guarantee the completeness of the reaction.

[0028] In this invention, any organic solvent that can fully dissolve the raw materials can enable the reaction to occur, but the reaction efficiency varies greatly. Aprotic solvents are preferred, and as a further preferred option, the organic solvent is chloroform or acetonitrile. In this case, various raw materials can be converted into products with a high conversion rate.

[0029] The amount of the organic solvent can dissolve the raw material well, and the amount of the organic solvent used for 0.2 mmol of p-methylbenzenesulfonylmethyl isonitrile is about 2 mL.

[0030] As preferred, the inorganic base is cesium carbonate, and the inorganic base has high catalytic reaction efficiency.

[0031] As further preferred, the 2,3,4,5-tetrasubstituted pyrrole compound is one of the compounds shown in formula (I-1) to formula (I-27).

[0032]

[0033]

[0034]

[0035]

[0036] In the above preparation method, the inorganic base and p-methylbenzenesulfonylmethyl isonitrile are generally commercially available products, which can be conveniently obtained on the market, and the allene ketone can be prepared by four steps of deprotonation of the corresponding substituted phenylacetylene by butyl lithium, reaction with paraformaldehyde to generate propargyl alcohol, subsequent bromination, and allene isomerization reaction and oxidation with the corresponding aldehyde.

[0037] Compared with the prior art, the preparation method of the present application has the advantages of one-pot completion, easy operation, simple post-treatment, wide substrate application range, and strong practicability. DETAILED DESCRIPTION

[0038] The present application will be further described below in combination with specific examples.

[0039] A 35ml Schlenk tube was replaced with nitrogen, and cesium carbonate, p-methylbenzenesulfonylmethyl isonitrile (III) and an organic solvent 2mL were added according to the raw material ratio in Table 1, mixed and stirred for 5min, and then allene ketone (II) was added. The reaction was heated to 80℃ and stirred for 30min. After the reaction was completed according to the reaction conditions in Table 2, filtration, silica gel sample mixing, and column chromatography purification were performed to obtain the corresponding 2,3,4,5-tetrasubstituted pyrrole compound (I), and the reaction process is shown in the following formula:

[0040]

[0041] Table 1

[0042]

[0043]

[0044]

[0045] Table 2

[0046]

[0047]

[0048] In Table 1, Me is methyl, OMe is methoxy, Ph is phenyl, a-naphth is a-naphthyl, 2,3-dihydrobenzofuran is 2,3-dihydrobenzofuran, furan is furanyl, thiophene is thienyl, 3,7-dimethyl-6-octena is 3,7-dimethyl-6-octene, n-Bu is n-butyl, β-naphth is β-naphthyl, cyclopropane is cyclopropyl.

[0049] In Table 2, T is reaction temperature, t is reaction time.

[0050] The structural confirmation data of the compounds prepared in Examples 1-27 are as follows:

[0051] The nuclear magnetic resonance (1H NMR, 13C NMR) and high resolution mass spectrometry (HRMS (ES-TOF)) detection data of the 2,3,4,5-tetrasubstituted pyrrole compound (I-1) prepared from Example 1 are as follows: 1 H NMR, 13 CNMR) and HRMS(ES + -TOF) detection data are as follows:

[0052]

[0053] 1 H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 7.86 (s, 2H), 7.45 (d, J = 7.2 Hz, 2H), 7.33-7.23 (m, 3H), 7.11-7.02 (m, 5H), 7.01-6.91 (m, 2H), 2.47-2.37 (m, 3H), 2.22 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 187.6, 144.6, 138.2, 136.7, 132.8, 132.6, 131.9, 130.5, 130.0, 129.7, 129.2, 129.2, 127.8, 127.5, 127.3, 127.1, 123.9, 21.6, 9.9; HRMS (ES-TOF) m / z: [M+H] + -TOF)m / z:[M+H] + Calcd for C 25 H 22NO3S 416.1315; Found 416.1317.

[0054] Nuclear magnetic resonance (NMR) of the 2,3,4,5-tetrasubstituted pyrrole compound (I-2) prepared in Example 2 1 H NMR and 13 C NMR) and HRMS (ES) + -TOF detection data are:

[0055]

[0056] 1 H NMR (400MHz, CDCl3) δ10.33(s,1H),7.81(d,J=8.4Hz,2H),7.33(d,J=8.1Hz,2H),7.28–7.25(m,2H), 7.08–7.06(m,3H),6.96–6.93(m,2H),6.83(d,J=7.9Hz,2H),2.39(s,3H),2.22(s,3H),2.19(s,3H); 13 CNMR (101MHz, CDCl3) δ187.2,144.5,142.8,138.3,133.9,132.9,132.2,130.5,1 29.9,129.5,129.3,128.2,127.8,127.3,126.9,123.9,21.6,21.5,9.9; HRMS(ES + -TOF)m / z:[M+H + Calcd for C 26 H 24 NO3S 430.1471; Found430.1472.

[0057] Nuclear magnetic resonance (NMR) of the 2,3,4,5-tetrasubstituted pyrrole compound (I-3) prepared in Example 3 1 H NMR and 13 CNMR) and HRMS (ES) + -TOF detection data are:

[0058]

[0059] 1H NMR (400 MHz, CDCI3) δ 10.35 (s, 1 H), 7.82 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.8 Hz, 3H), 7.15 (s, 1 H), 7.08 - 7.01 (m, 4H), 7.00 - 6.92 (m, 3H), 2.39 (s, 3H), 2.19 (s, 3H), 2.06 (s, 3H); 13 C NMR (101 MHz, CDCI3) δ 187.6, 144.6, 138.2, 137.2, 136.5, 133.0, 132.7, 132.5, 130.4, 130.1, 130.0, 129.8, 129.6, 127.8, 127.6, 127.3, 127.1, 126.3, 123.9, 21.6, 20.8, 9.9; HRMS (ES + -TOF) m / z: [M+H] + Calcd for C 26 H 24 NO3S 430.1471 ; Found 430.1475.

[0060] The 2,3,4,5-tetrasubstituted pyrrole compound (1-4) prepared from Example 4 was detected by NMR (1H NMR and 1 H NMR and 13 CNMR) and HRMS (ES + -TOF) detection data were as follows:

[0061]

[0062] 1 H NMR (400 MHz, CDCI3) δ 10.18 (s, 1 H), 7.85 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 7.4 Hz, 2H), 7.03 - 6.91 (m, 6H), 6.85 - 6.77 (m, 2H), 6.72 (t, J = 7.5 Hz, 1 H), 2.41 (s, 3H), 2.28 (s, 3H), 2.10 (s, 3H); 13 C NMR (101 MHz, CDCI3) δ 188.8 144.7, 138.1, 137.2, 136.1, 133.2, 132.2, 130.2, 130.2, 130.0, 128.5, 127.5, 127.4, 127.0, 124.7, 124.3, 21.6, 19.5, 9.8; HRMS (ES + -TOF) m / z: [M+H] + Calcd for C 26 H24 NO3S 430.1471 ; Found 430.1473.

[0063] The 2,3,4,5-tetrasubstituted pyrrole compound (NMR data of I-5 prepared from Example 5, 1 HNMR and 13 CNMR) and HRMS (ES + -TOF) data were as follows:

[0064]

[0065] 1 H NMR (400 MHz, CDC13) δ 10.48 (s, 1H), 7.78 (d, J = 7.9 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.13 - 7.06 (m, 3H), 7.04 - 6.95 (m, 2H), 6.52 (d, J = 8.5 Hz, 2H), 3.71 (s, 3H), 2.37 (s, 3H), 2.21 (s, 3H); 13 C NMR (101 MHz, CDC13) δ 186.2, 162.8, 144.4, 138.3, 133.1, 131.8, 131.8, 130.6, 130.1, 129.9, 129.1, 127.9, 127.3, 127.0, 123.7, 112.9, 55.3, 21.6, 10.0; HRMS (ES + -TOF) m / z: [M+H] + Calcd for C 26 H 24 NO4S 446.1421 ; Found 446.1429.

[0066] The 2,3,4,5-tetrasubstituted pyrrole compound (NMR data of I-5 prepared from Example 5, 1 H NMR and 13 CNMR) and HRMS (ES + -TOF) data were as follows:

[0067]

[0068] 1H NMR (400 MHz, CDC13) δ 10.53 (s, 1H), 7.77 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 1.8 Hz, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.15 - 7.08 (m, 3H), 7.03 - 6.96 (m, 2H), 6.44 (d, J = 8.4 Hz, 1H), 4.49 (t, J = 8.7 Hz, 2H), 2.91 (t, J = 8.7 Hz, 2H), 2.36 (s, 3H), 2.21 (s, 3H); 13 C NMR (101 MHz, CDC13) δ 186.1, 163.7, 144.3, 138.4, 133.3, 131.6, 131.5, 130.6, 130.3, 129.9, 129.3, 129.1, 127.9, 127.2, 127.0, 126.5, 123.7, 108.5, 72.0, 28.6, 21.6, 10.0; HRMS (ES + -TOF) m / z: [M+H] + Calcd for C 27 H 24 NO4S 458.1421; Found 458.1436.

[0069] The 2,3,4,5-tetrasubstituted pyrrole compound (I-7) prepared from Example 7 was analyzed by1H NMR 1 H NMR and 13 CNMR) and HRMS (ES + -TOF) detection data were as follows:

[0070]

[0071] 1 H NMR (400 MHz, CDC13) δ 10.53 (s, 1H), 7.77 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 1.8 Hz, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.15 - 7.08 (m, 3H), 7.03 - 6.96 (m, 2H), 6.44 (d, J = 8.4 Hz, 1H), 4.49 (t, J = 8.7 Hz, 2H), 2.91 (t, J = 8.7 Hz, 2H), 2.36 (s, 3H), 2.21 (s, 3H); 13C NMR (101 MHz, CDC13) δ 186.54, 164.9 (d, J = 252.3 Hz), 145.0, 144.7, 138.1, 132.9, 132.7, 132.6, 131.8 (d, J = 8.2 Hz), 130.6, 129.9 (d, J = 4.8 Hz), 129.6, 128.0, 127.4, 127.3, 123.9, 114.7 (d, J = 21.9 Hz), 21.6, 9.9; HRMS (ES + -TOF) m / z: [M + H] + Calcd for C 25 H 21 FNO3S 434.1221; Found 434.1225.

[0072] The 2,3,4,5-tetrasubstituted pyrrole compound (I-8) prepared from Example 8 was analyzed by NMR (1H NMR and 1 H NMR and 13 CNMR) and HRMS (ES + -TOF) detection data were as follows:

[0073]

[0074] 1 H NMR (400 MHz, CDC13) δ 10.36 (s, 1H), 7.82 (d, J = 7.0 Hz, 2H), 7.33 - 7.26 (m, 4H), 7.15 - 7.04 (m, 3H), 6.98 (d, J = 6.5 Hz, 2H), 6.91 (d, J = 7.8 Hz, 2H), 2.40 (s, 3H), 2.18 (s, 3H); 13 C NMR (101 MHz, CDC13) δ 186.3, 144.7, 138.2, 138.1, 135.0, 132.7, 132.6, 130.6, 130.1, 130.0, 129.4, 128.0, 127.8, 127.4, 127.3, 123.9, 21.6, 9.9; HRMS (ES + -TOF) m / z: [M + H] + Calcd for C 25 H 21 ClNO3S 450.0925; Found 450.0922.

[0075] The 2,3,4,5-tetrasubstituted pyrrole compound (I-9) prepared from Example 9 was analyzed by NMR (1H NMR and 1 H NMR and 13CNMR) and HRMS (ES + HRMS (ES-TOF) m / z: [M+H]+calcd for C

[0076]

[0077] 1 H NMR (400 MHz, CDC13) δ 10.24 (s, 1H), 7.84 (d, J = 7.2 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 7.24 (d, J = 7.0 Hz, 2H), 7.15 - 7.06 (m, 5H), 6.90 (d, J = 7.4 Hz, 2H), 2.41 (s, 3H), 2.18 (s, 3H); 13 C NMR (101 MHz, CDC13) δ 186.3, 144.7, 138.1, 135.4, 132.8, 132.6, 130.8, 130.6, 130.5, 130.2, 130.0, 129.3, 128.0, 127.4, 127.3, 126.8, 124.0, 21.6, 9.9; HRMS (ES-TOF) m / z: [M+H]+calcd for C + -TOF) m / z: [M+H]+calcd for C + BrNO3S 494.0420; Found 494.0423. 25 H 21 BrNO3S 494.0420; Found 494.0423.

[0078] The 2,3,4,5-tetrasubstituted pyrrole compound (I-10) prepared from Example 10 was analyzed by nuclear magnetic resonance (1H NMR and 1 H NMR and 13 C NMR) and HRMS (ES + -TOF) m / z: [M+H]+calcd for C

[0079]

[0080] 1 H NMR (400 MHz, CDC13) δ 10.24 (s, 1H), 7.84 (d, J = 7.2 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 7.24 (d, J = 7.0 Hz, 2H), 7.15 - 7.06 (m, 5H), 6.90 (d, J = 7.4 Hz, 2H), 2.41 (s, 3H), 2.18 (s, 3H); 13C NMR (101 MHz, CDC13) δ 188.1, 144.7, 138.1, 134.9, 133.7, 133.1, 132.2, 131.1, 130.7, 130.4, 130.2, 130.0, 129.7, 128.1, 127.7, 127.5, 127.1, 126.8, 126.1, 124.8, 124.3, 123.9, 21.6, 9.8; HRMS (ES + -TOF) m / z: [M+H] + Calcd for C 29 H 24 NO3S 466.1471; Found 466.1475.

[0081] The 2,3,4,5-tetrasubstituted pyrrole compound (I-11) prepared from Example 11 was analyzed by NMR (1H NMR and 1 H NMR and 13 C NMR) and HRMS (ES + -TOF) as follows:

[0082]

[0083] 1 H NMR (400 MHz, CDC13) δ 10.34 (s, 1H), 7.86 (d, J = 6.8 Hz, 2H), 7.39 - 7.26 (m, 6H), 7.16 (d, J = 7.2 Hz, 2H), 6.92 (s, 1H), 6.36 (s, 1H), 2.42 (s, 3H), 2.13 (s, 3H); 13 C NMR (101 MHz, CDC13) δ 171.7, 151.8, 146.3, 144.7, 138.1, 133.4, 132.9, 130.0, 129.2, 128.5, 128.1, 127.4, 124.2, 119.6, 112.3, 21.6, 9.7; HRMS (ES + -TOF) m / z: [M+H] + Calcd for C 23 H 20 NO4S 406.1108; Found 406.1113.

[0084] The 2,3,4,5-tetrasubstituted pyrrole compound (I-12) prepared from Example 12 was analyzed by NMR (1H NMR and 1 H NMR and 13 C NMR) and HRMS (ES + -TOF) as follows:

[0085]

[0086] 1 H NMR (400 MHz, CDC13) δ 10.27 (s, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 4.9 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 6.7 Hz, 3H), 7.13 (d, J = 7.8 Hz, 2H), 7.02 (d, J = 3.9 Hz, 1H), 6.67 (t, J = 4.4 Hz, 1H), 2.40 (s, 3H), 2.21 (s, 3H); 13 C NMR (101 MHz, CDC13) δ 178.6, 144.6, 141.8, 138.2, 134.6, 133.7, 133.2, 131.3, 130.5, 130.0, 129.7, 129.2 128.2, 127.4, 127.3, 124.0, 21.6, 9.9; HRMS (ES + -TOF) m / z: [M+H] + Calcd for C 23 H 20 NO3S2422.0879; Found 422.0882.

[0087] The 2,3,4,5-tetrasubstituted pyrrole compound (I-13) prepared from Example 13 was analyzed by NMR 1 H NMR and 13 C NMR) and HRMS (ES + -TOF) detection data were as follows:

[0088]

[0089] 1 H NMR (400 MHz, CDC13) δ 9.85 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.44 - 7.38 (m, 3H), 7.34 (d, J = 8.1 Hz, 2H), 7.21 - 7.18 (m, 2H), 4.98 - 4.91 (m, 1H), 2.43 (s, 3H), 2.22 (dd, J = 15.4, 5.5 Hz, 1H), 2.00 (s, 4H), 1.84 - 1.68 (m, 3H), 1.64 (s, 3H), 1.52 (s, 3H), 0.97 - 0.85 (m, 2H), 0.67 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDC13) δ 192.2, 144.6, 138.3, 133.7, 131.3, 131.2, 130.4, 130.2, 130.0, 128.7, 128.5, 128.1, 127.3, 124.8, 124.2, 47.1, 36.7, 29.3, 25.6, 25.1, 21.6, 19.2, 17.6, 9.6; HRMS (ES + -TOF) m / z: [M+H] + Calcd for C 28 H 34 NO3S 464.2254; Found 464.2263.

[0090] The 2,3,4,5-tetrasubstituted pyrrole compound (1-14) prepared from Example 14 was analyzed by NMR (1H NMR and 1 H NMR and 13 C NMR) and HRMS (ES + -TOF) as follows:

[0091]

[0092] 1 H NMR (400 MHz, CDC13) δ 9.81 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.46 - 7.38 (m, 3H), 7.34 (d, J = 8.1 Hz, 2H), 7.21 - 7.19 (m, 2H), 2.43 (s, 3H), 2.22 - 2.11 (m, 2H), 2.00 (s, 3H), 1.43 - 1.36 (m, 2H), 1.06 - 0.97 (m, 2H), 0.68 (t, J = 7.3 Hz, 3H); 13 C NMR (101 MHz, CDC13) δ 192.52, 144.61, 138.3, 133.7, 131.4, 130.1, 130.1, 130.0, 128.7, 128.5, 128.2, 127.3, 124.8, 39.7, 26.3, 22.1, 21.6, 13.5, 9.6; HRMS (ES + -TOF) m / z: [M+H] + Calcd for C 23 H 26 NO3S 396.1628; Found 396.1630.

[0093] The 2,3,4,5-tetrasubstituted pyrrole compound (1-15) prepared from Example 15 was analyzed by NMR (1H NMR and 1H NMR and 13 C NMR and HRMS (ES + -TOF) data are:

[0094]

[0095] 1 H NMR (400 MHz, CDC13) δ 10.29 (s, 1H), 7.81 (s, 2H), 7.40 (d, J = 7.5 Hz, 2H), 7.26 - 7.21 (m, 3H), 7.03 (t, J = 7.6 Hz, 2H), 6.86 - 6.80 (m, 4H), 2.39 (m, 3H), 2.20 (s, 3H), 2.18 (s, 3H); 13 C NMR (101 MHz, CDC13) δ 187.9, 144.5, 138.2, 136.8, 136.7, 132.7, 131.7, 130.4, 129.9, 129.7, 129.2, 128.5, 127.5, 127.3, 124.0, 21.6, 21.0, 9.9; HRMS (ES + -TOF) m / z: [M+H] + Calcd for C 26 H 24 NO3S 430.1471; Found 430.1473.

[0096] NMR (400 MHz, CDC13) δ 10.29 (s, 1H), 7.81 (s, 2H), 7.40 (d, J = 7.5 Hz, 2H), 7.26 - 7.21 (m, 3H), 7.03 (t, J = 7.6 Hz, 2H), 6.86 - 6.80 (m, 4H), 2.39 (m, 3H), 2.20 (s, 3H), 2.18 (s, 3H); 1 H NMR and 13 C NMR and HRMS (ES + -TOF) data are:

[0097]

[0098] 1 H NMR (400 MHz, CDC13) δ 10.29 (s, 1H), 7.81 (s, 2H), 7.40 (d, J = 7.5 Hz, 2H), 7.26 - 7.21 (m, 3H), 7.03 (t, J = 7.6 Hz, 2H), 6.86 - 6.80 (m, 4H), 2.39 (m, 3H), 2.20 (s, 3H), 2.18 (s, 3H); 13C NMR (101 MHz, CDC13) δ 187.2, 144.7, 138.2, 136.7, 132.5, 131.9, 131.7, 131.2, 130.0, 129.8, 129.7, 128.6, 127.8, 127.4, 127.3, 125.3, 124.7, 21.6, 19.9, 9.8; HRMS (ES + -TOF) m / z: [M + H] + Calcd for C 26 H 24 NO3S 430.1471; Found 430.1473.

[0099] The 2,3,4,5-tetrasubstituted pyrrole compound (I-17) prepared from Example 17 was subjected to nuclear magnetic resonance (1H NMR and 1 H NMR and 13 C NMR) and HRMS (ES + -TOF) detection data were as follows:

[0100]

[0101] 1 H NMR (400 MHz, CDC13) δ 10.24 (s, 1H), 7.82 (d, J = 7.9 Hz, 2H), 7.40 (d, J = 7.7 Hz, 2H), 7.29 - 7.24 (m, 3H), 7.06 (t, J = 7.6 Hz, 2H), 6.84 (d, J = 8.2 Hz, 2H), 6.59 (d, J = 8.2 Hz, 2H), 3.69 (s, 3H), 2.40 (s, 3H), 2.17 (s, 3H); 13 C NMR (101 MHz, CDC13) δ 187.5, 158.7, 144.5, 138.3, 136.7, 132.4, 131.8, 131.7, 130.0, 129.9, 129.8, 129.7, 129.6, 129.2, 129.2, 129.2, 127.6, 127.4, 127.3, 125.1, 124.0, 113.4, 55.2, 21.6, 9.9; HRMS (ES + -TOF) m / z: [M + H] + Calcd for C 26 H 24 NO4S 446.1421; Found 446.1424.

[0102] The 2,3,4,5-tetrasubstituted pyrrole compound (I-18) prepared from Example 18 was subjected to nuclear magnetic resonance (1H NMR and1 H NMR and 13 C NMR and HRMS (ES + -TOF) data were as follows:

[0103]

[0104] 1 H NMR (400 MHz, CDC13) δ 10.55 (s, 1H), 7.79 (d, J = 7.3 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 7.31 - 7.23 (m, 3H), 7.07 (t, J = 7.7 Hz, 2H), 6.93 - 6.85 (m, 2H), 6.75 (t, J = 8.7 Hz, 2H), 2.38 (s, 3H), 2.17 (s, 3H); 13 C NMR (101 MHz, CDC13) δ 187.5, 161.9 (d, J = 247.3 Hz), 144.6 (d, J = 3 Hz), 138.1, 136.6, 132.2, 132.1, 131.5, 130.0, 129.8, 129.2, 129.1, 128.8, 127.7, 127.4, 123.9, 114.9 (d, J = 21.6 Hz), 21.6, 9.8; HRMS (ES + -TOF) m / z: [M+H] + Calcd for C 25 H 21 FNO3S 434.1221; Found 434.1230.

[0105] NMR (400 MHz, CDC13) of 2,3,4,5-tetrasubstituted pyrrole compound (1-19) prepared from Example 19 1 H NMR and 13 C NMR and HRMS (ES + -TOF) data were as follows:

[0106]

[0107] 1 H NMR (400 MHz, CDC13) δ 10.55 (s, 1H), 7.79 (d, J = 7.3 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 7.31 - 7.23 (m, 3H), 7.07 (t, J = 7.7 Hz, 2H), 6.93 - 6.85 (m, 2H), 6.75 (t, J = 8.7 Hz, 2H), 2.38 (s, 3H), 2.17 (s, 3H); 13C NMR (101 MHz, CDC13) δ 187.3, 144.7, 138.1, 136.6, 132.1, 132.0, 131.8, 131.3, 131.0, 130.0, 130.0, 129.6, 129.1, 127.8, 127.4, 123.8, 121.5, 21.6, 9.8; HRMS (ES + -TOF) m / z: [M+H] + Calcd for C 25 H 21 BrNO3S 494.0420; Found 494.0424. NMR (1H and13C) and HRMS (ES 1 HNMR and 13 C NMR) and HRMS (ES + -TOF) data for 2,3,4,5-tetrasubstituted pyrrole compound (I-8) prepared from Example 20 are as follows:

[0108]

[0109] 1 H NMR (400 MHz, CDC13) δ 10.14 (s, 1H), 7.87 (d, J = 7.8 Hz, 2H), 7.37 - 7.26 (m, 7H), 7.05 (t, J = 7.6 Hz, 4H), 2.44 (s, 3H), 2.17 (s, 3H); 13 CNMR (101 MHz, CDC13) δ 187.0, 144.9, 138.0, 136.7, 136.6, 132.2, 131.0, 130.8, 130.1, 130.1, 129.7, 129.3 (d, J = 32.5 Hz), 128.9, 127.8, 127.5, 124.7 (d, J = 3.8 Hz), 123.89 (d, J = 270 Hz), 123.85, 21.7, 9.8; HRMS (ES + -TOF) m / z: [M+H] + Calcd for C 26 H 21 F3NO3S 484.1189; Found 484.1190.

[0110] NMR (1H and13C) and HRMS (ES 1 H NMR and 13 C NMR) and HRMS (ES + -TOF) data for 2,3,4,5-tetrasubstituted pyrrole compound (I-21) prepared from Example 21 are as follows:

[0111]

[0112] 1 H NMR (400 MHz, CDC13) δ 10.27 (s, 1H), 7.91 - 7.79 (m, 2H), 7.68 (d, J = 7.4 Hz, 1H), 7.58 (d, J = 6.9 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.44 - 7.27 (m, 7H), 7.07 - 6.96 (m, 2H), 6.86 (t, J = 7.6 Hz, 2H), 2.45 - 2.37 (m, 3H), 2.23 (s, 3H); 13 C NMR (101 MHz, CDC13) δ 187.8, 144.6, 138.2, 136.7, 132.7, 132.6, 132.0, 131.8, 130.3, 130.0, 129.9, 129.0, 128.2, 127.7, 127.5, 127.4, 127.4, 126.1, 126.0, 124.2, 21.6, 10.0; HRMS (ES + -TOF) m / z: [M+H] + Calcd for C 29 H 24 NO3S 466.1471; Found 466.1476.

[0113] The 2,3,4,5-tetrasubstituted pyrrole compound (I-22) prepared from Example 22 was analyzed by NMR 1 H NMR and 13 C NMR) and HRMS (ES + -TOF) detection data were as follows:

[0114]

[0115] 1 H NMR (400 MHz, CDC13) δ 9.38 (s, 1H), 7.84 (d, J = 8.3 Hz, 2H), 7.71 (d, J = 6.9 Hz, 2H), 7.63 (t, J = 7.3 Hz, 1H), 7.53 (t, J = 7.6 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 2.52 - 2.44 (m, 5H), 2.20 (s, 3H), 1.39 - 1.31 (m, 2H), 1.26 - 1.14 (m, 2H), 0.80 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDC13) δ 187.1, 144.6, 138.5, 138.3, 133.6, 132.3, 130.0, 129.4, 128.7, 128.4, 127.2, 124.6, 32.6, 24.6, 22.6, 21.6, 13.7, 9.1; HRMS (ES + -TOF) m / z: [M+H] + Calcd for C 23 H 26 NO3S 396.1628; Found 396.1633.

[0116] The 2,3,4,5-tetrasubstituted pyrrole compound (I-23) prepared from Example 23 was analyzed by NMR (1H NMR and 1 H NMR and 13 C NMR) and HRMS (ES + -TOF) as follows:

[0117]

[0118] 1 H NMR (400 MHz, CDC13) δ 9.65 (s, 1H), 7.80 (d, J = 7.9 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 2.70 (t, J = 7.9 Hz, 2H), 2.41 (s, 3H), 2.38 - 2.33 (m, 1H), 2.17 (s, 3H), 1.55 - 1.43 (m, 2H), 1.36 (q, J = 7.4 Hz, 2H), 1.25 (s, 2H), 1.02 (d, J = 4.2 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H); 13 CNMR (101 MHz, CDC13) δ 191.3, 144.4, 138.5, 131.1, 130.7, 129.9, 128.1, 127.1, 124.6, 33.2, 25.2, 22.7, 21.6, 18.6, 13.8, 11.4, 9.1; HRMS (ES + -TOF) m / z: [M+H] + Calcd for C 20 H 26 NO3S 360.1628; Found 360.1630.

[0119] The 2,3,4,5-tetrasubstituted pyrrole compound (I-24) prepared from Example 24 was analyzed by NMR (1H NMR and 1 H NMR and 13C NMR) and HRMS (ES) + The TOF detection data is as follows:

[0120]

[0121] 1 H NMR (400MHz, CDCl3) δ10.12(s,1H),7.92(d,J=7.9Hz,2H),7.36(dd,J=20.3,7.8Hz,4H),7.23(t,J=7.5Hz,1H ),7.08–6.94(m,7H),2.44(s,3H),1.73–1.63(m,1H),0.57(q,J=6.0,4.9Hz,2H),0.07(q,J=6.0,4.8Hz,2H); 13 C NMR (101MHz, CDCl3) δ187.5,144.6,138.0,136.8,133.1,133.0,131.9,131.4,1 30.8,129.8,129.1,128.2,127.9,127.6,127.4,127.0,21.6,7.3,5.9; HRMS(ES + -TOF)m / z:[M+H + Calcd for C 27 H 24 NO3S442.1471;Found 442.1474.

[0122] Nuclear magnetic resonance (NMR) of the 2,3,4,5-tetrasubstituted pyrrole compound (I-25) prepared in Example 25 1 H NMR and 13 C NMR) and HRMS (ES) + The TOF detection data is as follows:

[0123]

[0124] 1 H NMR (400MHz, CDCl3) δ9.62 (s, 1H), 7.71–7.53 (m, 5H), 7.47 (t, J = 7.5Hz, 2H), 7. 13(d,J=8.3Hz,5H),6.91–6.82(m,2H),4.08(s,2H),2.35(s,3H),1.84(s,3H); 13C NMR (101MHz, CDCl3) δ187.1,144.4,138.4,138.3,138.0,132.5,130.2,129.9,129.8 ,129.5,128.7,128.4,128.2,128.1,127.3,127.2,125.8,29.4,21.5,11.4; HRMS(ES + -TOF)m / z:[M+H + Calcd for C 26 H 237 NO3S 430.1471; Found 430.1479.

[0125] Nuclear magnetic resonance (NMR) of the 2,3,4,5-tetrasubstituted pyrrole compound (I-26) prepared in Example 26 1 H NMR and 13 C NMR) and HRMS (ES) + -TOF detection data are:

[0126]

[0127] 1 H NMR (400MHz, CDCl3) δ9.74(s,1H),7.85(d,J=7.9Hz,2H),7.40–7.31(m,5H),7.20(d,J=7.2Hz,2H),3.72(s,3H),2.43(s,3H),2.07(s,3H); 13 C NMR (101MHz, CDCl3) δ160.3,144.6,138.3,132.6,132.4,130.1,130.0,128.2,127.8,127.5,127.3,124.6,121.2,51.8,21.6,9.7; HRMS (ES + -TOF)m / z:[M+H + Calcd for C 29 H 19 NO4S 370.1108; Found370.1115.

[0128] Nuclear magnetic resonance (NMR) of the 2,3,4,5-tetrasubstituted pyrrole compound (I-27) prepared in Example 27 1 H NMR and 1 3 C NMR) and HRMS (ES) + -TOF detection data are:

[0129]

[0130] 1 H NMR (400 MHz, CDC13) δ 10.02 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.40 - 7.30 (m, 5H), 7.28 - 7.25 (m, 2H), 4.06 - 3.95 (m, 2H), 3.94 - 3.82 (m, 2H), 2.43 (s, 3H), 2.13 (s, 3H), 1.11 (t, J = 7.0 Hz, 6H); 13 C NMR (101 MHz, CDC13) δ 144.3, 138.5, 134.0 (d, J = 15.7 Hz), 132.7, 130.0, 129.9, 129.2 (d, J = 11.2 Hz), 127.9, 127.5, 127.3, 124.2 (d, J = 13.2 Hz), 119.8 (d, J = 220.8 Hz), 62.6 (d, J = 5.3 Hz), 21.6, 15.9 (d, J = 7.0 Hz), 9.8; HRMS (ES + -TOF) m / z: [M + H]+calcd for C + Calcd for C 22 H 27 NO5PS 448.1342; Found 448.1342.

Claims

1. A method for producing a 2,3,4,5-tetrasubstituted pyrrole compound, characterized by, The method comprises the following steps: adding inorganic base, allene ketone and p-methyl benzene sulfonyl methyl isonitrile into organic solvent, heating to react, and after the reaction is completed, the 2,3,4,5-tetra-substituted pyrrole compound is obtained after post-treatment. The structure of the allene ketone is shown in formula (II): The structure of the p-methyl benzene sulfonyl methyl isonitrile is shown in formula (III): The structure of the 2,3,4,5-tetra-substituted pyrrole compound is shown in formula (I): In the formulae (I) to (III), R 1 is phenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-methoxyphenyl, benzotetrahydrofuranyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, α-naphthyl, furanyl, thienyl, 3,7-dimethyl-6-octenyl or n-butyl; R 2 is phenyl, 4-methylphenyl, 2-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, β-naphthyl or n-butyl; The organic solvent is acetonitrile. The inorganic base is cesium carbonate. The reaction temperature is 70-90 DEG C.

2. The method for preparing the 2,3,4,5-tetrasubstituted pyrrole compound according to claim 1, characterized in that, The molar ratio of the allene ketone, the p-methyl benzene sulfonyl methyl isonitrile and the inorganic base is 2-2.2:1:2-2.

2.

3. The method for preparing the 2,3,4,5-tetrasubstituted pyrrole compound according to claim 1, characterized in that, The reaction time is 30-60 minutes.

4. The method for preparing the 2,3,4,5-tetrasubstituted pyrrole compound according to claim 1, characterized in that, The 2,3,4,5-tetra-substituted pyrrole compound is one of the compounds shown in formula (I-1)-formula (I-27).

5. A method for producing a 2, 3, 4, 5-tetrasubstituted pyrrole compound, characterized by, The method comprises the following steps: adding inorganic base, allene ketone and p-methyl benzene sulfonyl methyl isonitrile into organic solvent, heating to react, and after the reaction is completed, the 2,3,4,5-tetra-substituted pyrrole compound is obtained after post-treatment. The structure of the allene ketone is one of the following compounds The structure of the p-methyl benzene sulfonyl methyl isonitrile is shown in formula (III): The structure of the 2,3,4,5-tetra-substituted pyrrole compound is one of the following formulae:

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