2-cyanopyrrole compound as well as preparation method and application thereof

Abstract

The invention relates to a 2-cyanopyrrole compound as well as a preparation method and application thereof. The structural formula of the 2-cyanopyrrole compound is as follows: # imgabs0 #, in the formula, R1 is selected from any one of phenyl, 4-methylphenyl, 4-chlorphenyl, 2, 4-dichlorophenyl, cyclopropyl or tert-butyl, and R2 is selected from any one of phenyl, 4-methylphenyl, 4-chlorphenyl, 2, 4-dichlorophenyl, cyclopropyl or tert-butyl; r1 is selected from any one of phenyl, 3-fluorophenyl, 4-methoxyphenyl, 2-thienyl or 2-naphthyl, and R2 is selected from any one of phenyl, 3-fluorophenyl, 4-methoxyphenyl, 2-thienyl or 2-naphthyl. Compared with the prior art, the method has the advantages of simple and easily available raw materials, simple reaction operation, environmental friendliness and the like. The 2-cyanopyrrole compound synthesized by the method disclosed by the invention has a wide application prospect in the related fields of organic synthesis, medicinal chemistry and the like.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a 2-cyanopyrrole compound and a preparation method and application thereof. Background Art

[0002] 2-Cyanopyrrole compounds are an important class of organic molecular scaffolds with significant applications in organic synthesis, biopharmaceuticals, and materials science. For example, in the discovery of HMG-CoA reductase inhibitors, related organic molecules containing the 2-cyanopyrrole skeleton have been shown to possess excellent inhibitory activity (see Bratton, L.D. et al. Biorg. Med. Chem. 2007, 15, 5576-5589). Fully substituted 2-cyanopyrroles can act as MAPK inhibitors, playing a role in the treatment of inflammatory diseases by inhibiting the p38 MAP kinase pathway (see Bullington, J. et al. Biorg. Med. Chem. Lett. 2006, 16, 6102-6106).

[0003]

[0004] Over the past few decades, the synthesis of 2-cyanopyrrole compounds has primarily been through the introduction of a cyano group onto the pyrrole ring and the reaction of tetrazolyl compounds. However, methods for simultaneously constructing a pyrrole heterocycle and a cyano group are very limited. Therefore, from the perspective of synthetic methods and application prospects, it is of great significance to study the efficient synthesis of 2-cyanopyrrole compounds using simple and readily available reagents. The following synthetic methods have been reported in the literature:

[0005] (1) Synthesis of 2-cyanopyrrole from pyrrole compounds

[0006] In 2007, Xia Keshan's research group used amide compounds as substrates, and under the action of ethyl dichlorophosphate and DBU, after removing a molecule of water, the amide was converted into nitrile to prepare 2-cyanopyrrole (see reference: Kuo, C.-W. et al. Chem. Commun. 2007, 3, 301-303).

[0007]

[0008] In 2010, Behrouz's group completed the conversion of oximes to nitriles by heating under reflux in DMF under alkaline conditions. However, the raw materials required for this reaction are not readily available, limiting its application (see Rad, MN Setal. Synth. Commun. 2010, 40, 2429-2440).

[0009]

[0010] In 2015, Yu Shouyun's research group developed a new aldehyde cyanation reagent. The aldehyde group on pyrrole undergoes cyanation in the presence of CF3-BHA and a protic acid. This reaction proceeds through an oxime intermediate. The aldehyde first reacts with CF3-BHA to form an O-acyloxime intermediate. The acyloxime intermediate is then protonated and, after removing a proton and a carboxylic acid molecule, yields a 2-cyanopyrrole compound (see reference: An, X.-D. et al. Org. Lett. 2015, 17, 5064-5067).

[0011]

[0012] (2) Synthesis of 2-cyanopyrrole from tetrazole compounds

[0013] In 2000, the Invidiata group synthesized cyanopyrroles by thermally decomposing tetrazolyl[1,5-a]pyrimidine, tetrazolyl[1,5-b]pyridine, and tetrazolyl[1,5-a]pyridine. This method required extreme conditions and was not practical (see Simoni, D. et al. Tetrahedron Lett. 2000, 41, 2699-2703).

[0014]

[0015] In summary, there are still few methods reported in the literature for the direct synthesis of 2-cyanopyrrole compounds, and these reactions have disadvantages such as complex synthesis of reaction raw materials, harsh reaction conditions, and large substrate range limitations. Summary of the Invention

[0016] The present invention is directed to providing a 2-cyanopyrrole compound, its preparation method, and its application. The present invention has the advantages of readily available raw materials, simple reaction operations, and environmental friendliness. The present invention utilizes readily available compounds to develop a highly efficient, one-step synthesis method for constructing pyrrole heterocycles containing a cyano functional group, which has significant application value.

[0017] The purpose of the present invention can be achieved by the following technical solutions:

[0018] A 2-cyanopyrrole compound, the structural formula of the 2-cyanopyrrole compound is as follows:

[0019]

[0020] Among them, R 1 Any one selected from phenyl, 4-methylphenyl, 4-chlorophenyl, 2,4-dichlorophenyl, cyclopropyl or tert-butyl;

[0021] R 2 Any one selected from phenyl, 3-fluorophenyl, 4-methoxyphenyl, 2-thienyl or 2-naphthyl.

[0022] Furthermore, a partial representative structure of the 2-cyanopyrrole compound is one of the following compounds:

[0023]

[0024] The present invention also provides a method for preparing 2-cyanopyrrole compounds, which comprises the following steps:

[0025] Under an inert gas atmosphere, an eneamide compound, tert-butyl isocyanide and N-bromosuccinimide (NBS) are added to dichloromethane (DCM), stirred until the reaction is complete, and then separated and purified to obtain a 2-cyanopyrrole compound;

[0026] Wherein, the structural formula of the enamide compound is as follows:

[0027]

[0028] R 1 Any one selected from phenyl, 4-methylphenyl, 4-chlorophenyl, 2,4-dichlorophenyl, cyclopropyl or tert-butyl;

[0029] R 2 Any one selected from phenyl, 3-fluorophenyl, 4-methoxyphenyl, 2-thienyl or 2-naphthyl.

[0030] Furthermore, the inert gas includes nitrogen.

[0031] Furthermore, the olefin amide compound is selected from (Z)-N-styrylbenzamide, (Z)-N-(2-chlorostyryl)benzamide, (Z)-N-(3-fluorostyryl)benzamide, (Z)-N-(4-methoxystyryl)benzamide, (Z)-N-(2-(thiophen-2-yl)vinyl)benzamide, (Z)-N-(2-(naphthalene-2-yl)vinyl)benzamide, (Z)-N-(4-phenylbut-1-en-1-yl)benzamide, (Z)-N-(hex-1-en-1-yl)benzamide, (Z) -4-methyl-N-styrylbenzamide, (Z)-4-chloro-N-styrylbenzamide, (Z)-2,4-dichloro-N-styrylbenzamide, (Z)-N-styryl-2-naphthamide, (Z)-N-styrylcyclopropanecarboxamide, (Z)-N-styrylcyclohexanecarboxamide, (Z)-N-styryl-pivalamide, (Z)-N-styrylthiophene-2-carboxamide, (Z)-N-styrylfuran-2-carboxamide or (Z)-2,2,2-trifluoro-N-styrylacetamide.

[0032] Furthermore, the molar ratio of the enamide compound, tert-butyl isocyanide and N-bromosuccinimide is 1.0:(2.5-5.0):(1.0-1.5).

[0033] As a preferred technical solution, the molar ratio of the enamide compound, tert-butyl isocyanide and N-bromosuccinimide is 1.0:5.0:1.3.

[0034] Furthermore, the usage ratio of the enamide compound and dichloromethane is 0.3 mmol: (2.0-3.0 mL).

[0035] As a preferred technical solution, the usage ratio of the enamide compound and dichloromethane is 0.3 mmol:3.0 mL.

[0036] Furthermore, the stirring speed is 500-700 rpm,

[0037] The reaction temperature is 30-60°C and the reaction time is 8-16 hours.

[0038] As a preferred technical solution, the reaction temperature is 30-50° C. and the reaction time is 12-16 hours.

[0039] Furthermore, the specific preparation method of the 2-cyanopyrrole compound is as follows:

[0040] S1. Under an inert gas atmosphere, add an ene amide compound, tert-butyl isocyanide and N-bromosuccinimide (NBS) to dichloromethane (DCM), and stir to react to obtain a mixed solution;

[0041] S2. Monitoring the mixture obtained in step S1 by thin layer chromatography to complete the disappearance of the starting material and then completing the reaction, cooling the mixture to room temperature, and removing the solvent to obtain a crude product;

[0042] S3. The crude product obtained in step S2 is separated and purified by silica gel column chromatography to obtain a 2-cyanopyrrole compound.

[0043] Furthermore, in the silica gel column chromatography method, the developing solvent is a mixed solvent of petroleum ether and dichloromethane.

[0044] Furthermore, the volume ratio of petroleum ether to dichloromethane is 1:1-2.

[0045] In addition, the present invention also provides an application of 2-cyanopyrrole compounds in organic synthesis, medicinal chemistry and other related fields.

[0046] The principles of the present invention are as follows:

[0047] The reaction mechanism of the preparation method of 2-cyanopyrrole compounds is:

[0048]

[0049] Among them, R 1 is any one of phenyl, 4-methylphenyl, 4-chlorophenyl, 2,4-dichlorophenyl, cyclopropyl, and tert-butyl;

[0050] R 2 It is any one of phenyl, 3-fluorophenyl, 4-methoxyphenyl, 2-thienyl and 2-naphthyl.

[0051] This method efficiently synthesizes a series of 2-cyanopyrrole compounds using enamide as a raw material and tert-butyl isocyanide as the nitrogen source of the pyrrole heterocyclic skeleton and the source of the tert-butylamino and cyano functional groups. This method has the advantages of readily available raw materials, simple reaction operations, and environmental friendliness.

[0052] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0053] 1. The present invention uses cheap and readily available enamide compounds as raw materials and tert-butyl isocyanide as the nitrogen source of the pyrrole heterocyclic skeleton, the source of the tert-butylamine group and the cyano functional group, to efficiently synthesize a series of 2-cyanopyrrole compounds;

[0054] 2. The present invention has the advantages of simple and readily available raw materials, simple reaction operation, and environmental friendliness;

[0055] 3. The 2-cyanopyrrole compounds synthesized using the method of the present invention have broad application prospects in related fields such as organic synthesis and medicinal chemistry. DETAILED DESCRIPTION

[0056] The present invention is described in detail below with reference to specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and specific operation process, but the protection scope of the present invention is not limited to the following embodiments.

[0057] Unless otherwise specified, the equipment used in the following examples are all conventional equipment in the art; the reagents used are all commercially available products or prepared by conventional methods in the art unless otherwise specified. Anything not described in detail in the following examples can be achieved by conventional experimental means in the art.

[0058] The following embodiments of the present invention are described in detail with reference to specific embodiments. In the absence of conflict, the following embodiments and features in the embodiments may be combined with each other.

[0059] Example 1

[0060] This embodiment provides a method for preparing an N-(1-(tert-butyl)-2-(tert-butylamino)-5-cyano-4-phenyl-1H-pyrrol-3-yl)benzamide compound, and the specific steps are as follows:

[0061] (1) Under nitrogen protection, (Z)-N-phenylvinylbenzamide (67.0 mg, 0.30 mmol), DCM (3.0 mL), tert-butyl isocyanide (168 μL, 1.50 mmol), and NBS (69.4 mg, 0.39 mmol) were added sequentially to a 10 mL thick-walled pressure tube and stirred in an oil bath at 30 °C and 500 rpm for 12 h.

[0062] (2) Monitor by TLC until the starting material disappears, the reaction is complete and cooled to room temperature, and the solvent is removed to obtain a crude product;

[0063] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of petroleum ether and dichloromethane in a volume ratio of 1:1 as the developing solvent to obtain a white solid (103.8 mg, 83% yield), namely N-(1-(tert-butyl)-2-(tert-butylamino)-5-cyano-4-phenyl-1H-pyrrol-3-yl)benzamide compound with the structural formula:

[0064]

[0065] The melting point is 233-234℃.

[0066] The basic parameters of the compound are as follows:

[0067] 1H NMR (400MHz, CDCl3): δ7.76–7.72(m,2H),7.57–7.51(m,1H),7.49–7.42(m,7H),7.39–7.33(m,1H),3.38(s,1H),1.90(s,9H),1.10(s,9H);

[0068] 13 C NMR (101MHz, CDCl3): δ165.6,137.9,134.2,132.2,131.1,130.4,129.2,129.1,129.0,128.2,127.2,117.0,114.9,97.0,62.2,55.7,32.2,30.5;

[0069] HRMS(ESI)m / z:calcd for C 26 H 31 N4O[M+H] + 415.2492, found 415.2484.

[0070] In addition, this embodiment also provides an application of an N-(1-(tert-butyl)-2-(tert-butylamino)-5-cyano-4-phenyl-1H-pyrrol-3-yl)benzamide compound in organic synthesis, and the specific steps are as follows:

[0071] (1) Under nitrogen protection, N-(1-(tert-butyl)-2-(tert-butylamino)-5-cyano-4-phenyl-1H-pyrrol-3-yl)benzamide (124.4 mg, 0.30 mmol), DCM (2.0 mL), and trifluoromethanesulfonic acid (32 μL, 0.36 mmol) were added to a 10 mL thick-walled pressure tube in sequence, and the mixture was stirred in an oil bath at 6°C and 500 rpm for 12 h.

[0072] (2) Monitor by TLC until the starting material disappears, the reaction is complete and cooled to room temperature, and the solvent is removed to obtain a crude product;

[0073] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of ethyl acetate, petroleum ether, and triethylamine in a volume ratio of 50:100:1 as the developing solvent to obtain a white solid (75.2 mg, 70% yield), namely N-(2-amino-1-(tert-butyl)-5-cyano-4-phenyl-1H-pyrrol-3-yl)benzamide compound with the structural formula:

[0074]

[0075] The melting point is 101-102℃.

[0076] The basic parameters of the compound are as follows:

[0077] 1 H NMR (400MHz, CDCl3): δ7.80–7.70(m,2H),7.56–7.49(m,1H),7.49–7.36(m,7H),7.36–7.29(m,1H),4.25(s,2H),1.84(s,9H).

[0078] 13 C NMR (101MHz, CDCl3): δ166.2,138.1,133.5,132.8,132.2,131.0,129.1,129.0,128.9,128.2,127.4,117.8,105.0,91.7,60.6,31.0.

[0079] HRMS(ESI)m / z calcd for C 22 H 23 N4O[M+H] + 359.1866, found 359.1860.

[0080] Example 2

[0081] This example provides a method for preparing an N-(1-(tert-butyl)-2-(tert-butylamino)-5-cyano-4-(3-fluorophenyl)-4-phenyl-1H-pyrrol-3-yl)benzamide compound, which is substantially the same as that in Example 1, except that the starting material is (Z)-N-(3-fluorostyryl)benzamide (72.4 mg, 0.30 mmol) to obtain a white solid (101.1 mg, 78% yield), namely, N-(1-(tert-butyl)-2-(tert-butylamino)-5-cyano-4-(3-fluorophenyl)-4-phenyl-1H-pyrrol-3-yl)benzamide compound having the structural formula:

[0082]

[0083] The melting point is 229-230℃.

[0084] The basic parameters of the compound are as follows:

[0085] 1H NMR (400MHz, CDCl3): δ7.78–7.70(m,2H),7.57–7.50(m,1H),7.50–7.42(m,3H),7.42–7.35(m,1H),7.26–7.21(m, 1H),7.18(ddd,J=9.7,2.6,1.6Hz,1H),7.05(tdd,J=8.5,2.6,1.0Hz,1H),3.32(s,1H),1.89(s,9H),1.10(s,9H);

[0086] 19 F NMR (376MHz, CDCl3): δ-111.69;

[0087] 13 C NMR (101MHz, CDCl3): δ165.7, 164.3, 161.9, 138.2, 134.0, 133.3 (d, J = 8.0Hz), 132.2, 130.7 (d, J = 8.0Hz), 129.3, 129.1, 127.2, 124.7 (d, J = 3.0Hz), 116.4 (d, J = 53.3Hz), 115.5 (d, J = 61.3Hz), 115.0 (d, J = 12.1Hz), 97.1, 62.3, 55.7, 32.2, 30.5;

[0088] HRMS(ESI)m / z:calcd for C 26 H 30 FN4O[M+H] + 433.2398, found 433.2384.

[0089] Example 3

[0090] This example provides a method for preparing an N-(1-(tert-butyl)-2-(tert-butylamino)-5-cyano-4-(4-methoxyphenyl)-1H-pyrrol-3-yl)benzamide compound, which is substantially the same as that of Example 1, except that the starting material is (Z)-N-(4-methoxyphenyl)benzamide (76.0 mg, 0.30 mmol) to obtain a white solid (112.2 mg, 84% yield), namely, N-(1-(tert-butyl)-2-(tert-butylamino)-5-cyano-4-(4-methoxyphenyl)-1H-pyrrol-3-yl)benzamide compound having the structural formula:

[0091]

[0092] The melting point is 231-232℃.

[0093] The basic parameters of the compound are as follows:

[0094] 1 H NMR (400MHz, CDCl3): δ7.78–7.71(m,2H),7.56–7.49(m,2H),7.44(dd,J=8.3,6.8Hz,2H),7. 41–7.36(m,2H),6.96(d,J=8.8Hz,2H),3.81(s,3H),3.37(s,1H),1.88(s,9H),1.10(s,9H);

[0095] 13 C NMR (101MHz, CDCl3): δ165.6,159.5,137.8,134.2,132.1,130.4,130.1,129 .01,127.2,123.3,117.2,114.9,114.6,96.7,62.0,55.7,55.4,32.2,30.5;

[0096] HRMS(ESI)m / z:calcd for C 27 H 33 N4O2[M+H] + 445.2598, found 445.2597.

[0097] Example 4

[0098] This example provides a method for preparing an N-(1-(tert-butyl)-2-(tert-butylamino)-5-cyano-4-(thiophen-2-yl)-1H-pyrrol-3-yl)benzamide compound, which is substantially the same as that of Example 1, except that the starting material is (Z)-N-(2-(thiophen-2-yl)vinyl)benzamide (68.8 mg, 0.30 mmol), to obtain a white solid (70.8 mg, 56% yield), namely, N-(1-(tert-butyl)-2-(tert-butylamino)-5-cyano-4-(thiophen-2-yl)-1H-pyrrol-3-yl)benzamide compound having the structural formula:

[0099]

[0100] The melting point is 89-90℃.

[0101] The basic parameters of the compound are as follows:

[0102] 1H NMR (400MHz, CDCl3): δ7.91–7.79(m,2H),7.73(s,1H),7.60–7.52(m,1H),7.48(dd,J=8.2,6.7Hz,2H),7.41(dd,J =3.7,1.1Hz,1H),7.35(dd,J=5.2,1.2Hz,1H),7.12(dd,J=5.2,3.6Hz,1H),3.30(s,1H),1.88(s,9H),1.10(s,9H);

[0103] 13 C NMR (101MHz, CDCl3): δ165.6,138.4,134.0,132.2,131.8,129.1,128.0,127.3,126.7,126.0,123.8,117.1,114.6,96.6,62.4,55.7,32.2,30.5;

[0104] HRMS(ESI)m / z:calcd for C 24 H 29 N4OS[M+H] + 421.2057, found 421.2059.

[0105] Example 5

[0106] This example provides a method for preparing an N-(1-(tert-butyl)-2-(tert-butylamino)-5-cyano-4-(naphthalen-2-yl)-1H-pyrrol-3-yl)benzamide compound, which is substantially the same as that of Example 1, except that the starting material is (Z)-N-(2-(naphthalen-2-yl)vinyl)benzamide (82.0 mg, 0.30 mmol), to obtain a white solid (102.8 mg, 74% yield), namely, N-(1-(tert-butyl)-2-(tert-butylamino)-5-cyano-4-(naphthalen-2-yl)-1H-pyrrol-3-yl)benzamide compound having the structural formula:

[0107]

[0108] The melting point is 213-214℃.

[0109] The basic parameters of the compound are as follows:

[0110] 1H NMR (400MHz, CDCl3): δ7.98–7.95(m,1H),7.91(d,J=8.5Hz,1H),7.88–7.80(m,2H),7.77–7.71 (m,2H),7.62–7.45(m,5H),7.41(dd,J=8.3,6.9Hz,2H),3.43(s,1H),1.92(s,9H),1.12(s,9H);

[0111] 13 C NMR (101MHz, CDCl3): δ165.7,138.1,134.1,133.6,132.9,132.1,130.4,129.0,128.8,128 .5,128.2,128.2,127.8,127.1,126.6,126.6,117.1,115.2,97.2,62.2,55.7,32.2,30.5;

[0112] HRMS(ESI)m / z:calcd for C 30 H 33 N4O[M+H] + 465.2649, found 465.2641.

[0113] Example 6

[0114] This example provides a method for preparing an N-(1-(tert-butyl)-2-(tert-butylamino)-5-cyano-1H-pyrrol-3-yl)-4-methylbenzamide compound, which is substantially the same as that of Example 1, except that the starting material is (Z)-4-methyl-N-styrylbenzamide (71.2 mg, 0.30 mmol), and a white solid (105.0 mg, 82% yield) is obtained, namely, N-(1-(tert-butyl)-2-(tert-butylamino)-5-cyano-1H-pyrrol-3-yl)-4-methylbenzamide, having the structural formula:

[0115]

[0116] Melting point is 228-229℃

[0117] The basic parameters of the compound are as follows:

[0118] 1H NMR (400MHz, CDCl3): δ7.65 (d, J = 8.2Hz, 2H), 7.51–7.38 (m, 5H), 7.38–7.31 (m, 1H),7.24(d,J=8.0Hz,2H),3.39(s,1H),2.40(s,3H),1.89(s,9H),1.09(s,9H);

[0119] 13 C NMR (101MHz, CDCl3): δ165.6,142.7,138.0,131.2,131.1,130.4,129.6,12 9.1,128.9,128.1,127.2,117.1,115.0,96.8,62.0,55.6,32.2,30.4,21.6;

[0120] HRMS(ESI)m / z:calcd for C 27 H 33 N4O[M+H] + 429.2649, found 429.2642.

[0121] Example 7

[0122] This example provides a method for preparing an N-(1-(tert-butyl)-2-(tert-butylamino)-5-cyano-1H-pyrrol-3-yl)-4-chlorobenzamide compound, which is substantially the same as that of Example 1, except that the starting material is (Z)-4-chloro-N-styrylbenzamide (77.3 mg, 0.30 mmol), and a white solid (117.1 mg, 85% yield) is obtained, namely, N-(1-(tert-butyl)-2-(tert-butylamino)-5-cyano-1H-pyrrol-3-yl)-4-chlorobenzamide compound having the structural formula:

[0123]

[0124] The melting point is 209-210℃.

[0125] The basic parameters of the compound are as follows:

[0126] 1 H NMR (400MHz, CDCl3): δ7.72–7.63(m,2H),7.52(s,1H),7.47–7.31(m,7H),3.29(s,1H),1.88(s,9H),1.09(s,9H);

[0127] 13C NMR (101MHz, CDCl3): δ164.6,138.5,137.9,132.5,131.0,130.4,129.3,129.12,128.9,128.6,128.3,116.9,114.7,97.0,62.2,55.7,32.2,30.5;

[0128] HRMS(ESI)m / z:calcd for C 26 H 30 ClN4O[M+H] + 449.2103, found 449.2094.

[0129] Example 8

[0130] This example provides a method for preparing an N-(1-(tert-butyl)-2-(tert-butylamino)-5-cyano-1H-pyrrol-3-yl)-2,4-dichlorobenzamide compound, which is substantially the same as that of Example 1, except that the starting material is (Z)-2,4-dichloro-N-styrylbenzamide (87.6 mg, 0.30 mmol), and a white solid (99.0 mg, 68% yield) is obtained, namely, N-(1-(tert-butyl)-2-(tert-butylamino)-5-cyano-1H-pyrrol-3-yl)-2,4-dichlorobenzamide, having the structural formula:

[0131]

[0132] The melting point is 146-147℃.

[0133] The basic parameters of the compound are as follows:

[0134] 1 H NMR (400MHz, CDCl3): δ7.78 (s, 1H), 7.64 (d, J = 8.4Hz, 1H), 7.49–7.39 (m, 5H), 7.39 –7.32(m,1H),7.30(dd,J=8.4,2.0Hz,1H),3.29(s,1H),1.88(s,9H),1.13(s,9H);

[0135] 13 C NMR (101MHz, CDCl3): δ163.4,137.7,137.6,132.4,131.9,131.6,130.9,130 .6,129.32,129.0,128.3,127.8,116.8,114.7,97.3,62.2,55.8,32.2,30.5;

[0136] HRMS(ESI)m / z:calcd for C 26 H 29 Cl2N4O[M+H] + 483.1713, found 483.1709.

[0137] Example 9

[0138] This example provides a method for preparing an N-(1-(tert-butyl)-2-(tert-butylamino)-5-cyano-1H-pyrrol-3-yl)cyclopropanecarboxamide compound, which is substantially the same as that of Example 1, except that the starting material is (Z)-N-phenylvinylcyclopropanecarboxamide (56.2 mg, 0.30 mmol), and a white solid (85.9 mg, 76% yield) is obtained, namely, N-(1-(tert-butyl)-2-(tert-butylamino)-5-cyano-1H-pyrrol-3-yl)cyclopropanecarboxamide, having the structural formula:

[0139]

[0140] The melting point is 236-237℃.

[0141] The basic parameters of the compound are as follows:

[0142] 1 H NMR (400MHz, CDCl3): δ7.58–7.30(m,5H),6.97(s,1H),3.26(s,1H),1.84(s ,9H),1.46–1.29(m,2H),1.28–1.20(m,1H),1.10(s,9H),0.91–0.76(m,2H);

[0143] 13 C NMR (101MHz, CDCl3): δ172.3,138.6,131.5,131.4,128.8,128.5,127.7,117.1,115.4,94.8,60.9,54.5,31.6,30.2,13.7,6.7;

[0144] HRMS(ESI)m / z:calcd for C 23 H 31 N4O[M+H] + 379.2492, found 379.2488.

[0145] Example 10

[0146] This example provides a method for preparing an N-(1-(tert-butyl)-2-(tert-butylamino)-5-cyano-1H-pyrrol-3-yl) palmitamide compound, which is substantially the same as that of Example 1, except that the starting material is (Z)-N-styryl-pivalamide (61.0 mg, 0.30 mmol), and a white solid (74.0 mg, 63% yield) is obtained, namely, N-(1-(tert-butyl)-2-(tert-butylamino)-5-cyano-1H-pyrrol-3-yl) palmitamide compound having the structural formula:

[0147]

[0148] The melting point is 234-235℃.

[0149] The basic parameters of the compound are as follows:

[0150] 1 H NMR (400MHz, CDCl3): δ7.49–7.30(m,5H),7.00(s,1H),3.38(s,1H),1.85(s,9H),1.22(s,9H),1.08(s,9H);

[0151] 13 C NMR (101MHz, CDCl3): δ176.5,137.8,131.1,130.3,129.02,128.98,128.2,117.1,115.0,96.8,62.0,55.6,39.3,32.2,30.5,27.7;

[0152] HRMS(ESI)m / z:calcd for C 24 H 35 N4O[M+H] + 395.2805, found 395.2802.

[0153] The above description of the embodiments is intended to facilitate understanding and use of the invention by those skilled in the art. It will be apparent that those skilled in the art can readily make various modifications to these embodiments and apply the general principles described herein to other embodiments without requiring inventive effort. Therefore, the present invention is not limited to the above-described embodiments. Improvements and modifications made by those skilled in the art based on the disclosure of the present invention, without departing from the scope of the present invention, should be within the scope of protection of the present invention.

Claims

1. A 2-cyanopyrrole compound, characterized in that The structural formula of the 2-cyanopyrrole compound is as follows: Among them, R 1 Any one selected from phenyl, 4-methylphenyl, 4-chlorophenyl, 2,4-dichlorophenyl, cyclopropyl or tert-butyl; R 2 Any one selected from phenyl, 3-fluorophenyl, 4-methoxyphenyl, 2-thienyl or 2-naphthyl.

2. A 2-cyanopyrrole compound according to claim 1, characterized in that, Some representative structures of the 2-cyanopyrrole compounds are one of the following compounds:

3. A method for preparing a 2-cyanopyrrole compound according to claim 1 or claim 2, characterized in that: The specific steps are as follows: Under an inert gas atmosphere, an eneamide compound, tert-butyl isocyanide and N-bromosuccinimide are added to dichloromethane, stirred until the reaction is complete, and then separated and purified to obtain a 2-cyanopyrrole compound; Wherein, the structural formula of the enamide compound is as follows: R 1 Any one selected from phenyl, 4-methylphenyl, 4-chlorophenyl, 2,4-dichlorophenyl, cyclopropyl or tert-butyl; R 2 Any one selected from phenyl, 3-fluorophenyl, 4-methoxyphenyl, 2-thienyl or 2-naphthyl.

4. The method for preparing a 2-cyanopyrrole compound according to claim 3, wherein: The inert gas includes nitrogen.

5. The method for preparing a 2-cyanopyrrole compound according to claim 3, wherein: The enamide compound is selected from (Z)-N-styrylbenzamide, (Z)-N-(2-chlorostyryl)benzamide, (Z)-N-(3-fluorostyryl)benzamide, (Z)-N-(4-methoxystyryl)benzamide, (Z)-N-(2-(thiophen-2-yl)vinyl)benzamide, (Z)-N-(2-(naphthalene-2-yl)vinyl)benzamide, (Z)-N-(4-phenylbut-1-en-1-yl)benzamide, (Z)-N-(hex-1-en-1-yl)benzamide, (Z)-4 any one or more of -methyl-N-styrylbenzamide, (Z)-4-chloro-N-styrylbenzamide, (Z)-2,4-dichloro-N-styrylbenzamide, (Z)-N-styrylbenzamide, 2-naphthylcarboxamide, (Z)-N-styrylcyclopropanecarboxamide, (Z)-N-styrylcyclohexanecarboxamide, (Z)-N-styryl-pivalamide, (Z)-N-styrylthiophene-2-carboxamide, (Z)-N-styrylfuran-2-carboxamide or (Z)-2,2,2-trifluoro-N-styrylacetamide.

6. The method for preparing a 2-cyanopyrrole compound according to claim 3, wherein: The molar ratio of the enamide compound, tert-butyl isocyanide and N-bromosuccinimide is 1.0:(2.5-5.0):(1.0-1.5); The usage ratio of the enamide compound and dichloromethane is 0.3 mmol: (2.0-3.0 mL).

7. The method for preparing a 2-cyanopyrrole compound according to claim 3, wherein: The stirring speed is 500-700 rpm, The reaction temperature is 30-60°C and the reaction time is 8-16 hours.

8. The method for preparing a 2-cyanopyrrole compound according to claim 3, wherein: The specific preparation method of the 2-cyanopyrrole compound is as follows: S1. Under an inert gas atmosphere, add an ene amide compound, tert-butyl isocyanide and N-bromosuccinimide to dichloromethane, and stir to react to obtain a mixed solution; S2. Monitoring the mixture obtained in step S1 by thin layer chromatography to complete the disappearance of the starting material and then completing the reaction, cooling the mixture to room temperature, and removing the solvent to obtain a crude product; S3. The crude product obtained in step S2 is separated and purified by silica gel column chromatography to obtain a 2-cyanopyrrole compound.

9. The method for preparing a 2-cyanopyrrole compound according to claim 8, wherein: In the silica gel column chromatography method, the developing solvent is a mixed solvent of petroleum ether and dichloromethane; The volume ratio of the petroleum ether to dichloromethane is 1:1-2.

10. Use of the 2-cyanopyrrole compound according to claim 1 or claim 2 in the fields of organic synthesis and medicinal chemistry.

Images