A method for synthesizing substituted pyrrole compounds

Abstract

The present invention discloses a method for synthesizing substituted pyrrole compounds. The specific steps are as follows: under inert gas protection, an aryl-1-propyne compound, a nitrile compound, and a base are mixed in a molar ratio of 1:1.2:3 in an aprotic solvent for reaction, quenched by adding a saturated aqueous ammonium chloride solution, filtered, washed, evaporated to dryness under reduced pressure, and separated by column chromatography to obtain the substituted pyrrole compound. The present invention reacts under metal-free conditions, has readily available raw materials, has good substrate universality, and is simple to prepare and operate.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and in particular to a method for synthesizing substituted pyrrole compounds. Background Art

[0002] Pyrrole is a common pharmacophore in many natural products and an important structural fragment in medicinal chemistry, exhibiting antifungal, antiviral, antihyperlipidemic, and antitumor activities. Furthermore, pyrrole derivatives are widely used in materials chemistry and agriculture. Therefore, the development of new methods for the preparation of pyrrole derivatives is of great significance. The Paal-Knorr, Hantzsch, Van Leusen, and Barton reactions are classic reactions for constructing the pyrrole ring.

[0003] Classical pyrrole synthesis method

[0004]

[0005] However, in most cases, the raw materials used to prepare pyrrole derivatives are expensive and difficult to prepare, resulting in poor substrate universality. Many derivatives cannot be successfully prepared due to functional group restrictions. In recent years, transition-metal-catalyzed cyclization reactions and multi-component tandem coupling reactions have also attracted attention due to their high efficiency. However, these reactions require the use of expensive transition metals, cause metal contamination of the final product, and bring many inconveniences during post-reaction processing. At the same time, there are few examples of the synthesis of pyrrole derivatives without transition-metal catalysis reported in the literature.

[0006] Transition metal-catalyzed pyrrole synthesis method

[0007]

[0008] In general, pyrrole compounds are the core structures of numerous important physiologically active compounds and have extremely wide applications in organic chemistry and agriculture. However, the preparation methods for these compounds are plagued by numerous issues, including cumbersome operations, metal contamination, and poor substrate compatibility. Summary of the Invention

[0009] The present invention provides a method for synthesizing substituted pyrrole compounds with simple process, no metal catalysis and no additives.

[0010] The technical solutions adopted in the present invention are as follows:

[0011] A method for preparing a substituted pyrrole compound, comprising: reacting a compound represented by formula (I), a compound represented by formula (II), and a base in a molar ratio of 1:1.2:3 in an aprotic solvent under inert gas protection; quenching the mixture by adding a saturated aqueous ammonium chloride solution; filtering, washing, and evaporating to dryness under reduced pressure; and separating the mixture by column chromatography to obtain a product (III);

[0012]

[0013] Wherein, Ar is selected from any one of phenyl, substituted phenyl, naphthyl, and aromatic heterocycle, R 1 is selected from hydrogen or phenyl, R 2 Any one selected from phenyl, substituted phenyl, naphthyl, aromatic heterocycle, and alkyl.

[0014] Furthermore, the aprotic solvent is selected from any one of toluene, dioxane, ethylene glycol dimethyl ether, cyclopentyl methyl ether, and tetrahydrofuran, which helps to improve the yield.

[0015] Furthermore, the base is selected from sodium hexamethyldisilazide or potassium hexamethyldisilazide, which helps to improve the yield.

[0016] Furthermore, silica gel powder is added after quenching and filtering is performed.

[0017] Further, washing is performed with ethyl acetate or dichloromethane.

[0018] Furthermore, in the column chromatography separation, the eluent system PE:EA=150:1-10:1, and the separation effect is best under this eluent condition.

[0019] Furthermore, the reaction temperature is 80-100° C. and the reaction time is 12-18 hours, so that the reaction is complete and sufficient and the preparation efficiency of the product (III) is improved.

[0020] With respect to the prior art, the beneficial effects of the present invention are as follows:

[0021] The present invention uses aryl-1-propyne compounds as raw materials and obtains substituted pyrrole compounds by cyclization with nitrile compounds under alkaline conditions. The above reaction occurs under conditions without metal catalysts. The raw materials used are simple and easy to obtain, the substrate has good universality, and the preparation operation is simple. DETAILED DESCRIPTION

[0022] The present invention will be described in detail below based on preferred embodiments, and the purpose and effect of the present invention will become more apparent. The present invention will be further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0023] Example 1

[0024] Preparation and characterization of compound III-1:

[0025]

[0026] Under argon, compound I-1 (11.6 mg, 0.1 mmol) and compound II-1 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-1 as a white solid with a yield of 94%. 1 H NMR (500MHz, CDCl3) δ8.52 (s, 1H), 7.50–7.48 (m, 4H), 7.37–7.34 (m, 4H), 7.21–7.18 (m, 2H), 6.56 (d, J = 2.6Hz, 2H).

[0027] Example 2

[0028] Preparation and characterization of compound III-2:

[0029]

[0030] Under argon, compound I-1 (11.6 mg, 0.1 mmol) and compound II-2 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-2 as a white solid with a yield of 93%. 1 H NMR (500MHz, CDCl3): δ8.47(s,1H), 7.49–7.46(m,2H),7.40–7.37(m,2H),7.36–7.33(m,2H),7.20–7.15(m,3H),6.55(dd,J= 3.6, 2.6Hz, 1H), 6.51 (dd, J=3.6, 2.6Hz, 1H), 2.33 (s, 3H).

[0031] Example 3

[0032] Preparation and characterization of compound III-3:

[0033]

[0034] Under argon, compound I-1 (11.6 mg, 0.1 mmol) and compound II-3 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-3 as a white solid with a yield of 87%. 1 H NMR (500MHz, CDCl3): δ8.53(s,1H), 7.52–7.49(m,2H),7.46–7.43(m,2H),7.41–7.35(m,4H),7.21–7.18(m,1H),6.56(dd,J= 3.6, 2.6Hz, 1H), 6.53 (dd, J=3.7, 2.6Hz, 1H), 1.34 (s, 9H).

[0035] Example 4

[0036] Preparation and characterization of compound III-4:

[0037]

[0038] Under argon, compound I-1 (11.6 mg, 0.1 mmol) and compound II-4 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-4 as a white solid with a yield of 96%. 1H NMR(500MHz,DMSO-d6)δ11.32(s, 1H),7.87–7.84(m,2H),7.81–7.78(m,2H),7.68–7.65(m,2H),7.62–7.59(m,2H),7.40– 7.37(m,2H),7.27–7.24(m,2H),7.21–7.17(m,1H),6.65(dd,J=3.7,2.4Hz,1H),6.63(dd,J =3.6,2.4Hz,1H),2.59(t,J=7.6Hz,2H),1.62–1.56(m,2H),1.33–1.26(m,4H),0.87(t,J=7.0Hz,3H).

[0039] Example 5

[0040] Preparation and characterization of compound III-5:

[0041]

[0042] Under argon, compound I-1 (11.6 mg, 0.1 mmol) and compound II-5 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-5 as a white solid with a yield of 85%. 1 H NMR(500MHz,DMSO-d6)δ11.14(s, 1H),7.75–7.73(m,2H),7.71–7.68(m,2H),7.38–7.34(m,2H),7.18–7.14(m,1H),6.98– 6.95(m,2H),6.57-6.53(m,1H),6.46-6.43(m,1H),3.78(s,3H).

[0043] Example 6

[0044] Preparation and characterization of compound III-6:

[0045]

[0046] Under argon, compound I-1 (11.6 mg, 0.1 mmol) and compound II-6 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 18 hours. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 10:1) to obtain product III-6 as a white solid with a yield of 92%. 1 H NMR (500MHz, CDCl3) δ8.49 (s, 1H), 7.54 (d, J = 7.7Hz, 2H), 7.46–7.43 (m, 2H), 7.40 (t, J = 7.7Hz, 2H), 7.22 (t, J = 7.5Hz, 1H), 6.80(d,J=8.4Hz,2H),6.60(t,J=3.1Hz,1H),6.46(s,1H),3.00(s,6H).

[0047] Example 7

[0048] Preparation and characterization of compound III-7:

[0049]

[0050] Under argon, compound I-1 (11.6 mg, 0.1 mmol) and compound II-7 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-7 as a white solid with a yield of 73%. 1 H NMR(500MHz,DMSO-d6)δ11.28(s, J=2.6Hz,1H),7.83–7.80(m,2H),7.79–7.76(m,2H),7.41–7.35(m,4H),7.18(t,J=7.3Hz,1H), 7.15–7.12(m,1H),7.07–7.03(m,4H),6.60(dd,J=3.7,2.4Hz,1H),6.55(dd,J=3.7,2.4Hz,1H).

[0051] Example 8

[0052] Preparation and characterization of compound III-8:

[0053]

[0054] Under argon, compound I-1 (11.6 mg, 0.1 mmol) and compound II-8 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-8 as a white solid with a yield of 57%. 1 H NMR(500MHz,DMSO-d6)δ11.37(s, 1H),7.91–7.87(m,2H),7.80–7.76(m,2H),7.41–7.35(m,4H),7.22–7.18(m,1H),6.65(dd, J=3.7,2.4Hz,1H),6.62(dd,J=3.7,2.4Hz,1H).

[0055] Example 9

[0056] Preparation and characterization of compound III-9:

[0057]

[0058] Under argon, compound I-1 (11.6 mg, 0.1 mmol) and compound II-9 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-9 as a white solid with a yield of 72%. 1H NMR (500MHz, DMSO-d6) δ11.47(s, 1H),7.98(d,J=8.1Hz,2H),7.82–7.77(m,2H),7.71(d,J=8.2Hz,2H),7.40(t,J=7.8Hz, 2H),7.25–7.20(m,1H),6.80(dd,J=3.8,2.4Hz,1H),6.66(dd,J=3.8,2.4Hz,1H).

[0059] Example 10

[0060] Preparation and characterization of compound III-10:

[0061]

[0062] Under argon, compound I-1 (11.6 mg, 0.1 mmol) and compound II-10 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-10 as a white solid with a yield of 91%. 1 H NMR(500MHz, CDCl3)δ8.45(s,1H), 7.51–7.47(m,2H),7.46–7.42(m,2H),7.38–7.35(m,2H),7.20(d,J=7.6Hz,1H),7.08– 7.03(m,2H),6.55(dd,J=3.6,2.5Hz,1H),6.48(dd,J=3.7,2.6Hz,1H).

[0063] Example 11

[0064] Preparation and characterization of compound III-11:

[0065]

[0066] Under argon, compound I-1 (11.6 mg, 0.1 mmol) and compound II-11 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-11 as a white solid with a yield of 69%. 1 H NMR(500MHz,DMSO-d6)δ11.32(s, 1H),7.89–7.86(m,2H),7.81–7.78(m,2H),7.71–7.69(m,4H),7.47(t,J=7.7Hz,2H),7.40 –7.34(m,3H),7.21–7.18(m,1H),6.67(dd,J=3.6,2.4Hz,1H),6.63(dd,J=3.7,2.4Hz,1H).

[0067] Example 12

[0068] Preparation and characterization of compound III-12:

[0069]

[0070] Under argon, compound I-1 (11.6 mg, 0.1 mmol) and compound II-12 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution with stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-12 as a white solid with a yield of 57%. 1 H NMR (500MHz, DMSO-d6) δ11.10 (s, 1H), 7.75 (d, J = 7.4Hz, 2H), 7.65 (d, J = 8.8Hz, 2H), 7.36 (t, J = 7.8Hz, 2H), 7.15 (t, J = 7.3Hz, 1H),6.97(d,J=8.5Hz,2H),6.57–6.56(m,1H),6.47–6.46(m,1H),3.74(t,J=4.8Hz,4H), 3.12(t,J=4.8Hz,4H).

[0071] Example 13

[0072] Preparation and characterization of compound III-13:

[0073]

[0074] Under argon, compound I-1 (11.6 mg, 0.1 mmol) and compound II-13 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution with stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-13 as a white solid with a yield of 63%. 1 H NMR (500MHz, CDCl3) δ8.68(s,1H), 7.86(s,1H),7.83–7.77(m,3H),7.67(dd,J=8.6,1.9Hz,1H),7.57–7.53(m,2H),7.47–7.43 (m,1H),7.43–7.37(m,3H),7.25–7.22(m,1H),6.69(t,J=3.1Hz,1H),6.62(t,J=3.1Hz, 1H).

[0075] Example 14

[0076] Preparation and characterization of compound III-14:

[0077]

[0078] Under argon, compound I-1 (11.6 mg, 0.1 mmol) and compound II-14 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution with stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-14 as a white solid with a yield of 83%. 1H NMR(500MHz, DMSO-d6)δ11.64(s, J=2.7Hz,1H),8.40–8.36(m,1H),8.00–7.97(m,1H),7.90-7.88(m,1H),7.86–7.83(m,2H), 7.69(dd,J=7.2,1.3Hz,1H),7.61–7.54(m,3H),7.42–7.38(m,2H),7.23–7.18(m,1H),6.77 (dd,J=3.5,2.5Hz,1H),6.49(dd,J=3.5,2.3Hz,1H).

[0079] Example 15

[0080] Preparation and characterization of compound III-15:

[0081]

[0082] Under argon, compound I-1 (11.6 mg, 0.1 mmol) and compound II-15 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution with stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated ammonium chloride aqueous solution. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-15 as a white solid with a yield of 81%. 1 H NMR(500MHz, CDCl3)δ7.72(s,1H), 7.68–7.65(m,1H),7.44-7.39(m,3H),7.39–7.35(m,3H),7.31–7.26(m,2H),7.23–7.19(m, 2H),7.12–7.07(m,1H),6.99–6.96(m,2H),6.44(dd,J=3.7,2.6Hz,1H),6.42(dd,J=3.7, 2.6Hz,1H).

[0083] Example 16

[0084] Preparation and characterization of compound III-16:

[0085]

[0086] Under argon, compound I-1 (11.6 mg, 0.1 mmol) and compound II-16 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-16 as a light yellow solid with a yield of 75%. 1 H NMR (500MHz, CDCl3) δ10.09 (s, 1H), 7.68 (dd, J=7.8, 1.7Hz, 1H), 7.53–7.50 (m, 2H), 7.40–7.36 (m, 2H), 7.21–7.14 (m, 2H), 7.02–6.96(m,2H),6.67(dd,J=3.8,2.5Hz,1H),6.58(dd,J=3.8,2.8Hz,1H),4.00(s,3H).

[0087] Example 17

[0088] Preparation and characterization of compound III-17:

[0089]

[0090] Under argon, compound I-1 (11.6 mg, 0.1 mmol) and compound II-17 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-17 as a white solid with an 80% yield. 1 H NMR (500MHz, CDCl3) δ10.06(s,1H), 8.44(d,J=4.9Hz,1H),7.64(dd,J=12.3,4.5Hz,3H),7.54(d,J=8.0Hz,1H),7.36(t,J=7.6 Hz,2H),7.22(d,J=6.7Hz,1H),7.03–6.99(m,1H),6.77(t,J=3.2Hz,1H),6.60(t,J=3.2Hz,1H).

[0091] Example 18

[0092] Preparation and characterization of compound III-18:

[0093]

[0094] Under argon, compound I-1 (11.6 mg, 0.1 mmol) and compound II-18 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-18 as a yellow liquid with a yield of 92%. 1 H NMR(500MHz, CDCl3)δ8.25(s,1H), 7.47–7.44(m,2H),7.37–7.34(m,2H),7.22–7.17(m,1H),6.43(t,J=3.1Hz,1H),5.94(t,J =2.7Hz,1H),1.88-1.85(m,1H),0.92–0.88(m,2H),0.73–0.69(m,2H).

[0095] Example 19

[0096] Preparation and characterization of compound III-19:

[0097]

[0098] Under argon, compound I-1 (11.6 mg, 0.1 mmol) and compound II-19 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution with stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated ammonium chloride aqueous solution. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-19 as a yellow liquid with a yield of 76%. 1H NMR(500MHz, CDCl3)δ8.15(s,1H), 7.50–7.46(m,2H),7.41–7.36(m,2H),7.23–7.19(m,1H),6.47(t,J=3.1Hz,1H),6.06– 6.03(m,1H),3.15–3.06(m,1H),2.17–2.06(m,2H),1.87–1.79(m,2H),1.75–1.66(m,4H).

[0099] Example 20

[0100] Preparation and characterization of compound III-20:

[0101]

[0102] Under argon, compound I-1 (11.6 mg, 0.1 mmol) and compound II-20 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution with stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated ammonium chloride aqueous solution. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-20 as a yellow liquid with a yield of 84%. 1 H NMR(500MHz, CDCl3)δ8.11(s,1H), 7.44–7.41(m,2H),7.34–7.30(m,2H),7.16–7.12(m,1H),6.39(dd,J=3.5,2.7Hz,1H),5.99 (dd,J=3.5,2.7Hz,1H),1.33(s,9H).

[0103] Example 21

[0104] Preparation and characterization of compound III-21:

[0105]

[0106] Under argon, compound I-2 (11.6 mg, 0.1 mmol) and compound II-2 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-21 as a white solid with a yield of 67%. 1 H NMR (500MHz, CDCl3) δ8.52 (s, 1H), 7.44 (d, J = 8.1 Hz, 4H), 7.21 (d, J = 7.8 Hz, 4H), 6.54 (d, J = 2.6 Hz, 2H), 2.38 (s, 6H).

[0107] Example 22

[0108] Preparation and characterization of compound III-22:

[0109]

[0110] Under argon, compound I-3 (11.6 mg, 0.1 mmol) and compound II-2 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-22 as a white solid with a yield of 71%. 1 H NMR (500MHz, CDCl3) δ8.54 (s, 1H), 7.51–7.48 (m, 2H), 7.46–7.43 (m, 4H), 7.23 (d, J = 8.0Hz, 2H), 6.57 (d, J = 2.7Hz, 2H), 2.40 (s, 3H), 1.39 (s, 9H).

[0111] Example 23

[0112] Preparation and characterization of compound III-23:

[0113]

[0114] Under argon, compound I-4 (11.6 mg, 0.1 mmol) and compound II-2 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-23 as a white solid with a yield of 60%. 1 H NMR (500MHz, DMSO-d6) δ10.98(s, 1H),7.64(d,J=8.3Hz,2H),7.60(d,J=8.8Hz,2H),7.17(d,J=8.0Hz,2H),6.75(d,J=8.9 Hz,2H),6.49(dd,J=3.6,2.4Hz,1H),6.37–6.34(m,1H),2.91(s,6H),2.30(s,3H)

[0115] Example 24

[0116] Preparation and characterization of compound III-24:

[0117]

[0118] Under argon, compound I-5 (11.6 mg, 0.1 mmol) and compound II-2 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-24 as a white solid with a yield of 75%. 1 H NMR (500MHz, DMSO-d6) δ11.08(s, 1H),7.69(d,J=8.8Hz,2H),7.65(d,J=8.2Hz,2H),7.17(d,J=7.8Hz,2H),6.96(d,J=8.9 Hz, 2H), 6.50 (dd, J=3.6, 2.4Hz, 1H), 6.44 (dd, J=3.6, 2.4Hz, 1H), 3.77 (s, 3H), 2.30 (s, 3H).

[0119] Example 25

[0120] Preparation and characterization of compound III-25:

[0121]

[0122] Under argon, compound I-6 (11.6 mg, 0.1 mmol) and compound II-2 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-25 as a white solid with a yield of 56%. 1 H NMR (500MHz, DMSO-d6) δ11.29 (s, 1H), 7.89–7.86 (m, 2H), 7.67 (d, J = 8.2Hz, 2H), 7.36 (d, J = 7.9Hz, 2H), 7.20 (d, J = 8.2Hz, 2H), 6.62 (dd, J=3.7, 2.4Hz, 1H), 6.55 (dd, J=3.7, 2.4Hz, 1H), 2.31 (s, 3H).

[0123] Example 26

[0124] Preparation and characterization of compound III-26:

[0125]

[0126] Under argon, compound I-7 (11.6 mg, 0.1 mmol) and compound II-2 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-26 as a white solid with a yield of 73%. 1H NMR (500MHz, DMSO-d6) δ11.20 (s, 1H), 7.81–7.77 (m, 2H), 7.66 (d, J = 8.2Hz, 2H), 7.23–7.17 (m, 4H), 6.56–6.54 (m, 1H), 6.54 –6.52(m,1H),2.30(s,3H).

[0127] Example 27

[0128] Preparation and characterization of compound III-27:

[0129]

[0130] Under argon, compound I-8 (11.6 mg, 0.1 mmol) and compound II-2 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-27 as a white solid with a yield of 52%. 1 H NMR(500MHz,DMSO-d6)δ10.96(s, 1H),7.67(dd,J=7.9,1.3Hz,1H),7.50(d,J=8.3Hz,2H),7.43–7.40(m,1H),7.36–7.28(m,5H),7.26–7. 23(m,2H),7.13(d,J=8.0Hz,2H),6.29(dd,J=3.6,2.5Hz,1H),5.44(dd,J=3.6,2.4Hz,1H),2.27(s,3H).

[0131] Example 28

[0132] Preparation and characterization of compound III-28:

[0133]

[0134] Under argon, compound I-8 (11.6 mg, 0.1 mmol) and compound II-2 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-28 as a white solid with a yield of 90%. 1 H NMR (500MHz, CDCl3) δ8.58 (s, 1H), 8.46(dd,J=5.9,3.3Hz,1H),7.98–7.95(m,1H),7.88(d,J=8.1Hz,1H),7.62–7.55(m,4H),7.4 9(d,J=8.4Hz,2H),7.26(d,J=7.6Hz,2H),6.75–6.72(m,1H),6.67–6.63(m,1H),2.44(s,3H).

[0135] Example 29

[0136] Preparation and characterization of compound III-29:

[0137]

[0138] Under argon, compound I-9 (11.6 mg, 0.1 mmol) and compound II-2 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated aqueous ammonium chloride. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-29 as a light yellow solid with a yield of 60%. 1 H NMR (500MHz, CDCl3) δ8.40(s,1H), 7.57(d,J=7.8Hz,2H),7.46–7.41(m,4H),7.35–7.31(m,4H),7.26–7.22(m,2H),7.17(d,J =7.8Hz,2H),6.73(s,1H),2.39(s,3H).

[0139] Example 30

[0140] Preparation and characterization of compound III-30:

[0141]

[0142] Under argon, compound I-10 (11.6 mg, 0.1 mmol) and compound II-2 (12.4 mg, 0.12 mmol) were dissolved in 1.0 mL of toluene. Potassium hexamethyldisilazide (1.0 mol / L, 0.3 mL, 0.3 mmol) was added to the solution while stirring at room temperature. The temperature was raised to 100°C and the reaction was allowed to proceed for 12 h. After completion, the reaction was quenched by adding 3 drops of saturated ammonium chloride aqueous solution. The mixture was filtered through a small amount of silica gel powder, washed with ethyl acetate, and evaporated to dryness under reduced pressure. The mixture was separated by column chromatography (PE:EA = 150:1) to obtain product III-30 as a yellow-green liquid with a yield of 40%. 1 H NMR (500MHz, CDCl3) δ8.14(s,1H), 7.35–7.32(m,2H),7.22(t,J=7.9Hz,4H),7.07(s,1H),7.04–7.02(m,2H),6.98(dd,J=5.0, 1.3Hz, 1H), 6.83 (dd, J=3.5, 1.3Hz, 1H), 6.81 (dd, J=5.0, 3.5Hz, 1H), 6.56 (d, J=2.8Hz, 1H), 2.23 (s, 3H).

[0143] In addition to toluene, dioxane, ethylene glycol dimethyl ether, cyclopentyl methyl ether, and tetrahydrofuran can all be used as alternative solvents, but the yield is slightly lower than the optimal solvent, toluene. Sodium hexamethyldisilazane can also be used as the base, but the final yield is slightly lower than the optimal choice.

[0144] Those skilled in the art will understand that the foregoing descriptions are merely preferred embodiments of the invention and are not intended to limit the invention. Although the invention has been described in detail with reference to the foregoing examples, those skilled in the art will still be able to modify the technical solutions described in the foregoing examples or substitute equivalents for some of the technical features therein. Any modifications, equivalent substitutions, etc. made within the spirit and principles of the invention shall be included within the scope of protection of the invention.

Claims

1. A method for synthesizing a substituted pyrrole compound, characterized in that: The preparation method is as follows: under the protection of inert gas, in an aprotic solvent, the compound represented by formula (I), the compound represented by formula (II), and a base are mixed in a molar ratio of 1:1.2:3 for reaction, and then saturated ammonium chloride aqueous solution is added to quench, filtered, washed, evaporated to dryness under reduced pressure, and separated by column chromatography to obtain product (III); ； Wherein, Ar is selected from any one of phenyl, substituted phenyl, naphthyl, and aromatic heterocycle, R 1 is selected from hydrogen or phenyl, R 2 Any one selected from phenyl, substituted phenyl, naphthyl, aromatic heterocycle, and alkyl; The aprotic solvent is selected from any one of toluene, dioxane, ethylene glycol dimethyl ether, cyclopentyl methyl ether, and tetrahydrofuran; The base is selected from sodium hexamethyldisilazide or potassium hexamethyldisilazide.

2. The method for synthesizing a substituted pyrrole compound according to claim 1, wherein After quenching, silica gel powder was added and filtered.

3. The method for synthesizing a substituted pyrrole compound according to claim 1, wherein Wash with ethyl acetate or dichloromethane.

4. The method for synthesizing a substituted pyrrole compound according to claim 1, wherein In the column chromatography separation, the eluent system is PE:EA = 400:1~10:

1.

5. The method for synthesizing substituted pyrrole compounds according to claim 1, wherein The reaction temperature is 80~100°C and the reaction time is 12~18 hours.

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