Synthesis method of indole compounds
Through the [4+1] cyclization reaction method without metals and catalysts, the problem of using expensive catalysts and harsh conditions in the synthesis of existing indole compounds was successfully solved, and efficient, environmentally friendly and high-yield synthesis of indole compounds was achieved.
Patent Information
- Application Number
- CN202410497402.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-04-24
- Publication Date
- 2025-03-14
- Estimated Expiration
- 2044-04-24
AI Technical Summary
The existing synthesis methods of indole compounds require the use of expensive and unenvironmental transition metal catalysts, and the reaction conditions are harsh, the substrate application range is narrow, and the yield is low.
The [4+1] cyclization reaction method without metal and catalyst participation was adopted, and the target indole compounds were obtained by cyclizing reactions of compound 1 and compound 2 in an organic solvent, and the target indole compounds were obtained and purified by column chromatography.
Green and mild synthetic conditions are achieved, raw material costs are reduced, substrate application scope is expanded, and yield is improved to achieve a high yield of 96%.
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Figure CN118388387B_ABST
Abstract
Description
Technical Field
[0001] The invention relates to a method for synthesizing a compound, in particular to a method for synthesizing an indole compound. Background Art
[0002] Among heterocyclic compounds, the indole scaffold is considered to be one of the most promising skeletons found in natural products and synthetic sources, and has been shown to have a variety of biological activities, including anti-inflammatory, anti-HIV, anti-tuberculosis, anti-hypertension, etc., and is often used in the synthesis of analgesics, antidepressants and antibacterial drugs. Indole alkaloids, such as tryptamine, Alstonine, reserpine, ergotamine and vincristine, are famous for neurotransmitters, antipsychotics, antihypertensives, migraines and cancer chemotherapy, respectively. The indole synthesized by the present invention is a 2-olefin-substituted indole, and the basic skeleton of the 2-olefin-substituted indole is widely present in active drugs and exhibits very important pharmacological properties. For example, the article Flinderoles AC: Antimalarial Bis-indole Alkaloids from Flindersia Species reported that the drug Flinderole C has antimalarial effects; the article An Improved Manufacturing Process for Fluvastatin reported that the drug Fluvastatin has a lipid-lowering effect; and the article A Concise Asymmetric Total Synthesis of Aspidophytine reported that the drug SB-242784 osteoclast inhibitor has good insecticidal activity.
[0003] At present, the synthesis of indole and its derivatives requires the use of transition metals such as Cu, Pd, Rh, Ni, Co, or strong oxidants such as iodobenzene acetate in the reaction process. These catalysts are expensive and not environmentally friendly. At the same time, these synthesis methods also have the disadvantages of harsh reaction conditions, narrow substrate application range, and low yield. Summary of the invention
[0004] Purpose of the invention: The present invention aims to provide a method for synthesizing indole compounds without the involvement of metals and catalysts and under green and mild reaction conditions.
[0005] Technical solution: The method for synthesizing indole compounds of the present invention comprises the following steps: Compound 1 and Compound 2 undergo a [4+1] cyclization reaction in an organic solvent to obtain a target indole compound. The synthetic route is as follows:
[0006]
[0007] Where R 1is any one of H, Cl, or Br; wherein R 2 is any one of H, F or Br; R 3 It is any one of H, Me, OMe, Cl or Br.
[0008] Preferably, the reaction temperature is 60-100°C.
[0009] Preferably, the molar ratio of compound 1 to compound 2 is 1:1.2 to 1:2.
[0010] Preferably, the solvent for the reaction is tetrahydrofuran, dichloromethane or ethanol.
[0011] Preferably, the method for purifying the target product indole compound is: separation by column chromatography, wherein the column chromatography solid phase is column chromatography silica gel, and the mobile phase is a mixture of petroleum ether and ethyl acetate.
[0012] Preferably, the volume ratio of petroleum ether to ethyl acetate is 10:1 to 5:1.
[0013] Preferably, the synthesis method of compound 2 is:
[0014] (1) The carbonyl group of compound 3 undergoes a reduction reaction and is reduced to a hydroxyl group to obtain compound 4;
[0015] (2) Compound 4 undergoes a substitution reaction with triphenylphosphine hydrobromide to obtain compound 2;
[0016] The synthetic route is as follows:
[0017]
[0018] Preferably, in step (1), the reducing agent of the reduction reaction is sodium borohydride, and sodium borohydride is first added at -10 to 10° C., and then the temperature is raised to 60 to 100° C. for reaction. Preferably, the reaction solvent is ethanol or dichloromethane.
[0019] Preferably, in step (1), the purification method of compound 4 is: extraction with ethyl acetate.
[0020] After the reaction of step (1) is completed, water is added to quench the reaction, followed by extraction with ethyl acetate (50 mL x 3), and washing with saturated brine. After completion, anhydrous sodium sulfate is added to dry the reaction mixture, and the solvent is removed by rotary evaporation to obtain (2-aminophenyl)(phenyl)methanol or a derivative thereof.
[0021] Preferably, in step (2), the reaction temperature is 60-100° C. Preferably, the reaction solvent is acetonitrile.
[0022] Preferably, in step (2), after the reaction is completed, the product is washed thoroughly with ether until it becomes white, and then air-dried.
[0023] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) The synthesis method does not involve the participation of metals and catalysts, and the reaction conditions are green and mild; (2) The raw materials used in this method are easy to prepare and inexpensive; (3) The substrate used in this method has good tolerance and a wide range of applications; (4) The yield of indole compounds prepared by this method is as high as 96%. BRIEF DESCRIPTION OF THE DRAWINGS
[0024] Figure 1 The reaction route of the synthesis method of the present invention;
[0025] Figure 2 The H-NMR spectrum of (E)-3-phenyl-2-phenylvinyl-1H-indole synthesized in Example 1;
[0026] Figure 3 The C NMR spectrum of (E)-3-phenyl-2-phenylvinyl-1H-indole synthesized in Example 1;
[0027] Figure 4 The H-NMR spectrum of (E)-3-(4-fluorophenyl)-2-phenylvinyl-1H-indole synthesized in Example 2;
[0028] Figure 5 The C NMR spectrum of (E)-3-(4-fluorophenyl)-2-phenylvinyl-1H-indole synthesized in Example 2;
[0029] Figure 6 The H-NMR spectrum of (E)-3-(4-bromophenyl)-2-phenylvinyl-1H-indole synthesized in Example 3;
[0030] Figure 7 The C NMR spectrum of (E)-3-(4-bromophenyl)-2-phenylvinyl-1H-indole synthesized in Example 3;
[0031] Figure 8 The H-NMR spectrum of (E)-5-chloro-3-phenyl-2-phenylvinyl-1H-indole synthesized in Example 4;
[0032] Fig. 9 The C NMR spectrum of (E)-5-chloro-3-phenyl-2-phenylvinyl-1H-indole synthesized in Example 4;
[0033] Fig.10 The H-NMR spectrum of (E)-5-bromo-3-phenyl-2-phenylvinyl-1H-indole synthesized in Example 5;
[0034] Fig.11The C NMR spectrum of (E)-5-bromo-3-phenyl-2-phenylvinyl-1H-indole synthesized in Example 5;
[0035] Fig.12 H NMR spectrum of (E)-2-(2-methylphenylvinyl)-3-phenyl-1H-indole synthesized in Example 6;
[0036] Fig.13 The C NMR spectrum of (E)-2-(2-methylphenylvinyl)-3-phenyl-1H-indole synthesized in Example 6;
[0037] Fig.14 H NMR spectrum of (E)-2-(2-methoxyphenylvinyl)-3-phenyl-1H-indole synthesized in Example 7;
[0038] Fig.15 The C NMR spectrum of (E)-2-(2-methoxyphenylvinyl)-3-phenyl-1H-indole synthesized in Example 7;
[0039] Fig.16 H NMR spectrum of (E)-2-(2-chlorophenylvinyl)-3-phenyl-1H-indole synthesized in Example 8;
[0040] Fig.17 The C NMR spectrum of (E)-2-(2-chlorophenylvinyl)-3-phenyl-1H-indole synthesized in Example 8;
[0041] Fig.18 H NMR spectrum of (E)-2-(2-bromostyryl)-3-phenyl-1H-indole synthesized in Example 9;
[0042] Fig.19 The carbon NMR spectrum of (E)-2-(2-bromostyryl)-3-phenyl-1H-indole synthesized in Example 9. DETAILED DESCRIPTION
[0043] The technical solution of the present invention is further described below in conjunction with embodiments.
[0044] Example 1
[0045] The indole compounds of the present invention, when R 1 For H, R 2 For H, R 3 The name is (E)-3-phenyl-2-phenylvinyl-1H-indole, and its structural formula is:
[0046]
[0047] The compound synthesis method comprises the following steps:
[0048] Step 1: Preparation of 2-[(bromotriphenyl-5-phosphino)phenylmethyl]aniline
[0049]
[0050] (1) 10 mmol of 2-aminobenzophenone and 30 mL of ethanol were added to a 100 mL reaction flask to fully dissolve, 40 mmol of sodium borohydride was added in batches at 0° C., and the temperature was raised to 70° C. for reaction for 3 hours; after the reaction was completed, water was added to quench, and then ethyl acetate (50 mL x 3) was used for extraction, and saturated brine was used for washing. After the reaction was completed, anhydrous sodium sulfate was added for drying, and the solvent was removed by rotary evaporation to obtain (2-aminophenyl)(phenyl)methanol.
[0051] (2) Transfer (2-aminophenyl)(phenyl)methanol to a 100 mL reaction flask, add 10 mmol of triphenylphosphine hydrobromide, use 30 mL of acetonitrile to fully dissolve the reactants, and reflux at 80° C. for 12 hours. After the reaction is completed, wash the product with ether until it turns white and air-dry it.
[0052] The NMR data of this compound are: 1 H NMR(400MHz, DMSO-d6)δ7.92-7.87(m,3H),7.73(td,J=7.9,3.7Hz,7H),7.64(dd,J=12.0,7.5Hz,6H), 7.40-7.22(m,6H),7.06(t,J=7.6Hz,1H),6.79(d,J=8.2Hz,1H),6.67-6.56(m,2H),6.41-6.35(m,1H).
[0053] Step 2: Preparation of (E)-3-phenyl-2-phenylvinyl-1H-indole
[0054]
[0055] 0.2 mmol of cinnamaldehyde was put into a Schlenk tube, 0.24 mmol of the compound prepared in the first step was added, and a stirring bar was added, and finally 1 mL of tetrahydrofuran was added, and the reaction was carried out at 90° C. for 8 hours; after the reaction, the product was purified by column chromatography, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 8:1; with the help of TLC elution tracking detection, the eluate containing the target product was collected, the eluate of the target product was combined, and evaporated and concentrated to obtain (E)-3-phenyl-2-phenylvinyl-1H-indole.
[0056] like Figure 2 , the H NMR spectrum data of the compound is: 1H NMR (400MHz, CDCl3) δ8.28 (s, 1H), 7.76 (d, J = 7.9Hz, 1H), 7.64-7.60 (m, 2H), 7.56 (d, J = 15.3Hz, 2H), 7.45 (dd,J=10.4,7.2Hz,3H),7.41-7.35(m,3H),7.33-7.26(m,3H),7.22-7.17(m,1H),6.91(d,J=16.6Hz,1H).
[0057] like Figure 3 , the NMR carbon spectrum data of the compound is: 13 C NMR (101MHz, CDCl3) δ137.0,136.5,134.6,132.6,130.2,128.9,128.8,128 .3,127.8,127.4,126.7,126.5,123.7,120.5,119.8,118.9,118.0,110.8.
[0058] Example 2
[0059] The indole compounds of the present invention, when R 1 For H, R 2 For F, R 3 The compound is H, and its name is (E)-3-(4-fluorophenyl)-2-phenylvinyl-1H-indole, and its structural formula is:
[0060]
[0061] The compound synthesis method comprises the following steps:
[0062] Step 1: 2-[(bromotriphenyl-5-phosphino)(4-fluorophenyl)methyl]aniline
[0063]
[0064] (1) Add 10 mmol of (2-aminophenyl)(4-fluorophenyl)methanone to a 100 mL reaction flask, add 30 mL of ethanol to fully dissolve, add 40 mmol of sodium borohydride in batches at 5° C., raise the temperature to 90° C. and react for 1 hour; after the reaction is completed, add water to quench, extract with ethyl acetate (50 mL x 3), and wash with saturated brine. After the reaction is completed, add anhydrous sodium sulfate to dry, and remove the solvent by rotary evaporation to obtain (2-aminophenyl)(4-fluorophenyl)methanol.
[0065] (2) (2-Aminophenyl)(4-fluorophenyl)methanol was transferred to a 100 mL reaction flask, 10 mmol of triphenylphosphine hydrobromide was added, 30 mL of acetonitrile was used to fully dissolve the reactants, and the reaction was refluxed at 70° C. for 10 hours. After the reaction was completed, the product was fully washed with ether until it turned white and air-dried.
[0066] The NMR data of this compound are: 1 H NMR (400MHz, DMSO-d6) δ7.94-7.88(m,3H),7.74(td,J=7.8,3.7Hz,6H),7.69-7.59(m,6H),7.39(dd,J=4.3,2.3Hz,1H),7.23(ddt, J=7.6,5.5,2.2Hz,3H),7.14(t,J=8.7Hz,2H),7.07(t,J=7.6Hz,1H),6.78(d,J=8.2Hz,1H),6.65-6.49(m,2H),6.43-6.33(m,1H).
[0067] Step 2: Preparation of (E)-3-(4-fluorophenyl)-2-phenylvinyl-1H-indole
[0068]
[0069] 0.2 mmol of cinnamaldehyde was dissolved in a Schlenk tube, 0.3 mmol of the compound prepared in the first step was added, and a stirring bar was added, and finally 1 mL of ethanol was added, and the reaction was carried out at 60° C. for 15 hours; after the reaction, the product was purified by column chromatography, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 8:1; with the help of TLC elution tracking detection, the eluate containing the target product was collected, the eluate of the target product was combined, and evaporated and concentrated to obtain (E)-3-(4-fluorophenyl)-2-phenylvinyl-1H-indole.
[0070] like Figure 4 , the H NMR spectrum data of the compound is: 1 H NMR (400MHz, CDCl3) δ8.28 (s, 1H), 7.69 (d, J = 7.9Hz, 1H), 7.56-7.51 (m, 2H), 7.49-7.45 (m ,2H),7.40(t,J=7.6Hz,3H),7.34-7.29(m,2H),7.27-7.18(m,4H),6.91(d,J=16.6Hz,1H).
[0071] like Figure 5 , the NMR carbon spectrum data of the compound is: 13C NMR (101MHz, CDCl3) δ163.1,160.7,136.9,136.4,132.6,131.7,131.6,130.5,130.5,128 .9,128.3,127.9,127.6,126.5,123.8,120.6,119.6,117.8,117.7,115.8,115.6,110.8. 19 F NMR (376MHz,CDCl3)δ-115.6.
[0072] Example 3
[0073] The indole compounds of the present invention, when R 1 For H, R 2 Br, R 3 The name is (E)-3-(4-bromophenyl)-2-phenylvinyl-1H-indole, and its structural formula is:
[0074]
[0075] The compound synthesis method comprises the following steps:
[0076] Step 1: 2-[(bromotriphenyl-5-phosphino)(4-bromophenyl)methyl]aniline
[0077]
[0078] (1) Add 10 mmol of (2-aminophenyl)(4-bromophenyl)methanone to a 100 mL reaction flask, add 30 mL of ethanol to fully dissolve, add 40 mmol of sodium borohydride in batches at 0° C., raise the temperature to 90° C. and react for 1 hour; after the reaction is completed, add water to quench, extract with ethyl acetate (50 mL x 3), and wash with saturated brine. After the reaction is completed, add anhydrous sodium sulfate to dry, and remove the solvent by rotary evaporation to obtain (2-aminophenyl)(4-bromophenyl)methanol.
[0079] (2) Transfer (2-aminophenyl)(4-bromophenyl)methanol to a 100 mL reaction flask, add 10 mmol of triphenylphosphine hydrobromide, use 30 mL of acetonitrile to fully dissolve the reactants, and reflux at 90° C. for 8 hours. After the reaction is completed, wash the product with ether until it turns white and air-dry it.
[0080] The NMR data of this compound are: 1H NMR (400MHz, DMSO-d6) δ7.91 (td, J=7.4, 1.8Hz, 3H), 7.74 (td, J=7.9, 3.7Hz, 6H), 7.69-7.61 (m, 6H), 7.51-7. 39(m,3H),7.25-7.21(m,1H),7.18-7.03(m,3H),6.77(d,J=8.1Hz,1H),6.62-6.48(m,2H),6.40-6.33(m,1H).
[0081] Step 2: Preparation of (E)-3-(4-bromophenyl)-2-phenylvinyl-1H-indole
[0082]
[0083] 0.2 mmol of cinnamaldehyde was dissolved in a Schlenk tube, 0.25 mmol of the compound prepared in the first step was added, and a stirrer was added, and finally 1 mL of dichloromethane was added, and the mixture was reacted at 80° C. for 12 hours; after the reaction, the product was purified by column chromatography, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 6:1; with the help of TLC elution tracking detection, the eluate containing the target product was collected, the eluate of the target product was combined, and evaporated and concentrated to obtain (E)-3-(4-bromophenyl)-2-phenylvinyl-1H-indole.
[0084] like Figure 6 , the H NMR spectrum data of the compound is: 1 H NMR(400MHz, CDCl3)δ8.29(s,1H),7.71-7.62(m,3H),7.49-7.42(m,4H),7.41-7.37 (m,3H),7.31(td,J=8.1,7.7,1.2Hz,2H),7.21-7.16(m,2H),6.90(d,J=16.5Hz,1H).
[0085] like Figure 7 , the NMR carbon spectrum data of the compound is: 13 C NMR (101MHz, CDCl3) δ136.8,136.5,133.6,132.7,131.9,131.7,128.9,128.0,127.9,126.5,123.8,120.7,120.6,119.5,117.5,110.9.
[0086] Example 4
[0087] The indole compounds of the present invention, when R 1 Cl, R 2 For H, R 3The name is (E)-5-chloro-3-phenyl-2-phenylvinyl-1H-indole, and its structural formula is:
[0088]
[0089] The compound synthesis method comprises the following steps:
[0090] Step 1: 2-[(bromotriphenyl-5-phosphino)(phenyl)methyl)]-4-chloroaniline
[0091]
[0092] (1) Add 10 mmol of (2-amino-5-chlorophenyl)(phenyl)methanone to a 100 mL reaction flask, add 30 mL of ethanol to fully dissolve, add 40 mmol of sodium borohydride in batches at 5° C., raise the temperature to 60° C. and react for 4 hours; after the reaction is completed, add water to quench, extract with ethyl acetate (50 mL x 3), and wash with saturated brine. After the reaction is completed, add anhydrous sodium sulfate to dry, and remove the solvent by rotary evaporation to obtain (2-amino-5-chlorophenyl)(phenyl)methanol.
[0093] (2) Transfer (2-amino-5-chlorophenyl)(phenyl)methanol to a 100 mL reaction flask, add 10 mmol of triphenylphosphine hydrobromide, use 30 mL of acetonitrile to fully dissolve the reactants, and reflux at 70° C. for 10 hours. After the reaction is completed, wash the product with ether until it turns white and air-dry it.
[0094] The NMR data of this compound are: 1 H NMR (400MHz, DMSO-d6) δ7.93(td,J=7.3,1.7Hz,3H),7.76(td,J=7.9,3.8Hz,6H),7.68(dd,J=12.1,7.5Hz,6H),7.41-7. 21(m,6H),7.10(dd,J=8.8,2.4Hz,1H),6.79(dd,J=8.8,1.3Hz,1H),6.60(d,J=22.5Hz,1H),6.40(dd,J=2.6,1.1Hz,1H).
[0095] Step 2: Preparation of (E)-5-chloro-3-phenyl-2-phenylvinyl-1H-indole
[0096]
[0097] 0.2 mmol of cinnamaldehyde was dissolved in a Schlenk tube, 0.4 mmol of the compound prepared in the first step was added, and a stirring bar was added, and finally 1 mL of tetrahydrofuran was added, and the reaction was carried out at 100° C. for 6 hours; after the reaction, the product was purified by column chromatography, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 6:1; with the help of TLC elution tracking detection, the eluate containing the target product was collected, the eluate of the target product was combined, and evaporated and concentrated to obtain (E)-5-chloro-3-phenyl-2-phenylvinyl-1H-indole.
[0098] like Figure 8 , the H NMR spectrum data of the compound is: 1 H NMR (400MHz, CDCl3) δ8.39 (s, 1H), 7.67 (d, J = 2.0Hz, 1H), 7.54 (d, J = 5.2Hz, 4H), 7.46-7.41 (m, 3H ),7.36(t,J=7.5Hz,2H),7.29(dd,J=7.8,5.4Hz,2H),7.23-7.18(m,2H),6.92(d,J=16.5Hz,1H).
[0099] like Fig. 9 , the NMR carbon spectrum data of the compound is: 13 C NMR (101MHz, CDCl3) δ136.7,134.8,133.9,133.9,130.1,129.3,128.9,128.3,128.1,126.9,126.6,126.17,123.8,119.1,118.3,117.5,111.8.
[0100] Example 5
[0101] The indole compounds of the present invention, when R 1 Br, R 2 For H, R 3 The compound is H, and its name is (E)-5-bromo-3-phenyl-2-phenylvinyl-1H-indole, and its structural formula is:
[0102]
[0103] The compound synthesis method comprises the following steps:
[0104] Step 1: 2-[(bromotriphenyl-5-phosphino)(phenyl)methyl)]-4-bromoaniline
[0105]
[0106] (1) Add 10 mmol of (2-amino-5-bromophenyl)(phenyl)methanone to a 100 mL reaction flask, add 30 mL of ethanol to fully dissolve, add 40 mmol of sodium borohydride in batches at -10°C, raise the temperature to 70°C and react for 5 hours; after the reaction is completed, add water to quench, extract with ethyl acetate (50 mL x 3), and wash with saturated brine. After the reaction is completed, add anhydrous sodium sulfate to dry, and remove the solvent by rotary evaporation to obtain (2-amino-5-bromophenyl)(phenyl)methanol.
[0107] (2) Transfer (2-amino-5-bromophenyl)(phenyl)methanol to a 100 mL reaction flask, add 10 mmol of triphenylphosphine hydrobromide, use 30 mL of acetonitrile to fully dissolve the reactants, and reflux at 90° C. for 8 hours. After the reaction is completed, wash the product with ether until it turns white and air-dry it.
[0108] The NMR data of this compound are: 1 H NMR (400MHz, DMSO-d6) δ7.92 (t, J=7.8Hz, 3H), 7.80-7.66 (m, 13H), 7.42-7.23 (m,6H),7.19(dd,J=8.7,2.3Hz,1H),6.77-6.62(m,2H),6.53(d,J=2.3Hz,1H).
[0109] Step 2: Preparation of (E)-5-bromo-3-phenyl-2-phenylvinyl-1H-indole
[0110]
[0111] 0.2 mmol of cinnamaldehyde was dissolved in a Schlenk tube, 0.3 mmol of the compound prepared in the first step was added, and a stirrer was added, and finally 1 mL of tetrahydrofuran was added, and the mixture was reacted at 80° C. for 12 hours; after the reaction, the product was purified by column chromatography, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1; with the help of TLC elution tracking detection, the eluate containing the target product was collected, the eluate of the target product was combined, and evaporated and concentrated to obtain (E)-5-bromo-3-phenyl-2-phenylvinyl-1H-indole.
[0112] like Fig.10 , the H NMR spectrum data of the compound is: 1H NMR (400MHz, CDCl3) δ8.41 (s, 1H), 7.81 (d, J = 1.8Hz, 1H), 7.54-7.51 (m, 4H), 7.45-7.41 (m ,3H),7.38-7.31(m,3H),7.29(d,J=7.2Hz,1H),7.25-7.17(m,2H),6.93(d,J=16.6Hz,1H).
[0113] like Fig.11 , the NMR carbon spectrum data of the compound is: 13 C NMR (101MHz, CDCl3) δ136.7,135.1,133.9,133.7,130.1,130.0,128.9,128.4,128.1,126.9,126.6,126.3,122.2,118.2,117.5,113.7,112.3.
[0114] Example 6
[0115] The indole compounds of the present invention, when R 1 For H, R 2 For H, R 3 Me, named (E)-2-(2-methylphenylvinyl)-3-phenyl-1H-indole, its structural formula is:
[0116]
[0117] The compound synthesis method comprises the following steps:
[0118] Step 1: Preparation of 2-[(bromotriphenyl-5-phosphino)phenylmethyl]aniline
[0119]
[0120] (1) 10 mmol of 2-aminobenzophenone and 30 mL of ethanol were added to a 100 mL reaction flask to fully dissolve, 40 mmol of sodium borohydride was added in batches at 5° C., and the temperature was raised to 80° C. for reaction for 3 hours; after the reaction was completed, water was added to quench, and then ethyl acetate (50 mL x 3) was used for extraction, and saturated brine was used for washing. After the reaction was completed, anhydrous sodium sulfate was added to dry, and the solvent was removed by rotary evaporation to obtain (2-aminophenyl)(phenyl)methanol.
[0121] (2) Transfer (2-aminophenyl)(phenyl)methanol to a 100 mL reaction flask, add 10 mmol of triphenylphosphine hydrobromide, use 30 mL of acetonitrile to fully dissolve the reactants, and reflux at 60° C. for 15 hours. After the reaction is completed, wash the product with ether until it turns white and air-dry it.
[0122] The NMR data of this compound are: 1 H NMR(400MHz, DMSO-d6)δ7.92-7.87(m,3H),7.73(td,J=7.9,3.7Hz,7H),7.64(dd,J=12.0,7.5Hz,6H), 7.40-7.22(m,6H),7.06(t,J=7.6Hz,1H),6.79(d,J=8.2Hz,1H),6.67-6.56(m,2H),6.41-6.35(m,1H).
[0123] Step 2: Preparation of (E)-2-(2-methylphenylvinyl)-3-phenyl-1H-indole
[0124]
[0125] 0.2 mmol (E)-3-(o-tolyl) acrolein was placed in a Schlenk tube, 0.3 mmol of the compound prepared in the first step was added, a stirrer was added, and finally 1 mL of tetrahydrofuran was added, and the mixture was reacted at 80° C. for 9 hours. After the reaction, the product was purified by column chromatography, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1. With the help of TLC elution tracking detection, the eluate containing the target product was collected, the target product eluate was combined, and evaporated and concentrated to obtain (E)-2-(2-methylphenylvinyl)-3-phenyl-1H-indole.
[0126] like Fig.12 , the H NMR spectrum data of the compound is: 1 H NMR (400MHz, CDCl3) δ8.35 (s, 1H), 7.76 (d, J = 9.0Hz, 1H), 7.62 (dd, J = 8.1, 1.3Hz, 2H), 7.5 7-7.52(m,3H),7.45-7.39(m,2H),7.31(t,J=7.0Hz,1H),7.24-7.16(m,6H),2.50(s,3H).
[0127] like Fig.13 , the NMR carbon spectrum data of the compound is: 13 C NMR (101MHz, CDCl3) δ136.5,136.0,135.7,134.6,132.9,130.6,130.2,128.8,128.3 ,127.8,126.6,126.4,125.3,125.0,123.7,120.5,119.8,119.3,118.8,110.8,20.2.
[0128] Example 7
[0129] The indole compounds of the present invention, when R 1 For H, R 2 For H, R 3 It is OMe, named (E)-2-(2-methoxyphenylvinyl)-3-phenyl-1H-indole, and its structural formula is:
[0130]
[0131] The compound synthesis method comprises the following steps:
[0132] Step 1: Preparation of 2-[(bromotriphenyl-5-phosphino)phenylmethyl]aniline
[0133]
[0134] (1) 10 mmol of 2-aminobenzophenone and 30 mL of ethanol were added to a 100 mL reaction flask to fully dissolve, 40 mmol of sodium borohydride was added in batches at -5°C, and the temperature was raised to 90°C for reaction for 1 hour; after the reaction was completed, water was added to quench, and then ethyl acetate (50 mL x 3) was used for extraction, and saturated brine was used for washing. After the reaction was completed, anhydrous sodium sulfate was added for drying, and the solvent was removed by rotary evaporation to obtain (2-aminophenyl)(phenyl)methanol.
[0135] (2) Transfer (2-aminophenyl)(phenyl)methanol to a 100 mL reaction flask, add 10 mmol of triphenylphosphine hydrobromide, use 30 mL of acetonitrile to fully dissolve the reactants, and reflux at 70° C. for 10 hours. After the reaction is completed, wash the product with ether until it turns white and air-dry it.
[0136] The NMR data of this compound are: 1 H NMR(400MHz, DMSO-d6)δ7.92-7.87(m,3H),7.73(td,J=7.9,3.7Hz,7H),7.64(dd,J=12.0,7.5Hz,6H), 7.40-7.22(m,6H),7.06(t,J=7.6Hz,1H),6.79(d,J=8.2Hz,1H),6.67-6.56(m,2H),6.41-6.35(m,1H).
[0137] Step 2: Preparation of (E)-2-(2-methoxyphenylvinyl)-3-phenyl-1H-indole
[0138]
[0139] 0.2 mmol (E)-3-(2-methoxyphenyl) acrolein was dissolved in a Schlenk tube, 0.24 mmol of the compound prepared in the first step was added, and a stirrer was added, and finally 1 mL of dichloromethane was added, and the reaction was carried out at 90° C. for 10 hours; after the reaction, the product was purified by column chromatography, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 5:1; with the help of TLC elution tracking detection, the eluate containing the target product was collected, the eluate of the target product was combined, and evaporated and concentrated to obtain (E)-2-(2-methoxyphenylvinyl)-3-phenyl-1H-indole.
[0140] like Fig.14 , the H NMR spectrum data of the compound is: 1 H NMR (400MHz, CDCl3) δ8.44(s,1H),7.74(d,J=8.0Hz,1H),7.62(dd,J=8.2,1.4Hz,2H),7.56-7.51 (m,3H),7.44-7.32(m,4H),7.30-7.25(m,2H),7.19-7.14(m,1H),7.00-6.92(m,2H),3.93(s,3H).
[0141] like Fig.15 , the NMR carbon spectrum data of the compound is: 13 C NMR (101MHz, CDCl3) δ156.7,136.5,134.8,133.3,130.2,128.9,128.7,128.2,126.5 ,126.2,126.0,123.5,121.8,120.9,120.4,119.7,118.4,118.2,111.0,110.8,55.6.
[0142] Example 8
[0143] The indole compounds of the present invention, when R 1 For H, R 2 For H, R 3 It is Cl, named (E)-2-(2-chlorophenylvinyl)-3-phenyl-1H-indole, and its structural formula is:
[0144]
[0145] The compound synthesis method comprises the following steps:
[0146] Step 1: Preparation of 2-[(bromotriphenyl-5-phosphino)phenylmethyl]aniline
[0147]
[0148] (1) 10 mmol of 2-aminobenzophenone and 30 mL of ethanol were added to a 100 mL reaction flask to fully dissolve, 40 mmol of sodium borohydride was added in batches at 10° C., and the temperature was raised to 70° C. for reaction for 2 hours; after the reaction was completed, water was added to quench, and then ethyl acetate (50 mL x 3) was used for extraction, and saturated brine was used for washing. After the reaction was completed, anhydrous sodium sulfate was added for drying, and the solvent was removed by rotary evaporation to obtain (2-aminophenyl)(phenyl)methanol.
[0149] (2) Transfer (2-aminophenyl)(phenyl)methanol to a 100 mL reaction flask, add 10 mmol of triphenylphosphine hydrobromide, use 30 mL of acetonitrile to fully dissolve the reactants, and reflux at 90° C. for 12 hours. After the reaction is completed, wash the product with ether until it turns white and air-dry it.
[0150] The NMR data of this compound are: 1 H NMR(400MHz, DMSO-d6)δ7.92-7.87(m,3H),7.73(td,J=7.9,3.7Hz,7H),7.64(dd,J=12.0,7.5Hz,6H), 7.40-7.22(m,6H),7.06(t,J=7.6Hz,1H),6.79(d,J=8.2Hz,1H),6.67-6.56(m,2H),6.41-6.35(m,1H).
[0151] Step 2: Preparation of (E)-2-(2-chlorophenylvinyl)-3-phenyl-1H-indole
[0152]
[0153] 0.2 mmol of (E)-3-(2-chlorophenyl)acrolein was placed in a Schlenk tube, 0.3 mmol of the compound prepared in the first step was added, a stirrer was added, and finally 1 mL of ethanol was added, and the mixture was reacted at 60° C. for 15 hours. After the reaction, the product was purified by column chromatography, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 8:1. With the help of TLC elution tracking detection, the eluate containing the target product was collected, the eluate of the target product was combined, and evaporated and concentrated to obtain (E)-2-(2-chlorophenylvinyl)-3-phenyl-1H-indole.
[0154] like Fig.16 , the H NMR spectrum data of the compound is: 1H NMR (400MHz, CDCl3) δ8.41 (s, 1H), 7.74 (d, J = 7.0Hz, 1H), 7.63-7.52 (m, 6H), 7.45-7.39 (m, 2H), 7.33-7.26 (m, 3H), 7.23-7.09 (m, 3H).
[0155] like Fig.17 , the NMR carbon spectrum data of the compound is: 13 C NMR (101MHz, CDCl3) δ136.7,135.0,134.5,133.2,132.4,130.3,130.0,128.8,128 .7,128.2,127.1,126.8,126.3,124.0,122.9,120.6,120.4,120.0,119.8,110.9.
[0156] Example 9
[0157] The indole compounds of the present invention, when R 1 For H, R 2 For H, R 3 It is Br, and its name is (E)-2-(2-bromostyryl)-3-phenyl-1H-indole, and its structural formula is:
[0158]
[0159] The compound synthesis method comprises the following steps:
[0160] Step 1: Preparation of 2-[(bromotriphenyl-5-phosphino)phenylmethyl]aniline
[0161]
[0162] (1) 10 mmol of 2-aminobenzophenone and 30 mL of ethanol were added to a 100 mL reaction flask to fully dissolve, 40 mmol of sodium borohydride was added in batches at 0° C., and the temperature was raised to 70° C. for reaction for 4 hours; after the reaction was completed, water was added to quench, and then ethyl acetate (50 mL x 3) was used for extraction, and saturated brine was used for washing. After the reaction was completed, anhydrous sodium sulfate was added to dry, and the solvent was removed by rotary evaporation to obtain (2-aminophenyl)(phenyl)methanol.
[0163] (2) Transfer (2-aminophenyl)(phenyl)methanol to a 100 mL reaction flask, add 10 mmol of triphenylphosphine hydrobromide, use 30 mL of acetonitrile to fully dissolve the reactants, and reflux at 70° C. for 20 hours. After the reaction is completed, wash the product with ether until it turns white and air-dry it.
[0164] The NMR data of this compound are:1 H NMR(400MHz, DMSO-d6)δ7.92-7.87(m,3H),7.73(td,J=7.9,3.7Hz,7H),7.64(dd,J=12.0,7.5Hz,6H), 7.40-7.22(m,6H),7.06(t,J=7.6Hz,1H),6.79(d,J=8.2Hz,1H),6.67-6.56(m,2H),6.41-6.35(m,1H).
[0165] Step 2: Preparation of (E)-2-(2-bromostyryl)-3-phenyl-1H-indole
[0166]
[0167] 0.2 mmol of (E)-3-(2-bromophenyl)acrolein was dissolved in a Schlenk tube, 0.3 mmol of the compound prepared in the first step was added, and a stirring bar was added, and finally 1 mL of tetrahydrofuran was added, and the reaction was carried out at 90° C. for 9 hours; after the reaction, the product was purified by column chromatography, and the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 10:1; with the help of TLC elution tracking detection, the eluate containing the target product was collected, the eluate of the target product was combined, and evaporated and concentrated to obtain (E)-2-(2-bromostyryl)-3-phenyl-1H-indole.
[0168] like Fig.18 , the H NMR spectrum data of the compound is: 1 H NMR (400MHz, CDCl3) δ8.43 (s, 1H), 7.73 (d, J = 8.9Hz, 1H), 7.61-7.51 (m, 5H), 7 .42(dddd,J=7.2,5.4,2.8,1.2Hz,3H),7.36-7.28(m,2H),7.27-7.15(m,4H).
[0169] like Fig.19 , the NMR carbon spectrum data of the compound is: 13 C NMR (101MHz, CDCl3) δ136.7,134.9,134.5,133.2,132.4,130.3,130.0,128.8,128 .7,128.1,127.1,126.8,126.3,124.0,122.9,120.6,120.3,119.9,119.7,110.9.
Claims
1. A method for synthesizing an indole compound, characterized in that: Compound 1 and compound 2 undergo a [4+1] cyclization reaction in an organic solvent to obtain the target indole compound. The synthetic route is as follows: ； Where R 1 is any one of H, Cl, or Br; wherein R 2 is any one of H, F or Br; wherein R 3 It is any one of H, Me, OMe, Cl or Br; the reaction temperature is 60-100°C; the reaction solvent is tetrahydrofuran, dichloromethane or ethanol.
2. The method for synthesizing indole compounds according to claim 1, characterized in that: The molar ratio of compound 1 to compound 2 is 1:1.2-1:
2.
3. The method for synthesizing indole compounds according to claim 1, characterized in that: The purification method of the target product indole compound is: separation by column chromatography, wherein the column chromatography solid phase is column chromatography silica gel, and the mobile phase is a mixture of petroleum ether and ethyl acetate.
4. The method for synthesizing indole compounds according to claim 3, characterized in that: The volume ratio of petroleum ether to ethyl acetate is 10:1-5:
1.
5. The method for synthesizing indole compounds according to claim 1, characterized in that: The synthesis method of compound 2 is: (1) The carbonyl group of compound 3 undergoes a reduction reaction and is reduced to a hydroxyl group to obtain compound 4; (2) Compound 4 and triphenylphosphine hydrobromide undergo substitution reaction to obtain compound 2; The synthetic route is as follows: 。 6. The method for synthesizing indole compounds according to claim 5, characterized in that: In step (1), the reducing agent of the reduction reaction is sodium borohydride, which is first added at -10~10°C, and then the temperature is raised to 60~100°C for reaction.
7. The method for synthesizing indole compounds according to claim 5, characterized in that: In step (2), the reaction temperature is 60-100°C.
8. The method for synthesizing indole compounds according to claim 5, characterized in that: In step (1), the purification method of compound 4 is: extraction with ethyl acetate.