Indole derivative obtained by converting quinoline nitrogen-oxide and synthesis method thereof

Abstract

The invention relates to an indole derivative obtained by converting quinoline nitrogen-oxide and a synthesis method thereof. The chemical structural formula of the derivative is as shown in formula 2. The synthesis method comprises the following steps: adding a compound quinoline nitrogen-oxide as shown in a formula 1, dimethyl butynedioate and water serving as reaction raw materials into a 1, 2-dichloroethane solvent, carrying out a first heating and stirring reaction under the catalytic action of diphenyl phosphate, and after TLC monitors that the compound quinoline nitrogen-oxide as shown in the formula 1 is completely converted, carrying out a second heating and stirring reaction; and adding trichloroacetic acid and a dehydrating agent # imgabs0 # molecular sieve, carrying out a second heating and stirring reaction, monitoring the reaction by TLC until the reaction is complete, evaporating out the solvent, and purifying to obtain the product. The method has the advantages of being high in atom economy, mild in reaction condition, green, low in cost, high in conversion rate and the like, meanwhile, the method is a carbon recombination strategy for directly editing a molecular skeleton, and a new thought can be provided for later design optimization of drug molecules. The method can accelerate the drug discovery and development process, and has good theoretical value and application prospect. # imgabs1 #

Description

Technical Field

[0001] The invention belongs to the field of organic chemical synthesis, and specifically relates to an indole derivative obtained by converting quinoline nitrogen-oxide and a synthesis method thereof. Background Art

[0002] N-heterocyclic skeletons are widely present in various natural products, agrochemicals and drug molecules. In the past few decades, a variety of synthetic transformation strategies for constructing N-heterocyclic molecules have been successfully designed. Among them, skeleton editing is an extremely attractive strategy. Recently, scientists have made great progress in molecular editing and late functionalization, but the main focus is still on editing the peripheral C-H bonds of the molecular skeleton, while there are relatively few methods for direct editing of the molecular skeleton.

[0003] The methods for direct editing of molecular skeletons in the literature include:

[0004] Mark D. Levin et al. from the University of Chicago reported an N-pivaloyloxy-N-alkoxyamide reagent. This reaction uses an isomeric amide reagent to promote the intermolecular activation of aliphatic secondary amines and produce intramolecular CC bond coupling products, thereby achieving the nitrogen atom deletion reaction of secondary amines (SH Kennedy, BDD Herange, KJ Berger, MD Levin, Nature, 2021, 593, 223-227.). The reaction formula is as follows:

[0005]

[0006] The research group of Lu Hongjian from Nanjing University used the aminosulfonyl azide rearrangement reaction to convert the (n+1)-membered N-heterocycle into an n-membered ring (H.-T. Qin, W.-S. Cai, S. Wang, T. Guo, G.-G. Li, H.-J. Lu, Angew. Chem. Int. Ed., 2021, 60, 20678-20683.). The reaction formula is as follows:

[0007]

[0008] Professor Richmond Sarpong's research group used trifluoromethanesulfonylation of the pyrimidine core, followed by hydrazine-mediated skeleton remodeling, to condense a series of substituted pyrimidines into the corresponding pyrazoles (GL Bartholomew, F. Carpaneto, and R. Sarpong, J. Am. Chem. Soc., 2022, 144, 22309-22315.), and the reaction formula is as follows:

[0009]

[0010] Professor Mark D. Levin's research group used photochemical transformation to carry out the "carbon deletion" strategy on the nitrogen heteroaromatic ring to transform the quinoline skeleton into an indole skeleton (J.Woo1, AHChristian, SABurgess, Y.Jiang, UFMansoor, MDLevin, Science, 2022, 376, 527-532.), and the reaction formula is as follows:

[0011]

[0012] It can be seen that the current research on "molecular editing" that directly modifies the core skeleton of a molecule is still very limited and lacks universality, mainly because the structural range of the product is still relatively narrow, most methods require the use of active precursors such as carbenes, and the reaction conditions often involve metals or require light, which is environmentally unfriendly. Therefore, the development of practical and universal molecular editing methods has very important application value and research significance. Summary of the invention

[0013] The purpose of the present invention is to provide an indole derivative obtained by converting quinoline nitrogen-oxide and a synthesis method thereof, wherein the method uses a simple and readily available reaction substrate and relatively mild reaction conditions to efficiently achieve the conversion of a quinoline skeleton to an indole skeleton in one pot.

[0014] To achieve the above object, the technical solution adopted by the present invention is: an indole derivative obtained by converting quinoline nitrogen-oxide, whose chemical structure is shown in Formula 2:

[0015]

[0016] In formula 2, R1 is selected from one of alkyl, alkenyl, aryl, and aromatic heterocycle; R2 is selected from one of hydrogen, alkyl, ester, halogen, amine, nitro, and aryl; R3 is selected from one of hydrogen, ether, and aromatic ring; R4 is selected from one of hydrogen and alkyl.

[0017] To achieve the purpose of the invention, the present invention also provides a method for synthesizing the indole derivative obtained by converting the quinoline nitrogen-oxide mentioned above, which specifically comprises the following steps: adding the quinoline nitrogen-oxide of the compound of formula 1, dimethyl butynedioate and water as reaction raw materials into a 1,2-dichloroethane solvent, performing a first heating and stirring reaction under the catalysis of diphenyl phosphate, and after the quinoline nitrogen-oxide of the compound of formula 1 is completely converted by TLC monitoring, adding trichloroacetic acid and a dehydrating agent After the molecular sieve, a second heating and stirring reaction was carried out, and the reaction was monitored by TLC until it was complete. After the solvent was evaporated, purification was performed to obtain the product;

[0018] Wherein, the structural formula of the compound of formula 1, quinoline nitrogen-oxide, is In formula 1, R1 is selected from one of alkyl, alkenyl, aryl, and aromatic heterocycle; R2 is selected from one of hydrogen, alkyl, ester, halogen, amine, nitro, and aryl; R3 is selected from one of hydrogen, ether, and aromatic ring; R4 is selected from one of hydrogen and alkyl.

[0019] Preferably, the molar ratio of the compound of formula 1, quinoline nitrogen-oxide, dimethyl butynedioate, water and diphenyl phosphate is 1:2:10:0.1.

[0020] Preferably, the molar ratio between the quinoline nitrogen-oxide of the compound of formula 1 and trichloroacetic acid is 1:2.

[0021] Preferably, the first heating and stirring reaction temperature is 50-90°C, and the reaction time is 12-72h; the second heating and stirring reaction temperature is 80-120°C, and the reaction time is 8-24h.

[0022] Preferably, the first heating and stirring reaction temperature is 60° C., and the reaction time is 12 h; the second heating and stirring reaction temperature is 120° C., and the reaction time is 12 h.

[0023] Preferably, the ratio of the volume of the 1,2-dichloroethane to the molar amount of the quinoline nitrogen-oxide of the compound of formula 1 is 1 mL:0.1 mmol.

[0024] Preferably, the dehydrating agent The ratio of the mass of the molecular sieve to the molar amount of the compound quinoline nitrogen-oxide of formula 1 is 60 mg:0.1 mmol.

[0025] The synthetic reaction route involved in the present invention is as follows:

[0026]

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] (1) The present invention uses diphenyl phosphate to induce a cyclization rearrangement reaction involving quinoline nitrogen oxides and dimethyl butynedioate, and then removes the side chain through trichloroacetic acid to directly convert the quinoline ring into an indole ring; this method uses simple and readily available reaction substrates and relatively mild reaction conditions to efficiently achieve the transformation of the quinoline skeleton into the indole skeleton in one pot, thereby avoiding complex de novo synthesis.

[0029] (2) In the past, this conversion required 390nm LED illumination, and flow technology was required to achieve gram-scale. The present invention achieves gram-scale reaction in a simple thermodynamic manner, which is more practical.

[0030] (3) The present invention avoids the use of transition metals and adopts an organic catalytic mode, which reduces costs while not causing any heavy metal residues in the reaction process.

[0031] (4) The product of the present invention has a wide range of structures. The conversion of quinoline nitrogen oxide compounds to indole rings is completed through a one-pot synthesis of tandem reactions, and the reaction is efficient and fast. The reaction conditions are mild, insensitive to air or water, and simple to operate. It has the advantages of high atom economy, mild reaction conditions, green, low cost, and high conversion rate. At the same time, this method is a carbon recombination strategy for directly editing the molecular skeleton, which can provide new ideas for the later design optimization of drug molecules. The present invention can accelerate the process of drug discovery and development, and has good theoretical value and application prospects. DETAILED DESCRIPTION

[0032] The present invention is further described in detail below in conjunction with embodiments.

[0033] In the following examples, unless otherwise specified, quinoline nitrogen oxides, dimethyl butynoate and other reagents can be purchased from the market or obtained according to known literature reports; the experimental methods are usually carried out under conventional conditions or conditions recommended by the manufacturer.

[0034] The quinoline nitrogen oxide compound 1 used in the following examples was synthesized according to the method of references (Woo, J., Christian, AH, Burgess, SA, Jiang, Y., Mansoor, UF, Levin, MD Science, 2022, 376, 527-532.; Martinez, R., Ramon, DJ, Yus, MJ Org. Chem. 2008, 73, 9778–9780. Dhiman, AK, Gupta, SS, Sharma, R., Kumar, R., Sharma, UJ Org. Chem. 2019, 84, 12871-12880), and the characterization results of the unreported compounds 1l, 1n, 1o, 1q, and 1r are as follows:

[0035] 5-((tert-Butyloxycarbonyl)amino)-2-phenylquinoline-1-oxide (1l)

[0036]

[0037] Mp=205–207℃. 1 H NMR (400MHz, DMSO-d6) δ9.58 (s, 1H), 8.44 (d, J = 8.4Hz, 1H), 8.06 (d, J = 9.1Hz, 1H), 8.03 –7.97(m,2H),7.85–7.75(m,2H),7.71(d,J=9.1Hz,1H),7.57–7.47(m,3H),1.51(s,9H).13 C NMR (101MHz, DMSO-d6) δ153.7,143.5,142.3,135.4,133.2,130.1,129.5,129.4,128.0,124.1,122.5,122.4,120.2,115.4,79.6,28.1.

[0038] 6-((2-Acetoxybenzoyl)oxy)-2-(4-methoxyphenyl)quinoline-1-oxide (1n)

[0039]

[0040] 1 H NMR(400MHz,Chloroform-d)δ8.92(d,J=9.5Hz,1H),8.32–8.25(m,1H),8.09–7.99(m,2H),7.78–7.66(m, 3H),7.6–7.52(m,2H),7.48–7.41(m,1H),7.24–7.19(m,1H),7.09–7.02(m,2H),3.87(s,3H),2.31(s,3H). 13 C NMR(101MHz,Chloroform-d)δ169.9,162.7,160.8,151.5,150.0,144.8,140.6,135.2,132.4,13 1.3,130.1,126.5,125.49,125.47,124.9,124.3,124.2,122.6,122.2,119.2,113.9,55.6,21.2.

[0041] 3-Butyl-2-phenylquinoline 1-oxide (1o)

[0042]

[0043] Mp=128–129℃. 1 H NMR(400MHz,Chloroform-d)δ8.72(d,J=8.7Hz,1H),7.82(d,J=8.1Hz,1H),7.72–7.67(m,1H),7.66–7.59(m,2H),7.57–7.52( m,2H),7.50–7.45(m,1H),7.42–7.37(m,2H),2.54–2.48(m,2H),1.51–1.43(m,2H),1.27–1.17(m,2H),0.78(t,J=7.3Hz,3H). 13C NMR (101MHz, Chloroform-d) δ147.4,140.4,136.2,133.2,129.6,129.4,129.2,128.89,128.87,128.6,127.5,124.9,120.3,32.8,32.4,22.3,13.8.

[0044] 8-Methoxy-2-(4-methoxyphenyl)-5-methylquinoline 1-oxide (1q)

[0045]

[0046] Mp=138–140℃. 1 H NMR(400MHz,Chloroform-d)δ7.98–7.89(m,2H),7.73(d,J=8.9Hz,1H),7.46(d,J=8.9H z,1H),7.30(d,J=7.4Hz,1H),7.04–6.95(m,3H),3.99(s,3H),3.87(s,3H),2.57(s,3H). 13 C NMR (101MHz, Chloroform-d) δ160.3,152.7,146.5,135.6,131.6,131.4,128.9,127.0,126.2,123.2,121.4,113.6,112.3,57.7,55.5,19.2.

[0047] 5-Chloro-8-(2-(hept-2-yloxy)-2-oxoethoxy)-2-phenylquinoline-1-oxide (1r)

[0048]

[0049] 1 H NMR(400MHz,Chloroform-d)δ7.98(d,J=9.0Hz,1H),7.86–7.79(m,2H),7.50–7.37(m,5H),7.20(s,1H),5.00–4 .88(m,1H),4.76(d,J=1.6Hz,2H),1.56–1.45(m,1H),1.43–1.33(m,1H),1.20–1.13(m,9H),0.82–0.76(m,3H).

[0050] 13C NMR(101MHz,Chloroform-d)δ168.9,151.4,147.7,137.2,133.3,130.4,129.8,129.7,1 28.5,128.4,126.2,124.5,121.2,119.3,72.5,70.6,35.9,31.7,25.1,22.6,20.0,14.1.

[0051] Example 1

[0052] The synthetic route of (1H-indol-1-yl)(phenyl)methanone (2a) is as follows:

[0053]

[0054] Quinoline nitrogen oxide 1a (0.1 mmol), diphenyl phosphate (0.01 mmol), dimethyl butynedioate (0.2 mmol), and H2O (1.0 mmol) were added to a dried reaction tube in a ratio of 1:0.1:2:10. 1,2-dichloroethane (1.0 mL) was added to the mixture. The reaction system was stirred at 60°C for 12 h. After the conversion of quinoline nitrogen oxide 1a was complete, TLC was monitored, and then 1,2-dichloroethane (1.0 mL) was added. Molecular sieves (60 mg) and trichloroacetic acid (0.2 mmol), the reaction system was stirred at 120 ° C for 12 h, and after the reaction was completed as monitored by TLC, the solvent was evaporated to obtain a crude product, which was subsequently purified by column chromatography (the volume ratio of petroleum ether / ethyl acetate was 10 / 1) to obtain the target product (yield 80%).

[0055] Product spectrum analysis: 1 H NMR(400MHz,Chloroform-d)δ8.43(d,J=8.2Hz,1H),7.75(d,J=7.7Hz,2H),7.66–7.59(m,2 H),7.54(t,J=7.5Hz,2H),7.40(t,J=7.7Hz,1H),7.36–7.28(m,2H),6.63(d,J=3.7Hz,1H). 13 C NMR (101MHz, Chloroform-d) δ168.9,136.1,134.6,132.0,130.9,129.3,128.7,127.7,125.1,124.1,121.0,116.5,108.7.

[0056] Example 2

[0057] The synthetic route of 1-(1H-indol-1-yl)ethan-1-one (2b) is as follows:

[0058]

[0059] Except that 1b is used to replace the structural formula 1a in Example 1, the remaining steps are the same as Example 1, and the yield is 56%. Product spectrum analysis: 1 H NMR(400MHz,Chloroform-d)δ8.45(d,J=8.3Hz,1H),7.57(d,J=7.7Hz,1H),7.43(d,J=2.9 Hz,1H),7.36(t,J=7.8Hz,1H),7.29(d,J=7.5Hz,1H),6.65(d,J=3.7Hz,1H),2.65(s,3H). 13 C NMR (101MHz, Chloroform-d) δ168.8,135.6,130.5,125.4,125.3,123.8,121.0,109.3,24.2.

[0060] Example 3

[0061] The synthetic route of (1H-indol-1-yl)(p-tolyl)methanone (2c) is as follows:

[0062]

[0063] Except for using 1c to replace the structural formula 1a in Example 1, the remaining steps are the same as Example 1, and the yield is 89%. Product spectrum analysis: 1 H NMR(400MHz,Chloroform-d)δ8.41(d,J=8.2Hz,1H),7.66(d,J=7.9Hz,2H),7.62(d,J=7 .7Hz,1H),7.39(t,J=7.7Hz,1H),7.36–7.29(m,4H),6.62(d,J=3.7Hz,1H),2.47(s,3H). 13 C NMR (101MHz, Chloroform-d) δ168.9,142.8,136.1,131.7,130.8,129.6,129.4,127.9,124.9,123.9,121.0,116.4,108.4,21.8.

[0064] Example 4

[0065] The synthetic route of (1H-indol-1-yl)(3-methoxyphenyl)methanone (2d) is as follows:

[0066]

[0067] Except that 1d was used to replace the structural formula 1a in Example 1, the remaining steps were the same as in Example 1, and the yield was 84%. Product spectrum analysis: 1 H NMR(400MHz,Chloroform-d)δ8.39(d,J=8.2Hz,1H),7.57(s,1H),7.44–7.33(m ,2H),7.32–7.21(m,4H),7.15–7.07(m,1H),6.58(d,J=3.8Hz,1H),3.83(s,3H). 13 C NMR (101MHz, Chloroform-d) δ168.6,159.7,136.1,135.9,130.9,129.8,127.8,125.1,124.1,121.5,121.0,118.1,116.5,114.2,108.7,55.6.

[0068] Example 5

[0069] The synthetic route of 1H-benzo[f]indol-1-yl)(phenyl)methanone (2e) is as follows:

[0070]

[0071] Except for using 1e to replace the structural formula 1a in Example 1, the remaining steps are the same as Example 1, and the yield is 72%. Product spectrum analysis: 1 H NMR (400MHz, Chloroform-d) δ9.00 (s, 1H), 8.04 (d, J = 9.9Hz, 2H), 8.00–7.93 (m, 1H), 7.83–7. 73(m,2H),7.62(t,J=7.4Hz,1H),7.59–7.53(m,2H),7.52–7.43(m,3H),6.73(d,J=3.9Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ168.6,135.4,134.9,131.9,131.8,131.1,131.0,130.5,129.1,128.9,128.8,128.1,125.2,125.0,118.8,114.2,109.0.

[0072] Example 6

[0073] The synthetic route of (4-methyl-1H-indol-1-yl)(phenyl)methanone (2f) is as follows:

[0074]

[0075] Except that 1f is used to replace the structural formula 1a in Example 1, the remaining steps are the same as Example 1, and the yield is 73%. Product spectrum analysis: 1 H NMR(400MHz,Chloroform-d)δ8.21(d,J=8.3Hz,1H),7.75–7.66(m,2H),7.57(t,J=7.3Hz,1H),7. 49(t,J=7.5Hz,2H),7.29–7.20(m,2H),7.09(d,J=7.3Hz,1H),6.62(d,J=3.8Hz,1H),2.52(s,3H). 13 C NMR (101MHz, Chloroform-d) δ168.9,135.9,134.7,132.0,130.5,130.4,129.3,128.7,127.2,125.1,124.5,114.0,107.1,18.7.

[0076] Example 7

[0077] The synthetic route of (1H-indol-1-yl)(naphthalene-2-yl)methanone (2 g) is as follows:

[0078]

[0079] Except for using 1g to replace the structural formula 1a in Example 1, the remaining steps are the same as Example 1, and the yield is 79%. Product spectrum analysis: 1 H NMR(400MHz,Chloroform-d)δ8.47(d,J=8.2Hz,1H),8.26(s,1H),8.04–7.93(m,3H) ,7.82(d,J=8.5Hz,1H),7.71–7.57(m,3H),7.47–7.31(m,3H),6.65(d,J=3.7Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ168.9,136.2,134.8,132.4,131.8,130.9,130.3,12 9.1,128.7,128.4,128.0,127.9,127.3,125.4,125.1,124.1,121.0,116.5,108.7.

[0080] Example 8

[0081] The synthetic route of furan-2-yl(1H-indol-1-yl)methanone (2h) is as follows:

[0082]

[0083] Except that 1h was used to replace the structural formula 1a in Example 1, and the temperature of the first step was 70 degrees, the remaining operation steps were the same as Example 1, and the yield was 72%. Product spectrum analysis: 1 H NMR(400MHz,Chloroform-d)δ8.50(d,J=8.2Hz,1H),8.05(d,J=3.8Hz,1H),7.70(s,1H),7.61(d,J=7.6Hz, 1H),7.42(d,J=3.5Hz,1H),7.41–7.35(m,1H),7.35–7.28(m,1H),6.70(d,J=3.8Hz,1H),6.68–6.63(m,1H). 13 C NMR (101MHz, Chloroform-d) δ156.9,147.3,146.4,136.5,130.5,126.6,125.1,124.2,121.0,120.7,116.8,112.5,109.5.

[0084] Example 9

[0085] The synthetic route of (1H-indol-1-yl)(thiophen-2-yl)methanone (2i) is as follows:

[0086]

[0087] Except that 1i is used to replace the structural formula 1a in Example 1, and the temperature of the first step is 90 degrees, the remaining operation steps are the same as Example 1, and the yield is 51%. Product spectrum analysis: 1 H NMR(400MHz,Chloroform-d)δ8.41(d,J=8.2Hz,1H),7.76–7.65(m,3H),7.62(d,J=7.8Hz,1H ),7.39(t,J=7.7Hz,1H),7.32(t,J=7.5Hz,1H),7.20(t,J=4.3Hz,1H),6.68(d,J=3.7Hz,1H). 13 C NMR (101MHz, Chloroform-d) δ161.8,137.3,136.3,133.5,132.8,130.8,127.7,127.2,125.1,124.1,121.1,116.4,108.9.

[0088] Example 10

[0089] The synthetic route of (E)-1-(1H-indol-1-yl)-3-phenylprop-2-en-1-one (2j) is as follows:

[0090]

[0091] Except that 1j is used to replace the structural formula 1a in Example 1, the remaining steps are the same as Example 1, and the yield is 66%. Product spectrum analysis: 1 H NMR(400MHz,Chloroform-d)δ8.58(d,J=8.3Hz,1H),8.03(d,J=15.5Hz,1H),7.72–7.65(m,3H),7.63 (d,J=7.8Hz,1H),7.52–7.45(m,3H),7.42(t,J=7.8Hz,1H),7.37–7.27(m,2H),6.73(d,J=3.7Hz,1H). 13 C NMR (101MHz, Chloroform-d) δ164.4,146.7,136.0,134.6,130.9,130.7,129.2,128.5,125.2,124.7,123.9,121.0,117.4,117.0,109.3.

[0092] Embodiment 11

[0093] The synthetic route of cyclopropyl(1H-indol-1-yl)methanone (2k) is as follows:

[0094]

[0095] Except that 1k was used to replace the structural formula 1a in Example 1, the remaining steps were the same as in Example 1, and the yield was 56%. Product spectrum analysis: 1 H NMR(400MHz,Chloroform-d)δ8.41(d,J=8.2Hz,1H),7.67(d,J=3.8Hz,1H),7.55(d,J=7.7Hz,1H),7.35–7.2 8(m,1H),7.26–7.21(m,1H),6.65(d,J=3.7Hz,1H),2.30–2.22(m,1H),1.33–1.26(m,2H),1.11–1.02(m,2H). 13 C NMR (101MHz, Chloroform-d) δ172.4,135.8,130.5,125.05,124.98,123.6,120.9,116.6,109.0,14.1,9.9.

[0096] Example 12

[0097] The synthetic route of tert-butyl (1-benzoyl-1H-indol-4-yl)carbamate (21) is as follows:

[0098]

[0099] Except that 11 was used to replace the structural formula 1a in Example 1, the remaining steps were the same as in Example 1, and the yield was 54%. Product spectrum analysis: 1 H NMR(400MHz,Chloroform-d)δ8.06–7.96(m,2H),7.93(d,J=7.2Hz,2H),7.87(d,J=7.5Hz,1H),7.64–7.59 (m,1H),7.59–7.55(m,1H),7.55–7.47(m,2H),7.34(t,J=8.1Hz,1H),6.57(d,J=3.8Hz,1H),1.68(s,9H). 13 C NMR (101MHz, Chloroform-d) δ165.9,149.7,136.0,135.1,132.0,130.0,129.0,127.3,125.8,125.1,123.2,115.6,112.5,103.5,84.2,28.3.

[0100] Embodiment 13

[0101] The synthetic route of (4-nitro-1H-indol-1-yl)(phenyl)methanone (2m) is as follows:

[0102]

[0103] Except that 1m is used to replace the structural formula 1a in Example 1, and the temperature of the first step is 80 degrees, the remaining steps are the same as Example 1, and the yield is 53%. Product spectrum analysis: 1 H NMR(400MHz,Chloroform-d)δ8.79(d,J=8.2Hz,1H),8.28(d,J=8.1Hz,1H),7.82–7.74(m ,2H),7.73–7.65(m,1H),7.62–7.54(m,3H),7.51(t,J=8.2Hz,1H),7.42(d,J=3.7Hz,1H). 13 C NMR (101MHz, Chloroform-d) δ168.8,140.6,137.8,133.6,132.9,131.6,129.6,129.0,125.4,124.5,122.8,120.7,107.7.

[0104] Embodiment 14

[0105] The synthetic route of 1-(4-methoxybenzoyl)-1H-indol-5-yl-2-acetoxybenzoate (acetylsalicylic acid) (2n) is as follows:

[0106]

[0107] Except that 1n was used to replace the structural formula 1a in Example 1, the remaining steps were the same as in Example 1, and the yield was 68%. Product spectrum analysis: 1 H NMR(400MHz,Chloroform-d)δ8.39(d,J=8.9Hz,1H),8.30–8.26(m,1H),7.78–7.71(m,2H),7.65(td,J=7.8,1.7H z,1H),7.44–7.38(m,3H),7.21–7.15(m,2H),7.06–6.99(m,2H),6.62(d,J=3.7Hz,1H),3.91(s,3H),2.32(s,3H). 13 C NMR(101MHz,Chloroform-d)δ169.9,168.2,163.6,163.0,151.3,146.9,134.7,134.1,132.4,13 1.9,131.6,129.1,126.33,126.31,124.1,122.8,118.6,117.1,114.1,113.6,108.1,55.7,21.2.

[0108] Embodiment 15

[0109] The synthetic route of (2-butyl-1H-indol-1-yl)(phenyl)methanone (2o) is as follows:

[0110]

[0111] Except that 1o was used to replace the structural formula 1a in Example 1, the remaining steps were the same as in Example 1, and the yield was 53%. Product spectrum analysis: 1 H NMR(400MHz,Chloroform-d)δ7.79–7.69(m,2H),7.68–7.60(m,1H),7.55–7.49(m,3H),7.13(t,J=7.4Hz,1H),6.99(t,J=7.7 Hz,1H),6.86(d,J=8.3Hz,1H),6.49(s,1H),2.90–2.80(m,2H),1.69–1.57(m,2H),1.40–1.28(m,2H),0.89(t,J=7.3Hz,3H). 13CNMR(101MHz,Chloroform-d)δ170.1,143.2,137.3,135.5,133.2,130.0,129.5,128.9,122.6,122.5,120.0,114.2,107.4,31.2,28.7,22.5,14.0.

[0112] Example 16

[0113] The synthetic route of (5-chloro-1H-indol-1-yl)(phenyl)methanone (2p) is as follows:

[0114]

[0115] Except that 1p was used to replace the structural formula 1a in Example 1, the remaining steps were the same as in Example 1, and the yield was 60%. Product spectrum analysis: 1 H NMR(400MHz,Chloroform-d)δ8.35(d,J=8.8Hz,1H),7.73(d,J=7.6Hz,2H),7.6 3(t,J=7.4Hz,1H),7.60–7.50(m,3H),7.40–7.30(m,2H),6.56(d,J=3.7Hz,1H). 13 CNMR(101MHz,Chloroform-d)δ168.7,134.5,134.2,132.3,132.1,129.6,129.4,129.0,128.8,125.2,120.6,117.5,108.0.

[0116] Embodiment 17

[0117] The synthetic route of (7-methoxy-4-methyl-1H-indol-1-yl)(4-methoxyphenyl)methanone (2q) is as follows:

[0118]

[0119] Except that 1q was used to replace the structural formula 1a in Example 1, the remaining steps were the same as in Example 1, and the yield was 53%. Product spectrum analysis: 1 H NMR(400MHz,Chloroform-d)δ7.81–7.73(m,2H),7.40(d,J=3.6Hz,1H),7.00–6.97(m,1H),6.96– 6.91(m,2H),6.66(d,J=8.0Hz,1H),6.63(d,J=3.6Hz,1H),3.88(s,3H),3.64(s,3H),2.50(s,3H). 13C NMR (101MHz, Acetone-d6) δ168.1,164.5,147.1,132.6,129.0,128.0,124.2,123.1,114.6,106.9,105.7,56.0,55.7,17.9.

[0120] Embodiment 18

[0121] 2-(1-Benzoyl-4-chloro-1H-indol-7-yl)oxy)acetic acid heptyl ester (2r)

[0122]

[0123] Except that 1r was used to replace the structural formula 1a in Example 1, the remaining steps were the same as in Example 1, and the yield was 52%. Product spectrum analysis: 1 H NMR(400MHz,Chloroform-d)δ7.83–7.75(m,2H),7.65–7.56(m,1H),7.51–7.41(m,3H),7.15(d,J=8.4Hz,1H),6.73(d,J=3.6Hz,1H),6 .59(d,J=8.5Hz,1H),5.01–4.88(m,1H),4.40(s,2H),1.56–1.46(m,1H),1.46–1.36(m,1H),1.30–1.14(m,9H),0.86(t,J=6.9Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ168.3,167.7,145.6,134.3,133.2,131.8,130.1,129.6,1 28.6,126.8,123.2,119.4,109.0,105.6,72.6,66.9,35.8,31.6,25.0,22.6,20.014.1.

[0124]

[0125] As shown in Example 17 and Example 18, the present invention uses simple and readily available reaction substrates and relatively mild reaction conditions to efficiently achieve the transformation of quinoline skeletons in drugs and natural products into indole skeletons in one pot. This method can be used for the adjustment of molecular skeletons in the later stage, greatly simplifying the difficulty of synthetic routes and retrosynthetic analysis, and avoiding complex de novo synthesis.

Claims

1. An indole derivative obtained by converting quinoline nitrogen-oxide, characterized in that: Its chemical structure is shown in Formula 2: In formula 2, R1 is selected from one of alkyl, alkenyl, aryl, and aromatic heterocycle; R2 is selected from one of hydrogen, alkyl, ester, halogen, amine, nitro, and aryl; R3 is selected from one of hydrogen, ether, and aromatic ring; R4 is selected from one of hydrogen and alkyl.

2. A method for synthesizing an indole derivative obtained by converting quinoline nitrogen-oxide according to claim 1, characterized in that: The specific steps are as follows: adding quinoline nitrogen-oxide, dimethyl butynedioate and water as reaction raw materials into 1,2-dichloroethane solvent, performing a first heating and stirring reaction under the catalysis of diphenyl phosphate, and after the conversion of quinoline nitrogen-oxide of the compound of formula 1 is complete, TLC monitoring is performed, and then adding trichloroacetic acid and a dehydrating agent. After the molecular sieve, a second heating and stirring reaction was carried out, and the reaction was monitored by TLC until it was complete. After the solvent was evaporated, purification was performed to obtain the product; Wherein, the structural formula of the compound of formula 1, quinoline nitrogen-oxide, is R1 is selected from one of alkyl, alkenyl, aryl, and aromatic heterocycle; R2 is selected from one of hydrogen, alkyl, ester, halogen, amine, nitro, and aryl; R3 is selected from one of hydrogen, ether, and aromatic ring; R4 is selected from one of hydrogen and alkyl.

3. The method for synthesizing an indole derivative obtained by converting quinoline nitrogen-oxide according to claim 2, characterized in that: The molar ratio of the compound of formula 1, quinoline nitrogen-oxide, dimethyl butynedioate, water and diphenyl phosphate is 1:2:10:0.

1.

4. A method for synthesizing an indole derivative obtained by converting quinoline nitrogen-oxide according to claim 2 or 3, characterized in that: The molar ratio between the quinoline nitrogen-oxide compound of formula 1 and trichloroacetic acid is 1:

2.

5. A method for synthesizing an indole derivative obtained by converting quinoline nitrogen-oxide according to claim 2 or 3, characterized in that: The first heating and stirring reaction temperature is 50-90°C, and the reaction time is 12-72h; the second heating and stirring reaction temperature is 80-120°C, and the reaction time is 8-24h.

6. The method for synthesizing an indole derivative obtained by converting quinoline nitrogen-oxide according to claim 5, characterized in that: The first heating and stirring reaction temperature was 60°C, and the reaction time was 12h; the second heating and stirring reaction temperature was 120°C, and the reaction time was 12h.

7. A method for synthesizing an indole derivative obtained by converting quinoline nitrogen-oxide according to claim 2 or 3, characterized in that: The ratio of the volume of the 1,2-dichloroethane to the molar amount of the quinoline nitrogen-oxide compound of Formula 1 is 1 mL: 0.1 mmol.

8. A method for synthesizing an indole derivative obtained by converting quinoline nitrogen-oxide according to claim 2 or 3, characterized in that: The dehydrating agent The ratio of the mass of the molecular sieve to the molar amount of the compound quinoline nitrogen-oxide of formula 1 is 60 mg:0.1 mmol.

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