Indole derivatives obtained by converting quinoline nitrogen-oxides and a method for synthesizing the same

Abstract

The application relates to an indole derivative obtained by converting quinoline nitrogen-oxide and a synthesis method of the indole derivative, the chemical structural formula of the derivative is shown as formula 2; the synthesis method is as follows: quinoline nitrogen-oxide, dimethyl acetylene dicarboxylate and water are used as reaction raw materials and are added into 1,2-dichloroethane solvent, a first heating stirring reaction is carried out under the catalysis of diphenyl phosphate, after TLC monitoring shows that the conversion of quinoline nitrogen-oxide of formula 1 compound is complete, trichloroacetic acid and molecular sieve dehydrating agent are added, a second heating stirring reaction is carried out, the reaction is monitored until complete through TLC, the solvent is evaporated, and then purification is carried out to obtain the indole derivative. The method has the advantages of high atom economy, mild reaction condition, green, low cost, high conversion rate and the like, meanwhile, the method is a carbon recombination strategy for directly editing a molecular skeleton, can provide a new idea for late-stage design and optimization of a drug molecule, and can accelerate the drug discovery and development process, and has good theoretical value and application prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic chemical synthesis, and particularly relates to a kind of indole derivative obtained by converting quinoline nitrogen-oxide and a synthesis method thereof. BACKGROUND

[0002] N-heterocyclic skeleton is widely present in various natural products, agrochemicals and drug molecules. In the past few decades, various 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 post-functionalization, but mainly still editing the peripheral C-H bonds of the molecular skeleton, while the methods for directly editing the molecular skeleton are relatively few.

[0003] The methods for directly editing the molecular skeleton in the literature at present include:

[0004] Mark D. Levin et al. of the University of Chicago, USA reported N-tert-pentylcarbonyloxy-N-alkoxy amide reagent, which uses an anomeric amide reagent to promote the intermolecular activation of aliphatic secondary amine and produce intramolecular C-C bond coupling product, realizing the deletion reaction of nitrogen atom of secondary amine (S. H. Kennedy, B. D. Dherange, K. J. Berger, M. D. Levin, Nature, 2021, 593, 223-227.), the reaction formula is as follows:

[0005]

[0006] H.-J. Lu, Angew. Chem. Int. Ed., 2021, 60, 20678-20683.), the reaction formula is as follows:

[0007]

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

[0009]

[0010] Professor Mark D. Levin's research group used photochemical transformation to carry out "carbon deletion" strategy on the nitrogen heteroaromatic ring, and converted quinoline skeleton into indole skeleton (J. Woo1, A.H. Christian, S.A. Burgess, Y. Jiang, U.F. Mansoor, M.D. Levin, Science, 2022, 376, 527-532.). The reaction formula is as follows:

[0011]

[0012] It can be seen that the research on "molecular editing" for directly modifying the molecular core skeleton is still very limited at present, and it lacks universality. The main performance is that the structure range of the product is still narrow, and most of the methods need to use carbene and other active precursors, and the reaction conditions often involve metal or need light, which is not environmentally friendly. Therefore, it has very important application value and research significance to develop a practical and universal molecular editing method. SUMMARY

[0013] The purpose of the present application is to provide an indole derivative obtained by converting quinoline nitrogen-oxide and a synthesis method thereof. The method realizes the conversion of quinoline skeleton into indole skeleton through simple and easily available reaction substrates, relatively mild reaction conditions and one-pot high efficiency.

[0014] To achieve the above purpose, the technical scheme adopted by the present application is: an indole derivative obtained by converting quinoline nitrogen-oxide, the chemical structural formula of which is shown as 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; and R4 is selected from one of hydrogen and alkyl.

[0017] To achieve the purpose of the present application, the present application also provides a synthesis method of the above-mentioned indole derivative obtained by converting quinoline nitrogen-oxide, and the specific steps are as follows: taking quinoline nitrogen-oxide of formula 1 compound, dimethyl acetylenedicarboxylate and water as reaction raw materials, adding them into 1,2-dichloroethane solvent, and carrying out first heating and stirring reaction under the catalysis of diphenyl phosphate; after TLC monitoring that the conversion of quinoline nitrogen-oxide of formula 1 compound is complete, adding trichloroacetic acid and dehydrating agent molecular sieve, and carrying out second heating and stirring reaction, and then purifying after evaporating the solvent to obtain the product.

[0018] In the formula, the structural formula of the quinoline nitrogen-oxide of formula 1 compound is as follows: 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; and R4 is selected from one of hydrogen and alkyl.

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

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

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

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

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

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

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

[0026]

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

[0028] (1) The present application induces the cyclization rearrangement reaction of quinoline nitrogen-oxide compound and dimethyl acetylene dicarboxylate through diphenyl phosphate, and then removes the side chain through trichloroacetic acid to directly convert the quinoline ring into the indole ring; the method realizes the conversion from quinoline skeleton to indole skeleton through simple and easily obtained reaction substrates, relatively mild reaction conditions, and one-pot high efficiency, and avoids complex de novo synthesis.

[0029] (2) The conversion is realized through 390nm LED light irradiation in the prior art, and flow technology is needed when realizing kilogram-scale reaction; the present application realizes kilogram-scale reaction in a simple thermodynamic manner, and is more practical.

[0030] (3) The present application avoids the use of transition metals, adopts organic catalysis mode, reduces the cost, and the reaction process will not cause heavy metal residues.

[0031] (4) The product of the present application has a wide structure range, the conversion of quinoline nitrogen oxide compound to indole ring is completed by one-pot synthesis through a cascade reaction, the reaction is efficient and fast; the reaction condition is mild, not sensitive to air or water, simple to operate, has the advantages of high atom economy, mild reaction condition, green, low cost, high conversion rate, etc.; at the same time, the method is a carbon reorganization strategy for directly editing the molecular skeleton, which can provide new ideas for the late design and optimization of drug molecules. The present application can accelerate the process of drug discovery and development, and has good theoretical value and application prospect. DETAILED DESCRIPTION

[0032] The present application will be further described in detail below in combination with examples.

[0033] In the following examples, unless otherwise specified, quinoline nitrogen oxide compounds, dimethyl butyne acid and other reagents can be purchased or obtained according to the methods reported in the literature; the experimental methods are generally carried out according to the conventional conditions or the conditions recommended by the manufacturers.

[0034] The quinoline nitrogen oxide compound 1 used in the following examples was synthesized according to the method of the reference (Woo, J., Christian, A. H., Burgess, S. A., Jiang, Y., Mansoor, U. F., Levin, M. D. Science, 2022, 376, 527-532.; Martinez, R., Ramon, D. J., Yus, M. J. Org. Chem. 2008, 73, 9778-9780. Dhiman, A. K., Gupta, S. S., Sharma, R., Kumar, R., Sharma, U. J. Org. Chem. 2019, 84, 12871-12880), and the characterization results of the compounds 1l, 1n, 1o, 1q, 1r which have not been reported are as follows:

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

[0036]

[0037] M.p = 205-207 °C. 1 H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.44 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 9.1 Hz, 1H), 8.03-7.97 (m, 2H), 7.85-7.75 (m, 2H), 7.71 (d, J = 9.1 Hz, 1H), 7.57-7.47 (m, 3H), 1.51 (s, 9H).13 C NMR (101 MHz, DMSO-d6) δ 153.7, 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-acetyloxybenzoyl)oxy)-2-(4-methoxyphenyl)quinoline-1-oxide (In)

[0039]

[0040] 1 H NMR (400 MHz, Chloroform-d) δ 8.92 (d, J = 9.5 Hz, 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 (101 MHz, Chloroform-d) δ 169.9, 162.7, 160.8, 151.5, 150.0, 144.8, 140.6, 135.2, 132.4, 131.3, 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 (lo)

[0042]

[0043] M.p = 128 - 129 °C. 1 H NMR (400 MHz, Chloroform-d) δ 8.72 (d, J = 8.7 Hz, 1H), 7.82 (d, J = 8.1 Hz, 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 = 7.3 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 147.4, 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] M.p = 138-140 °C. 1 H NMR (400 MHz, Chloroform-d) δ 7.98 - 7.89 (m, 2H), 7.73 (d, J = 8.9 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.30 (d, J = 7.4 Hz, 1H), 7.04 - 6.95 (m, 3H), 3.99 (s, 3H), 3.87 (s, 3H), 2.57 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 160.3, 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-(heptan-2-yloxy)-2-oxoethoxy)-2-phenylquinoline-1-oxide (1r)

[0048]

[0049] 1 H NMR (400 MHz, Chloroform-d) δ 7.98 (d, J = 9.0 Hz, 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 = 1.6 Hz, 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 (101 MHz, Chloroform-d) δ 168.9, 151.4, 147.7, 137.2, 133.3, 130.4, 129.8, 129.7, 128.5, 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] The quinoline N-oxide compound 1a (0.1 mmol), diphenyl phosphate (0.01 mmol), dimethyl butyne diacid (0.2 mmol), H20 (1.0 mmol) were added into a dry reaction tube in a ratio of 1:0.1:2:10, 1,2-dichloroethane (1.0 mL) was added into the mixture, the reaction system was stirred at 60 °C for 12 h, after TLC monitoring that the quinoline N-oxide compound 1a was completely converted, molecular sieves (60 mg) and trichloroacetic acid (0.2 mmol) were added, the reaction system was stirred at 120 °C for 12 h, after TLC monitoring that the reaction was completed, the solvent was evaporated to obtain the crude product, which was then purified by column chromatography (petroleum ether / ethyl acetate, volume ratio 10 / 1) to obtain the target product (yield 80%). The quinoline N-oxide compound 1a (0.1 mmol), diphenyl phosphate (0.01 mmol), dimethyl butyne diacid (0.2 mmol), H20 (1.0 mmol) were added into a dry reaction tube in a ratio of 1:0.1:2:10, 1,2-dichloroethane (1.0 mL) was added into the mixture, the reaction system was stirred at 60 °C for 12 h, after TLC monitoring that the quinoline N-oxide compound 1a was completely converted, molecular sieves (60 mg) and trichloroacetic acid (0.2 mmol) were added, the reaction system was stirred at 120 °C for 12 h, after TLC monitoring that the reaction was completed, the solvent was evaporated to obtain the crude product, which was then purified by column chromatography (petroleum ether / ethyl acetate, volume ratio 10 / 1) to obtain the target product (yield 80%).

[0055] Product spectral analysis: 1 H NMR (400 MHz, Chloroform-d) δ 8.43 (d, J = 8.2 Hz, 1H), 7.75 (d, J = 7.7 Hz, 2H), 7.66 - 7.59 (m, 2H), 7.54 (t, J = 7.5 Hz, 2H), 7.40 (t, J = 7.7 Hz, 1H), 7.36 - 7.28 (m, 2H), 6.63 (d, J = 3.7 Hz, 1H). 13 C NMR (101 MHz, Chloroform-d) δ 168.9, 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] The procedure was the same as in Example 1 except that 1b was used instead of 1a in structural formula 1a. The yield was 56%. The product was analyzed spectroscopically: 1 H NMR (400 MHz, Chloroform-d) δ 8.45 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.43 (d, J = 2.9 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 6.65 (d, J = 3.7 Hz, 1H), 2.65 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 168.8, 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] The procedure was the same as in Example 1 except that 1c was used instead of 1a in structural formula 1a. The yield was 89%. The product was analyzed spectroscopically: 1 H NMR (400 MHz, Chloroform-d) δ 8.41 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 7.9 Hz, 2H), 7.62 (d, J = 7.7 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.36 - 7.29 (m, 4H), 6.62 (d, J = 3.7 Hz, 1H), 2.47 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 168.9, 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] The procedure was the same as in Example 1 except that 1d was used instead of 1a in structural formula 1a. The yield was 84%. The product was analyzed spectroscopically: 1 H NMR (400 MHz, Chloroform-d) δ 8.39 (d, J = 8.2 Hz, 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 = 3.8 Hz, 1H), 3.83 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 168.6, 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 (4-methyl-1H-indol-1-yl)(phenyl)methanone (2f) is as follows:

[0070]

[0071] The procedure was the same as in Example 1 except that 1e was used instead of 1a in structural formula 1a. The yield was 72%. The product was analyzed spectroscopically: 1 H NMR (400 MHz, Chloroform-d) δ 9.00 (s, 1H), 8.04 (d, J = 9.9 Hz, 2H), 8.00 - 7.93 (m, 1H), 7.83 - 7.73 (m, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.52 - 7.43 (m, 3H), 6.73 (d, J = 3.9 Hz, 1H). 13 C NMR (101 MHz, Chloroform-d) δ 168.6, 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] The procedure was the same as in Example 1 except that 1f was used instead of 1a in Example 1. The yield was 73%. The product was analyzed spectroscopically: 1 H NMR (400 MHz, Chloroform-d) δ 8.21 (d, J = 8.3 Hz, 1H), 7.75 - 7.66 (m, 2H), 7.57 (t, J = 7.3 Hz, 1H), 7.49 (t, J = 7.5 Hz, 2H), 7.29 - 7.20 (m, 2H), 7.09 (d, J = 7.3 Hz, 1H), 6.62 (d, J = 3.8 Hz, 1H), 2.52 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 168.9, 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 for furan-2-yl(lH-indol-l-yl)methanone (2h) is as follows:

[0078]

[0079] The procedure was the same as in Example 1 except that 1g was used instead of 1a in Example 1. The yield was 79%. The product was analyzed spectroscopically: 1 H NMR (400 MHz, Chloroform-d) δ 8.47 (d, J = 8.2 Hz, 1H), 8.26 (s, 1H), 8.04 - 7.93 (m, 3H), 7.82 (d, J = 8.5 Hz, 1H), 7.71 - 7.57 (m, 3H), 7.47 - 7.31 (m, 3H), 6.65 (d, J = 3.7 Hz, 1H). 13 C NMR (101 MHz, Chloroform-d) δ 168.9, 136.2, 134.8, 132.4, 131.8, 130.9, 130.3, 129.1, 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 for furan-2-yl(lH-indol-l-yl)methanone (2h) is as follows:

[0082]

[0083] Except that 1h was used instead of 1a in the structural formula 1 of Example 1, the first step temperature was 70 degrees, and the remaining operation steps were the same as Example 1, the yield was 72%. The product was analyzed by spectrum: 1 H NMR (400 MHz, Chloroform-d) δ 8.50 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 3.8 Hz, 1H), 7.70 (s, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.42 (d, J = 3.5 Hz, 1H), 7.41 - 7.35 (m, 1H), 7.35 - 7.28 (m, 1H), 6.70 (d, J = 3.8 Hz, 1H), 6.68 - 6.63 (m, 1H). 13 C NMR (101 MHz, Chloroform-d) δ 156.9, 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 synthesis route of (1H-indol-1-yl)(thiophen-2-yl)methanone (2i) is as follows:

[0086]

[0087] Except that 1i was used instead of 1a in the structural formula 1 of Example 1, the first step temperature was 90 degrees, and the remaining operation steps were the same as Example 1, the yield was 51%. The product was analyzed by spectrum: 1 H NMR (400 MHz, Chloroform-d) δ 8.41 (d, J = 8.2 Hz, 1H), 7.76 - 7.65 (m, 3H), 7.62 (d, J = 7.8 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.20 (t, J = 4.3 Hz, 1H), 6.68 (d, J = 3.7 Hz, 1H). 13 C NMR (101 MHz, Chloroform-d) δ 161.8, 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 synthesis route of (E)-1-(1H-indol-1-yl)-3-phenylprop-2-en-1-one (2j) is as follows:

[0090]

[0091] The procedure was the same as in Example 1 except that 1j was used instead of 1a in Example 1. The yield was 66%. The product was analyzed spectroscopically: 1 H NMR (400 MHz, Chloroform-d) δ 8.58 (d, J = 8.3 Hz, 1H), 8.03 (d, J = 15.5 Hz, 1H), 7.72 - 7.65 (m, 3H), 7.63 (d, J = 7.8 Hz, 1H), 7.52 - 7.45 (m, 3H), 7.42 (t, J = 7.8 Hz, 1H), 7.37 - 7.27 (m, 2H), 6.73 (d, J = 3.7 Hz, 1H). 13 C NMR (101 MHz, Chloroform-d) δ 164.4, 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] Example 11

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

[0094]

[0095] The procedure was the same as in Example 1 except that 1k was used instead of 1a in Example 1. The yield was 56%. The product was analyzed spectroscopically: 1 H NMR (400 MHz, Chloroform-d) δ 8.41 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 3.8 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.35 - 7.28 (m, 1H), 7.26 - 7.21 (m, 1H), 6.65 (d, J = 3.7 Hz, 1H), 2.30 - 2.22 (m, 1H), 1.33 - 1.26 (m, 2H), 1.11 - 1.02 (m, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 172.4, 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 (l-benzoyl-lH-indol-4-yl)carbamate (2l) is as follows:

[0098]

[0099] Except that 1l is used instead of 1a in structural formula 1 of Example 1, the remaining operation steps are the same as Example 1, and the yield is 54%. The product is analyzed by spectrum: 1 H NMR (400 MHz, Chloroform-d) δ 8.06-7.96 (m, 2H), 7.93 (d, J = 7.2 Hz, 2H), 7.87 (d, J = 7.5 Hz, 1H), 7.64-7.59 (m, 1H), 7.59-7.55 (m, 1H), 7.55-7.47 (m, 2H), 7.34 (t, J = 8.1 Hz, 1H), 6.57 (d, J = 3.8 Hz, 1H), 1.68 (s, 9H). 13 C NMR (101 MHz, Chloroform-d) δ 165.9, 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] Example 13

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

[0102]

[0103] Except that 1m is used instead of 1a in structural formula 1 of Example 1, the temperature of the first step is 80 degrees, and the remaining operation steps are the same as Example 1, and the yield is 53%. The product is analyzed by spectrum: 1 H NMR (400 MHz, Chloroform-d) δ 8.79 (d, J = 8.2 Hz, 1H), 8.28 (d, J = 8.1 Hz, 1H), 7.82-7.74 (m, 2H), 7.73-7.65 (m, 1H), 7.62-7.54 (m, 3H), 7.51 (t, J = 8.2 Hz, 1H), 7.42 (d, J = 3.7 Hz, 1H). 13 C NMR (101 MHz, Chloroform-d) δ 168.8, 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] Example 14

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

[0106]

[0107] The procedure was the same as in Example 1 except that 1n was used instead of 1a in Example 1. The yield was 68%. The product was analyzed spectroscopically: 1 H NMR (400 MHz, Chloroform-d) δ 8.39 (d, J = 8.9 Hz, 1H), 8.30 - 8.26 (m, 1H), 7.78 - 7.71 (m, 2H), 7.65 (td, J = 7.8, 1.7 Hz, 1H), 7.44 - 7.38 (m, 3H), 7.21 - 7.15 (m, 2H), 7.06 - 6.99 (m, 2H), 6.62 (d, J = 3.7 Hz, 1H), 3.91 (s, 3H), 2.32 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 169.9, 168.2, 163.6, 163.0, 151.3, 146.9, 134.7, 134.1, 132.4, 131.9, 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] Example 15

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

[0110]

[0111] The procedure was the same as in Example 1 except that 1o was used instead of 1a in Example 1. The yield was 53%. The product was analyzed spectroscopically: 1 H NMR (400 MHz, Chloroform-d) δ 7.79 - 7.69 (m, 2H), 7.68 - 7.60 (m, 1H), 7.55 - 7.49 (m, 3H), 7.13 (t, J = 7.4 Hz, 1H), 6.99 (t, J = 7.7 Hz, 1H), 6.86 (d, J = 8.3 Hz, 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 = 7.3 Hz, 3H). 13CNMR (101 MHz, Chloroform-d) δ 170.1, 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 synthesis route for (5-chloro-lH-indol-l-yl)(phenyl)methanone (2p) is as follows:

[0114]

[0115] The procedure was the same as in Example 1 except that 1p was used instead of structural formula la in Example 1. The yield was 60%. The product was analyzed spectroscopically: 1 H NMR (400 MHz, Chloroform-d) δ 8.35 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 7.60 - 7.50 (m, 3H), 7.40 - 7.30 (m, 2H), 6.56 (d, J = 3.7 Hz, 1H). 13 CNMR (101 MHz, Chloroform-d) δ 168.7, 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] Example 17

[0117] The synthesis route for (7-methoxy-4-methyl-lH-indol-l-yl)(4-methoxyphenyl)methanone (2q) is as follows:

[0118]

[0119] The procedure was the same as in Example 1 except that 1q was used instead of structural formula la in Example 1. The yield was 53%. The product was analyzed spectroscopically: 1 H NMR (400 MHz, Chloroform-d) δ 7.81 - 7.73 (m, 2H), 7.40 (d, J = 3.6 Hz, 1H), 7.00 - 6.97 (m, 1H), 6.96 - 6.91 (m, 2H), 6.66 (d, J = 8.0 Hz, 1H), 6.63 (d, J = 3.6 Hz, 1H), 3.88 (s, 3H), 3.64 (s, 3H), 2.50 (s, 3H). 13C NMR (101 MHz, Acetone-d6) δ 168.1, 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] Example 18

[0121] 2-(1 -benzoyl-4-chloro-1 H-indol-7-yl)oxy)heptan-2-yl acetate (2r)

[0122]

[0123] The remaining steps were the same as in Example 1 except that 1r was used instead of structural formula 1a in Example 1. The yield was 52%. The product was analyzed by spectroscopy: 1 H NMR (400 MHz, Chloroform-d) δ 7.83 - 7.75 (m, 2H), 7.65 - 7.56 (m, 1H), 7.51 - 7.41 (m, 3H), 7.15 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 3.6 Hz, 1H), 6.59 (d, J = 8.5 Hz, 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 = 6.9 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 168.3, 167.7, 145.6, 134.3, 133.2, 131.8, 130.1, 129.6, 128.6, 126.8, 123.2, 119.4, 109.0, 105.6, 72.6, 66.9, 35.8, 31.6, 25.0, 22.6, 20.0 14.1.

[0124]

[0125] As shown in Examples 17 and 18, the present application realizes the conversion of quinoline skeleton to indole skeleton in drugs and natural products by simple and easily available reaction substrates, relatively mild reaction conditions, and one-pot high efficiency. The method can be used for the adjustment of the late-stage molecular skeleton, greatly simplifying the synthetic route and the difficulty of retrosynthetic analysis, and avoiding complex de novo synthesis.

Claims

1. A method for the synthesis of indole derivatives obtained by conversion of quinoline N-oxides, characterized in that, The specific steps are: taking the compound quinoline nitrogen-oxide of formula 1, dimethyl acetylene dicarboxylate and water as the reaction raw materials, adding them into 1,2-dichloroethane solvent, and performing first heating and stirring reaction under the catalysis of diphenyl phosphate; after TLC monitoring shows that the conversion of the compound quinoline nitrogen-oxide of formula 1 is complete, adding trichloroacetic acid and dehydrating agent 5 Å molecular sieve, and then performing second heating and stirring reaction; after TLC monitoring shows that the reaction is complete, evaporating the solvent, and then purifying 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, heteroaryl; R2 is selected from one of hydrogen, alkyl, halogen, nitro, aryl; R3 is selected from one of hydrogen, aryl; R4 is selected from one of hydrogen, alkyl; or the structural formula of the compound of Formula 1 quinoline nitrogen-oxide is one of , , .

2. The method of claim 1, wherein the method is characterized by the steps of: a) reacting a quinoline N-oxide with a compound of formula (II) to form a compound of formula (III); and b) reacting the compound of formula (III) with a compound of formula (IV) to form the indole derivative of formula (I). The molar ratio between the compound quinoline nitrogen-oxide of formula 1, dimethyl acetylene dicarboxylate, water and diphenyl phosphate is 1:2:10:0.

1.

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

2.

4. The method for synthesizing indole derivatives by converting quinoline N-oxide according to claim 1 or 2, characterized in that, The first heating and stirring reaction temperature is 50-90 ℃, and the reaction time is 12-72 h; the second heating and stirring reaction temperature is 80-120 ℃, and the reaction time is 8-24 h.

5. The method of claim 4, wherein the method is characterized by the steps of: a) reacting a quinoline N-oxide with a compound of formula (II) to form a compound of formula (III); and b) reacting the compound of formula (III) with a compound of formula (IV) to form a compound of formula (I). The first heating and stirring reaction temperature is 60 ℃, and the reaction time is 12 h; the second heating and stirring reaction temperature is 120 ℃, and the reaction time is 12 h.

6. The method for synthesizing indole derivatives by converting quinoline N-oxide according to claim 1 or 2, characterized in that, The ratio between the volume of 1,2-dichloroethane and the molar amount of the compound quinoline nitrogen-oxide of formula 1 is 1 mL:0.1 mmol.

7. The method for synthesizing indole derivatives by converting quinoline N-oxide according to claim 1 or 2, characterized in that, The ratio between the mass of the dehydrating agent 5 Å molecular sieve and the molar amount of the compound quinoline nitrogen-oxide of formula 1 is 60 mg: 0.1 mmol.

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