A process for the preparation of an indeno[1,2-b]indol-10(5H)-one compound

Abstract

The application discloses a preparation method of an indeno[1,2-b]indol-10(5H)-one compound, which comprises the following steps: adding a palladium catalyst, a ligand, a base, an additive, a carbonyl source, a 2-amino phenyl acetylene compound and an iodine element into an organic solvent, and reacting at 100 DEG C for 20 hours; and after the reaction is completed, post-treatment is performed to obtain the indeno[1,2-b]indol-10(5H)-one compound. The preparation method is simple in operation, low in cost of starting materials, high in reaction efficiency, good in substrate compatibility, efficient and fast in one-step synthesis of the indeno[1,2-b]indol-10(5H)-one compound, and convenient to operate, and the practicability of the method is widened.

Description

TECHNICAL FIELD

[0001] The application belongs to the field of organic synthesis, and particularly relates to a preparation method of an indeno[1,2-b]indol-10(5H)-one compound. BACKGROUND

[0002] Indeno[1,2-b]indol-10(5H)-one is an important structural skeleton, which is widely present in natural products and drug molecules. For example, JH-IX-179 is a highly efficient and selective type 1 ATP competitive FLT3 inhibitor for treating acute myeloid leukemia (ACS Med. Chem. Lett. 2016, 7, 476-481). Compounds A and B are effective topoisomerase II inhibitors, which exhibit good anticancer activity in kidney cancer cells (HEK-293) (Bioorg. Med. Chem. Lett. 2012, 22, 2474-2479; Bioorg. Med. Chem. Lett. 2013, 23, 934-938).

[0003]

[0004] The carbonylation reaction provides an important method for directly and efficiently synthesizing carbonyl compounds (Chem. Rev. 2019, 119, 2090-2127). However, there are few reports on the synthesis of indeno[1,2-b]indol-10(5H)-one compounds based on the carbonylation reaction, and the application is not extensive at present, but it has great application potential and needs to be further studied.

[0005] Based on this, a method for efficiently and rapidly synthesizing indeno[1,2-b]indol-10(5H)-one compounds by a palladium-catalyzed carbonylation reaction is developed, which takes 2-aminophenylacetylene compounds as starting materials. SUMMARY

[0006] The application provides a preparation method of an indeno[1,2-b]indol-10(5H)-one compound.

[0007] A preparation method of an indeno[1,2-b]indol-10(5H)-one compound comprises the following steps: adding a palladium catalyst, a ligand, a base, an additive, a carbonyl source, a 2-aminophenylacetylene compound and elemental iodine into an organic solvent to react at 90-110 DEG C for 16-24 hours, and after the reaction is completed, post-treatment is performed to obtain the indeno[1,2-b]indol-10(5H)-one compound.

[0008] The structure of the 2-aminophenylacetylene compound is shown in formula (II):

[0009]

[0010] The structure of the indeno[1,2-b]indol-10(5H)-one compound is shown in formula (I):

[0011]

[0012] R 1 is H, C1-C6 alkyl, C1-C6 alkoxy, halogen or trifluoromethyl;

[0013] R 2 is H, C1-C6 alkyl, C1-C6 alkoxy, phenoxy or halogen.

[0014] The specific reaction formula is as follows:

[0015]

[0016] In the reaction, the carbon-carbon triple bond of the 2-aminophenylacetylene compound can be first coordinated with the elemental iodine. Then, the amino group of the 2-aminophenylacetylene compound attacks the carbon-carbon triple bond intramolecularly to generate an alkenyl iodine compound. Next, palladium inserts the alkenyl iodine to form an alkenyl palladium intermediate, and intramolecular C-H activation generates a cyclic palladium intermediate. Carbon monoxide released by formic acid inserts the cyclic palladium intermediate to generate an acyl palladium intermediate. Finally, reductive elimination gives the indeno[1,2-b]indol-10(5H)-one compound.

[0017] In the present application, the optional post-treatment process includes filtration, silica gel mixing, and finally column chromatography purification to obtain the corresponding indeno[1,2-b]indol-10(5H)-one compound. The column chromatography purification is a common technical means in the art.

[0018] As a preferred, R 1 is H, methyl, methoxy, F, Cl, Br or trifluoromethyl; R 2 is H, methyl, ethyl, n-propyl, n-butyl, methoxy, phenoxy, F, Cl or Br.

[0019] As a preferred, the reaction time is 20 hours, and it is difficult to ensure the completion of the reaction in a shorter reaction time.

[0020] As a preferred, the organic solvent is toluene, in which various raw materials can be converted into products at a higher conversion rate.

[0021] The amount of the organic solvent can be used to better dissolve the raw materials, and the amount of the organic solvent used for 0.1 mmol of 2-aminophenylacetylene compound is about 1.0 mL.

[0022] As a preferred, the palladium catalyst is palladium acetate, which has a high reaction efficiency among many palladium catalysts.

[0023] As a preferred, the ligand is tricyclohexylphosphine.

[0024] As a preferred, the base is cesium carbonate.

[0025] As a preferred, the additive is pivalic acid.

[0026] As a preferred, the carbonyl source is formic acid, and the molar ratio of the formic acid to the 2-aminophenylacetylene compound is 8-10:1.

[0027] As a further preferred, the indeno[1,2-b]indol-10(5H)-one compound is one of the compounds shown in formula (I-1) to formula (I-5):

[0028]

[0029]

[0030] In the above preparation method, the palladium acetate, tricyclohexylphosphine and formic acid are generally commercially available products, which can be conveniently obtained from the market, and the 2-aminophenylacetylene compound can be obtained by coupling the corresponding 2-iodoaniline and terminal alkyne, and then sulfonated quickly.

[0031] Compared with the prior art, the preparation method has the advantages of easy operation, simple post-treatment, low cost of starting materials, wide functional group tolerance of substrates, high reaction efficiency, one-step efficient and rapid synthesis of indeno[1,2-b]indol-10(5H)-one compound, and strong practicability. DETAILED DESCRIPTION

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

[0033] According to the raw material ratio of Table 1, 1.0 mL of palladium acetate, tricyclohexylphosphine, carbonyl source, cesium carbonate, pivalic acid, elemental iodine, 2-aminophenylacetylene compound (II) and organic solvent were added into a 15 mL Schlenk tube, and stirred uniformly, and then reacted at 100°C for 20 hours, as shown in Table 1. After the reaction was completed, filtration, silica gel sample mixing, and column chromatography purification were performed to obtain the corresponding indeno[1,2-b]indol-10(5H)-one compound (I), and the reaction process is shown in the following formula:

[0034]

[0035] Table 1: Raw material addition amount of examples 1-15

[0036]

[0037]

[0038] Table 2

[0039]

[0040] In Table 1 and Table 2, T is a reaction temperature, t is a reaction time, Me is a methyl group, Et is an ethyl group, OMe is a methoxy group, n Pr is a n-propyl group, n Bu is a n-butyl group.

[0041] The structural confirmation data of the compounds prepared in Examples 1 to 5 are as follows:

[0042] The nuclear magnetic resonance (1H NMR, 13C NMR) and high resolution (HRMS) detection data of the indeno[1,2-b]indol-10(5H)-one compound (I-1) prepared from Example 1 are as follows: 1 H NMR, 13 C NMR) and high resolution (HRMS) detection data of the indeno[1,2-b]indol-10(5H)-one compound (I-1) prepared from Example 1 are as follows:

[0043]

[0044] 1 H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 7.5 Hz, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.55 (s, 1H), 7.47 (d, J = 7.1 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.28 - 7.25 (m, 1H), 7.23 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 8.6 Hz, 1H), 2.39 (s, 3H), 2.34 (s, 3H).

[0045] 13 C NMR (101 MHz, CDCl3) δ 186.6, 156.9, 146.0, 139.4, 138.5, 135.7, 135.1, 134.9, 133.7, 130.4, 129.9, 127.1, 127.0, 123.5, 123.5, 122.8, 121.8, 120.7, 114.8, 21.8, 21.3.

[0046] HRMS (ESI-TOF) Calcd. For C 23 H 17 NO3S + [M+H] + : 388.1002; found: 388.1007.

[0047] The nuclear magnetic resonance (NMR) of the indeno[1,2-b]indol-10(5H)-one compound (I-2) prepared in Example 2 1 HNMR, 13 C NMR) and high resolution (HRMS) detection data are:

[0048]

[0049] 1 H NMR (400MHz, CDCl3) δ8.11(d,J=7.5Hz,1H),7.98(d,J=9.2Hz,1H),7.75(d,J=8.4Hz,2H),7.47(d,J=7.1Hz,1H),7.40(td,J=7.7 ,1.2Hz,1H),7.28–7.25(m,1H),7.24–7.21(m,2H),7.17(d,J=2.6Hz,1H),6.89(dd,J=9.2,2.6Hz,1H),3.82(s,3H),2.34(s,3H).

[0050] 13 C NMR (101MHz, CDCl3) δ186.5,158.1,157.0,146.0,138.4,135.5,134.9,134.8,133.6 ,130.3,129.8,126.9,124.3,123.4,122.7,121.8,116.1,115.1,102.4,55.7,21.7.

[0051] HRMS (ESI-TOF) Calcd.for C 23 H 17 NO4S + [M+H] + :404.0951;found:404.0956.

[0052] The nuclear magnetic resonance (NMR) of the indeno[1,2-b]indol-10(5H)-one compound (I-3) prepared in Example 3 was 1 HNMR, 13 C NMR) and high resolution (HRMS) detection data are:

[0053]

[0054] 1H NMR (400 MHz, CDC13) δ 8.10 (d, J = 7.5 Hz, 1H), 7.93 (s, 1H), 7.79 (d, J = 7.3 Hz, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.1 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.27 - 7.22 (m, 3H), 7.13 (d, J = 8.0 Hz, 1H), 2.49 (s, 3H), 2.35 (s, 3H).

[0055] 13 C NMR (101 MHz, CDC13) δ 186.6, 156.5, 146.0, 141.6, 138.4, 136.1, 135.3, 135.0, 133.7, 130.4, 129.7, 127.1, 127.0, 123.4, 122.7, 122.1, 121.0, 120.3, 115.3, 22.3, 21.8.

[0056] HRMS (ESI-TOF) Calcd. For C 23 H 17 NO3S + [M+H] + : 388.1002; found: 388.1007.

[0057] The H NMR, C NMR and high resolution (HRMS) data of the indeno[l,2-b]indol- 10(5H)-one compound (1-4) prepared from Example 4 are as follows: 1 H NMR, 13 C NMR) and high resolution (HRMS) data of the indeno[l,2-b]indol- 10(5H)-one compound (1-4) prepared from Example 4 are as follows:

[0058]

[0059] 1 H NMR (400 MHz, CDC13) δ 8.13 - 8.08 (m, 1H), 8.02 (d, J = 7.7 Hz, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.76 - 7.70 (m, 1H), 7.36 (s, 1H), 7.31 - 7.27 (m, 2H), 7.24 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 7.9 Hz, 1H), 2.66 (q, J = 7.6 Hz, 2H), 2.34 (s, 3H), 1.27 (t, J = 6.0 Hz, 3H).

[0060] 13C NMR (101 MHz, CDC13) δ 186.8, 157.5, 146.9, 146.1, 140.9, 138.9, 134.9, 132.4, 132.3, 130.4, 127.0, 125.6, 125.4, 123.7, 123.5, 123.0, 121.6, 120.6, 115.1, 28.9, 21.8, 15.1.

[0061] HRMS (ESI-TOF) Calcd. For C 24 H 19 NO3S + [M+H] + : 402.1158; found: 402.1161.

[0062] The nuclear magnetic resonance (1H NMR, 13C NMR) and high resolution (HRMS) detection data of the indeno[l,2-b]indol-10(5H)-one compound (1-5) prepared from Example 5 are as follows: 1 HNMR、 13 C NMR) and high resolution (HRMS) detection data of the indeno[l,2-b]indol-10(5H)-one compound (1-5) prepared from Example 5 are as follows:

[0063]

[0064] 1 H NMR (400 MHz, CDC13) δ 8.12 (dd, J = 6.9, 1.9 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.75 (dd, J = 6.5, 2.4 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 8.1, 2.1 Hz, 1H), 7.33 (ddd, J = 6.6, 5.8, 3.5 Hz, 2H), 7.29 - 7.26 (m, 2H), 2.37 (s, 3H).

[0065] 13 C NMR (101 MHz, CDC13) δ 184.8, 156.2, 146.3, 141.1, 140.1, 136.9, 134.7, 133.1, 132.8, 130.5, 127.0, 126.0, 1259, 124.2, 123.8, 123.2, 122.0, 120.8, 115.2, 21.8.

[0066] HRMS (ESI-TOF) Calcd. For C 22 H 14 ClNO3S + [M+H] +:408.0456; found: 408.0463.

Claims

1. A method for preparing an indeno[1,2-b]indol-10(5H)-one compound, characterized by, The method comprises the following steps: adding a palladium catalyst, a ligand, a base, an additive, a carbonyl source, a 2-amino phenyl acetylene compound and iodine into an organic solvent, and reacting at 90-110 DEG C for 16-24 hours; and after the reaction is completed, post-treatment is performed to obtain the indeno[1,2-b]indol-10(5H)-one compound. The 2-amino phenyl acetylene compound has the structure shown in formula (II). The indeno[1,2-b]indol-10(5H)-one compound has the structure shown in formula (I). R 1 is H, C1-C6alkyl, C1-C6alkoxy, halogen or trifluoromethyl; R 2 R is H, C1-C6alkyl, C1-C6alkoxy, phenoxy, or halogen; The organic solvent is toluene. The palladium catalyst is palladium acetate. The ligand is tricyclohexylphosphine. The base is cesium carbonate. The additive is pivalic acid. The carbonyl source is formic acid.

2. The method of producing an indeno[l,2-b]indol-10(5H)-one compound according to claim 1, characterized by, R 1 is H, methyl, methoxy, F, CI, Br or trifluoromethyl; R 2 is H, methyl, ethyl, n-propyl, n-butyl, methoxy, phenoxy, F, CI or Br.

3. The method of producing an indeno[l,2-b]indol-10(5H)-one compound according to claim 1, characterized by, The molar ratio of the 2-amino phenyl acetylene compound, the palladium catalyst, the ligand, the base, the additive and the iodine is 1:0.1-0.2:0.2-0.4:5-6:2-3:1.7-2.

0.

4. The method of producing an indeno[l,2-b]indol-10(5H)-one compound according to claim 1, characterized by, The molar ratio of the formic acid and the 2-amino phenyl acetylene compound is 8-10:

1.

5. The method of producing an indeno[l,2-b]indol-10(5H)-one compound according to claim 1, characterized by, The indeno[1,2-b]indol-10(5H)-one compound is one of the compounds shown in formula (I-1)-formula (I-5).

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