Preparation method of quaternary carbon indole compound

Abstract

The invention belongs to the field of chemical synthesis, and particularly relates to a method for catalytically synthesizing quaternary carbon indole compounds by DMAP. Specifically, in the presence of a catalyst DMAP, no transition metal catalyst or ligand is added, the 2-indolinone derivative shown in the formula C: # imgabs0 # is prepared from a compound shown in the formula A and a compound shown in the formula B, and the 2-indolinone derivative shown in the formula C: # imgabs0 # is obtained with good selectivity and yield, and R is phenyl or methyl.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and particularly relates to a method for preparing a quaternary carbon indole compound. Background Art

[0002] Functionalization of nitrogen-containing heterocyclic compounds has a wide range of applications in medicinal chemistry, agriculture, and materials science, and is an important research area in the field of organic chemistry. 2-Indolinone is an important class of nitrogen-containing heterocyclic compounds, which is widely present in many natural products and drug molecules. It has good biological activity and is a key structural motif of naturally occurring alkaloids, bioactive substances, dyes, and fluorescent probes. For example, Horsfiline is a 2-indolinone alkaloid derived from the traditional herbal medicine Phyllanthus macrophylla, native to South Asia, and has a certain analgesic effect; indigo carmine is one of the active ingredients of anti-leukemia drugs isolated from the traditional Chinese medicine Indigo Naturalis, and has a significant inhibitory effect on a variety of transplanted animal tumors.

[0003]

[0004] At present, the derivatization synthesis of 2-indolylone compounds is mainly carried out at the C-3 position of 2-indolylone. A large number of studies have shown that artificially synthesized 2-indolylone derivatives also have a wide range of biological activities, are effective nitrogen heterocyclic drug carriers, and are a class of organic small molecules with great potential for biomedical applications, such as antioxidant, antibacterial, anticonvulsant, antitumor, anti-HIV and neuroprotective activities. Since the 1990s, the drug application of 2-indolylone derivatives has made great progress. Among them, 2-indolylone drugs approved by the US FDA for the treatment of diseases include sunitinib, Nintedanib, ropinirole, Flindokalner, tenidap, XEN402, ziprasidone, Satavaptan, and simasanib.

[0005]

[0006] In 2009, Professor Stephen L. Buchwald's team reported a highly enantioselective Pd-catalyzed intermolecular coupling reaction of 3-substituted-2-indolinones and aromatic or vinyl bromides, in which two asymmetric sources of biaryl monophosphine ligands played a promoting role.

[0007]

[0008] In 2013, Professor Zhu Jieping's team developed a trichloroacetonitrile-mediated acid-catalyzed substitution reaction to convert 3-substituted-2-indolinones into 3,3'-disubstituted indolinones.

[0009]

[0010] In 2015, Professor Li Chaojun's team developed an efficient iron-catalyzed cross-dehydrogenation arylation reaction of 3-substituted-2-indolinones with active aromatics under air conditions to prepare a series of 3,3'-disubstituted indolinones in high yields.

[0011]

[0012] In 2016, Professor Liu Qiang's team developed a tetrabutylammonium fluoride (TBAF)-promoted self-oxidation reaction of the phenylmethylene difunctionalization of 2-indolinones with oxygen from air and ketones at room temperature, which provided a simple, economical, green and sustainable method for the synthesis of 3-hydroxy-2-indolinones.

[0013]

[0014] In 2024, Professor Qin Hui's team published a paper on the free radical coupling direct CH functionalization reaction of 2-hydroxyquinoxaline and 2-indolinone. The reaction conditions are simple, green, metal-free, ligand-free and base-free. It involves the construction of C(sp3)-C(sp2) bonds between methylene and methyne, providing a feasible green route for the synthesis of indolinone skeleton analogs with medium to excellent yields.

[0015]

[0016] Although there are many literatures on the CH functionalization reaction of 2-indolinone, most of them use expensive ligands and transition metal catalysts, poor selectivity or low yield. Summary of the invention

[0017] In order to achieve the technical purpose of the present invention, the technical solution of the present invention is:

[0018] The present invention first provides a compound of formula C, the structural formula of which is:

[0019]

[0020] Wherein, R is phenyl or methyl.

[0021] Another aspect of the present invention provides a method for preparing a compound of formula C, wherein a 2-indolinone derivative compound of formula C is prepared by reacting a compound of formula A with a compound of formula B in the presence of a catalyst.

[0022]

[0023] Wherein, R is phenyl or methyl.

[0024] The catalyst is DMAP, i.e., p-dimethylaminopyridine.

[0025] The molar ratio of the DMAP catalyst to the compound of formula A is most preferably 0.05:1.

[0026] The molar ratio of the compound of formula B to the compound of formula A is most preferably 3:1.

[0027] The reaction solvent may be ultra-dry toluene, acetonitrile, acetone or tetrahydrofuran, and ultra-dry toluene is most preferred.

[0028] The above reaction was carried out under vacuum and replaced with nitrogen, and the solvent was added under nitrogen purge.

[0029] The reaction temperature may be 20-130°C, such as room temperature to 130°C, most preferably 110°C.

[0030] The reaction time may be 2 to 24 hours, and most preferably 16 hours.

[0031] The preferred preparation method of the compound of formula C of the present invention is:

[0032]

[0033] The invention provides a green, economical and efficient method for synthesizing 2-indolinone derivatives, proposes to use cheap and commonly used DMAP as a catalyst, and to prepare a 2-indolinone derivative compound C from a compound of formula A and a compound of formula B with good selectivity and yield without adding any transition metal catalyst and ligand. The reaction functional group has good tolerance, simple operation and high stability, and has the potential for industrialization. DETAILED DESCRIPTION

[0034] In order to further understand the present invention, the preparation method of a quaternary carbon indole compound provided by the present invention is described in detail below in conjunction with the examples. It should be understood that these examples are only for further describing the features of the present invention in detail, and are not intended to limit the scope of the present invention or the scope of the claims of the present invention.

[0035] Embodiment 1:

[0036]

[0037] Add the raw material compound of formula A (97 mg, 0.5 mmol, 1.0 eq.), N-phenyl-2-indolinone (313.9 mg, 1.5 mmol, 3.0 eq.) and catalyst DMAP (3.0 mg, 0.025 mmol, 5% eq.) into a sealed tube; evacuate and replace with nitrogen, then add ultra-dry toluene (5 mL) under nitrogen purge; heat to 110°C in an oil bath and stir for 16 h; after monitoring the reaction with a spot plate (n-Hexane / EA=2 / 1), purify by column chromatography to obtain 80 mg of a yellow solid compound, and confirm the structure is correct by NMR, with a yield of 55% for the compound of formula C-1. 1 H NMR (400MHz, CDCl3) δ7.82–7.80(m,4H),7.64–7.26(m,13H),7.17(d,J=7.6Hz,1H),6.89(d ,J=7.6Hz,1H),3.67–3.61(m,2H),2.85–2.78(m,2H),2.54–2.43(m,4H),2.19–2.11(m,4H). 13 C NMR (100MHz, CDCl3) δ175.7,143.7,137.9,134.2,133.8,129.7,129.4,128.8,128.4,128. 3,127.5,126.7,124.7,123.5,109.8,54.3,53.5,34.0,26.1,25.1.HRMS(ESI)m / z:[M+Na] + Calculated for C 34 H 31 NNaO5S2 620.1536; Found620.1535.

[0038] Embodiment 2:

[0039]

[0040] Add the raw material compound of formula A (194 mg, 1.0 mmol, 1.0 eq.), N-methyl-2-indolinone (441.5 mg, 3 mmol, 3.0 eq.) and catalyst DMAP (6.1 mg, 0.05 mmol, 5% eq.) into a sealed tube; evacuate and replace with nitrogen, then add ultra-dry toluene (10 mL) under nitrogen purge; heat to 110° C. and stir in an oil bath for 16 h; after monitoring the reaction completion with a spot plate (n-Hexane / EA=2 / 1), purify by column chromatography to obtain 176 mg of a yellow solid compound, and confirm the structure is correct by NMR, with a yield of 66% for the compound of formula C-2. 1H NMR(400MHz,CDCl3)δ7.79–7.76(m,4H),7.62(t,J=7.6Hz,2H),7.53–7.49(m,4H),7.34(t,J=7.6Hz,1H),7.25(d,J=7.2Hz,1H),7.10(t,J=7.6Hz,1H),6.86(d,J=7.6Hz,1H),3.60–3.51(m,2H),3.15(s,3H),2.75–2.65(m,2H),2.41–2.25(m,4H),2.15–2.08(m,2H),2.03–1.96(m,2H). 13 C NMR(100MHz,CDCl3)δ176.2,143.9,137.9,133.8,129.3,128.8,128.4,127.6,124.6,123.0,108.4,54.4,53.5,33.8,26.3,26.1,25.1.HRMS(ESI)m / z:[M+Na] + Calculated for C 29 H 29 NNaO5S2 558.1379;Found558.1531.

Claims

1. A compound of formula C, characterized in that The structural formula is: Wherein, R is phenyl or methyl.

2. A method for preparing a compound of formula C, characterized in that: A 2-indolinone derivative compound of formula C is prepared by reacting a compound of formula A with a compound of formula B in the presence of a catalyst. Wherein, R is phenyl or methyl.

3. The preparation method according to claim 2, characterized in that: The reaction equation is:

4. The preparation method according to claim 2 or 3, characterized in that: The catalyst is p-dimethylaminopyridine.

5. The preparation method according to claim 2 or 3, characterized in that: The molar ratio of the catalyst to the compound of formula A is 0.05:

1.

6. The preparation method according to claim 2 or 3, characterized in that: The molar ratio of the compound of formula B to the compound of formula A is 3:

1.

7. The preparation method according to claim 2 or 3, characterized in that: The reaction is carried out in the presence of a solvent, and the reaction solvent is ultra-dry toluene, acetonitrile, acetone or tetrahydrofuran.

8. The preparation method according to claim 2, 3 or 7, characterized in that: The reaction was carried out under vacuum and replaced with nitrogen, and the solvent was added under nitrogen purge.

9. The preparation method according to claim 2, characterized in that: The reaction temperature is 20°C to 130°C.

10. The preparation method according to claim 2, characterized in that: The reaction time is 2 to 24 hours.

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