Synthesis method of diaryl quaternary carbon pyrazolone compound with chiral center

Abstract

The invention discloses a synthesis method of a diaryl quaternary carbon pyrazolone compound with a chiral center, and belongs to the field of organic synthesis. The method comprises the following steps: (1) at room temperature, taking ether as a solvent, adding silver oxide and substituted N-phenyl-3-(2-hydroxyphenyl) indole-2-ketone, and reacting for 6-12 hours; (2) performing column chromatography purification on the product to obtain an intermediate, taking a polar solvent or halogenated alkane as a solvent, adding alkali and substituted hydrazone, and reacting at 0-40 DEG C for 1-30 minutes; and (3) adding methyl iodide to continuously react for 1-12 hours to obtain the diaryl quaternary carbon pyrazolone compound with the chiral center as shown in the formula (I). According to the present invention, N-phenyl-3-(2-hydroxyphenyl) indole-2-one or a derivative thereof and substituted hydrazone are adopted as reactants to synthesize the diaryl quaternary carbon pyrazolone compound having the chiral center through the alkali start-up reaction, and the method has advantages of wide substrate universality, simple operation, mild condition and medium to excellent yield. (I)

Description

Technical Field

[0001] This invention relates to a method for synthesizing a diaryl quaternary carbon pyrazolone compound having a chiral center, belonging to the field of organic synthesis. Background Technology

[0002] Pyrazolone skeletons occupy an important position in medicinal chemistry due to their unique chemical structures and broad biological activities. In particular, the quaternary carbon pyrazolone skeleton has been identified as a key pharmacophore, possessing antibacterial, anti-inflammatory, and antitumor activities. Therefore, the synthesis methods of quaternary carbon pyrazolone have attracted considerable interest from researchers.

[0003] With the development of organic asymmetric catalysis, the study of organocatalytic asymmetric Michael addition reactions using pyrazolones as nucleophiles has become a continuously developing field. Because pyrazolones provide an activated methylene group, continuous functionalization reactions are possible, enabling the construction of complex heterocyclic skeleton molecules. Pyrazolopyran structures are one very important class of skeleton structures. However, examples of constructing pyrazolopyran compounds with quaternary carbon spirocyclic skeletons are still scarce in existing reports. Studies have shown that diaryl quaternary carbon pyrazolones have neuroprotective effects, exhibiting blood-brain barrier penetration and significant acetylcholinesterase inhibitory activity. However, current research is limited to diaryl quaternary carbon pyrazolones without chiral centers; therefore, developing diaryl quaternary carbon pyrazolone compounds with chiral centers has significant research and practical value.

[0004] In 2010, Zeng Chengchu's research group first reported the diarylation of pyrazolone via electrochemical oxidation of catechol, thus constructing diaryl quaternary carbon pyrazolone (Gao, XG; Yang, CW; Zhang, ZZ; Zeng, CC; Song, XQ; Hu, LM; Zhong, RG; She, YB, Electrochemical oxidation of substituted catechols in the presence of pyrazol-5-ones: characterization of products and reaction mechanism. Tetrahedron 2010, 66, 9880-9887.). Using acetate buffer solution, in the presence of pyrazolone, catechol was electrochemically oxidized using a constant current technique. However, the yield of this reaction was only 20% to 42%.

[0005]

[0006] In 2015, Cao Song's research group disclosed a method for constructing diaryl quaternary carbon pyrazolones using diaryl salts as arylation sources (Huang, T.; Ji, X.; Wu, W.; Liang, F.; Cao, S., Metal-free one-pot sequential direct diarylation of pyrazolin-5-ones with diaryliodonium salts. RSC Adv. 2015, 5, 66598-66601.). This method achieves direct diarylation of the active methylene group at the C4 position of pyrazolones in a mild and relatively high yield. However, even with the use of asymmetric diaryl salts, only the more electron-deficient aryl moiety is selectively transferred to the product, meaning that only quaternary carbon pyrazolones with the same aryl group are obtained.

[0007]

[0008] In 2024, Liu Bin's research group proposed a controllable method for the site-selective monoarylization, diarylization, and triarylization of pyrazolones with diaryliodonium salts (Liao, W.; Du, H.; Chen, M.; Xiong, Y.; Zhou, H.; Qin, T.; Liu, B., Sequential regioselective arylation of pyrazolones with diaryliodonium salts. Org. Biomol. Chem. 2024, 22, 708-713.). This method controls the arylization site of pyrazolones by adjusting the equivalent amounts of cuprous iodide and cesium carbonate, thereby constructing multi-substituted quaternary carbon pyrazolones. However, this method requires high reaction temperatures and can only yield quaternary carbon pyrazolones with the same aryl group.

[0009]

[0010] In 2024, Srihari, P.'s research group reported the successful diarylation of pyrazolones at the C4 position in good to moderate yields using in-situ generated aromatic hydrocarbons as aryl sources (Sudarshana, KA; Sarma, MJ; Radhakrishnan, M.; Chakravarty, S.; Srihari, P.; Mehta, G., A protocol for directly accessing geographical C-4 diarylated pyrazol-5(4H)-ones via tandem C–H aryne insertion and their inceptive neurobiological evaluation. Org. Biomol. Chem. 2024, 22, 714-719.). This group conducted preliminary assessments of the bioactivity of the synthesized diaryl quaternary carbon pyrazolone compounds, particularly in the field of central nervous system-related therapies. However, this method requires high reaction temperatures and long reaction times, and can only yield quaternary carbon pyrazolones with the same aryl group.

[0011]

[0012] Although the above-mentioned literature has achieved the construction of the diaryl quaternary carbon pyrazolone skeleton, these reports all use pyrazolone as the starting material and can only obtain quaternary carbon pyrazolone compounds with the same aryl group, which limits their application in biology and medicine. Summary of the Invention

[0013] To address the problems of low yield, harsh reaction conditions, difficulty in constructing chiral centers, and limited raw materials in existing technologies, the present invention aims to provide a method for constructing diaryl quaternary carbon pyrazolones with chiral centers based on the reaction of indigo-derived o-methylenebenzoquinone and hydrazone. This method can start from non-pyrazolone raw materials and features broad substrate applicability, simple operation, mild conditions, and high yield. More importantly, this method can obtain diaryl quaternary carbon pyrazolone compounds with chiral centers.

[0014] The reaction mechanism of this invention is as follows (taking the reaction of N-phenyl-3-(2-hydroxyphenyl)indol-2-one and diphenylhydrazone as an example): Using N-phenyl-3-(2-hydroxyphenyl)indol-2-one as a raw material, it is oxidized by silver oxide to generate o-methylenebenzoquinone. At the same time, diphenylhydrazone generates an anion under alkaline conditions, which attacks the electrophilic site of o-methylenebenzoquinone. After hydrogen migration, a nitrogen anion is formed, which then attacks the carbonyl carbon, and an intramolecular ring-opening and then ring-closing process is carried out to construct a quaternary carbon pyrazolone skeleton compound. By adding iodomethane to capture the oxygen anion, a stable diaryl quaternary carbon pyrazolone skeleton compound is obtained.

[0015]

[0016] To achieve the above-mentioned objectives, the technical solution adopted by this invention is as follows:

[0017] A method for synthesizing a diaryl quaternary carbon pyrazolone compound with a chiral center includes the following steps: (1) At room temperature, silver oxide and substituted N-phenyl-3-(2-hydroxyphenyl)indol-2-one are added as solvent in ether and reacted for 6-12 hours; (2) After the product is purified by column chromatography to obtain an intermediate, a base and substituted hydrazone are added as solvent in a polar solvent or a haloalkane and reacted at 0-40℃ for 1-30 minutes; (3) Iodomethane is added and the reaction continues for 1-12 hours to obtain the diaryl quaternary carbon pyrazolone compound with a chiral center as shown in formula (I):

[0018]

[0019] The base includes, but is not limited to, one or more of potassium carbonate, cesium carbonate, triethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane, and 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0020] In molar amounts, the amount of silver oxide is 1 to 2 times that of the substituted N-phenyl-3-(2-hydroxyphenyl)indol-2-one, the amount of base is 1 to 3 times that of the substituted N-phenyl-3-(2-hydroxyphenyl)indol-2-one, the amount of substituted hydrazone is 1 to 1.5 times that of the substituted N-phenyl-3-(2-hydroxyphenyl)indol-2-one, and the amount of iodomethane is 1 to 3 times that of the substituted N-phenyl-3-(2-hydroxyphenyl)indol-2-one.

[0021] The ether is dimethyl ether, diethyl ether, isopropyl ether, or tetrahydrofuran.

[0022] The polar solvents include, but are not limited to, N,N-dimethylformamide, N,N-dimethylacetamide, or dimethyl sulfoxide.

[0023] The haloalkane solvents include, but are not limited to, dichloromethane, 1,2-dichloroethane, or chloroform.

[0024] The chemical structural formula of the substituted N-phenyl-3-(2-hydroxyphenyl)indol-2-one is as follows: Where R 1 Selected from hydrogen, 5-methyl, 5-methoxy, 5-halogen, 6-methyl, 6-methoxy, 6-halogen, 7-methyl, 7-methoxy, 7-halogen, and 5,6-dimethyl, wherein the halogen is one of fluorine, chlorine, bromine, and iodine; R 2It is selected from phenyl or 2-naphthyl.

[0025] The chemical structural formula of the substituted hydrazone is as follows: Among them, Ar 1 Selected from: one of phenyl, 2-methylphenyl, 3-chlorophenyl, 3-methylphenyl, 4-chlorophenyl, 4-methylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-methoxyphenyl; Ar 2 Selected from: phenyl, 2-fluorophenyl, 3-bromophenyl, 3-methylphenyl, 4-methylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 4-nitrophenyl, 3,5-dichlorophenyl, 2-naphthyl, 2-thiophene.

[0026] In a preferred embodiment, the amount of silver oxide used is 1.5 times that of the substituted N-phenyl-3-(2-hydroxyphenyl)indol-2-one, in molar amounts.

[0027] In a preferred embodiment, the amount of the alkali used is twice the amount of the substituted N-phenyl-3-(2-hydroxyphenyl)indol-2-one, measured in molar amounts.

[0028] In a preferred embodiment, the amount of the substituted hydrazone is 1.5 times that of the substituted N-phenyl-3-(2-hydroxyphenyl)indol-2-one, measured in molar amounts.

[0029] In a preferred embodiment, the amount of iodomethane used is twice that of the substituted N-phenyl-3-(2-hydroxyphenyl)indol-2-one, measured in molar amounts.

[0030] In the above technical solution, after the reaction is completed, the product can be separated by simple column chromatography (the eluent is preferably petroleum ether: ethyl acetate = 40:1 to 20:1) to obtain the target product.

[0031] The above reaction process is shown below:

[0032]

[0033] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0034] 1. This invention is the first to realize the synthesis of diaryl quaternary carbon pyrazolone compounds with chiral centers by reacting N-phenyl-3-(2-hydroxyphenyl)indol-2-one or its derivatives with substituted hydrazones via a base-initiated reaction. This method has broad substrate applicability, is simple to operate, and operates under mild conditions, with moderate to excellent yields.

[0035] 2. The method of the present invention does not generate unclosed intermediates and can obtain cyclized products in one step.

[0036] 3. The compounds synthesized in this invention have potential pharmaceutical activity. Detailed Implementation

[0037] The present invention will be further described below with reference to specific embodiments.

[0038] Example 1:

[0039]

[0040] N-phenyl-3-(2-hydroxyphenyl)indol-2-one 1a (34.5 mg, 0.1 mmol), silver oxide (34.8 mg, 0.15 mmol), and diethyl ether (1.6 ml) were added sequentially to a reaction flask. The reaction was carried out at room temperature for 6 hours. After the reaction was completed, the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain an intermediate. Then, 2a (29.4 mg, 0.15 mmol), cesium carbonate (65.2 mg, 0.2 mmol), and N,N-dimethylformamide (1 ml) were added to the reaction flask. After the reaction was carried out at room temperature for 5 minutes, iodomethane (28.4 mg, 0.2 mmol) was added. The reaction was carried out at this temperature for 1.5 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate / water, the organic phase was retained, the solvent was evaporated, and the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 40:1) to obtain the target product 3a (44.3 mg), with a yield of 80%. The analysis of product 3a yielded the following results: 1 HNMR (400MHz, CDCl3): δ8.52(s,1H),8.02(d,J=8.5Hz,2H),7.78(d,J=8.1Hz,2 H),7.56(d,J=8.1Hz,1H),7.48(t,J=7.8Hz,2H),7.31-7.29(m,4H),7.24-7.22 (m,2H),7.20(t,J=7.7Hz,2H),6.99(d,J=8.2Hz,2H),6.86-6.82(m,2H),6.80( s,1H),6.33(s,1H),5.76(d,J=1.0Hz,1H),5.50(d,J=1.0Hz,1H),3.53(s,3H); 13C NMR (101MHz, CDCl3): δ177.3,156.7,152.2,148.1,143.8,143.2,141.6,138.3,131.2,130.9,129.8,129.4,129.1 ,128.8,128.3,127.8,125.3,123.3,121.8,121.5,119.63,119.56,116.7,114.5,110.4,101.3,95.5,65.0,57.0.

[0041] Example 2:

[0042]

[0043] N-naphthyl-3-(2-hydroxyphenyl)indol-2-one 1a (39.5 mg, 0.1 mmol), silver oxide (34.8 mg, 0.15 mmol), and diethyl ether (1.6 ml) were added sequentially to a reaction flask. The reaction was carried out at room temperature for 10 hours. After the reaction was completed, the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 3:1 eluent) to obtain an intermediate. Then, 2a (29.4 mg, 0.15 mmol), cesium carbonate (65.2 mg, 0.2 mmol), and dimethyl sulfoxide (1 ml) were added to the reaction flask. After reacting at 0 °C for 5 minutes, iodomethane (28.4 mg, 0.2 mmol) was added, and the reaction was carried out at this temperature for 1.5 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate / water, the organic phase was retained, the solvent was evaporated, and the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 40:1 eluent) to obtain the target product 3a (33.8 mg), with a yield of 56%. The analysis of product 3b yielded the following results: 1 H NMR (400MHz, CDCl3): δ8.80 (s, 1H), 8.06 (d, J = 7.7Hz, 2H), 7.82 (d, J = 8.1Hz, 2H), 7.70 (d,J=7.8Hz,2H),7.65(d,J=8.6Hz,2H),7.51(t,J=8.0Hz,2H),7.40-7.36(m,3H),7.32 -7.27(m,5H),7.25(d,J=7.1Hz,1H),7.11(dd,J=8.8,2.1Hz,1H),6.92(t,J=7.6Hz,1H ),6.84(s,1H),6.31(s,1H),5.57(d,J=1.3Hz,1H),5.04(d,J=1.3Hz,1H),3.55(s,3H); 13C NMR (101MHz, CDCl3): δ177.4,156.7,152.1,148.1,143.5,141.6,141.1,138.3,134.8,131.2,130.9,129.8,129.5,128.9,128.8,1 28.6,128.3,127.8,127.4,126.3,126.1,125.4,124.2,122.7,122.1,119.6,119.5,114.5,110.3,109.7,101.1,95.4,65.1,57.0.

[0044] Example 3:

[0045]

[0046] N-phenyl-3-(2-hydroxyphenyl)indol-2-one 1c (35.9 mg, 0.1 mmol), silver oxide (34.8 mg, 0.15 mmol), and diethyl ether (1.6 ml) were added sequentially to a reaction flask. The reaction was carried out at room temperature for 8 hours. After the reaction was completed, the product was subjected to simple column chromatography (petroleum ether:ethyl acetate = 3:1 eluent) to obtain an intermediate. Then, 2a (29.4 mg, 0.15 mmol), potassium carbonate (27.6 mg, 0.2 mmol), and dichloromethane (1 ml) were added to the reaction flask. The reaction was carried out at 40 °C for 5 minutes, followed by the addition of iodomethane (28.4 mg, 0.2 mmol). The reaction was carried out at this temperature for 5 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate / water, the organic phase was retained, and the solvent was evaporated. The product was subjected to simple column chromatography (petroleum ether:ethyl acetate = 30:1 eluent) to obtain the target product 3c (44.8 mg), with a yield of 79%. The analysis results of product 3c are as follows: 1 H NMR (400MHz, CDCl3): δ8.38 (s, 1H), 8.04 (d, J = 8.7Hz, 2H), 7.79 (d, J = 8.1Hz, 2H),7.49-7.44(m,3H),7.33-7.28(m,3H),7.24(d,J=7.4Hz,1H),7.16(t,J=8 .0Hz,3H),7.06(s,1H),6.92(d,J=7.6Hz,2H),6.78(d,J=9.8Hz,2H),6.32(s ,1H),5.73(d,J=1.5Hz,1H),5.43(d,J=1.4Hz,1H),3.53(s,3H),2.16(s,3H); 13C NMR (101MHz, CDCl3): δ177.4,156.9,152.1,148.0,143.7,141.5,140.8,138.3,131.4,131.22,131.18,130.0,129.8 ,129.0,128.8,128.3,127.8,125.3,124.2,123.0,119.5,118.8,115.7,114.8,110.5,101.2,95.5,65.0,57.0,20.7.

[0047] Example 4:

[0048]

[0049] N-phenyl-3-(2-hydroxyphenyl)indol-2-one 1d (36.3 mg, 0.1 mmol), silver oxide (34.8 mg, 0.15 mmol), and diethyl ether (1.6 ml) were added sequentially to a reaction flask. The reaction was carried out at room temperature for 12 hours. After the reaction was completed, the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 3:1 eluent) to obtain the intermediate. Then, 2a (29.4 mg, 0.15 mmol), triethylamine (20.2 mg, 0.2 mmol), and 1,2-dichloroethane (1 ml) were added to the reaction flask. After the reaction was carried out at room temperature for 5 minutes, iodomethane (28.4 mg, 0.2 mmol) was added. The reaction was carried out at this temperature for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate / water, the organic phase was retained, the solvent was evaporated, and the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 40:1 eluent) to obtain the target product 3d (48.0 mg), with a yield of 84%. The 3D analysis of the product yielded the following results: 1 HNMR (400MHz, CDCl3): δ8.39 (s, 1H), 8.02 (d, J = 8.6Hz, 2H), 7.78 (d, J = 7.8Hz, 2H) ,7.52(dd,J=8.9,5.4Hz,1H),7.49(t,J=8.0Hz,2H),7.36-7.26(m,4H),7.18(t,J =7.8Hz,2H),7.06-6.98(m,2H),6.90(d,J=8.4Hz,2H),6.81(t,J=7.3Hz,1H),6.7 4(s,1H),6.34(s,1H),5.75(d,J=1.5Hz,1H),5.46(d,J=1.4Hz,1H),3.53(s,3H); 13 C NMR (101MHz, CDCl3): δ176.8,158.8(d,J C-F=242.0Hz),156.2,152.2,148.2,143.5,141.6,139.8,138.2,130.8,130.0,129.1,128.9,128.5,127.7,125.5(d,J C-F =1.8Hz), 125.4, 124.2 (d, J) C-F =8.0Hz),119.6,119.3,117.6,117.4,116.3(d,J C-F =22.2Hz),115.7,114.0,110.2,101.3,95.5,64.7,57.0.

[0050] Example 5:

[0051]

[0052] N-phenyl-3-(2-hydroxyphenyl)indol-2-one 1e (37.5 mg, 0.1 mmol), silver oxide (34.8 mg, 0.15 mmol), and diethyl ether (1.6 ml) were added sequentially to a reaction flask. The reaction was carried out at room temperature for 7 hours. After the reaction was completed, the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 3:1 eluent) to obtain the intermediate. Then, 2a (29.4 mg, 0.15 mmol), 4-dimethylaminopyridine (24.4 mg, 0.2 mmol), and chloroform (1 ml) were added to the reaction flask. The reaction was carried out at 40 °C for 5 minutes, and then iodomethane (28.4 mg, 0.2 mmol) was added. The reaction was carried out at this temperature for 8 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate / water, the organic phase was retained, the solvent was evaporated, and the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 20:1 eluent) to obtain the target product 3e (44.3 mg), with a yield of 76%. The analysis of product 3e yielded the following results: 1 H NMR (400MHz, CDCl3): δ8.56 (s, 1H), 8.04 (d, J = 7.6Hz, 2H), 7.80 (dd, J = 7.8, 1.8Hz, 2H), 7. 49(t,J=8.0Hz,2H),7.34-7.28(m,3H),7.22(dd,J=15.4,7.3Hz,3H),7.15(d,J=8.8Hz,1H ),7.10(d,J=2.7Hz,1H),7.05(d,J=7.6Hz,2H),6.87-6.83(m,2H),6.41(dd,J=8.8,2.7Hz ,1H),6.33(s,1H),5.77(d,J=1.4Hz,1H),5.55(d,J=1.4Hz,1H),3.75(s,3H),3.52(s,3H);13 CNMR (101MHz, CDCl3): δ177.5,160.5,156.7,152.3,148.1,145.3,142.8,141.6,138.3,131.8,131.3,129.8,129.1, 128.8,128.3,127.7,125.3,120.0,119.5,117.4,115.1,114.8,110.5,106.9,106.2,101.2,95.5,64.4,57.0,55.2.

[0053] Example 6:

[0054]

[0055] N-phenyl-3-(2-hydroxyphenyl)indol-2-one 1f (42.3 mg, 0.1 mmol), silver oxide (34.8 mg, 0.15 mmol), and diethyl ether (1.6 ml) were added sequentially to a reaction flask. The reaction was carried out at room temperature for 11 hours. After the reaction was completed, the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the intermediate. Then, 2a (29.4 mg, 0.15 mmol), N,N-diisopropylethylamine (25.9 mg, 0.2 mmol), and N,N-dimethylformamide (1 ml) were added to the reaction flask. After the reaction was carried out at room temperature for 5 minutes, iodomethane (28.4 mg, 0.2 mmol) was added, and the reaction was carried out at 20 °C for 10 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate / water, the organic phase was retained, the solvent was evaporated, and the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 40:1) to obtain the target product 3f (45.4 mg), with a yield of 72%. The analysis of product 3F yielded the following results: 1 H NMR (400MHz, CDCl3): δ8.60(s,1H),8.01(dd,J=8.6,1.0Hz,2H),7.76(dd,J=8.0,1.6Hz,2H),7.63(d,J=2.1Hz,1H),7.49(t,J=7.5Hz,2H),7.34-7 .23(m,6H),7.09(dd,J=15.8,8.0Hz,3H),6.93-6.90(m,2H),6.82(s,1H) ,6.34(s,1H),5.79(d,J=1.4Hz,1H),5.61(d,J=1.4Hz,1H),3.52(s,3H); 13C NMR (101MHz, CDCl3): δ177.0,156.3,152.4,148.4,145.8,142.0,141.7,138.2,132.2,131.1,131.0,130.0,129. 3,128.9,128.4,127.7,125.5,123.7,123.6,122.5,121.1,119.6,118.3,113.7,110.1,101.4,95.6,64.6,57.0.

[0056] Example 7:

[0057]

[0058] 1 g (35.9 mg, 0.1 mmol) of N-phenyl-3-(2-hydroxyphenyl)indol-2-one, 34.8 mg (0.15 mmol) of silver oxide, and 1.6 ml of diethyl ether were added sequentially to the reaction flask. The reaction was carried out at room temperature for 12 hours. After the reaction was completed, the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 3:1 eluent) to obtain the intermediate. Then, 2a (29.4 mg, 0.15 mmol) of 1,4-diazadiphenyl ether was added to the reaction flask. Cyclo[2.2.2]octane (22.7 mg, 0.2 mmol) and dimethyl sulfoxide (1 ml) were reacted at room temperature for 5 minutes, followed by the addition of iodomethane (28.4 mg, 0.2 mmol). The reaction was continued at this temperature for 11 hours. After the reaction was complete, the reaction solution was extracted with ethyl acetate / water, the organic phase was retained, the solvent was evaporated, and the product was subjected to simple column chromatography (petroleum ether:ethyl acetate = 20:1 eluent) to obtain 3 g (43.1 mg) of the target product, with a yield of 76%. The analysis of the 3 g product yielded the following results: 1 H NMR (400MHz, CDCl3): δ8.74 (s, 1H), 8.05 (d, J = 7.5Hz, 2H), 7.83 (d, J = 7.0Hz, 2H),7.48(t,J=7.8Hz,2H),7.34-7.27(m,4H),7.25-7.13(m,3H),7.02(t,J=7 .7Hz,2H),6.68(t,J=7.2Hz,1H),6.52(s,1H),6.40(d,J=7.0Hz,2H),6.28(s ,1H),5.70(d,J=1.3Hz,1H),5.19(d,J=1.6Hz,1H),3.55(s,3H),2.29(s,3H); 13C NMR (101MHz, CDCl3): δ177.7,156.8,151.7,147.7,144.2,141.1,140.3,138.3,137.6,132.2,131.2,129.7(2C),1 28.8,128.2,128.1,127.9,125.3,124.3,119.5,116.8,115.7,115.4,112.4,110.7,101.0,95.4,65.4,57.2,20.0.

[0059] Example 8:

[0060]

[0061] N-phenyl-3-(2-hydroxyphenyl)indol-2-one 1h (37.9 mg, 0.1 mmol), silver oxide (34.8 mg, 0.15 mmol), and diethyl ether (1.6 ml) were added sequentially to a reaction flask. The reaction was carried out at room temperature for 8 hours. After the reaction was completed, the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain an intermediate. Then, 2a (29.4 mg, 0.15 mmol), cesium carbonate (65.2 mg, 0.2 mmol), and chloroform (1 ml) were added to the reaction flask. The reaction was carried out at 30 °C for 5 minutes, followed by the addition of iodomethane (28.4 mg, 0.2 mmol). The reaction was carried out at this temperature for 1 hour. After the reaction was completed, the reaction solution was extracted with ethyl acetate / water, the organic phase was retained, and the solvent was evaporated. The product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 40:1) to obtain the target product 3h (35.8 mg), with a yield of 61%. The analysis results of product 3h are as follows: 1 H NMR (400MHz, CDCl3): δ8.61 (s, 1H), 8.01 (d, J = 7.7Hz, 2H), 7.76 (dd, J = 8.0, 1. 6Hz,2H),7.49(t,J=8.0Hz,1H),7.36-7.22(m,6H),7.15(d,J=8.6Hz,1H),7.0 5(d,J=7.6Hz,2H),6.93(t,J=7.3Hz,1H),6.82(s,1H),6.78(dd,J=8.6,2.2Hz ,1H),6.34(s,1H),5.79(d,J=1.4Hz,1H),5.61(d,J=1.4Hz,1H),3.52(s,3H); 13C NMR (101MHz, CDCl3): δ177.0,156.3,152.4,148.4,145.7,142.0,141.7,138.2,135.5,132.0,131.0,130.0,129.3 ,128.9,128.4,127.7,125.5,121.1,120.7,120.5,119.61,119.57,118.4,113.8,110.1,101.4,95.6,64.5,57.0.

[0062] Example 9:

[0063]

[0064] N-phenyl-3-(2-hydroxyphenyl)indol-2-one 1a (34.5 mg, 0.1 mmol), silver oxide (34.8 mg, 0.15 mmol), and diethyl ether (1.6 ml) were added sequentially to the reaction flask. The reaction was carried out at room temperature for 6 hours. After the reaction was completed, the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 3:1 eluent) to obtain the intermediate. Then, 2b (31.5 mg, 0.15 mmol) and 1,8-diazabicyclo[5.4] were added to the reaction flask. Undecyl-7-ene (30.4 mg, 0.2 mmol) and N,N-dimethylformamide (1 ml) were reacted at room temperature for 5 minutes, followed by the addition of iodomethane (28.4 mg, 0.2 mmol). The reaction was continued at this temperature for 10 hours. After the reaction was complete, the reaction solution was extracted with ethyl acetate / water, the organic phase was retained, and the solvent was evaporated. The product was then subjected to simple column chromatography (petroleum ether:ethyl acetate = 30:1 eluent) to obtain the target product 3i (43.7 mg), with a yield of 77%. The analysis results of product 3i are as follows: 1 H NMR (400MHz, CDCl3): δ8.56(s,1H),7.88(d,J=8.5Hz,2H),7.78(dd,J=7.9,1.7Hz,2H),7.57(dd,J=8.1,1.1Hz,1H),7.32-7.26(m,5H),7.26-7.23(m, 2H),7.19-7.15(m,2H),6.98(d,J=7.6Hz,2H),6.86-6.79(m,3H),6.33(s,1 H),5.75(d,J=1.5Hz,1H),5.50(d,J=1.4Hz,1H),3.53(s,3H),2.39(s,3H); 13C NMR (101MHz, CDCl3): δ177.2,156.5,152.3,148.1,143.8,143.2,141.6,135.9,135.1,131.3,130.9,129.7,129.4,1 29.3,129.0,128.3,127.7,123.5,121.8,121.5,119.63,119.57,116.7,114.6,110.4,101.2,95.5,64.9,57.0,21.0.

[0065] Example 10:

[0066]

[0067] N-phenyl-3-(2-hydroxyphenyl)indol-2-one 1a (34.5 mg, 0.1 mmol), silver oxide (34.8 mg, 0.15 mmol), and diethyl ether (1.6 ml) were added sequentially to a reaction flask. The reaction was carried out at room temperature for 12 hours. After the reaction was completed, the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain an intermediate. Then, 2c (34.5 mg, 0.15 mmol), cesium carbonate (65.2 mg, 0.2 mmol), and 1,2-dichloroethane (1 ml) were added to the reaction flask. The reaction was carried out at 40 °C for 5 minutes, and then iodomethane (28.4 mg, 0.2 mmol) was added. The reaction was carried out at this temperature for 9 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate / water, the organic phase was retained, the solvent was evaporated, and the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 40:1) to obtain the target product 3j (45.2 mg), with a yield of 77%. The analysis of product 3j yielded the following results: 1 H NMR (400MHz, CDCl3): δ8.41(s,1H),8.12(d,J=1.9Hz,1H),8.01(d,J=8.2Hz,1H),7.79(d,J=7.4Hz,2H),7.57(d,J=8.2Hz,1H),7.40(t,J=8.1Hz,1H ),7.34-7.28(m,4H),7.24-7.17(m,4H),7.00(d,J=8.4Hz,2H),6.87(m,3H ),6.34(s,1H),5.76(d,J=1.5Hz,1H),5.52(d,J=1.4Hz,1H),3.53(s,3H); 13C NMR (101MHz, CDCl3): δ177.2,157.1,152.2,148.3,143.8,143.0,141.6,139.4,134.6,130.94,130.86,130.0,129.9,129.5,129. 1,128.4,127.8,125.1,122.9,121.7,121.5,119.8,119.2,117.1,116.9,114.2,110.4,101.3,95.5,77.3,77.0,76.7,65.1,57.0.

[0068] Example 11:

[0069]

[0070] N-phenyl-3-(2-hydroxyphenyl)indol-2-one 1a (34.5 mg, 0.1 mmol), silver oxide (34.8 mg, 0.15 mmol), and diethyl ether (1.6 ml) were added sequentially to a reaction flask. The reaction was carried out at room temperature for 7 hours. After the reaction was completed, the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain an intermediate. Then, 2d (34.5 mg, 0.15 mmol), triethylamine (20.2 mg, 0.2 mmol), and dichloromethane (1 ml) were added to the reaction flask. After reacting at room temperature for 5 minutes, iodomethane (28.4 mg, 0.2 mmol) was added, and the reaction was carried out at this temperature for 7 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate / water, the organic phase was retained, the solvent was evaporated, and the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain the target product 3k (48.7 mg), with a yield of 83%. The analysis results of product 3k are as follows: 1 H NMR (400MHz, CDCl3): δ8.49(s,1H),8.00(d,J=8.6Hz,2H),7.73(d,J=8.0Hz,2 H),7.57(d,J=8.2Hz,1H),7.48(t,J=7.7Hz,2H),7.31-7.28(m,3H),7.26-7.23 (m,1H),7.21(t,J=7.7Hz,3H),7.00(d,J=8.3Hz,2H),6.87-6.81(m,2H),6.78( s,1H),6.34(s,1H),5.77(d,J=1.0Hz,1H),5.53(d,J=1.0Hz,1H),3.53(s,3H); 13C NMR (101MHz, CDCl3): δ177.2,155.6,152.2,148.3,143.9,143.0,141.7,138.2,135.8,130.6,129.6,129.5,129. 1,129.0,128.9,128.7,125.5,122.8,121.7,121.5,119.8,119.5,116.9,114.1,110.2,101.3,95.5,64.8,57.0.

[0071] Example 12:

[0072]

[0073] N-phenyl-3-(2-hydroxyphenyl)indol-2-one 1a (34.5 mg, 0.1 mmol), silver oxide (34.8 mg, 0.15 mmol), and diethyl ether (1.6 ml) were added sequentially to a reaction flask. The reaction was carried out at room temperature for 6 hours. After the reaction was completed, the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain an intermediate. Then, 2e (31.5 mg, 0.15 mmol), 4-dimethylaminopyridine (24.4 mg, 0.2 mmol), and N,N-dimethylformamide (1 ml) were added to the reaction flask. The reaction was carried out at 0 °C for 5 minutes, and then iodomethane (28.4 mg, 0.2 mmol) was added. The reaction was carried out at this temperature for 7 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate / water, the organic phase was retained, the solvent was evaporated, and the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 25:1) to obtain the target product 3l (47.6 mg), with a yield of 84%. The analysis of product 3L yielded the following results: 1 H NMR (400MHz, CDCl3): δ8.55(s,1H),8.04(d,J=8.6Hz,2H),7.75(s,1H),7.58( d,J=8.2Hz,1H),7.49-7.43(m,3H),7.31(t,J=8.6Hz,2H),7.26-7.23(m,1H),7 .20-7.14(m,4H),7.01(d,J=8.4Hz,2H),6.88-6.83(m,2H),6.81(s,1H),6.34( s,1H),5.75(d,J=1.4Hz,1H),5.50(d,J=1.4Hz,1H),3.54(s,3H),2.33(s,3H); 13C NMR (101MHz, CDCl3): δ177.3,156.8,152.2,148.1,143.8,143.2,141.6,138.3,138.0,131.1,130.9,130.7,129.3,129 .0,128.8,128.1,128.0,125.3,125.2,123.4,121.8,121.5,119.6,116.7,114.6,110.4,101.2,95.5,65.0,57.0,21.4.

[0074] Example 13:

[0075]

[0076] N-phenyl-3-(2-hydroxyphenyl)indol-2-one 1a (34.5 mg, 0.1 mmol), silver oxide (34.8 mg, 0.15 mmol), and diethyl ether (1.6 ml) were added sequentially to the reaction flask. The reaction was carried out at room temperature for 11 hours. After the reaction was completed, the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 3:1 eluent) to obtain the intermediate. Then, 2f (39.6 mg, 0.15 mmol) and 1,8-diazabicyclo[5.4] were added to the reaction flask. Undecyl-7-ene (30.4 mg, 0.2 mmol) and N,N-dimethylformamide (1 ml) were reacted at room temperature for 5 minutes, followed by the addition of iodomethane (28.4 mg, 0.2 mmol). The reaction was continued at this temperature for 1.5 hours. After the reaction was complete, the reaction solution was extracted with ethyl acetate / water, the organic phase was retained, and the solvent was evaporated. The product was then subjected to simple column chromatography (petroleum ether:ethyl acetate = 35:1 eluent) to obtain the target product 3m (44.7 mg), with a yield of 72%. The analysis results of product 3m are as follows: 1 H NMR (400MHz, CDCl3): δ8.41(s,1H),7.98(d,J=7.6Hz,2H),7.63(d,J=1.8Hz,2H ),7.57(d,J=8.2Hz,1H),7.49(t,J=8.0Hz,2H),7.33-7.25(m,3H),7.21(t,J=7. 9Hz,2H),7.12(d,J=8.0Hz,1H),7.00(d,J=7.6Hz,2H),6.89-6.82(m,2H),6.78 (s,1H),6.36(s,1H),5.78(d,J=1.4Hz,1H),5.55(d,J=1.3Hz,1H),3.54(s,3H); 13C NMR (101MHz, CDCl3): δ177.1,154.0,152.2,148.6,144.0,142.9,142.0,138.0,135.1,134.0,130.3,129.8,129. 6,129.1,128.9,125.8,125.7,122.3,121.8,121.6,120.0,119.6,117.0,113.5,110.0,101.4,95.5,64.6,57.0.

[0077] Example 14:

[0078]

[0079] N-phenyl-3-(2-hydroxyphenyl)indol-2-one 1a (34.5 mg, 0.1 mmol), silver oxide (34.8 mg, 0.15 mmol), and diethyl ether (1.6 ml) were added sequentially to a reaction flask. The reaction was carried out at room temperature for 6 hours. After the reaction was completed, the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain an intermediate. Then, 2 g (36.9 mg, 0.15 mmol), cesium carbonate (65.2 mg, 0.2 mmol), and dimethyl sulfoxide (1 ml) were added to the reaction flask. After reacting at room temperature for 5 minutes, iodomethane (28.4 mg, 0.2 mmol) was added, and the reaction was carried out at this temperature for 5 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate / water, the organic phase was retained, the solvent was evaporated, and the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 35:1) to obtain the target product 3n (50.1 mg), with a yield of 83%. The analysis results of product 3n are as follows: 1 H NMR (400MHz, CDCl3): δ8.62 (s, 1H), 8.15 (dd, J = 8.7, 1.6Hz, 1H), 8.09-8.07 (m, 3H), 7 .83(t,J=8.4Hz,2H),7.73(d,J=7.9Hz,1H),7.62(d,J=8.2Hz,1H),7.52-7.43(m,4H) ,7.34-7.28(m,3H),7.25(t,J=7.9Hz,2H),7.06(d,J=8.3Hz,2H),6.97(s,1H),6.88- 6.81(m,2H),6.33(s,1H),5.75(d,J=1.4Hz,1H),5.53(d,J=1.4Hz,1H),3.55(s,3H); 13C NMR (101MHz, CDCl3): δ177.3,156.7,152.3,148.2,143.9,143.2,141.7,138.3,133.7,132.6,131.0,129.4,129.1,128.9,128.6,1 28.4,128.1,127.6,127.2,126.3,125.4,124.3,123.3,121.7,121.5,119.7,119.6,116.8,114.7,110.4,101.3,95.6,65.1,57.0.

[0080] Example 15:

[0081]

[0082] N-phenyl-3-(2-hydroxyphenyl)indol-2-one 1a (34.5 mg, 0.1 mmol), silver oxide (34.8 mg, 0.15 mmol), and diethyl ether (1.6 ml) were added sequentially to a reaction flask. The reaction was carried out at room temperature for 6 hours. After the reaction was completed, the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain an intermediate. Then, 2h (30.3 mg, 0.15 mmol), N,N-diisopropylethylamine (25.9 mg, 0.2 mmol), and N,N-dimethylformamide (1 ml) were added to the reaction flask. The reaction was carried out at 30 °C for 5 minutes, and then iodomethane (28.4 mg, 0.2 mmol) was added. The reaction was carried out at this temperature for 4 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate / water, the organic phase was retained, the solvent was evaporated, and the product was subjected to simple column chromatography (petroleum ether: ethyl acetate = 30:1) to obtain the target product 3o (41.9 mg), with a yield of 75%. The analysis of product 3O yielded the following results: 1 HNMR (400MHz, CDCl3): δ8.55(s,1H),7.99(d,J=7.7Hz,2H),7.55(d,J=8.1Hz,1H), 7.48(t,J=8.0Hz,2H),7.33-7.28(m,2H),7.26-7.22(m,2H),7.20(t,J=7.9Hz,2H) ,7.05-7.04(m,1H),6.99(d,J=7.6Hz,2H),6.92-6.9(m,1H),6.88-6.81(m,2H),6. 76(s,1H),6.38(s,1H),5.80(d,J=1.4Hz,1H),5.55(d,J=1.4Hz,1H),3.56(s,3H); 13C NMR (101MHz, CDCl3): δ176.6,153.3,152.4,148.4,143.9,143.1,141.6,138.1,135.1,130.6,129.4,129.2,129. 0,128.8,127.9,127.7,125.4,123.1,121.6,121.5,119.7,119.6,116.8,114.7,110.1,101.3,95.6,64.9,57.1.

[0083] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for synthesizing a diaryl quaternary carbon pyrazolone compound having a chiral center, characterized in that, The process includes the following steps: (1) At room temperature, silver oxide and substituted N-phenyl-3-(2-hydroxyphenyl)indol-2-one are added to the solvent in the presence of ether, and the reaction is carried out for 6-12 hours; (2) After the product is purified by column chromatography to obtain an intermediate, a base and substituted hydrazone are added to the solvent in the presence of a polar solvent or a haloalkane, and the reaction is carried out at 0-40°C for 1-30 minutes; (3) Iodomethane is added and the reaction is continued for 1-12 hours to obtain the diaryl quaternary carbon pyrazolone compound with a chiral center as shown in formula (I):

2. The method for synthesizing the diaryl quaternary carbon pyrazolone compound having a chiral center as described in claim 1, characterized in that, The chemical structural formula of the substituted N-phenyl-3-(2-hydroxyphenyl)indol-2-one is as follows: Where R 1 Selected from one of hydrogen, 5-methyl, 5-methoxy, 5-halogen, 6-methyl, 6-methoxy, 6-halogen, 7-methyl, 7-halogen, and 5,6-dimethyl; R 2 It is selected from phenyl or 2-naphthyl.

3. The method for synthesizing the diaryl quaternary carbon pyrazolone compound having a chiral center as described in claim 1, characterized in that, The chemical structural formula of the substituted hydrazone is as follows: Among them, Ar 1 Selected from: one of phenyl, 2-methylphenyl, 3-chlorophenyl, 3-methylphenyl, 4-chlorophenyl, 4-methylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-methoxyphenyl; Ar 2 Selected from: phenyl, 2-fluorophenyl, 3-bromophenyl, 3-methylphenyl, 4-chlorophenyl, 4-methylphenyl, 4-fluorophenyl, 4-bromophenyl, 4-methoxyphenyl, 4-nitrophenyl, 3,5-dichlorophenyl, 2-naphthyl, 2-thiophene.

4. The method for synthesizing the diaryl quaternary carbon pyrazolone compound having a chiral center as described in claim 1, characterized in that... In molar amounts, the amount of silver oxide is 1 to 2 times that of the substituted N-phenyl-3-(2-hydroxyphenyl)indol-2-one, the amount of base is 1 to 3 times that of the substituted N-phenyl-3-(2-hydroxyphenyl)indol-2-one, the amount of substituted hydrazone is 1 to 1.5 times that of the substituted N-phenyl-3-(2-hydroxyphenyl)indol-2-one, and the amount of iodomethane is 1 to 3 times that of the substituted N-phenyl-3-(2-hydroxyphenyl)indol-2-one.

5. The method for synthesizing the diaryl quaternary carbon pyrazolone compound having a chiral center as described in claim 1, characterized in that, The base mentioned in step (2) is one or more of potassium carbonate, cesium carbonate, triethylamine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane, and 1,8-diazabicyclo[5.4.0]undec-7-ene.

6. The method for synthesizing the diaryl quaternary carbon pyrazolone compound having a chiral center as described in claim 1, characterized in that: The ether mentioned in step (1) is dimethyl ether, diethyl ether, isopropyl ether or tetrahydrofuran.

7. The method for synthesizing the diaryl quaternary carbon pyrazolone compound having a chiral center as described in claim 1, characterized in that: The polar solvent in step (2) is N,N-dimethylformamide or dimethyl sulfoxide.

8. The method for synthesizing the diaryl quaternary carbon pyrazolone compound having a chiral center as described in claim 1, characterized in that: The haloalkane solvent mentioned in step (2) is dichloromethane, 1,2-dichloroethane, or chloroform.

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