A 4-benzylidene pyrazolone derivative and its synthesis method

Abstract

The present invention discloses a 4-benzylidene pyrazolone derivative and a synthesis method thereof, belonging to the technical field of organic synthesis. The 4-benzylidene pyrazolone derivative is obtained by reacting an α-ketoester with a 1,2-diaza-1,3-butadiene compound under the promotion of a phosphorus reagent; the raw materials used in the present invention are simple and easily available, and have good stability; the reaction conditions are mild, and the types of substituents on the synthesized 4-benzylidene pyrazolone product are rich and can be flexibly changed; the 4-benzylidene pyrazolone derivative provided by the present invention has rich drug activities, and provides candidate compounds for the design, synthesis and development of novel drug molecules containing a 4-benzylidene pyrazolone structure.

Description

Technical Field

[0001] The present invention relates to a 4-benzylidene pyrazolone derivative and a synthesis method thereof, belonging to the technical field of organic synthesis. Background Art

[0002] The pyrazolone structure is commonly present in natural products and drug molecules. Exploring efficient synthesis methods for such compounds has always been the research interest of organic synthesis researchers. 4-Benzylidene pyrazolone derivatives represent an important class of pyrazolone compounds, which have rich drug activities, such as anticancer activity (Chen, L. et al. J. Med. Chem. 2012, 55, 7037), HIV-1 integrase inhibitor (Neamati, N. et al. J. Med. Chem. 2008, 51, 1136), and H1N1 and H5N1 neuraminidase inhibitors (Liang, P.-H. Org. Lett. 2014, 16, 5060); moreover, such compounds are also important precursors for synthesizing lead compounds and functional molecules (Yang, L. and Zhong, G. et al. Org. Lett. 2019, 21, 7943; Feng, X. et al. Org. Lett. 2019, 21, 1632; Li, E.-Q. and Duan, Z. et al. Adv. Synth. Catal. 2019, 361, 1389); in addition, such compounds are also widely used as ligands (Li, F. et al. J. Am. Chem. Soc. 2011, 133, 15276) or dyes (Cui, Y.-P. et al. Dyes Pigment., 2009, 81, 27).

[0003] In view of this, the development of a concise and efficient method for synthesizing 4-benzylidene pyrazolone derivatives has high application value. Traditional synthetic methods rely on the Knoevenagel reaction of pyrazolone with aromatic aldehydes and ketones (Cristea, I. et al. Heterocyl. Commun. 1998, 4, 139; Shingare, M. S. et al. Synth. Commun. 2002, 32, 497), usually requiring reflux or microwave heating conditions. Although using ionic liquids as solvents can lower the reaction temperature to room temperature, this condition is only applicable to aromatic aldehyde substrates (Shingare, M. S. et al. Green Chem. 2002, 4, 266), with great limitations; N-propynoyl hydrazone compounds can also be transformed into 4-benzylidene pyrazolone derivatives via a tandem process of intramolecular cycloisomerization / 1,3-migration in the presence of gold catalysts (Zhan, Z.-P. et al. J. Org. Chem. 2015, 80, 9307), providing a new route for the synthesis of 4-benzylidene pyrazolone derivatives. However, the disadvantages such as the need to use transition metal catalysts and the cumbersome substrate synthesis route limit the application of this method. In addition, this reaction also undergoes a Knoevenagel condensation process with a relatively high reaction temperature (>100 °C); in the presence of an equivalent amount of iodine, pyrazolone can rapidly undergo a tandem Michael addition / cycloisomerization / oxidative dehydrogenation reaction with trans-2-hydroxy chalcone to form 4-benzylidene pyrazolone products (Bakthadoss, M. et al. Tetrahedron 2018, 74, 490). Although this reaction is highly efficient, it also requires high-temperature conditions (>100 °C); recently, the [5+1] cyclization reaction of Morita–Baylis–Hillman (MBH) carbonates with 2-allylidene malononitrile catalyzed by 1,4-diazabicyclo[2.2.2]octane (DABCO) provides a mild route for the synthesis of 4-benzylidene pyrazolone derivatives (Han, B. and Zhan, G. et al. New J. Chem. 2022, 46, 11617). However, the complex substrate synthesis route and the fixed substitution pattern of the products reduce the practicality of this reaction; the oxidative coupling reaction of 1,3-diarylpropenes with pyrazolone can also construct the 4-benzylidene pyrazolone structure at room temperature (Li, J., Xu, X. and Cheng, D. et al. Eur. J. Org. Chem. 2023, 26, e202201480). However, this method is only applicable to the synthesis of benzylidene vinyl-substituted 4-benzylidene pyrazolone derivatives.

[0004] Therefore, the development of a method for synthesizing 4-benzylidene pyrazolone derivatives with different substitution patterns at the benzylic position starting from simple, stable, and readily available raw materials under mild conditions remains a challenging topic worthy of research in organic synthesis. SUMMARY OF THE INVENTION

[0005] The present invention aims to provide a 4-benzylidene pyrazolone derivative and a method for synthesizing the same.

[0006] The mechanism of the present invention is as follows: The phosphorus reagent reacts with α-ketoester to form the Kukhtin-Ramirez adduct A; as a resonance form of A, the dipole B then undergoes nucleophilic attack on the 1,2-diaza-1,3-butadiene compound to form the intermediate C; C is transformed into the intermediate D via an intramolecular transesterification process and undergoes E2 elimination under the action of ethoxy anion to generate the 4-benzylidene pyrazolone product while eliminating phosphine oxide. The specific process is shown in the following formula:

[0007]

[0008] The present invention provides a 4-benzylidene pyrazolone derivative having the structural formula shown in Formula I:

[0009] I

[0010]

[0011] The 4-benzylidene pyrazolone derivative is obtained by reacting a 1,2-diaza-1,3-butadiene compound II

[0012] II

[0013]

[0014] with an α-ketoester III

[0015] III

[0016]

[0017] in the presence of a phosphorus reagent IV

[0018] IV

[0019] to promote the reaction.

[0020] The general reaction formula is:

[0021]

[0022] In the above structural formula, R 1 is selected from aryl, and R 3 is selected from hydrogen, halogen, alkyl, or alkoxy; R 2 and R4 selected from alkyl or aryl; R 5 、R 6 and R 7 are selected from bis(alkyl)amino, alkyl or aryl.

[0023] The present invention provides a method for synthesizing 4-benzylidenepyrazolone derivatives, comprising the following synthesis steps:

[0024] Dissolve the α-ketoester and 1,2-diazabutadiene compound in an organic solvent, place the resulting reaction mixture under low temperature and stir for 10 - 15 minutes, then dropwise add the diluted phosphorus reagent to the above reaction mixture within 5 - 15 minutes. The molar feeding ratio of the α-ketoester, 1,2-diazabutadiene compound and the phosphorus reagent is 1:1 - 2:1 - 1.2. After the dropping is completed, let the reaction naturally warm up to room temperature and continue stirring for 12 hours. After the reaction is completed, rotary evaporate to remove the solvent. The crude product is purified by silica gel column chromatography with 200 - 300 mesh. Use a mixed solution of petroleum ether - ethyl acetate with a volume ratio of 30:1 - 15:1 as the eluent, and calculate the yield of the obtained pure product. Depending on the target compound, the yield is 38 - 69%.

[0025] In the above synthesis method, the organic solvent includes the non-polar solvent toluene; one of the polar solvents tetrahydrofuran, dichloromethane, chloroform, acetonitrile, ethyl acetate. The dosage of the organic solvent is 5 - 20 mL / mmol of the α-ketoester.

[0026] In the above synthesis method, the low temperature is -45 ~ -78 °C.

[0027] In the above synthesis method, the phosphorus reagent includes one of hexamethylphosphorous triamide, tri-n-butylphosphine, tricyclohexylphosphine, triphenylphosphine and other three-coordinate phosphorus reagents containing phosphorus-nitrogen bonds and phosphorus-carbon bonds.

[0028] In the above synthesis method, the phosphorus reagent is diluted with an organic solvent and then added to the reaction system. The organic solvent is the same as the organic solvent in the reaction system, including one of toluene, tetrahydrofuran, dichloromethane, chloroform, acetonitrile, ethyl acetate; the concentration of the diluted phosphorus reagent is 0.20 - 0.24 mol / L.

[0029] The beneficial effects of the present invention:

[0030] (1) The raw materials used in the present invention are simple, easy to obtain and have good stability;

[0031] (2) The reaction conditions are mild, and the types of substituents on the 4-benzylidenepyrazolone product are rich and can be flexibly changed;

[0032] (3) The compounds synthesized by the present invention have rich pharmaceutical activities, providing candidate compounds for the design, synthesis and development of novel drug molecules containing 4-benzylidene pyrazolone structures. Detailed implementation manners

[0033] The technical solutions of the present invention will be described in detail below through specific examples. The listed examples are intended to illustrate the technical solutions of the present invention in detail, rather than limiting the protection scope of the present invention.

[0034] The 1,2-diaza-1,3-butadiene compounds used in the following examples were obtained by purchasing from the market or prepared from phenylhydrazine and ethyl 2-chloroacetoacetate with reference to known synthetic methods (see Preti, L.; et al. Eur. J. Org. Chem. 2010, 4312). Their general structural formula is II:

[0035] II

[0036]

[0037] The α-ketoester compounds used were obtained by purchasing from the market or prepared from ethyl oxalyl chloride and substituted benzene through Friedel-Crafts acylation reaction or from bromobenzene and diethyl oxalate through nucleophilic substitution reaction with reference to known synthetic methods (see Zhang, Z. et al. J. Org. Chem. 2008, 73, 3842 - 3847; Ashfeld, B. L. et al. Chem. Commun. 2014, 50, 10853). Their general structural formula is III:

[0038] III

[0039]

[0040] The general structural formula of the synthesized 4-benzylidene pyrazolone derivatives is I:

[0041] I

[0042]

[0043] In the above general structural formula: R 1 is selected from aryl, R 3 is selected from hydrogen, halogen, alkyl, alkoxy; R 2 , R 4 are selected from alkyl or aryl.

[0044] Example 1.

[0045] Synthesis of 4-benzylidene pyrazolone derivatives, in the general structural formula, R 1 = Ph, R 2 = Me, R 3 = H, R4 = Et.

[0046]

[0047] In a 25 mL Schlenk flask equipped with a magnetic stir bar, 1.0 mL of dichloromethane, 44 mg (0.20 mmol) of 1,2-diazabutadiene (R 1 = Ph, R 2 = Me) and 18 mg (0.10 mmol) of α-ketoester (R 3 = H, R 4 = Et) were successively added. The resulting reaction mixture was stirred at -78 °C for 10 minutes. Subsequently, 21.0 μL (0.12 mmol) of hexamethylphosphorous triamide diluted with 0.5 mL of dichloromethane was slowly added dropwise to the above reaction mixture within 10 minutes. Then the reaction was slowly warmed to room temperature and stirred for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation. The crude product was purified by silica gel column chromatography (200 - 300 mesh), and the eluent was petroleum ether (boiling range 60 - 90 °C): ethyl acetate with a volume ratio of 30:1 - 15:1 for gradient washing. 23 mg of pure red solid was obtained with a yield of 69%.

[0048] 1 H NMR (400 MHz, C6D6) δ 8.02 (d, J = 8.0 Hz, 2H, ArH), 6.92 (m, 4H, ArH), 6.66 (m, 4H, ArH), 4.00 (q, J = 7.1 Hz, 2H, COOEt), 1.08 (s, 3H, C(sp 2 )-Me), 0.81 (t, J = 7.0 Hz, 3H, COOEt); HRMS-ESI ([M+H] + ) Calcd for C 20 H 19 N2O3 335.1390; found 335.1390.

[0049] Example 2

[0050] Synthesis of 4-benzylidene pyrazolone derivatives, where in the structural general formula R 1 = Ph, R 2 = Me, R 3 = H, R 4 = t Bu.

[0051]

[0052] In a 25 mL Schlenk flask equipped with a magnetic stir bar, 1.0 mL of dichloromethane, 44 mg (0.20 mmol) of 1,2-diazabutadiene (R 1 = Ph, R 2 = Me) and 21 mg (0.10 mmol) of α-ketoester (R 3 = H, R 4 = t Bu) were successively added. The resulting reaction mixture was stirred at -45 °C for 10 minutes. Subsequently, 21.0 μL (0.12 mmol) of hexamethylphosphorous triamide diluted with 0.5 mL of dichloromethane was slowly added dropwise to the above reaction mixture within 10 minutes. After the addition was complete, the reaction was slowly warmed to room temperature and stirred for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation. The crude product was purified by silica gel column chromatography (200 - 300 mesh) to obtain the target compound 4-benzylidene pyrazolone derivative. The eluent was petroleum ether (boiling range 60 - 90 °C): ethyl acetate, with a volume ratio of 30:1 to 15:1, and gradient washing was performed. 19 mg of the pure red solid was obtained, with a yield of 52%.

[0053] 1 H NMR (400 MHz, C6D6) δ 8.04 (d, J = 8.0 Hz, 2H, ArH), 6.96 - 6.88 (m, 4H, ArH), 6.67 (m, 4H, ArH), 1.27 (s, 9H, O t Bu), 1.07 (s, 3H C(sp 2 )-Me); HRMS-ESI ([M+Na] + ) Calcd for C 22 H 22 N2NaO3 385.1523; found 385.1523.

[0054] Example 3

[0055] Synthesis of 4-benzylidene pyrazolone derivative, where R 1 = Ph, R 2 = Me, R 3 = Me, R 4 = Et.

[0056]

[0057] The synthesis procedure was basically the same as that in Example 1, and the differences are listed as follows:

[0058] The α-ketoester R 3 = Me was used in an amount of 19 mg (0.10 mmol), and the reaction time at room temperature was 12 hours. 22 mg of the pure red solid was obtained, with a yield of 63%.

[0059] 1 1H NMR (400 MHz, C6D6) δ 8.33 (d, J = 7.6 Hz, 2H, ArH), 7.24 (dd, J = 8.0 Hz, 2H, ArH), 7.12 (d, J = 8.0 Hz, 2H, ArH), 6.96 (dd, J = 7.4 Hz, 1H, ArH), 6.78 (d, J = 7.6 Hz, 2H, ArH), 4.34 (q, J = 7.2 Hz, 2H, COOEt), 1.95 (s, 3H, Ar-CH3), 1.46 (s, 3H, C(sp 2 )-Me), 1.13 (t, J = 7.0 Hz, 3H, COOEt); HRMS-ESI ([M+H] + ) Calcd for C 21 H 22 N2O3 349.1547; found 349.1547.

[0060] Example 4

[0061] Synthesis of 4-benzylidenepyrazolone derivatives, where R 1 = H, R 2 = Me, R 3 = OMe, R 4 = Et.

[0062]

[0063] The synthesis procedure is basically the same as that of Example 1, with the differences listed below:

[0064] The α-ketoester used, R 3 = OMe, with a dosage of 21 mg (0.10 mmol), and the reaction time at room temperature was 12 hours, obtaining 14 mg of pure red solid, with a yield of 38%.

[0065] 1 1H NMR (400 MHz, C6D6) δ 7.92 (d, J = 8.0 Hz, 2H, ArH), 6.80 (dd, J = 8.0 Hz, 2H, ArH), 6.70 (s, 2H, ArH), 6.52 (dd, J = 7.8 Hz, 1H, ArH), 6.12 (d, J = 8.8 Hz, 2H, ArH), 3.94 (q, J = 7.1 Hz, 2H, COOEt), 2.71 (s, 3H, Ar-OCH3), 1.09 (s, 3H, C(sp 2 )-Me), 0.71 (t, J = 7.2 Hz, 3H, COOEt); HRMS-ESI ([M+H] +)Calculated for C 21 H 21 N2O4 365.1496; found 365.1496.

[0066] Example 5

[0067] Synthesis of 4 - benzylidenepyrazolone derivatives, where R in the general structural formula 1 = Ph, R 2 = Me, R 3 = Cl, R 4 = Et.

[0068]

[0069] In a 25 mL Schlenk flask equipped with a magnetic stir bar, 1.0 mL of dichloromethane, 44 mg (0.20 mmol) of 1,2 - diaza - 1,3 - butadiene (R 1 = Ph, R 2 = Me) and 21 mg (0.10 mmol) of α - ketoester (R 3 = Cl, R 4 = Et) were successively added. The resulting reaction mixture was stirred at - 78 °C for 10 minutes. Subsequently, 21.0 μL (0.12 mmol) of hexamethylphosphorous triamide diluted with 0.6 mL of dichloromethane was slowly added dropwise to the above - mentioned reaction mixture, and the addition was completed within 10 minutes. Then the reaction was slowly warmed to room temperature and stirred for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation. The crude product was purified by silica gel column chromatography (200 - 300 mesh), and the eluent was petroleum ether (boiling range 60 - 90 °C): ethyl acetate with a volume ratio of 30:1 - 15:1 for gradient washing; 22 mg of pure red solid was obtained with a yield of 60%.

[0070] 1 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.4 Hz, 2H, ArH), 7.48 (d, J = 8.4 Hz, 2H, ArH), 7.40 (m, 4H, ArH), 7.20 (d, J = 6.6 Hz, 1H, ArH), 4.43 (q, J = 7.2 Hz, 2H, COOEt), 1.86 (s, 3H, C(sp 2 ) - Me), 1.36 (t, J = 7.1 Hz, 3H, COOEt); HRMS - ESI ([M + H] + )Calculated for C 20 H 18 ClN2O3 369.1000; found 369.1000.

[0071] Example 6

[0072] Synthesis of 4-benzylidenepyrazolone derivatives, where R in the general structural formula 1 = Ph, R 2 = Me, R 3 = Br, R 4 = Et.

[0073]

[0074] In a 25 mL Schlenk flask equipped with a magnetic stir bar, 1.0 mL of tetrahydrofuran, 44 mg (0.20 mmol) of 1,2-diazabutadiene (R 1 = Ph, R 2 = Me), and 26 mg (0.10 mmol) of α-ketoester (R 3 = Br, R 4 = Et) were successively added. The resulting reaction mixture was stirred at -78 °C for 10 minutes. Subsequently, 21.0 μL (0.12 mmol) of hexamethylphosphorous triamide diluted with 0.5 mL of tetrahydrofuran was slowly added dropwise to the above reaction mixture, and the addition was completed within 10 minutes. Then the reaction was slowly warmed to room temperature and stirred for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation. The crude product was purified by silica gel column chromatography (200 - 300 mesh), and the eluent was petroleum ether (boiling range 60 - 90 °C): ethyl acetate with a volume ratio of 30:1 - 15:1 for gradient washing. 26 mg of pure red solid was obtained with a yield of 63%.

[0075] 1 H NMR (400 MHz, C6D6) δ 8.29 (d, J = 7.6, 1.2 Hz, 2H, ArH), 7.24 (m, 2H, ArH), 7.08 (d, J = 8.4 Hz, 2H, ArH), 6.96 (dd, J = 7.4, 1H, ArH), 6.81 (d, J = 8.8, 2H, ArH), 4.30 (q, J = 7.1 Hz, 2H, COOEt), 1.28 (s, 3H, C(sp 2 )-Me), 1.12 (t, J = 7.1 Hz, 3H, COOEt); HRMS-ESI ([M+H] + ) Calcd for C 20 H 18 BrN2O3 413.0495; found 413.0495.

[0076] Example 7

[0077] Synthesis of 4-benzylidenepyrazolone derivatives, where R in the general structural formula1 = 4-MeC6H4, R 2 = Me, R 3 = H, R 4 = Et.

[0078]

[0079] The synthesis steps are basically the same as those in Example 1, and the differences are listed as follows:

[0080] The 1,2-diaza-1,3-butadiene (R 1 = 4-MeC6H4, R 2 = Me) used was 46 mg (0.20 mmol), and the reaction time at room temperature was 12 hours. 21 mg of pure red solid was obtained, and the yield was 61%.

[0081] 1 H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.8 Hz, 2H, ArH), 7.54 - 7.42 (m, 5H, ArH), 7.19 (d, J = 8.4 Hz, 2H, ArH), 4.43 (q, J = 7.1 Hz, 2H, COOEt), 2.34 (s, 3H, Ar-CH3), 1.82 (s, 3H, C(sp 2 )-Me), 1.36 (t, J = 7.2 Hz, 3H, COOEt); HRMS-ESI ([M+H] + ) Calcd for C 21 H 22 N2O3 349.1547; found 349.1547.

[0082] Example 8

[0083] Synthesis of 4-benzylidene pyrazolone derivatives, where R in the general structural formula 1 = 4-ClC6H4, R 2 = Me, R 3 = H, R 4 = Et.

[0084]

[0085] The synthesis steps are basically the same as those in Example 1, and the differences are listed as follows:

[0086] The 1,2-diaza-1,3-butadiene (R 1 = 4-ClC6H4, R 2 = Me) used was 50 mg (0.20 mmol), and the reaction time at room temperature was 12 hours. 23 mg of pure red solid was obtained, and the yield was 62%.

[0087] 1 1H NMR (400 MHz, C6D6) δ 8.11 (d, J = 8.8 Hz, 2H, ArH), 7.41 (d, J = 8.6 Hz, 2H, ArH), 7.28 (d, J = 1.2 Hz, 2H, ArH), 7.10 - 7.02 (m, 3H, ArH), 4.38 (q, J = 7.1 Hz, 2H, COOEt), 1.45 (s, 3H, C(sp 2 )-Me), 1.19 (t, J = 7.2 Hz, 3H, COOEt); HRMS-ESI ([M+H] + ) Calcd for C 20 H 18 ClN2O3 369.1000; found 369.1000.

[0088] Example 9

[0089] Synthesis of 4-benzylidenepyrazolone derivatives, where in the structural general formula R 1 = 4-BrC6H4, R 2 = Me, R 3 = H, R 4 = Et.

[0090]

[0091] The synthesis procedure is basically the same as that in Example 1, with the differences listed as follows:

[0092] The used 1,2-diaza-1,3-butadiene (R 1 = 4-BrC6H4, R 2 = Me) was used in an amount of 59 mg (0.20 mmol), and the reaction time at room temperature was 12 hours, obtaining 27 mg of pure red solid with a yield of 65%.

[0093] 1 1H NMR (400 MHz, C6D6) δ 8.01 (d, J = 8.2 Hz, 2H, ArH), 7.31 (d, J = 8.8 Hz, 2H, ArH), 7.18 (d, J = 1.6 Hz, 2H, ArH), 7.04 - 6.89 (m, 3H, ArH), 4.28 (q, J = 7.1 Hz, 2H, COOEt), 1.35 (s, 3H, C(sp 2 )-Me), 1.09 (t, J = 7.2 Hz, 3H, COOEt); HRMS-ESI ([M+H] + ) Calcd for C 20 H 18BrN2O3 413.0495; found 413.0495.

[0094] Example 10

[0095] Synthesis of 4-benzylidene pyrazolone derivatives, where R in the general structural formula 1 = Ph, R 2 = Et, R 3 = H, R 4 = Et.

[0096]

[0097] In a 25 mL Schlenk flask equipped with a magnetic stir bar, 1.0 mL of dichloromethane, 23 mg (0.10 mmol) of 1,2-diazabutadiene (R 1 = Ph, R 2 = Et) and 23 mg (0.10 mmol) of α-ketoester (R 3 = H, R 4 = Et) were successively added. The resulting reaction mixture was stirred at -78 °C for 10 minutes. Subsequently, 18.2 μL (0.10 mmol) of hexamethylphosphorous triamide diluted with 0.5 mL of dichloromethane was slowly added dropwise to the above reaction mixture, and the addition was completed within 10 minutes. Then the reaction was slowly warmed to room temperature and stirred for 12 hours. After the reaction was completed, the solvent was removed by rotary evaporation. The crude product was purified by silica gel column chromatography (200 - 300 mesh), and the eluent was petroleum ether (boiling range 60 - 90 °C): ethyl acetate with a volume ratio of 30:1 - 15:1, gradient washing; 21 mg of pure red solid was obtained with a yield of 60%.

[0098] 1 H NMR (400 MHz, C6D6) δ 8.29 (d, J = 7.6 Hz, 2H, ArH), 7.28 - 7.18 (m, 4H, ArH), 7.05 - 6.91 (m, 4H, ArH), 4.30 (q, J = 7.2 Hz, 2H, COOEt), 1.77 (q, J = 7.3 Hz, 2H, Et), 1.10 (t, J = 7.2 Hz, 3H, COOEt), 0.77 (t, J = 7.2 Hz, 3H, Et); HRMS-ESI ([M+H] + ) Calcd for C 21 H 21 N2O3 349.1547; found 349.1547.

Claims

1. A method for synthesizing 4-benzylidene pyrazolone derivatives, characterized in that: It is obtained by the reaction of a 1,2-diaza-1,3-butadiene compound with an α-ketoester promoted by a phosphorus reagent; the 1,2-diaza-1,3-butadiene compound has the structural formula shown in Formula II below: II ； The α-ketoester has the structural formula shown in Formula III below: III ； The phosphorus reagent IV has the structural formula shown in Formula IV below: IV ； The obtained 4-benzylidene pyrazolone derivative has the structural formula shown in I: I ； wherein R 1 is selected from aryl, R 3 is selected from hydrogen, halogen, alkyl or alkoxy; R 2 , R 4 are each independently selected from alkyl or aryl; R 5 , R 6 and R 7 are each independently selected from bis(alkyl)amino, alkyl or aryl; The synthesis method of the 4-benzylidene pyrazolone derivative is as follows: Dissolve the α-ketoester and 1,2-diazabutadiene compound in an organic solvent, and place the resulting reaction mixture at a low temperature of -45 to -78 o °C and stir for 10 to 15 minutes. Subsequently, add the diluted phosphorus reagent dropwise to the above reaction mixture within 5 to 15 minutes. The molar feeding ratio of the α-ketoester, 1,2-diazabutadiene compound, and phosphorus reagent is 1∶1~2∶1~1.

2. After the addition is complete, allow the reaction system to warm up to room temperature naturally and continue stirring for 12 hours. After the reaction is completed, rotary evaporate to remove the solvent. The crude product is purified by silica gel column chromatography with 200 to 300 mesh, and a mixed solution with a volume ratio of petroleum ether to ethyl acetate of 30:1 to 15:1 is used as the eluent to obtain the 4-benzylidene pyrazolone derivative; The phosphorus reagent is any one of hexamethylphosphorous triamide, tri-n-butylphosphine, tricyclohexylphosphine, and triphenylphosphine.

2. The synthetic method of the 4-benzylidene pyrazolone derivative according to claim 1, characterized in that: The organic solvent includes any one of toluene, tetrahydrofuran, dichloromethane, chloroform, acetonitrile, and ethyl acetate, and the amount of the organic solvent used is 5-20 mL / mmol of the α-ketoester.

3. The synthetic method of the 4-benzylidene pyrazolone derivative according to claim 1, characterized in that: The phosphorus reagent is diluted with an organic solvent and then added to the reaction system. The organic solvent is the same as the organic solvent in the reaction system, and the concentration of the diluted phosphorus reagent is 0.20~0.24 mol / L.

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