A method for preparing dihydropyrazole compounds containing quaternary carbon centers

Abstract

The invention discloses a method for preparing a dihydropyrazole compound containing a quaternary carbon center. The preparation method mainly uses an alkyl diazo compound as a raw material for reaction. The method has mild reaction conditions, good functional group tolerance and substrate universality, and can be produced on a gram scale. Moreover, no additional ligand needs to be added, and the method has excellent chemical selectivity, and is expected to be applied in the synthesis of related medicinal chemistry and pesticide products.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing a dihydropyrazole compound containing a quaternary carbon center. Background Art

[0002] Dihydropyrazoles are an important class of heterocyclic compounds that exist in natural products and drugs with biological activities, such as anti-asthmatic, antihypertensive, analgesic, antibacterial, anticancer, antidepressant and non-steroidal anti-inflammatory drugs ((a) M. Kissane and A. R. Maguire, Chem. Soc. Rev., 2010, 39, 845–883; (b) C. -H. Kuchentha and W. Maison, Synthesis, 2010, 719–740; (c) A. Sahoo, S. Yabanoglu, BN Sinha, G. Ucar, A. Basu and V. Jayaprakash, Bioorg. Med. Chem. Lett., 2010, 20, 132–136;).

[0003] Quaternary carbon centers are commonly found in various natural products and drug-related compounds. Due to their unique spatial structure, they have an important influence on the biological activity of dihydropyrazole natural products. However, the construction of quaternary carbon centers has always been a difficult point in organic synthesis. Although significant progress has been made in the effective construction of quaternary carbon centers in recent years, new methods that may have advantages in terms of functional group tolerance, ease of operation, and the use of readily available raw materials are still in great need ((a) K. Fuji, Chem. Rev., 1993, 93, 2037–2066; (b) M. Shimizu, Angew. Chem., Int. Ed., 2011, 50, 5998–6000;). How to efficiently and selectively construct dihydropyrazole compounds containing quaternary carbon centers is a very challenging topic in organic chemistry.

[0004] At present, there are many methods for synthesizing dihydropyrazole compounds, but there are few reports on methods for efficiently preparing dihydropyrazole compounds containing quaternary carbon centers from simple raw materials. There are three main methods for synthesizing dihydropyrazole compounds known at present: the first is the asymmetric synthesis of dihydropyrazoles by the [4+1] cycloaddition reaction of in situ derived azoene and sulfur ylides [J.-R.Chen, W.-R.Dong, M.Candy, F.-F.Pan, M.JorresandC.Bolm, J.Am.Chem.Soc., 2012, 134, 6924–6927], the second is the synthesis of racemic dihydropyrazoles using in situ derived azoene and diazoesters as 1,1-dipole C1 synthons (OA Attanasi, LD Crescentini, G.Favi, F.Mantellin i, S. Mantenuto and S. Nicolini, J. Org. Chem., 2014, 79, 83318338), and the third is to use the [4+1] cycloaddition reaction of diazo esters and in situ formed azoene promoted by Cu(Ⅱ) / bis(oxazoline) ligands to synthesize dihydropyrazoles containing quaternary carbon centers (Z. Wang, Y. Yang, F. Gao, Z. Wang, Q. Luo and L. Fang, Org. Lett., 2018, 20, 934–937). All of the above methods require the use of metals and ligands, and the reaction conditions are harsh and the substrate range is narrow, which limits the application of dihydropyrazole compounds in medicinal chemistry and natural product synthesis. Summary of the invention

[0005] In view of the shortcomings of the prior art, the present invention provides a method for preparing a dihydropyrazole compound containing a quaternary carbon center. The present invention provides a novel method for efficiently, economically and diversifiedly synthesizing a dihydropyrazole compound containing a quaternary carbon center by using a simple and readily available alkyl diazo compound as a raw material and reacting in one step. The method has readily available raw materials, simple operation, mild conditions, and a wide range of substrate applications, and provides a very efficient method for synthesizing important drug molecules and natural products containing a dihydropyrazole compound structural unit containing a quaternary carbon center.

[0006] The technical solution of the present invention is specifically as follows:

[0007] A method for preparing a dihydropyrazole compound containing a quaternary carbon center represented by formula (3) or formula (4), specifically, under the protection of an inert gas, a compound represented by formula (1), a catalyst and an organic solvent are contacted and reacted under visible light to obtain a compound represented by formula (3); or, under the protection of an inert gas, a compound represented by formula (1), a compound represented by formula (2), a catalyst and an organic solvent are contacted and reacted under visible light to obtain a compound represented by formula (4);

[0008]

[0009] in:

[0010] R 1 Selected from -CO2R 4 、-PO3R 5 One of;

[0011] R 2 and R 3 The same or different, and each independently selected from -CO2R 4 , -CD3, substituted or unsubstituted alkyl, one of aryl;

[0012] R 4 is selected from substituted or unsubstituted aryl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, C3-C 12 Alkyl, C 10 -C 30 Polycyclic alkyl, C4-C 10 One of the heterocyclic groups;

[0013] R 5 Selected from C2-C6 alkyl.

[0014] As a specific embodiment of the present invention, R 2 and R 3 The same or different, and each independently selected from -CO2R 4 , -CD3, C1-C6 alkyl, C1-C6 haloalkyl, and phenyl.

[0015] As a specific embodiment of the present invention, R 4 is selected from benzyl, halogenated benzyl, C1-C3 haloalkyl substituted benzyl, C1-C3 alkyl substituted benzyl, C1-C3 alkoxy substituted benzyl, C1-C6 alkyl, C1-C3 haloalkyl, C4-C6 cycloalkyl, C1-C6 alkyl substituted C4-C6 cycloalkyl, C3-C9 alkenyl, C 10 -C 26 One of polycycloalkyl, C4-C6 heterocyclic group and phenyl.

[0016] As a specific embodiment of the present invention, the compound represented by formula (1) is selected from benzyl 2-diazopropionate, benzyl 4-(trifluoromethyl)-2-diazopropionate, 2-chloro-6-fluorobenzyl-2-diazopropionate, 2-fluorobenzyl 2-diazopropionate, 2-chlorobenzyl 2-diazopropionate, 2,3-difluorobenzyl 2-diazopropionate, 2-methylbenzyl 2-diazopropionate, 2,6-dimethylbenzyl-2-diazopropionate, 2,4,6-trimethoxybenzyl 2-diazopropionate, (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-diazopropionate, (R)-3,6-dimethylheptyl-5-and-1-yl-2-diazopropionate, (5S, One of the following: 8S,9S,10S,13R,14S,17S)-10,13-dimethyl-17-(5-methylhexyl)hexahydro-1H-cyclopentylphenanthrene-2-yl-2-diazopropionate, 2-diazopropionic acid-3-bromopropyl ester, pentane-3-yl 2-diazopropionate, 2-diazopropionic acid cyclobutyl ester, (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl-2-diazopropionate, 2-diazopropionic acid phenyl ester, 2-diazopropionic acid ethyl ester, 2-diazopropionic acid tert-butyl ester, 2-diazopropionic acid isobutyl ester, 2-diazopropanoic acid benzyl ester-3,3,3-D3, (1-diazoethyl)phosphonic acid dimethyl ester, and 2-diazopropanoic acid benzyl ester.

[0017] As a specific embodiment of the present invention, the compound represented by formula (2) is selected from one of 2-diazohexanoic acid benzyl ester and 1-diazo-2,2,2-trifluoroethylbenzene.

[0018] As a specific embodiment of the present invention, the catalyst is selected from one of acid red, triethylamine, pentafluorophenol, 2,6-dichlorophenol, 2,6-dibromophenol, N,N-diisopropylethylamine and N,N,N'-trimethylethylenediamine; the organic solvent is selected from at least one of N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, ethylene glycol dimethyl ether, dichloromethane, 1,2-dichloroethane, 1,4-dioxane, chlorobenzene, trifluorotoluene, toluene, o-xylene, n-heptane and n-hexane.

[0019] As a specific embodiment of the present invention, in the preparation of the compound represented by formula (3), the molar volume ratio of the compound represented by formula (1), the catalyst and the organic solvent is 0.2-10 mmol: 0.002-10.0 mmol: 0.5-5.0 mL.

[0020] As a specific embodiment of the present invention, in the preparation of the compound represented by formula (4), the molar volume ratio of the compound represented by formula (1), the compound represented by formula (2), the catalyst and the organic solvent is 0.2-10mmol:0.4-20mmol:0.002-10.0mmol:0.5-5.0mL.

[0021] As a specific embodiment of the present invention, the wavelength of the visible light is 400-800 nm, the reaction temperature is 0-80° C., and the reaction time is within 50 hours. The heating process can be carried out by using an oil bath (such as silicone oil, paraffin oil, etc.) or other heating methods.

[0022] As a specific embodiment of the present invention, the reaction product is further subjected to post-treatment; preferably, the post-treatment comprises filtering, washing, removing the solvent under reduced pressure, and column chromatography separation and purification in sequence.

[0023] The beneficial effects of the present invention are:

[0024] (1) The main raw materials of the preparation method of the present invention are readily available alkyl diazo compounds, most of which can be commercial reagents, do not require special treatment, are low in price, and the preparation method is simple, which is convenient for industrial production;

[0025] (2) The wavelength of the light used in the preparation method of the present invention is within 400 to 800 nm, which is a kind of natural light, which is conducive to saving costs and reducing pollution to the environment, and is in line with the development concept of green chemistry;

[0026] (3) The reaction conditions involved in the preparation method of the present invention have good functional group tolerance and substrate universality, and can be produced on a gram scale;

[0027] (4) The preparation method of the present invention is efficient and diverse, and a dihydropyrazole compound containing a quaternary carbon center is constructed in one step, and N2 is the only by-product, which has extremely high step economy and atom economy;

[0028] (5) The preparation method of the present invention does not require the addition of additional ligands and has excellent chemical selectivity, and is expected to be applied in related medicinal chemistry and natural product synthesis. DETAILED DESCRIPTION

[0029] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described below in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0030] The wavelength of blue light in the following embodiments is 455 nanometers.

[0031] Example 1: 5-methyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylic acid dibenzyl ester

[0032]

[0033] Preparation method: Under the protection of inert gas, add 2-diazopropionic acid benzyl ester (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 78%). 1 HNMR (400MHz, CDCl3) δ7.52–7.29(m,10H),6.72(s,1H),5.27(s,2H),5.17(s,2H),3.54(d,J=17.6Hz,1H),2.83(d,J=17.6Hz,1H),1.54(s,3H). 13 CNMR(125MHz, CDCl3)δ173.52,161.93,142.09,135.50,135.00,128.74,128.69,128.66,128.63,1 28.60,128.57,128.53,128.40,128.22,128.09,127.97,77.24,69.87,67.73,66.90,41.21,24.21.

[0034] Example 2: Bis(3-(trifluoromethyl)benzyl)5-methyl-4,5-dihydropyrazole-3,5-dicarboxylate

[0035]

[0036] Preparation method: Under the protection of inert gas, add 4-(trifluoromethyl)-2-diazopropionic acid benzyl ester (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 81%). 1 HNMR (600MHz, CDCl3) δ7.71–7.43(m,10H),6.74(s,1H),5.30(s,2H),5.22(s,2H),3.54(d,J=17.6Hz,1H),2.87(d,J=17.6Hz,1H),1.57(s,3H). 13CNMR (150MHz, CDCl3) δ173.38,161.84,141.68,136.55,136.11,131.94,131.54,131.44,131.26,131.05,129.46,129.29,125.67,12 5.64,125.62,125.59,125.44,125.41,125.39,125.35,125.00,124.98,124.95,124.93,124.85,70.03,66.91,66.14,41.28,24.23. 19 FNMR(565MHz, CDCl3)δ-62.66,-62.75.

[0037] Example 3: Bis(2-chloro-6-fluorobenzyl)5-methyl-4,5-dihydropyrazole-3,5-dicarboxylate

[0038]

[0039] Preparation method: Under the protection of inert gas, add 2-chloro-6-fluorobenzyl-2-diazopropionate (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 69%). 1 HNMR(600MHz, CDCl3)δ7.38–7.25(m,4H),7.11–7.03(m,2H),6.73(s,1H),5.45( s,2H),5.37(s,2H),3.56(d,J=17.6Hz,1H),2.84(d,J=17.7Hz,1H),1.57(s,3H). 13CNMR(150MHz,CDCl3)δ173.38,163.11,162.88,161.83,161.44,161.21,1 41.79,136.77,136.74,136.51,136.48,131.33,131.26,131.07,131.01,1 25.75,125.73,125.64,125.62,121.49,121.37,121.07,120.96,114.61, 114.51,114.46,114.37,70.02,58.83,58.80,58.01,57.98,41.33,24.31. 19 FNMR(565MHz, CDCl3)δ-112.60,-113.01.

[0040] Example 4: 5-Methyl-4,5-dihydropyrazole-3,5-dicarboxylic acid bis(2-fluorobenzyl)

[0041]

[0042] Preparation method: Under the protection of inert gas, add 2-fluorobenzyl 2-diazopropionate (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 68%). 1 HNMR (600MHz, CDCl3) δ7.42(td,J=7.5,1.8Hz,1H),7.33(dtt,J=10.9,7.1,5.5Hz,3H),7.14(tdd,J=7.6,4.5,1.1Hz,2H),7.0 7(qd,J=8.8,1.1Hz,2H),6.71(s,1H),5.33(s,2H),5.24(s,2H),3.53(d,J=17.6Hz,1H),2.83(d,J=17.6Hz,1H),1.54(s,3H). 13CNMR (150MHz, CDCl3) δ173.50,161.99,161.93,160.41,160.34,142.00,130.96,130.93,130.88,130.81,130.79,130.53,130.48,124.45,1 24.43,124.35,124.32,122.87,122.78,122.36,122.27,115.90,115. 75,115.73,115.59,70.03,62.04,62.01,60.88,60.85,41.29,24.31. 19 FNMR (565MHz, CDCl3) δ-117.68 (p, J=8.2Hz).

[0043] Example 5: Bis(2-chlorobenzyl)5-methyl-4,5-dihydropyrazole-3,5-dicarboxylate

[0044]

[0045] Preparation method: Under the protection of inert gas, add 2-chlorobenzyl 2-diazopropionate (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 64%). 1 HNMR(600MHz, CDCl3)δ7.47–7.43(m,1H),7.42–7.34(m,3H),7.32–7.25(m,4H),6.75(s,1 H),5.37(s,2H),5.27(s,2H),3.58(d,J=17.6Hz,1H),2.86(d,J=17.6Hz,1H),1.58(s,3H). 13 CNMR (150MHz, CDCl3) δ173.44,161.84,141.99,134.25,133.81,133.41,132.78,130.4 8,130.25,130.07,129.96,129.71,127.17,127.06,70.14,65.44,64.24,41.36,24.34.

[0046] Example 6: Bis(2,3-difluorobenzyl)5-methyl-4,5-dihydropyrazole-3,5-dicarboxylate

[0047]

[0048] Preparation method: Under the protection of inert gas, add 2,3-difluoro-2-diazopropionic acid benzyl ester (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 78%). 1 HNMR(600MHz, CDCl3)δ7.20–7.14(m,3H),7.09(d,J=9.2Hz,3H),6.72(s,1H),5.33 (s,2H),5.25(s,2H),3.52(d,J=17.6Hz,1H),2.84(d,J=17.6Hz,1H),1.56(s,3H). 13 CNMR (150MHz, CDCl3) δ173.30,161.75,150.13,150.05,149.96,149.84,149.78,148.39,148.30,141.64,125.48,125.30,125.25,125.1 8,124.73,124.65,124.54,124.51,124.47,124.38,124.34,124.31, 118.19,118.08,117.76,117.65,70.05,61.39,60.28,41.25,24.25. 19 FNMR(565MHz, CDCl3)δ-57.57(tt,J=21.5,6.1Hz),-61.99(ddd,J=21.1,10.1,4.9Hz),-62.44–-62.56(m).

[0049] Example 7: Bis(2,4-dichlorobenzyl)5-methyl-4,5-dihydropyrazole-3,5-dicarboxylate

[0050]

[0051] Preparation method: Under the protection of inert gas, add 2,4-dichloro-2-diazopropionic acid benzyl ester (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 75%). 1HNMR(600MHz, CDCl3)δ7.40–7.31(m,3H),7.25–7.17(m,3H),6.69(s,1H),5.27(s,2 H),5.17(s,2H),3.48(d,J=17.6Hz,1H),2.80(d,J=17.6Hz,1H),1.52(s,3H).13CNMR (150MHz, CDCl3) δ173.30,161.72,141.73,135.63,135.02,134.54,132.02,131.41, 131.36,130.99,129.89,129.60,127.53,127.41,70.14,64.78,63.62,41.30,24.27.

[0052] Example 8: Bis(2-methylbenzyl)5-methyl-4,5-dihydropyrazole-3,5-dicarboxylate

[0053]

[0054] Preparation method: Under the protection of inert gas, add 2-methylbenzyl 2-diazopropionate (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 72%). 1 HNMR(600MHz, CDCl3)δ7.34(d,J=7.5Hz,1H),7.28–7.20(m,3H),7.17(t,J=7.5Hz,4H),6.74(s,1H),5.26( s,2H),5.17(s,2H),3.51(d,J=17.5Hz,1H),2.81(d,J=17.6Hz,1H),2.35(s,3H),2.31(s,3H),1.52(s,3H). 13CNMR(150MHz, CDCl3)δ173.54,161.98,142.00,137.10,137.07,133.58,133.01,130.59,130.43,1 29.48,129.46,129.00,128.66,126.20,126.08,69.99,66.31,65.28,41.36,24.22,19.03,18.90.

[0055] Example 9: Bis(2,6-dimethylbenzyl)5-methyl-4,5-dihydropyrazole-3,5-dicarboxylate

[0056]

[0057] Preparation method: Under the protection of inert gas, add 2,6-dimethylbenzyl 2-diazopropionate (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 60%). 1 HNMR(600MHz, CDCl3)δ7.15(dt,J=15.8,7.6Hz,2H),7.04(t,J=7.8Hz,4H),6.64(s,1H),5.34(d,J=1.7Hz ,2H),5.25(s,2H),3.47(d,J=17.6Hz,1H),2.77(d,J=17.6Hz,1H),2.40(s,6H),2.35(s,6H),1.51(s,3H). 13 CNMR(150MHz,CDCl3)δ173.91,162.28,142.23,138.59,138.45,131.73,131.22,1 29.20,128.92,128.56,128.46,70.11,62.99,62.03,41.42,24.39,19.86,19.72.

[0058] Example 10: Bis(3,5-dimethoxybenzyl)5-methyl-4,5-dihydropyrazole-3,5-dicarboxylate

[0059]

[0060] Preparation method: Under the protection of inert gas, add 2,4,6-trimethoxybenzyl 2-diazopropionate (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 78%). 1 HNMR(600MHz, CDCl3)δ6.76(s,1H),6.53(s,2H),6.46–6.38(m,4H),5.18(s,2H),5.0 9(s,2H),3.77(s,12H),3.54(d,J=17.6Hz,1H),2.84(d,J=17.6Hz,1H),1.55(s,3H). 13 CNMR(150MHz,CDCl3)δ173.48,161.93,161.12,161.01,141.99,137.80,1 37.33,106.38,105.96,100.47,69.96,67.60,66.84,55.44,41.31,24.27.

[0061] Example 11: Bis(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)5-methyl-4,5-dihydropyrazole-3,5-dicarboxylate

[0062]

[0063] Preparation method: Under the protection of inert gas, add (1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl 2-diazopropionate (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 72%). 1HNMR(600MHz, CDCl3)δ6.71–6.60(m,1H),4.86–4.80(m,1H),4.73–4.69(m,1H), 3.52–3.44(m,1H),2.79(ddd,J=17.5,13.5,11.3Hz,1H),1.71–1.67(m,4H),1.59 (s,2H),1.55(s,1H),1.54(d,J=6.9Hz,3H),1.35(d,J=3.3Hz,1H),1.09–1.03(m, 3H), 0.89 (dd, J=10.9, 4.5Hz, 14H), 0.76 (d, J=5.5Hz, 3H), 0.72 (d, J=7.0Hz, 3H). 13 CNMR(150MHz, CDCl3)δ173.73,173.59,173.56,161.98,161.90,143.17,143.06,142.93,76.32,76.29,76.27,75.35,75 .32,75.29,70.11,69.96,69.91,47.12,47.10,46.99,46.96,41.58,41.48,41.29,41.21,40.97,40.94,40.92,40.73,4 0.71,40.67,34.34,34.26,31.58,31.51,26.53,26.50,26.41,26.38,26.36,26.30,24.39,24.36,24.15,23.61,23.58,23.56,23.40,23.37,23.31,22.13,22.08,20.93,20.91,20.90,20.87,20.84,16.50,16.47,16.44,16.19,16.15,16.12.

[0064] Example 12: 5-adamantan-2-yl) 3-adamantan-2-yl 5-methyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylate

[0065]

[0066] Preparation method: Under the protection of inert gas, add adamantane-2-yl-2-diazopropionate (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 78%). 1 HNMR (600MHz, CDCl3) δ6.73(s,1H),5.06(s,1H),4.94(s,1H),3.55(d,J=17.5Hz,1H),2.83(d,J=1 7.5Hz,1H),2.07–1.91(m,9H),1.85(d,J=13.0Hz,8H),1.79–1.70(m,9H),1.56(d,J=10.5Hz,7H). 13 CNMR (150MHz, CDCl3) δ173.29,161.46,143.26,78.87,77.89,37.32,37.20,36.28,36.19,31.81,31.70,27.20,27.08,26.95,26.82,24.33.

[0067] Example 13: 3-(5S,8R,9S,10S,13R,14S,17R)-10,13-dimethyl-17-(R)-6-methylheptane-2-yl)hexahydro-1H-cyclopentylphenanthrene-2-yl)5-((5S,8S,9S,10S,13R,14S,17S)-10,13-dimethyl-17-(5-methylhexyl)hexahydro-1H-cyclopentan-2-yl)5-methyl-4,5-dihydropyrazole-3,5-dicarboxylate

[0068]

[0069] Preparation method: Under the protection of inert gas, add (5S, 8S, 9S, 10S, 13R, 14S, 17S)-10,13-dimethyl-17-(5-methylhexyl) hexahydro-1H-cyclopentylphenanthrene-2-yl-2-diazopropionate (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 71%). 1 HNMR(600MHz, CDCl3)δ6.65(s,1H),4.84(tt,J=11.3,4.9Hz,1H),4.72(tt,J=11.4,4.9Hz,1H),3.48(dd,J=17.6,2.4Hz,1H),2.77(d,J=17.6Hz,1H), 1.96(d,J=12.9Hz,2H),1.87–1.72(m,6H),1.68–1.52(m,9H),1.51(s,3H) ,1.37–1.22(m,18H),1.16–0.95(m,20H),0.91–0.81(m,27H),0.65(s,8H). 13 CNMR (150MHz, CDCl3) δ173.58,173.56,161.93,143.07,75.76,74.93,69.72,56.55,56.52, 56.40,54.34,54.29,44.84,44.72,42.72,41.35,40.12,40.08,39.64,36.91,36.76,36.30, 35.93,35.61,35.58,35.56,34.08,33.89,33.86,32.12,32.08,28.72,28.69,28.37,28.14,27.54,27.39,27.37,24.52,24.33,23.97,22.95,22.70,21.34,18.80,12.38,12.36,12.20.

[0070] Example 14: Bis(3-bromopropyl)5-methyl-4,5-dihydropyrazole-3,5-dicarboxylate

[0071]

[0072] Preparation method: Under the protection of inert gas, add 2-diazopropionic acid-3-bromopropyl ester (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 40%). 1 HNMR (600MHz, CDCl3) δ6.71 (s, 1H), 4.32 (t, J = 6.2Hz, 2H), 4.26 (td, J = 6.3, 1.3Hz, 2H), 3.43 (t, J = 6.7Hz, 1H),3.40(t,J=6.5Hz,1H),2.83(d,J=17.6Hz,1H),1.99(t,J=6.5Hz,2H),1.96–1.93(m,2H),1.56(s,3H). 13 CNMR (150MHz, CDCl3) δ173.69,162.08,142.13,69.97,63.24,62.27,48.66,48.24,41.34,28.27,28.12,24.30.

[0073] Example 15: 5-Methyl-4,5-dihydropyrazole-3,5-dicarboxylic acid di(pentyl)

[0074]

[0075] Preparation method: Under the protection of inert gas, add pentane-3-yl 2-diazopropionate (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 80%). 1 HNMR (600MHz, CDCl3) δ6.69 (s, 1H), 4.89 (p, J = 6.3Hz, 1H), 4.80 (tt, J = 7.3, 5.1Hz, 1H), 3.51(d,J=17.5Hz,1H),2.80(d,J=17.5Hz,1H),1.69–1.55(m,3H),0.92–0.83(m,15H). 13CNMR (150MHz, CDCl3) δ173.93,162.22,143.12,78.88,78.02,70.08,41.46,26.63,26.54,24.30,9.77,9.63.

[0076] Example 16: 5-Methyl-4,5-dihydropyrazole-3,5-dicarboxylic acid dicyclobutyl ester

[0077]

[0078] Preparation method: Under the protection of inert gas, add 2-diazopropionic acid cyclobutyl ester (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 78%). 1 HNMR (600MHz, CDCl3) δ6.67(s,1H),5.10(p,J=7.1Hz,1H),5.03–4.96(m,1H),3.48(d,J=17.6Hz,1H),2.78(d,J=17.6Hz,1H),2.37(tdt,J=15.5,8 .0,2.4Hz,4H),2.18(ddd,J=10.3,8.0,2.3Hz,2H),2.06(ttd,J=10.2,5. 2,2.8Hz,2H),1.80(t,J=10.2Hz,2H),1.63(d,J=9.1Hz,2H),1.53(s,3H). 13 CNMR (150MHz, CDCl3) δ173.29,161.72,142.61,70.47,69.70,41.22,30.44,30.42,30.30,24.35,13.61,13.48.

[0079] Example 17: 3-((R)-4,4-dimethyl-1,3-dioxolan-2-yl)methyl)5-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)5-methyl-4,5-dihydropyrazole-3,5-dicarboxylate

[0080]

[0081] Preparation method: Under the protection of inert gas, add (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-diazopropionate (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 67%). 1 HNMR (600MHz, CDCl3) δ6.76 (d, J=12.4Hz, 1H), 4.38 (qd, J=5.8, 1.7Hz, 1H), 4.32 (ddd, J=6.6, 4. 4,1.3Hz,1H),4.26(dd,J=5.5,2.1Hz,2H),4.22–4.20(m,1H),4.20–4.18(m,1H),4.10–4.06(m, 2H),3.79(ddd,J=8.6,5.9,0.8Hz,1H),3.75–3.72(m,1H),3.53(dd,J=17.6,3.5Hz,1H),2.84(d dd,J=17.6,2.7,0.8Hz,1H),1.57(d,J=1.0Hz,3H),1.42(d,J=2.7Hz,8H),1.36(d,J=3.5Hz,8H). 13 CNMR (150MHz, CDCl3) δ173.57,173.51,161.90,141.63,141.61,110.09,110.03,73.53,73.40,73.38,69.99 ,69.97,66.59,66.08,66.07,66.00,65.46,65.43,41.31,41.25,26.84,26.80,25.49,25.32,25.30,24.34.

[0082] Example 18: 5-Methyl-4,5-dihydropyrazole-3,5-dicarboxylic acid diphenyl ester

[0083]

[0084] Preparation method: Under the protection of inert gas, add 2-diazopropionic acid phenyl ester (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 41%). 1 HNMR(600MHz, CDCl3)δ7.41(q,J=7.1Hz,4H),7.31–7.26(m,2H),7.19(d,J=8.0Hz,2H),7.12 (d,J=8.0Hz,2H),6.97(s,1H),3.80(d,J=17.7Hz,1H),3.07(d,J=17.7Hz,1H),1.79(s,3H). 13 CNMR(150MHz, CDCl3)δ172.22,160.69,150.57,150.47,141.38,129.80,129.62,126.62,126.21,121.70,121.19,70.35,41.38,24.52.

[0085] Example 19: Diethyl 5-methyl-4,5-dihydropyrazole-3,5-dicarboxylate

[0086]

[0087] Preparation method: Under the protection of inert gas, add ethyl 2-diazopropionate (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 93%). 1 HNMR (600MHz, CDCl3) δ6.69(s,1H),4.27(q,J=7.1Hz,2H),4.19(q,J=7.2Hz,2H),3.49(d,J=1 7.6Hz, 1H), 2.80 (d, J = 0.9Hz, 1H), 1.53 (s, 3H), 1.32 (t, J = 7.1Hz, 3H), 1.27 (t, J = 7.1Hz, 3H). 13CNMR (151MHz, CDCl3) δ173.94,162.28,142.68,69.82,62.19,61.37,41.28,24.31,14.33,14.16.

[0088] Example 20: Di-tert-butyl 5-methyl-4,5-dihydropyrazole-3,5-dicarboxylate

[0089]

[0090] Preparation method: Under the protection of inert gas, add tert-butyl 2-diazopropionate (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 51%). 1 HNMR (600MHz, CDCl3) δ6.57 (s, 1H), 3.43 (d, J = 17.7Hz, 1H), 2.72 (d, J = 17.6Hz, 1H), 1.53 (s, 9H), 1.46 (s, 9H). 13 CNMR (150MHz, CDCl3) δ173.29,161.73,144.18,82.75,82.08,69.98,41.34,28.27,28.01,24.68.

[0091] Example 21: Di-sec-butyl 5-methyl-4,5-dihydropyrazole-3,5-dicarboxylate

[0092]

[0093] Preparation method: Under the protection of inert gas, add 2-diazopropionic acid isobutyl ester (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 90%). 1HNMR(600MHz, CDCl3)δ6.67(s,1H),4.25(t,J=6.9Hz,2H),4.17(t,J=6.9Hz,2H),3.53–3.46(m,1H ),2.80(dd,J=17.5,5.7Hz,1H),1.72–1.65(m,2H),1.62–1.54(m,4H),1.53(s,3H),0.92(s,12H). 13 CNMR (150MHz, CDCl3) δ174.01,162.36,142.75,70.66,69.91,64.88,64.05,41.39,37.41,3 7.26,34.27,34.24,26.15,26.09,25.23,25.17,24.35,22.57,22.53,16.47,16.41,11.29.

[0094] Example 22: 5-methyl-d3-4,5-dihydropyrazole-3,5-dicarboxylic acid dibenzyl ester-4,4-d2

[0095]

[0096] Preparation method: Under the protection of inert gas, add 2-diazopropane acid benzyl ester-3,3,3-D3 (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 68%). 1 HNMR (600MHz, CDCl3) δ7.41–7.31(m,10H),6.71(s,1H),5.27(s,2H),5.17(s,2H). 13 CNMR (150MHz, CDCl3) δ173.64,162.07,142.15,135.68,135.17,128.86,128.77,128.72,128.63,128.51,128.33,69.70,67.83,66.99.

[0097] Example 23: Tetramethyl (5-methyl-4,5-dihydropyrazole-3,5-diyl) bis (phosphonate)

[0098]

[0099] Preparation method: Under the protection of inert gas, add (1-diazoethyl)phosphonic acid dimethyl ester (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 77%). 1 HNMR (600MHz, CDCl3) δ6.38(s,1H),3.82–3.76(m,12H),3.31–3.22(m,1H),2.78(dd,J=17.1,14.0Hz,1H),1.39(d,J=14.8Hz,3H). 13 CNMR (150MHz, CDCl3) δ142.31,142.24,140.76,140.69,128.81,63.73,63.70,62.61, 62.58,54.65,54.61,53.50,53.46,53.41,53.38,53.36,43.69,43.55,21.78,21.74. 31 PNMR (243MHz, CDCl3) δ26.47 (dt, J = 23.8, 12.5Hz), 11.07 (p, J = 10.9Hz).

[0100] Example 24: Tetraethyl (5-methyl-4,5-dihydro-1H-pyrazole-3,5-diyl) bis (phosphonic acid)

[0101]

[0102] Preparation method: Under the protection of inert gas, add diethyl (1-diazoethyl)phosphonate (0.2mmol, 1.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 70%). 1 HNMR(600MHz, CDCl3) δ4.15(dtt,J=11.0,5.9,3.0Hz,8H),3.33–3.22(m,1H),2.78(m,1H),1.39(d,J=14.8Hz,3H),1.34–1.27(m,12H).

[0103] Example 25: 5-Butyl-3-dimethoxyphospho-4,5-dihydropyrazole-5-carboxylic acid benzyl ester

[0104]

[0105] Preparation method: Under the protection of inert gas, add (1-diazoethyl)phosphonic acid dimethyl ester (0.2mmol, 1.0equiv), 2-diazohexanoic acid benzyl ester (0.4mmol, 2.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 30%). 1 HNMR (600MHz, CDCl3) δ7.38–7.31(m,5H),5.17(s,2H),3.79–3.72(m,6H),3.41(dd,J=17.4,1.1Hz,1H),2.81(d,J=17 .4Hz,1H),1.88(td,J=12.7,4.7Hz,2H),1.83–1.76(m,2H),1.19(ddd,J=12.2,7.4,4.8Hz,2H),0.83(t,J=7.2Hz,3H). 31 PNMR(243MHz,CDCl3)δ11.19–10.81(m).

[0106] Example 26: 5-Benzyl-3-dimethoxyphospho-4,5-dihydropyrazole-5-carboxylic acid methyl ester

[0107]

[0108] Preparation method: Under the protection of inert gas, add dimethyl (1-diazoethyl)phosphonate (0.2mmol, 1.0equiv), methyl 2-diazo-3-phenylpropionate (0.4mmol, 2.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 59%). 1HNMR (600MHz, CDCl3) δ7.29(q,J=7.1Hz,3H),7.13(d,J=7.4Hz,2H),6.72(s,1H),3.75(t,J=1.2Hz,6H),3.69(d ,J=1.0Hz,3H),3.38(d,J=17.4Hz,1H),3.24(d,J=13.5Hz,1H),3.07(d,J=13.4Hz,1H),2.95(d,J=17.4Hz,1H).

[0109] Example 27: 5-Dimethoxyphospho-5-methyl-4,5-dihydropyrazole-3-carboxylic acid benzyl ester

[0110]

[0111] Preparation method: Under the protection of inert gas, add 2-diazopropionic acid benzyl ester (0.2mmol, 1.0equiv), (1-diazoethyl)phosphonic acid dimethyl ester (0.4mmol, 2.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 34%). 1 HNMR(600MHz, CDCl3)δ7.44–7.27(m,5H),6.55(s,1H),5.26(s,2H),3.82–3.76( m,6H),3.39–3.27(m,1H),2.84(dd,J=17.4,14.4Hz,1H),1.43(d,J=14.9Hz,3H). 31 PNMR (243MHz, CDCl3) δ25.80 (dt, J = 27.9, 13.2Hz).

[0112] Example 28: 3-(Dimethoxyphospho)-5-methyl-4,5-dihydropyrazole-5-carboxylic acid benzyl ester

[0113]

[0114] Preparation method: Under the protection of inert gas, add 2-diazopropionic acid benzyl ester (0.2mmol, 1.0equiv), (1-diazoethyl)phosphonic acid dimethyl ester (0.4mmol, 2.0equiv), acid red (1mol%) and dry trifluorotoluene (0.25mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 16%). 1 HNMR(600MHz, CDCl3)δ7.35(dd,J=16.7,8.6Hz,5H),6.78(s,1H),5.18(d,J=4.8Hz, 2H),3.80–3.73(m,6H),3.46(d,J=17.2Hz,1H),2.78(d,J=17.2Hz,1H),1.55(s,3H). 31 PNMR(243MHz,CDCl3)δ11.13–10.65(m).

[0115] Example 29: 5-Butyl-4,5-dihydropyrazole-3,5-dicarboxylic acid dibenzyl ester

[0116]

[0117] Preparation method: Under the protection of inert gas, add 2-diazopropionic acid benzyl ester (0.2mmol, 1.0equiv), 2-diazohexanoic acid benzyl ester (0.4mmol, 2.0equiv), acid red (1mol%) and dry trifluorotoluene (0.5mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 30%). 1 HNMR(600MHz, CDCl3)δ7.42–7.30(m,10H),6.75(s,1H),5.26(s,2H),5.20–5.13(m,2H),3.48(d,J =17.7Hz,1H),2.86(d,J=17.7Hz,1H),1.89–1.77(m,2H),1.25–1.06(m,4H),0.83(t,J=7.2Hz,3H). 13CNMR (150MHz, CDCl3) δ173.48,162.11,142.07,135.71,135.19,128.84,128.81,128. 72,128.64,128.53,128.50,73.59,67.80,66.98,39.78,37.73,26.64,22.72,13.88.

[0118] Example 30: 5-phenyl-5-trifluoromethyl-4,5-dihydropyrazole-3-carboxylic acid benzyl ester

[0119]

[0120] Preparation method: Under the protection of inert gas, add 2-diazopropionic acid benzyl ester (0.2mmol, 1.0equiv), 1-diazo-2,2,2-trifluoroethylbenzene (0.4mmol, 2.0equiv), acid red (1mol%) and dry trifluorotoluene (0.5mL) to a dry 4.0mL reaction bottle equipped with a magnetic stirrer. Place the above reaction solution on a blue light reactor and stir for 24 hours. Monitor the reaction by TLC. After the reaction is complete, cool to room temperature, filter the mixture with diatomaceous earth, wash with ethyl acetate, remove the solvent under reduced pressure, and directly separate and purify the crude product by column chromatography to obtain the target product (colorless oil, 23%). 1 HNMR (600MHz, CDCl3) δ7.42–7.33(m,10H),6.96(s,1H),5.28(s,2H),3.81–3.71(m,1H),3.43–3.35(m,1H). 13 CNMR (150MHz, CDCl3) δ161.52,141.47,136.60,135.41,129.27,129.08,128.79,128.69,128.65,126.61,73.78,73.60,67.32,41.32. 19 FNMR (565MHz,CDCl3)δ-78.44.

[0121] The above description is only a preferred specific implementation manner of the present invention, but the scope of protection of the present invention is not limited thereto. Any modifications, equivalent substitutions and improvements made by any technician familiar with the technical field within the technical scope disclosed by the present invention should be included in the scope of protection of the invention.

Claims

1. A method for preparing a dihydropyrazole compound containing a quaternary carbon center represented by formula (3) or formula (4), characterized in that: The preparation method comprises contacting the compound represented by formula (1), a catalyst and an organic solvent under the protection of an inert gas, and reacting them under the irradiation of visible light to obtain the compound represented by formula (3); or contacting the compound represented by formula (1), the compound represented by formula (2), a catalyst and an organic solvent under the protection of an inert gas, and reacting them under the irradiation of visible light to obtain the compound represented by formula (4); in: R 1 Selected from -CO2R 4 、-PO3R 5 One of; R 2 and R 3 The same or different, and each independently selected from -CO2R 4 , -CD3, substituted or unsubstituted alkyl, one of aryl; R 4 is selected from substituted or unsubstituted aryl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, C3-C 12 Alkyl, C 10 -C 30 Polycyclic alkyl, C4-C 10 One of the heterocyclic groups; R 5 Selected from C2-C6 alkyl; The compound represented by formula (1) is selected from the group consisting of benzyl 2-diazopropionate, benzyl 4-(trifluoromethyl)-2-diazopropionate, 2-chloro-6-fluorobenzyl-2-diazopropionate, 2-fluorobenzyl 2-diazopropionate, 2-chlorobenzyl 2-diazopropionate, 2,3-difluorobenzyl 2-diazopropionate, 2-methylbenzyl 2-diazopropionate, 2,6-dimethylbenzyl-2-diazopropionate, 2,4,6-trimethoxybenzyl 2-diazopropionate, (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 2-diazopropionate, (5S,8S,9S,10S,13R,14S,17S)-10,13-dimethyl-17-(5-methylhexyl)-2-diazopropionate One of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl-2-diazopropionate, phenyl 2-diazopropionate, ethyl 2-diazopropionate, tert-butyl 2-diazopropionate, isobutyl 2-diazopropionate, benzyl 2-diazopropanoate-3,3,3-D3, dimethyl (1-diazoethyl)phosphonate, benzyl 2-diazopropanoate, 2,4-dichlorobenzyl 2-diazopropionate, adamantane-2-yl-2-diazopropionate, and diethyl (1-diazoethyl)phosphonate; The compound represented by formula (2) is selected from 2-diazohexanoic acid benzyl ester and 1-diazo-2,2,2-trifluoroethylbenzene; The catalyst is acid red; the organic solvent is trifluorotoluene.

2. The preparation method according to claim 1, characterized in that: In the preparation of the compound represented by formula (3), the molar volume ratio of the compound represented by formula (1), the catalyst and the organic solvent is 0.2-10 mmol:0.002-10.0 mmol:0.5-5.0 mL.

3. The preparation method according to claim 1, characterized in that: In the preparation of the compound represented by formula (4), the molar volume ratio of the compound represented by formula (1), the compound represented by formula (2), the catalyst and the organic solvent is 0.2-10 mmol:0.4-20 mmol:0.002-10.0 mmol:0.5-5.0 mL.

4. The preparation method according to claim 1, characterized in that: The wavelength of the visible light is 400-800 nm, the reaction temperature is 0-80° C., and the reaction time is within 50 h.

5. The preparation method according to claim 1, characterized in that: It also includes post-processing the reaction product.

6. The preparation method according to claim 5, characterized in that: The post-treatment includes filtering, washing, removing the solvent under reduced pressure, and column chromatography separation and purification in sequence.

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