Process for the preparation of phosphorylated azabenzoacetophenone derivatives

Abstract

The application discloses a preparation method of phosphorylated azabenzoacetophenone derivatives, and comprises the following steps: a new electrochemical synthesis method for constructing the phosphorylated azabenzoacetophenone derivatives by using diphenyl phosphate as a phosphorylation reagent is provided, and compared with a traditional preparation method, the diphenyl phosphate as the phosphorylation reagent is not only cheap and easy to obtain, but also has higher atomic economy. Meanwhile, the electrocatalytic reaction condition is more moderate and efficient, the participation of transition metals and oxidants is avoided, and the call for 'green chemistry' is further responded.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, and specifically relates to a method for preparing phosphorylated azole acetophenone derivatives. Background Technology

[0002] Azoxyl acetophenone compounds possess important biological activities. In particular, nadiimidone compounds are promising antiepileptic drugs, and their derivatives exhibit a variety of pharmacological activities, such as antitumor, anticonvulsant, antithrombotic, anti-inflammatory, and antibacterial activities. Especially, α-substituted azole acetophenone derivatives can be used as inhibitors of various biological enzymes, and modified azole acetophenone derivatives have broad application prospects. Therefore, the synthesis of α-phosphorylated azole acetophenone compounds is of considerable research value. Furthermore, organic electrosynthesis is considered a "green" and sustainable alternative to traditional methods because it can maximize atomic efficiency and minimize reagent waste by replacing stoichiometric redox reagents with electric current.

[0003] In 2015, Wei et al. reported a synthetic method for constructing α-hydroxy ketone phosphate by direct phosphorylation of phosphate using diiodopentoxide / 1,8-diazabicyclo[5,4,0]undec-7-ene as a mediator and acetonitrile as a solvent at 80 °C (Tetrahedron, 2015, 71, 6901-6906).

[0004]

[0005] In 2023, Zhang et al. reported a method for the synthesis of α-functionalized acetophenone derivatives catalyzed by cuprous iodide. The reaction was carried out under mild conditions and had good functional group universality. The disadvantage is that a transition metal catalyst is required (Organic Chemistry Frontiers, 2023, 10, 605-610).

[0006]

[0007] In 2023, Wu's research group reported an efficient strategy for the direct α-C(sp3)-H sulfidation / selenization of azole acetophenone derivatives via electrocatalysis. The reaction used copper chloride as a catalyst and yielded the sulfidation product in 85% yield (Molecular Catalysis, 2023, 540, 113038).

[0008]

[0009] In summary, the literature on the α-C(sp3)-H reaction of ketone compounds, especially azole acetophenone derivatives, currently reported either uses traditional oxidants or transition metal catalysts, which not only increases the reaction cost but also imposes a burden on the environment. Summary of the Invention

[0010] The first objective of this invention is to provide a method for preparing phosphorylated azole acetophenone derivatives.

[0011] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0012] In a first aspect, the present invention provides a method for preparing phosphorylated azole acetophenone derivatives, comprising the following steps:

[0013]

[0014] Compound II and Compound III are mixed, and an electrolyte is added. The molar ratio of Compound II, Compound III, and electrolyte is 1:1 to 5:1 to 3 (preferably 1:3:2, 1:1:2, or 1:2:2). A solvent is then added. Under different anodic and cathode conditions, a direct current of 4 mA to 8 mA (preferably 4, 6, or 8 mA) is applied, and the temperature is 15°C to 40°C (preferably 20°C, 25°C, 30°C, or 40°C). The reaction is carried out for 3 to 9 hours (preferably 3, 5, 5.5, 6, 7, 8, or 9 hours) to obtain the phosphorylated azole acetophenone derivative.

[0015] The anode is selected from carbon cloth electrode, glassy carbon electrode, and platinum electrode;

[0016] The cathode is selected from carbon cloth electrode, platinum electrode, and nickel electrode;

[0017] The electrolyte is selected from tetrabutylammonium bromide, tetraethylammonium bromide, tetrabutylammonium tetrafluoroborate, and lithium perchlorate;

[0018] in,

[0019] R1 is selected from hydrogen, halogens (fluorine, chlorine, bromine, iodine), C1-C20 alkyl groups, C1-C20 alkoxy groups, etc.

[0020] R2 is selected from hydrogen, halogens (fluorine, chlorine, bromine, iodine), C1-C20 alkyl groups, C1-C20 alkoxy groups, etc. R3 is selected from hydrogen, halogens (fluorine, chlorine, bromine, iodine), C1-C20 alkyl groups, C1-C20 alkoxy groups, etc. R4 is selected from hydrogen, halogens (fluorine, chlorine, bromine, iodine), C1-C20 alkyl groups, C1-C20 alkoxy groups, etc. R5 is selected from hydrogen, halogens (fluorine, chlorine, bromine, iodine), C1-C20 alkyl groups, C1-C20 alkoxy groups, and so on. Alternatively, R2 and R3, along with carbon, form a six-membered ring (such as cyclohexane or benzene);

[0021] R6 is selected from hydrogen, halogens (fluorine, chlorine, bromine, iodine), C1-C20 alkyl groups, and C1-C20 alkoxy groups;

[0022] R7 is selected from hydrogen, halogens (fluorine, chlorine, bromine, iodine), C1-C20 alkyl groups, and C1-C20 alkoxy groups;

[0023] R8 is selected from hydrogen, halogens (fluorine, chlorine, bromine, iodine), C1-C20 alkyl groups, and C1-C20 alkoxy groups;

[0024] R 11 ~R 15 Each is independently selected from hydrogen and halogens (fluorine, chlorine, bromine, iodine).

[0025] Preferably, in compound II,

[0026] R1 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy,

[0027]

[0028] R2 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy, etc.

[0029]

[0030] R3 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy,

[0031]

[0032] R4 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy, etc.

[0033]

[0034] R5 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy,

[0035]

[0036] Alternatively, R2 and R3, along with carbon, form a six-membered benzene ring, with the following structure: Dashed lines indicate connection points;

[0037] R6 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, tert-butyl, methoxy, ethoxy, and tert-butoxy.

[0038] R7 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, tert-butyl, methoxy, ethoxy, and tert-butoxy.

[0039] R8 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, tert-butyl, methoxy, ethoxy, and tert-butoxy.

[0040] Most preferably, compound II has one of the following structures:

[0041]

[0042] The solvent is selected from acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, ethanol, methanol, and toluene.

[0043] The phosphorylated azole acetophenone derivatives are selected from one of the following structures:

[0044]

[0045] By adopting the above technical solution, the present invention has the following advantages and beneficial effects:

[0046] This invention provides a novel electrochemical synthesis method for constructing phosphorylated azole acetophenone derivatives using diphenylphosphoric acid as a phosphorylating agent. Compared to traditional preparation methods, diphenylphosphoric acid, as a phosphorylating agent, not only uses inexpensive and readily available raw materials but also offers higher atom economy. Furthermore, the electrocatalytic reaction conditions are milder and more efficient, avoiding the involvement of transition metals and oxidants, further responding to the call for "green chemistry."

[0047] This invention uses diphenylphosphoric acid as a phosphorylation reagent. Compared with the patent application with publication number CN115521258A, it uses green electrochemistry as the oxidation driving force to construct α-C(sp3)-O of phosphorylated azole acetophenone derivatives. Moreover, it does not require photocatalysts or metal catalysts, and has obvious advantages in "atom economy" and green environmental protection. Furthermore, this invention can achieve a 95% yield in just 5 hours at room temperature and in an air atmosphere. Obviously, the new method provided by this invention is superior to the comparative example. Attached Figure Description

[0048] Figure 1 This is a schematic diagram of the 1H NMR spectrum of compound I-1.

[0049] Figure 2 This is a schematic diagram of the carbon NMR spectrum of compound I-1.

[0050] Figure 3 This is a schematic diagram of the phosphine NMR spectrum of compound I-1. Detailed Implementation

[0051] To more clearly illustrate the present invention, the following description, in conjunction with preferred embodiments, further clarifies the invention. Those skilled in the art should understand that the specific descriptions below are illustrative rather than restrictive, and should not be construed as limiting the scope of protection of the present invention.

[0052] The specifications, purity, and manufacturers of the reagents used in this invention are shown in Table 1.

[0053] Table 1

[0054] Reagent Name factory purity Specification Diphenylphosphine Shanghai Titan Technology Co., Ltd. 98％ 25g α-Bromoacetophenone Shanghai Titan Technology Co., Ltd. 98％ 25g pyrazole Shanghai Titan Technology Co., Ltd. 98％ 25g Tetrabutylammonium bromide Shanghai Titan Technology Co., Ltd. 99％ 100g Anhydrous potassium carbonate Shanghai Titan Technology Co., Ltd. 99.99％ 500g 1,4-Dioxane Shanghai Titan Technology Co., Ltd. 99.7％ 500mL Anhydrous acetonitrile Ailan (Shanghai) Chemical Technology Co., Ltd. 99.9％ 500mL

[0055] The preparation method of compound II includes the following steps:

[0056]

[0057] Anhydrous potassium carbonate (36 mmol, 1.2 equivalents) was added to a 30 mL solution of 1,4-dioxane containing α-bromoacetophenone compounds (30 mmol, 1.0 equivalent) and pyrazole compounds (30 mmol, 1 equivalent). The reaction mixture was heated and stirred overnight at 60 °C. After the reaction was complete, the resulting mixture was extracted three times with water and ethyl acetate (3 x 30 mL). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated under vacuum, using petroleum ether / ethyl acetate as eluent, and purified by silica gel column chromatography to obtain analytical grade azoleacetophenone compound II.

[0058] α-Bromoacetophenone compounds are selected from one of the following structures:

[0059]

[0060] Pyrazole compounds are selected from one of the following structures:

[0061]

[0062] Example 1

[0063]

[0064] 1-Phenylacetyl-2-(1H-pyrazol-1-yl)ethyl-1-one, i.e., compound II-1 (0.5 mmol, 1 equivalent), and diphenylphosphoric acid, i.e., compound III-1 (1.5 mmol, 3.0 equivalent), were placed in a 50 mL three-necked flask, and tetrabutylammonium bromide was added simultaneously. nUsing [Bu4NBr] (1.0 mmol, 2 equivalents) as the electrolyte, and adding 10 ml of anhydrous acetonitrile (CH3CN) as the solvent, a carbon cloth electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 5 hours under a direct current of 6 mA and at room temperature. The solvent was evaporated, and the product was purified by dry column chromatography (eluting agent: petroleum ether / ethyl acetate = 100 / 50) to obtain the white solid target product compound I-1 with a yield of 95%. Figure 1 This is a schematic diagram of the 1H NMR spectrum of compound I-1. Figure 2 This is a schematic diagram of the carbon NMR spectrum of compound I-1. Figure 3 This is a schematic diagram of the phosphine NMR spectrum of compound I-1. 1 H NMR(400MHz, DMSO-d6)δ8.02(d,J=2.5Hz,1H),7.98(d,J=8.9Hz,1H),7.90–7.86(m, 2H),7.86–7.79(m,2H),7.67–7.50(m,7H),7.49–7.37(m,5H),6.25(t,J=2.1Hz,1H); 13 C NMR (151MHz, DMSO-d6) δ188.04(d,J=5.5Hz),141.66,133.73(d,J=65.9Hz),132.72(d,J=19.1Hz),131.93,131.64(d,J= 36.1Hz), 131.15 (t, J = 10.5Hz), 130.73 (d, J = 33.3Hz), 128.92, 128.81 (d, J = 8.1Hz), 128.47, 107.48, 80.97 (d, J = 4.4Hz); 31 P NMR(243MHz,DMSO-d6)δ33.10; HRMS(ESI-TOF)m / z[M+H] + Calcd forC 23 H 20 N2O3P403.1206, found 403.1213.

[0065] Example 2

[0066]

[0067] 1-(4-methylphenyl)-2-(1H-pyrazol-1-yl)ethyl-1-one, i.e., compound II-2 (0.5 mmol, 1 equivalent), and diphenylphosphoric acid, i.e., compound III-1 (1.5 mmol, 3.0 equivalent), were placed in a 50 mL three-necked flask, and tetrabutylammonium bromide was added simultaneously. nUsing [Bu4NBr] (1.0 mmol, 2 equivalents) as the electrolyte, and adding 10 ml of anhydrous acetonitrile (CH3CN) as the solvent, a carbon cloth electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 6 hours under a direct current of 6 mA and at room temperature. The solvent was evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 50) to obtain the white solid target product compound I-2, with a yield of 54%. 1 H NMR(400MHz, DMSO-d6)δ7.98(d,J=2.5Hz,1H),7.88(d,J=9.0Hz,1H),7.84–7.73(m,4H),7.69–7.50(m ,6H),7.46(td,J=7.7,3.7Hz,2H),7.41(s,1H),7.22(d,J=8.1Hz,2H),6.38–6.12(m,1H),2.29(s,3H); 13 C NMR (151MHz, DMSO-d6) δ187.42 (d, J = 4.4Hz), 144.57, 141.49, 132.63 (d, J = 18.3Hz), 131.79 (d, J = 3.4Hz), 131.10 (t, J = 10.4 Hz), 130.89 (d, J = 6.9 Hz), 129.30, 128.86, 128.74 (d, J = 10.1 Hz), 128.58 (d, J = 11.0 Hz), 107.33, 80.81 (d, J = 5.3 Hz), 21.19; 31 P NMR(243MHz,DMSO-d6)δ32.87; HRMS(ESI-TOF)m / z[M+H] + Calcd for C 24 H 22 N2O3P417.1363, found 417.1374.

[0068] Example 3

[0069]

[0070] 1-(4-fluorophenyl)-2-(1H-pyrazol-1-yl)ethyl-1-one, i.e., compound II-3 (0.5 mmol, 1 equivalent), and diphenylphosphoric acid, i.e., compound III-1 (1.5 mmol, 3.0 equivalent), were placed in a 50 mL three-necked flask, and tetrabutylammonium bromide was added simultaneously. nUsing [Bu4NBr] (1.0 mmol, 2 equivalents) as the electrolyte, and adding 10 ml of anhydrous acetonitrile (CH3CN) as the solvent, a carbon cloth electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 5 hours under a direct current of 6 mA and at room temperature. The solvent was evaporated, and the product was purified by dry column chromatography (eluting agent: petroleum ether / ethyl acetate = 100 / 50) to obtain the white solid target product compound I-3, with a yield of 83%. 1 H NMR(400MHz,DMSO-d6)δ8.00–7.91(m,4H),7.85–7.76(m,2H),7.64–7.50(m ,6H),7.49–7.41(m,3H),7.26(dd,J=9.8,7.9Hz,2H),6.25(t,J=2.1Hz,1H); 13 CNMR (151MHz, DMSO-d6) δ186.77 (d, J = 4.4Hz), 165.21 (d, J = 253.7Hz), 141.69, 132.70 (d, J = 18.6Hz), 131.93, 131.58 (d, J = 9. 5Hz), 131.11, 130.70 (d, J = 34.7Hz), 130.25, 128.78 (dd, J = 23.8, 12.8Hz), 115.93 (d, J = 22.1Hz), 107.47, 80.92 (d, J = 5.4Hz); 31 P NMR (243MHz, DMSO-d6) δ33.09; 19 F NMR(565MHz,DMSO-d6)δ-104.19; HRMS(ESI-TOF)m / z[M+H] + Calcd for C 23 H 19 FN2O3P 421.1112, found 421.1125.

[0071] Example 4

[0072]

[0073] 1-(4-chlorophenyl)-2-(1H-pyrazol-1-yl)ethyl-1-one, i.e., compound II-4 (0.5 mmol, 1 equivalent), and diphenylphosphoric acid, i.e., compound III-1 (1.5 mmol, 3.0 equivalent), were placed in a 50 mL three-necked flask, and tetrabutylammonium bromide was added simultaneously. nUsing [Bu4NBr] (1.0 mmol, 2 equivalents) as the electrolyte, and adding 10 ml of anhydrous acetonitrile (CH3CN) as the solvent, a carbon cloth electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 5.5 hours under a direct current of 6 mA and at room temperature. The solvent was evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 50) to obtain the white solid target product compound I-4, with a yield of 80%. 1 H NMR (400MHz, DMSO-d6) δ7.99–7.92(m,2H),7.89–7.84(m,2H),7.83–7.76(m,2H),7.65–7.53(m,6H),7.52–7.41(m,5H),6.25(t,J=2.1Hz,1H); 13 CNMR(151MHz,DMSO-d6)δ187.25(d,J=5.5Hz),141.67,138.78,132.65(d,J=19.4Hz),132.25,131.9 6,131.07(t,J=10.5Hz),130.26,128.87,128.74(d,J=11.2Hz),128.61,107.44,80.92(d,J=5.4Hz); 31 P NMR(243MHz,DMSO-d6)δ33.04; HRMS(ESI-TOF)m / z[M+H] + Calcdfor C 23 H 19 ClN2O3P437.0816, found 437.0828.

[0074] Example 5

[0075]

[0076] 1-(4-methoxyphenyl)-2-(1H-pyrazol-1-yl)ethyl-1-one, i.e., compound II-5 (0.5 mmol, 1 equivalent), and diphenylphosphine, i.e., compound III-1 (1.5 mmol, 3.0 equivalent), were placed in a 50 mL three-necked flask, and tetrabutylammonium bromide was added simultaneously. n Using [Bu4NBr] (1.0 mmol, 2 equivalents) as the electrolyte, and adding 10 ml of anhydrous acetonitrile (CH3CN) as the solvent, a carbon cloth electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 5 hours under a direct current of 6 mA and at room temperature. The solvent was evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 50) to obtain the target product compound I-5 as a white solid with a yield of 92%. 1H NMR(400MHz,DMSO-d6)δ7.98(d,J=2.5Hz,1H),7.87–7.76(m,5H),7.64–7.50( m,6H),7.49–7.40(m,3H),6.99–6.91(m,2H),6.27–6.23(m,1H),3.78(s,3H); 13 CNMR(151MHz,DMSO-d6)δ186.20(d,J=5.4Hz),163.65,141.44,132.64(d,J=17.9Hz),131.68,131.12(t,J=10.4Hz ),130.97,130.77(d,J=31.9Hz),128.75(dd,J=22.9,13.2Hz),126.11,114.08,107.34,80.71(d,J=5.4Hz),55.64; 31 P NMR(243MHz,DMSO-d6)δ32.82; HRMS(ESI-TOF)m / z[M+H] + Calcd for C 24 H 22 N2O4P433.1312, found 433.1325.

[0077] Example 6

[0078]

[0079] 1-(4-phenylphenyl)-2-(1H-pyrazol-1-yl)ethyl-1-one, i.e., compound II-6 (0.5 mmol, 1 equivalent), and diphenylphosphoric acid, i.e., compound III-1 (1.5 mmol, 3.0 equivalent), were placed in a 50 mL three-necked flask, and tetrabutylammonium bromide was added simultaneously. n Using [Bu4NBr] (1.0 mmol, 2 equivalents) as the electrolyte, and adding 10 ml of anhydrous acetonitrile (CH3CN) as the solvent, a carbon cloth electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 5 hours under a direct current of 6 mA and at room temperature. The solvent was evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 50) to obtain the white solid target product compound I-6, with a yield of 88%. 1H NMR(400MHz, DMSO-d6)δ8.02(d,J=2.5Hz,1H),7.99–7.90(m,3H),7.85–7.79(m,2H),7.75–7.67(m,4H ),7.64–7.58(m,3H),7.58–7.51(m,3H),7.50–7.43(m,5H),7.43–7.37(m,1H),6.27(t,J=2.2Hz,1H); 13 C NMR (151MHz, DMSO-d6) δ187.49(d,J=5.1Hz),145.14,141.60,138.53,132.64(d,J=18.1Hz),132.26,131.91,131.11(t,J= 11.1Hz), 129.20, 129.10, 128.86, 128.74 (d, J = 10.0Hz), 128.62, 127.05, 126.83 (d, J = 5.7Hz), 107.43, 80.92 (d, J = 4.4Hz); 31 PNMR(243MHz,DMSO-d6)δ32.91; HRMS(ESI-TOF)m / z[M+Na] + Calcd for C 29 H 23 N2O3NaP 501.1339, found 501.1351.

[0080] Example 7

[0081]

[0082] 1-(2-naphthyl)-2-(1H-pyrazol-1-yl)ethanethion, i.e., compound II-7 (0.5 mmol, 1 equivalent), and diphenylphosphine, i.e., compound III-1 (1.5 mmol, 3.0 equivalent), were placed in a 50 mL three-necked flask, and tetrabutylammonium bromide was added simultaneously. n Using [Bu4NBr] (1.0 mmol, 2 equivalents) as the electrolyte, and adding 10 ml of anhydrous acetonitrile (CH3CN) as the solvent, a carbon cloth electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 7 hours under a direct current of 6 mA and at room temperature. The solvent was evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 50) to obtain the white solid target product compound I-7, with a yield of 69%. 1H NMR(400MHz, DMSO-d6)δ8.59(d,J=2.0Hz,1H),8.13–8.05(m,2H),7.96–7.88(m,4H),7.87–7.79(m ,2H),7.67–7.51(m,8H),7.47(td,J=7.5,3.6Hz,2H),7.40(d,J=1.7Hz,1H),6.24(t,J=2.1Hz,1H); 13 C NMR (151MHz, DMSO-d6) δ187.91(d,J=4.4Hz),141.57,135.09,132.65(d,J=16.5Hz),131.95,131.78,131.53,131.10(t,J=10.4Hz),130 .75(t,J=17.4Hz),130.46,129.50,129.15,128.75(dd,J=22.1,13.7Hz),128.41,127.70,127.19,123.69,107.31,80.84(d,J=4.4Hz); 31 P NMR(243MHz,DMSO-d6)δ33.10; HRMS(ESI-TOF)m / z[M+H] + Calcd for C 27 H 22 N2O3P 453.1363, found 453.1375.

[0083] Example 8

[0084]

[0085] 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1-phenyl-1-ethyl ketone, i.e., compound II-8 (0.5 mmol, 1 equivalent), and diphenylphosphoric acid, i.e., compound III-1 (1.5 mmol, 3.0 equivalent), were placed in a 50 mL three-necked flask, and tetrabutylammonium bromide was added simultaneously. n Using [Bu4NBr] (1.0 mmol, 2 equivalents) as the electrolyte, and adding 10 ml of anhydrous acetonitrile (CH3CN) as the solvent, a carbon cloth electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 8 hours under a direct current of 6 mA and at room temperature. The solvent was evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 50) to obtain the white solid target product compound I-8, with a yield of 31%. 1H NMR (400MHz, DMSO-d6) δ7.87–7.78(m,2H),7.73–7.66(m,2H),7.64–7.51(m,8H),7.48–7.38(m,4H),5.74(s,1H),2.28(s,3H),1.88(s,3H); 13 C NMR (151MHz, DMSO-d6) δ188.25 (d, J = 5.5Hz), 149.53, 140.99, 133.67 (d, J = 30.4Hz), 132.56 (d, J = 19.5Hz), 131.71 (d, J = 59.6Hz ),131.09(d,J=9.6Hz),128.84,128.73(d,J=5.5Hz),128.56(d,J=13.7Hz),128.35,107.11,78.92(d,J=5.5Hz),13.23,10.28; 31 P NMR(243MHz,DMSO-d6)δ31.66; HRMS(ESI-TOF)m / z[M+H] + Calcd for C 25 H 24 N2O3P 431.1519, found 431.1529.

[0086] Example 9

[0087]

[0088] 2-(4-chloro-1H-pyrazol-1-yl)-1-phenyl-1-ethyl ketone, i.e., compound II-9 (0.5 mmol, 1 equivalent), and diphenylphosphine, i.e., compound III-1 (1.5 mmol, 3.0 equivalent), were placed in a 50 mL three-necked flask, and tetrabutylammonium bromide was added simultaneously. n Using [Bu4NBr] (1.0 mmol, 2 equivalents) as the electrolyte, and adding 10 ml of anhydrous acetonitrile (CH3CN) as the solvent, a carbon cloth electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 7 hours under a direct current of 6 mA and at room temperature. The solvent was evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 50) to obtain the white solid target product compound I-9, with a yield of 57%. 1 H NMR (400MHz, DMSO-d6) δ8.14(s,1H),7.93–7.86(m,3H),7.84–7.76(m,2H),7.65–7.52(m,7H),7.50(s,1H),7.46(td,J=7.8,3.4Hz,4H); 13C NMR(151MHz,DMSO-d6)δ187.58(d,J=5.5Hz),139.87,134.09,133.26,132.76(d,J=23.8Hz),131.10(d,J=11.0Hz ),130.34(d,J=50.2Hz),129.87,128.89(d,J=12.6Hz),128.65,128.53(d,J=8.3Hz),110.37,81.05(d,J=5.4Hz); 31 PNMR(243MHz,DMSO-d6)δ33.25; HRMS(ESI-TOF)m / z[M+H] + Calcd for C 23 H 19 ClN2O3P 437.0816, found 437.0825.

[0089] Example 10

[0090]

[0091] 2-(4-bromo-1H-pyrazol-1-yl)-1-phenyl-1-ethyl ketone, i.e., compound II-10 (0.5 mmol, 1 equivalent), and diphenylphosphoric acid, i.e., compound III-1 (1.5 mmol, 3.0 equivalent), were placed in a 50 mL three-necked flask, and tetrabutylammonium bromide was added simultaneously. n Using [Bu4NBr] (1.0 mmol, 2 equivalents) as the electrolyte, and adding 10 ml of anhydrous acetonitrile (CH3CN) as the solvent, a carbon cloth electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 5.5 hours under a direct current of 6 mA and at room temperature. The solvent was evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 50) to obtain a white solid target product compound I-10, with a yield of 63%. 1 H NMR (400MHz, DMSO-d6) δ8.13(s,1H),7.93–7.88(m,3H),7.83–7.76(m,2H),7.63–7.51(m,7H),7.51–7.43(m,5H); 13C NMR (151MHz, DMSO-d6) δ187.59(d,J=5.6Hz),141.91,134.13,133.29,132.80(d,J=24.7Hz),132.01,131.12(d,J =10.9Hz), 130.33 (d, J = 54.2Hz), 128.92 (d, J = 12.6Hz), 128.68, 128.56 (d, J = 8.6Hz), 94.34, 80.91 (d, J = 4.5Hz); 31 P NMR(243MHz,DMSO-d6)δ33.24; HRMS(ESI-TOF)m / z[M+H] + Calcd forC 23 H 19 BrN2O3P481.0311,found 481.0327.

[0092] Example 11

[0093]

[0094] 2-(4-iodo-1H-pyrazol-1-yl)-1-phenyl-1-ethyl ketone, i.e., compound II-11 (0.5 mmol, 1 equivalent), and diphenylphosphoric acid, i.e., compound III-1 (1.5 mmol, 3.0 equivalent), were placed in a 50 mL three-necked flask, and tetrabutylammonium bromide was added simultaneously. n Using [Bu4NBr] (1.0 mmol, 2 equivalents) as the electrolyte, and adding 10 ml of anhydrous acetonitrile (CH3CN) as the solvent, a carbon cloth electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 6 hours under a direct current of 6 mA and at room temperature. The solvent was evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 50) to obtain the white solid target product compound I-11, with a yield of 58%. 1 H NMR (400MHz, DMSO-d6) δ8.05 (d, J = 0.7Hz, 1H), 7.93–7.86 (m, 3H), 7.82–7.75 (m, 2H), 7.63–7.52 (m, 7H), 7.49–7.41 (m, 5H); 13C NMR(151MHz,DMSO-d6)δ187.60(d,J=5.5Hz),146.26,136.20,134.08,133.33,132.77(d,J=24.2Hz),131.11(d, J=10.9Hz),128.90(d,J=12.9Hz),128.67(d,J=4.0Hz),128.54(d,J=9.7Hz),80.56(d,J=5.4Hz),60.26,56.69; 31 P NMR(243MHz,DMSO-d6)δ33.08; HRMS(ESI-TOF)m / z[M+H] + Calcdfor C 23 H 19 IN2O3P 529.0173,found 529.0198.

[0095] Table 2

[0096] Example electrode electrolytes solvent Current / mA Temperature / °C Time / h Yield % 12 C(+)|C(-) <![CDATA[ n Bu4NBr]]> MeCN 6 25 5 22 13 C(+)|Pt(-) <![CDATA[ n Bu4NBr]]> MeCN 6 25 5 25 14 Gc(+)|Ni(-) <![CDATA[ n Bu4NBr]]> MeCN 6 25 5 nd 15 Pt(+)|Ni(-) <![CDATA[ n Bu4NBr]]> MeCN 6 25 5 nd 16 C(+)|Ni(-) <![CDATA[ n Et4NBr]]> MeCN 6 25 5 47 17 C(+)|Ni(-) <![CDATA[ n Bu4NBF4]]> MeCN 6 25 5 nd 18 C(+)|Ni(-) <![CDATA[LiClO4]]> MeCN 6 25 5 nd 19 C(+)|Ni(-) <![CDATA[ n Bu4NBr]]> DMSO 6 25 5 nd 20 C(+)|Ni(-) <![CDATA[ n Bu4NBr]]> DMF 6 25 5 50 21 C(+)|Ni(-) <![CDATA[ n Bu4NBr]]> DCM 6 25 5 41 22 C(+)|Ni(-) <![CDATA[ n Bu4NBr]]> MeOH 6 25 5 35 23 C(+)|Ni(-) <![CDATA[ n Bu4NBr]]> Toluene 6 25 5 23 24 C(+)|Ni(-) <![CDATA[ n Bu4NBr]]> MeCN 4 25 5 45 25 C(+)|Ni(-) <![CDATA[ n Bu4NBr]]> MeCN 8 25 5 37 26 C(+)|Ni(-) <![CDATA[ n Bu4NBr]]> MeCN 6 40 5 81 27 C(+)|Ni(-) <![CDATA[ n Bu4NBr]]> MeCN 6 20 5 86 28 C(+)|Ni(-) <![CDATA[ n Bu4NBr]]> MeCN 6 25 3 63 29 C(+)|Ni(-) <![CDATA[ n Bu4NBr]]> MeCN 6 25 7 95 30 C(+)|Ni(-) <![CDATA[ n Bu4NBr]]> MeCN 6 25 9 95 31 C(+)|Ni(-) <![CDATA[ n Bu4NBr]]> MeCN 6 25 5 72 32 C(+)|Ni(-) <![CDATA[ n Bu4NBr]]> MeCN 6 25 5 85

[0097] Examples 12-15

[0098] Screening of working electrode materials

[0099] 1-Phenylacetyl-2-(1H-pyrazol-1-yl)ethyl-1-one, i.e., compound II-1 (0.5 mmol, 1 equivalent), and diphenylphosphoric acid, i.e., compound III-1 (1.5 mmol, 3.0 equivalent), were placed in a 50 mL three-necked flask, and tetrabutylammonium bromide was added simultaneously. n Using [Bu4NBr] (1.0 mmol, 2 equivalents) as the electrolyte, and adding 10 ml of anhydrous acetonitrile (CH3CN) as the solvent, carbon cloth electrodes (Example 12), carbon cloth electrodes (Example 13), glassy carbon electrodes (Example 14), and platinum electrodes (Example 15) were used as the anode and cathode, respectively. The reaction was carried out for 5 hours under a direct current of 6 mA and at room temperature. The solvent was then evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 50) to obtain a white solid target product compound I-1, with corresponding yields of 22% (Example 12), 25% (Example 13), 0% (Example 14), and 0% (Example 15). The results compared with Example 1 show that the yield is optimal when using a carbon cloth electrode as the anode and a nickel electrode as the cathode.

[0100] Examples 16-18

[0101] Electrolyte selection

[0102] 1-Phenylacetyl-2-(1H-pyrazol-1-yl)ethyl-1-one, i.e., compound II-1 (0.5 mmol, 1 equivalent), and diphenylphosphine, i.e., compound III-1 (1.5 mmol, 3.0 equivalent), were placed in a 50 mL three-necked flask. 1.0 mmol of tetraethylammonium bromide (Example 16), tetrabutylammonium tetrafluoroborate (Example 17), and lithium perchlorate (Example 18) were added as electrolytes, respectively. 10 mL of anhydrous acetonitrile (CH3CN) was added as solvent. A carbon cloth electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 5 hours at room temperature with a direct current of 6 mA. The solvent was evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 50) to obtain a white solid target product, compound I-1, with corresponding yields of 47% (Example 16), 0% (Example 17), and 0% (Example 18), respectively. These results, compared with Example 1, indicate that the yield was optimal when tetrabutylammonium bromide was used as the electrolyte.

[0103] Examples 19-23

[0104] Solvent selection

[0105] 1-Phenylacetyl-2-(1H-pyrazol-1-yl)ethyl-1-one, i.e., compound II-1 (0.5 mmol, 1 equivalent), and diphenylphosphoric acid, i.e., compound III-1 (1.5 mmol, 3.0 equivalent), were placed in a 50 mL three-necked flask, and tetrabutylammonium bromide was added simultaneously. n Bu4NBr], 1.0 mmol, 2 equivalents) was used as the electrolyte, and 10 ml of dimethyl sulfoxide (Example 19), N,N-dimethylformamide (Example 20), dichloromethane (Example 21), methanol (Example 22), and toluene (Example 23) were added as solvents, respectively. A carbon cloth electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 5 hours under a direct current of 6 mA and at room temperature. The solvent was evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 50) to obtain a white solid target product compound I-1, with corresponding yields of 0% (Example 19), 50% (Example 20), 41% (Example 21), 35% (Example 22), and 23% (Example 23), respectively. The results compared with Example 1 show that the yield was optimal when anhydrous acetonitrile was used as the solvent.

[0106] Examples 24-25

[0107] Screening of operating current

[0108] 1-Phenylacetyl-2-(1H-pyrazol-1-yl)ethyl-1-one, i.e., compound II-1 (0.5 mmol, 1 equivalent), and diphenylphosphoric acid, i.e., compound III-1 (1.5 mmol, 3.0 equivalent), were placed in a 50 mL three-necked flask, and tetrabutylammonium bromide was added simultaneously. n Using [Bu4NBr] (1.0 mmol, 2 equivalents) as the electrolyte, and adding 10 ml of anhydrous acetonitrile (CH3CN) as the solvent, a carbon cloth electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 5 hours under direct current conditions of 4 mA (Example 24), 8 mA (Example 25), and room temperature, respectively. The solvent was evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 50) to obtain a white solid target product compound I-1, with corresponding yields of 45% (Example 24) and 37% (Example 25), respectively. The results compared with Example 1 show that the yield is optimal when using 6 mA as the operating current.

[0109] Examples 26-27

[0110] Screening of reaction temperature

[0111] 1-Phenylacetyl-2-(1H-pyrazol-1-yl)ethyl-1-one, i.e., compound II-1 (0.5 mmol, 1 equivalent), and diphenylphosphoric acid, i.e., compound III-1 (1.5 mmol, 3.0 equivalent), were placed in a 50 mL three-necked flask, and tetrabutylammonium bromide was added simultaneously. n Using [Bu4NBr] (1.0 mmol, 2 equivalents) as the electrolyte, and adding 10 ml of anhydrous acetonitrile (CH3CN) as the solvent, a carbon cloth electrode was used as the anode and a nickel electrode as the cathode. A direct current of 6 mA was applied, and the reaction was carried out at 40 °C (Example 26) and 20 °C (Example 27) for 5 hours, respectively. The solvent was evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 50) to obtain a white solid target product compound I-1, with corresponding yields of 81% (Example 26) and 86% (Example 27), respectively. The results compared with Example 1 show that 25 °C is the optimal reaction temperature for yield.

[0112] Examples 28-30

[0113] Screening of reaction time

[0114] 1-Phenylacetyl-2-(1H-pyrazol-1-yl)ethyl-1-one, i.e., compound II-1 (0.5 mmol, 1 equivalent), and diphenylphosphoric acid, i.e., compound III-1 (1.5 mmol, 3.0 equivalent), were placed in a 50 mL three-necked flask, and tetrabutylammonium bromide was added simultaneously. nUsing [Bu4NBr] (1.0 mmol, 2 equivalents) as the electrolyte, and adding 10 ml of anhydrous acetonitrile (CH3CN) as the solvent, a carbon cloth electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 3 hours (Example 28), 7 hours (Example 29), and 9 hours (Example 30) under direct current of 6 mA and room temperature, respectively. The solvent was evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 50) to obtain a white solid target product compound I-1, with corresponding yields of 63% (Example 28), 95% (Example 29), and 95% (Example 30), respectively. These results, compared with Example 1, indicate that the optimal yield was achieved with a reaction time of 5 hours.

[0115] Examples 31-32

[0116] Screening of raw material molar ratio

[0117] 1-Phenylacetyl-2-(1H-pyrazol-1-yl)ethyl-1-one, i.e., compound II-1 (0.5 mmol, 1 equivalent), and different equivalents of diphenylphosphoric acid, i.e., compound III-1 (0.5 mmol, 1.0 equivalent, Example 31) and (1.0 mmol, 2.0 equivalent, Example 32), were placed in a 50 mL three-necked flask, and tetrabutylammonium bromide was added simultaneously. n Using [Bu4NBr] (1.0 mmol, 2 equivalents) as the electrolyte, and adding 10 ml of anhydrous acetonitrile (CH3CN) as the solvent, a carbon cloth electrode was used as the anode and a nickel electrode as the cathode. The reaction was carried out for 5 hours under a direct current of 6 mA and at room temperature. The solvent was evaporated, and the product was purified by dry column chromatography (eluent: petroleum ether / ethyl acetate = 100 / 50) to obtain a white solid target product compound I-1, with corresponding yields of 72% (Example 31) and 85% (Example 32). The above results, compared with Example 1, show that the yield is optimal when 3 equivalents of compound III-1 are involved in the reaction.

[0118] Comparative Example 1

[0119]

[0120] Using the reaction described in patent application CN 115521257 A as a comparative example, the reaction conditions involve a copper salt metal catalyst and a high-valent iodine oxidant. A blue LED light source is required, along with an external photocatalyst, and the copper salt serves as the metal catalyst.

[0121] This invention eliminates the need for metal catalysts and utilizes green electrochemistry as the driving force for oxidation, significantly reducing reaction costs. In summary, the method provided by this invention is superior to the comparative example.

[0122] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-described technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A method for preparing a phosphorylated azole acetophenone derivative, characterized in that, Includes the following steps: Compound II and Compound III were mixed, and an electrolyte was added. The molar ratio of Compound II, Compound III and electrolyte was 1:1 to 5:1 to 3. Then a solvent was added. Under different anodic and cathode conditions, a direct current of 4 mA to 8 mA was applied, and the temperature was 15℃ to 40℃. The reaction was carried out for 3 to 9 hours to obtain the phosphorylated azole acetophenone derivative. Carbon cloth electrode and nickel electrode, carbon cloth electrode and carbon cloth electrode, and carbon cloth electrode and platinum electrode were used as anode and cathode, respectively; The electrolyte is selected from tetrabutylammonium bromide and tetraethylammonium bromide; The solvent is selected from acetonitrile, N,N-dimethylformamide, dichloromethane, methanol, and toluene; in, R1 is selected from hydrogen, halogen, C1-C20 alkyl, C1-C20 alkoxy, R2 is selected from hydrogen, halogen, C1-C20 alkyl, C1-C20 alkoxy, R3 is selected from hydrogen, halogen, C1-C20 alkyl, C1-C20 alkoxy, R4 is selected from hydrogen, halogen, C1-C20 alkyl, C1-C20 alkoxy, R5 is selected from hydrogen, halogens, C1-C20 alkyl groups, and C1-C20 alkoxy groups. Alternatively, R2 and R3, along with carbon, form a six-membered ring; R6 is selected from hydrogen, halogen, C1-C20 alkyl, and C1-C20 alkoxy. R7 is selected from hydrogen, halogen, C1-C20 alkyl, and C1-C20 alkoxy. R8 is selected from hydrogen, halogen, C1-C20 alkyl, and C1-C20 alkoxy. R 11 ~R 15 Each is independently selected from hydrogen and halogens.

2. The method for preparing phosphorylated azole acetophenone derivatives according to claim 1, characterized in that, In compound II, R1 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy, R2 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy, etc. R3 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy, R4 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy, etc. R5 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy, Alternatively, R2 and R3, along with carbon, form a six-membered benzene ring, with the following structure: Dashed lines indicate connection points; R6 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, tert-butyl, methoxy, ethoxy, and tert-butoxy. R7 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, tert-butyl, methoxy, ethoxy, and tert-butoxy. R8 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, tert-butyl, methoxy, ethoxy, and tert-butoxy.

3. The method for preparing phosphorylated azole acetophenone derivatives according to claim 2, characterized in that, Compound II has one of the following structures:

4. The method for preparing phosphorylated azole acetophenone derivatives according to claim 1, characterized in that, The phosphorylated azole acetophenone derivatives are selected from one of the following structures:

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