Benzophenone derivative as well as preparation method and application thereof

Abstract

The invention relates to the technical field of organic synthesis and preparation of drug intermediates, and provides a benzophenone derivative as shown in a formula I as well as a preparation method and application thereof. According to the invention, the ring opening of cyclopropyl ketone is realized by using cheap metal nickel, the synthesis of the benzophenone compound is realized under the action of weak base, the disubstituted benzophenone product is simply and efficiently synthesized through a single molecule reaction, and the method has the characteristics of economy, high efficiency, simplicity and convenience in operation and mild conditions.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis and pharmaceutical intermediate preparation technology, specifically to a benzophenone derivative, its preparation method, and its application. Background Technology

[0002] The benzophenone skeleton has attracted much attention from researchers due to its widespread presence in pharmacologically active natural products and its role as an important building block in synthesis. Currently, various structurally diverse and biologically active natural benzophenone compounds have been isolated from higher plants and fungi. Significant breakthroughs have been made in the synthesis of benzophenone in the past two decades, including Friedel-Crafts acylation, Suzuki-Miyaura coupling (boronic acid strategy), Suzuki-Miyaura carbonylation coupling, transition metal-catalyzed CH activation, and base catalysis. However, these methods all have certain limitations, such as the need for pre-functionalization, expensive catalysts, high cost, the need for pre-prepared catalysts, less-than-simple operation, demanding conditions (requiring strong bases), and substrate limitations.

[0003] Therefore, it is of great significance to develop new methods that are mild in terms of conditions, have broad functional group compatibility, and are suitable for large-scale production. Summary of the Invention

[0004] The purpose of this invention is to provide a benzophenone derivative, its preparation method, and its application, in order to solve the problems of existing methods for preparing the benzophenone skeleton structure, such as the need for pre-functionalization, expensive catalysts, high cost, the need for pre-prepared catalysts, inconvenient operation, harsh conditions (requiring strong bases), and limitations of the substrate.

[0005] To solve the above-mentioned technical problems, the present invention specifically provides the following technical solution: A benzophenone derivative, the structural formula of which is shown in Formula I: ; Formula I Wherein, R is independently selected from naphthalene ring, benzo[a]heterocyclic ring, thiophene, and benzene ring with substituents; the substituents are selected from halogen, methyl, tert-butyl, and methoxy.

[0006] Preferably, the compound is any one of the following compounds 1-21: .

[0007] The present invention also provides solvates of the above-mentioned benzophenone derivatives and pharmaceutically acceptable salts of the benzophenone derivatives.

[0008] The present invention also provides a method for preparing the above-mentioned benzophenone derivative, comprising the following steps: The arylcyclopropyl ketone derivative and carbene ligand were mixed with an organic solvent, and a nickel catalyst and base were added under nitrogen atmosphere. The mixture was stirred at 130 °C for 24 h. After the reaction was complete, the mixture was cooled to room temperature and the target product was obtained by silica gel chromatography. The molar ratio of the carbene ligand to the arylcyclopropyl ketone derivative is in the range of 0.2:1. The molar ratio of the nickel catalyst to the arylcyclopropyl ketone derivative is in the range of 0.1:1; The molar ratio of the base to the arylcyclopropyl ketone derivative is in the range of 2.5:1; The solvent is 1 ml.

[0009] Further, the arylcyclopropyl ketone derivative is selected from phenylcyclopropyl ketone, cyclopropyl(2-methylphenyl) ketone, cyclopropyl(3-methylphenyl) ketone, cyclopropyl(4-methylphenyl) ketone, p-tert-butylphenylcyclopropyl ketone, cyclopropyl(5,6,7,8-tetrahydronaphthyl-2-yl) ketone, cyclopropyl(3,4-dimethylphenyl) ketone, cyclopropyl(3,5-dimethylphenyl) ketone, cyclopropyl(2-methoxyphenyl) ketone, cyclopropyl(3-methoxyphenyl) ketone, cyclopropyl(3,4-dimethoxy ... One of the following: cyclopropyl(3,5-dimethoxyphenyl) methyl ketone, cyclopropyl(1,3-benzodioxolane-5-yl) methyl ketone, cyclopropyl(2,3-dihydro-1,4-benzodioxin-6-yl) methyl ketone, cyclopropyl(3-fluorophenyl) methyl ketone, cyclopropyl(4-fluorophenyl) methyl ketone, cyclopropyl(3-(trifluoromethyl)phenyl) methyl ketone, cyclopropyl(4-(trifluoromethyl)phenyl) methyl ketone, cyclopropyl([1,1'-biphenyl]-2-yl) methyl ketone, cyclopropyl(naphthyl-2-yl) methyl ketone; cyclopropyl(thiophene-2-yl) methyl ketone; The ligand is selected from 1,3-bis(1-adamantyl)chlorinated imidazole; The nickel catalyst is selected from bis-(1,5-cyclooctadiene) nickel; The alkali is selected from lithium tert-butoxide; The organic solvent is selected from m-xylene.

[0010] The eluent for the silica gel chromatography is a mixed solvent of petroleum ether and ethyl acetate, with a volume ratio of 20:1 to 5:1.

[0011] This invention also provides the application of the above-mentioned benzophenone derivative in the preparation of sunscreen products.

[0012] The present invention also provides a pharmaceutical composition comprising, as an active ingredient, a benzophenone derivative or a solvate thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0013] Furthermore, the dosage form of the pharmaceutical composition is an injection, a lyophilized powder for injection, a tablet, a powder, a granule, a capsule, a pill, a drop pill, or an oral solution.

[0014] Compared with the prior art, the present invention has the following advantages: This invention utilizes inexpensive nickel to achieve ring-opening of cyclopropyl ketone and synthesizes benzophenone compounds under the action of a weak base. It is a simple and efficient method to synthesize a disubstituted benzophenone product through a single-molecule reaction, which is economical, efficient, easy to operate and mild. Detailed Implementation

[0015] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0016] The benzophenone skeleton is the core structure of many important natural products, drugs, and sunscreens. Benzophenone-containing molecules exhibit a variety of biological activities, including anticancer and antibacterial properties, and are particularly prominent in their UV protection as sunscreens. This invention introduces different electron-donating and electron-withdrawing groups at both ends of the benzophenone conjugated system, forming a "push-pull" electronic structure. This significantly alters the molecule's electronic transition energy levels, thereby precisely controlling its maximum absorption wavelength to cover the ultraviolet region. Its basic skeleton is a highly conjugated π-electron system that effectively absorbs UV energy and releases it through harmless heat or fluorescence, thus protecting the skin.

[0017] This invention utilizes inexpensive nickel to achieve ring-opening of cyclopropyl ketone and synthesizes benzophenone compounds under the action of a weak base, thus synthesizing a new disubstituted benzophenone product simply and efficiently through self-reaction.

[0018] The arylcyclopropyl ketone derivatives used in this invention are referenced from Fukuyama, T., Kippo, T., Hamaoka, K. ScienceChinaChemistry Preparation was carried out. ,2019, 62, 1525-1528.

[0019] Nuclear Magnetic Resonance Spectrometer: JOEL Mass spectrometer: SYNAPT-G2 (Waters Corporation, USA, UCB-285) Example 1 Preparation method of compound 1 ((5-methyl-[1,1'-biphenyl]-2-yl)(phenyl) ketone:

[0020] Phenylcyclopropyl ketone (29.2 mg), bis-(1,5-cyclooctadiene)nickel (5.5 mg), 1,3-bis(1-adamantyl)imidazolium chloride (14.9 mg), and lithium tert-butoxide (40.0 mg) were added together to a reaction tube containing 1 mL of m-xylene solvent. The reaction was carried out in an anhydrous and oxygen-free environment at 130 °C in an oil bath for 24 hours. After the reaction was complete, the reaction solution was cooled. The reaction solution was separated and purified by silica gel chromatography using a gradient elution with petroleum ether:ethyl acetate = 20:1. After elution, the fraction containing the target compound was collected. The solvent was removed to obtain compound 1.

[0021] 1 H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.0 Hz, 2H), 7.41 (dd, J =20.8, 8.0 Hz, 2H), 7.31 – 7.23 (m, 6H), 7.22 – 7.13 (m, 3H), 2.49 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl3) δ 198.9, 141.5, 140.8, 140.5, 137.7, 136.2,132.7, 130.9, 130.0, 129.3, 129.0, 128.3, 128.1, 127.8, 127.3, 21.6 ppm. HRMS (ESI) m / z calculated value: C 20 H 16 O +H + 273.1274, Measured value: 273.1271.

[0022] Example 2 Preparation method of compound 2 (2',5-methyl-[1,1'-biphenyl]-2-yl)(2-methylphenyl) ketone:

[0023] Cyclopropyl (2-methylphenyl) ketone (32.1 mg), bis-(1,5-cyclooctadiene)nickel (5.5 mg), 1,3-bis(1-adamantyl)imidazolium chloride (14.9 mg), and lithium tert-butoxide (40.0 mg) were added together to a reaction tube containing 1 mL of m-xylene solvent. The reaction was carried out in an anhydrous and oxygen-free environment at 130 °C in an oil bath for 24 hours. After the reaction was complete, the reaction solution was cooled. The reaction solution was separated and purified by silica gel chromatography using a gradient elution with petroleum ether:ethyl acetate = 20:1. After elution, the fraction containing the target compound was collected. The solvent was removed to obtain compound 2.

[0024] 1 H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 7.20– 7.12 (m, 2H), 7.09 – 6.92 (m, 7H), 2.45 (s, 3H), 2.26 (s, 3H), 2.09 (s, 3H)ppm. 13 C NMR (100 MHz, CDCl3) δ 200.4, 141.6, 141.0, 140.3, 139.0, 138.1,137.9, 135.4, 131.4, 131.1, 130.7, 130.0, 129.8, 129.7, 129.6, 127.8, 127.3,125.2, 124.7, 21.6, 20.4, 20.3 ppm. HR-MS (ESI) m / z Calculated value: C 22 H 20 O +H + 301.1587 Measured value: 301.1586.

[0025] Example 3 Preparation method of compound 3 (3',5-methyl-[1,1'-biphenyl]-2-yl)(3-methylphenyl) ketone:

[0026] Cyclopropyl (3-methylphenyl) ketone (32.1 mg), bis-(1,5-cyclooctadiene)nickel (5.5 mg), 1,3-bis(1-adamantyl)imidazolium chloride (14.9 mg), and lithium tert-butoxide (40.0 mg) were added together to a reaction tube containing 1 mL of m-xylene solvent. The reaction was carried out in an oil bath at 130 °C for 24 hours under anhydrous and oxygen-free conditions. After the reaction was completed, the reaction solution was cooled. The reaction solution was separated and purified by silica gel chromatography using a gradient elution with petroleum ether:ethyl acetate = 20:1. After elution, the fraction containing the target compound was collected. The solvent was removed to obtain compound 3.

[0027] 1H NMR (400 MHz, CDCl3) δ 7.47 – 7.38 (m, 2H), 7.29 (s, 1H), 7.26 –7.12 (m, 3H), 7.11 – 6.99 (m, 3H), 6.95 (d, J = 7.2 Hz, 1H), 2.48 (s, 3H),2.28 (s, 3H), 2.24 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl3) δ 199.0, 141.7, 140.7,140.5, 137.8, 137.7, 137.6, 136.3, 133.4, 130.9, 130.5, 129.8, 129.3, 128.1,128.0, 127.9, 127.7, 127.2, 126.1, 21.6, 21.4, 21.3 ppm. HR-MS (ESI) m / z Calculated value: C 22 H 20 O +H + 301.1587 Measured value: 301.1586.

[0028] Example 4 Preparation method of compound 4 (4',5-methyl-[1,1'-biphenyl]-2-yl)(4-methylphenyl) ketone:

[0029] Cyclopropyl (4-methylphenyl) ketone (32.1 mg), bis-(1,5-cyclooctadiene)nickel (5.5 mg), 1,3-bis(1-adamantyl)imidazolium chloride (14.9 mg), and lithium tert-butoxide (40.0 mg) were added together to a reaction tube containing 1 mL of m-xylene solvent. The reaction was carried out in an anhydrous and oxygen-free environment at 130 °C in an oil bath for 24 hours. After the reaction was complete, the reaction solution was cooled. The reaction solution was separated and purified by silica gel chromatography using a gradient elution with petroleum ether:ethyl acetate = 20:1. After elution, the fraction containing the target compound was collected. The solvent was removed to obtain compound 4.

[0030] 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 7.6Hz, 1H), 7.29 – 7.20 (m, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz,2H), 7.02 (d, J = 7.6 Hz, 2H), 2.47 (s, 3H), 2.34 (s, 3H), 2.26 (s, 3H).ppm. 13 C NMR (100 MHz, CDCl3) δ 198.5, 143.6, 141.3, 140.4, 137.6, 137.0,136.4, 135.2, 131.0, 130.3, 129.1, 129.0, 128.9, 128.8, 127.4, 21.8, 21.6,21.2.ppm. HR-MS (ESI) m / z Calculated value: C 22 H 20 O +H + 301.1587 Measured value: 301.1584.

[0031] Example 5 Preparation method of compound 5 (4'-tert-butyl-5-methyl-[1,1'-biphenyl]-2-yl)(4-tert-butylphenyl) ketone:

[0032] 40.5 mg of p-tert-butylphenylcyclopropyl ketone, 5.5 mg of bis-(1,5-cyclooctadiene)nickel, 14.9 mg of 1,3-bis(1-adamantyl)imidazolium chloride, and 40.0 mg of lithium tert-butoxide were added together to a reaction tube containing 1 mL of m-xylene solvent. The reaction was carried out in an oil bath at 130 °C for 24 hours under anhydrous and oxygen-free conditions. After the reaction was complete, the reaction solution was cooled. The reaction solution was separated and purified by silica gel chromatography using a gradient elution with petroleum ether:ethyl acetate = 20:1. After elution, the fraction containing the target compound was collected. The solvent was removed to obtain compound 5.

[0033] 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 7.6Hz, 1H), 7.32 – 7.26 (m, 1H), 7.19 (d, J = 3.6 Hz, 3H), 2.48 (s, 3H), 1.28 (s, 9H), 1.23 (s, 9H) ppm. 13 C NMR (100 MHz, CDCl3) δ 198.6, 156.2, 150.0,141.6, 140.5, 137.6, 136.5, 135.4, 130.9, 130.0, 129.2, 128.8, 127.4, 125.1,124.9, 124.6, 35.1, 34.5, 31.3, 31.1, 21.6 ppm. HR-MS (ESI) m / z Calculated value: C 28 H 32 O +H + Measured value: 385.2526.

[0034] Example 6 Preparation method of compound 6 (4-methyl-2-(5,6,7,8-tetrahydronaphth-2-yl)phenyl)(5,6,7,8-tetrahydronaphth-2-yl) methyl ketone:

[0035] Cyclopropyl(5,6,7,8-tetrahydronaphth-2-yl) methyl ketone (40.1 mg), bis-(1,5-cyclooctadiene) nickel (5.5 mg), 1,3-bis(1-adamantyl)imidazolium chloride (14.9 mg), and lithium tert-butoxide (40.0 mg) were added together to a reaction tube containing 1 mL of m-xylene solvent. The reaction was carried out in an anhydrous and oxygen-free environment at 130 °C in an oil bath for 24 hours. After the reaction was complete, the reaction solution was cooled. The reaction solution was separated and purified by silica gel chromatography using a gradient elution with petroleum ether:ethyl acetate = 20:1. After elution, the fraction containing the target compound was collected. The solvent was removed to obtain compound 6.

[0036] 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 2.0Hz, 2H), 7.28 (s, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.03 – 6.91 (m, 3H), 6.88(d, J = 7.6 Hz, 1H), 2.71 (m, 8H), 2.46 (s, 3H), 1.75 (m, 8H) ppm. 13 C NMR (100MHz, CDCl3) δ 198.7, 142.7, 141.8, 140.3, 137.8, 136.9, 136.5, 136.1, 135.3,131.1, 131.0, 129.7, 129.2, 129.0, 128.9, 127.2, 126.1, 29.7, 29.4, 29.3,29.2, 23.3, 23.1, 23.0, 21.6 ppm. HR-MS (ESI) m / z Calculated value: C 28 H 28 O +H + Measured value: 381.2213; Actual value: 385.2525. Example 7 Preparation method of compound 7 (3,4-dimethylphenyl)(3',4',5-trimethyl-[1,1'-biphenyl]-2-yl) methyl ketone:

[0037] Cyclopropyl (3,4-dimethylphenyl) ketone (34.8 mg), bis-(1,5-cyclooctadiene)nickel (5.5 mg), 1,3-bis(1-adamantyl)imidazolium chloride (14.9 mg), and lithium tert-butoxide (40.0 mg) were added together to a reaction tube containing 1 mL of m-xylene solvent. The reaction was carried out in an anhydrous and oxygen-free environment at 130 °C in an oil bath for 24 hours. After the reaction was complete, the reaction solution was cooled. The reaction solution was separated and purified by silica gel chromatography using a gradient elution with petroleum ether:ethyl acetate = 20:1. After elution, the fraction containing the target compound was collected. The solvent was removed to obtain compound 7.

[0038] 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 4.8 Hz, 1H), 7.46 (t, J = 6.4Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.29 (d, J = 5.2 Hz, 1H), 7.21 (t, J = 6.4Hz, 1H), 7.08 (s, 2H), 6.97 (d, J = 4.0 Hz, 2H), 2.48 (s, 3H), 2.28 (s, 3H), 2.24 (s, 3H), 2.19 (s, 6H) ppm. 13 C NMR (100 MHz, CDCl3) δ 198.6, 142.3, 141.6,140.3, 138.2, 136.5, 136.4, 135.6, 135.5, 131.2, 131.0, 130.2, 129.5, 129.4,129.0, 128.1, 127.2, 126.4, 21.6, 20.1, 19.8, 19.7, 19.5 ppm. HR-MS (ESI) m / z Calculated value: C 24 H 24 O +H + Measured value: 329.1900; Actual value: 329.1899.

[0039] Example 8 Preparation method of compound 8 (3,5-dimethylphenyl)(3',5,5'-trimethyl-[1,1'-biphenyl]-2-yl) methyl ketone:

[0040] Cyclopropyl (3,5-dimethylphenyl) ketone (34.8 mg), bis-(1,5-cyclooctadiene)nickel (5.5 mg), 1,3-bis(1-adamantyl)imidazolium chloride (14.9 mg), and lithium tert-butoxide (40.0 mg) were added together to a reaction tube containing 1 mL of m-xylene solvent. The reaction was carried out in an oil bath at 130 °C for 24 hours under anhydrous and oxygen-free conditions. After the reaction was completed, the reaction solution was cooled. The reaction solution was separated and purified by silica gel chromatography using a gradient elution with petroleum ether:ethyl acetate = 20:1. After elution, the fraction containing the target compound was collected. The solvent was removed to obtain compound 8.

[0041] 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 7.6 Hz, 1H), 7.27 (m, 4H), 7.02(s, 1H), 6.85 (s, 2H), 6.77 (s, 1H), 2.48 (s, 3H), 2.24 (s, 6H), 2.20 (s, 6H)ppm. 13 C NMR (100 MHz, CDC l3 ) δ 199.1, 141.9, 140.6, 140.5, 137.8, 137.6,137.5, 136.5, 134.1, 130.8, 129.5, 128.8, 127.7, 127.6, 127.0, 21.6, 21.2,21.1 ppm. HR-MS (ESI) m / z Calculated value: C 24 H 24 O +H + Measured value: 329.1900; Actual value: 329.1899.

[0042] Example 9 Preparation method of compound 9 (2'-methoxy-5-methyl-[1,1'-biphenyl]-2-yl)(2-methoxyphenyl) ketone:

[0043] Cyclopropyl(2-methoxyphenyl) ketone (35.2 mg), bis-(1,5-cyclooctadiene)nickel (5.5 mg), 1,3-bis(1-adamantyl)imidazolium chloride (14.9 mg), and lithium tert-butoxide (40.0 mg) were added together to a reaction tube containing 1 mL of m-xylene solvent. The reaction was carried out in an anhydrous and oxygen-free environment at 130 °C in an oil bath for 24 hours. After the reaction was complete, the reaction solution was cooled. The reaction solution was separated and purified by silica gel chromatography using a gradient elution with petroleum ether:ethyl acetate = 10:1. After elution, the fraction containing the target compound was collected. The solvent was removed to obtain compound 9.

[0044] 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.0 Hz, 1H), 7.32 (dd, J = 7.6,2.0 Hz, 1H), 7.25 – 7.16 (m, 2H), 7.11 (d, J = 7.2 Hz, 3H), 6.81 (dt, J =22.4, 7.6 Hz, 2H), 6.66 (d, J = 8.4 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H), 3.64(s, 3H), 3.57 (s, 3H), 2.43 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl3) δ 196.7,158.1, 155.8, 141.2, 138.4, 137.9, 132.4, 131.8, 131.2, 130.7, 130.0, 129.5,128.9, 128.7, 127.7, 120.3, 119.5, 111.0, 109.9, 55.5, 54.9, 21.6 ppm. HR-MS (ESI) m / z Calculated value: C 22 H 20 O3+H + Measured value: 333.1486; Actual value: 333.1482. Example 10 Preparation method of compound 10 (3'-methoxy-5-methyl-[1,1'-biphenyl]-2-yl)(3-methoxyphenyl) ketone:

[0045] Cyclopropyl(3-methoxyphenyl) ketone (35.2 mg), bis-(1,5-cyclooctadiene)nickel (5.5 mg), 1,3-bis(1-adamantyl)imidazolium chloride (14.9 mg), and lithium tert-butoxide (40.0 mg) were added together to a reaction tube containing 1 mL of m-xylene solvent. The reaction was carried out in an anhydrous and oxygen-free environment at 130 °C in an oil bath for 24 hours. After the reaction was complete, the reaction solution was cooled. The reaction solution was separated and purified by silica gel chromatography using a gradient elution with petroleum ether:ethyl acetate = 10:1. After elution, the fraction containing the target compound was collected. The solvent was removed to obtain compound 10.

[0046] 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.6 Hz, 1H), 7.31 – 7.24 (m,3H), 7.22 – 7.06 (m, 3H), 6.99 – 6.93 (m, 1H), 6.86 – 6.75 (m, 2H), 6.73 –6.67 (m, 1H), 3.77 (s, 3H), 3.70 (s, 3H), 2.47 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl3) δ 198.6, 159.4, 159.3, 141.9, 141.2, 140.7, 139.1, 136.3, 130.8,129.3, 129.1, 127.9, 123.2, 121.6, 119.5, 114.4, 113.6, 113.3, 55.5, 55.2,21.6 ppm. HR-MS (ESI) m / z Calculated value: C 22 H 20 O3+H + Measured value: 333.1486.

[0047] Example 11 Preparation method of compound 11 (3',4'-dimethoxy-5-methyl-[1,1'-biphenyl]-2-yl)(3,4-dimethoxyphenyl) ketone:

[0048] Cyclopropyl(3,4-dimethoxyphenyl) ketone (41.2 mg), bis-(1,5-cyclooctadiene)nickel (5.5 mg), 1,3-bis(1-adamantyl)imidazolium chloride (14.9 mg), and lithium tert-butoxide (40.0 mg) were added together to a reaction tube containing 1 mL of m-xylene solvent. The reaction was carried out in an anhydrous and oxygen-free environment at 130 °C in an oil bath for 24 hours. After the reaction was complete, the reaction solution was cooled. The reaction solution was separated and purified by silica gel chromatography using a gradient elution with petroleum ether:ethyl acetate = 5:1. After elution, the fraction containing the target compound was collected. The solvent was removed to obtain compound 11.

[0049] 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.31 (m, 2H), 7.29 (s, 1H), 7.22 (dt,J = 8.4, 2.0 Hz, 2H), 6.88 – 6.77 (m, 2H), 6.71 (dd, J = 14.0, 8.4 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H), 3.73 (s, 3H), 2.47 (s, 3H) ppm. 13 CNMR (100 MHz, CDCl3) δ 197.9, 153.2, 148.8, 148.5, 148.3, 140.6, 140.2,136.5, 133.3, 130.7, 130.6, 128.7, 127.5, 125.7, 121.2, 112.4, 111.3, 111.0,109.7, 56.1, 56.0, 55.9, 55.8, 21.6 ppm. HR-MS (ESI) m / z Calculated value: C 24 H 24 O5+H + Measured value: 393.1697; Actual value: 393.1695.

[0050] Example 12 Preparation method of compound 12 (3',5'-dimethoxy-5-methyl-[1,1'-biphenyl]-2-yl)(3,5-dimethoxyphenyl) methyl ketone:

[0051] Cyclopropyl(3,5-dimethoxyphenyl) methyl ketone (41.2 mg), bis-(1,5-cyclooctadiene)nickel (5.5 mg), 1,3-bis(1-adamantyl)imidazolium chloride (14.9 mg), and lithium tert-butoxide (40.0 mg) were added together to a reaction tube containing 1 mL of m-xylene solvent. The reaction was carried out in an anhydrous and oxygen-free environment at 130 °C in an oil bath for 24 hours. After the reaction was complete, the reaction solution was cooled. The reaction solution was separated and purified by silica gel chromatography using a gradient elution with petroleum ether:ethyl acetate = 5:1. After elution, the fraction containing the target compound was collected. The solvent was removed to obtain compound 12.

[0052] 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.6 Hz, 1H), 7.29 (s, 1H), 7.25 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 2.4 Hz, 2H), 6.51 (t, J = 2.4 Hz, 1H), 6.41(d, J = 2.4 Hz, 2H), 6.27 (t, J = 2.4 Hz, 1H), 3.74 (s, 6H), 3.68 (s, 6H), 2.47 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl3) δ 198.4, 160.5, 160.4, 142.5, 141.2,140.7, 139.6, 136.2, 130.5, 129.0, 128.0, 107.8, 107.3, 105.4, 99.8, 55.6,55.3, 21.6 ppm. HR-MS (ESI) m / z Calculated value: C 24 H 24 O5+H + Measured value: 393.1697; Actual value: 393.1695.

[0053] Example 13 Preparation method of compound 13 (1,3-benzodioxolane-5-yl)(2-(1,3-benzodioxolane-5-yl)-4-methylphenyl) ketone:

[0054] Cyclopropyl (1,3-benzodioxolane-5-yl) ketone (38.0 mg), bis-(1,5-cyclooctadiene) nickel (5.5 mg), 1,3-bis(1-adamantyl)imidazolium chloride (14.9 mg), and lithium tert-butoxide (40.0 mg) were added together to a reaction tube containing 1 mL of m-xylene solvent. The reaction was carried out in an anhydrous and oxygen-free environment at 130 °C in an oil bath for 24 hours. After the reaction was complete, the reaction solution was cooled. The reaction solution was separated and purified by silica gel chromatography using a gradient elution with petroleum ether:ethyl acetate = 5:1. After elution, the fraction containing the target compound was collected. The solvent was removed to obtain compound 13.

[0055] 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 7.6 Hz, 1H), 7.25 – 7.16 (m,4H), 6.76 (s, 1H), 6.74 – 6.62 (m, 3H), 5.99 (s, 2H), 5.90 (s, 2H), 2.45 (s,3H) ppm. 13 C NMR (100 MHz, CDCl3) δ 197.1, 151.7, 147.9, 147.6, 147.0, 140.6,140.4, 136.4, 134.6, 132.6, 130.8, 128.8, 127.6, 127.2, 122.8, 109.4, 109.2,108.3, 107.6, 101.9, 101.1, 21.5 ppm. HR-MS (ESI) m / z Calculated value: C 22 H 16 O5+H + Measured value: 361.1071; Actual value: 361.1067. Example 14 Preparation method of compound 14 (2,3-dihydro-1,4-benzodioxin-6-yl)(2-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-methylphenyl) ketone:

[0056] Cyclopropyl (2,3-dihydro-1,4-benzodioxin-6-yl) methyl ketone (40.8 mg), bis-(1,5-cyclooctadiene) nickel (5.5 mg), 1,3-bis(1-adamantyl)imidazolium chloride (14.9 mg), and lithium tert-butoxide (40.0 mg) were added together to a reaction tube containing 1 mL of m-xylene solvent. The reaction was carried out in an anhydrous and oxygen-free environment at 130 °C in an oil bath for 24 hours. After the reaction was complete, the reaction solution was cooled. The reaction solution was separated and purified by silica gel chromatography using a gradient elution with petroleum ether:ethyl acetate = 5:1. After elution, the fraction containing the target compound was collected. The solvent was removed to obtain compound 14.

[0057] 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.0 Hz, 1H), 7.25 – 7.17 (m,3H), 6.82 – 6.75 (m, 2H), 6.72 (s, 2H), 4.27 (d, J = 5.2 Hz, 2H), 4.22 (d, J= 13.2 Hz, 6H), 2.45 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl3) δ 197.3, 147.8,143.2, 143.1, 143.0, 140.5, 140.2, 136.2, 134.1, 131.6, 130.8, 128.8, 127.3,124.5, 122.3, 119.5, 117.8, 117.1, 116.9, 64.7, 64.4, 64.3, 64.1, 21.5 ppm. HR-MS (ESI) m / z Calculated value: C 24 H 20 O5+H + 389.1384 Measured value: 389.1380.

[0058] Example 15 Preparation method of compound 15 (3'-fluoro-5-methyl-[1,1'-biphenyl]-2-yl)(3-fluorophenyl) methyl ketone:

[0059] Cyclopropyl (3-fluorophenyl) methyl ketone (32.8 mg), bis-(1,5-cyclooctadiene)nickel (5.5 mg), 1,3-bis(1-adamantyl)imidazolium chloride (14.9 mg), and lithium tert-butoxide (40.0 mg) were added together to a reaction tube containing 1 mL of m-xylene solvent. The reaction was carried out in an anhydrous and oxygen-free environment at 130 °C in an oil bath for 24 hours. After the reaction was complete, the reaction solution was cooled. The reaction solution was separated and purified by silica gel chromatography using a gradient elution with petroleum ether:ethyl acetate = 20:1. After elution, the fraction containing the target compound was collected. The solvent was removed to obtain compound 15.

[0060] 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 7.6Hz, 1H), 7.35 – 7.18 (m, 4H), 7.20 – 7.06 (m, 2H), 7.01 – 6.91 (m, 2H), 6.89– 6.79 (m, 1H), 2.49 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl3) δ 197.2, 163.8,163.6, 161.3(d, J CF = 245.3 Hz), 161.2(d, J CF = 246.5 Hz), 142.5(d, J CF = 7.7 Hz),141.4, 140.2, 139.8 (d, J CF = 6.8 Hz), 135.6, 130.9, 129.9 (d, J CF = 8.5 Hz), 129.8 (d, J CF = 7.6 Hz), 129.4, 128.5, 125.7 (d, J CF = 2.9 Hz), 124.9 (d, J CF =2.9 Hz), 119.9 (d, J CF = 21.3 Hz), 116.3 (d, J CF = 22.3 Hz), 115.9 (d, J CF = 21.9Hz), 114.4 (d, J CF = 20.7 Hz), 21.6 ppm. 19 F NMR (376 MHz, CDCl3) δ -112.3, -113.0 ppm. HR-MS (ESI) m / z Calculated value: C 20 H 14 F2O +H + Measured value: 309.1085; Actual value: 309.1086.

[0061] Example 16 Preparation method of compound 16 (4'-fluoro-5-methyl-[1,1'-biphenyl]-2-yl)(4-fluorophenyl) methyl ketone:

[0062] Cyclopropyl (4-fluorophenyl) methyl ketone (32.8 mg), bis-(1,5-cyclooctadiene)nickel (5.5 mg), 1,3-bis(1-adamantyl)imidazolium chloride (14.9 mg), and lithium tert-butoxide (40.0 mg) were added together to a reaction tube containing 1 mL of m-xylene solvent. The reaction was carried out in an oil bath at 130 °C for 24 hours under anhydrous and oxygen-free conditions. After the reaction was completed, the reaction solution was cooled. The reaction solution was separated and purified by silica gel chromatography using a gradient elution with petroleum ether:ethyl acetate = 20:1. After elution, the fraction containing the target compound was collected. The solvent was removed to obtain compound 16.

[0063] 1 H NMR (400 MHz, CDCl3) δ 7.66 – 7.61 (m, 2H), 7.42 (d, J = 7.6 Hz,1H), 7.31 – 7.23 (m, 2H), 7.22 – 7.15 (m, 2H), 6.98 – 6.84 (m, 4H), 2.48 (s,3H) ppm. 13 C NMR (100 MHz, CDCl3) δ 197.3, 165.6 (d, J CF = 253.6 Hz), 162.3 (d,J CF = 245.7 Hz), 141.1, 140.2, 136.4 (d, J CF = 3.3 Hz), 136.0, 134.1 (d, J CF = 3.1Hz), 132.6 (d, J CF = 9.3 Hz), 130.9, 130.6 (d, J CF = 8.2 Hz), 129.2, 128.1,115.5 (d, J CF = 3.1 Hz), 115.3 (d, J CF = 2.7 Hz), 21.6 ppm. 19 F NMR (376 MHz, CDCl3) δ -105.1, -114.8 ppm. HR-MS (ESI) m / z Calculated value: C 20 H 14 F2O +H + Measured value: 309.1084.

[0064] Example 17 Preparation method of compound 17 (5-methyl-3'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)(3-(trifluoromethyl)phenyl) ketone:

[0065] Cyclopropyl (3-(trifluoromethyl)phenyl) ketone (42.8 mg), bis-(1,5-cyclooctadiene)nickel (5.5 mg), 1,3-bis(1-adamantyl)imidazolium chloride (14.9 mg), and lithium tert-butoxide (40.0 mg) were added together to a reaction tube containing 1 mL of m-xylene solvent. The reaction was carried out in an anhydrous and oxygen-free environment at 130 °C in an oil bath for 24 hours. After the reaction was complete, the reaction solution was cooled. The reaction solution was separated and purified by silica gel chromatography using a gradient elution with petroleum ether:ethyl acetate = 20:1. After elution, the fraction containing the target compound was collected. The solvent was removed to obtain compound 17.

[0066] 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.58(t, J = 8.0 Hz, 2H), 7.45 (s, 1H), 7.36 (t, J = 8.0 Hz, 4H), 7.31 – 7.27 (m,1H), 2.52 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl3) δ 197.1, 142.2, 141.0, 140.2,138.3, 135.3, 132.5, 132.4, 130.9, 130.7, 130.6, 130.4, 130.0, 129.1, 129.0,128.8, 126.6(q, J CF = 3.9 Hz), 125.9, 125.8, 125.2, 124.9, 124.2, 124.1, 122.4,122.2, 21.6 ppm. 19 F NMR (376 MHz, CDCl3) δ -62.8, -62.9 ppm. HR-MS (ESI) m / z Calculated value: C 22 H 14 F6O +H + 409.1022 Measured value: 409.1020.

[0067] Example 18 Preparation method of compound 18 (5-methyl-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)(4-(trifluoromethyl)phenyl) ketone:

[0068] Cyclopropyl (4-(trifluoromethyl)phenyl) ketone (42.8 mg), bis-(1,5-cyclooctadiene)nickel (5.5 mg), 1,3-bis(1-adamantyl)imidazolium chloride (14.9 mg), and lithium tert-butoxide (40.0 mg) were added together to a reaction tube containing 1 mL of m-xylene solvent. The reaction was carried out in an anhydrous and oxygen-free environment at 130 °C in an oil bath for 24 hours. After the reaction was complete, the reaction solution was cooled. The reaction solution was separated and purified by silica gel chromatography using a gradient elution with petroleum ether:ethyl acetate = 20:1. After elution, the fraction containing the target compound was collected. The solvent was removed to obtain compound 18.

[0069] 1 H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.4Hz, 2H), 7.48 (t, J = 8.4 Hz, 3H), 7.39 – 7.24 (m, 4H), 2.51 (s, 3H) ppm. 13 CNMR (100 MHz, CDCl3) δ 197.2, 143.9, 142.0, 140.6, 140.5, 135.4, 134.2(q, J CF =32.8 Hz), 131.2, 130.2, 129.8, 129.5, 129.4, 128.7, 127.7, 125.4(q, J CF = 3.6Hz), 124.9, 122.7, 122.2, 21.7 ppm. 19 F NMR (376 MHz, CDCl3) δ -62.6, -63.1ppm. HR-MS (ESI) m / z Calculated value: C 22 H 14 F6O +H + 409.1022 Measured value: 409.1021.

[0070] Example 19 Preparation method of compound 19 ([1,1'-biphenyl]-4-yl)(5-methyl-[1,1':4',1''-triphenyl]-2-yl) methyl ketone:

[0071] Cyclopropyl([1,1'-biphenyl]-2-yl) methyl ketone (44.5 mg), bis-(1,5-cyclooctadiene) nickel (5.5 mg), 1,3-bis(1-adamantyl)imidazolium chloride (14.9 mg), and lithium tert-butoxide (40.0 mg) were added together to a reaction tube containing 1 mL of m-xylene solvent. The reaction was carried out in an anhydrous and oxygen-free environment at 130 °C in an oil bath for 24 hours. After the reaction was complete, the reaction solution was cooled. The reaction solution was separated and purified by silica gel chromatography using a gradient elution with petroleum ether:ethyl acetate = 20:1. After elution, the fraction containing the target compound was collected. The solvent was removed to obtain compound 19.

[0072] 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 2H), 7.58 – 7.49 (m,7H), 7.49 – 7.34 (m, 11H), 7.31 (t, J = 6.8 Hz, 2H), 2.52 (s, 3H) ppm. 13 C NMR(100 MHz, CDCl3) δ 198.4, 145.5, 141.1, 140.8, 140.7, 140.1, 140.0, 139.5,136.6, 136.4, 131.0, 130.7, 129.5, 129.3, 128.9, 128.8, 128.2, 127.8, 127.4,127.1, 127.0, 126.9, 21.6 ppm. HR-MS (ESI) m / z Calculated value: C 32 H 24 O +H + Measured value: 425.1900.

[0073] Example 20 Preparation method of compound 20 (4-methyl-2-(naphth-2-yl)phenyl)(naphth-2-yl)methyl ketone:

[0074] Cyclopropyl(naphthyl-2-yl)methyl ketone (39.2 mg), bis-(1,5-cyclooctadiene)nickel (5.5 mg), 1,3-bis(1-adamantyl)imidazolium chloride (14.9 mg), and lithium tert-butoxide (40.0 mg) were added together to a reaction tube containing 1 mL of m-xylene solvent. The reaction was carried out in an anhydrous and oxygen-free environment at 130 °C in an oil bath for 24 hours. After the reaction was complete, the reaction solution was cooled. The reaction solution was separated and purified by silica gel chromatography using a gradient elution with petroleum ether:ethyl acetate = 20:1. After elution, the fraction containing the target compound was collected. The solvent was removed to obtain compound 20.

[0075] 1 H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 5.6 Hz, 2H), 7.69 (ddd, J = 32.8, 16.8, 8.4 Hz, 5H), 7.56 – 7.31 (m,8H), 2.55 (s, 3H) ppm. 13 C NMR (100 MHz, CDCl3) δ 198.7, 141.5, 140.8, 138.1,136.6, 135.4, 135.1, 133.2, 132.5, 132.4, 132.3, 131.5, 129.6, 129.4, 128.4,128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 127.0, 126.6, 126.2, 126.0,125.1, 21.7 ppm. HR-MS (ESI) m / z Calculated value: C 28 H 20 O +H + Measured value: 373.1587.

[0076] Example 21 Preparation method of compound 21 (4-methyl-2-(thien-2-yl)phenyl)(thien-2-yl)methyl ketone:

[0077] Cyclopropyl(thiophene-2-yl) methyl ketone (24.0 mg), bis-(1,5-cyclooctadiene) nickel (5.5 mg), 1,3-bis(1-adamantyl)imidazolium chloride (14.9 mg), and lithium tert-butoxide (40.0 mg) were added together to a reaction tube containing 1 mL of m-xylene solvent. The reaction was carried out in an anhydrous and oxygen-free environment at 130 °C in an oil bath for 24 hours. After the reaction was complete, the reaction solution was cooled. The reaction solution was separated and purified by silica gel chromatography using a gradient elution with petroleum ether:ethyl acetate = 20:1. After elution, the fraction containing the target compound was collected. The solvent was removed to obtain compound 21.

[0078] 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 6.0 Hz, 1H), 7.40 (d, J = 8.0Hz, 2H), 7.25 – 7.18 (m, 2H), 7.00 – 6.93 (m, 2H), 6.91 – 6.86 (m, 1H), 2.46(s, 3H) ppm. 13 C NMR (100 MHz, CDCl3) δ 190.7, 144.9, 141.7, 140.7, 136.3,135.1, 134.6, 132.8, 131.0, 128.5, 128.3, 128.0, 127.7, 127.4, 126.2, 21.5ppm. HR-MS (ESI) m / z Calculated value: C 16 H 12 OS2+H + Measured value: 285.0402; Actual value: 285.0403.

Claims

1. A benzophenone derivative, characterized in that, The structural formula of the benzophenone derivative is shown in Formula I: ； Formula I Wherein, R is independently selected from naphthalene ring, benzo[a]heterocyclic ring, thiophene, and benzene ring with substituents; the substituents are selected from halogen, methyl, tert-butyl, and methoxy.

2. The benzophenone derivative according to claim 1, characterized in that: The benzophenone derivative is any one of the following compounds 1-21: 。 3. The solvate of the benzophenone derivative according to claim 1.

4. A pharmaceutically acceptable salt of the benzophenone derivative according to claim 1.

5. A method for preparing the benzophenone derivative according to any one of claims 1-2, characterized in that, Includes the following steps: The arylcyclopropyl ketone derivative and carbene ligand were mixed with an organic solvent, and a nickel catalyst and base were added under nitrogen atmosphere. The mixture was stirred at 125-135℃ for 20-28 h. After the reaction was complete, the mixture was cooled to room temperature and the target product was obtained by silica gel chromatography. The molar ratio of the carbene ligand to the arylcyclopropyl ketone derivative is in the range of 0.2:

1. The molar ratio of the nickel catalyst to the arylcyclopropyl ketone derivative is in the range of 0.1:1; The molar ratio of the base to the arylcyclopropyl ketone derivative is in the range of 2.5:

1.

6. The method according to claim 5, characterized in that, The arylcyclopropyl ketone derivatives are selected from phenylcyclopropyl ketone, cyclopropyl(2-methylphenyl) ketone, cyclopropyl(3-methylphenyl) ketone, cyclopropyl(4-methylphenyl) ketone, p-tert-butylphenylcyclopropyl ketone, cyclopropyl(5,6,7,8-tetrahydronaphthyl-2-yl) ketone, cyclopropyl(3,4-dimethylphenyl) ketone, cyclopropyl(3,5-dimethylphenyl) ketone, cyclopropyl(2-methoxyphenyl) ketone, cyclopropyl(3-methoxyphenyl) ketone, and cyclopropyl(3,4-dimethoxyphenyl) ketone. Cyclopropyl (3,5-dimethoxyphenyl) methyl ketone, cyclopropyl (1,3-benzodioxolane-5-yl) methyl ketone, cyclopropyl (2,3-dihydro-1,4-benzodioxin-6-yl) methyl ketone, cyclopropyl (3-fluorophenyl) methyl ketone, cyclopropyl (4-fluorophenyl) methyl ketone, cyclopropyl (3-(trifluoromethyl)phenyl) methyl ketone, cyclopropyl (4-(trifluoromethyl)phenyl) methyl ketone, cyclopropyl ([1,1'-biphenyl]-2-yl) methyl ketone, cyclopropyl (naphthyl-2-yl) methyl ketone; cyclopropyl (thiophene-2-yl) methyl ketone; The ligand is selected from 1,3-bis(1-adamantyl)chlorinated imidazole; The nickel catalyst is selected from bis-(1,5-cyclooctadiene) nickel; The alkali is selected from lithium tert-butoxide; The organic solvent is selected from m-xylene.

7. The method according to claim 5, characterized in that, The eluent for the silica gel chromatography is a mixed solvent of petroleum ether and ethyl acetate, with a volume ratio of 20:1 to 5:

1.

8. The use of the benzophenone derivatives according to claims 1-4 in the preparation of sunscreen products.

9. A pharmaceutical composition, characterized in that, It comprises, as an active ingredient, any one of the benzophenone derivatives or solvates thereof or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

10. The pharmaceutical composition according to claim 9, characterized in that, The dosage form of the pharmaceutical composition is injection, lyophilized powder for injection, tablet, powder, granule, capsule, pill, drop pill or oral solution.

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