A method for preparing a 2'-iodo[1,1'-biaryl]-2-dithiophosphonate compound

Abstract

The application discloses a preparation method of a 2'-iodo[1,1'-biaryl]-2-dithiophosphate compound, wherein phosphorus pentasulfide, alcohol, dianyl trifluoromethanesulfonic acid periodate, an organic ligand, a base, a catalyst and an organic solvent are mixed in a reaction container under an air atmosphere, and the mixture is reacted under stirring at 25-100 DEG C for 6-12 hours to obtain the corresponding 2'-iodo[1,1'-biaryl]-2-dithiophosphate compound. The application provides a method for efficiently and selectively synthesizing 2'-iodo[1,1'-biaryl]-2-dithiophosphate compounds by copper catalysis of phosphorus pentasulfide, alcohol and dianyl trifluoromethanesulfonic acid periodate. The reaction process is mild and easy to control. The method is simple and easy to implement, the catalyst is cheap and easy to obtain, the preparation is simple, and the method has a good industrial application prospect.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology and relates to a method for preparing 2'-iodo[1,1'-biaryl]-2-dithiophosphate compounds. Specifically, it relates to a novel method for preparing 2'-iodo[1,1'-biaryl]-2-dithiophosphate compounds by a copper-catalyzed, highly efficient cross-coupling reaction of diphosphorus pentasulfide with alcohols and diaryltrifluoromethanesulfonic acid high-iodide salt. Background Technology

[0002] 2'-Halo[1,1'-Biaryl]-2-dithiophosphates are an important class of organic compounds and building blocks for organic intermediates in organic synthesis, exhibiting excellent catalytic, optical, and biological activities. Iodinated compounds, in particular, benefit from the high reactivity of the iodine substituent, allowing for selective modification and wide applications in biology, medicine, optically active materials, and asymmetric catalytic synthesis. Furthermore, phosphorus and organophosphorus compounds are indispensable in living organisms, such as ADP, ATP, RNA, and the organophospholipid bilayer in the human body. However, naturally occurring dithiophosphates are difficult to find, and phosphorus mostly exists in nature as inorganic salts. Currently known organophosphonates are mostly synthesized through chemical methods.

[0003] In recent years, with the continuous expansion of the application fields of organophosphonates (especially as organic ligands and organic functional building blocks), market demand has also been increasing. The development of novel, environmentally friendly, and atom-economically efficient synthetic technologies has received increasing attention. Currently, the most common synthetic methods for 2'-halo[1,1'-biaryl]-2-organophosphonates mainly include: (a) Atherton-Todd reaction combined with sulfidation: carbon tetrachloride directly halogenates P(O)-H compounds, which are then cross-coupled with 2'-iodo-[1,1'-biphenyl]-2-thiols under the catalysis of triethylamine; after obtaining the thiophosphate, it reacts with Lawson's reagent to convert the P=O bond to a P=S bond, thereby obtaining the corresponding dithiophosphate; (b) Oxidative dehydrogenation coupling reaction: Using P(O)-H compounds as phosphorylation reagents, in the presence of transition metals such as palladium or nickel, oxidants (oxygen, tert-butanol peroxide, etc.) are used to promote the oxidative dehydrogenation reaction of P(O)-H compounds with 2'-iodo-[1,1'-biphenyl]-2-thiol compounds; after obtaining thiophosphate esters, they are further reacted with Lawson's reagent to convert the P=O bond to a P=S bond, thereby obtaining the corresponding dithiophosphate ester; (c) Cross-coupling reaction: using noble metal catalysts (palladium, silver, rhodium, ruthenium, etc.) in the presence of base to catalyze the cross-coupling reaction of P(S)-SH with 2-iodo-2'-iodo-[1,1'-biphenyl] compounds. However, the above methods generally employ air-sensitive reagents (P(O)-H compounds, carbon tetrachloride, etc.) and expensive transition metal catalysts (palladium, silver, rhodium, ruthenium, etc.). Furthermore, they suffer from drawbacks such as cumbersome experimental procedures, expensive and difficult-to-recycle catalysts, harsh reaction conditions, overlapping substrate applicability, low yields, and significant environmental pollution.

[0004] To date, the efficient synthesis of dithiophosphate compounds still faces several challenges, including raw material quality, production safety, and product stability and purity, making the synthesis technology quite difficult. Summary of the Invention

[0005] The purpose of this invention is to provide a method for synthesizing 2'-iodo[1,1'-biaryl]-2-dithiophosphate compounds by using inexpensive and readily available phosphorus pentasulfide as a thiophosphorylating agent and by utilizing inexpensive transition metal copper salts to catalyze the efficient cross-coupling reaction of its alcohol compounds and biaryltrifluoromethanesulfonic acid high-iodide salt, thereby overcoming the above-mentioned defects in the prior art.

[0006] To achieve the above-mentioned technical objectives, the present invention adopts the following technical solution: A method for preparing a 2'-iodo[1,1'-biaryl]-2-dithiophosphate compound comprises the following steps: Under an air atmosphere, phosphorus pentasulfide, an alcohol, a high-iodide salt of biaryltrifluoromethanesulfonic acid, an organic ligand, a base, a catalyst, and an organic solvent are placed in a reaction vessel and mixed. The mixture is then reacted at 25-100°C for 6-12 hours with stirring to obtain the corresponding 2'-iodo[1,1'-biaryl]-2-dithiophosphate compound. The reaction equation is shown below:

[0007] The catalyst is copper trifluoromethanesulfonate, and the organic ligand is 4,4'-bipyridine; R 1 It is selected from one of the following: hydrogen atom, methyl, methoxy, fluorine atom, chlorine atom, and trifluoromethyl; R 2 It is selected from one of the following: hydrogen atom, methyl, methoxy, fluorine atom, chlorine atom, and trifluoromethyl; R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, isopentyl, cyclopentyl, cyclohexyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 1,3-dichloro-2-propyl, 2-methoxyethyl, but-3-en-1-yl, and but-3-yn-1-yl.

[0008] In the above preparation method, the alkali is sodium bicarbonate.

[0009] In the above preparation method, the organic solvent is acetonitrile.

[0010] In the above preparation method, the molar ratio of biaryltrifluoromethanesulfonate high-iodide salt to phosphorus pentasulfide is 1:1~2; the molar ratio of biaryltrifluoromethanesulfonate high-iodide salt to alcohol is 1:4~10; the molar ratio of biaryltrifluoromethanesulfonate high-iodide salt to copper trifluoromethanesulfonate is 1:0.01~0.2; the molar ratio of biaryltrifluoromethanesulfonate high-iodide salt to 4,4'-bipyridine is 1:0.01~0.2; and the molar ratio of biaryltrifluoromethanesulfonate high-iodide salt to alkali is 1:1~2.

[0011] The beneficial effects of this invention are: The present invention provides a method for the efficient and selective synthesis of 2'-iodo[1,1'-biaryl]-2-dithiophosphate compounds by copper-catalyzed reaction of phosphorus pentasulfide with alcohols and diaryltrifluoromethanesulfonic acid high-iodide salt. The reaction process is mild and easy to control. While achieving high yield and high selectivity, the method is simple and easy to implement. Moreover, the catalyst used is inexpensive and readily available, and the preparation is simple, showing good prospects for industrial application. Attached Figure Description

[0012] Figure 1Bar graph showing the inhibition rate of different compounds on HepG2 cells. Detailed Implementation

[0013] The present invention will be further described below with reference to embodiments thereof: Testing and Analysis: In the following embodiments of the present invention, the structural analysis of the reaction products was performed using an Agilent GC / MS (6890N / 5973N) system equipped with an HP-5MS capillary column (30m × 0.45mm × 0.8μm) and a Bruker Avance-III 500 NMR analyzer. The selectivity and yield of the target products were analyzed using an Agilent GC 7820A gas chromatograph equipped with a flame ionization detector and an AB-FFAP capillary column (30m × 0.25mm × 0.25μm).

[0014] Example 1

[0015] Preparation of O,O-diethyl-S-(2'-iodo-[1,1'-biphenyl]-2-yl)-dithiophosphate: 85.6 mg (0.2 mmol) of [1,1'-biphenyl]-2,2'-trifluoromethanesulfonate high-iodide salt, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 92 mg (2 mmol) of ethanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere, followed by the addition of 1.0 mL of acetonitrile. The mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 87%.

[0016] Example 2

[0017] Preparation of O,O-diethyl-S-(2'-iodo-4,4'-dimethyl-[1,1'-biphenyl]-2-yl)-dithiophosphate: 91.2 mg (0.2 mmol) of 4,4'-dimethyl-[1,1'-biphenyl]-2,2'-trifluoromethanesulfonate periodide, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 92 mg (2 mmol) of ethanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere, followed by the addition of 1.0 mL of acetonitrile. The mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 88%.

[0018] Example 3

[0019] Preparation of O,O-diethyl-S-(2'-iodo-5,5'-dimethyl-[1,1'-biphenyl]-2-yl)-dithiophosphate: 91.2 mg (0.2 mmol) of iodine-5,5'-dimethyl-[1,1'-biphenyl]-2,2'-trifluoromethanesulfonate, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 92 mg (2 mmol) of ethanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere, followed by the addition of 1.0 mL of acetonitrile. The mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 86%.

[0020] Example 4

[0021] Preparation of S-(5,5'-difluoro-2'-iodo-[1,1'-biphenyl]-2-yl)-O,O-diethyl dithiophosphate: 92.8 mg (0.2 mmol) of 5,5'-difluoro-[1,1'-biphenyl]-2,2'-trifluoromethanesulfonate high-iodide salt, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 92 mg (2 mmol) of ethanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere, followed by the addition of 1.0 mL of acetonitrile. The mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 83%.

[0022] Example 5

[0023] Preparation of S-(4,4'-dichloro-2'-iodo-[1,1'-biphenyl]-2-yl)-O,O-diethyl dithiophosphate: 99.4 mg (0.2 mmol) of 4,4'-dichloro-[1,1'-biphenyl]-2,2'-trifluoromethanesulfonate high-iodide salt, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 92 mg (2 mmol) of ethanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere, followed by the addition of 1.0 mL of acetonitrile. The mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 84%.

[0024] Example 6

[0025] Preparation of O,O-diethyl-S-(2'-iodo-6-methyl-[1,1'-biphenyl]-2-yl)-dithiophosphate: 88.4 mg (0.2 mmol) of 6-hydro-6'-methyl-[1,1'-biphenyl]-2,2'-trifluoromethanesulfonate periodide, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 92 mg (2 mmol) of ethanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere, followed by the addition of 1.0 mL of acetonitrile. The mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 86%.

[0026] Example 7

[0027] Preparation of O,O-diethyl-S-(2'-iodo-4-methoxy-[1,1'-biphenyl]-2-yl)-dithiophosphate: 91.6 mg (0.2 mmol) of 4-hydro-4'-methoxy-[1,1'-biphenyl]-2,2'-trifluoromethanesulfonate periodide, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 92 mg (2 mmol) of ethanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere, followed by the addition of 1.0 mL of acetonitrile. The mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 83%.

[0028] Example 8

[0029] Preparation of O,O-diethyl-S-(2'-iodo-5-methoxy-[1,1'-biphenyl]-2-yl)-dithiophosphate: 91.6 mg (0.2 mmol) of 5-hydro-5'-methoxy-[1,1'-biphenyl]-2,2'-trifluoromethanesulfonate high-iodide salt, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 92 mg (2 mmol) of ethanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere, followed by the addition of 1.0 mL of acetonitrile. The mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 84%.

[0030] Example 9

[0031] Preparation of O,O-diethyl-S-(2'-iodo-6-methoxy-[1,1'-biphenyl]-2-yl)-dithiophosphate: 91.6 mg (0.2 mmol) of 6-hydro-6'-methoxy-[1,1'-biphenyl]-2,2'-trifluoromethanesulfonate periodide, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 92 mg (2 mmol) of ethanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere, followed by the addition of 1.0 mL of acetonitrile. The mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 85%.

[0032] Example 10

[0033] Preparation of S-(4-chloro-2'-iodo-[1,1'-biphenyl]-2-yl)-O,O-diethyl dithiophosphate: 92.6 mg (0.2 mmol) of 4-hydro-4'-chloro-[1,1'-biphenyl]-2,2'-trifluoromethanesulfonate with high iodide, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 92 mg (2 mmol) of ethanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere. Then, 1.0 mL of acetonitrile was added, and the mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 83%.

[0034] Example 11

[0035] Preparation of S-(5'-chloro-4'-fluoro-2'-iodo-[1,1'-biphenyl]-2-yl)-O,O-diethyl dithiophosphate: 96 mg (0.2 mmol) of 4-hydro-4'-fluoro-5'-chloro-[1,1'-biphenyl]-2,2'-trifluoromethanesulfonate periodide, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 92 mg (2 mmol) of ethanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere, followed by the addition of 1.0 mL of acetonitrile. The mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 80%.

[0036] Example 12

[0037] Preparation of O,O-diethyl-S-(2'-iodo-5'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)-dithiophosphate: 99.2 mg (0.2 mmol) of 5-hydro-5'-trifluoromethyl-[1,1'-biphenyl]-2,2'-trifluoromethanesulfonate high-iodide salt, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 92 mg (2 mmol) of ethanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere, followed by the addition of 1.0 mL of acetonitrile. The mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 86%.

[0038] Example 13

[0039] Preparation of O,O-diethyl-S-(2'-iodo-5-methoxy-5'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)-dithiophosphate: 105.2 mg (0.2 mmol) of 5-methoxy-5'-trifluoromethyl-[1,1'-biphenyl]-2,2'-trifluoromethanesulfonate high-iodide salt, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 92 mg (2 mmol) of ethanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere, followed by the addition of 1.0 mL of acetonitrile. The mixture was heated to 80 °C. o The reaction was stirred at C for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 81%.

[0040] Example 14

[0041] Preparation of O,O-dimethyl-S-(2'-iodo-[1,1'-biphenyl]-2-yl)-dithiophosphate: 85.6 mg (0.2 mmol) of [1,1'-biphenyl]-2,2'-trifluoromethanesulfonate high-iodide salt, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 64 mg (2 mmol) of methanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere, followed by the addition of 1.0 mL of acetonitrile. The mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 90%.

[0042] Example 15

[0043] Preparation of S-(2'-iodo-[1,1'-biphenyl]-2-yl)-O,O-dipropyl dithiophosphate: 85.6 mg (0.2 mmol) of [1,1'-biphenyl]-2,2'-trifluoromethanesulfonate high-iodide salt, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 120 mg (2 mmol) of propanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere. Then, 1.0 mL of acetonitrile was added, and the mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 84%.

[0044] Example 16

[0045] Preparation of S-(2'-iodo-[1,1'-biphenyl]-2-yl)-O,O-diisopropyl dithiophosphate: 85.6 mg (0.2 mmol) of [1,1'-biphenyl]-2,2'-trifluoromethanesulfonate high-iodide salt, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 120 mg (2 mmol) of isopropanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere. Then, 1.0 mL of acetonitrile was added, and the mixture was heated to 80 °C. oThe reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 86%.

[0046] Example 17

[0047] Preparation of O,O-dibutyl-S-(2'-iodo-[1,1'-biphenyl]-2-yl)-dithiophosphate: 85.6 mg (0.2 mmol) of [1,1'-biphenyl]-2,2'-trifluoromethanesulfonate high-iodide salt, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 148 mg (2 mmol) of butanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere, followed by the addition of 1.0 mL of acetonitrile. The mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 84%.

[0048] Example 18

[0049] Preparation of O,O-diisobutyl-S-(2'-iodo-[1,1'-biphenyl]-2-yl)-dithiophosphate: 85.6 mg (0.2 mmol) of [1,1'-biphenyl]-2,2'-trifluoromethanesulfonate periodide, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 148 mg (2 mmol) of isobutanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere. Then, 1.0 mL of acetonitrile was added, and the mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 86%.

[0050] Example 19

[0051] Preparation of O,O-diisopentyl-S-(2'-iodo-[1,1'-biphenyl]-2-yl)-dithiophosphate: 85.6 mg (0.2 mmol) of [1,1'-biphenyl]-2,2'-trifluoromethanesulfonate high-iodide salt, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 176 mg (2 mmol) of isoamyl alcohol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere, followed by the addition of 1.0 mL of acetonitrile. The mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 84%.

[0052] Example 20

[0053] Preparation of O,O-dicyclopentyl-S-(2'-iodo-[1,1'-biphenyl]-2-yl)-dithiophosphate: 85.6 mg (0.2 mmol) of [1,1'-biphenyl]-2,2'-trifluoromethanesulfonate high-iodide salt, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 172 mg (2 mmol) of cyclopentanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere, followed by the addition of 1.0 mL of acetonitrile. The mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 83%.

[0054] Example 21

[0055] Preparation of O,O-dicyclohexyl-S-(2'-iodo-[1,1'-biphenyl]-2-yl)-dithiophosphate: 85.6 mg (0.2 mmol) of [1,1'-biphenyl]-2,2'-trifluoromethanesulfonate high-iodide salt, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 200 mg (2 mmol) of cyclohexanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere, followed by the addition of 1.0 mL of acetonitrile. The mixture was heated to 80 °C. oThe reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 85%.

[0056] Example 22

[0057] Preparation of O,O-bis(2,2,2-trifluoroethyl)-S-(2'-iodo-[1,1'-biphenyl]-2-yl)-dithiophosphate: 85.6 mg (0.2 mmol) of [1,1'-biphenyl]-2,2'-trifluoromethanesulfonate periodide, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 200 mg (2 mmol) of 2,2,2-trifluoroethanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere, followed by the addition of 1.0 mL of acetonitrile. The mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 82%.

[0058] Example 23

[0059] Preparation of O,O-bis(2,2,2-trichloroethyl)-S-(2'-iodo-[1,1'-biphenyl]-2-yl)-dithiophosphate: 85.6 mg (0.2 mmol) of [1,1'-biphenyl]-2,2'-trifluoromethanesulfonate high-iodide salt, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 298 mg (2 mmol) of 2,2,2-trichloroethanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere, followed by the addition of 1.0 mL of acetonitrile. The mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 84%.

[0060] Example 24

[0061] Preparation of O,O-bis(1,3-dichloropropane-2-yl)-S-(2'-iodo-[1,1'-biphenyl]-2-yl)-dithiophosphate: 85.6 mg (0.2 mmol) of [1,1'-biphenyl]-2,2'-trifluoromethanesulfonate high-iodide salt, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 256 mg (2 mmol) of 1,3-dichloro-2-propanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere, followed by the addition of 1.0 mL of acetonitrile. The mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 82%.

[0062] Example 25

[0063] Preparation of O,O-bis(2-methoxyethyl)-S-(2'-iodo-[1,1'-biphenyl]-2-yl)-dithiophosphate: 85.6 mg (0.2 mmol) of [1,1'-biphenyl]-2,2'-trifluoromethanesulfonate high-iodide salt, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 152 mg (2 mmol) of 2-methoxyethanol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere, followed by the addition of 1.0 mL of acetonitrile. The mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 84%.

[0064] Example 26

[0065] Preparation of O,O-bis(3-butenyl)-S-(2'-iodo-[1,1'-biphenyl]-2-yl)-dithiophosphate: 85.6 mg (0.2 mmol) of [1,1'-biphenyl]-2,2'-trifluoromethanesulfonate periodide, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 144 mg (2 mmol) of 3-buten-1-ol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere. Then, 1.0 mL of acetonitrile was added, and the mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 82%.

[0066] Example 27

[0067] Preparation of O,O-bis(3-butynyl)-S-(2'-iodo-[1,1'-biphenyl]-2-yl)-dithiophosphate: 85.6 mg (0.2 mmol) of [1,1'-biphenyl]-2,2'-trifluoromethanesulfonate periodide, 44.4 mg (0.2 mmol) of phosphorus pentasulfide, 140 mg (2 mmol) of 3-buten-1-ol, 14.4 mg (0.04 mmol) of copper trifluoromethanesulfonate, 6.2 mg (0.04 mmol) of 4,4'-bipyridine, and 16.8 mg (0.2 mmol) of sodium bicarbonate were added to a Schlenk tube under air atmosphere, followed by the addition of 1.0 mL of acetonitrile. The mixture was heated to 80 °C. o The reaction was stirred for 12 hours. After the reaction was completed, the product was purified by column chromatography, and the yield of the target product was 83%.

[0068] As can be seen from the above embodiments, the method for the efficient and selective synthesis of 2'-iodo[1,1'-biaryl]-2-dithiophosphate compounds using phosphorus pentasulfide, alcohols, and diaryltrifluoromethanesulfonic acid high-iodide salt has advantages such as mild reaction conditions, inexpensive and readily available catalysts, and simple reaction steps. Furthermore, this method also has advantages such as wide substrate applicability, high yield, and high selectivity, providing an efficient method for synthesizing derivatives containing 2'-iodo[1,1'-biaryl]-2-dithiophosphates.

[0069] Cell viability assay: Cell viability was assessed using a CCK-8 assay kit (BS350B, Biosharp, China). HepG2 cells were cultured at 1 × 10⁶ cells per well. 4Cells were seeded at a density of [number] cells / well in 96-well plates and incubated for 12 hours. Subsequently, cells were treated with different compounds (3a, 3b, 3c, 3g, 3h, 4b, 4c, and 4e) at 10 μM concentrations for 24 hours. After treatment, 10 μL of CCK-8 solution was added to each well according to the manufacturer's instructions, and cells were incubated at 37 °C for another 1 hour. Absorbance at 450 nm was measured using a Bio-Rad microplate reader (SpectraMax M3, USA). Viability assay results are shown below. Figure 1 As shown, the compounds 3a (Example 1), 3b (Example 2), 3c (Example 3), 3g (Example 4), 3h (Example 5), 4b (Example 14), 4c (Example 15) and 4e (Example 17) synthesized in this invention all have a certain inhibitory effect on HepG2 liver cancer cells.

Claims

1. A method for preparing a 2'-iodo[1,1'-biaryl]-2-dithiophosphate compound, characterized in that: In an air atmosphere, phosphorus pentasulfide, alcohol, biaryltrifluoromethanesulfonic acid high-iodide salt, organic ligand, base, catalyst, and organic solvent are placed in a reaction vessel and mixed. The mixture is then reacted at 25–100 °C for 6–12 hours with stirring to obtain the corresponding 2'-iodo[1,1'-biaryl]-2-dithiophosphate compound. The reaction equation is shown below: ； The catalyst is copper trifluoromethanesulfonate, and the organic ligand is 4,4'-bipyridine; R 1 It is selected from one of the following: hydrogen atom, methyl, methoxy, fluorine atom, chlorine atom, and trifluoromethyl; R 2 It is selected from one of the following: hydrogen atom, methyl, methoxy, fluorine atom, chlorine atom, and trifluoromethyl; R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, isopentyl, cyclopentyl, cyclohexyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 1,3-dichloro-2-propyl, 2-methoxyethyl, but-3-en-1-yl, and but-3-yn-1-yl.

2. The preparation method according to claim 1, characterized in that: The alkali is sodium bicarbonate.

3. The preparation method according to claim 1, characterized in that: The organic solvent is acetonitrile.

4. The preparation method according to claim 1, characterized in that: The molar ratio of the diaryltrifluoromethanesulfonate high-iodide salt to phosphorus pentasulfide is 1:1~2; the molar ratio of the diaryltrifluoromethanesulfonate high-iodide salt to alcohol is 1:4~10; the molar ratio of the diaryltrifluoromethanesulfonate high-iodide salt to copper trifluoromethanesulfonate is 1:0.01~0.2; the molar ratio of the diaryltrifluoromethanesulfonate high-iodide salt to 4,4'-bipyridine is 1:0.01~0.2; and the molar ratio of the diaryltrifluoromethanesulfonate high-iodide salt to alkali is 1:1~2.

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