A redox click chemistry reaction for the synthesis of disulfide-based compounds

Abstract

The application belongs to the field of organic synthesis and relates to a redox click chemistry reaction for synthesizing a dithio compound. The method uses a thiol compound as a raw material, uses a sulfonyl fluoride compound and a base as reagents, and reacts in a solvent to generate the dithio compound. The method provides a new way for efficient synthesis of the dithio compound. Compared with a traditional synthesis method for converting a thiol into a dithio compound by using an equivalent strong oxidant for oxidation or catalytic oxidation, the synthesis method based on the redox click chemistry has the advantages of simple reaction condition, cheap and easily available reagent, rapid reaction, high yield, good functional group compatibility, insensitivity to water and oxygen, and the like, and most of the products do not need to be separated by a chromatographic column.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and relates to a redox click chemistry reaction for synthesizing disulfide compounds. Background Technology

[0002] Disulfide bonds are a ubiquitous structure in nature, widely found in natural products. They also play a crucial role in biological systems, being essential for the structure and function of many proteins. Therefore, disulfide compounds have been widely applied in the pharmaceutical, agrochemical, materials science, peptide mimicry, and self-assembled monolayer membrane industries.

[0003] In living organisms, the synthesis of disulfides via the oxidation of thiols is one of the most common synthetic routes. Efficient enzymatic reactions in vivo are difficult to achieve in vitro, so strong oxidizing agents are typically required in the chemical synthesis of thiols. Commonly used oxidizing agents include elemental iodine or bromine, hydrogen peroxide, metal salts or oxides, high-valence sulfur oxidants, and DEAD and its derivatives. The oxidation of thiols under strong oxidizing agents often produces over-oxidation products such as thiosulfinates, thiosulfonates, and sulfonic acids (Current Organic Chemistry, 2020, 24, 550–581). Furthermore, catalytic oxidation reactions using oxygen or air as oxidants can also convert thiols to disulfides. These reactions avoid the use of stoichiometric, expensive, or toxic oxidizing agents. However, under catalytic oxidation conditions, tertiary thiol substrates are often difficult to oxidize, and this method usually suffers from problems such as cumbersome catalyst preparation and low catalytic efficiency (Synthesis (Stuttg)., ​​2008, 2491–2509; Top.Curr.Chem., 2018, 376, 1–40; RSC Adv., 2014, 4, 13854–13881).

[0004] To address the aforementioned shortcomings of traditional disulfide compound synthesis methods, there is an urgent need to establish a highly efficient and selective method comparable to enzymatic reactions. This patent establishes a redox click chemistry reaction for the synthesis of disulfide compounds using a combination of sulfonyl fluoride compounds and a base as reagents. This reaction offers advantages such as simple reaction conditions, inexpensive and readily available reagents, rapid reaction, high yield, good functional group compatibility, insensitivity to water and oxygen, and the elimination of the need for column chromatography separation for most products. Summary of the Invention

[0005] The purpose of this invention is to provide a redox click chemistry method for synthesizing disulfide compounds. This method uses thiols as raw materials, reacting them with a reagent composition of sulfonyl fluorides and a base in a solvent via a highly efficient redox click chemistry reaction to generate disulfide compounds. The method established in this invention has the advantages of high yield, fast reaction, good selectivity, ease of operation, and good compatibility. This invention solves the problems of traditional disulfide compound synthesis methods, such as incompatibility with tertiary thiols, the need for metal catalysts, poor selectivity, low yield, and complex operation.

[0006] To achieve the above objectives, the technical solution of the present invention is as follows:

[0007] Select reagent compositions I and II that can oxidize thiols to disulfides;

[0008] It is a sulfonyl fluoride compound, selected from any one of the following compounds: A, B, C, D, E, and F, or an analogue thereof;

[0009]

[0010] II is a base, selected from one or more of the following in any proportion: triethylamine, methanolamine, ethanolamine, triethanolamine, 1,8-diazabicycloundec-7-ene, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, and 2-tert-butyl-1,1,3,3-tetramethylguanidine;

[0011] Preferably, the base is triethylamine or sodium carbonate.

[0012] The above-mentioned click chemistry reaction for synthesizing disulfide compounds uses thiol compounds of general formula (1) as raw materials and reacts them with reagent compositions in a solvent to generate symmetrical disulfide compounds of general formula (2).

[0013]

[0014] Among them, R 1 It is one of the following: a monosubstituted or polysubstituted benzene ring, a substituted or unsubstituted straight-chain alkane or cycloalkane, or a substituted or unsubstituted heterocycle.

[0015] Using thiol compounds of general formula (1) and (3) as raw materials, reacting them with reagent compositions in a solvent, an asymmetric disulfide compound of general formula (4) is generated;

[0016]

[0017] Among them, R 1 and R 2It is one of the following: a monosubstituted or polysubstituted benzene ring, a substituted or unsubstituted straight-chain alkane or cycloalkane, or a substituted or unsubstituted heterocycle, and R 1 and R 2 They are not the same.

[0018] Using the thiol compound represented by general formula (5) as a raw material, reacting it with a reagent composition in a solvent, generates the cyclic disulfide compound represented by general formula (6);

[0019]

[0020] Among them, R 1 It is one of the following: a monosubstituted or polysubstituted benzene ring, a substituted or unsubstituted straight-chain alkane or cycloalkane, or a substituted or unsubstituted heterocycle.

[0021] The solvent is selected from one or more of acetonitrile, ethyl acetate, dichloromethane, n-hexane, ethanol, water, borax buffer solution, and serum in any proportion;

[0022] Preferably, the solvent is acetonitrile, water, or a borax buffer solution.

[0023] The method for synthesizing symmetrical disulfide compounds based on click chemistry includes the following steps:

[0024] Step 1: Add the thiol compound, base, and solvent to the reaction vessel;

[0025] Step 2: Pass the sulfonyl fluoride compound into (when the sulfonyl fluoride compound is in a gaseous state) or add it (when the sulfonyl fluoride compound is in a liquid or solid state) the reaction vessel;

[0026] Step 3: At room temperature, continue stirring the reaction mixture until the preset reaction time has elapsed;

[0027] Step 4: Inject hydrochloric acid aqueous solution (1.00M) into the reaction system, extract the aqueous phase with organic solvent, combine the organic phases, dry, and rotary evaporate the solvent to obtain disulfide products.

[0028] Preferably, in step 1, the reaction vessel can be made of glass, plastic, or a metal that does not react with the reactants;

[0029] Preferably, in step 3, the stirring is vigorous, and the reaction time is 5 min–480 min.

[0030] The beneficial effects of this invention are as follows:

[0031] 1) The method established in this invention has the advantages of simple reaction conditions, inexpensive and readily available reaction reagents, rapid reaction, high yield, good functional group compatibility, insensitivity to water and oxygen, and no need for chromatography column separation of most products.

[0032] 2) This invention utilizes a simple and efficient click chemistry reaction to achieve the synthesis of practical disulfide compounds.

[0033] 3) This invention can achieve efficient reactions in mild physiological environments such as water, borax buffer solution, or serum.

[0034] 4) This invention achieves efficient derivatization of the drug captopril. Detailed Implementation

[0035] The specific embodiments of the present invention will be described in further detail below with reference to examples.

[0036] Example 1: Synthesis of symmetrical disulfide compounds using sulfonyl fluoride compound A

[0037] 1.1 Synthesis of symmetrical disulfide compound 2a

[0038]

[0039] To a 10 mL single-necked round-bottom flask, 77.1 mg (0.500 mmol) of compound 1a, 1.00 mmol of triethylamine, and 0.500 mL of acetonitrile were added, followed by the introduction of sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched in an alkaline aqueous medium. The mixture was then extracted with 3 × 5.00 mL (1.00 M) hydrochloric acid and 3 × 10.0 mL ethyl acetate. The organic phase was dried, and the solvent was rotary evaporated to give 75.1 mg of the target compound 2a, in 98% yield.

[0040] The target product 2a obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.19(m,4H),6.88(m,4H),3.82(s,6H),3.61(s,4H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ159.1,130.6,129.4,113.9,55.3,42.8.

[0041] 1.2 Synthesis of Symmetrical Disulfide Compound 2b

[0042]

[0043] To a 10 mL single-necked round-bottom flask, add 62.1 mg (0.500 mmol) of compound 1b, 1.00 mmol of triethylamine, and 0.500 mL of acetonitrile. Then, purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched in an alkaline aqueous medium. Extraction was then performed with aqueous hydrochloric acid (3 × 5.00 mL, 1.00 M) and ethyl acetate (3 × 10.0 mL). The organic phase was dried, and the solvent was rotary evaporated to give 60.4 mg of the target compound 2b, in 98% yield.

[0044] The target product 2b obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.25–7.20(m,4H),7.20–7.16(m,2H),7.16–7.12(m,4H),3.50(s,4H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ137.4,129.5,128.5,127.5,43.3.

[0045] 1.3 Synthesis of Symmetrical Disulfide Compound 2c

[0046]

[0047] To a 10 mL single-necked round-bottom flask, 71.1 mg (0.500 mmol) of compound 1c, 1.00 mmol of triethylamine, and 0.500 mL of acetonitrile were added, followed by the introduction of sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched in an alkaline aqueous medium. Extraction was then performed with aqueous hydrochloric acid (3 × 5.00 mL, 1.00 M) and ethyl acetate (3 × 10.0 mL). The organic phase was dried, and the solvent was rotary evaporated to give 69.2 mg of the target compound 2c, with a yield of 98%.

[0048] The target product 2c obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.22(m,4H),7.03(m,4H),3.60(s,4H); 13 C{ 1 H}NMR(126MHz,CDCl3)δ162.3(d,J C-F =246.4Hz), 133.2(d,J C-F =3.2Hz), 131.0(d,JC-F =8.4Hz), 115.5(d,J C-F =21.5Hz), 42.5.

[0049] 1.4 Synthesis of 2d Symmetrical Disulfide Compounds

[0050]

[0051] To a 10 mL single-necked round-bottom flask, 79.3 mg (0.500 mmol) of compound 1d, triethylamine (1.00 mmol), and acetonitrile (0.500 mL) were added, followed by the introduction of sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched in an alkaline aqueous medium. Extraction was then performed with aqueous hydrochloric acid (3 × 5.00 mL, 1.00 M) and ethyl acetate (3 × 10.0 mL). The organic phase was dried, and the solvent was rotary evaporated to give 77.3 mg of the target compound 2d, with a yield of 98%.

[0052] The target product obtained by the above synthesis method was subjected to 1H and 1C NMR spectra on 2d, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.27(m,2H),7.17(m,2H),7.14–7.10(m,4H),3.69(s,4H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ135.0,134.2,131.6,129.8,129.0,126.8,41.1.

[0053] 1.5 Synthesis of symmetrical disulfide compounds 2e

[0054]

[0055] To a 10 mL single-necked round-bottom flask, 79.3 mg (0.500 mmol) of compound 1e, 1.00 mmol of triethylamine, and 0.500 mL of acetonitrile were added, followed by the introduction of sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched in an alkaline aqueous medium. The mixture was then extracted with 3 × 5.00 mL (1.00 M) hydrochloric acid and 3 × 10.0 mL ethyl acetate. The organic phase was dried, and the solvent was rotary evaporated to give 77.3 mg of the target compound 2e, in 98% yield.

[0056] The target product 2e obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1H NMR (500MHz, CDCl3) δ7.31(m,4H),7.17(m,4H),3.59(s,4H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ135.9,133.4,130.7,128.7,42.5.

[0057] 1.6 Synthesis of Symmetrical Disulfide Compound 2f

[0058]

[0059] To a 10 mL single-necked round-bottom flask, add 90.2 mg (0.500 mmol) of compound 1f, 1.00 mmol of triethylamine, and 0.500 mL of acetonitrile. Then, purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched in an alkaline aqueous medium. Extraction was then performed with aqueous hydrochloric acid (3 × 5.00 mL, 1.00 M) and ethyl acetate (3 × 10.0 mL). The organic phase was dried, and the solvent was rotary evaporated to give 87.9 mg of the target compound 2f, in 98% yield.

[0060] The target product 2f obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.39(m,4H),7.22(m,4H),3.64(s,4H),1.36(s,18H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ150.5,134.3,129.2,125.5,43.0,34.6,31.4.

[0061] 1.7 Synthesis of 2g of symmetrical disulfide compounds

[0062]

[0063] To a 10 mL single-necked round-bottom flask, 1 g (62.1 mg, 0.500 mmol) of compound, 0.150 mmol of triethylamine, and 0.500 mL of acetonitrile were added, followed by the introduction of sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 1 h, and excess SO₂F₂ was quenched in an alkaline aqueous medium. Extraction was then performed with aqueous hydrochloric acid (3 × 5.00 mL, 1.00 M) and ethyl acetate (3 × 10.0 mL). The organic phase was dried, and the solvent was rotary evaporated to give 2 g (60.4 mg) of the target compound, with a yield of 98%.

[0064] The target product (2g) obtained by the above synthesis method was subjected to proton and carbon NMR spectra. The test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.42(m,4H),7.14(m,4H),2.35(s,6H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ137.5,134.0,129.9,128.6,21.1.

[0065] 1.8 Synthesis of symmetrical disulfide compounds (2h)

[0066]

[0067] To a 10 mL single-necked round-bottom flask, 70.1 mg (0.500 mmol) of compound 1 h, triethylamine (0.150 mmol), and acetonitrile (0.500 mL) were added, followed by the introduction of sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 1 h, and excess SO₂F₂ was quenched in an alkaline aqueous medium. Then, hydrochloric acid aqueous solution (3 × 5.00 mL, 1.00 M) was added, followed by extraction with ethyl acetate (3 × 10.0 mL). The organic phase was dried, and the solvent was rotary evaporated to give 68.3 mg of the target compound 2 h, with a yield of 98%.

[0068] The target product obtained by the above synthesis method was subjected to 1H and 1C NMR spectra after 2 hours. The test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.41(m,4H),6.85(m,4H),3.81(s,6H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ160.0,132.7,128.5,114.7,55.4.

[0069] 1.9 Synthesis of Symmetrical Disulfide Compound 2i

[0070]

[0071] To a 10 mL single-necked round-bottom flask, 64.1 mg (0.500 mmol) of compound 1i, 0.150 mmol of triethylamine, and 0.500 mL of acetonitrile were added, followed by the introduction of sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 1 h, and excess SO₂F₂ was quenched in an alkaline aqueous medium. The mixture was then extracted with aqueous hydrochloric acid (3 × 5.00 mL, 1.00 M) and ethyl acetate (3 × 10.0 mL). The organic phase was dried, and the solvent was rotary evaporated to give 62.4 mg of the target compound 2i, in 98% yield.

[0072] The target product 2i obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.46(m,4H),7.02(m,4H); 13 C{ 1 H}NMR(126MHz,CDCl3)δ162.7(d,J C-F =248.5Hz), 132.3(d,J C-F =3.3Hz), 131.4(d,J C-F =8.1Hz), 116.4(d,J C-F =22.5Hz). 1.10 Synthesis of symmetrical disulfide compounds 2j

[0073]

[0074] To a 10 mL single-necked round-bottom flask, 72.3 mg (0.500 mmol) of compound 1j, 0.150 mmol of triethylamine, and 0.500 mL of acetonitrile were added, followed by the introduction of sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 1 h, and excess SO₂F₂ was quenched in an alkaline aqueous medium. Extraction was then performed with aqueous hydrochloric acid (3 × 5.00 mL, 1.00 M) and ethyl acetate (3 × 10.0 mL). The organic phase was dried, and the solvent was rotary evaporated to give 70.4 mg of the target compound 2j, with a yield of 98%.

[0075] The target product 2j obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.39(m,4H),7.26(m,4H); 13 C{ 1 H}NMR(126MHz, CDCl3)δ135.2,133.7,129.4(×2).

[0076] 1.11 Synthesis of symmetrical disulfide compound 2k

[0077]

[0078] To a 10 mL single-necked round-bottom flask, 94.5 mg (0.500 mmol) of compound 1k, 0.150 mmol of triethylamine, and 0.500 mL of acetonitrile were added, followed by the introduction of sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 1 h, and excess SO₂F₂ was quenched in an alkaline aqueous medium. Extraction was then performed with aqueous hydrochloric acid (3 × 5.00 mL, 1.00 M) and ethyl acetate (3 × 10.0 mL). The organic phase was dried, and the solvent was rotary evaporated to give 92.1 mg of the target compound 2k, in 98% yield.

[0079] The target product 2k obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.44(m,4H),7.35(m,4H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ135.8,132.3,129.4,121.6.

[0080] 1.12 Synthesis of Symmetrical Disulfide Compound 2l

[0081]

[0082] To a 10 mL single-necked round-bottom flask, 123 mg (0.500 mmol) of compound 1L, 0.150 mmol of triethylamine, and 0.500 mL of acetonitrile were added, followed by the introduction of sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 1 h, and excess SO₂F₂ was quenched in an alkaline aqueous medium. Extraction was then performed with aqueous hydrochloric acid (3 × 5.00 mL, 1.00 M) and ethyl acetate (3 × 10.0 mL). The organic phase was dried, and the solvent was rotary evaporated to give 121 mg of the target compound 2L, with a yield of 99%.

[0083] The target product 2l obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.94 (m, 4H), 7.79 (m, 2H); 13 C{ 1 H}NMR(126MHz,CDCl3)δ139.1,133.0(q,J C-F=33.9Hz), 127.6(m), 122.8(q,J) C-F =273.2Hz), 121.9(m).

[0084] 1.13 Synthesis of Symmetrical Disulfide Compounds 2m

[0085]

[0086] To a 10 mL single-necked round-bottom flask, add 62.6 mg (0.500 mmol) of compound 1m, 0.150 mmol of triethylamine, and 0.500 mL of acetonitrile, and then purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 1 h, and excess SO₂F₂ was quenched in an alkaline aqueous medium. NaOH was then added to adjust the solution to alkalinity, and the solvent was rotary evaporated to give 60.8 mg of the target compound 2m, with a yield of 98%.

[0087] The target product 2m obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.24(m,4H),6.56(m,4H),3.77(s,4H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ147.2,134.0,125.6,115.4.

[0088] 1.14 Synthesis of Symmetrical Disulfide Compounds 2n

[0089]

[0090] To a 10 mL single-necked round-bottom flask, add 84.2 mg (0.500 mmol) of compound 1n, 1.00 mmol of triethylamine, and 0.500 mL of acetonitrile. Then, purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched in an alkaline aqueous medium. The mixture was then extracted with 3 × 5.00 mL (1.00 M) hydrochloric acid and 3 × 10.0 mL ethyl acetate. The organic phase was dried, and the solvent was rotary evaporated to give 82.0 mg of the target compound 2n, in 98% yield.

[0091] The target product 2n obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ2.06(m,6H),1.82(m,12H),1.67(m,12H); 13 C{1 H}NMR (126MHz, CDCl3) δ47.4, 43.2, 36.2, 30.1.

[0092] 1.15 Synthesis of Symmetrical Disulfide Compounds 2o

[0093]

[0094] To a 10 mL single-necked round-bottom flask, add 58.1 mg (0.500 mmol) of compound 1o, 1.00 mmol of triethylamine, and 0.500 mL of acetonitrile. Then, purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched in an alkaline aqueous medium. The mixture was then extracted with 3 × 5.00 mL (1.00 M) hydrochloric acid and 3 × 10.0 mL ethyl acetate. The organic phase was dried, and the solvent was rotary evaporated to give 56.5 mg of the target compound 2o, in 98% yield.

[0095] The target product 2o obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ2.69(m,2H),2.04(m,4H),1.78(m,4H),1.62(m,2H),1.36–1.16(m,10H); 13 C{ 1 H}NMR(126MHz, CDCl3)δ50.0,32.9,26.1,25.8.

[0096] 1.16 Synthesis of 2p Symmetric Disulfide Compounds

[0097]

[0098] To a 10 mL single-necked round-bottom flask, add 57.1 mg (0.500 mmol) of compound 1p, 1.00 mmol of triethylamine, and 0.500 mL of acetonitrile. Then, purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched in an alkaline aqueous medium. Extraction was then performed with aqueous hydrochloric acid (3 × 5.00 mL, 1.00 M) and ethyl acetate (3 × 10.0 mL). The organic phase was dried, and the solvent was rotary evaporated to give 55.5 mg of the target compound 2p, in 98% yield.

[0099] The target product 2p obtained by the above synthesis method was subjected to proton and carbon NMR spectra.

[0100] Spectral detection, test results are as follows:1 H NMR (500MHz, CDCl3) δ7.40(m,2H),6.35(m,2H),6.24(m,2H),3.70(s,4H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ150.3,142.6,110.8,109.0,35.7.

[0101] 1.17 Synthesis of symmetrical disulfide compounds 2q

[0102]

[0103] To a 10 mL single-necked round-bottom flask, 58.1 mg (0.500 mmol) of compound 1q, 0.150 mmol of triethylamine, and 0.500 mL of acetonitrile were added, followed by the introduction of sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 1 h, and excess SO₂F₂ was quenched in an alkaline aqueous medium. The mixture was then extracted with aqueous hydrochloric acid (3 × 5.00 mL, 1.00 M) and ethyl acetate (3 × 10.0 mL). The organic phase was dried, and the solvent was rotary evaporated to give 56.8 mg of the target compound 2q, in 99% yield.

[0104] The target product 2q obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.51 (dd, J=5.3, 1.2Hz, 2H), 7.17 (dd, J=3.6, 1.2Hz, 2H), 7.03 (dd, J=5.3, 3.6Hz, 2H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ135.8,135.7,132.3,127.8.

[0105] 1.18 Synthesis of symmetrical disulfide compound 2r

[0106]

[0107] To a 10 mL single-necked round-bottom flask, add 101 mg (0.500 mmol) of compound 1r, 1.00 mmol of triethylamine, and 0.500 mL of acetonitrile. Then, purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched in an alkaline aqueous medium. Extraction was then performed with aqueous hydrochloric acid (3 × 5.00 mL, 1.00 M) and ethyl acetate (3 × 10.0 mL). The organic phase was dried, and the solvent was rotary evaporated to give 98.7 mg of the target compound 2r, in 98% yield.

[0108] The target product 2r obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ2.69 (t, J = 7.4Hz, 4H), 1.68 (p, J = 7.4Hz, 4H), δ 1.39 (m, 4H), 1.35–1.22 (m, 32H), 0.89 (t, J = 7.0Hz, 6H); 13 C{ 1 H}NMR(126MHz, CDCl3)δ39.3,32.0,29.8,29.7(×2),29.6,29.5,29.3(×2),28.6,22.8,14.2.

[0109] 1.19 Synthesis of 2S Symmetrical Disulfide Compounds

[0110]

[0111] To a 10 mL single-necked round-bottom flask, add 59.1 mg (0.500 mmol) of compound 2s, triethylamine (1.00 mmol), and acetonitrile (0.500 mL), and then purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched in an alkaline aqueous medium. Extraction was then performed with aqueous hydrochloric acid (3 × 5.00 mL, 1.00 M) and ethyl acetate (3 × 10.0 mL). The organic phase was dried, and the solvent was rotary evaporated to give 57.5 mg of the target compound 2s, with a yield of 98%.

[0112] The target product 2s obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ2.69 (t, J = 7.4Hz, 4H), 1.68 (p, J = 7.4Hz, 4H), 1.40 (m, 4H), 1.34–1.26 (m, 8H), 0.90 (t, J = 6.9Hz, 6H); 13 C{1 H}NMR (126MHz, CDCl3) δ39.3,31.5,29.3,28.3,22.6,14.1.

[0113] 1.20 Synthesis of Symmetrical Disulfide Compounds 2t

[0114]

[0115] To a 10 mL single-necked round-bottom flask, add 69.1 mg (0.500 mmol) of compound 1t, triethylamine (1.00 mmol), and acetonitrile (0.500 mL), and purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched in an alkaline aqueous medium. Then, hydrochloric acid aqueous solution (3 × 5.00 mL, 1.00 M) and ethyl acetate (3 × 10.0 mL) were added for extraction. The organic phase was dried, and the solvent was rotary evaporated to give 67.3 mg of the target compound 2t, with a yield of 98%.

[0116] The target product 2t obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.32–7.26(m,4H),7.24–7.16(m,6H),2.98(m,4H),2.93(m,4H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ140.1,128.7,128.6,126.5,40.3,35.8.

[0117] 1.21 Synthesis of symmetrical disulfide compound 2u

[0118]

[0119] To a 10 mL single-necked round-bottom flask, add 62.6 mg (0.500 mmol) of compound 1u, triethylamine (0.150 mmol), and acetonitrile (0.500 mL), and then purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 1 h, and excess SO₂F₂ was quenched by purging into an alkaline aqueous medium. NaOH was then added to adjust the solution to alkalinity, and the solvent was rotary evaporated to give 60.9 mg of the target compound 2u, with a yield of 98%.

[0120] The target product 2u obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1H NMR (500MHz, CDCl3) δ7.20–7.14(m,4H),6.72(m,2H),6.60(m,2H),4.34(s,4H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ148.7,136.9,131.7,118.8,118.3,115.3.

[0121] 1.22 Synthesis of Symmetrical Disulfide Compounds 2v

[0122]

[0123] To a 10 mL single-necked round-bottom flask, add 93.2 mg (0.500 mmol) of compound 1v, triethylamine (1.00 mmol), and acetonitrile (0.500 mL), and then purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched in an alkaline aqueous medium. Then, hydrochloric acid aqueous solution (3 × 5.00 mL, 1.00 M) was added, followed by extraction with ethyl acetate (3 × 10.0 mL). The organic phase was dried, and the solvent was rotary evaporated to give 90.8 mg of the target compound 2v, in 98% yield.

[0124] The target product 2v obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ2.55(m,2H),2.47(m,2H),2.29(m,2H),2.07(m,2H),1. 95–1.79(m,4H),1.54–1.45(m,8H),1.42–1.32(m,8H),1.02(d,J=6.3Hz,6H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ211.0,58.0,52.4,51.5,36.9,34.6,29.8,27.8,23.9,22.3.

[0125] 1.23 Synthesis of Symmetrical Disulfide Compounds 2w

[0126]

[0127] To a 10 mL single-necked round-bottom flask, 57.1 mg (0.500 mmol) of compound 1w, triethylamine (0.150 mmol), and acetonitrile (0.500 mL) were added, followed by the introduction of sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 1 h, and excess SO₂F₂ was quenched in an alkaline aqueous medium. Extraction was then performed with aqueous hydrochloric acid (3 × 5.00 mL, 1.00 M) and ethyl acetate (3 × 10.0 mL). The organic phase was dried, and the solvent was rotary evaporated to give 55.5 mg of the target compound 2w, with a yield of 98%.

[0128] The target product 2w obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.28(m,2H),6.38(m,2H),2.11(s,6H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ157.1,140.9,114.8,112.8,11.5.

[0129] 1.24 Synthesis of symmetrical disulfide compound 2x

[0130]

[0131] To a 10 mL single-necked round-bottom flask, add 56.1 mg (0.500 mmol) of compound 1x, triethylamine (0.150 mmol), and acetonitrile (0.500 mL), and then purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 1 h, and excess SO₂F₂ was quenched in an alkaline aqueous medium. Then, hydrochloric acid aqueous solution (3 × 5.00 mL, 1.00 M) was added, followed by extraction with ethyl acetate (3 × 10.0 mL). The organic phase was dried, and the solvent was rotary evaporated to give 54.5 mg of the target compound 2x, in 98% yield.

[0132] The target product 2x obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ8.59 (m, 4H), 7.09 (t, J = 4.8Hz, 2H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ169.8,158.0,118.3.

[0133] 1.25 Synthesis of symmetrical disulfide compound 2y

[0134]

[0135] To a 10 mL single-necked round-bottom flask, 94.5 mg (0.500 mmol) of compound 1y, 0.150 mmol of triethylamine, and 0.500 mL of acetonitrile were added, followed by the introduction of sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 1 h, and excess SO₂F₂ was quenched in an alkaline aqueous medium. Extraction was then performed with aqueous hydrochloric acid (3 × 5.00 mL, 1.00 M) and ethyl acetate (3 × 10.0 mL). The organic phase was dried, and the solvent was rotary evaporated to give 92.2 mg of the target compound 2y, in 98% yield.

[0136] The target product 2y obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.64(m,2H),7.47–7.35(m,4H),7.18(m,2H); 13 C{ 1 H}NMR(126MHz, CDCl3)δ138.7,130.6(×2),130.0,125.9,123.2.

[0137] 1.26 Synthesis of symmetrical disulfide compound 2z

[0138]

[0139] To a 10 mL single-necked round-bottom flask, 94.5 mg (0.500 mmol) of compound 1z, 0.150 mmol of triethylamine, and 0.500 mL of acetonitrile were added, followed by the introduction of sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 1 h, and excess SO₂F₂ was quenched in an alkaline aqueous medium. The mixture was then extracted with aqueous hydrochloric acid (3 × 5.00 mL, 1.00 M) and ethyl acetate (3 × 10.0 mL). The organic phase was dried, and the solvent was rotary evaporated to give 92.2 mg of the target compound 2z, in 98% yield.

[0140] The target product 2z obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.54–7.49(m,4H),7.25(m,2H),7.06(m,2H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ136.2,133.0,128.3,128.0,127.0,121.1.

[0141] 1.27 Synthesis of symmetrical disulfide compound 2aa

[0142]

[0143] To a 10 mL single-necked round-bottom flask, 76.1 mg (0.500 mmol) of compound 1aa, 0.150 mmol of triethylamine, and 0.500 mL of acetonitrile were added, followed by the introduction of sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 1 h, and excess SO₂F₂ was quenched in an alkaline aqueous medium. The mixture was then extracted with aqueous hydrochloric acid (3 × 5.00 mL, 1.00 M) and ethyl acetate (3 × 10.0 mL). The organic phase was dried, and the solvent was rotary evaporated to give 74.1 mg of the target compound 2aa, in 98% yield.

[0144] The target product 2aa obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.47 (m, 4H), 7.20 (m, 4H), 2.91 (m, 2H), 1.26 (d, J = 7.0Hz, 12H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ148.3,134.4,128.3,127.3,33.8,24.0.

[0145] 1.28 Synthesis of symmetrical disulfide compound 2ab

[0146]

[0147] To a 10 mL single-necked round-bottom flask, 83.6 mg (0.500 mmol) of compound 1ab, 0.150 mmol of triethylamine, and 0.500 mL of acetonitrile were added, followed by the introduction of sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 1 h, and excess SO₂F₂ was quenched in an alkaline aqueous medium. The mixture was then extracted with aqueous hydrochloric acid (3 × 5.00 mL, 1.00 M) and ethyl acetate (3 × 10.0 mL). The organic phase was dried, and the solvent was rotary evaporated to give 81.5 mg of the target compound 2ab, in 98% yield.

[0148] The target product 2ab obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, DMSO-d6) δ10.07(br,2H),7.59(m,4H),7.42(m,4H),2.04(s,6H); 13 C{1 H}NMR(126MHz,DMSO-d6)δ168.5,139.5,130.1,129.4,119.7,24.0.

[0149] 1.29 Synthesis of symmetrical disulfide compound 2ac

[0150]

[0151] To a 10 mL single-necked round-bottom flask, 77.1 mg (0.500 mmol) of compound 1ac, 0.150 mmol of triethylamine, and 0.500 mL of acetonitrile were added, followed by the introduction of sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 1 h, and excess SO₂F₂ was quenched in an alkaline aqueous medium. Then, an aqueous solution of hydrochloric acid (1.00 M) was added, filtered, and the solvent was rotary evaporated to give 75.1 mg of the target compound 2ac, in 98% yield.

[0152] The target product 2ac obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, DMSO-d6) δ8.07(m,2H),7.86(m,2H),7.78(m,2H),7.54(m,2H); 13 C{ 1 H}NMR(126MHz,DMSO-d6)δ166.4,136.3,132.1,131.3,129.9,128.5,127.4.

[0153] 1.30 Synthesis of symmetrical disulfide compound 2ad

[0154]

[0155] To a 10 mL single-necked round-bottom flask, add 111 mg (0.500 mmol) of compound 1ad, 1.00 mmol of triethylamine, and 0.500 mL of acetonitrile / borax buffer solution (1:1). Then, introduce sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). Stir the reaction mixture at room temperature for 30 min. Excess SO₂F₂ is quenched in an alkaline aqueous medium. Afterward, adjust the solution to alkaline by adding NaOH, and rotary evaporate the solvent to obtain the target compound 2ad in 85% yield.

[0156] The target product 2ad obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1H NMR (500MHz, DMSO-d6) δ7.19(d,J=8.4Hz,2H),4.18(m,2H),3.10(dd,J=13.5,4.1Hz,2H),2.89(dd,J=13.5,10.1Hz,2H),1.38(s,18H); 13 C{ 1 H}NMR(126MHz,DMSO-d6)δ172.4,155.4,78.3,52.8,28.2,28.0.

[0157] 1.31 Synthesis of symmetrical disulfide compounds 2ae

[0158]

[0159] To a 10 mL single-necked round-bottom flask, add 154 mg (0.500 mmol) of compound 1ae, 0.500 mmol of triethylamine, and 0.500 mL of acetonitrile / borax buffer solution (1:1). Then, introduce sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). Stir the reaction mixture at room temperature for 30 min. Excess SO₂F₂ is quenched in an alkaline aqueous medium. Afterward, adjust the solution to alkaline by adding NaOH, and rotary evaporate the solvent to obtain the target compound 2ae in 98% yield.

[0160] The target product 2ae obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR(500MHz,D2O)δ4.75(dd,J=9.6,4.4Hz,2H),3.75(m,4H),3.63(t,J=6.3Hz,2H),3 .30(dd,J=14.3,4.4Hz,2H),2.96(dd,J=14.3,9.6Hz,2H),2.49(m,4H),2.08(m,4H); 13 C{ 1 ¹H NMR (126MHz, D₂O) δ 176.6, 176.3, 175.4, 171.9, 54.5, 52.5, 43.5, 38.6, 31.6, 27.6.1.32 Synthesis of symmetrical disulfide compound 2af

[0161]

[0162] To a 10 mL single-necked round-bottom flask, add 50 mg (0.0250 mmol) of compound 1af and 2.00 mL of saturated sodium carbonate solution (25 °C), and purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). Stir the reaction mixture at room temperature for 30 min, and quench excess SO₂F₂ in an alkaline aqueous medium. Then, extract with 3 × 5.00 mL (1.00 M) hydrochloric acid solution and 3 × 10.0 mL ethyl acetate. Dry the organic phase and rotary evaporate the solvent to give 49.3 mg of the target compound 2af, in 98% yield.

[0163] The target product 2af obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ3.73 (t, J=6.7Hz, 4H), 3.68–3.60 (m, 360H), 3.38 (s, 6H), 2.88 (t, J=6.7Hz, 4H); 13 C{ 1 ¹H NMR (126MHz, CDCl₃) δ 72.0, 70.6 (m), 69.7, 69.7, 59.1, 38.4.1.33 Synthesis of symmetrical disulfide compound 2af

[0164]

[0165] To a 10 mL single-necked round-bottom flask, add 50 mg (0.0250 mmol) of compound 1af, 440 mg of sodium carbonate, and 2.00 mL of serum, and then purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched in an alkaline aqueous medium. Then, hydrochloric acid aqueous solution (3 × 5.00 mL, 1.00 M) was added, followed by extraction with ethyl acetate (3 × 10.0 mL). The organic phase was dried, and the solvent was rotary evaporated to give 49.0 mg of the target compound 2af, with a yield of 98%.

[0166] The target product 2af obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ3.71 (t, J=6.7Hz, 4H), 3.66–3.58 (m, 360H), 3.36 (s, 6H), 2.86 (t, J=6.7Hz, 4H); 13 C{ 1 ¹H NMR (126MHz, CDCl₃) δ 71.9, 70.5, 70.4, 69.6, 59.0, 38.4, 1.34 Captopril derivatization

[0167]

[0168] To a 10 mL single-necked round-bottom flask, add 1 ag (109 mg, 0.500 mmol) of compound, triethylamine (1.00 mmol), and acetonitrile (0.500 mL), and purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched in an alkaline aqueous medium. Then, hydrochloric acid aqueous solution (3 × 5.00 mL, 1.00 M) and ethyl acetate (3 × 10.0 mL) were added for extraction. The organic phase was dried, and the solvent was rotary evaporated to give 2 ag of 106 mg of the target compound, with a yield of 98%.

[0169] The target product 2ag obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR(500MHz,DMSO-d6)δ4.28–4.15(m,2H),3.62–3.56(m,4H),3.02–2.83(m,4H), 2.69(m,2H),2.14(m,2H),1.96–1.89(m,4H),1.85(m,2H),1.09(d,J=6.7Hz,6H); 13 C{ 1 H}NMR(126MHz,DMSO-d6)δ173.3,172.3,58.4,46.5,41.2,36.9,28.7,24.4,16.5.

[0170] Example 2: Synthesis of symmetrical disulfide compounds using sulfonyl fluoride compound B

[0171] Synthesis of symmetrical disulfide compounds 2a-2m, 2p-2q

[0172]

[0173] To a 10 mL single-necked round-bottom flask, add thiol (0.500 mmol, 1.00 equiv), triethylamine (1.00 mmol), acetonitrile (0.500 mL), and sulfonyl fluoride compound B (0.125 mmol, 0.250 equiv). Stir the reaction mixture at room temperature for 1 h. Then, rotary evaporate the solvent, adding 1,1,2,2-tetrachloroethane as a solvent. 1 The yield was calculated using 1H NMR quantitative internal standard, and the yield results are shown in Table 1. The target compound was also subjected to 1H and 1C NMR spectra. The test results showed that the structure was the same as that of the corresponding target product in Example 1, with 2a-2m and 2p-2q.

[0174] Table 1 Synthesis of symmetric disulfide compounds from sulfonyl fluoride compound B

[0175]

[0176]

[0177]

[0178] Example 3: Synthesis of symmetrical disulfide compounds using sulfonyl fluoride compound C

[0179] 3.1 Synthesis of symmetrical disulfide compounds 2a-2n, 2p-2q, 2ah

[0180]

[0181] To a 10 mL single-necked round-bottom flask, add thiol (0.500 mmol, 1.00 equiv), triethylamine (1.00 mmol), acetonitrile (0.500 mL), and sulfonyl fluoride compound C (43.5 mg, 0.250 mmol). Stir the reaction mixture at room temperature for 1 h. Then, rotary evaporate the solvent, adding 1,1,2,2-tetrachloroethane as a solvent. 1 The yield was calculated using 1H NMR quantitative internal standard, and the yield results are shown in Table 2. The target compound was also subjected to 1H and 1C NMR spectra. The test results showed that the structure was the same as that of the corresponding target product in Example 1, which contains 2a-2n, 2p-2q, 2ah.

[0182] Table 2 Synthesis of symmetric disulfide compounds from sulfonyl fluoride compounds C

[0183]

[0184]

[0185]

[0186] In this embodiment, compound 2n,2ah was synthesized under the following conditions:

[0187] 3.2 Synthesis of Symmetrical Disulfide Compounds 2n

[0188]

[0189] To a 10 mL single-necked round-bottom flask, add 84.2 mg (0.500 mmol) of compound 1n, 1.00 mmol of 2-tert-butyl-1,1,3,3-tetramethylguanidine, 0.500 mL of acetonitrile, and 43.5 mg (0.250 mmol) of sulfonyl fluoride compound C. The reaction mixture was stirred at room temperature for 1 h. The solvent was then rotary evaporated, and 1,1,2,2-tetrachloroethane was added as a solvent. 1 The yield of compound 2n was calculated to be 98% by 1H NMR quantitative internal standard. 2n was further analyzed by 1H and 1C NMR spectra, and the results showed that its structure was the same as that of Examples 1 and 2n.

[0190] 3.3 Synthesis of symmetrical disulfide compound 2ah

[0191]

[0192] To a 10 mL single-necked round-bottom flask, add 63.1 mg (0.500 mmol) of compound 1ah, triethylamine (1.00 mmol), acetonitrile (0.500 mL), and sulfonyl fluoride compound C (43.5 mg, 0.250 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvent was then evaporated by rotary evaporation, and column chromatography was used to obtain 57.0 mg of the target compound 2ah in 98% yield.

[0193] The target product 2ah obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR(500MHz,DMSO-d6)δ9.84(br,2H),7.27(m,4H),6.76(m,4H); 13 C{ 1 H}NMR(126MHz,DMSO-d6)δ158.3,133.0,125.1,116.3.

[0194] Example 4: Synthesis of symmetrical disulfide compounds using sulfonyl fluoride compound D

[0195] Synthesis of symmetrical disulfide compounds 2a-2m, 2p-2q

[0196]

[0197] To a 10 mL single-necked round-bottom flask, add thiol (0.500 mmol, 1.00 equiv), triethylamine (1.00 mmol), acetonitrile (0.500 mL), and sulfonyl fluoride compound D (44.0 mg, 0.250 mmol). Stir the reaction mixture at room temperature for 8 h. Then, rotary evaporate the solvent, adding 1,1,2,2-tetrachloroethane as a solvent. 1The yield was calculated using 1H NMR quantitative internal standard, and the yield results are shown in Table 3. The target compound was also subjected to 1H and 1C NMR spectra. The test results showed that the structure was the same as that of the corresponding target product in Example 1, with 2a-2m and 2p-2q.

[0198] Table 3 Synthesis of symmetric disulfide compounds from sulfonyl fluoride compounds D

[0199]

[0200]

[0201] Example 5: Synthesis of symmetrical disulfide compounds using sulfonyl fluoride compound E

[0202] Synthesis of symmetrical disulfide compounds 2a-2m, 2o-2r

[0203]

[0204] To a 10 mL single-necked round-bottom flask, add thiol (0.500 mmol, 1.00 equiv), triethylamine (0.500 mmol), acetonitrile (0.500 mL), and sulfonyl fluoride compound E (41.0 mg, 0.125 mmol). Stir the reaction mixture at room temperature for 5-30 min. Then, rotary evaporate the solvent, adding 1,1,2,2-tetrachloroethane as a solvent. 1 The yield was calculated using 1H NMR quantitative internal standard, and the yield results are shown in Table 4. The target compound was also detected by 1H and 1C NMR spectra. The test results showed that the structure was the same as that of the corresponding target product in Example 1, with 2a-2m and 2o-2r.

[0205] Table 4 Synthesis of symmetric disulfide compounds from sulfonyl fluoride compounds E

[0206]

[0207]

[0208] Example 6: Synthesis of symmetrical disulfide compounds using sulfonyl fluoride compound F

[0209] Synthesis of symmetrical disulfide compounds 2a-2m, 2p-2q

[0210]

[0211] To a 10 mL single-necked round-bottom flask, add thiol (0.500 mmol, 1.00 equiv), triethylamine (1.00 mmol), acetonitrile (0.500 mL), and sulfonyl fluoride compound F (41.0 mg, 0.125 mmol). Stir the reaction mixture at room temperature for 1 h. Then, rotary evaporate the solvent, adding 1,1,2,2-tetrachloroethane as a solvent. 1 The yield was calculated using 1H NMR quantitative internal standard, and the yield results are shown in Table 5. The target compound was then subjected to 1H and 1C NMR spectra, and the structure was found to be the same as that of the corresponding target product in Example 1, specifically 2a-2m, 2p-2q.

[0212] Table 5 Synthesis of symmetric disulfide compounds from sulfonyl fluoride compound F

[0213]

[0214]

[0215]

[0216] Example 7: Synthesis of asymmetric disulfide compounds using sulfonyl fluoride compound A

[0217] 7.1 Synthesis of asymmetric disulfide compound 3a

[0218]

[0219] To a 10 mL single-necked round-bottom flask, add 168 mg (1.00 mmol) of compound 1n, 62.1 mg (0.500 mmol) of compound 1n, triethylamine (1.00 mmol), and acetonitrile (0.500 mL), and then purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched by purging into an alkaline aqueous medium. The solvent was rotary evaporated, and the mixture was separated by column chromatography to obtain 135 mg of the target compound 3a, in 93% yield.

[0220] The target product 3a obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.46(m,2H),7.11(m,2H),2.33(s,3H),2.04(m,3H),1.85(m,6H),1.65(m,6H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ136.1,135.9,129.5,127.1,50.7,42.6,36.1,30.0,21.1.

[0221] 7.2 Synthesis of asymmetric disulfide compound 3b

[0222]

[0223] To a 10 mL single-necked round-bottom flask, add 168 mg (1.00 mmol) of compound 1n, 64.1 mg (0.500 mmol) of 1i, triethylamine (1.00 mmol), and acetonitrile (0.500 mL), and then purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture is stirred at room temperature for 30 min, and excess SO₂F₂ is quenched by purging into an alkaline aqueous medium. The solvent is then removed by rotary evaporation, and column chromatography is used to obtain 144 mg of the target compound 3b, in 98% yield.

[0224] The target product 3b obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.53(m,2H),7.00(m,2H),2.05(m,3H),1.84(m,6H),1.67(m,6H); 13 C{ 1 H}NMR(126MHz,CDCl3)δ161.7(d,J C-F =245.7Hz), 134.5(d,J C-F =3.1Hz), 129.0(d,J C-F =8.1Hz), 115.8(d,J C-F =21.7Hz),51.0,42.6,36.1,29.9; HRMS(APCI-TOF)m / z:[M+H] + calc for C 16 H 20 FS2 + 295.0991, found 295.0990.

[0225] 7.3 Synthesis of Asymmetric Disulfide Compound 3c

[0226]

[0227] To a 10 mL single-necked round-bottom flask, add 168 mg (1.00 mmol) of compound 1n, 94.5 mg (0.500 mmol) of 1y, triethylamine (1.00 mmol), and acetonitrile (0.500 mL), and then purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched by purging into an alkaline aqueous medium. The solvent was rotary evaporated, and the mixture was separated by column chromatography to obtain 165 mg of the target compound 3c, in 93% yield.

[0228] The target product 3c obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.72(m,1H),7.48(m,1H),7.29(m,1H),7.15(m,1H),2.06(m,3H),1.85(m,6H),1.66(m,6H); 13 C{ 1 H}NMR(126MHz, CDCl3)δ141.9,130.0,129.0,128.7,124.7,122.9,51.2,42.5,36.0,29.9; HRMS(APCI-TOF)m / z:[M+H] + calc for C 16 H 20 BrS2 + 355.0190, found 355.0190.

[0229] 7.4 Synthesis of Asymmetric Disulfide Compounds 3d

[0230]

[0231] To a 10 mL single-necked round-bottom flask, add 168 mg (1.00 mmol) of compound 1n, 58.1 mg (0.500 mmol) of 1q, triethylamine (1.00 mmol), and acetonitrile (0.500 mL), and then purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched by purging into an alkaline aqueous medium. The solvent was rotary evaporated, and the mixture was separated by column chromatography to obtain 127 mg of the target compound 3d, with a yield of 90%.

[0232] The target product obtained by the above synthesis method was subjected to 1H and 1C NMR spectra on 3D, and the test results are as follows: 1H NMR (500MHz, CDCl3) δ7.33(dd,J=5.3,1.2Hz,1H),7.22(dd,J=3.6,1.2Hz,1H),6.93(dd,J=5.3,3.6Hz,1H),2.10(m,3H),1.92(m,6H),1.70(m,6H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ139.9,132.4,129.3,127.3,50.7,42.6,36.1,29.9.

[0233] 7.5 Synthesis of Asymmetric Disulfide Compounds 3e

[0234]

[0235] To a 10 mL single-necked round-bottom flask, add 116 mg (1.00 mmol) of compound 1o, 64.1 mg (0.500 mmol) of 1i, triethylamine (1.00 mmol), and acetonitrile (0.500 mL), and then purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched in an alkaline aqueous medium. The solvent was rotary evaporated, and the mixture was separated by column chromatography to obtain 107 mg of the target compound 3e, in 88% yield.

[0236] The target product 3e obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.51(m,2H),7.02(m,2H),2.81(m,1H),2.00(m,2H),1.77(m,2H),1.61(m,1H),1.43–1.15(m,5H); 13 C{ 1 H}NMR(126MHz,CDCl3)δ162.0(d,J C-F =246.3Hz), 133.8(d,J) C-F =3.3Hz), 129.6(d,J C-F =8.0Hz), 116.0(d,J C-F =22.0Hz), 50.0, 32.7, 26.1, 25.6.7.6 Synthesis of asymmetric disulfide compounds 3f

[0237]

[0238] To a 10 mL single-necked round-bottom flask, add 116 mg (1.00 mmol) of compound 1o, 72.3 mg (0.500 mmol) of 1j, triethylamine (1.00 mmol), and acetonitrile (0.500 mL), and then purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched in an alkaline aqueous medium. The solvent was rotary evaporated, and the mixture was separated by column chromatography to obtain 114 mg of the target compound 3f, in 88% yield.

[0239] The target product 3f obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.48(m,2H),7.28(m,2H),2.80(m,1H),2.00(m,2H),1.77(m,2H),1.60(m,1H),1.38–1.21(m,5H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ137.2,132.3,129.0,128.2,50.1,32.7,26.1,25.6.

[0240] 7.7 Synthesis of 3g of asymmetric disulfide compounds

[0241]

[0242] To a 10 mL single-necked round-bottom flask, add 116 mg (1.00 mmol) of compound 1o, 94.5 mg (0.500 mmol) of 1k, triethylamine (1.00 mmol), and acetonitrile (0.500 mL), and then purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture is stirred at room temperature for 30 min, and excess SO₂F₂ is quenched by purging into an alkaline aqueous medium. The solvent is then removed by rotary evaporation, and column chromatography is used to obtain 3 g of the target compound (147 mg), with a yield of 97%.

[0243] The target product 3g obtained by the above synthesis method was subjected to proton and carbon NMR spectra. The test results are as follows: 1 H NMR(500MHz, CDCl3)δ7.45–7.39(m,4H),2.80(m,1H),2.00(m,2H),1.77(m,2H),1.60(m,1H),1.39–1.21(m,5H); HRMS(APCI-TOF)m / z:[M+H] + calc for C 12 H 16 BrS2 +302.9877, found 302.9873.

[0244] 7.8 Synthesis of Asymmetric Disulfide Compounds (3h)

[0245]

[0246] To a 10 mL single-necked round-bottom flask, add 116 mg (1.00 mmol) of compound 1O, 62.6 mg (0.500 mmol) of 1M, triethylamine (1.00 mmol), and acetonitrile (0.500 mL), and then purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched by purging into an alkaline aqueous medium. The solvent was rotary evaporated, and column chromatography was used to separate the target compound into 95.8 mg over 3 h, with a yield of 80%.

[0247] The target product obtained by the above synthesis method was subjected to 1H and 1C NMR spectra after 3 hours. The test results are as follows: 1 H NMR (500MHz, CDCl3) δ7.36(m,2H),6.62(m,2H),3.74(br,2H),2.81(m,1H),2.03(m,2H),1.77(m,2H),1.61(m,1H),1.37–1.24(m,5H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ146.3,132.0,126.3,115.5,49.5,32.6,26.0,25.7.

[0248] 7.9 Synthesis of asymmetric disulfide compound 3i

[0249]

[0250] To a 10 mL single-necked round-bottom flask, add 116 mg (1.00 mmol) of compound 1o, 77.1 mg (0.500 mmol) of 1ac, triethylamine (1.00 mmol), and acetonitrile (0.500 mL), and then purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched in an alkaline aqueous medium. The solvent was rotary evaporated, and the mixture was separated by column chromatography to obtain 126 mg of the target compound 3i, in 94% yield.

[0251] The target product 3i obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1H NMR (500MHz, CDCl3) δ8.30(m,1H),7.94(m,1H),7.79(m,1H),7.44(m,1H),2.84(m,1H),2.02(m,2H),1.78(m,2H),1.60(m,1H),1.46–1.27(m,5H); 13 C{ 1 H NMR (126MHz, CDCl3)

[0252] δ171.6,139.8,131.7,130.0,129.0,128.1(×2),50.2,32.7,26.1,25.6; HRMS(ESI-TOF)m / z:[MH] - calc for C 13 H 15 O2S2 - 267.0513, found 267.0508.

[0253] 7.10 Synthesis of asymmetric disulfide compound 3j

[0254]

[0255] To a 10 mL single-necked round-bottom flask, add 116 mg (1.00 mmol) of compound 1o, 57.1 mg (0.500 mmol) of 1w, triethylamine (1.00 mmol), and acetonitrile (0.500 mL), and then purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched by purging into an alkaline aqueous medium. The solvent was rotary evaporated, and the mixture was separated by column chromatography to obtain 108 mg of the target compound 3j, with a yield of 95%.

[0256] The target product 3j obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR(500MHz, CDCl3) δ7.26(d,J=2.0Hz,1H),6.43(d,J=1.9Hz,1H),2.79(m, 1H),2.38(s,3H),2.05(m,2H),1.79(m,2H),1.63(m,1H),1.39–1.26(m,5H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ154.9,140.7,114.4,114.3,49.3,32.6,26.1,25.8,12.1.

[0257] Example 8: Synthesis of cyclic disulfide compounds using sulfonyl fluoride compound A

[0258] 8.1 Synthesis of cyclic disulfide compound 4a

[0259]

[0260] To a 10 mL single-necked round-bottom flask, add 111 mg (0.500 mmol) of compound 1ai, 2.00 mmol of triethylamine, and 0.500 mL of acetonitrile. Then, purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched in an alkaline aqueous medium. The solvent was rotary evaporated, and the mixture was separated by column chromatography (petroleum ether / ethyl acetate = 10:1) to give 69.4 mg of the target compound 4a, in 63% yield.

[0261] The target product 4a obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (500MHz, CDCl3) δ3.68(s,6H),3.57(m,2H),3.18(m,2H),3.12(m,2H),2.47( m,2H),2.33(t,J=7.5Hz,4H),1.92(m,2H),1.73–1.63(m,8H),1.53–1.43(m,4H); 13 C{ 1 H}NMR (126MHz, CDCl3) δ174.0,56.4,51.6,40.3,38.6,34.7,33.9,28.8,24.7.

[0262] 8.2 Synthesis of cyclic disulfide compound 4b

[0263]

[0264] To a 10 mL single-necked round-bottom flask, add 77.1 mg (0.500 mmol) of compound 1aj, 2.00 mmol of triethylamine, and 0.500 mL of acetonitrile. Then, purge with sulfuryl fluoride (SO₂F₂) gas (sulfonyl fluoride compound A). The reaction mixture was stirred at room temperature for 30 min, and excess SO₂F₂ was quenched in an alkaline aqueous medium. The solvent was rotary evaporated, and the mixture was separated by column chromatography (petroleum ether / ethyl acetate = 10:1) to give 74.6 mg of the target compound 4b, in 98% yield.

[0265] The target product 4b obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1H NMR (500MHz, Methanol-d4) δ3.55–3.46(m,2H),3.10–3.00(m,2H),2.94–2.84(m,2H); 13 C{ 1 H}NMR(126MHz,Methanol-d4)δ75.5,41.7.

[0266] Note: Through 1 Methods for Quantitative Calculation of Yield Using H NMR Nuclear Magnetic Resonance

[0267]

[0268] Taking Example 2,2a as an example, 77.1 mg (0.500 mmol) of compound 1a, 1.00 mmol of triethylamine, 0.500 mL of acetonitrile, and 43.5 mg (0.250 mmol) of sulfonyl fluoride compound B were added to a 10 mL single-necked round-bottom flask. The reaction mixture was stirred at room temperature for 1 h. The solvent was then rotary evaporated, and 28.7 mg of 1,1,2,2-tetrachloroethane was added as... 1 Yield was calculated using quantitative internal standard ¹H NMR. In the ¹H NMR spectra of Example 2, 2a, chemical shifts 7.26–6.86 represent the elution positions of H atoms on the benzene ring in sulfonyl fluoride compound B and structure 2a; chemical shift 6.00 represents the single elution position of the internal standard 1,1,2,2-tetrachloroethane; chemical shift 3.79 represents the elution position of the methylene group in sulfonyl fluoride compound B and the methoxy group in structure 2a; and chemical shift 3.61 represents the single elution position of the methylene group in structure 2a. Therefore, the yield of 2a was calculated using the peak area of ​​the internal standard at chemical shift 6.00 and the peak area of ​​the methylene group in structure 2a.

[0269] The method for determining the area of ​​the internal standard peak is as follows: S 内标 =2m 内标 / (M r内标 ×n 理论产物 ), where m 内标 : The mass of 1,1,2,2-tetrachloroethane added; M r内标 The relative atomic mass of 1,1,2,2-tetrachloroethane is 167.85 g / mol; n 理论产物 : The amount of substance of the product at a 100% yield (here, 0.25 mmol).

[0270] The yield of 2a is calculated as follows: w = S 实际 / S 理论 Among them, S 实际 Based on the above, when the internal standard peak area is 1.37, the peak area of ​​the methylene group in structure 2a at chemical shift 3.61 is calculated.理论 At a theoretical yield of 100%, the peak area of ​​the methylene group in structure 2a at a chemical shift of 3.61 is 4.

[0271] Therefore, the yield of Example 2,2a is w = 3.98 / 4 = 99.5%.

[0272]

[0273] The yield calculation method for other compounds is similar, and the reaction yield is determined by the internal standard peak and the specific product peak in the spectrum that is not affected by other peaks.

Claims

1. A method of synthesizing a dithioclass compound, characterized by: The method uses a thiol compound shown in general formula (1) and (3) as a raw material, reacts with a reagent composition in a solvent to generate an asymmetric disulfide compound shown in general formula (4); wherein R 1 and R 2 are one of a mono- or poly-substituted benzene ring, a substituted or unsubstituted straight-chain or cyclic alkane, a substituted or unsubstituted heterocycle, and R 1 and R 2 are not the same; The reagent composition is characterized in that: The reagent composition comprises I and II; I is a sulfonyl fluoride compound, and is selected from any one of the following compounds A, compound B, compound C, compound D, compound E, and compound F; II is a base, and is selected from one or more of triethylamine, methanolamine, ethanolamine, triethanolamine, 1,8-diazabicycloundec-7-ene, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, and 2-tert-butyl-1,1,3,3-tetramethylguanidine in any proportion.

2. The method for synthesizing disulfide compounds according to claim 1, characterized in that... The method comprises the following steps: Step 1: adding a thiol compound, a base, and a solvent into a reaction container; Step 2: when the sulfonyl fluoride compound is gaseous, the sulfonyl fluoride compound is introduced into the reaction container, or when the sulfonyl fluoride compound is liquid or solid, the sulfonyl fluoride compound is added into the reaction container; Step 3: continuously stirring the reaction mixture at room temperature until a preset reaction time; Step 4: injecting an aqueous hydrochloric acid solution into the reaction system, extracting the aqueous phase with an organic solvent, combining the organic phases, drying, and concentrating to obtain a disulfide product.

3. A method of synthesizing a dithioclass compound, characterized by: The method uses a thiol compound shown in general formula (5) as a raw material, reacts with a reagent composition in a solvent to generate a cyclic disulfide compound shown in general formula (6); wherein R is a mono- or poly-substituted benzene ring, a substituted or unsubstituted straight-chain alkane or cycloalkane, or a substituted or unsubstituted heterocycle; 1 wherein R is a mono- or poly-substituted benzene ring, a substituted or unsubstituted straight-chain alkane or cycloalkane, or a substituted or unsubstituted heterocycle; The reagent composition is characterized in that: The reagent composition comprises I and II; I is a sulfonyl fluoride compound, and is selected from any one of the following compounds A, compound B, compound C, compound D, compound E, and compound F; II is a base, and is selected from one or more of triethylamine, methanolamine, ethanolamine, triethanolamine, 1,8-diazabicycloundec-7-ene, pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, and 2-tert-butyl-1,1,3,3-tetramethylguanidine in any proportion.

4. The method for synthesizing disulfide compounds according to claim 3, characterized in that... The method comprises the following steps: Step 1: adding a thiol compound, a base, and a solvent into a reaction container; Step 2: when the sulfonyl fluoride compound is gaseous, the sulfonyl fluoride compound is introduced into the reaction container, or when the sulfonyl fluoride compound is liquid or solid, the sulfonyl fluoride compound is added into the reaction container; Step 3: continuously stirring the reaction mixture at room temperature until a preset reaction time; Step 4: injecting an aqueous hydrochloric acid solution into the reaction system, extracting the aqueous phase with an organic solvent, combining the organic phases, drying, and concentrating to obtain a disulfide product.

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