A hydroxyethyl disulfide, its preparation method and application

Abstract

The present invention provides a hydroxyethyl disulfide, a preparation method and an application thereof, belonging to the technical field of organic synthesis. That is, a method for directly synthesizing hydroxyethyl disulfide by electrocatalysis. The hydroxyethyl disulfide derivative is synthesized from readily available basic raw materials such as substituted ethylene oxide and sodium bromide. Compared with the traditional method for constructing asymmetric disulfides, the raw materials of this method are safe and non-toxic, use electricity as the energy source, have green, mild and efficient reaction conditions, and use benzyl acetyl disulfide as the sulfur source, avoiding the stench of traditional sulfides and providing a new way for the synthesis of asymmetric disulfides. The hydroxyethyl disulfide prepared by the present invention has certain anti-cancer cell proliferation activity, and has a good yield in gram-scale reactions, and has potential application prospects in industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a hydroxyethyl disulfide, a preparation method thereof, and an application thereof. Background Art

[0002] Polysulfides exist in a variety of therapeutic drugs and play unique roles. Sulfur, as a scaffold, is a ubiquitous structural unit in biomolecules. They act as bridges, adding extra stability to the three-dimensional structure of proteins, which is essential for protein folding and function.

[0003] In addition, in terms of pharmacology and pharmacokinetics, it is often regulated by the change of the position or quantity of sulfur elements in the structure. At the same time, disulfide bonds can effectively connect bioactive macromolecules by establishing reversible covalent bonds. Compounds containing disulfide bonds are widely present in nature. Disulfide bonds enhance the stability of higher-order structures, usually appearing in three forms: natural products, food chemistry, and medicinal chemistry. For example, the disulfide bridge in insulin, allicin, the main component in garlic, and the anticancer drug romidepsin, etc. These higher-order structures are also indispensable for the efficiency and specificity of biological actions. Therefore, disulfide bonds have very important research value and are one of the cores of modern drug development. Introducing disulfide groups to construct asymmetric disulfides has attracted great attention from organic synthesis workers in the past ten years.

[0004] The traditional method for constructing asymmetric disulfides is to gradually introduce sulfur atoms, that is, to construct S-S bonds, so as to achieve the synthesis of asymmetric disulfides. However, these methods still have certain limitations. For example, thiols have a strong pungent smell and require the use of transition metals, including precious metals.

[0005] In view of the above problems, developing disulfide reagents is the research focus of researchers in this field.

[0006] Patent CN1126466A relates to a new nitrate ester containing a disulfide compound group and a preparation method thereof. This compound can be used to treat diseases of the cardiac circulatory system, and the structure is shown as follows:

[0007]

[0008] Patent CN 108472384 B relates to disulfide drug conjugates, in which a linker containing a sulfur-containing carbon atom is conjugated to the cysteine sulfur atom of a targeting carrier through a disulfide bond. The sulfur-containing carbon atom is substituted by at least one hydrocarbon group or substituted hydrocarbon group, and wherein the linker is further conjugated to a drug moiety. This invention further relates to an activated linker-drug conjugate suitable for conjugating to a targeting carrier through a disulfide bond. It further relates to a method for preparing a hindered disulfide drug conjugate, and the structure is shown as follows:

[0009]

[0010] As a cheap and easily available renewable energy source, electrochemical reactions fully meet the requirements of sustainable development in today's era. In recent years, the use of electrocatalytic synthesis chemistry has attracted the interest of most organic synthesis researchers. Electrocatalytic conversion is considered a promising alternative method for organic synthesis under mild conditions. It provides a unique direct route to molecular structures that are usually difficult to synthesize using other reaction types. The development of electrocatalytic reactions is an attractive synthetic strategy in synthetic chemistry. Compared with transition metal catalysts, electrolytes have the advantages of low cost, strong synthetic versatility, non-toxic and environmentally friendly.

[0011] Therefore, the present invention provides a simple, green and efficient electrocatalytic construction of hydroxyethyl disulfide and its derivatization reaction. Summary of the Invention

[0012] In view of the above problems, the present invention provides a hydroxyethyl disulfide, its preparation method and application. Compared with the traditional method for constructing asymmetric disulfides, the raw materials of this method are safe and non-toxic, use electricity as the energy source, have green, mild and efficient reaction conditions, and use benzyl acetyl disulfide as the sulfur source, avoiding the odor of traditional sulfides, and providing a new route for the synthesis of asymmetric disulfides.

[0013] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0014] On the one hand, the present invention provides a hydroxyethyl disulfide and its derivatives, and the structural formula is shown in Formula I below:

[0015]

[0016] Wherein,

[0017] R 1 independently selected from unsubstituted or optionally substituted by one, two or more R a substituted with the following groups: C 1-16 alkyl, C 1-16 aryl, C 1-16 heteroalkyl;

[0018] R a independently selected from halogen, amino, hydroxy, cyano, nitro;

[0019] R 2 independently selected from H, halogen, nitro, cyano, and C of the following groups which are unsubstituted or optionally substituted by one, two or more R b substituted with the following groups: C 1-16 alkyl, C 1-16 alkoxy;

[0020] R b Independently selected from C 1-12 alkyl, halogen, amino, hydroxyl, cyano, nitro.

[0021] Preferably,

[0022] R 1 independently selected from unsubstituted or optionally substituted by one, two or more R a substituted with the following groups: C 1-12 alkyl, C 1-12 aryl, C 1-12 heteroalkyl;

[0023] R a independently selected from F, Cl, Br, I, amino, hydroxyl;

[0024] R 2 independently selected from H, halogen, nitro, cyano, and unsubstituted or optionally substituted by one, two or more R b substituted with the following groups of C 1-12 alkyl, C 1-12 alkoxy;

[0025] R b independently selected from C 1-6 alkyl, F, Cl, Br, I.

[0026] More preferably,

[0027] R 1 independently selected from unsubstituted or optionally substituted by one, two or more R a substituted with the following groups: thiophene, phenyl, biphenyl;

[0028] R a independently selected from F, Br;

[0029] R 2 independently selected from H, halogen, methyl, methoxy.

[0030] On the other hand, the present invention provides a method for preparing hydroxyethyl disulfide and its derivatives. Using substituted ethylene oxide as a raw material and benzyl acetyl disulfide as a disulfur source, hydroxyethyl disulfide is prepared under the action of an electrocatalytic system; the reaction equation is as follows:

[0031]

[0032] Preferably, the electrocatalytic system includes: a power source, an electrolyte, and a solvent.

[0033] Preferably, the power source can be a DC power source; the conditions of the DC power source are: voltage is 15V, current is 10mA.

[0034] The electrolyte described above is at least one of ammonium tetrabutylborate, sodium bromide, potassium iodide, and sodium iodide.

[0035] Preferably, the catalyst described above is at least one of ammonium tetrabutylborate, sodium bromide, and potassium iodide;

[0036] More preferably, the electrolyte described above is at least one of ammonium tetrabutylborate and sodium bromide;

[0037] Even more preferably, the electrolyte described above is sodium bromide.

[0038] The solvent described above is selected from at least one of 1,2-dichloroethane, dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, dichloromethane, and water;

[0039] Preferably, the solvent described above is selected from at least one of 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, dichloromethane, and water;

[0040] More preferably, the solvent described above is selected from at least one of acetonitrile, N,N-dimethylformamide, dichloromethane, and water;

[0041] Even more preferably, the solvent described above is selected from at least one of acetonitrile, dichloromethane, and water;

[0042] Even further preferably, the solvent described above is selected from water and acetonitrile.

[0043] Preferably, the ratio of the water and acetonitrile can be 1:1 - 6.

[0044] Preferably, the ratio of the water:acetonitrile is selected from 1:1, 1:2, 1:3, 1:4, 1:5, 1:6;

[0045] Preferably, the ratio of the water:acetonitrile in the mixed solvent is selected from 1:1, 1:2, 1:3, 1:4, 1:5;

[0046] More preferably, the ratio of the water:acetonitrile in the mixed solvent is selected from 1:2, 1:3, 1:4, 1:5;

[0047] Even more preferably, the ratio of the water:acetonitrile in the mixed solvent is selected from 1:3, 1:4, 1:5;

[0048] Even further preferably, the ratio of the water:acetonitrile in the mixed solvent is selected from 1:5.

[0049] The molar ratio of the described raw material 1 to raw material 2 is preferably 1:0.6 - 3; more preferably 1:0.7 - 2.9; still more preferably 1:0.8 - 2.8; further preferably 1:0.9 - 2.7; still further preferably 1:1.0 - 2.6; even more preferably 1:1.1 - 2.5; even more preferably 1:1.2 - 2.4; even more preferably 1:1.3 - 2.3; even more preferably 1:1.4 - 2.2; even more preferably 1:1.5 - 2.1; even more preferably 1:1.6 - 2.0; even more preferably 1:1.7 - 1.9; even more preferably 1:1.7 - 1.8.

[0050] Preferably, the molar ratio of the described electrolyte to raw material 1 is 0.001 - 7:1, and further preferably, it is 1 - 5:1.

[0051] Preferably, the molar ratio of the described sodium bromide to raw material 1 is 0.001 - 7:1; preferably 1 - 5:1; more preferably 2 - 7:1; further preferably 3 - 7:1; still further preferably 4 - 7:1.

[0052] The molar ratio of the described tetrabutylammonium tetrafluoroborate to raw material 1 is 0.001 - 7:1; preferably 1 - 5:1; more preferably 2 - 7:1; further preferably 3 - 7:1; still further preferably 4 - 7:1.

[0053] The molar ratio of the described sodium iodide to raw material 1 is 0.001 - 7:1; preferably 1 - 5:1; more preferably 2 - 7:1; further preferably 3 - 7:1; still further preferably 4 - 7:1.

[0054] The molar ratio of the described potassium iodide to raw material 1 is 0.001 - 7:1; preferably 1 - 5:1; more preferably 2 - 7:1; further preferably 3 - 7:1; still further preferably 4 - 7:1.

[0055] The molar ratio of the described sodium bromide to raw material 1 is 0.001 - 7:1; preferably 1 - 5:1; more preferably 2 - 7:1; further preferably 3 - 7:1; still further preferably 4 - 7:1.

[0056] On the other hand, the present invention provides the use of the above-mentioned hydroxyethyl disulfide and its derivatives or the hydroxyethyl disulfide and its derivatives prepared by the above-mentioned preparation method in the preparation of anticancer cell drugs.

[0057] Compared with the prior art, the present invention has the following beneficial effects:

[0058] The method for preparing hydroxyethyl disulfide according to the technical solution of the present invention is simple in operation, does not involve metals, has a wide range of applicable reaction substrates, good regioselectivity, high yield, and can synthesize a series of hydroxyethyl disulfides greenly and efficiently. The prepared compounds have certain anti-cancer cell proliferation activities and have broad application prospects in drug preparation, agrochemicals, and fluorescent materials.

[0059] Terms:

[0060] Hydroxyethyl disulfide: It is a very important polysulfide compound with a hydroxyl-derived structure and is a nucleophilic disulfide reagent.

[0061] Electrolyte: An electrolyte is a compound that can conduct electricity by itself when dissolved in an aqueous solution or in a molten state. According to its degree of ionization, it can be divided into strong electrolytes and weak electrolytes. Those that are almost completely ionized are strong electrolytes, and those that are only slightly ionized are weak electrolytes.

[0062] Solvent: It is a liquid that can dissolve solid, liquid, or gaseous solutes and then become a solution. Solvents usually have relatively low boiling points and are easy to volatilize, or can be removed by distillation, leaving the solute behind. Therefore, solvents cannot chemically react with solutes.

[0063] Tetrabutylammonium tetrafluoroborate: White crystalline powder. Slightly soluble in water (0.1 g / 100 mL) and methanol.

[0064] Sodium bromide: Colorless cubic crystal system crystals or white granular powders. Sodium bromide is slightly soluble in alcohol and can react with dilute sulfuric acid to form hydrogen bromide. Under acidic conditions, sodium bromide can be oxidized to liberate bromine.

[0065] Potassium iodide: It is an inorganic compound with the chemical formula KI, which is a colorless or white crystal, odorless and easily soluble in water and ethanol. The aqueous solution darkens when exposed to light and iodine is liberated. Brief Description of the Drawings

[0066] Figure 1 It is the hydrogen spectrum of the compound prepared in Example 1 of the present invention;

[0067] Figure 2 It is the carbon spectrum of the compound prepared in Example 1 of the present invention;

[0068] Figure 3 It is the hydrogen spectrum of the compound prepared in Example 2 of the present invention;

[0069] Figure 4 It is the carbon spectrum of the compound prepared in Example 2 of the present invention;

[0070] Figure 5 It is the hydrogen spectrum of the compound prepared in Example 3 of the present invention;

[0071] Figure 6 13C NMR spectrum of the compound prepared in Example 3 of the present invention;

[0072] Figure 7 1H NMR spectrum of the compound prepared in Example 4 of the present invention;

[0073] Figure 8 13C NMR spectrum of the compound prepared in Example 4 of the present invention;

[0074] Figure 9 1H NMR spectrum of the compound prepared in Example 5 of the present invention;

[0075] Figure 10 13C NMR spectrum of the compound prepared in Example 5 of the present invention;

[0076] Figure 11 1H NMR spectrum of the compound prepared in Example 6 of the present invention;

[0077] Figure 12 13C NMR spectrum of the compound prepared in Example 6 of the present invention;

[0078] Figure 13 1H NMR spectrum of the compound prepared in Example 7 of the present invention;

[0079] Figure 14 13C NMR spectrum of the compound prepared in Example 7 of the present invention;

[0080] Figure 15 1H NMR spectrum of the compound prepared in Example 8 of the present invention;

[0081] Figure 16 13C NMR spectrum of the compound prepared in Example 8 of the present invention;

[0082] Figure 17 1H NMR spectrum of the compound prepared in Example 9 of the present invention;

[0083] Figure 18 13C NMR spectrum of the compound prepared in Example 9 of the present invention;

[0084] Figure 19 1H NMR spectrum of the compound prepared in Example 10 of the present invention;

[0085] Figure 20 13C NMR spectrum of the compound prepared in Example 10 of the present invention;

[0086] Figure 21 1H NMR spectrum of the compound prepared in Example 11 of the present invention;

[0087] Figure 22 13C NMR spectrum of the compound prepared in Example 11 of the present invention. Detailed Description of the Invention

[0088] The above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments, can be combined arbitrarily. All the features explained in the specification of this case can be used in combination with any method form. Each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equivalent or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equivalent or similar features.

[0089] The present invention will be further described below in conjunction with specific embodiments. These embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The implementation methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, all percentages and fractions are by weight.

[0090] Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those well known to those skilled in the art. In addition, any methods and materials similar or equivalent to the described content can be applied to the method of the present invention. The preferred implementation methods and materials described herein are only for illustrative purposes.

[0091] The basic raw materials such as aryl ethylene oxide and sodium bromide involved in the present invention can all be obtained through commercial channels.

[0092] Example 1:

[0093] Place 12.0 mg (0.1 mmol) of 2-phenylethylene oxide, 40.4 mg - 70.7 mg (0.4 mmol - 0.7 mmol) of sodium bromide, and 11.88 mg - 59.4 mg (0.06 mmol - 0.3 mmol) of SS-benzylethane (peroxydisulfide) in a 25 mL test tube with a magnetic stir bar. After adding 5 mL of a mixed solution of acetonitrile and water at room temperature, stir for 6 hours under an electric current. After rotary evaporation, perform flash column chromatography to obtain the target product with a yield of 78%.

[0094]

[0095] 1 H NMR (400 MHz, Chloroform-d) δ 7.30–7.27 (m, 5H), 7.27–7.23 (m, 2H), 7.22–7.18 (m, 3H), 5.86 (dd, J = 8.6, 4.8 Hz, 1H), 3.85 (s, 2H), 2.81 (dd, J = 13.8, 8.6 Hz, 1H), 2.60 (dd, J = 13.8, 4.8 Hz, 1H), 2.06 (s, 3H).

[0096] 13 C NMR (101 MHz, CDCl 3)δ170.03, 138.92, 137.37, 129.36, 128.63, 128.35, 127.52, 126.56, 73.75, 44.41, 43.62, 21.17.

[0097] HR-ESI-MS m / z calcd. for C 17 H 18 O 2 S 2 [M + H] + : 318.0748, found: 318.0740.

[0098] Example 2:

[0099] 12.0 mg (0.1 mmol) of 2-phenyloxirane, 40.4 mg - 70.7 mg (0.4 mmol - 0.7 mmol) of sodium bromide, and 12.7 mg - 63.6 mg (0.06 mmol - 0.3 mmol) of SS-(4-methylbenzyl)ethane (peroxydisulfide) were placed in a 25 mL test tube with a stir bar. After adding 5 mL of a mixed solution of acetonitrile and water at room temperature, the mixture was stirred for 6 hours under an electric current. After evaporation to dryness, the target product was obtained by flash column chromatography with a 79% yield.

[0100]

[0101] 1 H NMR (400 MHz, Chloroform-d) δ 7.32 (d, J = 7.5 Hz, 2H), 7.26–7.18 (m, 5H), 7.11 (d, J = 7.7 Hz, 2H), 5.88 (dd, J = 8.8, 4.6 Hz, 1H), 3.86 (s, 2H), 2.86 (dd, J = 13.7, 8.8 Hz, 1H), 2.64 (dd, J = 13.8, 4.6 Hz, 1H), 2.31 (s, 3H), 2.09 (s, 3H).

[0102] 13 C NMR (101 MHz, CDCl 3 ) δ 170.03, 139.00, 137.28, 134.31, 129.33, 129.24, 128.53, 128.31, 126.53, 73.75, 44.42, 43.40, 21.17.

[0103] HR-ESI-MS m / z calcd. for C 18 H 20 O 2 S 2 [M + H]+ : 332.0905, found: 332.0896.

[0104] Example 3:

[0105] Place 12.0 mg (0.1 mmol) of 2-phenyloxirane, 40.4 mg - 70.7 mg (0.4 mmol - 0.7 mmol) of sodium bromide, and 16.6 mg - 82.8 mg (0.06 mmol - 0.3 mmol) of SS-(4-bromophenyl)ethane (peroxydisulfide) into a 25 mL test tube with a magnetic stir bar. After adding 5 mL of a mixed solution of acetonitrile and water at room temperature, stir for 6 hours under an electric current. After rotary evaporation, perform flash column chromatography to obtain the target product with a 75% yield.

[0106]

[0107] 1 H NMR (400 MHz, Chloroform-d) δ 7.44 (d, J = 8.0 Hz, 2H), 7.33 (dd, J = 12.7, 6.8 Hz, 3H), 7.24 (d, J = 7.5 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 5.89 (dd, J = 8.6, 4.9 Hz, 1H), 3.82 (s, 2H), 2.88 (dd, J = 13.8, 8.5 Hz, 1H), 2.69 (dd, J = 13.8, 5.0 Hz, 1H), 2.10 (s, 3H).

[0108] 13 C NMR (101 MHz, CDCl 3 ) δ 170.03, 138.75, 136.55, 131.74, 131.00, 128.69, 128.64, 128.44, 126.54, 121.53, 73.73, 44.52, 42.85, 21.16.

[0109] HR-ESI-MS m / z calcd. for C 19 H 22 O 2 S 2 [M + H] + : 346.1061, found: 346.1056.

[0110] Example 4:

[0111] 12.0 mg (0.1 mmol) of 2-phenyloxirane, 40.4 mg - 70.7 mg (0.4 mmol - 0.7 mmol) of sodium bromide, and 13.9 mg - 69.6 mg (0.06 mmol - 0.3 mmol) of SS-(4-chlorophenyl)ethane (peroxydisulfide) were placed in a 25 mL test tube with a magnetic stir bar. After adding 5 mL of a mixed solution of acetonitrile and water at room temperature, the mixture was stirred for 6 hours under an electric current. After evaporation to dryness, the target product was obtained by flash column chromatography with a 74% yield.

[0112]

[0113] 1 H NMR (400 MHz, Chloroform-d) δ 7.36–7.30 (m, 4H), 7.26 (t, J = 8.3 Hz, 5H), 5.89 (t, J = 6.7 Hz, 1H), 3.83 (s, 2H), 2.88 (dd, J = 13.8, 8.5 Hz, 1H), 2.70 (dd, J = 13.8, 4.9 Hz, 1H), 2.09 (s, 3H).

[0114] 13 C NMR (101 MHz, CDCl 3 ) δ 170.02, 138.77, 136.01, 133.44, 130.66, 128.78, 128.64, 128.44, 126.56, 73.75, 44.54, 42.80, 42.56, 21.16.

[0115] HR-ESI-MS m / z calcd. for C 17 H 17 ClO 2 S 2 [M+H] + : 352.0358, found: 352.0349.

[0116] Example 5:

[0117] 12.0 mg (0.1 mmol) of 2-phenyloxirane, 40.4 mg - 70.7 mg (0.4 mmol - 0.7 mmol) of sodium bromide, and 15.96 mg - 79.8 mg (0.06 mmol - 0.3 mmol) of SS-(4-(trifluoromethyl)benzyl)ethane (peroxydisulfide) were placed in a 25 mL test tube with a magnetic stir bar. After adding 5 mL of a mixed solution of acetonitrile and water at room temperature, the mixture was stirred for 6 hours under an electric current. After evaporation to dryness, the target product was obtained by flash column chromatography with a 77% yield.

[0118]

[0119] 1 1H NMR (400 MHz, Chloroform-d) δ 7.58 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.33 (q, J = 8.4, 7.3 Hz, 3H), 7.24–7.20 (m, 2H), 5.89 (dd, J = 8.4, 5.0 Hz, 1H), 3.90 (s, 2H), 2.86 (dd, J = 13.8, 8.4 Hz, 1H), 2.67 (dd, J = 13.8, 5.0 Hz, 1H), 2.09 (s, 3H).

[0120] 13 13C NMR (101 MHz, Chloroform-d) δ 144.26, 138.81, 127.86 (d, J = 96.4 Hz), 81.08–71.67 (m), 54.74, 29.81.

[0121] HR-ESI-MS m / z calcd. for C 17 H 16 F 3 O 2 S 2 [M+H] + : 386.0622, found: 386.0615.

[0122] Example 6:

[0123] 12.0 mg (0.1 mmol) of 2-phenyloxirane, 40.4 mg - 70.7 mg (0.4 mmol - 0.7 mmol) of sodium bromide, and 13.7 mg - 68.4 mg (0.06 mmol - 0.3 mmol) of SS-(4-methoxybenzyl)ethane (peroxydisulfide) were placed in a 25 mL test tube with a stir bar. After adding 5 mL of a mixed solution of acetonitrile and water at room temperature, the mixture was stirred for 6 hours under an electric current. After evaporation to dryness, the target product was obtained by flash column chromatography with an 84% yield.

[0124]

[0125] 11H NMR (400 MHz, Chloroform-d) δ 7.32 (td, J = 10.9, 9.8, 4.4 Hz, 5H), 7.24 (d, J = 7.3 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 5.89 (dd, J = 8.6, 4.8 Hz, 1H), 3.85 (s, 2H), 3.78 (s, 3H), 2.87 (dd, J = 13.8, 8.6 Hz, 1H), 2.66 (dd, J = 13.8, 4.8 Hz, 1H), 2.09 (s, 3H).

[0126] 13 13C NMR (101 MHz, CDCl 3 ) δ 170.04, 159.09, 138.97, 130.49, 129.28, 128.34, 126.57, 114.02, 77.38, 77.06, 73.79, 55.30, 44.48, 43.06, 21.17.

[0127] HR-ESI-MS m / z calcd. for C 18 18 20 10 3 2 2 [M + H] + : 348.0854, found: 348.0853.

[0128] Example 7:

[0129] 12.0 mg (0.1 mmol) of 2-phenyloxirane, 40.4 mg - 70.7 mg (0.4 mmol - 0.7 mmol) of sodium bromide, and 13.5 mg - 67.8 mg (0.06 mmol - 0.3 mmol) of SS-(3,4-dimethylbenzyl)ethane (peroxydisulfide) were placed in a 25 mL test tube with a stir bar. After adding 5 mL of a mixed solution of acetonitrile and water at room temperature, the mixture was stirred for 6 hours under an electric current. After evaporation to dryness, the target product was obtained by flash column chromatography with a 78% yield.

[0130]

[0131] 11H NMR (400 MHz, Chloroform-d) δ 7.32 (q, J = 6.4, 4.6 Hz, 3H), 7.23 (d, J = 7.6 Hz, 2H), 7.08 (d, J = 18.0 Hz, 3H), 5.89 (dd, J = 8.8, 4.6 Hz, 1H), 3.84 (s, 2H), 2.88 (dd, J = 13.8, 8.8 Hz, 1H), 2.66 (dd, J = 13.8, 4.7 Hz, 1H), 2.24 (s, 3H), 2.22 (s, 3H), 2.09 (s, 3H).

[0132] 13 13C NMR (101 MHz, CDCl 3 ) δ 170.03, 139.06, 136.87, 135.96, 134.65, 130.53, 129.84, 128.54, 128.30, 126.74, 126.50, 73.76, 44.47, 43.49, 21.16, 19.76, 19.48.

[0133] HR-ESI-MS m / z calcd. for C 19 18 22 11 2 1 2 [M + H] + : 346.1061, found: 346.1056.

[0134] Example 8:

[0135] 19.6 mg (0.1 mmol) of 2-([1,1-biphenyl]-4-yl)oxirane, 40.4 mg - 70.7 mg (0.4 mmol - 0.7 mmol) of sodium bromide, 14.5 mg - 72.6 mg (0.06 mmol - 0.3 mmol), 11.9 mg - 59.4 mg (0.06 mmol - 0.3 mmol) of SS-benzylethane (peroxydisulfide) were placed in a 25 mL test tube with a stir bar. After adding 5 mL of a mixed solution of acetonitrile and water at room temperature, the mixture was stirred for 6 hours under an electric current. After evaporation to dryness, the target product was obtained by flash column chromatography with a 78% yield.

[0136]

[0137] 11H NMR (400 MHz, Chloroform-d) δ 7.57–7.48 (m, 5H), 7.40 (t, J = 7.7 Hz, 3H), 7.29 (d, J = 6.6 Hz, 5H), 7.22 (d, J = 6.8 Hz, 1H), 5.90 (dd, J = 8.6, 4.9 Hz, 1H), 3.87 (s, 2H), 2.85 (dd, J = 13.7, 8.6 Hz, 1H), 2.64 (dd, J = 13.9, 4.8 Hz, 1H), 2.07 (s, 3H).

[0138] 13 13C NMR (101 MHz, CDCl 3 ) δ 170.08, 141.31, 140.61, 137.91, 137.41, 129.39, 128.85, 128.66, 127.57, 127.52, 127.34, 127.16, 127.05, 73.59, 44.31, 43.65, 21.21.

[0139] HR-ESI-MS m / z calcd. for C 23 19 22 11 2 1 2 [M + H] + : 394.1061, found: 394.1056.

[0140] Example 9:

[0141] 19.8 mg (0.1 mmol) of 2-(2-bromophenyl)oxirane, 40.4 mg - 70.7 mg (0.4 mmol - 0.7 mmol) of sodium bromide, and 11.9 mg - 59.4 mg (0.06 mmol - 0.3 mmol) of SS-benzylethane (peroxydisulfide) were placed in a 25 mL test tube with a stir bar. After adding 5 mL of a mixed solution of acetonitrile and water at room temperature, the mixture was stirred for 6 hours under an electric current. After evaporation to dryness, the target product was obtained by flash column chromatography with a 71% yield.

[0142]

[0143] 11H NMR (400 MHz, Chloroform-d) δ 7.54 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 6.6 Hz, 1H), 7.33–7.28 (m, 5H), 7.27 (d, J = 4.8 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 6.30 (dd, J = 8.7, 3.8 Hz, 1H), 3.96–3.89 (m, 2H), 2.95 (dd, J = 14.1, 3.8 Hz, 1H), 2.79 (dd, J = 14.1, 8.7 Hz, 1H), 2.13 (s, 3H).

[0144] 13 13C NMR (101 MHz, CDCl 3 ) δ 169.72, 138.35, 137.00, 133.03, 129.64, 129.39, 128.59, 127.72, 127.52, 127.49, 122.11, 77.37, 76.73, 72.98, 43.66, 43.29, 21.05.

[0145] HR-ESI-MS m / z calcd. for C 17 17 17 1 2 1 2 [M + H] + : 395.9853, found: 395.9849.

[0146] Example 10:

[0147] 13.8 mg (0.1 mmol) of 2-(4-fluorophenyl)oxirane, 40.4 mg - 70.7 mg (0.4 mmol - 0.7 mmol) of sodium bromide, and 11.9 mg - 59.4 mg (0.06 mmol - 0.3 mmol) of SS-benzylethane (peroxydisulfide) were placed in a 25 mL test tube with a stir bar. After adding 5 mL of a mixed solution of acetonitrile and water at room temperature, the mixture was stirred for 6 hours under an electric current. After evaporation to dryness, the target product was obtained by flash column chromatography with a 78% yield.

[0148]

[0149] 11H NMR (400 MHz, Chloroform-d) δ 7.36–7.26 (m, 5H)), 7.20 (dd, J=8.3, 5.5 Hz, 2H), 7.01 (t, J=8.6 Hz, 2H), 5.85 (dd, J=8.3, 5.1 Hz, 1H), 3.89 (s, 2H), 2.80 (dd, J=13.8, 8.4 Hz, 1H), 2.56 (dd, J=13.8, 5.1 Hz, 1H), 2.08 (s, 3H).

[0150] 13 13C NMR (101 MHz, CDCl 3 ) δ 169.92, 163.75, 137.33, 134.71, 134.68, 129.32, 128.60, 128.44, 128.35, 127.51, 115.55, 115.34, 77.34, 73.11, 44.09, 43.57, 21.11.

[0151] 19F NMR (376 MHz, Chloroform-d) δ -113.44.

[0152] HR-ESI-MS m / z calcd. for C 17 H 17 FO 2 S 2 [M+H] + : 336.0654, found: 336.0644.

[0153] Example 11:

[0154] 11.0 mg (0.1 mmol) of 2-thiophene ethylene oxide, 40.4 mg - 70.7 mg (0.4 mmol - 0.7 mmol) of sodium bromide, and 11.9 mg - 59.4 mg (0.06 mmol - 0.3 mmol) of SS-benzylethane (peroxydisulfide) were placed in a 25 mL test tube with a stir bar. After adding 5 mL of a mixed solution of acetonitrile and water at room temperature, the mixture was stirred for 6 hours under an electric current. After rotary evaporation, the target product was obtained by flash column chromatography with an 80% yield.

[0155]

[0156] Three examples were selected for MTT tests, with osimertinib (AZD-9291) as the positive control drug. The cells selected were HepG2 (human hepatocellular carcinoma cells), HeLa (cervical cancer cells), LO 2(Human normal hepatocytes). Analysis of the IC50 values of the compounds showed that this series of compounds had certain inhibitory activities against the above cell lines. The results are shown in the following table:

[0157] Table 1 In vitro anti-proliferative activities of some compounds

[0158]

[0159]

[0160] 1 H NMR(400MHz,Chloroform-d)δ7.33–7.32(m,1H),7.32–7.28(m,3H),7.28–7.25(m,2H),7.00–6.94(m,2H),6.18(dd,J=8.1,5.5Hz,1H),3.90(s,2H),2.92(dd,J=13.7,8.1Hz,1H),2.74(dd,J=13.8,5.5Hz,1H),2.07(s,3H).

[0161] 13 C NMR(101MHz,CDCl 3 )δ169.89,141.48,137.22,129.37,128.64,127.57,126.73,126.35,125.73,69.34,44.23,43.61,21.11.

[0162] HR-ESI-MS m / z calcd.for C 15 H 16 O 2 S 3 [M+H] + :324.0312,found:324.0310.

[0163] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than limiting the protection scope of the present invention. Any simple modification or equivalent replacement of the technical solution of the present invention by those of ordinary skill in the art shall not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A hydroxyethyl disulfide, characterized in that, its structural formula is as shown in Formula I below: wherein, R 1 independently selected from unsubstituted or optionally substituted by one, two or more R a substituted with the following groups: thiophene, phenyl, biphenyl; R a Independently selected from F, Br; R 2 independently selected from H, halogen, nitro, cyano, and unsubstituted or optionally substituted by one, two or more R b substituted C of the following groups 1-16 alkyl, C 1-16 alkoxy; R b Independently selected from C 1-12 alkyl, halogen, amino, hydroxy, cyano, nitro.

2. The hydroxyethyl disulfide according to claim 1, characterized in that, R 2 independently selected from H, halogen, nitro, cyano, and unsubstituted or optionally substituted by one, two or more R b substituted C of the following groups 1-12 alkyl, C 1-12 alkoxy; R b Independently selected from C 1-6 alkyl, F, Cl, Br, I.

3. A method for preparing the hydroxyethyl disulfide according to any one of claims 1-2, characterized in that, using a substituted ethylene oxide as a raw material and benzyl acetyl disulfide as a disulfur source, and under the action of an electrocatalytic system, the hydroxyethyl disulfide is prepared; the reaction equation is as shown below:

4. The preparation method according to claim 3, characterized in that, the electrocatalytic system includes: a power source, an electrolyte and a solvent; the power source is a DC power source; the conditions of the DC power source are: the voltage is 15V and the current is 10mA.

5. The preparation method according to claim 4, characterized in that, the electrolyte is selected from at least one of tetrabutylammonium tetrafluoroborate, sodium bromide, potassium iodide and sodium iodide.

6. The preparation method according to claim 4, characterized in that, the solvent is selected from at least one of 1,2-dichloroethane, dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide, dichloromethane and water.

7. The preparation method according to claim 6, characterized in that, the solvent is water and acetonitrile; the ratio of water to acetonitrile is selected from 1:1-6.

8. The preparation method according to claim 4, characterized in that, the molar ratio of the substituted ethylene oxide to benzyl acetyl disulfide is selected from 1:0.6-3.

9. The preparation method according to claim 4, characterized in that, the molar ratio of the electrolyte to the substituted ethylene oxide is 0.001-7:

1.

10. Use of the hydroxyethyl disulfide according to any one of claims 1-2 in the preparation of anticancer cell drugs.

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