Application of a Bilateral Disulfide Reagent in the Stepwise Synthesis of Asymmetric Disulfides

Abstract

The present invention relates to the technical field of organic synthesis, and specifically relates to the application of a bilateral disulfide reagent in the stepwise synthesis of asymmetric disulfides. The disulfide reagent in the present invention has the advantages of simple synthesis, simple reaction conditions, and high yield. Due to its symmetry, the disulfide reagent can undergo stepwise (secondary) nucleophilic substitution reactions with (pseudo)haloalkanes, and can be used for the synthesis of various asymmetric disulfides or bilateral modification of disulfides. It has strong practicability, wide substrate applicability, and high yield. It solves the problems of low yield caused by many by-products in the synthesis of disulfides by the thiol coupling method at present, poor functional group tolerance, side reactions caused by the instability of thiols, as well as the unpleasant smell and high toxicity generated during the synthesis process.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to the application of a bilateral disulfide reagent in the synthesis of asymmetric disulfides. Background Art

[0002] Disulfides refer to organic sulfur compounds containing a disulfide bond (-S-S-), with the general formula R-S-S-R'. Disulfides are widely present in nature and living organisms and are applied in medicine, pesticides, veterinary drugs, and polymer materials. For example: in peptide drugs, the process of slowly releasing thiols through persulfide bonds is used to achieve the effect of slow drug release, thereby improving the drug efficacy time and utilization rate. Persulfurated compounds naturally exist in foods such as fruits and vegetables, such as Alliaceae vegetables like garlic and onions, and fruits like durian. Among them, allicin is widely present in Alliaceae plants (such as garlic and onions), and it is an allyl ether structure containing a persulfide bond, which has antibacterial effects on a variety of Gram-positive and Gram-negative bacteria, and has unique inhibitory and killing effects on bacilli, fungi, viruses, amoeba protozoa, pinworms, etc.

[0003] In view of the important role of persulfurated compounds, organic synthesis chemists have been looking forward to a new method to efficiently construct such important and sensitive structures. At present, there are almost no methods for efficiently and practically constructing asymmetric persulfides. In most cases, double pre-functionalized thiols (phenols) are still used for nucleophilic substitution. This cannot meet the requirements of modern chemistry in terms of atom economy, reaction yield, step economy, and environmental protection evaluation.

[0004] In view of the above traditional methods for synthesizing disulfides, through long-term research and practice, the present invention has discovered a method for stepwise synthesizing asymmetric disulfides using a bilateral disulfide reagent. Summary of the Invention

[0005] The purpose of the present invention is to solve the problems of low yield caused by many by-products in the synthesis of disulfides by thiol coupling, poor functional group tolerance, side reactions caused by the instability of thiols, and unpleasant odors and high toxicity generated during the synthesis process.

[0006] To achieve the above purpose, the present invention discloses the application of a symmetric disulfide reagent in the synthesis of asymmetric disulfides, and uses the symmetric disulfide reagent to perform nucleophilic substitution with (pseudo)halohydrocarbons step by step to synthesize asymmetric disulfides.

[0007] The synthesis route of this asymmetric persulfide is as follows:

[0008]

[0009] Wherein: R 1Independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, phenyl, benzyl, pyridyl, methoxy, ethoxy, tert-butoxy;

[0010] R2 is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, methoxy, ethoxy.

[0011] R3 is independently selected from C 1-n alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, cyclopentyl, cyclohexyl, benzyl,

[0012] R4 is independently selected from C 1-n alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, cyclopentyl, cyclohexyl, benzyl,

[0013] X is any one of an iodine atom, a bromine atom, a chlorine atom, and a methanesulfonate group.

[0014] In the synthesis reaction, the base is any one or a combination of several of cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, triethylamine, sodium tert-butoxide, and DBU;

[0015] In the synthesis reaction, the solvent is one or any combination of dimethyl sulfoxide, methanol, ethanol, and isopropanol;

[0016] In the synthesis reaction, the reaction temperature is 0 to 30 °C.

[0017] The synthesis route of the novel persulfur reagent is as follows:

[0018]

[0019] In the synthesis reaction of the novel persulfur reagent, the additive is iodine and hydrogen peroxide

[0020] In the synthesis reaction of the novel persulfur reagent, the temperature is 0 - 30 °C;

[0021] In the synthesis reaction of the novel persulfur reagent, the solvent is methanol, ethanol, tert-butanol, and isopropanol

[0022] In the synthesis reaction of the novel persulfur reagent, the dosage of the additive is 1 - 20 equiv.

[0023] The synthesis mechanism of this asymmetric persulfide is as Figure 1As shown, first, for the reaction mechanism of the persulfurylation of the new persulfurizing reagent promoted by alkali, Cs2CO3 extracts a hydrogen atom from the carbonyl α-position of the new persulfurizing reagent to generate a carbanion intermediate A, and the intermediate A undergoes β-elimination to form R 2 SS - Intermediate B and stable propenone olefin C. Intermediate B undergoes a nucleophilic substitution reaction with IV to form the desired asymmetric persulfide VIII.

[0024] Compared with the prior art, the beneficial effects of the present invention are as follows: The commonly used synthesis method of existing asymmetric disulfides is obtained by coupling two thiols. Using this synthesis method, the thiols are prone to self-coupling, resulting in a low reaction yield, poor durability of functional groups, the generation of toxic and harmful unpleasant odors when using thiols, and it is not easy to prepare. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 It is a reaction mechanism diagram of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0026] The terms used herein: "I2" refers to iodine, "EtOH" refers to ethanol, and "Cs2CO3" refers to cesium carbonate. "C1-n" includes branched and straight-chain saturated hydrocarbon groups having a specific number of carbon atoms. For example, "C 1-10 alkyl" (or alkylene) is intended to be C1, C2, C3, C4, C5, C6, C7, C8, C9, and C 10 alkyl. Additionally, for example, "C 1-6 alkyl" represents an alkyl group having 1 to 6 carbon atoms. The alkyl group can be unsubstituted or substituted such that one or more of its hydrogen atoms are replaced by other chemical groups. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, tert-butyl), pentyl (such as n-pentyl, isopentyl, neopentyl), and the like.

[0027] Table 1. Structural formulas and names of corresponding compounds of asymmetric disulfides 1 - 11 prepared in the present invention

[0028]

[0029]

[0030]

[0031] Example 1

[0032] Synthesis route for preparing 4,4'-dithianediylbis(4-methylpentan-2-one)

[0033]

[0034] 4-Mercapto-4-methylpentan-2-one (7.92 g, 1.0 eq) was dissolved in 95% ethanol (50.0 mL). After cooling the mixture solution to 0 °C, a solution of iodine in ethanol (10.0 g iodine in 12.0 mL ethanol) was added dropwise. The mixture was stirred at room temperature for 12 h. After completion of the reaction, saturated aqueous NaHCO3 was added until pH > 7. The solution was concentrated in vacuo to remove EtOH and excess tert-butyl mercaptan. An appropriate amount of ethyl acetate was added, and the organic layer was washed with 10% NaHSO3 and brine. Finally, the organic layer was dried over Na2SO4, filtered, concentrated and purified by flash column chromatography to afford the desired product (6.9 g, 88%). 4-Mercapto-4-methylpentan-2-one (7.92 g, 1.0 eq) was dissolved in 95% ethanol (50.0 mL). After cooling the mixture solution to 0 °C, a solution of iodine in ethanol (10.0 g iodine in 12.0 mL ethanol) was added dropwise. The mixture was stirred at room temperature for 12 h. After completion of the reaction, saturated aqueous NaHCO3 was added until pH > 7. The solution was concentrated in vacuo to remove EtOH and excess tert-butyl mercaptan. An appropriate amount of ethyl acetate was added, and the organic layer was washed with 10% NaHSO3 and brine. Finally, the organic layer was dried over Na2SO4, filtered, concentrated and purified by flash column chromatography to give the desired product (6.9 g, 88%).

[0035] The 1H NMR analysis results of the obtained product are as follows: 1 H NMR (600 MHz, Chloroform-d) δ 2.59 (s, 4H), 2.03 (s, 6H), 1.29 (s, 12H).

[0036] The 13C NMR analysis results are as follows: 13 C NMR (151 MHz, Chloroform-d) δ 205.75, 53.89, 47.78, 31.82, 27.60.

[0037] The GC-MS analysis results are as follows:

[0038] GC-MS (EI, 70 ev): m / z (%) = 262 (M + , 1), 164 (20), 99 (100).

[0039] The ESI-MS analysis results are as follows:

[0040] HRMS (ESI) calcd for [M+H] + (C 12 H 22O2S2Na): 285.0953; found: 285.0956.

[0041] Example 2

[0042] To prepare 4-((3,5-dimethylisoxazol-4-yl)methyl)disulfanyl)-4-methylpentan-2-one, the reaction route is as follows:

[0043]

[0044] Step 1: Add Cs2CO3 (97.8 mg, 0.3 mmol, 1.5 equiv) and a stir bar dried in an oven to a 25 mL tube. Under N2, add (chloromethyl)benzene (25.2 mg, 0.5 mmol, 1.0 equiv), 4,4'-disulfanediyldi(4-methylpentan-2-one) (78.6 mg, 0.3 mmol, 1.5 equiv) and methanol (2.0 mL). Heat the reaction mixture at 30 °C for 10 h. Then, cool the reaction mixture to room temperature. After removing the solvent under reduced pressure, the pure product was obtained by silica gel column chromatography (eluent: petroleum ether), and a colorless oily pure product (43.1 mg, 85%) was obtained.

[0045] The results of 1H NMR analysis are as follows:

[0046] 1 H NMR (600 MHz, Chloroform-d) δ 7.36 - 7.28 (m, 4H), 7.26 (t, J = 6.8 Hz, 1H), 3.93 (s, 2H), 2.68 (s, 2H), 2.11 (s, 3H), 1.42 (s, 6H).

[0047] The results of 13C NMR analysis are as follows:

[0048] 13 C NMR (151 MHz, Chloroform-d) δ 206.41, 137.21, 129.22, 128.57, 127.51, 53.46, 49.28, 45.64, 32.02, 27.19.

[0049] The results of GC-MS analysis are as follows:

[0050] GC-MS (EI, 70 ev): m / z (%) = 254 (M + , 6), 99 (100), 91 (95).

[0051] The results of ESI-MS analysis are as follows:

[0052] HRMS (ESI) calcd for [M+Na]+ (C 13 H 18 OS2Na): 277.0691; found: 277.0696.

[0053]

[0054] Step 2: Add Cs2CO3 (97.8 mg, 0.3 mmol, 1.5 eq) and a stir bar dried in an oven to a 25 mL reaction tube. Under N2, add (chloromethyl)benzene (25.2 mg, 0.2 mmol, 1.0 eq), 4 - ((((3,5 - dimethylisoxazol - 4 - yl)methyl)disulfanyl)-4 - methylpentan - 2 - one (81.9 mg, 0.3 mmol, 1.5 eq) and methanol (2.0 mL). Heat the reactants at 30 °C for 10 h. Then, cool the reactants to room temperature. After removing the solvent under reduced pressure, obtain the pure product by silica gel column chromatography (eluent: petroleum ether), giving the pure product as a colorless oil (47.2 mg, 89%).

[0055] The results of 1H NMR analysis are as follows:

[0056] 1 1H NMR (600 MHz, Chloroform - d) δ 7.35 - 7.31 (m, 2H), 7.30 - 7.26 (m, 3H), 3.77 (s, 2H), 3.29 (s, 2H), 2.28 (s, 3H), 2.21 (s, 3H).

[0057] The results of 13C NMR analysis are as follows:

[0058] 13 13C NMR (151 MHz, Chloroform - d) δ 166.90, 159.33, 137.26, 129.28, 128.62, 127.57, 110.13, 43.66, 30.75, 11.15, 10.10.

[0059] The results of GC - MS analysis are as follows:

[0060] GC - MS (EI, 70 ev): m / z (%) = 265 (M + , 2), 110 (100), 91 (48), 68 (60).

[0061] The results of ESI - MS analysis are as follows:

[0062] HRMS (ESI) calcd for [M + H] + (C 13 H16 NOS2): 266.0668; found: 266.0673.

[0063] Example 3

[0064] To prepare tert-butyl 4-(4-(bromophenethyl)disulfanyl)piperidine-1-carboxylate, the reaction route is as follows:

[0065]

[0066] Step 1: Add Cs2CO3 (97.8 mg, 0.3 mmol, 1.5 eq), 1-bromo-4-(2-iodoethyl)benzene (55.8 mg, 0.2 mmol, 1.0 eq) and an oven-dried stir bar to a 25 mL tube. Under N2, add 1-(tert-butyldisulfanyl)pentan-3-one (78.6 mg, 0.3 mmol, 1.5 eq) and MeOH (2.0 mL). Heat the reaction mixture at 30 °C for 10 h. Then, cool the reaction mixture to room temperature. After removing the solvent under reduced pressure, the pure product was obtained by silica gel column chromatography (eluent: petroleum ether), and a colorless oil pure product (55.5 mg, 80%) was obtained.

[0067] The results of 1H NMR analysis are as follows:

[0068] 1 1H NMR (600 MHz, Chloroform-d) δ 7.40 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 2.91 (s, 4H), 2.74 (s, 2H), 2.14 (s, 3H), 1.42 (s, 6H).

[0069] The results of 13C NMR analysis are as follows:

[0070] 13 13C NMR (151 MHz, Chloroform-d) δ 206.30, 138.81, 131.56, 130.32, 120.24, 53.35, 49.28, 41.55, 34.98, 32.06, 27.25.

[0071] The results of GC-MS analysis are as follows:

[0072] GC-MS (EI, 70 ev): m / z (%) = 348 (M + , 2), 169 (10), 99 (100).

[0073] The results of ESI-MS analysis are as follows:

[0074] HRMS(ESI) calcd for [M+Na]+(C14H19OS2BrNa): 368.9953; found: 368.9948.

[0075]

[0076] Step 2: Add Cs2CO3 (97.8 mg, 0.3 mmol, 1.5 equiv), tert-butyl 4-iodopiperidine-1-carboxylate (62.2 mg, 0.2 mmol, 1.0 equiv) and an oven-dried stir bar to a 25 mL tube. Under N2, add 4-((4-bromophenethyl)disulfanyl)-4-methylpentan-2-one (104.1 mg, 0.3 mmol, 1.5 equiv) and methanol (2.0 mL). Heat the reaction mixture at 30 °C for 10 h. Then, cool the reaction mixture to room temperature. After removing the solvent under reduced pressure, the pure product was obtained by silica gel column chromatography (eluent: petroleum ether), giving the pure product as a colorless oil (61.4 mg, 71%).

[0077] The results of 1H NMR analysis are as follows:

[0078] 1 H NMR (600 MHz, Chloroform-d) δ 7.49 - 7.34 (m, 2H), 7.07 (d, J = 6.4 Hz, 2H), 4.02 (s, 2H), 2.96 - 2.87 (m, 4H), 2.84 - 1.81 (m, 3H), 1.95 (d, J = 12.0 Hz, 2H), 1.53 (d, J = 11.2 Hz, 2H), 1.45 (s, 9H).

[0079] The results of 13C NMR analysis are as follows:

[0080] 13 C NMR (151 MHz, Chloroform-d) δ 154.61, 138.80, 131.56, 130.32, 120.25, 79.65, 47.09, 43.32, 41.00, 34.97, 31.71, 28.40.

[0081] The results of electrospray mass spectrometry analysis are as follows:

[0082] HRMS(ESI) calcd for [M+Na] + (C 18 H 26 BrNO2S2Na): 454.0481; found: 454.0492.

[0083] Example 4

[0084] Preparation of 4-(((2,6-dichlorobenzyl)disulfanyl)methyl)-3,5-dimethylisoxazole, and the reaction route is as follows:

[0085]

[0086] Step 1: Add Cs2CO3 (97.8 mg, 0.3 mmol, 1.5 eq) and an oven-dried magnetic stir bar to a 25 mL reaction tube. Under N2, add 1,3-dichloro-2-(chloromethyl)benzene (39.0 mg, 0.2 mmol, 1.0 eq), 4,4'-dithiobis(4-methylpentan-2-one) (78.6 mg, 0.3 mmol, 1.5 eq) and MeOH (2.0 mL). Heat the reaction mixture at 30 °C for 10 h. Then, cool the reaction mixture to room temperature. After removing the solvent under reduced pressure, the pure product was obtained by silica gel column chromatography (eluent: petroleum ether), and a colorless oil pure product (52.9 mg, 82%) was obtained.

[0087] The results of 1H NMR analysis are as follows:

[0088] 1 H NMR (600 MHz, Chloroform-d) δ 7.28 (d, J = 8.1 Hz, 2H), 7.11 (t, J = 8.1 Hz, 1H), 4.28 (s, 2H), 2.75 (s, 2H), 2.12 (s, 3H), 1.43 (s, 6H).

[0089] The results of 13C NMR analysis are as follows:

[0090] 13 C NMR (151 MHz, Chloroform-d) δ 206.30, 135.86, 133.39, 129.05, 128.39, 53.37, 49.37, 41.05, 32.04, 27.06.

[0091] The results of electrospray mass spectrometry analysis are as follows:

[0092] HRMS (ESI) calcd for [M+Na] + (C 13 H 16 Cl2ONaS2): 344.9912; found: 344.9920.

[0093]

[0094] Step 2: Add Cs2CO3 (97.8 mg, 0.3 mmol, 1.5 equiv) and an oven-dried magnetic stir bar to a 25 mL reaction tube. Under N2, add 1,3-dichloro-2-(chloromethyl)benzene (39.1 mg, 0.2 mmol, 1.0 equiv), 4-(((3,5-dimethylisoxazol-4-yl)methyl)disulfanyl)-4-methylpentan-2-one (81.9 mg, 0.3 mmol, 1.5 equiv) and MeOH (2.0 mL). Heat the reaction mixture at 30 °C for 10 h. Then, cool the reaction mixture to room temperature. After removing the solvent under reduced pressure, the pure product was obtained by silica gel column chromatography (eluent: petroleum ether), giving the pure product as a colorless oil (55.5 mg, 83%).

[0095] The results of 1H NMR analysis are as follows:

[0096] 1 H NMR (600 MHz, Chloroform-d) δ 7.30 (d, J = 8.0 Hz, 2H), 7.14 (t, J = 8.0 Hz, 1H), 4.19 (s, 2H), 3.55 (s, 2H), 2.32 (s, 3H), 2.22 (s, 3H)

[0097] The results of 13C NMR analysis are as follows:

[0098] 13 C NMR (151 MHz, Chloroform-d) δ 166.99, 159.30, 135.79, 133.75, 129.06, 128.40, 109.95, 39.05, 31.49, 11.12, 10.09.

[0099] The results of GC-MS analysis are as follows:

[0100] GC-MS (EI, 70 ev): m / z (%) = 333 (M + , 2), 159 (18), 110 (100), 68 (50)

[0101] The results of ESI-MS analysis are as follows:

[0102] HRMS (ESI) calcd for [M+Na] + (C 13 H 13 Cl2NOS2Na): 355.9708; found: 355.9709.

[0103] Example 5

[0104] To prepare 4-((4-(tert-butyl)benzyl)disulfanyl)methyl)-3,5-dimethylisoxazole, the reaction route is as follows:

[0105]

[0106] Step 1: Add Cs2CO3 (97.8 mg, 0.3 mmol, 1.5 equiv) and an oven-dried magnetic stir bar to a 25 mL reaction tube. Under N2, add 1-(tert-butyl)-4-(chloromethyl)benzene (36.4 mg, 0.2 mmol, 1.0 equiv), 4,4'-dithiobis(4-methylpentan-2-one) (78.6 mg, 0.3 mmol, 1.5 equiv) and MeOH (2.0 mL). Heat the reaction mixture at 30 °C for 10 h. Then, cool the reaction mixture to room temperature. After removing the solvent under reduced pressure, the pure product was obtained by silica gel column chromatography (eluent: petroleum ether), and a colorless oil pure product (49.6 mg, 80%) was obtained.

[0107] The results of 1H NMR analysis are as follows:

[0108] 1 H NMR (600 MHz, Chloroform-d) δ 7.35 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 3.93 (s, 2H), 2.71 (s, 2H), 2.12 (s, 3H), 1.43 (s, 6H), 1.31 (s, 9H).

[0109] The results of 13C NMR analysis are as follows:

[0110] 13 C NMR (151 MHz, Chloroform-d) δ 206.48, 150.54, 134.04, 128.85, 125.51, 53.51, 49.28, 45.49, 34.52, 32.05, 31.29, 27.18.

[0111] The results of GC-MS analysis are as follows:

[0112] GC-MS (EI, 70 ev): m / z (%) = 310 (M + , 3), 147 (100), 99 (35).

[0113] The results of ESI-MS analysis are as follows:

[0114] HRMS (ESI) calcd for [M+Na] + (C 17 H 26OS2Na): 333.1317; found: 333.1323.

[0115]

[0116] Step 2: Add Cs2CO3 (97.8 mg, 0.3 mmol, 1.5 equiv) and an oven-dried magnetic stir bar to a 25 mL reaction tube. Under N2, add 1-(tert-butyl)-4-(chloromethyl)benzene (36.5 mg, 0.2 mmol, 1.0 equiv), 4-(((3,5-dimethylisoxazol-4-yl)methyl)disulfanyl)-4-methylpentan-2-one (81.9 mg, 0.3 mmol, 1.5 equiv), and MeOH (2.0 mL). Heat the reaction mixture at 30 °C for 10 h. Then, cool the reaction mixture to room temperature. After removing the solvent under reduced pressure, the pure product was obtained by silica gel column chromatography (eluent: petroleum ether), giving the pure product as a colorless oil (48.9 mg, 76%).

[0117] The results of 1H NMR analysis are as follows:

[0118] 1 H NMR (600 MHz, Chloroform-d) δ 7.35 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 3.76 (s, 2H), 3.32 (s, 2H), 2.27 (s, 3H), 2.21 (s, 3H), 1.30 (s, 9H).

[0119] The results of 13C NMR analysis are as follows:

[0120] 13 C NMR (151 MHz, Chloroform-d) δ 166.88, 159.34, 150.72, 134.12, 128.94, 125.54, 110.13, 43.41, 34.53, 31.31, 30.72, 11.11, 10.07.

[0121] The results of GC-MS analysis are as follows:

[0122] GC-MS (EI, 70 ev): m / z (%) = 321 (M + , 18), 257 (10), 147 (100), 110 (30), 68 (30).

[0123] The results of ESI-MS analysis are as follows:

[0124] HRMS (ESI) calcd for [M+Na] + (C 17H 23 NOS2Na): 344.1113; found: 344.1112.

[0125] Example 6

[0126] To prepare 4-((4-bromobenzyl)disulfanyl)methyl)-3,5-dimethylisoxazole, the reaction route is as follows:

[0127]

[0128] Step 1: Add Cs2CO3 (97.8 mg, 0.3 mmol, 1.5 equiv), 4-bromobenzyl chloride (55.8 mg, 0.2 mmol, 1.0 equiv) and an oven-dried magnetic stir bar to a 25 mL reaction tube. Under N2, add 1-(tert-butyldisulfanyl)pentan-3-one (78.6 mg, 0.3 mmol, 1.5 equiv) and MeOH (2.0 mL). Heat the reaction mixture at 30 °C for 10 h. Then, cool the reaction mixture to room temperature. After removing the solvent under reduced pressure, the pure product was obtained by silica gel column chromatography (eluent: petroleum ether), giving the pure product as a colorless oil (55.5 mg, 80%).

[0129] The results of 1H NMR analysis are as follows:

[0130] 1 H NMR (600 MHz, Chloroform-d) δ 7.40 (d, J = 8.2 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 2.91 (s, 4H), 2.74 (s, 2H), 2.14 (s, 3H), 1.42 (s, 6H).

[0131] The results of 13C NMR analysis are as follows:

[0132] 13 C NMR (151 MHz, Chloroform-d) δ 206.30, 138.81, 131.56, 130.32, 120.24, 53.35, 49.28, 41.55, 34.98, 32.06, 27.25.

[0133] The results of GC-MS analysis are as follows:

[0134] GC-MS (EI, 70 ev): m / z (%) = 348 (M + , 2), 169 (10), 99 (100).

[0135] The results of ESI-MS analysis are as follows:

[0136] HRMS(ESI) calcd for [M+Na] + (C 14 H 19 OS2BrNa): 368.9953; found: 368.9948.

[0137]

[0138] Step 2: Add Cs2CO3 (97.8 mg, 0.3 mmol, 1.5 equiv) and an oven-dried magnetic stir bar to a 25 mL reaction tube. Under N2, add 1-bromo-4-(chloromethyl)benzene (41.0 mg, 0.2 mmol, 1.0 equiv), 4-(((3,5-dimethylisoxazol-4-yl)methyl)disulfanyl)-4-methylpentan-2-one (81.9 mg, 0.3 mmol, 1.5 equiv) and MeOH (2.0 mL). Heat the reaction mixture at 30 °C for 10 h. Then, cool the reaction mixture to room temperature. After removing the solvent under reduced pressure, the pure product was obtained by silica gel column chromatography (eluent: petroleum ether), giving the pure product as a colorless oil (56.5 mg, 82%).

[0139] The results of 1H NMR analysis are as follows:

[0140] 1 1H NMR (600 MHz, Chloroform-d) δ 7.44 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 3.67 (s, 2H), 3.35 (s, 2H), 2.30 (s, 3H), 2.21 (s, 3H).

[0141] The results of 13C NMR analysis are as follows:

[0142] 13 13C NMR (151 MHz, Chloroform-d) δ 166.93, 159.28, 136.22, 131.72, 130.91, 121.57, 110.05, 42.81, 30.87, 11.16, 10.09.

[0143] The results of GC-MS analysis are as follows:

[0144] GC-MS (EI, 70 ev): m / z (%) = 345 (M + , 5), 110 (100), 68 (50).

[0145] The results of ESI-MS analysis are as follows:

[0146] HRMS(ESI) calcd for [M+Na]+ (C 13 H 14 BrNOS2Na): 365.9592; found: 365.9596.

[0147] Example 7

[0148] To prepare 4-(((4-(2-(2,6-difluorophenyl)-4,5-dihydrooxazol-4-yl)benzyl)disulfanyl)methyl)-3,5-dimethylisoxazole, the reaction route is as follows:

[0149]

[0150] Add Cs2CO3 (97.8 mg, 0.3 mmol, 1.5 equiv) and an oven-dried stir bar to a 25 mL reaction tube. Under N2, add 4-(chloromethyl)-3,5-dimethylisoxazole (29.1 mg, 0.2 mmol, 1.0 equiv), 4,4'-disulfanediyldi(4-methylpentan-2-one) (78.6 mg, 0.3 mmol, 1.5 equiv) and methanol (2.0 mL). Heat the reaction mixture at 30 °C for 10 h. Then, cool the reaction mixture to room temperature. After removing the solvent under reduced pressure, the pure product was obtained by silica gel column chromatography (eluent: petroleum ether), and a colorless oily pure product (46.4 mg, 85%) was obtained.

[0151] The results of 1H NMR analysis are as follows:

[0152] 1 H NMR (600 MHz, Chloroform-d) δ 3.61 (s, 2H), 2.64 (s, 2H), 2.33 (s, 3H), 2.22 (s, 3H), 2.09 (s, 3H), 1.37 (s, 6H).

[0153] The results of 13C NMR analysis are as follows:

[0154] 13 C NMR (151 MHz, Chloroform-d) δ 205.95, 166.79, 159.23, 110.29, 53.36, 49.22, 32.66, 31.93, 27.20, 11.24, 10.12.

[0155] The results of electrospray mass spectrometry analysis are as follows

[0156] HRMS (ESI) calcd for [M+Na] + (C 12 H 19NO2S2Na: 296.0749; found: 296.0755.

[0157]

[0158] Cs2CO3 (97.8 mg, 0.3 mmol, 1.5 equiv), 4-(4-(chloromethyl)phenyl)-2-(2,6-difluorophenyl)-4,5-dihydrooxazole (61.4 mg, 0.2 mmol, 1.0 equiv), and an oven-dried stir bar were charged into a 25 mL tube. Under N2, 4-(((3,5-dimethylisoxazol-4-yl)methyl)disulfanyl)-4-methylpentan-2-one (81.9 mg, 0.3 mmol, 1.5 equiv) and MeOH (2.0 mL) were added. The reaction mixture was heated at 30 °C for 10 h. Then, the reaction mixture was cooled to room temperature. After removing the solvent under reduced pressure, the pure product was obtained by silica gel column chromatography (eluent: petroleum ether), giving the pure product as a colorless oil (52.6 mg, 59%).

[0159] The results of 1H NMR analysis are as follows:

[0160] 1 H NMR (600 MHz, Chloroform-d) δ 7.44 - 7.39 (m, 1H), 7.29 (q, J = 7.9 Hz, 4H), 6.98 (t, J = 8.3 Hz, 2H), 5.47 - 5.42 (m, 1H), 4.80 (t, J = 9.4 Hz, 1H), 4.25 (t, J = 8.2 Hz, 1H), 3.75 (s, 2H), 3.32 (s, 2H), 2.28 (s, 3H), 2.20 (s, 3H).

[0161] The results of 13C NMR analysis are as follows:

[0162] 13 C NMR (151 MHz, Chloroform-d) δ 166.93, 161.21 (dd, J = 256.70, 6.04 Hz), 159.34, 157.56, 141.32, 136.73, 132.38 (t, J = 10.57 Hz), 129.68, 126.94, 111.90 (dd, J = 21.14, 4.53 Hz), 110.11, 74.70, 69.97, 43.33, 30.81, 11.16, 10.09.

[0163] The results of 19F NMR analysis are as follows:

[0164] 1919F NMR (564 MHz, Chloroform-d) δ -108.95.

[0165] The results of electrospray mass spectrometry analysis are as follows

[0166] HRMS (ESI) calcd for [M+Na] + (C 22 H 20 F2N2O2S2Na): 469.0827; found: 469.0841.

[0167] Example 8

[0168] tert-Butyl 4-(cyclohexyldisulfanyl)piperidine-1-carboxylate was prepared, and the reaction route was as follows:

[0169]

[0170] Step 1: Add Cs2CO3 (244.5 mg, 0.75 mmol, 1.5 equiv) and an oven-dried magnetic stir bar to a 25 mL tube. Under N2, add 4,4'-disulfanediyldi(4-methylpentan-2-one) (197.3 mg, 0.75 mmol, 1.5 equiv), iodocyclohexane (105.0 mg, 0.5 mmol, 1.0 equiv) and MeOH (5.0 mL). Heat the reaction mixture at 40 °C for 10 h. Then, cool the reaction mixture to room temperature. After removing the solvent under reduced pressure, the pure product was obtained by silica gel column chromatography (eluent: petroleum ether) to give 4-(cyclohexyldisulfanyl)-4-methylpentan-2-one as a colorless oil (104.5 mg, 85%).

[0171] The results of 1H NMR analysis are as follows:

[0172] 1 1H NMR (600 MHz, Chloroform-d) δ 2.73 (s, 2H), 2.68 (d, J = 3.6 Hz, 1H), 2.15 (s, 3H), 2.08 - 2.01 (m, 2H), 1.76 (d, J = 3.8 Hz, 2H), 1.59 (d, J = 10.3 Hz, 1H), 1.39 (s, 6H), 1.30 - 1.19 (m, 5H).

[0173] The results of 13C NMR analysis are as follows:

[0174] 13 13C NMR (151 MHz, Chloroform-d) δ 206.63, 53.50, 50.45, 48.64, 32.88, 32.09, 27.19, 25.89, 25.66.

[0175] The analysis results of gas chromatography-mass spectrometry are as follows:

[0176] GC-MS (EI, 70ev): m / z (%) = 246 (M + , 6), 148 (15), 99 (100), 83 (50), 55 (46).

[0177] The analysis results of electrospray mass spectrometry are as follows:

[0178] HRMS (ESI) calcd for [M+Na] + (C 12 H 22 OS2Na): 269.1004; found: 269.1009.

[0179]

[0180] Step 2: Add Cs2CO3 (97.8 mg, 0.3 mmol, 1.5 eq), tert-butyl 4-iodopiperidine-1-carboxylate (62.2 mg, 0.2 mmol, 1.0 eq) and an oven-dried magnetic stir bar to a 25 mL tube. Under N2, add 4-(cyclohexyldithio)-4-methylpentan-2-one (73.8 mg, 0.3 mmol, 1.5 eq) and MeOH (2.0 mL). Heat the reaction mixture at 30 °C for 10 h. Then, cool the reaction mixture to room temperature. After removing the solvent under reduced pressure, the pure product was obtained by silica gel column chromatography (eluent: petroleum ether), and a colorless oil pure product (43.1 mg, 65%) was obtained.

[0181] The analysis results of 1H NMR are as follows:

[0182] 1 1H NMR (600 MHz, Chloroform-d) δ 3.99 (s, 2H), 2.95 - 2.76 (m, 3H), 2.69 - 2.65 (m, 1H), 2.03 - 1.96 (m, 4H), 1.83 - 1.74 (m, 2H), 1.62 (s, 1H), 1.53 - 1.49 (m, 2H), 1.44 (s, 9H), 1.35 - 1.18 (m, 5H).

[0183] The analysis results of 13C NMR are as follows:

[0184] 1313C NMR (151 MHz, Chloroform-d) δ 154.64, 79.55, 49.99, 47.42, 43.21, 32.83, 32.61, 31.66, 28.40, 25.99, 25.61.

[0185] The results of electrospray mass spectrometry analysis are as follows:

[0186] HRMS (ESI) calcd for [M+Na] + (C 16 H 29 NO2S2Na): 354.1532; found: 354.1538.

[0187] Example 9

[0188] To prepare tert-butyl (R)-4-((4-phenylbutan-2-yl)disulfanyl)piperidine-1-carboxylate, the reaction route is as follows:

[0189]

[0190] Step 1: Add Cs2CO3 (244.5 mg, 0.75 mmol, 1.5 equiv) and an oven-dried magnetic stir bar to a 25 mL reaction tube. Under N2, add 4,4'-disulfanediyldi(4-methylpentan-2-one) (197.3 mg, 0.75 mmol, 1.5 equiv), (3-iodobutyl)benzene (130.0 mg, 0.5 mmol, 1.0 equiv) and MeOH (5.0 mL). Heat the reaction mixture at 30 °C for 10 h. Then, cool the reaction mixture to room temperature. After removing the solvent under reduced pressure, the pure product was obtained by silica gel column chromatography (eluent: petroleum ether) to give 4-methyl-4-((4-phenylbutan-2-yl)disulfanyl)pentan-2-one as a colorless oil (118.4 mg, 80%).

[0191]

[0192] Step 2: Add Cs2CO3 (97.8 mg, 0.3 mmol, 1.5 equiv), tert-butyl 4-iodopiperidine-1-carboxylate (62.2 mg, 0.2 mmol, 1.0 equiv) and an oven-dried magnetic stir bar to a 25 mL reaction tube. Under N2, add 4-methyl-4-((4-phenylbutan-2-yl)disulfanyl)pentan-2-one (88.8 mg, 0.3 mmol, 1.5 equiv) and MeOH (2.0 mL). Heat the reaction mixture at 30 °C for 10 h. Then, cool the reaction mixture to room temperature. After removing the solvent under reduced pressure, the pure product was obtained by silica gel column chromatography (eluent: petroleum ether) to give the pure product as a colorless oil (57.2 mg, 75%).

[0193] The results of 1H NMR analysis are as follows:

[0194] 1 H NMR(600MHz,Chloroform-d)δ7.29-7.26(m,2H),7.22-7.11(m,3H),4.45-4.42(m,1H),3.98(s,2H),3.58(d,J=12.6Hz,1H),3.28-3.26(m,1H),2.78-2.71(m,4H),2.00(d,J=19.2Hz,3H),1.94(d,J=8.7Hz,2H),1.45(s,9H),1.36-1.31(m,3H).

[0195] The results of 13C NMR analysis are as follows:

[0196] 13 C NMR(151MHz,Chloroform-d)δ154.61,141.42,128.36,125.92,47.34,45.76,43.20,37.54,33.05,31.69,28.41,28.38,27.53,20.61.

[0197] The results of electrospray mass spectrometry analysis are as follows:

[0198] HRMS(ESI)calcd for[M+Na] + (C 20 H 31 NO2S2Na):404.1688;found:404.1688.

[0199] Example 10

[0200] tert-Butyl 4-((2-(thiophen-2-yl)ethyl)disulfanyl)piperidine-1-carboxylate was prepared, and the reaction route was as follows:

[0201]

[0202] Step 1: Add Cs2CO3 (244.5 mg, 0.75 mmol, 1.5 equiv) and an oven-dried stir bar to a 25 mL reaction tube. Under N2, add 4,4'-disulfanediyldi(4-methylpentan-2-one) (197.3 mg, 0.75 mmol, 1.5 equiv), ethyl 2-(thiophen-2-yl)methanesulfonate (103.0 mg, 0.5 mmol, 1.0 equiv) and MeOH (5.0 mL). Heat the reaction mixture at 30 °C for 10 h. Then, cool the reaction mixture to room temperature. After removing the solvent under reduced pressure, the pure product was obtained by silica gel column chromatography (eluent: petroleum ether), giving 4-methyl-4-((2-(thiophen-2-yl)ethyl)disulfanyl)pentan-2-one as a colorless oil (116.5 mg, 85%).

[0203]

[0204] Step 2: Add Cs2CO3 (97.8 mg, 0.3 mmol, 1.5 equiv), tert-butyl 4-iodopiperidine-1-carboxylate (62.2 mg, 0.2 mmol, 1.0 equiv) and an oven-dried stir bar to a 25 mL reaction tube. Under N2, add 4-methyl-4-((2-(thiophen-2-yl)ethyl)disulfanyl)pentan-2-one (82.2 mg, 0.3 mmol, 1.5 equiv) and MeOH (2.0 mL). Heat the reaction mixture at 30 °C for 10 h. Then, cool the reaction mixture to room temperature. After removing the solvent under reduced pressure, the pure product was obtained by silica gel column chromatography (eluent: petroleum ether), giving the pure product as a colorless oil (49.5 mg, 69%).

[0205] The results of 1H NMR analysis are as follows:

[0206] 1 H NMR (600 MHz, Chloroform-d) δ 7.14 (d, J = 4.0 Hz, 1H), 6.93 (s, 1H), 6.84 (s, 1H), 4.02 (s, 2H), 3.19 (t, J = 7.4 Hz, 2H), 2.95 (t, J = 7.5 Hz, 2H), 2.84 (d, J = 9.3 Hz, 3H), 1.96 (d, J = 12.2 Hz, 2H), 1.53 (d, J = 10.9 Hz, 2H), 1.45 (s, 9H).

[0207] The results of 13C NMR analysis are as follows

[0208] 1313C NMR (151 MHz, Chloroform-d) δ 154.60, 142.35, 126.82, 125.04, 123.68, 79.62, 47.10, 43.33, 43.19, 41.23, 31.69, 29.75, 28.41.

[0209] The results of electrospray mass spectrometry analysis are as follows:

[0210] HRMS (ESI) calcd for [M+Na] + (C 16 H 25 NO2S3Na): 382.0940; found: 382.0949.

[0211] Example 11

[0212] To prepare 3,5-dimethyl-4-(((methyl-d3)disulfanyl)methyl)isoxazole, the reaction route is as follows:

[0213]

[0214] Step 1: Add Cs2CO3 (97.8 mg, 0.3 mmol, 1.5 eq) and an oven-dried stir bar to a 25 mL reaction tube. Under N2, add 4-(chloromethyl)-3,5-dimethylisoxazole (29.1 mg, 0.2 mmol, 1.0 eq), 4,4'-disulfanediyldi(4-methylpentan-2-one) (78.6 mg, 0.3 mmol, 1.5 eq) and methanol (2.0 mL). Heat the reactants at 30 °C for 10 h. Then, cool the reactants to room temperature. After removing the solvent under reduced pressure, the pure product was obtained by silica gel column chromatography (eluent: petroleum ether), and a colorless oily pure product (46.4 mg, 85%) was obtained.

[0215] The results of 1H NMR analysis are as follows:

[0216] 1 1H NMR (600 MHz, Chloroform-d) δ 3.61 (s, 2H), 2.64 (s, 2H), 2.33 (s, 3H), 2.22 (s, 3H), 2.09 (s, 3H), 1.37 (s, 6H)

[0217] The results of 13C NMR analysis are as follows:

[0218] 1313C NMR (151 MHz, Chloroform-d) δ 205.95, 166.79, 159.23, 110.29, 53.36, 49.22, 32.66, 31.93, 27.20, 11.24, 10.12.

[0219] The analysis results of gas chromatography - mass spectrometry are as follows:

[0220] GC-MS (EI, 70 ev): m / z (%) = 273 (M + , 2), 175 (50), 110 (100), 68 (85).

[0221] The analysis results of electrospray mass spectrometry are as follows:

[0222] HRMS (ESI) calcd for [M+Na] + (C 12 H 19 NO2S2Na): 296.0749; found: 296.0755.

[0223]

[0224] Step 2: Add Cs2CO3 (97.8 mg, 0.3 mmol, 1.5 eq) and an oven-dried magnetic stir bar to a 25 mL reaction tube. Under N2, add iodomethane-d3 (29.0 mg, 0.2 mmol, 1.0 eq), 4-(((3,5-dimethylisoxazol-4-yl)methyl)disulfanyl)-4-methylpentan-2-one (81.9 mg, 0.3 mmol, 1.5 eq) and MeOH (20 mL). Heat the reactants at 30 °C for 10 h. Then, cool the reactants to room temperature. After removing the solvent under reduced pressure, a pure product is obtained by silica gel column chromatography (eluent: petroleum ether), and a colorless oily pure product (32.0 mg, 83%) is obtained.

[0225] The analysis results of 1H nuclear magnetic resonance are as follows:

[0226] 1 1H NMR (600 MHz, Chloroform-d) δ 3.64 (s, 2H), 2.39 (s, 3H), 2.27 (s, 3H).

[0227] The analysis results of 13C nuclear magnetic resonance are as follows:

[0228] 13 13C NMR (151 MHz, Chloroform-d) δ 166.91, 159.33, 110.22, 30.20, 11.15, 10.06.

[0229] The analysis results of the gas chromatography-mass spectrometry are as follows:

[0230] GC-MS(EI, 70ev): m / z(%) = 192(M + , 2), 110(100), 68(75).

[0231] The analysis results of the electrospray mass spectrometry are as follows:

[0232] HRMS(ESI) calcd for [M+H] + (C7H9D3NOS2): 193.0543; found: 193.0547.

[0233] The above are only the preferred embodiments of the present invention, which are illustrative rather than restrictive to the present invention. Those skilled in the art understand that many changes, modifications, and even equivalents can be made within the spirit and scope defined by the claims of the present invention, but all will fall within the protection scope of the present invention.

Claims

1. Use of a bilateral disulfide reagent in the synthesis of an asymmetric disulfide, characterized in that, Using a bilateral disulfide reagent and R 3 -X, R 4 -X, where X = Cl, Br, I, and performing nucleophilic substitution in two steps to synthesize an asymmetric disulfide. The synthetic route of the asymmetric disulfide is as follows: Wherein: R 1 is methyl; R 2 is methyl; R 3 independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, cyclopentyl, cyclohexyl, benzyl, R 4 independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, cyclopentyl, cyclohexyl, benzyl, In the synthesis reaction, the base is cesium carbonate.

2. Use of a bilateral disulfide reagent in the synthesis of an asymmetric disulfide as described in claim 1, characterized in that, In the synthesis reaction, the solvent is one or any combination of dimethyl sulfoxide, methanol, ethanol, and isopropanol.

3. The use of a bilateral disulfide reagent as described in claim 1 in the synthesis of an asymmetric disulfide, characterized in that, In the synthesis reaction, the reaction temperature is 0 to 30 °C.

4. The use of a bilateral disulfide reagent as described in claim 1 in the synthesis of an asymmetric disulfide, characterized in that, The synthesis route of the bilateral disulfide reagent is as follows:

5. The use of a bilateral disulfide reagent as described in claim 4 in the synthesis of an asymmetric disulfide, characterized in that, In the reaction for synthesizing the bilateral disulfide reagent, the additive is iodine; in the reaction for synthesizing the bilateral disulfide reagent, the solvent is ethanol.

6. The use of a bilateral disulfide reagent as described in claim 5 in the synthesis of an asymmetric disulfide, characterized in that, In the reaction for synthesizing the bilateral disulfide reagent, the dosage of iodine is 1 - 20 equiv.

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