Preparation method of asymmetric disulfide compound

Abstract

The invention relates to the technical field of organic sulfur-containing compounds, in particular to a preparation method of an asymmetric disulfide compound. A conventional synthesis method of asymmetric disulfide depends on oxidative coupling or substitution reaction of mercaptan, the substrate compatibility is poor, excessive oxidizing agents are needed, the cost is high, and the method is not environmentally friendly. Aiming at the technical problem, the invention provides the preparation method of the asymmetric disulfide compound, and the asymmetric disulfide compound is a compound obtained by carrying out nucleophilic thioamidation reaction on 2-substituted-1, 2-benzisothiazoline-3-ketone and symmetric disulfide under the action of hydroiodic acid. According to the method, symmetric disulfide with stable properties is used for replacing foul and strong-corrosivity mercaptan in a traditional method to serve as a raw material, potential safety hazards in mercaptan operation are eliminated from the source, meanwhile, use of excessive oxidizing agents is avoided, the risk of environmental pollution is greatly reduced, and the method conforms to the green chemistry principle and has good application prospects.

Description

Technical Field

[0001] This invention relates to the field of organic sulfur-containing compounds, and specifically to a method for preparing an asymmetric disulfide compound. Background Technology

[0002] Disulfide compounds (RSS-R') are a class of sulfur-containing organic compounds with broad biological activity and synthetic value. Their structure consists of two sulfur atoms connected by a single bond, with different or identical hydrocarbon groups (R and R') attached to either end. Based on whether the hydrocarbon groups are identical, disulfides can be classified into symmetrical disulfides (R=R') and asymmetrical disulfides (R≠R'). Among these, asymmetrical disulfides, due to their structural diversity, play an irreplaceable role in medicinal chemistry, materials science, and organic synthesis. In the biopharmaceutical field, asymmetric disulfides are widely found in natural products and drug molecules. For example, some antibiotics (such as thiomycin) enhance their antibacterial activity through asymmetric disulfide structures; disulfide fragments in antiviral drugs (such as zalcitabine) can improve drug stability; in addition, asymmetric disulfides also serve as key structural units for protease inhibitors, used to treat diseases such as AIDS and hepatitis. US Patent (US005734081A) reports several asymmetric disulfides with therapeutic effects against HIV, such as the asymmetric disulfides represented by the following chemical structural formulas: , In the field of materials science, asymmetric disulfides can serve as precursors for functional materials. Through oxidation or reduction reactions, they can be used to construct sulfur-containing polymers such as sulfides, sulfoxides, and sulfones, which are then applied in conductive materials, optoelectronic materials, and polymer catalysts. For example, asymmetric disulfides containing aryl-alkyl structures can significantly improve the thermal stability and mechanical properties of polymers.

[0003] In the field of organic synthesis, asymmetric disulfides are key intermediates for constructing complex sulfur-containing molecules. They can introduce active fragments such as thiols and thiophenols by breaking the SS bond, and can be used to synthesize bioactive molecules such as thioamino acids and thioglycosides, or as ligands in metal-catalyzed reactions.

[0004] Despite the significant applications of asymmetric disulfides, their efficient and green synthesis remains challenging. Traditional methods primarily rely on the oxidative coupling or substitution reactions of thiols (RSH) and suffer from the following problems: (1) Thiols have a strong odor and are corrosive. They need to be operated in a fume hood and equipped with waste gas treatment equipment, which increases production costs and safety hazards.

[0005] (2) Thiols readily undergo self-coupling reactions, generating symmetrical disulfides (RSSR) impurities, making product separation and purification difficult; in addition, the reaction requires the use of excess oxidant (such as... , This can easily lead to excessive oxidation and damage sensitive functional groups.

[0006] (3) Traditional methods are difficult to be compatible with gaseous thiols (such as methanethiol, C It has poor applicability to thiol substrates containing sensitive groups (such as alkenes and alkynes). Summary of the Invention

[0007] The existing technologies have the following problems: conventional methods for synthesizing asymmetric disulfides rely on the oxidative coupling or substitution reaction of thiols, resulting in poor substrate compatibility, the need for excessive oxidants, high costs, and environmental unfriendliness. To address these problems, this invention provides a method for preparing an asymmetric disulfide compound, which is obtained by a nucleophilic thioamidation reaction of 2-substituted-1,2-benzisothiazolin-3-one with a symmetric disulfide under the catalysis of hydroiodic acid. The general chemical formula of the 2-substituted-1,2-benzisothiazolin-3-one is as follows: , The R group in the above general formula includes methyl, ethyl, isopropyl, n-butyl or benzyl and 4-sulfonamide phenyl; The general structural formula of the symmetrical disulfide is as follows: , In the above general formula, R 1 The groups include methyl, n-butyl, benzyl, or 2-methyl ester phenyl.

[0008] Preferably, the reaction solvent used in the nucleophilic thioamidation reaction includes one or more of dichloromethane, tetrahydrofuran, acetone, methanol, toluene, ethylene glycol, N,N-dimethylformamide, ethyl acetate, and acetonitrile.

[0009] Preferably, the reaction solvent is methanol.

[0010] Preferably, the reaction temperature of the nucleophilic thioamidation reaction is 0-60°C.

[0011] Preferably, the reaction temperature of the nucleophilic thioamidation reaction is 30°C.

[0012] Preferably, the nucleophilic thioamidation reaction takes 12 hours.

[0013] Preferably, the molar ratio between 2-substituted-1,2-benzisothiazolin-3-one, symmetrical disulfide, and hydroiodic acid is 0.2:0.1-0.3:0.2-0.8.

[0014] Preferably, the molar ratio between 2-substituted-1,2-benzisothiazolin-3-one, symmetrical disulfide, and hydroiodic acid is 0.2:0.3:0.6.

[0015] Preferably, NH4I is also added during the nucleophilic thioamidation reaction.

[0016] Preferably, the molar ratio of NH4I to hydroiodic acid is 1:1.

[0017] The present invention has the following beneficial effects: (1) This invention uses a stable symmetrical disulfide ( -SS- This method replaces the malodorous and highly corrosive thiols (RSH) used in traditional methods as a raw material, eliminating safety hazards in thiols handling (such as waste gas treatment requirements) at the source, while also avoiding excessive oxidants (such as... , The use of ) significantly reduces the risk of environmental pollution and is in line with the principles of green chemistry; (2) This invention utilizes symmetrical disulfide (C -SSC ), successfully constructed a methylthio-containing fragment (C -S-) asymmetric disulfides, such structures are of great value in drug design (e.g., targeting sulfur protein inhibitors) and material functionalization (e.g., self-healing polymers); (3) The R group in the 2-substituted-1,2-benzisothiazolin-3-one used in this invention covers methyl, ethyl, isopropyl, n-butyl, benzyl and 4-sulfonamide phenyl (which has biological activity). The groups include methyl, n-butyl, benzyl and 2-methyl ester phenyl (functional material precursor), which significantly expands the structural diversity of asymmetric disulfides and meets the application needs of different fields; (4) The reaction temperature of the present invention is optimized to 30°C, and methanol (a green solvent) is used as the solvent. No strong oxidant or high temperature conditions are required, which effectively avoids the generation of symmetrical disulfide impurities caused by the self-coupling of thiols in traditional methods, and the product selectivity is significantly improved. (5) This invention uses hydroiodic acid (HI) as a catalyst and ammonium iodide (N) as a catalyst. I) Additives (HI and N) The use of I (in a 1:1 molar ratio) efficiently promoted the nucleophilic thioamidation reaction, significantly improving the yield of the target product; (6) The method of the present invention does not use expensive metal catalysts (such as palladium and copper) and complex ligands, and the raw material cost is low; (7) The asymmetric disulfide synthesized by the method of the present invention can be used as a key intermediate for antibiotics, antiviral drugs and protease inhibitors. In the organic synthesis process, it can also be used as a thioreagent to introduce structural units such as thioethers and sulfoxides to improve the synthesis efficiency. Detailed Implementation

[0018] The present invention will be described in detail below with reference to embodiments. However, it should be understood that the following embodiments are merely illustrative examples of implementation of the present invention and are not intended to limit the scope of the present invention.

[0019] The reaction raw materials and reagents used in this invention are all commercially available or prepared according to methods reported in the literature.

[0020] Example 1

[0021] A method for synthesizing an asymmetric disulfide is as follows: In a 25 mL sealed tube, 0.2 mmol of 2-butyl-1,2-benzisothiazolin-3-one (CAS No.: 4299-07-4), 0.2 mmol of dimethyl disulfide, 2 mL of methanol, 0.6 mmol of HI, and 0.6 mmol of NH4I were added sequentially. After stirring at room temperature (25 °C) for 12 hours, the reaction solution was concentrated and separated by column chromatography to obtain the asymmetric disulfide (denoted as C1) with a yield of 85%. The reaction process is shown below: , The NMR characterization data of the target product C1 are as follows: 1 H NMR (300 MHz, CDCl3) δ 7.95 (dd, J = 8.0, 1.2 Hz, 1H), 7.51 - 7.42(m, 2H), 7.27 - 7.21 (m, 1H), 6.17 (brs, 1H), 3.47 - 3.41 (m, 2H), 2.41 (s,3H), 1.65 - 1.55 (m, 2H), 1.48 - 1.36 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H).

[0022] Example 2 is the same as Example 1, except that in Example 2, dichloromethane is added in place of methanol in Example 1, with the same volume of dichloromethane added. The yield of the target product C1 is 47%.

[0023] Example 3 is the same as Example 1, except that in Example 3, ethyl acetate is added in place of methanol in Example 1 at the same volume. The yield of the target product C1 is 54%.

[0024] Example 4 is the same as Example 1, except that in Example 4, an equal volume of N,N-dimethylformyl is added instead of methanol in Example 1. The yield of the target product C1 is 67%.

[0025] Example 5 is the same as Example 1, except that in Example 5, an equal volume of tetrahydrofuran is added instead of methanol in Example 1. The yield of the target product C1 is 60%.

[0026] Example 6 is the same as Example 1, except that in Example 6, acetone is added in the same volume instead of methanol as in Example 1. The yield of the target product C1 is 56%.

[0027] Example 7 is the same as Example 1, except that in Example 7, toluene is added in the same volume instead of methanol as in Example 1. The yield of the target product C1 is 71%.

[0028] Example 8 is the same as Example 1, except that the reaction time in Example 8 is 6 hours. The yield of the target product C1 is 62%.

[0029] Example 9 is the same as Example 1, except that the reaction time in Example 9 is 24 hours. The yield of the target product C1 is 84%.

[0030] Example 10 is the same as Example 1, except that the amount of dimethyl disulfide added in Example 10 is 0.1 mol. The yield of the target product C1 is 64%.

[0031] Example 11 is the same as Example 1, except that the amount of dimethyl disulfide added in Example 11 is 0.3 mol. The yield of the target product C1 is 64%.

[0032] Example 12 is the same as Example 1, except that the reaction temperature in Example 12 is 0°C. The yield of the target product C1 is 44%.

[0033] Example 13 is the same as Example 1, except that the reaction temperature in Example 13 is 60°C. The yield of the target product C1 is 79%.

[0034] Example 14 is the same as Example 1, except that the amount of methanol added in Example 14 is 1 mL. The yield of the target product C1 is 63%.

[0035] Example 15 is the same as Example 1, except that the amount of methanol added in Example 15 is 3 mL. The yield of the target product C1 is 81%.

[0036] Example 16 is the same as Example 1, except that the amount of hydroiodic acid added in Example 16 is 0.2 mol. The yield of the target product C1 is 40%.

[0037] Example 17 is the same as Example 1, except that the amount of hydroiodic acid added in Example 17 is 0.4 mol. The yield of the target product C1 is 57%.

[0038] Example 18 is the same as Example 1, except that the amount of hydroiodic acid added in Example 18 is 0.8 mol. The yield of the target product C1 is 85%.

[0039] Example 19 is the same as Example 1, except that the amount of NH4I added in Example 19 is 0 mmol. The yield of the target product C1 is 37%.

[0040] Example 20 is the same as Example 1, except that the amount of NH4I added in Example 20 is 0.2 mmol. The yield of the target product C1 is 55%.

[0041] Example 21 is the same as Example 1, except that the amount of NH4I added in Example 21 is 0.4 mmol. The yield of the target product C1 is 68%.

[0042] Example 22 is the same as Example 1, except that the amount of NH4I added in Example 22 is 0.8 mmol. The yield of the target product C1 is 85%.

[0043] Example 23

[0044] In a 25 mL sealed tube, 0.2 mmol of 2-substituted-1,2-benzisothiazolin-3-one, 0.2 mmol of symmetrical disulfide, 2 mL of methanol, 0.6 mmol of HI, and 0.6 mmol of NH4I were added sequentially. After stirring at room temperature (25 °C) for 12 hours, the reaction solution was concentrated and separated by column chromatography to obtain a series of asymmetric disulfides (denoted as C2, C3, C4, C5, C6, C7, and C8, respectively). The reaction process is shown below: , The chemical structural formulas of the obtained C2, C3, C4, C5, C6, C7, and C8 are shown below: The chemical structure of C2 (90% yield) is as follows: , The chemical structure of C3 (yield 88%) is as follows: , The chemical structure of C4 (79% yield) is as follows: , The chemical structure of C5 (76% yield) is as follows: , The chemical structure of C6 (77% yield) is as follows: , The chemical structure of C7 (73% yield) is as follows: , The chemical structure of C8 (60% yield) is as follows: , In the above structural formula, Me represents methyl and Bn represents n-butyl.

[0045] Example 24

[0046] In a 25 mL sealed tube, 0.2 mmol of 2-(4-sulfonamide phenyl)-1,2-benzisothiazolin-3-one (purchased from Chongqing Futeng Pharmaceutical Chemical Co., Ltd.), 0.2 mmol of dimethyl 2,2'-dithiodibenzoate (CAS: 5459-63-2), 2 mL of methanol, 0.6 mmol of HI, and 0.6 mmol of NH4I were added sequentially. After stirring at room temperature (25 °C) for 12 hours, the reaction solution was concentrated and separated by column chromatography to obtain asymmetric disulfide C9 in 60% yield. The chemical structure of C9 is as follows: ; The structural formula of the 2-(4-sulfonamide phenyl)-1,2-benzisothiazolin-3-one is as follows: .

[0047] Based on the above-described preferred embodiments of the present invention, and through the foregoing description, those skilled in the art can make various changes and modifications without departing from the inventive concept. The technical scope of this invention is not limited to the contents of the specification, but must be determined according to the scope of the claims.

Claims

1. A method for preparing an asymmetric disulfide compound, characterized in that, The asymmetric disulfide compound is obtained by nucleophilic thioamidation of a 2-substituted-1,2-benzisothiazolin-3-one with a symmetric disulfide under hydroiodic acid catalysis. The general structural formula of the 2-substituted-1,2-benzisothiazolin-3-one is as follows: ， The R group in the above general structural formula includes methyl, ethyl, isopropyl, n-butyl, benzyl, or 4-sulfonamide phenyl; The general structural formula of the symmetrical disulfide is as follows: ， In the above general formula, R 1 The groups include methyl, n-butyl, benzyl, or 2-methyl ester phenyl.

2. The method for preparing an asymmetric disulfide compound according to claim 1, characterized in that, The reaction solvent used in the nucleophilic thioamidation reaction includes one or more of the following: dichloromethane, tetrahydrofuran, acetone, methanol, toluene, ethylene glycol, N,N-dimethylformamide, ethyl acetate, and acetonitrile.

3. The method for preparing an asymmetric disulfide compound according to claim 2, characterized in that, The reaction solvent is methanol.

4. The method for preparing an asymmetric disulfide compound according to claim 1, characterized in that, The reaction temperature for the nucleophilic thioamidation reaction is 0-60℃.

5. The method for preparing an asymmetric disulfide compound according to claim 4, characterized in that, The reaction temperature for the nucleophilic thioamidation reaction is 30°C.

6. The method for preparing an asymmetric disulfide compound according to claim 1, characterized in that, The reaction time for the nucleophilic thioamidation reaction is 12 hours.

7. The method for preparing an asymmetric disulfide compound according to claim 1, characterized in that, The molar ratio between 2-substituted-1,2-benzisothiazolin-3-one, symmetrical disulfide, and hydroiodic acid is 0.2:0.1-0.3:0.2-0.

8.

8. The method for preparing an asymmetric disulfide compound according to claim 7, characterized in that, The molar ratio between 2-substituted-1,2-benzisothiazolin-3-one, symmetrical disulfide, and hydroiodic acid is 0.2:0.3:0.

6.

9. A method for preparing an asymmetric disulfide compound according to any one of claims 1-8, characterized in that, NH4I was also added during the nucleophilic thioamidation reaction.

10. The method for preparing an asymmetric disulfide compound according to claim 9, characterized in that, The molar ratio of NH4I to hydroiodic acid is 1:1.

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