Method for synthesizing disulfide compound

Abstract

The invention belongs to the field of fine organic synthesis and catalytic oxidation synthesis, and relates to a method for synthesizing disulfide compounds. According to the invention, various alkyl mercaptan skeleton raw materials developed by using a green catalytic oxidation method are oxidized to prepare corresponding products with a functional group disulfide bond structure. The method provided by the invention is mild in conditions in the tank reactor and the microchannel reactor, low in catalyst dosage, low in waste salt and waste water amount, high in product yield and purity under neutral reaction conditions, and capable of preparing a series of disulfide products with potential biological activity.

Description

Technical Field

[0001] This invention belongs to the field of fine organic synthesis and catalytic oxidation synthesis, and relates to a method for synthesizing disulfide compounds. Background Technology

[0002] Disulfide bonds exist in various bioactive molecules, fine functional chemicals, material monomers, and auxiliaries. For example, proteins form disulfide bonds through the self-coupling reaction of thiol oxidation on amino acid residues, resulting in stable spatial conformations. The diethyl disulfide backbone, an intermediate in the preparation of the broad-spectrum pesticide fungicide ethoxylate, also contains disulfide bonds, constructed through the reaction of ethane chloride and disodium disulfide, which generates a large amount of sulfur-containing wastewater during the reaction. Furthermore, disulfide bonds are dynamic chemical bonds and not entirely stable; they are easily reduced and broken, and can be oxidized again to reform disulfide bonds. Existing technologies offer many methods for constructing disulfide bonds from the corresponding thiol through oxidation, broadly categorized into two types: ① Oxidation processes using equivalent oxidants, where an oxidant equivalent to or exceeding the amount of the raw material is introduced into the reaction. Relatively well-studied oxidants include permanganates, metal oxides, and halogen oxidants; ② Catalytic oxidation processes, where homogeneous or heterogeneous catalysts are combined with the oxidant to achieve disulfide bond construction under mild conditions. Catalysts of this type include iron phthalocyanine and cobalt phthalocyanine. In summary, both strategies ① and ② currently suffer from problems such as complex operation, large reagent consumption, expensive catalysts, lack of economic feasibility, and severe environmental pollution. Therefore, it is necessary to continue developing a clean, efficient, and green oxidation method for synthesizing disulfide compounds. Summary of the Invention

[0003] The technical problem this invention aims to solve is the challenge posed by existing methods for preparing high-value functional fine chemicals, material monomers, and material additives containing disulfide bonds from thiol raw materials. These methods suffer from high catalyst usage, high catalyst prices, high oxidant usage, low economic efficiency, and high waste salt and wastewater content, making them unsuitable for true industrialization. To address these challenges, this invention develops an economically viable, feasible, and green catalytic oxidation process using both batch and microchannel methods. This provides a catalytic oxidation technology that can simply and efficiently catalytically oxidize various thiol derivatives to high-value-added disulfide ether products. Furthermore, this method uses less catalyst, has lower catalyst prices, requires less oxidant, produces high-purity products, facilitates product separation, minimizes environmental pollution, and yields high-value products, demonstrating genuine potential for industrial application.

[0004] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows: This invention discloses a method for synthesizing disulfide compounds, wherein thiol compound I reacts with a catalyst and an oxidant to generate disulfide compound II; in, When the thiol compound I is and At that time, the disulfide compound II formed is ; When the thiol compound I is and At that time, the disulfide compound II formed is ; When the thiol compound I is At that time, the disulfide compound II formed is ; When the thiol compound I is and At that time, the disulfide compound II formed is ; Wherein, the R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 Each is independently selected from H, substituted or unsubstituted C. 1~20 Alkyl, substituted or unsubstituted C 1~20 Alkoxy, substituted or unsubstituted aromatic groups, halogen, nitro, amino, cyano, carboxyl, ester, substituted or unsubstituted silyl; the substitution is selected from those substituted by any number of the same or different substituents; the substituents are selected from halogen, nitro, amino, cyano, carboxyl, ester, C 1~4 Alkyl and C 1~4 Any one or more of the alkoxy groups; n is an integer from 0 to 20.

[0005] In some embodiments, preferably, the R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 Each is independently selected from H, substituted or unsubstituted C. 1~10 Alkyl, substituted or unsubstituted C 1~10 Alkyl groups, or substituted or unsubstituted aromatic groups; the substitution is selected from those substituted by any number of the same or different substituents; the substituents are selected from halogens, C 1~4 Alkyl and C1~4 Any one or more of the alkoxy groups; n is an integer from 0 to 10.

[0006] In some embodiments, and more preferably, the R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 Each is independently selected from H, substituted or unsubstituted C. 1~6 Alkyl, or substituted or unsubstituted phenyl groups; the substitution is selected from those substituted by any number of the same or different substituents; the substituents are selected from halogens, C 1~2 Alkyl and C 1~3 Any one or more of the alkoxy groups; n is an integer from 0 to 6.

[0007] The halogens mentioned above are all selected from F, Cl, Br or I.

[0008] In some embodiments, the catalyst is any one or a combination of several of CuPd / SiO2, NaIO4, KIO4, KIO3, and Na[Fe(EDTA)]; and / or, the oxidant is any one or a combination of several of hydrogen peroxide, di-tert-butyl peroxide, dimethyl sulfoxide, air, and oxygen.

[0009] The CuPd / SiO2 can be commercially available or manufactured using existing technology (…). Nanoscale The catalyst was prepared by means of a mixture of Cu and Pd (19191-19202), wherein the molar ratio of Cu to Pd is preferably 1:1, and the total mass of Pd and Cu preferably accounts for 5% of the total mass of the catalyst.

[0010] In some embodiments, the molar ratio of the catalyst to the thiol compound I is (0.00001~0.1):1; and / or, when the oxidant is not air or oxygen, the molar ratio of the oxidant to the thiol compound I is (0.00001~10.0):1; and / or, when the oxidant is air or oxygen, the atmospheric pressure of the air or oxygen is 1.0~5.0 standard atmospheres; and / or, the reaction temperature is 0°C. o C~60 o C; and / or, the reaction time is 0.5 to 7.0 h.

[0011] In some embodiments, preferably, the reaction molar ratio of the catalyst to the thiol compound I is (0.0001~0.01):1, more preferably (0.0001~0.001):1, even more preferably (0.0003~0.0008):1, and most preferably 0.0005:1.

[0012] In some embodiments, preferably, when the oxidant is not air or oxygen, the reaction molar ratio of the oxidant to the thiol compound I is (0.0001~1.0):1, more preferably (0.0001~0.10):1, even more preferably (0.0001~0.01):1, and most preferably (0.0003~0.005):1.

[0013] In some embodiments, preferably, when the oxidant is air or oxygen, the atmospheric pressure of the air or oxygen is 1.0 to 3.0 standard atmospheres, more preferably 1.0 standard atmospheres.

[0014] In some embodiments, preferably, the reaction temperature is 20°C. o C~40 o C.

[0015] In some embodiments, preferably, the reaction time is 2.0 to 7.0 h, more preferably 4.0 to 7.0 h, even more preferably 4.0 to 6.0 h, and most preferably 5.0 h.

[0016] In some embodiments, the reaction is carried out using a conventional reaction apparatus or a microchannel reaction apparatus.

[0017] When the reaction is carried out using a conventional reaction apparatus, the organic solvent used is any one or a combination of several of the following: tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, ethanol, dichloroethane, chlorobenzene, fluorobenzene, tert-butanol, petroleum ether, cyclohexane, toluene, xylene, methanol, water, and ethyl acetate. Preferably, it is any one or a combination of several of the following: ethyl acetate, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, ethanol, tert-butanol, and petroleum ether. There are no special requirements for the amount of organic solvent used; it is sufficient to dissolve or disperse the solvent evenly.

[0018] The organic solvent can be recycled and reused.

[0019] In some embodiments, preferably, the reaction is carried out using a microchannel reaction device, and includes the following steps: Thiol compound I is mixed with a catalyst and an organic solvent to obtain a first mixture; an oxidant and an organic solvent are mixed to obtain a second mixture; the first and second mixtures are simultaneously pumped into a micromixer for mixing, and then further pumped into a microreactor of a microchannel reaction device for reaction to obtain disulfide compound II.

[0020] In some embodiments, when the reaction is carried out using a microchannel reaction apparatus, the organic solvent is any one or a combination of several of tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, ethanol, dichloroethane, chlorobenzene, fluorobenzene, tert-butanol, petroleum ether, cyclohexane, toluene, xylene, methanol, water, and ethyl acetate; and / or, the concentration of thiol compound I in the first mixture is 0.75 mmol / mL to 10.38 mmol / mL; and / or, the concentration of the oxidant in the second mixture is 0.027 mmol / mL to 9.078 mmol / mL.

[0021] In some embodiments, preferably, when the reaction is carried out using a microchannel reaction apparatus, the organic solvent is any one or a combination of several of ethyl acetate, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, ethanol, tert-butanol, and petroleum ether.

[0022] The organic solvent in the first mixture may be the same as or different from the organic solvent in the second mixture.

[0023] The organic solvent can be recycled and reused.

[0024] In some embodiments, preferably, the concentration of thiol compound I in the first mixture is 1.75 mmol / mL to 8.38 mmol / mL.

[0025] In some embodiments, more preferably, the concentration of thiol compound I in the first mixture is 2.75 mmol / mL to 7.38 mmol / mL.

[0026] In some embodiments, preferably, the concentration of the oxidant in the second mixture is 0.027 mmol / mL to 5.078 mmol / mL.

[0027] In some embodiments, more preferably, the concentration of the oxidant in the second mixture is 0.027 mmol / mL to 1.078 mmol / mL.

[0028] In some embodiments, and more preferably, the concentration of the oxidant in the second mixture is 0.027 mmol / mL to 0.500 mmol / mL.

[0029] In some embodiments, and most preferably, the concentration of the oxidant in the second mixture is 0.027 mmol / mL to 0.078 mmol / mL.

[0030] In some embodiments, when the reaction is carried out using a microchannel reaction device, the catalyst is any one or a combination of several of CuPd / SiO2, NaIO4, KIO4, KIO3, and Na[Fe(EDTA)]; and / or, the oxidant is any one or a combination of several of hydrogen peroxide, di-tert-butyl peroxide, and dimethyl sulfoxide; and / or, in the first mixture, the molar ratio of the catalyst to the thiol compound I is (0.00001~0.1):1; and / or, in the reaction, the molar ratio of the oxidant in the second mixture to the thiol compound I in the first mixture is controlled to be (0.00001~10.0):1.

[0031] In some embodiments, preferably, when the reaction is carried out using a microchannel reaction device, the molar ratio of the catalyst to the thiol compound I in the first mixture is (0.0001~0.01):1, more preferably (0.0001~0.001):1, even more preferably (0.0003~0.0008):1, and most preferably 0.0005:1.

[0032] In some embodiments, preferably, when the reaction is carried out using a microchannel reaction device, the molar ratio of the oxidant in the second mixture to the thiol compound I in the first mixture is controlled to be (0.0001~1.0):1, more preferably (0.0001~0.10):1, even more preferably (0.0001~0.01):1, and most preferably (0.0003~0.005):1.

[0033] In some embodiments, when the reaction is carried out using a microchannel reactor, the residence time in the microreactor is 2.0 min to 16.7 min; and / or, the reaction temperature is 0 °C. o C~60 o C.

[0034] In some embodiments, preferably, when the reaction is carried out using a microchannel reactor, the reaction residence time in the microreactor is 5.0 min to 16.7 min.

[0035] In some embodiments, more preferably, when the reaction is carried out using a microchannel reaction device, the reaction residence time in the microreactor is 10.0 min to 16.7 min.

[0036] In some embodiments, and more preferably, when the reaction is carried out using a microchannel reaction device, the reaction residence time in the microreactor is 12.0 min to 16.7 min.

[0037] In some embodiments, preferably, when the reaction is carried out using a microchannel reaction device, the reaction temperature is 20°C. o C~40 o C.

[0038] The flow rate of the first mixture pumped into the microreactor of the microchannel reaction device is 0.10 mL / min to 30.0 mL / min, preferably 0.10 mL / min to 10.0 mL / min, more preferably 0.10 mL / min to 5.0 mL / min, even more preferably 0.10 mL / min to 1.0 mL / min, and most preferably 0.39 mL / min to 0.41 mL / min.

[0039] The flow rate of the second mixture pumped into the microreactor of the microchannel reaction device is 0.10 mL / min to 30.0 mL / min, preferably 0.10 mL / min to 10.0 mL / min, more preferably 0.10 mL / min to 5.0 mL / min, and even more preferably 0.10 mL / min to 0.50 mL / min or 0.19 mL / min to 0.21 mL / min.

[0040] In some embodiments, when the reaction is carried out using a microchannel reaction device, the microchannel reaction device includes a connecting pipe, a first injection pump, a second injection pump, a micromixer, a microreactor, and a receiver; wherein the first injection pump and the second injection pump are connected in parallel to the micromixer via the connecting pipe; the micromixer, the microreactor, and the receiver are connected in series in sequence.

[0041] The micro mixer is either a Y-type micro mixer or a T-type micro mixer, preferably a Y-type micro mixer.

[0042] The microreactor is a tubular reactor, preferably made of polytetrafluoroethylene.

[0043] The microreactor is a tubular reactor with an inner diameter of 0.8 mm to 45.0 mm, preferably 0.8 mm to 20.0 mm, more preferably 0.8 mm to 10.0 mm, even more preferably 0.8 mm to 5.0 mm, and most preferably 1.0 mm.

[0044] The retention volume of the microreactor is 1 mL to 2000 mL, preferably 1 mL to 1000 mL, more preferably 1 mL to 500 mL, even more preferably 1 mL to 20 mL, and most preferably 10 mL.

[0045] Beneficial effects: (1) This invention utilizes a green catalytic oxidation method to develop various alkyl thiol skeleton raw materials for the oxidation of corresponding products with functional disulfide bond structures. The method provided by this invention operates under mild conditions in both batch reactors and microchannel reactors, with low catalyst dosage, low waste salt and wastewater volume, and the reaction is carried out under neutral conditions, resulting in high product yield and purity. Furthermore, it prepares a series of disulfide ether products with potential biological activity.

[0046] (2) The catalyst used in this invention has high activity, low dosage, is inexpensive and readily available, and can be industrialized.

[0047] (3) The catalytic oxidation reaction of the present invention is mild, requiring no high temperature and high pressure, and the reaction occurs at 0°C. o C~60 o Between C.

[0048] (4) The present invention uses a catalytic oxidation method, which uses a lower amount of catalyst compared to existing methods, and uses air, oxygen or other oxidants as oxidants to achieve a highly efficient, green and low-cost catalytic oxidation process.

[0049] (5) The organic solvent used in this invention is inexpensive, readily available, environmentally friendly, has minimal solvent loss, and can be recycled.

[0050] (6) The method provided by the present invention has high reaction efficiency and short reaction time in both batch reactor and microchannel reactor. It can complete the reaction in a short time, and the reaction energy consumption is low. It has no scale-up effect and is feasible for scale-up production.

[0051] (7) This invention achieves highly efficient catalytic conversion of alkyl thiols, aryl thiols, and heterocyclic thiols into disulfide products. The catalytic process is clean and efficient, yields various disulfide products with good purity, good atom economy, and easy separation and purification. This invention realizes a green manufacturing technology for a series of disulfide bond fine chemicals with diverse raw material and product structures and potential biomedical activity under this catalytic oxidation method.

[0052] (8) Compared with existing preparation methods, the significant advantages of this invention are: the reaction is a catalytic oxidation process, the reaction efficiency is high, the product purity is high, no expensive catalyst of equivalent quantity is required, inexpensive oxidant is used, and the reaction does not require high temperature and high pressure; under standard conditions, a series of products containing disulfide bonds are prepared by efficient batch or microchannel continuous flow technology. The reaction process of this invention is clean, efficient and safe, and the post-processing separation is simple, providing a very green chemical production process for the preparation of compounds containing disulfide bonds. One of the advantages of this process is that the reaction is efficient and there are no by-products, so after the reaction, the solvent can be removed to obtain pure products. It is highly operable, economical, safe and reliable. Attached Figure Description

[0053] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0054] Figure 1 This is a schematic diagram of the microchannel reaction device used in the embodiments of the present invention. Detailed Implementation

[0055] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0056] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0057] A schematic diagram of the microchannel reaction device used in the embodiments of the present invention is shown below. Figure 1 As shown, the microchannel reaction device includes a connecting pipe, a first injection pump, a second injection pump, a micromixer, a microreactor, and a receiver; wherein the first injection pump and the second injection pump are connected in parallel to the micromixer through the connecting pipe; the micromixer, the microreactor, and the receiver are connected in series in sequence.

[0058] The micro mixer is a Y-type micro mixer.

[0059] The microreactor is a tubular reactor, preferably made of polytetrafluoroethylene.

[0060] The microreactor is a tubular reactor with an inner diameter of 1.0 mm.

[0061] Example 1: Catalytic oxidation of ethanethiol to prepare diethyl disulfide – batch reaction process (using CuPd / SiO2 catalyst as an example)

[0062] In a clean, dry 250 mL round-bottom flask, under an air atmosphere, a bimetallic catalyst CuPd / SiO2 (10.0 mg, prepared according to existing techniques) was added sequentially. Nanoscale , 2020, 12, 19191-19202, Cu and Pd molar ratio 1:1, total mass of Pd and Cu accounting for 5% of total catalyst mass), organic solvent ethyl acetate (100 mL), reactant ethanethiol (50.0 g, 804.7 mmol), oxidant hydrogen peroxide (15 wt.% hydrogen peroxide aqueous solution containing 13.7 mg H2O2, 0.40 mmol), stirred at room temperature for 5 hours, organic phase was extracted with petroleum ether, and then the organic phase was distilled to remove organic solvent, yielding diethyl disulfide with a separation yield of 89.0% and sample purity of 99.5%.

[0063] The specific NMR data are as follows: 1 H NMR (500 MHz, CDCl3) δ 2.64 (q, J = 7.3 Hz, 4H), 1.26 (t, J = 7.3 Hz, 6H); 13 C NMR (125 MHz, CDCl3) δ 31.9, 13.4.

[0064] Example 2: Catalytic oxidation of propanethiol to prepare dipropyl disulfide – batch reaction process (using NaIO4 catalyst as an example)

[0065] In a clean, dry 250 mL round-bottom flask, under an air atmosphere, the following were added sequentially: NaIO4 (70.6 mg, 0.33 mmol) metal catalyst, tetrahydrofuran (100 mL) organic solvent, propanethiol (50.0 g, 656.5 mmol) reactant, and di-tert-butyl peroxide (47.9 mg, 0.33 mmol) oxidant. The mixture was stirred at room temperature for 5 hours. The organic phase was extracted with petroleum ether and water, and then the organic solvent was removed by distillation to obtain dipropyl disulfide. The yield was 86.5%, and the sample purity was 99.4%.

[0066] The specific NMR data are as follows: 1 H NMR (500 MHz, CDCl3) δ 2.60 (t, J = 7.2 Hz, 4H),1.71 – 1.57 (m, 4H), 0.93 (t, J = 7.3 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 40.1, 21.4, 12.0.

[0067] Example 3: Catalytic oxidation of n-pentanethiol to dipentyl disulfide – batch reaction process (using KIO4 catalyst as an example)

[0068] In a clean, dry 250 mL round-bottom flask, under air atmosphere, the following were added sequentially: metal catalyst KIO4 (55.2 mg, 0.24 mmol), organic solvent acetonitrile (100 mL), reactant n-pentanethiol (50.0 g, 480.0 mmol), and oxidant dimethyl sulfoxide (18.8 mg, 0.24 mmol). The mixture was stirred at room temperature for 5 hours. The organic phase was extracted with petroleum ether and water, and then the organic solvent was removed by distillation to obtain the product dipentyl disulfide. The yield was 83.0%, and the sample purity was 98.4%.

[0069] The specific NMR data are as follows: 1 H NMR (500 MHz, CDCl3) 2.68 (t, J = 7.5 Hz, 4H) 1.70 –1.64 (m, 4H), 1.40 – 1.33 (m, 8H), δ 0.90 (t, J = 7 Hz, 6H); 13 C NMR (125 MHz, CDCl3) δ 39.5 30.9, 29.1 22.4, 14.0.

[0070] Example 4: Catalytic oxidation of cyclohexylthiol to prepare dicyclohexyl disulfide – batch reaction process (using KIO3 catalyst as an example)

[0071] In a clean, dry 250 mL round-bottom flask, under an air atmosphere, the catalyst KIO3 (46.0 mg, 0.22 mmol) and organic solvent were added sequentially. N,N- Dimethylformamide (100 mL), cyclohexanethiol (50.0 g, 430.0 mmol) as the reactant, air at the opening of the reaction flask as the oxidant, 1 atm, stirred at room temperature for 5 hours, extracted with petroleum ether and water to obtain the organic phase, then distilled to remove the organic solvent, separated by column chromatography to obtain the product dicyclohexane disulfide, with a separation yield of 88.0% and a sample purity of 99.1%.

[0072] The specific NMR data are as follows: 1H NMR (400 MHz, CDCl3) δ 2.73 – 2.63 (m, 2H), 2.07 –2.01 (m, 4H), 1.81 – 1.73 (m, 4H), 1.64 – 1.58 (m, 2H), 1.35 – 1.21 (m, 10H); 13 C NMR (100 MHz, CDCl3) δ 50.0, 32.9, 26.1, 25.7.

[0073] Example 5: Catalytic oxidation of benzyl thiol to dibenzyl disulfide – batch reaction process (using Na[Fe(EDTA)] catalyst as an example)

[0074] In a clean, dry 250 mL round-bottom flask, under an air atmosphere, catalyst Na[Fe(EDTA)] (10.0 mg), organic solvent ethanol (100 mL), and reactant benzyl mercaptan (50.0 g, 402.6 mmol) were added sequentially. An oxygen balloon was used as the oxidant (1 atm). The mixture was stirred at room temperature for 5 hours. The organic phase was extracted with petroleum ether and water, and then the organic phase was distilled to remove the organic solvent. The product, dibenzyl disulfide, was separated by column chromatography with a yield of 84.5% and a purity of 98.5%.

[0075] The specific NMR data are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.25 – 7.12 (m, 10H), 3.50 (s, 4H); 13 C NMR (125 MHz, CDCl3) δ 136.3, 128.4, 127.4, 126.4, 42.2.

[0076] Example 6: Catalytic oxidation of 4-chlorobenzyl thiol to prepare di(4-chlorobenzyl) disulfide – batch reaction process [using KIO4 catalyst as an example]

[0077] In a clean, dry 250 mL round-bottom flask, under air atmosphere, the following were added sequentially: metal catalyst KIO4 (36.3 mg, 0.16 mmol), organic solvent tert-butanol (100 mL), reactant 4-chlorobenzyl mercaptan (50.0 g, 315.2 mmol), and oxidant hydrogen peroxide (using a 15 wt.% aqueous solution containing 5.4 mg of hydrogen peroxide, 0.16 mmol). The mixture was stirred at room temperature for 5 hours. The organic phase was extracted with petroleum ether and water, and then the organic phase was distilled to remove the organic solvent. The product, di(4-chlorobenzyl) disulfide, was obtained by column chromatography with a yield of 79.6% and a purity of 98.5%.

[0078] The specific NMR data are as follows: 1 H NMR (500 MHz, CDCl3) δ 7.26 – 7.19 (m, 4H), 7.11 –7.01 (m, 4H), 3.49 (s, 4H); 13 C NMR (125 MHz, CDCl3) δ 134.8, 132.6, 129.6,127.6.

[0079] Example 7: Catalytic oxidation of 1,8-octanedithiol to prepare cyclooctyl disulfide – batch reaction process (using KIO3 catalyst as an example)

[0080] In a clean, dry 250 mL round-bottom flask, under air atmosphere, catalyst KIO3 (30.0 mg, 0.14 mmol), petroleum ether (100 mL), reactant 1,8-octanedithiol (50.0 g, 280.3 mmol), and oxidant hydrogen peroxide (using a 15 wt.% aqueous solution containing 4.8 mg of hydrogen peroxide, 0.14 mmol) were added sequentially. The mixture was stirred at room temperature for 5 hours. The organic phase was extracted with petroleum ether and water, and then the organic phase was distilled to remove the organic solvent. The product, cyclooctyl disulfide, was separated by column chromatography with a yield of 74.7% and a purity of 98.9%.

[0081] The specific NMR data are as follows: 1 H NMR (400 MHz, CDCl3): δ 2.82 (t, 4H), 1.86 – 1.80 (m, 4H), 1.72 – 1.65 (m, 4H), 1.55 – 1.51 (m, 4H); 13 C NMR (100 MHz, CDCl3): δ39.2, 26.5, 25.5, 25.3.

[0082] Example 8: Catalytic oxidation of ethanethiol to prepare diethyl disulfide – a microchannel continuous flow reaction process (using CuPd / SiO2 catalyst as an example)

[0083] In a clean, dry round-bottom flask, under air atmosphere, a bimetallic catalyst CuPd / SiO2 (10.0 mg, prepared according to existing techniques) was added sequentially. Nanoscale , 2020, 12, 19191-19202, Cu and Pd molar ratio 1:1, total mass of Pd and Cu accounting for 5% of total catalyst mass), organic solvent ethyl acetate (50 mL), reactant ethanethiol (50.0 g, 804.7 mmol), stirred until homogeneous to obtain the first mixture. The first mixture was then drawn into a 120 mL glass syringe 1 for later use.

[0084] In another clean, dry round-bottom flask, under air atmosphere, add the oxidizing agent hydrogen peroxide (using a 15 wt.% aqueous solution containing 137.0 mg of hydrogen peroxide, 4.0 mmol) and the organic solvent ethyl acetate (50 mL), and stir until homogeneous to obtain a second mixture. Then, aspirate the second mixture into a 100 mL glass syringe 2 for later use.

[0085] Glass syringes 1 and 2 were fixed to two syringe pumps respectively. They were connected in parallel to a Y-type polytetrafluoroethylene (PTFE) mixer via connecting pipes. This Y-type mixer was connected to a 10 mL PTFE tubular microreactor (with an inner diameter of 1.0 mm). At room temperature, the flow rates of the two syringe pumps were adjusted, with syringe 1 at 0.41 mL / min and syringe 2 at 0.19 mL / min. The first and second mixtures were simultaneously pumped into the microreactor for oxidation. The reaction temperature was room temperature, and the reaction residence time was 16.7 min. After the reaction, the organic phase was extracted with petroleum ether and water. The organic solvent was removed by distillation of the organic phase to obtain diethyl disulfide, with a separation yield of 93.0% and a sample purity of 99.5%.

[0086] Example 9: Catalytic oxidation of propanethiol to prepare dipropyl disulfide – a microchannel continuous flow reaction process (using NaIO4 catalyst as an example)

[0087] In a clean, dry round-bottom flask, under an air atmosphere, the catalyst NaIO4 (70.6 mg, 0.33 mmol), the organic solvent tetrahydrofuran (50 mL), and the reaction starter propanethiol (50.0 g, 656.5 mmol) were added sequentially and stirred until homogeneous to obtain a first mixture. This first mixture was then aspirated into a 120 mL glass syringe for later use.

[0088] In another clean, dry round-bottom flask, under air atmosphere, hydrogen peroxide (15 wt.% aqueous solution containing 112 mg of hydrogen peroxide, 3.3 mmol) as the oxidant and tetrahydrofuran (50 mL) as the organic solvent were added and stirred until homogeneous to obtain a second mixture. This second mixture was then aspirated into a 100 mL glass syringe (2) for later use.

[0089] Glass syringes 1 and 2 were fixed to two syringe pumps respectively. They were connected in parallel to a Y-shaped polytetrafluoroethylene (PTFE) mixer via connecting pipes. This Y-shaped mixer was connected to a 10 mL PTFE tubular microreactor (with an inner diameter of 1.0 mm). At room temperature, the flow rates of the two syringe pumps were adjusted, with syringe 1 at 0.41 mL / min and syringe 2 at 0.19 mL / min. The first and second mixtures were simultaneously pumped into the microreactor for oxidation. The reaction temperature was room temperature, and the reaction residence time was 16.7 min. After the reaction, the organic phase was extracted with petroleum ether and water. The organic solvent was removed by distillation of the organic phase to obtain dipropyl disulfide, with a separation yield of 95.0% and a sample purity of 98.9%.

[0090] Example 10: Catalytic oxidation of n-pentanethiol to dipentyl disulfide – microchannel continuous flow reaction process (using KIO4 catalyst as an example)

[0091] In a clean, dry round-bottom flask, under an air atmosphere, catalyst KIO4 (55.2 mg, 0.24 mmol), organic solvent acetonitrile (50 mL), and reactant n-pentanethiol (50.0 g, 480.0 mmol) were added sequentially and stirred until homogeneous to obtain a first mixture. This first mixture was then aspirated into a 120 mL glass syringe for later use.

[0092] In another clean, dry round-bottom flask, under air atmosphere, hydrogen peroxide (15 wt.% aqueous solution containing 82 mg of hydrogen peroxide, 2.4 mmol) as the oxidant and acetonitrile (50 mL) as the organic solvent were added and stirred until homogeneous to obtain a second mixture. This second mixture was then aspirated into a 100 mL glass syringe (2) for later use.

[0093] Glass syringes 1 and 2 were fixed to two syringe pumps respectively. They were connected in parallel to a Y-type polytetrafluoroethylene (PTFE) mixer via connecting pipes. This Y-type mixer was connected to a 10 mL PTFE tubular microreactor (with an inner diameter of 1.0 mm). At room temperature, the flow rates of the two syringe pumps were adjusted, with syringe 1 at 0.41 mL / min and syringe 2 at 0.19 mL / min. The first and second mixtures were simultaneously pumped into the microreactor for oxidation. The reaction temperature was room temperature, and the reaction residence time was 16.7 min. After the reaction, the reaction solution was extracted with petroleum ether to obtain the organic phase. The product, dipentyl disulfide, was obtained by column chromatography with a yield of 92.0% and a purity of 98.5%.

[0094] Example 11: Catalytic oxidation of cyclohexanethiol to prepare dicyclohexyl disulfide – microchannel continuous flow reaction process (using KIO3 catalyst as an example)

[0095] In a clean, dry round-bottom flask, under an air atmosphere, the catalyst KIO3 (46.0 mg, 0.22 mmol) and the organic solvent were added sequentially. N,N Dimethylformamide (50 mL) and cyclohexanethiol (50.0 g, 430.0 mmol) were mixed thoroughly to obtain a first mixture. This first mixture was then drawn into a 120 mL glass syringe (S1) for later use.

[0096] In another clean, dry round-bottom flask, under air atmosphere, add the oxidizing agent hydrogen peroxide (using a 15 wt.% aqueous solution containing 73.0 mg of hydrogen peroxide, 2.2 mmol), and the organic solvent... N,N - Dimethylformamide (50 mL) was stirred until homogeneous to obtain a second mixture. This second mixture was then drawn into a 100 mL glass syringe (2) for later use.

[0097] Glass syringes 1 and 2 were fixed to two syringe pumps, respectively. They were connected in parallel to a Y-type polytetrafluoroethylene (PTFE) mixer via connecting pipes. This Y-type mixer was connected to a 10 mL PTFE tubular microreactor (with an inner diameter of 1.0 mm). At room temperature, the flow rates of the two syringe pumps were adjusted: syringe 1 at 0.40 mL / min and syringe 2 at 0.20 mL / min. The first and second mixtures were simultaneously pumped into the microreactor for oxidation. The reaction temperature was room temperature, and the reaction residence time was 16.7 min. After the reaction, the organic phase was extracted with petroleum ether, and the organic solvent was removed by distillation. The product, dicyclohexyl disulfide, was obtained by column chromatography with a yield of 93.0% and a purity of 98.3%.

[0098] Example 12: Catalytic oxidation of benzyl thiol to dibenzyl disulfide – microchannel continuous flow reaction process (using Na[Fe(EDTA)] catalyst as an example)

[0099] In a clean, dry round-bottom flask, under air atmosphere, catalyst Na[Fe(EDTA)] (10.0 mg), organic solvent ethanol (50 mL), and reactant benzyl mercaptan (50.0 g, 402.6 mmol) were added sequentially and stirred until homogeneous to obtain a first mixture. This first mixture was then aspirated into a 100 mL glass syringe for later use.

[0100] In another clean, dry round-bottom flask, under air atmosphere, potassium persulfate (540.6 mg, 2.0 mmol) and ethanol (50 mL) were added separately and stirred until homogeneous to obtain a second mixture. This second mixture was then aspirated into a 100 mL glass syringe (2) for later use.

[0101] Glass syringes 1 and 2 were fixed to two syringe pumps respectively. They were connected in parallel to a Y-type polytetrafluoroethylene (PTFE) mixer via connecting pipes. This Y-type mixer was connected to a 10 mL PTFE tubular microreactor (with an inner diameter of 1.0 mm). At room temperature, the flow rates of the two syringe pumps were adjusted, with syringe 1 at 0.40 mL / min and syringe 2 at 0.20 mL / min. The first and second mixtures were simultaneously pumped into the microreactor for oxidation. The reaction temperature was room temperature, and the reaction residence time was 16.7 min. After the reaction, the organic phase was extracted with petroleum ether, and the organic solvent was removed by distillation. The product, dibenzyl disulfide, was obtained by column chromatography with a yield of 94.5% and a purity of 98.6%.

[0102] Example 13: Catalytic oxidation of 4-chlorobenzylthiol to di(4-chlorobenzyl)disulfide – microchannel continuous flow reaction process [using KIO4 catalyst as an example]

[0103] In a clean, dry round-bottom flask, under air atmosphere, catalyst KIO4 (36.3 mg, 0.16 mmol), organic solvent ethanol (50 mL), and reactant 4-chlorobenzyl mercaptan (50.0 g, 315.2 mmol) were added sequentially and stirred until homogeneous to obtain a first mixture. This first mixture was then aspirated into a 100 mL glass syringe for later use.

[0104] In another clean, dry round-bottom flask, under air atmosphere, add the oxidant hydrogen peroxide (using a 15 wt.% aqueous solution containing 54.4 mg of hydrogen peroxide, 1.6 mmol) and the organic solvent ethanol (50 mL), and stir until homogeneous to obtain a second mixture. Then, aspirate the second mixture into a 100 mL glass syringe 2 for later use.

[0105] Glass syringes 1 and 2 were fixed to two syringe pumps respectively. They were connected in parallel to a Y-type polytetrafluoroethylene (PTFE) mixer via connecting pipes. This Y-type mixer was connected to a 10 mL PTFE tubular microreactor (with an inner diameter of 1.0 mm). At room temperature, the flow rates of the two syringe pumps were adjusted: syringe 1 flow rate was 0.39 mL / min, and syringe 2 flow rate was 0.21 mL / min. The first and second mixtures were simultaneously pumped into the microreactor for oxidation. The reaction temperature was room temperature, and the reaction residence time was 16.7 min. After the reaction, the organic phase was extracted with petroleum ether, and the organic solvent was removed by distillation. The product, di(4-chlorobenzyl) disulfide, was obtained by column chromatography, with the reaction solvent removed by distillation. The separation yield was 94.0%, and the sample purity was 99.2%.

[0106] Example 14: Catalytic oxidation of 1,8-octanedithiol to prepare cyclooctyl disulfide – a microchannel continuous flow reaction process (using KIO3 catalyst as an example)

[0107] In a clean, dry round-bottom flask, under an air atmosphere, catalyst KIO3 (29.9 mg, 0.14 mmol), organic solvent petroleum ether (50 mL), and reactant 1,8-octanedithiol (50.0 g, 280.3 mmol) were added sequentially and stirred until homogeneous to obtain a first mixture. This first mixture was then aspirated into a 120 mL glass syringe for later use.

[0108] In another clean, dry round-bottom flask, under air atmosphere, add the oxidant hydrogen peroxide (using a 15 wt.% aqueous solution containing 47.6 mg of hydrogen peroxide, 1.4 mmol) and the organic solvent petroleum ether (50 mL), and stir until homogeneous to obtain a second mixture. Then, aspirate the second mixture into a 100 mL glass syringe 2 for later use.

[0109] Glass syringes 1 and 2 were fixed to two syringe pumps, respectively. They were connected in parallel to a Y-type polytetrafluoroethylene (PTFE) mixer via connecting pipes. This Y-type mixer was connected to a 10 mL PTFE tubular microreactor (with an inner diameter of 1.0 mm). At room temperature, the flow rates of the two syringe pumps were adjusted: syringe 1 flow rate was 0.40 mL / min, and syringe 2 flow rate was 0.2 mL / min. The first and second mixtures were simultaneously pumped into the microreactor for oxidation. The reaction temperature was room temperature, and the reaction residence time was 16.7 min. After the reaction, the organic phase was extracted with petroleum ether, and the organic solvent was removed by distillation. The product, cyclooctyl disulfide, was obtained by column chromatography with a yield of 92.0% and a purity of 98.2%.

[0110] Comparative Example 1 References Synthesis The method reported in that literature (1998, 1587) is less effective than that of this invention. That literature uses an equivalent or excess of the highly toxic oxidant potassium permanganate (KMnO4), and requires an equivalent amount of the metal catalyst CuSO4•5H2O to assist in the reaction. This reaction is a heterogeneous process; the participation of equivalent catalysts and oxidants results in poor atom economy, severe environmental pollution, and lack of economic value.

[0111] Comparative Example 2 References Org. Chem. Front The method reported in that literature is comparable in effectiveness to that of the present invention. However, it requires 20% catalyst, which is expensive (Cs₂CO₃) and therefore not economically viable.

[0112] Comparative Example 3 References Molecules 2023, 28 , 6789. The method reported in that literature is comparable in effect to that of the present invention. However, it requires 5% catalyst, which is expensive as iodine (I2), and its reaction temperature is high, making it not truly economical.

[0113] This invention provides a clean and efficient green oxidation method: achieving highly efficient catalytic conversion of alkyl thiols or aryl thiols into disulfide ether products from raw materials. This catalytic oxidation method enables the green manufacturing technology of disulfide bond fine chemicals with diverse functional groups, diverse raw material and product structures, and potential biomedical activity. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment of the invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.

[0114] This invention provides a method for synthesizing disulfide compounds. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.

Claims

1. A method for synthesizing disulfide compounds, characterized in that, Thiol compound I reacts with a catalyst and oxidant to form disulfide compound II; in, When the thiol compound I is and At that time, the disulfide compound II formed is ; When the thiol compound I is and At that time, the disulfide compound II formed is ; When the thiol compound I is At that time, the disulfide compound II formed is ; When the thiol compound I is and At that time, the disulfide compound II formed is ; Wherein, the R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 Each is independently selected from H, substituted or unsubstituted C. 1~20 Alkyl, substituted or unsubstituted C 1~20 Alkoxy, substituted or unsubstituted aromatic groups, halogen, nitro, amino, cyano, carboxyl, ester, substituted or unsubstituted silyl; the substitution is selected from those substituted by any number of the same or different substituents; the substituents are selected from halogen, nitro, amino, cyano, carboxyl, ester, C 1~4 Alkyl and C 1~4 Any one or more of the alkoxy groups; n is an integer from 0 to 20.

2. The method according to claim 1, characterized in that, The R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 Each is independently selected from H, substituted or unsubstituted C. 1~10 Alkyl, substituted or unsubstituted C 1~10 Alkyl groups, or substituted or unsubstituted aromatic groups; the substitution is selected from those substituted by any number of the same or different substituents; the substituents are selected from halogens, C 1~4 Alkyl and C 1~4 Any one or more of the alkoxy groups; n is an integer from 0 to 10.

3. The method according to claim 1, characterized in that, The catalyst is any one or a combination of several of CuPd / SiO2, NaIO4, KIO4, KIO3 and Na[Fe(EDTA)]; and / or, the oxidant is any one or a combination of several of hydrogen peroxide, di-tert-butyl peroxide, dimethyl sulfoxide, air and oxygen.

4. The method according to claim 1, characterized in that, The molar ratio of the catalyst to the thiol compound I is (0.00001~0.1):1; and / or, when the oxidant is not air or oxygen, the molar ratio of the oxidant to the thiol compound I is (0.00001~10.0):1; and / or, when the oxidant is air or oxygen, the atmospheric pressure of the air or oxygen is 1.0~5.0 standard atmospheres; and / or, the reaction temperature is 0. o C~60 o C; and / or, the reaction time is 0.5 to 7.0 h.

5. The method according to claim 1, characterized in that, The reaction is carried out using a conventional reaction apparatus or a microchannel reaction apparatus.

6. The method according to claim 5, characterized in that, The reaction is carried out using a microchannel reaction device and includes the following steps: Thiol compound I is mixed with a catalyst and an organic solvent to obtain a first mixture; an oxidant and an organic solvent are mixed to obtain a second mixture; the first and second mixtures are simultaneously pumped into a micromixer for mixing, and then further pumped into a microreactor of a microchannel reaction device for reaction to obtain disulfide compound II.

7. The method according to claim 6, characterized in that, The organic solvent is any one or a combination of several of the following: tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, ethanol, dichloroethane, chlorobenzene, fluorobenzene, tert-butanol, petroleum ether, cyclohexane, toluene, xylene, methanol, water, and ethyl acetate; and / or, the concentration of thiol compound I in the first mixture is 0.75 mmol / mL to 10.38 mmol / mL; and / or, the concentration of the oxidant in the second mixture is 0.027 mmol / mL to 9.078 mmol / mL.

8. The method according to claim 6, characterized in that, The catalyst is any one or a combination of several of CuPd / SiO2, NaIO4, KIO4, KIO3, and Na[Fe(EDTA)]; and / or, the oxidant is any one or a combination of several of hydrogen peroxide, di-tert-butyl peroxide, and dimethyl sulfoxide; and / or, in the first mixture, the molar ratio of the catalyst to the thiol compound I is (0.00001~0.1):1; and / or, in the reaction, the molar ratio of the oxidant in the second mixture to the thiol compound I in the first mixture is controlled to be (0.00001~10.0):

1.

9. The method according to claim 6, characterized in that, The reaction residence time in the microreactor is 2.0 min to 16.7 min; and / or, the reaction temperature is 0 min. o C~60 o C.

10. The method according to claim 6, characterized in that, The microchannel reaction device includes a connecting pipe, a first injection pump, a second injection pump, a micromixer, a microreactor, and a receiver; wherein the first injection pump and the second injection pump are connected in parallel to the micromixer via the connecting pipe; the micromixer, the microreactor, and the receiver are connected in series in sequence.

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