Process for producing a trisulfide compound or a selenotrisulfide compound

Abstract

Disclosed is a method for producing a trisulfide compound or a selenotrisulfide compound. This production method includes: a step for oxidizing a disulfide compound with an oxidizing agent to obtain a sulfoxide compound; and a step for reacting the sulfoxide compound that has been obtained with a source of sulfur or a source of selenium to obtain a trisulfide compound or a selenotrisulfide compound.

Description

Technical Field

[0001] The present invention relates to a method for producing a trisulfide compound or a selenotrisulfide compound.

Background Art

[0002] A compound containing a covalent bond structure (-S-S-S-) formed by three sulfur atoms is called a trisulfide compound. Among trisulfide compounds, there are those used as flavors such as dimethyl trisulfide and dipropyl trisulfide, and those expected to be antioxidant components such as glutathione trisulfide.

[0003] As methods for producing trisulfide compounds, methods described in Patent Documents 1 to 2 and Non-Patent Document 1 are known.

[0004] A compound containing a covalent bond structure (-S-Se-S-) in which the central sulfur atom of trisulfide is replaced by a selenium atom is called a selenotrisulfide compound. Among selenotrisulfide compounds, compounds having anticancer activity such as glutathione selenotrisulfide have been found, and selenotrisulfide compounds have attracted attention as pharmaceuticals.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0006]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0007] An object of the present invention is to provide a method for producing a trisulfide compound or a selenotrisulfide compound that is safe and inexpensive.

Means for Solving the Problems

[0008] As a result of intensive efforts to solve the above problems, the present inventors have found that a trisulfide compound or a selenotrisulfide compound can be obtained by causing a disulfide compound or a thiol compound to pass through a sulfoxide compound by an oxidation reaction, and have completed the present invention.

[0009] That is, the present invention relates to the following (1) to (14). (1) A method for producing a trisulfide compound or a selenotrisulfide compound, comprising a step of oxidizing a disulfide compound with an oxidizing agent to obtain a sulfoxide compound, and a step of reacting the obtained sulfoxide compound with a sulfur source or a selenium source to obtain a trisulfide compound or a selenotrisulfide compound. (2) The method according to (1) above, wherein the step of obtaining a sulfoxide compound and the step of obtaining a trisulfide compound or a selenotrisulfide compound are carried out in one pot. (3) The method according to (1) or (2) above, wherein the oxidizing agent is potassium peroxymonosulfate, peracetic acid, hydrogen peroxide, hydrogen peroxide and methyltrioxorhenium or sodium periodate. (4) The sulfur source is sodium sulfide, potassium sulfide, sodium hydrogen sulfide, potassium hydrogen sulfide or hydrogen sulfide, and the selenium source is sodium selenide, potassium selenide, sodium hydrogen selenide, potassium hydrogen selenide or hydrogen selenide, and the method according to any one of (1) to (3) above. (5) The disulfide compound is R 1 -S-S-R 2 and the compound represented by, R 1 and R 2 may be the same or different, and each or together represents an alkyl group which may be substituted with one or more substituents selected from the substituent group A, and the substituent group A consists of a halogen atom, a hydroxy group, an amino group which may be substituted with one or more substituents selected from the substituent group B and an oxo group, and the substituent group B consists of an alkyl group which may be substituted with one or more substituents selected from the group consisting of a hydroxy group, an amino group and an oxo group and an acetyl group, and the method according to any one of (1) to (4) above. (6) The disulfide compound is R 3 -S-S-R 4 and the compound represented by, R 3 and R 4 may be the same or different, and represents a group obtained by removing the SH group from cysteine which may be protected with a protecting group or a group obtained by removing the SH group from a cysteine-containing peptide which may be protected with a protecting group, and the method according to any one of (1) to (4) above. (7) A method for producing a trisulfide compound or a selenotrisulfide compound, comprising a step of oxidizing a thiol compound with an oxidizing agent to obtain a sulfoxide compound, and a step of reacting the obtained sulfoxide compound with a sulfur source or a selenium source to obtain a trisulfide compound or a selenotrisulfide compound. (8) The method according to (7) above, wherein the step of obtaining a sulfoxide compound and the step of obtaining a trisulfide compound or a selenotrisulfide compound are carried out in one pot. (9) The method according to (7) or (8) above, wherein the oxidizing agent is potassium peroxymonosulfate, peracetic acid, hydrogen peroxide, hydrogen peroxide and methyltrioxorhenium or sodium periodate. (10) The method according to any one of (7) to (9) above, wherein the sulfur source is sodium sulfide, potassium sulfide, sodium hydrogen sulfide, potassium hydrogen sulfide, or hydrogen sulfide, and the selenium source is sodium selenide, potassium selenide, sodium hydrogen selenide, potassium hydrogen selenide, or hydrogen selenide. (11) The thiol compound is a compound represented by R 1 -SH, and R 1 represents an alkyl group which may be substituted with one or more substituents selected from the substituent group A. The substituent group A consists of a halogen atom, a hydroxy group, an amino group which may be substituted with one or more substituents selected from the substituent group B, and an oxo group. The substituent group B consists of an alkyl group which may be substituted with one or more substituents selected from the group consisting of a hydroxy group, an amino group, and an oxo group, and an acetyl group. The method according to any one of (7) to (10) above. (12) The thiol compounds are a compound represented by R 1 -SH and a compound represented by R 2 -SH. R 1 and R 2 are different and each represents an alkyl group which may be substituted with one or more substituents selected from the substituent group A. The substituent group A consists of a halogen atom, a hydroxy group, an amino group which may be substituted with one or more substituents selected from the substituent group B, and an oxo group. The substituent group B consists of an alkyl group which may be substituted with one or more substituents selected from the group consisting of a hydroxy group, an amino group, and an oxo group, and an acetyl group. The method according to any one of (7) to (10) above. (13) The thiol compound is a compound represented by R 3 -SH, and R 3 represents a group obtained by removing the SH group from cysteine which may be protected with a protecting group or a group obtained by removing the SH group from a cysteine-containing peptide which may be protected with a protecting group. The method according to any one of (7) to (10) above. (14) The thiol compounds are compounds represented by R 3 -SH and R 4 -SH. R 3 and R 4The method according to any one of the above (7) to (10), which represents a group obtained by removing the SH group from cysteine which may be protected with a protecting group or a group obtained by removing the SH group from a cysteine-containing peptide which may be protected with a protecting group.

Advantages of the Invention

[0010] The method for producing a trisulfide compound or a selenotrisulfide compound according to the present invention is safe and inexpensive.

Modes for Carrying Out the Invention

[0011] The method for producing a trisulfide compound or a selenotrisulfide compound according to an embodiment of the present invention includes a step of oxidizing a disulfide compound with an oxidizing agent to obtain a sulfoxide compound (Step 1), and a step of reacting the obtained sulfoxide compound with a sulfur source or a selenium source to obtain a trisulfide compound or a selenotrisulfide compound (Step 2).

[0012] In the above production method, Steps 1 and 2 may be carried out in one pot without isolating the sulfoxide compound.

[0013] The solvent used in Step 1 is not particularly limited as long as it dissolves the disulfide compound and the oxidizing agent and does not inhibit the oxidation reaction. Examples of such a solvent include water, an aqueous sulfuric acid solution, an aqueous ethanol solution, and an aqueous acetonitrile solution, and preferably water. The amount of the solvent used in Step 1 can be 1 mL to 500 mL with respect to 1 g of the disulfide compound, and preferably 10 mL to 20 mL.

[0014] Examples of the oxidizing agent used in Step 1 include potassium peroxymonosulfate (sold under a trade name such as Oxone (registered trademark)), peracetic acid, hydrogen peroxide, and sodium periodate. Hydrogen peroxide may be used together with a catalytic amount of methyltrioxorhenium. From the viewpoints of safety and cost, potassium peroxymonosulfate is a preferred oxidizing agent. The amount of the oxidizing agent used can be 0.8 to 2.0 equivalents, preferably 1.0 to 1.3 equivalents, relative to 1 equivalent of the disulfide compound.

[0015] The reaction temperature in Step 1 can be -20°C to 30°C, preferably -5°C to 5°C.

[0016] The reaction time in Step 1 can be 5 minutes to 24 hours, preferably 0.5 hours to 2 hours.

[0017] The solvent used in Step 2 is not particularly limited as long as it can dissolve the sulfoxide compound and the sulfur source or selenium source and does not inhibit the subsequent reaction. Examples of such solvents include water, sulfuric acid aqueous solution, ethanol aqueous solution, and acetonitrile aqueous solution, and preferably water. The amount of the solvent used in Step 2 can be 1 mL to 500 mL, preferably 10 mL to 20 mL, per 1 g of the sulfoxide compound.

[0018] Examples of the sulfur source used in Step 2 include sodium sulfide, potassium sulfide, sodium hydrogen sulfide, potassium hydrogen sulfide, and hydrogen sulfide. The amount of the sulfur source used can be 0.5 to 4.0 equivalents, preferably 0.9 to 1.2 equivalents, relative to 1 equivalent of the sulfoxide compound. Examples of the selenium source used in Step 2 include sodium selenide, potassium selenide, sodium hydrogen selenide, potassium hydrogen selenide, and hydrogen selenide. The amount of the selenium source used can be 0.5 to 4.0 equivalents, preferably 0.9 to 1.2 equivalents, relative to 1 equivalent of the sulfoxide compound.

[0019] The reaction temperature of Step 2 can be -20°C to 30°C, preferably -5°C to 25°C.

[0020] The reaction time of Step 2 can be 10 minutes to 2 days, preferably 0.5 hours to 2 hours.

[0021] When Steps 1 and 2 are carried out in one pot, examples of the reaction solvent include water, sulfuric acid aqueous solution, ethanol aqueous solution, and acetonitrile aqueous solution. Preferably, it is water. The amount of the solvent can be 1 mL to 500 mL per 1 g of the disulfide compound, preferably 10 mL to 20 mL. Examples of the oxidizing agent used include potassium peroxymonosulfate, peracetic acid, hydrogen peroxide (which may be used together with a catalytic amount of methyltrioxorhenium), and sodium periodate. Preferably, it is potassium peroxymonosulfate. The amount of the oxidizing agent used can be 0.8 equivalents to 2.0 equivalents per 1 equivalent of the disulfide compound, preferably 1.0 equivalent to 1.3 equivalents. The amount of the oxidizing agent used can be 0.8 equivalents to 2.0 equivalents per 1 equivalent of the disulfide compound, preferably 1.0 equivalent to 1.3 equivalents. Examples of the sulfur source used include sodium sulfide, potassium sulfide, sodium hydrogen sulfide, potassium hydrogen sulfide, and hydrogen sulfide. The amount of the sulfur source used can be 0.5 equivalents to 4.0 equivalents per 1 equivalent of the disulfide compound, preferably 0.9 equivalents to 1.2 equivalents. Examples of the selenium source used include sodium selenide, potassium selenide, sodium hydrogen selenide, potassium hydrogen selenide, and hydrogen selenide. The amount of the selenium source used can be 0.5 equivalents to 4.0 equivalents per 1 equivalent of the disulfide compound, preferably 0.9 equivalents to 1.2 equivalents. The reaction temperature can be -20°C to 30°C, preferably -5°C to 25°C. The reaction time can be 15 minutes to 2 days, preferably 1 hour to 4 hours.

[0022] In addition to Step 1 and Step 2, if necessary, it may also include a step of protecting functional groups such as hydroxy groups, carbonyl groups, amino groups, carboxy groups, etc. and a step of deprotecting the protected functional groups. The protecting groups for these functional groups and the protection / deprotection reactions are well-known to those skilled in the art, and appropriate protecting groups and protection / deprotection reactions can be selected by referring to "Greene's Protective Groups in Organic Synthesis" and the like.

[0023] As an example of the disulfide compound, R 1 -S-S-R 2 The compounds represented by are mentioned. R 1 and R 2 may be the same (i.e., symmetric disulfide compounds), and R 1 and R 2 may be different (i.e., asymmetric disulfide compounds). R 1 and R 2 may combine together to form the groups described below (i.e., cyclic disulfide compounds).

[0024] R 1 and R 2 represent alkyl groups which may be substituted with one or more substituents selected from the substituent group A. The substituent group A consists of a halogen atom, a hydroxy group, an amino group which may be substituted with one or more substituents selected from the substituent group B and an oxo group. The substituent group B consists of an alkyl group which may be substituted with one or more substituents selected from the group consisting of a hydroxy group, an amino group and an oxo group and an acetyl group. The number of carbon atoms of the alkyl group may be 1 to 6, and examples include a methyl group, an ethyl group, a propane-1-yl group, a propane-2-yl group (isopropyl group), a butane-1-yl group, a butane-2-yl group, a pentane-1-yl group, a pentane-2-yl group, a pentane-3-yl group, a hexane-1-yl group, a hexane-2-yl group and a 3-hexyl group.

[0025] The disulfide compound is R 1 -S-S-R 2When it is a compound represented by, the sulfoxide compound to be produced is R 1 -S(=O)-S-R 2 or R 1 -S-S(=O)-R 2 When it is a compound represented by, the trisulfide compound to be produced is R 1 -S-S-S-R 2 When it is a compound represented by, the selenotrisulfide compound to be produced is R 1 -S-Se-S-R 2 is a compound represented by.

[0026] As another example of the disulfide compound, a compound represented by R 3 -S-S-R 4 is mentioned. R 3 and R 4 may be the same (that is, a symmetric disulfide compound), and R 3 and R 4 may be different (that is, an asymmetric disulfide compound). R 3 and R 4 may combine together to form the groups described below (that is, a cyclic disulfide compound).

[0027] R 3 and R 4 represent a group obtained by removing the SH group from cysteine which may be protected by a protecting group or a group obtained by removing the SH group from a cysteine-containing peptide which may be protected by a protecting group. The length of the peptide is not particularly limited, but may be, for example, a peptide consisting of 2 to 10 amino acids, and preferably a peptide consisting of 2 to 5 amino acids. Examples of cysteine protected by a protecting group include cysteine in which the carboxy group and / or amino group is protected, and specifically, N-acetylcysteine and the like. A peptide protected by a protecting group refers to a peptide in which the C-terminal carboxy group, the N-terminal amino group and / or the side chain having a reactive functional group (for example, the amino group of a lysine residue, the carboxy group of an aspartic acid residue and a glutamic acid residue, etc.) are protected.

[0028] When the disulfide compound is R3 -S-S-R 4 When the compound is represented by, the resulting sulfoxide compound is R 3 -S(=O)-S-R 4 or R 3 -S-S(=O)-R 3 When the compound is represented by, the resulting trisulfide compound is R 3 -S-S-S-R 4 When the compound is represented by, the resulting selenotrisulfide compound is R 3 -S-Se-S-R 4 is a compound represented by.

[0029] A method for producing a trisulfide compound or a selenotrisulfide compound according to another embodiment of the present invention includes a step of oxidizing a thiol compound with an oxidizing agent to obtain a sulfoxide compound (step 1'), and a step of reacting the obtained sulfoxide compound with a sulfur source or a selenium source to obtain a trisulfide compound or a selenotrisulfide compound (step 2).

[0030] The above production method may be carried out in one pot without isolating the disulfide compound.

[0031] The solvent used in step 1' is not particularly limited as long as it dissolves the thiol compound and the oxidizing agent and does not inhibit the oxidation reaction. Examples of such solvents include, for example, water, sulfuric acid aqueous solution, ethanol aqueous solution, and acetonitrile aqueous solution, and preferably water. The amount of the solvent used in step 1' can be 1 mL to 500 mL per 1 g of the thiol compound, and preferably 10 mL to 20 mL.

[0032] The oxidizing agent used in step 1' and its amount are the same as those described in step 1.

[0033] The reaction temperature of step 1' can be -20°C to 30°C, and preferably -5°C to 5°C.

[0034] The reaction time of Step 1' can be from 10 minutes to 24 hours, preferably from 0.5 hour to 2 hours.

[0035] When Steps 1' and 2 are carried out in one pot, examples of the reaction solvent include water, sulfuric acid aqueous solution, ethanol aqueous solution, and acetonitrile aqueous solution. Preferably, it is water. The amount of the solvent can be from 1 mL to 500 mL per 1 g of the thiol compound, preferably from 10 mL to 20 mL. Examples of the oxidizing agent used include potassium peroxymonosulfate, peracetic acid, hydrogen peroxide (which may be used together with a catalytic amount of methyltrioxorhenium), and sodium periodate. Preferably, it is potassium peroxymonosulfate. The amount of the oxidizing agent used can be from 0.8 equivalent to 2.0 equivalents per 1 equivalent of the thiol compound, preferably from 1.0 equivalent to 1.3 equivalents. The amount of the oxidizing agent used can be from 0.8 equivalent to 2.0 equivalents per 1 equivalent of the thiol compound, preferably from 1 equivalent to 1.3 equivalents. Examples of the sulfur source used include sodium sulfide, potassium sulfide, sodium hydrogen sulfide, potassium hydrogen sulfide, and hydrogen sulfide. The amount of the sulfur source used can be from 0.5 equivalent to 4.0 equivalents per 1 equivalent of the thiol compound, preferably from 0.9 equivalent to 1.2 equivalents. Examples of the selenium source used include sodium selenide, potassium selenide, sodium hydrogen selenide, potassium hydrogen selenide, and hydrogen selenide. The amount of the selenium source used can be from 0.5 equivalent to 4.0 equivalents per 1 equivalent of the thiol compound, preferably from 0.9 equivalent to 1.2 equivalents. The reaction temperature can be from -20°C to 30°C, preferably from -5°C to 25°C. The reaction time can be from 15 minutes to 2 days, preferably from 1 hour to 4 hours.

[0036] In addition to Step 1' and Step 2, if necessary, it may also include steps of protecting functional groups such as hydroxy groups, carbonyl groups, amino groups, carboxy groups, etc. and steps of deprotecting the protected functional groups. Protecting groups for these functional groups and protection / deprotection reactions are well-known to those skilled in the art, and appropriate protecting groups and protection / deprotection reactions can be selected by referring to "Greene's Protective Groups in Organic Synthesis" and the like.

[0037] As an example of the thiol compound, R 1 -compounds represented by -SH can be mentioned. Two kinds of thiol compounds R 1 -SH and R 2 -SH may be used for the reaction. R 1 and R 2 are defined as described above.

[0038] When the thiol compound is a compound represented by R 1 -SH, the resulting sulfoxide compound is a compound represented by R 1 -S(=O)-S-R 1 , and the resulting trisulfide compound is a compound represented by R 1 -S-S-S-R 1 , and the resulting selenotrisulfide compound is a compound represented by R 1 -S-Se-S-R 1 . When the thiol compound is a compound represented by R 1 -SH and a compound represented by R 2 -SH, the resulting sulfoxide compounds are compounds represented by R 1 -S(=O)-S-R 1 , compounds represented by R 2 -S(=O)-S-R 2 , compounds represented by R 1 -S(=O)-S-R 2 and compounds represented by R 1 -S-S(=O)-R 2It is any of the compounds represented by or a mixture of these. In the case of a mixture, the desired sulfoxide compound can be separated if necessary. The resulting trisulfide compound is R 1 -S-S-S-R 1 represented by the compound, R 2 -S-S-S-R 2 represented by the compound and R 1 -S-S-S-R 2 represented by the compound, or any of these mixtures. The resulting selenotrisulfide compound is R 1 -S-Se-S-R 1 represented by the compound, R 2 -S-Se-S-R 2 represented by the compound and R 1 -S-Se-S-R 2 represented by the compound, or any of these mixtures. In the case of a mixture, the desired trisulfide compound or selenotrisulfide compound can be separated if necessary.

[0039] As another example of the thiol compound, a compound represented by R 3 -SH can be mentioned. The reaction may be carried out using two thiol compounds R 3 -SH and R 4 -SH. The definitions of R 3 and R 4 are as described above.

[0040] When the thiol compound is a compound represented by R 3 -SH, the resulting sulfoxide compound is a compound represented by R 3 -S(=O)-S-R 3 and the resulting trisulfide compound is a compound represented by R 3 -S-S-S-R 3 and the resulting selenotrisulfide compound is a compound represented by R 3 -S-Se-S-R 3 When the thiol compound is a compound represented by R 3 -SH and R 4When it is a compound represented by -SH, the sulfoxide compound to be generated is R 3 -S(=O)-S-R 3 a compound represented by, R 4 -S(=O)-S-R 4 a compound represented by, R 3 -S(=O)-S-R 4 a compound represented by, and R 3 -S-S(=O)-R 4 a compound represented by, or a mixture of any of these. When it is a mixture, the desired sulfoxide compound can be separated as necessary. The trisulfide compound to be generated is R 3 -S-S-S-R 3 a compound represented by, R 4 -S-S-S-R 4 a compound represented by, and R 3 -S-S-S-R 4 a compound represented by, or a mixture of any of these. The selenotrisulfide compound to be generated is R 3 -S-Se-S-R 3 a compound represented by, R 4 -S-Se-S-R 4 a compound represented by, and R 3 -S-Se-S-R 4 a compound represented by, or a mixture of any of these. When it is a mixture, the desired trisulfide compound or selenotrisulfide compound can be separated as necessary.

Example

[0041] Example 1

Chemical formula

[0042] Oxidized glutathione (GSSG) and an aqueous sulfuric acid solution were charged into a reaction vessel, and the temperature of this solution was adjusted. Here, peracetic acid (AcO 2 H), hydrogen peroxide (H 2 O 2 ), methyltrioxorhenium (MeReO 3) Sodium periodate (NaIO 4 ) and Oxone (registered trademark) were added in the amounts shown in Table 1 and reacted. The results of measuring the HPLC (high performance liquid chromatography) purity of the product (GS(=O)SG) after the reaction and the reaction conditions are shown in Table 1.

[0043]

Table 1

[0044] The HPLC conditions are as follows. Detector: Ultraviolet absorption photometer (measurement wavelength: 220 nm) Column: LiChrosorb RP-18 (Kanto Chemical, 4.0×250 mm, 5 μm) Column temperature: Constant temperature around 40 °C Mobile phase A: Aqueous phosphoric acid solution (pH 3) Mobile phase B: Methanol Liquid delivery of the mobile phase: The concentration gradient control is performed by changing the mixing ratio of mobile phase A and mobile phase B as follows.

Table 2

[0045] Example 2

Chemical formula

[0046] 10 g (13.97 mmol) of oxidized glutathione (GSSG) and 20 mL of 1 mol / L sulfuric acid aqueous solution were charged into a reaction vessel and cooled in an ice bath. Here, AcO 2H (8.7% acetic acid solution, 15.8 g, 18.1 mmol) was added dropwise and reacted for about 2 hours. Subsequently, after warming up to room temperature, the sulfur source shown in Table 2 was added and reacted for about 2 hours. After adding 27 mL of ethanol to the reaction solution, 3 mL of saturated aqueous sodium carbonate solution was added. After filtering the slurry, the crystals were washed with 20 mL of 50% aqueous ethanol solution. The collected crystals were dried under reduced pressure at room temperature to obtain glutathione trisulfide (product). The results and reaction conditions are shown in Table 3.

[0047]

Table 3

[0048] The HPLC conditions are the same as those described in Example 1.

[0049] Example 3

Chemical formula

[0050] 2.0 g (9.02 mmol) of α-lipoic acid and 40 mL of 75% aqueous ethanol solution were charged into a reaction vessel and cooled to an internal temperature of 0 °C. 3.4 g (10.20 mmol) of Oxone (registered trademark) was added here and reacted for about 2 hours. After filtering the inorganic salts in the reaction solution, it was washed with 7 mL of ethanol. 5.8 g (24.1 mmol) of sodium sulfide nonahydrate was added to the filtrate and reacted for about 1 hour. After dropping 7 mL of 3 mol / L sulfuric acid aqueous solution into this reaction solution, subsequently, 20 mL of water and 45 mL of ethyl acetate (AcOEt) were added, and extraction was performed with AcOEt. The aqueous layer was extracted twice with 20 mL of AcOEt, and the organic layers were combined and concentrated under reduced pressure. After adding 3 mL of ethanol to the concentrate to dissolve it, the solution was purified by an ODS column (YMC Dispo PackAT, mobile phase: acetonitrile aqueous solution) to obtain 0.7 g (2.39 mmol, HPLC purity: 100%) of α-lipoic acid trisulfide.

[0051] The HPLC conditions are as follows. Detector: Ultraviolet absorption photometer (measurement wavelength: 220 nm) Column: LiChrosorb RP-18 (Kanto Chemical, 4.0×250 mm, 5 μm) Column temperature: Constant temperature around 40 °C Mobile phase A: Aqueous phosphoric acid solution (pH 3) Mobile phase B: Methanol Liquid delivery of the mobile phase: The concentration gradient control is performed by changing the mixing ratio of mobile phase A and mobile phase B as follows. [Table 4] Flow rate: 1.0 mL / min

[0052] Example 4 [Chemical formula]

[0053] 1.0 g (4.16 mmol) of L-cysteine and 10 mL of 1 mol / L sulfuric acid aqueous solution were charged into a reaction vessel and cooled in an ice bath. 1.5 g (4.35 mmol) of Oxone (registered trademark) was added thereto and reacted for about 1 hour. Subsequently, 1.1 g (4.37 mmol) of sodium sulfide nonahydrate was added and reacted for about 3 hours. After 19 mL of 1 mol / L aqueous sodium hydrogen carbonate solution was added dropwise to the reaction solution, the slurry was filtered and washed with 10 mL of water. The wet crystals collected by filtration were dried under reduced pressure at room temperature to obtain 0.75 g (2.75 mmol, HPLC purity: 89%) of cysteine trisulfide.

[0054] The HPLC conditions are the same as those described in Example 1.

[0055] Example 5 [Chemical formula]

[0056] 1.0 g (3.08 mmol) of N,N'-diacetyl-L-cysteine and 10 mL of water were charged into a reaction vessel and cooled to an internal temperature of 1 °C. 1.25 g (3.72 mmol) of Oxone (registered trademark) was added thereto and reacted for about 3 hours. Subsequently, 8.5 mL (3.71 mmol) of a 0.44 mol / L aqueous sodium sulfide solution was added dropwise and reacted for about 3 hours. After adding 33 mL of acetonitrile to the reaction solution, the inorganic salts were filtered off and washed with 5 mL of acetonitrile. This filtrate was concentrated under reduced pressure using an evaporator, and the concentrate was purified by an ODS column (mobile phase: aqueous acetonitrile solution) to obtain 0.2 g (0.56 mmol) of N,N'-diacetyl-L-cystine trisulfide.

[0057] The HPLC conditions are as follows. Detector: Ultraviolet absorption photometer (measurement wavelength: 220 nm) Column: LiChrosorb RP-18 (Kanto Chemical, 4.0×250 mm, 5 μm) Column temperature: Constant temperature around 40 °C Mobile phase: 40% (v / v) aqueous acetonitrile solution Flow rate: 0.5 mL / min

[0058] Example 6

Chemical formula

[0059] 1.0 g (6.13 mmol) of N-acetyl-L-cysteine and 40 mL of a 20% aqueous acetonitrile solution were charged into a reaction vessel and cooled to an internal temperature of 5 °C. 3.4 g (10.14 mmol) of Oxone (registered trademark) was added thereto and reacted for about 2.5 hours. Subsequently, 1.5 g (6.12 mmol) of sodium sulfide nonahydrate was added and reacted for about 1 hour. After adding 33 mL of acetonitrile, the inorganic salts were filtered off and washed with 3 mL of acetonitrile. This filtrate was concentrated under reduced pressure using an evaporator, and the concentrate was purified by an ODS column (mobile phase: aqueous acetonitrile solution) to obtain 0.1 g (0.28 mmol) of N,N'-diacetyl-L-cystine trisulfide.

[0060] The HPLC conditions are the same as those described in Example 5.

[0061] Example 7

Chemical formula

[0062] Example 8

Chemical formula

[0063] The conditions for LC / MS are as follows. Detector: Photodiode array detector (measurement wavelength: 190 - 285 nm) Mass spectrometer (ESI method, negative mode, m / z 100 - 1500) Capillary voltage: 2.5 kV Ion source temperature: 150 °C Column: Meteoric Core C18 (YMC, 4.6 × 150 mm, 2.7 μm) Column temperature: Constant temperature around 40 °C Mobile phase A: 0.1% aqueous formic acid solution Mobile phase B: 0.1% formic acid acetonitrile solution Liquid delivery of mobile phase: The concentration gradient control is performed by changing the mixing ratio of mobile phase A and mobile phase B as follows.

Table 5

Claims

1. A step of oxidizing a disulfide compound with an oxidizing agent to obtain a sulfoxide compound, and a step of reacting the obtained sulfoxide compound with a sulfur source to obtain a trisulfide compound, wherein the oxidizing agent is potassium peroxymonosulfate, peracetic acid, hydrogen peroxide, hydrogen peroxide and methyltrioxorhenium or sodium periodate, the sulfur source is sodium sulfide, potassium sulfide, sodium hydrogen sulfide, potassium hydrogen sulfide or hydrogen sulfide, and the disulfide compound is (1) an acyclic compound represented by R1-S-S-R2, wherein R1 and R2 may be the same or different and each represents an alkyl group which may be substituted with one or more substituents selected from the substituent group A, the substituent group A consists of a halogen atom, a hydroxy group, an amino group which may be substituted with one or more substituents selected from the substituent group B and an oxo group, the substituent group B consists of an alkyl group which may be substituted with one or more substituents selected from the group consisting of a hydroxy group, an amino group and an oxo group and an acetyl group, or (2) a compound represented by R3-S-S-R4, wherein R3 and R4 may be the same or different and each represents a group obtained by removing an SH group from cysteine which may be protected with a protecting group or a group obtained by removing an SH group from a cysteine-containing peptide which may be protected with a protecting group, A method for producing a trisulfide compound.

2. The method according to claim 1, wherein the step of obtaining a sulfoxide compound and the step of obtaining a trisulfide compound are carried out in one pot.

3. The disulfide compound is R １ -S-S-R ２ and is an acyclic compound represented by R １ and R ２ may be the same or different and each represents an alkyl group which may be substituted with one or more substituents selected from the group of substituents A, The substituent group A consists of a halogen atom, a hydroxy group, an amino group which may be substituted with one or more substituents selected from the substituent group B and an oxo group, the substituent group B consists of an alkyl group which may be substituted with one or more substituents selected from the group consisting of a hydroxy group, an amino group and an oxo group and an acetyl group, The method according to claim 1 or 2.

4. The method according to claim 1 or 2, wherein the disulfide compound is oxidized glutathione.

5. The disulfide compound is R ３ -S-S-R ４ represented by the formula, and R ３ and R ４ which may be the same or different and represent a group obtained by removing the SH group from cysteine which may be protected with a protecting group or a group obtained by removing the SH group from a cysteine-containing peptide which may be protected with a protecting group, The method according to claim 1 or 2.

6. A step of oxidizing a thiol compound with an oxidizing agent to obtain a sulfoxide compound, and a step of reacting the obtained sulfoxide compound with a sulfur source to obtain a trisulfide compound, The oxidizing agent is potassium peroxymonosulfate, peracetic acid, hydrogen peroxide, hydrogen peroxide and methyltrioxorhenium or sodium periodate, The sulfur source is sodium sulfide, potassium sulfide, sodium hydrogen sulfide, potassium hydrogen sulfide or hydrogen sulfide, The thiol compound is (1) a compound represented by R1-SH, R1 represents an alkyl group which may be substituted with one or more substituents selected from the substituent group A, The substituent group A consists of a halogen atom, a hydroxy group, an amino group which may be substituted with one or more substituents selected from the substituent group B, and an oxo group, The substituent group B consists of an alkyl group which may be substituted with one or more substituents selected from the group consisting of a hydroxy group, an amino group and an oxo group, and an acetyl group, (2) a compound represented by R1-SH and a compound represented by R2-SH, R1 and R2 are different and each represents an alkyl group which may be substituted with one or more substituents selected from the substituent group A, The substituent group A consists of a halogen atom, a hydroxy group, an amino group which may be substituted with one or more substituents selected from the substituent group B, and an oxo group, The substituent group B consists of an alkyl group which may be substituted with one or more substituents selected from the group consisting of a hydroxy group, an amino group and an oxo group, and an acetyl group, (3) a compound represented by R3-SH, R3 represents a group obtained by removing the SH group from cysteine which may be protected with a protecting group or a group obtained by removing the SH group from a cysteine-containing peptide which may be protected with a protecting group, or (4) a compound represented by R3-SH and R4-SH, R3 and R4 are different and each represents a group obtained by removing the SH group from cysteine which may be protected with a protecting group or a group obtained by removing the SH group from a cysteine-containing peptide which may be protected with a protecting group, A method for producing a trisulfide compound.

7. The method according to claim 6, wherein the step of obtaining a sulfoxide compound and the step of obtaining a trisulfide compound are carried out in one pot.

8. The thiol compound is R １ -SH, and is a compound represented by R １ represents an alkyl group which may be substituted with one or more substituents selected from the substituent group A, The substituent group A consists of a halogen atom, a hydroxy group, an amino group which may be substituted with one or more substituents selected from the substituent group B, and an oxo group, The substituent group B consists of an alkyl group which may be substituted with one or more substituents selected from the group consisting of a hydroxy group, an amino group and an oxo group, and an acetyl group, The method according to claim 6 or 7.

9. The method according to claim 6 or 7, wherein the thiol compound is glutathione.

10. The thiol compound is R １ a compound represented by -SH and R ２ a compound represented by -SH, and R １ and R ２ each independently represents an alkyl group which may be substituted with one or more substituents selected from the group of substituents A, The substituent group A consists of a halogen atom, a hydroxy group, an amino group which may be substituted with one or more substituents selected from the substituent group B, and an oxo group, The substituent group B consists of an alkyl group which may be substituted with one or more substituents selected from the group consisting of a hydroxy group, an amino group and an oxo group, and an acetyl group, The method according to claim 6 or 7.

11. The thiol compound is R ３ -SH, and is a compound represented by R ３ represents a group obtained by removing the SH group from cysteine which may be protected by a protecting group, or a group obtained by removing the SH group from a cysteine-containing peptide which may be protected by a protecting group. The method according to claim 6 or 7.

12. The thiol compound is R ３ -SH and R ４ -SH, and is a compound represented by R ３ and R ４ each independently represents a group obtained by removing the SH group from cysteine which may be protected with a protecting group, or a group obtained by removing the SH group from a cysteine-containing peptide which may be protected with a protecting group, The method according to claim 6 or 7.

13. A step of oxidizing a disulfide compound with an oxidizing agent to obtain a sulfoxide compound, and A step of reacting the obtained sulfoxide compound with a selenium source to obtain a selenotrisulfide compound, A method for producing a selenotrisulfide compound.

14. The method according to claim 13, wherein the step of obtaining a sulfoxide compound and the step of obtaining a selenotrisulfide compound are carried out in one pot.

15. The method according to claim 13 or 14, wherein the oxidizing agent is potassium peroxymonosulfate, peracetic acid, hydrogen peroxide, hydrogen peroxide and methyltrioxorhenium or sodium periodate.

16. The method according to any one of claims 13 to 15, wherein the selenium source is sodium selenide, potassium selenide, sodium hydrogen selenide, potassium hydrogen selenide or hydrogen selenide.

17. The disulfide compound is R １ -S-S-R ２ and is a compound represented by R １ and R ２ may be the same or different and each or together represent an alkyl group which may be substituted with one or more substituents selected from the group of substituents A The substituent group A consists of a halogen atom, a hydroxy group, an amino group which may be substituted with one or more substituents selected from the substituent group B, and an oxo group, The substituent group B consists of an alkyl group which may be substituted with one or more substituents selected from the group consisting of a hydroxy group, an amino group and an oxo group, and an acetyl group, The method according to any one of claims 13 to 16.

18. The disulfide compound is R ３ -S-S-R ４ and is a compound represented by R ３ and R ４ which may be the same or different and represent a group obtained by removing the SH group from cysteine which may be protected with a protecting group or a group obtained by removing the SH group from a cysteine-containing peptide which may be protected with a protecting group, The method according to any one of claims 13 to 16.

19. A step of oxidizing a thiol compound with an oxidizing agent to obtain a sulfoxide compound, and A step of reacting the obtained sulfoxide compound with a selenium source to obtain a selenotrisulfide compound, A method for producing a selenotrisulfide compound.

20. The method according to claim 19, wherein the step of obtaining a sulfoxide compound and the step of obtaining a selenotrisulfide compound are carried out in one pot.

21. The method according to claim 19 or 20, wherein the oxidizing agent is potassium peroxymonosulfate, peracetic acid, hydrogen peroxide, hydrogen peroxide and methyltrioxorhenium or sodium periodate.

22. The method according to any one of claims 19 to 21, wherein the selenium source is sodium selenide, potassium selenide, sodium hydrogen selenide, potassium hydrogen selenide or hydrogen selenide.

23. The thiol compound is R １ -SH, and is a compound represented by R １ represents an alkyl group which may be substituted with one or more substituents selected from the substituent group A, The substituent group A consists of a halogen atom, a hydroxy group, an amino group which may be substituted with one or more substituents selected from the substituent group B, and an oxo group. The substituent group B consists of an alkyl group which may be substituted with one or more substituents selected from the group consisting of a hydroxy group, an amino group and an oxo group, and an acetyl group. The method according to any one of claims 19 to 22.

24. The thiol compound is R １ a compound represented by -SH and R ２ a compound represented by -SH, and R １ and R ２ each independently represents an alkyl group which may be substituted with one or more substituents selected from the group of substituents A, The substituent group A consists of a halogen atom, a hydroxy group, an amino group which may be substituted with one or more substituents selected from the substituent group B, and an oxo group. The substituent group B consists of an alkyl group which may be substituted with one or more substituents selected from the group consisting of a hydroxy group, an amino group and an oxo group, and an acetyl group. The method according to any one of claims 19 to 22.

25. The thiol compound is R ３ -SH, and is a compound represented by R ３ represents a group obtained by removing the SH group from cysteine which may be protected by a protecting group, or a group obtained by removing the SH group from a cysteine-containing peptide which may be protected by a protecting group, The method according to any one of claims 19 to 22.

26. The thiol compound is R ３ -SH and R ４ -SH, and is a compound represented by R ３ and R ４ each independently represents a group obtained by removing the SH group from cysteine which may be protected with a protecting group or a group obtained by removing the SH group from a cysteine-containing peptide which may be protected with a protecting group, The method according to any one of claims 19 to 22.

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