Method for producing exocyclic olefin derivatives

Abstract

The present invention provides a method for producing hemithioacetal derivatives with high yield, and a method for producing exocyclic olefin derivatives. [Solution] The method involves contacting a disulfide derivative represented by the following formula (I) with a reducing agent to produce an exocyclic olefin derivative. The reducing agent includes at least one selected from the group consisting of a metal-based reducing agent containing at least one metal selected from the group consisting of zinc, iron, palladium, and nickel; a silane-based reducing agent containing silicon; a reducing gas; a reducing inorganic salt; and a boron-based reducing agent containing boron. JPEG2026055675000040.jpg41120

Description

[Technical Field]

[0001] This invention relates to a method for producing exocyclic olefin derivatives. [Background technology]

[0002] Biotin is a useful compound used in various pharmaceuticals, food additives, and feed additives. Biotin is synthesized using the following manufacturing methods.

[0003] [ka]

[0004] Specifically, first, (3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione (hereinafter sometimes simply referred to as "thiolactone derivative") represented by formula (1A) and chloride (3-methoxypropyl)magnesium (hereinafter sometimes referred to as "coupling reagent") represented by formula (2A) are subjected to a coupling reaction to produce (3aS,6aR)-1,3-dibenzyl-4-hydroxy-4-(3-methoxypropyl)tetrahydro-1H-thieno[3,4-d]imidazole-2(3H)-one (hereinafter sometimes simply referred to as "hemithioacetal derivative") represented by formula (3A). Next, the hemithioacetal derivative is dehydrated to obtain (3aS,6aR)-1,3-dibenzyl-4-(3-methoxypropyridene)tetrahydro-1H-thieno[3,4-d]imidazole-2(3H)-one represented by formula (4A) (hereinafter sometimes simply referred to as "exocyclic olefin derivative"). Subsequently, the olefin is reduced and then cyclized to synthesize a sulfonium intermediate (5A). Finally, biotin is produced by malonic acid ester synthesis and deprotection of the benzyl group.

[0005] In this manufacturing method, hemithioacetal derivatives and exocyclic olefin derivatives are important synthetic intermediates for biotin, and much research has been conducted on their synthesis methods.

[0006] For example, Patent Document 1 describes a method for producing a hemithioacetal derivative by mixing a thiolactone derivative, a Grignard reagent, and a copper salt. According to the method described in Patent Document 1, by using a copper salt, hemithioacetal derivatives can be produced in a higher yield than in conventional Grignard reactions. As a result, exocyclic olefin derivatives can also be produced in high yield. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] International Publication No. 2022 / 260168 [Overview of the project] [Problems that the invention aims to solve]

[0008] However, while the method described in Patent Document 1 allows for the production of hemithioacetal derivatives in high yield on a scale of several hundred mg, reaction control becomes difficult during scaling up, and the generation of by-products is observed. There is a risk of by-product generation during mass production, indicating room for improvement.

[0009] Therefore, the present invention aims to provide a method for producing exocyclic olefin derivatives with high yield. [Means for solving the problem]

[0010] The inventors diligently conducted research to solve the above problems. They identified a by-product generated when producing a hemithioacetal derivative from a thiolactone derivative using a Grignard reagent and a copper salt, and estimated the mechanism by which this by-product is formed. Specifically, when a thiolactone derivative represented by formula (1A) is brought into contact with a coupling reagent (Grignard reagent) represented by formula (2A) to produce a hemithioacetal derivative represented by formula (3A), a ketone derivative represented by formula (I'A) is generated as a by-product. It was thought that a radical species is generated from the thiol of this ketone derivative, becoming an intermediate represented by formula (I''A), and that these radical species form a bond, resulting in the production of a disulfide derivative represented by the following formula (IA) (see formula below).

[0011] Furthermore, the inventors' studies revealed that the ease of producing the disulfide derivative varies depending on the reaction conditions. Specifically, it was found that the disulfide derivative is easily produced when the starting material concentration is higher than 0.1 mol / L and the reaction temperature is 15°C or higher. In particular, it was found that the disulfide derivative is easily produced when the thiolactone derivative and the coupling reagent are brought into contact and then exposed to an oxidizing agent, for example, in the presence of oxygen (in an air atmosphere). Although the reason is not clear, it is thought that oxidative coupling between two thiol molecules proceeds due to the action of oxygen as an oxidizing agent. In particular, it was found that oxidative coupling is more likely to occur when the thiolactone derivative and the coupling reagent are brought into contact in the presence of copper to increase their reactivity, and then an oxidizing agent (for example, oxygen) is present. Furthermore, when the coupling reagent (Grignard reagent) and the copper salt (including compounds derived from the copper salt), which are used as needed, are brought into contact with an acid after the reaction is complete, it was found that disulfide derivatives can be produced even if an oxidizing agent is present in the system. Moreover, it was found that disulfide derivatives can be produced even when an oxidizing agent is present when the obtained hemithioacetal derivative and ketone derivative are dehydrated to form exocyclic olefin derivatives.

[0012] [Chemical formula]

[0013] Furthermore, the inventors of the present invention have intensively studied methods for removing or reducing this disulfide derivative. As a result, surprisingly, they have found a reaction pathway that not only removes or reduces the disulfide derivative but also converts by-products into the target product. Thus, even if by-products are generated during scale-up, the target product can be recovered from the by-products, enabling the stable production of exocyclic olefin derivatives in high yields and leading to the completion of the present invention.

[0014] That is, the first aspect of the present invention encompasses the following inventions.

[0015] [1] A method for producing an exocyclic olefin derivative, comprising contacting a disulfide derivative represented by the following formula (I) with a reducing agent to produce an exocyclic olefin derivative represented by the following formula (4).

[0016] [Chemical formula]

[0017] In the above formula (I), R 1 and R 2 are each a hydrogen atom, an alkyl group that may have a substituent, an aralkyl group that may have a substituent, or an aryl group that may have a substituent, and R R 3 is -H, -CH3, -C2H5, -OR 4 , -C(=O)OR 4 , -C(=O)-NR 4 2, -CH2-OR 4 , -CH2-C(=O)OR 4 , -CH2-C(=O)-NR 4 2, -CH(CH3)-C(=O)OR 4 , -C2H5-OR 4 , -C2H5-C(=O)OR4 -C2H5-C(=O)-NR 4 2 is a monovalent group or cyano group represented by 2.

[0018] R 4 This is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group, or an optionally substituted aryl group.

[0019] [ka]

[0020] In equation (4) above, R 1 , R 2 and R 3 This is equivalent to what is expressed by formula (I) above.

[0021] [2] The reducing agent is a method for producing an exocyclic olefin derivative according to [1], comprising at least one metal-based reducing agent containing at least one metal selected from the group consisting of zinc, iron, palladium, and nickel; a silane-based reducing agent containing silicon; a reducing gas; a reducing inorganic salt; and a boron-based reducing agent containing boron.

[0022] [3] A method for producing an exocyclic olefin derivative according to [1] or [2], wherein the disulfide derivative represented by formula (I) and the reducing agent are brought into contact in the presence of at least one acid selected from the group consisting of acetic acid, hydrochloric acid, sulfuric acid, nitric acid, trifluoroacetic acid, formic acid, methanesulfonic acid, and p-toluenesulfonic acid.

[0023] [4] A method for producing an exocyclic olefin derivative according to [1] or [2], wherein the disulfide derivative represented by formula (I) and the reducing agent are brought into contact in a temperature range of 0°C to 120°C.

[0024] A second embodiment of the present invention encompasses the following inventions, which are novel compounds.

[0025] [5] Disulfide derivatives represented by the following formula (I).

[0026] [ka]

[0027] In the above formula, R 1 , R 2 , R 3 , and R 4 This is equivalent to equation (I) in [1] above.

[0028] A third embodiment of the present invention encompasses the following inventions.

[0029] [6] A method for producing a disulfide derivative, comprising contacting a thiolactone derivative represented by the following formula (1) with a coupling reagent represented by the following formula (2), and then producing a disulfide derivative represented by the following formula (I). Manufacturing method:

[0030] [ka]

[0031] In the above equation (1), R 1 and R 2 These are, respectively, a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group, or an optionally substituted aryl group.

[0032] [ka]

[0033] In equation (2) above, R 3 These are -H, -CH3, -C2H5, -OR4, -C(=O)OR4, and -C(=O)-NR. 4 2. -CH(CH3)-C(=O)OR 4 -C2H5-OR 4 -C2H5-C(=O)OR4 -C2H5-C(=O)-NR 4 2, which is a monovalent group or cyano group, R 4 This is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group, or an optionally substituted aryl group. X 1 X is a hydrogen atom or a metal atom, 2 It is a halogen atom,

[0034] [ka]

[0035] In the above equation (I), R 1 and R 2 This is equivalent to what is expressed in formula (1) above, and R 3 This is equivalent to what is expressed by formula (2) above.

[0036] [7] A method for producing a disulfide derivative according to [6], comprising contacting a thiolactone derivative represented by formula (1) with a coupling reagent represented by formula (2) to produce at least one compound selected from the group consisting of a hemithioacetal derivative represented by the following formula (3) and a ketone derivative represented by the following formula (I'), and then introducing an oxidizing agent into the reaction system to produce a disulfide derivative represented by formula (I);

[0037] [ka]

[0038] In equation (3) above, R 1 , R 2 and R 3 This is equivalent to what is represented by formulas (1) and (2) above,

[0039] [ka]

[0040] In the above equation (I'), R 1 , R 2 and R 3 This is equivalent to what is expressed by formula (I) above.

[0041] A fourth embodiment of the present invention encompasses the following invention.

[0042] [8] A method for producing an exocyclic olefin derivative, comprising producing a disulfide derivative represented by formula (I) by the method described in [6] or [7] above, and then contacting the obtained disulfide derivative represented by the following formula (I) with a reducing agent to produce an exocyclic olefin derivative represented by the following formula (4):

[0043] [ka]

[0044] In equation (4) above, R 1 , R 2 and R 3 This is equivalent to what is represented by formulas (1) and (2) above.

[0045] [9] A method for producing an exocyclic olefin derivative according to [8], comprising contacting a disulfide derivative represented by formula (I) with a reducing agent in the presence of an acid. [Effects of the Invention]

[0046] The present invention provides a method for increasing the yield of exocyclic olefin derivatives. Furthermore, the present invention facilitates the production of disulfide derivatives by handling the hemithioacetal derivative represented by formula (3) in the presence of an oxidizing agent, for example, in the atmosphere (air atmosphere, in the presence of oxygen).

[0047] Furthermore, by contacting this disulfide derivative with a reducing agent, the target exocyclic olefin derivative can be produced. Therefore, even if the disulfide derivative is produced, it can be converted back into the target product and recovered, thus the method of the present invention is highly robust and suitable for industrial production. [Modes for carrying out the invention]

[0048] [First aspect of the present invention] A first aspect of the present invention relates to a method for producing an exocyclic olefin derivative by contacting a disulfide derivative with a reducing agent in an acid-containing solvent. The details of one embodiment of the first aspect of the present invention will be described in order below.

[0049] <Disulfide derivatives> Disulfide derivatives are compounds represented by the following formula (I). These disulfide derivatives are one of the by-products that can be generated when producing hemithioacetal derivatives (see formula (3) below) from thiolactone derivatives (see formula (1) below) using a coupling reagent (see formula (2) below; Grignard reagent) below. Furthermore, these disulfide derivatives are more easily produced under the following conditions. Specifically, it has been found that disulfide derivatives are more easily produced as a by-product when producing hemithioacetal derivatives by creating an oxidizing agent in the reaction system (for example, in an atmosphere where oxygen is present). Moreover, it is preferable to contact the reaction mixture with an acid after the reaction is complete in order to treat the coupling reagent (Grignard reagent) and the copper salt (including compounds derived from the copper salt) used as needed, and in order to dehydrate the hemithioacetal derivative to produce an exocyclic olefin derivative. In this case, it has been found that disulfide derivatives are more easily produced when an oxidizing agent is present.

[0050] [ka]

[0051] In equation (I), R 1 and R2 These are a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group, or an optionally substituted aryl group, respectively. be.

[0052] R 3 -H, -CH3, -C2H5, -OR 4 , -C(=O)OR 4 -C(=O)-NR 4 2, -CH2-OR 4 -CH2-C(=O)OR 4 -CH2-C(=O)-NR 4 2. -CH(CH3)-C(=O)OR 4 -C2H5-OR 4 -C2H5-C(=O)OR 4 -C2H5-C(=O)-NR 4 2 is a monovalent group or cyano group represented by . 4 This is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group, or an optionally substituted aryl group.

[0053] (R 1 , and R 2 ) Below, R 1 , and R 2The case where each is an alkyl group independently will be described. The alkyl group may be linear or branched. The number of carbon atoms in the alkyl group is, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 6, even more preferably 1 to 3, and particularly preferably 1 or 2. The alkyl group may have substituents. Examples of substituents that an alkyl group may have include aryl groups with 6 to 22 carbon atoms (preferably 6 to 14, more preferably 6 to 10), alkoxy groups with 1 to 6 carbon atoms (preferably 1 to 3, more preferably 1 or 2), halogen groups, etc. The aryl group may be monocyclic or polycyclic (for example, bicyclic or tricyclic). The polycyclic group may be a fused ring. The aryl group is particularly preferably a phenyl group. The alkoxy group may be linear or branched. Examples of halogen groups include fluoro groups, chloro groups, bromo groups, iodo groups, etc. Preferably, substituents on an alkyl group are aryl groups having 6 to 14 carbon atoms, more preferably aryl groups having 6 to 10 carbon atoms, and particularly preferably phenyl groups. When an alkyl group has substituents, the number of substituents is preferably 1 to 5, more preferably 1 to 3, and particularly preferably 1 or 2.

[0054] Below, R 1 and R 2The case where each is an aralkyl group independently will be described. An aralkyl group means an alkyl group having one aryl group. That is, an aralkyl group is an alkyl group in which one of the hydrogen atoms of the alkyl group is substituted with an aryl group. The alkyl group may be linear or branched. The number of carbon atoms in the alkyl group is, for example, 1 to 10, preferably 1 to 6, more preferably 1 to 3, and even more preferably 1 or 2. The number of carbon atoms in the aryl group is, for example, 6 to 22, preferably 6 to 14, and more preferably 6 to 10. The aryl group may be monocyclic or polycyclic (for example, bicyclic or tricyclic). The polycyclic group may be a fused ring. The aryl group is particularly preferably a phenyl group. As the aralkyl group, an aralkyl group having 7 to 11 carbon atoms is preferred. Examples of preferred aralkyl groups include benzyl group, phenylethyl group, phenylpropyl group, phenylbutyl group, naphthylmethyl group, etc. The aralkyl group may have substituents. Examples of substituents that an aralkyl group may have include alkyl groups having 1 to 6 carbon atoms (preferably 1 to 3, more preferably 1 or 2), alkoxy groups having 1 to 6 carbon atoms (preferably 1 to 3, more preferably 1 or 2), carboxyl groups, halogen groups, and the like. Alkyl groups and alkoxy groups may be linear or branched. Examples of halogen groups include fluoro groups, chloro groups, bromo groups, and iodo groups. When an aralkyl group has substituents, the number of substituents is preferably 1 to 5, more preferably 1 to 3, and particularly preferably 1. When an aralkyl group has substituents, either the alkyl portion or the aryl portion of the aralkyl group may have substituents, or both may have substituents, but it is preferable that at least the aryl portion has substituents.

[0055] Below, R 1 or R 2The case where each is an aryl group independently will be described. The aryl group may be monocyclic or polycyclic (for example, bicyclic or tricyclic). The polycyclic group may be a fused ring. The number of carbon atoms in the aryl group is, for example, 6 to 22, preferably 6 to 14, more preferably 6 to 10. The aryl group is particularly preferably a phenyl group. The aryl group may have substituents. Examples of substituents that the aryl group may have include alkyl groups having 1 to 6 carbon atoms (preferably 1 to 3, more preferably 1 or 2), alkoxy groups having 1 to 6 carbon atoms (preferably 1 to 3, more preferably 1 or 2), carboxyl groups, halogen groups, etc. Alkyl groups and alkoxy groups may each be linear or branched. Examples of halogen groups include fluoro groups, chloro groups, bromo groups, iodo groups, etc. When the aryl group has substituents, the number of substituents is preferably 1 to 5, more preferably 1 to 3, and particularly preferably 1.

[0056] Note, R 1 and R 2 Considering that the final deprotection will be performed, it is preferable that the group be an aralkyl group, and particularly preferable that it be a benzyl group.

[0057] (R 3 ) R 3 -H, -CH3, -C2H5, -OR 4 , -C(=O)OR 4 -C(=O)-NR 4 2, -CH2-OR 4 -CH2-C(=O)OR 4 -CH2-C(=O)-NR 4 2. -CH(CH3)-C(=O)OR 4 -C2H5-OR 4 -C2H5-C(=O)OR 4 -C2H5-C(=O)-NR 4 2 is a monovalent group or cyano group represented by 2.

[0058] The aforementioned R 3 Under the basis of R4 is a hydrogen atom, an alkyl group which may have a substituent, an aralkyl group which may have a substituent, or an aryl group which may have a substituent. R 4 In, the alkyl group which may have a substituent, the aralkyl group which may have a substituent, and the aryl group which may have a substituent are the same groups as those described for the <R 1 , and R 2 >, and the preferred groups are also the same. R 4 is particularly preferably an alkyl group.

[0059] Among the above groups, R 3 is preferably -OR 4 , and at this time, R 4 is preferably an alkyl group. That is, R 3 is preferably an alkoxy group having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, still more preferably 1 to 3 carbon atoms, and particularly preferably 1 or 2 carbon atoms.

[0060] <Preferred disulfide derivative> Among the disulfide derivatives represented by the formula (I), [(4R,4’R,5S,5’S)-4,4’-[disulfanediyldibis(methylene)bis(1,3-dibenzyl-5-(4-methoxybutanoyl)imidazolidin-2-one] represented by the following formula (IA) can be mentioned as a preferred one. The disulfide derivative represented by the formula (IA) is a case where in the disulfide derivative represented by the formula (I), R 1 and R 2 are both benzyl groups (-Bn), and R 3 is -OR 4 (R 4 is a methyl group. That is, R 3 is a methoxy group).

[0061]

Chemical formula

[0062] The disulfide derivative represented by formula (I) is a novel compound and corresponds to the second embodiment of the present invention. Naturally, the disulfide derivative represented by formula (IA) is also a novel compound.

[0063] <Reducing agent> The reducing agent acts on at least the disulfide bond (SS) in the disulfide derivative represented by formula (I) above. This reducing agent includes at least one selected from the group consisting of a metal-based reducing agent containing at least one metal selected from the group consisting of zinc, iron, palladium, and nickel; a silane-based reducing agent containing silicon; a reducing gas (hydrogen gas, carbon monoxide gas, hydrocarbon gas); a reducing inorganic salt (sodium sulfite, sodium bisulfite, sodium thiosulfate); and a boron-based reducing agent containing boron (sodium borohydride, sodium cyanoborate, etc.).

[0064] Among these, metal-based reducing agents containing zinc, reducing inorganic salts such as sodium sulfite and sodium thiosulfate, and boronating reducing agents such as sodium borohydride are preferred, and metal-based reducing agents containing zinc are even more preferred.

[0065] Metallic reducing agents containing zinc can be used in combination with solvents containing acids (hereinafter also referred to as "acid solvents") as described later. Furthermore, by using a metallic reducing agent containing zinc, it is possible to suppress the side reaction in which the ketone group of the intermediate (derivative represented by formula (I') described later) produced by the reduction of the disulfide derivative is converted into an impurity (formula (I''')) in which the ketone group is reduced to an alcohol group, thereby increasing the recovery rate of the target product. In addition, using a metallic reducing agent containing zinc is preferable because it allows the process to proceed to the dehydration step, which is the next step after the reduction step, thus eliminating the need for a new dehydration step.

[0066] [ka]

[0067] Furthermore, when a reducing agent such as sodium sulfite or sodium borohydride is used, the yield (production rate) of the exocyclic olefin derivative can be increased without the use of acid. However, the boron reducing agent can also be used in the presence of acid.

[0068] <Solvent> The contact between the disulfide derivative represented by formula (I) and the reducing agent is preferably carried out in a solvent. Specifically, the following solvents are preferred.

[0069] Ether-based solvents: tetrahydrofuran (THF), diethyl ether, isopropyl ether, methyl tert-butyl ether (MTBE), cyclopentyl methyl ether (CPME), 4-methyltetrahydrofuran (MTHP), etc. Alcohol-based solvents: methanol, ethanol, propyl alcohol, butanol, etc. Aprotic polar solvents: dimethylformamide (DMF), N,N-dimethylformamide (DMA), etc. Aprotic nonpolar solvents: Toluene, hexane, heptane, etc. These are some examples.

[0070] <acid> In the present invention, in order to increase the yield of the exocyclic olefin derivative represented by formula (4), it is preferable to carry out the contact between the disulfide derivative represented by formula (I) and the reducing agent in the presence of an acid. During the contact between the disulfide derivative and the reducing agent, hemithioacetal derivatives and ketone derivatives, which are described in detail below, may be formed. It is thought that the presence of an acid causes dehydration of the hemithioacetal derivative and ketone derivative, and that these become exocyclic olefin derivatives, thereby increasing the yield of the exocyclic olefin derivative.

[0071] Specifically, the following acids can be used.

[0072] Organic acids: Formic acid, acetic acid, propionic acid, butyric acid, pivalic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. Inorganic acids: Hydrogen chloride (hydrochloric acid), hydrogen brominated water, sulfuric acid, nitric acid, etc.

[0073] Among these, acetic acid, hydrochloric acid, sulfuric acid, nitric acid, trifluoroacetic acid, formic acid, methanesulfonic acid, and p-toluenesulfonic acid are preferred because they are acids that can dissolve or dehydrate hemithioacetal derivatives and ketone derivatives. Considering post-treatment, formic acid and acetic acid are more preferred. Even if hemithioacetal derivatives and ketone derivatives are formed by contacting the disulfide derivative with a reducing agent, these acids can dehydrate them, allowing them to be converted into exocyclic olefin derivatives.

[0074] These acids can also be used as substitutes for the aforementioned solvents. In other words, under certain conditions, it is possible to use only these acids as solvents.

[0075] <Method of contact between disulfide derivatives and reducing agents (method for producing exocyclic olefin derivatives)> In this embodiment, an exocyclic olefin derivative can be produced by contacting a disulfide derivative with a reducing agent and reacting them. In this case, the components should be mixed so that they come into sufficient contact. The method of the present invention can be carried out under atmospheric pressure, reduced pressure, or pressurized conditions. Furthermore, the method of the present invention can be carried out not only in the presence of oxygen such as oxygen or air, but also in an inert gas atmosphere such as nitrogen, argon, or carbon dioxide.

[0076] The method of mixing each component is not particularly limited. For example, all components may be added to the reaction apparatus and mixed simultaneously. Alternatively, one component may be mixed beforehand, and the remaining components may be added sequentially and mixed. Each component can also be diluted with a solvent before being supplied to the reaction apparatus.

[0077] The amount of reaction solvent used is the amount when all components are mixed, but in order to facilitate contact with the reducing agent, it is preferable to use 0.1 ml to 300 ml of solvent per 1 g of the reaction mixture containing the disulfide derivative, and more preferably 1 ml to 40 ml.

[0078] While there are no particular restrictions on the amount of reducing agent used, it is preferable to use 0.1 moles to 100 moles, and more preferably 0.3 moles to 20 moles, in order to allow the reaction to proceed sufficiently and to obtain a high yield of the exocyclic olefin derivative per mole of disulfide derivative.

[0079] The temperature range for contacting the disulfide derivative with the reducing agent is not particularly limited, but it is preferably between 0°C and 200°C, and more preferably between 10°C and 140°C.

[0080] The reaction time is not limited and can be determined as appropriate while checking the reaction conversion rate described in the examples below. However, under the above reaction conditions, the reaction time is preferably between 1 minute and 72 hours, and between 1 minute and 24 hours.

[0081] In the present invention, the disulfide derivative can also be brought into contact with a reducing agent in the presence of an acid. As described above, the hemithioacetal derivative and ketone derivative produced by the contact of the disulfide derivative with the reducing agent can be obtained as an exocyclic olefin derivative.

[0082] When an acid is used, the amount of the acid used is not particularly limited. However, in order to sufficiently proceed with the reaction and increase the yield of the exocyclic olefin derivative with respect to 1 mol of the disulfide derivative, it is preferably 0.1 mol or more and 1000 mol or less, and more preferably 1 mol or more and 200 mol or less. When an acid is used, the above-preferred amount is the amount of the acid itself. For example, when an aqueous solution such as hydrochloric acid is used, it is the amount of hydrogen chloride itself. When 10% by mass of hydrochloric acid is used, the amount of hydrogen chloride contained is preferably 0.1 mol or more and 1000 mol or less with respect to 1 mol of the disulfide derivative. Further, when an organic acid such as formic acid or acetic acid is used, the organic acid itself can be used instead of the solvent.

[0083] Suitable mixing methods, reaction temperatures, and reaction times when an acid is used may be the same conditions as those when the disulfide derivative and the reducing agent are brought into contact with each other.

[0084] The exocyclic olefin derivative obtained by the above method can be purified by a known method.

[0085] <Exocyclic olefin derivative> The exocyclic olefin derivative obtained by bringing the disulfide derivative and the reducing agent into contact with each other is a compound represented by the following formula (4).

[0086]

Chemical formula

[0087] Here, R [[ID=2?]] 1 、R 2 and R 3 are synonymous with those represented by the above formula (I).

[0088] <Preferred exocyclic olefin derivative> Among the exocyclic olefin derivatives represented by formula (4), the exocyclic olefin derivative represented by the following formula (4A) is preferred. The exocyclic olefin derivative represented by formula (4A) is an exocyclic olefin derivative represented by formula (4), where R 1 and R 2 Both are benzyl groups (-Bn), and R 3 This is an example of a methoxy group (-OMe).

[0089] [ka]

[0090] In the present invention, as described above, when producing an exocyclic olefin derivative by contacting a disulfide derivative with a reducing agent, hemithioacetal derivatives and ketone derivatives may also be produced. These derivatives can be converted into exocyclic olefin derivatives by dehydration treatment. Next, these hemithioacetal derivatives and ketone derivatives will be described.

[0091] <Hemithioacetal derivatives> A hemithioacetal derivative is a compound represented by the following formula (3). This hemithioacetal derivative may be produced simultaneously when producing an exocyclic olefin derivative by contacting a disulfide derivative with a reducing agent.

[0092] [ka]

[0093] Here, R 1 , R 2 and R 3 This is equivalent to what is expressed by formula (I) above.

[0094] <Suitable hemithioacetal derivatives> Among the hemithioacetal derivatives represented by formula (3), (3aS,6aR)―1,3-dibenzyl-4-hydroxy-4-(3-methoxypropyl)tetrahydro-1H-thieno[3,4-d]imidazole-2(3H)-one, represented by the following formula (3A), is preferred. The hemithioacetal derivative represented by formula (3A) is a hemithioacetal derivative represented by formula (3), where R 1 and R 2 Both are benzyl groups (-Bn), and R 3 This is an example of a methoxy group (-OMe).

[0095] [ka]

[0096] <Ketone derivatives> The ketone derivative is a compound represented by the following formula (I'). This ketone derivative is a byproduct obtained by contacting and reacting the disulfide derivative with the reducing agent.

[0097] [ka]

[0098] Here, R 1 , R 2 and R 3 This is equivalent to what is expressed by formula (I) above.

[0099] <Suitable ketone derivatives> Among the ketone derivatives represented by formula (I'), the ketone derivative represented by the following formula (I'A) is preferred. The ketone derivative represented by formula (I'A) is characterized in that, in the ketone derivative represented by formula (I'), R 1 and R 2 Both are benzyl groups (-Bn), and R 3 This is an example of a methoxy group (-OMe).

[0100] [ka]

[0101] The hemithioacetal derivatives and ketone derivatives described above can be converted into exocyclic olefin derivatives by dehydration. Therefore, there is no problem even if these derivatives are obtained when disulfide derivatives are brought into contact with a reducing agent. Furthermore, it is presumed that hemithioacetal derivatives and ketone derivatives are unaffected even when in contact with a reducing agent.

[0102] When dehydrating hemithioacetal derivatives and ketone derivatives with acid, the same acids as those described above can be used. In particular, formic acid and acetic acid are preferred when considering post-treatment. The amount of acid used is, for example, 0.1 moles to 1000 moles, preferably 1 mole to 200 moles, when the total number of moles of hemithioacetal derivatives and ketone derivatives is considered as 1 mole. The temperature during acid treatment is not particularly limited, but is usually 0°C to 200°C, preferably 10°C to 140°C. The reaction time is, for example, 1 minute to 72 hours, preferably 1 minute to 24 hours.

[0103] [Third Embodiment of the Present Invention] A third embodiment of the present invention relates to a method for producing a disulfide derivative represented by formula (I) by contacting a thiolactone derivative represented by formula (1) below with a coupling reagent represented by formula (2) below and, optionally, a copper salt. The details of the third embodiment of the present invention will be described in order below. Note that redundant explanations of elements that are substantially the same as those described in the first embodiment will be omitted.

[0104] <Thiolactone derivatives> Thiolactone derivatives are compounds represented by the following formula (1).

[0105] [ka]

[0106] Here, R 1 and R 2 This is synonymous with the one represented by formula (I) above. Among the thiolactone derivatives represented by formula (1), considering their usefulness, the thiolactone derivative represented by the following formula (1A) ((3aS,6aR)-1,3-dibenzyltetrahydro-1H-thieno[3,4-d]imidazole-2,4-dione) is preferred. The lactone derivative represented by formula (1A) is the same as the lactone derivative represented by formula (1), where R 1 and R 2 Both are examples of the benzyl group (-Bn).

[0107] [ka]

[0108] <Coupling reagents> The coupling reagent is a compound represented by the following formula (2).

[0109] [ka]

[0110] In equation (2) above, R 3 This is equivalent to what is expressed by the above formula (I), and X 1 X is a hydrogen atom or a metal atom, 2 The atom is a halogen atom. Suitable metal atoms include, for example, magnesium and zinc. Suitable halogen atoms include, for example, chlorine, bromine, and iodine atoms. Due to its usefulness, magnesium chloride (3-methoxypropyl) can be suitably used as a coupling reagent.

[0111] By mixing and contacting the thiolactone derivative with the coupling reagent, hemithioacetal derivatives and ketone derivatives can be produced. In this case, depending on the reaction conditions, disulfide derivatives can also be produced. In particular, in order to increase the reaction efficiency between the thiolactone derivative and the coupling reagent and to increase the yield of disulfide derivatives, hemithioacetal derivatives, and ketone derivatives, it is preferable to include the copper salt described below in the reaction system.

[0112] <copper salts> The coupling reaction can be facilitated by further contacting the thiolactone derivative with the zinc reagent using a copper salt. The copper salt is not particularly limited, and either monovalent or divalent copper compounds can be used as a copper catalyst. Examples of specific copper catalysts include copper(I) chloride, copper(II) chloride, copper(I) bromide, copper(II) bromide, copper(I) cyanide, copper(I) 3-methylsalicylate, copper(I) mesitylene, copper(I) isopropoxy, copper(I) iodide, copper(II) iodide, copper(I) acetate, copper(II) acetate, copper(II) sulfate, copper(I) oxide, copper(II) oxide, copper(I) pivalate, and copper(II) pivalate. The copper catalyst in this reaction is preferably a monovalent copper compound, and more preferably a monovalent copper halide containing a halogen atom.

[0113] The amount of copper salt used can be determined as appropriate, but it is preferable to use 0.01 to 10 moles relative to the thiolactone derivative, more preferably 0.1 to 8 moles, and particularly preferably 1.0 to 5 moles. Naturally, the copper salt can be added later depending on the progress of the reaction, or it can be added in portions while monitoring the progress of the reaction.

[0114] <Solvent> The solvent used can be the same as that described in the reduction reaction of the disulfide derivative represented by formula (I), and a detailed explanation is omitted here. The amount of solvent used is not particularly limited, and is, for example, 0.1 mL to 300 mL per 1 g of thiolactone derivative, preferably 1 mL to 40 mL.

[0115] <Preferred method for producing disulfide derivatives> According to studies of the present invention, when a thiolactone derivative is brought into contact with a coupling reagent and a copper salt, a disulfide derivative represented by formula (1) can be produced depending on the reaction conditions. Among these, the following method is preferred.

[0116] Specifically, a thiolactone derivative is brought into contact with a coupling reagent and, if necessary, a copper salt to produce at least one compound selected from the group consisting of a hemithioacetal derivative represented by formula (3) and a ketone derivative represented by formula (I'). After producing these hemithioacetal derivatives and / or ketone derivatives, it is preferable to have an oxidizing agent present in the reaction system.

[0117] It is presumed that the presence of an oxidizing agent facilitates the occurrence of oxidative coupling, as described in "Means for Solving the Problem." To induce this oxidative coupling, the hemiothioacetal derivative and / or ketone derivative should be in the form of a radical derivative (radical form). Therefore, it is also possible to consider a temperature range in which they become radical forms. However, considering ease of operation, it is preferable to have an oxidizing agent present in the reaction system. In particular, it is preferable to have the oxidizing agent in the presence of an oxygen-containing atmosphere (for example, an air atmosphere) as this improves ease of operation.

[0118] Furthermore, the reaction between the thiolactone derivative and the coupling reagent to produce the hemithioacetal derivative and / or the ketone derivative can be carried out under an oxidizing atmosphere in the initial or intermediate stage. However, considering the yield and operability of the disulfide derivative, it is preferable to first produce the hemithioacetal derivative and / or the ketone derivative and then carry out the reaction under an oxidizing atmosphere. After producing the hemithioacetal derivative and / or the ketone derivative, the disulfide derivative can be produced by leaving the reaction mixture under an oxidizing atmosphere. In particular, the following production method is preferred.

[0119] After contacting the thiolactone derivative with a coupling reagent and, if necessary, a copper salt, the coupling reagent is treated and, if necessary, the copper salt is treated. Therefore, the reaction mixture (a mixture containing the derivative obtained in the reaction, the coupling agent used in the reaction, and the copper salt) is brought into contact with an acid. In this case, it is preferable to bring the reaction mixture and the acid into contact in the presence of an oxidizing agent (under conditions where oxygen is present, for example, in an air atmosphere). It has been found that treating the reaction mixture with acid in the presence of an oxidizing agent does not adversely affect the formation of the disulfide derivative. Therefore, in order to increase the yield of the disulfide derivative, hemithioacetal derivative, and / or the ketone derivative and to further improve operability, it is preferable to employ the following method.

[0120] First, preferred reaction conditions for the thiolactone derivative and the coupling reagent will be described. To prevent deactivation of the coupling reagent, it is preferable to first mix the thiolactone derivative, the coupling reagent, and the copper salt (if used) in an inert gas atmosphere such as nitrogen, argon, or carbon dioxide, ensuring sufficient contact. The method of mixing each component is not particularly limited. For example, all components may be added to the reaction apparatus simultaneously and mixed. Alternatively, one component may be mixed beforehand, and the remaining components added sequentially and mixed. Each component can also be diluted with a solvent before being supplied to the reaction apparatus. The reaction conditions described in Patent Document 1 can be adopted.

[0121] In the aforementioned inert gas atmosphere, hemithioacetal derivatives and ketone derivatives are produced. Subsequently, it is preferable to carry out the reaction in the presence of an oxidizing agent (for example, in an atmosphere where oxygen is present). That is, first, hemithioacetal derivatives and ketone derivatives are produced under conditions in an inert gas atmosphere, such that the coupling reagent and the copper salt used as needed are not deactivated. Then, when the reaction mixture is brought into contact with an acid, the disulfide derivatives can be suitably produced by maintaining the reaction in the presence of an oxidizing agent.

[0122] The reaction mixture is thought to contain, in addition to the disulfide derivative, hemithioacetal derivative, and ketone derivative, an intermediate represented by the following formula (3'). Furthermore, it is thought to contain a compound represented by formula (I'''').

[0123] [ka]

[0124] Here, R 1 , R 2 and R 3 This is equivalent to what is expressed by formula (I) above.

[0125] In the present invention, the oxidizing agent is not particularly limited, and known oxidizing agents can be used. Specifically, examples include oxygen, ozone, hydrogen peroxide, cumene hydroperoxide, sodium percarbonate, acetone peroxide, benzoyl peroxide, peracetic acid, di-tert-butyl peroxide, dimethyldioxirane, dimethyl sulfoxide, sulfuryl chloride, hypochlorous acid, chlorosuccinimide, bromine, bromosuccinimide, iodine, iodosuccinimide, and potassium ferricyanide. In particular, to obtain a disulfide derivative with good operability, it is preferable to contact the reaction mixture and the acid in an oxygen-containing atmosphere within the reaction system, for example, in the presence of air. The reaction should proceed in the presence of the oxidizing agent, for example, in the presence of air, for a time sufficient for the disulfide derivative to be produced. The reaction time at this time is preferably 1 minute or more and 72 hours or less. The temperature at which the acid and the reaction mixture are contacted in an oxidizing agent atmosphere is not particularly limited, for example, 0°C or more and 100°C or less, preferably 0°C or more and 70°C or less. As mentioned above, disulfide derivatives can also be produced by leaving the reaction mixture in the presence of an oxidizing agent in the absence of acid. In this case, the reaction time and conditions can be the same as those used when acid is involved.

[0126] In contacting the reaction mixture with the acid, the acid used is not particularly limited, and the same acid described in the first embodiment can be used. In particular, for processing the coupling reagent and obtaining the intermediate represented by formula (Ia) as a hemithioacetal derivative, it is preferable to use an inorganic acid such as 10 wt% hydrochloric acid or 10 wt% sulfuric acid. The amount of acid used is also not particularly limited, for example, 0.1 moles to 1000 moles per mole of thiolactone derivative, preferably 1 mole to 200 moles. The method of acid contact is also not particularly limited; the entire amount of acid can be brought into contact at once, or it can be brought into contact in multiple stages. Alternatively, the reaction mixture may be dissolved in a poorly water-soluble solvent such as toluene or xylene and brought into contact with an aqueous solution of the acid.

[0127] Furthermore, after processing the coupling reagent and intermediate with the aforementioned acid, the hemithioacetal derivative and ketone derivative can be contacted with an organic acid (a preferred organic acid as described in the first embodiment) for the purpose of dehydrating them (for the purpose of producing an exocyclic olefin derivative). Disulfide derivatives can also be produced by contacting them with an organic acid in the presence of an oxidizing agent. The conditions for using the organic acid are the same as those for using it in combination with a reducing agent in the "first embodiment," and the preferred conditions are also the same. In addition, when using an oxidizing agent, the same conditions as described above can be used, and the preferred conditions are also the same.

[0128] In the present invention, by contacting the reaction mixture with an acid under the above conditions in an air atmosphere, disulfide derivatives can be produced efficiently and with good operability.

[0129] In addition, hemithioacetal derivatives, ketone derivatives, and exocyclic olefin derivatives may also be produced during the production of disulfide derivatives. Exocyclic olefin derivatives are the target products, and hemithioacetal derivatives and ketone derivatives can be converted to exocyclic olefin derivatives by dehydration. Therefore, the presence of these derivatives in the reaction system does not pose any problem.

[0130] [Fourth Embodiment of the Present Invention] Next, a fourth embodiment will be described.

[0131] In the present invention, a disulfide derivative is produced from a thiolactone derivative according to the method described above (third embodiment), and the obtained disulfide derivative is brought into contact with a reducing agent. By bringing the disulfide derivative into contact with the reducing agent, an exocyclic olefin derivative represented by formula (4) can be produced. The conditions for contacting these can be those of the first embodiment. Furthermore, if the disulfide derivative is consistently produced from a thiolactone derivative, the hemithioacetal derivative and / or the ketone derivative may be present when it is brought into contact with the reducing agent. Moreover, the exocyclic olefin derivative may also be present.

[0132] When disulfide derivatives are produced from thiolactone derivatives, the conditions of the first embodiment can be adopted. However, when considering the thiolactone derivative as the basis, it is preferable to adopt the following conditions. For example, the amount of solvent used is preferably 0.1 ml to 300 ml per 1 g of thiolactone derivative, and more preferably 1 ml to 40 ml.

[0133] While there are no particular restrictions on the amount of reducing agent used, it is preferable to use 0.1 moles to 100 moles per mole of thiolactone derivative, and more preferably 0.3 moles to 20 moles, in order to allow the reaction to proceed sufficiently and to obtain a high yield of the exocyclic olefin derivative.

[0134] The temperature range and reaction time when contacting the disulfide derivative with the reducing agent can be the same as those described in the first embodiment.

[0135] Furthermore, in the fourth embodiment, since it is assumed that the hemithioacetal derivative and / or the ketone derivative are present, it is preferable to contact the disulfide derivative with the reducing agent in the presence of an acid. When using an acid, the conditions of the first embodiment can be adopted. When using an organic acid, the organic acid itself can be used as the solvent. For this reason, it is preferable to use formic acid, acetic acid, etc.

[0136] When considering the thiolactone derivative as the basis, the amount of acid used is, for example, 0.1 moles to 1000 moles of acid, preferably 1 mole to 200 moles, per mole of thiolactone derivative. In the presence of acid, the temperature range and reaction time can be the same as those described in the first embodiment.

[0137] The exocyclic olefin derivatives obtained by the above method can be purified by known methods. [Examples]

[0138] The present invention will be described in detail below with reference to examples. The examples listed below are merely specific examples of the present invention, and the present invention is not limited thereto.

[0139] <Ultra-high-performance liquid chromatography analysis> The purity of the examples and comparative examples was calculated and evaluated using the following ultra-high performance liquid chromatography (UPLC) method.

[0140] Equipment: ACQUITY UPLC (registered trademark) H-CLASS PLUS (Waters) Column: ACQUITY UPLC BEH C18 Column, 130A, 1.7μm, 2.1mm x 50 mm Guard column: ACQUITY UPLC@ BEH C18, 1.7 μm, VANGUARD Pre-Col Column temperature: 40℃ Sample temperature: Room temperature Sample injection volume: 1.0 μL Fluid delivery time: 6 minutes Detector: Ultraviolet-Vis absorbance spectrophotometer (PDA) Detection wavelength: 254nm) Detector: Mass spectrometer (QDa) Ionization mode: ESI positive Capillary voltage: 0.8kV Office voltage (sample cone voltage): 20 V Mass range: 60 - 600 Da Probe temperature: 600 °C.

[0141] The liquid feeding of the mobile phase was as described in Table 1 below. Also, the retention time was as shown in Table 2.

[0142]

Table 1

[0143]

Table 2

[0144] <Assay analysis> A high-purity sample obtained by column purification or crystallization was analyzed as a standard, and the concentration of the unknown sample in the solution was determined based on the following formula (i). (Unknown sample concentration mg / mL) = (area% of unknown sample peak) / (area% of standard sample peak) * (concentration of standard sample peak mg / mL) ····· (i).

[0145] The calculation formula for assay analysis is as shown in the following formula (ii). (Assay yield%) = (unknown sample concentration mg / mL) * (unknown sample volume mL) * (weight of mother liquor of unknown sample g) / (weight of collected unknown sample g) / (theoretical weight mg at 100% yield) * 100 ····· (ii).

[0146] <NMR analysis> Instrument: JNM-ECA400II (JEOL RESONANCE shasei 400MHz FT-NMR) Elements: 1 H and 13 C Type: solution Heavy solvent: CHLOROFORM-D.

[0147] (Example 1): Side reaction in the synthesis of an exocyclic olefin derivative (4A) from a thiolactone derivative (1A) <Method for producing disulfide derivatives>

[0148] [ka]

[0149] A 100 mL four-necked flask, heated and dried under vacuum, was sealed with nitrogen gas and copper(I) chloride (0.878 g, 8.86 mmol, 1.00 equiv.) was added. Super-dehydrated THF (9.0 mL, 3.0 v / w) was added, the mixture was stirred for 10 minutes, and cooled to 0°C. Magnesium chloride (3-methoxypropyl) (15.6 mL, 0.850 mol / L, 1.50 equiv.) was added dropwise over 10 minutes and the mixture was stirred. A THF solution of thiolactone derivative (1A, 3.00 g, 8.86 mmol, 1.00 equiv.) (22.5 mL, 22.5 v / w) was added dropwise at an internal temperature of 3-7°C and the mixture was stirred at 0°C for 1 hour.

[0150] After confirming the completion of the reaction by ultra-high performance liquid chromatography, the reaction system was opened, and toluene (30 mL, 10.0 v / w) was added in the presence of air (atmosphere), and the mixture was cooled to 0°C. 10% hydrochloric acid aqueous solution (30 mL, 10.0 v / w) was added dropwise at an internal temperature of 3-8°C, and the solution was raised to room temperature. After stirring for 1 hour, the organic phase and aqueous phase were separated, and the organic phase was further washed once with 10% hydrochloric acid aqueous solution (30 mL, 10.0 v / w) and three times with 30% ammonium chloride aqueous solution (30 mL, 10.0 v / w). 10% hydrochloric acid aqueous solution (30 mL, 10.0 v / w) was added to this organic phase (a mixed solution of 3A and I'A), and the mixture was stirred at 50°C for 5 hours.

[0151] Next, the mixture was cooled to room temperature to separate the organic and aqueous phases, and the organic phase was washed once with a 10% saline solution (30 mL, 10.0 v / w). The organic phase was dehydrated with anhydrous magnesium sulfate, and the solid was removed by filtration to obtain the solution.

[0152] Assay analysis using ultra-high-performance liquid chromatography with this solution yielded 71.6% for the target product, the exocyclic olefin derivative (4A), and 26.8% for the disulfide derivative (IA). Contact with aqueous hydrochloric acid confirmed that the reaction partially progressed to dehydration, resulting in the production of the exocyclic olefin derivative.

[0153] The results of the NMR analysis were as follows:

[0154] • Exocyclic olefin derivative (3A) 1 H-NMR(400MHz CHLOROFORM-d);δ 7.35-7.26(m,10H),5.50(t,1H),4.96(d,J=16.7Hz,1H),4.79(d,J=16.7Hz,1H),4.29(d, 1H),4.22(d,J=15.1 Hz,1H),4.08-4.04 (m, 2H),3.37(td,J=6.5,2.4Hz,2H),3.34(s,3H),2.99-2.95(m,2H),2.37-2.25(m,2H). 13 C-NMR(100MHz,CHLOROFORM-d);δ 207.4,160.1,136.9,135.8,128.8,128.6,128.0,127.9, 127.8,71.0,62.9,58.4,55.3,46.5,40.0,34.3, 22.8. ESI positive m / z 395.18 (M+H+).

[0155] • Disulfide derivatives (IA) 1H-NMR(400MHz,CHLOROFORM-d);δ 7.33-7.15(m,20H),5.04(d,J=15.6Hz,2H),4.68(d,J=15.6Hz,2H),4.17(d,J= 15.1 Hz,2H),3.99(d,J=8.2Hz,2H),3.79-3.74(m,4H),3.32-3.25(m,6H),3.23(s,6H),2.48-2.36(m,6H),2.26-2.18(m,2H),1.76-1.62(m, 6H). 13 C-NMR(100MHz,CHLOROFORM-d);δ 158.9,138.3,137.2,137.2,128.7,128.6,128.0,127.9, 127.6,127.3,123.4,71.3,64.6,59.0,58.5,46.5, 44.7, 37.2, 32.0. ESI positive m / z 823.35 (M+H+).

[0156] (Example 2): Contact between disulfide derivative and reducing agent <Method for producing exocyclic olefin derivatives>

[0157] [ka]

[0158] A THF solution was prepared by dissolving a mixture containing the exocyclic olefin derivative (4A) and disulfide derivative (IA) prepared in Example 1 in THF (the amount of THF relative to the mass of the mixture was 20 mL. The mass of the exocyclic olefin derivative (4A), calculated from the assay yield, was 2.41 g and 6.12 mmol, and the mass of the disulfide derivative (IA) was 0.39 g and 0.47 mmol). (For reference, Table 3 shows the peak areas of each component in this THF solution obtained by ultra-high-performance liquid chromatography.)

[0159] Next, 1 ml of the THF solution was heated to 50°C, and 1 ml of 10 wt% Na2SO3 aqueous solution (0.10 g, 0.793 mmol, 33.6 equiv relative to (IA)) was added as a reducing agent. The mixture was stirred for 21 hours to bring it into contact with the reducing agent. The reaction conditions and the results of analyzing the solution in contact with the reducing agent by ultra-high-performance liquid chromatography are shown in Table 3.

[0160] Examples 3, 4, and Comparative Example 1 Example 3 and Comparative Example 1 used the same THF solution containing the exocyclic olefin derivative (4A) and disulfide derivative (IA) as used in Example 2. In Example 4, a methanol solution of the same mixture containing the exocyclic olefin derivative (4A) and disulfide derivative (IA) as in Example 2 (with the same concentrations as the THF solution) was used.

[0161] In Example 3, 1 ml of acetic acid (57.2 mmol, 744 equiv relative to (IA)) was added to the mixture in Example 2, the temperature was raised to 70°C, and at the same temperature, zinc (165 mg, 2.52 mmol, 107.2 equiv relative to (IA)) was added as a reducing agent and the mixture was reacted for 24 hours.

[0162] In Example 4, NaBH4 (8.96 mg, 0.237 mmol, 10 equiv. (IA)) was added as a reducing agent to a methanol solution of the same concentration as in Example 2, and the mixture was reacted for 24 hours at a temperature of 25°C.

[0163] Comparative Example 1 is an example in which 1 ml of acetic acid was added to Example 3 and the mixture was reacted at 20°C for 1 hour.

[0164] [Table 3]

[0165] Compared to the reference example, it can be seen that the amount of exocyclic olefin (4A) is increased in all of Examples 2 to 4.

[0166] (Example 4): Synthesis of an exocyclic olefin derivative (4A) from a thiolactone derivative (1A)

[0167] [ka]

[0168] A 2000 mL four-necked flask, heated and dried under vacuum, was continuously supplied with nitrogen gas at 0.15 L / min until the workup, maintaining a nitrogen atmosphere. Thiolactone derivative (1A, 34.0 g, 100 mmol, 1.00 equiv.), copper(I) chloride (9.95 g, 100 mmol, 1.00 equiv.), and super-dehydrated THF (340 mL, 10.0 v / w) were added, and the mixture was cooled to 0°C and stirred. Magnesium chloride (3-methoxypropyl) (286 mL, 0.563 mol / L, 1.60 equiv.) was added dropwise over 25 minutes at an internal temperature of 0-5°C. The mixture was stirred at an internal temperature of 0-5°C for 1 hour, and the completion of the reaction was confirmed by ultra-high-performance liquid chromatography analysis.

[0169] Next, under an air atmosphere, toluene (340 mL, 10.0 v / w) was added, and 10% hydrochloric acid aqueous solution (340 mL, 10.0 v / w) was added dropwise at an internal temperature of 0-10°C, and the solution was raised to room temperature. After stirring for 2 hours, the organic phase and aqueous phase were separated, and the organic phase was further washed four times with 30% ammonium chloride aqueous solution (374 mL, 11.0 v / w, per wash) and once with 10% saline solution (340 mL, 10.0 v / w). The organic phase was dehydrated with anhydrous magnesium sulfate, and the solid was removed by filtration to obtain the solution. The solvent was removed from this solution under reduced pressure to obtain a crude product containing disulfide derivative (IA) (crude product containing hemithioacetal derivative (3A) and ketone derivative (I'A)) (45.0 g).

[0170] Furthermore, acetic acid (360 mL, 12.2 v / w) was added to the crude mixture and dissolved. The internal temperature was raised from 20°C to 80°C, and the mixture was stirred at the same temperature for 1 hour and 30 minutes. Zinc (9.96 g, 1.50 equiv.) was added at the same temperature and the mixture was stirred for a further 2 hours and 30 minutes, and the completion of the reaction was confirmed by ultra-high-performance liquid chromatography analysis.

[0171] The solution was cooled from 80°C to room temperature, and toluene (340 mL, 10.0 v / w) and Celite (15 g, 0.44 w / w) were added. This solution was filtered through a filter loaded with Celite and washed with toluene (340 mL, 10.0 v / w). After removing the solvent under reduced pressure, toluene (340 mL, 10.0 v / w) was added, and the mixture was washed once with 10% hydrochloric acid aqueous solution (340 mL, 10.0 v / w), three times with saturated sodium bicarbonate aqueous solution (340 mL, 10.0 v / w per wash), and once with 10% saline solution (340 mL, 10.0 v / w). The organic phase was dehydrated with anhydrous magnesium sulfate, and the solid was removed by filtration to obtain the solution. The solvent was removed from this solution under reduced pressure to obtain the crude exocyclic olefin derivative (4A) (40.1 g, isolation yield 101%, assay yield 97.2%).

Claims

1. A method for producing an exocyclic olefin derivative, comprising contacting a disulfide derivative represented by the following formula (I) with a reducing agent to produce an exocyclic olefin derivative represented by the following formula (4): 【Chemistry 1】 In the above formula (I), R １ and R ２ Each of these may have a hydrogen atom or a substituent. A aryl group, an optionally substituted aralkyl group, or an optionally substituted aryl group. R ３ is a monovalent group represented by -H, -CH ３ , -C ２ H ５ , -OR ４ , -C(=O)OR ４ , -C(=O)-NR ４ ２ , -CH ２ -OR ４ , -CH ２ -C(=O)OR ４ , -CH ２ -C(=O)-NR ４ ２ , -CH(CH ３ )-C(=O)OR ４ , -C ２ H ５ -OR ４ , -C ２ H ５ -C(=O)OR ４ , -C ２ H ５ -C(=O)-NR ４ ２ , or a cyano group. R ４ This is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group, or an optionally substituted aryl group. 【Chemistry 2】 In the above formula (4), R １ , R ２ and R ３ This is equivalent to what is expressed by formula (I) above.

2. The reducing agent comprises at least one selected from the group consisting of a metal-based reducing agent containing at least one metal selected from the group consisting of zinc, iron, palladium, and nickel; a silane-based reducing agent containing silicon; a reducing gas; a reducing inorganic salt; and a boron-based reducing agent containing boron. A method for producing an exocyclic olefin derivative according to claim 1.

3. A method for producing an exocyclic olefin derivative according to claim 1 or 2, comprising contacting the disulfide derivative represented by formula (I) with the reducing agent in the presence of at least one acid selected from the group consisting of acetic acid, hydrochloric acid, sulfuric acid, nitric acid, trifluoroacetic acid, formic acid, methanesulfonic acid, and p-toluenesulfonic acid.

4. The disulfide derivative represented by formula (I) and the reducing agent are brought into contact in a temperature range of 0°C to 120°C. A method for producing an exocyclic olefin derivative according to claim 1 or 2.

5. Disulfide derivatives represented by the following formula (I); 【Transformation 3】 In the above formula (I), R １ and R ２ Each of these may have a hydrogen atom or a substituent. A aryl group, an optionally substituted aralkyl group, or an optionally substituted aryl group. R ３ is -H, -CH ３ , -C ２ H ５ , -OR ４ , -C (=O) OR ４ , -C(=O)-NR ４ ２ ien-CH ２ -OR ４ ien-CH ２ -C (=O) OR ４ ien-CH ２ -C(=O)-NR ４ ２ , -CH(CH ３ ) - C (= O) OR ４ , -C ２ H ５ -OR ４ , -C ２ H ５ -C (=O) OR ４ , -C ２ H ５ -C(=O)-NR ４ ２ It is a monovalent group or cyano group represented by . R ４ This is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group, or an optionally substituted aryl group.

6. A method for producing a disulfide derivative, comprising contacting a thiolactone derivative represented by the following formula (1) with a coupling reagent represented by the following formula (2) to produce a disulfide derivative represented by the following formula (I). 【Chemistry 4】 In the above formula (1), R １ and R ２ These are, respectively, a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group, or an optionally substituted aryl group. 【Transformation 5】 In the above formula (2), R ３ is -H, -CH ３ , -C ２ H ５ , -OR ４ , -C (=O) OR ４ , -C(=O)-NR ４ ２ , -CH(CH ３ ) - C (= O) OR ４ , -C ２ H ５ -OR ４ , -C ２ H ５ -C (=O) OR ４ , -C ２ H ５ -C(=O)-NR ４ ２ It is a monovalent group or cyano group represented by, R ４ This is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group, or an optionally substituted aryl group. X １ X is a hydrogen atom or a metal atom, ２ It is a halogen atom, 【Transformation 6】 In the above formula (I), R １ and R ２ are synonymous with those represented by the above formula (1), and R ３ is synonymous with those represented by the above formula (2).

7. After bringing a thiolactone derivative represented by formula (1) into contact with a coupling reagent represented by formula (2) to produce at least one compound selected from the group consisting of a hemithioacetal derivative represented by formula (3) and a ketone derivative represented by formula (I'), A method for producing a disulfide derivative represented by formula (I) according to claim 5, wherein an oxidizing agent is present in the reaction system; 【Transformation 7】 In the above formula (3), R １ , R ２ and R ３ This is equivalent to what is represented by formulas (1) and (2) above, 【Transformation 8】 In the formula (I'), R １ , R ２ and R ３ are synonymous with those represented by the formula (I).

8. After producing the disulfide derivative represented by formula (I) by the method of claim 6 or 7, A method for producing an exocyclic olefin derivative, comprising contacting the obtained disulfide derivative represented by the following formula (I) with a reducing agent to produce an exocyclic olefin derivative represented by the following formula (4): 【Chemistry 9】 In the above formula (4), R １ , R ２ and R ３ This is equivalent to what is represented by formulas (1) and (2) above.

9. A method for producing an exocyclic olefin derivative according to claim 8, comprising contacting a disulfide derivative represented by formula (I) with a reducing agent in the presence of an acid.

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