Method for producing benzothiazole derivative

Abstract

To provide a novel method for producing a benzothiazole derivative.SOLUTION: The present invention provides a method for producing a benzothiazole derivative.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing a benzothiazole derivative. [Background technology]

[0002] Non-Patent Document 1 discloses the reactivity of 2-lithiobenzothiazole with electrophilic reagents and its use in the synthesis of α-hydroxycarbonyl compounds. Non-Patent Document 1 also discloses the synthesis of 2-lithiobenzothiazole from benzothiazole by adding n-BuLi to a THF solution containing benzothiazole at −78°C.

[0003] Non-Patent Document 2 discloses that an onium amide base generated in situ is used to form C(sp 2 )-H bond and C(sp 3 )-H bond by organocatalysis. Non-Patent Document 2 discloses the deprotonative functionalization of C(sp 2 )-H bond and activated C(sp 3 The use of methyltrimethylsilyl as a base for catalytic deprotonative functionalization of -H bonds is disclosed. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Bulletin of the Chemical Society of Japan, 61, 1988, 3637-3648 [Non-patent document 2] Chem. Commun., 48, 2012, 9771-9773 Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a novel method for producing a benzothiazole derivative. [Means for solving the problem]

[0006] C(SP) of benzothiazole 2 Conventional synthetic methods using n-BuLi, onium amide bases, etc. have been developed for -H activation. However, these conventional methods have the problem that the need for a base limits the benzothiazole skeleton that can be applied.

[0007] The present inventors have conducted extensive research to solve the above problems, and as a result have been able to successfully produce benzothiazole derivatives by utilizing electrolytic reactions.

[0008] Based on this finding, the present inventors have conducted further research and have completed the present invention. That is, the present invention includes the following method for producing a benzothiazole derivative.

[0009] Section 1. The following general formula (1): [ka] (In formula (1), R 1 is each R 1 are the same or different and each represent a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a nitro group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted alkylsulfanyl group, an optionally substituted acyl group, an optionally substituted acyloxy group, an optionally substituted alkylsulfonyloxy group, an optionally substituted aryl group, an optionally substituted arylsulfonyloxy group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryloxy-carbonyl group, an optionally substituted carbamoyl group, a tri-substituted silyl group, or a substituted amino group. In formula (1), m represents an integer of 1 to 4. In formula (1), R2 , and R 3 are the same or different and each represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group. A method for producing a benzothiazole derivative represented by the formula: The following general formula (2): [ka] (In formula (2), R 1 , and m are the same as in the above formula (1). a benzothiazole compound represented by the formula: The following general formula (3): [ka] (In formula (3), R 2 , and R 3 is the same as the above formula (1). and a ketone compound represented by A manufacturing method comprising a step of electrolytic reaction.

[0010] Section 2. The electrolytic reaction is (i) at least one electrolyte selected from the group consisting of tetrabutylammonium bromide (TBABr), lithium perchlorate (LiClO), magnesium perchlorate (Mg(ClO)), and tetrabutylammonium perchlorate (BuNClO); and (ii) at least one aprotic polar solvent selected from the group consisting of N,N-dimethylformamide (DMF), acetone, acetonitrile, dimethyl sulfoxide (DMSO), and tetrahydrofuran (THF); Item 2. The manufacturing method according to item 1, wherein the manufacturing method is carried out using an electrolyte solution containing

[0011] The present invention relates to a method for producing benzothiazole derivatives by electrolytic reaction, and is an environmentally friendly production method or a production method with a low environmental impact. The production method of the present invention is also useful for continuous production of benzothiazole derivatives, and can reduce production costs. The production method of the present invention is suitable for industrial production of benzothiazole derivatives.

[0012] Benzothiazole derivatives are useful in a wide range of fields, including pharmaceuticals and chemicals (additives). The method for producing a benzothiazole derivative of the present invention makes it possible to change the stereostructure and similar structures of the benzothiazole derivative as needed according to demand. The method for producing a benzothiazole derivative of the present invention will lead to support for the development of drug discovery (pharmaceuticals, etc.) and functional materials (chemicals, etc.) using benzothiazole derivatives. [Effects of the Invention]

[0013] The present invention can provide a new method for producing a benzothiazole derivative. DETAILED DESCRIPTION OF THE INVENTION

[0014] The present invention will be described in detail below. The embodiments of the present invention are intended to provide a better understanding of the gist of the invention, and unless otherwise specified, do not limit the content of the invention. It goes without saying that the present invention can be embodied in various forms without departing from the gist of the present invention.

[0015] In this specification, the terms "comprise" and "contain" are concepts that encompass all of "comprise," "consist essentially of," and "consist only of."

[0016] In this specification, when a numerical range is expressed as "A to B," it means "A or more and B or less."

[0017] In this specification, when parts, % and the like are used, they represent parts by mass, parts by weight, mass %, or weight % (wt%).

[0018] [1] Method for producing benzothiazole derivatives The present invention makes it possible to effectively produce benzothiazole derivatives by utilizing an electrolytic reaction.

[0019] The method for producing the benzothiazole derivative of the present invention comprises the steps of: A benzothiazole compound represented by the following general formula (2), [ka] (In formula (2), R 1 , and m are the same as in equation (1). and a ketone compound represented by the following general formula (3): [ka] (In formula (3), R 2 , and R 3 is the same as equation (1). It includes a step of electrolytic reaction, A benzothiazole derivative represented by the following general formula (1) is produced.

[0020] [ka] (In formula (1), R 1 is each R 1 are the same or different and each represent a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a nitro group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted alkylsulfanyl group, an optionally substituted acyl group, an optionally substituted acyloxy group, an optionally substituted alkylsulfonyloxy group, an optionally substituted aryl group, an optionally substituted arylsulfonyloxy group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryloxy-carbonyl group, an optionally substituted carbamoyl group, a tri-substituted silyl group, or a substituted amino group. In formula (1), m represents an integer of 1 to 4. In formula (1), R 2 , and R 3 are the same or different and each represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group.

[0021] The electrolytic reaction is preferably (i) at least one electrolyte selected from the group consisting of tetrabutylammonium bromide (TBABr), lithium perchlorate (LiClO), magnesium perchlorate (Mg(ClO)), and tetrabutylammonium perchlorate (BuNClO); and (ii) at least one aprotic polar solvent selected from the group consisting of N,N-dimethylformamide (DMF), acetone, acetonitrile, dimethyl sulfoxide (DMSO), and tetrahydrofuran (THF); The electrolytic solution containing

[0022] (1) Compound represented by general formula (2) As a substrate (raw material compound) for the electrolytic reaction, a benzothiazole compound represented by the following general formula (2) is used. [ka]

[0023] In formula (2), R 1 , and m are the same as in equation (1).

[0024] R 1 In formula (2), R 1 is each R 1are the same or different and each represent a hydrogen atom (unsubstituted), a halogen atom, a hydroxy group (-OH), a cyano group (nitrile group, -C≡N), a nitro group (-NO2), an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted alkylsulfanyl group, an optionally substituted acyl group, an optionally substituted acyloxy group, an optionally substituted alkylsulfonyloxy group, an optionally substituted aryl group, an optionally substituted arylsulfonyloxy group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryloxy-carbonyl group, an optionally substituted carbamoyl group, a tri-substituted silyl group, or a substituted amino group.

[0025] When formula (2) represents an unsubstituted benzothiazole compound, m=1 to 4 and R 1 = hydrogen atom (H), or m = 0, and the benzothiazole compound represented by general formula (2) becomes benzothiazole.

[0026] In the method for producing a benzothiazole derivative of the present invention, preferably, when m of the benzothiazole compound is 1 to 4, R 1 By adjusting the benzothiazole derivatives, unsubstituted or substituted with one or more substituents can be synthesized continuously and stably by utilizing an electrolytic reaction. The unsubstituted or substituted benzothiazole derivatives are useful in a wide range of fields, including pharmaceuticals and chemicals (additives).

[0027] The halogen atom is preferably a fluorine atom (F), a chlorine atom (Cl), a bromine atom (Br), or an iodine atom (I).

[0028] The alkyl (group) means a linear or branched alkyl group having one or more carbon atoms, preferably C 1-20 alkyl group, more preferably C 1-6 It is an alkyl group.

[0029] C 1-20The alkyl (group) means a straight-chain or branched-chain alkyl group having 1 to 20 carbon atoms, and is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, eicosyl, or the like.

[0030] C 1-6 The alkyl (group) means a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc.

[0031] Cycloalkyl (group) means a cyclic alkyl group, preferably C 3-8 It is a cycloalkyl group.

[0032] C 3-8 The cycloalkyl (group) means a cyclic alkyl group having 3 to 8 carbon atoms, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc., more preferably C 3-6 It is a cycloalkyl group.

[0033] The alkoxy (group) means a group in which a linear or branched alkyl group is bonded to an oxygen atom, and preferably C 1-20 is an alkoxy group, more preferably C 1-8 is an alkoxy group, more preferably C 1-6 It is an alkoxy group.

[0034] C 1-20The alkoxy (group) means a straight-chain or branched-chain alkoxy group having 1 to 20 carbon atoms, and preferred examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, isohexyloxy, 1,1-dimethylbutoxy, 2,2-dimethylbutoxy, 3,3-dimethylbutoxy, 2-ethylbutoxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, and eicosyloxy.

[0035] C 1-6 The alkoxy (group) means a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms, and preferably includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, and the like.

[0036] The alkylsulfanyl group means a group in which a straight-chain or branched-chain alkyl group is bonded to a sulfur atom, and preferably C 1-6 alkylsulfanyl group, more preferably C 1-4 It is an alkylsulfanyl group.

[0037] C 1-6 Alkylsulfanyl (group) is a group with a C attached to the sulfur atom. 1-6 It means a group to which an alkyl group is bonded, i.e., a linear or branched alkylsulfanyl group having 1 to 6 carbon atoms. 1-6 The alkylsulfanyl (group) is preferably methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, pentylsulfanyl, isopentylsulfanyl, neopentylsulfanyl, 1-ethylpropylsulfanyl, hexylsulfanyl, or the like.

[0038] C 1-6The alkylsulfonyl (group) refers to a group in which a C1-6 alkyl group is bonded to a sulfonyl group, i.e., a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms. 1-6 The alkylsulfonyl (group) is preferably methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl, or the like.

[0039] The term "alkoxy-carbonyl group" refers to a group in which an alkoxy group is bonded to a carbonyl group, and preferably C 1-20 Alkoxy-carbonyl groups, more preferably C 1-8 It is an alkoxy-carbonyl group.

[0040] Acyl (group) means alkanoyl or aroyl, preferably C 1-7 Alkanoyl groups, and C 7-11 It is an aroyl group.

[0041] C 1-7 The alkanoyl group is a straight or branched chain formyl or alkylcarbonyl group having 1 to 7 carbon atoms (i.e., C 1-6 alkyl-carbonyl), preferably formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl, and the like.

[0042] C 7-11 Aroyl (group) is an arylcarbonyl group having 7 to 11 carbon atoms (i.e., C 6-10 aryl-carbonyl), preferably benzoyl, etc.

[0043] The term "acyloxy group" refers to an alkanoyl group or an aroyl group bonded to an oxygen atom, and preferably represents a C 1-7 Alkanoyloxy group, and C 7-11 It is an aroyloxy group.

[0044] C 1-7 The alkanoyloxy (group) is preferably formyloxy, acetoxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy, tert-butylcarbonyloxy (pivaloyloxy), pentylcarbonyloxy, isopentylcarbonyloxy, neopentylcarbonyloxy, hexylcarbonyloxy, or the like, and more preferably acetoxy or pivaloyloxy.

[0045] C 7-11 The aroyloxy (group) is preferably benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy, or the like.

[0046] The aryl (group) means a monocyclic or polycyclic (fused) hydrocarbon group exhibiting aromaticity, and is preferably a C aryl group such as phenyl (Ph-), 1-naphthyl, 2-naphthyl, biphenyl, 2-anthryl, or fluorenyl. 6-14 is an aryl group, more preferably C 6-10 It is an aryl group.

[0047] C 6-10 The aryl (group) is preferably phenyl (Ph-), 1-naphthyl, 2-naphthyl, more preferably phenyl and 1-naphthyl.

[0048] The aryloxy (group) means a group in which the aryl group is bonded to an oxygen atom, and preferably C 6-14 An aryloxy group, more preferably C 6-10 It is an aryloxy group.

[0049] The aryloxy-carbonyl (group) means a group in which an aryloxy group is bonded to a carbonyl group, preferably C 6-14 An aryloxy-carbonyl group, more preferably C 6-10It is preferably an aryloxy-carbonyl group, and more preferably a phenoxy-carbonyl group.

[0050] The aralkyl (group) means a group in which an aryl group is substituted on an alkyl group, and preferably C 7-14 It is aralkyl.

[0051] C 7-22 Aralkyl groups are C 1-4 C in alkyl group 6-18 It means a group substituted with an aryl group, and preferred examples include benzyl, 1-phenylethyl, 2-phenylethyl, (naphthyl-1-yl)methyl, (naphthyl-2-yl)methyl, 1-(naphthyl-1-yl)ethyl, 1-(naphthyl-2-yl)ethyl, 2-(naphthyl-1-yl)ethyl, 2-(naphthyl-2-yl)ethyl, diphenylmethyl, fluorenylmethyl, trityl, and the like.

[0052] The arylsulfonyl group means a group in which an aryl group is bonded to a sulfonyl group, and preferably C 6-10 It is an arylsulfonyl group.

[0053] C 6-10 The arylsulfonyl group is C 6-10 It means a group in which an aryl group is bonded to a sulfonyl group, and is preferably phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, or the like.

[0054] The alkylsulfonyloxy (group) means a group in which an alkylsulfonyl group is bonded to an oxygen atom, and preferably C 1-6 It is an alkylsulfonyloxy group.

[0055] C 1-6 Alkylsulfonyloxy (group) is C 1-6 It means a group in which an alkylsulfonyl group is bonded to an oxygen atom, and preferred examples include methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy, and butylsulfonyloxy.

[0056] The arylsulfonyloxy (group) means a group in which an arylsulfonyl group is bonded to an oxygen atom, and preferably C 6-10 It is an arylsulfonyloxy group.

[0057] C 6-10 The arylsulfonyloxy group is C 6-10 It means a group in which an arylsulfonyl group is bonded to an oxygen atom, and preferred examples include phenylsulfonyloxy, 1-naphthylsulfonyloxy, and 2-naphthylsulfonyloxy.

[0058] A substituted amino group means an amino group in which at least one of the two hydrogen atoms is substituted with a group other than a hydrogen atom, and when both of the two hydrogen atoms are substituted with substituents, the substituents may be the same or different.

[0059] A trisubstituted silyl (group) is a silyl group having three identical or different substituents (e.g., C 1-6 Alkyl group, C 6-10 The silyl group is preferably a trialkylsilyl group (preferably a triC group) such as a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, or a tert-butyldimethylsilyl group. 1-6 Alkylsilyl group, more preferably triC 1-4 alkylsilyl group), tert-butyldiphenylsilyl group, triphenylsilyl group, etc.

[0060] The trisubstituted silyloxy (group) means a group in which a trisubstituted silyl group is bonded to an oxygen atom, and this group is preferably a trialkylsilyloxy group (preferably a triC group) such as a trimethylsilyloxy group, a triethylsilyloxy group, a triisopropylsilyloxy group, or a tert-butyldimethylsilyloxy group. 1-6 Alkylsilyloxy group, more preferably triC 1-4 alkylsilyloxy group), tert-butyldiphenylsilyloxy group, triphenylsilyloxy group, etc.

[0061] The substituent constituting the substituted amino group can be, for example, a protecting group for an amino group described in Protective Groups in Organic Synthesis, John Wiley and Sons (3rd edition, 1999), and preferably, 1-6 Alkyl group, C 1-6 Alkylsulfonyl, C 7-22 Aralkyl group, C 6-10 Aryl group, C 1-7 Alkanoyl group, C 7-11 Aroyl group, C 7-14 Aralkyl-carbonyl group, C 1-6 Alkoxy-carbonyl group, C 7-14 Aralkyloxy-carbonyl group, C 6-10 Arylsulfonyl, TriC 1-6 Alkylsilyl groups (e.g., tri-C 1-6 Protecting groups include alkylsilyl groups (eg, trimethylsilyl, tert-butyl(dimethyl)silyl).

[0062] The protecting group is a halogen atom, C 1-6 Alkyl group, C 1-6 It may be further substituted with an alkoxy group or a nitro group. Preferred protecting groups for amino groups include methyl (monomethyl or dimethyl), benzyl, trityl, acetyl, trifluoroacetyl, pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, trifluoromethanesulfonyl, p-toluenesulfonyl, and the like.

[0063] "Optionally substituted" means unsubstituted or having 1 to 5 (preferably 1 to 3) substituents at substitutable positions, and each substituent may be the same or different.

[0064] The "optionally substituted" substituent is preferably (1) a halogen atom, (2) a hydroxy group, (3) a cyano group, (4) a nitro group, (5) an azide group (azide group, -N3), (6) a substituted amino group, (7) a C 1-6 Alkyl group, (8)C 1-6 Alkoxy group, (9)C 3-8Cycloalkyl groups, (10)C 6-10 Aryl group, (11)C 7-22 Aralkyl group, (12)C 1-7 Alkanoyl group, (13)C 7-11 Aroyl group, (14)C 1-7 Alkanoyloxy group, (15)C 7-11 Aroyloxy group, (16)C 1-6 Alkoxy-carbonyl group, (17)C 1-6 Carbamoyl group optionally mono- or di-substituted with alkyl groups, (18) C 1-6 Alkyl sulfonyloxy group, (19)C 6-10 Arylsulfonyloxy group, (20)C 1-6 Alkylsulfanyl, (21) trisubstituted silyl group, (22) trisubstituted silyloxy group, (23) C 6-10 An aryloxy-carbonyl group and the like.

[0065] The "optionally substituted" substituent is more preferably a halogen atom, C 1-6 Alkyl, C 1-6 Examples of such alkoxy groups include alkoxy, acetyl, formyl, carbamoyl, azido, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldimethylsilyloxy, phenyl, cyclohexyl, dimethylamino, acetylamino, tert-butoxycarbonylamino, benzyloxycarbonylamino, methoxycarbonyl, and methylsulfanyl.

[0066] The substituents of "optionally substituted alkyl" or "optionally substituted alkoxy" include those selected from the above list of substituents (7)C 1-6 Alkyl groups and (11)C 7-22 Examples of substituents include those excluding aralkyl groups.

[0067] The substituents may also each further comprise one or more hydroxy groups, C 1-6 Alkyl group, C 1-6 It may be substituted with an alkoxy group, a halogen atom, a cyano group, a nitro group, a phenyl group, or the like.

[0068] m In formula (2), m represents an integer of 1 to 4. In formula (2), m represents an integer of 1 to 4, preferably m=1 to 3, more preferably m=1 to 2, and particularly preferably m=1.

[0069] In the method for producing a benzothiazole derivative of the present invention, preferably, when m of the benzothiazole compound is 1 to 4, R 1 By adjusting the benzothiazole derivatives, unsubstituted or substituted with one or more substituents can be synthesized continuously and stably by utilizing an electrolytic reaction. The unsubstituted or substituted benzothiazole derivatives are useful in a wide range of fields, including pharmaceuticals and chemicals (additives).

[0070] (2) Compound represented by general formula (3) As a substrate (raw material compound) for the electrolytic reaction, a ketone compound represented by the following general formula (3) is used. [ka]

[0071] In formula (3), R 2 , and R 3 is the same as equation (1).

[0072] R 2 , and R 3 In formula (3), R 2 , and R 3 are the same or different and each represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group.

[0073] In the method for producing a benzothiazole derivative of the present invention, preferably, R 2 , and R 3By adjusting the benzothiazole derivatives, unsubstituted or substituted with one or more substituents can be synthesized continuously and stably by utilizing an electrolytic reaction. The unsubstituted or substituted benzothiazole derivatives are useful in a wide range of fields, including pharmaceuticals and chemicals (additives).

[0074] The alkyl (group) means a linear or branched alkyl group having one or more carbon atoms, preferably C 1-20 alkyl group, more preferably C 1-6 It is an alkyl group.

[0075] C 1-20 The alkyl (group) means a linear or branched alkyl group having 1 to 20 carbon atoms, and is preferably methyl (for example, in the general formula (3), R 2 , and R 3 is methyl, and the ketone compound represented by general formula (3) is acetone), ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, eicosyl, etc.

[0076] C 1-6 The alkyl (group) means a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc.

[0077] Cycloalkyl (group) means a cyclic alkyl group, preferably C 3-8 It is a cycloalkyl group.

[0078] C 3-8The cycloalkyl (group) means a cyclic alkyl group having 3 to 8 carbon atoms, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc., more preferably C 3-6 It is a cycloalkyl group.

[0079] The aryl (group) means a monocyclic or polycyclic (fused) hydrocarbon group exhibiting aromaticity, and is preferably phenyl (Ph-) (for example, in general formula (3), R 2 , and R 3 is phenyl, and the ketone compound represented by general formula (3) is benzophenone (diphenyl ketone), 1-naphthyl, 2-naphthyl, biphenyl, 2-anthryl, fluorenyl, etc. 6-14 is an aryl group, more preferably C 6-10 It is an aryl group.

[0080] C 6-10 The aryl (group) is preferably phenyl (Ph-), 1-naphthyl, 2-naphthyl, more preferably phenyl and 1-naphthyl.

[0081] The heterocyclic group is an aromatic heterocyclic group containing at least one element selected from the group consisting of nitrogen (N), oxygen (O), and sulfur (S) (aromatic heterocyclic group).

[0082] The heterocyclic group is a sulfur-containing heteroaryl group such as a thiophenyl group (thiophene group or thienyl group), a thienylenyl group (or thiophenediyl group), a benzothienyl group (benzothiophene group), a dibenzothienyl group (dibenzothiophene group), a phenyldibenzothienylenyl group, or a dibenzothienylenylphenyl group.

[0083] The heterocyclic group is an oxygen-containing heteroaryl group such as a furanyl group (or a furan group), a benzofuranyl group (a benzofuran group), a dibenzofuranyl group (a dibenzofuran group), a phenyldibenzofuranyl group, or a dibenzofuranylphenyl group.

[0084] The heterocyclic group is a nitrogen-containing heteroaryl group such as a pyridyl group (or pyridine group), a pyridilenyl group (or pyridinediyl group), a pyrimidinyl group (or pyrimidine group), a pyrazyl group (or pyrazine group), a quinolyl group (or quinoline group), an isoquinolyl group (or isoquinoline group), a carbazolyl group (or carbazole group), a 9-phenylcarbazolyl group, an acridinyl group (or acridine group), a quinazolyl group (or quinazoline group), a quinoxalyl group (or quinoxaline group), a 1,6-naphthyridinyl group, a 1,8-naphthyridinyl group, or a porphyrin group (or porphyrin ring).

[0085] The heterocyclic group is a heteroaryl group containing two or more heteroatoms (for example, nitrogen and sulfur), such as a benzothiazolyl group (or a benzothiazole group) or a benzothiadiazole group.

[0086] Examples of the heterocyclic group include a pyrrole group, a silole group, a borole group, a phosphole group, a selenophene group, a germole group, an indole group, an indene group, a benzosilole group, a benzoborole group, a benzophosphole group, a benzoselenophene group, a benzogermole group, a dibenzosilole group, a dibenzoborole group, a dibenzophosphole group, a dibenzoselenophene group, a dibenzogermole group, a dibenzothiophene-5-oxide group, a 9H-fluoren-9-one group, and a dibenzothiophene-5,5-dioxide group.

[0087] The heterocyclic group may be an azabenzothiophene group, an azabenzofuran group, an azaindole group, an azaindene group, an azabenzosilole group, an azabenzoborole group, an azabenzophosphole group, an azabenzoselenophene group, an azabenzogermole group, an azadibenzothiophene group, an azadibenzofuran group, an azacarbazole group, an azafluorene group, an azadibenzosilole group, an azadibenzoborole group, an azadibenzophosphole group, an azadibenzoselenophene group, an azadibenzogermole group, an azadibenzothiophene 5-oxide group, an aza-9H-fluoren-9-one group, or an azadibenzothiophene 5,5-dioxide group. etc.

[0088] Examples of the heterocyclic group include a pyridazine group, a triazine group, a phenanthroline group, a pyrazole group, an imidazole group, a triazole group, an oxazole group, an isoxazole group, a thiazole group, an isothiazole group, an oxadiazole group, a thiadiazole group, a benzopyrazole group, a benzimidazole group, a benzoxazole group, a benzoxadiazole group, a 5,6,7,8-tetrahydroisoquinoline group, and a 5,6,7,8-tetrahydroquinoline group.

[0089] The heterocyclic group is preferably a pyridyl group, a pyrimidyl group, a pyrazyl group, a triazyl group, a triazolyl group, an oxazolyl group, an oxadiazolyl group, a thiazolyl group, a thiadiazolyl group, a quinolyl group, an acridinyl group, a phenanthrolyl group, a dibenzofuranyl group, a dibenzothienyl group, or the like.

[0090] "Optionally substituted" means unsubstituted or having 1 to 5 (preferably 1 to 3) substituents at substitutable positions, and each substituent may be the same or different.

[0091] The "optionally substituted" substituent is preferably (1) a halogen atom, (2) a hydroxy group, (3) a cyano group, (4) a nitro group, (5) an azide group (azide group, -N3), (6) a substituted amino group, (7) a C 1-6 Alkyl group, (8)C 1-6 Alkoxy group, (9)C 3-8 Cycloalkyl groups, (10)C 6-10 Aryl group, (11)C 7-22 Aralkyl group, (12)C 1-7 Alkanoyl group, (13)C 7-11 Aroyl group, (14)C 1-7 Alkanoyloxy group, (15)C 7-11 Aroyloxy group, (16)C 1-6 Alkoxy-carbonyl group, (17)C 1-6 Carbamoyl group optionally mono- or di-substituted with alkyl groups, (18) C 1-6 Alkyl sulfonyloxy group, (19)C 6-10 Arylsulfonyloxy group, (20)C 1-6Alkylsulfanyl, (21) trisubstituted silyl group, (22) trisubstituted silyloxy group, (23) C 6-10 An aryloxy-carbonyl group and the like.

[0092] The "optionally substituted" substituent is more preferably a halogen atom, C 1-6 Alkyl, C 1-6 Examples of such alkoxy groups include alkoxy, acetyl, formyl, carbamoyl, azido, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldimethylsilyloxy, phenyl, cyclohexyl, dimethylamino, acetylamino, tert-butoxycarbonylamino, benzyloxycarbonylamino, methoxycarbonyl, and methylsulfanyl.

[0093] The substituents may also each further comprise one or more hydroxy groups, C 1-6 Alkyl group, C 1-6 It may be substituted with an alkoxy group, a halogen atom, a cyano group, a nitro group, a phenyl group, or the like.

[0094] In the method for producing a benzothiazole derivative of the present invention, preferably, R 2 , and R 3 By adjusting the benzothiazole derivatives, unsubstituted or substituted with one or more substituents can be synthesized continuously and stably by utilizing an electrolytic reaction. The unsubstituted or substituted benzothiazole derivatives are useful in a wide range of fields, including pharmaceuticals and chemicals (additives).

[0095] (3) Electrolytic reaction process The benzothiazole compound represented by the general formula (2) and the ketone compound represented by the general formula (3) are subjected to an electrolytic reaction to produce the benzothiazole derivative represented by the general formula (1).

[0096] (i) Electrolyte In the electrolysis reaction, a benzothiazole derivative represented by general formula (1) is From the viewpoint of enabling continuous and stable synthesis, it is preferable to use (i) an electrolytic solution containing at least one electrolyte selected from the group consisting of tetrabutylammonium bromide (TBABr), lithium perchlorate (LiClO), magnesium perchlorate (Mg(ClO)), and tetrabutylammonium perchlorate (BuNClO).

[0097] In the electrolytic reaction, electrolytes other than the above-mentioned electrolytes may be used.

[0098] The electrolytes are p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, perchloric acid, sodium methanesulfonate, potassium methanesulfonate, lithium trifluoromethanesulfonate (LiCF3SO3), sodium trifluoromethanesulfonate, potassium trifluoromethanesulfonate, lithium chloride (LiCl), sodium chloride, potassium chloride, tetramethylammonium chloride, tetraethylammonium chloride, tetrabutylammonium chloride, lithium bromide (LiBr), sodium bromide, potassium bromide, tetramethylammonium bromide, tetraethylammonium bromide, tetrapropylammonium bromide, tetrabutylammonium bromide (TBABr), lithium iodide (LiI), lithium nitrate (LiNO3), sodium nitrate (NaNO3), potassium nitrate, tetramethylammonium nitrate, tetrabutylammonium nitrate, lithium perchlorate (LiClO4), sodium perchlorate (NaClO4), tetramethylammonium perchlorate, and perchlorate. Tetraethylammonium perchlorate, tetrabutylammonium perchlorate, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium hexafluorophosphate, lithium fluoroborate, 1-butyl-1-methylpyrrolidinium chloride, 1-butyl-1-methylpyrrolidinium bromide, 1-ethyl-1-methylpyrrolidinium bromide, 1-butylpyridinium chloride, 1-butylpyridinium bromide, 1-butyl-4-methylpyridinium bromide, 1-butyl-3-methylpyridinium chloride, 1- butyl-3-methylpyridinium bromide, 1-butyl-4-methylpyridinium chloride, 1-ethylpyridinium chloride, 1-ethylpyridinium bromide, 1-ethyl-2-methylpyridinium bromide, 1-ethyl-4-methylpyridinium bromide, 1-propylpyridinium chloride, tributyl-n-octylphosphonium bromide, tetrabutylphosphonium bromide, tributylhexadecylphosphonium bromide, trihexyl(tetradecyl)phosphonium chloride, and the like.

[0099] Examples of electrolytes include lithium tetrafluoroborate (LiBF), lithium hexafluorophosphate (LiPF), lithium bis(trifluoromethanesulfonyl)imide (Li[N(CFSO)]), lithium hexafluoroarsenate(V) (LiAsF), and lithium bis(oxalatoborate).

[0100] Examples of electrolytes include sodium tetrafluoroborate (NaBF), sodium hexafluorophosphate (NaPF), sodium bis(trifluoromethanesulfonyl)imide (Na[N(CFSO)]), sodium hexafluoroarsenate(V) (NaAsF), sodium bis(oxalatoborate), sodium halides, sodium thiocyanate (NaSCN), sodium pentacyanopropenide, sodium tetracyanopyrrolate, and sodium tricyanoimidazolate.

[0101] The electrolyte is preferably tetrabutylammonium bromide (TBABr), tetrabutylammonium tetrafluoroborate (Bu4NBF4), tetrabutylammonium chloride (Bu4NCl), tetrabutylammonium hexafluorophosphate (Bu4NPF6, or nBu4NPF6), or the like.

[0102] In the electrolytic reaction, the electrolyte may be used alone or in a mixture (blend) of two or more kinds.

[0103] (ii) Electrolyte From the viewpoint of being able to continuously and stably synthesize the benzothiazole derivative represented by general formula (1) in the electrolytic reaction, (ii) the electrolytic reaction is carried out using an electrolyte solution containing at least one aprotic polar solvent selected from the group consisting of N,N-dimethylformamide (DMF, anhydrous DMF, etc.), acetone, acetonitrile, dimethyl sulfoxide (DMSO), and tetrahydrofuran (THF).

[0104] In the electrolytic reaction, one type of electrolyte may be used alone, or two or more types may be mixed (blended) and used.

[0105] (iii) Electrodes and conductors The electrolytic reaction is preferably carried out using at least one electrode selected from the group consisting of magnesium (Mg), platinum (Pt, Pt plate, etc.), zinc (Zn), carbon (C), silver (Ag), iron (Fe), and lead (Pb), from the viewpoint of enabling continuous and stable synthesis of the benzothiazole derivative represented by general formula (1) in the electrolytic reaction.

[0106] The conducting wires connecting the electrodes are preferably made of copper (Cu) wire, platinum (Pt) wire, iron (Fe) wire, or the like.

[0107] (iv) Electrolytic reaction Concentration of components in electrolytic reactions (Benzothiazole compound concentration) In the electrolysis reaction, the amount of the benzothiazole compound represented by general formula (2) used is adjusted so that its concentration in the electrolyte (mM (mmol / L)) is preferably 10 mM to 500 mM, more preferably 50 mM to 300 mM, and even more preferably 100 mM to 200 mM, from the viewpoint of being able to continuously and stably synthesize the benzothiazole derivative represented by general formula (1) in the electrolysis reaction.

[0108] (Ketone compound concentration) In the electrolysis reaction, the amount of the ketone compound represented by general formula (3) used is adjusted so that its concentration in the electrolyte (mM (mmol / L)) is preferably 20 mM to 1,000 mM, more preferably 100 mM to 600 mM, and even more preferably 200 mM to 400 mM, from the viewpoint of being able to continuously and stably synthesize the benzothiazole derivative represented by general formula (1) in the electrolysis reaction.

[0109] (1 eq. of benzothiazole compound: equivalent of ketone compound) In the electrolytic reaction, the amount of the ketone compound represented by general formula (3) used is, in terms of equivalents (eq.) relative to the benzothiazole compound represented by general formula (2) (when the benzothiazole compound is taken as 1 equivalent), preferably 0.5 to 20 equivalents, more preferably 1 to 15 equivalents, even more preferably 1.5 to 10 equivalents, and particularly preferably 2 equivalents, from the viewpoint of being able to continuously and stably synthesize the benzothiazole derivative represented by general formula (1) in the electrolytic reaction.

[0110] (electrolyte concentration) In the electrolysis reaction, the amount of electrolyte used is adjusted so that the concentration (mM (mmol / L)) in the electrolytic solution is preferably 50 mM to 1,000 mM, more preferably 100 mM to 800 mM, and even more preferably 200 mM to 600 mM, from the viewpoint of being able to continuously and stably synthesize the benzothiazole derivative represented by general formula (1) in the electrolysis reaction.

[0111] (1 eq. of benzothiazole compound: equivalent of electrolyte) In the electrolysis reaction, the amount of electrolyte used is, in terms of equivalents (eq.) relative to the benzothiazole compound represented by general formula (2) (when the benzothiazole compound is taken as 1 equivalent), preferably 1 to 20 equivalents, more preferably 1.5 to 15 equivalents, even more preferably 2 to 10 equivalents, and particularly preferably 2.4 equivalents, in terms of molar ratio, from the viewpoint of being able to continuously and stably synthesize the benzothiazole derivative represented by general formula (1) in the electrolysis reaction.

[0112] Electrolysis reaction temperature The reaction temperature of the electrolysis reaction is preferably -50°C to room temperature (room temperature: 15°C to 30°C), more preferably -40°C to room temperature, and more preferably 0°C to room temperature, after the substrate is charged and the electrodes are connected and current is started. The electrolysis reaction is carried out, for example, at -50°C to 0°C (ice bath), more preferably -40°C to -5°C, more preferably -40°C to -10°C, and even more preferably -40°C to -20°C. The electrolysis reaction is preferably carried out at 0°C (ice bath) or room temperature (rt).

[0113] Reaction power of electrolytic reaction The reaction power for the electrolytic reaction is started at 5 mA to 100 mA after the substrate is introduced and the electrodes are connected, more preferably 8 mA to 80 mA, and even more preferably 10 mA to 60 mA.

[0114] The reaction power for the electrolytic reaction is determined by adding a substrate, connecting the electrodes, and applying a current of preferably 0.2 F / mol (based on benzothiazol mol, based on benzophenone mol) to 50 F / mol (Faraday unit F: 1F is the absolute value of the charge of 1 mol of electrons) based on the number of moles (mol) of the substrate benzothiazol compound represented by general formula (2) (when 1 mol of the benzothiazol compound is used) or the substrate ketone compound represented by general formula (3) (when 1 mol of the ketone compound is used), more preferably 0.4 F / mol to 20 F / mol, even more preferably 0.5 F / mol to 10 F / mol, and particularly preferably 1 F / mol (based on benzothiazol, based on benzophenone).

[0115] Electrolysis reaction time The electrolytic reaction is carried out by adjusting the reaction temperature and reaction power, and the reaction time is preferably 0.1 to 10 hours, more preferably 0.5 to 5 hours, and even more preferably 1 to 4 hours.

[0116] (4) Purification of benzothiazole derivatives after electrolysis After the current application is completed, the reaction solution is quenched (reaction is stopped) using water (H2O) or hydrochloric acid (HCl).

[0117] Next, the quenched reaction solution is transferred to a separatory funnel containing an aqueous solution of sodium thiosulfate (NaSO) (for example, a 10% aqueous solution), and the organic matter is extracted using a hexane / ethyl acetate (AcOEt) solution (for example, hexane / ethyl acetate = 4:1 (volume ratio)), and the benzothiazole derivative represented by general formula (1) is recovered.

[0118] Next, the extract (organic layer of hexane / ethyl acetate) is washed with saturated saline, and then the organic layer is dried using anhydrous magnesium sulfate (MgSO4) and concentrated under reduced pressure to obtain a crude product of the benzothiazole derivative represented by general formula (1).

[0119] Next, the crude product after vacuum concentration is recrystallized using a hexane / ethyl acetate solution (for example, hexane / ethyl acetate=4:1 (volume ratio)) to isolate and purify the benzothiazole derivative represented by general formula (1).

[0120] [2] Benzothiazole derivative represented by general formula (1) The product of the electrolytic reaction (target compound) is a benzothiazole derivative represented by the following general formula (1). [ka]

[0121] In formula (1), R 1 , and m are the same as in equation (2).

[0122] In formula (1), R 2 , and R 3 is the same as equation (3).

[0123] In formula (1), R 1 is each R 1are the same or different and each represent a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a nitro group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted alkylsulfanyl group, an optionally substituted acyl group, an optionally substituted acyloxy group, an optionally substituted alkylsulfonyloxy group, an optionally substituted arylsulfonyloxy group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryloxy-carbonyl group, an optionally substituted carbamoyl group, a tri-substituted silyl group, or a substituted amino group.

[0124] In formula (1), m represents an integer of 1 to 4.

[0125] In formula (1), R 2 , and R 3 are the same or different and each represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group.

[0126] In formula (1), R 1 , m, R 2 , and R 3 is the substrate (raw material compound) (1) Compound represented by general formula (2) , and (2) Compound represented by general formula (3) R 1 , m, R 2 , and R 3 The explanation in paragraph 1 applies.

[0127] The present invention relates to a method for producing benzothiazole derivatives by electrolytic reaction, and is an environmentally friendly production method or a production method with a low environmental impact. The production method of the present invention is useful for continuous production of benzothiazole derivatives and can reduce production costs. The production method of the present invention is suitable for industrial production of benzothiazole derivatives.

[0128] Benzothiazole derivatives are useful in a wide range of fields, including pharmaceuticals and chemicals (additives). The method for producing a benzothiazole derivative of the present invention makes it possible to change the stereostructure and similar structures of the benzothiazole derivative as needed according to demand. The method for producing a benzothiazole derivative of the present invention will lead to support for the development of drug discovery (pharmaceuticals, etc.) and functional materials (chemicals, etc.) using benzothiazole derivatives. [Example]

[0129] The embodiments of the present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0130] [1] Preparation of benzothiazole derivatives Example 1 Functionalization of benzothiazol C2-H by direct electrochemical reduction 1 [ka]

[0131] A glass H-shaped electrolytic cell, the electrodes of which were separated by a glass filter diaphragm, was thoroughly dried and placed under a nitrogen atmosphere. Both electrodes were Pt plates (1 cm × 2 cm).

[0132] Tetrabutylammonium bromide (TBABr) (cathode: 386.4 mg, 1.2 mmol; anode: 387.3 mg, 1.2 mmol) was added to both electrodes, and benzophenone (182.9 mg, 1.0 mmol) was added to the cathode. Anhydrous N,N-dimethylformamide (DMF) (4.0 mL x 2) was then added to both electrodes. Benzothiazol (67.6 mg, 0.5 mmol) was then added to the cathode, and stirring was initiated. Electroreduction was performed by applying 12 mA at 1.0 F / mol (Faraday unit, current per mole of benzothiazol).

[0133] After the current was applied, the cathode solution was quenched with HO (2 mL). The reaction solutions from both electrodes were added to a separatory funnel containing 20 mL of 10% NaSO solution, and the organic matter was extracted with hexane / ethyl acetate = 4:1 (volume ratio) (40 mL x 1). The organic matter was further extracted with hexane / ethyl acetate = 4:1 (volume ratio) (20 mL x 2). The combined organic layer was washed with saturated brine (10 mL x 1). The organic layer was then dried over anhydrous magnesium sulfate, filtered through a cotton plug, concentrated, and vacuumed to obtain the crude product.

[0134] The crude product was purified by recrystallization (solvent: hexane / ethyl acetate = 4:1 (volume ratio)) to obtain the target compound, benzo[d]thiazol-2-yldiphenylmethanol (67.8 mg, 0.21 mmol), in a yield of <43%.

[0135] Benzo[d]thiazol-2-yldiphenylmethanol was identified based on reference 1 (Reference 1: K. Inamoto, H. Okawa, H. Taneda, M. Sato, Y. Hirono, M. Yonemoto, S. Kikkawa, Y. Kondo, Chem. Commun. 2012, 48, 9771-9773.). 1 This was determined by 1 H NMR.

[0136] 1 H NMR(400MHz, CDCl3): δ 4.39(s, 1H), 7.29-7.42(m, 7H), 7.44-7.52(m, 5H), 7.83(d, J=8.0Hz, 1H), 8.02(d, J=8.0Hz, 1H)ppm.

[0137] Example 2 Functionalization of benzothiazol C2-H using the radical anion pool of benzophenone by electroreduction [ka]

[0138] A glass H-shaped electrolytic cell, the electrodes of which were separated by a glass filter diaphragm, was thoroughly dried and placed under a nitrogen atmosphere. Both electrodes were Pt plates (1 cm × 2 cm).

[0139] TBABr (cathode: 387.6 mg, 1.2 mmol; anode: 387.2 mg, 1.2 mmol) was added to both electrodes, and benzophenone (182.3 mg, 1.0 mmol) was added to the cathode. Anhydrous DMF (4.0 mL × 2) was then added to both electrodes. Stirring was started, and the mixture was immersed in an ice bath. Electroreduction was performed at 50 mA and 1.0 F / mol (based on benzophenone). The benzophenone radical anion was pooled.

[0140] After the current was applied, benzothiazol (67.1 mg, 0.5 mmol) was added to the cathode.

[0141] After 1 h, the cathode solution was quenched with HO (2 mL). The reaction solutions from both electrodes were added to a separatory funnel containing 20 mL of 10% NaSO solution, and the organic matter was extracted with hexane / ethyl acetate = 4:1 (volume ratio) (40 mL x 1). The organic matter was further extracted with hexane / ethyl acetate = 4:1 (volume ratio) (20 mL x 2). The combined organic layer was washed with saturated brine (10 mL x 1). The organic layer was then dried over anhydrous magnesium sulfate, filtered through a cotton plug, concentrated, and vacuumed to obtain the crude product.

[0142] The obtained crude product was purified by recrystallization (solvent: hexane / ethyl acetate = 4:1 (volume ratio)) to obtain the target product, benzo[d]thiazol-2-yldiphenylmethanol (72.6 mg, 0.23 mmol), in a yield of <46%.

[0143] Benzo[d]thiazol-2-yldiphenylmethanol was identified with reference to Reference 1. 1 This was determined by 1 H NMR.

[0144] 1H NMR (400MHz, CDCl3): δ4.41(s, 1H), 7.29-7.41(m, 7H), 7.43-7.52(m, 5H), 7.83(d, J=8.0Hz, 1H), 8.02(d, J=8.0Hz, 1H)ppm.

[0145] Example 3 Functionalization of benzothiazol C2-H by direct electrochemical reduction 2 [ka]

[0146] A glass H-shaped electrolytic cell, the electrodes of which were separated by a glass filter diaphragm, was thoroughly dried and placed under a nitrogen atmosphere. Both electrodes were Pt plates (1 cm × 2 cm).

[0147] TBABr (cathode: 386.1 mg, 1.2 mmol; anode: 385.6 mg, 1.2 mmol) and anhydrous DMF (4.0 mL × 2) were added to both electrodes. Subsequently, acetone (58.7 mg, 1.0 mmol) and benzothiazol (67.3 mg, 0.5 mmol) were added to the cathode, stirring was started, and electroreduction was performed by applying electricity at 12 mA and 1.0 F / mol (based on benzothiazol).

[0148] After the current was applied, the cathode solution was quenched with HO (2 mL). The reaction solutions from both electrodes were added to a separatory funnel containing 20 mL of 10% NaSO solution, and the organic matter was extracted with hexane / ethyl acetate = 4:1 (volume ratio) (40 mL x 1). The organic matter was further extracted with hexane / ethyl acetate = 4:1 (volume ratio) (20 mL x 2). The combined organic layer was washed with saturated brine (10 mL x 1). The organic layer was then dried over anhydrous magnesium sulfate, filtered through a cotton plug, concentrated, and vacuumed to obtain the crude product.

[0149] The target product, 2-(benzo[d]thiazol-2-yl)propan-2-ol, was identified by GCMS. 1The compound was detected by H NMR and identified with reference to Reference 2 (Reference 2: H. Chikashita, M. Ishibaba, K. Ori, K. Itoh, Bull. Chem. Soc. Jpn. 1988, 61, 3637-3648). 1 This was determined by 1 H NMR.

[0150] Example 4 (Consideration of reaction temperature, reaction power, and reaction time of electrolytic reaction) In Example 4, a method was investigated in which radical anions derived from benzophenone were generated and accumulated by electrolytic reduction, and then benzothiazole was added after applying current to functionalize C2-H.

[0151] (Experimental method) An H-type separated electrolytic cell was used, and Pt plates (1 cm x 2 cm) were used as the anode and cathode electrodes. 0.3 M Bu4NBr / DMF (4.0 mL x 2) was added to the anode and cathode, respectively, and benzophenone (1.2 mmol) was added only to the cathode.

[0152] (entry 7) (Step 1) At low temperature, the corresponding radical anion was generated and accumulated by electrolytic reduction using a current of 40 mA and 1.0 F / mol.

[0153] (Step 2) After the current was applied, benzothiazole (0.50 mmol) was added to the cathode in an ice bath to functionalize C2-H, and the yield of the corresponding product was evaluated.

[0154] [ka]

[0155] [ka]

[0156] After various investigations, we were able to obtain the target product, benzo[d]thiazol-2-yldiphenylmethanol, in 73% yield (entry 13) under the above conditions.

[0157] Example 5 (Study of electrolytes in electrolytic reactions) In Example 5, a method was investigated in which radical anions derived from benzophenone were generated and accumulated by electrolytic reduction, and then benzothiazole was added after applying current to functionalize C2-H.

[0158] (Experimental method) An H-type separated electrolytic cell was used, and Pt plates (1 cm x 2 cm) were used as the anode and cathode electrodes. 0.3 M Bu4NBr / DMF (4.0 mL x 2) was added to the anode and cathode, respectively, and benzophenone (1.0 mmol) was added only to the cathode.

[0159] (Step 1) At low temperature, the corresponding radical anion was generated and accumulated by electrolytic reduction using a current of 50 mA and 1.0 F / mol.

[0160] (Step 2) After the current was applied, benzothiazole (0.50 mmol) was added to the cathode in an ice bath to functionalize C2-H, and the yield of the corresponding product was evaluated.

[0161] [ka]

[0162] [ka]

[0163] After various investigations, we were able to obtain the target product, benzo[d]thiazol-2-yldiphenylmethanol, in 55% yield (entry 1) under the above conditions.

[0164] Example 6 (Study of benzothiazole derivatives) 1 H, and 13 C NMR spectra were measured using a Varian Mercury 300 or a JEOL JINM-ECS 400. CDCl was used as the solvent. 1 1 H NMR values ​​were reported based on 0.00 ppm of tetramethylsilane as the internal standard. 13 C NMR values ​​were reported based on 77.0 ppm.

[0165] Mass spectra were measured on a Thermo Scientific mass spectrometer Exactive Plus.

[0166] GC analysis was performed using a Shimadzu GC-2014 (oven temp: 130°C to 250°C 10°C / min, hold 15 min).

[0167] GC-MS analysis was performed using an Agilent 6890N equipped with an Agilent 5973N Mass Selective Detector and an Agilent 7890A equipped with an Agilent 5975C inert XL MSD with a Triple-Axis Detector.

[0168] Gel permeation chromatography (GPC) was performed on a Japan Analytical Industry LC-9210NEXT or LC-9130 equipped with a JAIGEL-1HH or JAIGEL-2HH column using CHCl3 as the eluent.

[0169] Thin layer chromatography (TLC) was performed using Merck's silica gel 60 N (spherical, neutral) 40 μm to 100 μm.

[0170] Unless otherwise stated, commercially available reagents were used.

[0171] Preparation of benzo[d]thiazol-2-yldiphenylmethanol (general procedure) [ka]

[0172] Pt plates (1 cm x 2 cm) were used as electrodes. An H-type electrolytic cell, with both electrodes separated by a glass filter diaphragm, was dried up and placed under a nitrogen atmosphere. Bu4NBr (TBABr) and DMF were added to the anode and cathode, respectively, to make a 0.3 M Bu4NBr / DMF solution (4.0 mL x 2). 10a (218.2 mg, 1.20 mmol) was added only to the cathode.

[0173] The sample was immersed in a thermostatic bath at -40°C and electrolytically reduced at 40 mA (1.0 F / mol) to generate and accumulate the corresponding ketyl radical.

[0174] After the current was applied, the cathode was immersed in an ice bath and 9a (67.6 mg, 0.500 mmol) was immediately added. After 1 h, 2 mL of HO was poured into the cathode, and the solutions from both electrodes and the electrolytic cell washings (40 mL hexane / AcOEt (v:v=4:1)) were transferred to a separatory funnel containing 10% aqueous sodium thiosulfate solution.

[0175] The organic and aqueous layers were separated, and the aqueous layer was extracted twice with hexane / AcOEt (v:v = 4:1). The combined organic layers were then washed with 10 mL of saturated brine. The mixture was dried over MgSO4 and concentrated under reduced pressure to obtain the crude product.

[0176] The crude product was purified by recrystallization in hexane / AcOEt (v:v=4:1) to give the target compound, benzo[d]thiazol-2-yldiphenylmethanol, as colorless crystals (116.4 mg, 0.367 mmol, 73% yield).

[0177] 1 H NMR (300 MHz, CDCl3) δ 4.57 (s, 1H), 7.26-7.38 (m, 7H), 7.41-7.50 (m, 5H), 7.80 (d, J = 6.9 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H) ppm; 13 C NMR (75 MHz, CDCl3) δ 81.1, 121.6, 123.3, 125.2, 126.1, 127.6, 128.1, 128.2, 135.9, 144.8, 152.8, 177.8 ppm; HRMS (ESI, positive) calculated for C 20 H 16 NOS ([M+H] + ): 318.0947, found 318.0933; R f = 0.45 (hexane / AcOEt (v:v = 4:1)).

[0178] (a) Preparation of (4-methylbenzo[d]thiazol-2-yl)diphenylmethanol [ka]

[0179] 9b (74.9 mg, 0.502 mmol) was synthesized using a similar procedure to the general procedure. The crude product was purified by flash chromatography (hexane / AcOEt (v:v=10:1)) to give the desired compound (4-methylbenzo[d]thiazol-2-yl)diphenylmethanol as a colorless liquid (140.2 mg, 0.423 mmol, 84% yield).

[0180] 1 H NMR (400 MHz, CDCl3) δ 2.69 (s, 3H), 4.90 (s, 1H), 7.16-7.36 (m, 8H), 7.40-7.50 (m, 4H), 7.56-7.63 (m, 1H) ppm; 13 C NMR (100 MHz, CDCl3) δ 18.3, 80.9, 118.9, 125.2, 126.7, 127.6, 128.0, 128.1, 133.4, 136.0, 145.2, 151.7, 175.9 ppm; HRMS (ESI, positive) calculated for C 21 H 18 NOS ([M+H] + ): 332.1104, found 332.1099; R f = 0.33 (hexane / AcOEt (v:v = 10:1)).

[0181] (b) Preparation of (6-methylbenzo[d]thiazol-2-yl)diphenylmethanol [ka]

[0182] 9c (74.7 mg, 0.501 mmol) was synthesized using a similar procedure to the general procedure. The crude product was purified by flash chromatography (hexane / AcOEt (v:v=10:1)) to give the desired compound (6-methylbenzo[d]thiazol-2-yl)diphenylmethanol as a white solid (128.3 mg, 0.387 mmol, 77% yield).

[0183] 1 H NMR (400 MHz, CDCl3) δ 2.41 (s, 3H), 4.76 (s, 1H), 7.18-7.33 (m, 4H), 7.39-7.48 (m, 7H), 7.54 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H) ppm; 13 C NMR (100 MHz, CDCl3) δ 21.4, 80.9, 121.1, 122.7, 127.56, 127.63, 127.95, 128.05, 135.2, 136.0, 144.9, 150.8, 176.7 ppm; HRMS (ESI, positive) calculated for C 21 H 18 NOS ([M+H] +): 332.1104, found 332.1108; R f = 0.25 (hexane / AcOEt (v:v = 10:1)).

[0184] (c) Preparation of (6-methoxybenzo[d]thiazol-2-yl)diphenylmethanol [ka]

[0185] 9f (82.1 mg, 0.497 mmol) was synthesized using a similar procedure to the general procedure. After removing salts and DMF using a short silica gel column (hexane / AcOEt (v:v=3:1)), the crude product was purified by recrystallization in hexane / AcOEt (v:v=4:1) to give the desired compound, (6-methoxybenzo[d]thiazol-2-yl)diphenylmethanol, as a colorless solid (141.2 mg, 0.406 mmol, 82% yield).

[0186] 1 H NMR (300 MHz, CDCl3) δ 3.83 (s, 3H), 4.47 (s, 1H), 7.06 (dd, J = 3.0, 9.0 Hz, 1H), 7.25 (d, J = 2.4 Hz, 1H), 7.29-7.39 (m, 6H), 7.41-7.51 (m, 4H), 7.87 (d, J = 9.6 Hz, 1H) ppm; HRMS (ESI, positive) calculated for C 21 H 18 NO2S ([M+H] + ): 348.1053, found 348.1048; R f = 0.38 (hexane / AcOEt (v:v = 4:1)).

[0187] (d) Production of (6-phenylbenzo[d]thiazol-2-yl)diphenylmethanol [ka]

[0188] The synthesis was carried out using 6-phenylbenzo[d]thiazole (9 g, 105.4 mg, 0.499 mmol) following a similar procedure to the general procedure. The crude product was purified by flash chromatography (hexane / AcOEt (v:v=10:1)) followed by preparative GPC to give the target compound (6-phenylbenzo[d]thiazol-2-yl)diphenylmethanol as a colorless liquid (114.2 mg, 0.290 mmol, 58% yield).

[0189] [ka]

[0190] After various investigations, we were able to obtain the desired product under the above conditions. (a) (4-methylbenzo[d]thiazol-2-yl)diphenylmethanol 84% (b) (6-methylbenzo[d]thiazol-2-yl)diphenylmethanol 77% (c) (6-methoxybenzo[d]thiazol-2-yl)diphenylmethanol 82% (d) (6-phenylbenzo[d]thiazol-2-yl)diphenylmethanol 58%

[0191] [2] Industrial Applicability The present invention relates to a method for producing benzothiazole derivatives by electrolytic reaction, and is an environmentally friendly production method or a production method with a low environmental impact. The production method of the present invention is useful for continuous production of benzothiazole derivatives and can reduce production costs. The production method of the present invention is suitable for industrial production of benzothiazole derivatives.

[0192] Benzothiazole derivatives are useful in a wide range of fields, including pharmaceuticals, chemicals (additives), pesticides, and partial structures of organic electronic materials. In particular, the development of methods for directly introducing functional groups into C2-H of benzothiazole derivatives is actively underway.

[0193] The method for producing a benzothiazole derivative of the present invention makes it possible to change the stereostructure and similar structures of the benzothiazole derivative as needed, which will lead to support for the development of drug discovery (medicines, etc.) and functional materials (chemicals, etc.) using the benzothiazole derivative.

Claims

1. The following general formula (1): 【Chemical 1】 (In formula (1), R 1 is each R 1 are the same or different and each represent a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a nitro group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkoxy group, an optionally substituted alkylsulfanyl group, an optionally substituted acyl group, an optionally substituted acyloxy group, an optionally substituted alkylsulfonyloxy group, an optionally substituted aryl group, an optionally substituted arylsulfonyloxy group, an optionally substituted alkoxy-carbonyl group, an optionally substituted aryloxy-carbonyl group, an optionally substituted carbamoyl group, a tri-substituted silyl group, or a substituted amino group. In formula (1), m represents an integer of 1 to 4. In formula (1), R 2 , and R 3 are the same or different and each represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted heterocyclic group. A method for producing a benzothiazole derivative represented by the formula: The following general formula (2): 【Chemistry 2】 (In formula (2), R 1 , and m are the same as in the above formula (1). a benzothiazole compound represented by the formula: The following general formula (3): 【Chemistry 3】 (In formula (3), R 2 , and R 3 is the same as the above formula (1). and a ketone compound represented by A manufacturing method comprising a step of electrolytic reaction.

2. The electrolytic reaction is (i) Tetrabutylammonium bromide (TBABr), lithium perchlorate (LiClO 4 ), magnesium perchlorate (Mg(ClO 4 ) 2 ), and tetrabutylammonium perchlorate (Bu 4 NClO 4 at least one electrolyte selected from the group consisting of (ii) at least one aprotic polar solvent selected from the group consisting of N,N-dimethylformamide (DMF), acetone, acetonitrile, dimethyl sulfoxide (DMSO), and tetrahydrofuran (THF); The method according to claim 1, wherein the method is carried out using an electrolyte solution containing:

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