Electrolytic oxidative cleavage of trolox amide

Abstract

This disclosure provides a method for preparing trolox amides by electro-oxidation. In some embodiments, this disclosure allows the reaction to proceed with reduced or no oxidant, providing a cleaner production method compared to conventional methods.

Description

[0001] Cross-references to related applications This application claims priority to Japanese Patent Application No. 2023-204269 (filed on December 1, 2023), which is incorporated herein by reference. Invention Field

[0002] This disclosure provides a method for the electrolytic oxidative pyrolysis of Trolox amide.

[0003] Background of the Invention International Publication No. WO 2009 / 061744 describes racemic 2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohex-1,4-dienyl)butyramide synthesized from racemic Trolox (6-hydroxy-2,5,7,8-tetramethylsomn-2-carboxylic acid), which can be used to treat and / or inhibit mitochondrial lesions and certain pervasive developmental disorders.

[0004] International Publication No. WO 2021 / 167095 describes the optical resolution of Trolox intermediates and their preparation method. It has been reported that α-tocopherol (vitamin E) can be converted into quinone form by electrolytic oxidation (J. Am. Chem. Soc. 2004, 126, 12441-12450 (Non-Patent Document 1)), but there are no reports on the electrolytic oxidation of Trolox derivatives disclosed in this application. Invention Overview In some aspects and embodiments, the inventors, through diligent study of trolox amide-related compounds, discovered a novel electrolytic oxidative pyrolysis method for trolox amide-related compounds, thereby completing this disclosure.

[0006] In some implementations, this disclosure provides the following items: [Project 1] Preparation method of compound I: [Chemical Formula 1] Includes the following steps: Electrolytic oxidation of compound II: [Chemical Formula 2] in R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 and R9 Each independently represents a hydrogen atom, halogen, or optionally substituted C atom. 1-6 Alkyl, optionally substituted C 1-6 Alkyl or -C(=O)NR A R B ,and R A and R B Each independently represents a hydrogen atom, and each C atom is optionally substituted. 1-6 Alkyl or optionally substituted C 1-6 Alkoxy groups, provided that the compound of formula I is not of formula III: [Chemical Formula 3] (Where R is (CH2CH2CH2CH(CH3)3CH3)) And the compound of formula II is not [Chemical Formula 4] (Where R is (CH2CH2CH2CH(CH3)3CH3)).

[0007] [Project 2] According to the method described in Project 1, where R 1 C is a hydrogen atom or an optional substituted C 1-6 alkyl.

[0008] [Project 3] According to any one of the methods described in the foregoing items, wherein R 1 It is a methyl group.

[0009] [Project 4] According to any one of the methods described in the foregoing items, wherein R 2 C is a hydrogen atom or an optional substituted C 1-6 alkyl.

[0010] [Project 5] According to any one of the methods described in the foregoing items, wherein R 2 It is a methyl group.

[0011] [Project 6] According to any one of the methods described in the foregoing items, wherein R 3 C is a hydrogen atom or an optional substituted C 1-6 alkyl.

[0012] [Project 7] According to any one of the methods described in the foregoing items, wherein R 3 It is a methyl group.

[0013] [Project 8] According to any one of the methods described in the foregoing items, wherein R 4 C is a hydrogen atom or an optional substituted C 1-6 alkyl.

[0014] [Project 9] According to any one of the methods described in the foregoing items, wherein R 4 It is a hydrogen atom.

[0015] [Project 10] According to any one of the methods described in the foregoing items, wherein R 5 C is a hydrogen atom or an optional substituted C 1-6 alkyl.

[0016] [Project 11] According to any one of the methods described in the foregoing items, wherein R 5 It is a hydrogen atom.

[0017] [Project 12] According to any one of the methods described in the foregoing items, wherein R 6 C is a hydrogen atom or an optional substituted C 1-6 alkyl.

[0018] [Project 13] According to any one of the methods described in the foregoing items, wherein R 6 It is a hydrogen atom.

[0019] [Project 14] According to any one of the methods described in the foregoing items, wherein R 7 C is a hydrogen atom or an optional substituted C 1-6 alkyl.

[0020] [Project 15] According to any one of the methods described in the foregoing items, wherein R 7 It is a hydrogen atom.

[0021] [Project 16] According to any one of the methods described in the foregoing items, wherein R 8 Hydrogen atom, optionally substituted C 1-6 Alkyl or -C(=O)NR A R B .

[0022] [Project 17] According to any one of the methods described in the foregoing items, wherein R 8 -C(=O)NR A R B .

[0023] [Project 18] According to any one of the above items, the method wherein R 9 C is a hydrogen atom or an optional substituted C 1-6 alkyl.

[0024] [Project 19] According to any one of the methods described in the foregoing items, wherein R 9 It is a methyl group.

[0025] [Project 20] According to the method described in any one of the foregoing items, R A and R B Each represents a hydrogen atom.

[0026] [Project 21] The method according to any one of the foregoing items, wherein the solvent is water or an aprotic polar solvent.

[0027] [Project 22] The method according to any one of the foregoing items, wherein the solvent is water and an aprotic polar solvent.

[0028] [Project 23] In any of the preceding items, the method uses a carbon-based electrode, a platinum-based electrode, or a stainless steel electrode, or a combination thereof, in the electrolytic oxidation process.

[0029] [Project 23A] According to any one of the methods described in the foregoing items, the electrode used in the electrolytic oxidation is: (1) A platinum foil electrode for the anode and a glassy carbon electrode for the cathode; (2) A platinum foil electrode for the anode and a platinum foil electrode for the cathode; (3) Glassy carbon electrode for anode and glassy carbon electrode for cathode; (4) Stainless steel electrode for anode and stainless steel electrode for cathode; (5) Platinum foil electrode, used as a glassy carbon electrode for the cathode; or (6) Glassy carbon electrode for the anode and stainless steel electrode for the cathode.

[0030] [Project 24] According to any one of the preceding items, in the method, at least one selected from DMA, MeCN, DMSO, DMF and THF is used as an aprotic polar solvent in the electrolytic oxidation.

[0031] [Project 24A] The method according to any one of the foregoing items, wherein DMA is used as an aprotic polar solvent in the electrolytic oxidation.

[0032] [Project 25] The method according to any one of the above items, wherein an alkali metal salt or a quaternary ammonium salt is used as an electrolyte in the electrolytic oxidation.

[0033] [Project 26] According to any one of the preceding items, in the method of said electrolytic oxidation, the electrolyte comprises at least one compound selected from the following: lithium tetrafluoroborate (LiBF4), lithium bromide (LiBr), tetrabutylammonium hexafluorophosphate (Bu4NPF6), tetrabutylammonium tetrafluoroborate (Bu4NBF4), sodium perchlorate, tetrabutylammonium bromide (Bu4NBr), and lithium chloride (LiCl).

[0034] [Project 26] According to any one of the preceding items, in the method of said electrolytic oxidation, the electrolyte comprises at least one compound selected from the following: lithium tetrafluoroborate (LiBF4), lithium bromide (LiBr), tetrabutylammonium hexafluorophosphate (Bu4NPF6), tetrabutylammonium tetrafluoroborate (Bu4NBF4), sodium perchlorate, tetrabutylammonium bromide (Bu4NBr), and lithium chloride (LiCl).

[0035] [Project 27] The method according to any one of the foregoing items, wherein a current of 10-100 mA is used in the electrolytic oxidation.

[0036] [Project 27A] The method according to any one of the foregoing items, wherein a current of 20-30 mA, 20 mA or 30 mA is used in the electrolytic oxidation.

[0037] [Project 28] The method according to any one of the foregoing items, wherein 5 mA / cm is used in electrolytic oxidation. 2 -10 A / cm 2 The current value per unit area of ​​the electrode.

[0038] [Project 28A] The method according to any one of the foregoing items, wherein 5 mA / cm is used in electrolytic oxidation. 2 and 10 A / cm 2 The current value per unit area of ​​the electrode.

[0039] [Project 29] The method according to any one of the foregoing items, wherein a voltage of 1-500 V is used in the electrolytic oxidation.

[0040] [Project 29A] The method according to any one of the foregoing items, wherein a voltage of 2V, 2.5V, 4V, 6V or 8V is used in the electrolytic oxidation.

[0041] [Project 29A] The method according to any one of the foregoing items, wherein 2-10, 2-8 or 6-8 F / mol is used as the electron equivalent in electrolytic oxidation.

[0042] [Project 30] The method according to any one of the foregoing items, wherein the following combination is used as a combination of electrolyte, electrolyte aprotic solvent and water in the electro-oxidation system: (1) Bu4NPF6, DMA and water; (2) Bu4NPF6, THF and water; (3) LiBr, MeCN and water; or (4) Bu4NBr, MeCN and water.

[0043] [Project 31] According to any one of the preceding items, in the method of electrolytic oxidation, the current is stopped after the reaction is completed.

[0044] [Project 32] The method according to any one of the foregoing items, wherein in the compound of formula I, R 8 R 9 The carbon atom bonded to OH is a chiral carbon.

[0045] [Project 33] According to any one of the methods described above, the compound of formula II is optically active and maintains optical purity in the electrolytic oxidation reaction of the compound of formula II.

[0046] [Project 34] According to any one of the methods described in the foregoing items, wherein the compound of formula I is... [Chemical Formula 5] And the compound of formula II is [Chemical Formula 6] .

[0047] [Project 35] According to the method of any one of the foregoing items, the compound of formula II is prepared by the following steps: optical resolution and amidation of the compound of formula III: [Chemical Formula 7] .

[0048] This disclosure is intended to enable the provision of one or more of the foregoing features in further combinations beyond those explicitly stated. Those skilled in the art will recognize further embodiments and advantages of this disclosure upon reading and understanding the following detailed description as necessary.

[0049] Advantages of the invention This disclosure provides a method for preparing the compound represented by Formula I in a manner with high reaction efficiency and simple post-processing. This disclosure allows for reactions to be carried out with reduced or no oxidant, providing a cleaner production method compared to conventional methods. This disclosure also reveals the ability to convert compound 2 to compound 1 in a yield at least comparable to conventional preparation methods. This means that the synthetic method for constructing compound 1 via electrolytic oxidation of the present disclosure can achieve a greener process with less waste.

[0050] Brief description of the attached figures Figure 1 The HPLC chromatogram of compound 1 is shown.

[0051] Figure 2 The HPLC chromatogram of compound 2 is shown.

[0052] Figure 3 The HPLC chromatogram of compound 3 is shown.

[0053] Detailed description This article provides further details on the Trolox amide electrolytic oxidation pyrolysis method.

[0054] definition Throughout this instruction manual, unless otherwise specified, singular expressions should be understood to include their plural forms. Therefore, singular articles (such as "a," "a kind," "the," etc.) should also be understood to include their plural forms, unless otherwise specified.

[0055] Furthermore, the terminology used herein should be understood to have the meanings commonly used in the art, unless otherwise specified. Therefore, unless otherwise defined, all terms and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In case of any discrepancy, this specification (including definitions) shall prevail.

[0056] The abbreviations used in this article have their conventional meanings within the scope of this field, unless otherwise specified.

[0057] The term "about" in this document, referring to numerical values ​​or parameters, includes variations in the value or parameter itself. Unless otherwise specified, for example, "about X" includes "X" itself as well as values ​​within an acceptable margin of error of ±10%.

[0058] As used herein, "Trolox" refers to 6-hydroxy-2,5,7,8-tetramethyl-2-carboxylic acid. The R-type is referred to as R-Trolox, and the S-type as S-Trolox. Trolox can be prepared by synthetic methods known to those skilled in the art, such as those described in US Patent Nos. 3,947,473, 4,003,919, and 4,026,907.

[0059] The term "electrolytic oxidation" as used in this article refers to an oxidation reaction that occurs at the electrolytic anode in water, aqueous solution, or aprotic solvent or a mixture thereof.

[0060] As used herein, "aprotic polar solvent" refers to a polar solvent lacking readily exchangeable or acidic hydrogen. Aprotic polar solvents include, but are not limited to, tetrahydrofuran (THF), 2-methyltetrahydrofuran, acetone, acetonitrile (MeCN), N-methylpyrrolidone, and dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), and dimethylformamide (DMF). DMA is preferred, but not limited to, its use.

[0061] The "time" used in this article for electrolytic oxidation refers to the time for which voltage is applied to the reactant or the time for which electricity is passed through the reactant in the reaction system.

[0062] As used herein, "electrode" refers to an electrical conductor used to contact non-metallic parts of a circuit. Electrodes can be carbon-based electrodes, platinum-based electrodes, stainless steel electrodes, or combinations thereof. Preferably, but not limited to, the electrode can be carbon.

[0063] As used herein, "electrolyte" is used in the sense commonly understood in the art. In some embodiments, alkali metal salts (such as lithium salts) or quaternary ammonium salts, such as Bu4NPF6, Bu4NBF4, Bu4NBr, Et4NPF6, LiBr, LiCl, LiBF4, etc., may be used. Bu4NBr is preferred, but not limited to, the use of electrolytes.

[0064] Any current value used in electrolytic oxidation may be used herein, typically 10 to 100 mA, or 20 to 30 mA, 20 mA, 30 mA, etc. In some embodiments, the current used in electrolytic oxidation may be stopped after the reaction is complete.

[0065] The current values ​​used in this article for electrolytic oxidation can be expressed as the current per unit area of ​​the electrode, for example, 5 mA / cm². 2 -10A / cm 2 10mA / cm 2 -1A / cm 2 100mA / cm 2 -1A / cm 210-100mA / cm 2 Etc. In some implementations, any range of values ​​can be used.

[0066] Any voltage value used in electrolytic oxidation may be used herein. In some embodiments, the voltage may be, for example, 1 to 500 V, 1 to 100 V, 1 to 10 V, 2 to 8 V, 4 to 8 V, or 2.5 V, etc.

[0067] Any electron equivalent value used in electrolytic oxidation may be used herein. In some embodiments, values ​​in any range may be used, such as 2-10 F / mol, 2-6 F / mol, 6-8 F / mol, etc.

[0068] In some embodiments, the combination of electrolyte and solvent is appropriately determined by those skilled in the art based on the embodiments shown herein. In some embodiments, they include, but are not limited to, combinations of electrolytes and solvents including: Bu4NPF6 with DMA and water, Bu4NPF6 with THF and water, LiBr with MeCN and water, Bu4NBr with MeCN and water, etc.

[0069] There is no limitation on the number of substituents in the group defined by "optionally substituted" or "substituted," as long as they are substituted. Unless otherwise stated, the description of each group also applies when that group is part of another group or a substituent.

[0070] The substituents in the "optionally substituted" group are selected from the following substituent group α. The group is optionally substituted by 1 to 5 identical or different substituents.

[0071] Although there are no particular restrictions on the type of substituent, if the atom to which the substituent is attached is an oxygen atom, nitrogen atom, or sulfur atom, the substituent is limited to the following substituents that can be attached to a carbon atom.

[0072] In some aspects and implementations, the substituent α can be: 1) Halogen atom 2) Hydroxyl group 3) Carboxyl group 4) Cyano 5) C 1-6 alkyl 6) C 2-6 alkenyl 7) C 2-6 acetylin 8) C 1-6 Alkoxy 9) C 1-6 Alkylthio 10) C 1-6 alkyl carbonyl 11) C 1-6 alkylsulfonyl 12) C 3-10 Alicyclic group 13) C 3-10 Aliphatic epoxy groups 14) C 6-10 Aryloxy 15) 5- or 6-membered heteroaryloxy 16) 4- to 10-membered non-aromatic heterocyclic groups 17) C 3-10 Alicyclic thiols 18) C 6-10 Aryl thiols 19) 5- or 6-membered heteroarylthio 20) 4- to 10-membered non-aromatic heterocyclic thiols 21) C 6-10 Aryl 22) 5- or 6-membered heteroaryl 23) 4- to 10-membered non-aromatic heterocycles 24) C 3-10 Alicyclic carbonyl 25) C 6-10 aryl carbonyl 26) 5- or 6-membered heteroaryl carbonyl group 27) 4- to 10-membered non-aromatic heterocyclic carbonyl groups 28) C 3-10 Alicyclic sulfonyl 29) C 6-10 arylsulfonyl 30) 5- or 6-membered heteroarylsulfonyl group 31) 4- to 10-membered non-aromatic heterocyclic sulfonyl groups (wherein substituents 12) to 31) are each optionally substituented by 1 to 5 or 1) of the group β of substituent set C 1-6 Alkyl substitution) 32) -NR 10a R 11a 33) -SO2-NR 10b R 11b 34) -NR 10c -C(=O)R 11c 35) -NR 10d -C(=O)OR 11d 36) -NR 12a -C(=O)NR 10e R11e 37) -NR 10f -C(=S)R 11f 38) -NR 10g -C(=S)OR 11g , 39) -NR 12b -C(=S)NR 10h R 11h 40) -NR 10i -SO2-R 11i 41) -NR 12c -SO2-NR 10j R 11j 42) -C(=O)OR 10k 43) -C(=O)NR 10l R 11k 44) -C(=O)NR 10m OR 11l 45) -C(=O)NR 12d -NR 10n R 11m 46) -C(=S)OR 10o 47) -C(=S)NR 10p R 11n 48) -C(=S)NR 10q OR 11o 49) -C(=S)NR 12e -NR 10r R 11p 50) -C(=NR 13a )R 10s 51) -C(=NR 13b )CHO 52) -C(=NR 13c )NR 10t R 11q 53) -C(=NR 13d )NR 12f -NR 10u R 11r 54) -NR 17c-C(=NR 13k )R 17d 55) -NR 12g -C(=NR 13e )-NR 10v R 11s 56) -NR 14 -C(=NR 13f )NR 12h -NR 10w R 11t 57) -OC(=O)R 10x 58) -OC(=O)OR 10y 59) -OC(=O)NR 10z1 R 11u 60) -NR 12i -NR 10z2 R 11v 61) -NR 10z3 OR 11w 62) -C(=N-OR 13a )R 10s 63) -C(=N-OR 13b CHO 64) -C(=N-OR 13c )NR 10t R 11q 65) -C(=N-OR 13d )NR 12f -NR 10u R 11r and 66) -C(=O)H, In some embodiments, the substituent β is selected from the following: 1) Halogen atom 2) Hydroxyl group 3) Carboxyl group 4) Cyano 5) C 3-10 Alicyclic group 6) C 1-6 Alkoxy 7) C 3-10 Aliphatic epoxy groups 8) C 1-6 Alkylthio 9) 5- or 6-membered heteroarylthio 10) C 6-10 Aryl 11) 5- or 6-membered heteroaryl 12) 4- to 10-membered non-aromatic heterocycles 13) C 1-6 alkyl carbonyl 14) C 3-10 Alicyclic carbonyl 15) C 6-10 aryl carbonyl 16) 5- or 6-membered heteroaryl carbonyl group 17) 4- to 10-membered non-aromatic heterocyclic carbonyl groups 18) -NR 15a R 16a , 19) -SO2-NR 15b R 16b , 20) -NR 15c -C(=O)R 16c , 21) -NR 17a -C(=O)NR 15d R 16d , 22) -C(=O)NR 15e R 16e , 23) -C(=NR 13g )R 15f , 24) -C(=NR 13h )NR 15g R 16f , 25) -NR 16g -C(=NR 13i )R 15h , 26) -NR 17b -C(=NR 13j )-NR 15i R 16h , 27) -C(=N-OR 13g )R 15f , and 28) -C(=N-OR 13h )NR 15g R 16f (wherein substituents 5 to 17 in substituent group β are each optionally replaced by 1 to 5 groups selected from halogen atoms, hydroxyl groups, cyano groups, carboxyl groups, and -NR groups.) 18a R18b (Substituents).

[0073] R 13a R 13b R 13c R 13d R 13a R 13b R 13c R 13d R 13e R 13f R 13g R 13h R 13i R 13j and R 13k Whether the two are the same or different, each is independently a hydrogen atom, a hydroxyl group, and a C. 1-6 Alkyl or C 1-6 Alkyl group.

[0074] R 10a R 10b R 10c R 10d R 10e R 10f R 10g R 10h R 10i R 10j R 10k R 10l R 10m R 10n R 10o R 10p R 10q R 10r R 10s R 10t R 10u R 10v R 10w R 10x R 10y R 10z1 R 10z2 R 10z3 R 11a R 11b R 11c R 11d R 11e R 11f R 11g R 11h R 11i R 11j R 11k R 11l R 11m R 11n R 11o R11p R 11q R 11r R 11s R 11t R 11u R 11v R 11w R 12a R 12b R 12c R 12d R 12e R 12f R 12g R 12h R 12i R 14 R 15a R 15b R 15c R 15d R 15e R 15f R 15g R 15h R 15i R 16a R 16b R 16c R 16d R 16e R 16f R 16g R 16h R 17a R 17b R 17c and R 17d Whether the two are the same or different, each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl groups (wherein the alkyl group is optionally surrounded by 1 to 3 identical or different groups selected from hydroxyl, cyano, C) 1-6 Alkoxy and -NR 18a R 18b (substituents), and R 18a and R 18b Whether the two are the same or different, each is independently a hydrogen atom or a carbon atom. 1-6 alkyl.

[0075] In some preferred embodiments, the substituent α is selected from the following: 1) Halogen atom 2) Hydroxyl group 3) Carboxyl group 4) Cyano 5) C 1-6 alkyl 6) C 1-6 Alkoxy 7) C 1-6 Alkylthio 8) C 1-6 alkyl carbonyl (where substituents 5) to 8) are each optionally substituted by 1 to 5 identical or different substituents selected from substituent group β) 9) C 3-10 Alicyclic group 10) C 3-10 Aliphatic epoxy groups 11) C 6-10 Aryloxy 12) 5- or 6-membered heteroaryloxy 13) 4- to 10-membered non-aromatic heterocyclic groups 14) C 3-10 Alicyclic thiols 15) C 6-10 Aryl thiols 16) 5- or 6-membered heteroarylthio 17) 4- to 10-membered non-aromatic heterocyclic thiols 18) C 6-10 Aryl 19) 5- or 6-membered heteroaryl 20) 4- to 10-membered non-aromatic heterocycles 21) C 3-10 Alicyclic carbonyl 22) C 6-10 aryl carbonyl 23) 5- or 6-membered heteroaryl carbonyl group 24) 4- to 10-membered non-aromatic heterocyclic carbonyl groups (wherein substituents 9) to 24) are each optionally replaced by 1 to 5 substituents from substituent group β or 1) C 1-6 Alkyl substitution) 25) -NR 10a R 11a 26) -SO2-NR 10b R 11b 27) -NR 10c -C(=O)R 11c 28) -NR 12a -C(=O)NR 10d R 11d 29) -NR 10e -SO2-R 11e 30) -NR 12b -SO2-NR 10f R 11f 31) -C(=O)NR 10g R 11g 32) -C(=NR 13a )R 10h 33) -C(=NR 13b )NR 10i R 11h 34) -NR 11f -C(=NR 13c )R 10g 35) -NR 12c -C(=NR 13d )-NR 10j R 11i 36) -C(=N-OR 13a )R 10h and 37) -C(=N-OR 13b )NR 10i R 11h .

[0076] In some preferred embodiments, the substituent group β is selected from the following: 1) Halogen atom 2) Hydroxyl group 3) Cyano 4) C 3-10 Alicyclic group 5) C 1-6 Alkoxy 6) C 1-6 Alkylthio 7) 5- or 6-membered heteroarylthioyl group 8) 5- or 6-membered heteroaryl 9) 4- to 10-membered non-aromatic heterocycles 10) C 1-6 alkyl carbonyl 11) C 3-10 Alicyclic carbonyl 12) C 6-10 aryl carbonyl 13) 5- or 6-membered heteroaryl carbonyl group 14) 4- to 10-membered non-aromatic heterocyclic carbonyl groups 15) -NR 15a R 16a 16) -NR 15b -C(=O)R 16b 17) -NR 17a -C(=O)NR 15c R 16c 18) -C(=O)NR 15d R 16d 19) -C(=NR 13e )R 15e 20) -C(=NR 13f )NR 15f R 16e 21) -NR 16f -C(=NR 13g )R 15g 22) -NR 17b -C(=NR 13h )-NR 15h R 16g 23) -C(=N-OR 13e )R 15e and 24) -C(=N-OR 13f )NR 15f R 16e (wherein substituents 4) to 14 in substituent group β are each optionally replaced by 1 to 5 groups selected from halogen atoms, hydroxyl groups, cyano groups, carboxyl groups, and -NR groups. 18a R 18b (substituents) R 13a R 13b R 13c R 13d R 13e R 13f R 13g and R 13h Whether the two are the same or different, each is independently a hydrogen atom, a hydroxyl group, and a C. 1-6 Alkyl or C 1-6 Alkyl group.

[0077] R 10a R 10b R 10c R 10d R 10e R 10f R 10g R 10h R 10i R 10j R 11a R 11b R 11cR 11d R 11e R 11f R 11g R 11h R 11i R 12a R 12b R 12c R 15a R 15b R 15c R 15d R 15e R 15f R 15g R 15h R 16a R 16b R 16c R 16d R 16e R 16f R 16g R 17a and R 17b Whether the two are the same or different, each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl groups (wherein the alkyl group is optionally surrounded by 1 to 3 identical or different groups selected from hydroxyl, cyano, C) 1-6 Alkoxy and -NR 18a R 18b (substituents), and NR 18a and R 18b Whether the two are the same or different, each is independently a hydrogen atom or a carbon atom. 1-6 alkyl.

[0078] In some preferred embodiments, the substituents in "optionally substituted" include the following substituents.

[0079] In some embodiments, a more preferred substituent group α is selected from the following: 1) Halogen atom 2) Hydroxyl group 3) Cyano 4) C 1-6 alkyl 5) C 1-6 Alkoxy 6) C 1-6 Alkylthio 7) C 1-6 alkyl carbonyl (wherein substituents 4) to 7) are each optionally substituted by 1 to 5 identical or different substituents selected from substituent group β) 8) 5- or 6-membered heteroaryloxy 9) 4- to 10-membered non-aromatic heterocyclic compounds 10) 5- or 6-membered heteroarylthioyl group 11) 4- to 10-membered non-aromatic heterocyclic thiols 12) C 6-10 Aryl 13) 5- or 6-membered heteroaryl 14) 4- to 10-membered non-aromatic heterocycles (wherein substituents 4) to 14) are each optionally substituented by 1 to 5 substituents selected from group β or 1) C 1-6 Alkyl substitution) 15) -NR 10a R 11a 16) -NR 11b -C(=O)R 10b 17) -NR 12a -C(=O)NR 10c R 11c 18) -C(=O)NR 10d R 11d 19) -C(=NR 13a )R 10e 20) -C(=NR 13b )NR 10f R 11e 21) -NR 11f -C(=NR 13c )R 10g 22) -NR 12b -C(=NR 13d )-NR 10h R 11g 23) -C(=N-OR 13a )R 10e and 24) -C(=N-OR 13b )NR 10f R 11e .

[0080] In some embodiments, a more preferred substituent group β is selected from the following: 1) Halogen atom 2) Hydroxyl group 3) Cyano 4) -NR 15a R 16a , 5) -NR 15b -C(=O)R16b , 6) -NR 17a -C(=O)NR 15c R 16c , 7) -C(=O)NR 15d R 16d , 8) -C(=NR 13e )R 15e , 9) -C(=NR 13f )NR 15f R 16e , 10) -NR 16f -C(=NR 13g )R 15g , 11) -NR 17b -C(=NR 13h )-NR 15h R 16g 12) -C(=N-OR 13e )R 15e , and 13) -C(=N-OR 13f )NR 15f R 16e , R 13a R 13b R 13c R 13d R 13e R 13f R 13g and R 13h Whether the two are the same or different, each is independently a hydrogen atom, a hydroxyl group, and a C. 1-6 Alkyl or C 1-6 Alkyl group.

[0081] R 10a R 10b R 10c R 10d R 10e R 10f R 10g R 10h R 11a R 11b R 11c R 11d R 11e R 11f R 11g R 12a R 12b R15a R 15b R 15c R 15d R 15e R 15f R 15g R 15h R 16a R 16b R 16c R 16d R 16e R 16f R 16g R 17a and R 17b Whether the two are the same or different, each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl groups (wherein the alkyl group is optionally surrounded by 1 to 3 identical or different groups selected from hydroxyl, cyano, C) 1-6 Alkoxy and -NR 18a R 18b (substituents), and R 18a and R 18b Whether the two are the same or different, each is independently a hydrogen atom or a carbon atom. 1-6 alkyl.

[0082] The "C" used in this article 1-6 "Indicates the number of carbon atoms from 1 to 6. Other numbers are interpreted similarly. For example, "C 1-4 "Indicates the number of carbon atoms from 1 to 4.

[0083] The term "heteroatoms" as used in this article refers to oxygen atoms, nitrogen atoms, sulfur atoms, etc.

[0084] As used in this article, "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. Fluorine and chlorine atoms are particularly preferred. "Halogen atom" is also called "halogen".

[0085] The "C" used in this article 1-6 Alkyl or C 1-6 "Alkyl group" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 6 carbon atoms. C 1-6 Alkyl groups are preferably "C" 1-4 Alkyl group, and more preferably C 1-3 Alkyl group. C 1-3 Specific examples of "alkyl" include methyl, ethyl, propyl, 1-methylethyl, etc. 1-4 Specific examples of "alkyl" include those for "C". 1-3 In addition to specific examples of "alkyl", it also includes butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, etc. 1-6 Specific examples of "alkyl" include those for "C". 1-4In addition to specific examples of "alkyl", it also includes pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl, etc.

[0086] The "C" used in this article 2-6 "Alkenyl" or "C" 2-6 "Alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing one or more carbon-carbon double bonds. 2-6 "Alkenyl" is preferably "C" 2-4 "Alkenyl". "C 2-6 Specific examples of "alkenyl" include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, etc.

[0087] The "C" used in this article 2-6 "Alkyne" or "C" 2-6 "Alkyne group" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group having one or more triple bonds. 2-6 "Alkyne group" is preferred to be "C" 2-4 "Alynyl". Specific examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl, 1-hexynyl, etc.

[0088] The "C" used in this article 3-20 "Alicyclic group" refers to a monocyclic or bicyclic non-aromatic hydrocarbon cyclic group having 3 to 20 carbon atoms, including those with partially unsaturated bonds, those with partially cross-linked structures, those with partially spirocyclic forms, and those with one or more carbonyl groups. "Alicyclic groups" include cycloalkyl, cycloalkenyl, and cycloynyl groups. 3-20 The alicyclic group is preferably "C". 3-10 "Alicyclic group", and more preferably "C" 3-7 Alicyclic group. 3-7 Specific examples of "alicyclic groups" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. 3-10 Specific examples of "alicyclic group" include those for "C" mentioned above. 3-7 In addition to specific examples of "alicyclic group", it also includes cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, etc.

[0089] "C" with a partially cross-linked structure 3-20 Specific examples of "alicyclic group" include, but are not limited to, those with the structures shown below.

[0090] [Chemical Formula 8] The "C" used in this article 3-20 "Alicyclic group" also includes compounds fused with aromatic rings. Specific examples include the groups shown below.

[0091] [Chemical Formula 9] .

[0092] The "C" used in this article 3-10 "Alicyclic group" refers to the above "C" 3-20 "Alicyclic group", where "C" 3-10 "Alicyclic group" is a monovalent group.

[0093] The "C" used in this article 6-10 "Aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms. 6-10 The aryl group can fuse with the aforementioned alicyclic or non-aromatic heterocyclic groups at any possible position. 6-10 Specific examples of "aryl" include phenyl, 1-naphthyl, 2-naphthyl, etc. 6-10 Preferred examples of "aryl" include phenyl. Specific examples of fused ring structures include groups shown below.

[0094] [Chemical Formula 10] [Chemical Formula 11] As used herein, "6- to 10-membered heteroaryl" refers to a monocyclic or bicyclic aromatic heterocyclic group consisting of 6 to 10 atoms, comprising 1 to 4 atoms independently selected from nitrogen, oxygen, and sulfur atoms. "6- to 10-membered heteroaryl" can be fused with the aforementioned "alicyclic" or "non-aromatic heterocyclic" groups at any possible position. "6- to 10-membered heteroaryl" is preferably "6-membered heteroaryl", more preferably pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl, and even more preferably pyridyl or pyrimidinyl. Specific examples of "6-membered heteroaryl" include pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl. Specific examples of "6- to 10-membered heteroaryl" include, in addition to the specific examples specified above for "6-membered heteroaryl", quinoxalinyl, triazolylpyridinyl, etc.

[0095] Specific examples of "9- or 10-membered heteroaryl" include, but are not limited to, compounds having the structures described below.

[0096] [Chemical Formula 12] [Chemical Formula 13] Specific examples of "5-membered heteroaryl" include, but are not limited to, thiophene, pyrrole, thiazole, isothiazole, pyrazole, imidazole, furan, oxazole, isoxazole, oxadiazole, thiadiazole, triazole, tetraazole, etc. The 5-membered heteroaryl is preferably pyrazole, imidazole, oxazole, triazole, tetraazole or thiadiazole, and more preferably imidazole or thiadiazole.

[0097] Specific examples of "5- or 6-membered heteroaryl" include the specific examples of "5-membered heteroaryl" and "6-membered heteroaryl" mentioned above. The aforementioned "5- or 6-membered heteroaryl" or "5- to 10-membered heteroaryl" can be combined with C 5-10 Alicyclic groups form fused ring structures, or with 5- to 10-membered non-aromatic heterocycles. Specific examples include the groups shown below.

[0098] [Chemical Formula 14] [Chemical Formula 15] [Chemical Formula 15] .

[0099] [Chemical Formula 16] .

[0100] As used herein, "4- to 20-membered non-aromatic heterocyclic group" refers to a monocyclic or bicyclic non-aromatic heterocycle composed of 4 to 20 atoms, containing 1 to 2 identical or different heteroatoms independently selected from nitrogen, oxygen, and sulfur atoms, including those with partially unsaturated bonds, those with partially cross-linked structures, and those with partially spirocyclic forms. "4- to 20-membered non-aromatic heterocyclic group" is preferably "4- to 6-membered non-aromatic heterocyclic group". Specific examples of "4- to 6-membered non-aromatic heterocyclic group" include azirrobutyl, pyrrolyl, piperidinyl, piperazine, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, etc. Azirrobutyl, pyrrolyl, piperidinyl, morpholinyl, and oxobutyl are particularly preferred. The non-aromatic heterocycle can form a fused ring with aryl or heteroaryl groups. The non-aromatic heterocycle also includes those with, for example, C 6-10Those fused with aryl or 5- or 6-membered heteroaryl groups. Furthermore, non-aromatic heterocycles can be formed by comprising one or more carbonyl, thiocarbonyl, sulfinyl, or sulfonyl groups. Non-aromatic heterocycles also include, for example, lactams, thiolactams, lactones, thiolactones, cyclic imides, cyclic carbamates, cyclic thiocarbamates, and other cyclic groups. In this respect, the oxygen atoms of the carbonyl, sulfinyl, and sulfonyl groups, and the sulfur atoms of the thiocarbonyl group, are not counted in the number of 4 to 20 members (ring size) or the number of heteroatoms constituting the ring. Specific examples of "4 to 20-membered non-aromatic heterocycles" include, but are not limited to, azahexacyclic butanes, pyrrolidines, piperidines, piperazines, morpholine, homopiperidines, oxacyclobutanes, tetrahydrofurans, tetrahydropyrans, and heterocycles having the following structures.

[0101] [Chemical Formula 17] Specific examples of "4- to 20-membered non-aromatic heterocycles" having partially cross-linked or spirocyclic structures include, but are not limited to, those having the structures shown below.

[0102] [Chemical Formula 18] .

[0103] Specific examples of "4-membered non-aromatic heterocycles" with partially unsaturated bonds include, but are not limited to, those with the structures shown below.

[0104] [Chemical Formula 19] .

[0105] Specific examples of "5-membered non-aromatic heterocycles" with partially unsaturated bonds include, but are not limited to, those with the structures shown below.

[0106] [Chemical Formula 20] .

[0107] Specific examples of "5-membered non-aromatic heterocycles" with partially cross-linked structures include, but are not limited to, those with the structures shown below.

[0108] [Chemical Formula 21] .

[0109] Specific examples of "5-membered non-aromatic heterocycles" that include carbonyl groups, thiocarbonyl groups, etc., include, but are not limited to, those having the structures shown below.

[0110] [Chemical Formula 22] .

[0111] Specific examples of "6-membered non-aromatic heterocycles" with partially unsaturated bonds include, but are not limited to, those with the structures shown below.

[0112] [Chemical Formula 23] .

[0113] Specific examples of "6-membered non-aromatic heterocycles" with partially cross-linked structures include, but are not limited to, those with the structures shown below.

[0114] [Chemical Formula 24] .

[0115] The "C" used in this article 1-6 "alkoxy" or "C" 1-6 "alkoxy group" refers to "C 1-6 Alkyloxy group, and C 1-6 The definition of "alkyl" is the same as that of "C" above. 1-6 Alkyl groups are the same. (C) 1-6 Alkoxy groups are preferred to be C 1-4 Alkyl group", and more preferably "C" 1-3 Alkyl group. 1-3 Specific examples of "alkoxy" include methoxy, ethoxy, propoxy, 1-methylethoxy, etc. 1-4 Specific examples of "alkoxy" include those related to "C". 1-3 In addition to the specific examples specified for "alkoxy", it also includes butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methylpropoxy, etc. 1-6 Specific examples of "alkoxy" include those related to "C". 1-4 In addition to specific examples of "alkoxy", it also includes pentoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, hexoxy, etc.

[0116] The "C" used in this article 3-6 "Aliphatic epoxy group" or "C" 3-6 "Aliphatic epoxy group" refers to (C 3-6 Alicyclic group)-O- group, and C 3-6 The alicyclic part is defined with C 3-6 The alicyclic groups are the same. "C 3-6 "Aliphatic epoxy group" includes "C 3-6 "Cycloalkoxy". "Cycloalkoxy" refers to "cycloalkyloxy", and the definition of "cycloalkyl" is the same as that of "cycloalkyl" above. "C" 3-6 Specific examples of "alicyclic oxy groups" include cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy.

[0117] The "C" used in this article 6-10 C of aryloxy group 6-10 The aryl moiety is defined as described above in C. 6-10 The aryl groups are the same. 6-10 The aryloxy group is preferably C6 or C6. 10 "Aryloxy group". "C 6-10 Specific examples of "aryloxy" include, but are not limited to, phenoxy, 1-naphthoxy, 2-naphthoxy, etc.

[0118] The 5- or 6-membered heteroaryl group of "5- or 6-membered heteroaryl" used in this article is defined in the same way as the "5-membered heteroaryl" or "6-membered heteroaryl" mentioned above. Specific examples of "5- or 6-membered heteroaryl" include, but are not limited to, pyrazoloxy, triazoloxy, thiazolyloxy, thiadiazolyloxy, pyridinoxy, pyridazinoxy, etc.

[0119] The 4-to-10-membered non-aromatic heterocyclic portion of "4-to-10-membered non-aromatic heterocyclic" used herein is defined the same as the "4-to-10-membered non-aromatic heterocyclic" described above. "4-to-10-membered non-aromatic heterocyclic" is preferably "4-to-6-membered non-aromatic heterocyclic". Specific examples of "4-to-10-membered non-aromatic heterocyclic" include, but are not limited to, tetrahydrofuranoxy, tetrahydropyranoxy, azacyclobutoxy, pyrrolidineoxy, piperidinoxy, etc.

[0120] The "C" used in this article 1-6 The C of "alkylthio" 1-6 The alkyl moiety is defined as described above (C). 1-6 Alkyl groups are the same. "C" 1-6 "alkylthio" is preferred to be "C 1-4 "alkylthio" and more preferably "C 1-3 "alkylthio" "C 1-6 Specific examples of "alkylthio" include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, isopropylthio, isobutylthio, tert-butylthio, sec-butylthio, isopentylthio, neopentylthio, tert-pentylthio, 1,2-dimethylpropylthio, etc.

[0121] The "C" used in this article 3-10 "Alicyclic thio" or "C" 3-10 "Alicyclic thio group" refers to (C 3-10 Alicyclic group)-S-group, and C 3-10 The alicyclic portion is defined as described above in C. 3-10 The alicyclic groups are the same. "C 3-10 "Alicyclic thio" is preferred to be "C" 3-6 Alicyclic thio group. 3-6 Specific examples of "alicyclic thiogroups" include, but are not limited to, cyclopropylthiogroup, cyclobutylthiogroup, cyclopentylthiogroup, and cyclohexylthiogroup.

[0122] The "C" used in this article 6-10 "Arylthio" or "C" 6-10 The C of the aryl thio group 6-10 The aryl moiety is defined as described above in C. 6-10 The aryl groups are the same. 6-10 "Aryl thiol" is preferably "C6 or C6". 10 "Arylthio" "C 6-10 Specific examples of "aryloxy" include, but are not limited to, phenylthio, 1-naphthio, 2-naphthio, etc.

[0123] The 5- or 6-membered heteroaryl group used in this article is defined in the same way as the "5- or 6-membered heteroaryl" or "5- or 6-membered heteroaryl" groups mentioned above. Specific examples of "5- or 6-membered heteroaryl" include, but are not limited to, pyrazolethio, triazolethio, thiazolethio, thiadiazolethio, pyridinethio, pyridazinthio, etc.

[0124] The 4-to-10-membered non-aromatic heterocyclic thio group used in this article has the same definition of the 4-to-10-membered non-aromatic heterocyclic part as described above. The 4-to-10-membered non-aromatic heterocyclic thio group is preferably a 4-to-6-membered non-aromatic heterocyclic thio group. Specific examples of the 4-to-10-membered non-aromatic heterocyclic thio group include, but are not limited to, tetrahydropyranthio and piperidinium thio.

[0125] The "C" used in this article 1-6 alkyl carbonyl" or "C 1-6 "alkyl carbonyl group" refers to the group defined by the above "C" 1-6 Alkyl-substituted carbonyl group. C 1-6 Alkyl carbonyl group is preferred to be C 1-4 Alkyl carbonyl group. 1-6 Specific examples of "alkyl carbonyl" include, but are not limited to, acetyl, propionyl, butyryl, etc.

[0126] The "C" used in this article 3-10 "Alicyclic carbonyl" or "C" 3-10 "Alicyclic carbonyl group" refers to the group that is subjected to the above "C" 3-10 "Alicyclic group substituted carbonyl group." C 3-10 "Alicyclic carbonyl group" is preferred to be "C 3-6 Alicyclic carbonyl group. 3-10 Specific examples of "alicyclic carbonyl" include, but are not limited to, cyclopropyl carbonyl and cyclopentyl carbonyl.

[0127] The "C" used in this article 6-10 "Aryl carbonyl" or "C" 6-10 "Aryl carbonyl group" refers to the group that is subjected to the above "C" 6-10 Aryl-substituted carbonyl group. 6-10The aryl carbonyl group is preferably C6 or C6. 10 "Aryl carbonyl" "C 6-10 Specific examples of "aryl carbonyl" include, but are not limited to, benzoyl, 1-naphthyl carbonyl, 2-naphthyl carbonyl, etc.

[0128] The term "5- or 6-membered heteroaryl carbonyl" or "5- or 6-membered heteroaryl carbonyl group" as used in this article refers to a carbonyl group substituted by the aforementioned "5- or 6-membered heteroaryl". Specific examples of "5- or 6-membered heteroaryl carbonyl" include, but are not limited to, pyrazolyl carbonyl, triazolyl carbonyl, thiazolyl carbonyl, thiadiazolyl carbonyl, pyridyl carbonyl, pyridazinyl carbonyl, etc.

[0129] As used herein, "4- to 10-membered non-aromatic heterocyclic carbonyl" or "4- to 10-membered non-aromatic heterocyclic carbonyl group" refers to a carbonyl group substituted by the aforementioned "4- to 10-membered non-aromatic heterocycle". "4- to 10-membered non-aromatic heterocyclic carbonyl" is preferably "4- to 6-membered non-aromatic heterocyclic carbonyl". Specific examples of "4- to 10-membered non-aromatic heterocyclic carbonyl" include, but are not limited to, azacyclic butyl carbonyl, pyrrolidinyl carbonyl, piperidinyl carbonyl, morpholinyl carbonyl, etc.

[0130] The "C" used in this article 1-6 alkylsulfonyl" or "C" 1-6 "alkylsulfonyl group" refers to the group defined by the above "C" 1-6 Alkyl-substituted sulfonyl group. C 1-6 Alkyl sulfonyl group is preferred to be C 1-4 Alkyl sulfonyl group. "C" 1-6 Specific examples of "alkylsulfonyl" include, but are not limited to, methylsulfonyl, propionylsulfonyl, butyrylsulfonyl, etc.

[0131] The "C" used in this article 3-10 "Alicyclic sulfonyl" or "C" 3-10 "Alicyclic sulfonyl group" refers to the group that is subjected to the above "C" 3-10 "Alicyclic group substituted with sulfonyl group." C 3-10 "Alicyclic sulfonyl" is preferred to be "C" 3-6 "Alicyclic sulfonyl" "C" 3-10 Specific examples of "alicyclic sulfonyl" include, but are not limited to, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, etc.

[0132] The "C" used in this article 6-10 "Arylsulfonyl" or "C" 6-10 "Arylsulfonyl group" refers to the group that is subjected to the above "C" 6-10 Aryl-substituted sulfonyl group. C 6-10 "Arylsulfonyl" is preferably "C6 or C2" 10 "Arylsulfonyl" "C 6-10Specific examples of "arylsulfonyl" include, but are not limited to, phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.

[0133] As used in this article, "5- or 6-membered heteroarylsulfonyl" or "5- or 6-membered heteroarylsulfonyl group" refers to a sulfonyl group substituted by the aforementioned "5- or 6-membered heteroaryl". Specific examples of "5- or 6-membered heteroarylsulfonyl" include pyrazolylsulfonyl, triazolylsulfonyl, thiazolylsulfonyl, thiadiazolylsulfonyl, pyridinylsulfonyl, pyridazinylsulfonyl, etc.

[0134] As used herein, "maintaining optical purity" means that when optical purity is measured before and after the reaction, there is no significant change in optical purity, and preferably a change of 20% ee or less. The change in optical purity when "maintaining optical purity" is, for example, 10% ee or less, 5% ee or less, 3% ee or less, 1% ee or less, or 0.5% ee or less.

[0135] Preferred implementation scheme Certain preferred embodiments of this disclosure are described below. The embodiments described below are provided for ease of understanding of this disclosure. The scope of this disclosure should not be limited to the following description. Therefore, appropriate modifications can be made within the scope of this disclosure by reference to the description herein. The following embodiments of this disclosure can be used independently or in combination thereof.

[0136] One embodiment of this disclosure provides a method for preparing a compound of formula I.

[0137] [Chemical Formula 25] Includes the following steps: Electrolytic oxidation of compound II in a solvent: [Chemical Formula 26] in R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 and R 9 Each independently represents a hydrogen atom, halogen, or optionally substituted C atom. 1-6 Alkyl, optionally substituted C 1-6 Alkyl or -C(=O)NR A R B ,and R A and RB Each independently represents a hydrogen atom, and each C atom is optionally substituted. 1-6 Alkyl or optionally substituted C 1-6 Alkoxy groups, provided that the compound of formula I is not of formula III: [Chemical Formula 27] (Where R is (CH2CH2CH2CH(CH3)3CH3)) And the compound of formula II is not [Chemical Formula 28] .

[0138] (Where R is (CH2CH2CH2CH(CH3)3CH3)).

[0139] In this disclosure, R 1 It can be a hydrogen atom or an optionally substituted C atom 1-6 alkyl.

[0140] In this disclosure, R 1 It can be methyl.

[0141] In this disclosure, R 2 It can be a hydrogen atom or an optionally substituted C atom 1-6 alkyl.

[0142] In this disclosure, R 2 It can be methyl.

[0143] In this disclosure, R 3 It can be a hydrogen atom or an optionally substituted C atom 1-6 alkyl.

[0144] In this disclosure, R 3 It can be methyl.

[0145] In this disclosure, R 4 It can be a hydrogen atom or an optionally substituted C atom 1-6 alkyl.

[0146] In this disclosure, R 4 It can be methyl.

[0147] In this disclosure, R 5 It can be a hydrogen atom or an optionally substituted C atom 1-6 alkyl.

[0148] In this disclosure, R 5 It can be methyl.

[0149] In this disclosure, R 6 It can be a hydrogen atom or an optionally substituted C atom 1-6alkyl.

[0150] In this disclosure, R 6 It can be methyl.

[0151] In this disclosure, R 7 It can be a hydrogen atom or an optionally substituted C atom 1-6 alkyl.

[0152] In this disclosure, R 7 It can be methyl.

[0153] In this disclosure, R 8 It can be a hydrogen atom or an optionally substituted C atom. 1-6 Alkyl or -C(=O)NR A R B .

[0154] In this disclosure, R 8 It can be -C(=O)NR A R B .

[0155] In this disclosure, R 9 It can be a hydrogen atom or an optionally substituted C atom 1-6 alkyl.

[0156] In this disclosure, R 9 It can be methyl.

[0157] In this disclosure, R A and R B Each can represent a hydrogen atom.

[0158] In this disclosure, the solvent may include water, preferably a mixture of water and aprotic polar solvents.

[0159] In this disclosure, the solvent may be water, and if desired, may be a proton polar solvent, preferably a mixture of both.

[0160] In this disclosure, during electrolytic oxidation, the electrode can be a carbon-based electrode, a platinum-based electrode, or a stainless steel electrode, or a combination thereof.

[0161] In this disclosure, during electrolytic oxidation, the electrode is advantageously a carbon-based electrode.

[0162] In this disclosure, in electrolytic oxidation, at least one selected from DMA, MeCN, DMSO, DMF and THF or combinations thereof can be used as the aprotic polar solvent.

[0163] In this disclosure, DMA can be advantageously used as the aprotic polar solvent in electrolytic oxidation.

[0164] In this disclosure, alkali metal salts or quaternary ammonium salts can be used as electrolytes in electrolytic oxidation.

[0165] In this disclosure, the electrolyte includes tetrabutylammonium hexafluorophosphate (Bu4NPF6), tetrabutylammonium tetrafluoroborate (Bu4NBF4), sodium perchlorate, tetrabutylammonium bromide (Bu4NBr), a chloride of lithium chloride (LiCl), lithium tetrafluoroborate (LiBF4), lithium bromide (LiBr), etc.

[0166] In this disclosure, the electrolyte includes tetrabutylammonium hexafluorophosphate (Bu4NPF6), tetrabutylammonium tetrafluoroborate (Bu4NBF4), sodium perchlorate, tetrabutylammonium bromide (Bu4NBr), or lithium chloride (LiCl), and at least one selected from lithium tetrafluoroborate (LiBF4) and lithium bromide (LiBr).

[0167] In this disclosure, Bu4NBr can be advantageously used as an electrolyte.

[0168] In this disclosure, for example, a current of 10-100 mA (e.g., 20-30 mA) can be used in electrolytic oxidation.

[0169] In this disclosure, for example, a current of 20 mA or 30 mA can be used in electrolytic oxidation.

[0170] In this disclosure, 5 mA / cm² can be used in electrolytic oxidation. 2 -10 A / cm 2 For example, 10 mA / cm 2 -1 A / cm 2 100 mA / cm 2 -1 A / cm 2 10-100 mA / cm 2 The value of the electrode is taken as the current value per unit area.

[0171] In this disclosure, any voltage value such as 1-500V, 1-100V, 1-10V, 2-8V, 4-8V, or 2.5V can be used in electrolytic oxidation.

[0172] In this disclosure, values ​​such as 2-10 F / mol, 2-8 F / mol, and 6-8 F / mol can be used as electron equivalents in electrolytic oxidation.

[0173] In this disclosure, in compounds of formula I, with R 8 R 9 The carbon atom bonded to OH can be an asymmetric carbon atom.

[0174] In this disclosure, the compound of formula II can be optically active and can maintain optical purity during the electrolytic oxidation process of the compound of formula II.

[0175] [Chemical Formula 29] ,and Compound II can be [Chemical Formula 30] .

[0176] In this disclosure, the compound of formula II can be prepared by the following steps: optical resolution and amidation of the compound of formula III: [Chemical Formula 31] .

[0177] The optical resolution of the compound of formula III can be performed by the method described in WO 2021 / 167095.

[0178] Preparation method In some embodiments, the compound of formula I in this disclosure is prepared by electrolytic oxidation of a compound of formula II. In some embodiments, the method of this disclosure includes the step of applying a voltage to a solution containing a compound of formula II.

[0179] Example The following embodiments, reference examples, test examples, etc. are provided to explain this disclosure in more detail, but this disclosure is not limited thereto.

[0180] DMA: Dimethylacetamide DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide MeCN: Acetonitrile THF: Tetrahydrofuran Bu4NPF6: Tetrabutylammonium hexafluorophosphate Bu4NBF4: Tetrabutylammonium tetrafluoroborate Bu4NBr: Tetrabutylammonium bromide NaClO4: Sodium perchlorate LiBF4: Lithium tetrafluoroborate LiBr: Lithium bromide LiCl: Lithium chloride The following analytical conditions are used in HPLC (High Performance Liquid Chromatography) analysis.

[0181] Reagent / Sample Solution: Acetonitrile: For liquid chromatography (FUJIFILM Wako Pure Chemical) or equivalent Trifluoroacetic acid: Premium grade (FUJIFILM Wako Pure Chemical) or equivalent Water: Test water prepared using an ultrapure water production system, etc.

[0182] Solvent: Acetonitrile.

[0183] Mobile phase: Mobile phase A: a water / trifluoroacetic acid mixture (2000:1). The mixture was prepared by mixing 2000 mL of water and 1 mL of trifluoroacetic acid. Degassed using an ultrasonic cleaner.

[0184] Mobile phase B: Acetonitrile / trifluoroacetic acid mixture (2500:1). The mixture was prepared by mixing 2500 mL of acetonitrile and 1 mL of trifluoroacetic acid. Degassed using an ultrasonic scrubber.

[0185] Syringe detergent: acetonitrile.

[0186] Devices and setup / conditions Device High-performance liquid chromatograph: UFLCXR (Shimadzu) or equivalent Electronic balance: XP205DRV (Mettler Toledo) or equivalent Ultrapure water production system: Milli-Q Advantage A10 (Merck) or equivalent Ultrasonic cleaner: US-4R (AS ONE) or equivalent Liquid Chromatography Setup / Conditions Detector: Ultraviolet absorption spectrophotometer (measurement wavelength: 235 nm) Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 150 mm, packed with octadecylsilane silica gel with a particle size of 3.5 μm for liquid chromatography. [Zorbax SB C18 (Agilent) or equivalent] Column temperature: approximately 35℃ constant temperature Mobile phase A: Water / trifluoroacetic acid mixture (2000:1) Mobile phase B: Acetonitrile / trifluoroacetic acid mixture (2500:1) Mobile phase delivery: The mixing ratio of mobile phase A and mobile phase B is changed in the following manner to control the concentration gradient.

[0187] Table 1 Time after injection (min) Mobile phase A (vol%) Mobile phase B (vol%) 0 to 25.0 98 → 0 2 → 100 25.0 to 33.0 0 100 33.0 to 33.1 0 → 98 100 → 2 33.1 to 40.0 98 2

[0188] Flow rate: 1.0 mL per minute Area measurement range: 33 minutes after sample solution injection (data collection time is 40 minutes). Injection volume: 5 μL Sample cooler temperature: approximately 25℃ constant temperature Mixer volume: 0.5 mL Syringe detergent: Acetonitrile Sample concentration: 2.5 μg / mL to 0.5 mg / mL Example of waveform processing parameter settings Minimum area: 5000 μV*second Minimum height: 100 μV Detection sensitivity: 50 μV / second Peak width: 1 second Output intensity range: -500 to 1000 mAU Output time range: 0 to 33 minutes.

[0189] Example 1 (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohex-1,4-dienyl)butyramide was synthesized by electrochemical oxidation. (R)-6-hydroxy-2,5,7,8-tetramethyl-2-carboxamide (125 mg, 0.501 mmol) and tetrabutylammonium hexafluorophosphate (194 mg, 0.501 mg) were dissolved in a solvent (5 mL) containing acetonitrile and water in a volume ratio of 6:1. A diaphragmless electrolytic cell was used with a platinum foil electrode as the anode and a glassy carbon electrode attached to the cathode, and a current of 30 mA was applied. After a total charge of 8 F / mol, HPLC showed the disappearance of (R)-6-hydroxy-2,5,7,8-tetramethyl-2-carboxamide and confirmed the formation of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexyl-1,4-dienyl)butyramide (conversion: 84.5%). The HPLC chromatogram of compound 1 is shown below. Figure 1 As shown, the HPLC chromatogram of compound 2 is as follows: Figure 2 As shown, and the HPLC chromatogram of this embodiment is as follows. Figure 3 As shown.

[0190] Example 2 Electrolyte investigation (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (125 mg, 0.501 mmol) and electrolyte (0.501 mmol) were dissolved in a 5 mL mixture of acetonitrile and water in a 6:1 volume ratio. A diaphragmless electrolytic cell was used with a platinum foil electrode as the anode and a glassy carbon electrode as the cathode, and a current of 30 mA was applied. After a total charge of 8 F / mol, HPLC was performed to determine (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexyl-1,4-dienyl)butyramide. The conversion to the target product is shown in Table 2.

[0191] Table 2 Electrolytes used Target compound conversion rate <![CDATA[Bu4NPF6]]> 84.5% <![CDATA[Bu4NBF4]]> 82.8% <![CDATA[NaClO4]]> 61.7% <![CDATA[Bu4NBr]]> 92.8% <![CDATA[LiBF4]]> 18.0% LiCl 31.1% LiBr 13.6%

[0192] Example 3 Investigation of nonprotic polar solvents (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (125 mg, 0.501 mmol) and tetrabutylammonium hexafluorophosphate (194 mg, 0.501 mg) were dissolved in a solvent (5 mL) containing the aprotic polar solvents listed in Table 3 and water in a volume ratio of 6:1. Electrolysis was performed using a diaphragmless electrolytic cell with a platinum foil electrode as the anode and a glassy carbon electrode as the cathode, and a current of 30 mA was applied. After a total charge of 6 F / mol was applied, HPLC was performed to determine (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexyl-1,4-dienyl)butyramide. The conversion rates to the target product are shown in Table 3.

[0193] Table 3 The nonprotic polar solvent used Target compound conversion rate MeCN 84.5% DMA 94.4% DMF 83.6% DMSO 54.4% THF 90.9%

[0194] Example 4 Electrode examination (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (125 mg, 0.501 mmol) and tetrabutylammonium hexafluorophosphate (194 mg, 0.501 mg) were dissolved in a solvent (5 mL) containing acetonitrile and water in a volume ratio of 6:1. A diaphragmless electrolytic cell was used, with the anode and cathode connected according to the combinations listed in Table 4, and a current of 30 mA was applied. After a total charge of 6 F / mol was applied, HPLC was performed to determine (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexyl-1,4-dienyl)butyramide. The results of conversion to the target product are shown in Table 4.

[0195] Table 4 anode used Cathode used Target compound conversion rate platinum foil Glassy carbon 84.5% platinum foil platinum foil 75.7% Glassy carbon Glassy carbon 88.4% Stainless steel Stainless steel 90.3% platinum foil Stainless steel 32.1% Glassy carbon Stainless steel 45.0%

[0196] The results in Table 4 show that the method can achieve good results even when the anode and cathode are glassy carbon or stainless steel electrodes, respectively, indicating that cheaper electrodes than platinum foil electrodes can be used.

[0197] Example 5 Electrolytic oxidation reaction using glassy carbon electrodes as both anode and cathode (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (125 mg, 0.501 mmol) and the electrolyte listed in Table 5 (0.501 mmol) were dissolved in a solvent (5 mL) containing the aprotic polar solvent listed in Table 5 and water in a volume ratio of 6:1. A diaphragmless electrolytic cell was used, with glassy carbon electrodes connected to the anode and cathode, and a current of 20 or 30 mA was applied. After a total charge of 6 F / mol, HPLC was performed to determine (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohex-1,4-dienyl)butyramide by HPLC. The conversion to the target product is shown in Table 5.

[0198] Table 5 The nonprotic polar solvent used Electrolytes used Current value Target compound conversion rate MeCN <![CDATA[Bu4NPF6]]> 30mA 88.4% MeCN <![CDATA[Bu4NBr]]> 30mA 89.8% MeCN LiBr 30mA 91.6% DMA <![CDATA[Bu4NPF6]]> 20mA 85.6% DMA <![CDATA[Bu4NBr]]> 20mA 57.0% DMA LiBr 20mA 83.4%

[0199] As described above, this disclosure is illustrated by way of various preferred embodiments. It should be understood that the scope of this disclosure should be limited only by its claims. It should be understood that any patent, any patent application, and any reference cited herein should be incorporated herein by reference in the same manner as specifically described herein.

[0200] Industrial applicability This disclosure is useful in pharmaceutical manufacturing.

Claims

1. Method for preparing compound I: [Chemical Formula 1] ， Includes the following steps: Electrolytic oxidation of compound II: [Chemical Formula 2] ； in R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 and R 9 Each independently represents a hydrogen atom, halogen, or optionally substituted C atom. 1-6 Alkyl, optionally substituted C 1-6 Alkyl or -C(=O)NR A R B ,and R A and R B Each independently represents a hydrogen atom, and each C atom is optionally substituted. 1-6 Alkyl or optionally substituted C 1-6 Alkoxy groups, provided that the compound of formula I is not of formula III: [Chemical Formula 3] (Where R is (CH2CH2CH2CH(CH3)3CH3)) And the compound of formula II is not [Chemical Formula 4] (Where R is (CH2CH2CH2CH(CH3)3CH3)).

2. The method according to claim 1, wherein R 1 C is a hydrogen atom or an optional substituted C 1-6 alkyl.

3. The method according to claim 1 or 2, wherein R 1 It is a methyl group.

4. The method according to any one of claims 1 to 3, wherein R 2 C is a hydrogen atom or an optional substituted C 1-6 alkyl.

5. The method according to any one of claims 1 to 4, wherein R 2 It is a methyl group.

6. The method according to any one of claims 1 to 5, wherein R 3 C is a hydrogen atom or an optional substituted C 1-6 alkyl.

7. The method according to any one of claims 1 to 6, wherein R 3 It is a methyl group.

8. The method according to any one of claims 1 to 7, wherein R 4 C is a hydrogen atom or an optional substituted C 1-6 alkyl.

9. The method according to any one of claims 1 to 8, wherein R 4 It is a hydrogen atom.

10. The method according to any one of claims 1 to 9, wherein R 5 C is a hydrogen atom or an optional substituted C 1-6 alkyl.

11. The method according to any one of claims 1 to 10, wherein R 5 It is a hydrogen atom.

12. The method according to any one of claims 1 to 11, wherein R 6 C is a hydrogen atom or an optional substituted C 1-6 alkyl.

13. The method according to any one of claims 1 to 12, wherein R 6 It is a hydrogen atom.

14. The method according to any one of claims 1 to 13, wherein R 7 C is a hydrogen atom or an optional substituted C 1-6 alkyl.

15. The method according to any one of claims 1 to 14, wherein R 7 It is a hydrogen atom.

16. The method according to any one of claims 1 to 15, wherein R 8 Hydrogen atom, optionally substituted C 1-6 Alkyl or -C(=O)NR A R B .

17. The method according to any one of claims 1 to 16, wherein R 8 -C(=O)NR A R B .

18. The method according to any one of claims 1 to 17, wherein R 9 C is a hydrogen atom or an optional substituted C 1-6 alkyl.

19. The method according to any one of claims 1 to 18, wherein R 9 It is a methyl group.

20. The method according to any one of claims 1 to 19, wherein R A and R B Each represents a hydrogen atom.

21. The method according to any one of claims 1 to 20, wherein the solvent is water or an aprotic polar solvent.

22. The method according to any one of claims 1 to 21, wherein the solvent is water and an aprotic polar solvent.

23. The method according to any one of claims 1 to 22, wherein in the electrolytic oxidation, the electrode is a carbon-based electrode, a platinum-based electrode, or a stainless steel electrode, or a combination thereof.

24. The method according to claim 21 or 22, wherein in the electro-oxidation, at least one selected from DMA, MeCN, DMSO, DMF and THF is used as an aprotic polar solvent.

25. The method according to any one of claims 1 to 24, wherein an alkali metal salt or a quaternary ammonium salt is used as the electrolyte in the electrolytic oxidation.

26. The method according to any one of claims 1 to 25, wherein in the electrolytic oxidation, the electrolyte comprises at least one compound selected from the group consisting of lithium tetrafluoroborate (LiBF4), lithium bromide (LiBr), tetrabutylammonium hexafluorophosphate (Bu4NPF6), tetrabutylammonium tetrafluoroborate (Bu4NBF4), sodium perchlorate, tetrabutylammonium bromide (Bu4NBr), and lithium chloride (LiCl).

27. The method according to any one of claims 1 to 26, wherein a current of 10-100 mA is used in the electrolytic oxidation.

28. The method according to any one of claims 1 to 27, wherein 5 mA / cm² is used in the electrolytic oxidation. 2 -10 A / cm 2 The current value per unit area of ​​the electrode.

29. The method according to any one of claims 1 to 28, wherein a voltage of 1-500 V is used in the electrolytic oxidation.

30. The method according to any one of claims 1 to 29, wherein the following combination as electrolyte, electrolyte aprotic solvent and water is used in the electro-oxidation system: (1) Bu4NPF6, DMA and water; (2) Bu4NPF6, THF and water; (3) LiBr, MeCN and water; or (4) Bu4NBr, MeCN and water.

31. The method according to any one of claims 1 to 30, wherein in electrolytic oxidation, the current is stopped after the reaction is complete.

32. The method according to any one of claims 1 to 31, wherein in the compound of formula I, R... 8 R 9 The carbon atom bonded to -OH is a chiral carbon.

33. The method according to any one of claims 1 to 32, wherein the compound of formula II is optically active and maintains optical purity in the electrolytic oxidation reaction of the compound of formula II.

34. The method according to any one of claims 1 to 33, wherein the compound of formula I is [Chemical Formula 5] ,and Compound II is [Chemical Formula 6] 。 35. The method according to any one of claims 1 to 34, wherein the compound of formula II is prepared by the following steps: optical resolution and amidation of the compound of formula III: [Chemical Formula 7] 。

Images