Oxidative cracking method of TROLOX amide

Abstract

The present disclosure provides a process for oxidative cleavage of Trolox amides. More particularly, the present disclosure provides a process for the preparation of a compound of formula I: # imgabs0 # comprising the step of contacting an oxidizing agent with a compound of formula II in a solvent, and the step of contacting a base with the solvent to promote a reaction between the compound of formula II and the oxidizing agent. # imgabs 1 # in the formula: R1, R2, R3, R4, R5, R6, R7, R8, and R9 each independently represent a hydrogen atom, a halogen, an optionally substituted C1-6 alkyl group, an optionally substituted C1-6 alkoxy group, or-C (= O) NRARB, and RA and RB each independently represent a hydrogen atom, an optionally substituted C1-6 alkyl group, or an optionally substituted C1-6 alkoxy group.

Description

Technical Field

[0001] The present disclosure provides a method for oxidative cleavage of Trolox amide. Background Art

[0002] International Publication No. WO 2009 / 061744 describes the synthesis of racemic 2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide from racemic Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), which can be used to treat and / or inhibit mitochondrial disorders and specific pervasive developmental disorders.

[0003] International Publication No. WO 2021 / 167095 describes optically resolved Trolox intermediates and methods for their production.

[0004] Citation List

[0005] Patent Literature

[0006] [PTL 1] International Publication No. WO 2009 / 061744

[0007] [PTL 2] International Publication No. WO 2021 / 167095 Summary of the invention

[0008] Solutions to the Problem

[0009] As a result of diligent research, the present inventors have completed the present disclosure by discovering a novel method for oxidative cleavage of Trolox amide-related compounds.

[0010] For example, the present disclosure provides the following items.

[0011] (Item 1)

[0012] A method for producing a compound of formula I:

[0013] [Chemical formula 1]

[0014]

[0015] It includes the steps of:

[0016] An oxidizing agent is contacted with a compound of formula II in a solvent:

[0017] [Chemical formula 2]

[0018] and

[0019] contacting a base with the solvent to promote the reaction between the compound of Formula II and the oxidizing agent;

[0020] in

[0021] 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, a halogen, an optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy or -C(=O)NR A R B ,and

[0022] R A and R B Each independently represents a hydrogen atom, an optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 Alkoxy.

[0023] (Item 1)

[0024] The method of item 1, where R 1 is a hydrogen atom or an optionally substituted C 1-6 alkyl.

[0025] (Item 3)

[0026] The method of item 1 or 2, where R 1 It's methyl.

[0027] (Item 4)

[0028] The method of any one of items 1 to 3, wherein R 2 is a hydrogen atom or an optionally substituted C 1-6 alkyl.

[0029] (Item 5)

[0030] The method of any one of items 1 to 4, wherein R 2 It's methyl.

[0031] (Item 6)

[0032] The method of any one of items 1 to 5, wherein R 3 is a hydrogen atom or an optionally substituted C 1-6 alkyl.

[0033] (Item 7)

[0034] The method of any one of items 1 to 6, wherein R 3 It's methyl.

[0035] (Item 8)

[0036] The method of any one of items 1 to 7, wherein R 4 is a hydrogen atom or an optionally substituted C 1-6 alkyl.

[0037] (Item 9)

[0038] The method of any one of items 1 to 8, wherein R 4 It's a hydrogen atom.

[0039] (Item 10)

[0040] The method of any one of items 1 to 9, wherein R 5 is a hydrogen atom or an optionally substituted C 1-6 alkyl.

[0041] (Item 11)

[0042] The method of any one of items 1 to 10, wherein R 5 It's a hydrogen atom.

[0043] (Item 12)

[0044] The method of any one of items 1 to 11, wherein R 6 is a hydrogen atom or an optionally substituted C 1-6 alkyl.

[0045] (Item 13)

[0046] The method of any one of items 1 to 12, wherein R 6 It's a hydrogen atom.

[0047] (Item 14)

[0048] The method of any one of items 1 to 13, wherein R 7 is a hydrogen atom or an optionally substituted C 1-6 alkyl.

[0049] (Item 15)

[0050] The method of any one of items 1 to 14, wherein R 7 It's a hydrogen atom.

[0051] (Item 16)

[0052] The method of any one of items 1 to 15, wherein R 8 is a hydrogen atom, an optionally substituted C 1-6 Alkyl or -C(=O)NR A R B .

[0053] (Item 17)

[0054] The method of any one of items 1 to 16, wherein R 8 is -C(=O)NR A R B .

[0055] (Item 18)

[0056] The method of any one of items 1 to 17, wherein R 9 is a hydrogen atom or an optionally substituted C 1-6 alkyl.

[0057] (Item 19)

[0058] The method of any one of items 1 to 18, wherein R 9 It's methyl.

[0059] (Item 20)

[0060] The method of any one of items 1 to 19, wherein R A and R B Each represents a hydrogen atom.

[0061] (Item 21)

[0062] The method of any one of items 1 to 20, wherein the solvent is a polar aprotic solvent.

[0063] (Item 22)

[0064] The method of any one of items 1 to 20, wherein the solvent is a polar protic solvent.

[0065] (Item 23)

[0066] The method of any one of items 1 to 20, wherein the solvent is selected from the group consisting of isopropyl acetate, ethyl acetate, tetrahydrofuran, 2-methyl-tetrahydrofuran, acetone, toluene, anisole, methyl tert-butyl ether, cyclopentyl methyl ether, methanol, ethanol, 2-propanol, 4-methyltetrahydropyran, acetonitrile, N-methylpyrrolidone and dimethyl sulfoxide.

[0067] (Item 24)

[0068] The method of any one of items 1 to 23, wherein the solvent is dimethyl sulfoxide.

[0069] (Item 25)

[0070] The method of any one of items 1 to 24, wherein the oxidant comprises an iron-containing compound.

[0071] (Item 26)

[0072] The method of any one of items 1 to 25, wherein the oxidizing agent is iron (III) chloride or iron (III) nitrate.

[0073] (Item 27)

[0074] The method of any one of items 1 to 26, wherein the oxidizing agent is iron (III) chloride hexahydrate.

[0075] (Item 28)

[0076] The method of any one of items 1 to 27, wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, diisopropylethylamine and aqueous ammonia.

[0077] (Item 29)

[0078] The method of any one of items 1 to 28, wherein the base is selected from the group consisting of sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine and aqueous ammonia.

[0079] (Item 30)

[0080] The method of item 29, wherein the base is sodium hydroxide.

[0081] (Item 31)

[0082] The method of any one of items 1 to 30, wherein the step of contacting an oxidant is carried out in a flow reactor.

[0083] (Item 32)

[0084] The method of item 31, wherein the inner diameter of the flow reactor in the step of contacting the oxidant is about 0.1 mm to about 100 mm.

[0085] (Item 33)

[0086] The method of item 31 or 32, wherein the residence time of the step of contacting the oxidant is less than 60 seconds.

[0087] (Item 34)

[0088] The method of item 33, wherein the residence time is from 0.1 seconds to 10 seconds.

[0089] (Item 35)

[0090] The method of any one of items 1 to 34, wherein the step of contacting with an oxidant is carried out at a temperature of 0°C to 100°C.

[0091] (Item 36)

[0092] The method of item 35, wherein the step of contacting with an oxidant is carried out at a temperature of 75°C or higher.

[0093] (Item 37)

[0094] The method of item 35, wherein the step of contacting with an oxidant is carried out at a temperature of 60°C to 90°C.

[0095] (Item 38)

[0096] The method of any one of items 1 to 37, wherein the step of contacting with a base is performed after the step of contacting with an oxidizing agent.

[0097] (Item 39)

[0098] The method of any one of items 1 to 38, wherein the step of contacting with a base is performed by contacting a base with the reaction mixture produced by the step of contacting with an oxidant.

[0099] (Item 40)

[0100] The method of any one of items 1 to 39, wherein the oxidizing agent is in the solvent in the step of contacting with a base.

[0101] (Item 41)

[0102] The method of any one of items 1 to 40, wherein the step of contacting with a base is carried out in a flow reactor.

[0103] (Item 42)

[0104] The method of item 41, wherein the inner diameter of the flow reactor in the step of contacting the base is about 0.1 mm to about 100 mm.

[0105] (Item 43)

[0106] The method of item 41 or 42, wherein the residence time of the step of contacting with the base is less than 60 seconds.

[0107] (Item 44)

[0108] The method of item 43, wherein the residence time is from 0.1 seconds to 10 seconds.

[0109] (Item 45)

[0110] The method of any one of items 1 to 44, wherein the step of contacting with a base is carried out at a temperature of 0°C to 100°C.

[0111] (Item 46)

[0112] The method of item 45, wherein the step of contacting with a base is carried out at a temperature of 60°C to 90°C.

[0113] (Item 47)

[0114] The method of item 45, wherein the step of contacting with an oxidant is carried out at a temperature of 75°C or higher.

[0115] (Item 48)

[0116] The method of any one of items 1 to 47, wherein in the compound of formula I, R 8 , R 9 The carbon atom connected to OH is an asymmetric carbon.

[0117] (Item 49)

[0118] The method of item 48, wherein the compound of formula II is an optically active substance and maintains optical purity in the reaction between the compound of formula II and the oxidizing agent.

[0119] (Item 50)

[0120] The method of any one of items 1 to 49, wherein the compound of formula I is

[0121] [Chemical formula 3]

[0122] and

[0123] The compound of formula II is

[0124] [Chemical formula 4]

[0125]

[0126] (Item 51)

[0127] The method of item 50, wherein the compound of formula II is prepared by the steps of optical resolution and amidation of a compound of formula III:

[0128] [Chemical formula 5]

[0129]

[0130] Advantageous Effects of the Invention

[0131] The present disclosure provides a method for preparing the compound represented by Formula I with high reaction efficiency through simple post-treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0132] [ Figure 1 ] Figure 1 A schematic diagram showing one example of the disclosed method using flow synthesis. DETAILED DESCRIPTION

[0133] The disclosure is described in more detail below. Throughout the entire specification, unless otherwise specifically stated, singular expressions should be understood as including the concept of its plural form. Therefore, unless otherwise specifically stated, singular articles (for example, "a", "an", "the", etc. in the case of English) should also be understood as including the concept of its plural form. In addition, unless otherwise specifically stated, the terms used herein should be understood to be used with the meaning commonly used in the field. Therefore, unless otherwise defined, all technical and scientific and technological terms used herein have the same meaning as commonly understood by those skilled in the art to which the disclosure belongs. In the event of a conflict, this specification (including definitions) shall prevail.

[0134] The present disclosure is further described in detail below.

[0135] Unless otherwise specifically stated, the abbreviations used herein have their conventional meanings in the art.

[0136] The term "about" herein with respect to a numerical value or parameter includes variations with respect to the numerical value or parameter itself. Unless otherwise specifically stated, "about X" includes, for example, "X" itself and a value having an acceptable error of ±10%.

[0137] As used herein, "Trolox" means 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. The R form is referred to as RTrolox and the S form is referred to as S Trolox. Trolox can be prepared by synthetic methods known to those skilled in the art, such as those described in U.S. Pat. No. 3,947,473, U.S. Pat. No. 4,003,919, and U.S. Pat. No. 4,026,907.

[0138] As used herein, "oxidant" refers to a compound that releases oxygen atoms. Examples include, but are not limited to, oxygen, hydrogen peroxide, periodic acid, potassium permanganate, iron (III), etc. Electrooxidation can also be performed.

[0139] As used herein, "base" refers to a substance that accepts a proton. Examples include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, diisopropylethylamine, and aqueous ammonia.

[0140] As used herein, "polar aprotic solvent" refers to a polar solvent lacking an acidic hydrogen. Examples include, but are not limited to, tetrahydrofuran, 2-methyl-tetrahydrofuran, acetone, acetonitrile, N-methylpyrrolidone, dimethyl sulfoxide, and the like. "Polar protic solvent" refers to a polar solvent having an acidic hydrogen.

[0141] As used herein, "residence time" refers to the time required for a fluid containing reaction system materials to pass through a portion of a reactor in a flowing reaction system.

[0142] The number of substituents in a group defined as "optionally substituted" or "substituted" is not particularly limited as long as they are substitutable. In addition, unless otherwise specifically stated, the description of each group also applies to the case where the group is a substituent or a part of another group.

[0143] The substituent in "optionally substituted" is selected from the substituent group α consisting of the following. The substituent is optionally substituted by 1 to 5 identical or different substituents. Although not particularly limited to the type of substituent, if the atom to which the substituent is attached is an oxygen atom, a nitrogen atom or a sulfur atom, the substituent is limited to the following substituents attached to a carbon atom.

[0144] Substituent group α includes

[0145] 1) Halogen atoms

[0146] 2) Hydroxyl

[0147] 3) Carboxyl

[0148] 4) Cyano

[0149] 5) C 1-6 alkyl

[0150] 6) C 2-6 Alkenyl

[0151] 7) C 2-6 Alkynyl

[0152] 8) C 1-6 Alkoxy

[0153] 9) C 1-6 Alkylthio

[0154] 10) C 1-6 Alkyl carbonyl

[0155] 11) C 1-6 Alkylsulfonyl

[0156] (wherein each substituent from 5) to 11) is optionally substituted with 1 to 5 identical or different substituents selected from substituent group β)

[0157] 12) C 3-10 Alicyclic groups

[0158] 13) C 3-10 Alicyclic oxy

[0159] 14) C 6-10 Aryloxy

[0160] 15) 5- or 6-membered heteroaryloxy

[0161] 16) 4- to 10-membered non-aryl heterocyclyloxy

[0162] 17) C 3-10 Alicyclic sulfhydryl

[0163] 18) C 6-10 Arylthio

[0164] 19) 5- or 6-membered heteroarylthio

[0165] 20) 4- to 10-membered non-aromatic heterocyclic thio

[0166] 21)C 6-10 Aryl

[0167] 22) 5- or 6-membered heteroaryl

[0168] 23) 4- to 10-membered non-aromatic heterocyclic ring

[0169] 24)C 3-10 Alicyclic carbonyl

[0170] 25)C 6-10 Arylcarbonyl

[0171] 26) 5- or 6-membered heteroarylcarbonyl

[0172] 27) 4- to 10-membered non-aromatic heterocyclic carbonyl

[0173] 28)C 3-10 Alicyclic sulfonyl

[0174] 29)C 6-10 Arylsulfonyl

[0175] 30) 5- or 6-membered heteroarylsulfonyl

[0176] 31) 4- to 10-membered non-aromatic heterocyclic sulfonyl

[0177] (wherein each substituent from 12) to 31) is optionally replaced by 1 to 5 substituent groups β or 1) C 1-6 Alkyl Substituted)

[0178] 32)-NR 10a R 11a

[0179] 33)-SO2-NR 10b R 11b

[0180] 34)-NR 10c -C(=O)R 11c

[0181] 35)-NR 10d -C(=O)OR 11d

[0182] 36)-NR 12a -C(=O)NR 10e R 11e

[0183] 37)-NR 10f -C(=S)R 11f

[0184] 38)-NR 10g -C(=S)OR 11g ,

[0185] 39)-NR 12b -C(=S)NR 10h R 11h

[0186] 40)-NR 10i -SO2-R 11i

[0187] 41)-NR 12c -SO2-NR 10j R 11j

[0188] 42)-C(=O)OR 10k

[0189] 43)-C(=O)NR 10l R 11k

[0190] 44)-C(=O)NR 10m OR 11l

[0191] 45)-C(=O)NR 12d -NR 10n R 11m

[0192] 46)-C(=S)OR 10o

[0193] 47)-C(=S)NR 10p R 11n

[0194] 48)-C(=S)NR 10q OR 11o

[0195] 49)-C(=S)NR 12e -NR 10r R 11p

[0196] 50)-C(=NR 13a )R10s

[0197] 51)-C(=NR 13b )CHO

[0198] 52)-C(=NR 13c )NR 10t R 11q

[0199] 53)-C(=NR 13d )NR 12f -NR 10u R 11r

[0200] 54)-NR 17c -C(=NR 13k )R 17d

[0201] 55)-NR 12g -C(=NR 13e )-NR 10v R 11s

[0202] 56)-NR 14 -C(=NR 13f )NR 12h -NR 10w R 11t

[0203] 57)-OC(=O)R 10x

[0204] 58)-OC(=O)OR 10y

[0205] 59)-OC(=O)NR 10z1 R 11u

[0206] 60)-NR 12i -NR 10z2 R 11v

[0207] 61)-NR 10z3 OR 11w

[0208] 62)-C(=N-OR 13a )R 10s

[0209] 63)-C(=N-OR 13b )CHO

[0210] 64)-C(=N-OR 13c )NR10t R 11q

[0211] 65)-C(=N-OR 13d )NR 12f -NR 10u R 11r and

[0212] 66)-C(=O)H,

[0213] Substituent group β is a group consisting of

[0214] 1) Halogen atoms,

[0215] 2) Hydroxyl,

[0216] 3) carboxyl group,

[0217] 4) cyano,

[0218] 5) C 3-10 alicyclic groups,

[0219] 6) C 1-6 Alkoxy,

[0220] 7) C 3-10 Alicyclic oxy group,

[0221] 8) C 1-6 Alkylthio,

[0222] 9) a 5- or 6-membered heteroarylthio group,

[0223] 10) C 6-10 Aryl,

[0224] 11) a 5- or 6-membered heteroaryl group,

[0225] 12) a 4- to 10-membered non-aromatic heterocyclic ring,

[0226] 13) C 1-6 Alkylcarbonyl,

[0227] 14) C 3-10 Alicyclic carbonyl,

[0228] 15) C 6-10 Arylcarbonyl,

[0229] 16) 5- or 6-membered heteroarylcarbonyl,

[0230] 17) a 4- to 10-membered non-aromatic heterocyclylcarbonyl group,

[0231] 18)-NR 15a R 16a ,

[0232] 19)-SO2-NR 15b R 16b ,

[0233] 20)-NR 15c -C(=O)R 16c ,

[0234] 21)-NR 17a -C(=O)NR 15d R 16d ,

[0235] 22)-C(=O)NR 15e R 16e ,

[0236] 23)-C(=NR 13g )R 15f ,

[0237] 24)-C(=NR 13h )NR 15g R 16f ,

[0238] 25)-NR 16g -C(=NR 13i )R 15h ,

[0239] 26)-NR 17b -C(=NR 13j )-NR 15i R 16h ,

[0240] 27)-C(=N-OR 13g )R 15f ,and

[0241] 28)-C(=N-OR 13h )NR 15g R 16f

[0242] (wherein each substituent from substituent group β) to 17) is optionally substituted by 1 to 5 substituents selected from halogen atoms, hydroxyl groups, cyano groups, carboxyl groups and -NR 18a R 18b The substituents of the group consisting of

[0243] R 13a , R 13b , R 13c , R 13d , R 13e , R 13f , R 13g , R 13h , R 13i , R13j and R 13k are the same or different and are each independently a hydrogen atom, a hydroxyl group, a C 1-6 Alkyl or C 1-6 Alkoxy,

[0244] 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 , R 11p , 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 , R12i , 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 are the same or different, each independently a hydrogen atom or a C 1-6 Alkyl (wherein the alkyl group is optionally selected from hydroxyl, cyano, C 1-6 Alkoxy and -NR 18a R 18b substituted with 1 to 3 identical or different substituents), and

[0245] R 18a and R 18b are the same or different, each independently a hydrogen atom or a C 1-6 alkyl.

[0246] Preferable examples of the substituent in "optionally substituted" include the following substituents.

[0247] Preferred substituent group α includes

[0248] 1) Halogen atoms

[0249] 2) Hydroxyl

[0250] 3) Carboxyl

[0251] 4) Cyano

[0252] 5) C 1-6 alkyl

[0253] 6) C 1-6 Alkoxy

[0254] 7) C 1-6 Alkylthio

[0255] 8) C 1-6 Alkyl carbonyl

[0256] (wherein each substituent from 5) to 8) is optionally substituted with 1 to 5 identical or different substituents selected from substituent group β)

[0257] 9) C 3-10 Alicyclic groups

[0258] 10) C 3-10 Alicyclic oxy

[0259] 11) C 6-10 Aryloxy

[0260] 12) 5- or 6-membered heteroaryloxy

[0261] 13) 4- to 10-membered non-aryl heterocyclyloxy

[0262] 14) C 3-10 Alicyclic sulfhydryl

[0263] 15) C 6-10 Arylthio

[0264] 16) 5- or 6-membered heteroarylthio

[0265] 17) 4- to 10-membered non-aromatic heterocyclic thio

[0266] 18) C 6-10 Aryl

[0267] 19) 5- or 6-membered heteroaryl

[0268] 20) 4- to 10-membered non-aromatic heterocyclic ring

[0269] 21)C 3-10 Alicyclic carbonyl

[0270] 22)C 6-10 Arylcarbonyl

[0271] 23) 5- or 6-membered heteroarylcarbonyl

[0272] 24) 4- to 10-membered non-aromatic heterocyclic carbonyl

[0273] (wherein each substituent from 9) to 24) is optionally replaced by 1 to 5 substituent groups β or 1) C 1-6 Alkyl Substituted)

[0274] 25)-NR 10a R 11a

[0275] 26)-SO2-NR 10b R 11b

[0276] 27)-NR 10c -C(=O)R11c

[0277] 28)-NR 12a -C(=O)NR 10d R 11d

[0278] 29)-NR 10e -SO2-R 11e

[0279] 30)-NR 12b -SO2-NR 10f R 11f

[0280] 31)-C(=O)NR 10g R 11g

[0281] 32)-C(=NR 13a )R 10h

[0282] 33)-C(=NR 13b )NR 10i R 11h

[0283] 34)-NR 11f -C(=NR 13c )R 10g

[0284] 35)-NR 12c -C(=NR 13d )-NR 10j R 11i

[0285] 36)-C(=N-OR 13a )R 10h and

[0286] 37)-C(=N-OR 13b )NR 10i R 11h

[0287] Substituent group β is preferably a group consisting of

[0288] 1) Halogen atoms

[0289] 2) Hydroxyl

[0290] 3) Cyano

[0291] 4) C 3-10 Alicyclic groups

[0292] 5) C 1-6 Alkoxy

[0293] 6) C 1-6 Alkylthio

[0294] 7) 5- or 6-membered heteroarylthio

[0295] 8) 5- or 6-membered heteroaryl

[0296] 9) 4- to 10-membered non-aromatic heterocyclic ring

[0297] 10) C 1-6 Alkyl carbonyl

[0298] 11) C 3-10 Alicyclic carbonyl

[0299] 12) C 6-10 Arylcarbonyl

[0300] 13) 5- or 6-membered heteroarylcarbonyl

[0301] 14) 4- to 10-membered non-aromatic heterocyclic carbonyl

[0302] 15)-NR 15a R 16a

[0303] 16)-NR 15b -C(=O)R 16b

[0304] 17)-NR 17a -C(=O)NR 15c R 16c

[0305] 18) -C(=O)NR 15d R 16d

[0306] 19)-C(=NR 13e )R 15e

[0307] 20)-C(=NR 13f )NR 15f R 16e

[0308] 21)-NR 16f -C(=NR 13g )R 15g

[0309] 22)-NR 17b -C(=NR 13h )-NR 15h R 16g

[0310] 23)-C(=N-OR13e )R 15e and

[0311] 24)-C(=N-OR 13f )NR 15f R 16e

[0312] (wherein each substituent from 4) to 14) in substituent group β is optionally substituted by 1 to 5 substituents selected from halogen atoms, hydroxyl groups, cyano groups, carboxyl groups and -NR 18a R 18b The substituent group consisting of

[0313] R 13a , R 13b , R 13c , R 13d , R 13e , R 13f , R 13g and R 13h are the same or different and are each independently a hydrogen atom, a hydroxyl group, a C 1-6 Alkyl or C 1-6 Alkoxy,

[0314] 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 11c , R 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 , R16g , R 17a and R 17b are the same or different, each independently a hydrogen atom or a C 1-6 Alkyl (wherein the alkyl group is optionally selected from hydroxyl, cyano, C 1-6 Alkoxy and -NR 18a R 18b substituted with 1 to 3 identical or different substituents), and

[0315] R 18a and R 18b are the same or different, each independently a hydrogen atom or a C 1-6 alkyl.

[0316] More preferred examples of the substituent in "optionally substituted" include the following substituents.

[0317] More preferred substituent group α includes

[0318] 1) Halogen atoms

[0319] 2) Hydroxyl

[0320] 3) Cyano

[0321] 4) C 1-6 alkyl

[0322] 5) C 1-6 Alkoxy

[0323] 6) C 1-6 Alkylthio

[0324] 7) C 1-6 Alkyl carbonyl

[0325] (wherein each substituent from 4) to 7) is optionally substituted with 1 to 5 identical or different substituents selected from substituent group β)

[0326] 8) 5- or 6-membered heteroaryloxy

[0327] 9) 4- to 10-membered non-aryl heterocyclyloxy

[0328] 10) 5- or 6-membered heteroarylthio

[0329] 11) 4- to 10-membered non-aromatic heterocyclic thio group

[0330] 12) C 6-10 Aryl

[0331] 13) 5- or 6-membered heteroaryl

[0332] 14) 4- to 10-membered non-aromatic heterocyclic ring

[0333] (wherein each substituent from 4) to 14) is optionally replaced by 1 to 5 substituent groups β or 1) C 1-6 Alkyl Substituted)

[0334] 15)-NR 10a R 11a

[0335] 16)-NR 11b -C(=O)R 10b

[0336] 17)-NR 12a -C(=O)NR 10c R 11c

[0337] 18) -C(=O)NR 10d R 11d

[0338] 19)-C(=NR 13a )R 10e

[0339] 20)-C(=NR 13b )NR 10f R 11e

[0340] 21)-NR 11f -C(=NR 13c )R 10g

[0341] 22)-NR 12b -C(=NR 13d )-NR 10h R 11g

[0342] 23)-C(=N-OR 13a )R 10e and

[0343] 24)-C(=N-OR 13b )NR 10f R 11e

[0344] Substituent group β is more preferably

[0345] 1) Halogen atoms,

[0346] 2) Hydroxyl,

[0347] 3) cyano,

[0348] 4)-NR 15a R 16a ,

[0349] 5)-NR 15b -C(=O)R 16b ,

[0350] 6)-NR 17a -C(=O)NR 15c R 16c ,

[0351] 7) -C(=O)NR 15d R 16d ,

[0352] 8)-C(=NR 13e )R 15e ,

[0353] 9)-C(=NR 13f )NR 15f R 16e ,

[0354] 10)-NR 16f -C(=NR 13g )R 15g ,

[0355] 11)-NR 17b -C(=NR 13h )-NR 15h R 16g

[0356] 12)-C(=N-OR 13e )R 15e ,and

[0357] 13)-C(=N-OR 13f )NR 15f R 16e

[0358] R 13a , R 13b , R 13c , R 13d , R 13e , R 13f , R 13g and R 13h are the same or different and are each independently a hydrogen atom, a hydroxyl group, a C 1-6 Alkyl or C 1-6 Alkoxy,

[0359] R 10a , R 10b , R 10c , R 10d , R 10e , R 10f , R 10g , R 10h , R11a , R 11b , R 11c , R 11d , R 11e , R 11f , R 11g , R 12a , R 12b , 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 are the same or different, each independently a hydrogen atom or a C 1-6 Alkyl (wherein the alkyl group is optionally selected from hydroxyl, cyano, C 1-6 Alkoxy and -NR 18a R 18b substituted with 1 to 3 identical or different substituents), and

[0360] R 18a and R 18b are the same or different, each independently a hydrogen atom or a C 1-6 alkyl.

[0361] “C 1-6 ” means the number of carbon atoms is 1 to 6. The same applies to other numbers. For example, “C 1-4 ” means the number of carbon atoms is 1 to 4.

[0362] The "hetero atom" refers to an oxygen atom, a nitrogen atom, a sulfur atom or the like.

[0363] The "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. In particular, a fluorine atom and a chlorine atom are preferred. The "halogen atom" is also referred to as "halogen".

[0364] “C 1-6 Alkyl" or "C 1-6 "Alkyl group" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 The alkyl group is preferably "C 1-4 Alkyl", more preferably "C 1-3 Alkyl". "C 1-3Specific examples of "alkyl" include methyl, ethyl, propyl, 1-methylethyl, etc. 1-3 Except for the specific examples specified by "alkyl", "C 1-4 Specific examples of "alkyl" include butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, etc. 1-4 Except for the specific examples specified by "alkyl", "C 1-6 Specific examples of the "alkyl" also include pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl and the like.

[0365] “C 2-6 "Alkenyl" or "C 2-6 "Alkenyl group" refers to a straight or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms containing one or more carbon-carbon double bonds. 2-6 "Alkenyl" is preferably "C 2-4 "C 2-6 Specific examples of "alkenyl" include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, and the like.

[0366] “C 2-6 Alkynyl" or "C 2-6 "Alkynyl group" refers to a straight or branched unsaturated aliphatic hydrocarbon group having one or more triple bonds. 2-6 "Alkynyl" is preferably "C 2-4 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, and the like.

[0367] “C 3-20 "Alicyclic group" refers to a monocyclic or bicyclic non-aromatic hydrocarbon ring group having 3 to 20 carbon atoms, including those having a partially unsaturated bond, those having a partially cross-linked structure, those having a partially spirocyclic form, and those having one or more carbonyl structures. "Alicyclic group" includes cycloalkyl, cycloalkenyl and cycloalkynyl. "C 3-20 The "alicyclic group" is preferably "C 3-10 Alicyclic group", more preferably "C 3-7 Alicyclic group". "C 3-7 Specific examples of the "alicyclic group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. 3-7 Except for the specific examples specified in "alicyclic group", "C 3-10Specific examples of the "alicyclic group" also include cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl and the like.

[0368] The partially cross-linked structure of "C 3-20 Specific examples of the "alicyclic group" include, but are not limited to, those having the structures shown below, and the like.

[0369] [Chemical formula 6]

[0370]

[0371] “C 3-20 The "alicyclic group" also includes a compound condensed to an aromatic ring. Specific examples thereof include the groups shown below and the like.

[0372] [Chemical formula 7]

[0373]

[0374] “C 3-10 "Alicyclic group" refers to a group in which "C 3-10 The alicyclic group is a monovalent group. 3-20 "Alicyclic group".

[0375] “C 6-10 "Aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms. 6-10 The "aryl group" may be fused to the above-mentioned "alicyclic group" or "non-aromatic heterocyclic group" at any possible position. 6-10 Specific examples of "aryl" include phenyl, 1-naphthyl, 2-naphthyl, etc. 6-10 Preferred examples of the "aryl group" include phenyl. Specific examples of the condensed ring structure include the groups shown below, etc.

[0376] [Chemical formula 8]

[0377]

[0378] [Chemical formula 9]

[0379]

[0380] "6- to 10-membered heteroaryl" refers to a monocyclic or bicyclic aromatic heterocyclic group consisting of 6 to 10 atoms, which contains 1 to 4 atoms independently selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms. "6- to 10-membered heteroaryl" can be fused to the above-mentioned "alicyclic group" or "non-aromatic heterocycle" at any possible position. "6- to 10-membered heteroaryl" is preferably a "6-membered heteroaryl", more preferably a pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl, and even more preferably a pyridyl or pyrimidinyl. Specific examples of "6-membered heteroaryl" include pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl. In addition to the specific examples specified for the above-mentioned "6-membered heteroaryl", specific examples of "6- to 10-membered heteroaryl" include quinoxalinyl, triazolopyridinyl, etc.

[0381] Specific examples of the "9- or 10-membered heteroaryl group" include, but are not limited to, compounds having the following structures and the like.

[0382] [Chemical formula 10]

[0383]

[0384] [Chemical formula 11]

[0385]

[0386] Specific examples of "5-membered heteroaryl" include, but are not limited to, thiophene, pyrrole, thiazole, isothiazole, pyrazole, imidazole, furan, oxazole, isoxazole, oxadiazole, thiadiazole, triazole, tetrazole, etc. The 5-membered heteroaryl is preferably pyrazole, imidazole, oxazole, triazole, tetrazole or thiadiazole, more preferably imidazole or thiadiazole.

[0387] Specific examples of the “5- or 6-membered heteroaryl group” include the specific examples of the above-mentioned “5-membered heteroaryl group” and “6-membered heteroaryl group”. The above-mentioned “5- or 6-membered heteroaryl group” or “5- to 10-membered heteroaryl group” may be combined with C 5-10 The alicyclic group forms a condensed ring structure, or forms a condensed ring structure with a 5- to 10-membered non-aromatic heterocyclic ring. Specific examples thereof include the groups shown below and the like.

[0388] [Chemical formula 12]

[0389]

[0390] [Chemical formula 13]

[0391]

[0392] [Chemical formula 14]

[0393]

[0394] "4- to 20-membered non-aromatic heterocyclic group" refers to a monocyclic or bicyclic non-aromatic heterocyclic ring consisting of 4 to 20 atoms, which, in addition to carbon atoms, also contains 1 to 2 identical or different heteroatoms independently selected from the group consisting of nitrogen atoms, oxygen atoms 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 a "4- to 6-membered non-aromatic heterocyclic group". Specific examples of "4- to 6-membered non-aromatic heterocyclic group" include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, etc. In particular, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and oxetanyl are preferred. Non-aromatic heterocyclic rings can form condensed rings with aryl or heteroaryl. Non-aromatic heterocyclic rings also include aryl and heteroaryl groups such as C 6-10 Aryl or 5- or 6-membered heteroaryl condensed ones.In addition, non-aryl heterocycle includes one or more carbonyl, thiocarbonyl, sulfinyl or sulfonyl.Non-aryl heterocycle also includes, for example, lactam, thiolactam, lactone, thiolactone, cyclic imide, cyclic carbamate, cyclic thiocarbamate and other cyclic groups.In this regard, the oxygen atom of carbonyl, sulfinyl and sulfonyl and the sulfur atom of thiocarbonyl are not included in the number (ring size) of 4 to 20 yuan or the number of heteroatoms constituting the ring.The specific examples of "4- to 20-membered non-aryl heterocycle" include, but are not limited to, azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, oxetane, tetrahydrofuran, tetrahydropyran, heterocycle with following structure etc.

[0395] [Chemical formula 15]

[0396]

[0397] Specific examples of the "4- to 20-membered non-aromatic heterocycle" having a partially cross-linked or spiro structure include, but are not limited to, those having the structures shown below and the like.

[0398] [Chemical formula 16]

[0399]

[0400] Specific examples of the "4-membered non-aryl heterocycle" having a partially unsaturated bond include, but are not limited to, those having the structures shown below and the like.

[0401] [Chemical formula 17]

[0402]

[0403] Specific examples of the "5-membered non-aryl heterocycle" having a partially unsaturated bond include, but are not limited to, those having the structures shown below and the like.

[0404] [Chemical formula 18]

[0405]

[0406] Specific examples of the "5-membered non-aryl heterocycle" having a partially cross-linked structure include, but are not limited to, those having the structures shown below and the like.

[0407] [Chemical formula 19]

[0408]

[0409] Specific examples of the "5-membered non-aryl heterocycle" containing a carbonyl group, a thiocarbonyl group and the like include, but are not limited to, those having the structures shown below and the like.

[0410] [Chemical formula 20]

[0411]

[0412] Specific examples of the "6-membered non-aryl heterocycle" having a partially unsaturated bond include, but are not limited to, those having the structures shown below and the like.

[0413] [Chemical formula 21]

[0414]

[0415] Specific examples of the "6-membered non-aryl heterocycle" having a partially cross-linked structure include, but are not limited to, those having the structures shown below, and the like.

[0416] [Chemical formula 22]

[0417]

[0418] “C 1-6 Alkoxy" or "C 1-6 "Alkoxy group" means "C 1-6 Alkyloxy", and "C 1-6 The definition of the "alkyl" part is the same as that of the "C 1-6 Alkyl" is the same. 1-6 "Alkoxy" is preferably "C 1-4 Alkoxy", more preferably "C 1-3 Alkoxy". "C 1-3 Specific examples of "alkoxy" include methoxy, ethoxy, propoxy, 1-methylethoxy, etc. 1-3 Except for the specific examples specified by "alkoxy", "C 1-4 Specific examples of "alkoxy" include butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methylpropoxy, etc. 1-4 Except for the specific examples specified by "alkoxy", "C 1-6Specific examples of the "alkoxy group" also include pentyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, hexyloxy and the like.

[0419] “C 3-6 Alicyclic oxy" or "C 3-6 "Alicyclic oxy group" means (C 3-6 alicyclic group)-O-group, and C 3-6 Definition of the alicyclic moiety and C 3-6 The alicyclic groups are the same. 3-6 Alicyclic oxy" includes "C 3-6 Cycloalkyloxy". "Cycloalkyloxy" means "cycloalkyloxy", and the definition of "cycloalkyl" part is the same as the above-mentioned "cycloalkyl". 3-6 Specific examples of the "alicyclic oxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.

[0420] “C 6-10 Aryloxy" C 6-10 The definition of the aryl moiety is the same as that of C 6-10 The aromatic groups are the same. 6-10 "Aryloxy" is preferably "C6 or C 10 Aryloxy". "C 6-10 Specific examples of "aryloxy" include, but are not limited to, phenoxy, 1-naphthyloxy, 2-naphthyloxy, and the like.

[0421] The 5- or 6-membered heteroaryl moiety of the “5- or 6-membered heteroaryloxy” is defined the same as the above-mentioned “5- or 6-membered heteroaryl”. Specific examples of the “5- or 6-membered heteroaryloxy” include, but are not limited to, pyrazolyloxy, triazolyloxy, thiazolyloxy, thiadiazolyloxy, pyridyloxy, pyridazinyloxy, and the like.

[0422] The 4- to 10-membered non-aryl heterocyclic moiety of the “4- to 10-membered non-aryl heterocyclic group” is defined the same as the above-mentioned “4- to 10-membered non-aryl heterocyclic group”. The “4- to 10-membered non-aryl heterocyclic group” is preferably a “4- to 6-membered non-aryl heterocyclic group”. Specific examples of the “4- to 10-membered non-aryl heterocyclic group” include, but are not limited to, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyloxy, pyrrolidinyloxy, piperidinyloxy, and the like.

[0423] “C 1-6 "Alkylthio" C 1-6 The definition of the alkyl part is the same as above 1-6 The alkyl groups are the same. 1-6 "Alkylthio" is preferably "C 1-4 Alkylthio", more preferably "C1-3 Alkylthio". "C 1-6 Specific examples of the “alkylthio group” include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, isopropylthio, isobutylthio, tert-butylthio, sec-butylthio, isopentylthio, neopentylthio, tert-pentylthio, 1,2-dimethylpropylthio and the like.

[0424] “C 3-10 Alicyclic thio" or "C 3-10 "Alicyclic thiol group" refers to (C 3-10 alicyclic group)-S-group, and C 3-10 The definition of the alicyclic moiety is the same as that of C 3-10 The alicyclic groups are the same. 3-10 The alicyclic thio group is preferably a 3-6 Alicyclic sulfur group". "C 3-6 Specific examples of the “alicyclic thio group” include, but are not limited to, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.

[0425] “C 6-10 Arylthio" or "C 6-10 The C 6-10 The definition of the aryl moiety is the same as that of C 6-10 The aromatic groups are the same. 6-10 "Arylthio" is preferably "C6 or C 10 Arylthio". "C 6-10 Specific examples of the "arylthio" include, but are not limited to, phenylthio, 1-naphthylthio, 2-naphthylthio, and the like.

[0426] The 5- or 6-membered heteroaryl moiety of the “5- or 6-membered heteroarylthio group” or the “5- or 6-membered heteroarylthio group” is defined the same as the above-mentioned “5- or 6-membered heteroaryl” or “6-membered heteroaryl”. Specific examples of the “5- or 6-membered heteroarylthio group” include, but are not limited to, pyrazolylthio, triazolylthio, thiazolylthio, thiadiazolylthio, pyridylthio, pyridazinylthio, and the like.

[0427] The 4- to 10-membered non-aryl heterocyclic moiety of the “4- to 10-membered non-aryl heterocyclic group” or the “4- to 10-membered non-aryl heterocyclic group” is defined the same as the above-mentioned “4- to 10-membered non-aryl heterocyclic group”. The “4- to 10-membered non-aryl heterocyclic group” is preferably a “4- to 6-membered non-aryl heterocyclic group”. Specific examples of the “4- to 10-membered non-aryl heterocyclic group” include, but are not limited to, tetrahydropyranylthio, piperidinylthio, and the like.

[0428] “C 1-6 Alkylcarbonyl" or "C 1-6 "Alkylcarbonyl group" refers to an alkylcarbonyl group 1-6Alkyl" substituted carbonyl. "C 1-6 "Alkylcarbonyl" is preferably "C 1-4 Alkylcarbonyl". "C 1-6 Specific examples of "alkylcarbonyl" include, but are not limited to, acetyl, propionyl, butyryl, and the like.

[0429] “C 3-10 Alicyclic carbonyl" or "C 3-10 The alicyclic carbonyl group is a 3-10 Alicyclic group" substituted carbonyl. "C 3-10 The alicyclic carbonyl group is preferably a 3-6 Alicyclic carbonyl group. 3-10 Specific examples of the "alicyclic carbonyl group" include, but are not limited to, cyclopropylcarbonyl, cyclopentylcarbonyl, and the like.

[0430] “C 6-10 Arylcarbonyl" or "C 6-10 "Arylcarbonyl group" refers to an arylcarbonyl group 6-10 Aryl" substituted carbonyl. "C 6-10 "Arylcarbonyl" is preferably "C6 or C 10 Arylcarbonyl". "C 6-10 Specific examples of the “arylcarbonyl group” include, but are not limited to, benzoyl, 1-naphthylcarbonyl, 2-naphthylcarbonyl, and the like.

[0431] “5- or 6-membered heteroarylcarbonyl” or “5- or 6-membered heteroarylcarbonyl group” refers to a carbonyl group substituted by the above-mentioned “5- or 6-membered heteroaryl”. Specific examples of “5- or 6-membered heteroarylcarbonyl” include, but are not limited to, pyrazolylcarbonyl, triazolylcarbonyl, thiazolylcarbonyl, thiadiazolylcarbonyl, pyridylcarbonyl, pyridazinylcarbonyl, and the like.

[0432] “4- to 10-membered non-aryl heterocyclylcarbonyl” or “4- to 10-membered non-aryl heterocyclylcarbonyl group” refers to a carbonyl group substituted by the above-mentioned “4- to 10-membered non-aryl heterocycle”. “4- to 10-membered non-aryl heterocyclylcarbonyl” is preferably a “4- to 6-membered non-aryl heterocyclylcarbonyl”. Specific examples of “4- to 10-membered non-aryl heterocyclylcarbonyl” include, but are not limited to, azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, morpholinylcarbonyl and the like.

[0433] “C 1-6 Alkylsulfonyl" or "C 1-6 "Alkylsulfonyl group" means an 1-6 Alkyl" substituted sulfonyl. "C 1-6 "Alkylsulfonyl" is preferably "C 1-4 Alkylsulfonyl". "C 1-6Specific examples of the “alkylsulfonyl group” include, but are not limited to, methylsulfonyl, propionylsulfonyl, butyrylsulfonyl, and the like.

[0434] “C 3-10 Alicyclic sulfonyl" or "C 3-10 The "alicyclic sulfonyl group" refers to the above-mentioned "C 3-10 Alicyclic group" substituted sulfonyl group. "C 3-10 The alicyclic sulfonyl group is preferably a 3-6 Alicyclic sulfonyl group. 3-10 Specific examples of the “alicyclic sulfonyl group” include, but are not limited to, cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl and the like.

[0435] “C 6-10 Arylsulfonyl" or "C 6-10 "Arylsulfonyl group" refers to an arylsulfonyl group replaced by the above-mentioned "C 6-10 Aryl" substituted sulfonyl. "C 6-10 The "arylsulfonyl" is preferably "C6 or C 10 Arylsulfonyl". "C 6-10 Specific examples of the “arylsulfonyl group” include, but are not limited to, phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, and the like.

[0436] The “5- or 6-membered heteroarylsulfonyl group” or “5- or 6-membered heteroarylsulfonyl group” refers to a sulfonyl group substituted with the above-mentioned “5- or 6-membered heteroaryl group”. Specific examples of the “5- or 6-membered heteroarylsulfonyl group” include pyrazolylsulfonyl, triazolylsulfonyl, thiazolylsulfonyl, thiadiazolylsulfonyl, pyridylsulfonyl, pyridazinylsulfonyl and the like.

[0437] As used herein, "maintaining optical purity" indicates that when the optical purity is measured before and after the reaction mentioned, the optical purity does not change significantly, and preferably indicates a change of 20% ee or less. When "maintaining optical purity", the change in 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.

[0438] (Preferred Implementation)

[0439] The preferred embodiments of the present disclosure are described below. The following embodiments are provided to facilitate understanding of the present disclosure. The scope of the present disclosure should not be limited to the following description. Therefore, it is apparent that those skilled in the art can make appropriate modifications within the scope of the present disclosure by referring to the description herein. The following embodiments of the present disclosure can be used alone or in combination.

[0440] One embodiment of the present disclosure provides a method for producing a compound of formula I:

[0441] [Chemical formula 23]

[0442]

[0443] It includes the steps of:

[0444] An oxidizing agent is contacted with a compound of formula II in a solvent:

[0445] [Chemical formula 24]

[0446] and

[0447] contacting a base with the solvent to promote the reaction between the compound of Formula II and the oxidizing agent;

[0448] in

[0449] 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, a halogen, an optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy or -C(=O)NR A R B ,and

[0450] R A and R B Each independently represents a hydrogen atom, an optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 Alkoxy.

[0451] In the present disclosure, R 1 It can be a hydrogen atom or an optionally substituted C 1-6 alkyl.

[0452] In the present disclosure, R 1 It may be methyl.

[0453] In the present disclosure, R 2 It can be a hydrogen atom or an optionally substituted C 1-6 alkyl.

[0454] In the present disclosure, R 2 It may be methyl.

[0455] In the present disclosure, R 3 It can be a hydrogen atom or an optionally substituted C 1-6 alkyl.

[0456] In the present disclosure, R 3 It may be methyl.

[0457] In the present disclosure, R 4 It can be a hydrogen atom or an optionally substituted C 1-6 alkyl.

[0458] In the present disclosure, R 4 It may be a hydrogen atom.

[0459] In the present disclosure, R 5 It can be a hydrogen atom or an optionally substituted C 1-6 alkyl.

[0460] In the present disclosure, R 5 It may be a hydrogen atom.

[0461] In the present disclosure, R 6 It can be a hydrogen atom or an optionally substituted C 1-6 alkyl.

[0462] In the present disclosure, R 6 It may be a hydrogen atom.

[0463] In the present disclosure, R 7 It can be a hydrogen atom or an optionally substituted C 1-6 alkyl.

[0464] In the present disclosure, R 7 It may be a hydrogen atom.

[0465] In the present disclosure, R 8 It can be a hydrogen atom, an optionally substituted C 1-6 Alkyl or -C(=O)NR A R B .

[0466] In the present disclosure, R 8 It can be -C(=O)NR A R B .

[0467] In the present disclosure, R 9 It can be a hydrogen atom or an optionally substituted C 1-6 alkyl.

[0468] In the present disclosure, R 9 It may be methyl.

[0469] In the present disclosure, R A and R B Each may represent a hydrogen atom.

[0470] In the present disclosure, the solvent may be a polar aprotic solvent.

[0471] In the present disclosure, the solvent may be a polar protic solvent.

[0472] In the present disclosure, the solvent may be selected from the group consisting of isopropyl acetate, ethyl acetate, tetrahydrofuran, 2-methyl-tetrahydrofuran, acetone, toluene, anisole, methyl tert-butyl ether, cyclopentyl methyl ether, methanol, ethanol, 2-propanol, 4-methyltetrahydropyran, acetonitrile, N-methylpyrrolidone and dimethyl sulfoxide.

[0473] In the present disclosure, the solvent may be dimethyl sulfoxide.

[0474] In the present disclosure, the oxidant may include an iron-containing compound.

[0475] In the present disclosure, the oxidizing agent may be iron (III) chloride or iron (III) nitrate.

[0476] In the present disclosure, the oxidizing agent may be iron (III) chloride hexahydrate.

[0477] In the present disclosure, the base may be selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, diisopropylethylamine and aqueous ammonia.

[0478] In the present disclosure, the base may be selected from the group consisting of sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine and aqueous ammonia.

[0479] In the present disclosure, the base may be sodium hydroxide.

[0480] In the present disclosure, the step of contacting with an oxidant may be performed in a flow reactor.

[0481] In the present disclosure, in the step of contacting an oxidant, the inner diameter of the flow reactor may be about 0.1 mm to about 100 mm. In the step of contacting an oxidant, the inner diameter of the flow reactor may be about 0.1 mm or more, about 0.2 mm or more, about 0.3 mm or more, about 0.4 mm or more, about 0.5 mm or more, about 0.6 mm or more, about 0.7 mm or more, about 0.8 mm or more, about 0.9 mm or more, about 1.0 mm or more, about 1.1 mm or more, about 1.2 mm or more, about 1.3 mm or more, about 1.4 mm or more, about 1.5 mm or more, about 1.6 mm or more, about 1.7 mm or more, about 1.8 mm or more, about 1.9 mm or more, about 2.0 mm or more, about 2.5 mm or more, about 3. 0mm or more, about 3.5mm or more, about 4.0mm or more, about 4.5mm or more, about 5.0mm or more, about 5.5mm or more, about 6.0mm or more, about 6.5mm or more, about 7.0mm or more, about 7.5mm or more, about 8.0mm or more, about 8.5mm or more, about 9.0mm or more, about 9.5mm or more, about 10mm or more, about 15mm or more, about 20mm or more, about 25mm or more, about 30mm or more, about 35mm or more, about 40mm or more, about 45mm or more, about 50mm or more, about 55mm or more, about 60mm or more, about 65mm or more mm or more, about 70 mm or more, about 75 mm or more, about 80 mm or more, about 85 mm or more, about 90 mm or more, or about 95 mm or more, or about 100 mm or less, about 95 mm or less, about 90 mm or less, about 85 mm or less, about 80 mm or less, about 75 mm or less, about 70 mm or less, about 65 mm or less, about 60 mm or less, about 55 mm or less, about 50 mm or less, about 45 mm or less, about 40 mm or less, about 35 mm or less, about 30 mm or less, about 25 mm or less, about 20 mm or less, about 15 mm or less, about 10 mm or less, about 9.5 mm or less mm or less, about 9.0 mm or less, about 8.5 mm or less, about 8.0 mm or less, about 7.5 mm or less, about 7.0 mm or less, about 6.5 mm or less, about 6.0 mm or less, about 5.5 mm or less, about 5.0 mm or less, about 4.5 mm or less, about 4.0 mm or less, about 3.5 mm or less, about 3.0 mm or less, about 2.5 mm or less, about 2.0 mm or less, about 1.9 mm or less, about 1.8 mm or less, about 1.7 mm or less, about 1.6 mm or less, about 1.5 mm or less, about 1.4 mm or less, about 1.3 mm or less, about 1.2 mm or less, about 1.1 mm or less, about 1.0 mm or less, about 0.9 mm or less, about 0.8 mm or less, about 0.7 mm or less, about 0.6 mm or less, about 0.5 mm or less, about 0.4 mm or less, about 0.3 mm or less, or about 0.2 mm or less, preferably 0.5 mm or more and about 20 mm or less, more preferably about 0.7 mm or more and about 15 mm or less, still more preferably about 0.5 mm or more and about 10 mm or less, particularly preferably about 1.0 mm or more and about 10 mm or less.

[0482] In the present disclosure, the residence time of the step of contacting the oxidant may be 60 seconds or less. The residence time of the step of contacting the oxidant may be 60 seconds or less, 50 seconds or less, 40 seconds or less, 30 seconds or less, 20 seconds or less, 10 seconds or less, 5 seconds or less, 4 seconds or less, 3 seconds or less, 2 seconds or less, or 1 second or less.

[0483] In the present disclosure, the residence time of the step of contacting the oxidant may be 0.1 to 10 seconds. The residence time of the step of contacting the oxidant may be 0.1 to 5 seconds.

[0484] In the present disclosure, the step of contacting with an oxidant may be performed at a temperature of 0° C. to 100° C. The step of contacting with an oxidant may be performed at 0° C. or higher, 5° C. or higher, 10° C. or higher, 15° C. or higher, 20° C. or higher, 25° C. or higher, 30° C. or higher, 35° C. or higher, 40° C. or higher, 50° C. or higher, 55° C. or higher, 60° C. or higher, 65° C. or higher, 70° C. or higher, 75° C. or higher, 80° C. or higher, 85° C. or higher, 90° C. or higher, or 95° C. or higher, or 100° C. or lower, 95° C. or lower, 90° C. or lower, 85° C. or lower , 80 ℃ or less, 75 ℃ or less, 70 ℃ or less, 65 ℃ or less, 60 ℃ or less, 55 ℃ or less, 50 ℃ or less, 45 ℃ or less, 40 ℃ or less, 35 ℃ or less, 30 ℃ or less, 25 ℃ or less, 20 ℃ or less, 15 ℃ or less, 10 ℃ or less, or 5 ℃ or less, preferably 30 ℃ or more and 100 ℃ or less, more preferably 65 ℃ or more and 95 ℃ or less, and even more preferably 60 ℃ or more and 90 ℃ or less.

[0485] In the present disclosure, the step of contacting with an oxidant may be performed at a temperature of 75° C. or higher.

[0486] In the present disclosure, the step of contacting with a base may be performed after the step of contacting with an oxidizing agent.

[0487] In the present disclosure, the step of contacting with a base may be performed by contacting a base with the reaction mixture generated by the step of contacting with an oxidant.

[0488] In the present disclosure, the oxidizing agent may be in a solvent in the step of contacting the base.

[0489] In the present disclosure, the step of contacting with a base may be performed in a flow reactor.

[0490] In the present disclosure, in the step of contacting with alkali, the inner diameter of the flow reactor may be about 0.1 mm to about 100 mm. In the step of contacting with alkali, the inner diameter of the flow reactor may be about 0.1 mm or more, about 0.2 mm or more, about 0.3 mm or more, about 0.4 mm or more, about 0.5 mm or more, about 0.6 mm or more, about 0.7 mm or more, about 0.8 mm or more, about 0.9 mm or more, about 1.0 mm or more, about 1.1 mm or more, about 1.2 mm or more, about 1.3 mm or more, about 1.4 mm or more, about 1.5 mm or more, about 1.6 mm or more, about 1.7 mm or more, about 1.8 mm or more, about 1.9 mm or more, about 2.0 mm or more, about 2.5 mm or more, about 3.0 mm or more. m or more, about 3.5 mm or more, about 4.0 mm or more, about 4.5 mm or more, about 5.0 mm or more, about 5.5 mm or more, about 6.0 mm or more, about 6.5 mm or more, about 7.0 mm or more, about 7.5 mm or more, about 8.0 mm or more, about 8.5 mm or more, about 9.0 mm or more, about 9.5 mm or more, about 10 mm or more, about 15 mm or more, about 20 mm or more, about 25 mm or more, about 30 mm or more, about 35 mm or more, about 40 mm or more, about 45 mm or more, about 50 mm or more, about 55 mm or more, about 60 mm or more, about 65 mm or more m or more, about 70 mm or more, about 75 mm or more, about 80 mm or more, about 85 mm or more, about 90 mm or more, or about 95 mm or more, or about 100 mm or less, about 95 mm or less, about 90 mm or less, about 85 mm or less, about 80 mm or less, about 75 mm or less, about 70 mm or less, about 65 mm or less, about 60 mm or less, about 55 mm or less, about 50 mm or less, about 45 mm or less, about 40 mm or less, about 35 mm or less, about 30 mm or less, about 25 mm or less, about 20 mm or less, about 15 mm or less, about 10 mm or less, about 9.5 m m or less, about 9.0 mm or less, about 8.5 mm or less, about 8.0 mm or less, about 7.5 mm or less, about 7.0 mm or less, about 6.5 mm or less, about 6.0 mm or less, about 5.5 mm or less, about 5.0 mm or less, about 4.5 mm or less, about 4.0 mm or less, about 3.5 mm or less, about 3.0 mm or less, about 2.5 mm or less, about 2.0 mm or less, about 1.9 mm or less, about 1.8 mm or less, about 1.7 mm or less, about 1.6 mm or less, about 1.5 mm or less, about 1.4 mm or less, about 1.3 mm or less, about 1.2 mm or less, about 1.1 mm or less, about 1.0 mm or less, about 0.9 mm or less, about 0.8 mm or less, about 0.7 mm or less, about 0.6 mm or less, about 0.5 mm or less, about 0.4 mm or less, about 0.3 mm or less, or about 0.2 mm or less, preferably about 0.5 mm or more and about 20 mm or less, more preferably about 0.7 mm or more and about 15 mm or less, still more preferably about 0.5 mm or more and about 10 mm or less, particularly preferably about 1.0 mm or more and about 10 mm or less.

[0491] In the present disclosure, the residence time of the step of contacting the alkali may be 60 seconds or less. The residence time of the step of contacting the alkali may be 60 seconds or less, 50 seconds or less, 40 seconds or less, 30 seconds or less, 20 seconds or less, 10 seconds or less, 5 seconds or less, 4 seconds or less, 3 seconds or less, 2 seconds or less, or 1 second or less.

[0492] In the present disclosure, the residence time of the step of contacting with the alkali may be 0.1 to 10 seconds. The residence time of the step of contacting with the alkali may be 0.1 to 5 seconds.

[0493] In the present disclosure, the step of contacting with a base may be performed at a temperature of 0°C to 100°C. The step of contacting with a base may be performed at 0°C or higher, 5°C or higher, 10°C or higher, 15°C or higher, 20°C or higher, 25°C or higher, 30°C or higher, 35°C or higher, 40°C or higher, 50°C or higher, 55°C or higher, 60°C or higher, 65°C or higher, 70°C or higher, 75°C or higher, 80°C or higher, 85°C or higher, 90°C or higher, or 95°C or higher, or 100°C or lower, 95°C or lower, 90°C or lower, 85°C or lower, The method is carried out at a temperature of 80°C or less, 75°C or less, 70°C or less, 65°C or less, 60°C or less, 55°C or less, 50°C or less, 45°C or less, 40°C or less, 35°C or less, 30°C or less, 25°C or less, 20°C or less, 15°C or less, 10°C or less, or 5°C or less, preferably 30°C or more and 100°C or less, more preferably 65°C or more and 95°C or less, and still more preferably 60°C or more and 90°C or less.

[0494] In the present disclosure, the step of contacting with an oxidant may be performed at a temperature of 75° C. or higher.

[0495] In the present disclosure, in the compound of formula I, 8 , R 9 The carbon atom to which the OH group is bonded may be an asymmetric carbon.

[0496] In the present disclosure, the compound of Formula II may be an optically active substance and maintain optical purity in the reaction between the compound of Formula II and an oxidizing agent.

[0497] In the present disclosure, the compound of formula I can be

[0498] [Chemical formula 25]

[0499] and

[0500] The compound of formula II can be

[0501] [Chemical formula 26]

[0502]

[0503] In the present disclosure, the compound of formula II can be prepared by the steps of optical resolution and amidation of the compound of formula III:

[0504] [Chemical formula 27]

[0505]

[0506] The optical resolution of the compound of formula III can be carried out by the method described in WO 2021 / 167095.

[0507] (Manufacturing method)

[0508] In the present disclosure, the compound of formula I is prepared by contacting an oxidant with a compound of formula II. The method of the present disclosure includes the step of contacting a base with the solvent to promote the reaction between the compound of formula II and the oxidant.

[0509] In one embodiment of the present disclosure, the oxidant may include an iron-containing compound. When using iron (III) chloride as an oxidant, the reaction endpoint may not be reached by a single input of reagent, but when an alkali is added, the reaction rate is significantly improved. At the same time, the addition of an alkali leads to the generation and precipitation of iron (III) hydroxide, so that a delayed reaction risk is found. If the hydroxide ions in the system react with iron (III) chloride and precipitate as iron hydroxide, the reaction endpoint (the risk of delayed reaction when adding an alkali) is directly reached. Iron (III) hydroxide is insoluble in water or solvents, and is difficult to retrieve after precipitation. In order to react more efficiently, it is preferred to strictly control the order and timing of adding the alkali.

[0510] In one embodiment of the present disclosure, the compound of Formula I can be made by flow synthesis.

[0511] Flow synthesis (also called flow chemistry) refers to a synthesis technology or manufacturing technology that performs chemical reactions in a "flow". Unstable raw materials or intermediates and dangerous reactions are not suitable for batch reactions, so scale-up must be considered. At the same time, flow synthesis can be performed at the optimal reaction time, the addition amount can be accurately managed, and an efficient reaction space can be provided. Therefore, flow synthesis is compatible with various reactions by connecting equipment and increasing / decreasing the number of flow manufacturing equipment. By combining the modules of the manufacturing equipment, the reaction space can be easily designed.

[0512] In the present disclosure, by applying the flow synthesis technique, reactions can be performed accurately and reproducibly at the appropriate time.

[0513] In one embodiment of the present disclosure, the compound of formula I is manufactured by an oxidation reaction using iron (III) chloride in a flow reactor. The reaction in the flow reactor does not require a separation solution, which is required in a batch reaction. It is difficult to accurately reproduce the process achieved by the flow reaction in a batch reactor. Due to the difficulty in stirring, it is difficult to scale up in a batch reaction. When iron (III) chloride is used instead of ferric nitrate, nitrosamines will not be produced by this reaction mechanism. The high-speed mixing and precise flow control of the flow synthesis technology have successfully improved the reaction efficiency and simplified the post-processing operation. The 10kg scale has been successfully manufactured using the method disclosed herein.

[0514] Figure 1 A schematic diagram showing an example of the method of the present disclosure using flow synthesis. The figure shows that compound 1 ((R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide) is obtained by mixing compound 2 ((R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide) and an aqueous solution of iron (III) chloride in a T-type mixer, allowing the reaction to proceed in a tubular reactor and mixing the reactants with an aqueous solution of sodium hydroxide in a subsequent T-type mixer.

[0515] It is to be understood that the following equilibrium reactions occur in the absence of a base.

[0516] [Chemical formula 28]

[0517]

[0518] Since the generated hydrochloric acid is trapped in the presence of a base, the reaction toward the right is accelerated to give the following reaction.

[0519] Compound 2 + 2FeCl3 + H2O + 2NaOH → Compound 1 + 2FeCl2 + 2NaCl + 2H2O

[0520] The following abbreviations may also be used in the Examples and Tables therein to simplify the description of the specification.

[0521] PEA:1-phenylethylamine

[0522] EtOAc: Ethyl acetate

[0523] i PrOAc:Isopropyl acetate

[0524] NMP: N-Methylpyrrolidone

[0525] DMA:Dimethylacetamide

[0526] DMF: N,N-dimethylformamide

[0527] MTBE: Methyl tert-butyl ether

[0528] DME:1,2-dimethoxyethane

[0529] 2-MeTHF:2-Methyltetrahydrofuran

[0530] MEK: Methyl Ethyl Ketone

[0531] DMS0: dimethyl sulfoxide

[0532] CDCl3: deuterated chloroform

[0533] MeOH: methanol

[0534] MeCN:Acetonitrile

[0535] IPA:2-Propanol

[0536] CPME: Cyclopentyl Methyl Ether

[0537] Trolox amide:(R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide

[0538] For the symbols used in NMR, δ refers to chemical shift, s refers to singlet, d refers to doublet, t refers to triplet, q refers to quartet, m refers to multiplet, and J refers to spin coupling constant.

[0539] The following analysis conditions were used in HPLC (high performance liquid chromatography) analysis.

[0540] (Reagent / Sample Solution)

[0541] Acetonitrile: for liquid chromatography (FUJIFILM Wako Pure Chemical) or equivalent Trifluoroacetic acid: special grade (FUJIFILM Wako Pure Chemical) or equivalent

[0542] Water: Test water produced by ultrapure water production system, etc.

[0543] (Solvent)

[0544] Acetonitrile

[0545] (Mobile Phase)

[0546] Mobile phase A: water / trifluoroacetic acid mixture (2000:1)

[0547] <Preparation Example> 2000 mL of water and 1 mL of trifluoroacetic acid were mixed and degassed using an ultrasonic cleaner.

[0548] Mobile phase B: acetonitrile / trifluoroacetic acid mixture (2500:1)

[0549] <Preparation Example> 2500 mL of acetonitrile and 1 mL of trifluoroacetic acid were mixed and degassed using an ultrasonic cleaner.

[0550] (Syringe detergent)

[0551] Acetonitrile

[0552] 1. Apparatus and Settings / Conditions

[0553] 1.1 Device

[0554] High performance chromatograph: UFLCXR (Shimadzu) or equivalent

[0555] Electronic balance: XP205DRV (Mettler Toledo) or equivalent

[0556] Ultrapure water production system: Milli-Q Advantage A10 (Merck) or equivalent

[0557] Ultrasonic cleaning machine: US-4R (AS ONE) or equivalent

[0558] 1.2 Setup / conditions for liquid chromatography

[0559] Detector: UV absorption spectrophotometer (measurement wavelength: 235nm)

[0560] Column: Octadecylsilyl silica gel for liquid chromatography with a particle size of 3.5 μm was loaded in a stainless steel tube with an inner diameter of 4.6 mm and a length of 150 mm.

[0561] [Zorbax SB C18 (Agilent) or equivalent]

[0562] Column temperature: Constant temperature around 35°C

[0563] Mobile phase A: water / trifluoroacetic acid mixture (2000:1)

[0564] Mobile phase B: acetonitrile / trifluoroacetic acid mixture (2500:1)

[0565] Delivery of mobile phase: The mixing ratio of mobile phase A to mobile phase B was varied in the following manner to control the concentration gradient.

[0566] [Table 1]

[0567]

[0568] Flow rate: 1.0mL / min

[0569] Area measurement range: 33 minutes after sample solution injection (data acquisition time is 40 minutes)

[0570] Injection volume: 5μL

[0571] Sample cooler temperature: Constant temperature around 25°C

[0572] Mixer volume: 0.5mL

[0573] Syringe detergent: acetonitrile

[0574] Sample concentration: 2.5μg / mL to 0.5mg / mL

[0575] <Example of Waveform Processing Parameter Setting>

[0576] Minimum area: 5000μV*second

[0577] Minimum height: 100μV

[0578] Detection sensitivity: 50μV / second

[0579] Peak width: 1 second

[0580] Output intensity range: -500 to 1000mAU

[0581] Output time range: 0 to 33 minutes

[0582] [Example]

[0583] (Example 1)

[0584] Elucidation of the reaction mechanism of oxidation reaction using iron (III) chloride (3)

[0585] To an isopropyl acetate solution (2 mL) of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (200 mg, 0.802 mmol) was added 4.2 equivalents of iron (III) chloride hexahydrate (910 mg, 3.37 mol) at 30° C. or less, and further added 2.1 equivalents of sodium hydroxide (67.4 mg, 1.69 mmol). After stirring for 1 hour, the degree of loss of the starting material was checked, and the remaining (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide was 0.2%.

[0586] (Example 2)

[0587] Elucidation of the reaction mechanism of oxidation reaction using iron (III) chloride (4)

[0588] To an isopropyl acetate solution (2 mL) of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (200 mg, 0.802 mmol) was added 4.2 equivalents of iron (III) chloride hexahydrate (910 mg, 3.37 mol) at 30° C. or less, and further added 2.1 equivalents of a base (1.69 mmol). After stirring for 1 hour, the degree of loss of the raw material was investigated, and the amount of the residual (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide was 0.2% or less.

[0589] [Table 2]

[0590]

[0591]

[0592] (Example 3)

[0593] Study on the Solubility of (R)-6-Hydroxy-2,5,7,8-Tetramethylchroman-2-carboxamide

[0594] The solubility of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide was studied.

[0595] [Table 3]

[0596] Value in percentage: g / 100g

[0597] Temperature(℃) 0 20 40 50 60 80 100 Isopropyl acetate 0.68 1.07 1.91 3.01 4.71 Ethyl acetate 0.83 1.28 2.24 3.97 THF 7.08 13.6 18.9 22.5 2-Methyl-THF 2.15 3.52 5.51 6.37 acetone 3.10 4.55 7.29 12.6 Toluene 0.048 0.12 0.18 0.45 1.22 2.17 Anisole 0.11 0.25 0.60 1.42 3.93 5.78 MTBE 0.23 0.35 0.59 0.78 CPME 0.35 0.61 0.95 1.77 3.34 4.48 Methanol 4.07 6.11 9.69 16.2 Ethanol 2.81 5.16 7.91 15.3 2-Propanol (IPA) 1.56 3.48 4.14 5.59 11.6 4-Methyltetrahydropyran 0.65 2.12 3.16 5.53 11.0 20.2 Acetonitrile 0.72 1.53 3.20 6.47 NMP 6.03 11.2 10.6 14.7 DMSO - 11.0 11.5 14.7

[0598] Among the above solvents, THF exhibits the highest solubility at 20° C. By using DMSO having higher safety as a solvent for the oxidation reaction from the viewpoint of safety, the following oxidation reaction was performed.

[0599] (Example 4)

[0600] Oxidation of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide solution with aqueous iron(III) chloride in a batch reactor using DMSO as solvent

[0601] To a DMSO solution (10 mL) of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (1 g, 4.01 mmol) was added 4.2 equivalents of iron (III) chloride hexahydrate (4.0 mol / L, 4.21 mL, 16.84 mmol) at 30°C or lower, and further added 4.0 equivalents of an aqueous sodium hydroxide solution (5.0 mol / L, 3.21 mL, 16.05 mmol), and the mixture was vigorously stirred. After stirring for 1 hour, the degree of loss of the raw material was checked, and (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide was reduced to 0.55%, and (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide was produced as the main product.

[0602] However, this method carries the risk of complete solidification in the flask if the mixture cannot be stirred vigorously. There is also a high risk of subsequent retrieval difficulties due to the difficulty in stirring. In view of the above, it is desirable to adopt a method that can complete the reaction using a flow reactor.

[0603] (Example 5)

[0604] Oxidation of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide with aqueous iron(III) chloride in a flow reactor using DMSO as solvent

[0605] Prepare 0.5mol / L (R) -6- hydroxy -2,5,7,8- tetramethyl chroman -2- formamide DMSO solution (reaction solution A). Prepare 4.0mol / L iron (III) chloride aqueous solution (reaction solution B). Prepare 5.0mol / L sodium hydroxide aqueous solution (reaction solution C). By using a tube with an inner diameter of 1.0mm, with a flow rate of 10mL / min, and with a flow rate of 5.25mL / min, these solutions are mixed in a T-type mixer (mixer 1) with an inner diameter of 1.0mm. After passing through mixer 1, by using a tube with an inner diameter of 1.0mm, the mixture is mixed with the reaction solution C conveyed in the same way in a second T-type mixer (internal diameter 1.0mm, mixer 2). The residence time between mixer 1 and mixer 2 is set to any time between 0.1 seconds and 10 seconds. The reaction solution discharged via mixer 2 is discharged from the flow reactor system using a tube with an inner diameter of 1.0mm for sampling. The solution was conveyed while the mixer 1, the mixer 2 and the connecting pipe were immersed and heated in a heating bath at 75° C. It was confirmed that the residual rate of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide was 2% or less, and the desired product (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide was produced with a productivity of 91%.

[0606] (Example 6)

[0607] Oxidation of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide with aqueous iron(III) chloride in a flow reactor using DMSO as solvent and separation of the products

[0608] Prepare 0.5mol / L (R) -6- hydroxy -2,5,7,8- tetramethyl chroman -2- formamide DMSO solution (reaction solution A). Prepare 4.0mol / L iron (III) chloride aqueous solution (reaction solution B). Prepare 5.0mol / L sodium hydroxide aqueous solution (reaction solution C). By using a tube with an inner diameter of 1.0mm, with a flow rate of 10mL / min, and with a flow rate of 5.25mL / min, these solutions are mixed in a T-type mixer (mixer 1) with an inner diameter of 1.0mm. After passing through mixer 1, by using a tube with an inner diameter of 1.0mm, the mixture is mixed with the reaction solution C conveyed in the same way in a second T-type mixer (internal diameter 1.0mm, mixer 2). The residence time between mixer 1 and mixer 2 is set to any time between 0.1 seconds and 10 seconds. The reaction solution discharged via mixer 2 is discharged from the flow reactor system using a tube with an inner diameter of 1.0mm for sampling. The solution was conveyed while mixer 1, mixer 2 and connecting pipe were immersed and heated in a 75°C heating bath. The residual rate of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-formamide was confirmed to be 2% or less, and the desired product (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide was produced at a productivity of 91%. The reaction solution discharged from the flow reactor was recovered in a receiving container adjusted to a temperature of 40°C for 18 minutes and 3 seconds, and 90g of 1mol / L hydrochloric acid aqueous solution was added dropwise. The mixture was then cooled to 20°C and 18g of concentrated hydrochloric acid was added dropwise. It was confirmed that the pH was below 0.5. Then 90g of water was further added dropwise, and the resulting crystals were filtered. The wet crystals were washed twice with 67.5g of 1mol / L hydrochloric acid aqueous solution and three times with 45g of water. The crystals were dried with a vacuum dryer heated to 60° C. to obtain 20.35 g of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide.

[0609] (Comparative Example 1)

[0610] Elucidation of the reaction mechanism of oxidation reaction using iron (III) chloride (1)

[0611] To a solution of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (200 mg, 0.802 mmol) in isopropyl acetate (2 mL) was added 2.1 equivalents of iron (III) chloride hexahydrate (455 mg, 1.69 mol) at 30° C. or less. When the extent of loss of the starting material was investigated after stirring for 1 hour, 73% of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide remained.

[0612] (Comparative Example 2)

[0613] Elucidation of the reaction mechanism of oxidation reaction using iron (III) chloride (2)

[0614] To a solution of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (200 mg, 0.802 mmol) in isopropyl acetate (2 mL) was added 4.2 equivalents of iron (III) chloride hexahydrate (910 mg, 3.37 mol) at 30° C. or less. When the extent of loss of the starting material was investigated after stirring for 1 hour, 21% of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide remained.

[0615] As described above, the present disclosure is illustrated by using its preferred embodiments. It is to be understood that the scope of the present disclosure should be interpreted only based on the claims. It is to be understood that any patent, any patent application, and any reference cited herein should be incorporated herein by reference as if their contents were explicitly described herein. This application is based on patent application No. 2022-158569 filed in Japan (filing date: September 30, 2022), the contents of which are incorporated herein in their entirety.

[0616] Industrial Applicability

[0617] The present disclosure can be used to prepare a medicament.

Claims

1. A method for producing a compound of formula I: [Chemical formula 1] It includes the steps of: An oxidizing agent is contacted with a compound of formula II in a solvent: [Chemical formula 2] and contacting a base with the solvent to promote the reaction between the compound of formula II and the oxidizing agent; wherein 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, a halogen, an optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy or -C(=O)NR A R B ,and R A and R B Each independently represents a hydrogen atom, an optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 Alkoxy.

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

3. The method according to claim 1 or 2, wherein R 1 It's methyl.

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

5. The method according to any one of claims 1 to 4, wherein R 2 It's methyl.

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

7. The method according to any one of claims 1 to 6, wherein R 3 It's methyl.

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

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

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

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

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

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

14. The method according to any one of claims 1 to 12, wherein R 7 is a hydrogen atom or an optionally substituted C 1-6 alkyl.

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

16. The method according to any one of claims 1 to 15, wherein R 8 is a hydrogen atom, an 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 is -C(=O)NR A R B .

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

19. The method according to any one of claims 1 to 18, wherein R 9 It's methyl.

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 a polar aprotic solvent.

22. The method according to any one of claims 1 to 20, wherein the solvent is a polar protic solvent.

23. The method according to any one of claims 1 to 20, wherein the solvent is selected from the group consisting of isopropyl acetate, ethyl acetate, tetrahydrofuran, 2-methyl-tetrahydrofuran, acetone, toluene, anisole, methyl tert-butyl ether, cyclopentyl methyl ether, methanol, ethanol, 2-propanol, 4-methyltetrahydropyran, acetonitrile, N-methylpyrrolidone and dimethyl sulfoxide.

24. The process according to any one of claims 1 to 23, wherein the solvent is dimethyl sulfoxide.

25. The method of any one of claims 1 to 24, wherein the oxidant comprises an iron-containing compound.

26. The method according to any one of claims 1 to 25, wherein the oxidizing agent is iron (III) chloride or iron (III) nitrate.

27. A method according to any one of claims 1 to 26, wherein the oxidizing agent is iron (III) chloride hexahydrate.

28. The process according to any one of claims 1 to 27, wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, diisopropylethylamine and aqueous ammonia.

29. The process according to any one of claims 1 to 28, wherein the base is selected from the group consisting of sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine and aqueous ammonia.

30. The process of claim 29, wherein the base is sodium hydroxide.

31. The method of any one of claims 1 to 30, wherein the step of contacting with an oxidant is performed in a flow reactor.

32. The method of claim 31, wherein the inner diameter of the flow reactor during the step of contacting an oxidant is about 0.1 mm to about 100 mm.

33. The method of claim 31 or 32, wherein the residence time of the step of contacting with an oxidant is 60 seconds or less.

34. The method of claim 33, wherein the residence time is from 0.1 seconds to 10 seconds.

35. The method according to any one of claims 1 to 34, wherein the step of contacting with an oxidant is carried out at a temperature of 0°C to 100°C.

36. The method of claim 35, wherein the step of contacting with an oxidant is performed at a temperature of 75°C or higher.

37. The method of claim 35, wherein the step of contacting with an oxidant is performed at a temperature of 60°C to 90°C.

38. The method according to any one of claims 1 to 37, wherein the step of contacting with a base is performed after the step of contacting with an oxidizing agent.

39. The method according to any one of claims 1 to 38, wherein the step of contacting with a base is performed by contacting a base with the reaction mixture produced by the step of contacting with an oxidizing agent.

40. The method of any one of claims 1 to 39, wherein the oxidizing agent is in the solvent during the step of contacting with a base.

41. The method according to any one of claims 1 to 40, wherein the step of contacting with a base is performed in a flow reactor.

42. The method of claim 41, wherein the inner diameter of the flow reactor in the step of contacting with a base is about 0.1 mm to about 100 mm.

43. The method according to claim 41 or 42, wherein the residence time of the step of contacting with an alkali is 60 seconds or less.

44. The method of claim 43, wherein the residence time is from 0.1 seconds to 10 seconds.

45. The method according to any one of claims 1 to 44, wherein the step of contacting with a base is carried out at a temperature of 0°C to 100°C.

46. ​​The method of claim 45, wherein the step of contacting with a base is performed at a temperature of 60°C to 90°C.

47. The method of claim 45, wherein the step of contacting with an oxidant is performed at a temperature of 75°C or higher.

48. The method according to any one of claims 1 to 47, wherein in the compound of formula I 8 , R 9 The carbon atom connected to OH is an asymmetric carbon.

49. The method of claim 48, wherein the compound of formula II is an optically active substance and maintains optical purity during the reaction between the compound of formula II and the oxidizing agent.

50. The method according to any one of claims 1 to 49, wherein the compound of formula I is [Chemical formula 3] and The compound of formula II is [Chemical formula 4] 51. The method of claim 50, wherein the compound of formula II is prepared by the steps of optical resolution and amidation of a compound of formula III: [Chemical formula 5]

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