Oxidative cleavage method of trolox amide

Abstract

The present disclosure provides an oxidative cleavage method of a Trolox amide. More particularly, the disclosure provides a method for producing a compound of formula I, the method including a step for contacting a compound of formula II with an oxidant in a solvent, and a step for contacting the solvent with a base to promote the reaction of the compound of formula II with the oxidant. In the formulae: R1, R2, R3, R4, R5, R6, R7, R8 and R9 each independently represent a hydrogen atom, a halogen, an optionally substituted C1-6alkyl, an optionally substituted C1-6 alkoxy, or -C(=O)NRARB; and RA and RB each independently represent a hydrogen atom, an optionally substituted C1-6 alkyl, or an optionally substituted C1-6 alkoxy.

Description

Oxidative cleavage of Trolox amides

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

[0002] 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 is useful for treating and / or suppressing mitochondrial disorders and certain pervasive developmental disorders.

[0003] WO 2021 / 167095 describes an optically resolved Trolox intermediate and a method for its preparation.

[0004] International Publication No. 2009 / 061744 International Publication No. 2021 / 167095

[0005] As a result of extensive research, the present inventors have discovered a novel method for oxidative cleavage of troloxamide-related compounds, and have completed the present disclosure.

[0006] For example, the present disclosure provides the following: (Item 1) Formula I: 1. A method for preparing a compound of formula II: with an oxidizing agent; and contacting said solvent with a base to promote the reaction of the compound of formula II with the oxidizing agent, wherein R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , and R ９ are each independently a hydrogen atom, a halogen atom, or an optionally substituted C １－６ Alkyl, optionally substituted C １－６ Alkoxy, or —C(═O)NR Ａ R Ｂ represents R Ａ and RＢ are each independently a hydrogen atom, an optionally substituted C １－６ Alkyl or optionally substituted C １－６ R represents an alkoxy group. １ is a hydrogen atom or an optionally substituted C １－６ Item 3. The method according to item 1, wherein R is alkyl. １ The method according to item 1 or 2, wherein R is methyl. ２ is a hydrogen atom or an optionally substituted C １－６ The method according to any one of items 1 to 3, wherein R is alkyl. ２ The method according to any one of items 1 to 4, wherein R is methyl. ３ is a hydrogen atom or an optionally substituted C １－６ Item 7. The method according to any one of items 1 to 5, wherein R is alkyl. ３ The method according to any one of items 1 to 6, wherein R is methyl. ４ is a hydrogen atom or an optionally substituted C １－６ The method according to any one of items 1 to 7, wherein R is alkyl. ４ The method according to any one of items 1 to 8, wherein R is a hydrogen atom. ５ is a hydrogen atom or an optionally substituted C １－６ 11. The method of any one of items 1 to 9, wherein R is alkyl. ５ The method according to any one of items 1 to 10, wherein R is a hydrogen atom. ６ is a hydrogen atom or an optionally substituted C １－６ 13. The method of any one of items 1 to 11, wherein R is alkyl. ６ The method according to any one of items 1 to 12, wherein R is a hydrogen atom. ７ is a hydrogen atom or an optionally substituted C １－６ 15. The method of any one of items 1 to 13, wherein R is alkyl. ７The method according to any one of items 1 to 14, wherein R is a hydrogen atom. ８ is a hydrogen atom, an optionally substituted C １－６ Alkyl, or —C(═O)NR Ａ R Ｂ The method according to any one of items 1 to 15, wherein R ８ is -C(=O)NR Ａ R Ｂ The method according to any one of items 1 to 16, wherein R ９ is a hydrogen atom or an optionally substituted C １－６ Item 19. The method of any one of items 1 to 17, wherein R is alkyl. ９ The method of any one of items 1 to 18, wherein R is methyl. Ａ and R Ｂand each represent a hydrogen atom. (Item 21) The method of any one of items 1 to 20, wherein the solvent is an aprotic polar solvent. (Item 22) The method of any one of items 1 to 20, wherein the solvent is a protic polar solvent. (Item 23) 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. (Item 24) The method of any one of items 1 to 23, wherein the solvent is dimethyl sulfoxide. (Item 25) The method of any one of items 1 to 24, wherein the oxidizing agent comprises an iron-containing compound. (Item 26) The method of any one of items 1 to 25, wherein the oxidizing agent is iron(III) chloride or iron(III) nitrate. (Item 27) The method of any one of items 1 to 26, wherein the oxidizing agent is iron(III) chloride hexahydrate. (Item 28) 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. (Item 29) 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. (Item 30) The method of item 29, wherein the base is sodium hydroxide. (Item 31) The method of any one of items 1 to 30, wherein the step of contacting the oxidizing agent is carried out in a flow reactor. (Item 32) The method according to Item 31, wherein in the step of contacting the oxidizing agent, the flow reactor has an inner diameter of about 0.1 mm to about 100 mm.(Item 33) The method of item 31 or 32, wherein the residence time in the step of contacting an oxidizing agent is 60 seconds or less. (Item 34) The method of item 33, wherein the residence time is 0.1 seconds to 10 seconds. (Item 35) The method of any one of items 1 to 34, wherein the step of contacting an oxidizing agent is carried out at a temperature of 0°C to 100°C. (Item 36) The method of item 35, wherein the step of contacting an oxidizing agent is carried out at a temperature of 75°C or higher. (Item 37) The method of item 35, wherein the step of contacting an oxidizing agent is carried out at a temperature of 60°C to 90°C. (Item 38) The method of any one of items 1 to 37, wherein the step of contacting a base is carried out after the step of contacting an oxidizing agent. (Item 39) The method of any one of items 1 to 38, wherein the step of contacting a base is carried out by contacting a base with the reaction mixture produced by the step of contacting an oxidizing agent. (Item 40) The method of any one of items 1 to 39, wherein in the step of contacting a base, the oxidizing agent is present in the solvent. (Item 41) The method of any one of items 1 to 40, wherein the step of contacting a base is carried out in a flow reactor. (Item 42) The method of item 41, wherein in the step of contacting a base, the inner diameter of the flow reactor is from about 0.1 mm to about 100 mm. (Item 43) The method of items 41 or 42, wherein the residence time in the step of contacting a base is 60 seconds or less. (Item 44) The method of item 43, wherein the residence time is 0.1 seconds to 10 seconds. (Item 45) The method of any one of items 1 to 44, wherein the step of contacting a base is carried out at a temperature of 0°C to 100°C. (Item 46) The method of item 45, wherein the step of contacting a base is carried out at a temperature of 60°C to 90°C. 47. The method of claim 45, wherein the step of contacting with an oxidizing agent is carried out at a temperature of 75° C. or higher. 48. In the compound of formula I, R. ８ , R ９and the carbon atom to which OH is bonded is an asymmetric carbon. (Item 49) The method according to any one of items 1 to 47, wherein the compound of formula II is an optically active substance, and the optical purity is maintained in the reaction of the compound of formula II with an oxidizing agent. (Item 50) The method according to item 48, wherein the compound of formula I is and the compound of formula II is 51. The method of any one of items 1 to 49, wherein the compound of formula II is a compound of formula III: 51. The method according to item 50, wherein the compound is produced by optically resolving the compound represented by the formula:

[0007] The present disclosure provides a method for preparing a compound represented by formula I with high reaction efficiency and simple post-treatment.

[0008] FIG. 1 shows a schematic diagram of an example of the disclosed method by flow synthesis.

[0009] The present disclosure will be described in more detail below. Throughout this specification, unless otherwise specified, singular expressions should be understood to include the plural concept. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, it should be understood that terms used in this specification are used in the sense commonly used in the relevant field unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the case of conflict, the present specification (including definitions) will prevail.

[0010] The present disclosure will be described in further detail below.

[0011] Abbreviations used herein have their conventional meaning within the art unless otherwise specified.

[0012] References herein to "about" a value or parameter include the variation that is directed to the value or parameter itself. For example, "about X" includes "X" itself as well as values ​​that allow for ±10% of error, unless otherwise specified.

[0013] As used herein, "Trolox" refers to 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid. The R-isomer is referred to as R-Trolox, and the S-isomer is referred to as S-Trolox. Trolox can be prepared by synthetic methods well known to those skilled in the art, for example, the methods described in U.S. Pat. Nos. 3,947,473, 4,003,919, and 4,026,907.

[0014] As used herein, the term "oxidizing agent" refers to a compound that releases oxygen atoms. Examples include, but are not limited to, oxygen, hydrogen peroxide, periodic acid, potassium permanganate, and trivalent iron. Electrooxidation may also be performed.

[0015] As used herein, the term "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.

[0016] As used herein, "aprotic polar solvent" refers to a polar solvent lacking acidic hydrogen. Examples include, but are not limited to, tetrahydrofuran, 2-methyl-tetrahydrofuran, acetone, acetonitrile, N-methylpyrrolidone, and dimethyl sulfoxide. "Protic polar solvent" refers to a polar solvent having acidic hydrogen.

[0017] As used herein, the term "residence time" refers to the time required for a fluid containing a reaction system material to pass through a reactor section in a flow reaction system.

[0018] The number of substituents in a group defined as "optionally substituted" or "substituted" is not particularly limited as long as substitution is possible. In addition, unless otherwise specified, the description of each group also applies when that group is a part or substituent of another group.

[0019] The substituents in "optionally substituted" are selected from the following group of substituents α, and may be substituted with 1 to 5 identical or different substituents. There are no particular limitations on the type of substituent, but when the atom to which a substituent is bonded is an oxygen atom, a nitrogen atom, or a sulfur atom, the substituents are limited to those below in which the atom to which the substituent is bonded is a carbon atom. The group of substituents α includes: 1) halogen atoms, 2) hydroxyl groups, 3) carboxyl groups, 4) cyano groups, 5) C １－６ Alkyl group 6) C ２－６ Alkenyl group 7) C ２－６ Alkynyl group 8) C １－６ Alkoxy group 9) C １－６ Alkylthio group 10) C １－６ Alkylcarbonyl group 11) C １－６ an alkylsulfonyl group (wherein each of the substituents 5) to 11) may be substituted with 1 to 5 identical or different substituents selected from the substituent group β); 12) C ３－１０ Alicyclic group 13)C ３－１０ Alicyclic oxy group 14) C ６－１０ 15) 5- or 6-membered heteroaryloxy group; 16) 4- to 10-membered non-aryl heterocyclic oxy group; 17) C ３－１０ Alicyclic thio group 18) C ６－１０ Arylthio group 19) 5- or 6-membered heteroarylthio group 20) 4- to 10-membered non-aryl heterocyclic thio group 21) C ６－１０ 22) 5- or 6-membered heteroaryl; 23) 4- to 10-membered non-aryl heterocycle; 24) C ３－１０ Alicyclic carbonyl group 25) C ６－１０ 26) 5- or 6-membered heteroarylcarbonyl group; 27) 4- to 10-membered non-aryl heterocyclic carbonyl group; 28) C ３－１０ Alicyclic sulfonyl group 29) C ６－１０30) a 5- or 6-membered heteroarylsulfonyl group; 31) a 4- to 10-membered non-aryl heterocyclic sulfonyl group; (provided that each of the substituents in 12) to 31) is selected from 1 to 5 of the substituent group β or the group 1) C １－６ 32) -NR, which may be substituted with an alkyl group １０ａ R １１ａ 33) -SO ２ -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 R １１ｅ 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 -SO ２ -R １１ｉ 41)-NR １２ｃ -SO ２ -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(=NR１３ｃ ) 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 66) —C(═O)H, and the substituent group β is 1) a halogen atom, 2) a hydroxyl group, 3) a carboxyl group, 4) a cyano group, 5) C ３－１０ Alicyclic group, 6)C １－６ an alkoxy group, 7) C ３－１０ alicyclic oxy group, 8) C １－６ an alkylthio group, 9) a 5- or 6-membered heteroarylthio group, 10) C ６－１０ aryl, 11) 5- or 6-membered heteroaryl, 12) 4- to 10-membered non-aryl heterocycle, 13) C １－６ Alkylcarbonyl group, 14) C ３－１０ alicyclic carbonyl group, 15) C６－１０ 16) an arylcarbonyl group, 17) a 4- to 10-membered non-aryl heterocyclic carbonyl group, 18) —NR １５ａ R １６ａ , 19)-SO ２ -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 , 28)-C(=N-OR １３ｈ ) NR １５ｇ R １６ｆ (However, in the substituent group β, each of the substituents 5) to 17) is a halogen atom, a hydroxyl group, a cyano group, a carboxyl group, -NR １８ａ R １８ｂ and R １３ａ , R １３ｂ , R １３ｃ , R １３ｄ , R １３ｅ , R １３ｆ , R １３ｇ , R １３ｈ , R １３ｉ , R １３ｊ , R １３ｋ are each independently the same or different and represent a hydrogen atom, a hydroxyl group, or C １－６ Alkyl group, C １－６ is an alkoxy group, 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 、R １２ｉ 、R １４ 、R １５ａ 、R １５ｂ 、R １５ｃ 、R １５ｄ 、R １５ｅ 、R １５ｆ 、R １５ｇ 、R１５ｈ , R １５ｉ , R １６ａ , R １６ｂ , R １６ｃ , R １６ｄ , R １６ｅ , R １６ｆ , R １６ｇ , R １６ｈ , R １７ａ , R １７ｂ , R １７ｃ , R １７ｄ are each independently the same or different and represent a hydrogen atom or C １－６ Alkyl group (the alkyl group is a hydroxyl group, a cyano group, a C １－６ Alkoxy group, —NR １８ａ R １８ｂ and R １８ａ , R １８ｂ are each independently the same or different and represent a hydrogen atom or C １－６ It is an alkyl group.

[0020] The substituents in "optionally substituted" are preferably the following. The substituent group α is preferably: 1) a halogen atom, 2) a hydroxyl group, 3) a carboxyl group, 4) a cyano group, 5) a C １－６ Alkyl group 6) C １－６ Alkoxy group 7) C １－６ Alkylthio group 8) C １－６ an alkylcarbonyl group (wherein each of the substituents 5) to 8) may be substituted with 1 to 5 identical or different substituents selected from the substituent group β); 9) C ３－１０ Alicyclic group 10)C ３－１０ Alicyclic oxy group 11) C ６－１０ 12) 5- or 6-membered heteroaryloxy group; 13) 4- to 10-membered non-aryl heterocyclic oxy group; 14) C ３－１０ Alicyclic thio group 15) C ６－１０ 16) 5- or 6-membered heteroarylthio group; 17) 4- to 10-membered non-aryl heterocyclic thio group; 18) C ６－１０ Aryl 19) 5- or 6-membered heteroaryl 20) 4- to 10-membered non-aryl heterocycle 21) C ３－１０Alicyclic carbonyl group 22) C ６－１０ 23) an arylcarbonyl group; 24) a 4- to 10-membered non-aryl heterocyclic carbonyl group; (provided that each of the substituents in 9) to 24) is selected from 1 to 5 of the substituent group β or the above-mentioned 1) C １－６ 25) -NR, which may be substituted with an alkyl group １０ａ R １１ａ 26) -SO ２ -NR １０ｂ R １１ｂ 27) -NR １０ｃ -C(=O)R １１ｃ 28)-NR １２ａ -C(=O)NR １０ｄ R １１ｄ 29)-NR １０ｅ -SO ２ -R １１ｅ 30)-NR １２ｂ -SO ２ -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 37)-C(=N-OR １３ｂ ) NR １０ｉ R １１ｈ The substituent group β is preferably a group selected from the group consisting of: 1) a halogen atom, 2) a hydroxyl group, 3) a cyano group, and 4) C ３－１０ Alicyclic group 5)C １－６ Alkoxy group 6) C １－６ 7) an alkylthio group; 8) a 5- or 6-membered heteroarylthio group; 9) a 4- to 10-membered non-aryl heterocycle; 10) C １－６Alkylcarbonyl group 11) C ３－１０ Alicyclic carbonyl group 12) C ６－１０ 13) an arylcarbonyl group; 14) a 4- to 10-membered non-aryl heterocyclic carbonyl group; 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 24)-C(=N-OR １３ｆ ) NR １５ｆ R １６ｅ (However, in the substituent group β, each of the substituents 4) to 14) is a halogen atom, a hydroxyl group, a cyano group, a carboxyl group, -NR １８ａ R １８ｂ and R １３ａ , R １３ｂ , R １３ｃ , R １３ｄ , R １３ｅ , R １３ｆ , R １３ｇ , R １３ｈ are each independently the same or different and represent a hydrogen atom, a hydroxyl group, or C １－６ Alkyl group, C １－６ is an alkoxy group, 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 , R １６ｇ , R １７ａ , R １７ｂ are each independently the same or different and represent a hydrogen atom or C １－６ Alkyl group (the alkyl group is a hydroxyl group, a cyano group, a C １－６ Alkoxy group, —NR １８ａ R １８ｂ and R is optionally substituted with 1 to 3 identical or different substituents selected from １８ａ , R １８ｂ are each independently the same or different and represent a hydrogen atom or C １－６ It is an alkyl group.

[0021] More preferred examples of the substituent in "optionally substituted" include the following substituents. The substituent group α is more preferably: 1) a halogen atom, 2) a hydroxyl group, 3) a cyano group, 4) a C １－６ Alkyl group 5) C １－６ Alkoxy group 6) C １－６ Alkylthio group 7) C １－６an alkylcarbonyl group (wherein each of the substituents 4) to 7) may be substituted with 1 to 5 identical or different substituents selected from substituent group β); 8) a 5- or 6-membered heteroaryloxy group; 9) a 4- to 10-membered non-aryl heterocyclic oxy group; 10) a 5- or 6-membered heteroarylthio group; 11) a 4- to 10-membered non-aryl heterocyclic thio group; 12) C ６－１０ 13) 5- or 6-membered heteroaryl; 14) 4- to 10-membered non-aryl heterocycle (provided that each of the substituents in 4) to 14) is selected from 1 to 5 of the substituent group β or the above 1) C １－６ 15) -NR, which may be substituted with an alkyl group 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 24)-C(=N-OR １３ｂ ) NR １０ｆ R １１ｅ The substituent group β is more preferably: 1) a halogen atom, 2) a hydroxyl group, 3) a cyano group, 4) —NR １５ａ R １６ａ , 5)-NR １５ｂ -C(=O)R １６ｂ , 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 , 13)-C(=N-OR １３ｆ ) NR １５ｆ R １６ｅ and R １３ａ , R １３ｂ , R １３ｃ , R １３ｄ , R １３ｅ , R １３ｆ , R １３ｇ , R １３ｈ are each independently the same or different and represent a hydrogen atom, a hydroxyl group, or C １－６ Alkyl group, C １－６ is an alkoxy group, 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 , 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 , R １７ｂare each independently the same or different and represent a hydrogen atom or C １－６ Alkyl group (the alkyl group is a hydroxyl group, a cyano group, a C １－６ Alkoxy group, —NR １８ａ R １８ｂ and R １８ａ , R １８ｂ are each independently the same or different and represent a hydrogen atom or C １－６ It is an alkyl group.

[0022] "C １－６ " means that the number of carbon atoms is 1 to 6. The same applies to other numbers, for example, "C １－４ " means that the number of carbon atoms is 1 to 4.

[0023] The term "heteroatom" refers to an oxygen atom, a nitrogen atom, a sulfur atom, or the like.

[0024] The term "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Of these, a fluorine atom and a chlorine atom are preferred. A "halogen atom" may also be referred to as a "halogen."

[0025] "C １－６ Alkyl" or "C １－６ "Alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. １－６ The alkyl group is preferably "C １－４ alkyl group," and more preferably "C １－３ "C alkyl group" is an example. １－３ Specific examples of the "alkyl group" include methyl, ethyl, propyl, 1-methylethyl, etc. １－４ Specific examples of the "alkyl group" include the above-mentioned "C １－３ In addition to the specific examples of the "alkyl group," butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, etc. are also included. １－６ Specific examples of the "alkyl group" include the above-mentioned "C １－４In addition to the specific examples of the "alkyl group," pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl, and the like can be mentioned.

[0026] "C ２－６ alkenyl" or "C ２－６ "Alkenyl group" means a straight-chain or branched unsaturated hydrocarbon group containing one or more carbon-carbon double bonds and having 2 to 6 carbon atoms. ２－６ As the "alkenyl group", preferably "C ２－４ "C is an alkenyl group." ２－６ Specific examples of the "alkenyl group" include, but are not limited to, a vinyl group, a 1-propylenyl group, a 2-propylenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a 2-methyl-1-propylenyl group, and a 2-methyl-2-propylenyl group.

[0027] "C ２－６ alkynyl" or "C ２－６ The term "alkynyl group" means a straight-chain or branched unsaturated aliphatic hydrocarbon group having one or more triple bonds. ２－６ As the "alkynyl group", preferably "C ２－４ Specific examples include, but are not limited to, an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 1-methyl-2-propynyl group, a 3-butynyl group, a 1-pentynyl group, and a 1-hexynyl group.

[0028] "C ３－２０ The term "alicyclic group" refers to a monocyclic or bicyclic non-aromatic hydrocarbon ring group having 3 to 20 carbon atoms, and includes groups having a partially unsaturated bond, a partially bridged structure, a partially spiro-bonded structure, and one or more carbonyl structures. The term "alicyclic group" encompasses cycloalkyl groups, cycloalkenyl groups, and cycloalkynyl groups. ３－２０ As the "alicyclic group", preferably "C ３－１０ Alicyclic group”, more preferably “C３－７ "C" is an alicyclic group. ３－７ Specific examples of the "alicyclic group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. ３－１０ Specific examples of the "alicyclic group" include the above-mentioned "C ３－７ In addition to the specific examples of the "alicyclic group", cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, etc. are also included.

[0029] "C" having a partially crosslinked structure ３－２０ Specific examples of the "alicyclic group" include, but are not limited to, those having the structures shown below.

[0030] Also, "C ３－２０ The "alicyclic group" also includes compounds in which an aromatic ring is condensed. Specific examples include the groups shown below.

[0031] "C ３－１０ The "alicyclic group" is defined as "C ３－２０ Among the "alicyclic groups," "C ３－１０ The term "alicyclic group" refers to a substituent in which the alicyclic group is a monovalent group.

[0032] "C ６－１０ "Aryl" means a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms. ６－１０ The "aryl" may be fused with the "alicyclic group" or "non-aryl heterocycle" at any possible position. ６－１０ Specific examples of "aryl" include phenyl, 1-naphthyl, 2-naphthyl, etc. ６－１０ A preferred example of the "aryl" is phenyl. Specific examples of the fused ring structure include the groups shown below.

[0033] The term "6- to 10-membered heteroaryl" refers to a monocyclic or bicyclic aromatic heterocyclic group composed of 6 to 10 atoms, including 1 to 4 atoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms. The "6- to 10-membered heteroaryl" may be fused with the aforementioned "alicyclic group" or "non-aryl heterocycle" at any possible position. Preferred examples of the "6- to 10-membered heteroaryl" include "6-membered heteroaryl," more preferably pyridyl, pyrazinyl, pyrimidyl, and pyridazinyl, and even more preferably pyridyl and pyrimidyl. Specific examples of the "6-membered heteroaryl" include pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl. Specific examples of the "6- to 10-membered heteroaryl" include those exemplified above as specific examples of the "6-membered heteroaryl," as well as quinoxalyl, triazolopyridyl, and the like.

[0034] Specific examples of the "9- or 10-membered heteroaryl" include, but are not limited to, those with the structures shown below.

[0035] Specific examples of the "5-membered heteroaryl" include, but are not limited to, thiophene, pyrrole, thiazole, isothiazole, pyrazole, imidazole, furan, oxazole, isoxazole, oxadiazole, thiadiazole, triazole, tetrazole, etc., preferably pyrazole, imidazole, oxazole, triazole, tetrazole, or thiadiazole, more preferably imidazole or thiadiazole.

[0036] Specific examples of the "5- or 6-membered heteroaryl" include the specific examples of the "5-membered heteroaryl" and "6-membered heteroaryl" mentioned above. In addition, the "5- or 6-membered heteroaryl" or "5- to 10-membered heteroaryl" includes C ５－１０ It may form a condensed ring structure with an alicyclic group or a condensed ring structure with a 5- to 10-membered non-aryl heterocycle. Specific examples include the groups shown below.

[0037] The term "4- to 20-membered non-aryl heterocyclic group" refers to a monocyclic or bicyclic non-aromatic heterocyclic ring composed of 4 to 20 atoms, which contains, in addition to carbon atoms, 1 to 2 identical or different heteroatoms independently selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms, and includes those having a partially unsaturated bond, a partially bridged structure, and a partially spiro-substituted heterocyclic ring. The "4- to 20-membered non-aryl heterocyclic group" is preferably a "4- to 6-membered non-aryl heterocyclic group." Specific examples of the "4- to 6-membered non-aryl heterocyclic group" include azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl. Among these, azetidinyl, pyrrolidinyl, piperidyl, morpholinyl, and oxetanyl are preferred. The non-aryl heterocycle may form a fused ring with an aryl or heteroaryl. For example, C ６－１０ Non-aryl heterocycles also include those fused with an aryl or a 5- or 6-membered heteroaryl. Furthermore, the non-aryl heterocycle may contain one or more carbonyls, thiocarbonyls, sulfinyls, or sulfonyls. For example, cyclic groups such as lactams, thiolactams, lactones, thiolactones, cyclic imides, cyclic carbamates, and cyclic thiocarbamates are also included in the non-aryl heterocycle. Here, the oxygen atoms of the carbonyls, sulfinyls, and sulfonyls and the sulfur atoms of the thiocarbonyls are not included in the number of 4 to 20 members (ring size) and the number of heteroatoms constituting the ring. Specific examples of "4- to 20-membered non-aryl heterocycles" include, but are not limited to, azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, oxetane, tetrahydrofuran, tetrahydropyran, and the like, as well as those with the structures shown below.

[0038] Specific examples of the "4- to 20-membered non-aryl heterocycle" having a partial bridge and spiro structure include, but are not limited to, those having the structures shown below.

[0039] Specific examples of the "four-membered non-aryl heterocycle" having a partial unsaturated bond include, but are not limited to, those having the structures shown below.

[0040] Specific examples of the "five-membered non-aryl heterocycle" having a partial unsaturated bond include, but are not limited to, those having the structures shown below.

[0041] Specific examples of the "five-membered non-aryl heterocycle" having a partially bridged structure include, but are not limited to, those having the structures shown below.

[0042] Specific examples of the "5-membered non-aryl heterocycle" containing carbonyl, thiocarbonyl, etc. include, but are not limited to, those having the structures shown below.

[0043] Specific examples of the "six-membered non-aryl heterocycle" having a partial unsaturated bond include, but are not limited to, those having the structures shown below.

[0044] Specific examples of the "six-membered non-aryl heterocycle" having a partially bridged structure include, but are not limited to, those having the structures shown below.

[0045] "C １－６ Alkoxy" or "C １－６ "Alkoxy group" means "C １－６ "C alkyloxy" １－６ The "C alkyl" moiety is １－６ "C" is synonymous with "alkyl." １－６ The "alkoxy" is preferably "C １－４ Alkoxy" is preferred, and "C １－３ "Alkoxy" is an example. １－３Specific examples of "alkoxy" include methoxy, ethoxy, propoxy, 1-methylethoxy, etc. １－４ Specific examples of "alkoxy" include the above-mentioned "C １－３ In addition to the specific examples of "alkoxy", butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methylpropoxy, etc. are also included. １－６ Specific examples of "alkoxy" include the above-mentioned "C １－４ In addition to the specific examples of "alkoxy", pentyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, hexyloxy, and the like can be mentioned.

[0046] "C ３－６ Alicyclic oxy" or "C ３－６ The term "alicyclic oxy group" refers to a group having a structure such as (C ３－６ (alicyclic group)-O- group, ３－６ The alicyclic moiety is C ３－６ It has the same meaning as an alicyclic group. ３－６ The "alicyclic oxy group" is defined as "C ３－６ "Cycloalkoxy group" refers to "cycloalkyloxy", and the "cycloalkyl" portion has the same meaning as the above-mentioned "cycloalkyl". ３－６ Specific examples of the "alicyclic oxy group" include a cyclopropoxy group, a cyclobutoxy group, a cyclopentoxy group, and a cyclohexoxy group.

[0047] "C ６－１０ C of "aryloxy group" ６－１０ The aryl moiety is the C ６－１０ It is synonymous with aryl. ６－１０ As the "aryloxy group," preferably "C ６ Or C １０ "An aryloxy group of C" is an example. ６－１０ Specific examples of the "aryloxy group" include, but are not limited to, a phenoxy group, a 1-naphthyloxy group, and a 2-naphthyloxy group.

[0048] The 5- or 6-membered heteroaryl moiety of the "5- or 6-membered heteroaryloxy group" has the same meaning as the above "5-membered heteroaryl" or "6-membered heteroaryl." Specific examples of the "5- or 6-membered heteroaryloxy group" include, but are not limited to, a pyrazolyloxy group, a triazolyloxy group, a thiazoyloxy group, a thiadiazoyloxy group, a pyridyloxy group, and a pyridazoyloxy group.

[0049] The 4- to 10-membered non-aryl heterocyclic moiety of the "4- to 10-membered non-aryl heterocyclic oxy group" has the same meaning as the above-mentioned "4- to 10-membered non-aryl heterocyclic ring". The "4- to 10-membered non-aryl heterocyclic oxy group" is preferably a "4- to 6-membered non-aryl heterocyclic oxy group". Specific examples of the "4- to 10-membered non-aryl heterocyclic oxy group" include, but are not limited to, a tetrahydrofuranyloxy group, a tetrahydropyranyloxy group, an azetidinyloxy group, a pyrrolidinyloxy group, and a piperidinyloxy group.

[0050] "C １－６ C of "Alkylthio group" １－６ The alkyl portion is the C １－６ It is synonymous with alkyl. １－６ As the "alkylthio group," preferably "C １－４ alkylthio group," and more preferably "C １－３ "C is an alkylthio group." １－６ Specific examples of the "alkylthio group" include, but are not limited to, a methylthio group, an ethylthio group, a propylthio group, a butylthio group, an isopropylthio group, an isobutylthio group, a tert-butylthio group, a sec-butylthio group, an isopentylthio group, a neopentylthio group, a tert-pentylthio group, and a 1,2-dimethylpropylthio group.

[0051] "C ３－１０ Alicyclic thio" or "C ３－１０ The "alicyclic thio group" is defined as (C ３－１０ alicyclic group)-S- group, ３－１０ The alicyclic moiety is the C ３－１０ It has the same meaning as an alicyclic group.３－１０ The "alicyclic thio group" is preferably "C ３－６ "C is an alicyclic thio group." ３－６ Specific examples of the "alicyclic thio group" include, but are not limited to, a cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group, a cyclohexylthio group, and the like.

[0052] "C ６－１０ arylthio" or "C ６－１０ C of "arylthio group" ６－１０ The aryl moiety is the C ６－１０ It is synonymous with aryl. ６－１０ As the "arylthio group," preferably "C ６ Or C １０ "An arylthio group represented by the formula "C ６－１０ Specific examples of the "arylthio group" include, but are not limited to, a phenylthio group, a 1-naphthylthio group, and a 2-naphthylthio group.

[0053] The 5- or 6-membered heteroaryl moiety of the "5- or 6-membered heteroarylthio" or "5- or 6-membered heteroarylthio group" has the same meaning as the above "5-membered heteroaryl" or "6-membered heteroaryl." Specific examples of the "5- or 6-membered heteroarylthio group" include, but are not limited to, a pyrazoylthio group, a triazoylthio group, a thiazoylthio group, a thiadiazoylthio group, a pyridylthio group, and a pyridazoylthio group.

[0054] The 4- to 10-membered non-aryl heterocyclic moiety of the "4- to 10-membered non-aryl heterocyclic thio" or "4- to 10-membered non-aryl heterocyclic thio group" has the same meaning as the above-mentioned "4- to 10-membered non-aryl heterocyclic ring". The "4- to 10-membered non-aryl heterocyclic thio group" is preferably a "4- to 6-membered non-aryl heterocyclic thio group". Specific examples of the "4- to 10-membered non-aryl heterocyclic thio group" include, but are not limited to, a tetrahydropyranylthio group, a piperidinylthio group, and the like.

[0055] "C １－６ alkylcarbonyl" or "C １－６The term "alkylcarbonyl group" refers to the above-mentioned "C １－６ "C" means a carbonyl group substituted with an "alkyl group." １－６ As the "alkylcarbonyl group," preferably, "C １－４ "C is an alkylcarbonyl group." １－６ Specific examples of the "alkylcarbonyl group" include, but are not limited to, an acetyl group, a propionyl group, and a butyryl group.

[0056] "C ３－１０ Alicyclic carbonyl" or "C ３－１０ The term "alicyclic carbonyl group" refers to the above-mentioned "C ３－１０ "C" means a carbonyl group substituted with an "alicyclic group." ３－１０ As the "alicyclic carbonyl group," preferably, "C ３－６ "C is an alicyclic carbonyl group." ３－１０ Specific examples of the "alicyclic carbonyl group" include, but are not limited to, a cyclopropylcarbonyl group, a cyclopentylcarbonyl group, and the like.

[0057] "C ６－１０ arylcarbonyl" or "C ６－１０ The term "arylcarbonyl group" refers to the above-mentioned "C ６－１０ "C" means a carbonyl group substituted with "aryl." ６－１０ As the "arylcarbonyl group," preferably, "C ６ or C １０ "An arylcarbonyl group of C ６－１０ Specific examples of the "arylcarbonyl group" include, but are not limited to, a benzoyl group, a 1-naphthylcarbonyl group, a 2-naphthylcarbonyl group, and the like.

[0058] The term "5- or 6-membered heteroarylcarbonyl" or "5- or 6-membered heteroarylcarbonyl group" refers to a carbonyl group substituted with the above-mentioned "5- or 6-membered heteroaryl". Specific examples of the "5- or 6-membered heteroarylcarbonyl group" include, but are not limited to, a pyrazoylcarbonyl group, a triazoylcarbonyl group, a thiazoylcarbonyl group, a thiadiazoylcarbonyl group, a pyridylcarbonyl group, and a pyridazoylcarbonyl group.

[0059] The term "4- to 10-membered non-aryl heterocyclic carbonyl" or "4- to 10-membered non-aryl heterocyclic carbonyl group" refers to a carbonyl group substituted with the above-mentioned "4- to 10-membered non-aryl heterocycle". The "4- to 10-membered non-aryl heterocyclic carbonyl group" is preferably a "4- to 6-membered non-aryl heterocyclic carbonyl group". Specific examples of the "4- to 10-membered non-aryl heterocyclic carbonyl group" include, but are not limited to, an azetidinylcarbonyl group, a pyrrolidinylcarbonyl group, a piperidinylcarbonyl group, a morpholinylcarbonyl group, and the like.

[0060] "C １－６ alkylsulfonyl" or "C １－６ The term "alkylsulfonyl group" refers to the same group as defined above in "C １－６ "C" means a sulfonyl group substituted with an "alkyl group." １－６ As the "alkylsulfonyl group", preferably "C １－４ "C is an alkylsulfonyl group." １－６ Specific examples of the "alkylsulfonyl group" include, but are not limited to, a methylsulfonyl group, a propionylsulfonyl group, a butyrylsulfonyl group, and the like.

[0061] "C ３－１０ Alicyclic sulfonyl" or "C ３－１０ The term "alicyclic sulfonyl group" refers to the same group as defined above in "C ３－１０ "C" means a sulfonyl group substituted with an "alicyclic group." ３－１０ As the "alicyclic sulfonyl group", preferably "C ３－６ "C is an alicyclic sulfonyl group." ３－１０Specific examples of the "alicyclic sulfonyl group" include, but are not limited to, a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group, a cyclohexylsulfonyl group, and the like.

[0062] "C ６－１０ arylsulfonyl" or "C ６－１０ The term "arylsulfonyl group" refers to the same group as defined above in "C ６－１０ "C" means a sulfonyl group substituted with "aryl." ６－１０ As the "arylsulfonyl group", preferably "C ６ or C １０ "An arylsulfonyl group of C ６－１０ Specific examples of the "arylsulfonyl group" include, but are not limited to, a phenylsulfonyl group, a 1-naphthylsulfonyl group, a 2-naphthylsulfonyl group, and the like.

[0063] The term "5- or 6-membered heteroarylsulfonyl" or "5- or 6-membered heteroarylsulfonyl group" refers to a sulfonyl group substituted with the above-mentioned "5- or 6-membered heteroaryl". Specific examples of the "5- or 6-membered heteroarylsulfonyl group" include a pyrazoylsulfonyl group, a triazoylsulfonyl group, a thiazoylsulfonyl group, a thiadiazoylsulfonyl group, a pyridylsulfonyl group, and a pyridazoylsulfonyl group.

[0064] In the present disclosure, "optical purity is maintained" means that the optical purity does not change significantly when measured before and after the reaction described, and preferably the change is within 20% ee. When "optical purity is maintained," the change in optical purity is, for example, within 10% ee, within 5% ee, within 3% ee, within 1% ee, or within 0.5% ee.

[0065] (Preferred Embodiments) Preferred embodiments of the present disclosure will be described below. The embodiments provided below are provided for a better understanding of the present disclosure, and the scope of the present disclosure should not be limited to the following description. Therefore, it is clear that those skilled in the art can make appropriate modifications within the scope of the present disclosure in light of the description herein. In addition, the following embodiments of the present disclosure can be used alone or in combination.

[0066] In one embodiment of the present disclosure, a compound of formula I: 1. A method for preparing a compound of formula II: with an oxidizing agent; and contacting said solvent with a base to promote the reaction of the compound of formula II with the oxidizing agent, wherein R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , and R ９ are each independently a hydrogen atom, a halogen atom, or an optionally substituted C １－６ Alkyl, optionally substituted C １－６ Alkoxy, or —C(═O)NR Ａ R Ｂ represents R Ａ and R Ｂ are each independently a hydrogen atom, an optionally substituted C １－６ Alkyl or optionally substituted C １－６ A method is provided in which:

[0067] In this disclosure, R １ is a hydrogen atom or an optionally substituted C １－６ It can be alkyl.

[0068] In this disclosure, R １ may be methyl.

[0069] In this disclosure, R ２ is a hydrogen atom or an optionally substituted C １－６It can be alkyl.

[0070] In this disclosure, R ２ may be methyl.

[0071] In this disclosure, R ３ is a hydrogen atom or an optionally substituted C １－６ It can be alkyl.

[0072] In this disclosure, R ３ may be methyl.

[0073] In this disclosure, R ４ is a hydrogen atom or an optionally substituted C １－６ It can be alkyl.

[0074] In this disclosure, R ４ can be a hydrogen atom.

[0075] In this disclosure, R ５ is a hydrogen atom or an optionally substituted C １－６ It can be alkyl.

[0076] In this disclosure, R ５ can be a hydrogen atom.

[0077] In this disclosure, R ６ is a hydrogen atom or an optionally substituted C １－６ It can be alkyl.

[0078] In this disclosure, R ６ can be a hydrogen atom.

[0079] In this disclosure, R ７ is a hydrogen atom or an optionally substituted C １－６ It can be alkyl.

[0080] In this disclosure, R ７ can be a hydrogen atom.

[0081] In this disclosure, R ８ is a hydrogen atom, an optionally substituted C １－６ Alkyl, or —C(═O)NR Ａ R Ｂ It could be.

[0082] In this disclosure, R ８ is -C(=O)NR Ａ R Ｂ It could be.

[0083] In this disclosure, R ９ is a hydrogen atom or an optionally substituted C １－６ It can be alkyl.

[0084] In this disclosure, R ９ may be methyl.

[0085] In this disclosure, R Ａ and R Ｂ may each represent a hydrogen atom.

[0086] In the present disclosure, the solvent may be an aprotic polar solvent.

[0087] In the present disclosure, the solvent may be a protic polar solvent.

[0088] 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-tertiary butyl ether, cyclopentyl methyl ether, methanol, ethanol, 2-propanol, 4-methyltetrahydropyran, acetonitrile, N-methylpyrrolidone, and dimethyl sulfoxide.

[0089] In the present disclosure, the solvent may be dimethyl sulfoxide.

[0090] In the present disclosure, the oxidizing agent may include a compound containing iron.

[0091] In the present disclosure, the oxidizing agent may be iron (III) chloride or iron (III) nitrate.

[0092] In the present disclosure, the oxidizing agent may be iron (III) chloride hexahydrate.

[0093] 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.

[0094] 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.

[0095] In the present disclosure, the base may be sodium hydroxide.

[0096] In the present disclosure, the step of contacting the oxidizing agent may be carried out in a flow reactor.

[0097] In the present disclosure, in the step of contacting the oxidizing agent, the inner diameter of the flow reactor may be about 0.1 mm to about 100 mm.In the step of bringing the oxidizing agent into contact, 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, 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, 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, about 95 mm or more, and 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, 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, about 0.2 mm or less.Preferably, the thickness is 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, even more preferably about 0.5 mm or more and about 10 mm or less, and particularly preferably about 1.0 mm or more and about 10 mm or less.

[0098] In the present disclosure, the residence time in the step of contacting the oxidizing agent may be 60 seconds or less, 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.

[0099] In the present disclosure, the residence time in the step of contacting the oxidizing agent may be 0.1 seconds to 10 seconds. The residence time in the step of contacting the oxidizing agent may be 0.1 seconds to 5 seconds.

[0100] In the present disclosure, the step of contacting with an oxidizing agent may be carried out at a temperature of 0° C. to 100° C. The step of contacting with an oxidizing agent may be carried out at a temperature of 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, and at a temperature of 100° C. or lower, 95° C. or lower, 90° C. or lower, 85° C. or lower, 80° C. or lower, 75° C. or lower, 70° C. or lower, 65° C. or lower, 60° C. or lower, 55° C. or lower, 50° C. or lower, 45° C. or lower, 40° C. or lower, 35° C. or lower, 30° C. or lower, 25° C. or lower, 20° C. or lower, 15° C. or lower, 10° C. or lower, or 5° C. or lower. Preferably, the temperature is 30°C or higher and 100°C or lower, more preferably 65°C or higher and 95°C or lower, and even more preferably 60°C or higher and 90°C or lower.

[0101] In the present disclosure, the step of contacting the oxidizing agent may be carried out at a temperature of 75°C or higher.

[0102] In the present disclosure, the step of contacting the base may be carried out after the step of contacting the oxidizing agent.

[0103] In the present disclosure, the step of contacting a base may be carried out by contacting a base with the reaction mixture produced by the step of contacting an oxidizing agent.

[0104] In the present disclosure, the oxidizing agent may be present in the solvent in the step of contacting the base.

[0105] In the present disclosure, the step of contacting the base may be carried out in a flow reactor.

[0106] In the present disclosure, in the step of contacting a base, the inner diameter of the flow reactor may be from about 0.1 mm to about 100 mm.In the step of contacting the base, the inner diameter of the flow reactor can 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, 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, 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, about 95 mm or more, and 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 六十八十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, 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, about 0.2 mm or less.Preferably, the thickness is 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, even more preferably about 0.5 mm or more and about 10 mm or less, and particularly preferably about 1.0 mm or more and about 10 mm or less.

[0107] In the present disclosure, the residence time in the step of contacting the base may be 60 seconds or less, 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.

[0108] In the present disclosure, the residence time in the step of contacting a base may be 0.1 seconds to 10 seconds. The residence time in the step of contacting a base may be 0.1 seconds to 5 seconds.

[0109] In the present disclosure, the step of contacting with a base may be carried out at a temperature of 0° C. to 100° C. The step of contacting with a base may be carried out at a temperature of 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, and at a temperature of 100° C. or lower, 95° C. or lower, 90° C. or lower, 85° C. or lower, 80° C. or lower, 75° C. or lower, 70° C. or lower, 65° C. or lower, 60° C. or lower, 55° C. or lower, 50° C. or lower, 45° C. or lower, 40° C. or lower, 35° C. or lower, 30° C. or lower, 25° C. or lower, 20° C. or lower, 15° C. or lower, 10° C. or lower, or 5° C. or lower. Preferably, the temperature is 30°C or higher and 100°C or lower, more preferably 65°C or higher and 95°C or lower, and even more preferably 60°C or higher and 90°C or lower.

[0110] In the present disclosure, the step of contacting the oxidizing agent may be carried out at a temperature of 75°C or higher.

[0111] In the present disclosure, in the compound of formula I, R ８ , R ９ and the carbon atom to which OH is attached may be an asymmetric carbon.

[0112] In the present disclosure, the compound of formula II may be an optically active substance, and the optical purity may be maintained in the reaction of the compound of formula II with an oxidizing agent.

[0113] In the present disclosure, the compound of formula I is wherein the compound of formula II is It could be.

[0114] In the present disclosure, the compound of formula II is represented by formula III: The compound of formula III can be prepared by optical resolution and amidation. The optical resolution of the compound of formula III can be carried out by the method described in WO2021 / 167095.

[0115] In the present disclosure, the compound of Formula I is prepared by contacting a compound of Formula II with an oxidizing agent. The method of the present disclosure includes contacting the compound of Formula II with a base to promote the reaction between the compound of Formula II and the oxidizing agent.

[0116] In one embodiment of the present disclosure, the oxidizing agent may include an iron-containing compound. When iron(III) chloride was used as the oxidizing agent, the reaction endpoint was not reached with a single addition of reagents. Adding a base, however, dramatically improved the reaction rate. However, the addition of a base was found to generate and precipitate iron(III) hydroxide, posing a risk of reaction delay. If hydroxide ions in the system react with iron(III) chloride to form iron hydroxide and precipitate, the reaction endpoint will not be reached (risk of reaction delay when adding a base). Iron(III) hydroxide is poorly soluble in water or solvents, and once precipitated, it is difficult to remove. To more efficiently proceed with the reaction, it is preferable to strictly control the order and timing of base addition.

[0117] In one embodiment of the present disclosure, the preparation of compounds of formula I may be carried out by flow synthesis.

[0118] Flow synthesis (also known as flow chemistry) is a synthesis and manufacturing technology in which chemical reactions occur in a "flow." Batch reactions are not suitable for the use of unstable raw materials or intermediates, and are also not suitable for dangerous reactions, so scale-up considerations are essential. In contrast, flow synthesis allows for optimal reaction times, allows precise input volume management, and can provide an efficient reaction space. By connecting equipment and increasing or decreasing the number of flow manufacturing equipment, it is possible to accommodate a variety of reactions. The reaction space can be easily designed by combining manufacturing equipment modules.

[0119] In the method of the present disclosure, the application of flow synthesis technology enables reactions to be carried out accurately and reproducibly at the appropriate time.

[0120] In one embodiment of the present disclosure, the compound of Formula I is produced by an oxidation reaction using iron(III) chloride in a flow reactor. Flow reactor reactions eliminate the need for liquid separation, which is required in batch reactions. It has been difficult to faithfully reproduce the process achieved by flow synthesis in a batch reactor. Scale-up of batch reactions is difficult due to mixing difficulties. When iron(III) chloride is used instead of iron nitrate, nitrosamines are not produced due to the reaction mechanism. The high-speed mixing and precise flow rate control of flow synthesis technology have successfully increased reaction efficiency and simplified post-processing. The method of the present disclosure has been successfully used to produce 10 kg scale products.

[0121] 1 shows a schematic diagram of an example of the disclosed method by flow synthesis, in which compound 2 ((R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide) and an aqueous solution of iron (III) chloride are mixed in a T-shaped mixer, the reaction proceeds in a tubular reactor, and the mixture is mixed with an aqueous solution of sodium hydroxide in another T-shaped mixer to obtain compound 1 ((R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide).

[0122] In the absence of base, the following equilibrium reaction is thought to occur: In the presence of a base, the generated hydrochloric acid is trapped, accelerating the reaction to the right, leading to the following reaction: Compound 2 + 2FeCl ３ +H ２ O+2NaOH→Compound 1+2FeCl ２ + 2NaCl + 2H ２ O

[0123] To simplify the description in the specification, the following abbreviations may be used in the examples and tables therein: PEA: 1-phenylethylamine EtOAc: ethyl acetate i PrOAc: Isopropyl acetate NMP: N-methylpyrrolidone DMA: Dimethylacetamide DMF: N,N-dimethylformamide MTBE: Methyl tertiary butyl ether DME: 1,2-dimethoxyethane 2-MeTHF: 2-methyltetrahydrofuran MEK: Methyl ethyl ketone DMSO: Dimethyl sulfoxide CDCl ３ : Deuterated chloroform MeOH: Methanol MeCN: Acetonitrile IPA: 2-propanol CPME: Cyclopentyl methyl ether Troloxamide: (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide As for the symbols used in NMR, δ means a chemical shift value, s means a singlet, d means a doublet, t means a triplet, q means a quartet, m means a multiplet, and J means a spin coupling constant.

[0124] The HPLC (high performance liquid chromatograph) analysis was carried out under the following analytical conditions.

[0125] (Reagents and test solutions) Acetonitrile: liquid chromatography grade (Fujifilm Wako Pure Chemical Industries, Ltd.) or equivalent Trifluoroacetic acid: special grade (Fujifilm Wako Pure Chemical Industries, Ltd.) or equivalent Water: water prepared for testing using an ultrapure water production device, etc.

[0126] (Dissolution solvent) Acetonitrile

[0127] (Mobile phase) Mobile phase A: Water / trifluoroacetic acid mixture (2000:1) <Preparation example> Mix 2000 mL of water and 1 mL of trifluoroacetic acid, and degas using an ultrasonic cleaner. Mobile phase B: Acetonitrile / trifluoroacetic acid mixture (2500:1) <Preparation example> Mix 2500 mL of acetonitrile and 1 mL of trifluoroacetic acid, and degas using an ultrasonic cleaner.

[0128] (Syringe cleaning solution) Acetonitrile

[0129] 1. Equipment and setting conditions 1.1 Equipment High-performance liquid chromatograph: Shimadzu Corporation UFLCXR type or equivalent Electronic balance: Mettler Toledo XP205DRV type or equivalent Ultrapure water production system: Merck Milli-Q Advantage A10 type or equivalent Ultrasonic cleaner: AS ONE US-4R type or equivalent

[0130] 1.2 Liquid chromatography setup conditions Detector: Ultraviolet absorption photometer (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 octadecylsilylated silica gel for liquid chromatography with a particle size of 3.5 μm [Agilent Zorbax SB C18 or equivalent] Column temperature: A constant temperature around 35°C Mobile phase A: Water / trifluoroacetic acid mixture (2000:1) Mobile phase B: Acetonitrile / trifluoroacetic acid mixture (2500:1) Mobile phase delivery: The concentration gradient is controlled by changing the mixing ratio of mobile phase A and mobile phase B as follows:

[0131] Flow rate: 1.0 mL per minute Area measurement range: 33 minutes after injection of sample solution (data collection time is 40 minutes) Injection volume: 5 μL Sample cooler temperature: constant temperature around 25°C Mixer capacity: 0.5 mL Syringe cleaning solution: acetonitrile Sample concentration: 2.5 μg / mL to 0.5 mg / mL

[0132] <Example of waveform processing parameter settings> Minimum area: 5000 μV*sec Minimum height: 100 μV Detection sensitivity: 50 μV / sec Peak width: 1 sec Output intensity range: -500 to 1000 mAU Output time range: 0 to 33 minutes

[0133] Example 1: Elucidation of the reaction mechanism of oxidation reaction using iron(III) chloride (3) To a solution (2 mL) of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (200 mg, 0.802 mmol) in isopropyl acetate, 4.2 equivalents of iron(III) chloride hexahydrate (910 mg, 3.37 mol) were added at 30° C. or below, followed by the addition of 2.1 equivalents of sodium hydroxide (67.4 mg, 1.69 mmol). After stirring for 1 hour, the disappearance of the raw materials was confirmed, and it was found that 0.2% of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide remained.

[0134] Example 2: Elucidation of the reaction mechanism of the oxidation reaction using iron(III) chloride (4) To a solution (2 mL) of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (200 mg, 0.802 mmol) in isopropyl acetate, 4.2 equivalents of iron(III) chloride hexahydrate (910 mg, 3.37 mol) were added at 30° C. or below, followed by the addition of 2.1 equivalents of a base (1.69 mmol). After stirring for 1 hour, the degree of disappearance of the raw materials was confirmed, and the remaining amount of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide was found to be 0.2% or less.

[0135] Example 3 Investigation of the Solubility of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide The solubility of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide was investigated.

[0136] Of the above solvents, THF showed the highest solubility at 20° C. Considering the safety of the solvent used in the oxidation reaction, it was decided to use the safer DMSO as the solvent for the subsequent oxidation reaction.

[0137] Example 4 Oxidation Reaction of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide with Aqueous Iron(III) Chloride Solution in DMSO as Solvent in a Batch Reactor To a DMSO solution (10 mL) of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (1 g, 4.01 mmol), 4.2 equivalents of iron(III) chloride hexahydrate (4.0 mol / L, 4.21 mL, 16.84 mmol) were added at 30° C. or lower, and 4.0 equivalents of aqueous sodium hydroxide solution (5.0 mol / L, 3.21 mL, 16.05 mmol) was added, followed by vigorously stirring. After stirring for 1 hour, the degree of disappearance of the raw materials was confirmed. It was found that (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide had disappeared 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.

[0138] However, this method has the risk of solidifying completely in the flask if strong stirring is not performed, making stirring difficult and resulting in a high risk of subsequent difficulty in removal. For this reason, it is desirable to adopt a method in which the reaction is completed using a flow-type reactor.

[0139] Example 5 Oxidation Reaction of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide with Aqueous Iron(III) Chloride Solution in a Flow Reactor Using DMSO as a Solvent A 0.5 mol / L DMSO solution of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide was prepared (Reaction Solution A). A 4.0 mol / L aqueous solution of iron(III) chloride was prepared (Reaction Solution B). A 5.0 mol / L aqueous solution of sodium hydroxide was prepared (Reaction Solution C). Using a tube with an inner diameter of 1.0 mm, Reaction Solution A was delivered at a flow rate of 10 mL per minute and Reaction Solution B was delivered at a flow rate of 5.25 mL per minute, and the mixture was mixed in a T-shaped mixer (Mixer 1) with an inner diameter of 1.0 mm. After passing through Mixer 1, the reaction mixture was mixed with reaction mixture C, which had been delivered in the same manner, in a second T-shaped mixer (1.0 mm inner diameter, Mixer 2) using a 1.0 mm inner diameter tube. The residence time between Mixer 1 and Mixer 2 was set to any time between 0.1 and 10 seconds. The reaction mixture discharged via Mixer 2 was discharged from the flow reactor system using a 1.0 mm inner diameter tube and sampled. Mixers 1 and 2 and the connecting tubes were submerged in a 75°C warm bath while being heated. It was confirmed that the residual rate of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide was 2% or less, and that the desired product, (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide, was produced in a 91% yield.

[0140] Example 6 Oxidation Reaction of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide with Aqueous Iron(III) Chloride Solution in a Flow Reactor Using DMSO as a Solvent and Isolation of the Product A 0.5 mol / L DMSO solution of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide was prepared (Reaction Solution A). A 4.0 mol / L aqueous solution of iron(III) chloride was prepared (Reaction Solution B). A 5.0 mol / L aqueous solution of sodium hydroxide was prepared (Reaction Solution C). Using a tube with an inner diameter of 1.0 mm, Reaction Solution A was delivered at a flow rate of 10 mL per minute and Reaction Solution B was delivered at a flow rate of 5.25 mL per minute, and the mixture was mixed in a T-shaped mixer (Mixer 1) with an inner diameter of 1.0 mm. After passing through Mixer 1, the reaction mixture was mixed with reaction mixture C, which had been delivered in the same manner, in a second T-shaped mixer (1.0 mm inner diameter, Mixer 2) using a 1.0 mm inner diameter tube. The residence time between Mixer 1 and Mixer 2 was set to any time between 0.1 and 10 seconds. The reaction mixture discharged via Mixer 2 was discharged from the flow reactor system using a 1.0 mm inner diameter tube and sampled. Mixers 1 and 2 and the connecting tubes were submerged in a 75°C warm bath while being heated. It was confirmed that the residual rate of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide was 2% or less, and that the desired product, (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide, was produced in a 91% yield. The reaction liquid discharged from the flow reactor was collected in a receiver temperature-controlled at 40°C for 18 minutes and 3 seconds, and 90 g of 1 mol / L aqueous hydrochloric acid was added dropwise. The mixture was then cooled to 20°C, and 18 g of concentrated hydrochloric acid was added dropwise. It was confirmed that the pH was 0.5 or less. An additional 90 g of water was then added dropwise, and the resulting crystals were filtered. The wet crystals were washed twice with 67.5 g of 1 mol / L aqueous hydrochloric acid and then three times with 45 g of water. The crystals were dried in a vacuum dryer heated to 60°C, yielding 20.35 g of (R)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide.

[0141] Comparative Example 1 Elucidation of the reaction mechanism of the oxidation reaction using iron(III) chloride (1) To a solution (2 mL) of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (200 mg, 0.802 mmol) in isopropyl acetate, 2.1 equivalents of iron(III) chloride hexahydrate (455 mg, 1.69 mol) was added at 30°C or lower. After stirring for 1 hour, the degree of disappearance of the raw material was confirmed, and it was found that 73% of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide remained.

[0142] Comparative Example 2 Elucidation of the Reaction Mechanism of the Oxidation Reaction Using Iron(III) Chloride (2) To a solution (2 mL) of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (200 mg, 0.802 mmol) in isopropyl acetate, 4.2 equivalents of iron(III) chloride hexahydrate (910 mg, 3.37 mol) was added at 30°C or lower, and the mixture was stirred for 1 hour. The degree of disappearance of the raw material was then confirmed, revealing that 21% of (R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide remained.

[0143] As described above, the present disclosure has been illustrated using preferred embodiments thereof, but it is understood that the scope of the present disclosure should be interpreted solely by the scope of the claims. It is understood that the patents, patent applications, and other documents cited in this specification are incorporated by reference into this specification in their entirety as if the contents themselves were specifically set forth herein. This application claims priority to Japanese Patent Application No. 2022-158569, filed with the Japan Patent Office on September 30, 2022, the entire contents of which are incorporated herein by reference.

[0144] The present disclosure is useful in the manufacture of pharmaceuticals.

Claims

1. Formula I: 【Chemistry 1】 A method for producing the compound, In the solvent, formula II: 【Chemistry 2】 The process of contacting the compound with an oxidizing agent, and The process includes a step of contacting the solvent with a base in order to promote the reaction between the compound of formula II and the oxidizing agent, During the ceremony, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , R ８ , and R ９ each independently represent a hydrogen atom, halogen, optionally substituted C １－６ alkyl, optionally substituted C １－６ alkoxy, or -C(=O)NR Ａ R Ｂ , R Ａ and R Ｂ Each of these independently consists of a hydrogen atom and a C atom which may be substituted. １－６ Alkyl or optionally substituted C １－６ Representing alkoxy, method.

2. (a) R １ However, hydrogen atoms, or C which may be substituted １－６ Alkyl; and / or (b) R2 is a hydrogen atom or an optionally substituted C1-6 alkyl group; and / or (c) R3 is a hydrogen atom or an optionally substituted C1-6 alkyl group; and / or (d) R4 is a hydrogen atom or an optionally substituted C1-6 alkyl group; and / or (e) R5 is a hydrogen atom or an optionally substituted C1-6 alkyl group; and / or (f) R6 is a hydrogen atom or an optionally substituted C1-6 alkyl group; and / or (g) R7 is a hydrogen atom or an optionally substituted C1-6 alkyl group; and / or (h) R8 is a hydrogen atom, an optionally substituted C1-6 alkyl, or -C(=O)NR A R B; and / or (i) R9 is a hydrogen atom or an optionally substituted C1-6 alkyl group; The method according to claim 1.

3. (a) R1 is methyl; and / or (b) R2 is methyl; and / or (c) R3 is methyl; and / or (d) R4 is a hydrogen atom; and / or (e) R5 is a hydrogen atom; and / or (f) R 6 is a hydrogen atom; and / or (g) R7 is a hydrogen atom; and / or (h) R 8 is -C(=O)NR A R B; and / or (i) R9 is methyl; The method according to claim 1.

4. R Ａ and R Ｂ The method according to claim 1, wherein each of the terms represents a hydrogen atom.

5. (a) The solvent is an aprotic polar solvent; or (b) The solvent is a protic polar solvent; or (c) The solvent is selected from the group consisting of isopropyl acetate, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, toluene, anisole, methyl tert-butyl ether, cyclopentyl methyl ether, methanol, ethanol, 2-propanol, 4-methyltetrahydropyran, acetonitrile, N-methylpyrrolidone, and dimethyl sulfoxide; or (d) The solvent is dimethyl sulfoxide; The method according to claim 1.

6. (a) The oxidizing agent comprises a compound containing iron; or (b) The oxidizing agent is iron(III) chloride or iron(III) nitrate; or (c) The oxidizing agent is iron(III) chloride hexahydrate; The method according to claim 1.

7. (a) 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; or (b) The base is selected from the group consisting of sodium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, and aqueous ammonia; or (c) The base is sodium hydroxide; The method according to claim 1.

8. The step of contacting the oxidizing agent is performed in a flow reactor. Optionally, here (a) In the step of contacting the oxidizing agent, the inner diameter of the flow reactor is approximately 0.1 mm to approximately 100 mm; and / or (b) The residence time in the step of contacting the oxidizing agent is 60 seconds or less, preferably 0.1 seconds to 10 seconds; The method according to claim 1.

9. (a) The step of contacting the oxidizing agent is carried out at a temperature of 0°C to 100°C; or (b) The step of contacting the oxidizing agent is carried out at a temperature of 75°C or higher; or (c) The step of contacting the oxidizing agent is carried out at a temperature of 60°C to 90°C; The method according to claim 1.

10. The method according to claim 1, wherein the step of contacting the base is performed after the step of contacting the oxidizing agent.

11. (a) The step of contacting the base is carried out by contacting the reaction mixture produced by the step of contacting the oxidizing agent with the base; and / or (b) In the step of contacting the base, the oxidizing agent is present in the solvent; The method according to claim 1.

12. The step of contacting the aforementioned base is performed in a flow reactor. Optionally, here (a) In the step of contacting the base, the inner diameter of the flow reactor is approximately 0.1 mm to approximately 100 mm; and / or (b) The residence time in the step of contacting the base is 60 seconds or less, preferably 0.1 seconds to 10 seconds; The method according to claim 1.

13. (a) The step of contacting the base is carried out at a temperature of 0°C to 100°C; or (b) The step of contacting the base is carried out at a temperature of 60°C to 90°C; or (c) The step of contacting the oxidizing agent is carried out at a temperature of 75°C or higher; The method according to claim 1.

14. In the compound of formula I, R ８ , R ９ The carbon atom to which the OH group is bonded is an asymmetric carbon, and optionally, the compound of formula II is an optically active compound, and optical purity is maintained in the reaction between the compound of formula II and the oxidizing agent. The method according to claim 1.

15. The compound of formula I is 【Transformation 3】 The compound of formula II is, 【Chemistry 4】 And optionally, here, the compound of formula II is formula III: 【Transformation 5】 The compound is produced by a process of optical resolution and amidation. The method according to claim 1.

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