Method for producing deoxynyboquinone derivative

Abstract

The present invention is a method for producing a deoxynyboquinone (DNQ) derivative, the method being characterized by performing a step for performing amidation and deprotection after a step for isolating a synthetic intermediate represented by general formula by crystallization, followed by performing a step for constructing a 2-pyridone ring by an acid treatment, a DNQ derivative obtained by the production method, and the intermediate. This production method makes it possible to produce a DNQ derivative with high yield and high purity via the intermediate that can be crystallized.

Description

Method for producing deoxynivoquinone derivatives

[0001] The present invention relates to a method for producing deoxynivalenone (DNQ) derivatives and synthetic intermediates.

[0002] NAD(P)H quinone oxidoreductase (NQO1) has been shown to be frequently expressed at much higher levels in lung cancer than in adjacent healthy tissues, and has attracted attention as a target for cancer therapy.

[0003] DNQ derivatives are known to be activated by NQO1 and to have pharmacological activities such as antitumor activity (see Patent Document 1 and Non-Patent Document 1).

[0004] Methods for producing DNQ derivatives are described in Patent Document 1, Non-Patent Document 1, and Non-Patent Document 2. For example, Patent Document 1 and Non-Patent Document 1 describe a method for producing isobutyldeoxyniboquinone (IB-DNQ) as shown in the following scheme. This method involves asymmetric coupling of a bisboronic acid ester with two types of iodoamide, followed by intramolecular cyclization using a palladium catalyst to construct a tricyclic skeleton, followed by deprotection of the protecting group of the phenolic hydroxyl group by acid treatment, followed by oxidation using a cobalt catalyst. The total yield of the final product, IB-DNQ, was 9%.

[0005]

[0006] Non-Patent Document 2 does not describe a method for producing IB-DNQ, but does disclose a method for producing a DNQ derivative by simultaneously constructing 2-pyridone rings at two reactive sites by acid treatment (see the scheme below).

[0007]

[0008] US Patent Application Publication No. 2015 / 0011509

[0009] Paul J. Hergenrother et al, Efficient NQO1 Substrates are Potent and Selective Anticancer Agents, ACS Chem. Biol. 2013, 8, 10, 2173-2183.Allan M. Prior and Dianqing Sun, Total synthesis of diazaquinomycins H and J using double Knorr cyclization in the presence of triisopropylsilane, RSC Adv. 2019, 9, 1759-1771.

[0010] In a method for producing IB-DNQ, which involves asymmetric coupling of a bisboronic acid ester with two types of iodoamides, followed by intramolecular cyclization using a palladium catalyst to construct a tricyclic skeleton, deprotection of the phenolic hydroxyl protecting group by acid treatment, and subsequent oxidation using a cobalt catalyst, the asymmetric coupling of the bisboronic acid ester with two types of iodoamides produces a homo-coupled product as a by-product in addition to the desired hetero-coupled product, necessitating purification by silica gel column chromatography and resulting in a low yield. As a result, the overall yield of IB-DNQ using this method is low (total yield of 9%).

[0011] Furthermore, we attempted to produce IB-DNQ by a method for producing a DNQ derivative by simultaneously constructing 2-pyridone rings at two reactive sites by acid treatment. As shown in the following scheme, by utilizing the reaction for constructing 2-pyridone rings at two sites by acid treatment, we were able to produce the above IB-DNQ in high yield without purification by silica gel column chromatography. However, we discovered a new problem: the purity of IB-DNQ was low.

[0012]

[0013] Therefore, an object of the present invention is to provide a method for producing a DNQ derivative, particularly a DNQ derivative such as IB-DNQ, in which one nitrogen atom of the 2-pyridone skeleton is substituted with a hydrogen atom and the other nitrogen atom of the 2-pyridone skeleton is substituted with an alkyl group, in high yield and with high purity, a DNQ derivative obtained by the production method, and a crystallizable synthetic intermediate.

[0014] As a result of intensive research to solve the above problems, the present inventors have found that a novel compound represented by formula (II) described below, which is obtained by stepwise construction of 2-pyridone rings at two positions by acid treatment, can be crystallized and purified with high efficiency. Furthermore, the present inventors have found that by using the compound represented by formula (II) obtained by the crystallization as a synthetic intermediate, a compound represented by formula (III) described below can be obtained in high yield and with high purity, thereby completing the present invention.

[0015] That is, the present invention provides: (1) a compound represented by formula (III):

[0016]

[0017] [In the formula, R ２ , R ３ , R ４ , R ５ and R ６ and each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.] A method for producing a compound represented by formula (I):

[0018]

[0019] [In the formula, R １ is a methyl group, a methoxymethyl group, a tert-butyl group, or an acetyl group, and R ２ , R ３ and R ５ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.

[0020]

[0021] [In the formula, R １ is a methyl group, a methoxymethyl group, a tert-butyl group, or an acetyl group, and R２ , R ３ and R ５ and each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.], a step (B) of isolating the compound represented by formula (II) obtained in the step (A) by crystallization, amidating the compound represented by formula (II) isolated in the step (B) with a compound represented by the following formula (IV), formula (V) or formula (VI), and １ Step (C) of deprotecting a compound of formula (IV):

[0022]

[0023] [In the formula, R ４ and R ６ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, and X is OR ８ , a halogen atom, an acyloxy group, a sulfonyloxy group, a phosphoryloxy group, or a hydroxy group, and R ７ and R ８ are the same or different and are a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, or R ７ and R ８ and together form a lower alkylene group.] Formula (V):

[0024]

[0025] [In the formula, R ６ is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, and R 9 is a linear or branched alkylidene group having 1 to 6 carbon atoms.] Formula (VI):

[0026]

[0027] [In the formula, R ４is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.] and step (D) of synthesizing the compound represented by formula (III) by treating the compound obtained in step (C) with an acid to newly construct a 2-pyridone ring. (2) The method according to (1), wherein step (A) comprises step (A1) of reducing the nitro group of the compound represented by formula (I). (3) The method according to (2), wherein step (A) comprises step (A2) of treating the compound obtained in step (A1) with an acid to construct a 2-pyridone ring, thereby obtaining the compound represented by formula (II). (4) R １ , R ３ and R ４ is a methyl group, and R ５ and R ６ is a hydrogen atom, and R ２ is CH ２ CH ３ , C.H. ２ CH ２ CH ３ , C.H. ２ CH (CH ３ ) ２ or (CH ２ ) ２ CH (CH ３ ) ２ (5) The method according to any one of (1) to (3), wherein the step (C) comprises a step (C1) of amidating the compound represented by formula (II) obtained in the step (B) with a compound represented by formula (IV), formula (V), or formula (VI), and １ (6) The method according to any one of (1) to (4), comprising a step (C2) of deprotecting a compound of formula (II):

[0028]

[0029] [In the formula, R １ is a methyl group, a methoxymethyl group, a tert-butyl group, or an acetyl group, and R ２ , R ３ and R ５ and each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.] A method for producing a compound represented by formula (I):

[0030]

[0031] [In the formula, R １ is a methyl group, a methoxymethyl group, a tert-butyl group, or an acetyl group, and R ２ , R ３ and R ５ and each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.], a step (A2') of treating the compound obtained in the step (A1') with an acid to form a 2-pyridone ring, thereby obtaining the compound represented by formula (II), and a step (B') of isolating the compound represented by formula (II) obtained in the step (A2') by crystallization.

[0032]

[0033] [In the formula, R ２ , R ３ , R ４ , R ５ and R ６ and each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.]

[0034]

[0035] [In the formula, R １ is a methyl group, a methoxymethyl group, a tert-butyl group, or an acetyl group, and R ２ , R ３ and R ５ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.

[0036]

[0037] [In the formula, R １ is a methyl group, a methoxymethyl group, a tert-butyl group, or an acetyl group, and R ２ , R ３ and R ５and each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.], a step (B) of isolating the compound represented by formula (II) obtained in the step (A) by crystallization, amidating the compound represented by formula (II) isolated in the step (B) with a compound represented by the following formula (IV), formula (V) or formula (VI), and １ Step (C) of deprotecting a compound of formula (IV):

[0038]

[0039] [In the formula, R ４ and R ６ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, and X is OR ８ , a halogen atom, an acyloxy group, a sulfonyloxy group, a phosphoryloxy group, or a hydroxy group, and R ７ and R ８ are the same or different and are a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, or R ７ and R ８ and together form a lower alkylene group.] Formula (V):

[0040]

[0041] [In the formula, R ６ is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, and R 9 is a linear or branched alkylidene group having 1 to 6 carbon atoms.] Formula (VI):

[0042]

[0043] [In the formula, R ４ is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.] and a step (D) of treating the compound obtained in the step (C) with an acid to newly construct a 2-pyridone ring, thereby synthesizing a compound represented by the formula (III). (8) A compound of formula (II):

[0044]

[0045] [In the formula, R １ is a methyl group, a methoxymethyl group, a tert-butyl group, or an acetyl group, and R ２ , R ３ and R ５ and each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.

[0046] According to the present invention, a compound represented by formula (III) can be produced in high yield and high purity. Furthermore, a compound represented by formula (II), which is a synthetic intermediate of the compound represented by formula (III), can be produced. Furthermore, the synthetic intermediate represented by formula (II) obtained according to the present invention is a novel compound that can be crystallized. By undergoing crystallization of the synthetic intermediate in the synthesis of the compound represented by formula (III), both high yield and high purity can be achieved.

[0047] An embodiment of the present invention will be described below.

[0048] The method of the present invention comprises reacting a compound of formula (III):

[0049]

[0050] [In the formula, R ２ , R ３ , R ４ , R ５ and R ６ and each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.], which includes steps (A) to (D) described below.

[0051] In the present invention, a halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0052] [Compound represented by formula (I)] In the present invention, a compound represented by formula (I):

[0053]

[0054] [In the formula, R １ is a methyl group, a methoxymethyl group, a tert-butyl group, or an acetyl group, and R ２ , R ３ and R ５are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.] is a compound that can be converted into a compound represented by formula (II) by a chemical conversion step.

[0055] The method for obtaining the compound represented by formula (I) is not particularly limited. For example, 2,5-dimethoxy-3-nitroaniline can be used as a starting material and subjected to reductive amination to obtain R ２ The resulting secondary amino group is amidated with an amidating reagent to form R ３ and R ５ For example, a method for introducing a moiety containing R ２ As an example of a method for introducing a substituent corresponding to R ２ When R is an isobutyl group, a method of reacting isobutylaldehyde with sodium triacetoxyborohydride can be used. ２ When is an n-propyl group, a method of reacting propionaldehyde with sodium triacetoxyborohydride can be used. As a method of amidating the secondary amino group, the secondary amino group generated by the reductive amination can be amidated under the same conditions as in the amidation reaction in step (C) described below, and a specific example is a method of amidating using 2,2,6-trimethyl-1,3-dioxin-4-one as an amidating reagent.

[0056] [Compound represented by formula (II)] In the present invention, a compound represented by formula (II):

[0057]

[0058] [In the formula, R １ is a methyl group, a methoxymethyl group, a tert-butyl group, or an acetyl group, and R ２ , R ３ and R ５ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.] is a novel compound that can be crystallized as described above. The present invention includes a compound represented by formula (II).

[0059] R１ is a methyl group, a methoxymethyl group, a tert-butyl group, or an acetyl group. These functional groups can be used as protecting groups for phenolic hydroxy groups, and can be deprotected in the step (C) described below. １ is preferably a methyl group.

[0060] R ２ is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. ２ is preferably a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 3-methylbutyl group, a 1,1-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1,2-dimethylpropyl group, a 1-ethylpropyl group, an n-hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a 2,3-dimethylbutyl group, Preferably, the alkyl group is a methyl group, an ethyl group, a 3,3-dimethylbutyl group, a 1-ethylbutyl group, or a 2-ethylbutyl group, more preferably a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 3-methylbutyl group, a 1,1-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1,2-dimethylpropyl group, or a 1-ethylpropyl group, more preferably an ethyl group, an n-propyl group, an i-butyl group, or a 3-methylbutyl group, and most preferably an n-propyl group or an i-butyl group.

[0061] R ３ and R ４ is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. ３ and R ４is preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 3-methylbutyl group, a 1,1-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1,2-dimethylpropyl group, a 1-ethylpropyl group, an n-hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a 2,3-dimethylbutyl group, a 3,3-dimethylbutyl group, Preferably, the alkyl group is a 1-ethylbutyl group, a 1-ethylbutyl group, or a 2-ethylbutyl group, more preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 3-methylbutyl group, a 1,1-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1,2-dimethylpropyl group, or a 1-ethylpropyl group, more preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, or a tert-butyl group, and most preferably a methyl group.

[0062] R ５ and R ６ is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. ５ and R ６is preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 3-methylbutyl group, a 1,1-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1,2-dimethylpropyl group, a 1-ethylpropyl group, an n-hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a 2,3-dimethylbutyl group, a 3,3-dimethylbutyl group, Preferably, the alkyl group is a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1,2-dimethylpropyl, or 1-ethylpropyl group, more preferably a hydrogen atom, a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, or tert-butyl group, and most preferably a hydrogen atom.

[0063] [Step (A)] Step (A) of the present invention is a step of converting the compound represented by formula (I) to the compound represented by formula (II). The reaction used in this step is not particularly limited. The conversion reaction preferably includes a reaction of reducing the nitro group in the compound represented by formula (I) to an amino group and a reaction of constructing a 2-pyridone ring. More preferably, it includes a reaction of converting the compound represented by formula (I) to an amino group by reducing the nitro group in the compound represented by formula (I) to a compound represented by formula (II) by treating the resulting compound with an acid to construct a 2-pyridone ring.

[0064] Examples of the reduction reaction include, but are not limited to, catalytic hydrogenation, sodium borohydride in the presence of a catalyst, hydrazine activated by a suitable catalyst, and reactions using metals such as zinc or tin. Examples of reaction solvents include ether solvents (diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, cyclopentyl methyl ether, methyl tert-butyl ether, etc.), alcohol solvents (methanol, ethanol, trifluoroethanol, n-propanol, 2-propanol, n-butanol, sec-butanol, t-butanol, pentanol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, etc.), and acetate solvents (methyl acetate, ethyl acetate, isopropyl acetate, etc.). Alcohol solvents are preferred, and methanol or ethanol is particularly preferred. The reduction reaction can be carried out by stirring the reaction mixture at a suitable temperature (eg, −80° C. to 100° C.) under normal pressure or under pressure for a certain period of time (eg, 0.1 to 24 hours).

[0065] The treatment with an acid may be carried out under conditions that allow the formation of a 2-pyridone ring. Examples of acids that can be used include, but are not limited to, hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, and para-toluenesulfonic acid. A reaction solvent is not necessarily required, but examples include alcoholic solvents (methanol, ethanol, trifluoroethanol, n-propanol, 2-propanol, n-butanol, sec-butanol, t-butanol, pentanol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, ethylene glycol, 1,3-propanediol, 1,4-butanediol, and 1,5-pentanediol). The reaction can be carried out by stirring the reaction mixture at an appropriate temperature (e.g., −80° C. to 100° C.) for a certain period of time (e.g., 0.1 to 24 hours).

[0066] [Step (B)] Step (B) of the present invention is a step of isolating the compound represented by formula (II) produced in the above-mentioned step (A) by crystallization.

[0067] The present invention is characterized in that the compound represented by formula (II) is crystallized in step (B), which makes it possible to remove impurities generated in the previous steps, thereby contributing to improving the purity of the compound represented by formula (III) that is finally obtained.

[0068] The temperature for the crystallization is not limited, but is preferably from -10°C to 50°C, more preferably from -5°C to 30°C.

[0069] Examples of solvents used in the crystallization include ether solvents (diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, cyclopentyl methyl ether, methyl tert-butyl ether, etc.), hydrocarbon solvents (hexane, heptane, benzene, toluene, etc.), alcohol solvents (methanol, ethanol, trifluoroethanol, n-propanol, 2-propanol, n-butanol, sec-butanol, tert-butanol, pentanol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, etc.), acetate ester solvents (methyl acetate, ethyl acetate, isopropyl acetate, etc.), halogenated solvents (dichloromethane, chloroform, carbon tetrachloride, etc.), acetonitrile, water, or a mixed solvent of at least two of them. As a mixed solvent of at least two kinds, a mixed solvent of ethyl acetate and hexane or heptane, or a mixed solvent of water and methanol is particularly preferred.

[0070] [Step (C)] In step (C), the compound represented by formula (II) isolated in step (B) is amidated with a compound represented by formula (IV), formula (V) or formula (VI) below, and two substituents R １ is a step of deprotecting the compound.

[0071]

[0072] [In the formula, R ４ and R ６ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, and X is OR ８ or a halogen atom, R ７ and R ８ are the same or different and are a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, or R ７ and R ８ and together form a lower alkylene group.

[0073]

[0074] [In the formula, R ６ is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, and R 9 is a linear or branched alkylidene group having 1 to 6 carbon atoms.

[0075]

[0076] [In the formula, R ４ is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.] [Regarding the order of amidation and deprotection in step (C)] In step (C), the deprotection may be carried out after the amidation, or the amidation may be carried out after the deprotection. Preferably, R １ Since the presence of , esterification does not proceed as a side reaction in the amidation, it is preferable to carry out the deprotection after the amidation.

[0077] [Amidation in Step (C)] The amidation reaction in step (C) is a reaction in which the compound represented by formula (II) obtained in step (B) is reacted with a compound represented by formula (IV), formula (V), or formula (VI) described below, so that the aniline amino group in the compound represented by formula (II) reacts with a carboxylic acid equivalent to form an amide bond.

[0078] Examples of the amidation method include a method of reacting with an acid chloride, an acid anhydride, or an ester. For example, a preferred example includes a method of amidating with a compound represented by formula (IV), formula (V), or formula (VI) described below to obtain a compound represented by formula (VII) below.

[0079]

[0080] The compound represented by formula (IV), formula (V) or formula (VI) can be prepared by amidating the compound represented by formula (II) to form a compound represented by formula (III) having a substituent R ４ and R ６ It is a compound for introducing a partial structure containing

[0081] When a compound represented by formula (IV) is used as an amidation reagent, a compound represented by formula (II) or a compound represented by formula (II) is used. １ The amino group of the intermediate obtained by removing one or both of R undergoes nucleophilic attack on the carbonyl group of the compound represented by formula (IV), resulting in elimination of X and the formation of a new amide bond. ７ is a hydrogen atom, or when R ７ When R is removed, the subsequent step may be carried out as is. ７ If remains after amidation, R ７ A reaction to remove the

[0082] When a compound represented by formula (V) is used as an amidation reagent, a compound represented by formula (II) or a compound represented by formula (II) is used. １ The amino group of the intermediate, in which one or both of the groups have been removed, undergoes nucleophilic attack on the carbonyl group of the compound represented by formula (V), opening the β-lactone ring of the compound represented by formula (V) and forming a new amide bond. After this, keto-enol tautomerization occurs to form R ９ A hydrogen atom is added to R ４ That is, the substituent R in formula (V) ９ is obtained by adding a hydrogen atom when the compound represented by formula (II) is amidated, and R ４ It is a substituent such that

[0083] When a compound represented by formula (VI) is used as an amidation reagent, a compound represented by formula (II) or a compound represented by formula (II) is used. １ The amino group of the intermediate, from which one or both of the groups have been removed, undergoes nucleophilic attack on one of the two ester carbonyl groups of the compound represented by formula (VI), cleaving the ester bond and forming a new amide bond. After this, acetone is eliminated, decarboxylated, and protonated. The protonation causes the bonded hydrogen atom to become R ６ Therefore, when a compound represented by formula (VI) is used as an amidation reagent, in the compound represented by formula (II) or (III) obtained by the present invention, R ６ is a hydrogen atom.

[0084] As described above, X in the compound represented by formula (IV) is a functional group that serves as a leaving group for the carboxylic acid equivalent in the amidation reaction. ８ , a halogen atom, an acyloxy group, a sulfonyloxy group, a phosphoryloxy group or a hydroxy group. Preferably, X is OR ８ , an acyloxy group, a hydroxy group or a halogen atom, and more preferably OR ８ is.

[0085] In the compound represented by formula (IV), X is OR ８ R in the case ７ and R ８ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, or R ７ and R ８ and together form a lower alkylene group. ７ and R ８ If are independent, R ７ and R ８are preferably a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 3-methylbutyl group, a 1,1-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1,2-dimethylpropyl group, a 1-ethylpropyl group, an n-hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a 2,3-dimethylbutyl group, R is preferably a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 3-methylbutyl group, a 1,1-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1,2-dimethylpropyl group, or a 1-ethylpropyl group, more preferably an ethyl group, an n-propyl group, an i-butyl group, or a 3-methylbutyl group, and most preferably an n-propyl group or an i-butyl group. ７ and R ８ When these are combined, R ７ and R ８ is a lower alkylene group. Examples of the lower alkylene group include linear, branched, or cyclic alkylene groups having 1 to 6 carbon atoms. Preferred lower alkylene groups are methylene, ethylene, trimethylene, isopropylidene, 1,1-cyclopentylidene, or 1,1-cyclohexylidene, and the most preferred is an isopropylidene group. Specific examples of the compound represented by formula (IV) include compounds represented by formula (IV) ４ is a methyl group, and R ６ is a hydrogen atom and X is OR ８ If R ７ is a hydrogen atom and R ８ is a methyl group, R ７ is a hydrogen atom and R ８ is an ethyl group, R ７ and R ８taken together form an isopropylidene group, 2,2,6-trimethyl-1,3-dioxin-4-one.

[0086] In the compound represented by formula (IV), R ８ If there is no ７ As mentioned above, ７ and R ８ If R is independent, ７ Specific examples of the compound represented by formula (IV) include those having a substituent group R ４ is a methyl group, and R ６ and R ７ When X is a hydrogen atom, examples thereof include acetoacetic acid where X is a hydroxy group and acetoacetic acid chloride where X is a halogen atom.

[0087] The most preferred compound represented by formula (IV) is 2,2,6-trimethyl-1,3-dioxin-4-one.

[0088] In the compound represented by formula (V), R ９ is a linear or branched alkylidene group having 1 to 6 carbon atoms. ９ is preferably a methylene group, an ethylidene group, a propylidene group, an isopropylidene group, a butylidene group, a 1-methylpropylidene group, a 2-methylpropylidene group, a pentylidene group, a 1-methylbutylidene group, a 2-methylbutylidene group, a 3-methylbutylidene group, a 1,2-dimethylpropylidene group, or a 2,2-dimethylpropylidene group, more preferably a methylene group, an ethylidene group, a propylidene group, an isopropylidene group, a butylidene group, a 1-methylpropylidene group, or a 2-methylpropylidene group, and most preferably a methylene group. ６ is a hydrogen atom and R ９ is a methylene group, 4-methyleneoxetan-2-one.

[0089] Specific examples of the compound represented by formula (VI) include R ４ is a methyl group, 5-(1-hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione.

[0090] When X is a hydroxy group, amidation is preferably carried out using a condensing agent, examples of which include N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and 1-[bis(dimethylamino)methylene]1-H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate.

[0091] The amidation reaction is preferably carried out in the presence of a solvent. Examples of the reaction solvent include ether solvents (diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, cyclopentyl methyl ether, methyl tert-butyl ether, etc.), hydrocarbon solvents (hexane, heptane, benzene, toluene, etc.), and amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.), with hydrocarbon solvents (hexane, heptane, benzene, toluene, etc.) and amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.) being more preferred, and toluene and N,N-dimethylformamide being particularly preferred.

[0092] In the "amidation" reaction in step (C), the reaction is preferably carried out in the presence of a base from the viewpoint of improving the product yield and / or shortening the reaction time. Preferred examples of the base include tertiary amines (triethylamine, N-methylmorpholine, ethyldiisopropylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc.), with ethyldiisopropylamine being particularly preferred.

[0093] The reaction temperature for the amidation reaction in step (C) is not limited, but is preferably from 50° C. to 200° C., more preferably from 80° C. to 180° C., and even more preferably from 100° C. to 150° C. If the reaction temperature is too low, the reaction tends not to proceed sufficiently.

[0094] [Deprotection in Step (C)] The deprotection reaction in step (C) is carried out by deprotecting two R protecting groups of the phenolic hydroxyl groups. １This refers to the reaction that removes

[0095] R １ When R is a methyl group, it can be deprotected with a Lewis acid such as boron tribromide or aluminum chloride, or hydrobromic acid. １ When R is a methoxymethyl group, it can be deprotected with trifluoroacetic acid, hydrogen chloride / ethyl acetate, hydrogen chloride / 1,4-dioxane, etc. １ When R is a tert-butyl group, it can be deprotected with trifluoroacetic acid, hydrogen chloride / ethyl acetate, hydrogen chloride / 1,4-dioxane, etc. １ When is an acetyl group, the protection can be removed with an aqueous solution of sodium hydroxide, an aqueous solution of sodium bicarbonate, or the like.

[0096] When the "deprotection" reaction of the methyl group is carried out in step (C), examples of the reaction solvent include hydrocarbon solvents (hexane, heptane, benzene, toluene, etc.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.), acetate ester solvents (methyl acetate, ethyl acetate, isopropyl acetate, etc.), halogenated solvents (dichloromethane, chloroform, carbon tetrachloride, etc.), and acetonitrile, and a mixed solvent of two or more of these may also be used. Hydrocarbon solvents (hexane, heptane, benzene, toluene, etc.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.), and halogenated solvents (dichloromethane, chloroform, carbon tetrachloride, etc.) are preferred, with toluene and dichloromethane being particularly preferred.

[0097] The reaction temperature for the "deprotection" reaction of the methyl group in step (C) is not limited, but is usually from -20°C to 150°C, preferably from 0°C to 100°C.

[0098] [Step (D)] Step (D) of the present invention is a step of treating the compound obtained in the step (C) with an acid to newly construct a 2-pyridone ring, thereby obtaining the compound represented by the formula (II).

[0099] The reaction conditions in step (D) include an acid, examples of which include, but are not limited to, hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, para-toluenesulfonic acid, etc.

[0100] A reaction solvent is not necessarily required in step (D), but a solvent such as an alcohol solvent (methanol, ethanol, trifluoroethanol, n-propanol, 2-propanol, n-butanol, sec-butanol, t-butanol, pentanol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, etc.) may be used.

[0101] The reaction temperature in step (D) is not limited, but is usually from -20°C to 100°C, preferably from 0°C to 50°C.

[0102] [Compound represented by formula (III)] In the present invention, the compound represented by formula (III) is a DNQ derivative. The present invention includes the compound represented by formula (III) produced by the above-mentioned method. The compound represented by formula (III) is preferably activated by NQO1 and has pharmacological activity such as antitumor activity. Specific examples of preferred compounds represented by formula (III) include R ３ and R ４ is a methyl group, and R ５ and R ６ is a hydrogen atom, and R ２ is an n-propyl group or an i-butyl group.

[0103] After obtaining the compound represented by formula (III) in step (D), the obtained compound represented by formula (III) may be purified. Examples of purification methods include crystallization, slurry washing, column chromatography, and the like. When the compound represented by formula (III) is a crystallizable compound, it is preferable to purify the compound by crystallization after obtaining the compound in step (D). By purifying the compound by crystallization, impurities generated in the previous steps can be removed, and the compound can be obtained with even higher purity.

[0104] Preferred solvents for use when compound (III) is obtained by crystallization include ether solvents (diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, cyclopentyl methyl ether, methyl tert-butyl ether, etc.), hydrocarbon solvents (hexane, heptane, benzene, toluene, etc.), alcohol solvents (methanol, ethanol, trifluoroethanol, n-propanol, 2-propanol, n-butanol, sec-butanol, tert-butanol, pentanol, hexanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol, ethylene glycol, 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, etc.), acetate solvents (methyl acetate, ethyl acetate, isopropyl acetate, etc.), halogenated solvents (dichloromethane, chloroform, carbon tetrachloride, etc.), acetonitrile, water, and mixed solvents of at least two of them. As the mixed solvent of at least two kinds, a mixed solvent of ethyl acetate and hexane or heptane, and a mixed solvent of dichloromethane and 2-propanol are particularly preferred.

[0105] The temperature for the crystallization is not limited, but is preferably from -10°C to 100°C, more preferably from -5°C to 80°C.

[0106] [Method for producing a compound represented by formula (II)] The present invention includes a method for producing a compound represented by formula (II), comprising: a step (A1') of reducing the nitro group of a compound represented by formula (I); a step (A2') of treating the compound obtained in step (A1') with an acid to construct a 2-pyridone ring, thereby obtaining a compound represented by formula (II); and a step (B') of isolating the compound represented by formula (II) obtained in step (A2') by crystallization.

[0107] The reduction reaction used in step (A1′) in the production method for the compound represented by formula (II) can be the same as the reduction reaction used in the production method for the compound represented by formula (III) described above.

[0108] The treatment with an acid in step (A2′) in the production method for the compound represented by formula (II) can be the same as the treatment with an acid for constructing a 2-pyridone ring to obtain the compound represented by formula (II) in the same manner as in the production method for the compound represented by formula (III).

[0109] As the crystallization solvent used in the crystallization step in step (B′) in the production method for the compound represented by formula (II), the same solvent for crystallizing the compound represented by formula (II) as in the production method for the compound represented by formula (III) described above can be used.

[0110] The compounds of the present disclosure can be prepared using the methods disclosed herein, as well as methods comprising certain modifications to the same that are obvious from the disclosures herein and methods known in the art. In addition to the teachings herein, conventional and well-known synthetic methods may be used. Synthesis of the compounds described herein can be achieved as described in the following examples. Reagents, where available, can be purchased commercially, for example, from Tokyo Kasei or other chemical manufacturers.

[0111] Examples related to the present invention are described below. In most cases, alternative techniques can be used. The examples are for illustrative purposes only and are not intended to limit the scope of the invention.

[0112] High performance liquid chromatography (HPLC) was used for purity analysis in the examples and comparative examples. In this specification, purity refers to the area percentage of the peak to be measured, based on the HPLC chromatogram obtained according to the following method, where the area of ​​all peaks excluding the blank peak is taken as 100%. The blank peak refers to the peak detected when a 50% aqueous acetonitrile solution is measured under the following HPLC measurement conditions.

[0113] (1) Sample Preparation A target sample (2 mg) is dissolved in 50% aqueous acetonitrile solution to make a total volume of 10 ml, and this is used as a measurement sample.

[0114] (2) HPLC The measurement sample prepared above is analyzed using HPLC under the following measurement conditions: [HPLC analysis conditions] HPLC apparatus: Nexela Lite (Shimadzu Corporation) Column: Kinetex C18 (Phenomenex), length 150 mm, inner diameter 4.6 mm, particle size 2.6 μm Mobile phase: (A) 0.1% trifluoroacetic acid / water, (B) 0.1% trifluoroacetic acid / acetonitrile Flow rate: 1.0 ml / min Gradient conditions: 25% of solution B until 4 minutes after the start of analysis, 75% of solution B from 4 to 14 minutes, held at 75% of solution B from 14 to 22 minutes, 25% of solution B from 22 to 23 minutes, held at 25% of solution B from 23 to 30 minutes. Detector: photodiode array detector (measurement wavelength: 280 nm) Column temperature: 35°C Injection volume: 5 µl.

[0115] (3) NMR The solvent names shown in the NMR data in the examples and comparative examples indicate the solvents used in the measurements. NMR spectra were measured using a JNM-ECZ-400S ( １ H NMR, 400 MHz) or JNM-ECS400 ( １ Measurements were performed using a H NMR (400 MHz) type instrument. Chemical shifts are expressed as δ (unit: ppm) relative to tetramethylsilane, and signals are expressed as s (singlet), d (doublet), t (triplet), m (multiplet), brs (broad singlet), and dd (double doublet).

[0116] (4) MS Mass spectrometry (MS) was performed by electrospray ionization (hereinafter referred to as ESI) using Agilent 1200 manufactured by Agilent Technologies.

[0117] Reference Example 1 Preparation of Compound I-1:

[0118]

[0119] Step E-1: Conversion of Compound VIII to Compound IX-1 2,5-Dimethoxy-3-nitroaniline (Compound VIII, 20 g, 100.92 mmol) was dissolved in ethyl acetate (200 ml) and stirred at room temperature. Subsequently, isobutyraldehyde (11.64 g, 161.5 mmol) and sodium triacetoxyborohydride (45.56 g, 215.0 mmol) were added to the reaction solution in three portions at 1-hour intervals. After stirring for 3 hours and 45 minutes from the first addition of the reagents, ethyl acetate (200 ml) was added. While stirring the reaction solution under ice cooling, 2 M aqueous potassium carbonate solution (300 ml) was added dropwise over 16 minutes. After the completion of the dropwise addition, the reaction vessel was removed from the ice bath, and the reaction solution was stirred at room temperature for 27 minutes. The reaction solution was then transferred to a separatory funnel. After separation, the organic phase was separated and washed with water (100 ml). The resulting organic phase was concentrated under reduced pressure, toluene (200 ml) was added, and the azeotropic dehydration procedure of again concentrating under reduced pressure was repeated three times, and finally toluene was added to obtain a toluene solution (199.77 g) of compound IX-1.

[0120] Step F-1: Conversion of Compound IX-1 to Compound I-1 A toluene solution of Compound IX-1 (199.77 g) was heated and stirred at 110°C for 15 minutes. Subsequently, 2,2,6-trimethyl-1,3-dioxin-4-one (21.52 g, 151.38 mmol) was added dropwise to the reaction solution over 8 minutes, and the mixture was heated and stirred for an additional 2 hours and 37 minutes. The reaction solution was stirred under ice cooling, and ethyl acetate (400 ml) and methanol (30 ml) were added. A 2M aqueous potassium carbonate solution (200 ml) was added dropwise to the reaction solution over 17 minutes. After the addition was complete, the reaction vessel was removed from the ice bath, and the mixture was stirred at room temperature for 35 minutes, followed by separation. The separated organic phase was then washed with 5% brine (200 ml), and the resulting organic phase was concentrated under reduced pressure. Further, methanol (200 ml) was added, and the solvent substitution procedure of concentrating under reduced pressure was repeated three times, and finally methanol was added to obtain a methanol solution of compound I-1 (380.9 g).

[0121] Example 1 Synthesis of 4,6-dimethyl-1-(2-methylpropyl)pyrido[3,2-g]quinoline-2,5,8,10(1H,9H)-tetraone (Compound III-1) by a method involving crystallization of Compound II-1:

[0122]

[0123] Steps A-1 and B-1: Conversion of Compound I-1 to Compound II-1 and Crystallization of Compound II-1 A reaction vessel containing a methanol solution of Compound I-1 (380.9 g) was purged with argon gas three times, after which Pd / C (2.98 g) was added and the mixture was purged with hydrogen gas. After stirring at room temperature for 5 hours and 16 minutes, the mixture was filtered using filter paper and a membrane. The resulting solution was concentrated under reduced pressure, and methanol was added to obtain a methanol solution of the intermediate (110.29 g). While stirring this solution under ice cooling, 1 M hydrochloric acid (54 ml) was added dropwise over 5 minutes. After the addition was complete, the reaction vessel was removed from the ice bath and stirred at room temperature for 1 hour. At this time, a white solid precipitated 5 minutes after the start of stirring at room temperature. The mixture was then ice-cooled again, and 2 M aqueous potassium carbonate solution (27 ml) was added dropwise over 5 minutes. After the dropwise addition was completed, the ice bath was removed, and the mixture was stirred at room temperature for 5 minutes. Dichloromethane (400 ml) was then added to dissolve the solid, and a separation operation was performed. Subsequently, the organic phase was separated and washed with 5% brine (100 ml). The resulting organic phase was concentrated under reduced pressure, and MeOH (200 ml) was added, followed by another concentration under reduced pressure. This solvent substitution operation was repeated three times. Methanol was then added to the residue obtained after the three solvent substitution operations, yielding compound II-1 (140.36 g) in a slurry form. Water (40 ml) was added dropwise to this slurry over 12 minutes with stirring. After the dropwise addition was completed, the mixture was stirred at room temperature for 1 hour, then cooled on ice, and further stirred for 4 hours and 52 minutes. Finally, the resulting solid was filtered and washed with an ice-cooled solvent mixture of methanol and water in a ratio of 1:1. The resulting solid was then dried under reduced pressure at 40°C for 3 hours and 46 minutes to obtain 7-amino-1-isobutyl-5,8-dimethoxy-4-methylquinolin-2(1H)-one (Compound II-1, 24.47 g) in a three-step yield of 84% and an HPLC purity of 99.8%. １ H-NMR (CDCl ３) δ: 6.19 (1H, d, J = 0.9Hz), 6.14 (1H, s), 4.47 (2H, brs), 4.20 (2H, brs), 3.81 (3H, s), 3.55 (3H, s), 2.52 (3H, d, J=0.9Hz), 1.86 (1H, sep, J=6.9Hz), 0.70 (6H, d, J=6.4Hz). LC / MS (ESI): m / z291 ([M+H] ＋ ).

[0124] Step C-1A: Conversion of Compound II-1 to Compound VII-1 Toluene (230 ml) was added to Compound II-1 (20 g, 68.9 mmol) and the mixture was stirred. N,N-Diisopropylethylamine (9.79 g, 75.8 mmol) was added, and the temperature was raised to 110°C. After stirring for 13 minutes, 2,2,6-trimethyl-1,3-dioxin-4-one (10.68 g, 75.8 mmol) was added dropwise over 7 minutes. After the addition was completed, the mixture was stirred for 3 hours and the reaction was tracked by HPLC. Since the starting compound II-1 remained, 2,2,6-trimethyl-1,3-dioxin-4-one (186.8 mg) and N,N-Diisopropylethylamine (173.8 mg) were added. After stirring for 33 minutes, the reaction vessel was removed from the oil bath and cooled on ice. Ethyl acetate (460 ml) and water (200 ml) were added to the reaction solution, and a separation operation was carried out. The separated organic phase was washed with 1 M hydrochloric acid (200 ml) and water (200 ml), and the obtained organic phase was concentrated under reduced pressure. Toluene (200 ml) was then added to the residue, and the azeotropic dehydration operation of concentrating under reduced pressure was repeated three times to obtain a toluene solution (50.79 g) of Compound VII-1.

[0125] Step C-1B: Conversion of Compound VII-1 to Compound X-1 To a 1M solution of boron tribromide in dichloromethane (400 ml), a toluene solution of Compound VII-1 diluted with dichloromethane (200 ml) was added dropwise over 45 minutes while stirring and ice-cooling. After the addition was complete, the temperature was raised to 40°C and the mixture was stirred for 19 hours and 31 minutes. After the reaction was completed, the reaction vessel was removed from the oil bath and allowed to cool. Water (228 ml) was then added dropwise over 48 minutes while stirring and ice-cooling. The mixture was then stirred at room temperature for 2 hours and 56 minutes, after which it was ice-cooled again, and methanol (688 ml) was added dropwise over 6 minutes, followed by stirring at room temperature for 13 hours and 40 minutes. The reaction solution was concentrated under reduced pressure, and then ethyl acetate (500 ml) and water (200 ml) were added, followed by a separation operation. The organic phase was separated, and ethyl acetate (500 ml) was added to the aqueous phase, followed by two more extraction operations. The resulting organic phase was concentrated under reduced pressure, ethanol (200 ml) was added, and the solvent was concentrated under reduced pressure again. This solvent substitution procedure was repeated three times to obtain an ethanol solution of Compound X-1 (119.02 g). Water (120 ml) was added dropwise to this solution over 10 minutes while stirring, and the mixture was stirred at room temperature for 15 hours and 55 minutes. The resulting solid was then filtered and dried under reduced pressure at 40°C to obtain Compound X-1 (16.94 g) in a 71% yield over two steps.

[0126] Step D-1: Conversion of Compound X-1 to Compound III-1 Compound X-1 (10.0 g, 28.9 mmol) was added to concentrated sulfuric acid (50 ml) and stirred at room temperature for 4 hours. The reaction solution was then ice-cooled, and water (750 ml) was added dropwise over 33 minutes, followed by the dropwise addition of aqueous ammonia (175 ml) over 34 minutes. After the dropwise addition was completed, the mixture was extracted three times with dichloromethane (500 ml), and the resulting organic phase was washed twice with water (500 ml) and concentrated under reduced pressure. Isopropanol was then added to the resulting residue, and the solvent substitution procedure of concentrating under reduced pressure was repeated three times, followed by stirring under ice cooling for 2 hours. The resulting solid was filtered, washed with isopropanol, and dried under reduced pressure at 40°C to obtain 4,6-dimethyl-1-(2-methylpropyl)pyrido[3,2-g]quinoline-2,5,8,10(1H,9H)-tetraone (Compound III-1, 5.01 g, purity 99.6%) in a 53% yield from Compound X-1 and a 32% yield from Compound VIII. The results are shown in Table 1. 1H-NMR (CDCl3) δ: 6.79 (1H, d, J = 0.9 Hz), 6.67 (1H, d, J = 0.9 Hz), 4.64 (2H, d, J = 7.3 Hz), 2.61 (6H, dd, J = 4.1 Hz, 0.9 Hz), 1.87 (1H, m), 0.92 (6H, d, J = 7.3 Hz). LC / MS (ESI): m / z 327 ([M+H]+).

[0127] Comparative Example 1 Synthesis of 4,6-dimethyl-1-(2-methylpropyl)pyrido[3,2-g]quinoline-2,5,8,10(1H,9H)-tetraone (Compound III-1) by constructing two 2-pyridone rings in one step:

[0128]

[0129] A solution of 2,5-dimethoxy-3-nitroaniline (Compound VIII, 10.0 g, 50.5 mmol) in tetrahydrofuran (100 ml) was added with isobutyraldehyde (5.1 ml, 55.6 mmol) and NaBH(OAc) at room temperature. ３(21.4 g, 101 mmol) was added and the mixture was stirred at room temperature for 7.5 hours. Isobutyraldehyde (0.92 ml, 10.1 mmol) was then added and the mixture was stirred at room temperature for 16.5 hours. After that, isobutyraldehyde (0.92 ml, 10.1 mmol) was further added and the mixture was stirred at room temperature for 4 hours. A 10% aqueous sodium bicarbonate solution (200 ml) was added to the reaction solution under ice cooling, followed by extraction with ethyl acetate (400 ml) and chloroform. The resulting organic phase was washed twice with water (100 ml). The addition of methanol and concentration under reduced pressure were repeated to obtain a methanol solution (500 ml) of compound IX-1. The atmosphere in the methanol solution of compound IX-1 was purged with argon, and then Pd / C (1.5 g, 10% w / w) was added. The reaction vessel was purged with hydrogen gas, and the mixture was stirred at room temperature for 6 hours. The reaction solution was then filtered through Celite, and the Celite was washed with methanol (100 ml). The resulting solution was concentrated under reduced pressure to obtain crude Compound XI (11.9 g). To a solution of crude Compound XI (1.19 g) in toluene (10 ml), N,N-diisopropylethylamine (1.93 ml, 11.1 mmol) was added, and the temperature was raised to 110°C. After heating and stirring for 5 minutes, 2,2,6-trimethyl-1,3-dioxin-4-one (10.68 g, 75.8 mmol) was added dropwise over 7 minutes. At 110°C, 2,2,6-trimethyl-1,3-dioxin-4-one (1.45 ml, 11.1 mmol) was added in four portions at 10-minute intervals. After stirring for 2.5 hours, the reaction had not yet completed, so N,N-diisopropylethylamine (351 μl, 2.2 mmol) and 2,2,6-trimethyl-1,3-dioxin-4-one (263 μl, 2.2 mmol) were added, and the mixture was stirred for 1 hour. Ethyl acetate (50 ml) was then added to the reaction mixture under ice cooling, and the mixture was washed twice with 1N HCl (15 ml) and with 10% brine (15 ml). The resulting organic phase was concentrated under reduced pressure to obtain crude Compound XII. A solution of crude Compound XII in dichloromethane (27 ml) was added to a 1M solution of boron tribromide in dichloromethane (40 ml, 40.1 mmol) at 0°C, and the mixture was stirred at 40°C for 23 hours.Subsequently, methanol (60 ml) was added to the reaction solution at 0°C, and the mixture was stirred at 40°C for 2 hours. The reaction solution was then concentrated under reduced pressure to obtain a crude product of Compound XIII. Concentrated sulfuric acid (20 ml) was added to the crude product of Compound XIII at room temperature, and the mixture was stirred for 2 hours. Water and 30% aqueous ammonia solution were added dropwise under ice cooling to neutralize the reaction solution. The mixture was then extracted four times with dichloromethane, and the resulting organic phase was filtered and concentrated under reduced pressure. The resulting residue was dissolved in a small amount of dichloromethane, and MTBE was added dropwise. The resulting solid was then filtered, washed with MTBE, and dried under reduced pressure to obtain 4,6-dimethyl-1-(2-methylpropyl)pyrido[3,2-g]quinoline-2,5,8,10(1H,9H)-tetraone (Compound III-1, 598 mg, purity 87.4%) from Compound VIII in a 36% yield. The results are shown in Table 1.

[0130] Reference Example 2 Preparation of Compound I-2:

[0131]

[0132] Step E-2: Conversion of Compound VIII to Compound IX-2 2,5-Dimethoxy-3-nitroaniline (Compound VIII, 1 g, 5.05 mmol) was dissolved in ethyl acetate (10 ml) and stirred at room temperature. Subsequently, propionaldehyde (579 μl, 8.08 mmol) and sodium triacetoxyborohydride (2.29 g, 10.8 mmol) were added to the reaction solution in three portions at 1-hour intervals. After stirring for 3 hours and 15 minutes from the first addition of the reagents, ethyl acetate (10 ml) was added. A 2M aqueous potassium carbonate solution (15 ml) was added dropwise to this reaction solution while stirring under ice cooling. After the addition was complete, the reaction vessel was removed from the ice bath, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was then transferred to a separatory funnel. After separation, the organic phase was separated and washed with water (5 ml). The resulting organic phase was concentrated under reduced pressure, toluene (10 ml) was added, and the azeotropic dehydration procedure of again concentrating under reduced pressure was repeated three times, and finally toluene was added to obtain a toluene solution (9.88 g) of compound IX-2.

[0133] Step F-2: Conversion of Compound IX-2 to Compound I-2 A toluene solution of Compound IX-2 (9.88 g) was heated and stirred at 110°C. Subsequently, 2,2,6-trimethyl-1,3-dioxin-4-one (988 μl, 7.58 mmol) was added dropwise to the reaction solution, and the mixture was heated and stirred for an additional 1 hour and 40 minutes. The reaction solution was stirred under ice cooling, and ethyl acetate (20 ml) and methanol (1.5 ml) were added. 2 M aqueous potassium carbonate solution (10 ml) was added dropwise to the reaction solution. After the addition was completed, a separation operation was performed. Next, the separated organic phase was washed with 5% saline (10 ml), and the resulting organic phase was concentrated under reduced pressure. Further, methanol (10 ml) was added, followed by concentration under reduced pressure, and this solvent substitution operation was repeated three times. Finally, methanol was added to obtain a methanol solution of Compound I-2 (18.98 g).

[0134] Example 2 Synthesis of 4,6-dimethyl-1-propylpyrido[3,2-g]quinoline-2,5,8,10(1H,9H)-tetraone (Compound III-2) via a process involving crystallization of Compound II-2:

[0135]

[0136] Steps A-2 and B-2: Conversion of Compound I-2 to Compound II-2 and Crystallization of Compound II-2 A reaction vessel containing a methanol solution of Compound I-2 (18.98 g) was purged with argon gas three times, after which Pd / C (150 mg) was added and the mixture was purged with hydrogen gas. After stirring at room temperature for 4 hours and 15 minutes, filtration was performed using a membrane. The resulting solution was concentrated under reduced pressure, and methanol was added to obtain a methanol solution of the intermediate (4.34 g). While stirring this solution at room temperature, 1 M hydrochloric acid (2.7 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The mixture was then ice-cooled, and 2 M aqueous potassium carbonate solution (1.35 ml) was added dropwise. After the completion of the addition, the ice bath was removed, and the mixture was stirred at room temperature for 10 minutes. Dichloromethane (20 ml) was added, and a liquid separation operation was performed. The organic phase was then separated and washed with 5% brine (5 ml). The obtained organic phase was concentrated under reduced pressure and recrystallized using ethyl acetate / hexane to obtain 7-amino-1-propyl-5,8-dimethoxy-4-methylquinolin-2(1H)-one (Compound II-2, 560 mg) in a three-step yield of 40%. １ H-NMR (CDCl ３ ) δ: 6.24 (1H, brs), 6.15 (1H, s), 4.56 (2H, t, J=7.3Hz), 3.81 (3H, s), 3 .58 (3H, s), 2.52 (3H, d, J=1.4Hz), 1.55 (2H, m), 0.79 (3H, t, J=7.3Hz). LC / MS (ESI): m / z277 ([M+H] ＋ ).

[0137] Step C-2A: Conversion of Compound II-2 to Compound VII-2 Toluene (5.75 ml) was added to Compound II-2 (500 mg, 1.81 mmol) and the mixture was stirred. N,N-Diisopropylethylamine (347 μl, 1.99 mmol) was added thereto, and the mixture was heated to 110°C. After heating and stirring for 5 minutes, 2,2,6-trimethyl-1,3-dioxin-4-one (260 μl, 1.99 mmol) was added dropwise. After the addition was completed, the mixture was stirred for 2 hours, and then the reaction vessel was removed from the oil bath and cooled on ice. Ethyl acetate (11.5 ml) and water (5 ml) were added to the reaction solution, and a separation operation was performed. The separated organic phase was washed with 1 M hydrochloric acid (5 ml) and water (5 ml), and the obtained organic phase was concentrated under reduced pressure. Toluene was then added to the residue, and the mixture was concentrated under reduced pressure. This azeotropic dehydration procedure was repeated three times to obtain a toluene solution of Compound VII-2 (1.3 g). Step B-2: From Compound II-2 Step C-2B: Conversion of Compound VII-2 to Compound X-2 A toluene solution of Compound VII-2 diluted with dichloromethane (5 ml) was added dropwise to a 1 M dichloromethane solution of boron tribromide (10 ml) with stirring and ice cooling. After the dropwise addition was completed, the temperature was raised to 40°C and the mixture was stirred for 18 hours. After the reaction was completed, the reaction vessel was removed from the oil bath and allowed to cool. Water (5.7 ml) was then added dropwise with stirring and ice cooling. The mixture was then stirred at room temperature for 1 hour, ice-cooled again, and methanol (17.2 ml) was added dropwise, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and then ethyl acetate (12.5 ml) and water (5 ml) were added, followed by separation. The organic phase was separated, and ethyl acetate (12.5 ml) was added to the aqueous phase, followed by two more extraction operations, and the resulting organic phase was concentrated under reduced pressure to obtain Compound X-2.

[0138] Step D-2: Conversion of Compound X-2 to Compound III-2 Compound X-2 was added to concentrated sulfuric acid (52.5 ml) and stirred at room temperature for 1.5 hours. The reaction solution was then ice-cooled, and water (37.5 ml) was added dropwise, followed by aqueous ammonia (6 ml). After the addition was complete, the mixture was extracted three times with dichloromethane (25 ml), and the resulting organic phase was washed twice with water (10 ml) and concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, and the mixture was heated to reflux, followed by the addition of hexane. After stirring at room temperature for 3 hours, the resulting solid was filtered and washed with hexane / ethyl acetate (1 / 1). This gave 4,6-dimethyl-1-propylpyrido[3,2-g]quinoline-2,5,8,10(1H,9H)-tetraone (Compound III-2, 327 mg, purity 94.2%) in a 58% yield from Compound II-2 and a 23% yield from Compound VIII. The results are shown in Table 1. 1H-NMR (CDCl3) δ: 6.78 (1H, d, J = 0.9 Hz), 6.68 (1H, d, J = 1.4 Hz), 4.46 (2H, m), 2.61 (6H, dd, J = 6.4 Hz, 1.4 Hz), 1.61 (2H, m), 1.04 (3H, t, J = 7.3 Hz). LC / MS (ESI): m / z 311 ([M+H]+).

[0139] As described above, when compound III-1, a deoxyniboquinone derivative, was produced by the production method of the present invention (Example 1), it was shown that compound III-1 could be obtained with higher purity while maintaining a similarly high yield from compound VIII, compared to when compound III-1 was produced with reference to the production method described in Non-Patent Document 2 (Comparative Example 1). Similarly, when compound III-2, also a deoxyniboquinone derivative, was produced by the production method of the present invention (Example 2), it was also shown that compound III-2 could be obtained with high yield and high purity. It is believed that when the production method of the present invention was used, the synthetic intermediates compounds II-1 and II-2 could be purified by crystallization, which is why deoxyniboquinone derivatives were obtained with high yield and high purity.

[0140]

Claims

1. Formula (III): [In the formula, R ２ , R ３ , R ４ , R ５ and R ６ and each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. [In the formula, R １ is a methyl group, a methoxymethyl group, a tert-butyl group, or an acetyl group; R ２ , R ３ and R ５ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.] from a compound represented by formula (II): [In the formula, R １ is a methyl group, a methoxymethyl group, a tert-butyl group, or an acetyl group; R ２ , R ３ and R ５ each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.], a step (B) of isolating the compound represented by formula (II) obtained in the step (A) by crystallization, amidating the compound represented by formula (II) isolated in the step (B) with a compound represented by the following formula (IV), formula (V) or formula (VI), and １ Step (C) of deprotecting a compound represented by formula (IV): [In the formula, R ４ and R ６ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, and X is OR ８ , a halogen atom, an acyloxy group, a sulfonyloxy group, a phosphoryloxy group, or a hydroxy group; R ７ and R ８ are the same or different and each is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, or R ７ and R ８ and taken together form a lower alkylene group. [In the formula, R ６ is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms; R 9 is a linear or branched alkylidene group having 1 to 6 carbon atoms.] Formula (VI): [In the formula, R ４ is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.], and a step (D) of treating the compound obtained in the step (C) with an acid to newly construct a 2-pyridone ring, thereby synthesizing the compound represented by formula (III).

2. The method according to claim 1, wherein the step (A) comprises a step (A1) of reducing the nitro group of the compound represented by formula (I).

3. The method according to claim 2, wherein the step (A) includes a step (A2) of treating the compound obtained in the step (A1) with an acid to construct a 2-pyridone ring, thereby obtaining the compound represented by formula (II).

4. R １ , R ３ and R ４ is a methyl group, R ５ and R ６ is a hydrogen atom, R ２ CH ２ CH ３ , C.H. ２ CH ２ CH ３ , C.H. ２ CH (CH ３ ) ２ Or (CH ２ ) ２ CH (CH ３ ) ２ The method according to any one of claims 1 to 3, wherein 5. The step (C) comprises a step (C1) of amidating the compound represented by formula (II) obtained by the step (B) with a compound represented by formula (IV), formula (V) or formula (VI), and a step (C2) of amidating the compound obtained in the step (C1) with two R １ The method according to any one of claims 1 to 3, further comprising a step (C2) of deprotecting 6. Formula (II): [In the formula, R １ is a methyl group, a methoxymethyl group, a tert-butyl group, or an acetyl group; R ２ , R ３ and R ５ and each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. [In the formula, R １ is a methyl group, a methoxymethyl group, a tert-butyl group, or an acetyl group; R ２ , R ３ and R ５ and each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.], a step (A2') of treating the compound obtained in the step (A1') with an acid to construct a 2-pyridone ring to obtain the compound represented by formula (II), and a step (B') of isolating the compound represented by formula (II) obtained in the step (A2') by crystallization.

7. Formula (III): [In the formula, R ２ , R ３ , R ４ , R ５ and R ６ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. [In the formula, R １ is a methyl group, a methoxymethyl group, a tert-butyl group, or an acetyl group; R ２ , R ３ and R ５ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.] from a compound represented by formula (II): [In the formula, R １ is a methyl group, a methoxymethyl group, a tert-butyl group, or an acetyl group; R ２ , R ３ and R ５ each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.], a step (B) of isolating the compound represented by formula (II) obtained in the step (A) by crystallization, amidating the compound represented by formula (II) isolated in the step (B) with a compound represented by the following formula (IV), formula (V) or formula (VI), and １ Step (C) of deprotecting a compound represented by formula (IV): [In the formula, R ４ and R ６ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, and X is OR ８ , a halogen atom, an acyloxy group, a sulfonyloxy group, a phosphoryloxy group, or a hydroxy group; R ７ and R ８ are the same or different and each is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, or R ７ and R ８ and taken together form a lower alkylene group. [In the formula, R ６ is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms; R 9 is a linear or branched alkylidene group having 1 to 6 carbon atoms.] Formula (VI): [In the formula, R ４ is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.], and a step (D) of treating the compound obtained in the step (C) with an acid to newly construct a 2-pyridone ring, thereby synthesizing the compound represented by formula (III).

8. Formula (II): [In the formula, R １ is a methyl group, a methoxymethyl group, a tert-butyl group, or an acetyl group; R ２ , R ３ and R ５ each independently represents a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.

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