WO2025047770A1 - Method for producing deoxynyboquinone derivative - Google Patents

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 deoxynipoquinone derivatives

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

NAD(P)H quinone oxidoreductase (NQO1) has been shown to be expressed at much higher levels in lung cancer than in adjacent healthy tissues, and is attracting attention as a target for cancer treatment.

DNQ derivatives are activated by NQO1 and are known to have pharmacological activity, including antitumor activity (see Patent Document 1 and Non-Patent Document 1).

　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, which is then deprotected by acid treatment to remove the protecting group of the phenolic hydroxyl group, followed by oxidation using a cobalt catalyst. The total yield of the final product, IB-DNQ, was 9%.

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 reaction sites through acid treatment (see scheme below).

US Patent Application Publication No. 2015/0011509

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.

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

In addition, we attempted to produce IB-DNQ using a method for producing a DNQ derivative by simultaneously constructing 2-pyridone rings at two reaction sites through acid treatment. As shown in the scheme below, by utilizing a reaction that constructs 2-pyridone rings at two sites through 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.

The present invention aims to provide a method for producing DNQ derivatives, particularly DNQ derivatives such as IB-DNQ, in which the nitrogen atom of one 2-pyridone skeleton is substituted with a hydrogen atom and the nitrogen atom of the other 2-pyridone skeleton is substituted with an alkyl group, in high yield and with high purity, a DNQ derivative obtained by this production method, and a synthetic intermediate that can be crystallized.

The inventors conducted intensive research to solve the above problems and discovered that a novel compound represented by formula (II) described below, which is obtained by stepwise constructing 2-pyridone rings at two positions by acid treatment, can be crystallized and purified with high efficiency. They also discovered 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 high purity, which led to the completion of the invention.

That is, the present invention relates to a compound represented by formula (1) (III):

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

[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.]
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, 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.]
a step (A) of producing a compound represented by the formula (II) obtained in the step (A) by crystallization; a step (B) of isolating the compound represented by the formula (II) isolated in the step (B) by amidation with a compound represented by the following formula (IV), formula (V) or formula (VI) and deprotecting two substituents R ¹ ;
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; 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 are each a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, or R ⁷ and R ⁸ taken together are a lower alkylene group.]
Formula (V):

[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):

[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 synthesizing a compound represented by the formula (III) by treating the compound obtained in the step (C) with an acid to newly construct a 2-pyridone ring;
A method comprising:
(2) The step (A)
The method according to (1), comprising a step (A1) of reducing the nitro group of the compound represented by formula (I).
(3) The step (A)
The method according to (2), comprising 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 the formula (II).
(4) The method according to any one of (1) to (3), wherein R ¹ , R ³ and R ⁴ are methyl _groups , R ⁵ and R ⁶ are hydrogen atoms, _and R ² is CH _{2 CH 3} , CH ₂ CH _{2 CH 3 , CH 2 CH (} CH ₃ ) ₂ or (CH ₂ ) 2 CH(CH 3 ) 2.
(5) The step (C) is
A step (C1) of amidating the compound represented by formula (II) obtained by step (B) with a compound represented by formula (IV), formula (V) or formula (VI); and
The method according to any one of (1) to (4), further comprising a step (C2) of deprotecting two R ^1s of the compound obtained in the step (C1).
(6) Formula (II):

[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.]
A method for producing a compound represented by the following formula:
Formula (I):

[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.]
a step (A1') of reducing the nitro group of a compound represented by formula (II), a step (A2') of constructing a 2-pyridone ring by treating the compound obtained by the step (A1') with an acid to obtain a compound represented by formula (II), and a step (B') of isolating the compound represented by formula (II) obtained by the step (A2') by crystallization.
A method comprising:
(7) Formula (III):

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

[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.]
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, 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.]
a step (A) of producing a compound represented by the formula (II) obtained in the step (A) by crystallization; a step (B) of isolating the compound represented by the formula (II) isolated in the step (B) by amidation with a compound represented by the following formula (IV), formula (V) or formula (VI) and deprotecting two substituents R ¹ ;
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; 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 are each a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, or R ⁷ and R ⁸ taken together are a lower alkylene group.]
Formula (V):

[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):

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

[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.]
A compound represented by the formula:

The present invention makes it possible to produce a compound represented by formula (III) in high yield and high purity. It also makes it possible to produce a compound represented by formula (II), which is a synthetic intermediate of the compound represented by formula (III). The synthetic intermediate represented by formula (II) obtained by 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), it is possible to achieve both high yield and high purity.

The following describes an embodiment of the present invention.

The method of the present invention is a method of producing a compound of formula (III):

[In the formula, R ² , R ³ , R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms.]
The method for producing a compound represented by the formula (I) includes steps (A) to (D) described below.

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

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

[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 compound capable of producing a compound represented by formula (II) by a chemical conversion process.

The method for obtaining the compound represented by formula (I) is not particularly limited, but includes a method in which 2,5-dimethoxy-3-nitroaniline is used as a starting material, a substituent corresponding to R ² is introduced by reductive amination, and the resulting secondary amino group is amidated with an amidation reagent to introduce a moiety containing R ³ and R ^5. As an example of a method for introducing a substituent corresponding to R ² into 2,5-dimethoxy-3-nitroaniline by reductive amination, when R ² is an isobutyl group, a method in which isobutyraldehyde and sodium triacetoxyborohydride are reacted is exemplified. Similarly, when R ² is an n-propyl group, a method in which propionaldehyde and sodium triacetoxyborohydride are reacted is exemplified. As a method for amidating the secondary amino group, the secondary amino group generated by the reductive amination can be amidated under the same conditions as the amidation reaction in step (C) described below, and a specific example is a method in which 2,2,6-trimethyl-1,3-dioxin-4-one is used as an amidation reagent.

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

[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.]
The compound represented by the formula (II) is a novel compound capable of crystallization as described above. The present invention includes the compound represented by the formula (II).

^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. ^R1 is preferably a methyl group.

R ² is a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. R 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-dimethyl butyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, or 2-ethylbutyl group, more preferably methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1,1-dimethylpropyl group, 2,2-dimethylpropyl group, 1,2-dimethylpropyl group, or 1-ethylpropyl group, more preferably ethyl group, n-propyl group, i-butyl group, or 3-methylbutyl group, and most preferably n-propyl group or i-butyl group.

R ³ and R ⁴ are each a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. R ³ and R ⁴ are 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, a 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, a n-propyl group, an i-propyl group, a n-butyl group, an i-butyl group, a sec-butyl group, a tert-butyl group, a 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, a n-propyl group, an i-propyl group, a n-butyl group, an i-butyl group, a sec-butyl group, or a tert-butyl group, and most preferably a methyl group.

R ⁵ and R ⁶ are each a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms. R ⁵ and R ⁶ are 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, a 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, a n-propyl group, an i-propyl group, a n-butyl group, an i-butyl group, a sec-butyl group, a tert-butyl group, a 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, a n-propyl group, an i-propyl group, a n-butyl group, an i-butyl group, a sec-butyl group, or a tert-butyl group, and most preferably a hydrogen atom.

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

The reduction reaction includes, but is 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.), among which alcohol solvents are preferred, and methanol or ethanol are particularly preferred. The reduction reaction can be carried out by stirring the reaction mixture at normal pressure or under pressure at an appropriate temperature (e.g., -80°C to 100°C) for a certain period of time (e.g., 0.1 to 24 hours).

The treatment with the acid may be carried out under conditions that allow the construction 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).

[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.

The present invention is characterized in that in step (B), the compound represented by formula (II) is crystallized, which makes it possible to remove impurities that have been produced in the previous steps. This also contributes to improving the purity of the compound represented by formula (III) that is finally obtained.

The crystallization temperature is not limited, but is preferably -10°C or higher and 50°C or lower, and more preferably -5°C or higher and 30°C or lower.

Preferred solvents for use in the crystallization include, for example, ether-based solvents (diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, cyclopentyl methyl ether, methyl tert-butyl ether, etc.), hydrocarbon-based solvents (hexane, heptane, benzene, toluene, etc.), alcohol-based 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-based solvents (methyl acetate, ethyl acetate, isopropyl acetate, etc.), halogen-based solvents (dichloromethane, chloroform, carbon tetrachloride, etc.), acetonitrile, water, or a mixture of at least two of these solvents. As a mixture of at least two types of solvents, a mixture of ethyl acetate and hexane or heptane, or a mixture of water and methanol is particularly preferred.

[Step (C)]
Step (C) is a step of amidating the compound represented by formula (II) isolated in step (B) with a compound represented by formula (IV), formula (V) or formula (VI) below, and deprotecting the two substituents ^R1 .

[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, X is OR ⁸ or a halogen atom, 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 taken together are 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, and R ⁹ is a linear or branched alkylidene group having 1 to 6 carbon atoms.]

[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. It is preferable to carry out the deprotection after the amidation, since the presence of ^R1 , which is a protecting group for a phenolic hydroxy group, prevents esterification from proceeding as a side reaction in the amidation.

[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 later, so that the aniline amino group of the compound represented by formula (II) reacts with a carboxylic acid equivalent to form an amide bond.

A method of amidation includes a method of reacting with an acid chloride, an acid anhydride, or an ester. For example, a preferred example is a method of amidation with a compound represented by formula (IV), formula (V), or formula (VI) described below to obtain a compound represented by formula (VII) below.

The compound represented by formula (IV), formula (V) or formula (VI) is a compound for amidating the compound represented by formula (II) and introducing a partial structure including the substituents ^R4 and ^R6 of the compound represented by formula (III).

When a compound represented by formula (IV) is used as an amidation reagent, the amino group of a compound represented by formula (II) or an intermediate obtained by removing one or both of the two R ¹ from a compound represented by formula (II) nucleophilically attacks the carbonyl group of a compound represented by formula (IV), eliminating X and forming a new amide bond. At this time, when R ⁷ is a hydrogen atom or when R ⁷ is removed together with the formation of the amide bond, the subsequent step may be carried out as is, but when R ⁷ other than a hydrogen atom remains after amidation, a reaction for removing R ⁷ may be appropriately carried out.

When a compound represented by formula (V) is used as an amidation reagent, the amino group of a compound represented by formula (II) or an intermediate obtained by removing one or both of the two R ¹ from a compound represented by formula (II) undergoes nucleophilic attack on the carbonyl group of a 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, a hydrogen atom is added to R ⁹ by keto-enol tautomerization, resulting in R ^4. That is, the substituent R ⁹ in formula (V) is a substituent that becomes R ⁴ when a hydrogen atom is added during the amidation of a compound represented by formula (II).

When a compound represented by formula (VI) is used as an amidation reagent, the amino group of a compound represented by formula (II) or an intermediate obtained by removing one or both of the two R ¹ from a compound represented by formula (II) nucleophilically attacks one of the two ester carbonyl groups of a compound represented by formula (VI), the ester bond is cleaved, and a new amide bond is formed. After this, elimination of acetone, decarboxylation, and protonation proceed. Since the hydrogen atom bonded by the protonation corresponds to R ⁶ , when a compound represented by formula (VI) is used as an amidation reagent, R ⁶ is a hydrogen atom in the compound represented by formula (II) or formula (III) obtained by the present invention.

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. X is OR 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 .

In the compound represented by formula (IV), when X is OR ⁸ , R 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 taken together form a lower alkylene group. When ^{R 7} and R ⁸ are independent, R ⁷ and R ⁸ 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-dimethyl Preferably, R 7 is a lower butyl group, a 3,3-dimethylbutyl group, a 1-ethylbutyl group, or a 2-ethylbutyl group, more preferably a methyl group, an ethyl group, a n-propyl group, an i-propyl group, a n-butyl group, an i-butyl group, a sec-butyl group, a tert-butyl group, a 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, a n-propyl group, an i-butyl group, or a 3-methylbutyl group, and most preferably an n-propyl group or an i-butyl group. When R ⁷ and R ⁸ are taken together, R ⁷ and R ⁸ are a lower alkylene group. The lower alkylene group includes a linear, branched, or cyclic alkylene group having 1 to 6 carbon atoms. Preferred lower alkylene groups are methylene, ethylene, trimethylene, isopropylidene, 1,1-cyclopentylidene or 1,1-cyclohexylidene, and most preferably isopropylidene.Specific examples of the compound represented by formula (IV) include, when ^R4 is a methyl group, ^R6 is a hydrogen atom and X is ^OR8 , methyl acetoacetate in which ^R7 is a hydrogen atom and ^R8 is a methyl group, ethyl acetoacetate in which ^R7 is a hydrogen atom and ^R8 is an ethyl group, and 2,2,6-trimethyl-1,3-dioxin-4-one in which ^R7 and ^R8 taken together are an isopropylidene group.

In the compound represented by formula (IV), when ^R8 is not present, the above-mentioned substituents that can be used as ^R7 when ^R7 and ^R8 are independent can be used as ^R7 . Specific examples of the compound represented by formula (IV), when ^R4 is a methyl group and ^R6 and ^R7 are hydrogen atoms, include acetoacetic acid in which X is a hydroxy group and acetoacetic acid chloride in which X is a halogen atom.

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

In the compound represented by formula (V), R ⁹ is a linear or branched alkylidene group having 1 to 6 carbon atoms. R 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. A specific example of the compound represented by formula (V) is 4-methyleneoxetan-2-one in which R ⁶ is a hydrogen atom and R ⁹ is a methylene group.

A specific example of the compound represented by formula (VI) is 5-(1-hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione, in which R ⁴ is a methyl group.

When X is a hydroxy group, it is preferable to carry out the amidation using a condensation agent. Examples of condensation agents that can be used include N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-[bis(dimethylamino)methylene]1-H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphate, etc.

The amidation reaction is preferably carried out in the presence of a solvent. Examples of reaction solvents 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.

In the "amidation" reaction in step (C), it is preferable to carry out the reaction in the presence of a base from the viewpoint of improving the product yield and/or shortening the reaction time. Here, the base is preferably, for example, a tertiary amine (triethylamine, N-methylmorpholine, ethyldiisopropylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc.), and particularly preferably ethyldiisopropylamine.

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 low, the reaction tends not to proceed sufficiently.

[Deprotection in step (C)]
The deprotection reaction in step (C) refers to a reaction for removing two ^R1s which are protecting groups for a phenolic hydroxyl group.

When R ¹ is a methyl group, deprotection can be performed with a Lewis acid such as boron tribromide or aluminum chloride, or hydrobromic acid, etc. When R ¹ is a methoxymethyl group, deprotection can be performed with trifluoroacetic acid, hydrogen chloride/ethyl acetate, hydrogen chloride/1,4-dioxane, etc. When R ¹ is a tert-butyl group, deprotection can be performed with trifluoroacetic acid, hydrogen chloride/ethyl acetate, hydrogen chloride/1,4-dioxane, etc. When R ¹ is an acetyl group, deprotection can be performed with an aqueous solution of sodium hydroxide, an aqueous solution of sodium bicarbonate, etc.

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 solvents (methyl acetate, ethyl acetate, isopropyl acetate, etc.), halogen solvents (dichloromethane, chloroform, carbon tetrachloride, etc.), and acetonitrile, and a mixture of two or more of these may be used. Hydrocarbon solvents (hexane, heptane, benzene, toluene, etc.), amide solvents (N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.), and halogen solvents (dichloromethane, chloroform, carbon tetrachloride, etc.) are preferred, with toluene and dichloromethane being particularly preferred.

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.

[Step (D)]
The 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).

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

A reaction solvent is not necessarily required in step (D), but a solvent such as an alcohol-based 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.

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.

[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 those in which R ³ and R ⁴ are methyl groups, R ⁵ and R ⁶ are hydrogen atoms, and R ² is an n-propyl group or an i-butyl group.

After the compound represented by formula (III) is obtained by 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 compound that crystallizes, it is preferable to purify the compound by crystallization after obtaining the compound by step (D). By purifying the compound by crystallization, it is possible to remove impurities generated in the previous steps and obtain the compound with even higher purity.

Preferred solvents for use when compound (III) is obtained by crystallization include, for example, 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.), halogen solvents (dichloromethane, chloroform, carbon tetrachloride, etc.), acetonitrile, water, and mixed solvents of at least two of these. As a mixture of at least two types of solvents, a mixture of ethyl acetate and hexane or heptane, and a mixture of dichloromethane and 2-propanol are particularly preferred.

The crystallization temperature is not limited, but is preferably -10°C or higher and 100°C or lower, and more preferably -5°C or higher and 80°C or lower.

[Method for producing the 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 a nitro group of a compound represented by formula (I); a step (A2') of constructing a 2-pyridone ring by treating the compound obtained in the step (A1') with an acid to obtain a compound represented by formula (II); and a step (B') of isolating the compound represented by formula (II) obtained in the step (A2') by crystallization.

The reduction reaction used in step (A1') in the method for producing the compound represented by formula (II) can be the same as the reduction reaction used in the method for producing the compound represented by formula (III) described above.

The acid treatment in step (A2') in the method for producing the compound represented by formula (II) can be the same as the acid treatment for constructing a 2-pyridone ring to obtain the compound represented by formula (II) as in the method for producing the compound represented by formula (III) described above.

As the crystallization solvent used in the crystallization step in step (B') in the method for producing the compound represented by formula (II), the same solvent for crystallizing the compound represented by formula (II) as in the method for producing the compound represented by formula (III) described above can be used.

The compounds of the present disclosure can be prepared using the methods disclosed herein, as well as certain modifications of the methods 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 may be accomplished as described in the examples below. Reagents, where available, may be purchased commercially, for example, from Tokyo Kasei or other chemical manufacturers.

Below are examples related to the present invention. 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.

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 when the area of all peaks excluding the blank peak is taken as 100% based on the HPLC chromatogram obtained according to the following method. The blank peak refers to the peak detected when a 50% aqueous acetonitrile solution is measured under the following HPLC measurement conditions.

(1) Sample Preparation Dissolve the target sample (2 mg) in 50% aqueous acetonitrile solution to make a total volume of 10 ml to prepare a measurement sample.

(2) HPLC
The measurement sample prepared above is analyzed using HPLC under the following measurement conditions.
[HPLC analysis conditions]
HPLC device: 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,
From 4 minutes to 14 minutes, solution B is 75%.
Solution B was maintained at 75% from 14 minutes to 22 minutes.
From 22 to 23 minutes, solution B is 25%.
Retain 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.

(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 H NMR, 400 MHz) model made by JEOL Ltd. Chemical shifts are expressed as δ (unit: ppm) based on tetramethylsilane, and signals are expressed as s (singlet), d (doublet), t (triplet), m (multiplet), brs (broad singlet), and dd (double doublet), respectively.

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

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

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 reagent, ethyl acetate (200 ml) was added. This reaction solution was cooled with ice and stirred while 2M aqueous potassium carbonate solution (300 ml) was added dropwise over 16 minutes. After the dropwise addition, the reaction vessel was removed from the ice bath and the reaction solution was stirred at room temperature for 27 minutes. Then, the reaction solution was transferred to a separatory funnel, and after a separation operation, 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 mixture was concentrated under reduced pressure again. This azeotropic dehydration procedure was repeated three times, and finally toluene was added to obtain a toluene solution of compound IX-1 (199.77 g).

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. Then, 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 another 2 hours and 37 minutes. The reaction solution was stirred under ice cooling, and ethyl acetate (400 ml) and methanol (30 ml) were added dropwise to the reaction solution. A 2M aqueous potassium carbonate solution (200 ml) was added dropwise to the reaction solution over 17 minutes. After the dropwise addition, the reaction vessel was removed from the ice bath, and the mixture was stirred at room temperature for 35 minutes, and then a liquid separation operation was performed. Next, the separated organic phase was washed with 5% saline (200 ml), and the obtained organic phase was concentrated under reduced pressure. Further, methanol (200 ml) was added, and the solvent replacement 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).

[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 via a step of crystallizing compound II-1:

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 replaced with argon gas three times, and then Pd/C (2.98 g) was added and replaced with hydrogen gas. Then, after stirring at room temperature for 5 hours and 16 minutes, a filtration operation was performed using filter paper and a membrane. The obtained solution was concentrated under reduced pressure, and methanol was added to obtain a methanol solution of the intermediate (110.29 g). 1M hydrochloric acid (54 ml) was added dropwise to this solution over 5 minutes while stirring under ice cooling. After the dropwise addition, 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. Next, the mixture was ice-cooled again, and 2M aqueous potassium carbonate solution (27 ml) was added dropwise over 5 minutes. After the dropwise addition, 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. The organic phase was then separated and washed with 5% saline (100 ml). The organic phase obtained was concentrated under reduced pressure, MeOH (200 ml) was added, and the mixture was concentrated under reduced pressure again. This solvent replacement operation was repeated three times. Methanol was then added to the residue obtained after the three solvent replacement operations, and a slurry-like compound II-1 (140.36 g) was obtained. Water (40 ml) was added dropwise to this slurry over 12 minutes while stirring. After the dropwise addition, 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 ice-cooled methanol and water mixed in a ratio of 1:1, and the resulting solid was 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) with a three-step yield of 84% and an HPLC purity of 99.8%. ¹ H-NMR (CDCl ₃ ) δ: 6.19 (1H, d, J = 0.9 Hz), 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 = 0.9 Hz), 1.86 (1H, sep, J = 6.9 Hz), 0.70 (6H, d, J = 6.4 Hz). LC/MS (ESI): m/z 291 ([M+H] ⁺ ).

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 stirred. N,N-diisopropylethylamine (9.79 g, 75.8 mmol) was added thereto, and the temperature was raised to 110 ° C. Then, after heating and 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 completion of the dropwise addition, the mixture was stirred for 3 hours, and the reaction was tracked by HPLC. Since the raw material 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. Then, 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 performed. 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 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.

Step C-1B: Conversion of Compound VII-1 to Compound X-1 A toluene solution of Compound VII-1 diluted with dichloromethane (200 ml) was dropped over 45 minutes into a 1M solution of boron tribromide in dichloromethane (400 ml) while stirring under ice cooling. After the dropwise addition, 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, and then water (228 ml) was dropped over 48 minutes while stirring under ice cooling. Then, the mixture was stirred at room temperature for 2 hours and 56 minutes, and then cooled again on ice, and methanol (688 ml) was dropped over 6 minutes, and the mixture was stirred 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, and a liquid separation operation was performed. The organic phase was separated, and ethyl acetate (500 ml) was added to the aqueous phase, and extraction operations were performed twice. The organic phase obtained was concentrated under reduced pressure, ethanol (200 ml) was added, and the solvent replacement procedure of concentrating under reduced pressure again 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 filtered and dried under reduced pressure at 40°C to obtain compound X-1 (16.94 g) in two steps (71%).

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 dropwise addition of aqueous ammonia (175 ml) over 34 minutes. After completion of the dropwise addition, 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. The resulting residue was then added with isopropanol, and the solvent replacement operation 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 yield of 53% from compound X-1 and in a yield of 32% 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]+).

[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:

To a solution of 2,5-dimethoxy-3-nitroaniline (compound VIII, 10.0 g, 50.5 mmol) in tetrahydrofuran (100 ml), isobutyraldehyde (5.1 ml, 55.6 mmol) and NaBH(OAc) ₃ (21.4 g, 101 mmol) were added at room temperature, and the mixture was stirred at room temperature for 7.5 hours. Then, isobutyraldehyde (0.92 ml, 10.1 mmol) was added, and the mixture was stirred at room temperature for 16.5 hours. After that, isobutyraldehyde (0.92 ml, 10.1 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After adding a 10% aqueous sodium bicarbonate solution (200 ml) to the reaction solution under ice cooling, the mixture was extracted with ethyl acetate (400 ml) and chloroform. The obtained organic phase was washed twice with water (100 ml). Then, the addition of methanol and concentration under reduced pressure were repeated, and a methanol solution (500 ml) of compound IX-1 was obtained. After the methanol solution of compound IX-1 was purged with argon, Pd/C (1.5 g, 10% w/w) was added. Then, the reaction vessel was purged with hydrogen gas, and the mixture was stirred at room temperature for 6 hours. Then, the reaction solution was filtered through Celite, and the Celite was washed with methanol (100 ml). The resulting solution was concentrated under reduced pressure to obtain a crude product of compound XI (11.9 g). To a solution of the crude product of 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. Then, the mixture was heated and stirred for 5 minutes, and 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 did not terminate, 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. Then, ethyl acetate (50 ml) was added to the reaction solution under ice cooling, and the mixture was washed twice with 1N HCl (15 ml) and with 10% saline (15 ml). The obtained organic phase was concentrated under reduced pressure to obtain a crude product of compound XII. A dichloromethane (27 ml) solution of the crude product of compound XII was added to a dichloromethane solution (40 ml, 40.1 mmol) of 1M boron tribromide at 0° C., and the mixture was stirred at 40° C. for 23 hours. Then, methanol (60 ml) was added to the reaction solution at 0° C., and the reaction solution was stirred at 40° C. for 2 hours, and the reaction solution was 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. Then, the mixture was extracted four times with dichloromethane, and the obtained organic phase was filtered and then concentrated under reduced pressure. The obtained residue was dissolved in a small amount of dichloromethane, and MTBE was added dropwise. The resulting solid was filtered, washed with MTBE, and dried under reduced pressure to give 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%) in a yield of 36% from Compound VIII. The results are shown in Table 1.

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

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. Then, 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 reagent, 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 completion of the dropwise addition, the reaction vessel was removed from the ice bath and the reaction solution was stirred at room temperature for 30 minutes. Then, the reaction solution was transferred to a separatory funnel, and after a separation operation, 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 mixture was concentrated under reduced pressure again. This azeotropic dehydration procedure was repeated three times, and finally toluene was added to obtain a toluene solution of compound IX-2 (9.88 g).

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. Then, 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 another 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. A 2M 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 obtained organic phase was concentrated under reduced pressure. Further, methanol (10 ml) was added, and the solvent replacement operation of concentrating under reduced pressure was repeated three times, and finally methanol was added to obtain a methanol solution of Compound I-2 (18.98 g).

[Example 2]
Synthesis of 4,6-dimethyl-1-propylpyrido[3,2-g]quinoline-2,5,8,10(1H,9H)-tetraone (compound III-2) by a method via a step of crystallizing compound II-2:

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 replaced with argon gas three times, and then Pd/C (150 mg) was added and replaced with hydrogen gas. Then, the mixture was stirred at room temperature for 4 hours and 15 minutes, and then filtered using a membrane. The resulting solution was concentrated under reduced pressure, and methanol was added to obtain a methanol solution of an intermediate (4.34 g). While stirring this solution at room temperature, 1M hydrochloric acid (2.7 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Next, the mixture was cooled with ice, and 2M 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, and then dichloromethane (20 ml) was added, and a liquid separation operation was performed. Subsequently, the organic phase was separated and washed with 5% saline (5 ml). The obtained organic phase was concentrated under reduced pressure and recrystallized from ethyl acetate/hexane to give 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 = 7.3 Hz), 3.81 (3H, s), 3.58 (3H, s), 2.52 (3H, d, J = 1.4 Hz), 1.55 (2H, m), 0.79 (3H, t, J = 7.3 Hz). LC/MS (ESI): m/z 277 ([M+H] ⁺ ).

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 stirred. N,N-diisopropylethylamine (347 μl, 1.99 mmol) was added thereto, and the temperature was raised to 110° C. Then, 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 completion of the dropwise addition, the mixture was stirred for 2 hours, and 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 1M hydrochloric acid (5 ml) and water (5 ml), and the obtained organic phase was concentrated under reduced pressure. Then, toluene was added to the residue, and the azeotropic dehydration operation of concentrating under reduced pressure 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 dichloromethane solution (10 ml) of 1M boron tribromide while stirring under ice cooling. After the dropwise addition, 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, and then water (5.7 ml) was added dropwise while stirring under ice cooling. Then, the mixture was stirred at room temperature for 1 hour, and then cooled again on ice, and methanol (17.2 ml) was added dropwise, and the mixture was stirred 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, and a liquid separation operation was performed. 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.

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 dropwise addition of aqueous ammonia (6 ml). After completion of the dropwise addition, 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 addition of hexane. After stirring at room temperature for 3 hours, the resulting solid was filtered and washed with hexane/ethyl acetate = 1/1 to obtain 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 58% yield from compound II-2 and 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]+).

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

 

 

Claims (8)

Formula (III):

[In the formula, R ² , R ³ , R ⁴ , R ⁵ and R ⁶ each independently represent 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):

[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.]
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, 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.]
a step (A) of producing a compound represented by the formula (II) obtained in the step (A) by crystallization; a step (B) of isolating the compound represented by the formula (II) isolated in the step (B) by amidation with a compound represented by the following formula (IV), formula (V) or formula (VI) and deprotecting two substituents R ¹ ;
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; 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 are each a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, or R ⁷ and R ⁸ taken together are a lower alkylene group.]
Formula (V):

[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):

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

[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.]
A method for producing a compound represented by formula (I):

[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.]
a step (A1') of reducing the nitro group of a compound represented by formula (II), a step (A2') of constructing a 2-pyridone ring by treating the compound obtained by the step (A1') with an acid to obtain a compound represented by formula (II), and a step (B') of isolating the compound represented by formula (II) obtained by the step (A2') by crystallization.
A method comprising: Formula (III):

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

[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.]
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, 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.]
a step (A) of producing a compound represented by the formula (II) obtained in the step (A) by crystallization; a step (B) of isolating the compound represented by the formula (II) isolated in the step (B) by amidation with a compound represented by the following formula (IV), formula (V) or formula (VI) and deprotecting two substituents R ¹ ;
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; 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 are each a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, or R ⁷ and R ⁸ taken together are a lower alkylene group.]
Formula (V):

[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):

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

[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.]
A compound represented by the formula: