JP2001233859A - New method for producing anti-helicobacter pylori compound and its intermediate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an anti-Helicobacter pylori compound, and to provide an intermediate for producing the compound. SOLUTION: This method for synthesizing a 1-hydroxyquinon-4-one derivative represented by the general formula (2), characterized by subjecting an oxide derivative represented by the general formula (1) to a reducing reaction. The method for producing the oxide derivative represented by the general formula (1), characterized by oxidizing a compound represented by the general formula (3). And a quinoline derivative represented by the general formula (4) or its 1-oxide.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an intermediate which is useful for producing a drug, an anti-Helicobacter pylori agent, and a method for producing the same.

[0002]

2. Description of the Related Art Helicobacter pylori (Helicobacte)
r pylori) is a pathogenic bacterium discovered in 1983, and has peptic ulcers (eg, gastric or duodenal ulcers),
Inflammation (eg gastritis), diseases of the upper gastrointestinal tract such as gastric cancer, M
It is said that ALT (mucosa-associatedlymphoid tissue) is a background agent of Linha species or chronic heart disease. At present, studies on the treatment of Helicobacter pylori infection are being actively conducted, and many such treatments have been reported as follows, including those for the purpose of eradication and those for the prevention of recurrence. For example, single drug administration such as bismuth, antibiotics, proton pump inhibitor (PPI) or anti-ulcer drug, or multiple drug combination method combining the above drugs (two drug combinations, three drug combinations)
(Internal Medicine, Special Issue, Vol. 78, No. 1, 1996, Nankodo). However, the above-mentioned treatments still have to be solved, for example, the frequency of administration, the need for large doses more than the usual dose, the occurrence of diarrhea and constipation due to drug administration, the development of resistant bacteria, etc. There are many points. Under such circumstances, the present applicant has found an excellent anti-Helicobacter pylori agent (JP-A-11-29479). The active ingredient 1-hydroxyquinolin-4-one-based compound of the Helicobacter pylori agent was obtained by a fermentation method.

As a conventional chemical synthesis method, a chemical synthesis method of a 2-alkenylquinolin-4-one compound has been known, but the final compound obtained by the production method is the active ingredient 1 of the aforementioned Helicobacter pylori agent. Unlike hydroxy-quinolin-4-one compounds, it is reported that hydroxy is not present at the 1-position of the quinoline skeleton (European Patent Publication 374765).

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide an intermediate for producing an excellent anti-Helicobacter pylori agent and a method for producing the same.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies to obtain a 1-hydroxyquinolin-4-one derivative obtained by a fermentation method in advance by chemical synthesis.
The present invention has been completed by finding a synthesis method via a useful novel intermediate shown below. The present synthesis method and intermediates have also made it possible to obtain 1-hydroxyquinolin-4-one derivatives and their analogs, which are anti-Helicobacter perylori compounds. That is, the present invention specifically relates to the general formula

[0006]

Embedded image (The symbols in the formula have the following meanings: R ¹ : optionally substituted C ₁ -C ₂₀ alkyl, optionally substituted cycloalkyl, optionally substituted C ₁
-C ₂₀ alkylsilyl, optionally substituted arylsilyl, optionally substituted C ₁ -C ₂₀ alkylarylsilyl, optionally substituted C ₁ -C ₂₀ alkoxycarbonyl, optionally substituted C ₁ -C ₂₀ alkylsulfonyl,
Or optionally substituted arylsulfonyl R ² : optionally substituted C ₁ -C ₂₀ alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted C ₁ -C ₂₀ alkoxycarbonyl, carboxyl, optionally substituted mono- or di-substituted C ₁ -C ₂₀ alkylaminocarbonyl, or optionally substituted mono- or di-substituted arylaminocarbonyl R ³ : optionally substituted C ₁ -C ₂₀ alkyl or optionally substituted C ₂ -C ₂₀ alkenyl. The same applies hereinafter. Wherein the oxide derivative (1) represented by the general formula is subjected to a reduction reaction.

[0007]

Embedded image (The symbols in the formulas have the same meanings as described above.) 1-Hydroxyquinolin-4-one. Preferably R ³ is alkenyl. Further, the present invention provides a compound represented by the general formula

[0008]

Embedded image Characterized by oxidizing

[0009]

Embedded image It is a manufacturing method of. General formula

[0010]

Embedded image Or a 1-oxide form thereof.

[0011]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.
In the present specification, “carbon chain” means one carbon atom unless otherwise specified.
A straight or branched carbon chain having from 20 to 20 is meant. “C ₁ -C ₂₀ alkyl” includes methyl, ethyl, isopropyl, heptyl, nonyl, undecyl, icosyl and the like. “C ₂ -C ₂₀ alkenyl” includes vinyl, 1-propenyl, 2-heptenyl, 1-nonenyl,
2-nonenyl, 1-undecyl, 2-undecyl and the like can be mentioned. "Cycloalkyl" includes 3 carbon atoms
And 8 to 8 saturated carbocycles, such as cyclopropyl or cyclohexyl. "Halogen" is I, Br, F or Cl.

The "aryl" is a 6- to 14-membered carbocyclic aryl or the heterocyclic aryl, and is preferably phenyl, naphthyl, pyridyl, thienyl, oxazole, thiazole or the like. “C ₁ -C ₂₀ alkylsilyl” means a silyl substituted with one to three of the above-mentioned alkyls, such as trimethylsilyl, triisopropylsilyl, or t-butyldimethylsilyl. "C ₁ -C
_"20 alkylarylsilyl" means the above-mentioned silyl substituted with 1 to 3 alkyl and aryl, and is, for example, t-butyldiphenylsilyl. "C ₁ -C ₂₀ alkoxycarbonyl" means a group in which -O-carbonyl is bonded to the above-mentioned alkyl, for example, methoxycarbonyl or t-
Butoxycarbonyl and the like. “C ₁ -C ₂₀ alkylsulfonyl” means a group in which a sulfonyl is bonded to the above-mentioned alkyl, such as methanesulfonyl or benzylsulfonyl. “Arylsulfonyl” means a group in which a sulfonyl is bonded to the above-mentioned aryl, such as benzenesulfonyl or p-toluenesulfonyl. `` Optionally substituted mono- or di-substituted C <sub>1</sub> -C <sub>20</sub> alkylaminocarbonyl '' or `` optionally substituted mono- or di-substituted arylaminocarbonyl '' is the above-mentioned optionally substituted alkyl or substituted And one or two of the above-mentioned aryl which may be substituted with a hydrogen atom of aminocarbonyl, such as methylaminocarbonyl, dimethylaminocarbonyl, butylaminocarbonyl, phenylaminocarbonyl or diphenylaminocarbonyl. “Acyl” is a group in which a carbonyl is bonded to the above-mentioned alkyl or aryl, and is, for example, acetyl, benzoyl or the like.

As long as the object of the present invention is achieved, “optionally substituted” is not particularly limited as long as it is a substituent that can be produced by those skilled in the art. Specifically, "substituted alkyl",
Substituents in "substituted cycloalkyl", "substituted alkylsilyl", "substituted aryl" or "substituted arylsilyl" are any substituents such as alkyl, alkenyl, alkynyl, hydroxy ,
Indicates that it may be substituted with a substituent such as amino, mono- or di-substituted alkylamino, nitro, carboxyl, alkoxycarbonyl, or oxo (= O). Further, those substituents may be protected by a suitable protecting group.

[0014] The present invention intermediates, alkyl is preferably even if R ¹ is substituted, further preferably is an alkyl or substituted optionally with R ¹ alkyl and R ³ may be substituted is has been replaced Alkenyl which may be present is preferred. Depending on the type of the substituent of the present invention, a geometric isomer or a tautomer may exist, but the present invention includes a separated form or a mixture of these isomers. Further, the compound of the present invention may have an asymmetric carbon atom, and (R) -form and (S) -form optical isomers based on this may exist. The present invention embraces all of these optical isomer mixtures and isolated ones.

The compound (4) of the present invention may form a base addition salt or a salt with an acid depending on the type of the substituent.
Such salts are pharmaceutically acceptable salts, preferably inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, and oxalic acid. Acid addition salts with organic acids such as acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, or glutamic acid, sodium, potassium And inorganic bases containing metals such as magnesium, calcium, or aluminum, salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, or ornithine, and ammonium salts. Furthermore, the present invention also includes various hydrates, solvates and polymorphic substances of the compound (4) of the present invention and salts thereof.

(Preparation Method) The compound of the present invention and its pharmaceutically acceptable salt can be prepared by applying various known synthetic methods by utilizing the characteristics based on the basic skeleton or the type of the substituent. Can be. At that time, depending on the type of the functional group, it is effective for production technology to replace the functional group with an appropriate protecting group at the stage of raw material or intermediate, that is, a group that can be easily converted to the functional group. There is. Thereafter, the desired compound can be obtained by removing the protecting group as necessary. Examples of such a functional group include a hydroxyl group, an amino group, and a carboxyl group.
As such a protecting group, for example, Green (Green)
e) and Wuts, “ProtectiveGroups”
in Organic Synthesis ", 2nd edition, and these may be appropriately used depending on the reaction conditions. Hereinafter, the intermediate of the present invention and a method for producing the intermediate will be described in detail. First manufacturing method

[0017]

Embedded image This production method comprises subjecting an oxyto derivative (1) or a quinoline compound (3) represented by the general formula to a reduction reaction to give a 1-hydroxyquinolin-4-one compound (2) or 1H-quinolin-4.
This is a method for obtaining an -one compound (4). This reduction reaction is carried out in the presence of a palladium catalyst such as palladium-carbon (Pd-C) and a hydrogen donor such as 1,4-cyclohexadiene which are used in the reduction reaction with the oxytoxide (1) or the quinoline compound (3). Organic solvents inert to the reaction, for example, aromatic hydrocarbons such as benzene, toluene or xylene, ethers such as cyclohexanediene, tetrahydrofuran (THF), dioxane, diethyl ether, dichloromethane, 1,2-dichloroethane (DCE) ), Or a halogenated hydrocarbon such as chloroform, a solvent such as pyridine, N, N-dimethylformamide (DMF), ethyl acetate, or acetonitrile, or without a solvent. The reaction temperature is appropriately selected depending on the type of the reactive derivative. Second manufacturing method

[0018]

Embedded image This production method is a method for obtaining the oxide compound (1) of the present invention by oxidizing the quinoline compound represented by the general formula (3). This oxidation reaction is carried out by the quinoline compound (3)
M-chloroperbenzoic acid (m-CPBA) used in the oxidation reaction
The reaction is carried out in the presence of a peroxide or a metal oxide such as a halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane (DCE), and chloroform. The reaction temperature is appropriately selected depending on the type of the base chamber. Third manufacturing method

[0019]

Embedded image (In the formula, R ⁴ represents 1-halogenated alkyl, and R ⁵ represents 1-alkylalkenyl or alkenyl. The same applies hereinafter.) In the present production method, 1-halogenated halogen represented by the general formula (5) is used. In this method, an alkene compound (6) is obtained by reacting an alkyl compound with a vinyl metal compound. This reaction is DIBA
An organic solvent inert to the reaction in the presence of an aluminum hydride reagent such as L or another metal reagent and a vinyl metal compound formed from an alkyne, and a palladium catalyst such as (tetrakistriphenylphosphine) palladium, for example, a hydrocarbon such as hexane , Aromatic hydrocarbons, ethers, pyridine, or a solvent such as DMF. The reaction temperature is appropriately selected depending on the type of the base chamber. 4th manufacturing method

[0020]

Embedded image (In the formula, R ⁶ represents C ₁ -C ₂₀ alkyl. The same applies hereinafter.) The present production method comprises reacting a quinoline oxide compound represented by the general formula (7) with an acid halide to form a 1-alkyl halide. This is a method for obtaining compound (5). The reaction is carried out using an acid halide with respect to the quinoline oxyto compound (7) in the presence or absence of a metal salt base or an organic base, in an organic solvent inert to the reaction, for example, aromatic hydrocarbons, ethers , Halogenated hydrocarbons, pyridine,
The reaction is performed in a solvent such as DMF, ethyl acetate, or acetonitrile. The reaction temperature is appropriately selected depending on the type of the substrate. Fifth manufacturing method

[0021]

Embedded image This production method comprises reacting a quinolone compound represented by the general formula (8) with an alkyl halide, a silyl halide, or an acid halide to form a quinoline compound (3).
Is a way to get The reaction is carried out using an alkyl halide, a silyl halide, an acid halide, or the like with respect to the quinolone compound (8), in the presence or absence of a metal salt base or an organic base, in an organic solvent inert to the reaction. , For example, aromatic hydrocarbons such as benzene, toluene, xylene,
Cyclohexanediene, tetrahydrofuran (TH
F), dioxane, ethers such as diethyl ether,
Dichloromethane, 1,2-dichloroethane (DCE),
Alternatively, the reaction is performed in a solvent such as a halogenated hydrocarbon such as chloroform, pyridine, N, N-dimethylformamide (DMF), ethyl acetate, or acetonitrile. The reaction temperature is appropriately selected depending on the type of the substrate. 6th manufacturing method

[0022]

Embedded image (The symbol R7 in the formula means C ₁ -C ₁₇ alkyl.
The same applies hereinafter. This production method is a method for obtaining a hydroxyalkenyl compound (10) by reacting an aldehyde compound represented by the general formula (9) with a vinyl metal compound. This reaction is DI
In the presence of an aluminum hydride such as BAL or a vinyl metal compound generated from another metal reagent and alkyne, an organic solvent inert to the reaction, for example, hydrocarbons such as hexane, aromatic hydrocarbons, ethers, pyridine, or This is performed in a solvent such as DMF. The reaction temperature is appropriately selected depending on the type of the base chamber. 7th manufacturing method

[0023]

Embedded image (The symbol R ⁸ in the formula means acyl. The same applies hereinafter.)

This production method is a method for obtaining an acyloxyalkenyl compound (11) by reacting a hydroxyalkenyl compound represented by the general formula (10) with an acid halide or an acid anhydride. The reaction is carried out by using an acid halide, an acid anhydride or the like with the hydroxyalkenyl compound (10) in the presence or absence of a metal salt base or an organic base, in an organic solvent inert to the reaction, for example, benzene. , Toluene, xylene and other aromatic hydrocarbons, cyclohexanediene, tetrahydrofuran (TH
F), dioxane, ethers such as diethyl ether,
Dichloromethane, 1,2-dichloroethane (DCE),
Alternatively, the reaction is performed in a solvent such as a halogenated hydrocarbon such as chloroform, pyridine, N, N-dimethylformamide (DMF), ethyl acetate, or acetonitrile. The reaction temperature is appropriately selected depending on the type of the substrate. Eighth manufacturing method

[0025]

Embedded image

This production method comprises the steps of: an acyloxyalkenyl compound represented by the general formula (11) and a metal compound such as palladium;
In this method, an alkenyl compound (12) is obtained by reacting with a phosphorus compound such as phosphine or a hydrogen donor such as formic acid. In the present reduction reaction, in the presence of an acyloxyalkenyl compound (13) and a palladium catalyst such as palladium acetate, a hydrogen donor such as formic acid, and a phosphite or phosphine such as triethyl phosphite or an organic solvent inert to the reaction, for example, benzene , Toluene, or xylene and other aromatic hydrocarbons, cyclohexanediene, tetrahydrofuran (THF), dioxane, diethyl ether and other ethers, dichloromethane, 1,2-dichloroethane (DCE), and halogenated hydrocarbons such as chloroform , Pyridine, N, N-dimethylformamide (DM
The reaction is performed in a solvent such as F), ethyl acetate, or acetonitrile, or without a solvent. The reaction temperature is appropriately selected depending on the type of the reactive derivative. 9th manufacturing method

[0027]

Embedded image This production method is based on 2-methylquinoline-N represented by the general formula (13).
-By reacting an oxide compound with an acid anhydride
-A method for obtaining an acyloxymethyl compound (14). The reaction is carried out in the presence of an acid anhydride or the like with respect to the 2-methylquinoline-N-oxide compound (13), an organic solvent inert to the reaction, for example, aromatic hydrocarbons such as benzene, toluene, and xylene;
Cyclohexanediene, tetrahydrofuran (TH
F), dioxane, ethers such as diethyl ether,
Dichloromethane, 1,2-dichloroethane (DCE),
Alternatively, the reaction is performed in a solvent such as a halogenated hydrocarbon such as chloroform, pyridine, N, N-dimethylformamide (DMF), ethyl acetate, or acetonitrile. The reaction temperature is appropriately selected depending on the type of the substrate. 10th manufacturing method

[0028]

Embedded image This production method comprises reacting a 2-acyloxymethyl compound represented by the general formula (14) with an acid or a base.
This is a method for obtaining a 2-hydroxymethyl compound (15). The reaction is carried out by reacting the 2-acyloxymethyl compound (14) with an inorganic acid such as hydrochloric acid or sulfuric acid, an acid such as an organic sulfonic acid such as p-toluenesulfonic acid, an inorganic base such as sodium hydroxide, or an organic acid. In addition to organic bases such as amines, organic solvents inert to the reaction in the presence of water, alcohol, or amine, for example, aromatic hydrocarbons such as benzene, toluene, and xylene, cyclohexanediene, tetrahydrofuran (THF), Ethers such as dioxane and diethyl ether; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane (DCE) or chloroform; and solvents such as pyridine, N, N-dimethylformamide (DMF), ethyl acetate, and acetonitrile It takes place inside. The reaction temperature is appropriately selected depending on the type of the substrate. Although the production method and the synthesis method of the present invention have been described in detail, the present invention also includes a combination of the above-mentioned production methods in order to obtain an anti-Helicobacter pylori compound. As a preferred combination, the above compound (1) is used as a raw material and subjected to the above-mentioned second production method, and then subjected to the third production method to obtain a 1-hydroxyquinolin-4-one compound. The present invention has enabled a total chemical synthesis of anti-Helicobacter phyllo compounds. The following is an example of a total synthesis scheme of a typical anti-Helicobacter phylloyl agent.

[0029]

Embedded image (The symbol Hal in the formula means halogen.)

[0030]

Embedded image

(Production Method of Starting Compound) The starting compound of the above-mentioned production method is commercially available or can be easily synthesized by a method known to those skilled in the art. For example, the starting compound of the compound of the present invention can be obtained by carrying out a reaction according to the method described in the document of J. Am. Chem. Soc., 70, 2402 (1948).

[0032]

According to the present invention, the synthetic route to the final anti-Helicobacter pylori compound and the novel intermediate via it are as described above. That is, the present invention is useful as a novel synthetic method for producing a quinolone derivative useful as an anti-Helicobacter pylori compound and an analog thereof, and as an intermediate via the process.

[0033]

The present invention will be described below in more detail with reference to examples. The compounds of the present invention are not limited to the compounds described in the following examples. ^{In 1} H and ¹³ C NMR, tetramethylsilane (δ 0.00 ppm) was used as an internal standard. The following abbreviations are used in the following examples. SCC: silica gel column chromatography, TL
C: thin-layer chromatography, THF: tetrahydrofuran, DMF: N, N-dimethylformamide Example 1 4-benzyloxy-2,3-dimethylquinoline 2,3-dimethyl-1H-quinolin-4-one 2.000 g (11.56 mmol)
Was suspended in 20 ml of DMF. 4.792 g of potassium carbonate (34.68 mm
ol) and 2.196 g (17.34 mmol) of benzyl chloride 6
Stirred at 0 ° C. for 29 hours. After filtration, 60 ml of ethyl acetate was added to the filtrate, and the mixture was washed six times with 10 ml of water. After concentration, the residue was purified by SCC (hexane-ethyl acetate = 3/1) to obtain 2726 mg of the title compound as a colorless solid.

¹ H NMR (CDCl ₃ ) δ 2.34 (3 H, s), 2.69 (3 H, s), 5.05 (2 H, s), 7.37-7.52
(6H, m), 7.60 (1H, ddd, J = 7.0Hz, 7.0Hz & 1.0Hz), 8.0
0-8.02 (2H, m) ¹³ CNMR (CDCl ₃ ) δ12.5,24.2,76.1,121.7,121.8,122.7,125.5,12
8.0, 128.4, 128.7, 128.7, 136.7, 147.8, 159.5, 160.
8 TLC: Rf 0.43 (hexane-ethyl acetate 1/1)

Example 2 4-Benzyloxy-2,3-dimethylquinoline-1-oxide 2316 mg (9.30 mmol) of the compound obtained in Example 1 was dissolved in 46 ml of chloroform. After the temperature was adjusted to 0 ° C., 1846 mg (10.7 mmol) of m-chloroperbenzoic acid (m-CPBA) was added and the mixture was added at 30 ° C.
And stirred at room temperature for 22 hours. After concentration, the residue was purified by SCC (ethyl acetate → chloroform-methanol = 20/1) to obtain 2100 mg of the title compound as a colorless solid. ¹ H NMR (CDCl ₃ ) δ 2.36 (3 H, s), 2.79 (3 H, s), 5.06 (2 H, s), 7.30-7.50
(5H, m), 7.60 (1H, dd, J = 9.0Hz & 9.0Hz), 7.75 (1H, d
d, J = 9.0Hz & 9.0Hz), 8.04 (1H, d, J = 9.0Hz), 8.77 (1H,
d, J = 9.0Hz) TLC: Rf 0.25 (ethyl acetate)

Example 3 4-benzyloxy-2-chloromethyl-3-methylquinoline 886.8 mg (3.18 mmol) of the compound obtained in Example 2 was dissolved in 17 ml of acetonitrile. 879mg potassium carbonate
(6.36 mmol) and 787 mg of p-toluenesulfonyl chloride
(4.13 mmol) was added and the mixture was stirred at room temperature for 34 hours. After filtration, the filtrate was concentrated. The residue was purified by SCC (hexane-ethyl acetate = 5/1) to give the title compound 56 as a colorless solid.
2.1 mg were obtained. _{^{1 HNMR (CDCl 3) δ2.51 (}} 3H, s), 4.87 (2H, s), 5.09 (2H, s), 7.40-7.60
(6H, m), 7.68 (1H, ddd, J = 8.0Hz, 8.0Hz & 1.0Hz), 8.0
4 (1H, d, J = 8.0Hz), 8.07 (1H, d, J = 8.0Hz) TLC: Rf 0.36 (hexane-ethyl acetate 5/1)

Example 4 4-benzyloxy-3-methyl-2- (2-nonenyl) quinoline 66 mg (0.59 mmol) of 1-octyne was added with 0.95 M
0.62 ml (0.65 mmol) of a diisobutylaluminum hydride (DIBAL) hexane solution was added. Stirred at 60 ° C. for 7 hours. After returning to room temperature, hexane was distilled off with a vacuum pump. This was dissolved in 0.1 ml of THF. 12.8 mg of the compound obtained in Example 3 and 21.7 mg of Pd (PPh ₃ ) ₄
It was dissolved in 0.1 ml of HF. The solution containing the previously prepared vinyl aluminum compound was added thereto, and the mixture was stirred at room temperature for 26 hours. After adding 0.03 ml of water, 0.3 ml of ethyl acetate was added. After filtration, the filtrate was concentrated. The residue was purified by SCC (hexane-ethyl acetate = 8/1) to obtain 3.2 mg of the title compound as a yellow liquid. ¹ H NMR (CDCl ₃ ) δ 0.86 (3 H, t, J = 7.0 Hz), 1.20-1.40 (8 H, m), 2.02 (2 H, d
t, J = 7.0Hz & 7.0Hz), 2.37 (3H, s), 3.72 (2H, dd, J = 6.0
Hz & 1.0Hz), 5.06 (2H, s), 5.48 (1H, dtt, J = 15.0Hz,
7.0Hz & 1.0Hz), 5.67 (1H, dtt, J = 15.0Hz, 6.0Hz & 1.0
Hz), 7.26-7.55 (6H, m), 7.63 (1H, ddd, J = 8.0Hz, 7.0H
z & 1.0Hz), 8.02 (1H, dd, J = 8.0Hz & 1.0Hz), 8.05 (1H,
d, J = 7.0Hz) TLC: Rf 0.50 (hexane-ethyl acetate 5/1)

Example 5 4-benzyloxy-3-methyl-2- (2-nonenyl) quinoline-1
-Oxide 5.8 mg (0.015 mmol) of the compound obtained in Example 4 was dissolved in 0.1 ml of chloroform. m-chloroperbenzoic acid (m-CPB
A) A 0.1 mg solution of 3.2 mg (0.018 mmol) in chloroform at 0 ° C.
And stirred at 0 ° C. for 1 hour. After concentration, the residue is S
Purification by CC (toluene-ethyl acetate = 2/1) gave 2.9 mg of the title compound as a yellow liquid. ¹ H NMR (CDCl ₃ ) δ 0.85 (3 H, t, J = 7.0 Hz), 1.15-1.40 (8 H, m), 1.99 (2 H,
dt, J = 7.0Hz & 7.0Hz), 2.36 (3H, s), 3.95 (2H, d, J = 7.
0Hz), 5.04 (3H, s), 5.55-5.75 (2H, m), 7.35-7.60 (6H,
m), 7.71 (1H, dd, J = 7.0Hz & 7.0Hz), 8.03 (1H, d, J = 7.
0Hz), 8.79 (1H, d, J = 7.0Hz) TLC: Rf 0.38 (toluene-ethyl acetate 2/1)

Example 6 1-Hydroxy-3-methyl-2- (2-nonenyl) -1H-quinoline
-4-one 1.8 mg (0.0046 mmol) of the compound obtained in Example 5 and 10%
-A mixture of 1 mg of palladium carbon under a stream of argon,
0.1 ml of 1,4-cyclohexadiene was added. After stirring at room temperature for 1 hour, filtration was performed. After concentration, the residue was purified by SCC (benzene-acetone = 3/2) to obtain 1.3 mg of the title compound as a colorless solid. ¹ H NMR (CD ₃ OD) δ 0.85 (3 H, t, J = 7.0 Hz), 1.22-1.38 (8 H, m), 2.00-2.06
(2H, m), 2.21 (3H, s), 3.78 (2H, br d, J = 4,0Hz), 5.58
-5.61 (2H, m), 7.43 (1H, ddd, J = 8.0Hz, 7.0Hz & 1.0H
z), 7.75 (1H, ddd, J = 8.0Hz, 7.0Hz & 1.0Hz), 7.97 (1H,
br d, J = 8.0Hz), 8.29 (1H, dd, J = 8.0Hz & 1.0Hz) ¹³ CNMR (CD ₃ OD) δl1.5,14.3, 23.6, 29.8, 30.3, 32.6, 32.8, 33.5, 1
16.0, 116.3, 124.3, 124.6, 125.2, 126.2, 133.1, 13
5.1, 140.9, 152.1, 175.5 (br) TLC: Rf 0.27 (benzene-acetone 3/2)

Example 7 2-Acetoxymethyl-4-benzyloxy-3-methylquinoline 3394 mg (14.10 mmol) of the compound obtained in Example 2 was dissolved in 16 ml of acetic anhydride, and the solution was stirred at room temperature.
Time stirred. After putting on 100 g of ice, the precipitated solid was collected by filtration and washed 10 times with 10 ml of distilled water. After concentration, the residue was purified by SCC (hexane: ethyl acetate = 2: 1) to obtain 3563 mg of the title compound as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ 2.18 (3H, s), 2.38 (3H, s), 5.09 (2H, s), 5.39 (2H,
s), 7.38 -7.54 (6H, m), 7.67 (1H, ddd, J = 7.0Hz, 7.0H
z & 1.0Hz), 8.05 (1H, dd, J = 7.0Hz & 1.0Hz), 8.08 (1
(H, d, J = 7.0Hz) TLC: R _f 0.36 (n-hexane-AcOEt2 / 1)

Example 8 4-Benzyloxy-2-hydroxymethyl-3-methylquinoline 3970 mg (12.17 mmol) of the compound obtained in Example 7 was dissolved in 60 ml of methanol. 730mg sodium hydroxide
(18.25 mmol) dissolved in 20 ml of distilled water was added and stirred at room temperature for 12 hours. The pH was adjusted to 7 with 1N hydrochloric acid. After concentration,
The residue was purified by SCC (hexane: ethyl acetate = 2: 1) to obtain 2749 mg of the title compound as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ2.23 (3H, s), 4.81 (2H, s), 5.09 (2H, s), 5.28 (1H, b
rs), 7.38 -7.54 (6H, m), 7.68 (1H, ddd, J = 9.0Hz, 9.
0Hz & 1.0Hz), 8.06 (1H, d, J = 9.0Hz), 8.07 (1H, d, J =
9.0Hz) TLC: R _f 0.50 (n-hexane-AcOEt 1/1)

Example 9 4-benzyloxy-3-methylquinoline-2-carbaldehyde 50 mg (0.18 mmol) of the compound obtained in Example 8 was dissolved in 2 ml of chloroform. 157 mg (1.80 mmol) of manganese dioxide
And stirred at room temperature for 42 hours. Manganese dioxide was collected by filtration. After concentration of the filtrate, the residue was purified by SCC (hexane: ethyl acetate = 8: 1) to give the title compound (43 mg) as a colorless solid.
I got ¹ H-NMR (CDCl ₃ ) δ 2.71 (3H, s), 5.19 (2H, s), 7.40-7.55 (5H, m), 7.6
4 (1H, dd, J = 8.0Hz & 8.0Hz), 7.76 (1H, dd, J = 8.0
Hz & 8.0Hz), 8.10 (1H, d, J = 8.0Hz), 8.22 (1H, d, J =
8.0Hz), 10.33 (1H, s) TLC: R _f 0.50 (n-hexane-AcOEt 5/1)

Example 10 4-benzyloxy-2- (1-hydroxy-2-nonenyl) -3-
867 mg (7.87 mmol) of methylquinoline 1-octyne was dissolved in 20 ml of hexane under a stream of argon. 0.95M diisobutylaluminum hydride (D
IBAL) Add 9.2 ml (8.66 mmol) of hexane solution and add
Time stirred. After returning to room temperature, hexane was distilled off with a vacuum pump. After purging with argon, 8 ml of THF was added, and the mixture was cooled to -40 ° C. Compound 145 obtained in Example 9
A solution of 4 mg (5.25 mmol) in 20 ml of THF was added, and the mixture was stirred at -40 ° C for 2 hours and then heated to room temperature. Sodium sulfate decahydrate was added and stirred at room temperature for 16 hours. Ethyl acetate (20 ml) was added to carry out celite filtration. After concentrating the filtrate, the residue
Purification by CC (hexane: ethyl acetate = 6: 1) gave 889 mg of the title compound as a colorless liquid. ¹ H-NMR (CDCl ₃ ) δ 0.86 (3H, t, J = 8.0 Hz), 1.20 -1.40 (8H, m), 2.04 (2
H, dt, J = 7.0Hz & 7.0Hz), 2.29 (3H, s), 5.07 (2H, d,
J = 5.0Hz), 5.29 (1H, d, J = 7.0Hz), 5.43 (1H, dd, J
= 15.0Hz & 7.0Hz), 5.84 (1H, dt, J = 15.0Hz & 7.0H
z), 7.37-7.55 (6H, m), 7.67 (1H, dd, J = 8.0Hz & 8.0
Hz), 8.06 (2H, m) TLC: R _f 0.50 (n-hexane-AcOEt 5/1)

Example 11 2- (1-acetoxy-2-nonenyl) -4-benzyloxy-3-
Methylquinoline 889 mg (2.29 mmol) of the compound obtained in Example 10 was dissolved in 15 ml of pyridine. 0.33 ml (3.43 mmol) of acetic anhydride was added and stirred at 60 ° C. for 22 hours. After adding 172 mg of ethanol, pyridine was distilled off azeotropically with toluene. SC to residue
Purification by C (hexane: ethyl acetate = 6: 1) gave 584.5 mg of the title compound as a yellow liquid. ¹ H-NMR (CDCl ₃ ) δ 0.84 (3H, t, J = 8.0Hz), 1.20 -1.30 (6H, m), 1.33-
1.49 (2H, m), 2.17 (3H, s), 2.42 (3H, s), 5.06 (2H,
s), 5.79 (1H, dt, J = 15.0Hz & 6.0Hz), 5.88 (1H, dd,
J = 15.0Hz & 9.0Hz), 6.48 (1H, d, J = 9.0Hz), 7.37-
7.52 (6H, m), 7.64 (1H, ddd, J = 7.0Hz, 7.0Hz & 1.0Hz),
8.03 (1H, dd, J = 7.0Hz & 1.0Hz), 8.12 (1H, d, J =
7.0Hz) TLC: R _f 0.43 (n-hexane-AcOEt 5/1)

Example 12 2.6 mg (0.057 mmol) of 4-benzyloxy-3-methyl-2- (2-nonenyl) quinolinic acid were dissolved in 0.1 ml of dioxane. 9.3 mg (0.092 mmol) of triethylamine, 15.3 mg (0.092 mmol) of triethyl phosphite, 5.2 mg of palladium acetate
(0.023 mmol), and then the compound 20m obtained in Example 11 was added.
g (0.046 mmol) in 0.1 ml of dioxane was added and stirred at 60 ° C. for 1 hour. After concentration, the residue was purified by SCC (hexane: ethyl acetate = 8: 1) to give 5.3m of the title compound as a yellow liquid.
g was obtained. ¹ H-NMR (CDCl ₃ ) δ 0.86 (3H, t, J = 7.0 Hz), 1.20 -1.40 (8H, m), 2.02 (2
H, dt, J = 7.0Hz & 7.0Hz), 2.37 (3H, s), 3.72 (2H, dd,
J = 6.0Hz1.0Hz), 5.06 (2H, s), 5.48 (1H, dtt, J = 1
5.0Hz, 7.0Hz_.0Hz), 5.67 (1H, dtt, J = 15.0Hz, 6.0Hz
& 1.0Hz), 7.26-7.55 (6H, m), 7.63 (1H, ddd, J = 8.0H
z, 7.0Hz & 1.0Hz), 8.02 (1H, dd, J = 8.0Hz & 1.0Hz),
8.05 (1H, d, J = 7.0Hz) TLC: R _f 0.50 (n-hexane-AcOEt 5/1)

Claims (3)

[Claims] 1. A compound of the general formula (The symbols in the formula have the following meanings: R ¹ : optionally substituted C ₁ -C ₂₀ alkyl, optionally substituted cycloalkyl, optionally substituted C ₁
-C ₂₀ alkylsilyl, optionally substituted arylsilyl, optionally substituted C ₁ -C ₂₀ alkylarylsilyl, optionally substituted C ₁ -C ₂₀ alkoxycarbonyl, optionally substituted C ₁ -C ₂₀ alkylsulfonyl,
Or optionally substituted arylsulfonyl R ² : optionally substituted C ₁ -C ₂₀ alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted C ₁ -C ₂₀ alkoxycarbonyl, carboxyl, optionally substituted mono- or di-substituted C ₁ -C ₂₀ alkylaminocarbonyl, or optionally substituted mono- or di-substituted arylaminocarbonyl R ³ : optionally substituted C ₁ -C ₂₀ alkyl or optionally substituted C ₂ -C ₂₀ alkenyl. ## STR00002 ## wherein the oxide derivative (1) represented by the formula (1) is subjected to a reduction reaction. (The symbols in the formula have the same meanings as described above.) 2. A compound of the general formula (Wherein R ¹ , R ² and R ³ have the meanings of the symbols described in claim 1). (Wherein R ¹ , R ² and R ³ have the meanings of the symbols described in claim 1). 3. A compound of the general formula (Wherein R ¹ , R ² and R ³ have the meanings of the symbols described in claim 1) or a 1-oxide form thereof.