JP2001316369A - Method of producing quinoline derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method of efficiently producing quinoline derivatives that is useful as a synthetic intermediate for medicines, agrochemicals and the like through shortened steps with industrial advantage. SOLUTION: The objective quinoline derivative (V) [wherein individual symbols in formula (V) and formulas (I) through (IV) are cited in the specification] is produced by allowing quinoline-carbaldehyde of formula (I) to react with a compound selected from a phosphonium salt compound of formula (II), a phosphonate compound of formula (III) and a phosphonate compound of formula (IV) in the presence of a base, followed by hydrolysis of the reaction product.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a quinoline derivative. The quinoline derivative obtained in the present invention is useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals and the like, and for example, (E) -3- (4 ′-(4 ″ -fluorophenyl)-
2'-Cyclopropylquinolin-3'-yl) propenaldehyde is the rate-limiting enzyme in cholesterol biosynthesis.
It is an important synthetic intermediate for quinoline-based mevalonolactone derivatives known as inhibitors of MG-CoA reductase.

[0002]

2. Description of the Related Art Quinoline derivatives such as (E) -3-
As a method for synthesizing (4 ′-(4 ″ -fluorophenyl) -2′-cyclopropylquinolin-3′-yl) propenaldehyde, cis-1-one in tetrahydrofuran is used.
Ethoxy-2- (tri-n-butylstannyl) ethylene is reacted with butyllithium, and then -60 to -78 ° C.
With 4- (4'-fluorophenyl) -2-cyclopropylquinoline-3-carbaldehyde and hydrolyzing the obtained vinyl ether compound in the presence of an acid catalyst, or 4- (4'-fluoro Phenyl) -2-cyclopropylquinoline-3-carbaldehyde is reacted with alkoxycarbonylmethylphosphonate to give the corresponding α, β-unsaturated carboxylic acid ester, and then the ester portion of this compound is converted to a metal such as diisobutylaluminum hydride. A method is known in which a hydride is converted into an alcohol by reduction, and then oxidized using an oxidizing agent such as activated manganese dioxide (see JP-A-1-279866).

[0003]

In the above-mentioned method, the organotin compound used is difficult to obtain industrially, and -60
The reaction must be carried out at an extremely low temperature of -78 ° C, and there is a problem that special reaction equipment is required. In the above method, it is difficult to handle the metal hydride used in reducing the ester moiety. In addition, each method requires a plurality of steps until the target product is obtained.
It is not necessarily advantageous as an industrial method for producing quinoline derivatives such as 3- (4 '-(4 "-fluorophenyl) -2'-cyclopropylquinolin-3'-yl) propenaldehyde.

Accordingly, an object of the present invention is to provide a method for producing a quinoline derivative efficiently and industrially advantageously in a shorter process by using a chemical which is industrially easily available and easy to handle. It is in.

[0005]

According to the present invention, the above objects have been achieved by the general formula (I)

[0006]

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(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ may each independently be a hydrogen atom, a halogen atom, a trifluoromethyl group, a trifluoromethoxy group, or a protected group. Hydroxyl group, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent Represents an optionally substituted alkoxyl group or an optionally substituted aryloxy group)) (hereinafter abbreviated as quinoline carbaldehyde (I)). In the presence of a base, the following compounds (a) to (c): (a) general formula (II)

[0008]

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(Wherein R ⁷ and R ⁸ each independently represent a hydrogen atom, an alkyl group which may have a substituent, an acyl group which may have a substituent or a substituent. Represents an aralkyl group, or together represents an alkylene group, an arylene group or an aralkylene group, and R ⁹ is an alkyl group optionally having a substituent or an aryl group optionally having a substituent. And X represents a halogen atom.) (Hereinafter abbreviated as phosphonium salt (II)), (b)
General formula (III)

[0010]

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Wherein R ⁷ , R ⁸ and R ⁹ are as defined above (hereinafter abbreviated as phosphonate (III)) or (c)
General formula (IV)

[0012]

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(Wherein R ⁹ is as defined above,
R ¹⁰ and R ¹¹ are each independently a hydrogen atom, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent or It represents an aralkyl group which may have a group, or together represent an alkylene group, an arylene group or an aralkylene group. A) a phosphonate compound (hereinafter abbreviated as phosphonate (IV)) represented by the following general formula (V):

[0014]

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(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above) (hereinafter abbreviated as quinoline derivative (V)) Is achieved by providing a manufacturing method of

In a preferred embodiment, R ¹ , R ² , R
³ and R ⁶ are hydrogen atoms, R ⁴ is a halogen atom, and R ⁵ is an alkyl group having 1 to 6 carbon atoms or 3 to 6 carbon atoms.
R ⁷ and R ⁸ are each independently an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group, a naphthyl group or a benzyl group, or Is an alkylene group having 2 to 6 carbon atoms or an arylene group having 6 to 10 carbon atoms, R ⁹ is an alkyl group having 1 to 6 carbon atoms or a phenyl group, and R ¹⁰ and R ¹¹ are each independently a carbon atom. Numbers 1-6
Or a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group, a naphthyl group or a benzyl group, or an alkylene group having 2 to 6 carbon atoms or an arylene group having 6 to 10 carbon atoms together. .

In a further preferred embodiment, R ⁴ is a fluorine atom, and R ⁷ and R ⁸ are each independently an alkyl group having 1 to 6 carbon atoms, or together form an alkylene group having 2 to 6 carbon atoms. R ¹⁰ and R ¹¹ are each independently an alkyl group having 1 to 6 carbon atoms or together are an alkylene group having 2 to 6 carbon atoms.

[0018]

BEST MODE FOR CARRYING OUT THE INVENTION In the above formula, R ¹ , R ² , R ³ ,
The alkyl group represented by R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ is preferably a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms. And examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and a tert-butyl group. These alkyl groups may have a substituent,
Examples of such a substituent include a hydroxyl group; an alkoxyl group having preferably 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group.

The cycloalkyl group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ¹⁰ and R ¹¹ is preferably a cycloalkyl group having 3 to 6 carbon atoms. Examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. These cycloalkyl groups may have a substituent, such as a hydroxyl group; a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group,
a C1-C6 alkyl group such as a t-butyl group; a C1-C4 alkoxyl group such as a methoxy group, an ethoxy group, a propoxy group or a butoxy group; a phenyl group, a p-methoxyphenyl group; An aryl group having preferably 6 to 10 carbon atoms such as a p-chlorophenyl group is exemplified.

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁹ , R
The aryl group represented by ¹⁰ and R ^11, preferably include an aryl group having 6 to 10 carbon atoms, such as phenyl group, and a naphthyl group. These aryl groups may have a substituent, such substituents include
For example, a hydroxyl group; preferably an alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and a tert-butyl group; a methoxy group, an ethoxy group, a propoxy group, a butoxy group Preferably an alkoxyl group having 1 to 4 carbon atoms; and an aryl group preferably having 6 to 10 carbon atoms such as a phenyl group, a p-methoxyphenyl group and a p-chlorophenyl group.

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ ,
The aralkyl group represented by R ⁸ , R ¹⁰ and R ¹¹ preferably has an alkyl group having 1 to 6 carbon atoms, and the aryl moiety preferably has 6 to 10 carbon atoms.
And an aralkyl group having an aryl group such as a benzyl group and a naphthylmethyl group. These aralkyl groups may have a substituent, such as a hydroxyl group; a methyl group, an ethyl group,
Preferably it has 1 to 6 carbon atoms such as propyl group, isopropyl group, butyl group, isobutyl group and tert-butyl group.
An alkyl group; a methoxy group, an ethoxy group, a propoxy group and a butoxy group, preferably an alkoxyl group having 1 to 4 carbon atoms; a phenyl group, a p-methoxyphenyl group, a p-
An aryl group having preferably 6 to 10 carbon atoms such as a chlorophenyl group is exemplified.

The halogen atom represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and X includes, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like. Is mentioned.

The alkoxyl group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ is preferably a linear or branched alkoxyl group having 1 to 4 carbon atoms. Examples include a methoxy group, an ethoxy group, a propoxy group and a butoxy group. These alkoxyl groups may have a substituent, such as a hydroxyl group; an alkoxyl group having preferably 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group; a phenyl group , P-methoxyphenyl group, p-chlorophenyl group and the like, preferably an aryl group having 6 to 10 carbon atoms.

The aryloxy group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ includes an aryloxy group preferably having an aryl group having 6 to 10 carbon atoms as the aryl moiety. For example, a phenoxy group, a tolyloxy group, a naphthyloxy group and the like can be mentioned. These aryloxy groups may have a substituent, for example, a hydroxyl group; a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-group.
a C1-C6 alkyl group such as an tert-butyl group; a C1-C4 alkoxyl group such as a methoxy group, an ethoxy group, a propoxy group or a butoxy group; a phenyl group, a p-methoxyphenyl group; An aryl group having preferably 6 to 10 carbon atoms such as a p-chlorophenyl group is exemplified.

The hydroxyl group represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ may be protected, and the protecting group for the hydroxyl group may be a protecting group usually used for protecting a hydroxyl group. The group is not particularly limited as long as it is a group, for example, an aralkyl group such as a benzyl group; a trisubstituted silyl group such as a trimethylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group; a methoxymethyl group, a 1-ethoxyethyl group, Acetal-type protecting groups such as a tetrahydrofuranyl group and a tetrahydropyranyl group are exemplified.

The acyl group represented by R ⁷ and R ⁸ is, for example, an alkylcarbonyl group having a linear or branched alkyl group having 1 to 6 carbon atoms as an alkyl moiety, preferably an acetyl group; Preferably, the aryl moiety includes an arylcarbonyl group having an aryl group having 6 to 10 carbon atoms. These acyl groups may have a substituent, for example, a hydroxyl group; a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group,
a C1-C6 alkyl group such as a t-butyl group; a C1-C4 alkoxyl group such as a methoxy group, an ethoxy group, a propoxy group or a butoxy group; a phenyl group, a p-methoxyphenyl group; An aryl group having preferably 6 to 10 carbon atoms such as a p-chlorophenyl group is exemplified.

The alkylene group represented by R ⁷ and R ⁸ together with R ¹⁰ and R ¹¹ is preferably a straight-chain or branched-chain alkylene group having 2 to 6 carbon atoms. Group, propylene group, butylene group, pentylene group and the like. The arylene group represented by R ⁷ and R ⁸ together with R ¹⁰ and R ¹¹ is preferably an arylene group having 6 to 10 carbon atoms, for example, an o-phenylene group, a 2,3-naphthalenediyl group And the like. The aralkylene group represented by R ⁷ and R ⁸ together with R ¹⁰ and R ¹¹ preferably has an alkylene group having 2 to 6 carbon atoms as an alkylene moiety, and preferably has 6 to 10 carbon atoms as an arylene moiety. Aralkylene group having an arylene group of, for example, a 1,2-benzo-2-butene group,
2,3-naphth-2-butene group and the like.

The quinoline carbaldehyde (I) and the quinoline derivative (V) are preferably R ¹ , R ² , R ³
And R ⁶ is a hydrogen atom, R ⁴ is a halogen atom, and R ⁵ is an alkyl group having 1 to 6 carbon atoms or 3 to 6 carbon atoms.
And 6 is a cycloalkyl group.

More preferred quinoline carbaldehyde (I) and quinoline derivative (V) include R ¹ , R ² ,
R ³ and R ⁶ are hydrogen atoms, R ⁴ is a fluorine atom, and R ⁵ is an alkyl group having 1 to 6 carbon atoms or 3 to 6 carbon atoms.
And 6 is a cycloalkyl group.

More preferred quinoline carbaldehyde (I) and quinoline derivative (V) include R ¹ , R ² ,
Compounds in which R ³ and R ⁶ are a hydrogen atom, R ⁴ is a fluorine atom, and R ⁵ is an isopropyl group or a cyclopropyl group.

Phosphonium salt (II) and phosphonae
(III), preferably R ⁷And R⁸Each
Each independently represents an alkyl group having 1 to 6 carbon atoms;
Chloroalkyl group, phenyl group, naphthyl group or ben
A zyl group or a group having 2 to 6 carbon atoms
A alkylene group or an arylene group having 6 to 10 carbon atoms
R⁹Is an alkyl group having 1 to 6 carbon atoms or a phenyl group
The compound which is is mentioned.

As more preferred phosphonium salts (II) and phosphonates (III), R ⁷ and R ⁸ are each independently an alkyl group having 1 to 6 carbon atoms, or together with an alkylene having 2 to 6 carbon atoms. R ⁹
Is a C1-C6 alkyl group or a phenyl group.

As the phosphonate (IV), R ⁹ is preferably an alkyl group having 1 to 6 carbon atoms or a phenyl group, and R ¹⁰ and R ¹¹ are each independently an alkyl group having 1 to 6 carbon atoms, Compounds that are a cycloalkyl group, a phenyl group, a naphthyl group, or a benzyl group having 6, or an alkylene group having 2 to 6 carbon atoms or an arylene group having 6 to 10 carbon atoms together.

As a more preferred phosphonate (IV), R ⁹ is an alkyl group having 1 to 6 carbon atoms or a phenyl group, and R ¹⁰ and R ¹¹ are each independently 1 to 6 carbon atoms.
Or together with 2 to 2 carbon atoms
And 6 is an alkylene group.

The process for producing the quinoline derivative (V) according to the present invention comprises the step of reacting the quinoline carbaldehyde (I) with one of the phosphonium salts (II), phosphonates (III) and phosphonates (IV) in the presence of a base. It is characterized by reacting with a compound and then hydrolyzing. That is, as shown in the following Scheme 1, an active intermediate (phosphorane compound) generated by the action of a base on phosphonium salt (II), phosphonate (III) or phosphonate (IV) and quinoline carbaldehyde (I) (Step 1) and a step of hydrolyzing the acetal group portion or imino group portion of the product (ia) or (ib) obtained by the reaction (Step 2). In this production method, the phosphonium salt (I
I), phosphonate (III) or phosphonate (I
An active intermediate (phosphorane compound) generated by the action of a base on V) can be isolated and subjected to a reaction with quinoline carbaldehyde (I), and such a method is also included in the present invention.

[0036]

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(In the formula, each symbol is as defined above.)

In the method of the present invention, quinoline carbaldehyde (I) is reacted with a phosphonium salt (II) in the presence of a base,
By reacting with phosphonate (III) or phosphonate (IV), the active intermediate (phosphorane compound) generated in the reaction system is immediately reacted with quinoline carbaldehyde (I), and the product obtained by such reaction is purified or purified. By hydrolyzing without purification, the quinoline derivative (V) can be advantageously produced.

Hereinafter, the method of the present invention will be described step by step.

[Step 1] Quinolinecarbaldehyde (I)
With phosphonium salt (II), phosphonate (III) or phosphonate (IV) in the presence of a base

Examples of the phosphonium salt (II) include (1,3-dioxolan-2-ylmethyl) triphenylphosphonium bromide and (1,3-dioxolan-2).
-Ylmethyl) triphenylphosphonium iodide and the like. Examples of the phosphonate (III) include diethyl phosphonoacetaldehyde diethyl acetal and dimethyl phosphonoacetaldehyde dimethyl acetal. Examples of the phosphonate (IV) include diethyl-2- (cyclohexylamino) vinyl phosphonate, dimethyl-2- (cyclohexylamino) vinyl phosphonate, and the like.

The amount of the phosphonium salt (II), phosphonate (III) or phosphonate (IV) to be used is preferably in a range of 1 to 10 moles, more preferably 1 to 2 moles per mole of quinoline carbaldehyde (I). The range is more preferred.

As the base, for example, sodium carbonate,
Alkali metal carbonates such as potassium carbonate; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; methyl lithium, ethyl lithium, n-butyl lithium,
sec-butyllithium, tert-butyllithium,
Organic lithium compounds such as phenyllithium; alkylmagnesium halides such as methylmagnesium chloride and ethylmagnesium bromide; lithium amide, sodium amide, potassium amide, lithium diethylamide, lithium diisopropylamide, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilyl Metal amides such as amides and bromomagnesium diisopropylamide; lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide,
Metal alkoxides such as potassium tert-butoxide; and alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride. Among them, active intermediates (phosphorane compounds) to be formed
Sodium hydride, n
It is preferable to use -butyllithium, tert-butyllithium, potassium tert-butoxide. The amount of the base used is not particularly limited, but from the viewpoint of smoothly proceeding the reaction, usually 0.1 mol or more is used per 1 mol of the phosphonium salt (II), phosphonate (III) or phosphonate (IV). Is preferably used in a range of 0.5 to 2 mole times.

This step is preferably performed in the presence of a solvent. The solvent that can be used is not particularly limited as long as it does not adversely affect the reaction, for example, pentane, hexane,
Aliphatic hydrocarbons such as heptane, cyclohexane and methylcyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene; alcohols such as methanol, ethanol, isopropanol, n-butanol and tert-butanol; diethyl ether, diisopropyl ether and tert- Ethers such as butyl methyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; nitriles such as acetonitrile and benzonitrile; nitrogen-containing aromatic ring compounds such as pyridine; dimethylformamide; Amides such as methylpyrrolidone, N, N'-dimethylimidazolidinone, hexamethylphosphoric triamide; dimethylsulfoxide, N, N,
N ', N'-tetramethylethylenediamine, ammonia; or mixtures thereof. Among them, from the viewpoint of the stability of the active intermediate (phosphorane compound) generated in the reaction system, aromatic hydrocarbons such as benzene, toluene, and xylene; diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, Ethers such as dioxane; dimethylformamide and dimethylsulfoxide are preferred. The amount of the solvent to be used is not particularly limited, but is usually preferably from 1 to 200 times by weight, more preferably from 5 to 20 times by weight, based on quinoline carbaldehyde (I).

The reaction temperature depends on the phosphonium salt (I
I), phosphonate (III) or phosphonate (I
V), the type of base, the type of solvent,
Usually, the range of -100 to 100 ° C is preferable, and -50 to 3
A range of 0 ° C. is more preferred. Further, the reaction time varies depending on the reaction temperature, but is usually preferably in the range of 0.1 to 24 hours.

The reaction is carried out in an atmosphere of an inert gas such as argon under the conditions of phosphonium salt (II) and phosphonate (III).
Alternatively, it is preferable to dissolve phosphonate (IV) in a solvent, add a base to this solution, add quinoline carbaldehyde (I), and stir at a predetermined temperature. After the completion of the reaction, the reaction mixture was poured into water, extracted with an organic solvent such as ethyl acetate or hexane, and, if necessary, the extract was washed with water, a saturated aqueous solution of sodium chloride, an aqueous solution of sodium hydrogen carbonate, and the like. After drying with a drying agent such as anhydrous magnesium sulfate, the crude product is obtained by concentration. The obtained crude product is further subjected to a step of hydrolyzing an acetal group portion or an imino group portion, if necessary, after further purification using ordinary purification means such as recrystallization, distillation, and column chromatography. Alternatively, it can be directly subjected to a hydrolysis step without performing the purification.

[Step 2] Step of hydrolyzing the acetal group portion or imino group portion of the product of Step 1

In this step, general hydrolysis reaction conditions in which an acid acts in a solvent containing water can be used.
Although there is no particular limitation on the amount of water used, usually, it is preferably used in an amount of 1 mol or more, and preferably 1 to 10 mol times, per 1 mol of quinoline carbaldehyde (I) used as a raw material in the previous step. Is more preferred.

Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and perchloric acid; organic acids such as acetic acid, propionic acid, p-toluenesulfonic acid, methanesulfonic acid and oxalic acid, and hydrates thereof. Or its salt is mentioned.
The amount of the acid used is not particularly limited, but it is usually preferably 0.01 to 5 times the amount of the quinolinecarbaldehyde (I) used as a raw material in the previous step.

The hydrolysis step is preferably performed in the presence of a solvent. The solvent used is not particularly limited as long as it does not adversely affect the reaction. For example, methanol, ethanol, propanol, isopropanol, butanol, s
alcohols such as ec-butanol and tert-butanol; ethers such as diethyl ether, tetrahydrofuran and dimethoxyethane; pentane, hexane, heptane, octane, petroleum ether, benzene, toluene,
Hydrocarbons such as xylene; dimethylformamide, N-
Examples include amides such as methylpyrrolidone, N, N'-dimethylimidazolidinone, and hexamethylphosphoric triamide; nitriles such as acetonitrile; dimethyl sulfoxide; and a mixed solvent thereof. The amount of the solvent used is not particularly limited, but is usually preferably 1 to 200 times the weight of the quinoline carbaldehyde (I) used as a raw material in the previous step.

The reaction temperature varies depending on the kind of the acid used and the kind of the solvent, but is usually preferably in the range of 0 to 100 ° C. In addition, the reaction time depends on the reaction temperature,
Usually, the range of 1 to 24 hours is preferable.

The quinoline derivative (V) thus obtained can be isolated and purified by a method generally used for isolating and purifying organic compounds. For example, if necessary, a base such as aqueous sodium hydrogen carbonate solution or sodium methoxide is added to the reaction solution after the reaction to neutralize the acid, followed by extraction with an organic solvent such as diethyl ether, ethyl acetate or methylene chloride. . If necessary, the extract is washed with water, a saturated aqueous solution of sodium chloride, an aqueous solution of sodium hydrogen carbonate or the like to remove acidic substances and water-soluble substances, and dried over a drying agent such as anhydrous sodium sulfate and anhydrous magnesium sulfate. After concentration, the resulting crude product is purified by distillation, chromatography, recrystallization and the like.

The quinoline carbaldehyde (I) used as a raw material in the present invention, for example, 4- (4'-fluorophenyl) -2-cyclopropylquinoline-3-carbaldehyde is 2-amino-4'-fluorobenzophenone And 3-cyclopropyl-3-oxopropanoate in the presence of an acid catalyst to give 4- (4'-fluorophenyl) -2-cyclopropylquinoline-3-carboxylate (Journal of Organic Chemistry ( J. Org. Chem.), Vol. 31, 289.
9 (1966); Heterocycles (Hetero)
cycle, vol. 50, p. 479 (1999)), and the ester portion of this compound is reduced with various metal hydrides such as diisobutylaluminum hydride to give 4-
(4'-fluorophenyl) -2-cyclopropyl-3
-Hydroxymethylquinoline is obtained, and this compound is then converted to pyridinium chlorochromate, oxalyl chloride /
It can be produced by oxidizing with dimethyl sulfoxide / tertiary amine (Swern oxidation), sulfur trioxide pyridine complex or the like (see JP-A-1-279866).

The phosphonium salt (II), for example, (1,3-dioxolan-2-ylmethyl) triphenylphosphonium bromide can be easily synthesized by, for example, reacting bromoacetaldehyde ethylene acetal with triphenylphosphine. . Phosphonates (III), for example diethylphosphonoacetaldehyde diethylacetal, can be synthesized by reacting bromoacetaldehyde diethylacetal with triethyl phosphite. Phosphonates (IV), for example diethyl-2- (cyclohexylamino) vinylphosphonate, can be synthesized by hydrolyzing the acetal part of diethylphosphonoacetaldehyde diethylacetal and reacting the resulting aldehyde with cyclohexylamine ( Organic Synthesis, 53, 4
4 (1973)).

[0055]

EXAMPLES The present invention will now be described specifically with reference to examples, but the present invention is not limited to these examples.

Example 1 1.55 g of (1,3-dioxolan-2-ylmethyl) triphenylphosphonium bromide in an argon atmosphere
(3.61 mmol) in anhydrous dimethyl sulfoxide 1
0.0 ml was added and dissolved, and tert-butyllithium (1.51 M, n-pentane solution) 2.4 was added to this solution.
0 ml (3.62 mmol) was added dropwise at 20-30 ° C over 2 minutes. After stirring the mixture at room temperature for 15 minutes, 1.00 g of 4- (4′-fluorophenyl) -2-cyclopropylquinoline-3-carbaldehyde was added to the solution.
(3.44 mmol) in anhydrous dimethyl sulfoxide 5 m
The resulting solution was added dropwise over 20 minutes at 20-30 ° C. After the addition was completed, the mixture was stirred at the same temperature for 90 minutes. 10 ml of water was added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted twice with 20 ml of hexane, and the previously separated organic layer and the extract were combined and washed twice with 10 ml of water.
After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. After adding and dissolving 20 ml of tetrahydrofuran to the obtained crude product, 10 ml of 2 mol / L hydrochloric acid was added, and the mixture was allowed to stand at room temperature for 30 minutes. Tetrahydrofuran was distilled off from this mixture under reduced pressure, and the obtained red residue was dissolved in 10 ml of chloroform. Then, 30 ml of hexane and 50 ml of a saturated aqueous solution of sodium hydrogencarbonate were added to carry out liquid separation, and the organic layer was separated. The aqueous layer was extracted twice with 50 ml of hexane, and the organic layer and the extract separated previously were combined and concentrated. The resulting crude product was purified by column chromatography to give the following physical properties as pale yellow crystals. 0.99 g (yield 90.9%) of (E) -3- (4 '-(4 "-fluorophenyl) -2'-cyclopropylquinolin-3'-yl) propenaldehyde having the following formula:

Melting point: 124-132 ° C. ¹ H-NMR (600 MHz, CDCl ₃ , TMS, pp
m) δ: 1.08-1.13 (2H, m, CH ₂ ),
_{1.41-1.45 (2H, m, CH 2} ), 2.32-
2.38 (1H, m, CH), 6.45 (1H, dd,
J = 8, 16 Hz), 7.22-7.25 (4H, m,
Ar-H), 7.35-7.39 (2H, m, Ar-
H), 7.56 (1H, d, J = 16 Hz), 7.67
(1H, ddd, J = 3, 6, 8 Hz, Ar-H),
7.98 (1H, d, J = 8 Hz, Ar-H), 9.5
1 (1H, d, J = 8 Hz).

Example 2 60% oily sodium hydride 165 under an argon atmosphere
mg (4.12 mmol) of tetrahydrofuran 825
The temperature was raised to 60 ° C. while stirring in mg. 386 mg (4.94 mmol) of anhydrous dimethyl sulfoxide was added to this solution.
Was dissolved in 825 mg of tetrahydrofuran, and a solution obtained was added dropwise. After stirring for 2 hours, the mixture was cooled to 20 ° C.
Next, under an argon atmosphere, (1,3-dioxolan-2
-Ylmethyl) triphenylphosphonium bromide2.
21 g (5.15 mmol) of tetrahydrofuran
While stirring in 84 g, a previously prepared mixture of sodium hydride, anhydrous dimethyl sulfoxide and tetrahydrofuran was added, and after stirring for 1 hour, the mixture was cooled to 0 ° C. To this solution was added 4- (4'-fluorophenyl)-
2-cyclopropylquinoline-3-carbaldehyde 1.
00 g (3.44 mmol) in 4 g of tetrahydrofuran
Was added dropwise over 5 minutes at 0-5 ° C., and after completion of the dropwise addition, the mixture was stirred at the same temperature for 60 minutes. After adding 5 g of water to the reaction mixture, the solvent was distilled off under reduced pressure.
The precipitated solid was dissolved in 10 g of toluene and 2 g in 10 g of water.
Washed twice. 10 ml of 0.5 mol / L hydrochloric acid was added, and 5
After stirring for an hour, the mixture was allowed to stand, the lower layer was separated, and the organic layer was washed successively with 10 g of a saturated aqueous solution of sodium hydrogencarbonate and 10 g of water. The solvent was distilled off, and the obtained crude product was purified by column chromatography to obtain (E) -3- (4 ′-(4 ″).
-Fluorophenyl) -2'-cyclopropylquinolin-3'-yl) propenaldehyde 0.93 g (yield 8
5.4%).

Example 3 Under an argon atmosphere, 10 ml of tetrahydrofuran was added to and dissolved in 1.05 g (4.12 mmol) of diethylphosphonoacetaldehyde diethyl acetal.
The solution was cooled to -20 ° C, and 2.60 ml of n-butyllithium (1.6 M, n-hexane solution) (4.1 ml) was added to the solution.
6 mmol) was added dropwise at -30 to -20 ° C over 5 minutes. After stirring the mixture for 1 hour at the same temperature,
1.00 g of 4- (4'-fluorophenyl) -2-cyclopropylquinoline-3-carbaldehyde (3.44 m
mol) was dissolved in 10 ml of tetrahydrofuran, and the solution was added dropwise at −30 to −20 ° C. over 5 minutes. After completion of the addition, the mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was added to 100 ml of ice water, extracted three times with 50 ml of ethyl acetate, and the combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated. 20 ml of toluene and 10 m of 10% aqueous solution of perchloric acid were added to the obtained residue.
and heated at 40-50 ° C. for 1 hour. The mixture was cooled to room temperature, neutralized with an aqueous solution of sodium hydrogen carbonate, and extracted three times with 50 ml of toluene. The extracts were combined, washed with saturated saline, dried over anhydrous sodium sulfate,
1.6 g of a crude product obtained by concentration was purified by column chromatography to obtain (E) -3- (4 ′-(4 ″-).
(Fluorophenyl) -2'-cyclopropylquinoline-
0.92 g of 3'-yl) propenaldehyde (yield 8
4.5%).

Example 4 98.3 mg of sodium hydride in an argon atmosphere
The solution obtained by suspending (4.10 mmol) in 10 ml of tetrahydrofuran was cooled to -10 to -5 ° C, and 1.34 g (5.13 mmol) of diethyl-2- (cyclohexylamino) vinylphosphonate was added to this solution. Was dissolved in 10 ml of tetrahydrofuran, and the solution obtained was added dropwise over 5 minutes. After completion of the addition, 1 ° C. was added at −10 to −5 ° C.
Stirred for hours. A solution obtained by dissolving 1.00 g (3.44 mmol) of 4- (4′-fluorophenyl) -2-cyclopropylquinoline-3-carbaldehyde in 20 ml of tetrahydrofuran was added to this solution.
The mixture was added dropwise at 5 ° C. over 5 minutes, and after completion of the addition, the mixture was heated to reflux temperature and stirred for 1 hour. After the reaction mixture was cooled to room temperature, it was added to 300 ml of ice water and 100 ml of ethyl acetate.
The extract was extracted twice, and the extracts were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated. 20 ml of toluene and 1.5 g of oxalic acid dihydrate (1
1.9 mmol) was dissolved in 20 ml of water, and the mixture was heated at 60 to 70 ° C. for 1 hour. The mixture was cooled to room temperature and the organic and aqueous layers were separated. The aqueous layer was extracted twice with 20 ml of toluene. The extract was combined with the organic layer previously separated, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated, and 1.6 g of a crude product obtained by purification was purified by column chromatography to obtain (E)- 3- (4 '
-(4 "-fluorophenyl) -2'-cyclopropylquinolin-3'-yl) propenaldehyde 0.95 g
(86.5% yield).

[0061]

According to the present invention, there is provided a quinoline derivative useful as a synthetic intermediate for pharmaceuticals and agricultural chemicals, for example, a quinoline-based mevalonolactone derivative known as an inhibitor of HMG-CoA reductase, which is a rate-limiting enzyme in cholesterol biosynthesis. An important synthetic intermediate (E) -3- (4′-
A quinoline derivative such as (4 "-fluorophenyl) -2'-cyclopropylquinolin-3'-yl) propenaldehyde can be produced efficiently and industrially advantageously in a short process.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Hiroshin Tamai 2-28 Kurashiki-cho, Nakajo-cho, Kitakanbara-gun, Niigata F-term in Kuraray Co., Ltd. (Reference) 4C031 BA07 4H039 CA62 CF30

Claims (3)

[Claims] 1. A compound of the general formula (I) (Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a trifluoromethoxy group, an optionally protected hydroxyl group, Alkyl group which may have a group, cycloalkyl group which may have a substituent, aryl group which may have a substituent, aralkyl group which may have a substituent, substituent A quinoline carbaldehyde represented by the following formulas (a) to (c) in the presence of a base: (A) Formula (I)
I) (Wherein, R ⁷ and R ⁸ are each independently a hydrogen atom, an alkyl group which may have a substituent, an acyl group which may have a substituent, or an aralkyl which may have a substituent. Represents a group or together is an alkylene group,
Represents an arylene group or an aralkylene group, R ⁹ represents an alkyl group which may have a substituent or an aryl group which may have a substituent, and X represents a halogen atom. A) a phosphonium salt compound represented by the general formula (III): (Wherein R ⁷ , R ⁸ and R ⁹ are as defined above), or (c) a general formula (IV): Wherein R ⁹ is as defined above, R ¹⁰ and R
¹¹ each independently has a hydrogen atom, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent or a substituent Represents an optionally substituted aralkyl group, or together represents an alkylene group, an arylene group or an aralkylene group. A) a phosphonate compound represented by the formula:
Wherein the compound is reacted with any one of the following compounds and then hydrolyzed: (Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above). 2. R ¹ , R ² , R ³ and R ⁶ are a hydrogen atom, R ⁴ is a halogen atom, and R ⁵ is an alkyl group having 1 to 6 carbon atoms or a cycloalkyl having 3 to 6 carbon atoms. R ⁷ and R ⁸ are each independently an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group, a naphthyl group or a benzyl group, or R 2 is an alkylene group having 2 to 6 carbon atoms or an arylene group having 6 to 10 carbon atoms, R ⁹ is an alkyl group having 1 to 6 carbon atoms or a phenyl group, and R ¹⁰ and R ¹¹ are each independently 1 to 6 carbon atoms. An alkyl group having 3 to 3 carbon atoms
6 is a cycloalkyl group, a phenyl group, a naphthyl group or a benzyl group, or together has 2 to 2 carbon atoms.
The method for producing a quinoline derivative according to claim 1, which is an alkylene group having 6 or an arylene group having 6 to 10 carbon atoms. 3. R ³ is a fluorine atom, and R ⁷ and R ⁸
Are each independently an alkyl group having 1 to 6 carbon atoms,
Or together, an alkylene group having 2 to 6 carbon atoms, and R ¹⁰ and R ¹¹ are each independently an alkyl group having 1 to 6 carbon atoms, or together, an alkylene group having 2 to 6 carbon atoms 3. The method for producing a quinoline derivative according to claim 2, wherein