JPH0827114A - Manufacture of quinolinecarboaldehyde - Google Patents

Abstract

PURPOSE:To obtain a quinolinecarboaldehyde compound in high yield by oxidiz ing 2-cyclopropyl-4-(4-fluorophenyl)-3-hydroxymethylquinoline in the presence of a specific nitrosyl free radical derivative with a hypohalite. CONSTITUTION:2-Cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboaldehyde is obtained by oxidizing 2-cyclopropyl-4-(4-fluorophenyl)-3-hydroxymethylquinoline. This oxidation reaction is carried out in the presence of a nitrosyl free radical derivative of formula I or formula II (X<1> and X<2> are each H, a halogen, OH, a 1-5C alkyl, a 5-6C cycloalkyl, a 1-5C alkoxy, a 1-10C acyloxy, etc., or X<1> and X<2> together form O; R<1> to R<4> are each a 1-5C alkyl; m is 0 to 1) with a hypohalite. Preferable examples of the nitrosyl free radical derivative include 2,2,6,6-tetramethylpiperidine-1-oxyl, etc. Further, potassium bromide or sodium bromide is preferably added into the reaction system.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing quinolinecarbaldehyde. More specifically, 2-cyclopropyl-4- (4-fluorophenyl) quinoline-3-carbaldehyde, which is useful as a synthetic intermediate for an HMG-CoA reductase inhibitor that is a cholesterol lowering agent, can be easily and efficiently produced. Regarding the method.

[0002]

2. Description of the Prior Art 2-Cyclopropyl-4- (4-fluorophenyl) quinoline-3-carbaldehyde is HM
An intermediate useful as a G-CoA reductase inhibitor,
Conventionally, chromic acid has been used as a method for oxidizing 2-cyclopropyl-4- (4-fluorophenyl) -3-hydroxymethylquinoline to 2-cyclopropyl-4- (4-fluorophenyl) quinoline-3-carbaldehyde. The oxidation method used and the method using a dimethyl sulfoxide-dehydrating agent (for example, swern oxidation method) have been used.

[0003]

However, in the above method, there are problems of waste liquid treatment due to the production of environmentally harmful chromium ions, and the production of odorous dimethylsulfide.
It is hard to say that this is an industrially advantageous method. Therefore, an object of the present invention is to oxidize 2-cyclopropyl-4- (4-fluorophenyl) -3-hydroxymethylquinoline to give 2-cyclopropyl-4- (4-fluorophenyl) quinoline-3-carbaldehyde. An object of the present invention is to provide a simple and industrially advantageous manufacturing method.

[0004]

DISCLOSURE OF THE INVENTION As a result of studying various oxidation methods to solve such problems, the present inventors have found that there is no problem of waste liquid treatment and bad odor as described above, and a good yield and The present invention has been completed by finding an industrially advantageous manufacturing method.

That is, the gist of the present invention is that (1) 2-cyclopropyl-4- (4-fluorophenyl) -3-hydroxymethylquinoline is represented by the formula (I) or the formula (II):

Embedded image (In the formula, X ¹ and X ² are the same or different and each is a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 5 to 6 carbon atoms, an alkoxy group having 1 to 5 carbon atoms. , An acyloxy group having 1 to 10 carbon atoms, -C
(O) NH ₂ ,-(alkylene having 1 to 4 carbon atoms)-
C (O) NH ₂ , -C (O) OH,-(C 1 -C 4 alkylene) -CO ₂ H or -C (O) O- (C 1 -C 5 alkyl), or X ¹ and X ² together represent an oxygen atom; R ¹ , R ² , R
³ and R ⁴ are the same or different and each represents an alkyl group having 1 to 5 carbon atoms. m represents an integer of 0 or 1, and n represents an integer of 0 or 1 to 12. ) In the presence of a nitroxyl radical derivative represented by the formula (4), the method relates to a method for producing 2-cyclopropyl-4- (4-fluorophenyl) quinoline-3-carbaldehyde, which comprises oxidizing with a hypohalite.

Further, in the present invention, (2) the nitroxyl radical derivative is 2,2,6,6-tetramethylpiperidine-1-oxyl, 4-oxo-2,2,6,6-tetramethylpiperidine-1. -Oxyl, 4-hydroxy-
2,2,6,6-tetramethylpiperidine-1-oxyl, 4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-acetoxy-2,2,6,
6-Tetramethylpiperidine-1-oxyl, 4-benzoyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-acetamido-2,2,6,6
-Tetramethylpiperidine-1-oxyl, di (2,2
2,6,6-Tetramethylpiperidine-1-oxyl-
4-yl) succinate and di (2,2,6,6-tetramethylpiperidin-1-oxyl-4-yl) sebaconate, which is one or more selected from the group consisting of the above (1),

(3) The amount of the nitroxyl radical derivative used is 0.00 based on 2-cyclopropyl-4- (4-fluorophenyl) -3-hydroxymethylquinoline.
The production method according to (1) above, which is 5 to 0.05 equivalents;

(4) The method according to (1) above, wherein the hypohalite is sodium hypochlorite, calcium hypochlorite or potassium hypochlorite, and (5) hypohalite. The production method according to (1) above, wherein the amount used is 1.05 to 1.8 equivalents relative to 2-cyclopropyl-4- (4-fluorophenyl) -3-hydroxymethylquinoline, and

(6) The production method according to any one of (1) to (5) above, wherein 0.05 to 0.5 equivalent of potassium bromide or sodium bromide is further added to the reaction system.

In the nitroxyl radical derivative represented by the formula (I) and the formula (II) used in the present invention, X ¹ and X ² are the same or different and each is a hydrogen atom, a halogen atom, a hydroxyl group, or a carbon number of 1 to 5. Alkyl group of 5 to 6 carbon atoms
A cycloalkyl group, an alkoxy group having 1 to 5 carbon atoms, an acyloxy group having 1 to 10 carbon _{atoms, -C (O) NH 2,} -
(Alkylene having 1 to 4 carbon atoms) -C (O) NH ₂ ,
-C (O) OH,-(alkylene having 1 to 4 carbon atoms)
-CO ₂ H or -C (O) O-or indicating the (alkyl having 1 to 5 carbon atoms) or X ¹ and X ^2, is an oxygen atom together.

The halogen atom as X ¹ and X ² is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; the alkyl group having 1 to 5 carbon atoms is, for example, a methyl group, an ethyl group, a propyl group or a butyl group. Or pentyl group; carbon number 5
A cycloalkyl group having 6 to 6 is, for example, a cyclopentyl group or a cyclohexyl group; an alkoxy group having 1 to 5 carbon atoms is, for example, a methoxy group, an ethoxy group, a propoxy group, a butoxy group or a pentoxy group; For example, an acetyloxy group, an ethyl ketooxy group or a benzoyloxy group,-(alkylene having 1 to 4 carbon atoms) -C (O) NH ₂ is, for example, -CH ₂ C.
(O) NH ₂ ;-( having 1 to 4 carbon atoms alkylene) -
CO ₂ H is, for example, —CH ₂ —CO ₂ H; and —C.
(O) O- (alkyl having 1 to 5 carbons) is, for example,
C (O) O- (methyl, ethyl, propyl, butyl or pentyl).

R ¹ , R ² , R ³ and R ⁴ represent the same or different alkyl groups having 1 to 5 carbon atoms. m represents an integer of 0 or 1, and n represents an integer of 0 or 1 to 12. ^{1 to} 5 carbon atoms as R ¹ , R ² , R ³ and R ⁴
The alkyl group of is, for example, a methyl group, an ethyl group, a propyl group, a butyl group or a pentyl group.

Preferably, X ¹ and X ² are hydrogen atoms,
The oxygen atom or hydroxyl group is replaced by R ¹ , R ² , R ³ and R ⁴
Represents a methyl group, and m represents 1.

Specific examples of these nitroxyl radical derivatives include 2,2,6,6-tetramethylpiperidine-1-oxyl and 4-oxo-2,2,6,6-.
Tetramethylpiperidine-1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4- Acetoxy-2,2
6,6-Tetramethylpiperidine-1-oxyl, 4-
Benzoyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-acetamido-2,2
6,6-Tetramethylpiperidine-1-oxyl, di (2,2,6,6-tetramethylpiperidin-1-oxyl-4-yl) succinate and di (2,2,6)
6-tetramethylpiperidin-1-oxyl-4-yl) sebaconate and the like can be mentioned. In the present invention, although not particularly limited, these may be used alone or in combination of two or more kinds. Among them, 2,2,6,6-tetramethylpiperidine-1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-oxo-2,2,
6,6-Tetramethylpiperidine-1-oxyl and the like are preferable.

The amount of such nitroxyl radical derivative used is 2-cyclopropyl-4- (4-
The amount is usually 0.005-0.05 equivalents, preferably 0.01-0.02 equivalents, relative to fluorophenyl) -3-hydroxymethylquinoline. If the amount of the nitroxyl derivative used is less than this range, the reaction becomes slow, and if the amount is too large, it is uneconomical.

Examples of the hypohalite used in the present invention include sodium hypochlorite, calcium hypochlorite, potassium hypochlorite and the like, which are not particularly limited, but can be obtained at low cost. Sodium hypochlorite is preferably used because it is easy to handle. The amount of these hypohalites used is 2-cyclopropyl-
It is generally 1.05 to 1.8 equivalents, preferably 1.1 to 1.5 equivalents, relative to 4- (4-fluorophenyl) -3-hydroxymethylquinoline. If the amount of hypohalite used is less than this range, the reaction is slow and unreacted substances remain. Also, if more than this range, by-products are generated,
This is because the excess hypohalite cannot be discarded unless it is treated.

The combination of the hypohalous acid salt and the nitroxyl radical derivative is not particularly limited and is appropriately selected and used. For example, when sodium hypochlorite is used as the hypohalous acid salt, any nitroxyl radical derivative may be present, for example, 2,2,6,6-tetramethylpiperidine-1-oxyl, 4-hydroxy-. 2, 2, 6, 6-
Tetramethylpiperidine-1-oxyl or the like is used.

In the present invention, the reaction is further promoted by adding a compound serving as a bromine ion source to the reaction system. Therefore, potassium bromide, sodium bromide or the like may be added. In this case, the amount of the compound serving as the bromine ion source used is 2-cyclopropyl-4-
It is usually used in an amount of 0.05 to 0.5 equivalents, preferably 0.1 to 0.2 equivalents, relative to (4-fluorophenyl) -3-hydroxymethylquinoline.

The pH of the reaction system may be adjusted as appropriate, and it is preferable to add an alkali to adjust the pH of the system to 8-9, especially around 8.6 in order to accelerate the reaction.
Examples of the alkali include caustic soda, sodium carbonate, sodium hydrogen carbonate and the like, and are not particularly limited.

The reaction temperature is usually -3 to 10 ° C, preferably 0 to 5 ° C. If the reaction temperature is lower than this range, the aqueous phase is likely to freeze and the reaction becomes slow. If it is high, side reactions are likely to occur. The reaction time varies depending on the reaction temperature, the type of nitroxyl radical derivative, the amount used, etc., but is usually 30 minutes to 12 hours.

In the reaction of the present invention, the reaction solvent is preferably methylene chloride, chloroform, 1,2-dichloroethane, ethyl acetate, etc., and is converted into 2-cyclopropyl-4- (4-fluorophenyl) -3-hydroxymethylquinoline. It is preferable to use 5 to 10 times the amount.

In the present invention, the reaction solution obtained by the above method is separated, the organic layer is washed with saturated saline and the like, and the crystals obtained are washed with isopropyl ether, diethyl ether, benzene, toluene or cyclohexane. By doing so, it can be easily purified, and operations such as recrystallization are unnecessary.

[0023]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. Example 1 2-Cyclopropyl-4- (4-fluorophenyl)-
3-Hydroxymethylquinoline (19.7 g, 67 mmol) was dissolved in 200 ml of methylene chloride, and potassium bromide (0.1 g) was added.
A solution prepared by dissolving 8 g (6.7 mmol) in 100 ml of water was added. It was cooled to 1 ° C. with stirring and 104 mg (0.67) of 2,2,6,6-tetramethylpiperidine-1-oxyl.
Mmol) was added. 120 ml of 0.7 mol of sodium hypochlorite solution was added dropwise, and the mixture was stirred at 0 to 5 ° C for 5 hours. A saturated sodium hydrogen carbonate solution was added dropwise so that the pH of the reaction solution would be 8.6. After the reaction was completed, the reaction solution was separated, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. Then, magnesium sulfate was separated, the solvent was distilled off under reduced pressure, and the crystals were washed with isopropyl ether and dried to give the desired 2-cyclopropyl-4- (4-fluorophenyl) quinoline-3-carbaldehyde 18. 7 g was obtained. The purity was 99.3% and the yield was 96%. IR (KBr) cm ^-1 ; 1700,770 melting point; 151 ° C

Example 2 2-Cyclopropyl-4- (4-fluorophenyl)-
123 g (0.419 mol) of 3-hydroxymethylquinoline was dissolved in 980 ml of methylene chloride to give 10 parts of potassium bromide.
A solution of g (84 mmol) in 374 ml of water was added. The mixture was cooled to 3 ° C. with stirring, and 1.3 g (8.3 mmol) of 2,2,6,6-tetramethylpiperidine-1-oxyl was added. 1.4 mol sodium hypochlorite solution 374
ml was added dropwise, and the mixture was stirred at 1-2 ° C for 5 hours. After the reaction was completed, the reaction solution was separated, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. Then, magnesium sulfate was separated, the solvent was distilled off under reduced pressure, and the crystals were washed with isopropyl ether and dried to give the desired 2-cyclopropyl-4- (4-fluorophenyl) quinoline-3-carbaldehyde 114. 9 g was obtained. The purity was 99.2% and the yield was 94.2%. IR (KBr) cm ^-1 ; 1700,770 melting point; 151 ° C

[0025]

EFFECTS OF THE INVENTION According to the production method of the present invention, there are no problems such as generation of heavy metal ions and generation of malodor, which have been problems in the conventional method, and it is easy to carry out 2-cyclopropyl-4- (4-fluorophenyl). ) It has become possible to produce quinoline-3-carbaldehyde. Further, when the production method of the present invention is used, it is industrially advantageous in that the purification process is simplified.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Yoshio Ohara 722 Tsuboi-cho, Funabashi-shi, Chiba 1 Nissan Chemical Industries, Ltd. Central Research Laboratory

Claims (6)

[Claims] 1. 2-Cyclopropyl-4- (4-fluorophenyl) -3-hydroxymethylquinoline represented by the formula (I) or (II): [In the formula, X ¹ and X ² are the same or different and each is a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group having 1 to 5 carbon atoms, a cycloalkyl group having 5 to 6 carbon atoms, an alkoxy group having 1 to 5 carbon atoms. , An acyloxy group having 1 to 10 carbon atoms, -C
(O) NH ₂ ,-(alkylene having 1 to 4 carbon atoms) -C (O) N
H ₂ , -C (O) OH,-(alkylene having 1 to 4 carbon atoms) -CO ₂ H or -C (O) O- (alkyl having 1 to 5 carbon atoms), or X ¹ and X ² together represents an oxygen atom, and R ¹ , R ² , R ³ and R ⁴ represent the same or different alkyl groups having 1 to 5 carbon atoms. m represents an integer of 0 or 1, and n represents an integer of 0 or 1 to 12. ] 2-Cyclopropyl- which is characterized by being oxidized with a hypohalite in the presence of a nitroxyl radical derivative represented by
Process for producing 4- (4-fluorophenyl) quinoline-3-carbaldehyde. 2. The nitroxyl radical derivative is 2,
2,6,6-tetramethylpiperidine-1-oxyl,
4-oxo-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-methoxy-
2,2,6,6-tetramethylpiperidine-1-oxyl, 4-acetoxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-benzoyloxy-2,
2,6,6-tetramethylpiperidine-1-oxyl,
4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxyl, di (2,2,6,6-tetramethylpiperidin-1-oxyl-4-yl) succinate and di (2,2,2 The production method according to claim 1, which is one or more selected from the group consisting of 6,6-tetramethylpiperidin-1-oxyl-4-yl) sebacone. 3. The use amount of the nitroxyl radical derivative is 0.00 based on 2-cyclopropyl-4- (4-fluorophenyl) -3-hydroxymethylquinoline.
The production method according to claim 1, which has an amount of 5 to 0.05 equivalents. 4. The method according to claim 1, wherein the hypohalite is sodium hypochlorite, calcium hypochlorite or potassium hypochlorite. 5. The amount of hypohalite used is 1.05 to 1.8 equivalents relative to 2-cyclopropyl-4- (4-fluorophenyl) -3-hydroxymethylquinoline. The manufacturing method described. 6. The method according to claim 1, wherein 0.05 to 0.5 equivalent of potassium bromide or sodium bromide is further added to the reaction system.