JPH10251233A - Production of methylquinolines - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject high-purity compound useful as an intermediate for medicines by simple distillation without causing side reactions by self- polymerization, by reacting an aromatic primary amine with a hydroxybutanal containing an α,γ-keto alcohol skeleton in the presence of an acid. SOLUTION: An aromatic primary amine of formula I (R<1> to R<4> are each H, a 1-4C alkyl, etc.), especially preferably aniline is reacted with >=1mol based on the aniline derivative of a 4C ketone or aldehyde containing an α,γ-keto alcohol skeleton of formula II (one of R<5> , R<6> and R<7> is methyl and the others are H), especially preferably 4-hydroxy-2-butanal in the presence of an acid such as hydrochloric acid or sulfuric acid of 0.8-5 times mol of the aniline derivative at 70-150 deg.C under reflux or under pressure (<=20kg/cm<2> G) for about two hours to give a methylquinoline of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a methylquinoline or a derivative thereof (hereinafter referred to as methylquinolines).
And a method for producing the same. More specifically, there are few by-products,
The present invention relates to a method for producing methylquinolines with high yield using raw materials that can be easily handled.

[0002]

2. Description of the Related Art Methylquinolines are compounds useful as pharmaceutical intermediates, and a method for producing them by the reaction of an aromatic primary amine with an aldehyde or ketone having active methylene has been known. I have. For example, Skra
up (Ber., 15, 893 (1882)), Doe
bner Miller (Ber., 16, 1664)
(1883)), Rohde (Ber., 20, 191).
1 (1887)) et al. Synthesized the corresponding quinoline derivative by reacting the corresponding α, β-unsaturated aldehyde with aniline.

[0003] Manske (Can. J. Reseac)
h, 20 B, 133 (1942 )), Utermohl
en (J. Org. Chem., 8 , 544, (194)
3)) et al. Synthesized the corresponding quinoline derivative by reacting the corresponding α, β-unsaturated carbonyl compound with aniline.

[0004]

However, in each of these methods, an unsaturated aldehyde or unsaturated ketone is used as a raw material. These compounds are easily decomposed or polymerized by acids, bases, heat, light and the like. D above
In each of the reactions of obner-Miller and Skraup, the reaction system is acidic, and the unsaturated compound is liable to undergo self-polymerization and side reactions due to decomposition, in addition to the condensation reaction with the desired aniline. In particular, it was difficult to obtain a high-purity product by distillation, since the N-ethyl compound and the N-butyl compound produced by the side reaction have boiling points close to those of the target methylquinolines. In addition, its flash point is lower than room temperature and its toxicity is high, so that it is difficult to handle for industrial use.

On the other hand, a method for synthesizing 4-methylquinoline from aniline and 4-methoxy-2-butanone has also been disclosed in Cam.
as proposed by pbell (KN Cam
pbell, I .; J. Schaffner, J .; Am.
Chem. Soc. , 62 , 86 (1945)), it is industrially difficult to obtain the raw material 4-methoxy-2-butanone by this method, and according to this proposal, the reaction is carried out in an alcohol solvent, and Since the aniline yield was not high, it was not practical.

[0006] The inventors of the present invention have studied the raw materials in place of unsaturated aldehydes or unsaturated ketones. Is significantly suppressed, so that the amount of generated impurities can be significantly reduced. In particular, it has been found that since impurities which are difficult to separate by distillation, such as N-ethyl form and N-butyl form, are not substantially produced, a product of high purity can be obtained by simple distillation. Also, hydroxybutanals have low toxicity and flammability and are easy to handle.

[0007]

The present invention provides a process for producing methylquinolines, which comprises reacting an aromatic primary amine with hydroxybutanal having an α, γ-keto alcohol skeleton in the presence of an acid. It is.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, examples of the aromatic primary amine as a substrate include aniline or an aniline derivative having a substituent having no active methylene on its benzene ring, for example, a compound of the following formula (1). However, the present invention is not limited to these. Of these aromatic primary amines, aniline is particularly preferred.

[0009]

Embedded image (In the formula, R ^{1 to} R ⁴ represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, an alkoxy group having 1 to 4 carbon atoms, and a halogen group (F, Cl, Br).)

The hydroxybutanal used in the present invention to react with an aromatic primary amine and cyclize to form methylquinolines is represented by the following formula (2).
A C ₄ ketone or aldehyde having a keto alcohol backbone, 4-hydroxy-2-butanal, 3-hydroxy-2-methyl propanal, 3-hydroxy -
Examples thereof include 1-butanal and the like.
Hydroxy-2-butanal is preferred. The amount of use may be at least 1 time mol with respect to the substrate (aniline derivative), but is preferably used at 1.2 to 1.5 times mol.

[0011]

Embedded image (Wherein, one of R ⁵ , R ⁶ , and R ⁷ is a methyl group, and the rest is hydrogen)

The method of the present invention is intended to provide various methylquinolines represented by the following general formula (3) by combining the aromatic primary amine with hydroxybutanal, for example,
Methylquinoline (lepidine), 8-chloro-4-methylquinoline, 3-methylquinoline, 2-methylquinoline and the like can be produced.
Suitable for the production of methylquinoline (lepidine) and its derivatives.

[0013]

Embedded image (Wherein, R ^{1 to} R ⁴ and R ⁵ , R ⁶ , and R ⁷ are as described above).

The reaction is carried out in the presence of an acid. In this case, the acid is a Bronsted acid such as hydrochloric acid, sulfuric acid, phosphoric acid, etc.
It is to be understood that Lewis acids such as toluenesulfonic acid, iron chloride and the like are also included, of which hydrochloric acid or sulfuric acid is particularly preferred. The used amount is 0.8 to 5 times mol, preferably 1.0 to 3 times mol for the substrate.

The reaction is carried out at a temperature of 70 to 150 ° C. under reflux or under pressure (autogenous pressure: 20 kg / cm ² G or less).
When the reaction temperature is low, the progress of the reaction is slow, and when it is high, a polymer is easily formed. A reaction time of usually 2 hours is sufficient.

[0016]

EXAMPLES The present invention will be described with reference to examples, but the present invention is not limited to these examples. The product was analyzed by neutralizing the reaction solution with alkali, diluting the organic layer with methanol, and performing gas chromatography (GC / I
Quantification was performed using S).

Example 1 279 g of aniline and concentrated hydrochloric acid 3
44 g are mixed and heated to 110 ° C. with stirring. To this, 317 g of 4-hydroxy-2-butanal is added over about 1 hour. After maintaining at that temperature for 1 hour, it was cooled to room temperature. The reaction solution was subjected to GC / IS analysis after alkali decomposition. The N-ethyl form and the N-butyl form were not detected in the organic layer after alkali neutralization. The reaction yield of 4-methylquinoline (based on aniline) was 42.1 mol%. Table 1 shows the results.

Example 2 Concentrated sulfuric acid 3 was added to 279 g of aniline.
27 g are mixed and heated to 110 ° C. To this, 317 g of 4-hydroxy-2-butanal is added over about 1 hour. After maintaining at that temperature for 1 hour, it was cooled to room temperature. The reaction solution was subjected to GC / IS analysis after alkali decomposition. The organic layer after alkali neutralization contains N-ethyl compound and N
-Butyl compound was not detected. The reaction yield of 4-methylquinoline (based on aniline) was 42.9 mol%. Table 1 shows the results.

Example 3 383 g of o-chloroaniline
The mixture is mixed with 344 g of concentrated hydrochloric acid and heated to 110 ° C. To this, 317 g of 4-hydroxy-2-butanal is added over about 1 hour. After maintaining at that temperature for 1 hour, it was cooled to room temperature. The reaction solution was subjected to GC / IS analysis after alkali decomposition. The N-ethyl form and the N-butyl form were not detected in the organic layer after alkali neutralization. The reaction yield of 8-chloro-4-methylquinoline was 38.3 mol%.
(Vs. o-chloroaniline). Table 1 shows the results.

Comparative Example 1 279 g of aniline and concentrated hydrochloric acid 3
44 g are mixed and heated to 110 ° C. with stirring. To this, 231 g of methyl vinyl ketone is added over about 1 hour. After maintaining at that temperature for 1 hour, it was cooled to room temperature. The reaction solution was subjected to GC / IS analysis after alkali decomposition. The reaction yield of 4-methylquinoline (based on aniline) was 41.0 mol%, but considerable amounts of N-ethyl and N-butyl were formed in the organic layer after alkali neutralization. Table 1 shows the results.

Comparative Example 2 383 g of o-chloroaniline
The mixture is mixed with 344 g of concentrated hydrochloric acid and heated to 110 ° C. To this, 231 g of methyl vinyl ketone is added over about 1 hour. After maintaining at that temperature for 1 hour, it was cooled to room temperature. The reaction solution was subjected to GC / IS analysis after alkali decomposition. The reaction yield of 8-chloro-4-methylquinoline is 3
Although it was 7.8 mol% (based on o-chloroaniline), considerable amounts of N-ethyl and N-butyl were formed in the organic layer after alkali neutralization. Table 1 shows the results.

[0022]

[Table 1] 4MQ 4-methylquinoline 8C-4MQ 8-chloro-4-methylquinoline 4-H-2-Bu'al 4-hydroxy-2-butanal

[0023]

According to the present invention, hydroxybutanal is used as a raw material, so that decomposition and polymerization of the raw material do not occur as compared with the conventional method using an unsaturated aldehyde or unsaturated ketone, and N-ethyl The formation of difficult-to-separate by-products such as N-butyl and N-butyl is suppressed, so that high-purity products can be obtained by simple distillation, and low toxicity and flammability. It is economically advantageous.

Claims (2)

[Claims] 1. A process for producing methylquinolines, comprising reacting an aromatic primary amine with hydroxybutanal having an α, γ-keto alcohol skeleton in the presence of an acid. 2. The method according to claim 1, wherein the aromatic primary amine is aniline or 1 to 1.
2. The method for producing methylquinolines according to claim 1, which is an aniline derivative substituted with a substituent having no four active methylene groups.