JPH04270267A - Production of 7-chloroquinaldine - Google Patents

Abstract

PURPOSE:To obtain high-purity 7-chloroquinaldine in an industrial way in high yield. CONSTITUTION:A reaction is made in an inert solvent in the presence of a base between 4-fluoro-2-nitrobenzaldehyde and acetone followed by ring closure reaction simultaneously with reduction in the presence of an acid, thus obtaining a high-purity 5-fluoro-2-halomethylbenzothiazole in high yield.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing highly purified 7-chloroquinaldine, which is useful as an intermediate for the synthesis of anti-inflammatory agents.

0002

[Prior Art] A method for producing 7-chloroquinaldine is described in Journal of Organic Chemistry, 8.
Vol., page 544 (1943), a method is known in which crotonaldehyde and metachloroaniline are reacted in the presence of a mineral acid. In the above method, a mixture of 7-chloroquinaldine and 5-chloroquinaldine (isomers are hereinafter referred to as the same) with a composition ratio of 7:3 can be obtained with a yield of 60%. It has been difficult to separate chloroquinaldine and obtain highly purified 7-chloroquinaldine, which is required as a raw material for pharmaceuticals.

On the other hand, as a method for producing unsubstituted quinaldine, Berichte der Organischen Hemie, 4
Vol. 1, p. 2692 (1908) proposes a method for obtaining unsubstituted quinaldine by reacting orthonitrobenzaldehyde with acetone, further reducing the nitro group with zinc powder, and simultaneously ring-closing it, but the yield is low. was as low as 50%, which was still not sufficient for an industrial production method.

0004

[Problems to be Solved by the Invention] The present invention solves the problems of conventional methods and is a method that does not produce isomers, and is capable of producing highly pure 7-7-
This was done to provide a method for obtaining chloroquinaldine with good yield.

[0005]

[Means for Solving the Problems] In view of the above circumstances, the present inventor has conducted repeated research on a method for producing 7-chloroquinaldine, which does not contain isomers and is desired as a raw material for pharmaceuticals. When 4-chloro-2-nitrobenzaldehyde in which the benzene nucleus was substituted with a chloro group was reacted with acetone, the reaction proceeded smoothly and an oily substance was obtained. This oil was further reduced and ring-closed at the same time, and it was recognized that highly pure 7-chloroquinaldine containing no isomers could be obtained in high yield, and the present invention was completed.

That is, the present invention provides 4-
The present invention provides a method for producing 7-chloroquinaldine, which is characterized by reacting chloro-2-nitrobenzaldehyde and acetone, and further carrying out reduction and ring-closing reactions simultaneously in the presence of an acid.

The present invention will be explained in detail below. First, in the operation of the present invention, 4-chloro-2-nitrobenzaldehyde and acetone are reacted in the presence of a base to obtain an oily substance. The bases used in this case include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium carbonate, calcium hydroxide, trisodium phosphate, and dihydrogen phosphate. Inorganic bases such as sodium, sodium dihydrogen phosphate, potassium fluoride, or triethylamine, pyridine, diazabicyclo[2.2.2]octane,
Although organic bases such as diazabicycloundecene can be used, inorganic bases such as sodium hydroxide, sodium carbonate, and sodium phosphates are preferably used. Moreover, the above-mentioned inorganic base may be used in an aqueous solution without any problem.

Regarding the molar ratio of 4-chloro-2-nitrobenzaldehyde and acetone, either may be used in excess, but usually the molar ratio of acetone is equal to or more, preferably 5 to 5.
Use 20 times the mole or more. The reaction temperature is -50 to 50°C, preferably 0 to 20°C, although the reaction proceeds satisfactorily below room temperature.

[0009] Next, the obtained oil is reduced with a reducing agent to cause a ring-closing reaction and to obtain 7-chloroquinaldine. As the reducing agent used in this case, metal powders such as iron, zinc, and tin, and sulfur compounds such as sodium sulfide, sodium hydrosulfide, and sodium dithionite can be used. Catalytic hydrogenation may also be carried out using Raney nickel, palladium on carbon, platinum oxide, or the like as a catalyst. Among these, reduction with iron powder or catalytic hydrogenation is industrially preferred. The amount of the reducing agent to be used is 1 to 5 times equivalent, preferably 1 to 1.2 times equivalent, based on 4-chloro-2-nitrobenzaldehyde.

[0010] As the acid, mineral acids such as hydrochloric acid, sulfuric acid, and nitric acid, or organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid are used. However, these acids may be used alone, but
More than one kind may be mixed and used. Among them, it is preferable to use hydrochloric acid, sulfuric acid, acetic acid, etc. There is no particular restriction on the amount of acid used, but it may be diluted with water and used also as a solvent, and other solvents may be added if necessary. The reaction temperature is from room temperature to 150°C, preferably from 40 to 100°C. Further, although normal pressure is sufficient as the reaction pressure, the reaction may be carried out under increased pressure. Note that 4-chloro-2-nitrobenzaldehyde used as a raw material can be easily obtained by brominating 4-chloro-2-nitrotoluene and further hydrolyzing it.

[0011]

[Effects of the Invention] The method of the present invention uses 4-chloro-2-nitrobenzaldehyde in which the benzene nucleus is substituted with chlorine as a raw material and reacts it with acetone in the presence of a base, so that the reaction proceeds smoothly. An oily substance was obtained. When the obtained oil was further reduced in the presence of an acid, a ring-closing reaction occurred at the same time, and highly purified 7-chloroquinaldine was obtained in a high yield. In this way, the method of the present invention
Unlike conventional methods, there is no need to separate 5-chloroquinaldine (isomers), and it is now possible to provide highly pure 7-chloroquinaldine, which is required as a raw material for anti-inflammatory agents (medicines). be. Hereinafter, the present invention will be specifically illustrated by examples.

0012

[Example 1] In a four-necked flask equipped with a thermometer, a stirrer, and a reflux condenser, 18.6 g (100 mmol) of 4-chloro-2-nitrobenzaldehyde and 100 ml of acetone were placed.
1 and 50 ml of water were added, and the mixture was cooled to 10-15°C with ice water. Next, 2.1 g (20 mmol) of anhydrous sodium carbonate was dissolved in 50 ml of water, and the mixture was heated at the same temperature with stirring for 30 minutes.
The mixture was added dropwise for 0 minutes, and stirring was continued for an additional 2 hours. After the reaction 1
N hydrochloric acid was added dropwise until the pH of the solution reached 3 to 4°C. Acetone was distilled off, 100 ml of water was added, and the mixture was further extracted twice with 500 ml of dichloromethane. The organic layer was dried over anhydrous sodium carbonate and then evaporated to obtain 25.0 g of a light brown oily substance.

Furthermore, 25.0 g of the light brown oily substance, 100 ml of acetic acid, and 50 ml of 35% hydrochloric acid were placed in a four-necked flask equipped with a thermometer, a stirrer, and a reflux condenser, and 22 g of iron powder was added at room temperature.
2.3 g (0.4 mol) was added gradually. An exotherm began and the reaction temperature rose to 70°C. After the exotherm ended, the mixture was heated on an oil bath and stirred at 80° C. for an additional 2.5 hours. During this time, 5.6 g (0.1 mol) of iron powder was further added. Cool the reaction mixture and add 20% aqueous sodium hydroxide solution 9 under ice cooling.
It was added dropwise into 50ml. Extraction was performed with 1300 ml of dichloromethane, and the organic layer was taken out and washed with 950 ml of water. Insoluble matter precipitated during this period was removed by suction filtration through diatomaceous earth. The organic layer was dried over anhydrous sodium sulfate and then concentrated to give 7-chloroquinaldine with a melting point of 73 to 75°C at 15.4
I got g. The yield was 86.7% and the purity was 99%. Furthermore, analysis by gas chromatography revealed that the isomer 5-chloroquinaldine was not contained.

[0014]

Example 2 The same procedure as in Example 1 was carried out except that potassium carbonate was used instead of sodium carbonate. As a result, 7
-12.9g of chloroquinaldine was obtained. The yield was 72.
6%, and the purity was 99%.

[Example 3]

The same procedure as in Example 1 was carried out except that 26.1 g (0.4 mol) of zinc powder was used instead of iron powder. As a result, 7
-15.2g of chloroquinaldine was obtained. The yield was 85.
6%, and the purity was 99%.

Claims (1)

[Claims] 1. 7-, which is characterized by reacting 4-chloro-2-nitrobenzaldehyde with acetone in the presence of a base, and further carrying out a ring-closing reaction simultaneously with reduction in the presence of an acid.
Method for producing chloroquinaldine.