JPH06199800A - Production of 2-chloromethylquinoline - Google Patents

Abstract

PURPOSE:To provide a production method capable of readily producing 2- chloromethyluinoline of high purity in a high yield. CONSTITUTION:This method for production of 2-chloromethylquinoline is characteristically carried out by reacting quinaldine with chlorine in the presence of a deacidifying agent at >=27 deg.C and <40 deg.C. There are used 1.0 to 2.0 equivalent of an anhydrous alkaline carbonate as the deacidifying agent and 1.3 to 2.0 equivalent chlorine gas.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing 2-chloromethylquinoline.

[0002]

2. Description of the Related Art 2-Chloromethylquinoline is used as a synthetic intermediate for pharmaceuticals. To manufacture it, quinaldine is chlorinated and the alkyl side chain is chlorinated. The method of doing is generally used. As a conventional technique for chlorinating quinaldine, a method using trichloroisocyanuric acid for the purpose of avoiding the use of chlorine, which is highly toxic and difficult to be charged in an appropriate amount, is known (Japanese Patent Laid-Open No. 61-280475). Is 53.5%. A method of chlorinating N-chlorosuccinimide and benzoyl peroxide as a catalyst is also known, but the yield is only 36%.

On the other hand, in order to prevent the formation of a by-product dichloromethyl derivative, quinaldine is oxidized and then chlorinated with boron trifluoride and tosyl chloride (J. Gem.
Chem. (USSR 1945, vol. 16, p. 331)
Is known, but the yield from oxide is only 68%. Similarly, a method is known in which quinaldine oxide is acetylated with acetic anhydride and hydrolyzed to give 2-quinolinemethanol, and this is chlorinated with thionyl chloride, but the yield is very low. Furthermore, French Patent No. 139456
In No. 2, there is a method of using chlorine in the presence of an acid or fuming sulfuric acid and a radical initiator or under irradiation of ultraviolet rays, but there is a drawback that a large amount of sulfuric acid must be removed at the time of post-treatment of the reaction product.

As an improved method, there is West German Patent No. 1204231, which is chlorinated by reacting chlorine in carbon tetrachloride in the presence of a deoxidizing agent at 40 to 80 ° C., preferably 60 to 65 ° C. 2-Chloromethylquinoline is obtained with a yield of 60%.

These conventional techniques require separation of the dichloromethyl derivative produced as a by-product, even though an expensive chlorinating agent is used, and the yield of the improved method of West Germany is low. , 2-chloromethylquinoline cannot be easily obtained in high yield.

[0006]

In order to solve the above-mentioned problems, the inventors of the present invention have proposed the above-mentioned West German Patent No. 120423.
As a result of investigating the reaction conditions such as the deoxidizing agent and the reaction temperature disclosed in No. 1, it was found that 2-chloromethylquinoline can be easily produced with high purity and high yield under specific conditions, The present invention has been completed.

That is, the gist of the present invention relates to a method for producing 2-chloromethylquinoline, which comprises reacting quinaldine and chlorine in the presence of a deoxidizer under a temperature condition of 27 ° C. or higher and lower than 40 ° C. Is.

In the present invention, the chlorination reaction of quinaldine is carried out under a temperature condition of 27 ° C or higher and lower than 40 ° C, preferably 30 ° C to 35 ° C. This control of the reaction temperature is extremely important, and when the reaction temperature is 40 ° C. or higher, the production of a by-product dichloromethyl derivative increases, and at 60 to 65 ° C., which is the preferable reaction temperature in the prior art, the dichloromethyl derivative is dichloromethylated. The methyl form has increased dramatically and the yield has been extremely reduced. Also,
When the temperature is lower than 27 ° C, the production of by-products is suppressed, but the reaction does not proceed with a large amount of unreacted substances remaining, and the unreacted substances remain even if the reaction solution is heated to 30 to 35 ° C after chlorine aeration. Does not decrease,
Conversely, 2-chloromethylquinoline produced reacts with residual chlorine, and by-products increase.

The reaction time is usually 1 to 6 hours, preferably 1 to 3 hours. This reaction is exothermic and requires external cooling during the introduction of chlorine.

Chlorine as a chlorinating agent is usually 1.3 to
2.0 equivalents, preferably 1.3-1.4 equivalents,
If it is less than 1.3 equivalents, unreacted raw materials remain, and if it is more than 2.0 equivalents, the produced chloromethyl compound is further chlorinated to increase by-products.

In the present invention, a deoxidizing agent is added to the reaction solution for the purpose of removing the acid by-produced in the reaction. An example of the deoxidizing agent usable for this purpose is anhydrous alkali carbonate. Specifically, anhydrous sodium carbonate, anhydrous potassium carbonate and the like can be advantageously used. The amount of the deoxidizer used is usually 1.0 to
It is 2.0 equivalents, preferably 1.0 to 1.5 equivalents. If it is less than 1.0 equivalent, the acid produced cannot be sufficiently neutralized,
This is because the reaction yield is lowered, and when it exceeds 2.0 equivalents, chlorination proceeds further to produce a dichloro compound. The solvent used in the reaction in the present invention is not particularly limited as long as it is an inert solvent, and examples thereof include chloroform and ethylene chloride.

2-Chloromethylquinoline produced by the method of the present invention is extracted and purified from the reaction solution by aerating residual chlorine after the reaction with air or nitrogen to remove it from the reaction system. The desired 2-by neutralization, solvent purification, etc.
Chloromethylquinoline can be obtained with high purity and high yield.

[0013]

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 40 g (0.2793 mol) of quinaldine, 100 ml of chloroform and 29.6 g of anhydrous sodium carbonate were placed in a reaction vessel.
(0.2793 mol), and warmed to 30 ° C.
At −38 ° C., 25.8 g (0.3634 mol) of chlorine gas was introduced for 3 hours to cause a reaction. After the reaction, the temperature was cooled to room temperature, and excess chlorine was driven out of the reaction system by passing dry air. Contents at the end of reaction (unreacted product, target product, by-product)
Were 5.7%, 90.8% and 3.5%, respectively. 5.8% dilute hydrochloric acid was flown into the reaction product to transfer the target product to the aqueous layer and neutralized with alkali. The crystallization product is collected by filtration,
After drying, 2-chloromethylquinoline was obtained with a yield of 79%. The crystals were recrystallized from heptane (mp54.5
C). The yield from quinaldine was 66.4%, and the content by HPLC was 99.5% or more.

Example 2 40 g (0.2793 mol) of quinaldine, 100 ml of chloroform and 38.5 g of anhydrous potassium carbonate were placed in a reaction vessel.
(0.2793 mol), and warmed to 30 ° C.
At −35 ° C., 25.8 g (0.3634 mol) of chlorine gas was introduced for 3 hours to cause a reaction. The composition of the content obtained by treating in the same manner as in Example 1 was 5.4% unreacted product, 90.7% target product, and 3.8% by-product.
The yield of chloromethylquinoline was 79.7%. It was recrystallized from heptane in the same manner as in Example 1, and the yield from quinaldine was 66.6%, and the HPLC content was 99.5% or more.
Obtained chloromethylquinoline.

Example 3 40 g (0.2793 mol) of quinaldine, 100 ml of ethylene chloride and 29.6 g of anhydrous sodium carbonate were placed in a reaction vessel.
(0.2793 mol), and warmed to 30 ° C.
At −38 ° C., 25.8 g (0.3634 mol) of chlorine gas was introduced for 2 hours to cause a reaction. The composition of the content obtained by treating in the same manner as in Example 1 was 2.9% unreacted product, 93.1% target product, and 4.0% by-product. Obtained 2
The yield of -chloromethylquinoline was 79.8%.
It was recrystallized from heptane in the same manner as in Example 1, and the yield from quinaldine was 67.0%, and the HPLC content was 29.5% or more.
-Chloromethylquinoline was obtained.

Example 4 40 g (0.2793 mol) of quinaldine, 100 ml of ethylene chloride and 44.4 g of anhydrous sodium carbonate were placed in a reaction vessel.
(0.4189 mol), and warm to 30 ° C.
At −38 ° C., 26.9 g (0.3775 mol) of chlorine gas was introduced for 2 hours to cause a reaction. The composition of the content obtained by treating in the same manner as in Example 1 was 2.5% unreacted material, 93.5% target material, and 4.0% by-product. Obtained 2
The yield of -chloromethylquinoline was 80.0%.
It was recrystallized from heptane in the same manner as in Example 1, and the yield from quinaldine was 67.1% and the HPLC content was 29.5% or more.
-Chloromethylquinoline was obtained.

Comparative Example 1 The composition of the content obtained in the same manner as in Example 1 except that the reaction temperature was 43 to 50 ° C. was 0.9% unreacted product, 66.5% target product, and 16 byproducts. It was 0.8%. Recrystallization from heptane as in Example 1 yield 3 from quinaldine
2-Chloromethylquinoline was obtained with 8.0% and an HPLC content of 95.0%.

Comparative Example 2 The composition of the content obtained in the same manner as in Example 1 except that the reaction temperature was 20 to 25 ° C. was 48.1% unreacted product, 34.6% target product, and 1 byproduct. It was 0.6%. There were many unreacted substances and the removal of 2-chloromethylquinoline was abandoned.

[0019]

INDUSTRIAL APPLICABILITY By the method of the present invention, 2-chloromethylquinoline can be easily produced with high purity and high yield.

Claims (3)

[Claims] 1. A process for producing 2-chloromethylquinoline, which comprises reacting quinaldine and chlorine in the presence of a deoxidizing agent under a temperature condition of 27 ° C. or higher and lower than 40 ° C. 2. The production method according to claim 1, wherein 1.0 to 2.0 equivalents of anhydrous alkali carbonate are used as a deoxidizing agent. 3. The production method according to claim 1, wherein 1.3 to 2.0 equivalents of chlorine gas is used.