JP3240201B2 - Method for producing chloropyrazines - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing chloropyrazines represented by the following general formula (1), namely, 2-chloropyrazine, 2,3-dichloropyrazine and / or 2,6-dichloropyrazine. . All of these compounds are useful as intermediates of pharmaceuticals and agricultural chemicals. General formula (1):

Embedded image (In the formula, X is located at the 3- or 6-position, and represents a hydrogen atom or a chlorine atom.)

[0002]

2. Description of the Related Art A compound represented by the general formula (1) wherein X is a hydrogen atom, that is, 2-chloropyrazine, is prepared by using pyrazine 1-oxide as a raw material and chlorinating with phosphorus oxychloride. J. Or
g. Chem. , 28 1682-6 (1963). This manufacturing method is based on pyrazine 1
The oxide must be produced from pyrazine, 2
It requires a process and is not an economical manufacturing method. A method for producing 2-chloropyrazine directly from pyrazine and chlorine is shown in U.S. Pat. No. 2,396,066, but this method must be performed in a gas phase reaction requiring extensive equipment,
In addition, there is a disadvantage that a severe reaction condition of 250 to 600 ° C. is required.

[0003] Next, with respect to a method for producing a compound represented by the general formula (1) wherein X is a chlorine atom, that is, 2,3-dichloropyrazine and / or 2,6-dichloropyrazine, French Patent Specification 1,457,96
No. 3 discloses a method of using 2-chloropyrazine as a raw material and chlorinating the same with chlorine or chlorine and phosphorus oxychloride. In this method, first, 2-chloropyrazine, which is a raw material, must be produced from pyrazine in two steps, which is not a simple method. Further, a method for producing these dichloropyrazine directly from pyrazine and chlorine is disclosed in U.S. Pat. No. 2,524,431. It must be carried out under conditions, and the yield of dichloropyrazine is at most 40-45%.

As described above, in order to obtain chloropyrazines directly from pyrazine by the conventional technique, production must be carried out under severe conditions and with a large-scale gas-phase reaction, and the yield is low. In addition, producing dichloropyrazine from pyrazine by a liquid phase reaction under mild conditions requires a plurality of steps and is not economical. In addition, a method for producing dichloropyrazine directly from pyrazine by a liquid phase reaction has not been known at all.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a method for producing chloropyrazines directly from pyrazine by a liquid phase reaction, which can overcome such disadvantages of the prior art.

[0006]

Means for Solving the Problems The present inventors have studied various methods for producing chloropyrazines directly from pyrazine by a liquid phase reaction. As a result, it was difficult to chlorinate pyrazine with a chlorinating agent by a liquid phase reaction using a chlorinated hydrocarbon such as carbon tetrachloride as a solvent under no solvent or a non-polar solvent, but in a polar solvent. It has been found that when pyrazine is reacted with a chlorinating agent, pyrazine is easily chlorinated, and the present invention has been completed.

That is, the present invention relates to a method for producing a chloropyrazine represented by the above general formula (1), which comprises reacting pyrazine with a chlorinating agent in a polar solvent.

In the method of the present invention, pyrazine is dissolved in a polar solvent and reacted while introducing a chlorinating agent at a predetermined temperature into the solution, or conversely, introducing the chlorinating agent into the polar solvent at a predetermined temperature. After that, the reaction is usually carried out by adding pyrazine, or by any method.

The polar solvent used in the method of the present invention includes:
N, N-dimethylformamide, N-methyl-2-pyrrolidone, N, N-dimethylacetamide, hexamethylphosphoramide and the like can be mentioned, among which N, N-dimethylformamide is preferable. Regarding the amount of the polar solvent used, 2,3-dichloropyrazine and 2,3-dichloropyrazine
When 6-dichloropyrazine is mainly produced, the more polar solvent used, the more the 2,6-dichloropyrazine is 2,6-dichloropyrazine.
When the target substance is 2,3-dichloropyrazine, the larger the amount of the polar solvent used, the more preferable it is because the production ratio to dichloropyrazine is high. It is preferable to select the amount of the polar solvent to be used in the range of 1 to 5 moles per mol of pyrazine, depending on the intended product of the present invention. The method of the present invention does not require the addition of a non-polar solvent, but may optionally add a solvent such as carbon tetrachloride.

The chlorinating agent used in the method of the present invention includes:
Chlorine, sulfuryl chloride, phosphorus oxychloride, sulfur chloride, etc.
Commonly known chlorinating agents can be mentioned,
Chlorine and sulfuryl chloride are preferred to achieve good yields. The amount of the chlorinating agent depends on the target substance to be produced. For example, when N, N-dimethylformamide is used as a polar solvent, in order to mainly produce 2-chloropyrazine, it is preferable to use a chlorinating agent in a molar amount of 1 to 2 times as much as that of pyrazine. In order to mainly produce dichloropyrazine and 2,6-dichloropyrazine, it is appropriate to use the chlorinating agent in an amount of more than 2 times and 5 times the mole of pyrazine.

[0011] The reaction temperature is preferably from room temperature to 150 ° C.
When the chlorinating agent is chlorine, the reaction proceeds even at 20 ° C. or lower, but since the viscosity of the reaction solution increases and stirring becomes considerably difficult, 30 to 100 ° C. is more preferable from the viewpoint of operability and yield of the reaction. . The reaction time depends on the rate of introduction of the chlorinating agent. The reaction may be carried out in a short time by increasing the rate of introduction, or in a long time by decreasing the rate. Usually, 0.5 to 10 hours is appropriate.

The isolation of the product from the reaction solution is usually carried out by
It can be performed by a commonly used method. For example,
The reaction-terminated liquid is added to water and then made alkaline with an alkaline substance such as sodium hydroxide or the like without adding an alkaline substance, and the product is extracted with an extractant comprising an organic solvent such as toluene. Then, the extracted oil layer is directly subjected to distillation to remove the extractant and the reaction solvent first, or the extracted oil layer is washed with water to remove the reaction solvent to the aqueous layer, and then subjected to distillation to remove the extractant first. Then, the product is rectified under reduced pressure to isolate 2-chloropyrazine, 2,6-dichloropyrazine and 2,3-dichloropyrazine in this order.

[0013]

EXAMPLES The present invention will be further described with reference to examples, but the present invention is not limited to these examples. In addition, the yield of chloropyrazines (based on pyrazine) in each Example is collectively shown in Table 1 below.

Example 1 150 g (1.87 mol) of pyrazine and 274 g (3.75 mol) of N, N-dimethylformamide were charged into a four-necked flask equipped with a stirrer, a thermometer and a chlorine blowing tube, and stirred. While maintaining the internal temperature at 58 to 72 ° C, chlorine 3
12 g (4.40 mol) were introduced over 2.6 hours and kept at this temperature for a further 0.5 hour. Thereafter, the reaction mixture was cooled, added to 3 liters of water with stirring, and then extracted three times with toluene. The obtained toluene layer was analyzed by gas chromatography using diethylene glycol-n-butyl ether as an internal standard substance, and the yield of chloropyrazines was determined.

Example 2 The operation was carried out in the same manner as in Example 1 except that the reaction temperature was 35 to 43 ° C.

Example 3 The procedure of Example 1 was repeated, except that N, N-dimethylformamide and chlorine were used in 2.5 times and 1.8 times the amounts used in Example 1, respectively. Was.

Example 4 The procedure of Example 1 was repeated except that N, N-dimethylformamide was used in an amount of 0.75 times the amount used in Example 1.

Example 5 100 g (1.25 mol) of pyrazine and 183 g (2.50 mol) of N, N-dimethylformamide were charged into a four-necked flask similar to that of Example 1, and the internal temperature was adjusted to 66 to 100% with stirring.
Keep at 70 ° C. and add 109 g (1.54 mol) of chlorine to 2.5
It was introduced over time and cooled immediately after the introduction. Thereafter, post-processing was performed in the same manner as in Example 1.

Example 6 The operation was carried out in the same manner as in Example 5 except that the reaction temperature was 65 to 68 ° C. and the introduction time of chlorine was 5 hours.

Example 7 A four-necked flask equipped with a stirrer, a thermometer and a dropping funnel was charged with 10 g (0.125 mol) of pyrazine and 18.3 g (0.250 mol) of N, N-dimethylformamide and stirred. Under the condition, the internal temperature was kept at 67 to 72 ° C., and 42.2 g (0.313 mol) of sulfuryl chloride was added dropwise from the dropping funnel over 1.2 hours, and then kept at the same temperature for 0.5 hour. Thereafter, post-processing was performed in the same manner as in Example 1.

Example 8 The operation was carried out in the same manner as in Example 7 except that 25.3 g (0.187 mol) of sulfuryl chloride was used.

Example 9 10 g (0.125 mol) of pyrazine and 24.8 g of N-methyl-2-pyrrolidone were charged into a four-necked flask equipped with a stirrer, a thermometer and a chlorine blowing tube, and the mixture was stirred and stirred at an internal temperature. While maintaining the temperature at 37-42 ° C., 18.2 g of chlorine (0.25 g).
7 mol) was introduced over 1.7 hours, and for a further 0.5 hour,
It was kept at the same temperature. Thereafter, post-processing was performed in the same manner as in Example 1.

Comparative Example The operation was carried out in the same manner as in Example 1 except that carbon tetrachloride was used instead of N, N-dimethylformamide. The yields of 2,3-dichloropyrazine and 2,6-dichloropyrazine were all traces.

[0024]

[Table 1]

[0025]

According to the method of the present invention, it is possible to produce chloropyrazines directly from pyrazine in a liquid phase reaction in a suitable yield.

──────────────────────────────────────────────────の Continuation of the front page (56) References JP-A-56-86174 (JP, A) MERCK INDEX ELEV NTH EDITION, page 1418-1419, 8959. Sulfuryl Chloride (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 241/16 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. A process for producing chloropyrazines represented by the following general formula (1), wherein pyrazine is reacted with a chlorinating agent in a polar solvent. General formula (1): (In the formula, X is located at the 3- or 6-position, and represents a hydrogen atom or a chlorine atom.) 2. The method according to claim 1, wherein the polar solvent is N, N-dimethylformamide. 3. The method according to claim 2, wherein the chlorinating agent is chlorine. 4. The method according to claim 2, wherein the chlorinating agent is sulfuryl chloride.