JPS609028B2 - Method for producing S-pyridylisothiuronium N-oxide hydrohalide - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an improved method for producing S-pyridylysothiuronium N-oxide hydrohalide.

That is, the production of S-pyridylysothiuronium N-oxide hydrohalide, which is characterized by reacting halogenopyridine N-oxide with thiourea in an organic solvent at a temperature not exceeding 60 qC. It is about law. S-pyridyl isothiuronium N-oxide hydrohalide, such as S-2-pyridylysothiuronium N-oxide hydrochloride, can easily be converted into 2-mercapto pyridine N-oxide by alkaline decomposition. It can lead to
It is useful as a synthetic intermediate for 2-mercapto pyridine N oxide and its metal salts, which have fungicidal properties.

The production of S-pyridylisoturonium N-oxide hydrohalide has been carried out in the past, for example, in J.J. am. chem. S ratio 72
4362 ('50), 2-bromopyridine N
- Oxide/hydrobromide was reacted with thiourea in anhydrous alcohol at reflux temperature for 1.0 hours with a yield of 72%,
S-2-pyridylysothiuronium N-oxide hydrobromide is obtained.

Also, J. chem. Soc. 2 in 1960 2941
-Chlorpyridine N oxide is mixed with thiourea in ethyl alcohol, also at reflux temperature. Feed time reaction 6
S-2-pyridylisothiuronium N. with 0% yield
Obtaining oxide/hydrochloride. Furthermore, pharmaceutical journals 81 6
In 14, 2-chloropyridine-N-oxide was similarly mixed with thiourea in absolute alcohol at reflux temperature. The desired product was obtained with a yield of 81% after an hourly reaction. On the other hand, in US Pat. No. 2,745,826, a reaction mixture obtained by reacting 2-frompyridine with 40% peracetic acid is
The mixture was cooled to 5° C., a suspension of thiourea in inpropyl alcohol was added thereto, and the mixture was reacted at reflux temperature to obtain the desired product with a yield of 70%.

The present inventors investigated the production of S-2-pyridylisothiuronium N-oxide hydrohalide by the methods described in these documents, but were unable to obtain sufficiently satisfactory results. For example, 2-chloropyridine N
- Oxide hydrochloride was mixed with thiourea in anhydrous ethyl alcohol at reflux temperature in 1. The yield of the desired S-2-pyridylisothiuronium N-oxide hydrochloride was 58.2%, and many other tar-like by-products were obtained. . The present inventors conducted various studies aimed at obtaining S-2-pyridylisothiuronium N-oxide hydrochloride in good yield while suppressing the formation of tar-like substances as by-products. It was confirmed that the amount of the product produced changes significantly depending on the reaction temperature.

That is, purified 2-chloropyridine N. Oxide hydrochloride was reacted with an equimolar amount of thiourea in anhydrous ethyl alcohol at room temperature for 6.0 hours to obtain S-2-pyridyl'isothiuronium N.oxide hydrochloride in a yield of 92.6%. When the same reaction was carried out under the same conditions using ethyl alcohol as a reagent, the yield of the target product was 93.7%. Also, when equimolar amounts of 2-chloro pyridine N oxide were added in ethyl alcohol, the yield of the target product was 93.7%. It was found that a similar yield could be obtained by reacting with thiourea in the presence of concentrated hydrochloric acid.When the influence of reaction temperature on this reaction was investigated, it was found that when the reaction was carried out at room temperature for a feeding time of 92. 7%, 95.5% for 2 unique reactions
with a yield of S-2-piIJ dil isothiuronium N.
We were able to obtain oxide/hydrochloride. Further, at a reaction temperature of 4,000 ℃, the yield was 93.2%, and at a temperature of 6,000 ℃, the yield decreased sharply to 52.5%. When the reaction mother liquor at 60 qo was concentrated under reduced pressure, a large amount of tar-like material was obtained, but the components of this material are unknown.

Based on the above findings, the present inventors have established a method for obtaining S-pyridylisothiuronium N.oxide, hydrohalide salt with improved yield, and have accomplished the present invention. That is, the present invention provides halogenopyridine/N.

Oxide or its hydrohalide salt is reacted with thiourea or its hydrohalide salt in an organic solvent or a halogenopyridine. N.Oxide is reacted with thiourea in the presence of hydrohalic acid in an organic solvent to obtain S-pyridylysothiuronium N.Oxide hydrohalide at a reaction temperature not exceeding 6000°C. It is characterized by causing a reaction. The halogenopyridine-N-oxide which is the raw material of the present invention may be any halogenopyridine-N-oxide having a halogen atom in the pyridine nucleus.
Chlorpyridine, 2-frompyridine, etc. are used.

As the solvent used in the present invention, an organic solvent is used.

Particularly preferred organic solvents are those that dissolve both halogenopyridine N-oxide or its hydrohalide salt and thiourea, and the resulting S-pyridylysothiuronium-N-oxide. A solvent with low solubility in hydrohalides is preferred. Alcohols and amides are particularly preferred.Other organic solvents include
Hydrocarbons, ketones, esters When using ethers, carboxylic acids, and halogenated hydrocarbons, they dissolve both of the raw materials, making it difficult for the reaction to occur, but the results are not very good. Good results can be obtained when these solvents are used in combination with alcohols and amides.
Among amides, dimethylformamide, dimethylacetamide, etc. are good solvents as they dissolve both well.

Alcohols include methyl alcohol/ethyl alcohol, n-propyl alcohol, inpropyl alcohol, n-butyl alcohol, isobutyl alcohol,
Lower alcohols such as secondary butyl alcohol are preferred.

These alcohols do not need to be used in anhydrous state as stated in the literature. The amount of alcohol to be used is not particularly limited, but good results can usually be obtained by using 500 to 2000 M per mole of halogenopyridine-N-oxide. The theoretical ratio of halogenopyridine N oxide to thiourea of 1:1 is sufficient, and no particular advantage is observed even if an excess of thiourea is used.

If a strong acidic component such as hydrochloric acid is present in this reaction, the reaction can be significantly accelerated.However, as a method of coexisting hydrochloric acid in the reaction system, it is also possible to add it in the form of the hydrochloride of the raw material halogenopyridine N-oxide. You can also use it in the form of thiourea hydrochloride.

Quite simply, a sufficient effect can be obtained by simply adding the necessary amount of concentrated hydrochloric acid to the reaction system. Alternatively, gaseous hydrochloric acid may be absorbed into the reaction system. By directly introducing concentrated hydrochloric acid into the system, water enters the reaction system, but under the temperature conditions of the present invention, this amount of water does not have any particular adverse effect.

It is sufficient to use hydrochloric acid in an equimolar amount to that of halogenopyridine/N/oxide. Regarding the reaction temperature, which is an important factor in the present invention, the temperature does not exceed 6000°C, especially from room temperature to 4°C.
A range of 000 is preferred.

If it exceeds 60 qo, the amount of tar-like by-products will increase and the yield of the target S-pyridylisothiuronium N*oxide hydrohalide will decrease.

It is ideal if the halogenopyridine N oxide used as the raw material of the present invention is sufficiently purified.
In order to obtain it, it must be separated and obtained only by complicated purification methods from the reaction mixture obtained in the N-oxygenation step of halogenopyridine, resulting in a considerably low yield.

In order to eliminate such drawbacks, the method of the present invention is improved by adopting the following embodiment in which it is directly connected to the N-oxidation step of halogenopyridine. That is, the N-oxygenation reaction of halogenopyridine is usually carried out by oxidizing the halogenopyridine with an oxidizing agent such as peracid or hydrogen peroxide-acetic acid (sulfuric acid catalyst), or hydrogen peroxide-tungstic acid.

Therefore, the reaction mixture obtained by such a method contains either acetic acid or water, or both. There is no particular influence of acetic acid on the production reaction of isothiuronium salts of halogenopyridine/N-oxide, but since the solubility of isothiuronium salts is slightly higher than that of alcohols, it is possible to use S-pyridyl-isothiuronium-N-oxide by that much. The yield of oxide hydrohalide is reduced. Furthermore, if a large amount of water is introduced, there is a risk of undesirable side reactions occurring, so it is preferable to minimize the amount of water present. From the above reaction mixture,
Removal of acetic acid and water can be achieved by distilling the reaction mixture under reduced pressure. An organic solvent, preferably an alcohol, is added to the unpurified crude halogenopyridine N oxide obtained in this way, and thiourea and concentrated hydrochloric acid are added, and the reaction is carried out at room temperature to obtain a sufficiently satisfactory yield. The desired S-pyridyl isothiuronium N-oxide hydrohalide can be obtained. When crude halogenopyridine/N-oxide is used, there is a risk that halogenopyridine that has not been completely consumed in the N-oxidation step may be mixed into the raw material; Oxide is the best.

The solubility of S-pyridylisothiuronium hydrohalide is lower than that of S-pyridyl isothiuronium N-oxide halogen. Since the solubility is higher than that of hydrochloride, it is impossible for S-pyridyl isothiuronium hydrohalide to be mixed into the target S-pyridyl isothiuronium N oxide hydrohalide. Despised. When the reaction is carried out in this manner, the purification in the N-oxygenation step is not performed, so the amount of halogenopyridine N-oxide lost in the purification step is effectively converted into isothiuronium salt, resulting in a significantly lower yield. Improved.

The remarkable effects of the present invention will be shown below using Examples.

Examples 1 to 2 0.1 mole of 2-chloropyridine N oxide was dissolved in 50 parts of ethyl alcohol, and separately 0.1 mole of thiourea and 10 parts of concentrated hydrochloric acid were dissolved in 150 parts of ethyl alcohol. Mix and conduct the base reaction at the temperature shown in the table below.

Isochuronium salt begins to precipitate at about 3 powder level. After reacting for a predetermined time, the mixture was filtered through a G-3 glass filter, washed with ethyl alcohol, and then vacuum dried. The yield of the obtained S-2-pyridyl isothiuronium hydrochloride was as shown in the following table. Example 3 0.5 mol of 2-chloropyridine N oxide was dissolved in 250 mol of inpropyl alcohol, and 0.5 mol of 2-chloropyridine N oxide was dissolved in 250 mol of thiourea.
．． 5 mol, concentrated hydrochloric acid 50 birds, inpropyl alcohol 75
0' and dissolve.

When the two were mixed and stirred at room temperature, the solution became homogeneous after a certain period of time, and then the hydrochloride of isothuronium salt began to precipitate. After reacting at room temperature for 6 hours, the crystals were separated in a furnace, washed with inpropyl alcohol, and vacuum dried. 5%
S-2-pyridylisothiuronium N.oxide hydrochloride was obtained in a yield of . Examples 4-5 2-Chlorpyridyl.N.

When 0.02 mole of oxide hydrochloride and 0.02 mole of thiourea were reacted in 40% absolute alcohol at room temperature for 6 hours, the yield of S-2-pyridylisothiuronium N. Oxide hydrochloride was obtained.When the same reaction was carried out using commercially available ethyl alcohol, the yield was 93.7.
It was %. Examples 6 to 7 0.1 mole of 2-chloropyridine/N-oxide and 0.1 mole of thiourea were added to commercially available Natanol 200', and 10% of concentrated hydrochloric acid was added, reacted at room temperature for 1 day, and then separated in the furnace. ,
Washed and dried S-2-pyridylysoturonium.

N.Oxide hydrochloride was obtained with a yield of 88.4%. When the same reaction was further carried out with the addition of 13M permanent acetic acid, the yield of the target product was 87.4%.

Comparative Example 2 0.02 mol of 2-chloropyridine N oxide hydrochloride and 0.02 mol of thiourea were reacted in 40' of anhydrous ethyl alcohol at reflux temperature for 1 hour, resulting in S-2 pyridyl isothiuronium. - The yield of N-oxide hydrochloride was 56.2%.

Example 8 0.5 mol of 2-chloropyridine and 0.30 ml of sodium pyrophosphate were placed in a separate flask and heated to 700 ml.
Heat to 0.

To this was added dropwise an acetic acid solution containing 41% peracetic acid and 4% hydrogen oxide in an amount equivalent to 1.27 mol peracetic acid over a period of 2 hours. During this time, the reaction temperature is maintained between 70 and 8000C. After reacting for an additional 4 hours at the same temperature, the reaction solution was divided into halves and one half was concentrated under reduced pressure to a volume of about 1/milk volume. Add 5% of inpropyl alcohol to the resulting concentrate.
0.00 and 0.30 mol of thiourea were added, followed by a sintering reaction for 2 hours at room temperature, and the precipitated crystals were placed in a furnace. After washing with inpropyl alcohol and drying, 2-S-pyridylisothiuronium N-oxide hydrochloride was obtained after 44.7 days. The melting point of this product was 157o0.
The yield was 86.9% based on the charged 2-chloropyridine. The remaining half was concentrated under reduced pressure, and the resulting beard extract was adjusted to pH 1O with 20% sodium hydroxide.
Unreacted 2-chloropyridine is eliminated by azeotropic distillation of water.

The Isonai liquid obtained in this) was extracted with chloroform, and the obtained chloroform liquid was concentrated to give 2-chloropyridine.

25.9 r of N-oxide was obtained. This is preparation 2-
This corresponds to a yield of 80% based on chlorpyridine. Examples 9 to 15 0.025 mol of 2-chloropyridine N-oxide hydrochloride and 0.025 mol of thiourea were placed in an Erlenmeyer flask, and 50 mol of a solvent as shown in the table below was added thereto, followed by reaction at room temperature for one day.

After the reaction, the resulting crystals were filtered through a glass filter, washed with a sufficient amount of ethyl alcohol, unreacted raw materials were removed, and weighed after drying (Example 9 and Comparative Examples 3 to 8). Same reaction as 3 to 8 with 15 ethyl alcohol as solvent
When 0M was used in combination, the yield was significantly improved. Example
10-15

Claims (1)

[Claims] 1. Reacting halogenopyridine N oxide or its hydrohalide salt with thiourea or its hydrohalide salt in an organic solvent, or reacting halogenopyridine N oxide in an organic solvent in the presence of hydrohalic acid. S-pyridylisothiuronium N oxide is reacted with thiourea to obtain S-pyridylisothiuronium N oxide hydrohalide at a reaction temperature not exceeding 60°C.・Production method of oxide/hydrohalide.