JP3011493B2 - Method for producing 4-alkyl-3-thiosemicarbazide - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to the production of 4-alkyl-3-thiosemicarbazide which is an important compound as a raw material for synthesizing medicines and agricultural chemicals.

[0002]

2. Description of the Related Art As a method for producing 4-alkyl-3-thiosemicarbazide, (A) a method comprising reacting an alkyl isothiocyanate with hydrazine hydrate (CA Vol.
69: 26739X), (B) a method of reacting alkylammonium 4-alkyldithiocarbamate with hydrazine hydrate (U.S. Pat. No. 4,237,066), and (C) sodium alkyldithiocarbamate with hydrazine hydrate Is known in the presence of a metal catalyst (EP 308,225).

[0003]

However, the method (A) is not practical because of the high cost of the alkyl isothiocyanate, and the method (C) has a problem in that the crystals are colored depending on the catalyst used, and the method (C) has a high quality. It is not suitable for industrial production of 4-alkyl-3-thiosemicarbazide. In the method (B), 1,3-alkylthiourea is produced as a by-product to lower the yield, and it is difficult to separate and purify the by-product from the target substance. Therefore, the method (B) has a high purity of 4-alkyl-3-thiosemicarbazide. Cannot be obtained, and none of the conventional methods is a satisfactory production method.

Accordingly, an object of the present invention is to produce by-products of 1,3-alkylthiourea from inexpensive alkali salts of alkyldithiocarbamic acids easily obtained by reacting alkylamine, carbon disulfide and alkali hydroxide. An object of the present invention is to provide a method for industrially producing a high-purity 4-alkyl-3-thiosemicarbazide while suppressing it.

[0005]

As a result of intensive studies on a method for producing 4-alkyl-3-thiosemicarbazide starting from an alkali alkyldithiocarbamate,
Alkyldithiocarbamic acid is easily decomposed into alkylamine and carbon disulfide on the acidic side rather than neutral, and the alkylamine formed by decomposition is converted to 1,3-dialkylthiourea via alkylammonium alkyldithiocarbamate. It was found that the reaction occurred, and based on these results, the conditions for suppressing the side reaction were examined, and the present invention was reached.

The present invention relates to an alkyl dithiocarbamate, ie, starting from a compound of formula (1)
In the production of 3-thiosemicarbazide, that is, formula (2), an alkyldithiocarbamate alkali salt is heated with an equivalent amount of a strong acid in an aqueous solution having a pH of 9 or more in which hydrazine coexists to remove generated hydrogen sulfide out of the system. This is a method for producing a 4-alkyl-3-thiosemicarbazide with high yield and high purity.

[0007]

The reaction route of the present invention is presumed to be such that, after the conversion of an alkali alkyldithiocarbamate to a hydrazinium alkyldithiocarbamate, hydrogen sulfide is eliminated to convert it to 4-alkyl-3-thiosemicarbazide. 3 ".

Embedded image (In the formula, M represents an alkali metal, HA represents an acid, R represents an alkyl group, and R ′ represents an alkyl group or a hydrogen atom.)

By the method of the present invention, it has become possible to suppress the by-product of 1,3-alkylthiourea, which is considered to be due to the following "Chemical Formula 4". According to the present invention, the decomposition of alkyldithiocarbamic acid into alkylamine is suppressed as much as possible, and as a result, the by-product of 1,3-alkylthiourea is suppressed. It becomes possible to produce thiosemicarbazide.

Embedded image (However, M represents an alkali metal, HA represents an acid, R represents an alkyl group, and R ′ represents an alkyl group or a hydrogen atom.)

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The alkali alkyldithiocarbamate used in the present invention includes sodium methyldithiocarbamate, sodium ethyldithiocarbamate, sodium propyldithiocarbamate, sodium isopropyldithiocarbamate, sodium butyldithiocarbamate, sodium sec-butyldithiocarbamate, sodium tert-butyldithiocarbamate, potassium methyldithiocarbamate, potassium ethyldithiocarbamate, potassium propyldithiocarbamate,
Potassium isopropyldithiocarbamate, potassium butyldithiocarbamate, potassium sec-butyldithiocarbamate, potassium tert-butyldithiocarbamate, sodium N, N-dimethyldithiocarbamate,
Sodium N, N-diethyldithiocarbamate,
Examples thereof include potassium N-dimethyldithiocarbamate and potassium N, N-diethyldithiocarbamate, with sodium methyldithiocarbamate and potassium methyldithiocarbamate being particularly preferred.

As the alkyldithiocarbamic acid alkali salt, an aqueous solution obtained by reacting the corresponding alkylamine with carbon disulfide and sodium hydroxide or potassium hydroxide can be used as it is.

Examples of hydrazine include anhydrous hydrazine, hydrazine hydrate, hydrazine hydrochloride, hydrazine hydrochloride,
Hydrazine sulfate, neutral hydrazine sulfate, hydrazine phosphate and the like can be used, but anhydrous hydrazine and hydrated hydrazine, particularly hydrated hydrazine, are preferable. As the hydrated hydrazine, commercially available hydrazine having a concentration of 60% or 100% can be used, or the hydrazine can be used at a reduced concentration as needed.

The amount of hydrazine used is preferably from 1.1 to 20.0 mol, preferably from 1.1 to 3.0 mol, per mol of the alkali alkyldithiocarbamate.

The acid used in the present invention is a strong acid such as hydrochloric acid, sulfuric acid, phosphoric acid, and P-toluenesulfonic acid, and hydrochloric acid and sulfuric acid are particularly preferable.

The amount of acid used is of particular importance in the present invention and has a very large effect on yield and quality. The acid used is preferably 0.98 to 1.00 equivalent with respect to 1 mol of the alkyldithiocarbamic acid alkali salt. However, when a free alkali hydroxide is present, the acid used is 0.98 to 1.0 mol based on the total number of moles of the alkali metal alkyldithiocarbamate plus the number of moles of the free alkali hydroxide. 00 equivalents are appropriate. It is particularly preferable to keep the number of equivalents at 1.

In place of hydrazine and acid, hydrazine hydrochloride, hydrazine hydrochloride, hydrazine sulfate, hydrazine sulfate, hydrazine phosphate, or other strong acid salts of hydrazine can be used partially or entirely. When a strong acid salt of hydrazine is used partially or entirely in place of hydrazine and acid, the total number of equivalents of acid salt of hydrazine and the number of equivalents of acid is added to 1 mol of alkali salt of alkyldithiocarbamic acid. Is 0.98 to 1.00 equivalent.

In the method of the present invention, it is essential to maintain the pH of the reaction solution at 9 or more in the presence of hydrazine. Normally, this condition is achieved by mixing an alkyl dithiocarbamate alkali salt and an equivalent strong acid in an aqueous hydrazine solution. That is, in the presence of an excess of hydrazine, an alkali salt of alkyldithiocarbamic acid: strong acid =
As long as it satisfies 1: 1 (equivalent ratio), the pH becomes 9 or more, and the method of the present invention can be carried out without any trouble.

In particular, when an alkali salt of alkyldithiocarbamic acid is used, the equivalent ratio of the alkali salt of alkyldithiocarbamic acid to the strong acid must be 1. When the strong acid is small relative to the alkali alkyldithiocarbamate, the salt is extremely stable and does not react under the conditions of the present invention, and the alkali alkyldithiocarbamate remains unreacted. Will result in lower rates. However, since the alkyldithiocarbamic acid alkali salt is removed from the system as an aqueous solution,
Product quality does not decrease. In addition, when the strong acid is large relative to the alkali salt of alkyldithiocarbamic acid, the pH of the reaction system is increased.
Cannot be maintained at 9 or more, the by-product of 1,3-alkylthiourea cannot be suppressed, resulting in a decrease in yield and a decrease in product quality.

[0018] The reaction temperature of the present invention is from 60 to 120 ° C, preferably from 90 to 110 ° C. At a temperature lower than this range, the reaction does not proceed sufficiently, and a high yield cannot be obtained. If the temperature is higher than this range, by-products are formed and the product is colored, so that the object of high quality and high yield cannot be achieved.

In the preferred temperature range of the method of the present invention, when a strong acid is added to an alkali alkyldithiocarbamate in the presence of hydrazine at a pH of 9 or more, the reaction immediately proceeds to form 4-alkyl-3-thiosemicarbazide. At the same time, hydrogen sulfide is generated. Therefore, in order to make the reaction proceed smoothly, it is preferable to control the rate of addition of the strong acid and to control the rate of generation of hydrogen sulfide.

The reaction time is generally 0.5 to 10 hours, preferably 0.5 to 4 hours.

The reaction pressure is not particularly limited. In order to remove hydrogen sulfide smoothly, it is carried out at normal pressure or reduced pressure within the temperature range of the present invention.

The removal of hydrogen sulfide proceeds automatically and smoothly as long as it is carried out under the above conditions. However, if necessary, a further effect can be brought about by simultaneously distilling off some of the water.

As a preferred reaction method when using hydrated hydrazine, an alkali solution of an alkyldithiocarbamate and a strong acid are added to an aqueous solution of hydrated hydrazine while maintaining the equivalent ratio of the alkali salt of alkyldithiocarbamate: strong acid to 1: 1. And a method in which a strong acid is gradually added to a mixture of hydrazine hydrate and an alkali salt of alkyldithiocarbamic acid to cause a reaction, and the like.

[0024]

EXAMPLES The present invention will now be described specifically with reference to examples, but the present invention is not limited to these examples. The purity of 4-alkyl-3-thiosemicarbazide is analyzed by liquid chromatography.

Example 1 116.5 g (1.50 g of a 40% aqueous solution of monomethylamine)
Mol) and 116.5 g of pure water were charged into a 1-liter glass flask equipped with a stirrer, a thermometer and a condenser, and 114.2 g (1.50 mol) of carbon disulfide was added at 10 ° C.
It was added in 15 minutes at the following temperature. Next, 104.2 g (1.25 mol) of a 48% aqueous sodium hydroxide solution was added in 90 minutes while maintaining the temperature at 10 ° C. or lower. After adding sodium hydroxide, the mixture was stirred at 10 ° C for 4 hours and at 45 ° C for 2 hours.
Monomethylamine, carbon disulfide and water were distilled off under reduced pressure at a pot temperature of 45 ° C. or less over 3 hours to obtain 254.0 g of a white dry product. 400.0 g of acetone was added to the dried product, and the mixture was stirred for 2 hours and cooled to 10 ° C. to separate crystals. The crystals were washed with 200.0 g of acetone and dried in a vacuum dryer at 30 ° C. for 16 hours to obtain 179.7 g (1.09 mol) of crystals of sodium monomethyldithiocarbamate dihydrate.

50 equipped with a stirrer, thermometer and distillation apparatus
100% hydrazine 3 in a 0 ml glass flask
3.0 g (0.660 mol) and 260.0 g of pure water were charged. Next, the mixture was heated to 102 ° C. in a nitrogen atmosphere, and an aqueous solution in which 82.6 g (0.500 mol) of sodium monomethyldithiocarbamate dihydrate obtained by the above method was dissolved in 116.9 g of pure water, and 50.7 g of 36% hydrochloric acid (0.500
Mol) was simultaneously added dropwise over 2 hours with a metering pump. During this time, water and hydrogen sulfide were distilled off. Estimated distillate volume is
Aqueous sodium monomethyldithiocarbamate solution and 36
% Was 250.2 g, which was the same as the combined amount of hydrochloric acid. Furthermore, while adding 130.0 g of pure water in one hour,
Water and residual hydrogen sulfide were distilled off, and the amount of distilled water was set at 130.0 g, which is the same as the amount of added water. The reaction solution was cooled to 68 ° C, a small amount of 4-methyl-3-thiosemicarbazide was added as seed crystals, and the mixture was slowly cooled to 15 ° C.
The reaction solution was stirred at 15 ° C. for 30 minutes to separate crystals. After washing the crystal with 50.0 g of pure water, the crystal was dried at 50 ° C.
And dried for 8 hours. The yield of 4-methyl-3-thiosemicarbazide was 42.4 g, the purity was 98.8%, and the melting point was 1.
At 37.8 ° C., the yield based on sodium monomethyldithiocarbamate was 79.7%. The pH of the reaction solution was 12 or more at the start of the reaction, and 10.1 at the end of the reaction.

Example 2 82.6 g of sodium monomethyldithiocarbamate dihydrate synthesized in the same manner as in Example 1 was placed in a 500 ml glass flask equipped with a stirrer, a thermometer and a condenser.
500 mol), 33.0 g of 100% hydrazine hydrate
(0.660 mol) and 150.0 g of pure water.
Next, it is heated to 102 ° C. in a nitrogen atmosphere,
0.7 g (0.500 mol) was added dropwise by a metering pump in 2 hours. After dropwise addition of 36% hydrochloric acid, the mixture was stirred at 102 to 104 ° C for 1 hour. During the reaction, the formed hydrogen sulfide was distilled off through a condenser. The reaction solution was cooled to 68 ° C., and a small amount of 4-methyl-3-thiosemicarbazide was added as seed crystals,
Cool slowly to 15 ° C. The reaction solution is kept at 15 ° C for 30 minutes.
After stirring for minutes, the crystals were separated. The crystals were washed with 50.0 g of pure water and dried in a vacuum drier at 50 ° C. for 8 hours. The yield of 4-methyl-3-thiosemicarbazide was 40.9 g, the purity was 98.7%, the melting point was 137.0 ° C, and the yield based on sodium monomethyldithiocarbamate was 76.8%. The pH of the reaction solution was 12 or more at the start of the reaction,
At the end of the reaction, it was 10.0.

Example 3 77.7 g (1.00 mol) of a 40% aqueous solution of monomethylamine and 76.9 g of pure water were charged into a 500 ml glass flask equipped with a stirrer, a thermometer and a condenser.
38.1 g (0.500 mol) of carbon disulfide were added at a temperature below 10 ° C. in 15 minutes. Next, 69.8 g (0.500 mol) of a 28.7% aqueous sodium hydroxide solution was added in 15 minutes while maintaining the temperature at 10 ° C. or lower. After the addition of the aqueous sodium hydroxide solution, the mixture was stirred at 20 ° C for 2 hours and at 30 ° C for 1 hour. Under reduced pressure, at a pot temperature of 45 ° C. or lower, monomethylamine, carbon disulfide, and water were distilled off over 1.5 hours.
4.3 g of a concentrate were obtained. Then, the stirrer, the thermometer and the condenser were mounted again, and 100% hydrazine hydrate 3 was added.
3.0 g (0.660 mol) and 79.2 g of pure water were added. Next, the mixture was heated to 102 ° C. in a nitrogen atmosphere, and 50.7 g (0.500 mol) of 36% hydrochloric acid was added dropwise over 2 hours using a metering pump. After dropwise addition of 36% hydrochloric acid, the mixture was stirred at 102 to 104 ° C for 1 hour. During the reaction, the formed hydrogen sulfide was distilled off through a condenser. The reaction mixture was cooled to 66 ° C, a small amount of 4-methyl-3-thiosemicarbazide was added as seed crystals, and the mixture was slowly cooled to 15 ° C. Reaction solution at 15 ° C
For 30 minutes to separate crystals. 50.0 g of crystals in pure water
And dried in a vacuum dryer at 50 ° C. for 8 hours. 4
The yield of -methyl-3-thiosemicarbazide was 40.4.
g, purity 98.2%, melting point 137.3 ° C., yield based on carbon disulfide 75.5%. The pH of the reaction solution was 12 or more at the start of the reaction, and 10.3 at the end of the reaction.
It was.

COMPARATIVE EXAMPLE 1 In a device similar to that of Example 2, 66.1 g (0.400 mol) of sodium monomethyldithiocarbamate dihydrate was added.
25.0 g (0.500 mol) of hydrazine hydrated with 0% and 93.5 g of pure water were charged, and at 30 ° C., 19.5 g of concentrated sulfuric acid was added.
g, the pH was adjusted to 8.5, and then 104 ° C in a nitrogen atmosphere.
For 4 hours. During the reaction, the formed hydrogen sulfide was distilled off through a condenser, and 3.7 g of concentrated sulfuric acid was added in several portions to maintain the pH at 7 to 9. Reaction solution at 70 ° C
Then, a small amount of 4-methyl-3-thiosemicarbazide was added as seed crystals, and the mixture was slowly cooled to 15 ° C.
The reaction solution was stirred at 15 ° C. for 30 minutes to separate crystals. The crystals were washed with 50.0 g of pure water and dried in a vacuum dryer at 50 ° C. for 8 hours. The yield of 4-methyl-3-thiosemicarbazide is 22.8 g, the purity is 97.1%, and the melting point is 135.8.
At C, the yield based on sodium monomethyldithiocarbamate was 52.6%.

[0030]

According to the present invention, an alkyldithiocarbamic acid alkali salt which can be industrially easily obtained from an alkylamine, carbon disulfide and an alkali hydroxide is used as a raw material to produce a 1,3-alkylthiourea. A high-quality 4-alkyl-3-thiosemicarbazide can be produced in a high yield while preventing production, and is of great industrial significance as compared with the prior art.

──────────────────────────────────────────────────の Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07C 337/00 CA (STN) REGISTRY (STN)

Claims (7)

(57) [Claims] 1. A 4-alkyl-3-thiosemicarbazide comprising heating an alkali salt of an alkyldithiocarbamic acid and a strong acid in an aqueous solution having a pH of 9 or more in the presence of hydrazine, and removing generated hydrogen sulfide out of the system. Manufacturing method. 2. An alkali metal salt of an alkyldithiocarbamic acid having the general formula: (Wherein M is an alkali metal, R is an alkyl group, R ′ represents an alkyl group or a hydrogen atom), and 4-alkyl-3-thiosemicarbazide has the general formula: The method according to claim 1, wherein the compound is a compound represented by the formula: wherein R represents an alkyl group and R 'represents an alkyl group or a hydrogen atom. 3. The method according to claim 1, wherein the reaction temperature is 60 to 120 ° C. 4. The process according to claim 1, wherein a reaction solution of the alkyldithiocarbamic acid alkali salt with an alkylamine, carbon disulfide and an alkali hydroxide is used as it is. 5. The hydrazine according to claim 1, wherein hydrazine is selected from anhydrous hydrazine, hydrazine hydrate, hydrazine hydrochloride, hydrazine hydrochloride, hydrazine sulfate, neutral hydrazine sulfate and hydrazine phosphate. Manufacturing method. 6. The method according to claim 1, wherein hydrochloric acid, sulfuric acid, phosphoric acid, or p-toluenesulfonic acid is used as the strong acid. 7. The method according to claim 1, wherein water in the reaction system is distilled off during the reaction.