JP2706517B2 - Novel disulfide and method for producing tolnaftate using the disulfide as a raw material - Google Patents

Description

The present invention relates to a novel compound N, N'-dimethyl-N, N'-bis (m-tolyl) thiuram disulfide and tolnaftate useful as a therapeutic agent for athlete's foot and the like. From the disulfide raw material.

[Prior Art] Conventionally, tolnaftate has been used as a therapeutic agent for athlete's foot and the like, and various production methods have been known so far. For example, a method comprising reacting N-methyl- (m-tolyl) thiocarbamoyl chloride with β-naphthol in an acetone solvent in the presence of an acid neutralizing agent (West German Patent No. 3042)
No. 785), or N-methyl-m-toluidine and β
A method of reacting naphthylchlorothioformate (eg, German Patent No. 3042785, Pharmaceutical Journal 68,335) and the like. However, these methods use thiophosgene in the production of thiocarbamoyl chloride or chlorothioformate as a raw material. Is hard to say.

[Problem to be Solved by the Invention] An object of the present invention is to solve the above-mentioned difficulties of the prior art. That is, an object of the present invention is to provide a method which can be industrially carried out safely and advantageously, and which can smoothly produce high-purity tolnaftate.

[Means for Solving the Problems] As a result of intensive studies to achieve the above object, the present inventor has found that a specific N, N'-dimethyl-N, N'-bis (m-tolyl) thiuram disulfide ( Hereinafter, N-methyl-N- (m-tolyl) thiocarbamoyl chloride (hereinafter abbreviated as a specific chloride) can be obtained by reacting with chlorine using a specific disulfide as a raw material. The present inventors have obtained a novel finding that tolnaphthate can be obtained safely and advantageously by performing a condensation reaction between a specific chloride and β-naphthol.

Thus, the present invention has been completed on the basis of the above-mentioned findings, and comprises reacting N, N'-dimethyl-N, N'-bis (m-tolyl) thiuram disulfide with chlorine to produce N-methyl-N- A novel method for producing tolnaftate, which comprises producing (m-tolyl) thiocarbamoyl chloride and then subjecting the N-methyl-N- (m-tolyl) thiocarbamoyl chloride to a β-naphthol condensation reaction. To provide.

The specific disulfide used as a raw material in the present invention has the formula Is a novel compound not described in the literature, but can be easily synthesized by various generally known methods. As an example, an aqueous solution of sodium N-methyl-N- (m-tolyl) dithiocarbamate is obtained by the reaction of N-methyl-m-toluidine, carbon disulfide and caustic such as sodium hydroxide. It can be synthesized by oxidation using an oxidizing agent such as sodium hypochlorite or hydrogen peroxide. Accordingly, the present invention provides a novel compound, N, N'-dimethyl-N,
The present invention also provides a novel method of N'-bis (m-tolyl) thiuram disulfide and a method for producing the same.

In the present invention, tolnaftate can be produced smoothly and advantageously using the above-mentioned specific disulfide as a raw material.

First, a specific disulfide is reacted with chlorine gas in a solvent to generate a specific chloride [N-methyl-N- (m-tolyl) thiocarbamoyl chloride]. As the reaction solvent, various solvents can be used without particular limitation. For example, a solvent that does not react with a specific chloride such as benzene, toluene, xylene, chlorobenzene, or a halogenated hydrocarbon is preferable. Is preferably about 4 to 10 times the specific disulfide. As the temperature of the chlorination reaction, 0 to 50 ° C can be adopted, but 20 to 30 ° C is particularly preferable. The molar ratio of chlorine to the specific disulfide can be selected from a wide range of 0.9 to 1.5, but is preferably about 1.0 to 1.2. If the molar ratio is too small, the yield of the specific chloride will be low. If the molar ratio is too large, by-products such as sulfur chloride will increase, which is not preferable in any case. After the chlorination reaction, part or all of the solvent can be recovered by distillation. The distillation temperature is preferably 125 ° C. or lower. If it is too high, the specific chloride is decomposed, which is not preferable. Since the solubility of by-product sulfur and the like is reduced by recovering the solvent, by-product sulfur crystals can be separated by filtration or the like after the solvent is recovered. By using such a method, the coexisting sulfur in tolnaftate, which will be described later, can be reduced.

Next, the specific chloride synthesized as described above is subjected to a condensation reaction with β-naphthol, whereby the target product tolnaphthate can be obtained. As the reaction solvent, various solvents can be used without particular limitation,
For example, when a solvent such as benzene, toluene, xylene, chlorobenzene, or a halogenated hydrocarbon is used,
It is particularly preferable because the condensation reaction can be carried out without using a neutralizing agent. The solvent here may be the same as or different from the solvent in the chlorination reaction. The amount of the solvent used can be selected from the range of about 2 to 5 times that of β-naphthol. The molar ratio of β-naphthol is 1.0 to 3.0, preferably 1.5
Approximately 2.5 may be employed. If the molar ratio is too small, a diadduct is formed by a side reaction, and if the molar ratio is too large, there is a disadvantage in yield because tolnaphthate dissolves in β-naphthol. The method of adding the specific chloride to the reaction system may be a lump or a gradual method such as dropping. The reaction temperature is selected from a wide range of 70 to 120 ° C, but is preferably about 80 to 100 ° C.
The reaction time varies depending on the temperature and the like.
Time is employed. During the reaction, by-product hydrogen chloride gas can be driven out of the system by passing an inert gas such as nitrogen gas into the system, which is advantageous in terms of promoting the reaction.

After completion of the condensation reaction, the remaining hydrochloric acid is neutralized with an alkali hydroxide such as caustic soda, an alkali carbonate such as soda ash, washed with water, and the solvent is distilled and recovered. The distillation temperature is
The temperature is preferably 150 ° C. or lower, and if it is too high, there is a problem that sublimation of β-naphthol becomes severe. By adding a solvent having a low solubility of tolnaftate, such as methanol or ethanol, to the residual liquid after the recovery of the solvent, tolnaftate can be crystallized. The precipitated crystals are filtered and washed with a crystallization solvent to obtain crude tolnaftate. In this crude tolnaftate, sulfur by-produced in the chlorination step coexists, so that the purity of the tolnaftate is 80%.
About 95%. At this stage, the yield of tolnaftate for the specific disulfide can be 75-80%. By recrystallizing the crude tolnaftate using a solvent such as an acetone / ethanol system or an acetone / isopropanol system, pure white refined tolnaftate can be obtained.

In the present invention, the alkali metal salt and chlorine are reacted by using the alkali metal salt of N-methyl-N- (m-tolyl) dithiocarbamic acid used in the synthesis of the above specific disulfide as a raw material, A specific chloride [N-methyl-N- (m-tolyl) thiocarbamoyl chloride] is produced via a specific disulfide [N, N'-dimethyl-N, N'-bis (m-tolyl) thiuram disulfide]. be able to. Then, the specific chloride and β-naphthol are subjected to a condensation reaction, whereby tolnaphthate can be produced smoothly and advantageously. The first-stage chlorination step can be performed according to the above-mentioned chlorination step of the specific disulfide, and the second-stage condensation reaction is as described above.

[Examples] Next, examples of the present invention will be described more specifically. However, it is needless to say that the present invention is not limited by the description.

Example 1. <Synthesis of specific disulfide> In a 500 ml four-necked flask equipped with a thermometer, a cooling condenser, a stirrer, and a dropping funnel, 60.5 g of N-methyl-m-toluidine and 40 g of carbon disulfide were placed. ,
While maintaining the system temperature at 30 ° C., 200 g of a 10% aqueous sodium hydroxide solution was added dropwise over 2 hours. Further, the reaction was carried out by continuing stirring at the same temperature for 2 hours, and N-methyl-N- (m-
An aqueous solution of sodium tolyl) dithiocarbamate is obtained.
This aqueous solution is transferred to a 1000 ml beaker, and oxidized with a 16% by volume aqueous solution of sodium hypochlorite while maintaining the temperature at 30 to 40 ° C. The precipitated yellow crystals were separated by filtration, washed with water, and dried to obtain 88 g of N, N'-dimethyl-N, N'-bis (m-tolyl) thiuram disulfide. The yield based on the starting material N-methyl-m-toluidine is 90%.

The melting point of the obtained specific disulfide is 175.5 to 177.0 ° C., and the infrared absorption spectrum (FIG. 1), EI-MASS spectrum (second), FD-MASS spectrum (FIG. 3), ¹ H-NMR
Spectrum (Fig. 4) and analytical value of sulfur content 32.6% by weight
(Calculated value is 32.7%) and so on, N,
It was confirmed to be N'-dimethyl-N, N'-bis (m-tolyl) thiuram disulfide.

Assignment of ¹ H-NMR for the above formula of the compound (CDC1 _3, δpp
m): a: 2.40 (6H), f: 3.72 (6H), b to e: 7.23 (8H).

<Synthesis of specific chloride> 88 g of the specific disulfide obtained above and 220 ml of toluene were charged into a 500-ml four-necked flask equipped with a thermometer, a cooling condenser, a stirrer, and a gas injection tube. 17.5g of chlorine while keeping at ~ 30 ℃
The chlorination reaction is performed by blowing over time. Thereafter, the temperature is raised and 110 ml of toluene is recovered by distillation at 90 to 100 ° C.
When cooled to normal temperature, sulfur coexisting in the specific disulfide precipitates. By filtering this, 190 g of a toluene solution of the specific chloride [N-methyl-N- (m-tolyl) thiocarbamoyl chloride] is obtained. Was.

<Condensation reaction> 130 g of β-naphthol and 340 ml of toluene were charged into a four-neck flask having a capacity of 1000 ml equipped with a thermometer, a cooling condenser, a dropping funnel, a hydrochloric acid absorption trap, and a stirrer. After dissolving the naphthol, 190 g of the above-mentioned toluene solution of the specific chloride is dropped at a temperature of 80 to 90 ° C. over 2 hours. When the reaction starts, hydrochloric acid gas is generated and absorbed by the trap. After the completion of the dropwise addition, the mixture was stirred at the same temperature for 2 hours to complete the reaction, and then neutralized with dilute sodium hydroxide and separated. After distilling and recovering toluene from the upper solvent layer under reduced pressure, 450 ml of methanol is gradually added thereto with stirring while keeping the remaining liquid at 50 to 60 ° C. Tolnaftate precipitates with the addition of methanol. After the addition of methanol was completed, the mixture was cooled to 20 ° C., filtered, washed with 200 ml of methanol and dried to obtain 103 g of pale yellow crude tolnaftate. The purity of the crude tolnaftate by liquid chromatography was 95%.

<Purification> To 103 g of the crude tolnaftate obtained above, 220 ml of acetone, 440 ml of isopropanol, and 5 g of activated carbon were added and recrystallized to obtain 90 g of pure white pure tolnaftate. The yield based on the specific disulfide corresponds to 65.3%. The melting point of this purified tolnaftate was 110 to 111 ° C., and the purity by liquid chromatography was 99.8%.

[Effects of the Invention] The novel compound N, N'-dimethyl-N, N'-bis (m-tolyl) thiuram disulfide of the present invention uses the conventionally dangerous thiophosgene by using it as a raw material. In addition, it has an excellent effect that tolnaftate can be produced industrially safely and advantageously.

[Brief description of the drawings]

The accompanying drawing shows the molecular structure of N, N'-dimethyl-N, N'-bis (m-tolyl) thiuram disulfide of Example 1,
FIG. 1 shows infrared absorption spectrum, FIG. 2 shows EI-MASS spectrum, and FIG. 3 shows FD-MA.
SS spectrum and FIG. 4 show the ¹ H-NMR spectrum, respectively.

Claims (5)

(57) [Claims] 1. N, N'-dimethyl-N, N'-bis (m-tolyl) thiuram disulfide. 2. An N, N'-dimethyl-N, N'-bis (m-tolyl) thiuram disulfide, characterized by oxidizing an alkali metal N-methyl-N- (m-tolyl) dithiocarbamate. Production method. 3. The reaction of N-methyl-m-toluidine, carbon disulfide and caustic alkali to form N-methyl-N- (m-
N, N'- characterized by obtaining an alkali metal salt of (tolyl) dithiocarbamic acid and oxidizing the alkali metal salt.
A method for producing dimethyl-N, N'-bis (m-tolyl) thiuram disulfide. 4. A method for producing N-methyl-N- (m-tolyl) thiocarbamoyl chloride by reacting N, N'-dimethyl-N, N'-bis (m-tolyl) thiuram disulfide with chlorine. Characteristic N-methyl-N- (m-
A method for producing tolyl) thiocarbamoyl chloride. 5. The reaction of N, N'-dimethyl-N, N'-bis (m-tolyl) thiuram disulfide with chlorine to produce N-methyl-N- (m-tolyl) thiocarbamoyl chloride. The N-methyl-N- (m-tolyl)
A method for producing tolnaphthate, comprising subjecting thiocarbamoyl chloride and β-naphthol to a condensation reaction.