JPS6284068A - Production of 2(3h)-benzthiazolone substituted in the 3-position - Google Patents

Abstract

PURPOSE:Ring opening of a 2(3H)-iminobenzthiazoline substituted in the 3-position is effected in the presence of an alkali metal or alkaline earth metal hydroxide, then the ring is closed with an acid to make the production of the titled compound advantageous in industry. CONSTITUTION:A 2(3H)-iminobenzthiazoline substituted in the 3-position is allowed to react with an alkali metal or alkaline earth metal hydroxide in water or water-organic solvent mixed solvent to give an alkali metal or alkaline earth metal salt of an N-substituted o-mercapto-N-phenyl urea. Then, the product is treated with an acid to effect ring closure whereby 2(3H)-benzthiazolone substituted in the 3-position which is used as an intermediate of medicines or agricultural chemicals is obtained with industrial ease in a short time in high yield and purity.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides an industrially advantageous method for producing 2(8■)-benzthiazolones substituted at the 8-position, which are important as intermediates for the production of pharmaceuticals, agricultural chemicals, etc. (Regarding this.

Conventionally, various methods for synthesizing 2(8H)-benzthiazolones substituted at the 8-position have been proposed, and for example, the following methods are known.

a) A method of hydrolyzing a 2(8H)-iminobenzthiazoline compound using an aromatic sulfonic acid (Japanese Patent Publication No. 1986-
Publication No. 428).

b) A method in which a 2(8E[)-iminobenzthiazoline compound is ring-opened with an alkali metal hydroxide in the absence of water and further ring-closed with an acid (Japanese Patent Application Laid-open No. 16875/1987).

0) A method in which a 2(8H)-iminobenzthiazoline compound is nitrosated and then thermally decomposed.

However, method a) produces a large amount of by-products and has an extremely low yield of about 25-40%, and method b)
In the initial stage of the reaction, extremely water-free conditions, which are considered to be industrially extremely difficult, are required, and method C) involves the use of ecologically and physically dangerous intermediates in the treatment process, etc. Neither method was satisfactory as an industrial production method.

In view of the above, the present inventors have completed the present invention after various studies in order to improve these drawbacks and produce 2(8H)-benzthiazolones substituted at the 8-position with industrial advantage. Ta.

That is, the present invention provides nitrogen substitution by reacting a 2(8H)-iminobenzthiazoline compound substituted at the 8-position with an alkali metal or alkaline earth metal hydroxide in water or a water-organic solvent mixture system. ortho-mercapto-N
- It is characterized in that an alkali metal salt of a phenylurea compound is obtained and then treated with an acid to cyclize it.

The present invention provides a method for producing 2(8EI)-benzthiazolones substituted at the 8-position.

The reaction according to the method of the present invention proceeds according to the following reaction formula.

[In the above formula, R1 and R2 are the same or different and each represents a hydrogen atom, a halogen atom, an alkyl group (preferably a lower alkyl group), an alkoxyl group (preferably a lower alkoxyl group), a hydroxyl group, a nitro group or a sulfone group. Show or both are nuclear! Sometimes they can be combined to indicate a naphthalene nucleus. R represents an optionally substituted alkyl group, cycloalkyl group, or phenyl group,
These groups can also be bonded to the nucleus at the 0-position to form a ring, and are preferably 01 to Is alkyl groups (this is a vinyl group, methyl group, ethyl group, methoxy group, ethoxy group,
or may be substituted with a phenyl group, hydroxyl group, lower alkoxyl group, etc., which may be substituted with a chloro atom, etc.), phenyl group (this is a methyl group, ethyl group, hydroxyl group, methoxy group, ethoxy group) or may be substituted with a chlorine atom, etc.),
It is a cyclohexyl group. M represents an alkali metal or an alkaline earth metal, and n is 1 or 2. ] In the present invention, the 2(8H)-iminobenzthiazoline compound substituted at the 8-position represented by the general formula (1) used as a raw material is disclosed in, for example, JP-A No. 58-9767 or JP-A-Sho 58-9767. It can be produced by the method described in Japanese Patent No. 54-109970.

The reaction temperature for ring cleavage to formula (2) is 60 to 200°C
can be selected within the range of 80 to 140℃, preferably 80 to 140℃
It is. Although the reaction proceeds below 60°C, it takes a long time to complete the reaction, which is industrially disadvantageous. When the temperature exceeds 200°C, a large amount of by-products are produced, which tends to lead to a decrease in yield.

゛ Examples of the alkali metal or alkaline earth metal hydroxide used in this reaction include barium hydroxide, calcium hydroxide, potassium hydroxide and sodium hydroxide, with sodium hydroxide being particularly preferred. The amount of such hydroxide to be used is at least stoichiometric with respect to the compound of general formula (1) as a raw material, but in order to avoid side reactions, it is sufficient to use 2 to 6 times the mole, preferably 2.5 to 6 times the mole. Preference is given to four times the molar amount of alkali metal or alkaline earth metal hydroxide.

Water is preferred as the reaction solvent, but a water-organic solvent mixture may also be used. In this case, the organic solvent is not particularly limited as long as it is inert to the reaction, and examples include n-hexane, benzene, and toluene. The amount of such a solvent used is preferably an amount sufficient to serve as a solvent for the alkali metal or alkaline earth metal hydroxide used, but since the reaction of the present invention proceeds even in a suspended state, its use is There is no particular restriction on the amount. It is usually 0.2 to 80 times the weight of the raw material, preferably 0.5 to 10 times the weight. Of course, even if the weight exceeds 80 times, the XJ reaction will proceed, but the volumetric efficiency will decrease, which is industrially disadvantageous.

The end point of the reaction can be confirmed by determining the complete disappearance of the starting compounds in the reaction system by instrumental analysis, such as liquid chromatography. Although it is possible to precipitate crystals from the reaction solution and then separate them by filtration or by removing the reaction solvent, it is operationally advantageous to carry out the acid treatment in the next step without separating them. be.

Acid treatment is usually carried out in two steps, the first step being the general formula (
2) When adding about an equivalent amount of acid to the compound to form 0-mercaptophenyl urine represented by general formula (3), the treatment temperature is usually in the range of -20 to 90°C, but preferably -11
The temperature is 0 to 20°C.

After such acid treatment, a catalytic or excess amount of acid is subsequently added to carry out the cyclization reaction.

In this treatment, the precipitated crystals may be separated from the reaction solution after the previous acid treatment, or the subsequent acid treatment may be performed as is, or the treatment may be performed using a solvent or diluent system. It is preferable to carry out the reaction in an aqueous medium containing an acid, and the amount of the solvent to be used at this time is not particularly limited.

In addition, the treatment temperature is usually 40 to 100°C, preferably 60°C.
~90°C.

Through this subsequent acid treatment, the cyclization reaction from the compound of general formula (3) to the target compound of general formula (4) proceeds.

The acid used in the acid treatment is generally an inorganic acid such as hydrochloric acid or sulfuric acid. The progress of the reaction is monitored by instrumental chromatography, and the reaction is terminated when all of the compound of general formula (3) has disappeared. The 2(8H)-benzthiazolones substituted at the 8-position are removed from the reaction solution, for example, after pH adjustment, by Oki filtration or the like.

Thus, by the method of the present invention, the desired 8-position-substituted 2(2(
8EI)-benzthiazolones are obtained, which may be purified by recrystallization if necessary.

The present invention will be explained below with reference to Examples.

Example 1 8-methyl-2-iminobenzthiazoline 41, IP,
Sodium hydroxide 25.0? and water 85? The mixture consisting of is stirred for 8 hours at 110-115°C. After the reaction is complete,
Add the reaction solution to 400 ml of ice water. Add inside. While maintaining the temperature at 0 to 10°C, the pH value is adjusted to 6 with 10% hydrochloric acid, and the precipitated N-methyl-N-(2-mercapto-phenyl)-urea is isolated by filtration. Isolated J-1? , ? El 1i4
- Tohi Hkelh 尤、二pl 礒、IF
1 ＾ ρζ Shaved it O＾ ＾? and stir at 80°C for 80 minutes. After cooling, the FEE value was adjusted to 8, and the precipitated crystals were filtered, isolated, and dried to obtain 8-
Methyl-2(8H)-benzthiazolone (40.7PC yield 95.8%) was obtained. Purity: 97.2%.

H3 Example 2 8-Methyl-2(8H]-benzthiazolone 40.
4P (yield 98.7%) was obtained. Purity: 95.8%
.

Example 8 The same reaction and post-treatment as in Example 1 were carried out, except that an equimolar amount of 8-ethyl-2-iminobenzthiazoline was used instead of 8-methyl-2-iminobenzthiazoline, and 8 of the following structure was obtained. -Ethyl-2(8H)-benzthiazolone 4B, OF (yield 92.1%) was obtained. Purity: 96
．． 0%.

Zhan H2CH3 Example 4 4-chloro-8-methyl-2-iminobenzthiazoline 49.7? , sodium hydroxide 25.0? and water 85p
The mixture consisting of is stirred at 100-105° C. for 8 hours.

After the reaction is completed, the reaction solution is added to 400 tons of ice water. 0-1
While maintaining the temperature at 0°C, the pH value was adjusted to 6 with 10% hydrochloric acid, and the precipitated N-methyl-N-(6-chloro-2-mercapto-phenyl)-urine was isolated by filtration. Immediately add the isolated wet product to 10% hydrochloric acid 800? In addition to
Stir for 16 minutes at 90°C. After cooling, the pH value was adjusted to 8, and the precipitated crystals were filtered, isolated, and dried to obtain 4-chloro-8-methyl-2(8H)-benzthiazolone 49.
IP (yield 95.4%) was obtained. Purity: 97.0
%.

Example 5 8-phenyl-2-iminobenzthiazoline 56.6
), sodium hydroxide 25.0 ? , xylene 100i
and 805 L of water is stirred at 885-90° C. for 4 hours. Thereafter, it is cooled to -5°C. Adjust the pH value to 6 with 10% hydrochloric acid while keeping it at -5 to '5℃, and immediately
0% hydrochloric acid 800? and stir at 90°C for 15 minutes.

Subsequently, xylene was concentrated, the PR value was adjusted to 8 after cooling, and the precipitated crystals were filtered, isolated, and dried to obtain 8-phenyl-2(8H)-benzthiazolone 58.9 P (yield 89.7) with the following structure. %] with a purity of 794.6%.

Example 6 Equimolar amount of 8-methyl-6,7-benzo-2 (8EI) in place of 8-phenyl-2-iminobenzthiazoline
- The same reaction and post-treatment as in Example 5 were carried out except for using benzthiazoline, and 8-methyl-6 of the following structure was
,7-benzo-2(8H,l-benzthiazolone 51.
45' (vehicle collection 88.θ%) was obtained. Purity 92.1%.

Product 3 Example 7-12 Instead of 8-methyl-2-iminobenzthiazoline,
The same reaction and post-treatment as in Example 1 were carried out except that equimolar amounts of the compound corresponding to general formula (1) having the residues R1, R1 and R2 listed in the following table were used, and the substituents listed in the following table were A compound corresponding to general formula (4) having R, R1 and R2 was obtained in the yield shown in the following table.

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Claims (1)

[Claims] A 2(3H)-iminobenzthiazoline compound substituted at the 3-position is reacted with an alkali metal or alkaline earth metal hydroxide in water or a water-organic solvent mixture to produce a nitrogen-substituted ortho-mercapto compound. - Obtaining an alkali metal or alkaline earth metal salt of an N-phenylurea compound, and then treating this with an acid to cyclize it, 3-
A method for producing 2(3H)-benzthiazolones substituted at the position.