JPS5835199B2 - Seizouhou - Google Patents

Description

[Detailed description of the invention] The present invention is based on the general formula %formula% (However, in the formula, R represents a lower alkyl group.

) It relates to a method for producing a 2-hydroxy-5-alkylthiazolo[3,2-b]-8-triazole derivative represented by The object of the present invention is to obtain these compounds in high yield and industrially advantageously.

As a result of various studies on new production methods for these compounds, the present inventors found that 2-imino-3-amino-4-alkyl-4
- It has been found that a highly purified target product can be produced in high yield and industrially advantageously by thermally reacting thiazoline hydrochloride with phosgene in a nonpolar solvent.

Conventionally known method (Japanese Patent Application Publication 1973-3)
No. 0192), 2-imino-3-amino-4-methyl-4-thiazoline hydrochloride (I) is reacted with chloroformic acid alkyl ester in the presence of sodium hydroxide to obtain 2-imino-3-amino-4-methyl-4-thiazoline hydrochloride (I).
The compound imino-3-alkoxycarbonylamide-4-methyl-4-thiazoline (n) is then produced by reaction with sodium methylate to form the desired 2-hydroxy-5-methylthiazolo[3.2-b)-s This is a method for producing triazole (III), and the reaction formula is as follows.

(In the formula, R, R and R" represent a lower alkyl group.

That is, according to the known method, the reaction is carried out in two stages, and it requires an alkyl chloroformate and an expensive alcoholade, so it cannot be said to be an industrially advantageous method.

The present inventors have detailed the raw material 2-imino-3-amino-4
-As a result of examining various properties of alkyl-4-thiazoline hydrochloride (I), it was found that the amino group at the 3-position of the thiazole ring is strongly basic, coordinates with hydrochloric acid, and has the properties of a primary amine.
It was found that the imino group at the 2nd position does not coordinate with hydrochloric acid and is chemically inert, and the 3rd position is selectively incyanatized by reaction with phosgene. to form 2imino-3-incyanato-4-alkyl-4thiazoline (IV), which is immediately ring-closed to form the desired 2-hydroxy-5-alkylthiazolo[3.2-b]-8-
The present invention was achieved by discovering that it becomes triazole (In).

The reaction formula for this is as follows.

(In the formula, R represents a lower alkyl group.

That is, the present invention provides 2-imino-3-amino-4-alkyl-4-thiazoline hydrochloride (1) represented by the following general formula (wherein R represents a lower alkyl group) in an organic solvent or This is an industrially advantageous method in which a highly pure target product can be obtained at once by carrying out a hot introduction reaction of dry phosgene in water, preferably a chlorinated nonpolar solvent such as chlorobenzene or orthodichlorobenzene.

In carrying out the reaction, the reaction is carried out at 60-150°C, preferably at 90-110''G to produce the first stage of semimicrolide (IV), followed by
By heating to 00 to 180°C, preferably 130 to 150"'C, a dehydrochlorination reaction occurs, producing the intermediate incyanato compound (V), which is then ring-closed to give the target product (
III).

The reaction proceeds when the amount of phosgene is equimolar to the raw material, but 1 mole or more may be used to complete the reaction.

White crystals are obtained by cooling after the reaction or by distilling off the solvent.

If necessary, it can be recrystallized from hot water or alcohols.

Next, examples of the present invention will be shown.

Example 1 2-hydroxy-5-ethylthiazolo C5-2b) -
s-triazole 2-imino-3-amino-4-ethyl-4-thiazoline hydrochloride 52 was suspended in 40 cc of orthodichlorobenzene, and 630 cc of dry phosgene was introduced at 100° C. over about an hour.

After introducing a certain amount of phosgene, the reaction solution was heated to 140℃ for 3
The mixture was heated and stirred for hours.

After the reaction was completed, the mixture was cooled, and the white crystals were dried separately and washed with a small amount of water to obtain crystals of the desired product 3.81.

Melting point: 215-216°C Example 2 2-hydroxy-5-methylthiazolo [3.2b, 1)
-8-) Suspend 5 g of lyazole 2-imino-3-amino-4-methyl-4-thiazoline hydrochloride in 40 cc of chlorobenzene and
At 0"C, 740cc of dry phosgene was introduced over a period of about one hour.

After the introduction of phosgene, the reaction solution was cooled, and the white crystals were dried separately with E and washed with a small amount of water to obtain the desired product 4.61.

Melting point: 208-210°C. Example 3 A thermometer, a reflux condenser, and a gas blowing tube were attached to a 500 rnl 4-diameter flask equipped with a stirrer, and 2-imino-3-amino-4-ethylthiazoline hydrochloride 542 and monochlorobenzene 270 PDMF 3 translation were added to the flask. 1 and mixed.

While stirring this mixture, the temperature of the mixture was maintained at 100° C., and phosgene gas was blown into it through the introduction tube.

82.8P of phosgene was introduced in about 2.5 hours.

The by-product chloride gas was absorbed into water and recovered.

After completing the blowing of phosgene, the reaction rate was maintained for 20 minutes to complete the reaction, and then the reaction system was degassed by passing N2 gas.

The reaction product, which had become a pale yellow slurry, was cooled, filtered through an absorption filter to remove the product, and dried.

Yield: 50 g, m, p, 168-181°C.

This product is crude 2-hydroxy-5-ethylthiazolo[3
・2-b) -s triazole, which was treated with 5% Na
After dissolving in an OH aqueous solution to remove a trace amount of insoluble matter, the solution was acidified with acetic acid.

One of the precipitated crystals was taken, washed with water, and dried to obtain the desired product 41.71 as a white powder.

Melting point 216-220°C.

Claims (1)

[Claims] A method for producing a compound represented by the general formula (in the formula, R represents a lower alkyl group), which is characterized by reacting a compound represented by the formula (in the formula, R represents a lower alkyl group) with phosgene. .