DE1695668B2 - Process for the preparation of 3-isothiazolones - Google Patents

Description

R ^v h

IO

wherein Y is a hydrogen atom, an alkyl group with 1 to 18 carbon atoms, a cycloalkyl group with 3 to 6 carbon atoms, an aralkyl group with up to 10 carbon atoms, an aryl group, the 3,4-dichlorophenyl group, a low molecular weight dialkylaminoalkyl group, a saturated acyclic aliphatic acyl group with 1 up to 8 carbon atoms , a sulfonyl group, a cyano group or a carbamoyl group of the general formula

means where R "is an alkyl group having 1 to 18 carbon atoms, a low molecular weight alkylsulfonyl group, an arylsulfonyl group or a carbalkoxyalkyl group of the general formula

denotes where R ¹ "is a low molecular weight alkyl group and R ^{lv is} an alkylene group having 1 to 4 carbon atoms, or where R" is an aryl group of the general formula

45

denotes where R ^{v is} a low molecular weight alkyl group, a halogen atom, a nitro group or alkoxy group having 1 to 4 carbon atoms and η is an integer from 0 to 3 and R and R ¹ denote hydrogen atoms, chlorine or bromine atoms or low molecular weight alkyl groups, since
characterized in that there is a disulfide amide of the general formula

X O

—SCH— CHC — NHY

wherein X and Z are hydrogen atoms or low molecular weight alkyl groups, with at least 3 Molar equivalents of chlorine, bromine, sulfuryl chloride, sulfuryl bromide, N-chlorosuccinimide or N-bromosuccinimide in an inert non-aqueous solvent implemented and - if 4- or 5-chloro- or bromo-3-isothiazolones were obtained - these

50

55

b5, if desired, is reacted in a manner known per se with bromine, chlorine, sulfuryl chloride, sulfuryl bromide, N-chlorosuccinimide or N-bromosuccinimide and the 4-chloro-5-bromo- or 4-bromo-5-chloro-3-isothiazolones obtained in the customary manner isolated or - if 3-hydroxyisothiazole was obtained - this is reacted, if desired, with 1 mole of sulfurychloride per mole of 3-hydroxyisothiazole and the 4,5-dichloro-3-isothiazolone obtained is isolated in the usual way. 2. The method according to claim 1, characterized in that a conventional acid scavenger is added to the reaction mixture.

The invention relates to the preparation of 3-isothiazolones the general formula

25th

wherein Y is a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, a cycloalkyl group having 3 up to 6 carbon atoms, an aralkyl group with up to 10 carbon atoms, an aryl radical, the 3,4-dichlorophenyl group, a low molecular weight dialkylaminoalkyl group, a saturated acyclic aliphatic group Acyl group having 1 to 8 carbon atoms, a sulfonyl group, a cyano group or a carbamoyl group the general formula

—C-NHR "

Il ο

means where R "is an alkyl group having 1 to 18 carbon atoms, a low molecular weight alkylsulfonyl group, an arylsulfonyl group or a carbalkoxyalkyl group of the general formula

R ¹ "-OC-R ^lv

denotes in which R ^{111 is} a low molecular weight alkyl group and R ^{lv is} an alkylene group having 1 to 4 carbon atoms, or in which R "is an aryl group of the general formula

R ^v / i

means where R ^{v is} a low molecular weight alkyl group, a halogen atom, a nitro group or alkoxy group having 1 to 4 carbon atoms and η is an integer from 0 to 3 and R and R ^{1 are} hydrogen atoms, chlorine or bromine atoms or low molecular weight alkyl groups, according to the method characterized in the above claims.

If Y in the above formula is a hydrogen atom, the products of the process can also be used in the tautomeric form as 3-hydroxyisothiazoles.

If above of low molecular weight alkyl, alkylsulfonyl or dialkylaminoalkyl groups are mentioned, the alkyl groups each contain 1 to 4 carbon atoms. Typically the alkyl group can then be a methyl, ethyl, propyl, isopropyl or butyl group be.

Chlorine and sulfuryl chloride are the preferred halogenating agents.

With an excess of halogenating agent, the isothiazolone can be in the 4- and / or 5-position be halogenated. If 5 molar equivalents of halogenating agent are available, one occurs Monohalogenation. 7 molar equivalents of halogenating agent are required for dihalogenation.

Isothiazolones with different halogen substituents in the 4- and 5-positions are prepared by halogenation of the isothiazolone already halogenated in one of the two positions in question. If, for example, a 4-bromo-5-chloro-3-isothiazo is desired, this can be done by bromination of a 5-chloro-3-isothiazolone or obtained by chlorination of a 4-bromo-3-isothiazolone. The starting isothiazolone is prepared by cyclizing a disulfide amide in the manner indicated at the beginning. the Cyclization of the disulfide amide occurs at any temperature. Generally and preferably leads however, they are selected in the range from 0 to 100 ° C. as Inert non-aqueous solvents are used, for example, benzene, toluene, xylene, ethyl acetate or Ethylene dichloride.

During the cyclization, isothiazolonium salts are formed together with the isothiazolones if Y a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, or an aralkyl group having up to Means 10 carbon atoms. A conventional acid scavenger can preferably be added to the reaction product be added to the formation of isothiazolonium ίο salt to prevent. Typical acid scavengers include tertiary amines such as Pyridine and triethylamine. The isothiazolonium salts can also be converted into the free isothiazolones by treating them in the usual way with water or weak organic bases.

In any case, the process products can be separated from the reaction solution in a manner known per se such as by distillation, crystallization or filtration. so

The disulfide amides which are cyldized to form the isothiazolones are known and can be found in can be produced in various ways. Typically, a «- or j? -Mono- or disubstituted Acrylate or such an acrylic acid reacted with thioacetic acid. After the reaction is complete the product is hydrolyzed to form a jS-mercaptopropionic acid to obtain, which in turn is oxidized to the disulfidic acid. This material is then turned into a Diacid chloride disulfide converted, and this in turn is converted with ammonia or substituted ammonia derivatives, such as alkylamine, aniline, an amide, cyanamide, a sulfonamide or urea.

The process products obtained according to the invention and their salts are valuable compounds because of their biocidal properties. Particularly noteworthy in this regard is their ability to destroy microorganisms, such as bacteria, algae and fungi.

example 1

3-hydroxyisothiazole and
5-chloro-3-hydroxyisoithiazoI

In a 1-1 three-necked flask equipped with a mechanical stirrer, thermometer and dropping funnel, 500 ml of ethylene dichloride and 20.8 g (0.1 mol) of dithiodipropionamide were mixed together. This mixture was stirred at 10 to 15 ° C and 42.5 g (0.306 mol) of sulfuryl chloride was added dropwise over 2 hours. After the addition was complete, the reaction sludge was allowed to ^{warm to 25 to 30 °} C. and stirred overnight in order to ensure complete conversion. The reaction sludge was then filtered and the precipitate dissolved in 150 ml of hot water. The aqueous solution was filtered to remove some insoluble material and then chilled in ice to give, after filtration and drying, 4.0 g of S-chloro-S-hydroxyisothiazole as a dark yellow crystalline solid, m.p. 95 bis 96 ⁰ C. The aqueous FiJtrat was then continuously extracted with ether. The ether extract was dried over magnesium sulfate and evaporated to give 11.1 g of 3-hydroxyisothiazole, which crystallized to a white crystalline solid on cooling from benzene-hexane, m.p. 75 to 76 ^° C.

Example 2

2-methyl-3-isothiazolone and
5-chloro-2-methyl-3-isothiazolone

To a slurry of 70.9 g (0.3 mol) of dithio-N, N'-ethylene dichloride dimethyldipropionamid in 1 1 121.5 g (0.9 mol) of sulfuryl chloride were added at 10 to 15 ⁰ C for 1.5 hours . After the addition, the reaction sludge was allowed to ^{warm to 20 to 25 °} C. and was stirred overnight in order to ensure complete conversion. The sludge was then filtered and gave 37.1 g of 2-methyl-3-isothiazolone hydrochloride, which could be converted into the free 3-isothiazolone by continuous ether extraction from water. The ethylene dichloride filtrate, when evaporated to about half the volume, gave an additional amount (30.5 g) of less pure hydrochloride. Full evaporation of the Äthylendichloridfiltrates 24.7 g oily residue which yielded 2-methyl-3-isothiazolone 5-Chloro-on sublimation at 0.1 mm (40 to 60 ⁰ C) yielded 11.5 g, mp = 44 to 47 ° C.

Example 3
2- (3,4-dichlorophenyl) -4-methyl-3-isothiazolone

12.8 g of dithio (3 ', 4'-dichloro) diisobutyranilide (0.0234 mol) was slurried in 250 ml of ethylene dichloride and a solution of 9.5 g (0.0702 mol) of sulfuryl chloride in 25 ml of ethylene dichloride was made added dropwise at 25 to 30 ^° C. over the course of one hour. The slurry was stirred overnight to ensure complete conversion and then filtered to give 8.6 g of gray 2- (3,4-dichlorophenyl) -4-methyl-3-isothiazolone, mp = 160-161 ° C. The product was recrystallized from ethyl acetate and then had a melting point of M. = 161 to 163 ° C.

Example 4
2- (N-ethylcarbamoyl) -3-isothiazolone

In 2500 ml of ethylene dichloride, 210.3 g (0.60 mol) of dithio-N, N'-bis (ethylcarbamoyl) dipropionamide were added at 10

Slurried up to 15 ° C. Nitrogen was bubbled through the slurry to remove hydrochloric acid formed in the reaction, and 243 g (1.80 mol) of sulfuryl chloride was added dropwise over 2 hours. Then allowed the mud to 25 to 3O ⁰ C and stirred him overnight to ensure complete reaction. Thereafter, the ethylene dichloride was stripped from the reaction solution, a yellow oily residue being obtained. This was recrystallized from benzene-ligroin (90 to 12O ⁰ C) umkrista'Jisiert to give 142 g of cream-colored 2- (N-Äthylcarbamoyl) -3-isothiazolone obtained, mp = 97 to lore.

Example 5

4-methyl-3-hydroxyisothiazole and
S-ChloM-methyl-S-hydroxyisothiazole

11.8 g (0.05 mol) of dithiodiisobutyramide were in Slurried 200 ml of ethylene dichloride. A solution of 21.3 g (0.15 mol) of sulfuryl chloride in 30 ml of ethylene dichloride was added slowly at 20-25 ° C. After the addition, the mixture was stirred overnight to make one to ensure full implementation. Filtration then gave 9.15 g of a mixture more solid Isothiazolonium chlorides which were heated in 100 ml of water and then filtered. Upon drying, one obtained 2.85 g of 5-chloro-4-methyl-3-hydroxyisothiazole, mp = 122 ° C. Subsequent cooling of the aqueous solution in Ice yielded 2.4 g of solid 4-methyl-3-hydroxyisothiazole, m.p. = 100 to 105 ° C.

Example 6
4-Bromo-5-chloro-3-hydroxyisothiazole

To a solution of 100 ml Äihylacetat and 6.8 g ■> (0.05 mol) of S-chloro-S-hydroxyäsothiazol that according to Example 1 was prepared at 0 ⁰ C a solution of 8 g (0.05 MoI) Bromine in 25 ml of ethyl acetate was added. After the addition, the red reaction solution was allowed to warm to room temperature and, after 1 hour, the solvent was removed under reduced pressure. This gave 13.7 g of a dark orange solid. Treatment of this solid with water gave, after drying, 8.7 g of 4-bromo-5-chloro-3-hydroxyisothiazole, mp = 145 to 147 ° C. after recrystallization from ethyl acetate.

Example 7
4,5-dichloro-3-hydroxyisothiazole

To a solution of 5.1 g (0.050 mole) of 3-hydroxyisothiazole, which had been prepared according to Example 1, in 100 ml of ethyl acetate 6.75 g (0.050 mole) of sulfuryl chloride were added during 20 minutes at 60 ⁰ C. A white precipitate suddenly formed. After stirring for 2 hours, the reaction mixture was allowed to warm to room temperature. A small amount of solid material was then filtered off and the solvent removed under reduced pressure. In this way, 3.7 g of one was obtained

j <> rubbery solid obtained by treatment with Water and, after drying, gave 3.2 g of 4,5-dichloro-3-hydroxyisothiazole. F. = 15! up to 154 ° C Recrystallize from benzene-ethanol.

Claims (1)

Patent claims: 1. Process for the preparation of 3-sothiazolones of the general formula -C-NHR " il ο