DE1695668C3 - Process for the preparation of 3-isothiazolones - Google Patents

Description

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

If there is 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 obtained by bromination of a 5-chloro-3-isothiazolone or by chlorination of a 4-bromo-3-isothiazolone. The starting isothiazolone is prepared by cyclizing a disulfidamide in the manner indicated at the beginning. The disulfidamide is cyclized at any temperature. Generally and preferably, however, it is carried out in the range of O to 10O ⁰ C out. Benzene, toluene, xylene, ethyl acetate or ethylene dichloride, for example, are used as inert non-aqueous solvents.

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 10 carbon atoms means Preferably a common acid scavenger can be added to the reaction product can be added to prevent the formation of the isothiazolonium salt. Typical acid scavengers are for example tertiary amines such as pyridine and triethylamine. The isothiazolonium salts can also be converted into the free isothiazolones by mixing them with water in the usual way 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.

The disulfidamides that form the isothiazolones cyclized are known and can be made in various ways. Typically becomes a <x- or / ϊ-mono- or disubstituted one Acrylate or such an acrylic acid reacted with thioacetic acid. After the reaction is complete the product is hydrolyzed to obtain an O-mercaptopropionic acid, which in turn becomes the disulfidic acid is oxidized. This material is then converted to a diacid chloride disulfide and this becomes t> o in turn 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 h5 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-hydroxyisothiazole

In a 1-1 three-necked flask fitted with a mechanical stirrer, thermometer and dropping funnel, 500 ml of ethylene dichloride and 20.8 g (0.1 mol) Dithiodipropionamide mixed together. This mixture was stirred at 10 to 15 ° C, and 42.5 g Sulfuryl chloride (0.306 MoS) was added dropwise over 2 hours. After the Addition, the reaction sludge was allowed to warm to 25 to 30 ° C and stirred it overnight to one to ensure full implementation. 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 remove, and then chilled in ice to, after filtration and drying, 4.0 g of 5-chloro-3-hydroxyisothiazole as a dark yellow crystalline solid, m.p. 95 to 96 ° C. The aqueous filtrate was then extracted continuously 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, F. - 75 bis 76 ° C.

Example 2

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

To a slurry of 70.9 g (03 mol) of dithio-N, N'-dimethyldipropionamide in 1 liter of ethylene dichloride, 121.5 g (0.9 mol) of sulfuryl chloride were added at 10 to 15 ° C. over a period of 1.5 hours. After the addition, the reaction slurry was allowed to warm to 20-25 ° C. and stirred overnight 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 gave an additional amount (30.5 g) of less pure hydrochloride on evaporation to about half its volume. Full evaporation of the Äthylendichloridfiltrates 24.7 g oily residue which was on sublimation at 0.1 mm (40 to 6O ⁰ C) 11.5 g of 5-chloro-2-methyl-3-isothiazolone revealed F. = 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) were suspended 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 added dropwise at 25 to 30 ° C added over an hour. The mud was stirred overnight to full Ensure reaction, and then filtered, yielding 8.6 g of gray 2- (3,4-dichlorophenyl) -4-methyl-3-isothiazolone, F. = 160 to 161 "C. The product was recrystallized from ethyl acetate and then possessed a melting point M.p. = 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 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 30 ⁰ C heat and rührie 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 Benzo'-Lisroin (90 to 120 ⁰ C) to give 142 g of cream-colored 2- (N-ÄthyIcarbamoyl) -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 dithiodiisobutyiamide were slurried in 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 to 25 ⁰ C. After the addition, the mixture was stirred overnight to ensure complete conversion. Filtration then gave 9.15 g of a mixture of solid isothiazolonium chlorides which were heated in 100 ml of water and then filtered. On drying, 2.85 g of S-ChloM-methyl-S-hydroxyisothiazole, mp = 122 ° C., were obtained. Subsequent cooling of the aqueous solder in ice gave 2.4 g of solid 4-methyl-3-hydroxyisothiazole. F. = 100 to 105 ° C.

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

To a solution of 100 ml of ethyl acetate and
(0.05 mole) of S-chloro-S-hydroxyisothiazole, which was prepared according to Example 1, was added at 0 ⁰ C a solution of 8 g (0.05 mol) of 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-hydroxyisothiazoi

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 was removed under reduced pressure. There was thus obtained 3.7 g of a gummy solid which upon treatment with water and after drying gave 3.2 g of 4,5-dichloro-3-hydroxyisothiazole. F. = 151 to 154 ° C after recrystallization from benzene-ethanol.

Claims (2)

Patent claims: 1. Process for the preparation of 3-isothiazolones the general formula if desired in a manner known per se with bromine, chlorine, sulfuryl chloride, sulfuryl bromide, N-chlorosuccinimide or N-bromosuccinimide converts and the 4-chloro-5-bromo- or 4-bromo-5-chloro-3-isothiazolones obtained isolated in the usual way or - if 3-hydroxyisothiazole was obtained - this, if desired, is reacted with 1 mole of sulfuric chloride per mole of 3-hydroxyisothiazole and the resultant 4,5-dichloro-3-isothiazolone isolated in the usual way. 2. The method according to claim 1, characterized in that that a conventional acid scavenger is added to the reaction mixture. wherein Y is a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, a cycloalkyl group π with 3 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 group aliphatic acyl group having 1 to 8 carbon atoms, a sulfonyl group, a cyano group or a carbamoyl group of the general formula —C-NHR " I! ο means in which 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 -OCT - 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 The invention relates to the preparation of 3-isothiazolones the general formula N-Y 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 -R ^v n 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, characterized in that that you have a disulfidamide of the general formula X O means in which 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 Il R " ¹ - OC- R ' ^x denotes in which R ¹ "is a low molecular weight alkyl group and R ^{IV is} an alkylene group having 1 to 4 carbon atoms, or in which R" is an aryl group of the general formula —SCH — CHC-NHY I. ζ 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 and - if 4- or 5-chloro- or bromine-3- isothiazolone were obtained - this R ^v h 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 are} hydrogen atoms, chlorine or bromine atoms or low molecular weight alkyl groups, according to the method characterized in the above claims.