DE1695668A1 - Process for the preparation of 3-isothiazolones and 3-hydroxyisothiazoles - Google Patents

Description

Independence Mall West

Philadelphia, PA. 19 105

Process for the preparation of 3-isothiazolones and 3-

Hydroxylsothiazoles

Priority:

dated March 9, 1967 based on US patent application
Serial No.621 770

The invention relates to a process for the preparation of substituted 3-isothiazolones and 3-hydroxyisothiazoles by reacting a disulfide amide with a halogenating agent. Connections made in this way possess biocidal activity and are particularly effective as a means of controlling microorganisms.

The invention relates to a new process for the preparation of substituted 3-isothiazolones and 3-Hydroxyiaothiaaolen. In particular, the invention relates to a process for the preparation of compounds of the general formula

109817/2164

R ^J

(D

wherein Y is a hydrogen atom, an alkyl group of 1 to 18 Carbon atoms, a cyoloalkyl group with 3 to 6 carbon atoms, an aralkyl group having up to 10 carbon atoms, an aryl group, a halogen atom or a through aryl group substituted before a low molecular weight alkyl group, a low molecular weight dialkylaminoalkyl group, an alkylaoyl group having one to 8 carbon atoms, a sulfonyl group, cyano group or a carbamoyl group of the general Structural formula

-C-NHR

means R and R hydrogen atoms, halogen atoms or low molecular weight Are alkyl groups and R is an alkyl group with one to 18 carbon atoms, a low molecular weight alkylsulfonyl group, an arylsulfonyl group, a halogen atom or a duroh substituted a low molecular weight alkyl group Arylsulfonyl group or a carbalkoxyalkyl group

the general structural formula

o 109817/2164

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

where II is a low molecular weight alkyl group, a halogen atom, a nitro group or an alkoxy group having one to k carbon atoms and η is an integer from 0 to 3.

It should be noted that Formula I is a proper designation for all made by the novel process of the invention Connections is. However, due to the tautomeric nature of these compounds, the following formula is somewhat more accurate in those cases in which Y is a hydrogen atom:

(II)

Such compounds represented by Formula II are commonly referred to as "3-Hydroxyisothiazoles" (here temporarily referred to as "isothiazoles"), while all other compounds according to formula II are better known as "3-isothiazolones" (hereinafter referred to as "Isothiazolones") '.vi; r'lcii. Xm tu rl I can partially denote the latter designation

10 9 8 17/2164 bad original

can be used to designate any of the compounds according to formula I.

When the term "low molecular weight" is used in conjunction with certain terms such as alkyl, cycloalkyl, aralkyl, alkylsulfonyl, etc., this is intended to mean that the alkyl group or the alkyl portion of the group has from one to k carbon atoms. Typically the alkyl group or moiety can be methyl, ethyl, propyl, isopropyl or butyl.

The isothiazolones are made by the cyclization of a disulfidamide, which is represented by the general formula

(-SCH-CHC-NHY) ₀ (III) I ^Λ

is represented in which X and Z are hydrogen atoms or low molecular weight Denote alkyl groups and Y is as defined above. Such a cyclization takes place by reacting the disulfidamide with a halogenating agent. Typical halogenating agents are, for example, chlorine, bromine, sulfuryl chloride, suI-furyl bromide, N-chlorosuocinimide, N-bromosuccinimide, etc. chlorine and sulfuryl chloride are the preferred halogenating agents.

The cyclization of the disulfide amide takes place when 3 Mo! Equivalents of halogenating agents, or more specifically halogen, are used in the reaction. If there is an excess of halogenating agent, the isothiazolone in the k- and / or 5-position of the formula I can be halogenated. When 5 molar equivalents

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Halogenating agents are available, one takes place Monohalogenation. 7 molar equivalents of halogenating agent are required for dihalogenation.

The production of isothiazolones with different halogen substituents in the 4- and 5-positions takes place by halogenation of the isothiazolone already halogenated in one of the two positions in question. For example, if a 4-bromo-5-chloro-3-isothiazole is desired, one can this by bromination edhes 5-chloro ~ 3 ~ isothiazolone or obtained by chlorination of a 4-bromo-3-isothiazolone. That Starting isothiazolone is of course prepared by cyclizing a disulfidamide, as described above. Methods and variants here, which can be referred to as "secondary halogenation", are obvious to the person skilled in the art.

The temperature is not critical for the reaction, i.e. the cyclization takes place at any temperature. In general and preferably, however, it is carried out in the range from 0 to 100.degree.

The reaction is carried out in an inert non-aqueous solvent, such as benzene, toluene, xylene, ethyl acetate, ethylene dichloride and so on.

During the cyclization, isothiazolonium salts are formed together with the isothiazolones if Y in the formula TII Hydrogen atom, an alkyl group containing one to 18 carbon atoms or an aralkyl group with up to 10 carbon atoms

^109817/2164 BADOR ₁ GtNAL

- ο -

means. Such salts have the following structural formula:

R OH

(IV)

N-Y (halogen)

wherein Y has the meaning just given above and R and R have the same meaning as in formula I. If desired or if necessary, an acid scavenger can be incorporated into the reaction medium to prevent the formation of the iaothiazolonium salt to prevent. Typical acid scavengers that can be used are, for example, tertiary amine bases such as Pyridine and triethylamine. It should be noted at this point that the isothiazolonium salts also convert into the free isothiazolones can be converted or neutralized by treating them with water or weak organic bases. Such Methods are of course obvious to a person skilled in the art.

Any known method can be used to obtain those obtained by the novel process described herein Separate products from the reaction solution. In general, the separation takes place by distillation, crystallization, Filtration and so on.

The disulfide amides, which cyclize to form the isothiazolones

are known and can be made in various ways will. Typically an alpha- or beta- mono-

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or disubstituted acrylate or such an acrylic acid reacted with thioacetic acid. When the reaction is complete, the product is hydrolyzed to form a beta-mercaptopropionic acid to obtain, which in turn is oxidized to the disulfidic acid. This material is then converted into a diacid chloride disulfide converted, and this in turn is converted with ammonia or substituted ammonia derivatives such as alkylamine, aniline, Amide, cyanaraid, sulfonamide, urea, etc. As noted above, numerous methods can be used to obtain these disulfide amides, and many of the same are Easily available in commercial quantities. There are of course variations in their production depending on the in efaem special case used substituents.

The isothiazolones represented by formula I and their salts represented by formula IV are particularly valuable Compounds because of their biocidal properties. Particularly noteworthy in this regard is their ability to create microorganisms, such as bacteria, algae and fungi, to control. The properties these new compounds are reproduced in pending German patent applications that follow U.S. patent applications Serial No. 672 427 and 672 437 correspond.

The following examples serve to further illustrate the new process according to the invention, but not as a limitation dos of inventiveness.

ORIGINAL

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- 8th -
EXAMPLE I

Manufacture of 3-hydroxyisothiazole and S-chlorine - ^ - hydroxyisothia-

zol

In a 1 liter 3-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 10-15 ° C. and 42.5 g (0.3O6 mol) of sulfuryl chloride was added dropwise over 2 hours. After the addition was complete, the reaction slurry was allowed to warm to 25-30 ° C. and stirred overnight to ensure complete reaction. 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 , k.0 g of 5-chloro-3-hydroxyisothiazole as a dark yellow crystalline solid, m.p. 95 to 96 C. The aqueous filtrate was then continuously extracted with ether. The ether extract was dried over magnesium sulfate and evaporated to leave 11.1 g of 3-hydroxyisothiazole which on cooling from benzene-hexane to a white crystalline solid, F. 75 bis

EXAMPLE II

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

10 9.817 / 2164

To a sludge of 70.9 g (O, T mol) dithio-N.N'-dimethyldipropio "

namid in one liter of ethylene dichloride were used at 10 to 15 ° C for 1.5 hours 121.5 g (0.9 mol) of sulfuryl chloride added. After the addition, the reaction sludge was left warm up to 20 to 25 ° C and stir it overnight, to ensure that the implementation is complete. The sludge was then filtered to remove 37 »1 g of 2-methyl-3-isothiazolone hydrochloride to give, which by continuous ether extraction from water in the free 3-isothiazolone could be converted. The ethylene dichloride filtrate on evaporation to about half the volume gave an additional amount (30.5g.) of less pure hydrochloride. Complete evaporation of the ethylene dichloro filtrate resulted

24.7 g oily residue which on sublimation at 0.1 mm (40 to 60 ⁰ C) 11.5 g of S-chloro ^ -methyl ^ -isothiazolone, P. 44 to 47 ° C, resulted.

EXAMPLE III
Preparation of 2- (3,4-Diehlophenyl) -4-methyl-3-isothiazolone

12.8 g dithio (3, 4'-dichloro) diisobutyranilide (0.0234 mol) were suspended in 250 ml of ethylene dichloride, one Solution of 9.5 g (0.0702 mol) of sulfuryl chloride in 25 ml of ethylene dichloride was added dropwise at 25-30 ° C over one hour. The slurry was stirred overnight to ensure completion of the reaction, and then filtered to give 8.6 g of gray 2- (3,4-dichlorophenyl) -% - mothyl-3-isotijiazolon to give, P. 160 to 16 ° C. The product was recrystallized from ethyl acetate and then dried

109817/2164

a melting point P. is equal to 16 l to 163 ° G.

EXAMPLE TV Production of 2- (N-EthylcarbaBoyl) -3-isothiazolone

210.3 g (0.60 mol) of dithio-N, N ^r his - (ethylcarbamoyl) dipropionamide were suspended at 10 to 15 ° C. in 2500 ml of ethylene dichloride. Nitrogen was bubbled through the slurry to remove hydrogen chloride formed in the reaction, and 243 g (1.80 moles) of sulfuryl chloride was added dropwise over 2 hours. The sludge was then allowed to ^{warm to 25 to 30 °} C. and stirred overnight in order to ensure complete conversion. After this time, the ethylene dichloride was stripped from the reaction solution to leave a yellow oily residue, which was recrystallized from benzene-ligroin (90 to 120 ° C), 142 g of cream-colored 2- (N-ethylcarbamoyl) -3-isothiazolone received, pp. 97 to 101 ⁰ C.

EXAMPLE V

Production of 4-methyl-3-hydroxyisothiazole and. methyl-3-hydroxyisothiazole

11.8 g (0.05 mole) of the disulfide amide dithiodiisobutyramide were slurried in 200 ml of ethylene chloride. 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

109817/2164

-H-

the mixture was stirred overnight to ensure complete conversion. Filtration then gave 9.15 g of a mixture solid isothiazolonium dhloride that is dissolved in 100 ml of water heated and then filtered in order to dry 2.85 g of S-chloro - ^ - methyl ^ -hydroxyisothiazole, mp 122 ° C result. Subsequent cooling of the aqueous solution in ice gave 2.4 g of solid 4-methyl-3-hydroxyisothiazole, mp 100 bis 105 ° C.

EXAMPLE 6 Manufacture of% -Bromo-5-chloro-3-hydroxyi8othiazal

To a solution of 100 ml of ethyl acetate and 6.8 g (0.05 mol) of 5-chloro-3-hydroxyisothiazole, prepared according to Example I ₁ , a solution of 8 g (0.05 mol) of bromine in 25 was added at 0.degree ml of ethyl acetate added. After the addition, the red reaction solution was allowed to warm to room temperature and after one hour the solvent was removed under reduced pressure to leave 13.7 g of a dark orange solid. Treatment of this solid with water gave, after drying, 8.7 g of ^ -Bromo-S-chloro ^ -hydroxyisothiazole, mp to 147 ° C., from ethyl acetate.

EXAMPLE 7 Preparation of 4,5-dichloro-5-hydroxyisothiazole

To a solution of 5.1 g (0.050 mol) of 3-hydroxyisothiazole, prepared according to Example 1, in 100 ml of ethyl acetate, 6.75 g (0.050 mol) of sulfuryl chloride were added for 20 minutes at 60 C

109817/2164 ORIGINAL INSPECTED

- 12 - 4

given. 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. 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. i5i to 15 ¹ ^ ⁰ C after recrystallization from benzene-ethanol.

109817/2164

Claims (1)

- 13 PATENT CLAIMS 1. Process for the preparation of 3-rIsothiazolones of the general my formula R ¹ * W-Y wherein Y is a hydrogen atom, an alkyl group of 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, a halogen atom or an aryl group substituted by a low molecular weight alkyl group, a low molecular weight dialkylaminoalkyl group, an alkylaoyl group with 1 to 8 carbon atoms, a sulfonyl group, a Cyano group or a carbamoyl group of the general formula -C-NHR
0 II bcideu-tet, where R is an alkyl group with 1 to 18 carbon atoms, a low molecular weight alkylsulfonyl group, an arylsulfonyl group, an halogen atom or an arylsulfonyl group substituted by a low molecular weight alkyl group or an aryl group (Jar alkoxy.ylkyl group of the general formula 109817/2164 O TTT * IV denotes in which R ^{111 is} a low molecular weight alkyl group and r ^{iv is} an alkylene group having 1 to 4 carbon atoms or an aryl group of the general formula R ^V n is, in which R before low molecular weight alkyl group, a halogen atom, a nitro group or alkoxy group ait ibis h carbon atoms and η is an integer from 0 to 3 and R and R denote hydrogen atoms, halogen atoms or low molecular weight alkyl groups, characterized by the fact that an Oisulfidamid der general formula XO Jl (-SCHtCHC-NHY) ₂ wherein X and Z are hydrogen atoms or low molecular weight alkyl groups mean cyclized. 2. The method according to claim 1, characterized in that one the cyclization is carried out by reacting the disulfide amide with at least 3 Nfol equivalents of a halogenating agent. 17/2164 3. The method according to claim 2, characterized in that the cyclization is carried out in an inert non-aqueous solvent. k. Process according to Claim 3, characterized in that the halogenating agent used is chlorine, bromine, sulfuryl chloride, sulfuryl bromide, N-chlorosuccinimide or N-bromosuccinimide, 5. The method according to claim 2, characterized in that the halogenating agent is used in an amount of at least 5 molar equivalents. 6. The method according to claim 2, characterized in that the halogenating agent in an amount of at least 7 molar equivalents used. 7. The method according to Anspruc-h 1, characterized in that Y represents an alkyl group having from one to 18 carbon atoms or an aralkyl group having up to 10 carbon atoms. 8. The method according to claim 7, characterized in that a 3iiureabfangraittel is added to the Iloaktionsmediuni. 9. The method according to claim i, characterized in that » 1 'a, / as η e is often fa torn or means a carbamoyl group. ! η. Method according to Claim J, characterized in that - η fm: Carb imoy] group and l'J ^s _o ino alkyl group · "with i to 109817/2164 - means 16 carbon atoms. 11. The method according to claim 5 »characterized in that the compound is then with one of the halogen halogenated various halogenated in the preparation of the compound. 109817/2164