Preparation of isothiazolones

Preparation of 3-isothiazolones by a single-kettle synthesis from a 3,3'-dithiodipropionic acid, a 3-thiopropionic acid, or their related acid halide by reacting sequentially with a thionyl halide (if the (di)acid halide has not previously been formed), followed by reaction with a halogenating agent, then a primary amine and base, and then with a halogenating agent.

This invention relates to a process for the preparation of 3-isothiazolones 
by a single-kettle synthesis from a 3,3'-dithiodipropionic acid, a 
3-thiopropionic acid, or their related acid halide by reacting 
sequentially with thionyl halide (if the (di)acid halide has not 
previously been formed), followed by reaction with about one equivalent of 
a halogenating agent, then about two equivalents of primary amine and 
base, and then with a halogenating agent (about two equivalents) to 
achieve the unhalogenated isothiazolone. Preparation of a 
(di)thiopropion-N,N'-diamide as a separate step is avoided. 
If the (di)acid is used as the starting material, isolation and handling of 
the hydrolytically sensitive (di)acid chloride can be avoided. Further 
halogenation to the 5-halo- or 4,5-dihaloisothiazolone is also possible, 
either by addition of additional halogen or halogenating agent in the 
final stage, by further treatment of the isolated unhalogenated 
isothiazolone, or by co-feed of the intermediate after reaction with 
amine, along with additional halogen or halogenating agent, to a second 
reaction vessel. 
2-Substituted isothiazolones, 4-halo-, 5-halo-, and 
4,5-dihaloisothiazolones are well-known as efficacious chemicals for the 
control of living organisms, especially as biocidal chemicals. See for 
example U.S. Pat. Nos. 4,205,431; 4,265,899. 
A conventional route to manufacture, as described inter alia in U.S. Pat. 
No. 3,761,488 and European Patent Application No. 95907, involves the 
preparation of a 3-mercapto-N-substituted propionamide (or 
3,3'-dithio-N,N'-substituted propionamide), followed by halogenation to 
produce the desired non-halogenated isothiazolone product. Preparation of 
the halogenated or dihalogenated isothiazolone can be accomplished by use 
of higher ratios of halogen/amide. Preparation of the mercaptopropionamide 
may require several preparative steps, involving costly or difficultly 
obtainable intermediates, especially when the amine functionality needed 
to form the amide is less reactive, such as when it is cycloalkyl or aryl. 
Halogen includes chlorine or bromine or both; chlorine is the preferred 
halogen. The same definition of halogen applies to halogenating agents. 
Luttringhaus et al., [Angew. Chem. Int. Ed. Eng., 3, 67 (1964); Liebigs 
Ann. Chem. 679, 123 (1964)] reported low yields of saturated 
isothiazolidines by sequential, separate kettle reaction of dithiodiacid 
with thionyl chloride, then chlorine, and then amine with pyridine base 
but did not carry the reaction through to the active isothiazolones. 
In a similar manner, Kharasch et al. [J. Org. Chem., 28, 1901 (1963)] 
produced a saturated six-membered ring from a 4-thiobutyric acid 
precursor. 
This invention provides a new path to the known biocidally active 
isothiazolones which have a variety of uses including uses in cooling 
towers, paper mills, metal working, oil fields, latex, cosmetics, house 
cleaners, laundry, textile, plastic and resins, wood, leather and hides, 
photography, fuel, paints, swimming pools, medical devices, 
pharmaceuticals, food and feed preservations, disinfectants and 
sanitizers. 
The process involved the following reaction sequence: 
##STR1## 
As starting primary amines in the present reaction, there may be used alkyl 
amines, preferably C.sub.1 to C.sub.8 alkylamines, cycloalkyl amines, 
preferably cyclohexyl amine, aryl amines, such as phenyl amine, 
4-chlorophenyl amine, and the like, alkaryl amines, such as benzyl amine, 
and other moieties which will not interfere with the 
halogenation/cyclization reaction. Particularly preferred is n-octylamine. 
(The amine must be a primary amine for the desired product to be 
obtained.) 
As suitable dithiodiacids (VI, supra), 3,3'-dithiodipropionic acid is most 
preferred, especially if it is desired to convert the resulting 
isothiazolone to chlorinated derivatives, such as 
4,5-dichloroisothiazolone. Other starting acids may 
include 3,3'- dithio-2,2'-dialkyldipropionic acid, 
3,3'-dithio-2,2'-dichlorodipropionic acid and the like. Other groups may 
be substituted in the 2 and/or 2' position if they do not interfere with 
the halogenation or ring closure reactions. Starting with 
dithiodimethylpropionic acid and extending the final halogenation reaction 
will result in the formation of the desirable 
4-methyl-5-halo-2-substituted isothiazolone. Such dithiodiacids are 
commercially available or readily prepared from published procedures. 
As suitable thioacids (V, supra), 3-thiopropionic acid is most preferred, 
especially if it is desired to convert the isothiazolone to chlorinated 
derivatives, such as the 4,5-dichloroisothiazolone. Other starting acids 
may include 3-thio-2-(lower alkyl)propionic acid and 
3-thio-2-chloropropionic acid. Other groups may be substituted in the 
2-position if they do not interfere with the halogenation/ring closure 
reactions. Starting with, 3-thio-2-methylpropionic acid and extending the 
final halogenation reaction will result in the formation of the desired 
4-methyl-5-halo-2-substituted isothiazolone. 
Thioacids are commercially available or readily prepared from published 
procedures. The corresponding acid halides are also suitable starting 
materials. 
If thionyl halides are used either to prepare the (di)acid halide (IV, 
supra) in situ or separately, thionyl chloride and thionyl bromide are 
preferred with; thionyl chloride being most preferred. It is possible to 
prepare the (di)acid halide by other means, such as with phosphorus 
trichloride, phosphorus tribromide, or acetyl chloride, but the 
by-products of this conversion are less desirable when the one-kettle 
synthesis sequence is continued. 
The diacid halide (IV) is then treated with a halogenating agent to afford 
the halothio propionyl halide (III, supra). The halogenating agent is 
preferably chlorine or bromine; with chlorine being most preferred. Other 
halogenating agents include sulfuryl chloride, sulfuryl bromide, 
N-chlorosuccinimide, N-bromosuccinimide, and the like. 
It is necessary to use an acid scavenger to react with any excess acid. Any 
organic or inorganic base may be used as the scavenger; tertiary amines 
and nitrogenous cyclic compounds unaffected by the reaction conditions are 
preferred, with trialkyl amines being most preferred. 
The halothiopropionyl halide (III, supra) is then treated with an amine of 
the formula; RNH.sub.2, where R is as defined above, to afford the ring 
closed isothiazidine (II, supra) which is halogenated to afford the 
desired, active isothiazolone (I, supra). 
The reaction sequence (halogenation;amidation-halogenation) is conducted at 
a temperature in the range of from about -20.degree. C. to about 
35.degree. C. to minimize side reactions, although temperatures outside 
that range may be used. Inert or substantially inert solvents may be used, 
such as halobenzenes for example, chlorobenzene and the like or halo 
aliphatics. Reaction times for the sequence are of the order of from about 
one-half hour to about three hours per step, (the formation of the 
(di)acid halide in situ may be conducted over a longer time period, such 
as from about one to about ten hours). 
The ratios of (di)acid or (di)acid halide to halogen are kept at about 1:1 
during the initial addition of halogen. At least two moles of reactive 
amine and an equivalent amount of acid scavenger are then added. The final 
halogenation is best controlled by using about two moles of halogen when 
the desired product is the non-halogenated isothiazolone. The 
non-halogenated isothiazolone may be isolated, stabilized, and purified by 
known methods, or may be used directly for further halogenation. 
If the 5-haloisothiazolone (Ib, supra) is desired, an additional four 
equivalents of halogenating agent may be added during the final reaction 
step. A preferred method would be to add the crude unhalogenated 
isothiazidine concurrently with about four equivalents of halogen to a 
second reaction vessel, in-line with the first, so that the overall 
reaction is conducted in one operation. 
If it is desired to prepare the 4,5-dihaloisothiazolone (Ib, supra) without 
isolation of any intermediate, the unhalogenated aminated intermediate may 
be added together with the necessary additional halogen (about six 
equivalents) into a second reaction vessel, as described above for the 
5-halo compound.

EXPERIMENTAL EXAMPLE 1 
Preparation of 3-n-Octylisothiazolone from 3,3'-Dithiodipropionic acid 
To a 500 ml flask fitted with a mechanical stirrer, nitrogen inlet, and an 
outlet to a 10% sodium hydroxide trap was charged 20g(0.095M) of 
3,3'-dithiodipropionic acid, 200 ml of chlorobenzene and 0.25 ml of 
pyridine. An addition funnel containing 24.9 g (0.21 M) of thionyl 
chloride was added and the thionyl chloride was added dropwise. The 
mixture was warmed to 45.degree. C. and stirred for 2.5 hours. The mixture 
was not homogeneous and was stirred overnight. (The reaction was still not 
quite homogeneous but was carried on at this point.) The mixture was 
reheated to 45.degree. C. and sparged for 15 min with nitrogen. The 
remaining thionyl chloride was removed by stripping under house vaccuum 
for 1 hr and then 50 ml of chlorobenzene was charged. The mixture was 
cooled to -20.degree. C. and 6.8 g (0.096 M) of chlorine was added over 16 
min. After stirring 0.5hr the mixture was warmed to 0.degree.-5.degree. C. 
and a solution of 24.6 g (0.188 M) of n-octyl amine and 9.2 g (0.188 M) of 
triethyl amine in 100 ml of chlorobenzene was added dropwise such that the 
reaction temperature remained below 5.degree. C. (addition time 1.75 hr). 
The solution was allowed to warm and then heated to 35.degree. C. During 
this time the reaction thickened and then thinned out. Chlorine (13.5 g, 
0.19 M) was then fed over 40 min at 35.degree. C. and the mixture was 
stirred for an additional 1 hr. The reaction mixture was washed with 
3.times.400 ml of water and then the solvent was removed under vaccuum to 
yield 36g of 3-n-octylisothiazolone as a dark oil. Analysis by capillary 
gas chromatography indicated a yield of 21.8 g (53.7%) of 
3-n-octylisothiazolone. 
EXAMPLE 2 
Preparation of 3,3'-Dithiodipropionyl chloride 
To a 300 ml round bottom flask fitted with a mechanical stirrer, nitrogen 
inlet and an outlet to a 10% sodium hydroxide trap was charged 169 g (1.42 
M) of thionyl chloride and 100 g (0.48 M) of 3,3'-dithiodipropionic acid. 
The slurry was stirred and 0.5 ml of pyridine was charged. The mixture was 
stirred overnight. Excess thionyl chloride was then removed under house 
vacuum at room temperature until bubbling ceased and then for an 
additional 1.5 h at 40.degree.-50.degree. C. The resulting orange liquid 
of 3,3'-dithiodipropionyl chloride was used in Example 3 without further 
purification. 
EXAMPLE 3 
Preparation of 3-n-Octylisothiazolone 
The process of Example 1 was repeated, except that the product of Example 2 
was diluted with chlorobenzene, cooled to -20.degree. C. and chlorinated. 
Analysis indicated a 59.6% yield of 3-n-octylisothiazolone. 
In a similar manner, cyclohexylamine may be substituted for n-octylamine to 
afford 3-cyclohexylisothiazolone. 
EXAMPLE 4 
Preparation of 3-n-Octylisothiazolone from 3-thiopropionic acid 
By following substantially the procedure of Example 1 and by substituting 
3-thiopropionic acid for the dithiodiacid described therein a white solid 
of 3-n-octylisothiazolone precipitated during the exothermic portion of 
the reaction. Analysis of the final reaction mixture by high pressure 
liquid chromatography indicates a 45.9% yield of the 
3-n-octylisothiazolone.