Process for the preparation of 1,2-benzisothiazolin-3-ones

A process for making a 2-alkylbenzisothiazolinone which comprises reacting a bisamide of formula ##STR1## in water or an organic liquid containing water with a bisulphite or bisulphite release agent to form a Bunte salt and converting the Bunte salt under alkaline conditions to 2-alkyl-BIT. R is alkyl. Preferred substituents R are butyl, hexyl, 2-ethylbutyl and 2-ethylhexyl.

The present invention relates to a process for making 
1,2-benzisothiazolin-3-ones and to the use of compounds made thereby as 
industrial biocides. 
1,2-Benzisothiazolin-3-ones (hereinafter "BIT") have long been known 
including their use as industrial biocides. 
There exist three common methods for making BIT as disclosed in GB 848,130. 
The first method involves making a 2-halogenothiobenzoyl halide and 
reacting this with a primary amine to obtain a N-substituted BIT. The 
2-halogenothiobenzoyl halide is generally made by cleaving the disulphide 
bond of 2,2'-dithio-bis-benzoic acid with halogen and simultaneously or 
sequentially converting the carboxylic acid groups to acid halides. 
A second method involves making a 2-halogenothiobenzamide and cyclising 
this compound in the present of acid or alkali. The 
2-halogenothiobenzamide is typically made by converting 
2,2'-dithio-bis-benzoic acid to bisamide and thereafter cleaving the 
disulphide bond with halogen. The halogen is often chlorine as provided by 
sulphuryl chloride. 
A third method involves the disproportionation of 
2,2'-dithio-bis-benzamides by heating in the presence of sodium hydroxide 
solution. 
Owing to increasing environmental pressures there is a growing need to 
avoid processes involving the cleavage of the disulphide bond in bisamide 
precursors by halogen when making BIT's since these can given rise to 
pentahalophenols, especially pentachlorophenols. Thus, alternative methods 
of converting 2,2'-dithiobisamides (hereinafter "Bisamide") to BIT by 
non-halogen cyclisation have been sought. 
One such method is the disproportionation of bisamide in alkali in the 
presence of oxygen or an oxygen release agent as disclosed in EP 187,349. 
This method gives high yields of BIT itself and 6-chloro-BIT. No examples 
of N-alkyl-BIT derivatives are recorded. 
The disulphide bond of bisamides may also be cleaved using bisulphite which 
results in the formation of Bunte salts which may then be cyclised under 
alkaline conditions to give BIT's. Such a general reaction for making 
Bunte salts and BIT's has been disclosed by Tyrrell (Tetrahedron Letters 
26 1753 (1985)) using bisamide precursors containing an amino substituent 
in the amide group. Only the one example is given in this disclosure where 
a 47% yield of the Bunte salt was obtained from a bisamide having a 
piperidinyl group in the amido substituent. The preparation of two further 
BIT derivatives containing a N-ethyl-piperidinyl and N-ethyl-pyrrolidinyl 
group have also been disclosed by Baggaley et al in J.Med.Chem 28 
1661-1667, 1985 using the Bunte salt as intermediate but the overall yield 
of BIT from bisamide is again low at 22% and 21% yield, respectively. This 
preparative method does not appear to have been pursued further due 
possibly to the sensitivity of the method to the substituents found in the 
case of di-phenyl disulphide as disclosed by Lecher (et al) in J.O.C. 20 
475 (1955). Here it is disclosed that good yields of Bunte salts were 
obtained in the case of bis-(3nitrophenyl) disulphide, bis-(2-aminophenyl) 
disulphide, bis-(2-benzoylaminophenyl) disulphide and a poor yield from 
di-phenyl disulphide. No Bunte salt was identified from 
bis-(2-nitrophenyl) disulphide, bis-(2-methoxyphenyl) disulphide and 
2,2'-dithiobisbenzothiazole. Because the yield of Bunte salts from 
di-phenyl disulphides is clearly influenced by the nature of the 
2-substituent in particular there is no indication in Lecher whether the 
presence of 2-carbonamido groups as in bisamides will give high yields of 
Bunte salts. 
We have now found that some bisamides can be converted to Bunte salts in 
high yield by reaction with bisulphite and especially a bisulphite-release 
agent and that the Bunte salts so obtained may be readily converted to 
BIT. The yield of N-alkyl-BIT using this process is higher than that 
obtained using the method disclosed in EP 187,349. 
According to the present invention there is provided a process for making 
BIT of formula 1 
##STR2## 
which comprises reacting a bisamide of formula 2 
##STR3## 
in water or an organic liquid containing water with a bisulphite or a 
bisulphite-release agent or a mixture thereof; 
wherein 
R is hydrogen, cycloalkyl, alkyl, alkyl substituted by hydroxy, halogen, 
C.sub.1-6 -alkoxy, carboxy, carbonamide, sulphonamide, nitrile or aryl or 
optionally substituted aryl; 
X is halogen, nitro, alkoxy or nitrile; and 
n is from 0 to 4. 
When R is alkyl it may be linear or branched and is preferably C.sub.1-20 
-alkyl, more preferably C.sub.1-12 -alkyl and especially C.sub.1-8 -alkyl. 
Examples of such groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, 
iso-butyl, tert-butyl, amyl, i-amyl, n-hexyl, i-hexyl, 2-ethylbutyl, 
n-heptyl, n-octyl, i-octyl, 2-ethylhexyl, n-decyl and n-dodecyl. 
When R is cycloalkyl, the alicyclic ring preferably contains up to 8 carbon 
atoms such as cyclopropyl and especially cyclohexyl. 
When R is aryl it preferably contains up to 10 carbon atoms and is 
especially phenyl. 
When R is substituted aryl, the substituent may be as described for 
substituted alkyl. 
When R is alkyl substituted by aryl, the aryl group is preferably phenyl 
and is especially benzyl and more especially 2-phenylethyl. The phenyl 
ring in these substituted alkyl groups may itself be further substituted 
as described for substituted aryl but it is preferably unsubstituted. 
Halogen means fluorine, iodine, bromine and especially chlorine. 
Preferably n is zero. 
The bisulphite-release agent may be any agent giving rise to bisulphite ion 
in aqueous media and is preferably sulphur dioxide in aqueous alkaline 
media and especially metabisulphite. 
The reaction of the bisamide with a bisulphite or bisulphite-release agent 
may be catalysed by oxygen or a metal such as copper, iron and cobalt 
which may be present as a salt. 
When R is H in the BIT of formula 1, the BIT may be prepared in the form of 
its salt with an alkali metal or ammonia. Examples of alkali metals are 
potassium and especially lithium or sodium. 
It is especially preferred that R is unsubstituted alkyl or 2-phenylethyl. 
Good results have been obtained when R is methyl, n-butyl, n-hexyl, 
i-hexyl, n-octyl, 2-phenylethyl, 2-ethylbutyl and 2-ethylhexyl. 
The bisulphite or metabisulphite is preferably present in the form of a 
water-soluble salt such as an alkali metal or ammonium salt. Preferred 
alkali metals are lithium, potassium and especially sodium. 
Metabisulphite is preferred since in many instances it gives higher yields 
of the Bunte salt and hence BIT. 
The amount of bisulphite or bisulphite-release agent is preferably at least 
one mole and more preferably at least two moles for each mole of bisamide. 
Generally, there is no advantage in using a large excess of bisulphite or 
bisulphite-release agent. Thus, the amount of metabisulphite is preferably 
less than 8 moles and especially less than 5 moles of metabisulphite for 
each mole of bisamide. Higher yields of N-alkyl-BIT have been obtained 
with from 2.5 to 3 moles, for example 2.75 moles of metabisulphite for 
each mole of bisamide. In the case of bisulphite, the amount of bisulphite 
is preferably less than 10 moles and especially less than 8 moles 
bisulphite for each mole of bisamide. 
As noted hereinbefore, water can be the medium in which the bisamide is 
reacted with bisulphite or bisulphite-release agent and this has been 
found an effective reaction medium for BIT itself (formula I, R is H) and 
N-C.sub.1-2 -alkyl-BIT's. However, for N-substituted-BIT's, the reaction 
medium is preferably an organic liquid. 
The organic liquid may be hydrophilic or hydrophobic but is preferably 
hydrophilic. 
When the organic liquid is hydrophobic it is preferably a solvent for the 
bisamide and may be an aliphatic hydrocarbon, chlorinated aliphatic 
hydrocarbon, an ether, ester or an aromatic hydrocarbon. Examples of 
hydrophobic organic liquids are methylene chloride, chloroform, carbon 
tetrachloride, trichloroethylene, perchloroethylene, trichloroethane, 
n-heptane, petroleum ether, diethyl ether, ethylacetate and toluene. 
Where the organic liquid is hydrophobic the bisulphite or 
bisulphite-release agent may be dissolved in water and the bisamide 
converted to the Bunte salt by mixing the two phases. The Bunte salt is 
water soluble and is retained in the aqueous phase whereupon it may be 
readily separated by simple phase disengagement. 
When the organic liquid is hydrophilic, it is preferably a glycol, ketone, 
carbitol, amide, sulphoxide and especially alcohol. Examples of such 
solvents are ethylene glycol, diethylene glycol, propylene glycol, 
acetone, methylethylketone, methyl and ethylcarbitol, dimethylformamide, 
dimethylacetamide, dimethylsulphoxide, methanol, ethanol, propanol, 
isopropanol, butanol, isobutanol and tert butanol including mixtures 
thereof. Methanol, ethanol and ethylene glycol are especially preferred, 
especially methanol. 
It is also preferred that the hydrophilic liquid contains sufficient water 
to dissolve the bisulphite or bisulphite-release agent. In the case of 
bisulphite, the amount of water is preferably greater than 5%, more 
preferably greater than 10% and especially greater than 20% relative to 
the amount of organic liquid. It is also preferred that the amount of 
water is less than 100%, more preferably less than 70% and especially less 
than 50% relative to the weight of organic liquid. 
In the case of metabisulphite, the amount of water is preferably at least 
1% more preferably at least 2% and especially at least 4% relative to the 
weight of organic liquid. The amount of water is preferably less than 20%, 
more preferably less than 15% and especially less than 12% relative to the 
weight of organic liquid. Good results have been obtained when the amount 
of water relative to the organic liquid is from 6 to 10% and especially 
about 8%. 
The bisulphite or metabisulphite may be added to the organic liquid as an 
aqueous solution or slurry but is preferably added in solid form to the 
bisamide in the organic liquid. This is particularly advantageous in the 
case of metabisulphite. 
The formation of the Bunte salt is very facile and can be carried out by 
heating the bisamide, bisulphite and/or bisulphite-release agent in the 
organic liquid at temperatures below 100.degree. C. For convenience, it is 
preferred to carry out the reaction under reflux in water, the organic 
liquid or organic liquid/water mix. 
The Bunte salt may be isolated by any method known to the art such 
filtration or evaporation of the water, organic liquid or organic 
liquid/water mix. In one preferred method a hydrophobic liquid which is a 
non-solvent for the Bunte salt is added to remove the hydrophilic liquid 
or hydrophilic liquid/water mix as an azeotrope. Another preferred method, 
where the organic liquid is hydrophilic, is to add more water to effect 
separation/sedimentation of the Bunte salt. This latter method has been 
found particularly effective for N-alkyl-BIT's containing more than three 
carbon atoms in the alkyl chain. 
Examples of preferred hydrophobic liquids which form azeotropic mixtures 
with water and/or hydrophilic liquid are xylene, toluene, hexane, 
cyclohexane and methylcyclohexane. 
The preferred hydrophobic liquid which forms an azeotrophic is toluene. 
The Bunte salt so obtained can be converted in high yield, which in most 
instances is quantitative, by treating the Bunte salt with alkali, 
especially aqueous alkali liquor. Preferably, the alkali is an alkali 
metal or ammonium hydroxide, carbonate or bicarbonate. Hydroxides are 
preferred. Preferred alkali metals are lithium, potassium and especially 
sodium. 
The amount of alkali is relatively unimportant, but is generally a large 
excess relative to the amount of Bunte salt. It is preferred that the 
amount of alkali in the aqueous alkali liquor is sufficient to give a pH 
above 9, more preferably above 11 and especially above 13. 
Cyclisation of the Bunte salt to form a BIT occurs rapidly in the presence 
of alkali and generally this reaction can be carried out at 20-30.degree. 
C. Higher temperatures are not normally required. 
When the Bunte salt has been isolated this can treated directly with 
aqueous alkali solution when the N-substituted BIT separates as either an 
oil or a solid. 
When the Bunte salt is present in a hydrophobic liquid as a dispersion, 
this dispersion can be treated with aqueous alkali whereupon the BIT 
dissolves in the hydrophobic liquid on its formation. The BIT can then be 
isolated by removal of the hydrophobic liquid by any convenient method 
such as evaporation or steam stripping of the liquid. 
Depending on the actual BIT and its subsequent commercial usage it is 
sometimes convenient to choose a hydrophobic liquid in which the BIT is to 
be subsequently formulated since this eliminates the need to first isolate 
the BIT. 
As noted hereinbefore the bisamide is obtained from 2,2'-dithiobis-benzoic 
acid (hereinafter DTBA) which is often contaminated by polysulphides of 
formula 3 
##STR4## 
wherein X and n are as defined hereinbefore; and 
p is 1 or 2. 
When the DTBA containing these polysulphides is converted to bisamide the 
bisamide also contains these polysulphide contaminants. On conversion of 
such bisamide to BIT using halogen to cleave the disulphide bond the 
presence of these polysulphides adversely affects the yield of BIT. The 
presence of polysulphides and other contaminants in the bisamide can also 
result in unacceptable discoloration of the BIT. 
It has now been found that these polysulphides can also be reacted with 
bisulphite or bisulphite-release agent to give Bunte salts in high yield 
and that a BIT obtained from these polysulphides or bisamide containing 
polysulphides exhibits a more acceptable colour than that obtained when 
the disulphide bond is cleaved by halogen. 
According to a further aspect of the invention there is provide a process 
for making BIT which comprises reacting a polysulphide of formula 4 or 
bisamide of formula 2 which contains a polysulphide of formula 4 in water, 
or an organic liquid containing water with bisulphite and/or 
metabisulphite or mixture thereof; 
##STR5## 
wherein R, X, n and p are as hereinbefore defined. 
When the polysulphide of formula 4 is present as a contaminant in the 
bisamide it is preferably less than 50%, more preferably less than 20% and 
especially less than 10% by weight relative to the weight of bisamide. 
As noted hereinbefore, one of the methods for making a BIT is by reacting a 
2-halogenothiobenzoyl halide with a primary amine or ammonia. The 
2halogenothiobenzoyl halide is made by cleaving the disulphide bond of 
DTBA with halogen and either simultaneously or sequentially forming the 
acid halide. If the DTBA contains polysulphides, then the reaction 
products with a primary amine or ammonia are a BIT and mixed bisamides of 
formulae 2 and 4. The yields of BIT are thereby reduced. It has now been 
found that these mixtures of BIT and mixed bisamides can be converted to 
high quality BIT by treating the mixture with bisulphite or 
bisulphite-release agent to convert the BIT and the mixed bisamides to 
their Bunte salts and subsequently treating the Bunte salt with alkali to 
form BIT. 
According to a still further aspect of the invention there is provided a 
process for making a BIT of formula 1 
##STR6## 
which comprises treating a mixture of BIT of formula 1 and bisamide of 
formula 5 
##STR7## 
wherein X, R and n are defined hereinbefore; and 
q is 0,1 or 2; 
in water or an organic liquid containing water with bisulphite or 
bisulphite-release agent or a mixture thereof. 
BIT's are known industrial biocides and according to another aspect of the 
invention there is provided the use of BIT's made by the processes of this 
invention as industrial biocides, especially as fungicides and in 
particular as paint film fungicides and fungicides for plastics materials. 
The invention is further described in more detail in the following examples 
wherein all references are to parts by weight unless indicated to the 
contrary.

EXAMPLE 1 
Preparation of N-n-butyl-BIT using metabisulphite 
A mixture of crude dithio-2,2'-bis(N-n-butylbenzamide) (60% dry weight 
bisamide and polysulphides, 13% by weight N-n-butyl 
benzisothiazolin-3-one, remainder unidentified) (12.8 parts), sodium 
metabisulphite (11.4 parts), methanol (59 parts) and water (5 parts) was 
heated and stirred at reflux for 4 hours. The reaction mix was then 
cooled, stirred at 20-25.degree. C. with decolorising carbon (0.5 parts) 
for 30 mins and then filtered. Toluene (65 parts) was added to the 
filtrate and the majority of the methanol/water was removed by azeotropic 
distillation whereupon the Bunte salt was obtained as a suspension in 
toluene. Water (100 parts) was added to the toluene suspension and the pH 
of the aqueous phase raised above 13.25 by addition of 47% sodium 
hydroxide solution. After stirring for 30 min at 20-25.degree. C. the 
Bunte salt had completely cyclised to N-n-butyl-BIT which dissolved in the 
toluene phase. The toluene phase was separated, washed with water 
(2.times.25 parts) and the toluene removed by evaporation. N-n-butyl-BIT 
was obtained as a yellow oil (10.8 parts). Yield based on crude bisamide 
is 95% theory. 
EXAMPLE 2 
Preparation of N-n-butyl-BIT using bisulphite 
A mixture of dithio-2,2'-bis-(N-n-butylbenzamide) (86.5% by dry weight, 
rest unidentified) (4.0 parts), methanol (15.6 parts) and sodium 
bisulphite solution (58.5% SO.sub.2, 4.93 parts sodium bisulphite, 13.2 
parts water) was heated and stirred at reflux for 2 hours. The reactants 
was then cooled, stirred with decolorising carbon (0.1 part) at 
20-25.degree. C. for 10 minutes and filtered. The solid was washed with 
methanol/water (2:1) (10 parts) and the washing combined with the 
filtrate. 47% sodium hydroxide liquor was added to the filtrate to raise 
the pH above 13.5 and stirring continued for 30 mins at 20-25.degree. C. 
to convert the Bunte salt to BIT. The BIT was then extracted into toluene 
(50 parts) and the toluene phase separated and washed with water 
(2.times.25 parts). Finally, the toluene was removed by distillation 
whereupon the N-n-butyl-BIT was recovered as a pale yellow oil (2.42 
parts). Yield based on bisamide is 70% theory. 
COMATIVE EXAMPLE A 
Preparation of N-n-butyl-BIT using oxygen 
A mixture of dithio-2,2'-bis(N-n-butylbenzamide) (58.8% dry weight 
bisamide, 9.2% N-n-butyl-BIT, remainder unidentified) (20.5 parts), water 
(200 parts), methanol (20 parts) and sodium hydroxide aqueous liquor (47% 
sodium hydroxide; 12.8 parts) were stirred at 55.degree. C. for 24 hours 
whilst bubbling oxygen gas through the reaction mix at a rate of 3 ml gas 
per second. 
The reactants were then cooled and the N-n-butyl-BIT extracted into 
dichloromethane (200 parts). The organic phase was separated, washed with 
water (2.times.110 parts) and dried over anhydrous sodium sulphate. The 
dichloromethane was then evaporated leaving the N-n-butyl-BIT as a dark 
oil (9.4 parts). Yield is 49.5%. This is a much lower yield than that 
obtained using the method of Example 2 and especially that of Example 1. 
EXAMPLE 3 
Preparation of N-n-hexyl-BIT using metabisulphite 
Crude dithio-2,2'-bis(N-n-hexylbenzamide) (30 parts at 99% strength, 
0.063M) was dissolved in methanol (155 parts). Water (13.1 parts) and 
sodium metabisulphite (31.1 parts) was added and the reactants stirred at 
reflux for 6 hours. The reactants were then cooled, toluene (169 parts) 
were added and the majority of the methanol and water was removed as an 
azeotrope by heating whereupon the Bunte salt was obtained as a suspension 
in toluene. Water (155 parts) was added followed by caustic soda liquor 
(43.3 parts, 47% (w/w) strength) and the reactants stirred for 1 hour at 
40-45.degree. C., when the Bunte salt cyclised to form N-n-hexyl-BIT which 
dissolved in the toluene phase. 
Activated carbon (1.13 parts) in water (16 parts) was then added and the 
reactants stirred for a further 40 minutes at 40-45.degree. C. After 
screening, the toluene layer was removed, washed with water and finally 
the toluene removed by distillation. The product was obtained as a pale 
yellow oil (24.72 parts at 96.8% strength; 80.3% theory). 
EXAMPLE 4 
Preparation of N-2-ethylhexyl-BIT using metabisulphite 
This was prepared by a similar process to that described in Example 3 above 
except using dithio-2,2'-bis(N-2-ethylhexylbenzamide) (29.78 parts, 0.063 
M) in place of the butyl analogue. The product was obtained as a pale oil 
(23.93 parts, 70.3% theory). 
EXAMPLE 5 
Preparation of N-2-ethylbutyl-BIT using metabisulphite 
This was also prepared by a similar process to that described in Example 3 
except using dithio-2,2'-bis(N-2-ethylbutylbenzamide) (20.3 parts, 0.043M) 
and sodium metabisulphite () 16.35 parts) in place of the butyl analogue 
and the amount of metabisulphite in this example. 
The product was obtained as a dark yellow oil which solidified on standing 
(12.0 parts, 50% theory). The yield of BIT in this example was reduced 
owing to filtration of the toluene phase after cyclisation of the 
benzamide precursor to form the BIT which removed product.