Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-04-26
2003-08-19
Stockton, Laura L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06608208
ABSTRACT:
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-(3-nitrophenyl) 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′-dithiobis-benzothiazole. 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
which comprises reacting a bisamide of formula 2
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
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
1-20
-alkyl, more preferably C
1-12
-alkyl and especially C
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-ethylphenyl. 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-ethylphenyl.
Good results have been obtained when R is methyl, n-butyl, n-hexyl, i-hexyl, n-octyl, 2-ethylphenyl, 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
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 bisulphi
Pillsbury & Winthrop LLP
Stockton Laura L.
Zeneca Limited
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