L,2-Benzisothiazolin-3-ones

The tautomeric equilibrium between the hydroxy, 154a, and oxo, 154b, forms of l,2-benzisothiazolin-3-one is shifted to the right (Scheme 57) [76AHC(S1), p. 312 81G71 84CHEC-I(6)131] a conclusion supported by X-ray structural determinations of some derivatives of 154 e.g., R = Cl [69AX(B)2349]. 

Fuller S.J., Denyer S.P, Hugo W.B., Pemberton D., Woodcock P.M., Buckley A.J. (1985) The mode of action of l,2-benzisothiazolin-3 one on Staphylococcus aureus. Lett Appl Microbiol, 1, 13-15. 

The combination of 5-chloro-2-methyl-4-isothiazolin-3-one (CIT) and 2-methyl-4-isothiazolin-3-one (MIT) was described by Elsom in 1988 as probably the most cost effective biocide for industrial preservation. This combined product, along with the benzyl derivative (l,2-benzisothiazolin-3-one - BIT) either on their own or combined with other actives comprise the majority of modem wet-state biocides currently in use. 

A sample of a standard calcium carbonate slurry was received from a large manufacturer in the USA. This sample was subjected to preservative efficacy testing according to the ASTM E 723-91 test protocol. Preservative treated samples were inoculated with a mixed bacterial inoculum containing organisms with a known tolerance or resistance to BIT (l,2-Benzisothiazolin-3-one). Untreated controls were included for reference purposes. The test procedure is outlined below. 

This study was designed to evaluate the performance of commonly used biocides against the performance of a new liquid blend. In order to choose an effective preservative package, the two main criteria the biocide must have, are (i) to be approved by the US Food and Drug Administration (FDA) under sections 21 CFR 176.170 and 21 CFR 176.180 which cover components of paper and paperboard in contact with foods and (ii) to be designated as a safe biocide (low toxicity, non-sensitiser, easy to handle). The three most commonly used products (i) 5-chloro-2-methyl-4-isothiazolin-3-one + 2-methyl-4-isothiazolin-3-one, (ii) 1,5-pentanedial and (iii) l,2-benzisothiazolin-3-one, currently meet the above criteria. The new liquid blend, l,2-dibromo-2,4-dicyanobutane -I- 2-bro-mo-2-nitropropane-l,3-diol was also designed to meet the criteria. 

Saccharin is the generic name for l,2-benzisothiazolin-3-one-1,1-dioxide and has been used for over 100 years, since its discovery by Fahlberg and Remsen in 1879 and the first production patent granted in 1885. Saccharin is a white crystalline product the sodium salt of saccharin is the commonly used form in the soft drinks industry. Solubility is excellent and stability under food and drink processing conditions is also excellent. 

Saccharin 218 is obtained by KMn04 oxidation of o-methylbenzenesulfonamide 217 (Scheme 126). Various V-alkylsaccharins 219 (n = 2) and A-alkyl-l,2-benzisothiazolin-3-one A-oxides 219 (n= 1) are conveniently prepared in moderate to good yields by the reaction of A-alkyl(0-methylarene)sulfonamides with (diacetoxyiodo)benzene in the presence of iodine under irradiation with a tungsten or mercury lamp <1999T14885, CHEC-III(4.05.9.1.2)599>. 

H(55)1759>. N-Unsubstituted l,2-benzisothiazolin-3-ones 344 (R = H R = H, Cl, OMe R = H, Cl, OMe) can be prepared in a chlorine-free synthesis by cyclization of 2-sulfenamoylbenzoates 342 (R = OR, R = NH2) which are prepared by amination of thiosalicylates with hydroxylamine-O-sulfonic acid. N-Substituted sulfenamoylbenzoates, prepared by transamination with different amines, can be cyclized to N-substituted 1,2-benzisothiazolin-3-one 344 (R = PhCH2,/ -MeOC6H4CH2,/>-ClC6H4CH2) <2003H(60)1855>. 

A versatile synthetic approach to 4-hydroxy-1,2-benzothiazines was discovered by Abe and co-workers3-. 2-phenacyl-l,2-benzisothiazolin-3-ones (8 R = Ar) with strong base produce 3-benzoyl-4-hydroxy-2//-l,2-benzo-thiazine 1,1-dioxides (9 R = Ar) (Eq. 2). Yields up to 93% could be obtained using sodium ethoxide in ethanol. 

The benzisothiazoline ester 8 (R = OR ) is isomerized to a 1,2-benzo-thiazine-3-carboxylic ester (12) by sodium ethoxide in ethanol7,8 or by sodium methoxide in dimethyl sulfoxide.9 This rearrangement appears to be more sensitive to reaction conditions and solvent than the rearrangement of 2-phenacyl-l,2-benzisothiazolin-3-ones such as 8 (R = Ar) (Eq. 2), and two laboratories8,9 report unsatisfactory attempts to rearrange compound 8 (R = OMe) to 12 (R = Me) with sodium methoxide in methanol. 

The crystal and molecular structure of l,2-benzisothiazolin-3-one (31) have been determined. Both C—S and S—N bonds are single.46... 

Synthesis of l,2-Benzisothiazolin-3-ones and their 1,1-Dioxides.-From 2-(Methylsulphinyl)benzamides and Thionyl Chloride. The reaction of 2-(methylsulphinyl)benzamides with thionyl chloride, a novel and convenient... 

Synthesis of l,2-Benzisothiazolin-3-one 1,1-Dioxides from 2-Aminobenzo-nitriles and SO - 2,6-02N(Me0)C6H3CN is reduced and the 2,6-NH2(MeO)CeH3CN is treated with NaN02 followed by SO2 to give 3-amino-... 

Physical Properties of l,2-Benzisothiazolin-3-ones. - The infrared spectra of A -substituted isobenzothiazolinone 1,1-dioxides have been measured and characteristic frequencies for the S-N stretching vibration discussed. The medium bands at 819-870 cm are assigned to the S-N stretching. 

IT based products offer some key advantages as noted in Table 1. For in-can biocide activity, the two IT based products most commonly used are 5-chloro-2-methyl-4-isothiazolin-3-one (CIT) / 2-methyl-4-isothiazolin-3-one (MIT) (CIT/MIT are sold together in a ratio of 3 parts CIT and 1 part MIT) and l,2-benzisothiazolin-3-one (BIT) Table 1 shows the advantages of FD type biocides. In many parts of the world, IT combined with FD biocides are very popular. They offer key advantages such as increased killing power and enhanced stability of CIT/MIT. 

Biocides may be used to inhibit the growth of microorganisms. A preferred biocide is Proxel GXL from Zeneca Specialties at a final concentration of 0.0001-0.5% (20). Proxel GXL is a solution of l,2-benzisothiazolin-3-one in dipropylene glycol and water. 

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