Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-24
2002-04-23
Solola, T. A. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C564S192000
Reexamination Certificate
active
06376680
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of 3-isothiazolone mixture free of 4,5-dichloro-2-methyl-4-isothiazolin-3-one impurity, useful for stabilized isothiazolone compositions.
BACKGROUND OF THE INVENTION
Many 3-isothiazolones are biologically active antimicrobial agents which exhibit biocidal activities towards many microbes such as fungi, bacteria, algae and the like. In particular, a mixture of 2-methyl-4-isothiazolin-3-one of formula (I) and 5-chloro-2-methyl-4-isothiazolin-3-one of formula (II) is known as an effective biocide having both excellent stability and long-lasting activity, and commercially used as preservatives in various products such as paints, cosmetics, surfactants, agricultural chemicals, food additives and the like.
The isothiazolone compounds exhibit potent activities when they are employed in the form of a mixture thereof owing to a synergistic effect. The activity of the mixture depends on the mix ratio, and is known to be maximized when the content of the compound (II) is higher than that of the compound (I). Many efforts have been, therefore, made to develop an improved process for preparing an effective mixture of the compounds (I) and (II). Most prior methods are directed to effectively control or remove nitrosamine precursors generated during the preparation of the mixture of the compounds (I) and (II) using a disulfide compound as the starting material.
However, a mixture of the compounds (I) and (II) prepared in accordance with a conventional method contains 4,5-dichloro-2-methyl-4-isothiazolin-3-one of formula (III) as an inactive component:
Reaction Scheme 1, shown below, represents a process for preparing a mixture of the compounds (I) and (II) using a disulfide compound as the starting material, e.g., as is disclosed in EP Patent No. 95,907:
In Reaction Scheme 1, a disulfide compound of formula (C) is amidated with methylamine of formula (D) to obtain N,N′-dimethyl-3,3′-dithiodipropionamide of formula (A-2), which is then subjected to a chlorination/cyclization reaction using a halogenating agent, e.g., chlorine to obtain the desired mixture of the compounds (I) and (II).
The reaction sequence shown in Reaction Scheme 1 generates, however, a significant amount of the compound of formula (III) which is a well-known, potent skin irritant. Further, the result of an animal test has also shown that the skin exposed to the dichloro compound of formula (III) becomes sensitized, i.e., the exposed skin becomes further irritated by the action of the 5-chloro compound of formula (II) (see Bruze et al., Dermatosen 5, 165-168 (1987)).
Meanwhile, U.S. Pat. No. 5,068,338 describes N-methyl-3-(N-methylamino)-aminopropionamide of formula (F) as one of the impurities generated via Reaction Scheme 2 during the preparation of the mixture of the compounds (I) and (II):
In this Scheme, N-methylacrylamide of formula (E), which is formed by the decomposition of the compound of formula (A-2), undergoes a 1,4-adduction reaction with methylamine of formula (D), producing N-methyl-3-(N-methylamino)aminopropion-amide (F). The compound of formula (F) is a nitrosamine precursor, and it may further react with N-methylacrylamide (E) to produce another nitroamine precursor.
The U.S. Pat. No. 5,068,338 also discloses that the nitrosamine precursor of formula (F) may subsequently convert to N-methyl-3-(N-nitroso)aminopropionamide (B), a suspected carcinogen, by the action of a metal nitrate (NO
x
) which is a stabilizer added in formulating an isothiazolone composition, as shown in Reaction Scheme 3:
In accordance with Examples of the above-cited patent, the nitrosamine precursor is present in an amount ranging from 0.5% (5,000 ppm) to 1.1% (11,000 ppm) in N,N′-dimethyl-3,3′- dithiodipropionamide of formula (A-2) after the amidation, and the nitrosamine is present in an amount ranging from 750 to 1650 ppm in 15% isothiazolone composition.
Many efforts have been, therefore, made to prepare a mixture of the compounds (I) and (II) which is substantially free of the nitrosamine precursor. For instance, U.S. Pat. Nos. 4,939,266, 5,068,338 and 5,312,827 disclose processes for controlling the amount of the nitrosamine and nitrosamine precursor produced during the preparation of the mixture of the compounds (I) and (II) to a range of 100 ppm or less by using separation techniques such as ion exchange, recrystallization and solvent extraction, or by using a nucleophilic scavenger of N-methylacrylamide (E), as shown in Reaction Scheme 4:
However, these methods have many disadvantages. That is, the ion exchange, recrystallization and solvent extraction methods have the problems of low product yields and long process cycle time. Further, in case of the scavenger method, the production of N-methyl-3-N-nitroso)aminopropionamide of formula (B) may be controlled by reacting N-methyl-3-mercaptopropionamide of formula (A-1) with chlorine gas in an organic solvent. However, a process based on this scavenger method tends to generate an increased amount of the dichloro compound impurity of formula (III), because N-methyl-3- mercaptopropionamide of formula (A-1) reacts with chlorine, generating more heat than N,N′-dimethyl-3,3′-dithiopropionamide of formula (A-2) does.
Accordingly, the methods disclosed in the above patents have severe limitations when the mixture of the compounds (I) and (II) is to be used in products such as cosmetics and medicines, i.e., they have problems in terms of the production time, product yield and, in particular, toxicity of the impurities present in the product.
The present inventors have endeavored to develop a process for preparing a mixture of the compounds (I) and (II) which is substantially free of impurities. As a result, the presence of harmful 4,5-dichloro-2-methyl-4-isothiazolin-3-one (III) in the mixture was defined and it has been found that the compound (III) present in the mixture can be controlled by maintaining the reaction temperature at a range of 5 to 20° C., by way of using a mixed solvent system to internally dissipate the heat of reaction, which may be combined with an optional means for external cooling.
SUMMARY OF THE INVENTION
Accordingly, it is a primary object of the present invention to provide a process for preparing a mixture of 2-methyl-4-isothiazolin-3-one and 5-chloro-2-methyl-4-isothiazolin-3-one as an active ingredient, which is substantially free of 4,5-dichloro-2-methyl-4-isothiazolin-3-one impurity.
It is another object of the present invention to provide a stabilized isothiazolone composition comprising said mixture.
In accordance with one aspect of the present invention, there is provided a process for preparing a mixture of 2-methyl-4-isothiazolin-3-one of formula (I) and 5-chloro-2-methyl-4-isothiazolin-3-one of formula (II) which comprises reacting N-methyl-3-mercaptopropionamide of formula (II) or N,N′-dimethyl-3,3′-dithiodipropionamide of formula (A-2) or a mixture thereof dissolved in a first organic solvent with a chlorinating agent dissolved in a second organic solvent which is different from the first organic solvent, while maintaining the reaction temperature in the range of 5 to 20° C. to obtain said mixture substantially free of 4,5-dichloro-2-methyl-4-isothiazolin-3-one of formula (III):
In accordance with a further aspect of the present invention, there is provided a process for preparing a mixture of 2-methyl-4-isothiazolin-3-one (I) and 5-chloro-2-methyl-4-isothiazolin-3-one (II) which further comprises centrifuging the mixture of the compounds (I) and (II) obtained by the chlorination step to obtain the mixture containing nitrosamine or nitrosamine precursors in an amount of less than 5 ppm.
In accordance with another aspect of the present invention, there is provided a stabilized isothiazolone aqueous solution: which comprises water and (A) a biologically effective amount of a mixture of 2-methyl-4-isothiazolin-3-one (I) and 5-chloro-2-methyl-4-isothiazolin-3-one (II) which is prepared by the inventive process; a
Hahn Soon-Jong
Kim Jin-Man
Kim Seung-Hwan
Lim Jin-Soo
Anderson Kill & Olick PC
SK Chemicals Co. Ltd.
Solola T. A.
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