Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-07-09
2003-05-13
Lambkin, Deborah C. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C544S310000
Reexamination Certificate
active
06562979
ABSTRACT:
BACKGROUND OF THE INVENTION
Substituted-benzisothiazole herbicidal agents are described in U.S. Pat. No. 5,484,763 and WO 99/14216, among many other publications, and are highly desirable crop-selective components of good pesticide management programs. Said substituted-benzisothiazole herbicidal agents are prepared from benzisothiazole and heteroarylisothiazole compounds.
Methods to prepare benzisothiazole and heteroarylisothiazole compounds (“isothiazoles”) are known in the literature. However, the only known single-step process requires harsh reaction conditions and affords maximum product yields of only 38%. This poor yield decreases markedly when the heteroarylisothiazole ring is substituted (Canadian Journal of Chemistry, 1973, 51, 1741). Such yields and reaction conditions are not amenable to large scale preparation or manufacturing conditions.
The two-step syntheses of said isothiazoles require the isolation of intermediates, resulting in undue solvent waste load on the environment. In addition, these syntheses require harsh reaction conditions, utilize expensive reagents and result in only marginally acceptable overall yields, even for relatively unsubstituted isothiazoles. (Journal of Chemical Research, Synop., 1979, 395 and Journal of the Chemical Society, Perkin II, 1977, 1114.)
Thus, it is an object of the present invention to provide a single-step process for the preparation of substituted benzisothiazole compounds which is amenable to large scale preparation.
It is another object of this invention to provide a means of obtaining a substituted benzisothiazole compound in good yield under relatively mild reaction conditions from readily available starting materials and reagents.
It is a further object of the invention to provide an environmentally sound commercial source of substituted benzisothiazole intermediates for the preparation of important substituted-benzisothiazole herbicidal agents.
SUMMARY OF THE INVENTION
There is provided a process for the preparation of a benzisothiazole compound of formula I
wherein
Y is hydrogen or halogen;
R is CO
2
R
3
, C
1
-C
6
alkyl optionally substituted with one or more halogen, C
1
-C
6
alkoxy, CO
2
R
1
or COR
2
groups, or
a 6-membered heterocyclic ring optionally substituted with one or more halogen, CN, NO
2
, C
1
-C
6
alkyl, C
1
-C
6
haloalkyl, C
1
-C
6
alkoxy or C
1
-C
6
haloalkoxy groups; and
R
1
, R
2
and R
3
are each independently hydrogen, C
1
-C
6
alkyl or NH
2
which process comprises reacting a compound of formula II
wherein Y and R are as described hereinabove with an ammonia source in the presence of a solvent.
Also provided is a method for the use of the formula I compound in a process to manufacture herbicidally active substituted-benzisothiazole agents.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the single-step preparation of a substituted benzisothiazole compound from an appropriate 2-acylphenylthiocyanate precursor. Said benzisothiazole compounds are useful as key intermediates in the preparation of important herbicidal agents such as those described in U.S. Pat. No. 5,484,763 and WO 99/14216. Such herbicidal agents are critical to the production and quality of the global food supply. The efficient preparation of such herbicidally active compounds in an environmentally sound manner is a constant challenge.
The process of the invention provides a single step preparation of a substituted benzisothiazole compound of formula I, wherein formula I is as described hereinabove, from readily available starting materials and under relatively mild reaction conditions allowing effective large scale commercial production. Preferred formula I compounds prepared by the process of the present invention are those compounds wherein R is C
1
-C
6
alkyl or CO
2
R
3
, and R
3
is C
1
-C
6
alkyl. More preferred formula I compounds are those compounds wherein Y is hydrogen or F and R is C
1
-C
6
alkyl or CO
2
R
3
.
The term halogen as used in the specification and claims designates chlorine, fluorine, bromine or iodine. The term haloalkyl designates an alkyl group, C
n
H
2n+1
which contains from one halogen atom to 2n+1 halogen atoms. The term, 6-membered heterocyclic ring, designates a 6-membered aromatic ring system containing one or two heteroatoms selected from O, N or S and which is connected through a carbon atom. Examples of 6-membered heterocyclic ring include: pyridine, pyrimidine, pyran, thiopyran or the like.
In accordance with the process of the invention, a benzisothiazole of formula I may be conveniently prepared by reacting an appropriately substituted 2-acylphenylthiocyanate of formula II with an ammonia source such as ammonia, ammonium hydroxide, an ammonium salt, for example ammonium chloride, ammonium acetate, ammonium trifluoroacetate or the like, or any of the conventional means of sourcing ammonia in the presence of a solvent, preferably a polar solvent. The reaction is illustrated in flow diagram I wherein Y and R are as described hereinabove.
Formula II compounds may be readily prepared by conventional procedures such as the reaction of sodium thiocyanate with the appropriately substituted benzoyl compound of formula III in the presence of bromine and an acid. The reaction is illustrated in flow diagram II.
Solvents suitable for use in the process of the invention include polar solvents such as water, alcohols, organic acids, esters and aprotic solvents such as dioxane or acetonitrile. Preferred solvents are water, dioxane or lower alkyl alcohols, e.g. methanol, ethanol, propanol, isopropanol, or the like, or a mixture thereof.
The ammonia source may be any of the conventional means of introducing ammonia such as ammonia gas, ammonium hydroxide, ammonium salts or the like, preferably ammonium hydroxide or an ammonium salt. The ammonium salts operable in the inventive process are those salts which have sufficient solubility in the particular solvent employed. Examples of suitable ammonium salts include trifluoroacetate, acetate, nitrate, sulfamate, chloride, sulfate, and the like, preferably acetate or trifluoroacetate.
In the process of the invention, reaction temperature is directly related to reaction rate, thus increased temperatures lead to increased reaction rates. However, excessively high temperatures may lead to undesired side reactions and decreased product yield and purity. A suitable reaction temperature range may be about room temperature to the reflux temperature of the particular solvent used.
In actual practice, a 2-acylphenylthiocyanate compound of formula II is treated with an ammonia source, preferably ammonium hydroxide or an ammonium salt in the presence of a solvent, preferably a polar solvent, more preferably water, dioxane or a lower alkyl alcohol such as a C
1
-C
4
alkyl alcohol, e.g. methanol or isopropanol, or a mixture thereof, at a temperature range of about room temperature to the reflux temperature of the solvent. When the reaction is complete, the desired formula I benzisothiazole product is isolated using conventional procedures such as extraction, filtration, chromatography, or the like.
In the process of the invention, the amount of the ammonia source is not narrowly critical and amounts of about 1 to 5 molar equivalents, preferably about 1 to 3 molar equivalents, may be employed. It is to be understood, greater amounts of the ammonia source, i.e. greater than 5 molar equivalents, may be employed, however, no advantage may be gained.
The compounds of formula I are useful as intermediates in the manufacture of substituted-benzisothiazole herbicidal agents. Accordingly, in one embodiment of the invention, the formula I compound prepared from the formula II compound, as described hereinabove, may be reacted with a cyclic compound of formula IVa or IVb
wherein
R
4
and R
5
are each independently hydrogen, C
1
-C
6
alkyl, C
1
-C
6
haloalkyl, C
3
-C
6
cycloalkyl, C
3
-C
6
cyclohaloalkyl, or R
4
and R
5
may be taken together with the atoms to which they are attached to form a ring in which R
4
R
5
represents a 5- o
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Keil & Weinkauf
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