Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-22
2001-07-24
Morris, Patricia L. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S266200
Reexamination Certificate
active
06265424
ABSTRACT:
FIELD OF THE INVENTION
This invention provides new compounds that are useful as insecticides and acaricides, and methods of controlling insects and mites using the compounds. The compounds are of particular interest for their activity against whitefly.
BACKGROUND OF THE INVENTION
There is an acute need for new insecticides and acaricides. Insects and mites are developing resistance to the insecticides and acaricides in current use. At least 400 species of arthropods are resistant to one or more insecticides. The development of resistance to some of the older insecticides, such as DDT, the carbamates, and the organophosphates, is well known. But resistance has even developed to some of the newer pyrethroid insecticides and acaricides. Therefore a need exists for new insecticides and acaricides, and particularly for compounds that have new or atypical modes of action.
US patent application Ser. No. 09/048,601, filed Mar. 26, 1998, dicloses a genus of insecticidal 3-(substituted phenyl)-5-thienyl-1,2,4-triazoles. The disclosed compounds are primarily active against mites and aphids. It has now been discovered that a particular subclass of the genus disclosed in the '601 application have greatly improved activity against other insects, such as whitefly.
SUMMARY OF THE INVENTION
This invention provides novel substituted thienyl triazole derivatives especially useful for the control of insects and mites.
More specifically, the invention provides novel insecticidally active compounds of the formula (1)
wherein
R
1
and R
2
are independently F or Cl; and
a) R
3
is CH
3
and R
4
is Cl or Br, or
b) R
3
and R
4
are both Br.
DETAILED DESCRIPTION
Synthesis
Compounds of formula (1) can be prepared by the methods described in U.S. Pat. Nos. 5,380,944 and 5,284,860 (Production Methods 1, 2 and 3).
A process for preparing compounds of formula (1) is illustrated in the following Scheme I:
The first step of this process involves preparation of the thioamide starting material. The thioamide is converted to the thioimidate using dimethyl sulfate in 1,4-dioxane. Any known imidate forming procedure known in the literature can be used for this transformation. Common methylating agents such as methyliodide, methylbromide and dimethyl sulfate can be used. Any common solvent compatible with the reaction conditions can be used, with toluene, acetonitrile, 1,4-dioxane, THF, and 1,2-dichloroethane most convenient. Reaction temperatures range from RT to the reflux temperature of the solvent. The thioimidate can be isolated as its salt or used directly without isolation in the next transformation.
The thioimidate is next acylated with 3-methyl-2-thiophenecarbonyl chloride (“acid chloride”) to give the acyl thioimidate adduct. Any known acylation conditions can be used for this transformation. Any common organic and inorganic base can be used, with Na
2
CO
3
, NaHCO
3
, pyridine and triethylamine most convenient. Preferred solvents include 1,4-dioxane, THF, dichloromethane, and 1,2-dichloroethane, but any solvent compatible with the reaction conditions can be used. Reaction temperatures in the 0° to 60° C. range are suitable, with temperatures near RT most convenient. The acyl thioimidate is isolated by dilution of the reaction mixture with water and filtration followed by air drying. This acyl thioimidate is typically of sufficient purity to be used directly in the following cyclization step.
The acyl thioimidate is cyclized to the 1,2,4-triazole ring system by treatment with methylhydrazine. The methylhydrazine can be added neat or as a solution in a compatible solvent such as water. Any solvent compatible with the reaction conditions can be used, with toluene, 1,4-dioxane, THF, and short chain alcohols preferred. The methylhydrazine can be added all at once to the reaction mixture, or added in portions over a 1 hour time period. The cyclization can be carried out in the temperature range of RT to reflux temperature of the solvent being used. Ratios of the intermediate 3 to its off-isomer 4 range from 6:1 to 40:1 depending upon the reaction conditions used.
It is convenient to use 1,4-dioxane at a cyclization temperature of 80° C. to give a 30:1 ratio of isomers. Workup consists of removal of the solvent followed by crystallization from a suitable solvent such as 95% EtOH. Alternately, the reaction mixture can be diluted with water and filtered to provide the intermediate 3. Air drying provides product of sufficient purity for the next bromination step.
The last two steps illustrated in Scheme I are the bromination of triazole 3 to give the dibromo intermediate 2, followed by removal of one of the bromine atoms. Any standard brominating reagent known in the literature can be used, with Br
2
being the most convenient. Two to five molar equivalents of Br
2
can be used at temperatures from 25° to reflux temperature of the solvent. Time of reaction range from 1 hour to 24 hours. Any solvent compatible with bromination conditions can be used such as 1,4-dioxane, 1,2-dichloroethane, and acetic acid. The generated HBr can be neutralized by running the reaction in the presence of a proton acceptor such as sodium acetate. It was found most convenient to run the reaction in acetic acid with sodium acetate using four equivalents of Br
2
.
The dibromo analogue 2 can be isolated or one may proceed directly into the next chemical transformation, if desired, without isolation. In the last step, zinc dust is added to the reaction mixture to reduce off the 5-bromine on the thiophene ring. Any known methods of aromatic halogen reduction could be used, but zinc dust was found most convenient. Two to three equivalents of zinc can be used; the extra molar equivalents were needed to reduce unreacted Br
2
. The temperature of the reduction ranged from 25° to 90° C. This reduction is highly selective and leaves the 4-bromine of the thiophene ring unaffected. The product is conveniently isolated by dilution of the reaction mixture with water followed by filtration.
A preferred synthetic method is illustrated in the following Scheme II:
Conditions for each step in Scheme II are as follows: a) H
2
S/Et
3
N/Pyridine, −20° C., b) (CH
3
O)
2
SO
2
, 1,4-dioxane, 80° C.,
c) pyridine, 4-bromo-TAC, 30° C.,
d) MeNHNH
2
/H
2
O, 1,4-Dioxane, 80° C.
The 4-bromo-3-methyl-2-thiophenecarbonyl chloride used in step c of Scheme I can be prepared using the procedure illustrated in Scheme III:
Conditions for each step in Scheme III are as follows:
e) Br
2
/succinimide, f) 10% Pd/C, DPPP, 0.2 mol %, CO pressure, EtOH, NaOAc, g) i) 2 Br
2
/2 NaOAc/HOAc, 80° C., ii) Zn dust, HOAc/H
2
O, h) NaOH/H
2
O, i) SOCl
2
/DMF, 1,2-DCE.
Scheme III illustrates use of ethyl 3-methyl-2-thiophenecarboxylate as the intermediate utilized in step g, but any short chain alkylester of 3-methyl-2-thiophenecarboxylic acid may be used. These include, but are not limited to, methyl, ethyl, propyl or butyl. Most convenient are methyl or ethyl esters of 3-methyl-2-thiophenecarboxylic acid.
Methyl 3-methyl-2-thiophenecarboxylate may be prepared by a Grignard reaction of 2-bromo-3-methylthiophene with dimethylcarbonate. Either the methyl or ethyl ester of 3-methyl-2-thiophene carboxylic acid may be prepared by Fisher esterification with the appropriate alcohol, or by reaction of 3-methyl-2-thiophenecarboxylic acid chloride with the appropriate alcohol.
Yet another process for preparing compounds of formula (1) is illustrated in Scheme IV:
Yet another process for preparing compounds of formula (1) is illustrated in the following reaction Scheme V:
The N-((methyl)benzenesulfonylamino)-(2-fluoro-6-chlorophenyl)chloroimine used in the final step is prepared as disclosed in U.S. Pat. No. 5,380,944. In one of its aspects, therefore, the invention provides a process for preparing 3-(2-chloro-6-fluorophenyl)-1-methyl-5-(4-bromo-3-methyl-2-thienyl)-1H-1,2,4-triazole which comprises:
a) reacting 4,5-dibromo-2-cyano-3-methylthiophene with zinc dust to provide the required 4-bromo-2-cyano-3-methylthiophene starting material;
b) reacting the 4-bromo-2-cyano-3-methylthi
Ash Mary L.
DeVries Donald H.
Dintenfass Leonard P.
Gifford James M.
Hamilton Christopher T.
Dow AgroSciences LLC
Mixan Craig E.
Morris Patricia L.
Stuart Donald R.
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