FI62527B - ANVAENDNING AV N-ALKYL-2 ', 4'-DINITRO-6'-TRIFLUORMETHYL DIPHENYLAMIN SAOSOM RODENTICIDER - Google Patents

Description

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Patent and Registration Office · MInvKMixl- <"> EKJSMMrÄS 30.09.82 (32) (33) (31) Aimed at« taikuus — ftuftrd Priorities Company, 307 East McCarty Street, Indianapolis,

Indiana 1 + 6206, USA (72) Barry Allen Dreikorn, Indianapolis, Indiana, USA (7k) Oy Kolster Ab (5 ^) N-alkyl-2 ', 1 + * - dinitro 6'-trifluoromethyldiphenylamines use as a rodenticide - Användning av N-alkyl-2 ', 1 +'-dinitro-6'-trifluoromethyldiphenylaminer sasom rodentieider

The invention relates to the use of N-alkyl-2 ', 41-dinitro-6'-trifluoromethyldiphenylamines of the formula I as rodenticides f ° 2 Bj2

0 ^ y y-H1 I

CF R5

3 K

wherein R is methyl, ethyl or propyl; R 1 is fluorine, chlorine, bromo-2 s iodine or trifluoromethyl and R and R independently represent fluorine, chlorine, bromine or trifluoromethyl.

Preferred compounds of formula I are those wherein R is methyl 3α, wherein R, R and R are halogen.

Compounds corresponding to the diphenylamines of the invention have been described previously in the literature, for example in U.S. Patent No. 3,948,990. However, no previous publication has disclosed 2,62527 that compounds of this type have activity that could be used as rodenticides. Secondary diphenylamines are known in the art as fungicides and insecticides.

It has now surprisingly been found that the alkyl substituent of diphenylamine causes rats to better accept the bait containing the active substance.

The new compounds of the formula I cannot always be prepared by simple, direct methods and are therefore prepared according to a multi-step process. It would be expected that such compounds could be synthesized by direct reaction of substituted N-alkylaniline with 2-chloro-3,5-dinitrobenzotrifluoride. Alternatively, it could be considered to prepare the corresponding N-H-diphenylamine and alkylate the nitrogen with an alkyl iodide or similar alkylating agent. With the exception of compounds in which either the 2- or 6-position is unsubstituted, neither method was found to be useful. In this case, one of the implementations of the following method must be used.

It has long been known that the number of rats and mice must be limited. Rats and mice are known to be carriers of numerous diseases, of which swine fever is one of the best known. These harmful animals, living together with humans, also pollute and contaminate their habitats and destroy buildings and their furniture by building tunnels and nests. Animals also consume food and contaminate what they do not consume. The rat community can consume or destroy significant amounts of nutrients in a grain store.

Several rodenticides have been and are still in use. Metal-lipid toxins such as arsenic and thallium compounds are still used, but they apparently pose a serious danger to humans and beneficial animals. Organic chemical toxins, of which warfarin is best known, are very widely used and have been effective. However, resistance to these toxins is developing in rodents.

Rodentises are usually given to rats and mice mixed with food. The concentration of rodenticide in the mixture is adjusted so that rodents consume an amount that is either acutely or chronically lethal. It is not advantageous to prepare mixtures so concentrated that the rodent dies immediately or even soon after eating. Rodents and especially rats are smart enough? 5 2 7 visit to understand the connection between eating and dying if the interval is very short. Thus, it is best practice to adjust the rodentide concentration so that rodents are poisoned after eating multiple doses of poison.

Under special conditions, rodenticide is sometimes mixed with drinking water or made into "infectious powders" which are placed in the passageways used by rodents. Once the rodents have passed through a loose poison path, they lick their feet clean and thus ingest the rodenticide.

The compounds of the invention may be prepared by reacting a) an aniline compound of the formula R 2 N, NHR 16 V / R 5 wherein R 1, R 2 and R 2 are as defined in formula I and R 2 is hydrogen, methyl, ethyl or propyl -halogen-5-nitrobenzotrifluoride, is reacted with a compound, f1 7 0? Ν — S> -x I m CF3 17 16 wherein R is hydrogen or nitro, provided that R is hydrogen 17 when R is nitro, the compound from step a) wherein R is hydrogen is alkylated, c) the compound from step b) wherein R is hydrogen is nitrated and c) the compound from step d) without the desired halogen substituents is halogenated if necessary.

4 62527 A. R7 '/' Λ ΐ / ~ \.

OzN-- · ^ ^, · —ha I o + H — N — R® ------ “\ p3 </" 'S / ”\ 3

OzN-- · ^ —halo + HzN-- · ^ --R6. =.

CRs R10 f 0aN__./ \. „Re

• T =

6f3 r10

•B

P

c

•B

7 ° R7 1-1 / ~ \ f / ^ 'X e / *

OaN — p, · --- N --- ^ * - R -----

• "V

Cra o ------ \ /, possible product ^ - nitration --- halogenation 5 62527

In the above formulas, the groups R 1, R 2 and R 2 ® mean 12, respectively, R, R and R or each of them may represent hydrogen. The process may be carried out using as starting material aniline having some or all of the desired substituents R 1 -R 2 of the product or unsubstituted aniline depending on the substituents of the desired product. Halogen substituents on the aniline ring may be added at the end of the process.

The term "halo" means that the benzotrifluoride ring is substituted with any suitable halogen atom. Chlorine and fluorine atoms are preferred and chlorine is usually most suitable.

NO r12 2% • - *, · --- · ν B. 0 N— / halo + HN— · R11 • = r / = * CF R15 a ¥ ° a μ (r 'oH (VR ”--- - 6f r1 5 3 f 'R /.

ON- / Vn- / V-R ”8 w ν = · χ

Af R15 • a. mnlkJol lirien product ------ halogenation 6 62527

The alkylation step of the above embodiment B is sterically hindered by the action of ortho substituents on the aniline ring. Thus, the groups R, R and R denote the groups R, R and R, respectively, except that at least one of the groups R and R represents hydrogen. It is preferred to use as an starting material aniline having the trifluoromethyl substituents of the desired product but lacking a halogen substituent and adding a halogen atom in the final halogenation reaction.

The individual steps of the above process are conventional in organic chemistry and are carried out in a manner known per se. The coupling reactions linking the aniline and benzotrifluoride rings are most easily performed at relatively low temperatures, in the range of -20 ° C to + 10 ° C in dimethylformamide in the presence of sodium hydride. Other media are also useful. The reactions can be carried out, for example, in alkanols such as ethanol, in which the reaction temperature may be higher, in the range of 10-25 ° C. Other solvents, including ketones such as acetone and methyl ethyl ketone and ethers such as diethyl ether and tetrahydrofuran, are satisfactory reaction solvents.

Generally, a strong base is required for acid scavenging. Sodium hydride, as mentioned above, is generally the most suitable base, but bases such as inorganic bases, for example sodium hydroxide and sodium carbonate, and organic amines, for example pyridine and triethylamine, as well as a simple excess of the starting aniline, can also be used.

The nitration of the benzotrifluoride ring is readily performed with concentrated nitric acid in acetic acid solution at room temperature. The reaction is conventional nitration and can be carried out with other common nitration reagents with a mixture of municipal concentrated nitric and sulfuric acids at elevated temperature. With the exception of the acids themselves, no solvents are used in the nitration reactions.

The N-alkylation of diphenylamines is carried out using reagents such as dialkyl sulfate or alkyl halide in the presence of a base. If dialkyl sulfate is used, the preferred reaction solvent is acetone. Other solvents such as tetrahydrofuran, dioxane and diethyl ether are useful, as are alkanes such as hexane and octane. Dimethylformamide is the preferred solvent for 7,62527 alkylations with alkyl halides, although acetone is also excellent. Other solvents mentioned above may also be used.

Preferred bases for alkylation reactions are those having a dehydrating effect, especially sodium carbonate. However, other inorganic bases such as alkali metal carbonates, bicarbonates and hydroxides can be used as well as alkali metal hydrides.

The amount of base used depends on the reaction temperature. The higher the reaction temperature, the greater the excess of base required. If the reaction temperature is room temperature, a small excess of a base such as 2 moles of base per mole of diphenylamine may be used. If very high reaction temperatures, such as 10 ° C, are used, large excesses of base, about 10-fold, must be used.

It should be noted that it is important to avoid contamination of the alkylation reaction with water.

In general, alkylations with dialkyl sulfates are best performed at a temperature of about 80 ° C, although temperatures ranging from room temperature to reflux temperature may be used. Conditions close to room temperature, such as 20-35 ° C, are preferred for alkylations with an alkyl halide, but elevated temperatures, always as high as 150 ° C, may be used.

Halogenation of the aniline ring is relatively simple. The chlorinations are best performed with elemental chlorine in acetic acid or methylene chloride or an equivalent halogenated solvent. The brominations are also easily carried out with elemental bromine in an acidic medium, but other common brominating agents such as N-bromosuccinimide and dibromoisocyanuric acid are also very effective.

Iodination is best performed using iodine monochloride as the reagent.

If the compound to be prepared does not have a 4-substituent, it is often necessary to protect the 4-position before halogenation. This is preferably done using a sulfonic acid as a protecting group because it can be easily added and easily removed.

The substituted anilines and phenyl halides used as starting materials are readily obtained by conventional methods described in the chemical literature.

8 62527

Trifluoromethyl-substituted anilines are best prepared by conventional methods by first forming a carboxylic acid-substituted aniline having acid groups at the positions of the desired trifluoromethyls. The acid group is fluorinated with sulfur tetrafluoride.

It is known that fluorinated aniline compounds are often prepared by first attaching a diazonium fluoroborate salt to the position where the fluorine atom is desired. The salt is then decomposed by heat, leaving the fluorine atom in the desired position. Alternatively, as recently observed, fluorine atoms can be attached to the phenyl ring by means of elemental fluorine at very low temperatures.

Rats and mice are killed by applying to sites commonly used by rats and mice an effective amount of a rodenticide composition comprising an inert carrier and an effective amount of a diphenylamine compound of formula I as the active ingredient.

The utility of this invention has been demonstrated by the administration of compounds of formula I to rodents in laboratory experiments. The following results of typical experiments show the excellent efficacy of the compounds of formula I as rodenticides.

The first set of experiments to be presented was performed by mixing the compounds with cereal-based animal food and the treated food was administered to male Albi norotes of the Spraque-Dawley breed. The composition of the food used was as follows

Ingredient Percentage

Corn flour, yellow 42.3%

Oats, ground 10.0%

Wheat, medium grinding 10.0%

Soybean food, solvent extracted, peeled, 50% 18.0%

Skimmed milk, dried 5.0%

Alfalfa flour, dehydrated, 17% 2.5%

Whey, fully dried 1,0%

Fishmeal, with solubles 4.0%

Animal fat, beef fat 2.0%

Dicalcium phosphate, restaurant grade 0.5%

Calcium carbonate 1.0%

Salt 0.3%

Trace element mixture 0.2%

Vitamin blend 0.6%

Methionine hydroxy analogue 0.1% total 100.00 9 62527

The compounds of formula I were mixed with the above food portions at the concentrations shown in the following tables. In each experiment, control rats were fed the same, untreated diet.

In each experiment, the treated food was dosed to a treatment group of 4-5 rats with an unlimited amount of food, and water was additionally given. Rats were weighed individually at death or at the end of each experiment. The experiments lasted 10 days if the rats survived.

The following tables show the nutrient concentrations of the compounds, in parts per million (ppm) of food, the number of days from the start of treated food dosing in rats until each rat died and the weight change, positive or negative, for each rat after 10 days of experiment.

Compound of Example 1, 25 ppm

Rat no; Date of death Weight change 1 5 -64 g 2 4 -38 g 3 3 -35 g 4 4 -53 g 5 4 -44 g

Compound of Example 2, 15 ppm

Rat no; Date of death Weight change 1 5 -43 g 2 4 -42 g 3 3 -37 g 4 3 -28 g 5 3 -37 g

Compound of Example 3, 100 ppm

Rat no; Date of death Weight change 1 6 -61 g 2 7 -76 g 3 5 -72 g 4 5 -68 g 5 5 -58 g

The second set of experiments presented was performed in essentially the same manner, except that the experimental animals were wild domestic mice (Mus musculus) and that a different food mixture was used. In these experiments, the weight change of the animals was not measured.

10 62527

Compound of Example 4, 50 ppm Animal no; Date of death 1 3 2 5 3 3 4 3 5 2 Compound of Example 5, 50 ppm

Animal No: Date of death 1 3 2 2 3 4 4 3 5 3

The excellent rodenticide results obtained with the present compounds are evident from the values. It can be seen that the compounds are effective at very low concentrations. Moreover, most importantly, the compounds kill rats with certainty, but not immediately. As mentioned, a good rodenticide allows several or all of the rats or mice to ingest the poisonous diet for some time before the animals begin to die. It will be appreciated that the compounds of formula I, when used in appropriate concentrations, will act in a preferred safe but delayed manner.

The compounds of formula I are effective in limiting the number of rats and mice in general. They can be used, for example, to control the following species.

House mouse (Mus musculus)

Isorotta (Rattus norvegicus)

Black Rat (R. Rattus Rattus)

Lattiarotta (R.r. frugivorus)

White-footed Mouse (Peromyscus leucopus)

Stray Rat (Neotoma cinerea)

Field mouse (Microtus pennsyvanicus)

The compounds of the formula I can also be used for controlling rodents other than rats and mice.

The compounds of the invention effectively control the number of rats and mice by both acute and chronic toxicity. Appropriate control of the concentration of the compound in the iodenticide composition 11,62527 allows the number of rats and mice to be reduced by immediately poisoning the animals or causing chronic poisoning by multiple doses.

However, as shown, the delayed lethal effect of the compounds is an important factor in their utility as rodenticides. The maximum advantage of the present invention is achieved by placing a rodenticidal composition in the sites used by rats and mice containing the compound at a concentration that is not acutely lethal by a single meal, but that causes a lethal effect within at least two meals and preferably by multiple meals. Thus, it is preferred to use a sufficiently large amount of rodenticide composition so that all members of the community receive the composition twice or more.

The rat consumes about 5-50 grams of food per day; the mouse consumes about 1-5 grams per day depending on the age, size and state of health of the animal in each case. A person skilled in the art of pest control can estimate the number of animals in a community and can place an appropriate amount of processed food or other compositions in the animal passageways to obtain an effective amount for each animal.

Although the term "eating" has been used above, Rodenicide can also be applied as infectious powders and compositions in drinking water.

Rodenticidal compositions are based on inert carriers including nutrients, drinking water and finely divided solids. Nutrient-based compositions, which are preferred inert carriers, can be composed of any edible substance, as rats and mice are omnivorous. These compositions may contain, for example, cereals, meat by-products or fats. Cereal nutrients that can be used in rodenticide compositions include substances such as oatmeal, ground or crushed corn, soybean products, wheat and wheat by-products, waste rice, and the like. All grains can form the basis of these compositions. Sweetening and flavoring agents may also be added to enhance the bait.

Fat-based rodenticide compositions are generally prepared from inert ingredients such as peanut butter, other peanut butter, milk solids, animal fats, vegetable oils and the like. Rodenticidal compositions are sometimes also based on animal products such as bone meal and meat products, including animal by-products.

12 625 2 7

Adhesive powders are formed from rodenticide compositions dispersed in powdered solids. Almost all powders can be used, including talc, chalk, ground clays, flour, nut shell powder, and the like, including ground stone.

Rodenticide compositions used in drinking water are suspensions or dispersions of the compounds. The compounds are relatively sparingly soluble in water, and thus it is usually necessary to grind the compound finely and suspend it. Suspending agents are commonly used in the pharmaceutical field and are selected from the group consisting of thickeners such as carvoxymethylcellulose, polyvinylpyrrolidone, gelatin and alginates, and surfactants such as lecithin, alkylphenol polyethylene ethylene oxide esters of polyene ethylene ethylene sulfonate and naphthalene sulfonates, naphthalene ethylene sulfonates. It is also sometimes possible to use anti-foaming silicones, glycols, sorbitol and sugars as suspending agents.

The concentration of the compound in the composition depends on the compound used, as their potency varies, depending on the rate at which the community is to be reduced and also on other factors. For example, if a community can be isolated so that their only food and water supply is a todenticide composition, the concentration may apparently be lower than if multiple food sources are available. Generally, rodenticide compositions contain about 5-2000 parts per million (ppm) of the composition. More preferably, concentrations of about 10 to 500 ppm are used, although it will be appreciated that concentrations both above and below said range are effective and even recommended under certain conditions.

The following examples illustrate the preparation of typical compounds of formula I. The products of the examples were identified by nuclear magnetic resonance analysis, microelement analysis, thin layer chromatography and in some cases mass spectrophotometry and infrared analysis.

Example 1 2,4,6-Trichloro-N-ethyl-21,4'-dinitro-61-trifluoromethyl-diphenylamine An amount of 3.5 g of sodium hydride obtained as an oil dispersion was washed with petroleum ether and placed in a flask with 20 ml of anhydrous dimethylformamide. The suspension was cooled to about -10 ° C and the flask was nitrogen protected. A solution of 8 grams of N-ethyl-2,4,6-trichloroaniline in 20 ml of 13,62527 anhydrous dimethylformamide was added over 5 minutes and the mixture was stirred for 1 hour keeping the temperature constant. A solution of 8.1 grams of 2-chloro-5-nitrobenzotrifluoride in 20 ml of dimethylformamide was then added over 5 minutes, and the resulting mixture was stirred for 6 hours, during which time the temperature was allowed to rise to ambient temperature. The mixture was then poured onto ice and water was added until the total volume was about 1 liter. The precipitate formed was filtered off and washed with pentane to give 7.7 grams of 2,4,6-trichloro-N-ethyl-4'-nitro-2'-trifluoromethyldiphenylamine.

Two grams of the above intermediate was heated with 15 mL of acetic acid until dissolved. The solution was cooled to room temperature and 5 ml of concentrated nitric acid was added dropwise over 10 minutes. The reaction mixture was then stirred at room temperature. After two days, a large amount of water was added to the reaction mixture, and the precipitate was filtered off and purified by silica gel column chromatography using toluene as an eluent. Evaporation of the product-containing fractions gave 0.2 grams of pure 2,4,6-trichloro-N-ethyl-24'-dinitro-6'-trifluoromethyldiphenyl8amine as an oil, with NMR peaks at 1.23, 4.01, 7.38 , 8.55 and 8.76 ppm.

Example 2 2,4,6-Trichloro-N-methyl-2 ', 4'-dinitro-61-trifluoromethyl-diphenylamine 10 grams of 2,4,6-trichloro-N-methylaniline were reacted with 11 grams of 2-chloro-5 nitrobenzotrifluoride according to the above procedure except that the temperature was room temperature and the reaction time was about 2 hours. 5 grams of 2,4,6-trichloro-N-methyl-4'-nitro-2'-trifluoromethyldiphenylamine were obtained, which was nitrated as described in Example 1. 2 grams of pure product with a melting point of 125-126 ° C were obtained.

Theoretical Observed C 37.80% 37.98% H 1.57% 1.54% N 9.45% 9.52%

Cl 23.96% 24.05%

Example 3 2,4-Dibromo-N-methyl-2'-N1-dinitro-6'-trifluoromethyl-diphenylamine 27 grams of 2-chloro-3,5-dinitrobenzotrifluoride were added to 14,62527 in 20 grams of aniline and 75 ml of ethanol. After brief stirring at room temperature, a small sample of the desired intermediate was seeded in the reaction mixture and a precipitate formed immediately. The precipitate was separated by filtration to give 28.5 grams of 2,4-dinitro-6-trifluoromethyldiphenylaraine.

The intermediate was N-methylated in two different ways, both of which are shown for clarity.

A. 3.3 grams of the diphenylamine intermediate was taken up in 15 ml of dimethylformamide and 1.3 grams of sodium hydride was added, generating heat. After 1 1/2 hours, a further 2 ml of methyl iodide was added and the mixture was warmed slightly. After two hours, the mixture was added to a large amount of cold water and the aqueous layer was removed by decantation. the residual oil was taken up in diethyl ether and mixed with magnesium sulfate and charcoal. After the solids were removed by filtration, the solution was evaporated to dryness to give 2.4 grams of a dark red oil which solidified on cooling. The solid was heated with petroleum ether, cooled and filtered to give 2.4 grams of N-methyl-2,4-dinitro-6-trifluoromethyldiphenylamine, m.p. 84-86 ° C.

B. 11 grams of the diphenylamine intermediate were combined with 45 ml of dioxane, 14 grams of sodium carbonate and 6 ml of dimethyl sulfate and the mixture was stirred at reflux for 24 hours. Then, 12 milliliters of dimethyl sulfate and 10 grams of sodium carbonate were added, and the mixture was stirred at reflux temperature for a further 2 hours. The mixture was then poured into water and stirred for 4 hours. The aqueous layer was removed by decantation and the residue was taken up in ethylene chloride and filtered. About 10 grams of crude N-methyl-2,4-dinitro-6-trifluoromethyldiphenylamine were obtained.

The methylene chloride solution obtained in B was brominated without purification by the addition of excess elemental bromine. The solution was stirred and then allowed to stand for 1 hour and washed with water and sodium bisulfite solution. The organic solution was then filtered and evaporated to dryness and the residue recrystallized from ethanol to give 11 grams of 2,4-dibromo-N-methyl-2 ', 4'-dinitro-6'-trifluoromethyldiphenylamine, m.p. 110 ° C.

, 5 62527

Theoretical Observed C 33.70% 22.95% H 1.62% 1.86% N 8.42% 8.52%

Example 4 2,4-Dibromo-6-chloro-N-methyl-2 ', 41-dinitro-61-trifluoromethyldiphenylamine 2.5 grams of the product of Example 3 were dissolved in 10 ml of methylene chloride and the solution was saturated with gaseous elemental chlorine. After standing for 2 hours, the solution was evaporated to dryness in vacuo and the residue was recrystallized from ethanol to give 2.1 g of product, m.p. 139-141 ° C.

Theoretical Observed C 31.52% 31.78% H 1.32% 1.35% N 7.88% 8.10%

Example 5 2,4,6-Tribromo-N-methyl-21,41-dinitro-6'-trifluoromethyldiphenylamine 2.5 grams of the product of Example 3 were dissolved in 25 ml of diethyl ether and 1.5 ml of concentrated sulfuric acid. The solution was stirred at room temperature while adding 0.7 grams of dibromoisocyanuric acid. After stirring for 30 minutes, 0.7 grams of dibromoisocyanuric acid and 1.5 milliliters of sulfuric acid were added again and the addition was repeated after stirring for 15 minutes. 5 minutes after the last addition, the reaction mixture was diluted with 50 ml of diethyl ether and filtered. The organic layer was washed three times with 10% sodium carbonate solution, dried over magnesium sulfate and evaporated to dryness. The residue was recrystallized from ethanol to give 2.4 grams of 2,4,6-tribromo-N-methyl-2 ', 41-dinitro-6'-trifluoromethyldiphenylamine, m.p. 150-151 ° C.

Theoretical Observed C 29.10% 29.02% H 1.22% 1.06% N 7.27% 7.29% 16 62527

Example 6 2,4,6-Trichloro-21,4 * -dinitro-N-propyl-6- * trifluoromethyldiphenylamine Prepared in the first step of Example 3, 5 grams of the diphenylamine intermediate was alkylated with propyl iodide in 80 ml of dimethylformamide in the presence of 20 grams of sodium carbonate. The reaction mixture was stirred at 110 ° C for 72 hours. The intermediate was recovered by cooling the reaction product with water, extracting with methylene chloride and evaporating the solvent in vacuo. The residue was taken up in acetic acid and the solution was saturated with chlorine and stirred at reflux for 4 hours. The product was purified by pouring the mixture into water, extracting with methylene chloride, washing the extract with sodium bicarbonate solution and then with water and finally chromatographing on a silica gel column with pentane: toluene (5: 1). The yield was 0.35 grams of 2,4,6-trichloro-21,41-dinitro-N-propyl-6'-trifluoromethyldiphenylamine, (oily liquid).

Theoretical Observed C 40.66% 40.66% H 2.35% 2.22% N 8.89% 8.71%

Cl 22.50% 22.45%