NO143025B - DIFENYLAMINE COMPOUNDS WITH RODENTICID EFFECT - Google Patents

Description

The present invention relates to new rodenticide-active diphenylamine compounds with small alkyl substituents on the amino nitrogen. One of the phenyl rings is substituted with dinitrotrifluoromethyl and the other is preferably substituted with halogen or pseudohalogen groups.

As is well known, attempts are being made to regulate the spread of rats and mice. Rats and mice are known carriers of many diseases, of which bubonic plague is the best known. The plague-carrying animals also pollute and infect the areas in which they live and destroy buildings and their contents by digging tunnels and building nests. The animals also eat large amounts of food and pollute what is not eaten. A colony of rats in a grain store can eat and destroy large quantities of grain.

Many types of rodenticides or rodenticides have been and are still in use. Metal poisons such as arsenic and thallium compounds are still used, but obviously pose a danger to people and farm animals. Organic chemical poisons, of which warfarin is the best known, are used very extensively and have been of great benefit. However, the rodents have developed resistance to these poisons.

The rodenticides are usually provided for rats and mice in the form of mixtures with food for the animals. The concentration of rodenticide in the mixture is adjusted so that the rodents eat a quantity of the rodenticide that is either acutely or chronically fatal. It is an advantage not to make the mixture so concentrated that the rodent dies immediately or soon after eating the poison mixture. Rodents and especially rats are intelligent enough to understand the connection between feeding and death if this time interval is too short. Thus, the best practice is to adjust the concentration of the rodenticide so that the rodents will be poisoned during a series of

bushings or iiiat intakes.

In special cases, the rodent poisons are mixed in the drinking water or produced as "track powders" which are placed in the streets used by the rodents. After the animals have passed through the loose poison powder, they lick their feet clean and thereby ingest the rodent poison.

Tertiary diphenylamines according to the present invention have not previously been known. However, secondary diphenylamines are known as fungicides and insecticides. One must be aware that the prior art in the field will not enable a reader to prepare the present compounds, which will be explained in more detail later. Diphenylamines have so far not been known as rodenticides.

According to the present invention, diphenylamine compounds with rodenticidal action have been provided, and these compounds are characterized by having the formula:

where R is methyl, ethyl or propyl; R"*" is fluorine, chlorine, bromine,

2 3 4 or cyan; R is hydrogen, fluorine, chlorine or bromine; R and R

is each hydrogen, fluorine, chlorine or methyl; and R<5> is hydrogen, fluorine, chlorine or bromine.

Two particularly preferred and effective compounds are 2,4,6,-trichloro-N-methyl-2',4<1->dinitro-6'-trifluoromethyldiphenylamine and 2,4,6-tribromo-N-methyl-2', 4'-dinitro-6'-trifluoromethyldiphenylamine.

In the following, all the relevant compounds will be referred to as diphenylamines for the sake of simplicity, although certain compounds should be named differently according to the nomenclature rules.

The new compounds of formula I cannot be prepared

by simple direct methods and are therefore produced using multi-step methods. One would assume that such compounds could be synthesized by direct reaction of a substituted N-alkylaniline with 2-chloro-3,5-dinitrobenzotrifluoride. Alternatively, one could assume that

it was possible to prepare the corresponding N-H-diphenylamine and alkylate the nitrogen with alkyl iodide or a similar alkylating agent. However, except for such compounds which have either the 2- or 6-position unsubstituted, none of these methods have been shown to work. For the overwhelming majority of the connections in question, one of the specified designs must be used.

In the above formula, R 6 , R 7 , R 8 , R 9 and R<10> denote

12 3 4 "5

the same groups as R , R , R-^, R and R respectively, or they denote hydrogen. The process can be carried out from aniline bearing some or all of the desired R 1 to R 5 substituents in the product, or with an unsubstituted aniline, depending on the substituents in the final product. The halogen and nitro substituents on the aniline ring can be introduced at the end of the process. Thus, only any cyan, methyl or trifluoromethyl substituents on the aniline ring need be present before the two rings are coupled. The final nitration in the above process will not only introduce the 2-nitro group into the benzotrifluoride ring but may possibly also introduce a nitro group on the aniline ring when such a group is desired.

The term "hal" denotes that the benzotrifluoride ring can be substituted with a suitable halogen atom. Chlorine and fluorine are preferred, and chlorine is usually most appropriate.

The alkylation step in embodiment B above is sterically hindered by ortho substituents on the aniline ring. Consequently, the groups have

11 12 13 lk 15

R , R , R , R and R respectively the same meanings as

12 3 4 5 12

R, R, R, R and R except that at least one of the groups R

15

and R represents hydrogen. It is an advantage to use a starting aniline which has cyan, nitro, methyl or trifluoromethyl substituents on the final product but lacks the halogen substituents, and to introduce the halogen atoms during the final halogenation reactions.

The individual steps in the above procedure are not unusual in organic chemistry and are performed as a skilled organic comedian would assume. The coupling reactions which unite the aniline and benzotrifluoride rings are carried out most easily at relatively low temperatures in the range -20 to 10° in dimethylformamide and in the presence of sodium hydride. Other media can also be used. The reaction can be carried out e.g. in alkanols such as ethanol and then the reaction temperatures can be higher in the range 10 to 25°. Other solvents such as ketones of the type acetone and methyl ethyl ketone, and ethers including diethyl ether and tetrahydrofuran are also satisfactory solvents.

In general, a strong base is required as an acid neutralizer. Sodium hydride as mentioned above is usually the most favorable base but other bases such as e.g. inorganic bases of the type sodium hydroxide and sodium carbonate and organic tertiary amines such as pyridine and triethylamine and a simple excess of aniline starting material can be used.

Nitration of the benzotrifluoride ring has been carried out simply with concentrated nitric acid in acetic acid solution at room temperature. The reaction is not an unusual nitration and can be carried out with other common nitrating agents such as e.g. a mixture of concentrated nitric acid and sulfuric acid at an elevated temperature. No solvents are used for the nitration reactions other than the acids themselves.

N-alkylation of the diphenylamines is carried out with reagents such as dialkyl sulfate or an alkyl halide in the presence of base. When dialkyl sulfate is used, the preferred reaction solvent is acetone. Other solvents such as tetrahydrofuran, dioxane or diethyl ether can also be used in the same way as alkanes such as hexane and octane. Dimethylformamide is the best solvent for alkylations with alkyl halides, although acetone is also excellent. Other solvents as above can be used.

Preferred bases for use during the alkylation reactions are those which have a dehydrating effect, particularly sodium carbonate. However, other inorganic bases such as alkali metal carbonates, bicarbonates or hydroxides can be used, as can alkali metal hydrides.

The amount of base used depends on the reaction temperature. At a higher reaction temperature during the alkylation step, larger amounts of base are required. When the reaction temperature is approximately room temperature, a small excess of base is required, for example 2 mol of base per moles of diphenylamine. When using very high reaction temperatures such as 100°, there should be a large excess of base, in the range of 10 times theoretical.

It will be appreciated that it is important to avoid contamination of the alkylation mixture with water.

In general, alkylations with dialkyl sulfates are best carried out at approx. 80 o, although temperatures between approx. room temperature and return temperature can be used. Conditions close to room temperature, for example 20 to 35°C, are preferred for alkylation with alkyl halide, but elevated temperatures up to 150°C can be used.

Halogenation of the aniline ring is relatively simple. Chlorination is usually best carried out with elemental chlorine in acetic acid or in methylene chloride or a similar halogenated solvent. Brominations are also easily carried out with elemental bromine in an acidic medium, but other typical brominating agents such as N-bromo-succinimide and N-dibromoisocyanuric acid are also quite effective.

Iodination is best done with iodine monochloride as reagent.

When a compound without a ^-substituent is to be prepared, it will often be necessary to block the ^-position before halogenation. It is most advantageous to use a sulphonic acid as a protecting group because it can be easily introduced and easily removed.

The starting materials substituted anilines and phenyl halides are easily prepared in ways described in the literature.

Trifluoromethyl-substituted anilines are best prepared

as chemists will realize by first forming a carboxylic acid-substituted aniline with the acid groups at the positions where trifluoromethyl groups are desired. The acid groups are fluorinated with sulfur tetrafluoride.

The fluorinated aniline compounds are often prepared by first making a diazonium fluoroborate salt at the position where the fluorine atom is desired. The salt is then decomposed in heat to bind a fluorine atom in the desired position. Alternatively, it has recently been found that fluorine atoms can be introduced into phenyl rings with elemental fluorine at very low temperatures.

The following examples showing the preparation of typical compounds of formula I are given to ensure that organic chemists can easily prepare any desired compound. The example products were identified by nmr analysis, elemental micro-analysis, thin layer chromatography and in some cases mass spectrophotometry and IR analysis. All percentages and proportions are weight percentages and parts by weight.

Example 1

2 , h , 6- trichloro- N~ ethyl- 2'. k 1~ dinitro~ 6' trifluoromethyldiphenylamine. 3.5 g of sodium hydride prepared as an oil dispersion was washed with petroleum ether and filled into a flask with 20 ml of anhydrous dimethylformamide. The suspension was cooled to approx. -10° and the flask protected with nitrogen. A solution of 8 g of N-ethyl-2,k,6-trichloroaniline in 20 ml of anhydrous dimethylformamide was added over 5 minutes, and the mixture stirred for 1 hour while keeping the temperature constant. A solution of 8.1 g of 2-chloro-5-nitrobenzotrifluoride in 20 ml of dimethylformamide was added over 5 minutes and the entire mixture stirred for 6 hours, while the temperature was allowed to rise to room temperature. The mixture was then poured over ice and filled to a total volume of approx. 1 liter of water. The precipitate formed was filtered off, washed with pentane and gave 7.7 S 2,4,6-trichloro-N-ethyl-4<1>,-nitro-2'-trifluoromethyldiphenylamine. 2 g of the above intermediate was heated with 15 ml of acetic acid until it dissolved. The solution was cooled to room temperature and 5 ml of concentrated nitric acid added dropwise over 10 minutes. The reaction mixture was stirred at room temperature. After two days, the reaction mixture was quenched with a large amount of water and the precipitate was filtered off and purified by column chromatography on silica gel with toluene as eluent. Evaporation of the product-containing fractions gave 0.2 g of pure 2,k,6-trichloro-N-ethyl-2',k1-dinitro-6'-trifluoromethyldiphenylamine as an oil, NMR peaks at 1.23, ^»°1 » 7.38, 8.55 and 8.76 ppm. Example 2 2, 4 . 6-trichloro-N-methyl 1-2'. 4'-dinitro-6'-trifluoromethyldiphenylamine. 10 g of 2,4,o-trichloro-N-methylaniline was reacted with 11 g of 2-chloro-5-nitrobenzotrifluoride according to the above procedure except that the temperature was room temperature and the reaction time approx. 2 hours. 5 g of 2,4,6-trichloro-N-methyl-4<1->nitro-2'-trifluoromethyldiphenylamine were worked up and nitrated according to the procedure in example 1. The process gave 2 g of pure substance, m.p. 125-126°C

Example 3

2, 4- dibromo- N- methyl~ 21, 4'- dinitro- 6'- trifluoromethyldiphenylamine.

27 g of 2-chloro-3,5-dinitrobenzotrifluoride were added

20 g of aniline and 75 ml of ethanol. After brief stirring at room temperature, the reaction mixture was inoculated with a small sample of the desired intermediate and a precipitate immediately formed. The precipitate was filtered off and identified as 28.5 g of 2,3-dinitro-6-trifluoromethyldiphenylamine.

The intermediate was N-methylated in two different ways, both of which will be explained.

A. 3.3g of intermediate products diphenylamine were taken up in

15 ml of dimethylformamide and 1.3 g of sodium hydride added. The mixture was stirred at room temperature and 1.5 ml of methyl iodide added while heat was generated. After 1.5 hours, a further 2 ml of methyl iodide were added and the mixture heated slightly. After a further 2 hours, the reaction mixture was added to a large amount of cold water and the aqueous layer decanted off. The remaining oil was dissolved in diethyl ether and stirred with magnesium sulfate and activated carbon. After filtering off solids, the solution was evaporated to dryness to give 2.4 g of dark red oil which solidified on cooling. The solid was heated with petroleum ether, cooled and filtered to give 2.4 g of N-methyl-2, i|~dinitro-6-trifluoromethyldiphenylamine, m.p. 84-86°.

B. 11 g of the intermediate diphenylamine was mixed with 45 ml of dioxane, 14 g of sodium carbonate and 6 ml of dimethyl sulfate and stirred at reflux temperature for 2k hours. 12 ml of additional dimethyl sulfate and 10 g of sodium carbonate were then added and the mixture stirred at reflux temperature for 2 hours. It was poured into water and stirred for k hours. The aqueous layer was decanted and the residue taken up in methylene chloride and filtered. The solute was identified as pa. 10 g crude N-methyl-2,4-dinitro-6-trifluoromethyldiphenylamine.

The methylene chloride solution prepared under Section B was brominated without further purification by addition of an excess of elemental bromine. The solution was stirred and left for 1 hour and then washed with water and sodium bisulphite solution. The organic solution was filtered and evaporated to dryness and the residue recrystallized from ethanol to give 11 g of 2,4-dibromo-N-methyl-21,k1-dinitro-6'-trifluoromethyldiphenylamine, m.p. 110°.

Example k 2,4-dibromo-6-chloro-N-methyl-2',k'-dinitro-61-trifluoromethyldiphenylamine, 2.5 g of the product from example 3 was dissolved in 10 ml of methylene chloride and the solution saturated with elementary gaseous chlorine After standing for 2 hours, the solution was evaporated to dryness in vacuo and the residue recrystallized from ethanol to give 2.1 g of product, m.p. 139-141°. Example 5 2 . k. 6-, fcribromo-N-methyl-2', k'-dinitro-6'-trifluoromethyldiphenylamine.

2.5 g of product from example 3 was dissolved in 25 ml of diethyl ether and 1.5 ml of concentrated sulfuric acid. The solution was stirred at room temperature while 0.7 g of dibromoisocyanuric acid was added. After stirring for 30 minutes, 0.7 g of dibromoisocyanuric acid and 15 ml of sulfuric acid were added again, and the addition was repeated after a further 15 minutes of stirring. 5 minutes after the last addition, the reaction mixture was diluted with 50 ml

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 evaporation residue was recrystallized from ethanol to give 2.4 g of 2,4,6-tribromo-N-methyl-2',4'-dinitro-6'-trifluoromethyldiphenylamine, m.p. 150-151°.

Example 6 2.4.6-trichloro-2',4'-dinitro-N-propyl-6'-trifluoromethyldiphenylamine. 5 g of diphenylamine intermediate prepared during the first step of Example 3" was alkylated with propyl iodide in 80 ml of dimethylformamide in the presence of 20 g of sodium carbonate. The reaction mixture was stirred at 110° for 72 hours. The intermediate was recovered by quenching the reaction with water, extracting the product with methylene chloride and evaporating the solvent in vacuo. The evaporation residue was dissolved in acetic acid and the solution saturated with chlorine, and stirred under reflux for 4 hours. The product was purified by precipitation in water, extraction with methylene chloride, washing the extract with sodium bicarbonate solution and water and finally chromatography on a silica gel column with pentane:toluene equal to 5 sl. Yield was 0.35 g of 2,4,6-trichloro-2',4'-dinitro-N-propyl-6'-trifluoromethyldiphenylamine, an oily liquid.

Example 7

2-chloro-4-cyano-N-ethyl-2',4'-dinitro-6'-trifluoromethyldiphenylamine

50 g of 4-aminobenzonitrile, 500 ml of n-butyl alcohol, 114 g of 2-chloro-3,5-dinitrobenzotrifluoride and 47 g of triethylamine were added to a 1 liter flask and the reaction mixture was stirred at reflux for 4 days. The mixture was then allowed to cool, and the volatiles were evaporated under vacuum. The crude product was purified by chromatography on a silica gel column with 9:1 toluene-ethyl acetate as eluent. The purified product was then recrystallized from ethanol which gave 19.8 g of 4-cyano-

2<1>,4'-dinitro-6-trifluoromethyldiphenylamine.

5 g of the above intermediate product was mixed with 12.5 g of sodium carbonate and 10 ml of ethyl iodide in 25 ml of methyl ethyl ketone,

and the mixture was stirred under reflux for 4 days. The mixture was then cooled and 250 ml of water was added. The reaction mixture was then extracted 3 times with dichloromethane, and the organic phases were combined, dried over sodium sulfate,

filtered and evaporated to dryness under vacuum. The crude product was purified by chromatography as described in the first step, and this gave 0.45 g of 4-cyano-N-ethyl-2',4<1->dinitro-6'-trifluoromethyldiphenylamine, m.p. 53-55°C.

About. 2 g of the crude product obtained above, before chromatography, was dissolved in 125 ml of acetic acid, and chlorine was bubbled through the solution at room temperature for half an hour. mix-

none was then evaporated under vacuum and heated to give a solid which was purified by chromatography as described in the first step above. The purified product constituted 0.82 g of 2-chloro-4-cyano-N-ethyl-2',4'-dinitro-6'-trifluoromethyldiphenylamine,

m.p. 135-136°C.

Example 8

2, 3, 4, 5, 6- pentachloro- N- methyl- 2', 4'- dinitro- 6'- trifluoromethyldiphenylamine

5 g of sodium hydride was mixed with 50 ml of dimethylformamide

in a 250 ml flask, and the suspension was cooled to -10°C. The flask was filled with nitrogen gas and a solution of 10 g of 2,3,4,5,6-pentachloro-N-methylaniline in 50 ml of dimethylformamide was added over 10 minutes. The temperature was maintained at -10°C and the mixture was stirred for 1 hour. A solution of 8.1 g of 2-chloro-5-nitrobenzotrifluoride in 50 ml of dimethylformamide was then added over 15 minutes, and the mixture was then allowed to

heated with stirring for 6 hours. The mixture was then poured over ice, and the volume adjusted to 1.8 liters of water. The mixture was then extracted with diethyl ether, and the organic phase was dried and evaporated to dryness under vacuum. The resulting oil was recrystallized from hexane to give 3.25 g of 2,3,4,5,6-pentachloro-N-methyl-4'-nitro-6<1->trifluoromethyldiphenyl-

amine, m.p. 153-154°C.

1.85 g of the intermediate obtained was suspended in

40 ml of trifluoroacetic acid and 0.37 g of ammonium nitrate in 12 ml of trifluoroacetic acid were added dropwise. The reaction mixture was stirred at 45-50°C for 2 hours, and the reaction was then quenched with 100 ml of water. The mixture was stirred for 16 hours, and the aqueous phase decanted off. Recrystallization of the product from ethanol gave 0.74 g of 2,3,4,5,6-pentachloro-N-methyl-2<1>,4'-dinitro-6'-trifluoromethyldiphenylamine, mp 159-161°C.

Example 9

2, 6- dichloro- 4- cyano- N- methyl- 2', 4'- dinitro- 6'- trifluoromethyldiphenylamine

3.9 g of 4-cyano-2<1>,4'-dinitro-6<1->trifluoromethyldiphenylamine, obtained as indicated in Example 7, was dissolved in 25 ml of acetone. To this solution, 10 g of sodium carbonate and 10 ml of dimethyl sulfate were added, and the mixture was stirred under reflux for 5 1/2 hours. 25 mL of water was then added and the reaction mixture was stirred at constant temperature for an additional 1 h

hour. After this, 100 ml of water was added, the mixture was stirred for 16 hours, and the solids were then separated by filtration and washed with water. The solids were recrystallized from ethanol to give 2.85 g of 4-cyano-N-methyl-2<1>,4'-dinitro-6'-trifluoromethyldiphenylamine.

2.1 g of the obtained intermediate was dissolved in 100 ml of acetic acid, and the mixture was stirred at reflux temperature while chlorine gas was bubbled through the mixture for 4 1/2 hours. The mixture was then allowed to cool and evaporated to dryness under vacuum. The solids thus obtained were recrystallized from ethanol and this gave 2.1 g of 2,6-dichloro-4-cyano-N-methyl-2',4'-dinitro-6'-trifluoromethyldiphenylamine, m.p. 192°C. Example 10

2, 4, 6- trichloro- 3- fluoro- N- methyl- 2', 4'- dinitro- 6'- trifluoromethyldiphenylamine

19.8 g of 3-fluoroaniline was combined with 24.1 g of 2-chloro-3,5-dinitrobenzotrifluoride in 100 ml of ethanol. The mixture was stirred under reflux overnight and then cooled. The solids thus formed were separated by filtration and

recrystallized from ethanol, and this gave 15.9 g of 3-fluoro-2',4'-dinitro-6'-trifluoromethyldiphenylamine, m.p. 147-148°C. 4 g of the intermediate thus obtained was combined with 25 ml of acetone, 10 g of sodium carbonate and 10 ml of dimethyl sulphate. The mixture was stirred under reflux for 4 hours, and 25 ml of water was then added. The mixture was stirred under reflux for an additional 1 hour, and an additional 100 mL of water was added.

The mixture was then stirred at ambient temperature overnight. The aqueous layer was then decanted, and the organic layer was purified by chromatography over silica gel, eluting with toluene. The purified product amounted to 2.4 g of 3-fluoro-N-methyl-2',4<1->dinitro-6<1->trifluoromethyldiphenylamine,

m.p. 108-109°C.

2.3 g of the thus obtained intermediate was dissolved in 100 ml of acetic acid, and chlorine was bubbled through the mixture while it was stirred at reflux temperature for 2 hours. The mixture was cooled and evaporated to dryness under vacuum, and the solids were purified by chromatography over silica gel using toluene as eluent. The product thus obtained amounted to 0.56 g of 2,4,6-trichloro-3-fluoro-N-methyl-2',4'-dinitro-6'-trifluoromethyldiphenylamine, m.p. 137-139°C.

Example 11

2, 4, 6- tribromo- N- ethyl- 2', 4'- dinitro- 6'- trifluoromethyldiphenylamine

25 g of aniline and 36.3 g of 2-chloro-3,5-dinitrobenzotrifluoride were combined in 200 ml of ethanol, and the mixture was stirred at reflux under nitrogen for 4 hours. The reaction mixture was then cooled and the resulting precipitate was separated by filtration to give 45 g of 2,4-dinitro-6-trifluoromethyldiphenylamine. 5 g of this intermediate was combined with 20 g of sodium carbonate and 11 ml of ethyl iodide in 150 ml of acetone, and the mixture was stirred under reflux for 72 hours. The mixture was then evaporated to dryness under vacuum and the crude product was purified by chromatography on a silica gel column using 1:10 ethyl acetate:toluene as eluent. The purified product amounted to 5.6 g of N-ethyl-2,4-dinitro-6-trifluoromethyldiphenylamine. 5.5 gave this intermediate product was dissolved in 100 ml of dichloromethane, and 10 ml of bromine was added. The mixture was stirred for 16 hours at room temperature, after which the solids thus obtained were separated by filtration and recrystallized from ethanol. The product was 5.4 g of 2,4-dibromo-N-ethyl-2<1>,4'-dinitro-6<1->trifluoromethyldiphenylamine, m.p. 131-132°C. 2 g of this intermediate was added to 50 ml of diethyl ether, and 25 ml of concentrated sulfuric acid was added. 4 g of N-bromosuccinimide was then added over 2 hours while maintaining the reaction mixture at ambient temperature, and this gave 67 g of 2,4,6-tribromo-N-ethyl-2<1>,4'-dinitro- 6'-trifluoromethyldiphenylamine, a glassy product.

Example 12

2, 4, 6- trichloro- 3, N- dimethyl- 2', 4'- dinitro- 6'- trifluoromethyldiphenylamine

25 g of 3-methylaniline was dissolved in 200 ml of n-butyl alcohol,

and 26 g of triethylamine and 63.2 g of 2-chloro-3,5-dinitrobenzotrifluoride were added. The mixture was stirred under reflux for 16 hours and then cooled. The precipitate obtained was separated by filtration and recrystallized from ethanol and this gave 73.5 g of 3-methyl-2',4'-dinitro-61-trifluoromethyldiphenylamine, m.p. 129-130.5°C.

20 g of this intermediate was dissolved in 130 ml of acetone, and 51.2 g of sodium carbonate and 51.2 g of dimethyl sulfate were added. The mixture was stirred under reflux for 24 hours, 200 ml of water

was added and the mixture was stirred with heating for an additional 1 hour. An additional 600 mL of water was added and the mixture was stirred at ambient temperature for 3 days. The solids were then separated by filtration and recrystallized from ethanol to give 12.7 g of 3,N-dimethyl-21,4'-dinitro-6'-tri-'fluoromethyldiphenylamine.

2 g of this intermediate was dissolved in 100 ml of acetic acid, and chlorine gas was bubbled through the mixture for 1 hour at ambient temperature, after which the mixture was stirred without additional gas for 1 1/2 hours. The mixture was then evaporated to dryness under vacuum and the residue recrystallized from ethanol to give 2.05 g of 2,4,6-trichloro-3,N-dimethyl-2<1>,4'-dinitro-6'- trifluoromethyldiphenylamine, m.p. 90-91°C. Example 13

4- cyano- N- ethyl- 2', 4'- dinitro- 6'- trifluoromethyldiphenylamine

This product was obtained as shown in Example 7 above-

for .

Example 14

2, 4, 6- tribromo- 3, N- dimethyl- 2', 4'- dinitro- 6'- trifluoromethyldiphenylamine

2 g of 3,N-dimethyl-2',4'-dinitro-6'-trifluoromethyldiphenylamine, obtained as indicated in Example 12, was dissolved in 15 ml of acetic acid and 15 ml of water. 5 ml of bromine was added and the mixture was stirred for 1 hour at ambient temperature, after which it was stirred under reflux for 4 hours. The mixture was then stirred at ambient temperature overnight and a large amount of water was added. The solids were separated by filtration and recrystallized from ethanol to give 2.21 g of 2,4,6-tribromo-3,N-dimethyl-2<1>,4'-dinitro-6'-trifluoromethyldiphenylamine, m.p. 117-118.5°C.

Example 15

2, 6- dichloro- 4- cyano- N- 2', 4'- dinitro- 6'- trifluoromethyldiphenylamine

4 g of 4-cyano-N-ethyl-2<1>,4'-dinitro-6'-trifluoromethyldiphenylamine, obtained as shown in example 7, was dissolved in 130

ml of acetic acid, and chlorine gas was bubbled through the mixture under reflux for 3 hours. The mixture was then allowed to stand at ambient temperature overnight, and was then evaporated to dryness under vacuum. The residue was purified by chromatography over a silica gel column with toluene:ethyl acetate (9:1) as eluent. The purified product amounted to 0.99 g of 2,6-dichloro-4-cyano-N-ethyl-2',4'-dinitro-6-trifluoromethyldiphenylamine, m.p. 118-120°C.

Example 16

2,4-difluoro-N-methyl-2','4'-dinitro-6 1-trifluoromethyldienylamine

10 g of 2,4-difluoroaniline and 10.5 g of 2-chloro-3,5-dinitrobenzotrifluoride were dissolved in 100 ml of methanol, and the mixture was stirred under reflux for 16 hours. It was then cooled and filtered and the solids recrystallized from ethanol to give 4.92 g of 2,4-difluoro-2<1>,4'-dinitro-6'-trifluoromethyldiphenylamine, m.p. 89.5-90°C. 2.6 g of this intermediate was combined with 18 ml of acetone, 6.8 g of sodium carbonate and 6.8 ml of dimethyl sulfate. The mixture was stirred under reflux for 4 hours, and 50 ml of water was then added. The mixture was stirred under reflux for an additional 1 hour, and an additional 100 mL of water was added. The mixture was then stirred at ambient temperature overnight. The aqueous layer was then decanted, and the organic layer purified by chromatography over silica gel using toluene as eluent. The purified product amounted to 0.82 g of 2,4-difluoro-N-methyl-2<1>,4'-dinitro-6<1->trifluoromethyldiphenylamine, m.p. 108-109°C. Example 17 2,4-dibromo-6-chloro-N-ethyl-2',4'-dinitro-6'-trifluoromethyldiphenylamine 2 g 2,4-dibromo-N-ethyl-2<1>,4'-dinitro- 6<1->trifluoromethyl-diphenylamine, prepared as indicated in Example 11, was dissolved in 100 ml of acetic acid, and chlorine gas was bubbled through the mixture while heating and stirring for 2 hours under reflux. The reaction mixture was then chromatographed over silica gel with toluene as eluent, and the product fractions were combined and evaporated to dryness to give 0.5 g of 2,4-dibromo-6-chloro-N-ethyl-2',4'-dinitro -6'-trifluoromethyldiphenylamine, m.p. 49-51°C.

Example 18

4- bromo- N- methyl- 2', 4'- dinitro- 6'- trifluoromethyldiphenylamine

34.1 g of N-methyl-2,4-dinitro-6-trifluoromethyldiphenylamine, prepared as indicated in Example 11, was dissolved in 150 ml of acetic acid, and 35.2 g of bromine in 50 ml of acetic acid was added dropwise. The reaction mixture was then filtered to give 40 g

of substantially pure 4-bromo-N-methyl-2',4<1->dinitro-6'-trifluoromethyldiphenylamine, m.p. 167-168°C.

Example 19

4- bromo- N- ethyl- 2', 4'- dinitro- 6'- trifluoromethyldiphenylamine

15.7 g of 4-bromoaniline was combined with 150 ml of n-butyl alcohol and 12.3 g of 2-chloro-3,5-dinitrobenzotrifluoride. The mixture was stirred at reflux for 16 hours, cooled and evaporated to dryness under vacuum. The residue was washed with hot toluene and filtered. The filtrate was evaporated to dryness under vacuum and the residue was recrystallized from ethanol to give 17 g of 4-bromo-2<1>,4'-dinitro-6'-trifluoromethyldiphenylamine.

2.6 g of this intermediate was dissolved in 13 ml of methyl ethyl ketone, and 6.5 g of sodium carbonate and 4 ml of ethyl iodide were added. The mixture was then stirred under reflux for 4 days, and was then added to 200 ml of water, and the aqueous mixture was extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness under vacuum. The residue was purified by chromatography over silica gel with toluene as eluent. The product-containing fractions were combined and evaporated to dryness, yielding 0.24 g of 4-bromo-N-ethyl 1.-2 1 , 4'-dinitro-6'-trifluoromethyldiphenylamine, which showed the following elemental analysis:

Example 20 2,6-dichloro-N-methyl-2',4'-dinitro-4,6'-bis(trifluoromethyl)diphenylamine 10 g of 4-trifluoromethylaniline and 8.4 g of 2-chloro-3,5-di- nitrobenzotrifluoride was added to 100 ml of ethanol, and the mixture was refluxed for 3 days. The mixture was then cooled and evaporated to dryness. The residue was dissolved in toluene and filtered, and the filtrate was evaporated to dryness under vacuum. The residue was recrystallized from ethanol, and this gave 4.4 g of 2,4-dinitro-4<1>,6-bis(trifluoromethyl)diphenylamine.

5.3 g of this intermediate was dissolved in acetone,

and 13 g of sodium carbonate and 13 ml of dimethyl sulfate were added. The mixture was stirred under reflux for 3 hours, 50 ml of water

was added, the mixture was stirred under heating for 1 hour,

and approx. 200 ml of water was added. The mixture was stirred overnight at ambient temperature and then filtered. The solids were recrystallized from ethanol to give 3.9 g of N-methyl-2,4-dinitro-4<1>,6-bis(trifluoromethyl)disphenylamine. 2 g of this intermediate was dissolved in 150 ml of acetic acid, and chlorine was bubbled through the mixture with stirring and reflux for 3 hours. The mixture was then cooled at ambient temperature for 16 hours, and was evaporated to dryness under vacuum. The residue was recrystallized from ethanol, and this gave 1.6 g of 2,6-dichloro-N-methyl-2',4<1->dinitro-4,6<1->bis(trifluoromethyl)diphenylamine, m.p. 98.5-99°C.

The effect of the rodenticides of the invention has been investigated by giving compounds of formula I to rodents in laboratory tests. The following reports from typical trials illustrate the powerful action of the rodenticides of Formula I.

The first series of experiments to be described was carried out by mixing the compounds in question with animal feed of the grain type and feeding the treated feed to male albino rats of the Sprague-Dawley strain. The feed used had the following composition:

Compounds of formula I were mixed with parts of the above for in concentrations described below, Control rats were given the same for each experiment without poison.

A treatment group of k or 5 rats was given the option of unlimited food and unlimited access to water. Rats were weighed individually at death or at the end of each experiment spanning 10 days if the rats survived,

The tables below reproduce the concentration of the compounds in the feed in ppm for (ppm), the number of days after the rats started eating the treated feed calculated from the day of death and the weight change, positive or negative, in each rat after the 10-day experiment .

The second series of experiments to be described was carried out in the same way, except that the experimental animals were wild house mice (Mus musculus) and a different species was used. In these trials, the animals' weight change was not recorded.

The good results obtained with the above compounds will be evident from the figures. It can be seen that the compounds are effective at very low concentrations. Furthermore, it is very important that the compounds kill the rats with certainty, but not immediately. As previously mentioned, a good rat poison should make it possible for many or all rats or mice in a colony to eat the poison before the animals begin to die. It is clear that the compounds of formula I when used in the correct concentrations work in the desired safe but delayed manner.

The present invention can thus be used to reduce the spread of rats or mice whereby an effective amount of rodenticide containing an effective rodenticidal concentration of the above compounds is laid out in a place visited by the rats or mice. The relevant rat poisons usually consist of inert carriers and effective poison concentrations of the available diphenylamine compounds.

By effectively regulating the spread of rats and mice

can e.g. The following plague-carrying animals are combated with the correct use of the present invention:

house mouse (Mus musculus)

Norway rat (Rattus norvegicus)

black rat (R. rattus rattus)

roof rat (R. r. frugivorus)

white-footed mouse (Peromyscus leucopus)

pack rat (Neotoma cinerea)

barley mouse (Microtus pennsylvanicus)

Professionals in the field will understand that the present invention can also be used to combat rodents other than rats and mice. Since such other rodents are often desirable, it is considered that combating them does not fall within the scope of ordinary use of the invention. However, the invention can be used for such purposes if combating other rodents in special cases is desirable.

Rats and mice are effectively combated by both acute and chronic poisoning. Correct adaptation of the concentration of the poison in the preparation used will, as is understood, make it possible to reduce the spread of rats or mice either by immediately poisoning the animals, or by chronically poisoning them over several pre-intakes.

However, as explained, the delayed lethal effect of the compounds in question is an important factor for them to be used successfully as rodenticides. The maximum effect of the invention is achieved by laying out in the areas where the rats or

the mice go, a poison preparation containing a concen-

tion of the toxic compound which is not acutely fatal after a single meal, but which contributes to a lethal effect during at least two meals and preferably a larger number of meals. Consequently, it is also preferred to provide a sufficiently large amount of the rodent poison so that all members of the tribe have the opportunity to eat the preparation two or more times.

A rat eats approx. 5 to 50 g of food per day, a mouse consumes approx. 1 to 5 g per day depending in all cases on the age, size and health of the animals. A plague control specialist can estimate the number of animals in a colony and can lay out the correct amounts of poison treated for the animals' areas.

Although the invention is described on the basis of poisons, it can also be used by adding the rodent poison in the form of trace powders or drinking water mixtures. It will be understood that such preparations are used in the same way as poisons, in that the concentrations are adapted to the intake of the poison. The concentration of compounds in the preferred drinking water or pre-powder preparation is adjusted so that it becomes an effective rodenticide with two or more water intakes or foot cleanings respectively. The term "lining" or the like hereby includes both water intake and such foot-cleaning licking as mentioned at the beginning.

The rodent poisons are based on inert carriers consisting of food for the animals, drinking water and finely powdered solids. Preparations which are based on various animal foods, and which are preferred inert carriers, may consist of any edible compound since rats and mice are omnivores. For example, such preparations may consist of grains, by-products from meat production or fatty substances. Grain products that can be used include products such as oat flour, ground grain or maize, soybean products, wheat and wheat by-products, waste rice and the like. All types of grain can be the basis of such premixes. Sweeteners and flavor enhancers can also be added to increase food attraction.

Fatty rat poisons are most often made on the basis of inert ingredients such as peanut butter, other nut butters, milk substances, animal fat, vegetable oils and the like. Rat poison preparations are also sometimes based on animal products such as bone meal and various meat products including animal by-products.

Trace powders are composed of the rodent poison dispersed

in powdered solids. Practically every powder can be used, i.a. talc, chalk, ground clay, flour, nut shell flour and the like, i.a. powdered rock.

Rodent poison preparations in drinking water consist of suspensions or dispersions of these substances. The compounds are relatively water insoluble and it is therefore usually necessary to grind the compounds into fine particle form and suspend them in water. Suspension agents are used with advantage and are chosen from thickeners such as carboxymethyl cellulose, polyvinylpyrrolidone, gelatin or alginates as well as surfactants such as lecithin, alkylphenol polyethylene oxide adducts, alkyl sulphates, naphthalene sulphonates, alkylbenzene sulphonates and polyoxyethylene sorbitan esters. Sometimes you can also use silicone anti-foaming agents, glycols, sorbitol and sugars as suspension mid-1.

The time for laying out rat poison in places where

a colony of rats or mice is not essential.

There are no seasons when a rodent colony is particularly sensitive or particularly immune to rodent poisons. It is usually an advantage to first lay out a pre-bait in the colony consisting of untreated, i.e. non-toxic pre-mix. Preferably, as mentioned, one should give a poisonous preparation in sufficient quantity to last long enough for the colony's residents to eat at least twice.

The concentration of the compounds in the preparations depends

of the chosen compound, since they have different effects,

on how quickly you want the population to be reduced and other factors. If e.g. If the rat colony can be isolated so that its only food or water source becomes poisonous, the concentration should obviously be lower than if there are many different food sources. In general, the rodenticide should contain concentrations of 5 to 2000 ppm. Concentrations of 10 to 500 ppm are preferably used, although it will be understood that the amount of both

above and below this will be effective and even desirable in unusual cases.

It will also be clear that additives and attractants of various kinds can be advantageously added to the preparations. Such lures•are e.g. odorants, sex hormones and flavorings of the type that are usually used in rat poisons and they can be used with advantage to break through the rats' suspicions.

Claims (3)

1. Diphenylamine compounds with rodenticidal action, characterized in that they have the formula: where R is methyl, ethyl or propyl; R is fluorine, chlorine, bromine 2 3 4 or cyan; R is hydrogen, fluorine, chlorine or bromine; R and R are each hydrogen, fluoro, chloro or methyl; and R 1 is hydrogen, fluorine, chlorine or bromine. 2. Diphenylamine compound according to claim 1, characterized in that it consists of 2,4,6-trichloro-N-methyl-2<1>,4'-dinitro-6<1->trifluoromethyldiphenylamine. 3. Diphenylamine compound according to claim 1, characterized in that it consists of 2,4,6-tribromo-N-methyl-2',4<1->dinitro-6<1->trifluoromethyldiphenylamine.