IE43614B1

IE43614B1 - Diphenylamines

Info

Publication number: IE43614B1
Application number: IE1766/76A
Authority: IE
Original assignee: Lilly Co Eli
Priority date: 1976-07-21
Filing date: 1976-08-10
Publication date: 1981-04-08
Also published as: AU1725076A; EG12450A; BG28845A3; NL7610048A; SU628811A3; GB1548702A; PL192659A1; GR61183B; YU214876A; CH605615A5; DE2640462A1; IL50259A0; FI762497A; CA1097372A; IL50259A; NO143023C; PT65677B; ATA664176A; FR2359116A1; IE43614L

Abstract

The present invention relates to novel diphenylamines having small alkyl substituents on the amino nitrogen, which are useful as intermediates for the preparation of rodenticidal diphenylamines. One phenyl ring has 2,4dinitro-6-trifluoromethyl substitution, and the other is substituted with no more than one methyl or trifluoromethyl group. The diphenylamines have the following structure: I X-4869

Description

The present invention relates to novel diphenylamines having small alkyl substituents^ on the amino nitrogen, which are useful as intermediates for the preparation of rodenticidal diphenylamines. One phenyl ring has 2,4dinitro-6-trifluoromethyl substitution, and the other is substituted with no more than one methyl or trifluoromethyl group.

This invention belongs to the rodenticidal and organic chemical arts and provides new intermediates for the preparation of rodenticides.

Rodenticides have long been the subject of research. Rats and mice carry many diseases, and create havoc when they share the habitations of mankind. They soil and contaminate buildings, and destroy buildings and their contents by their tunneling and nest building. The animals, when present in numbers, consume or contaminate great amounts of food.

Many kinds of rodenticides have been discovered and many are still in use. Probably the best all round existing rodenticide is the organic chemical compound. Warfarin ( Warfarin is a Trade Mark ) . Rodents, however, are developing resistance to existing rodenticides. The metallic poisons, such as arsenic and thallium compounds, are used to a degree but are obviously quite dangerous to people and to useful animals.

Tertiary diphenylamines such as those of this invention have not previously been known. Secondary diphenylamines, however, have previously been known to be fungicides and insecticides. -243614 The present invention provides novel diphenylamine compounds of the formula wherein R represents methyl, ethyl or propyl; 2 R and R independently represent hydrogen, methyl or trifIuoromethyl; R3 represents hydrogen or methyl; 3 provided that no more than one of R , R and R represents a group other than hydrogen.

The present invention also provides a process for preparing novel diphenylamine compounds of formula I wherein the symbols have the meanings stated above, which comprises reacting a 2-halo-3,5-dinitrobenzotrifluoride compound of the formula (II) wherein X is halo, with an aniline compound of the formula NH ( III ) ε -3wherein r\ R2, and R3 are as defined above; followed by N-alkylating the compound so obtained.

All of the compounds described in this document will be named as diphenylamines for the sake of consistency even though the rules of nomenclature might call for some compounds to be named otherwise.

All percentages and parts described hereafter refer to percentages and parts by weight, and all temperatures are on the Celsius scale.

The following exemplary compounds are mentioned only to ensure that the reader fully understands the invention.

N,2-dimethyl-2', 4'-dinitro-6'-trifluoromethy1diphenylamine N-ethyl-3-methyl-2',4'-dinitro-61-trifluoromethyl diphenylamine 4-methyl-21,4'-dinitro-N-propyl-61-trifluoromethy Idiphenylamine 2- methyl-21,4'-dinitro-N-propyl-6'-trifluoro0 methyldiphenylamine 2,4-dinitro-N-propyl-3',6-bis(trifluoromethyl)diphenylamine N-ethyl-2,4-dinitro-2',6-bis(trifluoromethyl)diphenylamine 3- methy1-2',4'-dinitro-N-propyl-6'-trifluorome thy Idiphenylamine N-ethyl-4-methyl-2',4'-dinitro-6'-trifluoromethyl diphenylamine The preferred compounds of this invention are Nmethy1-2,4-dinitro-6-trifluoromethyIdiphenylamine, N-443614 ethyl-2,4-dinitro-6-trifluoromethyldiphenylamine, 2,4dinitro-N-propyl-6-trifluoromethyldiphenylamine, N-methyl2,4-dinitro-3',6-bis(trifluoromethyi)diphenylamine, and Nmethy1-2,4-dinitro-21,6-bis(trifluoromethyi)diphenylamine.

The compounds of formula I are made by the following process.

OaN—·; IjlOa / OF.3 ,r~ OaN—ρ·—y*— R (IV ) alkylation _\ / •--A |< · zZ \ /Z \ ir-.N—* >—N—< R'’ \ / Xn the above formula, the term halo refers to any of the four common halogen atoms, of which chlorine and fluorine are preferred and chlorine is usually the most convenient. Compounds of formula IV above are disclosed in Patent Specification No. 40692.

The individual steps of the above process are not extraordinary in organic chemistry, and are conducted as a skilled organic chemist would expect. The coupling reactions which join the aniline and benzotrifluoride rings are most readily carried out at relatively low temperatures -543614 in the range of -20° to 10° in dimethylformamide in the presence of sodium hydride. Other media are likewise useful. The reactions may be carried out, for example, in alkanols such as ethanol, in which solvents the reaction temperature may be higher, in the range of 10° to 25°.

Other solvents, including ketones such as acetone and methyl ethyl ketone and ethers including diethyl ether and tetrahydrofuran, are satisfactory reaction solvents.

In general, a strong base is needed to serve as .0 acid scavenger. Sodium hydride, as mentioned above, is generally the most useful base, but other bases including inorganic bases such as sodium hydroxide and sodium carbonate, and organic tertiary amines such as pyridine and triethylamine, as well as a simple excess of the aniline ' starting compound, may be used.

N-Alkylation of the diphenylaroines is performed with reagents such as a dialkyl sulfate or an alkyl halide in the presence of a base. When a dialkyl sulfate is used, the preferred reaction solvent is acetone. Other solvents, such as tetrahydrofuran, dioxane and diethyl ether, are also useful, as are alkanes such as hexane and octane. Dimethylformamide is the preferred solvent for alkylations with alkyl halides, although acetone is also excellent. Other solvents as described above may be used.

The preferred bases for use in the alkylation reactions are those which have a dehydrating effect, particularly sodium carbonate. However, other inorganic bases, such as the alkali metal carbonates, bicarbonates and hydroxides, can be used, as can the alkali metal hydrides. -64 3 614 The amount of base used depends upon the reaction temperature. The higher the reaction temperature in the alkylation step, the greater excess of base is needed. When the reaction temperature is approximately ambient, a small excess of base should be used, such as 2 moles of base per mole of diphenylamine. When very high reaction temperatures such as 100° are used, a large excess of base should be used, in the range of 10-fold.

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

In general, alkylations with diaikyl sulfates are best performed at about 80°, although temperatures from approximately room temperature to the reflux temperature may be used. Conditions close to room temperature, such as from 20° to 35°, are preferred for alkyl halide alkylations, but elevated temperatures up even to as high as 150° may be used.

The starting substituted anilines and phenyl halides are readily obtained by methods which are commonly known in the chemical literature.

The trifluoromethyl-substituted anilines are best prepared, as chemists will recognize, by first obtaining a carboxylic acid-substituted aniline having the acid groups at the locations of the desired trifluoromethyls. The acid group is fluorinated with sulfur tetrafluoride.

The following Examples, showing the preparation of typical compounds of formula I, are presented to ensure that organic chemists can easily obtain any desired compound. -7The products of the Examples were identified by nuclear magnetic resonance analysis, elemental microanalysis, thin-layer chromatography, and in some instances, by mass spectrophotometry and infrared analysis.

Example 1_ N-methy1-2,4-dinitro-6-trifluoromethyldiphenylamine A 27 g. portion of ,2-chloro-3,5-dinitrobenzotrifluoride was added to 20 g. of aniline and 75 ml. of ethanol. After brief stirring at room temperature, the reaction ) mixture was seeded with a small sample of the desired intermediate product, and a precipitate formed immediately.

The precipitate was separated by filtration and identified as 28.5 g. of 2,4-dinitro-6-trifluoromethyldiphenylamine.

The intermediate product was N-methylated in two different ways, both of which will be shown for the sake of clarity.

A. A 3.3 g. portion of the intermediate diphenylamine was taken up in 15 ml. of dimethylformamide, and 1.3 g. of sodium hydride was added. The mixture was stirred at room temperature, and 1.5 ml. of methyl iodide was added with the evolution of heat. After 1-1/2 hours, another 2 ml. of methyl iodide was added, and the mixture was warmed slightly. After 2 hours more, the reaction mixture was added to a large amount of cold water, and the aqueous layer was decanted. The remaining oil was taken up in diethyl ether and stirred with magnesium sulfate and charcoal.

After the solids were filtered away, the solution was evaporated to dryness to produce 2.4 g. of a dark red oil, which solidified upon cooling. The solid was heated with -8petroleum ether, cooled and filtered to produce 2.4 g. of N~methyl-2,4-dinitro-6-trifluoromethyldiphenylamine, m.p. 84-86°.

Theoretical Found c 49.28% 49.24% H 2.95 3.05 N 12.31 12.31 11 g. of the intermediate diphenylamine were combined with 45 ml. of dioxane, 14 g. of sodium car10 bonate and 6 ml. of dimethyl sulfate and stirred at reflux temperature for 24 hours. Twelve ml. of additional dimethyl sulfate and 10 g. of sodium carbonate were then added, and the mixture was stirred at reflux temperature for 2 hours more. Xt was then poured into water and stirred for 4 hours. The aqueous layer was then decanted and the residue was taken up in methylene chloride and filtered. The solute was identified as approximately 10 g. of crude N-methyl2,4-dinitro-6-trifluoromethyldiphenylamine.

Example 2 2,4-dinitro-N-propyl-6-trifluoromethyldiphenylamine A 5 g. portion of the diphenylamine intermediate prepared in the first step of Example 1 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 product was recovered by quenching the reaction mixture with water, extracting with methylene chloride, and evaporating the solvent under vacuum. Purification of the crude product on a silica gel chromatographic column, eluting with toluene, produced 1.2 -943614 g. of pure product, a liquid, NMR peaks at 0.93 (triplet), 1.35-2.05, 3.59, 6.45-6.78, 6.82-7.38, 8.63 and 8.76 ppm. Example 3_ N-methyl-2,4-dinitro-21,6-bis(trifluoromethyl)diphenylamine Following the general process of Example 1, 4.8 g. of 2-aminobenzotrifluoride was coupled with 8.1 g. of 2chloro-3,5-dinitrobenzotrifluoride to produce 4.5 g. of 2,4-dinitro-2‘,6-bis(trifluoromethyl)diphenylamine, after purification over a silica gel column with methylene chloride LO as the eluting solvent.

A 2 g. portion of the above intermediate was alkylated with 5 ml. of dimethyl sulfate in acetone in the presence of sodium carbonate. The product was recrystal- lized from ethanol to produce 75 mg. of N-methyl-2,4-di· 5 nitro-2',6- -bis(trifluoromethyl)diphenylamine, m.p. 148- 149°C. Theoretical Found C 44.02% 43.73% H 2.22 2.26 0 N 10.27 10.09 Example 4 N,4-dimethyl-2’,41-dinitro-61-trifluoromethyldiphenylamine A 10 g. portion of p-toluidine was coupled with 12.6 g. of 2-chloro-3,5-dinitrobenzotrifluoride in ethanol according to the general process of Example 1. The intermediate product was recovered by filtration and identified as 10.1 g. of 4-methy1-2',4'-dinitro-6’-trifluoromethyldiphenylamine. -104 3 61 4 A 1 g. portion of the above intermediate was alkylated with 5 ml. of methyl iodide in 12 ml. of acetone in the presence of 5 g. of sodium carbonate. The mixture was stirred at reflux temperature for 96 hours. The mixture was then evaporated to dryness and the residue was digested with two 150-ml. portions of hot hexane. The hexane was filtered hot, and the filtrate was evaporated to dryness under vacuum. The residue was recrystallized from ethanol to produce 750 mg. of N,4-dimethyl-2',4'-dinitro-6'-tri10 fluoromethyldiphenylamine, m.p. 124-125°.

Theoretical Found c 50.71% 50.51% H 3.40 3.35 N 11.83 11.75 Example 5, N-methyl-2,4-dinitro-31,6-bis(trifluoromethyl)diphenylamine g. of 3-aminobenzotrifluoride was coupled with 16.8 g. of 2-chloro-3,5-dinitrobenzotrifluoride in 200 ml. of anhydrous ethanol at reflux temperature overnight.

The ethanol was then removed under vacuum and the product was separated from the hydrochloride salt byproduct by dissolving it in toluene. The toluene was then evaporated under vacuum and the intermediate product was recrystallized from ethanol to produce about 13 g. of 2,4-dinitro-3',625 bis(trifluoromethyl)diphenyIamine, m.p. 99-100°.

A 4 g. portion of the above intermediate was then alkylated with 10 ml. of dimethyl sulfate in acetone in the -1.143614 presence of sodium carbonate according to the process of Example IB. The product was recrystallized from ethanol to collect 2 g. of N-methy1-2,4-dinitro-3',6-bis(trifluoromethyl idiphenylamine, m.p. 108-109°.

Theoretical Found C 44.02% 44.01% H 2.22 2.35 N 10.27 10.23 Example £ ) Ν,2-dimethy1-21,41-dinitro-6'-trifluoromethyIdiphenylamine 15g. of o-toluidine were coupled with 18.9 g. of 2-chloro-3,5-dinitrobenzotrifluoride in 150 ml. of ethanol at reflux temperature overnight. A precipitate formed when the mixture was cooled. The precipitate was collected and identified as 6.8 g. of 2-methy1-2',4'-dinitro-6 '-trifluoromethyIdiphenylamine.

The above intermediate was alkylated with 20 ml. of dimethyl sulfate in 25 ml. of acetone in the presence of 12 g. of sodium carbonate. The mixture was held at reflux temperature for 24 hours, and was then diluted with 50 ml. of water. The aqueous layer was decanted and the residue was taken up in methylene chloride, washed with water, filtered, and evaporated to dryness. The residue left after evaporating was purified by chromatography on a silica gel column with 1:1 pentane:methylene chloride as the eluting solvent. Four g. of pure N,2-dimethy1-2',4'-dinitro-6'trifluoromethyldiphenylamine, m.p. 106-108°, was collected. -124 3 614 Theoretical Found c 50.71% 50.88« H 3.40 3.46 N 11.83 12.08 The intermediates of formula I are used in the preparation of an important series of rodenticides by halogenating or nitrating the aniline ring appropriately.

The reactions follow the usual practice of organic chemistry.

For example, halogenations are usually best performed with the elemental halogen in acetic acid, or in methylene chloride or the like halogenated solvent, including chloroform or carbon tetrachloride. Room temperature halogenation is usually effective, but increased speed of reaction is obtainable by slight elevation of the reaction temperature in the range of 25-50°. Chlorination is best done with the elemental gaseous halogen, but bromination may be done with such agents as N-bromosuccinimide and dibromoisocyanuric acid, although reaction with elemental bromine is usually quite satisfactory.

Iodination is best carried out with iodine monochloride as the reagent.

When a compound having no 4-substituent is to be made, it will often be necessary to block the 4-position before halogenating. It is most convenient to use a sulfonic acid as the blocking group, because it is readily added and readily removed.

Insertion of nitro groups on the aniline ring is readily accomplished with concentrated nitric acid in acetic acid solution at room temperature. Other nitration re-1343614 actions may also be used, such as a mixture of concentrated nitric and sulfuric acids at elevated temperatures. Xn general, no solvent is used in nitration reactions other than the acids themselves.

Claims

1. A diphenylamine compound of the formula noz r R ,·—1 r J—1 Z % ι / \ 3 OzN—/·—Ν—N*—R La (I) wherein R represents methyl, ethyl or propyl; 1

2 5 R and R independently represent hydrogen, methyl or trifluoromethyl; R 3 represents hydrogen or methyl; 12 3 provided that no more than one of R , R and R represents a group other than hydrogen. lo 2. A compound of Claim 1 wherein R 1 represents hydrogen or trifluoromethyl.

3. A compound of Claim 1 or 2 wherein R represents hydrogen or trifluoromethyl.

4. A compound of any of claims 1 to 3 wherein 15 R represents hydrogen.

5. N-methyl-2,4-dinitro -6-trif luoromethyldiphenylamine

6. 2,4-Dinitro-N~propyl-6-trifluoromethyIdiphenylamine

7. N-methyl-2,4-dinitro-3',6-bis(trifluoromethyl)diphenylamine

8. N-methyl-2,4-dinitro-2',6-bis(trifluoromethyl)diphenylamine. -154 3 614

9. A compound of formula I substantially as hereinbefore described in any one of the forgoing Examples.

10. A process for preparing a diphenylamine compound of formula I as claimed in any one of claims 1 to 9 5 which comprises reacting a 2-halo-3,5-dinitrobenzotrifluoride compound of the formula (II) Wherein X is halo, with an aniline compound of the formula R 2 R 1 J i (III) 12 3 0 wherein R , R and R are as defined above; followed by N-alkylating the compound so obtained.

11. A process according to claim 10 for preparing a diphenylamine compound of formula I, substantially as 5 hereinbefore described with particular reference to any one of the Examples.

12. A diphenylamine compound of formula I whenever prepared by a process according to claim 10 or 11.