FI65235C - FREQUENCY REQUIREMENT FOR THE PROCESSING OF N-PHENYL-N'-BENZOYL CARBAMID ANVAENDBARA VID VETERINAERMEDICIN - Google Patents

Description

1 65235

Method for the preparation of N-phenyl-N'-benzoylureas for veterinary use

Divided by application 770137 5

The present invention relates to a process for the preparation of novel N-phenyl-N'-benzoylureas for veterinary use.

It is already known that certain benzoyl ureas, such as, for example, N- (2,6-dichlorobenzoyl) -N1- (4-chloro- or 3,4-dichlorophenyl) urea, have insecticidal properties (cf. DE 2,123,236). .

It has been found that the formula I

15 R2 ^ _ _ XR

CO-NH-CO-NH - ^ <1)

20 novel N-phenyl-N'-benzoylureas wherein R

represents haloalkyl having 1 or 2 carbon atoms, 1 2 R represents hydrogen or halogen, R represents halogen, alkyl or alkoxy, the alkyl or alkoxy moiety having 1 to 3 carbon atoms and X represents an oxygen or sulfur atom and n is a number from 0 to 3 , wherein the possible substituents R 2 of the phenyl ring are always identical to each other, have strong insecticidal properties.

The novel N-phenyl-N'-benzoylureas of formula I are prepared by administration

30 a) of formula II

RX

20-35

substituted anilines of formula III

2 65235

With benzoyl isocyanates according to R 11 - - CO - MCO (III), wherein R, 1 2

R, R and X have the same meaning as above, if desired in the presence of a solvent, or b) by giving formula IV

RX v.

10 (IV)

substituted phenyl isocyanates of formula V

R 1 --CO-NH 2 (V) 2 O 12

with R, R, R and X

have the same meaning as above, if desired in the presence of a solvent.

Surprisingly, the novel N-phenyl-N'-benzoylureas have been found to have a considerably better insecticidal activity than the closely known known compounds of similar structure and direction. The substances according to the invention thus represent technical progress in the field.

If 3-chloro-4-trifluoromethylaniline and 2-chlorobenzoyl isocyanate are used as starting materials in process a) and 3-chloro-4-trifluoromethoxyphenyl isocyanate and 2,6-difluorobenzamide can be shown in process b) according to the following groups of formulas. by: 35 3 65235 a) f3co - {/ + C1 rn

Cl _ j 5 / T \\ - CO-NCO iF3CO - (^ \ rm-CO-fffl-CO - / ^). Cl b) -v FTCO- / VnCO + 10 3 \ = j C1 / - <h- \

\ £ - c ° -rm2— * ^ co ^ -nh-co - ^ - cc-Q

F Cl F

15

Formulas (II) - (V) define commonly used starting materials. Preferably R 1 "represents hydrogen or chlorine and R 2" means fluorine, chlorine, bromine, iodine, methyl, ethyl, nitro or ethoxy.

The substituted anilines (II) used as starting materials are known and can be prepared by methods known from the literature (ver. E.g. J.Org.Chem.25, 25 (1960), 965 and 25 (1964), 1 * Am.Soc. 73 ( 1951); Bull.Soc.Chin.

France 4, (1957), 531; Z obsc. Chin. 35, (1965), 1377 eng. translation; Am. Soc. 83 (1961), 4360 and U.S. Patent 3,387,037). Amino groups can be converted to isocyanite groups according to conventional methods, for example by reaction with phosgene to give the corresponding phenyl isocyanates (IV).

Examples are: 4-trifluoromethoxy, 4-trifluoromethylthio, 3-trifluoromethoxy, 3-trifluoromethylthio, 2-trifluoromethoxy, 2-35 trifluoromethylthio, 3-chloro-4-trifluoromethoxy, 3-chloro-4 65235 η 4 -4-Trifluoromethylthio, 4-difluoromonochloromethylthio, 3-chloro-4-difluoromonochloromethylthio, 2-chloro-4-difluoromethylchloromethylthio, 4- (2-chloro-1,2,2-trifluoromethoxy) -, 3-chloro-4- (2-chloro-1,2,2-trifluoroethoxy) -5-aniline or phenyl isocyanate.

Further benzoyl isocyanates (III) used as starting materials are known (cf. J. Org. Chem. 30 (12), pp. 4306-4307 (1965)) as are benzamides (V) (cf. Beilstein's "Handbuch der organischen Chemie"). Bd. 9, p. 336).

Examples are: 2-methyl, 2-ethyl, 3-methyl, 3-ethyl, 4-methyl, 4-ethyl, 2-chloro, 4-chloro, 2,4- dichloro, 2,4-difluoro, 2,6-dichloro, 2,6-difluoro, 2-fluoro, 2-bromo, 2-iodo, 2-nitro, 3-nitro, 4 -nitro, 2-methoxy, 2-ethoxy-15 and 2,3,6-trichlorobenzoyl isocyanate or benzamide.

The process for the preparation of the N-phenyl-N'-benzoylureas according to the invention is preferably carried out using suitable solvents or diluents. These are practically all inert organic solvents. These include, in particular, aliphatic and aromatic, optionally chlorinated hydrocarbons, such as benzene, toluene, heissin, methylene chloride, chloroform, carbon tetrachloride, chlorobenzene or ethers, for example diethyl and dibutylene ether, dioxane, further ketones, further ketones, for example acetone, for example acetone and propionitrile.

The reaction temperature can be varied within wide limits. Usually work in the area. The working range is usually Q-120 ° C, preferably 70-85 ° C.

The reaction is usually allowed to proceed under normal pressure.

The starting materials are preferably used in equimolar proportions to carry out the process. An excess of one of the reaction components does not provide a substantial advantage.

Typically, the reaction components are added to one of the 35 solvents shown. The substituted phenyl isocyanates (IV) used in reaction variant b) can be added, either as such or without isolation between them, as a reaction mixture obtained from the reaction of amine and phosgene. This reaction mixture is preferably mixed with benzamide (V) in one of the above-mentioned solvents.

The reactions are carried out under the conditions described above and the precipitated products are isolated in the usual manner by filtration, washing and, if appropriate, recrystallization.

the compounds are obtained as crystals and have a sharp melting point of 10.

As often mentioned, the N-phenyl-N'-benzoylureas according to the invention have an excellent insecticidal action. They are effective in veterinary medicine against animal parasites (ectoparasites), such as parasitic fly larvae.

The compounds of the invention are not toxic to warm-blooded animals. They are effective against normal sensitive and resistant grades at all stages of development. The pests mentioned above include: 20 From the block Isopoda e.g. Oniscus weapon New, Armadillidium Vulgare, Porcellio scaber.

From the block Diplopoda e.g. Blaniulus guttulatus.

From the block Chiplopoda e.g. Geophilus carpophagus, Scutigera spec.

25 From the block Symphyla e.g. Scutigerella Immaculata.

From the block Thysanura e.g. Lepisma saccharina.

From the block Collembola e.g. Onychiurus armatus.

From the block Orthoptera e.g. Blatta orientalis, Periplaneta Americana, Leucophaea maderae, Blattella germanica, Acheta 30 domesticus, Gryllotapla spp., Locusta migratoria migratorioi-des, Melanoplus differentialis, Schistocerca gragaria.

From the block Dermaptera e.g. Forficula auricularia.

From the block Isoptera e.g. Reticulitermes spp.

From the block Anoplura e.g. Phylloxera vastatrix, Pemphigus spp., 35 Pediculus humanus corporis, Haematopinus spp., Linognatus spp. From the block Mallophaga e.g. Trichodectes spp., Damulinea spp.

6 65235

From the block Thysanoptera e.g. Hercinothrips femoralis,

Thrips tabaci.

From the block Meteroptera e.g. Eurygaster spp., Dysdercus intermedius, Piesma quadrata, Cimex lectularius, Rhodnius 5 prolixus, Triatoma spp.

From the block Homoptera e.g. Aleurodes brassicae, Bemisia tabaci, Trialeurodes vaporariorum. Aphis gossypii, Brevicoryne brassicae, Gryptomyzus ribis, Doralis fabae, Doralis pomi, Eriosoma lanigerum Hyalopterus arundinis, Macrosiphum avenae, Myzus spp., Photorodon humuli, Rhopalosiphum padi, Empoasca spp., Eus Laodelphax striatellus, Nilaparvate lugens, Aonidiella aurantii, Aspidiotus hederae. Pseudococcus spp., Psylla spp.

From the block Lepidoptera e.g. Pectinophora gossypiella, Bupalus piniarisu, Cheinatobia brumata, Lithocolletis blancardella, Hyponomeuta padella, Plutella maculipennis, Malacosoma neustria, Euproctis chrysorrhoea, Lymantria spp., Bucculatrix th. Feltia spp., Earias Insulana, Heliothis spp., Laphygma exigua, Mamestra brassicae, Feltia spp., Earias Insulana, Heliothis spp., Laphygma exigua, Mamestra brassicae, Panolis f1ammes, Prodenia litura, Spodopteropsa spp. Pieris spp .. Chili spp., Pyrausta nu-25 bilalis, Ephestia kuehniella, Galleria mellonella, Cacoecia podana, Capua retiqulana, Choristoneura fumiferana, Clydia ambiguella, homona magnanima, Tortrix viridana.

From the block Coleoptera, e.g. Atomaria spp., Otyzaephilus surinamensis, Anthonomus spp., Sitophilus spp., Otiorrhynchus sulcatus. Cosmopolites sordidus, Ceuthorrhynchus assimilis, Hypera 35 postica, Dermestes spp., Trogederma spp., Anthrenus spp.,

Attagenus spp., Lyctus spp., Meligethes aeneus, Ptimus spp., 7 65235

Niptus hololeucus, Gibbium Psylloides, Melolontha Melo-lontha, Amphimallon solstitialis, Costelytra Zealand. From the block Hymenoptera e.g. Diprion spp., Hoplocampa spp., Lasius spp., Monomorium pharaonis, Vespa spp.

5 From the block Diptera e.g. Aedes spp., Anopheles spp., Culex spp. Drosophila melanogaster, Musca spp., Fannia spp., Calliphora erythrocephala, Lucilia spp., Chrysomyia spp., Cuterebra spp., Gastrophilus spp., Hyppobosca , Stomoxys spp., Oestrus spp., Hypoderma spp., Tabanus spp., Tannia 10 SPP · / Bibio hortolanus, Oscinella frit, Phorbia spp., Pego-myia hyoscyami, Geratitis capitata, Dacus oleae, Tipula paludosa.

From the block Siphonaptera e.g. Xenopsylia cheopis, Ceratophyllys spp.

The active ingredient according to the invention is used in a manner known in the veterinary art, such as orally, for example as tablets, capsules, beverages, granules, dermally, for example by dipping, spraying, pouring (pour-on and spot-on) and applying powder, and parenterally. for example by injection. Example

Experiment with parasitic fly larvae

Solvent: 35 parts by weight of ethylene polyglycol monomethyl ether; 35 parts by weight of nonylphenol poly-25 glycol ether

To prepare a suitable active ingredient preparation, 30 parts by weight of each active ingredient are mixed with the indicated amount of solvent containing the above-mentioned amount of emulsifier and the dilute thus obtained is diluted to the desired concentration.

30-50 fly larvae (Lucilia cuprina) are placed in 3 test tubes containing approximately 1 cm of horse meat. 0.5 ml of the active substance preparation is applied to this horsemeat.

After 24 hours, the rate of destruction of the larvae is determined in pro-35 cent In this case, 100% means that all larvae 8 65235 have died, and 0% that none of the larvae have died.

The active substances, active substance concentrations and results are shown in the following table.

5 Table (Test with parasitic flight larvae)

Resistant Lucilia cuprina strain

Active ingredient Active ingredient- Degree of destruction eg No. concentration 10 _ PPm _% _ 76 0.001 100 0.0001 100 0.00001 85 21 0.001 100 15 0.0001 100 0.00001 100 20 0.001 100 0.0001 90 0.00001 90 20 18 0.001 100 0.0001 100 0.00001 100

Preparation Examples 25 Example 1 / C1 O -CO-NH-CO-NH-O - OCF3 N \ ~~ 30 Cl 5.4 g (0.03 mol) of 4-trifluoromethoxyaniline dissolved in 80 cm3 of toluene are added at 60 ° C in a solution of 6.5 g (0.03 mol) of 2,5-dichloro-35 benzoyl isocyanate in 20 cm3 of toluene. The mixture is stirred for 2 hours at 80 ° C, part of the solvent 9 65235 is removed by distillation in vacuo and the precipitated product is filtered off with suction. After drying, 10 g (84.5% of theory) of analytical grade N- (4-trifluoromethoxyphenyl) -N '- (2,6-dichlorobenzoyl) urea with a melting point of 202 DEG C. are obtained.

As shown in Example 1, the following compounds are obtained, allowing optimization of yields:

Of - <- scf3 -CO-NH-CO-NH- y 2

Eg R Melting Yield No. point (% of theory) 15 _i! S ___ 2 2,6-F 181 75.0 3 2-F 143 44.5 4 2 ~ CH3 208 47.0 20 5 2-Cl 117 58 .0 6 2,6-Cl 213 60.5 7 2-Br 135 55.0 8 2,3,6-Cl 216 45.0 9 2-J 158 33.0 10 65235 r | -C 0 -NH-C 0 - (- - -) - - SCF 3

Melting point Yield 5 2 ($ theoretical

Eg Rn * Op \ sesta) 10 2,6-F 214 83.0 10 11 2-F 189 67.0

R 1 -N-N-CO-NH-CO-NH-N-N 2 -SCF 2 12 2,6-Cl 228 77.0 15 13 2-Cl 189 64.0 14 2,3,6-Cl 209 32 .0 15 2-J 187 41.5 16 2-CH3 169 41.5 17 2-Br 190 53.0 20 Cl rL- ^ T ^ -CO-NH-CO-NH- ^ OCF ^ -CHFCl 18 2, 6-F 207 90.0 25 19 2-Br 192 82.5 20 2.6-Cl 183 49.0 21 2-Cl 187 75.0 22 2-F 187 61.0 23 2-CH ^ 206 30 24 H 203 61.5 25 2-OCH-j 103 39.5 26 2.5-Cl 162 61.5 27 2.4-Cl 179 75.5 11 6 5 235 ci ~ CQ ~ NH ~ CQ ~ WH "^ r ~ ^ ~ 0CF3

Melting point Yield c Eg R (from theoretical number (° C)) 28 2-F 161 40.0 29 2.6-F 204-205 51.0 10 30 2-C1 194 76.0 31 2,6-Cl 204 82.0 32 2-J 165 27.5 33 2-Br 177 68.5 34 2-OCH3 175 38.5 15 35 2 ~ CH3 182 36 2.4-Cl 201 89.5 37 2,5-Cl 150 58,5 38 2,3,6-Cl 201,5 34,0 -V1 20 r | - ^ 2 ^ -cq-nh-co-nh- ^ y — scf3 39 2,6- Cl 211 71.5 40 2-Cl 195 73.0 25 41 2-J 171 60.0 42 2-Br 189 59.0 43 2-F 162 81.0 44 2.6-F 188 70.5 45 2 -CH 168 30 46 H 208 50.0 47 2,4-Cl 184 86.0 ocf3 R1 - ^ ^ - CO-NH-CQ-NH · ^ - ^ 35 48 2,6-F 176 92.5 12 65235 OCF, RTT ~ ^ y-CO-NH-CO-NH - ^ "^) ·? Melt- Yield

Eaim. Pieta,.

5 -o_ (° C) 11¾18 - 49 2,6-Cl 200 53.5 50 2-Cl 154 58.5 51 2-Br 150 37.0 52 2-CH5 216 10 53 2-F 138 68.0 54 2,4-Cl 146 52.5 55 H 179 76.0 56 2-J 151 38.5 15 H 2) - CO-NH-CO-, H- (3-OCF 2 57 2-CH 3 190 62.0 58 2-C1 198 88.0 20 59 2,6-Cl 202 84.5 60 2-F 181-182 58.5 61 2.6-F 226 74.0 62 2-Br 190 74.5 63 H 225 92.5 25 6b 2,3,6-Cl 163 47.0 65 2-J 176 74.0 66 2-0CH3 148 37.5 67 2,4-Cl 176.5 84.5 68 2.5-Cl 166-167 87.5 30 - ^ - ~ ^ ~ C0-N11-C0-NH- ^ ~ ^) ocf3 69 2,6-F 172 77.0 35 70 2.6-Cl 211 92.5 71 2- F 138 87.0 13 65 2 35

R 1 - ^ ^ c G-NH-G

5 OCF3 Melting Yield

Eg R2 point (from theoretical number (° C)) 10 72 2-C1 137 73.5 73 2-Br '134-135 71.0

Rn <T ~ yOO-NH-CO-NH-^ y-SCF2C1 15 ~ 74 2-F 153 49.0 75 2-Br 172 71.0 76 2.6-F 183 54.5 77 2-CH3 166 82 .5 20 78 2-Cl 182 78.5 79 2.6-Cl 188 87.0 80 2.3.6-Cl 188 60.5 81 all H 186 85.0 25 Cl

Rn_7 ^ ^ "C0" NH "C0" NH "^^ ~ SCF2C1 83 2,6-F 193 61.0 84 2.6-Cl 191 56.5 30 85 2-Cl 191 66.0 86 2-CH 165 87 2-F 3 160 73.0 88 2-Br 180 49.5 35 65235 14

Example 89 _ Cl (f 'V CO-NH-CO-NH Μ V OC F, W \ = / 3 10

A solution of 50.8 g (0.25 moles) of 4-trifluoromethoxyphenyl isocyanate in 100 ml of toluene was added to 38.9 g (0.25 moles) of 2-chlorobenzamide dissolved in 500 ml of toluene. toluene at 100 ° C. The mixture was stirred for 3 1/2 hours at 105 ° C and then cooled to 30 ° C. The precipitated product was filtered and washed with cold toluene. The product obtained was then dried to give 76.3 g (85% of theory) of N- (4-trifluoromethoxyphenyl) -N- (2-chlorobenzoyl) urea, m.p. 196 ° C. The product was recrystallized from toluene to give a melting point of 198 ° C.

The other compounds shown in the table on pages 9-13 were prepared in an analogous manner.

Claims (2)

A process for the preparation of N-phenyl-N'-benzoylureas of the formula (I) for use in veterinary medicine, wherein R 2 - / 1-CO-NH-CO-NH-// (!) N 1 = J V-Ar 1 10 wherein in the formula R represents 1. haloalkyl having 1 or 2 carbon atoms, R represents hydrogen or halogen, R represents halogen, C 1-4 alkyl or C 1-4 alkoxy, X represents an oxygen or sulfur atom, and n is a number from 0 to 3 , 2 15 wherein the possible substituents R of the phenyl ring are always identical to one another, characterized in that a) the substituted anilines of the formula II r1 ^ Nh2 20 are reacted with the benzoyl isocyanates of the formula III V -CO-NCO (III) wherein R, R, R, X and n have the same meaning as above, if desired in a solvent or b) the substituted phenyl isocyanates of the formula IV RX -NCO (IV) are reacted with the formula V 65235 Rn-^ -CO -NH 2 (V) 1 2, wherein R, R, R, X and n mean the same as above. 65235 For the preparation of N-phenyl-N'-benzoyl-urea with the formula (I) in veterinary medicine 5 ^ CO-NH-CO-NH "7 ^ · ^ (I) color R starch for haloalkyl with 1 or 2 colaters , R 1 is a substituent 10 or halogen, R is a halogen, C 1-4 alkyl or C 1-4 alkoxy, X is a substituent or a hydrogen atom, or a nitrogen or an aryl substituent R 2 The phenyl ring is optionally substituted with a compound having the formula (a) as an substituent on an aniline compound of formula 15 RX ^, -V with a benzoylcyanate compound of formula 5-0 -CO-NCO (III) 1 2 of R, R, R, X and in the case of an enriched form, optionally in the form of a solution, or 25 (b) a substituent on the phenyl isocyanate of formula J0) '"CO« O 30 H of the benzamide in the formulation