DK146016B

DK146016B - ANALOGY PROCEDURE FOR THE PREPARATION OF SALICYLANILIDES

Info

Publication number: DK146016B
Application number: DK295167A
Authority: DK
Inventors: Arthur Allan Patchett; Helmut Mrozik; Dale Richard Hoff
Original assignee: Merck & Co Inc
Priority date: 1966-06-07
Filing date: 1967-06-06
Publication date: 1983-05-24
Also published as: GR33859B; DK146016C; DE1618709C3; ES341316A1; NL6707849A; BE699632A; NL141088B; DE1618709B2; IL27982A; BR6790160D0; FR1605533A; DE1618709A1; GB1183641A

Description

i 1Λ 6 016i 1Λ 6 016

Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte salicylanilider, der er effektive til behandling af parasitiske sygdomme.The present invention relates to an analogous process for the preparation of novel salicylanilides which are effective in the treatment of parasitic diseases.

5 De omhandlede salicylanilider har den i kravet angivne almene formel I, hvori R^ og R2 er H, Cl, Br, F,I eller N02, idet mindst en af dem er forskellig fra H, hvor er H,The salicylic anilides of the present invention have the general formula I of claim 1 wherein R 1 and R 2 are H, Cl, Br, F, I or NO 2, at least one of which is different from H, where H is

Cl, Br, OH eller alkoxy med 1-5 C-atomer, Z er H eller a-cetyl, ét af symbolerne R^ og R^ betyder 10 . -O- 15 *6 R7 og det andet af symbolerne R,. og R^ betyder H, Cl, Br, CF^ eller alkoxy med 1-5 C-atomer, hvor Q står for 0, S, S02> CO eller O.CH2, Rg er H, Br eller Cl, er H, Br, Cl, CF^ 2ø eller alkyl med højst 5 C-atomer, og Rg er H, F, Cl, Br, CN, N02 eller alkoxy med 1-5 C-atomer, idet mindst ét af symbolerne R^, og Rg betyder hydrogen. Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i kravets kendetegnende del angivne.Cl, Br, OH or alkoxy having 1-5 C atoms, Z is H or α-cetyl, one of the symbols R 1 and R 2 means 10. -O- 15 * 6 R7 and the other of the symbols R,. and R 1 is H, Cl, Br, CF 2 or alkoxy of 1 to 5 C atoms where Q represents O, S, SO 2> CO or O.CH 2, R 9 is H, Br or Cl is H, Br , Cl, CF 2 O or alkyl of not more than 5 C atoms and R 9 is H, F, Cl, Br, CN, NO 2 or alkoxy of 1-5 C atoms, with at least one of the symbols R hydrogen. The process according to the invention is characterized by the characterizing part of the claim.

2525

Opfindelsen omfatter også fremstillingen af salte af disse forbindelser, såsom metalsalte, f.eks. af natrium, kalium, calcium, kobber eller jern, og aminsalte, såsom af pyridin, piperazin, methylamin eller ethanolamin.The invention also encompasses the preparation of salts of these compounds, such as metal salts, e.g. of sodium, potassium, calcium, copper or iron, and amine salts such as of pyridine, piperazine, methylamine or ethanolamine.

3030

De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser er effektive anthelmintiske stoffer, der især er effektive mod parasiter af arterne Fasciola gigantica og Fasciola hepatica, der angriber indvoldene på får og kvæg.The compounds of the present invention are effective anthelmintic agents, particularly effective against parasites of the species Fasciola gigantica and Fasciola hepatica, which attack the intestines of sheep and cattle.

35 Forbindelserne er endvidere i nogen grad effektive mod nema-toder, især af arten Haemonchus contortus hos får, og de har endvidere en påviselig aktivitet mod migrerende ascarider 2 14601 β hos svin. Dette gælder især for forbindelser, hvor eller er nitro. F.eks. er 3-nitro-5-brom-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid aktive over for Ascaria suum hos svin i det migrerende stadium og bevirker en udpræget 5 reduktion af lungepatologi og af antallet af larver, som når frem *-il lungerne i infektionens begyndelsesstadium.Furthermore, the compounds are somewhat effective against nematodes, especially of the species Haemonchus contortus in sheep, and they also have a detectable activity against migratory ascarides 2 14601 β in pigs. This is especially true for compounds where or are nitro. Eg. 3-nitro-5-bromo-3'-chloro-4 '- (p-chlorophenoxy) -salicylanilide is active against Ascaria suum in pigs in the migratory stage and causes a pronounced 5 reduction of lung pathology and of the number of larvae which reaches * to the lungs at the onset of infection.

De effektive doser varierer i afhængighed af dyrenes tilstand mellem 1 og 300 mg/kg, fortrinsvis 2-50 mg/kg af 10 dyrets vægt. Forbindelserne kan indføres oralt sammen med dyrenes foder eller drikkevand, idet de aktive forbindelser hensigtsmæssigt blandes med bærestoffer, fortyndingsmidler eller næringsmidler.Depending on the condition of the animals, the effective doses vary between 1 and 300 mg / kg, preferably 2-50 mg / kg of the animal's weight. The compounds can be introduced orally with the animal's feed or drinking water, the active compounds being suitably mixed with carriers, diluents or nutrients.

15 Fra dansk patentskrift nr. 114 291 kendes nært beslægtede salicylanilider, som dog er phenoxy- eller halogenphe-noxysubstituerede i 2'-stillingen, og som har baktericid virkning.Danish Patent Specification No. 114,291 discloses closely related salicylanilides, which are however phenoxy or halogenophenoxy substituted at the 2 'position and which have bactericidal activity.

20 Fra dansk patentskrift nr. 111 418 kendes 2'-hydroxy-sali-cylanilider med anthelmintisk virkning. Deres virkning er imidlertid de her omhandlede forbindelsers virkning langt underlegen.Danish Patent No. 111,418 discloses 2'-hydroxy-salicylicanilides having anthelmintic effect. However, their effect is far inferior to the effect of the compounds of this invention.

25 Opfindelsen forklares nærmere ved hjælp af følgende eksempler.The invention is further explained by the following examples.

EKSEMPEL AEXAMPLE A

30 Rotter blev eksperimentelt inficeret med. en fåreleverik- te Fasciola heptatica og holdt på en normal diæt. Infektionen fik lov at skride frem på naturlig måde i 12 uger. Rotterne blev derpå behandlet med en enkelt oral dosis af den i den følgende tabel angivne forbindelse i form af en vandig suspension indeholdende 2 ?ό methylcellulose. Lægemid- 14601 6 3 let administreres i en mængde på 300 mg pr. kg legemsvægt. På behandlingstidspunktet vejede dyrene ca. 450 g.30 Rats were experimentally infected with. a sheep-delivered Fasciola heptatica and kept on a normal diet. The infection was allowed to progress naturally in 12 weeks. The rats were then treated with a single oral dose of the compound given in the following table in the form of an aqueous suspension containing 2? Methyl methyl cellulose. Drug is readily administered in an amount of 300 mg per day. kg body weight. At the time of treatment, the animals weighed approx. 450 g.

Ca. 5 dage efter behandling blev rotterne slået ihjel, og deres galdegange blev undersøgt for infektionsgrad. Resul-5 taterne er opsummeret i følgende tabel:Ca. Five days after treatment, the rats were killed and their bile duct was examined for infection rate. The results are summarized in the following table:

Terapeutisktherapeutically

Rotte Forbindelse respons ^ * 10 1 3,5-dibrom-4'-(p-bromphenoxy)- komplet salicylanilid * 2 3,5-dibrom-3'-chlor-4'-phenoxy komplet * 3 5-nitro-3'-chlor-4(p-chlor- komplet phenoxy)-salicylanilid * 4 3,5-dibrom-4'-(m-methyl-p- komplet 15 chlorphenoxy)-salicylanilid ** 5 3,5-dibrom-4'-(p-nitrophenoxy)- moderat salicylanilidRat Compound Response * 10 1 3,5-dibromo-4 '- (p-bromophenoxy) - complete salicylanilide * 2 3,5-dibromo-3'-chloro-4'-phenoxy complete * 3 5-nitro-3' -chloro-4 (p-chloro-complete phenoxy) -salicylanilide * 4 3,5-dibromo-4 '- (m-methyl-p-complete-chlorophenoxy) -salicylanilide ** 5 3,5-dibromo-4'- (p-nitrophenoxy) - moderate salicylanilide

Denne betegnelse angiver, at alle leverikterne i gal- 20 degangen er døde.This designation indicates that all the liver livers in the bile duct have died.

****

Indikerer tilstedeværelsen af nogle leverikter (levende) .Indicates the presence of some liver cells (live).

EKSEMPEL B 25EXAMPLE B 25

Grupper på tre dyr eksperimentelt inficeret med fåremave-ormen Haemonchus contortus behandles ni dage efter infektionen med en enkelt oral dosis af de i det følgende angivne forbindelser i form af en vandig suspension i en 2 pro-30 cents methylcellulose i de ligeledes angiven doser. Værtsdyrene slås ihjel en dag senere, og maven undersøges for tilstedeværelse af orme. Det fundne antal sammenlignes med antallet for tilbageholdte grupper og ubehandlede kontrolgrupper, og effektiviteten udtrykkes som procentvis reduktion .Groups of three animals experimentally infected with the sheep stomach worm Haemonchus contortus are treated nine days after infection with a single oral dose of the following compounds in the form of an aqueous suspension in a 2 percent methylcellulose at the doses also indicated. The host animals are killed a day later and the stomach is examined for the presence of worms. The number found is compared to the number of detained groups and untreated control groups, and the efficiency is expressed as a percentage reduction.

4 1460164 146016

Forbindelse Dosis Gennemsnit- Procentvis ligt antal reduktion orme 3-nitro~5-brom- 12,5 mg/kg 27 58 5 3'-chlor-4'-(p- chlor-phenoxy)-sa- 50,0 mg/kg 0 100 licylanilid 3-brom-5-nitro- 12,5 mg/kg 43 33 oMot^enoxyfea- 50’° «9/kg 18 72 licylanilid 200,0 mg/kg 0 100 10Compound Dose Average - Percentage reduction of worms 3-nitro ~ 5-bromo-12.5 mg / kg 27 58 5 3'-chloro-4 '- (p-chloro-phenoxy) -sa-50.0 mg / kg 0 100 licylanilide 3-bromo-5-nitro-12.5 mg / kg 43 33 oMoteneoxyphene-50 ° 9 / kg 18 72 licylanilide 200.0 mg / kg 0 100 10

Kontrolgruppe 10 63Control group 10 63

Kontrolgruppe 20 65Control group 20 65

Kontrolgruppe 30 60 15Control group 30 60 15

EKSEMPEL CEXAMPLE C

Får eksperimentelt inficeret med ikke-kønsmodne F. hepa-tica behandles med de i det følgende angivne forbindelser 20 i de ligeledes angivne mængder. Behandlingen foretages o-ralt fire uger efter infektion, dvs. på et tidspunkt, hvor leverikterne er på et ikke-kønsmodent stadium, under anvendelse af gelatinekapsler indeholdende lægemidler. Dyrene slås ihjel ca. ni uger efter behandling, og deres galde-25 gange og lever undersøges for tilstedeværelse af levende eller døde ikter. Resultaterne er sammenlignet med resultater opnået på kontrolgrupper, der ikke modtog nogen me-dikation: 5 146016 Lægemiddel Dosis Får Legems- Leverikte nr. vægt kg. Levende Døde 3.5- dibrom- 20 mg/kg 210 29 00 3'-chlor-4'- 228 35 0 66 (p-chlorphe- 197 36 0 49 5 noxy)-salicy- 217 38 0 34 lanilid 220 30 00 181 31 1 30 209 33 0 26 180 34 10 0 40 mg/kg 187 31 0 46 203 33 0 26 1U 176 35 0 12 198 36 0 57 179 38 0 26 160 39 0 25 154 40 08 166 41 00 15 3,5-dibrom- 100 mg/kg 226 39 17 10 4'-(p-brom- 178 40 0 0 phenoxy)-sa-licylanilidSheep experimentally infected with non-sexually mature F. hepatica are treated with the following compounds 20 in the amounts also indicated. Treatment is taken orally four weeks after infection, ie. at a time when the liver is at a non-maturing stage, using gelatin capsules containing drugs. The animals are killed approx. nine weeks after treatment, and their bile-25 times and liver are examined for the presence of living or dead ICTs. The results were compared with results obtained on control groups that did not receive any medication: 5 146016 Drug Dosage Sheep Body Liver Weight no. Living Dead 3.5-Dibromo-20 mg / kg 210 29 00 3'-Chloro-4'-228 35 0 66 (p-Chlorophen-197 36 0 49 5 noxy) -Salicy-217 38 0 34 Lanilide 220 30 00 181 31 1 30 209 33 0 26 180 34 10 0 40 mg / kg 187 31 0 46 203 33 0 26 1U 176 35 0 12 198 36 0 57 179 38 0 26 160 39 0 25 154 40 08 166 41 00 15 3.5- dibromo 100 mg / kg 226 39 17 10 4 '- (p-bromo-178 40 0 0 phenoxy) -sa-licylanilide

Kontrol 121 47 0 105 31 0 20 192 O*0 208 6 0Control 121 47 0 105 31 0 20 192 O * 0 208 6 0

Som det fremgår af ovennævnte tabel reducerer begge forbindelserne i væsentlig grad antallet af levende ikter ved behandlingen af dyr i sammenligning med de kontroldyr, i hvil-25 ke ikten florerer. Det vil bemærkes, at virkningen opnås på ikke-kønsmodne ikter, som er yderst resistente og praktisk taget ikke-responsive for kemoterapeutika.As shown in the above table, both compounds substantially reduce the number of live ICTs in the treatment of animals compared to the control animals in which the ICTs thrive. It will be noted that the effect is achieved on non-sexually mature nests which are highly resistant and practically non-responsive to chemotherapeutics.

EKSEMPEL 1 30 - 3.5- dibrom-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid.EXAMPLE 1 - 3,5-dibromo-3'-chloro-4 '- (p-chlorophenoxy) salicylanilide.

Dette eksempel illustrerer den generelle proces til dannelse af salicylaniliderne, hvorved Q i formel I er i para-35 6 1460 16 stilling til aminonitrogenatomet.This example illustrates the general process for forming the salicylanilides, whereby Q of formula I is in para position to the amino nitrogen atom.

a. 2-chlor-4-nitrophenyl-p-chlorphenylether.a. 2-Chloro-4-nitrophenyl-β-chlorophenyl ether.

5 En blanding af 108 g (0,842 mol) p-chlorphenol, og 58 g kaliumhydroxid omrøres mekanisk i en 1-liter 3-halset kolbe, der er udstyret med termometer, indtil en homogen opløsning er dannet. I dette tidsrum, ca. 10 minutter, stiger temperaturen til ca 90 °C. Derpå tilsættes 90 g af en 173 g 10 (0,901 mol) portion af 3,4-dichlor-dinitrobenzen, og tempe raturen hæves forsigtigt til ca. 120 °C. En exoterm reaktion begynder, hvorved temperaturen af reaktionsblandingen stiger til 150 °C. Temperaturen falder ved henstand til 120 °C, og de resterende 83 g dichlornitrobenzen tilsættes.A mixture of 108 g (0.842 mol) of p-chlorophenol and 58 g of potassium hydroxide are mechanically stirred in a 1-liter 3-neck flask equipped with a thermometer until a homogeneous solution is formed. During this time, approx. 10 minutes, the temperature rises to about 90 ° C. Then, 90 g of a 173 g of 10 (0.901 mole) portion of 3,4-dichlorodinitrobenzene are added and the temp is gently raised to ca. 120 ° C. An exothermic reaction begins, whereby the temperature of the reaction mixture rises to 150 ° C. The temperature drops to 120 ° C and the remaining 83 g of dichloro-nitrobenzene is added.

15 Blandingen opvarmes langsomt til 130 °C, den exoterme reaktion sætter igen ind, hvorved temperaturen stiger til ca.The mixture is heated slowly to 130 ° C, the exothermic reaction sets in again, raising the temperature to approx.

150 °C. Reaktionsmassen afkøles til 110 °C, hvorefter 250 ml vand tilsættes hurtigt under kratig omrøring til dannelse af et krystallinsk bundfald. Blandingen filtreres, vaskes 20 med vand, og det faste stof opløses i 800 ml kogende ethanol. Opløsningen inddampes, indtil krystallisation starter. Etheren fås som gule krystaller, 142 g, smp: 105 - 107 °C.150 ° C. The reaction mass is cooled to 110 ° C, then 250 ml of water is rapidly added with vigorous stirring to form a crystalline precipitate. The mixture is filtered, washed with water and the solid dissolved in 800 ml of boiling ethanol. The solution is evaporated until crystallization starts. The ether is obtained as yellow crystals, 142 g, mp: 105 - 107 ° C.

Ved omkrystallisation af kogende ethanol fås 136 g 2-chlor- 4-nitrophenyl-p-chlorphenylether, smp: 106 - 108 °C.Recrystallization from boiling ethanol gives 136 g of 2-chloro-4-nitrophenyl-p-chlorophenyl ether, mp: 106 - 108 ° C.

25 b. 4-amino-2-chlorpheny1-p-chlorphenylether.B. 4-Amino-2-chlorophenyl-β-chlorophenyl ether.

De i trin a dannede 136 mg 2-chlor-4-nitrophenyl-p-chlor- phenylether hydrogeneres ved stuetemperatur og et hydro-30 , 2 gentryk pa 2,8 kg/cm i 800 ml ethanol med 4 teskefulde Raney-nikkel, indtil den teoretiske mængde hydrogen er optaget (8 timer).The 136 mg of 2-chloro-4-nitrophenyl-p-chlorophenyl ether formed in step a is hydrogenated at room temperature and a hydro-30, 2 repetitive pressure of 2.8 kg / cm in 800 ml of ethanol with 4 teaspoons of Raney nickel until the theoretical amount of hydrogen is absorbed (8 hours).

katalysatoren frafiltreres, og opløsningsmidlet afdampes fuldstændigt under højt vakuum, hvorved fås 132 g brun o- 7 UB016 lie, som stivner til et gråt stof, smp: 72 - 74 °C. Dette anvendes uden yderligere behandling til næste trin.the catalyst is filtered off and the solvent is evaporated completely under high vacuum to give 132 g of brown o-UB016 Ile, which solidifies to a gray substance, mp: 72-74 ° C. This is applied without further processing to the next step.

c. 3,5-dibrom-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid.c. 3,5-dibromo-3'-chloro-4 '- (p-chlorophenoxy) -salicylanilide.

5 62,3 g (0,243 mol) 4-amino-2-chlorphenyl-p-chlorphenyl-ether og 72,5 g (0,245 mol) 3,5-dibrom-salicylsyre suspenderes i 725 ml chlorbenzen og omrøres mekanisk. 8,6 ml phosphortrichlorid tilsættes i en langsom strøm. Blandingen opvarmes til kogning i 3 timer, filtreres varm og inddampes i vakuum til ca. 450 ml. Der dannes en tyk opslæmning* der henstilles ved stuetemperatur, ældes i 2 timer, filtreres og vaskes med petroleumbenzin. Efter tørring i vakuum ved ^ 50 °C i 24 timer fås 98 g urent produkt, smp: 163 - 165 “C:62.3 g (0.243 mol) of 4-amino-2-chlorophenyl-p-chlorophenyl ether and 72.5 g (0.245 mol) of 3,5-dibromo-salicylic acid are suspended in 725 ml of chlorobenzene and stirred mechanically. 8.6 ml of phosphorus trichloride are added in a slow stream. The mixture is heated to boiling for 3 hours, filtered hot and evaporated in vacuo to ca. 450 ml. A thick slurry is formed * which is left at room temperature, aged for 2 hours, filtered and washed with petroleum gasoline. After drying in vacuo at 50 ° C for 24 hours, 98 g of crude product is obtained, mp: 163 - 165 ° C:

Ved omkrystallisation af en blanding af benzen og petroleumbenzin, fås 85 g rent 3,5-dibrom-3'-chlor-4'-(p-chlorphenoxy )-salicylanilid, smp: 164 - 166 °C.Recrystallization of a mixture of benzene and petroleum gas gives 85 g of pure 3,5-dibromo-3'-chloro-4 '- (p-chlorophenoxy) -salicylanilide, mp: 164 - 166 ° C.

2o EKSEMPLER 2-5Examples 2-5

En i eksempel 1 angiven fremgansmåde følges ved anvendelse af ækvivalente mængder p-chlornitrobenzen i stedet for 3,4-dichlornitrobenzen i trin a med phenolerne, som er an-25 givet i nedennævnte tabel til dannelse af den tilsvarende ether, som derefter reduceres i overensstemmelse med trin b til dannelse af aminforbindelsen, som er anført i tabellen.A procedure as described in Example 1 is followed by using equivalent amounts of p-chloro nitrobenzene instead of 3,4-dichloro nitrobenzene in step a with the phenols given in the table below to form the corresponding ether which is then reduced accordingly. with step b to form the amine compound listed in the table.

Denne aminforbindelse omsættes med 3,5-dibromsalicylsyre i overensstemmelse med trin c til dannelse af det anførte 30 salicylanilid.This amine compound is reacted with 3,5-dibromosalicylic acid in accordance with step c to give the above salicylic anilide.

8 1460168 146016

Eksempel Phenol- Ether Salicylanilid SmeltepunktExample Phenol-Ether Salicylanilide Melting point

forbindelse DCconnection DC

2 phenol 4-amino- 3,5-dibrom-41 - phenyl- phenoxysali- 5 phenyle- cylanilid ther 152 - 153 3 m-trifluor- 4-amino- 3,5-dibrom-4'- methylphe-- phenyl-m- (m-trifluor- nol trifluor- methylpheno-2 phenol 4-amino-3,5-dibromo-41-phenylphenoxysaliphenylsilanilide ther 152 - 153 3 m-trifluoro-4-amino-3,5-dibromo-4'-methylphe-phenyl-m - (m-trifluoranol trifluoromethylphenol)

Tn methylphe- xy)-salicyla- nylether nilid 115 - 117 4 cyano- 4-amino- 3,5-dibrom- phenol phenyl-p- 41 -(p-cyanphe- cyanphe- noxy)-salicyla- nylether nilid 225 - 227 15 5 p-nitro- 4-amino- 3,5-dibrom- phenol phenyl-p- 4'-(p-nitro- nitrophe- phenoxy)-sali- nylether cylanilid 214 - 216 20Tn methylphenylsalicylicanyl ether nilide 115 - 117 4 cyano-4-amino-3,5-dibromo-phenol phenyl-p-41 - (p-cyanophecyanophenoxy) -salicylicanyl ether nilide 225 - 227 5 p-Nitro-4-amino-3,5-dibromo-phenol phenyl-p-4 '- (p-nitro-nitrophen-phenoxy) -salinyl ether cylanilide 214 - 216

Hvis ovennævnte fremgangsmåde gentages, idet der i stedet for de beskrevne phenoler anvendes de tilsvarende thiophe-noler, fås de tilsvarende thioethere, som omdannes til de tilsvarende phenylthiosalicylanilider.If the above process is repeated, using the corresponding thiophenols instead of the phenols described, the corresponding thioethers are obtained which are converted to the corresponding phenylthiosalicylanilides.

25 EKSEMPLER 6-16 3,5-dibrom-3,-chlor-4'-(p-chlor-m-methylphenoxy)-salicylanilid.EXAMPLES 6-16 3,5-dibromo-3, -chloro-4 '- (p-chloro-m-methylphenoxy) -salicylanilide.

3030

En blanding af 45 g (0,17 mol) 4-amino-2,4'-dichlor-3'-methylbiphenylether, 48,6 g 3,5-dibromsalicylsyre (0,17 mol) og 6,1 ml (0,07 mol) phosphortrichlorid i 1000 ml chlorbenzen omrøres og koges i 3 timer. Reaktionsblandingen filtreres varmt gennem et sintret glasfilter. Filtratet inddampes på dampbad under et vakuum på 15 til 20 mmHg.A mixture of 45 g (0.17 mol) of 4-amino-2,4'-dichloro-3'-methylbiphenyl ether, 48.6 g of 3,5-dibromosalicylic acid (0.17 mol) and 6.1 ml (0, Phosphorus trichloride in 1000 ml of chlorobenzene is stirred and boiled for 3 hours. The reaction mixture is filtered hot through a sintered glass filter. The filtrate is evaporated on a steam bath under a vacuum of 15 to 20 mmHg.

146016 9146016 9

Inddampningsresten omkrystalliseres af benzen, hvorved fås 33 g 3,5-dibrom-3'-chlor-4'-(p-chlor-m-methylphenoxy)-sali-cylanilid, smp: 173 -174 °C.The residue is recrystallized from benzene to give 33 g of 3,5-dibromo-3'-chloro-4 '- (p-chloro-m-methylphenoxy) -sali-silanilide, mp: 173 -174 ° C.

3 Når ovennævnte fremgangsmåde gentages med ækvivalente mængder af nedennævnte ether i stedet for 4-amino-2,4'-dichlor-3'-methylbiphenylether, fås følgende salicylanilider.3 When the above procedure is repeated with equivalent amounts of the ether mentioned below instead of 4-amino-2,4'-dichloro-3'-methylbiphenyl ether, the following salicylanilides are obtained.

Eksem- Ether Salicylanilid SmeltepunktEczema-Ether Salicylanilide Melting point

10 pel___°C10 µl ___ ° C

7 4-aminophenyl-p- 3,5-dibrom-4'-(p- 172 - 173 bromphenylether bromphenoxy)-salicylanilid 8 4-aminophenyl-p- 3,5-dibrom-4'-(p- 166 - 168 chlorphenylether chlorphenoxy)-sali- 15 cylanilid 9 4-aminophenyl-o- 3,5-dibrom-41 -(o- 161 -.162 chlorphenylether chlorphenoxy) - salicylanilid 10 4-aminophenyl-o- 3,5-dibrom-4'-(o- 170 - 171 bromphenylether bromphenoxy)-sali- 20 cylanilid 11 4-amino-2-chlor- 3,5-dibrom-3'-chlor- 148 - 149 diphenylether 4'-phenoxy-salicyl- anilid 12 4-aminophenyl-m- 3,5-dibrom-4'-(m- 158 - 160 bromphenylether bromphenoxy)-sali- 25 cylanilid 13 4-aminophenyl-p- 3,5-dibrom-41 -(p- 129 - 130 fluorphenylether fluorphenoxy)-sa- licylanilid 14 4-amino-2-tri- 3,5-dibrom-31 -tri- 85 - 87 fluor-methylphe- fluormethyl-4'-(p- (etherat) nyl-p-chlorphe- chlorphenoxy)-sali- 30 nylether cylanilid 15 4-aminophenyl-m- 3,5-dibrom-4'-(m-me- 149 - 150 methyl-p-chlor- thyl-p-chlorphé- phenylether noxy)-salicylanilid 16 4-amino-2-me- 3,5-dibrom-3'-metho- 183 - 184 thoxy-phenyl-m,p- xy-4'-(m,p-dichlor- dichlor-phenyl- phenoxy )-salicyl- 5 ether anilid 146016 ίο7 4-Aminophenyl-p-3,5-dibromo-4 '- (p-172 - 173 bromophenyl ether bromophenoxy) -salicylanilide 8 4-aminophenyl-p-3,5-dibromo-4' - (p-166 - 168 chlorophenyl ether chlorophenoxy) -salisylsilanilide 9 4-aminophenyl-o-3,5-dibromo-41 - (o-161 -.162 chlorophenyl ether chlorophenoxy)-salicylanilide 10 4-aminophenyl-o-3,5-dibromo-4'- (o-170 - 171 bromophenyl ether bromophenoxy) salicylanilide 11 4-amino-2-chloro-3,5-dibromo-3'-chloro-148 - 149 diphenyl ether 4'-phenoxy-salicylic anilide 12 4-aminophenyl -m-3,5-dibromo-4 '- (m-158-160 bromophenyl ether bromophenoxy) -salysilanilide 13 4-aminophenyl-p-3,5-dibromo-41 - (p-129-130 fluorophenyl ether fluorophenoxy) -salicylic anilide 14 4-amino-2-tri-3,5-dibromo-31-tri-85-87 fluoromethylpheofluoromethyl-4 '- (p- (etherate) nyl-p-chloro-chlorophenoxy) - salinyl ether cylanilide 4 4-aminophenyl-m-3,5-dibromo-4 '- (m-me-149-150 methyl-p-chloroethyl-p-chlorophenylphenyl ether noxy) -salicylanilide 16 4-amino 2-Me-3,5-dibromo-3'-metho-183-184 thoxy-phenyl-m, p-xy-4'- (m, p-dichloro-dichloro-phenyl-phenoxy) -salicylic ether anilide 146016

De i eksemplerne 7 — 16 anvendte ethere fremstilles ifølge eksempel 1 a og b og eksempel 2, idet der anvendes ækvivalente mængder af den pågældende halogennitrobenzen og substitueret phenol i stedet for henholdsvis 3,4-dichlor-5 nitrobenzen og p-chlorphenol. De tilsvarende thioethere kan anvendes til fremstilling af phtnylthio-salicylaniliderne.The ethers used in Examples 7 - 16 are prepared according to Examples 1 a and b and Example 2, using equivalent amounts of the halogenated nitrobenzene and substituted phenol in place of 3,4-dichloro-5 nitrobenzene and p-chlorophenol, respectively. The corresponding thioethers can be used to prepare the phenylthio-salicylanilides.

EKSEMPLER 17 - 21 3,3',5-trichlor-4'-(p-chlorphenoxy)-salicylanilid.EXAMPLES 17 - 21 3,3 ', 5-trichloro-4' - (p-chlorophenoxy) salicylanilide.

En blanding af 25,4 g (0,1 mol) 4-amino-2,4-dichlorbiphe-10 nylether, 20,7 g (0,1 mol) 3,5-dichlorsalicylsyre og 3,5 ml phosphortrichlorid i 300 ml chlorbenzen omrøres og koges i 3 timer. Den filtreres, og filtratet afkøles på isbad i 3 timer. De dannede krystaller filtreres og vaskes med petroleumbenzin, hvorved fås 32 g produkt, smp.s 159 - 162 °C.A mixture of 25.4 g (0.1 mole) of 4-amino-2,4-dichlorobiphenyl ether, 20.7 g (0.1 mole) of 3,5-dichlorosalicylic acid and 3.5 ml of phosphorus trichloride in 300 ml chlorobenzene is stirred and boiled for 3 hours. It is filtered and the filtrate is cooled in an ice bath for 3 hours. The crystals formed are filtered and washed with petroleum gas to give 32 g of product, mp 159 - 162 ° C.

15 Det omkrystalliseres 3 gange af benzen, hvorved fås 16,1 g 3,3',5-trichlor-4'-(p-chlorphenoxy)-salicylanilid,smp.: 161,5 - 162,5 °C.It is recrystallized 3 times by benzene to give 16.1 g of 3,3 ', 5-trichloro-4' - (p-chlorophenoxy) -salicylanilide, mp: 161.5 - 162.5 ° C.

Ovennævnte fremgangsmåde gentages med ækvivalente mængder af nedennævnte reagens til dannelse af de angivne salicyl-20 anilider:The above procedure is repeated with equivalent amounts of the below reagent to form the indicated salicylanilides:

Eksem- Salicylsyrefor- Ether- Salicylanilid Smelte-Eczema - Salicylic Acid For- Ether- Salicylanilide Melt-

pel bindelse forbindelse punkt °Cpel bond compound point ° C

18 3-bromsalicyl- 4-amino-2- 3-brom-3'- 201 - 202 syre chlorphe- chlor-4'- (p- nyl-p-chlor-chlorphenoxy)-phenylether salicylanilid 19 3,5,6-tri-brom- 4-amino-2- 3,5,6-tribrom- 234 - 235 salicylsyre chlorphenyl-3'-chlor-4'- p-chlor- (p-chlorphe- phenylether noxy)-salicyl- anilid 20 3,5,6-trichlor- 4-amino-2- 3,5,6-trichlor-211 -212 salicylsyre chlorphenyl-3'-chlor-4'- p-chlorphe- (p-chlorphe- nylether noxy)-salicyl anilid 21 3,5-dibrom-6- 4-amino-2- 3,5-dibrom-6- 202 (dek.) hydroxy-salicyl- chlorphenyl-hydroxy-3'-chlor- syre p-chlor-m- 4'-(p-chlor-m- methylphe- methylphenoxy)- nylether salicylanilid 146016 11 EKSEMPEL 22 4-amino-4'-fluordiphenylsulfid.18 3-bromosalicyl-4-amino-2- 3-bromo-3'-201 - 202 acid chloro-chloro-4'- (phenyl-p-chloro-chlorophenoxy) -phenyl ether salicylanilide 19 3,5,6- tri-bromo-4-amino-2- 3,5,6-tribromo-234 - 235 salicylic acid chlorophenyl-3'-chloro-4'-p-chloro (p-chlorophenylphenyl ether noxy) -salicylic anilide 3 5,6-Trichloro-4-amino-2- 3,5,6-trichloro-211-212 salicylic acid chlorophenyl-3'-chloro-4'-p-chlorophe- (p-chlorophenyl ether noxy) -salicyl anilide 21 3,5-dibromo-6- 4-amino-2- 3,5-dibromo-6- 202 (dec.) Hydroxy-salicylic-chlorophenyl-hydroxy-3'-chloro-acid p-chloro-m-4 ' - (p-chloro-m-methylphenethylphenoxy) nyl ether salicylanilide EXAMPLE 22 4-Amino-4'-fluorodiphenylsulfide.

En opløsning af 30 g 4-fluor-41-nitrophenylsulfid i 300 ml ethanol reduceres ved stuetemperatur med hydrogen og 2,5 g Raney-nikkel-katalysator under et tryk på 2,8 kg/cm . Efter at den teoretiske mængde hydrogen er absorberet frafiltre-res katalysatoren, og filtratet inddampes i vakuum til en 10 olie, som stivner ved henstand. Efter pulverisering af det faste stof i en morter og vask med petroleumbenzin, fås 24 g praktisk taget rent 4-amino-4'-fluordiphenylsulfid, smp: 63 - 65 °C.A solution of 30 g of 4-fluoro-41-nitrophenyl sulfide in 300 ml of ethanol is reduced at room temperature with hydrogen and 2.5 g of Raney nickel catalyst under a pressure of 2.8 kg / cm. After absorbing the theoretical amount of hydrogen, the catalyst is filtered off and the filtrate is evaporated in vacuo to an oil which solidifies on standing. After pulverizing the solid in a mortar and washing with petroleum gasoline, 24 g of virtually pure 4-amino-4'-fluorodiphenyl sulfide are obtained, mp: 63-65 ° C.

15 EKSEMPEL 23 3.5- dibrom-4'-(p-fluorphenylthio)-salicylanilid.EXAMPLE 23 3.5-Dibromo-4 '- (p-fluorophenylthio) salicylanilide.

2o En blanding af 24,3 g 4-amino-4'-fluordiphenylsulfid, 32,8 g 3,5-dibrom-salicylsyre og 3,9 ml phosphortrichlorid i 340 ml chlorbenzen koges i 3 timer. Blandingen filtreres i varm tilstand, og filtratet inddampes til lille rumfang, indtil der sker en udkrystallisation. 50 ml petroleumbenzin til-25 sættes til afslutning af krystallisationen. Ved omkrystallisation af det urene produkt af methanol fås 43 g 3,5-di-brom-4' - (p-fluorphenylthio)-salicylanilid., smp: 154 - 157 °C.A mixture of 24.3 g of 4-amino-4'-fluorodiphenyl sulfide, 32.8 g of 3,5-dibromo-salicylic acid and 3.9 ml of phosphorus trichloride in 340 ml of chlorobenzene is boiled for 3 hours. The mixture is filtered in hot state and the filtrate is evaporated to a small volume until crystallization occurs. 50 ml of petroleum gasoline is added to complete the crystallization. Recrystallization of the crude product from methanol gives 43 g of 3,5-di-bromo-4 '- (p-fluorophenylthio) -salicylanilide., Mp: 154 - 157 ° C.

EKSEMPEL 24 30 3.5- diiod-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid.EXAMPLE 24 3.5-diiodo-3'-chloro-4 '- (p-chlorophenoxy) -salicylanilide.

En blanding af 31,0 g 4-amino-2,41-dichlorbiphenylether, 47,4 g 3,5-diiodsalicylsyre og 4,3 ml phosphortrichlorid 35 i 235 ml chlorbenzen koges i 3 timer. Den varme opløsning dekanteres fra en uopløselig remanens, og det urene produkt udskilles af opløsningen ved afkøling til stuetemperatur.A mixture of 31.0 g of 4-amino-2,41-dichlorobiphenyl ether, 47.4 g of 3,5-diodes salicylic acid and 4.3 ml of phosphorus trichloride 35 in 235 ml of chlorobenzene is boiled for 3 hours. The hot solution is decanted from an insoluble residue and the crude product is separated by the solution upon cooling to room temperature.

12 14601612 146016

Ved omkrystallisation af benzen fås 27,8 g 3,5-diiod-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid, smp: 168 - 170 °C.Recrystallization of benzene gives 27.8 g of 3,5-diiodo-3'-chloro-4 '- (p-chlorophenoxy) -salicylanilide, mp: 168-170 ° C.

EKSEMPEL 25 3,3',5-tribrom-4'-(p-bromphenoxy)-salicylanilid.EXAMPLE 25 3,3 ', 5-tribromo-4' - (p-bromophenoxy) salicylanilide.

5 En blanding af 18,4 g (0,0534 mol) 4-amino-2,4'-dibrombi-phenylether, 15,8 g (0,053 mol) 3,5-dibromsalicylsyre og 1,82 ml phosphortrichlorid i 150 ml chlorbenzen omrøres og koges i 3 timer. Den filtreres warm, og filtratet afkøles til stuetemperatur i 17 timer. Der dannes grønne krystaller, 10 som filtreres. Filtratet vaskes med 2,5 N saltsyre (25 ml) og 25 ml mættet natriumchloridopløsning. Det organiske lag tørres over magnesiumsulfatopløsning, inddampes til en fast masse, som forenes med den første portion krystaller. Produktet omkrystalliseres to gange af benzen, behandles med 15 aktive kul og omkrystalliseres fire gange af benzen til dannelse af 12 g 3,3',5-tribrom-4'-(p-bromphenoxy)-salicylani-lid, smp.: 185 - 186 °C.A mixture of 18.4 g (0.0534 mole) of 4-amino-2,4'-dibromobi-phenyl ether, 15.8 g (0.053 mole) of 3,5-dibromo-salicylic acid and 1.82 ml of phosphorus trichloride in 150 ml of chlorobenzene Stir and cook for 3 hours. It is filtered warm and the filtrate is cooled to room temperature for 17 hours. Green crystals are formed, 10 which are filtered. The filtrate is washed with 2.5 N hydrochloric acid (25 ml) and 25 ml saturated sodium chloride solution. The organic layer is dried over magnesium sulfate solution, evaporated to a solid mass which is combined with the first batch of crystals. The product is twice recrystallized from benzene, treated with 15 active coals and recrystallized four times by benzene to give 12 g of 3,3 ', 5-tribromo-4' - (p-bromophenoxy) -salicylanilide, mp: 185 - 186 ° C.

EKSEMPEL 26 3,5-dibrom-3'-chlor-4'-(o,p-dichlorphenoxy)-salicylanilid.EXAMPLE 26 3,5-Dibromo-3'-chloro-4 '- (o, p-dichlorophenoxy) -salicylanilide.

20 En blanding af 38,2 g (0,132 mol) 4-amino-2,2’,4-trichlor-biphenylether, 39,1 g (0,132 mol) 3,5-dibromsalicylsyre og 4,5 ml phosphortrichlorid i 350 ml chlorbenzen omrøres og koges i 3 timer. Den filtreres varm, og filtratet afkøles til stuetemperatur i 2 timer. Derved fås hvide krystaller 25 (40 g)j som omkrystalliseres 3 gange af benzen og 2 gange af ethanol, hvorved fås 23,9 g 3,5-dibrom-3'-chlor-4'-(o,p-dichlorphenoxy)-salicylanilid, smp: 149 - 151 °C.A mixture of 38.2 g (0.132 mole) of 4-amino-2,2 ', 4-trichloro-biphenyl ether, 39.1 g (0.132 mole) of 3,5-dibromosalicylic acid and 4.5 ml of phosphorus trichloride in 350 ml of chlorobenzene Stir and cook for 3 hours. It is filtered warm and the filtrate is cooled to room temperature for 2 hours. Thereby, white crystals (25 g) are obtained which are recrystallized 3 times by benzene and 2 times by ethanol to give 23.9 g of 3,5-dibromo-3'-chloro-4 '- (o, p-dichlorophenoxy) salicylic anilide, mp: 149 - 151 ° C.

146016 13 EKSEMPEL 27 3,5-dibrom-3'-chlor-4'-(m,p-dichlorphenoxy)-salicylanilid.EXAMPLE 27 3,5-Dibromo-3'-Chloro-4 '- (m, p-dichlorophenoxy) -salicylanilide.

5 En blanding af 37,5 g (0,13 mol) 4-amino-2,3',4'-trichlorbi-phenylether, 37,2 g (0,13 mol) 3,5-dibromsalicylsyre og 4,4 ml phosphortrichlorid i 400 ml chlorbenzen omrøres og koges i 3 timer. Den filtreres varm, og filtratet afkøles til dannelse af hvide krystaller. De omkrystalliseres 2 lø gange med benzen, hvorved fås 32 g 3,5-dibrom-3'-chlor-4'-(m,p-dichlorphenoxy)-salicylanilid, smp: 193,5 - 194,5 °C.A mixture of 37.5 g (0.13 mol) of 4-amino-2,3 ', 4'-trichlorobiphenyl ether, 37.2 g (0.13 mol) of 3,5-dibromo salicylic acid and 4.4 ml phosphorus trichloride in 400 ml of chlorobenzene is stirred and boiled for 3 hours. It is filtered hot and the filtrate is cooled to form white crystals. They are recrystallized 2 times with benzene to give 32 g of 3,5-dibromo-3'-chloro-4 '- (m, p-dichlorophenoxy) -salicylanilide, mp: 193.5 - 194.5 ° C.

EKSEMPEL 28 15 5-brom-3-nitro-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid.EXAMPLE 28 5-Bromo-3-nitro-3'-chloro-4 '- (p-chlorophenoxy) -salicylanilide.

En blanding af 33,3 g, (0,132 mol), 4-amino-2,4'-dichlor-biphenylether 34,4 g (0,132 mol) 5-brom-3-nitro-salicylsyre og 4,5 ml (0,0513 mol) phosphortrichlorid i 350 ml chlorben-20 zen omrøres og koges i 3 timer i en 1-liter kolbe. Blandingen filtreres varm, og filtratet henstilles til afkøling og inddampes til en mørk olie. 25 ml benzen tilsættes, og blandingen henstilles i 17 timer. Krystallerne frafiltre-res og vaskes to gange med benzen over en sintret glasfil-25 terdigel. De omkrystalliseres en gang af ethanol og opløses dernæst i 75 ml dimethylformamid og 25 ml vand, hvortil der er sat 250 ml ethanol. Der opvarmes, indtil der er opnået en klar opløsning. Denne afkøles langsomt til stuetemperatur og derefter på is, indtil krystallisationen er af-30 sluttet. Krystallerne frafiltreres, vaskes med ethanol og tørres i vakuum ved 50 °C, hvorved fås 42,0 g 5-brom-3-ni-tro-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid, smp: 150 -152 °C.A mixture of 33.3 g, (0.132 mole), 4-amino-2,4'-dichloro-biphenyl ether 34.4 g (0.132 mole) of 5-bromo-3-nitro-salicylic acid and 4.5 ml (O, Phosphorus trichloride in 350 ml of chlorobenzene is stirred and boiled for 3 hours in a 1 liter flask. The mixture is filtered hot and the filtrate is allowed to cool and evaporated to a dark oil. 25 ml of benzene is added and the mixture is allowed to stand for 17 hours. The crystals are filtered off and washed twice with benzene over a sintered glass filter crucible. They are recrystallized once by ethanol and then dissolved in 75 ml of dimethylformamide and 25 ml of water to which are added 250 ml of ethanol. Heat until a clear solution is obtained. This is cooled slowly to room temperature and then on ice until crystallization is complete. The crystals are filtered off, washed with ethanol and dried in vacuo at 50 ° C to give 42.0 g of 5-bromo-3-nitro-3'-chloro-4 '- (p-chlorophenoxy) -salicylanilide, mp: 150 -152 ° C.

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Ved anvendelse af ækvivalente mængder 5-nitro-salicylsyre eller 3-brom-5-nitro-salicylsyre i stedet for 5-brom-tro-salicylsyre ved ovennævnte fremgangsmåde dannes henholdsvis 5-nitro-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid 5 (smp: 200 - 202 DC) eller 3-brom-5-nitro-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid (smp: 213 - 214 °C).Using equivalent amounts of 5-nitro-salicylic acid or 3-bromo-5-nitro-salicylic acid in place of 5-bromo-tro-salicylic acid in the above process, respectively, 5-nitro-3'-chloro-4 '- chlorophenoxy) salicylanilide 5 (mp: 200-202 DC) or 3-bromo-5-nitro-3'-chloro-4 '- (p-chlorophenoxy) salicylanilide (mp: 213 - 214 ° C).

EKSEMPEL 29 10 3,5-dibrom-4'-chlor-3'-(p-chlorphenoxy)-salicylanilid.EXAMPLE 29 3,5-Dibromo-4'-chloro-3 '- (p-chlorophenoxy) -salicylanilide.

Hette eksempel illustrerer fremstillingen af salicylanili-der, hvor Q i formel I er i meta-stilling til amid-nitrogenet. Eksempel 1 a og b gentages til dannelse af 4-amino-15 2-chlorphenyl-p-chlorphenylether. Den således dannede ether (10 g) acetyleres med 10 ml benzen og 6,5 ml eddikesyre ved omrøring ved stuetemperatur i 15 minutter. Der afkøles, og produktet henstilles til krystallisation. Ved filtrering fås 12 g 4-acetylamino-2,41-dichlorbiphenylether, smp: 142 20 - 143 °C. 10 g af dette produkt suspenderes i 100 ml eddi- kesyrehydrid og afkøles til 0 °C. Det nitreres dernæst ved tildrypning af en opløsning af 5,35 ml koncentreret salpetersyre og 1,78 ml eddikesyreanhydrid under kraftig omrøring, medens temper at· u-r en opretholdes ved 0 °C. Efter at til-25 sætningen er afsluttet omrøres i yderligere 1 time ved 0 °C. Blandingen hældes derefter i 100 ml isvand, og produktet bringes til at udkrystallisere. Ved filtrering fås 6,6 g 4-acetylamino-2,4'-dichlor-5-nitrobiphenylether, smp: 132 -136 °C. Dette omkrystalliseres 2 gange af ethanol, hvorved 30 fås 4 g med et smeltepunkt på 145 - 146 °C. 1 g af den dannede nitro-forbindelse koges i 10 ml ethanol på dampbad. En opløsning af 0,75 g kaliumhydroxid i 2 ml vand tilsættes. Den opvarmes i 15 minutter på dampbad. Pro-35 duktet udkrystalliserer ved stuetemperatur, filtreres og vaskes med 30 % vandig ethanol, hvorved fås 750 mg 4-ami- 146016 15 no-2,41-dichlor-5-nitrobiphenylether, smp: 186 - 188 °C.The above example illustrates the preparation of salicylic anilides where Q of formula I is in meta position to the amide nitrogen. Examples 1 a and b are repeated to give 4-amino-2-chlorophenyl-β-chlorophenyl ether. The ether (10 g) thus formed is acetylated with 10 ml of benzene and 6.5 ml of acetic acid by stirring at room temperature for 15 minutes. It is cooled and the product is allowed to crystallize. Filtration gives 12 g of 4-acetylamino-2,41-dichlorobiphenyl ether, mp: 142 20 - 143 ° C. 10 g of this product is suspended in 100 ml of acetic anhydride and cooled to 0 ° C. It is then nitrated by dripping a solution of 5.35 ml of concentrated nitric acid and 1.78 ml of acetic anhydride with vigorous stirring while maintaining a temperature of 0 ° C. After the addition is complete, stir for an additional 1 hour at 0 ° C. The mixture is then poured into 100 ml of ice water and the product is crystallized. Filtration gives 6.6 g of 4-acetylamino-2,4'-dichloro-5-nitrobiphenyl ether, mp: 132-136 ° C. This is recrystallized twice by ethanol to give 30 g of a melting point of 145 - 146 ° C. 1 g of the formed nitro compound is boiled in 10 ml of ethanol on a steam bath. A solution of 0.75 g of potassium hydroxide in 2 ml of water is added. It is heated for 15 minutes in a steam bath. The product crystallizes at room temperature, filtered and washed with 30% aqueous ethanol to give 750 mg of 4-amine no-2,41-dichloro-5-nitrobiphenyl ether, mp: 186 - 188 ° C.

En opløsning af 0,6 g af ovennævnte produkt i 75 ml ethanol og 3,2 ml koncentreret svovlsyre koges under kraftig omrø-5 ring. Til den dannede opløsning sættes en opløsning af 3,05 g natriumnitrat i 7 ml vand så hurtigt, som det er muligt af hensyn til gasudviklingen. Kogningen fortsættes i 1 time efter st tilsætningen er afsluttet. Reaktionsblandingen filtreres varm, og filtratet inddampes i vakuum til ca. 25 10 ml. Det fortyndes dernæst med vand, indtil krystallisationen sætter ind. 2,4'-dichlor-5-nitro-biphenyletheren omkrystalliseres af ethanol, derefter af petroleumbenzin-ether til et smeltepunkt på 93 °C. Produktet hydrogeneres ved fremgangsmåden ifølge eksempel 1 b. Den således dannede u-15 rene 5-amino-2,4'-dichlorbiphenylether anvendes uden rensning i næste trin. .A solution of 0.6 g of the above product in 75 ml of ethanol and 3.2 ml of concentrated sulfuric acid is boiled under vigorous stirring. To the solution formed, a solution of 3.05 g of sodium nitrate in 7 ml of water is added as quickly as possible for gas evolution. The cooking is continued for 1 hour after completion of the addition. The reaction mixture is filtered hot and the filtrate is evaporated in vacuo to ca. 10 ml. It is then diluted with water until crystallization begins. The 2,4'-dichloro-5-nitro-biphenyl ether is recrystallized from ethanol, then from petroleum gasoline ether to a melting point of 93 ° C. The product is hydrogenated by the procedure of Example 1 b. The thus-obtained pure 5-amino-2,4'-dichlorobiphenyl ether is used without purification in the next step. .

En blanding af 9 g af ovenævnte amin, 12,6 g 3,5-dibrom-sali-cylsyre og 1,45 ml phosphortrichlorid i 150 ml chlorbenzen 20 omrøres og koges i 3 timer. Den filtreres varm og inddampes. Den olieagtige remanens omkrystalliseres af benzen og omkrystalliseres af vandig ethanol, hvorved fås 11 g 3,5-dibrom-4'-chlor-3,-(p-chlorphenoxy)-salicylanilid, smp: 165 - 167 "C.A mixture of 9 g of the above amine, 12.6 g of 3,5-dibromo-salicylic acid and 1.45 ml of phosphorus trichloride in 150 ml of chlorobenzene 20 is stirred and boiled for 3 hours. It is filtered hot and evaporated. The oily residue is recrystallized from benzene and recrystallized from aqueous ethanol to give 11 g of 3,5-dibromo-4'-chloro-3, - (p-chlorophenoxy) -salicylanilide, mp: 165 - 167 ° C.

25 Når ovennævnte fremgangsmåde gentages under anvendelse af ækvivalente mængder af nedennævnte phenolforbindelser eller phenylthioforbindelser i stedet for p-chlorphenol, og når der anvendes ækvivalente mængder halogennitrobenzener, der 30 er beskrevet i det efterfølgende, i stedet for 3,4-dichlor-nitrobenzen, fås det tilsvarende salicylanilid med Q i formel I knyttet til meta-stillingen af amid-nitrogenatomet.When the above procedure is repeated using equivalent amounts of the below phenol compounds or phenylthio compounds in place of p-chlorophenol and when equivalent amounts of halo nitrobenzenes described below are substituted for 3,4-dichloro-nitrobenzene, the corresponding salicyl anilide having Q in formula I attached to the meta position of the amide nitrogen atom.

EKSEMPEL 30 35 - 3,5-dibrom-4'-(p-brombenzensulfonyl)-salicylanilid.Example 30 35 - 3,5-dibromo-4 '- (p-bromobenzenesulfonyl) salicylanilide.

16 14601616 146016

En blanding af 28,2 g 4-amino-4'-brombiphenylsulfon, 25,8 g 5.5- dibrom-salicylsyre og 2,5 ml phosphortrichlorid i 300 ml chlorbenzen koges under kraftig omrøring i 3 timer. Den varme opløsning filtreres og inddampes, indtil krystallisa- 3 tionen sætter igang. Krystallerne filtreres og omkrystalliseres af dimethylformamid, hvorved fås 47 g 3,5-dibrom-4 '-(p-brombenzensulfonyl)-salicylanilid, smp: 283 - 285 °C, dekomp.A mixture of 28.2 g of 4-amino-4'-bromobiphenylsulfone, 25.8 g of 5.5-dibromo-salicylic acid and 2.5 ml of phosphorus trichloride in 300 ml of chlorobenzene is boiled under vigorous stirring for 3 hours. The hot solution is filtered and evaporated until crystallization starts. The crystals are filtered and recrystallized from dimethylformamide to give 47 g of 3,5-dibromo-4 '- (p-bromobenzenesulfonyl) -salicylanilide, mp: 283 - 285 ° C, decomp.

10 Når ovennævnte fremgangsmåde gentages med ækvivalente mængder af ovennævnte salicylsyre-forbindelser i stedet for 3.5- dibromsalicylsyre, fås det tilsvarende benzen-sulfonyl-salicylanilid.When the above procedure is repeated with equivalent amounts of the above-mentioned salicylic acid compounds instead of 3.5-dibromo-salicylic acid, the corresponding benzenesulfonyl-salicylanilide is obtained.

15 De tilsvarende sulfinyl-forbindelser fås ved at gentage o-vennævnte fremgangsmåde under anvendelse af biphenylsul-foxid i stedet for biphenylsulfonen.The corresponding sulfinyl compounds are obtained by repeating the o-friend mentioned process using biphenyl sulfoxide instead of the biphenyl sulfone.

EKSEMPEL 51 20 3.5- dibrom-4'-benzoyl-salicylanilid.EXAMPLE 51 3,5-Dibromo-4'-benzoyl-salicylanilide.

Fremgangsmåden ifølge eksempel 1 c følges under anvendelse af 4-amino-benzophenon i stedet for 4-amino-2-chlorphe-25 nylether til dannelse af 3,5-dibrom-4'-benzoyl-salicylanilid, smp: 220 - 222 °C.The procedure of Example 1c is followed using 4-amino-benzophenone instead of 4-amino-2-chlorophenyl ether to give 3,5-dibromo-4'-benzoyl-salicylanilide, mp: 220 - 222 ° C .

EKSEMPEL 32 30 3,5-dibrom-3'-chlor-4'-(p-chlorbenzyloxy)-salicylanilid.EXAMPLE 32 3,5-Dibromo-3'-chloro-4 '- (p-chlorobenzyloxy) -salicylanilide.

Fremgangsmåden ifølge eksempel 1 c følges under anvendelse af m-chlor-p-(p-chlorbenzyloxy)-anilin i stedet for 4-ami-no-2-chlorphenyl-p-chlorphenylether til dannelse af 3,5-35 dibrom-3'-chlor-41 -(p-chlorbenzyloxy)-salicylanilid, smp: 208 - 209 °C.The procedure of Example 1c is followed using m-chloro-β- (β-chlorobenzyloxy) -aniline instead of 4-amino-2-chlorophenyl-β-chlorophenyl ether to give 3.5-35 dibromo-3 ' -chloro-41 - (p-chlorobenzyloxy) -salicylanilide, mp: 208 - 209 ° C.

17 EKSEMPEL 33 146016 3.5- dibrom-4,-chlor-3'-(p-chlorphenoxy)-salicylanilid.EXAMPLE 33 3.5-Dibromo-4, -chloro-3 '- (p-chlorophenoxy) -salicylanilide.

5 En opløsning af 29,6 g (0,1 mol) 3,5-dibrom-salicylsyre i 400 ml methanol-fri dimethyl formamid behandles med 7 g (0,1 mol) kaliummethoxid. Kaliumsaltet behandles dernæst med 100 ml 1 mol svovltrioxid i dimethylformamid ved 15 -20 °C. Efter henstand i 10 minutter behandles denne blanding 10 med 25,4 g (0,1 mol) 3-p-chlorphenoxy-4-chloranilin, og den dannede opløsning henstilles ved stuetemperatur i 30 minutter. Opløsningen fortyndes med 4 rumfang vand, og bundfaldet opsamles ved filtrering og vaskes med vand. Det urene produkt opløses i 300 ml benzen og renses og tørres ved a-15 zeotropisk destillation. Ved omkrystallisation af benzen fås rent 3,5-dibrom-4'-chlor-3'-(p-chlorphenoxy)-salicylanilid, smp: 167 - 169 °C.A solution of 29.6 g (0.1 mole) of 3,5-dibromo-salicylic acid in 400 ml of methanol-free dimethyl formamide is treated with 7 g (0.1 mole) of potassium methoxide. The potassium salt is then treated with 100 ml of 1 mole of sulfur trioxide in dimethylformamide at 15-20 ° C. After standing for 10 minutes, this mixture 10 is treated with 25.4 g (0.1 mole) of 3-p-chlorophenoxy-4-chloroaniline and the resulting solution is allowed to stand at room temperature for 30 minutes. The solution is diluted with 4 volumes of water and the precipitate is collected by filtration and washed with water. The crude product is dissolved in 300 ml of benzene and purified and dried by α-15 zeotropic distillation. Recrystallization of benzene gives pure 3,5-dibromo-4'-chloro-3 '- (p-chlorophenoxy) -salicylanilide, mp: 167 - 169 ° C.

EKSEMPEL 34 20 3.5- dibrom-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid.EXAMPLE 34 3.5-Dibromo-3'-Chloro-4 '- (p-chlorophenoxy) -salicylanilide.

En opløsning af 2,96 g (0,01 mol) 3,5-dibromsalicylsyre og 1,01 g (0,01 mol) triethylamin i 20 ml tørt acetonitril sæt-25 tes ved 0 - 20 °C til 2,53 g (0,01 mol) N-ethyl-5-phenyl-isoxazolium-3'-sulfonat i 20 ml acetonitril. Blandingen omrøres, indtil en klar opløsning er dannet, og der tilsættes en opløsning af 2,54 g (0,01 mol) 3-chlor-4-(p-chlorphenoxy)-anilin og 1,01 g (0,01 mol) triethylamin i 20 ml tørt ace-30 tonitril ved 0-20 °C. Blandingen omrøres i 15 - 20 timer, hvorefter opløsningen inddampes. Remanensen udrives med vand, og det urene produkt opsamles ved filtrerina. Ved omkrvs-tallisation af benzenpetroleumsnaphtha fås rent 3,5-dibrom-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid, smp: 164 - 166 °C.A solution of 2.96 g (0.01 mole) of 3,5-dibromosalicylic acid and 1.01 g (0.01 mole) of triethylamine in 20 ml of dry acetonitrile is added at 0-20 ° C to 2.53 g (0.01 mole) of N-ethyl-5-phenyl-isoxazolium-3'-sulfonate in 20 ml of acetonitrile. The mixture is stirred until a clear solution is formed and a solution of 2.54 g (0.01 mole) of 3-chloro-4- (p-chlorophenoxy) aniline and 1.01 g (0.01 mole) is added. triethylamine in 20 ml of dry acetonitrile at 0-20 ° C. The mixture is stirred for 15-20 hours, after which the solution is evaporated. The residue is triturated with water and the crude product is collected by filtration. By recirculating benzene petroleum naphtha, pure 3,5-dibromo-3'-chloro-4 '- (p-chlorophenoxy) -salicylanilide is obtained, mp: 164 - 166 ° C.

EKSEMPEL 35 18 146016 5-brom-3-nitro-3,-chlor-4'-(p-chlorpherioxy)-salicylanilid.EXAMPLE 35 5-Bromo-3-nitro-3, -chloro-4 '- (p-chloropherioxy) -salicylanilide.

5 2,62 g (0,01 mol) 3-nitro-5-brom-salicylsyre koges med 25 ml thionylchlorid i 2 timer. Overskud af thionylchlorid af-destilleres ved atmosfærisk tryk, remanensen skylles to gange med benzen og omrøres dernæst i 2 timer med en ether-opløsning af ammoniak. Overskud af ether og ammoniak afde-10 stilleres ved atmosfærisk tryk. Remanensen opløses i 25 ml chloroform, og der tilsættes 0,68 g (0,01 mol) bortrifluor-etherat. Chloroformen afdampes, og remanensen opløses i 75 ml chlorbenzen. 2,54 g (0,01 mol) 3-chlor-4-(p-chlorphen-oxy)-anilin sættes til chlorbenzen-opløsningen af bortri-15 fluorid-amid-komplekset, og blandingen opvarmes på dampbad i 30 minutter. Reaktionsblandingen afkøles, vaskes med vand og inddampes i vakuum til ca. 30 ml. Den dannede tykke opslæmning filtreres og vaskes med petroleumsnaphtha.. Ued omkrystallisation af ethanol fås rent 5-brom-3-nitro-3'-20 chlor-41-(p-chlorphenoxy)-salicylanilid, smp: 150 - 152 °C.2.62 g (0.01 mole) of 3-nitro-5-bromo-salicylic acid are boiled with 25 ml of thionyl chloride for 2 hours. Excess thionyl chloride is distilled off at atmospheric pressure, the residue is rinsed twice with benzene and then stirred for 2 hours with an ether solution of ammonia. Excess ether and ammonia are distilled off at atmospheric pressure. The residue is dissolved in 25 ml of chloroform and 0.68 g (0.01 mole) of boron trifluoro etherate is added. The chloroform is evaporated and the residue is dissolved in 75 ml of chlorobenzene. 2.54 g (0.01 mole) of 3-chloro-4- (p-chlorophenoxy) aniline are added to the chlorobenzene solution of the boron trifluoride-amide complex and the mixture is heated on a steam bath for 30 minutes. The reaction mixture is cooled, washed with water and evaporated in vacuo to ca. 30 ml. The thick slurry formed is filtered and washed with petroleum naphtha. Without recrystallization of ethanol pure 5-bromo-3-nitro-3'-20 chloro-41- (p-chlorophenoxy) -salicylanilide is obtained, mp: 150 - 152 ° C.

EKSEMPEL 36 3,5-dibrom-3'-chlor-4,-(p-chlorphenoxy)-salicylanilid.EXAMPLE 36 3,5-Dibromo-3'-Chloro-4- (p-chlorophenoxy) -salicylanilide.

25 - 72,5 g (0,25 mol) 3,5-dibrom-salicylsyre koges med 55 ml thionylchlorid i 2 timer i 350 ml benzen. Benzenet og overskud af thionylchlorid afdampes i vakuum, og remanensen gen-opløses i 80 ml benzen. Denne benzenopløsning sættes dernæst i løbet af 10 minutter under kraftig omrøring til en opløsning af 62,3 g (0,245 mol) 4-amino-2-chlorphenyl-p-chlor-phenylether i 250 ml 15 % natriumhydroxid. Reaktionsblandingen omrøres i 60 minutter efter tilsætning af syrechlo-ridet er afsluttet. Opløsningens pH-værdi indstilles på 6, og det urene produkt udskilles af opløsningen. Ued omkrystallisation af benzenpetroleumsnahptha, fås rent 3,5-di- 1460 ΐ 6 19 brom-31-chlor-4'-(p-chlorphenoxy)-salicylanilid, smp: 164 -166 °C.25 - 72.5 g (0.25 mol) of 3,5-dibromo-salicylic acid are boiled with 55 ml of thionyl chloride for 2 hours in 350 ml of benzene. The benzene and excess thionyl chloride are evaporated in vacuo and the residue redissolved in 80 ml of benzene. This benzene solution is then added over 10 minutes with vigorous stirring to a solution of 62.3 g (0.245 mol) of 4-amino-2-chlorophenyl-p-chlorophenyl ether in 250 ml of 15% sodium hydroxide. The reaction mixture is stirred for 60 minutes after the addition of the acid chloride is completed. The pH of the solution is set to 6 and the crude product is separated from the solution. Without recrystallization of benzene petroleum naphtha, pure 3,5-di-1460 ΐ 6 19 bromo-31-chloro-4 '- (p-chlorophenoxy) -salicylanilide, mp: 164 -166 ° C, is obtained.

EKSEMPEL 37 5 3-nitro-3-brom-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid.EXAMPLE 37 3-Nitro-3-bromo-3'-chloro-4 '- (p-chlorophenoxy) -salicylanilide.

En opløsning af 9,2 g (0,1 mol) N-methy1-acetimidylchlorid i 150 ml toluen behandles ved -10 °C med 26,2 g (0,1 mol) 3-nitro-5-brom-salicylsyre. Reaktionsblandingen opvarmes til 25 - 30 °C, og 25,4 g (0,1 mol) 3-chlor-4-p-chlorphenoxy-anilin tilsættes. Reaktionsblandingen henstilles i 20 minutter ved stuetemperatur, hvorefter reaktionsblandingen opvarmes til 80 °C i 30 minutter. Det urene produkt udkrystalli-15 seres ved fortynding med methanol. Ved omkrystallisation af acetone-methanol fås rent 3-nitro-5-brom-31-chlor-4' -(p-chlorphenoxy)-salicylanilid, smp: 149 - 150 °C.A solution of 9.2 g (0.1 mole) of N-methyl-acetimidyl chloride in 150 ml of toluene is treated at -10 ° C with 26.2 g (0.1 mole) of 3-nitro-5-bromo-salicylic acid. The reaction mixture is heated to 25-30 ° C and 25.4 g (0.1 mole) of 3-chloro-4-p-chlorophenoxy-aniline are added. The reaction mixture is allowed to stand for 20 minutes at room temperature, after which the reaction mixture is heated to 80 ° C for 30 minutes. The crude product is crystallized by dilution with methanol. Recrystallization from acetone-methanol gives pure 3-nitro-5-bromo-31-chloro-4 '- (p-chlorophenoxy) -salicylanilide, mp: 149-150 ° C.

EKSEMPEL 38 20 3-nitro-5-brom-31-chlor-4’-(p-chlorphenoxy)-salicylanilid.EXAMPLE 38 3-Nitro-5-bromo-31-chloro-4 '- (p-chlorophenoxy) salicylanilide.

En blanding af 26,2 g (0,1 mol) 3-nitro-5-brom-salicylsyre og 25,4 g (0,1 mol) 3-chlor-4-p-chlorphenoxy-anilin i 400 25 ml toluen koges under omrøring. Det ved dannelsen af amidet frigjorte vand fjernes ved azeotropisk destillation i løbet af 12 timer. Reaktionsblandingen inddampes til 100 ml, og produktet udskilles af opløsningen ved afkøling.A mixture of 26.2 g (0.1 mole) of 3-nitro-5-bromo-salicylic acid and 25.4 g (0.1 mole) of 3-chloro-4-p-chlorophenoxy-aniline in 400 ml of toluene is boiled. under stirring. The water released by the amide formation is removed by azeotropic distillation over 12 hours. The reaction mixture is evaporated to 100 ml and the product is separated from the solution by cooling.

Det urene produkt opsamles ved filtrering og vaskes med 30 toluen. Ved omkrystallisation af acetone-methanol fås rent 3-nitro-5-brom-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid, smp: 149 - 150 °C.The crude product is collected by filtration and washed with toluene. Recrystallization from acetone-methanol gives pure 3-nitro-5-bromo-3'-chloro-4 '- (p-chlorophenoxy) -salicylanilide, mp: 149-150 ° C.

Når der ved ovennævnte reaktion anvendes enten phenyl-3-ni-35 tro-5-brom-salicylat, methyl-3-nitro-5-brom-salicylat, phenyl-3-nitro-5-brom-thiol-salicylat, 3-nitro-5-brom-thiolsalicylsyre eller 3-nitro-5-bromsalicylethylcarbamat 20 146016 i stedet for 3-nitro-5-bromsalicylsyre, fås det identiske produkt, dus. 3-nitro-5-brom-31-chlor-4*-(p-chlorphenoxy)-salicylanilid.When the above reaction is used, either phenyl 3-nitro-5-bromo salicylate, methyl 3-nitro-5-bromo salicylate, phenyl 3-nitro-5-bromo-thiol salicylate, 3- nitro-5-bromo-thiolsalicylic acid or 3-nitro-5-bromosalicylethylcarbamate instead of 3-nitro-5-bromosalicylic acid, the identical product is thus obtained. 3-nitro-5-bromo-31-chloro-4 * - (p-chlorophenoxy) -salicylanilid.

5 EKSEMPEL 39 3,5-dibrom-3'-chlor-4'-(p-chlorphenoxy)-salicyanilid.EXAMPLE 39 3,5-Dibromo-3'-Chloro-4 '- (p-chlorophenoxy) -salicyanilide.

En suspension af 29,6 g (0,1 mol) 3,5-dibrom-salicylsyre i: 10 300 ml tetrahydrofuran afkøles til -10 °C under omrøring og behandles samtidig med 10,1 g (0,1 mol) triethylamin og 10,8 g (0,1 mol) ethylchlorformiat. Opløsningen omrøres i 30 minutter ved -10 °C, hvorefter 25,4 g (0,1 moi) 3-chlor- 4-(p-chlorphenoxy)-anilin tilsættes, og reaktionsblandingen 15 henstilles ved stuetemperatur. Blandingen inddampes til 1/10 rumfang, og produktet opsamles ved filtrering og vaskes med tetrahydrofuran og vand. Efter tørring i vakuum fås rent 3,5-dibrom-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid, smp: 173 - 175 °C.A suspension of 29.6 g (0.1 mole) of 3,5-dibromo-salicylic acid in: 300 ml of tetrahydrofuran is cooled to -10 ° C with stirring and treated simultaneously with 10.1 g (0.1 mole) of triethylamine and 10.8 g (0.1 mole) of ethyl chloroformate. The solution is stirred for 30 minutes at -10 ° C, then 25.4 g (0.1 mL) of 3-chloro-4- (p-chlorophenoxy) aniline are added and the reaction mixture is allowed to stand at room temperature. The mixture is evaporated to 1/10 volume and the product is collected by filtration and washed with tetrahydrofuran and water. After drying in vacuo, pure 3,5-dibromo-3'-chloro-4 '- (p-chlorophenoxy) -salicylanilide is obtained, mp: 173 - 175 ° C.

2020

Ovennævnte reaktion kan også udføres ved anvendelse af me-thylchlorformiat eller. p,henylchlorformiat i stedet for ethylchlorformiat.The above reaction may also be carried out using methyl chloroformate or. p, henyl chloroformate instead of ethyl chloroformate.

25 EKSEMPEL '40 3-nitro-5-brom-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid.EXAMPLE 40 3-Nitro-5-bromo-3'-chloro-4 '- (p-chlorophenoxy) -salicylanilide.

En blanding af 50 g 3-nitro-5-bromsalicylsyre og 200 ml 30 thionylchlorid koges, indtil udviklingen af h.ydrogenchlo-rid er ophørt. Blandingen filtreres, og inddampes til en olie. Efter skylning med p-dioxan i vakuum omrøres det urene syrechlorid med 400 ml dioxan ved stuetemperatur. En koncentreret vandig opløsning indeholdende 65 g natriumazid sæt-35 tes hurtigt til syrechloridet. Reaktionsblandingen henstilles i 2 timer ved stuetemperatur, hvorefter den inddampes 146016 21 til lille rumfang, og remanensen vaskes med vand på en tragt. Det urene azid lufttørres og behandles dernæst med 48 g 3-chlor-4-(p-chlorphenoxy)-anilin i 300 ml chlorben-zen ved stuetemperatur. Reaktionsblandingen henstilles i 3 17 timer, hvorefter udfældningen af produktet indledes ved tilsætning af ethanol. Derved fås efter filtrering og tørring rent 3-nitro-5-brom-3'-chlor-4'-(p-chlorphenoxy)-sali-cylanilid, smp: 148 - 150 °C.A mixture of 50 g of 3-nitro-5-bromosalicylic acid and 200 ml of thionyl chloride is boiled until the development of hydrogen chloride has ceased. The mixture is filtered and evaporated to an oil. After rinsing with p-dioxane in vacuo, the crude acid chloride is stirred with 400 ml of dioxane at room temperature. A concentrated aqueous solution containing 65 g of sodium azide is rapidly added to the acid chloride. The reaction mixture is allowed to stand for 2 hours at room temperature, then evaporated to a small volume and the residue is washed with water on a funnel. The crude azide is air dried and then treated with 48 g of 3-chloro-4- (p-chlorophenoxy) aniline in 300 ml of chlorobenzene at room temperature. The reaction mixture is allowed to stand for 17 hours, after which the precipitation of the product is initiated by the addition of ethanol. Thereby, after filtration and drying, pure 3-nitro-5-bromo-3'-chloro-4 '- (p-chlorophenoxy) -salicylanilide is obtained, mp: 148-150 ° C.

10 EKSEMPEL 41 5-brom-3-nitro-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid.EXAMPLE 41 5-Bromo-3-nitro-3'-chloro-4 '- (p-chlorophenoxy) -salicylanilide.

3,33 g (0,013 mol) 4-amino-2,4'-dichlorphenylether og 3,40 g 15 5-brom-3-nitro-salicylsyre i 15 ml triethylphosphit opvarmes med 1,2 g ethyldichlorphosphit i 1 time på dampbad. Reaktionsblandingen hældes dernæst i vand, og det urene produkt udfældes af opløsningen. Ved omkrystallisation af di-methylformamid/ethanol/vand 3:10:1 fås 0,8 g 5-brom-3-ni-20 tro-3 '-chlor-4'-(p-chlorphenoxy)-salicylanilid, smp: 150 -152 °C.3.33 g (0.013 mol) of 4-amino-2,4'-dichlorophenyl ether and 3.40 g of 5-bromo-3-nitro-salicylic acid in 15 ml of triethyl phosphite are heated with 1.2 g of ethyl dichlorophosphite for 1 hour on a steam bath. The reaction mixture is then poured into water and the crude product is precipitated by the solution. Recrystallization of dimethylformamide / ethanol / water 3: 10: 1 gives 0.8 g of 5-bromo-3-nitro-3 '-chloro-4' - (p-chlorophenoxy) -salicylanilide, mp: 150 -152 ° C.

Ovennævnte reaktion kan også udføres ved anvendelse af en ækvivalent mængde tetraethylpyrophosphit eller diethyl-25 chlorphosphit i stedet for ethyldichlorphosphit.The above reaction can also be carried out using an equivalent amount of tetraethyl pyrophosphite or diethyl chlorophosphite in place of ethyl dichlorophosphite.

EKSEMPEL 42 3,5-dibrom-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid.EXAMPLE 42 3,5-Dibromo-3'-Chloro-4 '- (p-chlorophenoxy) -salicylanilide.

3030

En blanding af 29,6 g (0,1 mol) 3,5-dibrom-salicylsyre og 16,2 g (0,1 mol) N,N1-carbonyldiimidazol i 150 ml tetrahy-drofuran henstilles i 30 minutter ved stuetemperatur, hvorefter 25,4 g (0,1 mol) 3-chlor-4-(p-chlorphenoxy)-anilin 35 tilsættes. Reaktionsblandingen henstilles i 17 timer, hvorefter opløsningen inddampes i vakuum. Remanensen udrives 22 146016 med kold 1 N saltsyre, filtreres, vaskes med 1 N saltsyre og vand og lufttørres. Ued omkrystallisation af benzen fås rent 3,5-dibrom-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid, smp: 174 - 175 °C.A mixture of 29.6 g (0.1 mole) of 3,5-dibromo-salicylic acid and 16.2 g (0.1 mole) of N, N1-carbonyldiimidazole in 150 ml of tetrahydrofuran is allowed to stand for 30 minutes at room temperature, then 25.4 g (0.1 mole) of 3-chloro-4- (p-chlorophenoxy) aniline are added. The reaction mixture is allowed to stand for 17 hours, after which the solution is evaporated in vacuo. The residue is triturated with cold 1N hydrochloric acid, filtered, washed with 1N hydrochloric acid and water and air dried. Without recrystallization of benzene, pure 3,5-dibromo-3'-chloro-4 '- (p-chlorophenoxy) -salicylanilide is obtained, mp: 174 - 175 ° C.

5 EKSEMPEL 43 3-nitro-5-brom-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid.EXAMPLE 43 3-Nitro-5-bromo-3'-chloro-4 '- (p-chlorophenoxy) -salicylanilide.

En suspension af 26,2 g (0,1 mol) 3-nitro-5-brom-salicyl-syre og 25,4 g (0,1 mol) 3-chlor-4-(p-chlorphenoxy)-anilin i 150 ml ethylacetat behandles med 21 g ethoxyacetylen. Blandingen koges i 2 timer, hvorefter overskud af ethoxyacetylen og ethylacetat fradestilleres. Remanensen omkrys-15 talliseres af acetone-methanol, hvorved fås rent 3-nitro- 5-brom-3'-chlor-41-(p-chlorphenoxy)-salicylanilid, smp: 148 - 151 °C.A suspension of 26.2 g (0.1 mole) of 3-nitro-5-bromo-salicylic acid and 25.4 g (0.1 mole) of 3-chloro-4- (p-chlorophenoxy) aniline in 150 ml of ethyl acetate is treated with 21 g of ethoxyacetylene. The mixture is boiled for 2 hours, after which excess ethoxyacetylene and ethyl acetate are distilled off. The residue is recrystallized from acetone-methanol to give pure 3-nitro-5-bromo-3'-chloro-41- (p-chlorophenoxy) -salicylanilide, mp: 148 - 151 ° C.

EKSEMPEL 44 20 - 3,5-dibrom-4'-chlor-3'-(p-chlorphenoxy)-salicylanilid.EXAMPLE 44 - 3,5-Dibromo-4'-chloro-3 '- (p-chlorophenoxy) salicylanilide.

2,1 g (10 mmol) dicyclohexylcarbodiimid sættes under omrøring til en blanding af 2,96 g (10 mmol) 3,5-dibromsalicyl-25 Syre og 2,54 g (10 mmol) 4-chlor-3-(p-chlorphenoxy)-ani-lin. Blandingen henstilles ved stuetemperatur i 24 timer, hvorefter reaktionsblandingen opvarmes til 50 °C, og di-cyclohexyl-urinstoffet frafiltreres. Produktet udkrystalliserer ved afkøling af benzen-filtratet. Ued omkrystalli-5^ sation af benzen fås rent 3,5-dibrom-4'-chlor-3'-(p-chlor-phenoxy)-salicylanilid, smp: 168 - 169 °C.2.1 g (10 mmol) of dicyclohexylcarbodiimide is added with stirring to a mixture of 2.96 g (10 mmol) of 3,5-dibromosalicylic acid and 2.54 g (10 mmol) of 4-chloro-3- (p chlorophenoxy) anilino-lin. The mixture is allowed to stand at room temperature for 24 hours, then the reaction mixture is heated to 50 ° C and the di-cyclohexyl urea is filtered off. The product crystallizes by cooling the benzene filtrate. Without recrystallization of benzene, pure 3,5-dibromo-4'-chloro-3 '- (p-chloro-phenoxy) -salicylanilide is obtained, mp: 168 - 169 ° C.

EKSEMPEL 45 55 3,5-dibrom-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid.EXAMPLE 45 3,5-dibromo-3'-chloro-4 '- (p-chlorophenoxy) salicylanilide.

12 g (0,1 mol) bortrichlorid sættes til en opløsning af 146016 23 76,2 g (0,3 mol) 3-chlor-4-(p-chlorphenoxy)-anilin og 35 g (0,3 mol) triethylamin i 1 liter benzen. Reaktionsblandingen henstilles ved stuetemperatur i 20 minutter, hvorefter aminoboranet udfældes ved tilsætning af petroleumsether. 29,6 5 g (0,1 mol) 3,5-dibromsalicylsyre og 7,7 g (0,1 mol) amino-boran suspenderes i 400 ml benzen, og blandingen koges i 10 minutter. Reaktionsblandingen afkøles dernæst til 40 °C og vaskes med 100 ml 0,1 N saltsyre og vand. Opløsningen inddampes til lille rumfang, og produktet udkrystalliserer 10 ved stuetemperatur. Ved omkrystallisation af benzen fås rent 3,5-dibrom-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid, smp 171 - 173 °C.12 g (0.1 mole) of boron trichloride are added to a solution of 76.2 g (0.3 mole) of 3-chloro-4- (p-chlorophenoxy) aniline and 35 g (0.3 mole) of triethylamine in 1 liter of benzene. The reaction mixture is allowed to stand at room temperature for 20 minutes, after which the aminoborane is precipitated by the addition of petroleum ether. 29.6 5 g (0.1 mole) of 3,5-dibromo salicylic acid and 7.7 g (0.1 mole) of amino borane are suspended in 400 ml of benzene and the mixture is boiled for 10 minutes. The reaction mixture is then cooled to 40 ° C and washed with 100 ml of 0.1 N hydrochloric acid and water. The solution is evaporated to a small volume and the product crystallizes out at room temperature. Recrystallization of benzene gives pure 3,5-dibromo-3'-chloro-4 '- (p-chlorophenoxy) -salicylanilide, mp 171 - 173 ° C.

EKSEMPEL 46 15 3-nitro-5-brom-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid.EXAMPLE 46 3-nitro-5-bromo-3'-chloro-4 '- (p-chlorophenoxy) -salicylanilide.

En blanding af 25,4 g (0,1 mol) 3-chlor-4-(p-chlorphenoxy)-anilin og 25,8 g (0,1 mol) tetraethylpyrophosphit i 220 ml 20 diethylphosphit opvarmes på dampbad i 1,5 timer. 26,2 g (0,1 mol) og 3-nitro-5-brom-salicylsyre tilsættes, og opvarmningen fortsættes i 2 timer. Reaktionsblandingen afkøles, og produktet udfældes ved tilsætning af 1 liter vand.A mixture of 25.4 g (0.1 mole) of 3-chloro-4- (p-chlorophenoxy) aniline and 25.8 g (0.1 mole) of tetraethyl pyrophosphite in 220 ml of diethyl phosphite is heated on a steam bath for 1.5 hours. hours. 26.2 g (0.1 mole) and 3-nitro-5-bromo-salicylic acid are added and heating is continued for 2 hours. The reaction mixture is cooled and the product precipitates by the addition of 1 liter of water.

Ved omkrystallisation af acetone-methanol fås rent 3-nitro-25 5-brom-3'-chlor-41-(p-chlorphenoxy)-salicylanilid, smp: 149 - 150 °C.Recrystallization from acetone-methanol gives pure 3-nitro-5-bromo-3'-chloro-41- (p-chlorophenoxy) -salicylanilide, mp: 149-150 ° C.

EKSEMPEL 47 30 3,5-dibrom-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid.EXAMPLE 47 3,5-Dibromo-3'-Chloro-4 '- (p-chlorophenoxy) -salicylanilide.

Til en opløsning af 25,4 g (0,1 mol) 3-chlor-4-(p-chlorphenoxy )-anilin i 150 ml o-dichlorbenzen sættes 10,1 g (0,1 mol) triethylamin og derefter 5,11 g (0,03 mol) phosphoroxy-35 chlorid under afkøling. Blandingen omrøres i 20 minutter ved 20 - 25 °C, hvorefter 29,6 g (0,1 mol) 3,5-dibromsali- 24 146016 cylsyre tilsættes, og den dannede opløsning koges i 3 timer. Reaktionsblandingen afkøles, filtreres, vaskes med vand og tørres over natriumsulfat. Tørringsmidlet frafiltreres, og produktet udfældes ved tilsætning af n-hexan. Ved omkry-5 stallisation af benzen fås 3,5-dibrom-3'-chlor-4'-(p-chlor-phenoxy)-salicylanilid, smp: 173 - 175 °C.To a solution of 25.4 g (0.1 mole) of 3-chloro-4- (p-chlorophenoxy) aniline in 150 ml of o-dichlorobenzene is added 10.1 g (0.1 mole) of triethylamine and then 5.11 g (0.03 mole) of phosphorus oxychloride on cooling. The mixture is stirred for 20 minutes at 20-25 ° C, then 29.6 g (0.1 mole) of 3,5-dibromosalic acid are added and the resulting solution is boiled for 3 hours. The reaction mixture is cooled, filtered, washed with water and dried over sodium sulfate. The desiccant is filtered off and the product precipitates by the addition of n-hexane. Recrystallization of benzene gives 3,5-dibromo-3'-chloro-4 '- (p-chloro-phenoxy) -salicylanilide, mp: 173 - 175 ° C.

EKSEMPEL 48 10 3,5-dibrom-41-chlor-31-(p-chlorphenoxy)-salicylanilid.EXAMPLE 48 3,5-Dibromo-41-Chloro-31- (p-chlorophenoxy) salicylanilide.

Til en opløsning af 25,4 g (0,1 mol) 4-chlor-3-(p-chlorphe-noxy)-anilin i 20 ml o-dichlorbenzen sættes samtidig 10,1 g (0,1 mol) triethylamin og 8,2 g (0,05 mol) ethyldichlor-15 phosphat ved 0-50 °C. Blandingen bringes gradvis til stuetemperatur og henstilles i 2 timer, hvorefter 29,6 g (0,1 mol) 3,5-dibromsalicylsyre tilsættes. Reaktionsblandingen koges i 4 timer ved 180 °C, hvorefter opløsningen inddampes i vakuum. Produktet udfældes ved tilsætning af 20 benzen og opsamles ved filtrering. Efter tørring fås rent 3,5-dibrom-4'-chlor-3,-(p-chlarphenoxy)-salicylanilid, smp: 168 - 169 °C.To a solution of 25.4 g (0.1 mole) of 4-chloro-3- (p-chlorophenoxy) aniline in 20 ml of o-dichlorobenzene was added simultaneously 10.1 g (0.1 mole) of triethylamine and 8 , 2 g (0.05 mole) of ethyl dichloro-phosphate at 0-50 ° C. The mixture is gradually brought to room temperature and allowed to stand for 2 hours, after which 29.6 g (0.1 mole) of 3,5-dibromo-salicylic acid are added. The reaction mixture is boiled for 4 hours at 180 ° C, then the solution is evaporated in vacuo. The product is precipitated by the addition of 20 benzene and collected by filtration. After drying, pure 3,5-dibromo-4'-chloro-3- (p-chlorophenoxy) -salicylanilide is obtained, mp: 168 - 169 ° C.

Ved ovennævnte reaktion kan salicylanilidet også fås ved anvendelse af ethyldichlorphosphat i stedet for diethyl-25 chlorphosphat.In the above reaction, the salicyl anilide can also be obtained using ethyl dichlorophosphate instead of diethyl chlorophosphate.

EKSEMPEL 49 3-nitro-5-brom-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid.Example 49 3-nitro-5-bromo-3'-chloro-4 '- (p-chlorophenoxy) -salicylanilide.

25,4 g (0,1 mol) 3-chlor-4-(p-chlorphenoxy)-anilin opløses i 450 ml benzen, og til denne opløsning sættes under afkø-30 ling 17,5 g (0,1 mol) N-butyl-dichlorphosphit og 20,2 g (0,2 mol) triethylamin. Blandingen omrøres i 2 timer ved stuetemperatur, hvorefter den afkøles til 10 °C, og det udfældede triethylamin-hydrohalogenid frafiltreres. Til ami-dophosphit-opløsningen sættes 26,2 g (0,1 mol) 3-nitro-5-35 bromsalicylsyre, og blandingen koges i 5 timer. Reaktions-blandingen afkøles og filtreres, og produktet omkrystalliseres ved tilsætning af 2 rumfang ethanol. Produktet opsam- 146016 25 les ved filtrering, og efter tørring fås rent 3-nitro-5-brom-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid, smp: 148 -149 °C.25.4 g (0.1 mole) of 3-chloro-4- (p-chlorophenoxy) aniline are dissolved in 450 ml of benzene and to this solution 17.5 g (0.1 mole) of N are added under cooling. -butyl dichlorophosphite and 20.2 g (0.2 mole) of triethylamine. The mixture is stirred for 2 hours at room temperature, then cooled to 10 ° C and the precipitated triethylamine hydrohalide is filtered off. To the amidophosphite solution is added 26.2 g (0.1 mole) of 3-nitro-5-35 bromosalicylic acid and the mixture is boiled for 5 hours. The reaction mixture is cooled and filtered, and the product is recrystallized by adding 2 volumes of ethanol. The product is collected by filtration and after drying pure 3-nitro-5-bromo-3'-chloro-4 '- (p-chlorophenoxy) -salicylanilide is obtained, mp: 148 -149 ° C.

5 EKSEMPEL 50 3.5- dibrom-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid.EXAMPLE 50 3.5-Dibromo-3'-Chloro-4 '- (p-chlorophenoxy) -salicylanilide.

Til en opløsning af 25,4 g (0,1 mol) 3-chlor-4-(p-chlorphe-10 noxy)-anilin i 180 ml xylen ved 0 - 5 °C sættes 7,4 g (0,05 mol) ethyldichlorphosphit. Reaktionsblandingen koges i 2 -3 timer, indtil udviklingen af hydrogenchlorid ophører.To a solution of 25.4 g (0.1 mole) of 3-chloro-4- (p-chlorophenoxy) -aniline in 180 ml of xylene at 0-5 ° C is added 7.4 g (0.05 mole) ) ethyl dichlorophosphite. The reaction mixture is boiled for 2 -3 hours until the development of hydrogen chloride ceases.

29.6 g (0,1 mol) 3,5-dibromsalicylsyre tilsættes, og kogningen fortsættes i 4 timer. Opløsningen inddampes til 60 15 ml, og produktet omkrystalliseres ved tilsætning af 50 ml n-hexan. Ved omkrystallisation af benzen fås rent 3,5-di-brom-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid, smp: 172 -175 °C.29.6 g (0.1 mole) of 3,5-dibromo salicylic acid are added and boiling is continued for 4 hours. The solution is evaporated to 60 mL and the product is recrystallized by adding 50 mL of n-hexane. Recrystallization of benzene gives pure 3,5-di-bromo-3'-chloro-4 '- (p-chlorophenoxy) -salicylanilide, mp: 172 -175 ° C.

20 EKSEMPEL 51 3.5- dibrom-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid.EXAMPLE 51 3.5-Dibromo-3'-Chloro-4 '- (p-chlorophenoxy) -salicylanilide.

5.6 ml (0,06 mol) phosphortrichlorid sættes ved stuetempe-25 ratur til en opløsning af 32,5 g (0,13 mol) 3-chlor-4-(p- chlorphenoxy)-anilin i 400 ml chlorbenzen. Opløsningen henstilles i 10 minutter, hvorefter den koges i 4 timer, indtil alt hydrogenchlorid er frigjort. Opløsningen afkøles til stuetemperatur, uopløseligt materiale frafiltreres og 30 det urene phosphorazo-mellemprodukt fås ved inddampning i vakuum. 5,54 g (18,7 mmol) 3,5-dibromsalicylsyre sættes til en opløsning af 5 g (9,4 mmol) phosphorazo-mellemproduktet i 50 ml chlorbenzen. Blandingen opvarmes til 110 °C i 2,5 timer, hvorefter den filtreres og inddampes til 40 ml. Pro-35 duktet krystalliserer ved afkøling og opsamles ved filtrering, og efter vask med kold chlorbenzen og petroleumse- 26 146016 ther fås rent 3,5-dibrom-3'-chlor-4'-(p-chlorphenoxy)-sali-cylanilid, smp: 170 - 173 °C.5.6 ml (0.06 mol) of phosphorus trichloride is added at room temperature to a solution of 32.5 g (0.13 mol) of 3-chloro-4- (p-chlorophenoxy) aniline in 400 ml of chlorobenzene. The solution is allowed to stand for 10 minutes, then boiled for 4 hours until all hydrogen chloride is released. The solution is cooled to room temperature, the insoluble material is filtered off and the crude phosphorazo intermediate is obtained by evaporation in vacuo. 5.54 g (18.7 mmol) of 3,5-dibromo salicylic acid are added to a solution of the 5 g (9.4 mmol) phosphorazo intermediate in 50 ml of chlorobenzene. The mixture is heated to 110 ° C for 2.5 hours, then filtered and evaporated to 40 ml. The product crystallizes on cooling and is collected by filtration, and after washing with cold chlorobenzene and petroleum ether, pure 3,5-dibromo-3'-chloro-4 '- (p-chlorophenoxy) -sali-cilanilide is obtained. mp: 170 - 173 ° C.

EKSEMPEL 52 5 3,5-dibrom-3'-chlor-4,-(p-chlorphenoxy)-salicylanilid.EXAMPLE 52 3,5-Dibromo-3'-Chloro-4- (p-chlorophenoxy) -salicylanilide.

7,62 g (0,03 mol) 3-chlor-4-(p-chlorphenoxy)-anilin opvarmes til 150 - 180 °C i en nitrogenatmosfære med 0,27 .g (0,01 10 mol) fint fordelt aluminiummetal, indtil praktisk taget alt aluminium er forbrugt. Blandingen suspenderes i 75 ml chlor-benzen, og til denne suspension sættes under omrøring 2,96 g (0,01 mol) 3,5-dibromsalicylsyre i 25 ml chlorbenzen. Efter at den exoterme reaktion, der forløber, er ophørt, af-15 sluttes reaktionen ved kogning af blandingen i 1 time.7.62 g (0.03 mol) of 3-chloro-4- (p-chlorophenoxy) aniline are heated to 150-180 ° C in a nitrogen atmosphere of 0.27 g (0.01 10 mol) of finely divided aluminum metal, until practically all aluminum is consumed. The mixture is suspended in 75 ml of chlorobenzene and to this suspension is added, with stirring, 2.96 g (0.01 mole) of 3,5-dibromo-salicylic acid in 25 ml of chlorobenzene. After the exothermic reaction proceeding has ceased, the reaction is terminated by boiling the mixture for 1 hour.

Blandingen afkøles og filtreres, og filtratet vaskes med fortyndet saltsyre til fjernelse af eventuelt ureageret a-min. Opløsningen inddampes dernæst i vakuum til ca. 50 ml, og den dannede tykke opslæmning filtreres og vaskes med 20 petr.oleumsnaphtha. Remanensen opløses i varm benzen, filtreres, og filtratet afkøles til stuetemperatur. Produktet udfældes ved tilsætning af petroleumsnaphtha, og efter filtrering og tørring fås 3,5-dibrom-31-chlor-4(p-chlorphe-noxy)-salicylanilid, smp: 171 - 172 °C.The mixture is cooled and filtered, and the filtrate is washed with dilute hydrochloric acid to remove any unreacted α-min. The solution is then evaporated in vacuo to ca. 50 ml and the resulting thick slurry is filtered and washed with 20 petroleum naphtha. The residue is dissolved in hot benzene, filtered and the filtrate is cooled to room temperature. The product is precipitated by the addition of petroleum naphtha and, after filtration and drying, 3,5-dibromo-31-chloro-4 (p-chlorophenoxy) salicylanilide is obtained, mp: 171 - 172 ° C.

25 EKSEMPEL 53 3-nitro-5-brom-31-chlor-4'-(p-chlorphenoxy)-salicylanilid.EXAMPLE 53 3-Nitro-5-bromo-31-chloro-4 '- (p-chlorophenoxy) salicylanilide.

30 Ti2 en opløsning af 39,4 g (0,1 mol) bis-(2,4-dinitrophe-nyl)-carbonat i 200 ml ethylacetat sættes i løbet af 3 timer 25,4 g (0,1 mol) 3-chlor-4-(p-chlorphenoxy)-anilin ved stuetemperatur. Carbamatet udfældes ved tilsætning af petro-leumsether og isoleres ved filtrering og vask med petroleums-55 ether. Carbamatet blandes med 26,2 g (0,1 mol) 3-nitro-5-brom-salicylsyre, og blandingen opvarmes til smeltning ved 115 °C i 55 minutter. Smelten opløses i 40 ml acetone, og 146016 27 produktet udkrystalliseres ved tilsætning af 180 ml methanol, hvorved fås efter filtrering og tørring rent 3-nitro- 5-brom-3'-chlor-4'-(p-chlorphenoxy)-salicylanilid, smp: 148 - 131 °C.To a solution of 39.4 g (0.1 mole) of bis- (2,4-dinitrophenyl) carbonate in 200 ml of ethyl acetate, 25.4 g (0.1 mole) of 3 chloro-4- (p-chlorophenoxy) -aniline at room temperature. The carbamate is precipitated by the addition of petroleum ether and isolated by filtration and washing with petroleum 55 ether. The carbamate is mixed with 26.2 g (0.1 mole) of 3-nitro-5-bromo-salicylic acid and the mixture is heated to melt at 115 ° C for 55 minutes. The melt is dissolved in 40 ml of acetone and the product is crystallized by the addition of 180 ml of methanol to give, after filtration and drying, pure 3-nitro-5-bromo-3'-chloro-4 '- (p-chlorophenoxy) -salicylanilide, mp: 148-131 ° C.

5 EKSEMPEL 54 2-acetoxy-3'-chlor-4'-(p-chlorphenoxy)-3,5-dibrombenzanilid.EXAMPLE 54 2-Acetoxy-3'-chloro-4 '- (p-chlorophenoxy) -3,5-dibromobenzanilide.

10 En blanding af 31,3 g (0,123 mol) 4-aminor2,4'-dichlorbiphe-nylether og 90 ml vandfri toluen koges under omrøring, og en opløsning af 43,7 g 2-acetoxy-3,5-dibrombenzoylchlorid i 125 ml toluen tildryppes. Efter 6 timers kogning henstilles reaktionsblandingen til afkøling til stuetemperatur og 15 inddampes derpå i vakuum til en brun olie. Denne optages i chloroform og vaskes med fortyndet saltsyre og fortyndet natriumbicarbonatopløsning og inddampes atter i vakuum til en brun olie. Denne omkrystalliseres af en benzen-petro-leumsbenzenblanding og omkrystalliseres derefter to gange 20 af isopropanol, hvorved fås 33,5 g 2-acetoxy-3'-chlor-4 ' -(p-chlorphenoxy)-3,5-dibrombenzanilid, smp: 147 - 148 °C.A mixture of 31.3 g (0.123 mole) of 4-amino2,4'-dichlorobiphenyl ether and 90 ml of anhydrous toluene is boiled with stirring, and a solution of 43.7 g of 2-acetoxy-3,5-dibromobenzoyl chloride in 125 ml. ml of toluene is added dropwise. After boiling for 6 hours, the reaction mixture is allowed to cool to room temperature and then evaporated in vacuo to a brown oil. This is taken up in chloroform and washed with dilute hydrochloric acid and dilute sodium bicarbonate solution and evaporated again in vacuo to give a brown oil. This is recrystallized from a benzene-petroleum benzene mixture and then twice recrystallized from isopropanol to give 33.5 g of 2-acetoxy-3'-chloro-4 '- (p-chlorophenoxy) -3,5-dibromobenzanilide, m.p. 147 - 148 ° C.

EKSEMPEL 55 25 3,5-dibrom-3'-chlor-41-(p-brom-m-trifluormethylphenoxy)- salicylanilid.EXAMPLE 55 3,5-Dibromo-3'-Chloro-41- (p-bromo-m-trifluoromethylphenoxy) - salicylanilide.

Til en kogende opløsning af 0,925 g (0,00252 mol) 4-amino-4 '-brom-2-chlor-31-trifluormethylbiphenylether i 5 ml to-^ luen dryppes en opløsning af 0,899 g (0,00252 mol) 2-ace-toxy-3,5-dibrombenzoylchlorid i 5 ml toluen under kraftig omrøring. Når tilsætningen er afsluttet, fortsættes kogningen i ialt 6 timer. Blandingen henstilles i 17 timer til udkrystallisation, og krystallerne opsamles ved filtre-ring. Udbyttet er 0,800 g urent 2-acetoxy-3,5-dibrom-3'-chlor-41-(p-brom-m-trifluormethylphenoxy)-benzanilid. Det-To a boiling solution of 0.925 g (0.00252 mol) of 4-amino-4 '-bromo-2-chloro-31-trifluoromethylbiphenyl ether in 5 ml of toluene, a solution of 0.899 g (0.00252 mol) of acetoxy-3,5-dibromobenzoyl chloride in 5 ml of toluene with vigorous stirring. When the addition is complete, the cooking is continued for a total of 6 hours. The mixture is allowed to crystallize for 17 hours and the crystals are collected by filtration. The yield is 0.800 g of crude 2-acetoxy-3,5-dibromo-3'-chloro-41- (p-bromo-m-trifluoromethylphenoxy) -benzanilide. That-

Claims

1460 1 6 teas is suspended in 9 ml of ethanol and boiled in a steam bath. To the boiling reaction mixture is added a solution of 0.57 g of potassium hydroxide in 3 ml of water. A clear solution is formed immediately. In an even hot state, this is made acidic with concentrated hydrochloric acid. Thereby, a brown precipitate is formed which is collected by filtration and washed with water. The precipitate is recrystallized several times by benzene-petroleum benzene · to give brown crystals, mp: 165 -168 ° C. The product is recrystallized from aqueous ethanol to form crystals, melting at 168 - 169 ° C. P_a t_e n t_k_r_a_v_: Analogous process for the preparation of salicylanilides of the general formulaϊ R1 OZ. R5 ^ A ^ - CO-HH-R4 I / Λ R2 R3 wherein R ^ and R2 are H, Cl, Br, F, I or NO2, at least one of which is different from H, where R ^ is H, Cl , Br, OH or alkoxy having 1-5 C atoms, Z is H or acetyl, one of the symbols R 1 and R 2 means "Q-fVR8 R 6 R 7 and the other of the symbols R C1, Br, CF2 or alkoxy having 1-5 C atoms where Q represents O, S, SO2, CO or O.CH2, Rf1 is H, Br, or Cl, R6 is H, Br, Cl, CF or alkyl of not more than 5 C atoms and R 9 is H, F, Cl, Br, CN, NOZ or alkyl of 1-5 C atoms, with at least one of the