March 19'70
NOTES
297
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pin-11-one (19); material from a similar preparation was re11 [4-(2-Hydroxyethyl)-l-piperazinyl] -2-trifluoromethoxydicrystallized from dilute PIIeAc to give crystals, mp 230-232". benz[bJ] [l,l]oxazepine (3).--A mixture of 400 mg (0.87 mmol) of 11 .HC1, 400 mg of P20j,and 4 ml of PoC13 was heated a t reflux Anal. (CljHllF3N202): C, H, F, N. The filtrate was rendered temperature for 18 hr. The product was isolated as described alkaline (XHdOH) to give 180 mg ( 6 8 7 ) of 5 as yellow crystals, for 2. The ethereal soliition of 3 thus obtained was treated with mp 140-143'. Two recrystallizations from dilute 1IeAc gave ethereal H2S04to give a white solid having an indefinite melting mp 146-148". Anal. (CzoHzaF3X40):C, F, X ; H : calcd, 3.42; point. This material was reprecipitated from acetone with found, 5.88. Et20 to give 173 nig ( 3 3 5 ) of the bis-bisulfate salt of 3. Anal. (C4aH2oF,S303,2H2S01): C, H, F, N, S. 11 [4-(2-Chloroethy1)-1-piperazinyl]-2-trifluoromethoxydibenz [ b f ][1,4]oxazepine (4).-Repetition of the above experiment a,a,a-Trifluorotoluic Acid n i t h 1.26 g of 11.HC1, 1.26 g of P40j, and 12.6 ml of freshly (SNitrofurfurylidene) hydrazides opened POcl3 gave 1.02 g of an oil that was chromatographed on a synthetic magnesia-silica absorbent. The material (360 mg) eliited by 1% Aclfe-CH2C12 crystallized from Et20-petroleum DEANE. WELCH, ether (bp 30-60") to give 201 mg (17%) of white crystals, mp Research Division, Salsbury Laboratories, 103-105". Further elutioii of the column with more polar solCharles City, Iowa 60616 vents failed to give any appreciable material. Anal. (C2OH19C1F3Na02): C, H, C1, X. HARRYS.NAKAUE, p-Trifluoromethoxybenzanilide was prepared by SchotteiiBauman acylation of p-trifluoromethoxyaniline with PhCOC1. Department of Agricultural Chemistry, The amide was recrystallized from AclIe-C8He to give crystals, Oregon State CniveTsity, Corvallis, Oregon 97331 mp 18.5-187". .4nal. (ClaHloF3N02):C, H, F, X. N-Benzoyl-2-nitro-4'-trifluoromethoxydipheny~amine (13).A N D ROBERT D. TATXI: h ~rispensionof 10.38 g (0.037 mol) of p-trifluoromethoxybenzanilide and 7.7 g 10.037mol) of PClj in 185 ml of CsH6 \vas heated Animal Science Research and Development, a t reflux temperature for 1 hr. The solution was evaporated, Ag~icultztralDepartment, The Dow Chemical Company, and C6H6 addition and removal vias repeated twice. The crude Nulland, Ji'rchzgan 48640 imino chloride was dissolved in 75 ml of E t & and added dropwise to a NeOH soliitioii of o-SaOC8HdS02 (prepared from 2.0 g Received September 26, 1969 (0.037 mol) of S a O l f e , 5.15 g (0.037 mol) of o-nitrophenol, and 80 ml of IIeOH). The mixtiire \vas rtirred at room temperature Our interest in trifluoromethylbenzamides' and for 3 hr and di.*tributed between E t 2 0 and H 2 0 . The dried extract \vas evaporated, and the residue was dissolved in hexane; anilides2 as antiprotozoal agents prompted ub to prethe soliition deposited 13.09 g of o-nitrophenyl S-(p-fri'uoropare a series of nitrofurfurylidene derivatives of a,a,aniethos!/phenyl)benrinzidate (12) as white needles, mp 80-82". trifluorotoluic acids. The activities of some 5-triA soliitioii of criide 12 in 130 ml of o-ClZCsHawas heated a t fluoromethyl furfurylidene derivatives have been rereflux temperature for 1.75 hr. The solvent was removed by steam distillation, and the residue was extracted with C H ~ C I Z . ported and the utility of 3,5-dinitrosalicylic acid ( 5 4 The di,ied extract was evaporated, and the residue was recrystaltrofurfury1idene)hydrazide (DNSSF) is also k n o ~ n . ~ lized from acetoile-hexane to give 11.9 g (80%) of 13 as yellow The synthesis and screening of a series of compounds needles, nip 122-123". Anal. (C20H13F3iY20a): C, H, F, h'. bearing both trifluoromethylbeiizoyl and nitrofur2-Nitro-4'-trifluoromethoxydiphenylamine(14).--A mixture of furylidene moieties seemed worthwhile to determine 7.60 g t18.9 mmol) of the S-benzoyl derivative 13, 46 ml of ethanol, and 24 1111of 10% S a O H was heated a t reflux temperature what effect replacement of a DSSSF nitro group xvith for 1 hr. The cooled solution was diluted ( H 2 0 ) to give 5.60 g CF, would have on activity. (9gCC) of orange crptals, mp 68-70". h similar preparation \vas The compounds prepared for testing are listed in recrystallized from lIeOH-H20 to give crystals, mp 68-70'. I. Primary emphasis was placed on structureq Table .4nal. ( C I ~ H ! ~ F ~ ? ; Y O C,~ H, ) : F, N. 4-Methyl-2'- fS-methyl-p-trifluoromethoxyani1ino)-1-piper- similar to DSSKF or which might conceivably imitate azinecarboxanilide (18).-A solution of 5.6 g (18.8 mmol) of 14 its i n v w o pathways. The synthesis steps were conin 58 ml of lIeAc n-as treated with 5.8 g of powdered KOH and ventional and were accomplished via the acid chloride1.8 ml of Me2SO4. The mixture was swirled for 5 min, 4.0 ml of 5-nitrofurfural hydrazone route (2, 7, 8) or, for the hIe2SObwas added, and the mixture was boiled 5 min. An addiother compounds, by treating the appropriate acid tional 2.8 g of KOH and 2.8 g of RIe2SOa Tvere added, and t,he mixtiire was swilled 5 min, boiled for 5 min, and distributed hydrazide with 5-nitro-2-furaldehyde. between C H G and H?O. The dried organic solution was Each compound was tested for efficacy against cocevaporated, and the residue was azetropically evaporated with cidiosis in chickens, histomoniasis (blackhead) in toluene to give 6.00 g of crude ~~~-methyl-d-nit1.0-4'-tri~uoroturkeys, helminthiasis in chickens and mice, and for methor!/dLphenylamine (15) as an oil. inhibition of bacteria cultured in vitro. Growth promoX mixture of 5.80 g (18.6 mmol) of crude 15 and 8 g of wet Itaney Xi was hydrogenated to give 5 . 2 g of b-amino-~Ymethyltion and feed efficiency effects were also determined in C'-frI1Ruoroniethoryd~phenylamine(16) as a n amber oil. poultry and swine. The only bignificant activities Acylation of 5.0 g of 16 with phenyl chloroformate in pyridine found were for blackhead and growth-feed efficiency ; a5 dezcribed above furnished 7.9 g of phenyl Z-(,V-methyZ-pthese results are shown in Table I. The most effective tri~ILoromethozyani1lizo)carbanilate(17). Treatment of 17 with 8 ml of 1-methylpiperazine in 120 ml of compound tested (6) was structurally similar to DKC& a. described in the preparation of 10 gave 18 as an oil. SNF; however, the antiblackhead activity did not apTreatment with 1 *HCI I' gave 7.30 g (87Yc from 14) of 4-methyl&'-(.~-?neth?/l-p-tri'$uo~omethoxyanilino)-1 - piperazinecarboxanilide proach that of DSSSF. This represents another example of replacement of hydrochloride as white crystals, mp 235-238'. A sample recrvstallized from EtOH-Et20 had mD 238-240'. Anal. (C20H23KO2 with CF3 in a biologically active molecule without F ~ N .~HoC I~) . c, H, F, N. complete loss of activity.'J 5-Methvl-11-i4-methvl-l-oi~erazinvl~-2-trifluoromethoxv-5H(1) D. E. K e l c h , R R Baron, and B -1 Burton J .Veil Chem 12, 299 dibenz[b,ej[1,4] diazepink (5):LA mix;ui-e of 300 mg (0.68 "01) (1969) of 4-met hy1-2'-(S-methyl- p - trifluoromethoxyanilino) - 1-piper( 2 ) D E K e l c i i a n d R R Baron tbzd 1 2 , 9 5 i (1969). azinecarboxanilide (18) and 285 mg (2.0 mmol) of P206in 3 ml (3) R E. Bambur,, H I< T a t k i n and K K. JTjckoff, J Heterocgcl of P0Cl3 was stirred a t reflux temperature for 3.5 hr. The cooled Chem 6 , 9 5 (1968) mixtiire was cautiously diluted (H2O) and filtered to give 25 mg (4) E Rerndt, H \ a n Eisen B G. Held, and R D. Vatne, J U e d . Chem , 12, 371 (1969). (125;;) of crude 6,10-dihyclro-j-meIhy1-11H-dibenz[b,e] [1,4]diaee-
-
3~
r .
I
.\111.1.
Experimental Section" General Synthesis Scheme for 2 , 7 , and 8.-The chloride of t81ie appropriate (0.10 mol) was prepared by heating at reflux for ahout 4 hr in exces. SOCI?. SOClr was removed iiiider vaciiiim and the residue ineat o r ill CtiH,) was slowly added to 0.10 mol of .i-nitro-%-fiirf~~ral hydrazone in about 7 3 nil of pyritliiie cooled below 40". After stirring at rciom temperature for O..i fir, the mixture was poiired intr) ic,e-H& arid the solid re(,overed by filtration. General Synthesis Scheme for 1, 3-6, and 9.--A solutiuii of the appropriate acid hydrazide' f0.O.i mol) and .i-iiitro-2-furaldehy~le (0.0a mol) in aboiit 300 nil of EtOH wa. stirred and heated at reflux for 0.5 hr. The resulting thivk, yellow suspension was rooled and filtered atid the re3idiie reciptallized. Hydrazides for 3-5 and 9.-Fi.-cher esterificatioii of the appropriate acid'J gave the methyl ester.9 The ester was then heated at reflux for several hour.? in EtOII with excess hydrazine hydrate arid then concentrated under vaciiiim to give the hydrazide \vhich was recrystallized from C6H6. The resiilts are given below. See Table 11. Biological Methods.-The eitiracy of 1-9 against, Hislornonus ui&agiidis was determined i i i Bi,oad Breast,ed Bronze or Broad 8.5) \ \ h e r e analyse- are indiciiterl uirl? Ihi .vmiluls uf t h e elements. analytical results ohtained for thaw pl?iiieiits i v e r t \vitliin = O , k < ; of t h e tileoretical \~alllP*.
(6) o-'rrifiuorometl~?lhenauii. ar-lil aiici ,ritlt? a r e a\.ailal)le f r o m Pierce ('l~ernicalC o . , Rockford. Ill. ( 7 ) T i l e hydrazides for 1 a n d 6 a l e i l e s c r i l i d i n ref 1 . '8) J. I,ichtenberper a n d F. \\-pi?*, Bull. 10) The esters used in t h e preparation of 4 anri 9 a r e described in rei 1.
I1
Hi,ea>ted \Vhit e tiirkeys. Poiilb i,e:ii ed iii wire-bot t.om t';igt'wet'e oi,a11y iiiociilated with approximately 1000 embryoti;rtc.rl cecal worm (Hetemkis ya,lZinarum) ova per bird at, approsimai(~1y 6 weeks of age. Prior experimentation had confirmed the prc.-elice of H . nzeleagTidis in these ova. 411 tests were 28 (lay- i : i duration. Tiirkeys were infected on the first day of the i e y t . Sledicated feed w a l given the first 21 daj-r aiid nonmedicated i h r firial 7 days of each experiment. The criteria of efficac,y wvt't? (1) the absence of typical blackhead recal or liver lwioti+ :it, i~ostmoriem examination and ( 2 ) the rate of mortalit!.. l'hc findings were cumpared with infertetl, iinmedicated c o i i t ml- i r i each experimeiit , ( i t % W t ti aiid feed efficienc,y h t i i d i e ~were coiidiicted 0 t h 1,roiif.ri.ype vhivki or turkey poults iii battery brooder.. Testa were lit' .I ~ v ~ e dnration ks with medicated feed provided ad libitum thi~oiigho i i t the 4-week period. Each bird was weighed iiiitially tititi : t i ihe end of 4 weeks and the mean kyeight gain and feed coriver,~ion of each ted groiip were cumpared to that o f control groirps t'wi iionmedicated feed. Swine growth aiid feed conversion .si iidir, were aimilarly conducnted on yoiing pigs. r)ata were evaluat et1 for significance at P 5 0.05 using anal of varianve and 1 3 i t 1 can multiple range techniqiies. For a compound to be ratell effective, the medicated groiipa had to show a statistically -igiiificant improvement over iir~timedicatedcontrols.
Acknowledgments.---The aut liors wish to thank S 11,. IT-. Dunkel and 11r. H. 1"latzke for assistance u-ith sonit1 of the syntheses :ind A[r>. C. Barker :ind A h . AI. C ' m . for obtaining t h e :ari:il\-ticnl data. The stntistic*:\l evaluations ~ e Oht~airled e by 11r. .J. S a r v e ~ o ~ i .
