NOTES
May 1966
Nitrofuryl Heterocycles. 11.' 2-Alkyl-6-(5-nitro-2-furyl)-3(2H)-ppridazinones and 4,5-Dihydro Derivatives HOMER A. BURCHA N D LOUISE. BENJAMIN Chettiistry Dizlision, The .Vorwich Pharmacal Company, A'orwich, n'ew York Received October 18. 1965
A continuing search for new nitrofuran antimicrobial agents led to the synthesis of 4,5-dihydro-6-(5-nitro-2furyl)-3(2H)-pyridaeinone (IIIa). Because of the significant biological activity of IIIa, additional synthetic work in this area was initiated to study the effect of structure modifications on activity. Chemistry.-The 4,5-dihydro-3(2H)-pyridazinone ring system is commonly prepared by condensing a y-keto acid or ester with hydrazine. A survey of the literature revealed that /3-(2-furoyl)propionic acid (I) had been prepared in three steps from 2-acetylfuran (2H)-pyridazinby Iinott. 4,5-Dihydro-6-(2-furyl)-3 one (Ha) was prepared from acid I by Knott and from the ethyl ester of I by Holland and A m ~ t u t z . ~Thus, acid I was condensed with the appropriate alkyl hydrazines to give pyridazinones 11 (see Scheme I). SCHEME I HzNNHR
WCOCHzCH&O~H
I
- .
I1
i
HzSOn "03
IV
111
Sitration of I1 took place readily in mixed acid sohtion at low temperatures to give 111. The nitro group was assigned t'o the 5-positrionof the furan ring on the basis of the work of R i n k e ~ and , ~ on the observance of asymmetric and symmetric st,ret,chingvibrations of the nit,ro group at 1515 and 1308 ern-', respectively, in t'he infrared.5 Furthermore, the ultraviolet spec362 mp) was quite similar to the trum of IIIa (A,, spect,rum of 5-nitro-2-furaldehyde acetylhydrazone (A,, 363 m,u).6 Finally, the nit,ration product I11 was extremely sensit,ive t o aqueous alkali. Nitrofuran derivatives are frequently unstable in Ohe presence of aqueous alkali, giving dark brown solutions or tars.' The base lability of 111 became more apparent when the alkylation of IIIa (R = H) tvit,h methyl iodide in niethanolic sodium methylate solut,ion was at(1) For the previous paper in this series see H. R. Snyder, Jr., and L. E. Benjamin, J . M e d . Chem., 9, 402 (19663. (23 E. B. K n o t t , J . Chem. Soc., 1190 (1947). (3) D. G. Holland and E. D. Amstutz, Rec. Trau. Chim.. 83, 1047 (1964). (4) I. V. Rinkes, ibid., 51, 349 (1932). ( 5 ) L. J. Bellamy, "The Infrared Spectra of Complex Rlolecules," John Wiley and Sons, Inc., Kew York. N. Y . , 1958, p p 203, 297. (6) F. F. Ebetino, .I. J. Carroll, and G . Gever, J . Med. P h a r m . Chem.. 6, 513 (19623. ( 7 ) .\. P. Dunlop and F. S . Peters, "The Furans, ' IEeinhold Publisliing Cory.. S e a P o r k , N . 1., 1953, p 149.
425
tempted. Only tar was obtained. Therefore, the %alkyl derivat,ives of 111 were prepared by condensing acid I with the appropriat,ely subst,it,uted alkyl hydrazine and nitratmirig the product'. Overend and Wigginss reported the oxidation of 4,5dihydro-6-methyl-3(2H)-pyridazinone to 6-methyl-3(2H)-pyridazinone using bromine in acet'ic acid solution. A similar oxidation of dihydropyridazinone I11 gave pyridazinone IV. When pyridazinone IVa (R = H) was treated wit'h an equivalent' of sodium hydroxide or methoxide in met'hanol solution, a sodium salt was formed. This salt was except,ionally stable in aqueous solution. Treatment of t,his sodium salt with methyl iodide in methanol solut'ion gave the Nmethyl derivative IVb (R = CH,). This product was ident'ival in all respects with the product, obt,ained by the oxidation of IIIb (R = CH,). On this basis, t'he methyl group was assigned to t,he 2-position of t'he pyridazinone ring. The higher alkyl derivatives of IVa were also prepared by alkylat,ion. All compounds reported in t'his paper have been assigned t,he ketonic struct'ure based on the observance of a strong carbonyl stretching band at 1653-1680 cm-1 in the infrared.5 The physical and analyt,ical properties of these compounds are given in Table I. Screening Results.-The in vitro and in vivo antmibacterial testing data were determined using the methods described previously. hnticoccidial screening in chickens against a strain of Eimeria tenella was carried out as described by Johnson and O'Connor.lo These data are given in Table 11. As a class of compounds the pyridazinones I V show bet't'er antibacterial activity than the dihydropyridazinones 111. ill1 of the compounds demonstrated anticoccidial activity against Eimeria tenella at) dose levels comparable to t'he level of nitrofurazone, a known coccidiostat. The most active compounds (IIIa and IVa and b) are those in which R = H or CH3. Therefore, it can be concluded that, substihtion of alkyl groups at the 2-position (R) does not enhance significantly the artticoccidial actfivit8y. Toxicological studies on selected compounds are in progress. Experimental Section All melting points were determined on a hot stage (AIel-Temp) melting apparatus and are uncorrected. 4,5-Dihydro-6-( 2-furyl)-3(2Hj-pyridazinone (IIa j.-A mixture of 48.0 g (0.28 mole) of p-(2-furoyl)propionic acid2 and 17.0 g (0.29 mole) of 8570 hydrazine hydrate was heated on a steam bath for 75 min. The mixture was poured slowly with stirring into cold aqueous Na2C03 solution. The solids were filtered and recrystallized from water (charcoal) to give the product as colorless needles. Other derivatives of I1 were prepared from the appropriate alkylhydrazine. 4,5-Dihydro-6-(5-nitro-2-furylj-3(2H)-pyridazinone (IIIa).To 400 ml of concentrated H2S04 chilled to 5" was added in small portions with stirring 51.5 g (0.31 mole) of IIa. The resulting solution was chilled to 0" by means of an ice-salt bath. The temperature was kept below 5' while a solution of 50 ml of concentrated HNO, (sp gr 1.42) in 100 ml of concentrated H & 0 4 was added dropwiseduringO.5 hr. Stirringin thecold was continued for 15 min after which time the mixture was poured slowly with vig-
( 8 ) W.G. Orerend and L. F. Wiggins, J . Chem. Soc., 242 (1947). (9) F. F. Ebetino, \\-. F. Carey, and B. F. Stevenson, J . M e d . Chem.. t, 633 (1963). (10) C. A. Johnson a n d .J. O'Connor, Poultrg Scz., 44, 5% (1965). (11) FuracinP.
'The Bacteriostatic EfTectiveiiesh of I -Alk>1-3-(3, i-dichloropheny1)ureas
iiito 2 1. of vracketl iw :illti viater. T h e crude prodi1c,t collected by fillration arid led tlioroiighly with Taler. Ilecrystallization from glacial ai.etic* m.id (charcoal) gave the prodikct as short yellow needles. Other tlt,rivativel: of I11 were prepared similarly. 6 45-Nitro-2-furyl)-3(2H)-pyridazinone(IVa).----I riiisture i l f 41.8 g (0.2 mole) of IIIa ill 200 nil of glacial :tc,etic acid uxc heated to 90". Bromine ( 2 nil) w:is added with drriiig. W'heii HI3r evolutioa began, the reriiainilig bromine (total of 32 g, 0.2 mole) was added :it siich a rate as tn maintain a temperature of 90-96". When he zidditiorr \vas completed, the mistine XLY he:ited a t 100" for 30 min. The mixture was rooled, diluled vith waler, :tnd filtered, and the r e d u e was washed thoroughly with m ~ t e r . The yield of critde protiiirt melting at 293-295' n i s :N.0 g (94:; ). Foiir rec allizat ions from climethylformnniiclc. (1~11:ircoal)gave pale yellow rryst:ils. IT% mis prepared 5iniii ~ r o i i stirring i
wts
1:1rIy.
2-Ethyl-6-(5-nitro-2-furyl)-3(2Hi-pyridazinone(IVc).----A 111istiireof 50.0 g (0.24 mole) of IVa and 13.0 g (0.24 mole) i ) f s i ) i l i i i m methoxide iii 1000 1111 of methanol was refluxed with .tiwing for 3 hr. E ~ h y iodide l ( 5 0 nil) \\-as added and refluxiiig was cont iriiml overnight. The solvents were evaporated under diriiiiiished pressure on n steam b a t h arid the residue was shaken wit11 500 nil of cold .5(,-;, SaOH soliilion. T h e rrude pro(1uc.t \vas filtered, uadied thororighl>. with Iv:itPr. aiid recryatdlizetl from ~ l l l l l ~ ~ lc>t~lalloi ~lls i l ~ ~ i : i r c ~1. o : lmlr. ~ l l r . l l t ~ l l l ~ t ~s e p n r a i ~ t:~ iq p:ii~ y c ~ l l iievtlle~. i~~~ I\'h t i i i ~ l1T.d x v ( w 1 ) i ~ ~ p ; i from r ~ d the sippropri:it~ :I11;y I i I idi iIC>.
Acknowledgments. --\\-c \\.ish to express our gmtit utlc i o lJT. 0. Smith and 73. F. Stel-eii.zoii and grou]> f o r tecaliiiicd assistaticc tluriiig t 1 1 ~1)rei)aratioli of I ~ K W
