September 10G7
5-SULVANILAh.lIDO L)EHIVBTIVES 01.' US-'rHIAZINES
being on the side of the cyclopropaiie ring remote from these protoiis. anti-2'-Aminospiro( 1,4-benzodioxan-2,1 '-cyclopropane) (9c). -The anti acid above was converted via the mixed carboxyliccarbonic anhydride procediire3" to t,he azide, which on pyrolysis gave the isocyanate. Blkaline hydrolysis3a of the isocyanate -zave the amine (4555), isolated as the hydrochloride. mD 211213" (from 2-propanol). Anal. Calcd for CloHIlS02.HC1: C. 56.20:, H., 5.62:, C1. .. .. . ~, 16.60. Found: C, 56.27; H, 5.67; C1, '16.45. N,N'-Bis [2'-syn-spiro( 1,4-benzodioxan-2,1 '-cyclopropyl)] urea.-The syn acid was converted via the mixed carboxyliccwboiiic anhydride procedure3%to the azide. This was pyrolyzed to give the crude isocyanate, which was hydrolyzed with alkali.3. When cold, the reaction mixture was filtered. From the filtrate, the amine hydrochloride (6%) was isolated by extraction with dilute HC1. The solid filtered from the reaction was recrystallized from ethanol to give the urea (53%): mp 213-216"; umax 3370, 164.5 cm-l. Anal. Calcd for C~,I€?ON~O;: N, 7.37. Foiind: K,7.40. ss!/n-2'-Aminospiro( 1,4-benzodioxan-2,1'-cyclopropane) (Sc). A.-The K,N'-disubstituted urea above was treated with 2 equiv of phthalic anhydride according to Manske.lo Aft,er trituration with aqueous NaHC03, the product was recrystallized from ethanol to give syn-2'-N-phthalimidospiro(l,4-benzodioxan-2,1'-cyclopropane) (697,): mp 164-167"; umax 1790, 1745, 1730 cm-l. A suspension of this derivative in ethanol was treated under reflux with an equimolar quantity of hydrazine for 15 min. The hot reaction mixture was acidified with HC1 and, when cold, it was filtered. The filtrate was basified and extracted with ether, and the ether extract was treated with gaseous HC1 to precipitate the amine hydrochloride (79%), mp 220-222'. B.--Alternatively, the crude isocyanate obtained on pyrolysis of the azide derived from the syn acid was hydrolyzed with con-
-
as-Triazines.
883
centrated HCl3 to give in one step the amine hydrochloride (62% from the acid), mp 220-222'. Anal. Calcd for CIOHllNO~.HC1: C, 56.20; H, 5.66; C1, 16.60. Found: C, 56.35; H, 5.61; C1, 16.44. anti-2'-Guanidinospiro( 1,4-benzodioxan-2,1 '-cyclopropane) Sulfate (2b).-The free anti amine, isolated from the hydrochloride, mp 211-213', was heated at 90" for 5 hr with l-amidiiio3,5-dimethylpyrazole sulfate' (1 equiv) in water. The product (13co) was obtained by filtration from the cooled reactiou mixture and subsequent recrystallization from water. It had mp 288-290'. dnal. Calcd for C1~H&;,02.0.5Hk304: C, 49.25; H, 5.26; ?J, 15.67. Found: C, 49.52; H, 5.59; K, 15.58. synn-2'-Guanidinospiro(1,4-benzodioxan-2,l '-cyclopropane) syn amine hydrochloride (mp 220-222") Tosylate (2a).-The was converted to the tosylate salt by t'reatment of an aqueous solution of the hydrochloride with 1 equiv of p-toluenesulfonic acid. The tosylate salt was refluxed in 95yo ethanol with cyanamide (10 equiv) for 16 hr. The mixture was concentrated uiider vacuum and treated with ether. The precipitated material was recrg-stallized from water to give the product (goyo), mp 175-177". Anal. Calcd for Cl'I113S302.CiH803S: C, 55.23; H, 5 . 3 7 ; N, 10.73. Found: C, 55.09; H, 5.07; N, 10.51.
Acknowledgment.--We wish to thank our colleagues in the Pharmacology Department' of Pfizer Ltd. for supplying us with the biological result's reported in this paper, N r . P. R. Wood for the microanalyses, and Mr, J. Zoro for his competent assistance. Also, we acknowledge the help of Dr. J. Feeney of .Varian Associates in obtaining a confirmatory lOO-lIc,/sec spectrum on compound 3 (R = (XI3).
I. 5- Sulfanilamido Derivatives and Intermediates' IF7.E. T A F TAND ~ 12. G. SHEPHERD
Organic Cheniital Reseuich Sectzon, Leclerle Laboratorzes Diuzsion, -1nierztan Cyanainitl Company, Pearl Rzcei, 'Yew York 10965
Receioed March 16, 1967
A series of as-triaziiies bearing 6-alkyl (or hydrogen) and 3- and/or 5-chloro, -methoxy, -methylthio, -oxo, or -thioxo groups has been prepared. The 5 position has been established as more reactive than the 3 toward iiricleophilic substitution with sulfanilamide anion. The 3-siilfaiiilamido-as-triaziiies have good solubility but have little or no oral antibact,erialactivity against infections iri mice.
Cntil the present study, exploration of the sulhave been used successfully in such reactions, the alkyl fanilamido-as-triazine series was extremely limited, analogs are unstable to these conditions and yield only two examples of this series having been r e c ~ r d e d . ~ , ~water-soluble products, presumably as a result of ring These were 3-sulfanilamido-as-triazines bearing benzo3 cleavage. or phenyl4 substituents in the 5 and 6 positions. h possible alternative route appeared to be the reacSimpler sulfariilamido-as-triazines appeared accessible tion of a methoxy- or methylthio-as-triazine with through 3-amino-,j 3-amino-6-methyl-,6 and 3-aminosodium sulfanilamide, a route which had been employed 5,6-dimethyl-~s-triazines.~However, attempts to couin the s-triazine series.' Furthermore, a displacement ple these amines with p-nitro- or p-acetylaminobenreaction had been effected with ammonia on 6-methylzenesulfonyl chloride gave complex mixtures which a~-triasine-3,6-dithione.~ During the course of our work, yielded none of the desired products. Although 3examples of niethylthio displacements from as-triazines aniino-j,lj-diplienS 1- and 3-aini1ioberizo-as-triazi1ies by hydrazineg and by ammonia were reported.I0 A suitable intermediate for such a reaction appeared to be 5,6-dimethyl-3-methylthio-~s-triazine, accessible (1) Presented i n p a r t a t t h e 150th National Meeting of the American Chemical Society, Atlantic City, N. J., S e p t 12-17, 1965, Abstracts, p 12P. through the corresponding 3-thione. Repetition of ( 2 ) T o whom correspondence should be addressed a t Acadian Instruments, P. 0. Box 342, Don JIills, Ontario, Canada. ( 3 ) F. J. Wolf, K. Pfister, 3rd, R . RI. TT-ilson, J r . , and C. A. Robinson, J . A m . Chem. Soc., 7 6 , 3551 (1954). (1) G. IT. Raiziss, L. TV. Clemence, a n d 31. Freifelder, ibid., 63, 2739 (19-11). (5) J. G . Erickson. ibid., 7 4 , 4706 (1952). (6) Prepared b y t h e method of ref 3 b y Drs. J. Semb a n d R. B. hngier of these laboratorieu; m p 180'. .471uZ. Calcd for CpHcNa: N, 51.0. Found: N, 51.1.
(7) (a) H. Bretschneider a n d JV. Klotzer, Monatsh., 87, 120 (1956); (b) M-.E. Taft. H. bI. Krazinski, F. C. Schaefer, a n d R. G . Shepherd, J . X e d . Chem., 8 , 784 (1965). (8) E. .i. Falco, E . Pappas, a n d G. H. Hitchings, J . A m . Chem. Soc., 7 8 , 1938 (1956). (9) D. Libermann a n d R . Jacquier, Bull. SOC.Chim. France, 383 (1961). (10) Burroughs Wellcome a n d Co., British P a t e n t 802,122 (1958) ; Chem. Ahstr., 53, 7216e (1959).
4
5
7
6
i
R;ine\ SI
SH.011
H
k
10
11
12
two reported preparationsllllLof the latter gave products which had somewhat similar properties t o those reported, but which proved to be the mono- and bisthiosemicarbazones of biacetyl. Refluxing the monothiosemicarbazone in aqueous potassium carbonate, or heating it to 1SO" at atmospheric pressure and under vacuum, failed to effect the desired cyclization.'3 On completion of these experiments, the first reported p r e p a r a t i ~ n ' ~of 3,3-dichloro-as-triazine appeared. This compound was obtained in low yield from as-triazi1ie-3,S-dione and "aged" POCl, in the preseiic~ of triethylamine. We effected a similar transformation with 6-methyl-as-triazine-3,5-dione" (1, bee Scheme I) and fresh reagent grade POC1, to obt alii 3,5-dichloro-Ci-methyl-as-triazine (2) in a yield of 3.5%. llethoxylation of 2 yielded 3,5-dimethoxy-Oiricth) 1-as-triazine (3), which, upon treatment with 5odium sulfanilamide in refluxing methanol, underwent f a n k methoxy displacement to yield hulfanilaniido3-methoxy-6-methyl-as-triazine (4) .I6 Since 4 might well have had the alternative structure, ~~-sulfanilamido-j-niethoxy-6-methyl-as-triazine,its orientation was established through two sequences, both originating with 6-methyl-as-triazin-5-one-3-thionel) (5, bee Scheme I). Dethiatiori of 5 to yield 6-methylas-triaziri-3-one (6) is apparently the first successful transformation of this type i i i the as-triazine series. reportedI7 attempt to clethisttc the corresponding 6h i z 1~ tlerivntive caused 11) drolj s i b to 6-berizj l-ast rinziiic-X,3-dioiic illstcad. &Isimilar attempt to dethiate ns-tnazitie-:S.T,-c~ithioiic led to products which mere' IIot (hracterized.'* Thionatioii of 6 was effected in (11) N g PI1 I3uii-Hoi, Ng D Xuong, a n d F Uinon, J Chem S o t . 71'3 (19i6) (12) J Rlosa, A r t h Z'harm 288, 465 (19.55) 113) \\ e n i 4 1 to tlianh 3119s 11 11. K r a ~ i n s h ifor performing these rxk)eil mente (14) C Grundmann, H Schroeder, a n d R Ratz, J . Org. Chem., 23, 1522 (1958) ( 1 5 ) 3 Haiipault aiid L Daniel. Comrd K ~ n d 186, , 1216 (1928) ( 1 6 ) Reaction of 2 direct15 n i t t i wdiiim sulfanilamide resulted in inrindtiun of d. co~nl,lex~ n i x t i i r ~ ( 1 7 ) I Ilorigaiilt I C a t i i l a i i i . i i i < l 1' ( ha1)ricr C u i i i / , l / < i t r d 208, t j j i ( I O Fl)
13
p) ridine at 105" to
J
ield G-iiieth~l-as-triasluo-j-t,liiollc
(7). When this reaction was attempted a t reflux, extensive decomposition resulted 111 a low yield of the desired product. lIethylation of 7 gave &methyl-;niethylthio-as-tri:izine (8), which, oil reaction with sodium sulfanilamide, yielded 3-sulfttriilarnido-6-incth~1as-triazine (9). The latter wa5 d s o prepared 11) x i n1terri:itive w(pence. Thicmation of lo8 (or of 517) > ielded timethyl-as-triazine-3,5-dithion(l (11),* \vl-hic*h,on methylation, gave the 3,5-bis(methylthio) derivative (12).!j Reaction of 12 with sodium sulfanilamide yiolded .isulf anilamido-6-m~~thyl-3-methylthio-as-triaziric (13) . Hydrogenolysis of the methylthio group in 13 g:tve :I sulfanilainido-6-metli~1-as-triazine identical in all resspects with 9, prepared through the previou? u 1 1 equivocal seque~ice,thus confirming the orient at i o i \ of 13, as showi. 1Iethoxylation of 13 gave nininly :I product of the biliiie Rf value :is the previoudy pwpared 4, whoae atruiture was in doubt. ,I c~ompariaon of this product xith 4 through their infrared and ultraviolet spectra rtrid Rf values confirmed that they w r c l identical. 'rhus, higher reactivity of the 3 position over the 3 position 111 3 and 12 is established. Preferential aubstitution at the 5 positioii ( i t t 11v as-triazines, deriioristrated in this work and alw in thck itmination* of G-methyl-as-triazine-~S,3-(~ithione, ( cloubtlYo i i the \trurture assigriineiits of Crruridm, , et al., l 4 111 thcv reactions of X,3-dicliloro-cth-t r i a i i i v with v;~rioii+riucLleophiles. These :tuthors ~ s s u i i i ( ~ ( 1 preferential displucement of the :S-chloro rather that1 the 3-chloro substituent by a fallac.iou5 analog\ wit11 the reactivity of 2,4-dichloropyrimidine toward nurleophiles.lg (18) One of the a.,igni.d ctiricturei, i-etliox\-i-metti\ I t l i i o - t i - i t 1 i / i n e I probablj correct since a ti\o-,tep preferential substitution at liaq been postulated b i R G Shepherd a n d J I. redrick, cgclzc Chem , 4, 298 (1865) (19) ReaLtion uf 2 l-ilicllloiop\rimidine \ \ i O i \ 1 1 8 \ i e l i f a a m r i l r i r r of t t i e t n o possible aminocliloro derivatives a n d n i t t i 1 mole of mi.thoxide \ields onlv 2-chlaro-i-irietii~,\\ ptrimidine See I1 J l i i o n n 'I IIC I ' \ i i t n i < I i r i e b " Inlrrscienie I ' u l i l i ~ l i i ~ b Inc , N e \ ! 1 0 1 6 L 1 lclb2 188 201 i l w beti ief 18, r, 2'1 1
The structures of the tautomeric oxygen- and sulfurcontaining as-triazines herein described are the oxo and thioxo forms, rather than the hydroxy and mercapto forms. This is to be expected on the basis of the structure of as-tria~ine-3,5-dione,~~ 2- and 4pyrimidinoneslZ1 and 2- and 4-pyrimidinethi0nes.~~ These as-triazin-5-ones display strong absorption due to ring-carbonyl stretching in the 1650-em-' region. Our as-triazine-5-thiones show strong absorption in the 1193-1200-~m-~ region, slightly higher than the region reported by Spinnerz3 to be characteristic of a number of a- and y-thioxo azines and diazines and assigned by him to thiocarbonyl stretching. Data on the riew as-triazine intermediates are compiled in Table I. The 6-alkyl homologs of 9 and 13 in Table I1 were prepared by routes completely analogous to those outlined in Scheme I. Orientation of the 6alkyl homologs of 13 was assumed to be the same as in the &methyl series. These riew 5-sulfanilamido-as-triazines had little or no oral antibacterial activity as tested (Table 11);24 one showed activity just below the lethal dose. Four compounds exhibited blood concentrations so low that the intrinsic activity based on attained blood level is uncertain. Great variation is apparent in the solubility of these sulfonamides, from those of extremely low solubility to the very soluble 5-sulfanilamido-3-methoxy-Bmethyl-as-triazine (1000-1500 mg %, see Table 11). Although the data are limited, the pKa values of these 5-sulfanilamido-as-triazines are consistent with the meta-substituent constantsz5of the R3 substituents: H, U , = 0; OCH3, U , = 0.115; SCHI, U , = 0.144.
i
._
Experimental Sectionz6 3,5-Dichloro-6-methyl-as-triazine (2).-Triethylamine (65.8 g, 0.650 mole) was added slowly with stirring to 199 g (1.30 moles) of ice-cooled POC18. 6-Methylas-triazine-3,5-dione15 (41.3 g, 0.325 mole) was added to the resulting slurry and the mixture was refluxed with stirring for 15 min. After cooling, the dark brown solution was extracted with ten 200-ml portions of hexane. Concentration of the extracts left a brown crystalline residue, which was vacuum sitblimed a t 80-90" (1.0 mm) to yield light yellow crystals (12.1 g ) melting a t 41.5-44'. Continuous extraction of the reaction mixture with hexane for 3 days yielded 6.7 g of additional material. A second sublimation yielded very pale yellow crystals for analysis. Lower yields (9-15Yc) resulted with twice as much POCIS or twice the reaction time. 3,5-Dimethoxy-6-methyl-as-triazine (3).-A solution of 2 (4.35 g, 0.0265 mole) in 20 ml of methanol was treated by slow addition, with stirring, of a solution prepared by dissolving 1.22 g (0.053 g-atom) of Na in 50 ml of methanol. After removal of NaC1, the filtrate was concentrated to dryness. The residue was extracsted with 60 ml of hexane and the filtered extract was cooled to 0". 5-Sulfanilamido-3-methoxy-6-methyl-as-triazine (4). Method 1.-Sulfanilamide (1.68 g, 9.78 mmoles) was dissolved in a solution of 0.225 g (9.78 mg-atoms) of N a in 10 ml of dry methanol. (20) J . .Jon65 and ,J. Grit, Collection Czech. Chem. Commun.. 16, 2155 1961). (21) D. J . Brown, E. Hoerger, and S.F. Mason J . Chem. S o c . , 211 (1955). (22) A . Albert and G. 13. liarlin. ibid., 3129 (1962). (23) E. Spinner, ib a n i ~ l sKw.. , Trui.. Ciiim., 69, 1552 (1950). (1954), gave no preparative details f o r this compound.
x, mp _-----____-------_
CHsOH
nil of refluxiiig ethaiiol gave 5 6 5 of bis(thiosemicarbazone) aiid, from the filtrate, 127; of the moiiothiosemicarbazoiie. Both were ideiitified b3- meltiiig poiiit aiid ir spectral comparinoiih with aiitheiitic samples. I-iider the conditions of Biiu-Hoi', et a/.," iisiiig refluxing acetic arid, there resiilted a 345, yield of hi,~(thiosemicarbazoire) (variable nip 270" dec, lit.*8 mp 255' aiid 272'; vmnx 1495, 1595 cm-'; C, H, X, aiid S aiialyses). Biacetyl S-Methy1thiosemicarbazone.-A mixture of 23.3 g (0.100 mole) of S-methylthiosemicarbazide and 86.0 g (1.00 mole) of biacetyl was stirred at room temperature for 2 hr. The solution was stirred with an equal volume of ethyl ether with cooling t o effect separatioii of a brown viscous oil. The ether layer was decanted and the oil was stirred with 112 ml of a 5% sodium carbonate solution. The resulting light yellow solid (12.4 g, 7zc;) melted at 139.5-141.5". A portion (1.00 g) was dissolved in 20 nil of a 4 :1 mixtitre of 90-100" petroleum etherethanol (charcoal), giving light yellow crytals (0.4i g, mp 1411420). Anal. Calcd for C6HlIS3SO: C , 41.6: H, 6.4: 5, 24.2. Foiuid: C, 42.1; H, 6.6; K,24.2. 6-Methyl-as-triazine-3,5-dithione (11).g-A powdered mixture of 108 (15.7 g, 0.100 mole) and 22.2 g (0.100 mole) of P2S5in 80 ml of pyridine m-as stirred at reflux for 2 hr. The solution was concentrated to about half-volume at 50" under an oil pump and the residue was drowned in 300 ml of water with stirring. The precipitate was filtered and dissolved (mostly) in 100 ml of 1 KaOH. The filtrate on cooling and acidifying to p H 3 with 6 S HCl, yielded an orange-yellow solid, 14.7 g (85%), mp 204" dec. .4 portion (0.32 g) was recrystallized from 10 ml of ethaiiol (charcoal) to yield orange-yellow crystals (90 mg) melting a t 221" dec (lit.s 215-21ia), vmnx 1115, 1224 cm-'. Anal. Calcd for C , H S C, 30.2; H, 3.2; T,26.4, S,40.3. Foulid: C, 30.9; H,Y.3; 5,26.3; Y, 40.3. Paper Chromatography.-The chromatograms were run on Whatman No. 1 paper iii descending fashion, using for developmerit the top layer of a 9 : 1 : 8 BitOH-SH3-H20 system. The dried sheets were examined iinder aii ultraviolet lamp for quenchiug or flnoreaceiice. The sheets were sprayed with 5 :1:6 BuOHScOH-BnONO followed (after 2 miri) by a 0.1% butanol solution of X-(l-iiaphthyl)ethyleiiediamitiedihydrochloride. The presence of a primary arylamiiio group was indicated by a purple color.
Acknowledgment.-We are indebted t o 11r. L. Brancone and associates for the analytical data and to A h . W. rulmor, -\Ir. G. AIorton, and associates for the spectrowopic data herein (28) 13 4 Gingras T Snprrinclinh and C H R a x l e i C I ? , I C h ~ m 40, 1057 (1062)
