and dried to give 5.20 g (835~:,nip 233-248'). Recrystallization from EtOH gave material with mp 249-231" dec. The IIV spectral data are given in Table 111. Anal. (C~H7ClN602) C, H, S.
Methyl
3-Hydroxy-6-chloropyrazinecarboxylate (XII).-A
holiition of S a x 0 2 (7.0 g, 0.1 mole) in concentrated H28Or (73 nil) was added with stirring to a mixture of IIa (18.7 g, 0.10 mole) in concentrated HzSOa (73 ml), and the resulting soliltion was stirred for 1 hr. The reaction mixture was poured over ice (.iOO g ) and the resulting aqueoiis solution was extracted with foiir 250-ml portions of EtOAc. The EtOAc was dried (MgHOa) and evaporated rinder reduced pressure to give 18.0 g (965;.;), nip 122-124'. Recrystallization from niethylcyclohexane gave material nit,h mp 127-129". Anal. (CsHjClIi203) C, H, N. Pyrazinyl-lH-1,2,4-triazoles(VIII).-The general procedtu.es for the preparation of the (pyrazinecarboxamido)guanidines ( I ) applies as well to the preparation of the triazoles since, in most instances, a mixture of the two was obtained. This mixture was readily separated by taking advantage of the amphoteric propei,ties of the triazoles. Routes B and E produced the least : u " n t of YIII, iindoitbtedly due to the milder reaction conditions. Typical examples follow.
Pyrazine Diuretics.
VII.
3-Amino-5-( 3-amino-5-trifluoromethylpyrazinyl)-lH-l,2,4-triazole (VIIId).-Aminogiianidine hydrochloikle (15.22 g, 0.137 mole) was added to a solrition of Ka (2.88 g, 0.125 g-atom) in iLIeOH (150 ml) and the mixture was stirred a t room temperature for 1 hr. The mixtiire was filtered to remove NaC1 and the filt,rate was evaporated under reduced pwsiire to a thick paste. I1 (S = H, Y = CF,, L.52 g, 0.01.5 mole) was added and this mixture was heated on the steam bath for 2 min. H 2 0 (50 ml) was added aiid the mixture was filtered. This solid was Ik. The filtrate was neutralized with HOAc aiid the precipitate was filtered, washed (HZO), and dried to give i?IId, 0.97 g.
3-Amino-5-( 3-amino-6-chloropyrazinyl)-lH-l,2,4-triazole (4.0 g, 0.0173 mole) was pulverized
(VIIIa). Method F.-Ia
and placed in a large test tube. .4 stream of S2 was admitted and the tube was heated to 290' for 30 min. After cooling, the product was dissolved in 3";. HCI and clarified with I h r c o . This solution was made strongly basic with IOc;; S a O H and again treated with Darco. This soltition, lvhen neiitralised with IlOAc arid cooled to O0, gave VIIIa. Method G.--Yl& ( 0 . 5 g, 0.0016 mole) was disaolved in 5 : 1IICl and warmed on the steam bath for 1.5 min. Neutralization of the cooled (0") solution gave 0.20 g of VIIIa.
N-Amidino-3-substituted Pyrazinecarboxamides
JAMES H. JOSES, TT'ILBTJR J. HOLTZ, .4.\D EDWARD J. CRAGOE, JR. .lfcrck Sharp
Cy:
D o h t ~ ~Rescaith e Laboratories, Dit iaion of .Tfc?ck Le. Co., In(., ll'eat P o d , I'ennsilkania Receiaecl October 2, 1968
The synthesi;. of a ierieb of ~-aniidiiio-3-ri1bjtitutedpyraziliecal.bosnrr~ider,priiicipd). by the i,eacticiii of n methyl 3-subytituted pyraziiiecarboxylate with guanidine, is described. The intermediate 3-substituted pyraxii~ecarboxylateuwere generally prepared by a ~iucleophilicdiiplacemelit reactioii iiivolviiig the appropriate :(-bromopyrazinecarboxylates which in turn were prepared from the corresponding 3-aminopyrazii:ecarhoxylates. When the 3 substituent was methoxy, mercapto, methyhercapto, or snbstituted amino the compounds were geilerally less active than their 3-amino analogs in the normal or adrenalectomized DOC9 loaded rats. The 8-hydroxy compounds were exceptions since they were as potent as their 3-amino aiialogs in the latter teat.
Certain S-amidino-3-aminopyrazinecarboxamides' possess interesting and useful diuretic properties; therefore, it was of interest to determine the effect of various substituents in the 3 position on the diuretic activity. The S-amidino-3-substituted pyrazinecarboxamides (IVa-p) examined in this study were prepared by the reaction of a methyl 3-substituted pyrazinecarboxylate (111) with guanidine according to the method described earlier2 (see Scheme I). An exception to this method, noted in Scheme I, involves the synthesis of S-amidino3-hydroxy-6-chloropyrazinecarboxamide(IVq) by the action of nitrous acid on the corresponding 3-amino analog (V). I t is interesting to note that there is no attack on the guanidine moiety, even in the presence of excess nitrous acid. The most useful method for the preparation of the intermediate methyl 3-substituted pyrazinecarboxylates (111) involved the nucleophilic displacement of the 3-halogen of the methyl 3-bromopyrazinecarboxylates (11). .A wide variety of nucleophiles attack the 3-position halogen without affecting the halogen in the 6 position even when the reagent was present in excess. I n a n attempt t o determine if displacement was occurring to
any extent a t the 6 position, methyl X-bromo-6chloropyrazinecarboxylate (IIb) was treated with SH3 in DA\ISO. The progreis of the reaction was checked readily by the periodic examination of a reaction mixture sample using tlc. The only product that could be detected, and eventually isolated in good yield, proved to be methyl 3-amino-G-chloropyrazinecarboxylate (Ib). compounds IIId. e, and j were prepared by diazotization3 of the appropriate methyl 3aminopyrazinecarboxylate in concentrated HZSOJ followed by treatment of the diazonium salt with methanol or water to introduce a 3-methoxy or 3-hydroxy group. Methyl 6- bromo- 3 - methylaminopyraziriecarboxylate (IIIh) was prepared via 1,3-dimethyll~mazine~ which was hydrolyzed to 3-methylaminopyraziriecarboxylic acid,j then esterified, and, finally. brominated. Ellingson and Henry6 have reported the preparation of methyl 3-bromopyrazi~iecarboxylate(IIn) by diazotization of the 3-amino compound7 (Ia) in 4'370 HBr containing Br?. This method waq readily adapted to the synthesis of compounds Ib-e by adding sufficient acetic acid to assure the dissolution of the ester in the reaction medium (3) T h i s method has been described by A . E. E r i c k s o n a n d P. E . Spoeri, J . A m . C h e m . S o r . , 68, 401 (1916). (4) .\. .\llierl, 11. .T. Iiroryn, a n d 11. C . 9 . \l-ood .I. Ciirm. So
