Noms
Septcmber 19GO
946
(2b).-A solution of 1.61 g (0.01 mol) of 4-(5-methyl-1,3,4oxadiazol-2-yl)pyridine,* 1.50 g (0.011 mol) of MeI, and 10 ml of MeOH was heated under reflux for 1 hr. An orange solid, 1.60 g, mp 150-250", separated and was collected. Three recrystallizat,ions (MeOH-H20) gave 0.31 g (10%) of orange needles, mp 275-277" dec, uv 217 ( E 17,900) and 278 mp ( E 19,1 200). Anal. (CgHloINaO) C, H, I, N. l-Methyl-4-(5-methyl-l,3,4-thiadiazol-2-yI)pyridinium Iodide (2c).-A solution of 1.77 g (0.01 mol) of 4-(5-methyl-1,3,4-thiadiazol-2-yl)pyridine,g 1 mi of BleI, and 10 ml of MeOH was heated under reflux for 2 hr. Upon cooling 2.58 g (81%) of a yellow solid, mp 225-230°, separated and was collected. Two recrystallizations (MeOH) gave yellow prisms, mp 226-227" dec, 2a,Z= NH; X =C1 3 uv 218 ( e 18,100) and 287 mp ( 6 16,400). Anal. ( C ~ H ~ O I K ~ S ) b,Z =O;X = I C, H, I, N, S. l-MethyI-4-(5-tetrazoIyl)pyridinium Chloride (3).--9 mixt'ure c,Z=S;X=I of 7.8 g (0.053 mol) of 4-(5-tetrazolyl)pyridinelO and 10 ml of Reaction of 4-(5-methyl-l,2,4-triaz01-3-yl)pyridine,~MeCl mas heated a t 130" in a glass-lined steel bomb for 18 hr. The excess MeC1 was allowed to evaporate, and the colorless 4- (5-methyl-l,3,4-oxadiazol-2-yl)pyridine,4- (5-methresidue was recrystallized (MeOH-H20) to provide 3.2 g (31%) of yl- 1,3,4-thiadiazol-2-yl) pyridine, and 4-(5-tetrazcolorless crystals, mp 238-239". Four recrystallizations gave o1yl)pyridine'O with nIeCl or Ale1 provided the desired the analytical sample, mp 235' dec, uv 277 mp ( e 13,600). Anal. quaternary salts 2 a 3 3. For the synthesis of animidaz(CiHsClXs) C, H, C1, N. N-(Formylmethy1)isonicotinamidine Diethyl Acetal (4).-A olyl analog, 4-cyanopyridine was converted by the solution of 20.8 g (0.20 mol) of 4-cyanopyridine and 1.1 g (0.02 method of Schaefer and Peters" to methyl isonicotinmol) of NaOMe in 200 ml of RleOH was stirred a t room temperaimidate, which was allowed to react with aminoacetture for 20 hr. To this solution of methyl isonicotinimidate was aldehyde diethyl acetal to yield the amidino acetal 4. added 52 ml (0.20 mol) of 3.8 A- HCl in EtOH and 26.6 g (0.20 Acidic cyclization of 4 gave the imidazolylpyridine 5, mol) of aminoacetaldehyde diethyl acetal. The solution was heat,ed under reflux for 4 hr and was Concentrated under reduced which was quaternized to the desired salt 6. pressure. The residual oil was treated with 160 ml of 0.5 N NH SaOH, and the resultant mixture was extracted with CHC13. The CHC13extract was dried (MgSO,) and concentrated to give a (EtO)2CHCH2N= C white solid. Recrystallization (EtOAc-petroleum ether (bp 30-60")) gave 34.1 g (72%) of colorless crystals, mp 92-94'. 4 Several recrystallizations provided the analytical sample, mp 93-94', uv 265 mp ( e 3900). Anal. (C&&302) C, H, N. 4-(2-ImidazolyI)pyridine (5).-To 30 ml of 12 X H2SOa TYas added in portions 2.3 g (0.01 mol) of 4. The solution was then heated for 30 min on a steam bath, cooled, and made basic by H H the dropwise addition of 10 N NaOH. The solution was ex5 6 tracted with CHC18. The CHC1, solution was dried (MgSO4) and concentrated to a white solid. Two recrystallizations Compounds 2a-q 3, and 6 (0.5-3.0 mmol/lig) were (EtOAc-petroleum ether) gave 0.5 g (33Yc)of colorless crystals, administered orally as saline solutions to male mice mp 211-212", uv 290 mp ( e 15,390). Anal. (CsHiN3) C, H, K. (Carworth Farms, 18-25 g) ; controls received an equal l-Methyl-4-(2-imidazolyl)pyridiniumChloride (6).--A mixture volume of vehicle. Blood glucose levels were deterof 2.9 g (0.02 mol) of 5 and 5 ml of NeC1 was heated at 120" in a mined12 3 and 5 hr after dosing by the method of Hoffglass-lined steel bomb for 18 hr. The excess hIeCl was allowed to evaporate, and the solid residiie \vas recrystallized (EtOH) man13 as adapted for the Technicon AutoAnalyzer. three times t o provide 2.5 g iG4Cc)of pale yellow crystals, mp Glucose concentrations were not different from controls, 277-278" dec, uv 345 mp ( e 21,510). Anal. (C~HIOKZCI) C, H, except for an uninteresting slight nondose related hypoC1, N.
glycemia following administration of 2b. Experimental Sectionla
l-MethyI-4-(5-methyI-l,2,4-triazoI-3-yI)pyridiniumChloride (2a).-A mixture of 3.0 g (0.019 mol) of 4-(5-methyl-1,2,4triazol-3-y1)pyridines arid 10 ml of MeCl was heated for 20 hr a t 85" in a glass-lined steel bomb. The excess MeCl was allowed to evaporate, and the residual solid was recrystallized (EtOH) to provide 1.2 g (30%) of colorless crystals, mp 290-291" dec. Three recrystallizations gave colorless needles, mp 281-284" dec, uv 283 mp ( e 13,400). Anal. (CgHllC1N,.0.25H20) C, H, C1; K: calcd: 26.1; found, 26.7. l-Methyl-4-(5-methyl-l,3,4-oxadiazol-2-yl)pyridinium Iodide (8) I-.Postovskii and N . N. Vereshchagina, J. Gen. Chem. L'SSR, 29, 2105 (1959). (9) F. H. hIcMillan, F. Leonard, R. I. Meltzer, and J. A. King. J. A m . l'harm. Assoc., 42, 457 (1953). (IO) D. D. Libman and R. Slack, J. Chem. Soc., 2253 (1956). (11) F. C . Schaefer and G . A. Peters, .I. Ory. Chrm.. 26, 412 (1961). (12) 'leatin:: data was supplied b y Urs. U. A . Bliokena and S. J. Riggi of the Metabolic Chemotherapy Department of these laboratories. (13) W.S. Hoffman, J. B i d . Chem.. 120, 51 (1937). (14) Melting points were determined in a Hershberg apparatus and are iincorrectcd. Microanalyses were performed by hlr. I,. &I. Brancone and
s t a f f ; where analyses are indicated only by symbols of the elements, analytical results obtained for those elements were within 0.47, of the theoretical values. U v spectra were recorded in MeOH solution with a Cary 11 speotrophotometer by Mr. W. Fulmor and staff.
4-Azolylpyridine 1-Oxides. Analogs of the Hypoglycemic 4-Azolylpyridinium Salts VICTORJ. BAUER, WILLIAM J. FANSHAWVE, G n E w H m E. WTIEGAND, .LSD 8. R . PAFIR
Organic Chemical Research Soction, I,ctlerlc. Laboratories, ii Division o,f A v w i c a n C?/unanLirlCompany, Pearl R i w r , .\-ew 170rk 10.965 Received X a y 23, 1969
A number of 4-azolylpyridinium salts, iiicludiiig the pyrazolyl- (la),l i~oxazolyl- (lb),2 thinzolyl- ( l ~ ) , ~ (1) V. J. Bauer, H. P. Dalalian, W.J. Fanshawe, S. R. Safir. E. C. Tocus, and C . R. Roshart. J . > I d Chem., 11, 981 (1968). ( 2 ) V. J . Aarirr. IT.J. Fanshawe. H. P . Dalalian, and S. R . Safir, ib!d., 11, 984 (lues); 1). A. Ulickens and S,J. Riggi, T'osicol. A p p l . I'hurmucol., 14, 393 (1969). (3) G. E. Wiegand, V. J. Bauer. S. R. Safir, D. A. Blickens, and S. J. Riggi, J. M e d . Chem., 12, 891 (1969).
