KOTES
September 1969 (Sa,S04), alid charcoaled to give 107 g of y ~ l l o woil. Distillation
through a 7.5-cm Vigreux coliimn gave 98.8 g ( 9 3 5 ) of crude e.;tct'. .A c ~ ~ tciit e r served ns aii:tlyt,ic:al sample. p-Chlorophenylglyoxylic Acid.- -A mixtiir? of 37 1111 (O.;$> 111ok:) of PhC'1, 48.4 g (0.:3.5 mole) of ethoxalyl chloride, a n d 200 ml of ('lzCHCH(.'I? \ V R ~c d e d t o 0'. \Vith stirring 47 g (0.:3.5 mole) of .41C& \v:ih :itldctL :1( 0' diii,itig ;%()mill. The mist iiw was stirred :30 nliti nloi'e : t ~0" wild wai,rned gindiially over ;$O m i i i l i p to 43" n-here a brisk evolritioii of IICl began. Heating was iiiterrupted ~ultilthe fTCl evoliition stopped. The mixtiire was stirred on the st,eam bath for 3 hr, cooled, and poured onto a mixture of 200 g of ice arid 200 ml of 12 S HC1. Steam distillation removed the solvelit; the brown tar remaining was taken into Et20 and the aqlleonb phase was extracted with EtnO. The combined Et20 extractb were washed with H20 followed by dilute HC1, charcoaled, and dried (XazS04) to give 57 g of brown glim. The gum was taker1 up ill hot P h H and hexane was added to the cloud point,. On cooling there was obtained 21.7 g (33%) of crude tan solid, mp 89-91', lit? mp 90". 2-Chloroethyl Pyruvate Diethyl Ketal (3).--A mixture of 15.0 g (0.1 mole) of 2-chloroethyl pyrrlvate, 26 ml (0.13 mole) of ethyl orthoformate, I.,? g of p-toliieiiesiilfonic acid monohydrate, and 24 ml of absolute EtOH was allowed to stand 48 hr and then refluxed 8 hr. Using a minimum amount of heat, low-boiling compolierits were removed at the aspirator and the residiie x a s poured into ice water containing 40 ml of 5%, NaHC0,. After extraction into 1,2-dichloroethane, the organic phase was washed with HzO until the washings were neutral, dried, charcoaled, and stripped to give a residue of yellow oil. Careful removal of forerun in a 5-cm Vigreux column gave the crude product, 13.7 g (GI%), bp 106-113" ( 6 mm). On redistillation a center cut furnished the analytical sample. 2-Chloropropyl Phenylglyoxylate (9).-To a stirred soliition of 25.5 g (0.17 mole) of phenylglyoxylic acid in 100 ml of DhIF was added 23.5 ml (0.17 mole) of E t J followed by 17.5 ml (0.17 mole) of 1-bromo-2-chloropropaiie. With the protection of a drying tithe the mixtiire was stirred on the steam bath 5 hr and cooled. The precipitate was filtered and washed with 25 ml of hexane. The DLIF soliltion was poured into ice water, the oil was taken int,o CHCL, and the aqiieoiis phase was extrackd with CHCI,. The hexane extract was concentrated and taken into CHCI,. The combined CHClr extracts were washed with 27, NaHCO, and HrO, dried:(Na?S04), charcoaled, and concentrated to ail oil which was fractionated i n a 7.5-cm Vigreux column to yield 12.1 g ( 3 1 5 ~ ) .A center cut served as analytical sample. 2-Chloroethyl m-Nitrophenylglyoxylate (lFi).-m-Xitrobenzaldehyde was converted iiito the cyaiiohydriii using the procediire of Buck.Q Without characterizatioii the cyanohydrin was hydrolyzed by heating iii coilcentrated HC1 on the steam bath 18 hr to give m-nitromandelic acid,10 mp 114-116', in 20% yield. This acid was esterified with 2-chloruethanol in 88% yield to give Anal. (Clo2-chloroethyl m-nitromaridelate (26), mp 86-87'. HloCINOj) C, H, C1. N-Bromosucciriimide (4.25 g, 0.0238 mole) was stirred in 100 ml of refluxing CC1,. To this was added a solution of 6.2 g (0.0238 mole) of 2-chloroethyl m-nitromandelate in 75 ml of CCL. After 12 hr of heating uiider reflux the mixture was cooled and the solid was filtered off and discarded. A drop of allyl alcohol was added to decolorize. The solution was dried (NaS04) and charcoaled. After the solvent was removed by careful distillation on the steam bath the oily residue distilled to give 837, yield of 15, bp 162-164' (0.02 mm).
Acknowledgment.-The authors are indebted for spectroscopic data to Dr. R. Kullnig and staff and for elementary analytical data to N r . IC Fleischer and staff.
(8) F. Kronke, Chem. Ber., 80, 298 (1947). (9) J. S.Buck, J . Am. Chem. Soc., 66, 3388 (1933). (10) A . Fredga andlI. Andersson,lArkiu_Kemi, Minernl:Geol., 7 (1940): Chem. A h s t r . , _ S S , _ 3 9 0 3 ~ ( 1 ~ ~ 1 ) .
14B, (18)
043
Quaternary Oxazolylpyridinium Salts, Oral Hypoglycemic Agents (;RI.:WHF:N
E. WI~;(:AXI),\ ' I , . I Y >J.R t3 {[V:R, S. I:. S \F'~II, Orguni~,~
' h ~ i t ~h'c'swwh i ~ ~ i l
D. A. BLicici:ss,
AXU
Scc,f iorc
S. J. I ~ I G G I
Department of Metabolic Chemotherapy, 1,rclarle Laboratories, A Division of American C,r/annii/ir/ Company, Pearl River, AYew York 20966 Received April 14, 1969
A number of quaternary azolylpyridinium salts, including members of the pyrazolyl-, isoxazolyl-,*-4 and 1,2,4-oxadiaz~lylpyridinium~ salt families, have been found to display hypoglycemic activity in laboratory animals. As part of a comprehensive development of this lead, we have investigated the replacement of the azolyl ring with other five-membered heterocycles. We describe herein the synthesis of some novel 4-(oxazoly1)pyridinium salts. The 4-(oxazoly1)pyridinium salts 6-12 (Table I) were obtained by quaternization of the appropriate oxazolylpyridine bases 1, 2, and 3. The base 1 was prepared as described by Dadkah and Prijns.6 The
1,R=H
3
2, R=CH3
4
6-11
5
12
bases 2 and 3 mere obtained by dehydration of the amido ket'ones 4 and 5,' respect'ively, using a procedure developed by Ott, et U Z . , ~ for the preparation of aryloxazoles. I n the nmr spectrum of t'he base 1 the pyridyl protons appear as two doublets a t 6 7.73 and 8.75. Upon quaternization to 6, these signals shift to new values of 6 8.42 and 9.02. These changes, a downfield displacement of both doublets, as well as a smaller separation between chemical shifts, are diagnostic (1) V. J. Bauer, H . P. Dalalian, W.J. Fanshawe, S. R. Safir, E. C. Tocus. and C. R . Boshart. J . Med. Chem., 11, 981 (1968). (2) V. J. Bauer, W. J. Fanshawe, H. P. Dalalian, and S. R . Safir. ibicf., 11, 984 (1968). ( 3 ) S.J. Riggi, D . .4.Blickens, and C. R. Boshart, Diabetes, 17, 646 (1968). (4) D . A. Bliokens and S. J. Riggi, Tozicol. A p p l . Phnmacol., 14, 393 (1969): Diabetes, in press. (5) W.J . Fanshawe, V. J. Bauer, S. R. Bafir, D. A. Blickens, and S. J. Riggi, J . Med. Chem., 12, 381 (1969). (6) M. Dadkah and B . Prijns, Helv. Chim. Acta. 46, 375 (1962).
(7) S.van der Meer, H. Kofmsn, and H. Veldstra, Rec. Trau. Chim. P a y s Bas, 72, 236 (1963). (8) D . G. O t t , F. N. Hayes, and V. N. Kerr, J . Amer. Chem. Sac., 78, 1941 (1958).
Soms
of pyridine quaternization',? and demonstrate that :&ylation has occurred on the pyridine rather than the oxazole nitrogen. Hypoglycemic Activity."---Sxllne solutions of compounds \yere admnistered by gavage t o male CF-1 niicc (Carirorth Farms, 25-30 g) a t dose> of 1.5 and 3.0 mniol/lrg; controls received an equal volume of vehicle.. Blood samples (0.05 inl) obtained from retrobulbar plexuses 3 arid 5 hr after dosing were i using the method of Hoffman"l :ii adapted for the Twhnicon AutoAnalyzer. Blood glucosc 15 as decreabed 21-9Oc/, following the administration of oxazolylpyridinium salts (Table I ) . Further studies are in progrew to conipare the potency, toxicity, arid mode of :Lction of thcse agents with those of other hypoglyrrniic
reflux for 1 hr :tiid cooled. The superiiatant liquid was tlecanteti, excess 1 -I'NaOH was added tu the tarry residrie, arid the oily mixture was extracted with CIIC1,. The CHC13 d u t i o i i is dried (RIgSOr) aiid cr)nceiitrated wider reduced pressiirt' t i i ILII off-white solid. Siiblimation at 90" (12 nim) gave 0.95 g (595; j of colorless needle., nip Z - X I " , I I V 310 nip ( e 20,XZI). .lital. (CrHaNIO) C, H , ?;. l-iMethyl-4-(2-oxazolyl)pyridiniumChloride (6). ~ - Arriixt i i t v of 2.1 g (0.014 niol) of ~-(L'-oxazoI~I)pyridiiie (l)F atid 3 1111 lleC1 was heated at, 1003 for 4 hr i i i a glass-lineti steel h i i r i t ) . The excess l1eC:l war; allo~vetl evaporate and the solid residut. \vas recrystallized (i-PrOII) t,o give 0.3 g (20';;) of off-white crystals, nip 244" tfec, IIV :$I2 mp ( e 16,900). A n d . ( C ~ H Q C ~ N L ) .
drugh. Experimental Section11 Isonicotinamidoacetone (4).--TCJ a cold solution of freshly prepared isonicot~inoyl chloride12 !from 20 g (0.16 mol) of isonicotinic acid] in 1.50 in1 of dry pyridine was added, in portions, 17.6 g (0.16 mol) of aminoacetorie h y d r o c h l ~ r i d e la~t such a rate that the temperature never rose above 10". The mixture was &wed t o come slow1y to room temperature, stirred for 1 hr, poiired into 1.5 1. of ice, and extracted with CHC1,. The CHCl, aolution wa.7 dried (lIgSOa), decolorized (Darco), and cunceii[rated under rediiced pressure to a brown solid. liecryatallization (EtOH) gave 6.5 g (2551) of tan Three recry~tallizations (EtOH-perita crystals, mp 143-144". Anal. (CsH,&,On) C, H, N. 4-(5-Methyl-2-oxazolyl)pyridine(Z).---To a solution of 3.6 g (0.03 mol) of 4 in 54 ml of AcnO was added 4.4 ml of 85% H3P01. rition was heated under reflux for 3 hr, then cooled, aiid olvent was decanted. The tarry residue was treated with excess 1 'I' XaOH, which caused precipit,atiori of au off-white solid. Three recrystallizations (€120) gave 1.3 g (40%) of colorless crystals, mp 99-loo", I N 289 nip ( € 15,600). The analytical sample was obtained by sublimation a t 60" (0.1 mm). Anal. (CgH,?r'zO) C, H, N. 4-(2-Methyl-5-oxazolyl)pyridine(3).--To a suspension of 1.8 g 10.01 m i l l ) of 4-acetylaminoacetylpyridine (5)' in 27 ml of AczO \ Y Z I Sadded 2.2 ml of 8.57, H ~ P O I . The mixture was heated under ( $ 4 ) Tei.liniraI assistance of 31r. E. I u k e , 3Ir. H. Siegriest, a n d Miss I,. \Vi11 is greatly appreciated. ( I O ) \V. S. Hoffman, J . B i d . Cheffk.,120, 51 (1937). 1 1 1 ) illnltinp points were determined in a Heruhberg apparatus and are iincorrected. hlicroanalyses were performed h y M r . L. M. Brancone and * l u f f . \Vilere analrses are indicated only by symbols of t h e elements, arlal.stica1 results obtained for rhose elements were within +0.4:% of t h e ilitmrrtical values. C v spectra were determined b y M r . W. Fulmor ancl .-tuff i n MeOII with a C a r s 11 si~ectropbotometer. ( 1 2 ) I€. Meyer and B. G r a f , Chem. Ber., 61, 2206 (1928). ( I : $ \ I-. P. EllingPr and .'i.A . Goldberg, J . Chen. Soe., 263 (1947).
Hypoglycemic Quaternary Azolylpj ridiniutti Salts. Inactive Analogs
A% number of quaternary :izolylpyridinium halt.;, including member> of the pyrazolyl-, iwxazolyl-,2 1,2.-l.-osadiazolyl-,' ~ x a z o l y l - , m ~ t l thiazolylpyridiriiuni) salt families, have been found t o display interesting hypoglycemic activity in laboratory animals, arid l-methy1-4-(3-rnethyl-.i-isoxazolyl)pyridiniumchloride (1) has been chosen6,' for study as it potential nntidiubetic drug. Other rlas of uzolylpyridiniuni s:tlt have been examined arid found to lack hypoglycemic activity in mice. In this report, we describe the syrithe and properties of these compounds (1) \ . J Bauer 11 I' 1)alalian \\ I I anbliane, and S It Safir, .7 lfed. Chem , 11,981 (1968) ( 2 ) V. J. Bauer W I 1 a n q l i a n i . I I €' 1)alalian and Y I< Safir, zbrrl 11, 98%(1968). (3) W. J. Frtnstiant-. 1'. .1. I3aiin.. S, I t . Bafir, I). A . Illickens. and S. .I.
