SOTES
September 190'3
94 1
TABLE I1 ~-AMINOPROPIONATESa R1CH2CHR2COORIe
RfETHYL
NO.
%
Reaction time, days
I l p , ' C (mm)
yield
5 5 7
HCI mp, " C
Formula,
CioHiqN02 183-184 109-110 (15)d 12 CioHi9NOz 157-158 107-108 (18)e 13 Cl4H26xZO4 203-204.3 138-140 (2) 14 66-68 (2) CnHz1NOz 14-5-146 1,i 7 88-90 (2) Ci3Hz,SO? 164-16.i 7 143-145 (2) C16H23?jOL 180-1 81 16 r 17 120-122 (19)f CqHnSO, 165-166 18 7 76-78 ( 2 ) CiiHuKOS 148-149 19 1.25 76-78 ( 2 ) ~ CiiHziKO2 133-134 2 100-104 (1)h CiiHiiXO, 138-1 5gh 20 a Substituents R' and R2 in esters 11-20 are identical with those listed for hydroxamic acids 1-10, respectively, in Table I. 6 Et ester. All compounds were analyzed for C, H. Analytical results obtained were within 3 ~ 0 . 3 %of theoretical values. d J. F. Areni, D. H. Koerts, and P. Plieger, Rec. Trav. Chim., 75, 1454 (1956), gave bp 106-108" (11 mm). e P. Bieber, Compt. Rend., 231, 291 (1950), gave bp 102-103" (18 mm). f A. Vystrcil and S. Hudecek, Chem. Listy, 44,262 (1950), gave bp 112' (13 mm). 0 11. I. Barron, C:. H. * P. 1,. Hall, I. L. Natoff, H. F. Ridley, R. G. W. Spickett, and D. K . Vallance, J. M e d . Chem., 8 , 836 (1965), gave bp 60' (0.05"). Sorithwick and R. T. Crouch, J . Am. Chem. Soc., 75, 3413 (1953), gave bp 145-147' (7 mm) and mp 164-165", respectively. 1l
b
74 78 60 90 80 85 91 95 80 62
-
Table 111. These results show that the duration of action of the hydroxamates is more prolonged than that of the esters. T.ABLEI11 EFFECT O F ~-AMIXOPROPIONOHYDROXAMIC ACIDS AND ~ I E T H Y p-AMINOPROPIONATES L ON ARTERIALBLOODPRESSURE O F THE ANESTHETIZED CAT'
Compd
Dose, mg/k
Blood pressure fall, mmb
Duration,c min
23 45 5 25 10 60 10 2.5 35 4 25 70 10 5 5 40 5 n 10 40 30 5 25 120 40 5 >120 50 5.?I 6 5 70 >80 >120 6 10 65 2.i >>120 90 6 23 1 7 4.?I 23 25 30 8 5 9 25 40 10 45 25 >GO 25 11 50 5 12 25 (25)d 1 25 13 15 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 PhH 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 EtJ 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.Rt3 {[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).
