Journal of .lIedicinal Chemistry, 1970, Vol. 13, S o . 4 737
NOTES
-
SCHEMI.: I [&y>OCH2CHJ
HNK,
Nla, X
e C1 lb, X = OSO,C;H;
2
3
TABLE I1 I n Vitro ANTIMICROBIAL DATA(TUBE DILUTION TKST;LIIC V A L U I :I~N pglml) K. Compd
'a 2b
S. aureusn
E.
P.
coli*
vulgarisC
13
1.6
23
6.2
6.2
C. 1'. moniaed albicans vaginalis pneii-
3.1
100
12
'C
2d 2e 2f 2g 2h 2i 2i 2k
23 25 , 0i 50 12 3.1 35
12
3.1 3.1 6.2 12 1.6 1.6 12
2 ,j
25
50
12 35 50
30 12
35
2 c5
6.2
AIetruiiidazole a Staphylococcus aureus. Escherichia coli. garis. d Klebsiella pneumoniae.
100
0.39 0.19 0.78 0.10 0.39 0.19 0.78 0.19 0.78 0.78 0.10
1.6 Proteus vul-
mmol) was suspended in 25 ml of concd &SO4 and 1.5 ml of "03 (d = 1.48) was added dropwise a t 5'. After stirring for 0.5 hr the mixture was poured on ice, the aq solution was made alkaline with aq NH3 and the solid product was filtered, washed with HzO, and recrystallized from EtOH, mp C, H, N. 137-141'; yield 2.0 g (347,). Anal. (ClrHlaN40a) 2-(2-Furyl)-5-(2-di-n-butylaminoethoxy)pyrimidine~ HCL9-(2-Furyl)-5-(2-p-toluenesulfonyloxyethoxy)pyrimidine (2.08 g, -5.77 mmol) and 2.33 g (18.1 mmol) of n-BuaNH in 60 ml of EtOH was refluxed for 20 hr. EtOH and excessive BuzNH were removed by distillation, the residue was dissolved in HzO and the aq solution was extracted with CHZClz. The solution was dried (Na2S04) and the solvent removed. The residue tvas dissolved in i-PrOH-Et20 and HC1 in Et20 wm added. The solid hydrochloride was filtered off and recrystd from i-PrOH, mp 168-173'; yield 0.90 g (44y0). Anal. (ClsH&1N3O2) C, HI C1, N. 2-(5-Nitro-2-furyl)-5-(2-di-n-butylaminoethoxy)pyrimidine (3c).-2- (2-Furyl)-5- (2-di - n - buty1aminoethoxy)pyrimidine.HC1 (0.90 g, 2.54 mmol) was suspended in 3 ml of concd &SO4 and 0.255ml of HXOs (d = 1.48) was added at, 5". After stirring for 0.5 hr the mixture was poured onto ice, the resulting aq mixture was neutralized with concd KH3 and the insoluble mnterial recrystallized from i-PrOH-Hz0, mp 83-85' ; yield 413 mg (43%). Anal. (Ci8Hz6N4O4) C , H, N.
Reassignment of the Absolute Configuration of 3-Acetoxyquinuclidine Methiodide and the Absolute Configuration of Receptor-Bound Acetylcholine B. BELLEAU AKD PETERPACLING Department of Biochemistry, University of Ottawa, Ottawa, Canada, and Department of Chemistry, Unicersity College, London, London, England
The resolution and absolute configurations of (+)and (-)-3-acetoxyquinuclidine methiodide have recently been reported.' It was noted that only one 1.6 lg/ml in our test. The most active compound in vitro is 2-(5-nitro-2-furyl)-5-(2-N-n-propylpipera- of the optical enantiomers is a substrate of acetylcholinesterase (AChE) and is a muscarinic agonist. zinoethoxy)pyrimidine dihydrochloride (3k) with an This enantiomer was assigned the ( 8 ) configuration AIIC of 0.10 pg/ml. Some of the compounds were by the method of asymmetric sulfoxide synthesis2 investigated in vivo against a subcutaneous T . vaginalis as applied to (+)-3-quinuclidinol. This assignment infection in mice and proved to be active by oral appliled to the conclusion that the bridgehead carbon atom cation. Preliminary results indicate that in vivo of the biologically active enantiomer occupies a position activity of 2-(5-nitro-2-furyl)-5-(2-pyrrolidinoethoxy)equivalent to the methyl substituent of (8)-(+)-ppyrimidine (3d) is comparable to metronidazole. methylacetylcholine (I), the enantiomer which is a ubstrate of AChE and possesses muscarinic activity Experimental Section2 equivalent to that of acetylcholine (ACh).' I n the meantime, the crystal structures of the CY- and p2-(2-Furyl)-5-(2-p-toluenesulfonyloxyethoxy)pyrimidine(lb). -2-(2-Furyl)-5-(2-hydroxyethoxy)pyrimidine (10.3 g, 50 mmol) methyl-ACh isomers have been analyzed by Chothia was dissolved in 100 ml of pyridine, 9.53 g (50 mmol) of p-TsC1 and Pauling, 3 , 4 and their conformation was discussed was added and the mixture was stirred for 1,5 hr. The solution in relation to hydrolysis by AChE.5 The results led was poured into HzO, the insoluble prodiict was filtered and us to question the configurational assignment of (+)recrystd from PhlIe, mp 154-155"; yield 8.6 g (48%). Anal. 3-quinuclidino11 and after reexamination of the experi( C i ~ H 1 6 ~ a o jN, S ) S. 2-(2-Furyl)-5-(2-diethylaminoethoxy)pyrimidine (2b).-2-(2mental data it is evident that the dextrorotatory enFuryl>5-(2-chloroethoxy)pyrimidine (7.85 g, 38.3 mmol) and antiomer possesses the ( S ) rather than the ( R ) con10.42 g (0.142 mol) of Et&H was heated in 80 ml EtOH a t figuration. It follows that the previous analysis of 70-80" for 18 hr. The solvent and excess amine were removed by results' requires reinterpretation. distillation, the residue was mixed with H20 and extracted with CHZCL. The solution was dried (K2C03) and CHZCL was reAccording to the rules governing asymnietric sulmoved, yielding a crystalline compound, mp 4749'; yield 5.1 g foxide synthesis,2 alcohols corresponding to stereo(51%). A n a l . (C14H18N3O2)C, H , N. 2-(5-Nitro-%-furyl)-5-(2-diethylaminoethoxy)pyrimidine (3b)2- (2-Furyl)-5- (2-diethy1aminoethoxy)pyrimidine (5.0 g, 19.1
(2) hlelting points are uncorrected a n d taken on a Tottoli melting point apparatus (Fa. W. Buchi, Switzerland). Where analytical results are indicated only b y symbols of t h e elements or functions, values found for those elements or functions mere within 2 ~ 0 . 4 %of t h e calculated values,
(1) J. B. Robinson, B. Belleau, and E. Cox, J. .Wed. Chem., 12, 848 (1969). (2) hl. M. Green, hl. Axelrod, and hI. hIislow. J. Amer. Chem. Soc., 88, 861 (1966). (3) C. Chothia and P Pauling. Chem. Commun.. 626 (1969). (4) C . Chothia and P Pauling, zbid., 746 (1969). ( 5 ) C. Chothia and P. Pauling, Nature, 229, 919 (1969).
formula 11 yield aii e x c e s of tlie ( -i-(iS)-eti:~iitioiii(,i. of meth) 1 11-tolylwlfoxide. Having obt:tiiied :in rxce-. of the latter from (+)-X-c~uiriuclidiiio1,' it follow tliat configuration I1 nliere S = H , .\I = C'H2N+ :ind I . = CH(CH2)2:q)plie+. I i i tlie RS iiomc~ric1:iturc Iio\\-cver, tlie siihititueiit +eqiie~ic(~ i i i cicciw.irig ordc.1. of prioriticly i i HO, CH2S+.CH(
