Aug. 5, 1!ml
ALKYLAND ARYLAMINO-PYRIMIDINES A N D PURINES [CONTRIBUTIOS FROM
THE
3971
LILLYRESEARCH LABORATORIES, INDIANAPOLIS 6, IND.]
Exchange Amination. Alkyl and Arylamino-pyrimidines and Purines B Y CALVERT W. WHITEHEAD AND JOHN J. TRAVERSO RECEIVED DECEMBER 28, 1959 Pyrimidine amine functions were exchanged with primary alkyl, aralkyl and arylamine groups t o yield the corresponding Nsubstituted 4-amino-, 6-amino- and 2-aminopyrimidines. This exchange reaction was particularly useful in t h e synthesis of 4-substituted amino-2, and 6-hydroxypyrimidines as well as 1,3-dialkyl-6-substituted aminouracils. Adenine was converted t o 6-benzylamino-, 6-furfurylamino- and 6-phenylaminopurine b y t h e same reaction.
N-Alkyl and N-arylamino-pyrimidines and pu- 4-benzylamino-6-hydroxypyrimidine,4-anilino-6rines have been prepared almost exclusively by hydroxypyrimidine and 6-hydroxy-4-m-methylnucleophilic displacement of chloro, mercapto or benzylaminopyrimidine. 4-Amino-6-hydroxy-2alkoxy groups with amines. This procedure is methylpyrimidine underwent exchange amination limited by the availability of appropriate chloro, to yield 4-benzylamino-6-hydroxy-2-rnethylpyrimimercapto or alkoxy intermediates. Pyrimidines dine, 4-hydroxy-2-methyl-6-phenethylaminopyrimand purines having primary amino or imino func- idine and 4-anilino-6-hydroxy-2-methylpyrimidine. tions on a carbon adjacent t o an endocyclic nitroAll the reactions of primary amines with pyrimigen are, however, readily available. This paper dylamines, described above, were carried out in the describes the direct conversion of a number of presence of an acid catalyst, ie., the amine hythese aminopyrimidines and 6-aminopurine t o drochloride. Two reactions were performed to their N-alkyl-, N-aralkyl- and N-arylamino-deriva- determine whether an acid catalyst was actually tives. required, In the absence of an acid n-heptylAlkyl and arylamines were allowed t o react with amine and benzylamine each underwent obscure 6-amino-2,4-dimethylpyrimidine hydrochloride, a t reactions with 4-amino-6-hydroxypyrimidine.A an elevated temperature, t o give excellent yields of low yield of 1,3-di-n-heptylurea was obtained with 6-anilino-, 6-(3’,4’-dimethoxyphenethy1amino)-,6- n-heptylamine. Benzylamine yielded a product benzylamino-, 6-n-heptylamino-, 6-cyclohexylamino- having an empirical formula C18Hl7N3Oj as deand 6-n-butylamino-2,4-dimethylpyrimidines. The termined from its elemental analysis. I t s ultraboiling point as well as other physical properties of violet absorption spectrum is pyrimidine-like with the cyclohexyl derivative are identical t o those two maxima; log a M a t 230 mp is 4.52, and a t previously reported for 6-cyclohexylamino-2,4- 259 mp is 3.79. The infrared spectrum supports dimethy1pyrimidine.l Methiodides were prepared the pyrimidine structure and absorption bands of the 6-benzylamino- and 6-n-heptylamino-2,4- a t 2.92, 6.02 and 6.21 p indicate the presence of dimethylpyrimidines, resulting in well defined NH, amide-like carbonyl and benzyl groupings, respectively. These results suggest the structure solid derivatives. The primary and secondary amine groups of 1-benzyl-4-benzylamino-6 - keto- 1,6- dihydropyrimi4-amino-6-n-octylaminopyrimidine were both re- dine or 3-benzyl-4-benzylamino-6-keto-1,6-dihyplaced when heated with benzylamine hydrochlo- dropyrimidine. Either of these products obtained ride. The product, 4,6-bis-benzylaminopyrimi-from benzylamine or 1,3-di-n-heptylurea obtained dine, was identical t o an authentic sample of this from n-heptylamine must result by complex prepared2 from 4,6-dichloropyrimidine and benzyl- transpositions involving a ring cleavage. The mechanism of this ring cleavage could be similar amine. Very few 4-alkylamino-, or 4-arylamino-, 2- or to that proposed by Taylor6 for the reactions of 6-hydroxypyrimidines have been reported. Those alkylamines with aminopteridines. Since the rewith benfound in the literature were prepared by the hy- actions of 4-amino-6-hydroxypyrimidine drolysis of a 2- or 6-alkylmercapto or alkylsulfonyl zylamine and with n-heptylamine in the absence of group. 3-5 The exchange amination reaction re- an acid catalyst did not give consistent results, ported here is particularly useful in the synthesis the presence of an acid catalyst is considered of pyrimidines of this type. Cytosine was heated essential in effecting a definable exchange aminawith a mixture of benzylamine hydrochloride and tion resulting in the formation of the 4-substibenzylamine to give an 80% yield of 4-benzyl- tuted amino-6-hydroxypyrimidines. A catalyst amino-2-hydroxypyrimidine.Slightly lower yields was therefore used in all the exchange reactions. of 4-anilino-2-hydroxypyrimidine and 2-hydroxy-4- When 2-amino-4-hydroxypyrimidine(isocytosine) phenethylaminopyrimidine were obtained when was treated with an alkyl or arylamine hydrochlocytosine was treated with aniline hydrochloride ride, under the same conditions used for the 4and with phenethylamine hydrochloride. In a and 6-aminopyrimidines, there was no observable gave reaction and unchanged isocytosine was recovered. similar manner 4-amino-6-hydro~ypyrimidine~ The reaction between 2-amino-4,6-dimethylpy( 1 ) R. Hull, B. J. Lovell, H. T. Openshaw, I.. C . P a y m a n and A. R. rimidine and benzylamine hydrochloride gave a low T o d d , J . Chem. Soc., 357 (194F). yield of 2-benzylamino-4,6-dimethylpyrimidine. (2) C . W. Whitehead a n d J. J. Traverso, THISJ O U R N A L , 80, 2185 Contributions of the two adjacent endocyclic (195% (3) J. M. Sprague and T. B. J o h n s o n , ibid., 67, 2252 (1935). nitrogens would appear t o retard an exchange of (4) F. H. S. C u r d , M. I. Davis, E . C. Owen, F L. Rose and G. A . the 2-amine function, but further examination of P. T u e y , J . Chem. Soc., 370 (1946). ( 5 ) H. L. Wheeler and T. B. Johnson, A m . Chem. J . , 31, 596 (1904).
(6) E. C. Taylor, THISJOURNAL, 74, 1651 (1952)
CALVERT Lv, LvHITEHE,ID
3972
AND JOHN
J. TRAVERSO
Vol. 82
TABLE I KiyN, SHR2
Nq RJ
Ri
R2
R3
hl.p., ' C .
Yield,
%
Formula
C a r b o n , 70 Calcd. Found
CHJ n-C.iHg CHs 108" 91 C ~ O H ~ ~ S S66.99 66.86 CH3 C~HS CHI 102* 53 CiiHisSa $3 Ci2HigS3 CH3 CH, 135" CH, 78-81d 71 C13H1:,Sa C6HjCHz CHs CHa CHI x-C~HI:, 16Se 70 C13H23NB CH? ClaH130?f CH, 200' 69 C10H2iSs02 H 266 64 CiuHsR'sO 63.16 64.06 OH CsHj OH CgHjCHi H 217-218 79 CllHllSeO 65.67 65.54 C6Hb(CHg)2 H 67.21 63 C12H131\;30 66.95 OH 182-185 H C6H: OH 24&250 13 CioHgYs0 64.16 64.16 C6HsCHi OH 65.67 65.83 H 37 CllHl1NsO 230-234 39 Ci2HiiS30 66.95 67.04 H CaHgh OH 210-220 CH3 CsHb OH 270 57 CuHiiS30 CHs CsHjCHs OH 225-227 60 CiiH13~30 66.95 66.94 CH3 CsHj(CH?)? OH 221 65 Ci3HiiS~0 B.p. at 0.75 mm. * B.p. 165' a t 1 mm. B.p. a t 0.5 mm. B.p. 155" a t 0.4 mm. phenethyl. 0 B.p. a t 1 mm. 4-Methylbenzyl.
--
Hydrogen, % Calcd. Found
Sitrogen, % Calcd. Found
23.44 23.45 21.09 21.27 20.47 20.43 19.70 19.46 18.99 18.45 14.62 14.09 22.45 22.64 4.85 4.94 20.88 20.90 5.51 5.66 19.52 19.43 6.09 5.59 22.45 22.10 4.85 5.10 20.88 20.87 5,5l 5.83 19.52 19.86 6.09 6.49 20.88 20.78 19.52 19.43 6.09 6.01 18.33 18.40 f 3.4-Dimethyl e B.p. at 1 mm. 9.57
9.75
the reaction conditions is necessary before this Experimental may be considered a fact. 2,4-Dimethyl-6-substitutedAminopyrimidines (Table I). I t was particularly interesting t o find the ex- --A mixture of 15 g. (0.1 mole) of B-amino-2,4-diniethylchange amination reaction could occur when both pyrimidine hydrochloride and a 10% molar excess of the appropriate amine was sealed in a glass tube. This was ring nitrogens of the pyrimidine were substituted heated a t 170" in a furnace for 20 hours. The cooled conwith alkyl groups or when amino-imino tauto- tent of the tube was poured into dilute S H I O H . The prodmerism does not exist between the extranuclear uct was extracted with ether, dried over MgSOa and disand endonuclear nitrogens. When 1,3-dimethy1-6- tilled under reduced pressure. In some cases the products and were recrystallized from a mixture of ethyl aminouracil was treated separately with the hy- crystallized aceiate and petroleum ether. drochlorides of furfurylamine, benzylamine and 6-Benzylamino-2,4-dimethylpyrimidineMethiodide.n-heptylamine, the products were 1,3-dimethyl- Three grams of 6-benzylamino-2,4-dimethylpyrimidine and 2.5 g. of methyl iodide in 50 ml. of ethyl acetate were boiled 6-furfurylaminouraci1,6-benzylamino-l,3-dimethylunder reflux for 16 hr. The separated solid was recrystaluracil and 1,3-dimethyl-B-n-heptylaminouracil.lized from ethanol; yield 4.5 g. (827,), m.p. 190-192". These 1,3-dialkyl-6-substitutedaminouracils are Anal. Calcd. for CllH191h-3: S , 11.26. Found: S , believed to be the first representatives of their 11.49. type. Previously reported methods of pyrimidine 2,4-Dimethyl-6-n-heptylaminopyrimidineyethiodide: synthesis cannot be applied in their preparation. yield 72%, (as described above), m.p. 70-i2 . Anal. Adenine reacted with benzylamine hydrochloride Calcd. for C14H261Na: K, 11.56. Found: S , 11.31. 4,6-Bis-benzylaminopyrimidinefrom 4-Amino-6-n-octylto yield 6-benzylaminopurine and with furfuryl- aminopyrimidine.-A mixture of 4 g. (0.018 mole) of 4amine hydrochloride to yield 6-furfurylamino- amino-6-n-octyl-aminopyrimidine,* 2.56 g. (0.018 mole) of purine (kinetin). Aniline hydrochloride and aden- benzylamine hydrochloride and a few drops of benzylamine ine gave 6-anilinopurine which required a number of was heated at 170" for 2 hr. The cooled residue was waslied with ether and then with alcohol t o yield 1 g. of insoluble recrystallizations before i t was free of color. Guan- solid. The solid was recrystallized from ethanol; m.p. ine did not appear t o react with the amine hydro- 236-237". This was identical to a sample of 4,6-bischlorides and adenosine was degraded to adenine. benzylaminopyrimidin e. 4-Alkylamino- and 4-Arylamino-2-hydroxypyrimidines.Ultraviolet absorption of the parent primary 5.5 g. (0.077 mole) of cytosine with an equal molar pyrimidylamines and their products, the alkyl- To amount of the appropriate amine hydrochloride was added amino- and arylaminopyrimidines, were determined enough of the free amine to wet the solids. The mixture in neutral, acid and basic alcohol solutions (Table was heated in an oil-bath a t 165" for 6 hr. The solid residue dissolved in dilute alcohol, clarified with carbon, conI). Similarity in the absorption characteristics was centrated and allowed to crystallize. of each parent compound and its derivative sup4-Substituted Amino-6-hydroxypyrimidines (Table I ).ports the structure of the latter. Most of the T o one-tenth mole (11.1 9.) of 4-amino-6-hydroxypyrimidine2 was added 0.1 mole of the appropriate amine hydropyrimidines were titrated and the pK,) values chloride with sufficient free amine to moisten the mass. The determined in 66y0 N,N-dimethylformamide are mixture was placed in an oil-bath a t tempeiatures of 145of the order of those expected (Table I). 170". Considerable foaming and bubbling occurred which ceased after 1-4 hr. The residue was triturated with Acknowledgments.-The authors thank Wm. water, the solid product collected and recrystallized from Brown, Howard Hunter, George Maciak and ethanol. 6-Hydroxy-2-methyl-4-substitutedAminopyrimidines Ralph Hughes for the elemental analysis and (Table I).-To 12.5 g. (0.1 mole) of 4-amino-6-hydroxy-2Harold Boaz, Donald Woolf and Leland Howard methylpyrimidine was added 0.1 mole of the appropriate for the titration and ultraviolet data. amine hydrochloride and 10 ml. of the free amine. The
ALKYLA N D ARYLAMINO-PYRIMIDINES AND P U R I N E S
Aug. 5, 1960
3973
TABLE I1 ULTRAVIOLET SPECTRA^ AND PK'. VALUES* -Neutral-Pyrimidine
PK.'
Amax, mp
log
ah1
Ultraviolet spectra ----Acid----. log a h r
Amax, mp
215 208 4.32 4.49 254 3.59 256 252 3.95 3.81 248 4.24 10.9 6-SHCsHs-4-OH 280 4.24 4.49 218 4.34 224 11.7 6-NHCsHi-4-OHC 4.42 214 6-NH2-4-OH-2-CH3 2 53 3.67 258 253 3.98 3.84 6-NHCiH;-4-OH-2-CH: 12.2 4.50 223 257 258 4.20 3.94 3.99 262 225 4.10 224 4.09 4.09 228 2-h'H2-4,6-di-CH3 290 298 3.76 3.67 290 3.67 237 232 4.32 4.27 4.29 238 2-NHCiHi-4,6-di-CH3C 3.9 297 310 3.76 3.68 298 3.60 266 266 4.31 4.31 266 4.31 6-NH2-1,3-di-CH,-2.4-di-Oc 267 4.30 269 4.29 267 6-ru"C5H~O-l,3-di-CH3-2,4-di-OC 4.31 268 4.32 268 4.34 268 4.32 6-SHC7Hi-1,3-di-CH3-2,4-di-Oc 282 278 3.99 3.85 267 4-NHz-2-OH 4.8,>13 3.74 286 4.03 266 4.00 4-NHCiHi-2-OHc 3.8, 13.5 283 4.15 285 3.95 4.0, 13.6 3.97 2 83 4-NHCsH,-2-OHc 4.11 268 300 12.9 294 4.17 4-XHCsHs-2-OH 4.26 293 4.26 259 220sh 3.94 232sh 244 4.28 259 4.20 244 4.20 6.3 2755h 4.28 263 275sh 5.8 290 4.24 3.55 260 14 4.27 264 14 4.40 262 14 274 3.82 3.83 220 3.9; 10.8 3.94 255 3.92 286 a The ultraviolet spectra were determined in 95% ethanol; in %yoethanol with 50 X of 2 N HC1 per 3.3 ml. and in 957, ethanol with 50 Xof 1.7 iV KOH per 3.3 ml. * The pK,' values were determined in 667" X,N-dimethylformamide. c CiH,= benzyl, CsHsO = furfuryl, CaH9 = phenethyl, 0 = carbonyl oxygen. 6-KHz-4-OH
< 2 . 5 , 11.3
> > >
mixture was heated a t 145' in the oil-bath. After 0.5-1 hr. the mass melted and then became solid. Water was added, stirred and the solid collected. The solid product was recrystallized from ethanol. Reaction of n-Heptylamine with 4-Amino-6-hydroxypyrim(20 g.) was idine in Absence of Acid.-n-Heptylamine heated with 10 g. of 4-amino-6-hydroxppyrimidine a t 140' for 4 days. During this time bubbling did not occur as was observed with the amine hydrochlorides and 4-amino-6hydroxypyrimidine. The cooled mixture was extracted with ethyl acetate. Six grams of starting 4-amino-6-hydroxypyrimidine remained undissolved. The filtrate was diluted with ether to precipitate 3 g. of solid. When recrystallized from ethyl acetate it melted a t 88-89' and was identical to an authentic sample of 1,3-di-n-heptylurea. Reaction of Benzylamine with 4-Amino-6-hydroxypyrimidine in Absence of Acid.-Ten grams of 4-amino-6-hydroxypyrimidine was heated with 20 g. of benzylamine a t 160170" for 4 hr. There was a vigorous evolution of vapors that tested basic. After cooling, the mixture partially crystallized and the solid was collected. This was recrystallized The from ethyl acetate; yield 0.5-1 g., m.p. 127-130'. ultraviolet absorption in ethanol showed two maxima a t 230 and 260 mp. There were no titratable groups between pH 3.5 and 13. The infrared absorption showed a band a t 2.92 p resulting from an S H group, an intense band a t 6.02 cc from an amide-like carbonyl group and a band a t 6.21 due t o the aromatic benzene rings. Characteristics of the product suggest the structure 3-benzyl-4-benzylamino-6keto-l,6-dihydropyrimidine or l-benzyl-4-benzylamino-6keto-1 ,6-dih ydropyrimidine. Anal. Calcd. for C1kH1iNaO: C, 74.35; H, 5.89; N, 14.46. Found: C,73.76; H,6.23; N, 14.03. 2-Benzylamino-4,6-dimethylpyrimidine.-One-tenthmole ( 12.3 g.) of 2-amino-4,6-dimethylpyrimidinewas mixed
with 0.1 mole of benzylamine hydrochloride and heated a t 160' for 5 hr. The cooled residue was triturated with water and the solid collected. The product was recrystallized from alcohol; yield 2 g., m.p. 107'. Anal. Calcd. for C13H15iY3: C, 73.21; H , 7.09; N. 19.07, Found: C, 72.98; H , 7.06; IT,19.34. 1,3-Dimethyl-6-substituted Aminouraci1s.-One-tenth mole (15.5 8.) of 1,3-dimethyl-6-aminouracil was mixed with 0.1 mole of the appropriate amine hydrochloride and 15 nil. of the free amine. The mixture was heated a t 145' and bubbling continued for 3 hr. Water was added to che cooled mixture and the products crystallized from ethyl acetate. 1,3-~imethyl-6-furfurylaminouracil: yield 65%, m.p. 190-191 . Anal. Calcd. for CllH13~303: C, 56.16; H, 5.57; N, 17.86. Found: C, 56.35; H , 5.32; N, 17.81. 6-Benzylamino-l,3-dimethyluracil:yield 75%, m.p. 143144'. Anal. Calcd. for C13H1sx302: C, 63.66; H , 6.16; IT, 17.13. Found: C, 63.58; H , 6.15; S , 16.95. 1,3-Dimethyl-6-n-heptylaminouracil:yield 707,, m.p. 85-86'. Anal. Calcd. for C13H23N302: C, 61.63; H , 9.15. Found: C, 61.32, H , 9.38. 6-Benzylaminopurine.--A mixture of 2.5 g. of adenine, 2.5 g. of benzylamine hydrochloride and 5 g. of benzylamine was heated a t 165-170" for 8 hr. The reaction mixture was extracted with warm ethanol leaving approximately 1 g. of unreacted adenine. The filtrate was clarified with carbon, concentrated and cooled to yield 1.5 g. (5470) of 6-benzylaminopurine, m.p. 225' (reported? 229'). 6-Furfurylaminopurine (kinetin) was prepared in the same manner described for the above benzyl derivative; yield 577,, m.p. 266" (reported*266-267'). (7) C. G. Skinner and W. Shive, THISJOURNAL, 77, 6692 (1966). ( 8 ) C. 0.Miller, F.Skoog, F.S Okumura, hl. H. Von Saltza and F.M Strong, i b i d . , 71, 2662 (1966),
6-Phenylaminopurine was prepared by the method used for the benzyl derivative. Alpproximately2 g . of highly colored product was Obtained that melted a t about 245'.
[CONTRIBUTION FROM THE
After several crystallizations from alcohol it melted at 278" 278-281"). (9) G. H. Hitchings and G. B. Elion, U. S. P a t e n t 2,691,654; Oct. 12, 1954 (C. A , , 60, 1933 (1956)).
DEPARTMENT O F PHARMACOLOGY, MEDICAL COLLEGE
OF VIRGINIA,
RICHMOSD, \'IRGINIA]
The Isolation and Structure of a Ketoamide Formed in the Metabolism of Nicotine' BY HERBERT MCKENNIS, JR., EDWARD R. BOW MAN^
A N D LENNOX B.
TURNBULL
RECEIVED JANUARY 14, 1960 Administration of ( - )-nicotine or ( - )-cotinine to the dog leads to the excretion of a chloroform soluble amphoteric metabolite which has been separated in crystalline form. Hydrolysis of the metabolite in acidic or basic solution resulted in the formation of methylamine and an oxo acid. The latter yielded y-(3-pyridyl)-butyric acid upon reduction by the Wolff-Kishner procedure. A Beckmann rearrangement of the oxime from the oxo acid afforded 3-pyridylacetic acid. In consequence the metabolite is assigned the structure y-(3-pyridyl)-~-oxo-N-methylbutyramide.
The metabolism of (-)-nicotine in the dog leads3 to the excretion of (-)-cotinhe and a variety of Koenig positive components. The r61e of cotinine in the metabolism of nicotine in both the dog and the human is evinced in many ways including metabolism to ( -)-desmethylcotinine in the former4 and hydroxycotinine in both specie^.^'^ During studies on the metabolism of (-)cotinine and (-)-nicotine i t was observed4 that the urine of dogs following administration of (-)cotinine contained a chloroform-soluble metabolite which, in contrast to cotinine, hydroxycotinine and desmethylcotinine, was removed from aqueous solution by Dowex 1 (OH-). Chromatographic evidence has indicated the possible presence of this same substance in the urine of both humans and dogs following administration of (-)-nicotine. In the current studies (-)-cotinine has been administered to dogs in quantities sufficient to permit isolation of this new metabolite and subsequent structural determination by the reactions
The pooled urine from mongrel dogs following administration of ( - ) -cotinine was made alkaline with ammonia and then exhaustively extracted with chloroform. An acidic aqueous solution of the residue obtained by evaporation of the chloroform was placed upon a column of Dowex 50 (H+) which removed all of the Koenig positive components. An ammoniacal eluate of the resin was passed through a column of Dowex 21K (OH-) or Dowex 1 (OH-). The effluent contained the Koenig positive compounds cotinine, desmethylcotinine and hydroxycotinine which have been subjected to previous study. By elution with dilute acid or copious quantities of water an additional Koenig positive compound was obtained in crude form. The aqueous solution of this metabolite was concentrated to a yellow oil. A solution of the latter in chloroform was chromatographed on alumina to obtain a crystalline product (I) which melted a t 114-118' after recrystallization from benzene. The compound in solution showed no OH
n
n
0
N
/I
I1
CrH,NCH,-C-CH,-C-NCH,
I1
+ lg~o"H+ -
L
Wolff -Kishner reduction
+ CsH4RCHzCHnCHzCOOH
(hydrolysis)
I11
CHBSH~
0
I1
CsHINCHZ-C-CH2COOH
NH20H +
IV (I) For preliminary reports see: E. R . Bowman, L. B . Turnbull a n d H. McKennis, Jr., Fed. Proc.. 18, 371 (1959); Bull. V a . Serlion A m . Chcm. SOC.,86, 184 (1959). Aided b y grants from t h e Tobacco I n d u s t r y Research Committee a n d t h e American Tobacco Company. ( 2 ) Public Health Research Fellow of t h e National H e a r t Institute. (3) (a) H. McKennis, Jr., L. B. T u r n b u l l a n d E. R . Bowman, Tars JOURNAL, 79, 6342 (1957); (b) ibid., 80, 6597 (1958). (4) H.McKennis, Jr., L. B. Turnbull, E. R . Bowman and E. Wada, ibid., 81,3931 (1959). (5) E . R. Bowman, L. B. Turnbull a n d H. McKennis, Jr., J . Pharmacol. E@. Therap., 147, 92 (1959).
POC13 oxime
V
.C
(Hydrolysis)
C~H~NCHQCOOH VI
optical rotation. The analyses for C, H and N were in good agreement with the empirical formula C1oHizN20z. The analytical data and positive Koenig reaction of the compound immediately suggested a 3pyridyl compound derived from the metabolic oxidation of cotinine. The metabolite yielded a crystalline oxime (11) and upon reduction under Wolff -Kishner conditions yielded y(3-pyridy1)butyric acid (111). The latter was identified by
