SOTES
September 1967 baniate ion intermediate.; The carbamate ion is unstable and is rapidly decarboxylated to free amine and CO,. Xormeperidine ethyl carbamate (111) was prepared for evaluation in the expectation that hydrolysis of the ethyl ester would be follon-ed in I ~ P Obj. a facile decarboxylation to normeperidine. Sormeperidine monosuccinamide (IT') w a b prepared for evaluation 011 the basis of the ivell-established facilitation of hydrolysis of monoamides of dicarboxylic acids capable of forming cyclic anhydrides."' Xormeperidine pyruvamide (V)was prepared in the expectation that pyruvamides, like pyruvate esters, would undergo facile hydrolysis. Electron-n-ithdrawing substituents in the acid moiety of esters are known t o accelerate the second-order alkaline hydrolysis rates, and the rate of alkaline hydrolysis of ethyl pyruvate \vas found to be particularly high.**g Furthermore, Sudborough found ethyl pyruvate t o rindergo suhs t a n t i d hydrolysis even in water.'" C,H, COOEt
0 -.
R
I. R = CH,, 11, R = H 111, R = COOEt IV, R = COCH,CH,COOH V, R = COCOCH,,
Pharmacological Evaluation.-In t'he mouse hot' plate test' for analgesic act'ivity, normeperidine ethyl carbamate (111) showed a mouse ED,, of 20.15 mg/kg (18.56-21.75) with a duration of 162 min." The route of administration was subcutaneous and t'he figures in parentheses are the limits of error in probit analysis. I n the hot wire tail-n-it'hdrawil test in the Wistar rat', I11 showed a rat ED,, of 64.0 mg/kg (33.7-121.6). The route of' administrat'ion \vas oral. JIeperidine was run side by side on a blind basis, and the two compounds !rere found to be approximately equipotent by this procedure.12 The compound showed no toxicity or physical dependence capacity (capacity to suppress abstinence symptoms in morphine-dependent monkeys) :it doses ranging from 1.0 to 130.0 mg/kg.I3 The interest in normeperidine ethyl carbamate (111) lies in it,s reasonably high potency order with no physical dependence capacity, in the range of doses tested. Sormeperidine monosuccinamide (IV) and normeperidine pyruvaniide (V)showed no analgesic effect up to 100 mg/kg in the mouse hotplate test." S o physical dependence capacit'y or toxic effects were noted for either compound at doses of 2.0-40.0 mg/kg.'4 \V. Dittert and T. Higuchi, J . Pharm. Sci., 63,852 ( 1 9 6 3 ~ . A I . L. Bender, J . Am. Ckem. Soc., 79, 1258 (1957); R I . I,. R m d e r . T.
961 Experimental Section':
Normeperidine Ethyl Carbamate (1IIj.-To a stirred, icecooled solution of normeperidine hydrochloride (8.07 g, 0.03 mole, Winthrop, mp 134-137') in CHCl, (25 ml) were added triethylamine (6.00 g, 0.06 mole) in CHCls (15 ml) and (dropwise) ethyl chloroformate (3.24 g, 0.03 mole, Eastman) in CHCL (15 ml). The solution was stirred in the cold for 2 hr and then at room t,emperature overnight. Ether was added to complete precipitation of triethylamine hydrochloride, and the precipitate was filtered The filtrate was washed twice with water, dried (Na2S04), and evaporated under reduced pressure to a light brown oily residue. The residue was dissolved in Skellysolve A and cooled and rubbed to induce crystallizat'ion. The crystalline product was recrystallized four times from Skellgsolve .4 to yield 4.03 g of colorless crystals: mp 37-38'; XEXl3 3.82 (ester C=O), 5.95 (carbamate C=O), 6.25, 14.40 (aryl ring), 8.0 fi (ester C-0-C). .Inal. Calcd for C17H~,N04: C, 66.86: H, 7.59; S , 4.59. Fonnd: C, 66.96; H, 7.63; N,4.79. Normeperidine Monosuccinamide (IV).--8 solution of normeperidine hydrochloride (15 g, 0.055 mole) in water (25 ml) was treated with excess concentrated XH4OH. The suspension was extracted three times (CHC1,) and the extract was dried (Ka2SOa) and evaporated to dryness under reduced pressure. The residue was treated with succinic anhydride (5.,3 g, 0.055 mole) and the mixture was heated on the steam bath for 1 hr. The oily reactioii product war rubbed to induce crystallization, and then recrgstallized twice from benzene: yield 12.80 g; mp 130-133"; XE? 2.85 (OH), 5.82 (broad, ester and acid C=O), 6.10 (amide C=O). 6.23, 14.40 (aryl ring), 8.05 u (ester C-0-C). Anal. Calcd for C&,SOa: C, 64.8.5: H, 6.95; S , 4.20. Found: C, 63.07; H, 7.09; N,4.44. Normeperidine Pyruvamide (V).-To u .elution of pyruvic acid ( 3 3 2 g, 0.04 mole, Eastman, redistilled) in CHC1, (20 ml) was added SOCl? (4.76 g, 0.04 mole), and the solution wa? heated under reflux for 1 hr. To the stirred, refluxing solution, a solution of normeperidine hydrochloride (5.30 g, 0.02 mole) and triethylamine (2.02 g, 0.02 mole) in CHCl:] ( 2 5 ml) was added dropwise over the course of 45 min, and refliixing was continued for an additional 75 min. The mixtiire was extracted three times with water, and the CHClj layer was dried (SasH04)and evaporated to dryness tinder reduced pressure. Crystallization from SkellyRecrystallizatioii solve B yielded 4.68 g of prodiict, mp 92-94'. from Skellysolve B, with Sorit treatment, yielded the analytical sample: mp 94-96'; X",iJ,3 5.82 (ester and ketone C=O), 6.10 (amide C=O), 6.25, 14.40 (aryl ring), 8.1 fi (ester C-0-C ). Anal. Calcd for C ~ ~ H ~ I N OC,I :67.31: H. 6.98: S , 4.62. Foiind: C, 6i.22: H, 7.04; K,4.70. (14) G. .I. Deneau and AI. H. S.ae\-ers, .iddenduin t o tlie Minutes of tlie Committee on D r u g Addiction and Narcotics, Xational Academy of s-irnceqSational Research Council, 1965. (15) Melting points, determined on a Fisher-Jolin~Iiot stage. are corrected. Infrared aljsorgtion spectra were determined in CHCIs on a Beckman model IR5.1 recording spectrophotometer. hlicroanal) see were carried out 11). J l r . J. E'. .\licino. lletriclien, N . .J. Skellysolvr .\ refer? t o petrolriini etlier, hp 40-60°.
~~-4,5-Dihydroxy-2-pyridylalanine, an Analog of 3,4-Dihydroxyphenylalanine' S. J. NORTONA N D EDWARD S INDERS
151 L.
16) ('lion-, and F. Cliloupek, i b i d . , 80, 5380 (1958). T . Higuclii and T. Miki, ibid., 83,3899 (1961); T.Higuchi, 'r. Miki, (i) \. C . .4'hah, and A. K . Herd, ibid., 86, 3655 (1963). ( 8 ) C. K. Ingold, "Structure and AIechanisms in Organic Chemistry,"
liell and Sons, London, 1953. (9) L. P. Hammett, "Physical Organic Chemistry," AIcGraw-Hill Hook (lo., Inc., New York, N . T.,1940. (10) J. J. Sudborough, J . C h e n . Soc., 101, 1227 (1912). 1111 We are indebted t o Dr. N . B. Eddy, National Institutes of Health, f o r these d a t a ; cf. N. R . E d d y a n d D. Leimbach, J . Pharmqcol, E z p t l . T h e r a p . , 107, 385 (1953). (12) I r e are indebted t o Dr. Maxwell Gordon, Smith Kline and French I.alioratories, through whose courtesy these tests were carried out. ( 1 3 ) TVe are indebted t o Drs. C,. .\. Denean and R I . H. SeeverR, University ( I f llirliigsin, for these d a t a .
Department
S o r t h Texas State University, Denton, Texas
0.f Chemistry,
Keceived Decembei 18. 1.966
We wish to report the synthesis of ~~-3,5-dihydroxy2-pyridylalanine, a structural analog of 3,4-dihydroxyphenylalanine (DOPA). I n previous studies amino acid analogs containing the pyridine ring in place of (1) This work was supported in g a r t by grants from T h e Robert .1.\Velch Foundation of Texas (Grant No. R-133) and from t h e I:. 8. Public Health Service (Grant KO.-311 07599-04).
