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I. V. Micovic et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2011±2014
2013
loss of righting re¯ex.16 Since all of the observed eects
were reversed by s.c. injection of naloxone hydrochlo-
ride (1 mg/kg) it was concluded that they were opioid-
receptor mediated.
(5 h, 20ꢁC), treated with 10%, K2CO3 solution (2 mL),
extracted (Et2O) and concentrated. The residual oil17
(>98% purity, cap. GC) was precipitated as mono-
oxalate salt from anh. Et2O. Yield: 55 mg (78%), white
powder.
The pharmacological testing was performed according
to the methodology published earlier.16
Conclusion
A simple and ecient synthesis of 4-methyl fentanyl, a
super potent narcotic analgesic, was accomplished. The
compound is a prototype of a novel class of fentanyl
analogues, 4-alkyl fentanyls, which are currently being
prepared by the same methodology and will provide
further insights into the SAR. In the key step, a novel
method for the N-phenylation of secondary aliphatic
amides was disclosed, providing access to various tertiary
N-phenyl amides not readily accessible by other routes.
Finally, it has been proven that the central analgesic
activity in this series of anilidopiperidines is in¯uenced
only by the steric requirements of a group in the posi-
tion 4 of the piperidine ring rather than its chemical
nature. Further examples with more voluminous 4-alkyl
substituents (Et, Pr, i-Pr etc.) are expected to provide
clear corelation with the activity of known compounds
possesing other substituents (carbomethoxy, methoxy-
methyl etc.) in the same possition.
References and Notes
1. The Merck Index, 12th Ed. Merck & Co., Inc., NJ, 1996.
2. (a) Casy, A. F.; Par®tt, R. T. Opioid Analgesics; Plenum
NY, 1986. (b) Casy, A. F. Opioid Receptors and Their Ligands,
in Advances in Drug Research; Testa, B., Ed.; Academic:
London, 1989; Vol. 18 pp 178. (c) Micovic, I. V.; Ivanovic,
M. D.; Vuckovic, S.; Jovanovic-Micic, D.; Beleslin, D.;
Dosen-Micovic, L. J.; Kiricojevic, V. D. Heterocyclic Com-
munications 1998, 4, 171 and the references cited therein. (d)
Micovic, I. V.; Roglic, G. M.; Ivanovic, M. D.; Dosen-
Micovic, Lj.; Kiricojevic, V. D.; Popovic; J. B. J. Chem. Soc.,
Perkin Trans. 1 1996, 2041. (e) US Patent 5,489,689; 1996. (f)
US Patent 4,179,569; 1979. (g) Van Daele, P. G. H.; De
Bruyn, M. F. L.; Boey, J. M.; Sanczuk, S.; Agten, J. T. M.;
Janssen, P. A. J. Arzneim-Forsch. (Drug Res.) 1976, 26, Nr.
8, 1521.
3. Kudzma, L. V.; Severnak, S. A.; Benvenga, M. J.; Ezell, E.
F.; Ossipov, M. H.; Knight, V. V.; Rudo, F. G.; Spencer, H.
K.; Spaulding, T. C. J. Med. Chem. 1989, 32, 2534.
4. Ivanovic, M. D. The Syntheses of Fentanyl Analogues;
Ph.D. Thesis, Chemistry Dept., University of Belgrade, 1998.
5. Kapnang, H.; Charles, G. Tetrahedron Lett. 1983, 24, 3233.
6. Commercially available from Aldrich1; Cat. No. 15,373-7
7. March, J. Advanced Organic Chemistry; John Wiley &
Sons: New York, 1992; p 971.
Experimental
Amide 3. Alcohol 2 (2.0 g, 10.5 mmol) in propionitrile
(40 mmol) is added dropwise to a stirred mixture of
H2SO4 (96%, 20 mL) and propionitrile (15 mmol, 5ꢁC,
10 min). After 4 h (t<0ꢁC), the mixture is added to 10%
K2CO3 solution (foaming, pH>7), extracted (CH2Cl2),
dried (MgSO4) and concd. The residue is puri®ed by
dry ¯ash chromatography (30 g SiO2, hexane/EtOAc
gradient) yielding pure amide 3 as oil. Yield: 1.83 g
(72%).
8. March, J. Advanced Organic Chemistry, John Wiley &
Sons: New York, 1992; p 657.
9. (a) Barton, D. H. R.; Blazejewski, J.-C.; Charpiot, B.;
Finet, J.-P.; Lester, D. J.; Motherwell, W. B.; Papoula, M. T.
B.; Stanforth, S. P. J. Chem. Soc., Perkin Trans 1 1985, 2667.
(b) Barton, D. H. R.; Bhatnagar, N. Y.; Blazejewski, J.-C.;
Charpiot, B.; Finet, J.-P.; Lester, D. J.; Motherwell, W. B.;
Papoula, M. T. B.; Stanforth, S. P. J. Chem. Soc., Perkin
Trans. 1 1985, 2657. (c) Wittig, G.; Clauss, K. Justus Liebigs
Ann. Chem. 1952, 578, 136. (d) Blicke, F. F.; Oakdale, U. O.;
Smith, F. D. J. Am. Chem. Soc. 1931, 53, 1025.
10. Encyclopedia of Reagents for Organic Synthesis, Vol. 4;
Paquette, L. A., Ed.; John Wiley & Sons: New York, 1995.
p 2221
11. Encyclopedia of Reagents for Organic Synthesis, Vol. 4;
Paquette, L. A., Ed.; John Wiley & Sons: New York, 1995. p
2854,
Amide 4. A typical phenylating procedure. A solution of
dried amide 3 (1.0 g, 4.1 mmol) and 18-crown-6 (distilled
from NaH, 1.3 g, 5 mmol) in diglyme (5 mL) is injected
to stirred suspension of KH (35%, 4.4 mmol, 10 mL
diglyme) under Ar. After 10 min (H2 evolution), solid
diphenyliodonium chloride (1.90 g, 6.0 mmol) is added
in one portion (mildly exothermal reaction, yellow col-
oration). After 4 h (40±50ꢁC, external heating) the mix-
ture is poured into H2O (200 mL), extracted (toluene),
concd (10 torr, 90ꢁC) and puri®ed (dry ¯ash chromato-
graphy, 20 g SiO2, hexane/EtOAc gradient). Amide 4 is
obtained as yellow glassy solid (0.61 g, 46%). Unreacted
amide 3 is eluted with MeOH.
12. Green, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 2nd Ed.; John Wiley & Sons: New York,
1992; p 317.
13. Olah, G. A.; Narang, S. C.; Gupta, B. G. B.; Malhotra, R.
J. Org. Chem. 1979, 44, 1247.
14. Janssen, P. A. J.; Niemegeers, C. J. E.; Dony, J. G. H.
Arzneim.-Forsch (Drug Res.) 1963, 13, 502.
15. Tallarida, R. J.; Murray, R. B. Manual of Pharmacologic
Calculations with Computer Programs, 2nd Ed.; Springer
Verlag: New York, 1986.
16. Vuckovic, S.; Ivanovic, M.; Prostran, M.; Todorovic, Z.;
Ristovic, Z.; Micovic, I.; Beleslin, D. Jpn. J. Pharmacol. 1998,
78, 523.
17. Spectral data for 6. IR (cm 1): 3061, 3026, 2933, 2810,
2774, 1659, 1594, 1493, 1477, 1453, 1420, 1373, 1351, 1311,
4-Methyl fentanyl 6. A mixture of amide 4 (50 mg,
0.16 mmol) and Me3SiI (0.1 g, 0.50 mmol) in dichloro-
ethane (2 mL) under Ar is stirred and heated (80ꢁC, 8 h),
then treated successively with concd HCl (0.5 mL) and
10% K2CO3 solution (10 mL), and concd. The crude
product 5 (oil, ꢀ40 mg, ꢀ100%) is mixed together with
Et3N (32 mg, 0.32 mmol) and phenethyl iodide (60 mg,
0.26 mmol) in dry acetonitrile (1 mL) under Ar, stirred