4-methyl-fentanyl, biotransformation
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Bioorganic & Medicinal Chemistry Letters 10 (2000) 2011±2014
The Synthesis and Preliminary Pharmacological Evaluation of
4-Methyl Fentanyl
Ivan V. Mic ovic ,
a
Milovan D. Ivanovic ,
b,
* Sonja M. Vuckovic,
c
Milica S
Ï
. Prostran,
c
Ljiljana DosÏ en-Mic ovicÂ
a
and Vesna D. KiricojevicÂ
b
a
Faculty of Chemistry, University of Belgrade, Studentski Trg 16, PO Box 550, Yu-550 11001, Belgrade, FR Yugoslavia
b
Institute of Chemistry, Technology and Metallurgy, Centre for Chemistry, NjegosÏeva 12, PO Box 815, Belgrade, FR Yugoslavia
c
Department of Clinical Pharmacology, Pharmacology and Toxicology, Medical Faculty, PO Box 840, Dr. Subotica 1,
Belgrade, FR Yugoslavia
Received 4 May 2000; revised 27 June 2000; accepted 3 July 2000
AbstractÐThe synthesis of 4-methyl fentanyl, a prototype of a novel class of fentanyl analogues has been eected in 5 steps,
starting from N-ethoxycarbonyl-4-piperidone (
20% overall yield). In the key step, N-phenylation of secondary aliphatic amide
intermediare was achieved by a novel reaction, using diphenyliodonium chloride for the phenyl group transfer. Preliminary phar-
macological results indicate that 4-methyl fentanyl is a super potent narcotic analgesic, about four times more potent than fentanyl.
#
2000 Elsevier Science Ltd. All rights reserved.
Introduction
This hypothesis can be readily proven by the synthesis
of 4-alkyl fentanyl analogues, where the analgesic
potency would depend entirely on the steric factor. In
addition, this novel series would provide better SAR for
fentanyl analogues in general and possibly, some new,
promising opioid analgesics.
Fentanyl
1
is a well known and clinically widely used
narcotic analgesic, about 50±100 times more potent
than morphine in humans. Due to its high potency and
generally favourable pharmacological pro®le, numerous
analogues have been synthesised in the past three
decades.
2
While sufentanil,
1
alfentanil,
1
lofentanil
1
and
remifentanil,
1
(Fig. 1), have been used clinically as
narcotic analgesics, other structurally closely related
compounds exhibit dierent pharmacological activities,
e.g., antihistaminic (astemizole,
1
levocabastine
1
), tran-
quillising (droperidol
1
), antidiarrheal (loperamide
1
) and
antiarrhythmic (lorcainide
1
).
Results and Discussion
Here we report the synthesis of the ®rst member of this
series, 4-methyl fentanyl 6, as well as the synthetic
approach
4
suitable for the preparation of higher homo-
logues, (Scheme 1). First, N-benzyl 4-piperidone was
converted
5
to carbamate 1
6
using ethyl chloroformate,
then it was reacted with MeMgI to yield alcohol 2
(
85%). Next, the reaction of 2 with propionitrile (via
tert carbocation intermediate) under the conditions of
Ritter reaction
7
(concd H
2
SO
4
,0
C, 4 h), aorded amide 3
(
70% yield after dry ¯ash chromatography). Attempts
to N-phenylate this amide, or the model compound, N-
(1-methyl-cyclohexyl)-acetamide, using various mod-
i®cation of Goldberg reaction
8
(PhBr, K
2
CO
3
, cat.
CuBr) were unsuccessful. Similarly, when amide 3 or the
model amide were ®rst N-metalated (KH, diglyme, 20
,
30min), then treated with triphenylbismuth carbonate,
9
a highly ecient phenylating reagent for enolate anions,
only the starting compound was isolated. Finally, the
phenylation of N-metalated amides was eected with
Analgesic activity of the anilidopiperidines is greatly
enhanced by the presence of a substituent in the position
4 of the piperidine ring.
2f
The chemical nature of the sub-
stituent apparently has little in¯uence on the activity, since
groups
2f
as diverse as carbomethoxy, methoxymethyl,
hydroxymethyl, methylketo and aryl
3
all produce sig-
ni®cant increase (2±30 times) in the potency compared
to fentanyl. Rather it seems that the activity depends
primarily on the voluminosity of the substituent.
*Corresponding author. Tel./fax: +381-11-636-061 or +381-11-636-
995; e-mail: vpetka@eunet.yu
0960-894X/00/$ - see front matter
#
2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00394-2
2012
I. V. MicÂovic et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2011±2014
Figure 1.
Scheme 1.
diphenyliodonium chloride.
10
The addition of 18-crown-
6 ether (
100 mol%) substantially accelerated the meta-
lation and phenylation step and improved the yields.
Thus, N-(1-methyl-cyclohexyl)-N-phenyl-acetamide and
the amide 4 were isolated in
70 and 40±50% yields
respectively, after dry ¯ash chromatography. The main
contaminant in both cases was the starting secondary
amide (20±50%). The procedure appears to be of a
more general scope and it is currently being investi-
gated. Interestingly, the phenylation is completely
unsuccessful if a tertiary amino group is present in the
molecule, although no explanation is available pre-
sently. Thus, when 1-N-benzyl or 1-N-phenethyl analo-
gues of 3 were subjected to the same procedure, only a
complete decomposition was observed. In the last steps
of the synthesis, the carbamate moiety in amide 4 was
removed quantitatively, using Me
3
SiI
11
in boiling
dichloroethane (1.5 equiv 80
C, 8 h). A number of other
deprotection procedures
12
(KOH, ethylene glycol, 100
C;
KOH, i-PrOH, 18-C-6, 80
C; n-PrOK, n-PrOH, 18-C-6,
100
C; HBr (48%), 80
C; Me
3
SiCl, NaI, MeCN
13
) either
caused complete decomposition or failed
13
to eect the
cleavage. Remarkably, the ethyl carbamate group was
stable towards both a strong nucleophile (MeMgI) and
in concd H
2
SO
4
. The intermediary secondary piperidine
5 was isolated without puri®cation and smoothly alkyl-
ated with phenethyl iodide to aord 4-methyl fentanyl
6 (
20% overall yield from 1). Spectral data (IR,
13
NMR (250MHz),
C NMR (APT, 60MHz), and MS
[EI]), were fully consistent with the assigned structure.
The 4-methyl fentanyl 6 was precipitated as mono-
oxalate salt and tested for analgesic activity using rat
tail withdrawal test
14
and fentanyl citrate as a standard.
The ED
50
and 95% con®dence limits were estimated
from dose-response curve using the standard computer
program.
15
The relative potency of 4-methyl fentanyl was found to
be 3.8 (3.2±4.4) times higher than fentanyl, while the
time peak of the activity as well as the duration of the
action seemed to be equal to fentanyl (Table 1). Also,
higher doses of 4-methyl fentanyl (>8
ED
50
for
analgesia) produced fentanyl-like neurotoxic eects
such as stiness of the tail (Straub tail), catalepsy and
Table 1. Analgesic activity of intraperitoneal 4-methyl fentanyl in rat
a
4-Methyl fentanyl
(n=24)
Fentanyl
(n=23)
ED
50
(mg/kg of free base)
0.0028
0.0105
Con®dence limits
0.0023±0.0033
0.006±0.018
Time of peak action of ED
50
(min)
10±15
10±15
Duration of action of ED
50
(min)
30±40
30±40
1
H
a
n=Number of animals employed to produce dose±response curve.
I. V. MicÂovic et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2011±2014
2013
(5 h, 20
C), treated with 10%, K
2
CO
3
solution (2mL),
extracted (Et
2
O) and concentrated. The residual oil
17
(>98% purity, cap. GC) was precipitated as mono-
oxalate salt from anh. Et
2
O. Yield: 55mg (78%), white
powder.
loss of righting re¯ex.
16
Since all of the observed eects
were reversed by s.c. injection of naloxone hydrochlo-
ride (1mg/kg) it was concluded that they were opioid-
receptor mediated.
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) Mic ovic , I. V.; Ivanovic ,
M. D.; Vuckovic, S.; Jovanovic -Mic ic , D.; Beleslin, D.;
DosÏ en-Mic ovic , L. J.; Kiricojevic ,V.D.Heterocyclic Com-
munications 1998, 4, 171 and the references cited therein. (d)
Mic ovic , I. V.; Roglic , G. M.; Ivanovic , M. D.; DosÏ en-
Mic ovic , 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 Aldrich
1
; Cat. No. 15,373-7
7. March, J. Advanced Organic Chemistry; John Wiley &
Sons: New York, 1992; p 971.
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,
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.; Mic ovic , I.; Beleslin, D. Jpn. J. Pharmacol. 1998,
78, 523.
17. Spectral data for 6. IR (cm
ÿ
1
): 3061, 3026, 2933, 2810,
2774, 1659, 1594, 1493, 1477, 1453, 1420, 1373, 1351, 1311,
Experimental
Amide 3. Alcohol 2 (2.0 g, 10.5mmol) in propionitrile
(40mmol) is added dropwise to a stirred mixture of
H
2
SO
4
(96%, 20mL) and propionitrile (15mmol,
ÿ
5
C,
10min). After 4 h (t<0
C), the mixture is added to 10%
K
2
CO
3
solution (foaming, pH>7), extracted (CH
2
Cl
2
),
dried (MgSO
4
) and concd. The residue is puri®ed by
dry ¯ash chromatography (30 g SiO
2
, hexane/EtOAc
gradient) yielding pure amide 3 as oil. Yield: 1.83 g
(72%).
Amide 4. A typical phenylating procedure. A solution of
dried amide 3 (1.0 g, 4.1mmol) and 18-crown-6 (distilled
from NaH, 1.3 g, 5mmol) in diglyme (5mL) is injected
to stirred suspension of KH (35%, 4.4mmol, 10mL
diglyme) under Ar. After 10min (H
2
evolution), solid
diphenyliodonium chloride (1.90 g, 6.0mmol) is added
in one portion (mildly exothermal reaction, yellow col-
oration). After 4 h (40±50
C, external heating) the mix-
ture is poured into H
2
O (200mL), extracted (toluene),
concd (10 torr, 90
C) and puri®ed (dry ¯ash chromato-
graphy, 20 g SiO
2
, hexane/EtOAc gradient). Amide 4 is
obtained as yellow glassy solid (0.61 g, 46%). Unreacted
amide 3 is eluted with MeOH.
4-Methyl fentanyl 6. A mixture of amide 4 (50mg,
0.16mmol) and Me
3
SiI (0.1 g, 0.50mmol) in dichloro-
ethane (2mL) under Ar is stirred and heated (80
C, 8 h),
then treated successively with concd HCl (0.5mL) and
10% K
2
CO
3
solution (10mL), and concd. The crude
product 5 (oil,
40mg,
100%) is mixed together with
Et
3
N (32mg, 0.32mmol) and phenethyl iodide (60mg,
0.26mmol) in dry acetonitrile (1mL) under Ar, stirred
2014
I. V. MicÂovic et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2011±2014
1247, 1159, 1111, 1078, 1028, 996, 811, 750, 701.
1
H NMR (
d
,
CDCl
3
): 0.96 (t, J=7.30, CH
3
), 1.68 (s, CH
3
), 1.71±1.81 (m),
1.85 (q, J=7.50, CH
2
), 2.04±2.08 (m), 2.19 (td, J
d
=2.40,
J
t
=12.0), 2.52±2.58 (m); 2.74±2.81 (m); 7.1±7.42 (m, 10H
Ar
).
13
30.76 (CH
2
); 33.75 (CH
2
); 37.15 (2CH
2
); 50.42 (2CH
2
); 59.14
(CH
2
); 60.53 CH
2
); [125.99; 127.98; 128.35; 128.62; 128.95;
130.53 (CH
Ar
)]; 140.33 (C
Ar
); 141.33 (C
Ar
); 174.37 (C
O) MS
(EI): 350 (M
+
; 0,4); 260 (18); 259 (100); 110 (34); 106 (22);
105 (10).
C NMR (ppm, CDCl
3
, APT): 9.45 (CH
3
); 21.05 (CH
3
);
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