Preparation of Fentanyl Labeled with Carbon-14

Article abstract of DOI:10.1134/S1066362218010071

A convenient synthetic pathway for ¹⁴C labeling of fentanyl [N-(1-phenethyl-4-piperidinyl)- propionanilide], a widely used narcotic analgesic agent, with good radiochemical yield was developed.

Full text of DOI:10.1134/S1066362218010071

ISSN 1066-3622, Radiochemistry, 2018, Vol. 60, No. 1, pp. 42–44. © Pleiades Publishing, Inc., 2018.
Published in Russian in Radiokhimiya, 2018, Vol. 60, No. 1, pp. 41–43.
Preparation of Fentanyl Labeled with Carbon-141
M. Namia, M. Dabiria, G. Shirvanib, M. A. Ahmadi Faghihb, and M. Javaheri*b
a Faculty of Chemistry, Shahid Beheshti University, G.C., Evin, Tehran 1983963113, Iran
b Applied Radiations Research School, Nuclear Science & Technology Research Institute,
P.O. Box 11365-3486, Iran
*e-mail: mjavaheri@aeoi.org.ir
Received March 20, 2017
Abstract—A convenient synthetic pathway for 14C labeling of fentanyl [N-(1-phenethyl-4-piperidinyl)-
propionanilide], a widely used narcotic analgesic agent, with good radiochemical yield was developed.
Keywords: Opioid, Fentanyl, carbon-14
DOI: 10.1134/S1066362218010071
Fentanyl is a synthetic l-opioid receptor agonist
O
O
widely used for surgical analgesia and alleviation.
O
HN
N
N
However, various fentanyl analogs can cause the abuse
and fatalities in humans, which led to the synthesis of
some stronger and safer analogs [1]. Over the last four
decades, structure–activity relationship and molecular
modeling studies of fentanyl analogs provided consid-
erable insight into the key structural features and phar-
macophore elements required for high-affinity binding
to the l-receptor [2, 3]. A number of structural ele-
ments required for the analgesic activity of the fentanyl
class of compounds were revealed, and novel potent
fentanyl analogs were synthesized [4]. The stronger
potency of fentanyl compared to that of morphine is
largely due to its high lipophilicity facilitating its pene-
tration into the central nervous system [5]. Further
studies of the mechanism of action and metabolism of
fentanyl require synthesis of fentanyl labeled with 14C.
The synthesis pathway is shown in Schemes 1–3.
N
H2,
PhNH2
Zn, AcOH
EtCOCl
DCE
N
10% Pd/C
N
N
H
4
3
2
1
Scheme 1. Scheme of the synthesis of N-(4-piperidinyl)-
propionanilide (4).
OTs
OH
14CN
14COOH
(c)
14CH2
14CH2
Cl
(a)
(b)
(d)
[14C]5
[14C]6
[14C]8
[14C]7
Scheme 2. Scheme of the synthesis of 2-phenyl[1-14C]ethyl
p-toluenesulfonate [14C]8. (a) K14CN, EtOH, thiourea;
(b) water, H2SO4, glacial acetic acid, reflux, 1 h; (c) dry
THF, Zn(BH4)2; (d) TsCl, BnNMe2, K2CO3.
EXPERIMENTAL
O
Barium [14C]carbonate was converted to potassium
cyanide according to the standard procedure [6]. The
IR spectra were recorded on a Bruker FT-IR Vector22
O
N
OTs
14CH2
K2CO3
DMF
N
1
instrument, and the H NMR spectra, on a Varian
N
+
Unity Plus 400 spectrometer (400 MHz). Radioactivity
was determined with a Beckman LS6500 liquid scintil-
lation spectrometer. The mass spectra were taken on a
Finnigan TSQ-70 instrument.
14CH2
[14C]9
N
[14C]8
H
4
1 The text was submitted by the authors in English.
Scheme 3. Scheme of the synthesis of [14C]fentanyl.
42

PREPARATION OF FENTANYL LABELED WITH CARBON-14
43
filtrate was concentrated on a rotary evaporator, and
the residue was treated with a 30% aqueous NaOH
solution. The aqueous solution was extracted with eth-
yl acetate (2 × 4 mL), the extract was dried over anhy-
drous sodium sulfate, and the solvent was removed in a
vacuum. The crude compound 4 thus obtained was
recrystallized from petroleum ether; yield 1.5 g (93%).
IR (KBr), ν, cm–1: 3374, 3031, 2944, 2825, 1657,
4-Anilino-N-benzylpiperidine (2). To a mixture of
N-benzylpiperidin-4-one 1 (0.01 mol, 1.89 g), aniline
(0.01 mol), and activated zinc (0.04 mol), 90% aque-
ous acetic acid (0.16 mol) was added in portions. The
mixture was stirred at room temperature for 24 h and at
70°C on a water bath for an additional 12 h. After the
reaction completion, the mixture was diluted with
methanol and filtered. The filtrate was concentrated in
a vacuum and then neutralized with a 30% ammonium
hydroxide solution to pH 10. The crude product was
collected by filtration and recrystallized with petro-
leum ether to obtain the pure product in 84% yield
(2.2 g). IR (KBr), ν, cm–1: 3440 (N–H stretching),
3255, 3020, 2936, 2842,1615, 1526, 1490, 1372, 1318,
1
1591, 695. H NMR [CDCl3, δ (ppm)]: 0.95 (t, 3H),
1.25 (dq, 2H), 1.56 (br.s, 1H), 1.74 (br.d, 2H), 1.91
(q, 2H), 2.11 (br.t, 2H), 3.10 (br.d, 2H), 4.66–4.79
(m, 1H), 7.13 (d, Ar–H), 7.14 (d, Ar–H), 7.37 (m, Ar–
H). Mass spectrum (m/z): 233 [M + 1].
2-Phenyl[1-14C]acetic acid [14C]6. A solution of
benzyl chloride (2.0 g, 15.8 mmol) in EtOH (4 mL)
was added dropwise over a period of 45 min to a solu-
tion of potassium [14C]cyanide (500 mg, 7.4 mmol,
697 MBq) in water (1.5 mL), and the mixture was re-
fluxed for 6 h. Thiourea (42 mg, 5.55 mmol) and EtOH
(2 mL) were added, and the mixture was refluxed for
a further 1 h. The solution was concentrated under re-
duced pressure and partitioned between Et2O and wa-
ter. The organic phase was washed with water, dried,
and evaporated to obtain crude benzyl cyanide [14C]5
as a yellow oil. Water (4 mL), concentrated H2SO4
(4 mL) and glacial acetic acid (4 mL) were added to
this product, and the mixture was refluxed for 1 h.
Then, the mixture was diluted with water (50 mL) and
extracted with Et2O (3 × 10 mL). The organic extract
was dried and evaporated to give 2-phenyl[1-14C]acetic
acid [14C]6 as beige crystals [7] (625 mg, 4.5 mmol,
1
1255, 1087, 977, 862, 751, 690. H NMR [400 MHz,
CDCl3, δ (ppm)]: 1.50 (dq, 2H), 2.10 (br.d, 2H), 2.30
(br.t, 2H), 2.60 (s, 2H), 2.90 (br.d, 2H), 3.35 (m, 1H),
3.50 (br.s, 1H), 7.10–7.40 (m, Ar–H). Mass spectrum
(m/z): 267 [M + 1].
N-(1-Benzyl-4-piperidinyl)propionanilide (3). To
a solution of 2 (8 mmol, 2.1 g) in 5 mL of 1,2-di-
chloroethane, propionyl chloride (24 mmol) was added
dropwise, and the resulting mixture was stirred at am-
bient temperature for 3 h. After the reaction comple-
tion, the mixture was poured slowly to a 5% aqueous
NaOH solution (5 mL) with continuous stirring. The
resulting alkaline solution was extracted with dichloro-
methane (3 × 4 ml), and the organic phase was dried
over anhydrous sodium sulfate and concentrated under
reduced pressure to obtain the crude product, which
was purified as its hydrochloride: colorless crystals,
yield 2.6 g (91%). The corresponding free base was
obtained by decomposition of its hydrochloride salt
with a 30% NaOH solution, followed by recrystalliza-
tion from petroleum ether; colorless compound 3, yield
2.3 g (91%). IR (KBr), ν, cm–1: 3430, 2941, 2822,
1659 (C=O), 1495, 1370, 1260 (C–N stretching), 1150,
1
425 MBq, 61%). H NMR [CDCl3, δ (ppm)]: 7.24–
7.39 (m, 5H, ArH); 3.63 (s, 2H). Mass spectrum (m/z):
139 [M + 1].
2-Phenyl[1-14C]ethanol [14C]7. To 500 mg
(340 MBq) of [1-14C]6, 1.5 mL of dry THF and then
3.0 mL of a 0.66 M solution of Zn(BH4)2 (2 mmol) in
2 mL of THF were added. The contents were refluxed
and then cooled to room temperature, and the excess
hydride was quenched with 0.25 mL of dilute H2SO4
(2 N). Then, the reaction mixture was saturated with
anhydrous K2CO3, and the organic layer was sepa-
rated. The residue was extracted with 2 × 2 mL of
THF. The combined organic extracts were dried over
anhydrous K2CO3 and then concentrated under reduced
pressure to yield 412 mg (320 MBq, 94%) of 2-phenyl-
[1-14C]ethanol [14C]7. Mass spectrum (m/z): 125 [M + 1].
1
1090, 705. H NMR [CDCl3, δ (ppm)]: 0.94 (t, 3H),
1.30–1.40 (m, 2H), 1.70–1.80 (m, 2H), 1.85 (q, 2H),
2.10 (m, 2H), 2.65 (m, 2H), 3.30 (t, 2H), 4.58–4.67 (m,
1H), 7.10–7.30 (m, Ar–H). Mass specrum (m/z): 323
[M + 1].
N-(4-Piperidinyl)propionanilide (4). A solution of
3 (7 mmol, 2.2 g) in 5 mL of methanol–acetic acid
mixture (3 : 2) was taken in a 25-mL thick-walled hy-
drogenation vessel containing 10 wt % Pd/C catalyst.
The hydrogen gas was then fed into the vessel using a
Parr apparatus at 50°C. After the hydrogen uptake
ceased, the mixture was filtered through Celite. The
2-Phenylethyl p-toluenesulfonate [14C]8. TsCl
(858 mg, 4.5 mmol) was added over a period of 1 h
(6 portions at 10-min intervals) to a stirred suspension
RADIOCHEMISTRY Vol. 60 No. 1 2018

44
NAMI et al.
of alcohol [14C]7 (366 mg, 284 MBq, 3 mmol),
BnNMe2 (405 mg, 3 mmol), and K2CO3 (1.2 g,
9 mmol) in water (2 mL) at 20–25°C. A 1 M aqueous
KOH solution (1.5 mL) was continuously added using
a microfeeder to the reaction mixture so as to maintain
pH 10 (monitored with a pH meter). The mixture was
stirred at the same temperature for an additional 1 h.
To decompose excess TsCl, N,N-dimethylethylene-
diamine (100 mg) was added to the mixture, and the
mixture was stirred for 10 min. Water was added, and
the solution was extracted with EtOAc (2 × 4 mL). The
organic phase was washed with water and concentrated
NaCl solution, dried (Na2SO4), and concentrated. The
obtained crude tosylate was sufficiently pure (yield
the overall radiochemical yield was as low as 18% [9].
In this case, the label is introduced into sites resistant
to metabolic extraction. In our procedure, the label was
introduced into the position adjacent to the piperidine
nitrogen atom. The synthesis starts with the reaction of
potassium [14C]cyanide with benzyl chloride to obtain
benzyl [14C]cyanide. Its acid hydrolysis yields
2-phenyl[1-14C]acetic acid, which, in turn, is reduced
with Zn(BH4)2 to obtain 2-phenyl[1-14C]ethanol. This
product is converted to tosylate by the reaction with
TsCl. Finally, the condensation of the radioactive and
nonradioactive fragments is performed. This procedure
is novel, and the overall radiochemical yield based on
potassium [14C]cyanide was 26%.
1
90%, 421.2 mg, 255.6 MBq) [8]. H NMR [400 MHz,
CDCl3, δ (ppm)]: 2.43 (s, 3H), 2.96 (t, 2H, J 7.1 Hz),
4.22 (t, 2H, J 7.1 Hz), 7.13 (m, 2H), 7.18–7.34 (m,
5H), 7.63 (m, 2H). IR (KBr), ν, cm–1: 2955, 1596,
1458, 1366, 1277, 1108, 968. Mass spectrum (m/z):
279 [M + 1].
ACKNOWLEDGMENTS
The authors are grateful to Dr. M. Amini (Tehran
University of Medical Science, Faculty of Pharmacy)
and Mrs. J. Karimi (AEOI) for measuring the 1H NMR
spectra and radioactivity of the samples, respectively.
The authors also gratefully acknowledge the help of
Department of Chemistry, Shahid Beheshti University.
[14C]Fentanyl [14C]9. A 10-mL two-necked round-
bottomed flask was charged with 2.5 mL of acetoni-
trile and 20 mmol of anhydrous K2CO3, and tetrabu-
tylammonium bromide (10 mol %) and compound 4
(2.0 mmol) were added. Then, compound [14C]8
(390 mg, 237 MBq, 2.5 mmol) was added slowly with
stirring, and the reaction mixture was refluxed with
stirring until the reaction was complete (monitored by
TLC). The reaction mixture was then filtered to re-
move solid residues. The filtrate was concentrated in a
vacuum to obtain a dark colored solid residue. The
residue was purified by crystallization to give the pure
compound. Colorless crystalline solid, yield 50%
(420 mg, 118 MBq). IR (KBr), ν, cm–1: 2941, 2822,
1657, 1592, 1493, 1381, 1264, 1122, 1052, 732, 700,
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