Improved method for the total synthesis of thiofentanyl

Article abstract of DOI:10.1002/jhet.3983

Thiofentanyl is a potent analgesic and anesthetic drug that belongs to the microreceptor agonist group and is mainly used in animal's anesthesia. We present an optimized synthesis route for synthesis of thiofentanyl using nanocatalysts such as MCM-41-SO₃H and SBA-15-Ph-PrSO₃H as green, heterogeneous and recyclable catalysts according to the strategy. The intermediate 2-(thiophen-2-yl) ethyl methanesulfonate (1) easily obtained after conversion of the alcohol functional group into the mesylate leaving group using methanesulfonyl chloride (97% yield). The alkylation of commercially available 4-piperidone monohydrate hydrochloride with 2-(thiophen-2-yl) ethyl methanesulfonate in the presence of phase transfer catalyst was then carried out giving N-[2-(2-thienyl) ethyl]-4-piperidone (2) with 90% yield. N-[2-(2-thienyl)ethyl]-4-piperidone was then reacted with aniline in the presence of MCM-41-SO₃H catalyst giving the imine derivative which reduced with sodium triacetoxyborohydride to N-phenyl-1-(2-(thiophen-2-yl)ethyl) piperidine-4-amine (ANTP) (4) with 80% yield. ANTP was finally acylated using propionyl chloride to achieve thiofentanyl (5) with 90% yield. High yields, mild reaction conditions, decreased reaction times, and convenient workup were the advantages of this method compared to the previous work.

Full text of DOI:10.1002/jhet.3983

Received: 22 January 2020
DOI: 10.1002/jhet.3983
Revised: 4 March 2020
Accepted: 15 March 2020
A R T I C L E
Improved method for the total synthesis of thiofentanyl
M. J. Taghizadeh
| S. J. Hosseini | S. M. Moosavi | H. Parsa
Department of Chemistry, Faculty of
Abstract
Science, University of Imam Hossein,
Tehran, Iran
Thiofentanyl is a potent analgesic and anesthetic drug that belongs to the micro-
receptor agonist group and is mainly used in animal's anesthesia. We present an
optimized synthesis route for synthesis of thiofentanyl using nanocatalysts such as
MCM-41-SO3H and SBA-15-Ph-PrSO3H as green, heterogeneous and recyclable
catalysts according to the strategy. The intermediate 2-(thiophen-2-yl) ethyl
methanesulfonate (1) easily obtained after conversion of the alcohol functional
group into the mesylate leaving group using methanesulfonyl chloride (97% yield).
The alkylation of commercially available 4-piperidone monohydrate hydrochlo-
ride with 2-(thiophen-2-yl) ethyl methanesulfonate in the presence of phase trans-
fer catalyst was then carried out giving N-[2-(2-thienyl) ethyl]-4-piperidone (2)
with 90% yield. N-[2-(2-thienyl)ethyl]-4-piperidone was then reacted with aniline
in the presence of MCM-41-SO3H catalyst giving the imine derivative which
reduced with sodium triacetoxyborohydride to N-phenyl-1-(2-(thiophen-2-yl)ethyl)
piperidine-4-amine (ANTP) (4) with 80% yield. ANTP was finally acylated using
propionyl chloride to achieve thiofentanyl (5) with 90% yield. High yields, mild
reaction conditions, decreased reaction times, and convenient workup were the
advantages of this method compared to the previous work.
Correspondence
M. J. Taghizadeh, Department of
Chemistry, Faculty of Science, University
of Imam Hossein, Tehran, Iran.
Email: mohammadjavadtaghizadeh31@
yahoo.com
1 | INTRODUCTION
Among various types of analgesic compounds,
anilidopiperidines including Fentanyl(50-100 × Mor-
Natural medicines are directly derived from plant or animal
extraction, but semisynthetic drugs are the result of a
change in the structure of natural drugs, and full-
synthesized drugs are the result of a process of laboratory
synthesis without the simulation of natural drugs. The natu-
ral drugs which developed by pharmacists are consequences
of research under the medicine that our ancestors used in
the whole world, on the other hand, the improvement of
full-synthesized drugs requiring research and development
of chemical reactions in the field of organic chemistry. The
process of synthesis of full-synthesized drugs can be con-
trolled and modified by chemists. Accordingly, the effect of
synthetic drugs sometimes becomes so much stronger than
natural compounds.1 Opioid analgesics are a collection of
natural and chemical compounds that are also reputed to
quasi-morphine or opioid drugs.2,3 Various examples of opi-
oid analgesics are shown in Table 1.4
phine), Carfentanil (7000-8000× Morphine), Lofentanil
(5000-6000 × Morphine), and others,5 which belong to
the synthetic opioids class, provide the most potential as
analgesics. Anilidopiperidines, due to the fast onset and
short duration of action, act in the central nervous sys-
tem to decrease pain and are extensively used in surgical
anesthesia as the citrate salt at doses ranging from 2 to
50 μg/kg. Features including, low-molecular weight, high
potency, and lipid solubility of fentanyles make them
suitable for delivery via transdermal therapeutic system.6
Fentanyl and its derivatives are used in various medical
conditions such as observant patients, managing postop-
erative pains, in obstetrics and also in various orthopedic
interventions. Fentanyl transdermal patches are useful in
controlling chronic cancer pain,7 due to the slow and
controlled release of the drug over several days, Many
fentanyl analogues have been synthesized5,8–14 as
J Heterocyclic Chem. 2020;1–7.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

2
TAGHIZADEH ET AL.
TABLE 1
Various examples of opioid analgesics
Opium alkaloids and derivatives
Thebaine
Oripavine
Codeine
Morphine
Semisynthetic derivatives of opium alkaloids
Oxycodone
Etorphine
Hydromorphone
Buprenorphine
Synthetic opioids
Anilidopiperidines
Carfentanyl
Sufentanil
Thiofentanyl
Fentanyl
Other common opioids
Methadone
Phenylpiperidines
Ketobemidone
Tramadol
Pethidine
potential candidates for novel drugs, to establish the
structure-activity relationship and to investigate the opi-
oid receptors. Lots of works have been performed on the
synthesis of fentanyl and its derivatives.15,16 However,
limited works have been accomplished on the synthesis
of thiofentanyl. The effect of the thiofentanyl drug is
almost similar to carfentanil, and has been used in vari-
ous formulations such as thiofentanyl-xylazine,
thiofentanyl-medetomidine, and formulations containing
muscle relaxants for relaxation and disability of ani-
mals.17,18 Synthetic route for producing thiofentanyl is
similar to that of fentanyl, but in first step, 2-(thiophen-
2-yl) ethyl methanesulfonate is substituted instead of
phenethyl bromide. In this research, the alternative and
optimized synthesis of thiofentanyl is described. The five-
step strategy produced thiofentanyl through a convenient

TAGHIZADEH ET AL.
3
and efficient method using reusable and highly efficient
heterogeneous catalysts in excellent yields (75%-80%).
catalyst to synthesize N-[2-(2-thienyl)ethyl]-4-piperidone
(NTP) (2) with 55% to 90% yield (Table 2, entry 1-6). This
method is very simple and efficient and the reaction per-
formed under mild conditions and at room temperature.
N-alkylation step was not performed in absence of PTC
(entry 7, 8). The use of the PTC benzyltriethyl ammo-
nium chloride (TEBA) resulted in the synthesis of NTP
(entry 1-6). Although, the Cs2CO3 has been reported as
the base in recent work,17 no meaningful difference was
observed using K2CO3 as the base and the product was
obtained with 90% yield (entry 1).
The reaction of ketone 2 with aniline in the presence of
acid catalysts at different conditions provided imine 3 with
about 60% to 90% yield (Scheme 2). The carbonyl group of
compound 2 is coordinated with proton of acid catalyst
which activates it toward nucleophilic attack of aniline. The
imine was slowly hydrolyzed on silica gel, so the column
chromatography was not used for workup and purification.
Therefore, the imine reacted with the reductive agents in
situ. The investigation of various solvents was shown in
Table 3 and DCM was found to be the best choice. Acid cat-
alysts were next investigated, in the condensation of aniline
with ketone. Acid catalysts such as MCM-41-SO3H, SBA-
15-Ph-PrSO3H, acetic acid, and and so on have been used.
And nanocatalyst MCM-41-SO3H (entry 6) gave a better
yield. The reaction occurs inside the pores on the surface of
which sulfonic acid groups were supported that are capable
of hydrogen bonding with the carbonyl oxygen of the NTP.
Interaction between oxygen of carbonyl group and sulfonic
acid groups results in higher susceptibility to nucleophilic
attack on carbonyl groups for imine formation20–21
(Scheme 3). Finally, the acetylation reaction of the amine
group with propionyl chloride was performed in the pres-
ence of different bases. Between the used bases, due to the
similarity in yields and availability and safety, triethylamine
was the best choice. This reaction was carried out within
2 hours at 90% yield (Table 4).
2 | RESULTS AND DISCUSSION
Synthesis of the target, thiofentanyl, started with the prepara-
tion of 2-(thiophen-2-yl) ethyl methanesulfonate from the
2-thiophen ethanol (Scheme 1).19 The reaction of 2-(Thiofene-
2-yl) ethanol and methanesulfonyl chloride in presence of
triethylamine and dry dichloromethane solvent under a nitro-
gen atmosphere, gave this product with excellent yield (97%).
This reaction was carried out initially at zero temperature
and continued at ambient temperature. High cost and low
availability to 2-(thiophen-2yl) ethyl methanesulfonate and
use of this substance as starting material in preparation of thi-
ofentanyl caused 2-(thiophen-2yl) ethyl methanesulfonate (1)
to be synthesized. Of course, synthesis of 2-thiofen ethyl bro-
mide and 2-thiofen ethyl chloride was also studied but the
desired yields were not achieved. Therefore, 2-(thiophen-2yl)
ethyl methanesulfonate was used as the primary substance in
the N-alkylation step.
In the next step, the alkylation of commercially avail-
able 4-piperidone monohydrate hydrochloride with
2-(thiophen-2-yl)ethyl methanesulfonate carried out in
presence or absence of phase transfer catalyst (PTC)
SCHEME 1 Synthesis of 2-(thiophen-2yl) ethyl
methanesulfonate
TABLE 2
for N-alkylation step
Optimization of catalyst
Entry
Catalyst
Time (h)
Yield (%)a
1
2
20 mol% TEBA
20 mol% TEBA
10 mol% TEBA
30 mol% TEBA
20 mol% TEBA
20 mol% TEBA
Polyethylene glycol-300
20 mol% TEBA
—
2 mmol K2CO3
2 mmol Cs2CO3
2 mmol Cs2CO3
2 mmol Cs2co3
1 mmol K2CO3
1 mmol Cs2CO3
2 mmol K2CO3
—
24
24
24
24
24
24
24
24
24
24
90
90
3
60
4
70
5
55
6
60
7
No product
No product
No product
No product
8
9
2 mmol K2CO3
2 mmol Cs2CO3
10
—
aIsolated yield.

4
TAGHIZADEH ET AL.
SCHEME 2 Synthesis of thiofentanyl
TABLE 3
Optimized conditions for synthesis of ANTP
Entry
Catalyst
Solvent
Toluene
THF
Temperature
Time (h)
Yield (%)a
1
Imination
Reduction
Imination
Reduction
Imination
Reduction
Imination
Reduction
Imination
Reduction
Imination
Reduction
Imination
Reduction
Imination
Reduction
PTSA
Reflux
RT
24
24
24
24
10
10
8
40
NaBH4
2
3
4
5
6
7
8
PTSA
Toluene
THF
Reflux
RT
45
50
65
55
80
50
75
LiAlH4
Acetic acid
LiAlH4
DCM
RT
Acetic acid
NaBH(OAc)3
MCM-41-SO3H
LiAlH4
DCM
RT
8
DCM
RT
5
10
5
MCM-41-SO3H
NaBH(OAc)3
MCM-41-SO3H
NaBH(OAc)3
SBA-15-Ph PrSO3H
NaBH(OAc)3
DCM
RT
5
Toluene
DCM
Reflux
RT
12
12
5
5
Abbreviation: ANTP, N-phenyl-1-(2-(thiophen-2-yl)ethyl) piperidine-4-amine.
aIsolated yield.
3 | EXPERIMENTAL
3.1 | General
further purification. All the organic solvents were pur-
chased from commercial suppliers and were purified
according to standard procedures. Analytical thin layer
chromatography (TLC) for monitoring reactions was
performed using Merck 0.2 mm silica gel 60F-254 Al-
plates using ethyl acetate and n-hexane as eluents.
All chemicals were purchased from Merck, Fluka, and
Sigma-Aldrich companies and were used without

TAGHIZADEH ET AL.
5
3.3 | Characterization of Nano catalyst
SBA-15-Ph-PrSO3H
In this work, SBA-15-Ph-PrSO3H was synthesized
according to the explained procedure in literature.24
3.4 | Synthesis
3.4.1 | 2-(Thiophen-2-yl) ethyl
methanesulfonate (1)
A mixture of triethylamine (1.50 mmol), 2-(Thiofene-
2-yl)ethanol (1 mmol) and anhydrous dichloromethane
(dry; 15 mL) was stirred at the room temperature under a
nitrogen atmosphere for 1 hour. It was cooled to 0ꢀC to
5ꢀC with ice-salt bath and then methanesulfonyl chloride
(1.50 mmol) was added dropwise in 10 minutes. The mix-
ture was warmed to ambient temperature under a nitro-
gen atmospheric pressure and stirred for 2 hours. After
completion of the reaction (TLC, 2 hours), the mixture
SCHEME 3 Proposed mechanisms for formation of N-phenyl-
1-(2-(thiophen-2-yl)ethyl) piperidine-4-amine
TABLE 4
Optimized conditions for synthesis of thiofentanyl
Entry
Catalyst
Et3N
Solvent
DCM
Time (h)
Yield (%)a
1
2
3
4
5
6
2
2
2
2
2
2
90
75
90
90
70
75
transfered to
a separatory funnel and partitioned
Et3N
CH3CN
DCM
(CH2Cl2/H2O) and the organic layer was separated. The
organic phase was washed with saturated NaHCO3 solu-
tion and brine (NaCl/H2O). The combined organic
extracts were dried over MgSO4, filtered and concen-
trated under reduced pressure to afford 2-(thiophen-2-yl)
ethyl methanesulfonate as light brown oil (0.20 g, 97%),
Rf = 0.54 (3:7 EtOAc/hexane); 1HNMR (250 MHz,
CDCl3) δ = 7.91 (dd, J = 4.8 Hz, 0.6 Hz, 1H), 6.95 (dd,
J = 5.4 Hz, 3.6 Hz, 1H), 6.91 to 6.90 (m, 1H), 4.42 (t,
J = 6.6 Hz, 2H), 3.27 (t, J = 6.6 Hz, 2H), 2.92 (s, 3H); 13C
NMR (60.2 MHz, CDCl3) d 138.1, 127.1, 126.2, 124.5,
69.7, 37.4, 29.8. Anal. calcd (%) for C7H10O3S2: C,
40.76; H, 4.89; O, 23.27; S, 31.08. Found: C, 40.56; H,
4.99; O, 23.32; S, 31.13.
DIPEA
Pyridine
DIPEA
Pyridine
DCM
CH3CN
CH3CN
aIsolated yield.
Column chromatography was accomplished using
Merck Silica gel 60 (0.063-0.200 mm). Infrared spectra
were obtained using a Perkin-Elmer Spectrom-100 FT-
1
IR spectrometer. H NMR (250 500 MHz) and 13C NMR
(60 120 MHz) spectra were recorded with CDCl3 as sol-
vent at ambient temperature and tetramethylsilane as
internal standard. Mass spectra were recorded on an
Agilent Technologies, Model: 5975C VL MSD by EI
mass spectrometry on a Q-TOF instrument. All yields
refer to the isolated products.
3.4.2 | N-[2-(2-Thienyl) ethyl]-
4-piperidone (2)
20 mol% TEBA and K2CO3 (10 mmol) was dissolved in
3.2 | Characterization of nano catalyst
MCM-41-SO3H
dry acetonitrile (25 mL) in a round-bottom flask
equipped with a stir bar and a condenser. The mixture
was stirred 15 minutes at 60ꢀC, and then was added
4-piperidone monohydrate hydrochloride (10 mmol) in
little portions. The mixture was stirred for 1 hour at 60ꢀC
and then 2-(thiophen-2-yl) ethyl methanesulfonate
(5 mmol) was added dropwise. The resulting suspension
was vigorously stirred and refluxed at 80ꢀC for 24 hours.
After completion of the reaction (TLC, 24 hours), the
mixture was filtrated and transferred to a separator
In this work, MCM-41 was synthesized according to the
explained procedure in literature22 MCM-41 was
sulfonated by covalently bonded sulfonic acid on the
inside surface of pores to provide the silica-supported
nanomaterial with Bronsted acid properties. Then was
reacted with chlorosulfonic acid to give a white powder
that was named MCM-41-SO3H.23

6
TAGHIZADEH ET AL.
funnel and partitioned (CH2Cl2//H2O). The organic
phase was washed with saturated NaHCO3 solution and
brine (NaCl/H2O). The combined organic extracts were
dried over MgSO4, filtered and concentrated under
reduced pressure to afford N-[2-(2-thienyl) ethyl]-
4-piperidone as a light yellow oil (0.941 g,90%), Rf = 0.25
(40:60 EtOAc/hexane), IR (KBr) (νmax, cm−1): 3100, 2951,
2823, 2793, 1714, 1353, 1224, 1123, 851 710; 1H NMR
(250 MHz, CDCl3) δ = 7.14 (dd, J = 5.4 Hz, 1.2 Hz, 1H),
6.92 (dd, J = 5.4 Hz, 3.6 Hz, 1H), 6.84 (dq, J = 3.6 Hz,
1.2 Hz, 1H), 3.04 (t, J = 7.2 Hz, 2H), 2.82 (t, J = 6.0 Hz,
4H), 2.77 (t, J = 7.2 Hz, 2H), 2.48 (t, J = 6.0 Hz, 4H); 13C
NMR (60 MHz, CDCl3) d 209.0, 142.4, 126.6, 124.7, 123.7,
60.4, 53.0, 41.3, 28.3. Anal. calcd (%) for C11H15NOS: C,
63.12; H, 7.22; N, 6.69; O, 7.64; S, 15.32. Found: C,
63.15; H, 7.32; N, 6.59; O, 7.61; S, 15.32.
3.4.4 | Thiofentanyl (5)
N-phenyl-1-(2-(thiophen-2-yl) ethyl) piperidine-4-amine
(1 mmol) and triethylamine (2 mol) was dissolved in
methylene chloride (25 mL) in a round bottom flask
equipped with a stir bar. It was stirred at ambient tem-
perature for 1 hour. The solution was cooled to 0ꢀC to
5ꢀC with ice-salt bath and then propionyl chloride
(2 mmol) was added dropwise in 10 minutes. The
resulting mixture was stirred for 1 hour at ambient tem-
perature. After completion of the reaction, the mixture
transferred to a separator funnel. The mixture was par-
titioned (CH2Cl2/H2O). The organic phase was washed
with saturated NaHCO3 solution and brine (NaCl/H2O).
The combined organic extracts were dried over MgSO4,
filtered and concentrated in vacuum to give light brown
oil. The oily mixture was purified by column chromatog-
raphy (4:6 EtOAc/hexane) to give 5 as light yellow solid
(0.308 g, 90%), Rf = 0.21 (50:50 EtOAc/hexane), IR (KBr;
νmax, cm−1): 2932, 2805, 1640, 1595, 1496, 1391, 1269,
3.4.3 | N-Phenyl-1-(2-(thiophen-2-yl)
ethyl) piperidine-4-amine (4)
1
1055, 707; HNMR (500 MHz, CDCl3) δ = 7.38 to 7.33
Aniline (1 mmol), N-[2-(2-thienyl) ethyl]-4-piperidone
(1 mmol) and MCM-41-SO3H (0.02 g) was taken up in
methylene chloride (25 mL) in a round-bottom flask
equipped with a stir bar. The light brown solution was
stirred at ambient temperature for 5 hours. Then, slow
addition of sodium triacetoxyborohydride (2 mmol) was
applied in small portions. The reaction mixture was
stirred at ambient temperature for 5 hours. After com-
pletion of the reaction, the mixture was filtrated and
transferred to a separator funnel. The mixture was par-
titioned (CH2Cl2/H2O). The organic phase was washed
with saturated NaHCO3 solution and brine (NaCl/H2O).
The combined organic extracts were dried over MgSO4,
filtered and concentrated in vacuum to give light brown
oil. The oily mixture was purified by Column chroma-
tography (6:4 EtOAc/hexane) to give 4 as light yellow
solid (0.982 g,80%), Rf = 0.31 (60:40 EtOAc/hexane), IR
(KBr; νmax, cm−1): 3423, 3285, 2933, 2804, 2763, 1601,
1526, 1496, 1317, 1269, 746, 705, 693; 1H NMR
(150 MHz, CDCl3) δ = 7.18 to 7.15 (m, 2H), 7.13 (dd,
J = 5.4 Hz, 1.2 Hz, 1H), 6.92 (dd, J = 5.4 Hz, 3.6 Hz,
1H), 6.84 to 6.82 (m, 1H), 6.69 (tt, J = 7.2 Hz, 0.6 Hz,
1H), 6.62 to 6.58 (m, 1H), 1.52 (S, 1H), 2.24-3.31 (m,
1H), 3.33 (t, J = 6.6 Hz, 2H), 2.95 to 2.93 (m, 2H), 2.68
(t, J = 6.6 Hz, 2H), 2.22 (td, J = 13.2 Hz, 2.4 Hz, 2H),
2.10 to 2.07 (m, 2H), 1.54-1.51 (m, 2H); 13C NMR
(62 MHz, CDCl3) d 147.1, 142.9, 129.3, 126.6, 124.6,
123.5, 117.2, 113.3, 60.0, 52.4, 49.9, 32.6, 28.0; Mass spec-
trum (EI, 70 eV), m/z (Irel, %): [М]+ 300 (3), 189 (98),
132 (84), 146 (100), 118 (83), 97 (99). Anal. Calcd for
C17H22N2S: C, 71.29; H, 7.74; N, 9.78; S, 11.19.
Found: C, 71.35; H, 7.71; N, 9.80; S, 11.18.
(m, 3H), 7.09 to 7.06 (m, 2H), 6.88 (dd, J = 4.8 Hz,
3.0 Hz, 1H), 6.77 to 6.75 (m, 1H), 4.67 (tt, J = 12.0 Hz,
4.2 Hz, 1H), 2.97 to 2.92 (m, 4H), 2.61 to 2.58 (m, 2H),
2.17 (td, J = 12.0 Hz, 1.8 Hz, 2H), 1.91 (q, J = 7.8 Hz,
2H), 1.81 to 1.78 (br s, 1H), 1.40 (qd, J = 11.4 Hz, 3.6 Hz,
2H), 1.00 (t, J = 7.8 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 173.5, 142.6, 138.8, 130.4, 129.3, 128.3, 126.6, 124.5,
123.4, 60.0, 53.0, 52.1, 30.5, 28.5, 27.8, 9.6; Mass spectrum
(EI, 70 eV), m/z (Irel, %): [М + 1]+ 343 (3), 189 (70),
245 (96), 146 (100), 97 (75), 57 (62). Anal. Calcd for
C20H26N2OS: C, 70.14; H, 7.65; N, 8.18; O, 4.67; S, 9.36.
Found: C, 70.34; H, 7.55; N, 8.23, O, 4.69; S, 9.39.
4 | CONCLUSIONS
In this work, we have illustrated preferable and improved
method for the synthesis of thiofentanyl. The mesylated
thiophene ethanol obtained after reaction of thiophene eth-
anol with mesyl chloride. Then, the alkylation of 4-
piperidone monohydrate hydrochloride with 2-(thiophen-
2-yl) ethyl methanesulfonate in the presence of catalyst was
carried out with 90% yield. NTP was then reacted with ani-
line in the presence of MCM-41-SO3H catalyst giving the
imine derivative which reduced with sodium
triacetoxyborohydride to N-phenyl-1-(2-(thiophen-2-yl)
ethyl)piperidine-4-amine with 80% yield. Finally, acylation
of N-phenyl-1-(2-(thiophen-2-yl) ethyl) piperidine-4-amine
carry out by using propionyl chloride to achieve thi-
ofentanyl with high yield. The total synthesis of thi-
ofentanyl with this condition was accomplished in four
steps with 90% yield. The mentioned synthesis method,

TAGHIZADEH ET AL.
7
[14] L. V. Kudzma, S. A. Severnak, M. J. Benvenga, E. F. Ezell,
M. H. Ossipov, V. V. Knight, F. G. Rudo, H. K. Spencer,
T. C. Spaulding, J. Med. Chem. 1989, 32, 2542.
[15] Y. G. Suh, K. H. Cho, D. Y. Shin, Arch. Pharm Res. 1998,
21, 72.
[16] S. H. Zee, W. K. Wang, J. Chin. Chem. Soc. 1980, 27, 149.
[17] C. A. Valdez, R. N. Leif, B. P. Mayer, Plos One. 2014, 9,
e108250.
proposes several advantages of short reaction times, high
yields, mild condition, simplicity, and easy workup com-
pared to the other conventional methods of synthesis.
ORCID
M. J. Taghizadeh https://orcid.org/0000-0003-2661-
0870
[18] G. E. Zeiler, L. C. Meyer, Vet. Anesth. Analg. 2017, 44, 1006.
[19] S. Srimurugan, K. Murugan, C. Chen, Chem. Pharm. Bull.
2009, 57, 1424.
[20] E. Ali, M. Naimi-Jamal, M. Dekamin, Sci Iran. 2013, 20, 592.
[21] M. Eslami, M. G. Dekamin, L. Motlagh, A. Maleki, Green
Chem. Lett. Rev. 2018, 11, 36.
[22] H. Sepehrian, M. Ghannadi-Maragheh, S. Waqif-Husain,
R. Yavari, A. Khanchi, J. Radioanal, Nucl. Chem. 2007,
275, 153.
[23] Z. Dolatkhah, S. Javanshir, A. S. Sadr, J. Hosseini, S. Sardari,
J. Chem. Inf. Model. 2017, 57, 1257.
REFERENCES
[1] T. H. Stanley, J. Pain. Symptom. Manage. 1992, 7, S7.
[2] T. H. Stanley, T. D. Egan, H. Van Aken, Anesth Analg. 2008,
106, 462.
[3] H. Hemmings, T. Egan, Foundations and Clinical Application,
Expert Consult-Online and Print, 2013.
[4] S. Offermanns, W. Rosenthal, Encyclopedia of Molecular
Pharmacology, Springer Science & Business Media. 2008.
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
[5] I. V. Mίcονίc, M. D. Ivanovic, S. Vuckovic, D. Jovanovic-Micic,
ꢀ
ꢀ
ꢀ
ꢀ
D. Beleslin, L. Dosen-Micovic, V. D. Kiricojevic, Heterocycl
Commun. 1998, 4, 171.
[6] M. Crowley, Chemical Control, London: Springer, 2016.
[7] W. Jeal, P. Benfield, Drugs. 1997, 53, 138.
[24] D. Zareyee, S. M. Moosavi, A. Alaminezhad, J. Mol. Catal. A:
Chem. 2013, 378, 231.
ꢀ
ꢀ
[8] V. Kiricojevic, M. Ivanovic, I. Micovic, J. Djordjevic, G. Roglic,
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
L. Dosen-Micovic, J. Serb. Chem. Soc. 2002, 67, 802.
ꢀ
ꢀ
ꢀ
[9] I. V. Micovic, M. D. Ivanovic, S. M. Vuckovic, M. Š. Prostran,
ꢀ
ꢀ
ꢀ
L. Došen-Micovic, V. D. Kiricojevic, Bioorg. Med. Chem. Lett.
2000, 10, 2014.
[10] I. V. Micovic, G. M. Roglic, M. Ivanovic, L. Dosen-Micovic,
V. D. Kiricojevic, J. B. Popovic, J. Chem. Soc. 1996, 16, 2050.
[11] J. P. H. Orr Brian Jr, G. H. Klemm, K. G. Tomazi, U.S. Patent
No 8,946,433, 2015.
[12] P. L. Feldman, M. K. James, M. F. Brackeen, J. M. Billota,
S. V. Schuster, A. P. Lahey, M. W. Lutz, M. R. Johnson,
H. J. Leighton, J. Med. Chem. 1991, 34, 2208.
How to cite this article: Taghizadeh MJ,
Hosseini SJ, Moosavi SM, Parsa H. Improved
method for the total synthesis of thiofentanyl.
J Heterocyclic Chem. 2020;1–7. https://doi.org/10.
1002/jhet.3983
[13] P. D. Van, M. B. De, J. Boey, S. Sanczuk, J. Agten, P. Janssen,
Arznei Mittleforsch. 1976, 26, 1531.