An Operationally Simple Synthesis of Fentanyl Citrate

Full text of DOI:10.1080/00304948.2017.1374129

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: 0030-4948 (Print) 1945-5453 (Online) Journal homepage: http://www.tandfonline.com/loi/uopp20
An Operationally Simple Synthesis of Fentanyl
Citrate
Andrew J. Walz & Fu-Lian Hsu
To cite this article: Andrew J. Walz & Fu-Lian Hsu (2017) An Operationally Simple Synthesis
of Fentanyl Citrate, Organic Preparations and Procedures International, 49:5, 467-470, DOI:
10.1080/00304948.2017.1374129
To link to this article: http://dx.doi.org/10.1080/00304948.2017.1374129
Published online: 29 Sep 2017.
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Date: 02 October 2017, At: 02:11

Organic Preparations and Procedures International, 49:467–470, 2017
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2017.1374129
OPPI BRIEF
An Operationally Simple Synthesis
of Fentanyl Citrate
Andrew J. Walz and Fu-Lian Hsu
Edgewood Chemical Biological Center, U.S. Army, Edgewood, Maryland
Fentanyl is a synthetic opioid developed by Janssen and co-workers over 40 years ago
and is currently used for chronic pain management.1 The medical importance of fentanyl
has inspired synthetic interest since its discovery. A general synthetic scheme beginning
with commercially available 4-piperidones is shown in Figure 1.
Figure 1 General synthesis of fentanyl.
Various methodologies have been explored utilizing this general scheme. Some of
these include a thermally mild route developed by Valdez and coworkers.2 Also seen
were zinc metal based reductive aminations.3,4 An ionic liquid mediated alkylation was
employed by Saidi et al.5 A double reductive amination approach was performed in a
one-pot procedure to provide fentanyl hydrochloride in 40% overall yield.6
The work presented here demonstrates an operationally simple preparation of fenta-
nyl as the pharmaceutically relevant citrate salt. The efficient methodology employs
Received January 5, 2017; in final form April 12, 2017.
Address correspondence to Andrew J. Walz, Research and Technology Directorate, U.S. Army,
Edgewood Chemical Biological Center (ECBC), Aberdeen Proving Ground, MD 21010–5424.
E-mail: andrew.j.walz.civ@mail.mil
This article not subject to U.S. copyright law.
467

468
Walz and Hsu
organic acid salt formation with precipitation and a recrystallization as the sole means of
purification over four synthetic transformations. This overall process follows on our pre-
vious work involving carfentanil.7 The synthetic chemistry is shown in Scheme 1.
Scheme 1
Beginning with commercially available 1-benzyl-4-piperidone, reductive amination
with triacetoxyborohydride was accomplished.8 The crude material was subjected to
amide bond formation using propionyl chloride. Following a basic work-up, the crude
amide was treated with oxalic acid to form precipitated N-(1-benzylpiperidin-4-yl)-N-
phenylpropionamide oxalate 1 in 74% yield for the two synthetic steps. Catalytic transfer
hydrogenation with ammonium formate was performed on oxalate 1.9 Generation of the
free base was not required for the hydrogenation to proceed in an acceptable yield. This
is the first reported application of transfer hydrogenation in the synthesis of fentanyl.
The free piperidone amine was alkylated with (2-chloroethyl)benzene. After an aque-
ous work-up, the crude product was isolated by precipitation with citric acid. Recrystalli-
zation from 25:1 isopropanol:ethanol provided fentanyl citrate 2 in 72% yield from the
oxalate salt intermediate.
Fentanyl citrate 2 was synthesized from commercially available 1-benzyl-4-piperi-
done with an overall yield of 53% over four synthetic steps. One intermediate and the
final product were purified by organic salt formation with precipitation and recrystalliza-
tion to provide this medically significant analgesic.
Experimental Section
Starting materials were purchased from Aldrich Chemical Co. (Milwaukee, WI). NMR spectra
were obtained on a JEOL 400 MHz spectrometer and chemical shifts (d) are reported in parts
per million (ppm) downfield from tetramethylsilane. Elemental analyses were performed on a
PerkinElmer Series II 2400 CHNS/O Elemental Analyzer with acetanilide as the standard.
N-(1-Benzylpiperidin-4-yl)-N-phenylpropionamide oxalate 110
Sodium borohydride (0.90 g, 23.9 mmol) was suspended in 20 mL of 1,2-dichloroeth-
ane under a nitrogen atmosphere and cooled in an ice water bath. Acetic acid (4.30 g,
71.6 mmol) was added dropwise with an addition funnel. It was rinsed with 10 mL of

An Operationally Simple Synthesis of Fentanyl Citrate
469
1,2-dichloroethane. The mixture was removed from the ice water bath and stirred at
room temperature for 16 h. A solution of 1-benzyl-4-piperidone (3.00 g, 15.9 mmol),
aniline (2.62 g, 17.4 mmol), acetic acid (0.96 g, 15.9 mmol), and 12 mL of 1,2-
dichloroethane was added dropwise with an addition funnel. It was rinsed with 10 mL
of 1, 2 dichloroethane. The mixture was stirred for 24 h at room temperature. The
reaction mixture was poured over 100 mL of a 2 M aqueous sodium hydroxide solu-
tion and extracted with chloroform (3 £ 100 mL). The combined organic extracts
were dried with sodium sulfate, filtered, and the volatiles were evaporated providing
4.40 grams of the reductive amination product. The residue was taken up in 120 mL
1,2-dichloroethane and propionyl chloride (7.36 g, 79.5 mmol) was added with a
syringe. The mixture was heated to reflux under a nitrogen atmosphere for 20 h. The
reaction mixture was allowed to cool to room temperature and the volatiles were
evaporated. The residue was taken up with 100 mL of saturated aqueous sodium
bicarbonate and 100 mL of chloroform. The organic layer was separated. The aqueous
layer was washed with chloroform (2 £ 100 mL). The combined organic extracts
were dried with sodium sulfate, filtered, and the volatiles were evaporated providing
5.70 g of a tan oil. The residue was dissolved in 15 mL of isopropanol and the solu-
tion was gently warmed. Oxalic acid (2.21 g, 17.5 mmol) in 5 mL of water was added
with an addition funnel. It was rinsed with 2 mL of water followed by 3 mL of isopro-
panol. The mixture was allowed to cool to room temperature and was placed in a
refrigerator for 24 h. The white precipitate obtained was filtered, washed with ice
bath cooled isopropanol, and dried to provide 5.52 g of the oxalate salt 1 in 70%
yield. An analytical sample was prepared by recrystallization from methanol. mp
1
213–215ꢀC; H NMR (CD3OD) d 7.49–7.41 (m, 8 H), 7.19 (d, 2 H, J D 6.41 Hz),
4.80–4.73 (m, 1 H), 4.22 (s, 2 H), 3.44 (br d, 2 H, J D 12.36 Hz), 3.10 (br t, 2 H, J D
10.72 Hz), 2.04 (br d, 2 H, J D 13.23 Hz), 1.95 (q, 2 H, J D 7.33 Hz), 1.69–1.60 (m,
2 H), 0.96 (t, 3 H, J D 7.33 Hz); 13C NMR (CD3OD) d 175.75, 165.21, 137.99,
130.92, 129.97, 129.82, 129.60, 129.19, 128.97, 128.89, 59.97, 51.42, 49.98, 27.99,
27.31, 8.51.
Anal. Calcd for C23H28N2O5: C, 66.97; H, 6.84; N, 6.79. Found: C, 66.87; H, 6.99; N,
6.76.
Fentanyl citrate 2
N-(1-Benzylpiperidin-4-yl)-N-phenylpropionamide oxalate 1 (2.76 g, 6.15 mmol) and
ammomium formate (1.94 g, 30.08 mmol) were added to 80 mL of nitrogen sparged
methanol. 10% Palladium on carbon (0.60 g) was added and the reaction mixture was
heated at reflux for 18 h. The reaction mixture was allowed to cool to room temperature
and filtered through celite. The celite pad was washed with methanol and the filtrate was
concentrated. The residue was taken up with 75 mL of saturated aqueous sodium bicar-
bonate and 75 mL of chloroform. The organic layer was separated. The aqueous layer
was washed with chloroform (2 £ 75 mL). The combined organic extracts were dried
with sodium sulfate, filtered, and the volatiles were evaporated. To the residue was added
(2-chloroethyl)benzene (0.951 g, 6.77 mmol), sodium carbonate (2.41 g, 22.80 mmol),
potassium iodide (0.40 g, 2.41 mmol), and 50 mL of 4-methyl-2-pentanone. The mixture
was heated at reflux for 24 h. The mixture was allowed to cool to room temperature and
diluted with 50 mL each of chloroform and water. The organic layer was separated and
the aqueous mixture was with chloroform (2 £ 75 mL). The combined organic extracts
were dried with sodium sulfate, filtered, and the volatiles were evaporated. This

470
Walz and Hsu
deprotection/alkylation reaction sequence and work-up were performed again. The crude
residues were combined, dissolved in 29 mL of isopropanol, and heated in a 50ꢀC water
bath. Citric acid (2.38 g, 12.39 mmol) was added. The mixture was allowed to cool to
room temperature for 24 h. The precipitate was agitated and gently heated to provide a
solid. The solid was filtered and recrystallized from 80 mL of 25:1 isopropanol:ethanol to
provide 4.68 g of fentanyl citrate 2 in 72% yield. mp 148–150ꢀC (lit mp 149–151ꢀC)11;
1H NMR (CD3OD) d 7.50–7.42 (m, 7 H), 7.29–7.18 (m, 3 H), 4.80–4.74 (m, 1 H), 3.61
(br d, 2 H, J D 11.91 Hz), 3.22–3.18 (m, 2 H), 3.10–2.97 (m, 4 H), 2.69 (2 H, d,
J D 27.93 Hz), 2.65 (d, 2 H, J D 27.48 Hz), 2.04 (br d, 2 H, J D 12.82 Hz), 1.96 (q, 2 H,
J D 7.33 Hz), 1.78–1.69 (m, 2 H), 0.97 (t, 3 H, J D 7.33 Hz); 13C NMR (CD3OD)
d 178.11, 174.77, 173.59, 138.02, 136.72, 130.04, 129.68, 128.92, 128.59, 128.56,
126.77, 72.94, 57.44, 51.70, 50.11, 43.45, 30.07, 28.03, 27.50, 8.58.
Anal. Calcd for C28H36N2O8: C, 63.62; H, 6.86; N, 5.30. Found: C, 63.32; H, 7.14; N,
5.60.
Acknowledgments
The authors wish to thank the Defense Threat Reduction Agency Joint Science and
Technology Office (DTRA-JSTO) for their support of this work under Project #CB3662.
We would also like to thank Mr. Kenneth Sumpter for running the elemental analyses.
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