Synthesis of 4-anilinopiperidine methyl esters, intermediates in the production of carfentanil, sufentanil, and remifentanil

Article abstract of DOI:10.1016/j.tetlet.2013.11.058

Two spirodiaza intermediates have been made and employed in the synthesis of 4-anilinopiperidine methyl esters. These intermediates can be utilized in the production of commercial synthetic analgesics carfentanil, sufentanil, and remifentanil.

Full text of DOI:10.1016/j.tetlet.2013.11.058

Accepted Manuscript
Synthesis of 4-anilinopiperidine methyl esters, intermediates in the production
of carfentanil, sufentanil, and remifentanil
Andrew J. Walz, Fu-Lian Hsu
PII:
S0040-4039(13)02005-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.11.058
TETL 43853
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 October 2013
14 November 2013
16 November 2013
Please cite this article as: Walz, A.J., Hsu, F-L., Synthesis of 4-anilinopiperidine methyl esters, intermediates in the
production of carfentanil, sufentanil, and remifentanil, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/
j.tetlet.2013.11.058
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Synthesis of 4-anilinopiperidine methyl esters,
intermediates in the production of carfentanil, sufentanil, and remifentanil
Andrew J. Walz* and Fu-Lian Hsu
Research and Technology Directorate, U.S. Army, Edgewood Chemical Biological
Center (ECBC), Aberdeen Proving Ground, MD 21010-5424, United States
Abstract:
N
R N
N
O
R = Bn or CH2CH2Ph
Two spirodiaza intermediates have been made and employed in the synthesis of
4-anilinopiperidine methyl esters. These intermediates can be utilized in the production
of commercial synthetic analgesics carfentanil, sufentanil, and remifentanil.
Keywords:
Anilinopiperidine methyl esters
Cyclization
Sufentanil
Carfentanil
Remifentanil
N,N-Dimethylformamide dimethyl acetal
4-Anilidopiperidines are potent synthetic opioids employed as analgesics
worldwide.1 Janssen and coworkers have produced many potent and clinically useful
*Corresponding author. Tel.: +1-410-436-2078; fax: +1-410-436-7291; e-mail: andrew.j.walz.civ@mail.mil

compounds.2-5 A potent, short acting analog was later developed by Feldman et
al.6(Figure 1) These analgesics have been prescribed as potent sedatives for large
animals (carfentanil) and humans (sufentanil and remifentanil).
The synthesis of these compounds, as developed by Janssen, incorporated the
stepwise conversion of the C-4 nitrile of 1-benzyl-4-(phenylamino)piperidine-4-
carbonitrile to a methyl ester.(Figure 2)
The synthesis utilized a sulfuric acid-mediated nitrile conversion to an amide
followed by basic hydrolysis to a carboxylic acid. The acid was then alkylated to the
methyl ester using methyl iodide in DMSO. This methodology has been applied to both
the N1-benzyl and N1-(2-phenylethyl) substituted piperidines.

The analgesic potency of the synthetic opioids generated interest in improving
the original chemistry used to produce them. With the N1-benzyl substituted
piperidines, work was done on both the nitrile and amide functional group
transformations. The nitrile to amide conversion was accomplished using
DMSO/hydrogen peroxide.7 The conversion of the nitrile to a hydantoin as a precursor
to the carboxylic acid was accomplished.8 The C-4 carboxylic acid was formed from the
amide employing acidic conditions.9 Kiessling and McClure applied trimethyloxonium
tetrafluoroborate to the amide to form an imidate which was then converted to the
methyl ester.10 A direct conversion of the amide to the methyl ester utilizing methanolic
p-toluenesulfonic acid was reported.11
Utilization of N1-(2-phenylethyl) substituted piperidines in Figure 2 results in a
more direct synthesis of carfentanil. The Janssen reaction sequence was employed yet
was limited by a 14% isolated yield for the amide formation.3,12 Reiff and Sollman
developed an alternative amide synthesis.13 Formylation of the aminonitrile was
followed by imidate formation in methanolic HCl with concomitant formyl group
cleavage. The imidate was hydrolyzed to the amide in a 49% isolated yield for the three
step process. The DMSO/peroxide mediated amide formation has been successfully
applied in an 84% yield.14 The reaction reported was done at less than 100 milligram
scale with no spectral data reported. A similar basic peroxide reaction was reported with
a 44% yield of the amide on a multigram scale.15 As with the benzyl series, the amide
was converted to the methyl ester via a carboxyl group.
This letter reports improvements on the synthesis of 4-anilinopiperidine methyl
esters 4a,b as seen in Scheme 1. The chemistry utilizes 4,4-(2-phenyl-2,4-diaza-4-

oxo-cyclopentane)piperidines 3a,b. The literature references compound 3a but not as
an intermediate in the synthesis of 4-anilinopiperidine methyl esters.16 17,18
,
Hydrolysis of nitriles to amides utilizing trifluoroacetic acid and sulfuric acid has
also been reported.19 This methodology was applied to compounds 1a,b to provide
amides 2a,b which were purified by recrystallization from toluene. It should be noted
that the use of sodium hydroxide to neutralize the acid and hydrolyze the presumed
intermediate imidate was necessary for consistently good yields of 2b while ammonium
hydroxide could be used for the work up of 2a.
N,N-Dimethylformamide dimethyl acetal has been shown to convert amides to
methyl esters.20 When reacted with compounds 2a,b in methanol at 65°C, cyclization to
the phenyl-2,4-diaza-4-oxo-cyclopentane ring was overwhelmingly favored over methyl
ester formation. After evaporation of the volatiles, crude 3a,b were both recrystallized
from toluene. In our hands, overnight refluxing of 2a or 2b in trimethyl orthoformate
produced negligible cyclization products.

The conversion of the spirodiaza intermediate 3a to methyl ester 4a was
achieved in methanol with 1.2 to 1.4 molar equivalents of sulfuric acid at 95°C in a
pressure bottle. The same methanolysis of 3b was accomplished but was particularly
sensitive to the amount of acid utilized with 1.2 equivalents of sulfuric acid being
optimal. Increasing the amount of sulfuric acid led to extended reaction times and an
increase in unwanted side reactions. It should be noted that following an aqueous work
up, the organic extracts containing compound 4b were filtered through Celite on top of
a 10 g layer of activated basic Brockmann I alumina to decolorize the solution. Both
4a,b were purified by conversion to their oxalate salts in ethanol. A two step/one pot
conversion of 2a to 4a was attempted but generated a by-product which could not be
separated by recrystallization.
The three-step transformation of nitriles 1a,b to the methyl esters 4a,b has been
improved over the existing literature methods. The reactions were operationally simple
and no chromatographic purifications were required. No reactions were run for greater
than 16 h and none exceeded a reaction temperature of 95°C. Nitrile hydrolysis was
accomplished in good yields for both the N1-benzyl and N1-(2-phenylethyl) piperidines
using trifluoroacetic acid and sulfuric acid. While the conversion of 1a to 2a did not
distinguish itself from the existing methodology, the 78% isolated yield of 2b did
demonstrate a notable improvement. The N,N-dimethylformamide dimethyl acetal
cyclization reaction clearly improved this transformation in terms of reaction conditions
and length compared with literature precedents. The same cyclization of 2a to 3a had
been previously accomplished by an overnight amine formylation followed by a seven
day reflux in triethyl orthoformate.15 Janssen accomplished a similar cyclization with

formamide and an inorganic acid at 170°C for 12 h.16,17 Good yields were obtained with
either N1-benzyl or N1-(2-phenethyl) substituted intermediates. Finally, the
methanolysis of the 4,4-(2-phenyl-2,4-diaza-4-oxo-cyclopentane)piperidines 3a,b were
cleanly accomplished to efficiently provide the 4-anilinopiperidine methyl esters.
Supplementary Material
Experimental procedures are reported with copies of the NMR and mass spectra.
Acknowledgements
The authors would like to thank Dr. Sari Paikoff at the Defense Threat Reduction
Agency-Joint Science and Technology Office (DTRA-JSTO) for funding this work under
contract (CBCALL12-TAS-2-0130).
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