Ugi reaction for the synthesis of 4-aminopiperidine-4-carboxylic acid derivatives. Application to the synthesis of carfentanil and remifentanil

Article abstract of DOI:10.1016/j.tetlet.2010.03.120

A two-step sequence involving an Ugi four-component reaction was developed for the preparation of 4-aminopiperidine-4-carboxylic acid derivatives. This strategy has led to the successful preparation of two drugs carfentanil and remifentanil in shorter times and better yields than previously described methods.

Full text of DOI:10.1016/j.tetlet.2010.03.120

Tetrahedron Letters 51 (2010) 2983–2985
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ugi reaction for the synthesis of 4-aminopiperidine-4-carboxylic acid
derivatives. Application to the synthesis of carfentanil and remifentanil
*
Sandra Malaquin, Mouhamad Jida, Jean-Claude Gesquiere, Rebecca Deprez-Poulain, Benoit Deprez ,
*
Guillaume Laconde
Biostructures and Drug Discovery, INSERM U761, Faculté de Pharmacie, Université Lille Nord de France, Lille F-59006, France
PRIM Pôle de Recherche Interdisciplinaire sur le Médicament, Lille F-59000, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A two-step sequence involving an Ugi four-component reaction was developed for the preparation of 4-
aminopiperidine-4-carboxylic acid derivatives. This strategy has led to the successful preparation of two
drugs carfentanil and remifentanil in shorter times and better yields than previously described methods.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 15 February 2010
Revised 24 March 2010
Accepted 30 March 2010
Available online 3 April 2010
Keywords:
Ugi reaction
Remifentanil
Carfentanil
Mumm rearrangement
In the last two decades, multicomponent reactions (MCR) have
demonstrated themselves to be very powerful in the synthesis of
natural products, as well as in combinatorial chemistry.1 The com-
bination of three or more different series of reagents allows the
straightforward construction of large libraries while accepting a
broad variety of chemical functionality.2–4 By far, most applications
of MCRs described are in the area of drug discovery where it is of-
ten crucial to access rapidly and efficiently a large diversity of
structures.5 Indeed, the ease of performance, the time-saving as-
pect, the versatility, the diversity of obtained scaffolds, and the
very large chemical space explored have urged medicinal chemists
to use MCRs. The Ugi four-component condensation (Ugi-4CC) rep-
resents a powerful method to quickly assemble in one-pot N-acyl
amino acid amides from a primary amine, a carbonyl compound,
a carboxylic acid, and an isocyanide as starting reagents.6
obtained amide hydrolyzed, the aniline acylated and finally the
acylaminoacid must be methylated. This reaction sequence is not
very powerful because
a-substituted nitriles are known to be resis-
tant to hydration.8
Also N-acylation is particularly difficult in the case of gem
disubstituted piperazines. Optimized methods for the N-acylation
and esterification steps were published for remifentanil.9 Recently,
a more efficient four-step synthesis involving a Stecker reaction
was described. However the yield of the synthesis does not exceed
25%.10
In this Letter, we show that the Ugi reaction can be a good
alternative method that uses the same ketone precursors for the
synthesis of 4-aminopiperidine-4-carboxylic acid derivatives. Ke-
tones can be indeed involved in a Ugi MCR which is synthetically
Several potent l-opioid agonists display a common 4-phenylam-
inopiperidine-4-carboxylic acid methyl ester substructure (Fig. 1).
Remifentanil is a potent ultra short-acting analgesic drug and carf-
entanil is one of the most potent opioids used in veterinary medi-
cine.7 The standard synthesis of these drugs consists of eight steps
O
O
O
R
N
N
N
OMe
OMe
OMe
O
O
O
O
among which is the preparation of a key
a-aminonitrile via Strecker
N
R
N
N
reaction. This -substituted nitrile must be hydrated and the
a
OMe
* Corresponding authors. Tel.: +33 320 964 947; fax: +33 320 964 709.
E-mail addresses: benoit.deprez@univ-lille2.fr (B. Deprez), guillaume.laconde@
univ-lille2.fr (G. Laconde).
URLs: http://www.drugdiscoverylille.org (B. Deprez), http://www.u761.lille.
inserm.fr (G. Laconde).
opioid scaffold
carfentanil
remifentanil
-agonists.
Figure 1. Piperidine amino acid
l
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.120

2984
S. Malaquin et al. / Tetrahedron Letters 51 (2010) 2983–2985
Table 1
O
Entry
Concn (M)
Aniline
(equiv)
Ketone
(equiv)
Temp (°C)
Yield (%)
NH2
N
OMe
OH
1
2
3
4
5
6
7
8
9
0.125
0.125
0.125
0.125
0.125
0.05
0.2
0.125
0.2
1
1.25
2
1
1
1
1
1
1
1
1
1
1.25
2
1
1
1
1
25
25
25
25
25
25
25
55
55
27
26
22
25
24
10
50
67
82
CN
Ugi strategy
+
O
O
O
N
R
N
R
Figure 2. Synthetic strategy.
O
O
N
O
O
N
a.
O
NH2
+
NC
N
H
+
+
OH
O
N
N
H
N
O
O
1
H+
N
N
N
N
1
Scheme 2. Mumm rearrangement for piperidone derivative.
Scheme 1. Formation of piperidine derivative
conditions: (a) MeOH, room temp or 55 °C, 24 h.
1 via Ugi-4CC. Reagents and
simpler and more efficient than the Strecker reaction. The Ugi reac-
tion is especially interesting because it can be completed fast and
without side-products. This is attributed to the high energy con-
tent of the isocyanide and to the stability of the product formed
which contains two amide bonds. Due to subsequent irreversibility
of this isocyanide addition reaction there is no asymmetric version
of the Ugi reaction.3 This can be an issue when the target com-
O
O
a
N
N
N
OMe
H
O
O
N
N
pound is a chiral
a amino-acid derivative. In these conditions,
the asymmetric versions of the Strecker reaction remain the route
of choice.11 However in the case of symmetrical 4,4-disubtituted
piperidines the Ugi reaction will demonstrate its superiority, as de-
scribed hereafter.
Our approach to synthesize carfentanil and remifentanil, in only
two steps and high yield, involves the Ugi four-component reaction
driven by 1-cyclohexenyl isocyanide (Fig. 2).12
2
1
Scheme 3. Formation of carfentanil 2 via methanolysis. Reagents and conditions:
(a) AcCl 10%/MeOH, 24 h.
The first step of the synthesis of carfentanil is the Ugi reaction
between propionic acid, aniline, 4-phenylethylpiperidone, and 1-
cyclohexenyl isocyanide (Scheme 1) in methanol for 24 h.
We designed a set of screening conditions to determine the fac-
tors that have a significant effect on the yield of the reaction: con-
centration, stoichiometry of amine and ketone, and temperature.
The results are shown in Table 1.
mino amides arising from 1-cyclohexenyl isocyanide leads to the
formation of primary amides. Then Keating and Armstrong demon-
strated that carboxylic acid or esters could be obtained from N-
acylaminoamides via the formation of münchones with water or
alcohol as nucleophile.12 The synthesis of carfentanil 2 was
achieved by methanolysis of 1 in 10% AcCl in MeOH15 at room tem-
perature for 24 h (Scheme 3), in an excellent 70% overall yield after
purification.16
We explored the utility of this procedure for the synthesis of
remifentanil (Scheme 4). The optimized conditions were applied
for the condensation of propionic acid, aniline, 3-(4-oxo-piperi-
dine-1-yl)-propionic acid methyl ester and 1-cyclohexenyl isocya-
nide. 3-(4-oxo-piperidine-1-yl)-propionic acid methyl ester was
synthesized in one step from the piperidone. The piperidone can
be synthesized from b-alanine methyl ester and 8,8-dimethyl-3-
oxo-8-azonia-bicyclo[3.2.1]octane iodide ‘IDABO’17 or by Michael
addition of methylacrylate on piperidone.10
*********
Excess of aniline or ketone failed to deliver good con-
versions (entries 2–5 vs 1). Increasing concentration to 0.2 M al-
lowed reaching 50% yield at room temperature (entry 7 vs 1 and
6). Increasing temperature to 55 °C allowed excellent yields (en-
tries 8 and 9). Precursor 1 was thus obtained in 82% yield in one
step.
The mechanism for the Ugi reaction with piperidone is depicted
in Scheme 2. The 4-anilino group at the piperidine quaternary car-
bon is particularly unreactive.13 However, in this particular situa-
tion, the acylated isoamide readily undergoes cyclization to form
the spiro[4.5]bicyclic intermediate of the Mumm rearrangement
to give the desired product 1 in mild conditions with an excellent
yield.
The a-acylamino amide 3 was successfully obtained. The meth-
anolysis of 3 was achieved and gave remifentanil 4 in quantitative
yield.18 Remifentanil was thus obtained in 67% overall yield (76%
from piperidone) as compared to 25% previously reported.
N-Cyclohexenyl amides are known in the literature to be
convertible: Rosendahl and Ugi14 found that hydrolysis of N-acyla-

S. Malaquin et al. / Tetrahedron Letters 51 (2010) 2983–2985
2985
11. Zuend, S. J.; Coughlin, M. P.; Lalonde, M. P.; Jacobsen, E. N. Nature 2009, 461,
968–970.
12. Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1995, 117, 7842–7843.
13. 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,
2534–2542.
14. Rosendahl, F. K.; Ugi, I. Ann. Chem. 1963, 666, 65–67.
15. Lin, Q.; Blackwell, H. E. Chem. Commun. 2006, 27, 2884–2886.
O
b.
N
NH2
NC
+
+
+
OH
O
N
N
H
O
O
O
N
16. Procedure for preparing 1: 1-cyclohexenyl isocyanide (47 mg, 50.2
0.44 mmol) was added to solution of propionic acid (33 mg, 32.9
0.44 mmol), aniline (41 mg, 40.1
l
l
L,
L,
3
a
l
L, 0.44 mmol), 4-phenylethylpiperidone
OMe
(90 mg, 0.44 mmol) in MeOH (2.2 mL) at room temperature and the solution
was heated at 55 °C and stirred for 24 h. The solvent was removed under
reduced pressure, and the residue was dissolved in EtOAc (5 mL). The organic
solution was washed with satd aq NaHCO3 (2 Â 2.5 mL) and brine (2.5 mL) and
dried (MgSO4), and the solvent was removed under reduced pressure. The
crude product was purified either via HPLC/MS preparative with gradient
starting from 10% MeOH/90% H2O/0.1% ammonia reaching 100% MeOH/0.1%
ammonia. The product was obtained in 82% yield (165 mg). [(M+H)] = 460
(100%) 1H NMR (CDCl3, 300 MHz): d 0.94 (t, J = 7.4 Hz, 3H), 1.20 (t, J = 6.6 Hz,
2H), 1.65 (dd, J = 32.8/5.6 Hz, 4H), 2.05 (m, 2H), 1.99–2.20 (m, 5H), 2.52–2.90
(m, 7H), 3.04 (d, J = 12 Hz, 2H), 3.68 (q, J = 7.0 Hz, 1H), 6.08 (s, 1H), 7.15–7.38
(m, 9H), 8.25 (s, 1H). 13C NMR (CDCl3, 75 MHz): d 9.33, 18.41, 21.85, 22.56,
24.23, 28.28, 30.31, 32.07, 32.78, 50.14, 59.30, 64.15, 114.09, 126.53, 128.33,
128.60, 128.63, 128.92, 129.04, 129.54, 130.28, 130.60, 132.73, 138.52, 139.41,
O
a.
OMe
c.
O
O
N
OMe
O
N
H
N
4
170.15, 176.27. Procedure for preparing 2: Acetyl chloride (133.5 mg, 121 lL,
O
OMe
1.7 mmol) was added to a solution of the compound 1 (77 mg, 0.17 mmol) in
MeOH (2.8 mL) at room temperature and the solution was heated at 55 °C and
stirred for 24 h. The solvent was removed under reduced pressure, and the
residue was dissolved in EtOAc (5 mL). The organic solution was washed with
satd aq NaHCO3 (2 Â 2.5 mL) and brine (2.5 mL) and dried (MgSO4), and the
solvent was removed under reduced pressure. The crude product was purified
either via HPLC/MS preparative with gradient starting from 10% MeOH/90%
H2O/0.1% ammonia reaching 100% MeOH/0.1% ammonia. The product was
obtained in 86% yield (59 mg). [(M+H)] = 395 (100%): 1H NMR (CDCl3,
300 MHz): d 0.96 (t, J = 7.4 Hz, 3H), 1.89 (m, 4H), 2.35 (d, J = 12 Hz, 2H), 2.80
(m, 6H), 3.07 (d, J = 12 Hz, 2H), 3.80 (s, 3H), 7.13–7.42 (m, 8H), 7.43 (m, 3H). 13C
NMR (CDCl3, 75 MHz): d 9.13, 29.11, 31.93, 49.25, 52.39, 59.12, 61.64, 126.54,
128.61, 128.65, 129.05, 129.55, 130.41, 138.83, 173.53, 174.41.
Scheme 4. Formation of remifentanil 4 via Ugi-4CC and methanolysis. Reagents
and conditions: (a) K2CO3, methyl acrylate, MeOH; (b) MeOH, 55 °C, 24 h; (c) AcCl
10%/MeOH, 24 h.
In summary, we have developed an efficient and original proce-
dure for the synthesis of carfentanil and remifentanil using the Ugi
reaction. This strategy in mild conditions is suitable for the synthe-
sis of novel structurally varied l-opioid agonists and should prove
valuable in library synthesis. As well, being straightforward, rapid
and efficient it could be used for the synthesis of radiolabeled fluo-
roalkyl derivatives of carfentanil or remifentanil.19
17. Willand, N.; Folleas, B.; Boutillon, C.; Verbraeken, L.; Gesquiere, J.-C.; Tartar, A.;
Deprez, B. Tetrahedron Lett. 2007, 48, 5007–5011.
18. Procedure for preparing 3: 1-cyclohexenyl isocyanide (117 mg, 124.9
1.0 mmol) was added to solution of propionic acid (74 mg, 74.8
1.0 mmol), aniline (93 mg, 91.2
l
l
L,
L,
a
l
L, 1.0 mmol), 3-(4-oxo-piperidine-1-yl)-
Acknowledgements
propionic acid methyl ester (186 mg, 1.0 mmol) in MeOH (5 mL) at room
temperature and the solution was heated at 55 °C and stirred for 24 h. The
solvent was removed under reduced pressure, and the residue was dissolved in
EtOAc (10 mL). The organic solution was washed with satd aq NaHCO3
(2 Â 5 mL) and brine (5 mL) and dried (MgSO4), and the solvent was removed
under reduced pressure. The crude product was purified either via HPLC/MS
preparative with gradient starting from 10% MeOH/90% H2O/0.1% ammonia
reaching 100% MeOH/0.1% ammonia. The product was obtained in 86% yield
(379 mg). [(M+H)] = 442 (100%) 1H NMR (CDCl3, 300 MHz): d 0.95 (t, J = 7.5 Hz,
3H), 1.62 (d, J = 5.4 Hz, 2H), 1.72 (d, J = 7.2 Hz, 2H), 1.91 (q, J = 7.2 Hz, 4H), 2.17
(m, 4H), 2.55 (m, 6H), 2.78 (m, 4H), 3.67 (s, 3H), 6.10 (s, 1H), 7.22 (m, 2H), 7.40
(m, 3H), 8.21 (s, 1H). 13C NMR (CDCl3, 75 MHz): d 9.36, 21.97, 22.51, 24.06,
28.16, 30.24, 31.05, 33.24, 50.01, 51.87, 52.63, 64.37, 113.89, 128.81, 129.43,
130.35, 132.74, 139.54, 170.13, 172.16, 176.16. Procedure for preparing 4:
We are grateful to the institutions that support our laboratory
(Inserm, Université de Lille2, Institut Pasteur de Lille). We thank
also the following institutions or companies: CAMPLP and Water-
s.inc for technical support. This project was supported by Conseil
Régional Nord-Pas de Calais, DRRT PRIM 2008-07 PRIM-SP.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.03.120.
acetyl chloride (26 mg, 233 lL, 3.3 mmol) was added to a solution of the
compound 3 (147 mg, 0.33 mmol) in MeOH (5.5 mL) at room temperature and
the solution was heated at 55 °C and stirred for 24 h. The solvent was removed
under reduced pressure, and the residue was dissolved in EtOAc (10 mL). The
organic solution was washed with satd aq NaHCO3 (2 Â 5 mL) and brine (5 mL)
and dried (MgSO4), and the solvent was removed under reduced pressure. The
crude product was purified either via HPLC/MS preparative with gradient
starting from 10% MeOH/90% H2O/0.1% ammonia reaching 100% MeOH/0.1%
ammonia. The product was obtained in 88% yield (94 mg). [(M+H)] = 377
(100%) 1H NMR (DMSO-d6, 300 MHz): d 0.81 (t, J = 7.2 Hz, 3H), 1.47 (m, 2H),
1.76 (q, J = 7.2 Hz, 2H), 2.05 (d, J = 13.2 Hz, 2H), 2.25 (t, J = 10.2 Hz, 2H), 2.36 (m,
2H), 2.45 (m, 2H), 3.53 (s, 3H), 3.64 (s, 3H), 7.35 (m, 2H), 7.47 (m, 3H). 13C NMR
(DMSO-d6, 75 MHz): d 9.59, 28.81, 32.06, 33.28, 49.52, 51.73, 52.24, 53.28,
62.28, 129.11, 129.86, 130.99, 139.54, 172.83, 173.27, 173.53.
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