A facile and regioselective synthesis of rimonabant through an enamine-directed 1,3-dipolar cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2008.02.132

Rimonabant is a high-potency cannabinoid type-1 (CB₁) receptor inverse agonist that has recently been approved in the European Union as a treatment for obesity. Current methods of synthesis require several steps that have long reaction times and/or lack regioselectivity. Here we present a novel, regioselective synthesis of rimonabant though an enamine-directed 1,3-dipolar cycloaddition. In addition, we present a new and more reactive hydrazonoyl halide for the generation of the requisite nitrile imine dipole.

Full text of DOI:10.1016/j.tetlet.2008.02.132

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2789–2791
A facile and regioselective synthesis of rimonabant through
an enamine-directed 1,3-dipolar cycloaddition
Sean R. Donohue a,b,*, Christer Halldin b, Victor W. Pike a
a Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10, Rm B3 C346A,
10 Center Drive, Bethesda, MD 20892, USA
b Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-17176 Stockholm, Sweden
Received 18 January 2008; revised 22 February 2008; accepted 22 February 2008
Available online 29 February 2008
Abstract
Rimonabant is a high-potency cannabinoid type-1 (CB1) receptor inverse agonist that has recently been approved in the European
Union as a treatment for obesity. Current methods of synthesis require several steps that have long reaction times and/or lack regio-
selectivity. Here we present a novel, regioselective synthesis of rimonabant though an enamine-directed 1,3-dipolar cycloaddition. In
addition, we present a new and more reactive hydrazonoyl halide for the generation of the requisite nitrile imine dipole.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: CB1 Receptor; 1,5-Diarylpyrazole; Rimonabant; 1,3-Dipolar cycloaddition
1. Introduction
(2) is immediately treated with a substituted-phenylhydr-
azine hydrochloride in ethanol for 20 h. The crude mixture
of product hydrazones (3 and 4) are isolated by filtration,
dried under vacuum and then heated at reflux in acetic acid
for 24 h, yielding a mixture of regioisomeric pyrazoles (5
and 6).5 After column purification, 6 is hydrolyzed to the
corresponding carboxylic acid (7) under basic conditions.
In final steps, 1 or one of its cognates is formed by conver-
sion of the appropriate acid into the acyl chloride and addi-
tion of 1-aminopiperidine. Although this is an effective
method for the production of several 1,5-diarylpyrazole
CB1 receptor ligands, it has several limitations. These
include several steps with long reaction times, structural
modification limited by the few commercially available
substituted-phenylhydrazines and lack of regioselectivity.
It has long been known that 1,5-diarylpyrazoles can be
rapidly and regioselectively synthesized through a 1,3-dipo-
lar cycloaddition reaction, with the appropriate dipolaro-
phile and nitrile imine dipole (Scheme 2).9,10 However, we
have not found a reported route for 1 or its cognates
through this synthetic pathway. Here we fill-in this gap
by describing a regioselective synthesis of 1, that can be
extended to its cognates, through an enamine-directed
Cannabinoid type-1 (CB1) receptors are promising tar-
gets for the therapeutic treatment of several neurobiologi-
cal disorders. Rimonabant (AcompliaÒ or ZimultiÒ, 1),1
a selective CB1 receptor inverse agonist, has recently been
approved in the European Union (EU) for the treatment
of obesity. Its therapeutic potential may extend to the treat-
ment of addiction2 and neurodegenerative diseases.3 At
present there are only a few published routes for its synthe-
sis.4–7 The 1,5-diarylpyrazole core of 1 has been the subject
of extensive structure–activity relationship studies to define
more strictly the key structural requirements for an
improved pharmacological profile within this structural
class.8
The usual method for the synthesis of 1 and its cognates
employs a base-catalyzed reaction of the enolate of a
substituted-propiophenone with diethyl oxalate for 16 h
(Scheme 1). The resulting diketone ester lithium enolate
*
Corresponding author. Tel.: +1 301 451 3909; fax: +1 301 480 5112.
E-mail address: donohues@intra.nimh.nih.gov (S. R. Donohue).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.132

2790
S. R. Donohue et al. / Tetrahedron Letters 49 (2008) 2789–2791
Cl
Cl
Cl
O
Cl
O
NH
HN
O
OLi
O
N
O
O
N
O
+
a
b
O
O
O
O
Cl
Cl
Cl
Cl
4, major
2
3, minor
c
N
NH
O
O
O
OH
O
O
N
N
N
N
d
N
e, f
N
N
Cl
Cl
Cl
+
Cl
N
Cl
Cl
Cl
Cl
5, minor
Cl
Cl
Cl
Cl
6, major
7
1
Scheme 1. Synthesis of 1. Reagents and conditions: (a) LiHMDS, Et2O, diethyl oxalate, ꢀ78 °C; (b) 2,4-dichlorophenylhydrazine HCl, EtOH; (c) AcOH,
D; (d) KOH, MeOH; (e) SOCl2, toluene; (f) 1-aminopiperidine, TEA, DCM.
O
O
Although this method requires near stoichoimetric
amounts of air and moisture-sensitive TiCl4, it is known
to generate enamines rapidly to near completion for a
range of ketones and aldehydes. Equally important, the fol-
lowing work-up is simple and allows the crude enamine to
be used in the next step without further purification.
Hence, this was the method of choice for the synthesis
of 1 (Scheme 2). Also, the morpholine enamine derived
from 4-chlorophenylacetone yielding a 1,2-disubstituted-
propene dipolarophile (9, Scheme 3) was prepared in order
to provide additional evidence for the regioselective
outcome of our new route.
O
O
O
O
+
+ N
-
N
N
R'
R'
N
N
N
R
R
R
R''
R''
R''
Scheme 2. Synthesis of 1,5-diarylpyrazole from a 1,3-dipolar cycloaddi-
tion reaction.
1,3-dipole cycloaddition. Moreover, during the course of
this investigation we have identified a new and more reac-
tive hydrazonoyl halide for the generation of the requisite
nitrile imine dipole.
Chloro[(2,4-dichlorophenyl)hydrazono]ethyl
acetate
(10)13 is a well-known precursor for the base-catalyzed
in situ generation of a nitrile imine. Furthermore, the
resulting nitrile imine would combine with morpholine
enamine (8) to give the 1,5-diarylpyrazole base core of 1.
The hydrazonoyl chloride (10) was synthesized by treating
ethyl 2-chloro-acetoacetate with the diazonium salt of 2,4-
dichloroaniline giving an air-stable and easy to handle solid
(Scheme 4). However, this hydrazonoyl chloride has low
reactivity for in situ generation of the nitrile imine. In order
to increase reactivity of the hydrazonoyl chloride, we used
the Finkelstein reaction to exchange the chlorine atom with
an iodine atom to give 11.
2. Results and discussion
The generation of a morpholine enamine from 40-chloro-
propiophenone was a logical starting point for the forma-
tion of the requisite 1,1-disubstituted-propene enamine
dipolarophile (8, Scheme 3). This is because its electron
pairing with a corresponding nitrile imine would regioselec-
tively form the 1,5-diarylpyrazole core of 1. There are sev-
eral known routes to the synthesis of enamines. The most
attractive route for our purpose was a modification of
the procedure introduced by White and Weingarten.11,12
Indeed, in our experiments the reaction of 8 with 10 in
the presence of triethylamine (3 equiv) required raised
O
N
O
O
O
a
Cl
I
O
O
NH2
Cl
Cl
Cl
8
N
N
NH
NH
Cl
a
b
Cl
Cl
O
a
N
O
Cl
Cl
10
11
Cl
Cl
9
Scheme 4. Synthesis of hydrazonoyl halides 10 and 11. Reagents,
conditions and yields: (a) HCl, NaNO2, AcONa, ethyl 2-chloro-aceto-
acetate; (b) NaI, acetone: Yield: 92% for 11.
Scheme 3. Synthesis of enamines 8 and 9. Reagents and conditions: (a)
morpholine, DIPEA, TiCl4, toluene. Yields: 83% for 8 and 87% for 9.

S. R. Donohue et al. / Tetrahedron Letters 49 (2008) 2789–2791
2791
O
O
N
NH
O
O
O
R1
OH
O
N
N
NH
N
N
a
b
c, d
N
8
+
N
Cl
Cl
N
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
10, R1 = Cl
11
Cl
6
7
1
, R1 = I
Scheme 5. Synthesis of 1 through a 1,3-dipolar cycloaddition reaction. Reagents, conditions and yields: (a) TEA (3 equiv), DME, rt, 22%; (b) LiOH, THF,
H2O; (c) (COCl)2, DMF(cat), DCM, (d) 1-aminopiperidine, TEA, DCM, 67%.
Cl
MH-002795). Mr. S. R. Donohue was also supported with
a studentship under the NIH-Karolinska Institutet Gradu-
O
O
N
ate Training Partnership in Neuroscience.
a
N
9
Cl
+
11
Supplementary data
Cl
12
Experimental details and molecular characterization
Scheme 6. Synthesis of 12 through a 1,3-dipolar cycloaddition reaction.
Reagents, conditions and yield: (a) toluene, TEA (3 equiv), D, 11%.
1
(i.e., Mp, H NMR, 13NMR, LC–MS, GC–MS, HRMS,
and elemental analysis) are available. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2008.02.132.
temperatures (>60 °C) and gave significant discoloration of
the reaction solution. In contrast, the reaction of 8 with 11
in the presence of triethylamine (3 equiv) proceeded at
room temperature to give yields similar to that with 10 at
raised temperature (22 vs 19%) (Scheme 5). At the same
time there was very little discoloration of the reaction solu-
tion. In order to complete our synthesis of 1, the ethyl ester
of 6 was hydrolyzed to 7 under basic conditions. Then 7
was converted into the acyl chloride, to which was added
1-aminopiperidine.
References and notes
´
1. Rinaldi-Carmona, M.; Barth, F.; Heaulme, M.; Shire, D.; Calandra,
´
B.; Congy, C.; Martinez, S.; Maruani, J.; Neliat, G.; Caput, D.;
´
Ferrara, P.; Soubrie, P.; Breliere, J. C.; Le Fur, G. FEBS Lett. 1994,
350, 240–244.
2. Henningfield, J. E.; Fant, R. V.; Buchhalter, A. R.; Stitzer, M. L. CA
Cancer J. Clin. 2005, 55, 281–299.
3. Glass, M.; van Dellen, A.; Blakemore, C.; Hannan, A. J.; Faull, R. L.
Neuroscience 2004, 123, 207–212.
To provide additional evidence for the regioselective
outcome, the 1,2-disubstituted-propene enamine (9) was
treated with 11 in the presence of triethylamine (3 equiv)
(Scheme 6). This gave slightly lower yields of ring product
(11%) and also required higher temperature (90 °C).
In conclusion, we have developed a novel regioselective
approach to 1 through an enamine-directed 1,3-dipole
cycloaddition reaction. The regioselective outcome was
verified through the synthesis of the 1,4-diarylpyrazole
(12). In addition, we have developed a new, more reactive
hydrazonoyl halide precursor (11) for the in situ generation
of a nitrile imine.
4. Vayron, P.; Daumas, M.; Sole, R.; Dlubala, A. French Patent
FR2873372, 2006.
5. Seltzman, H. H.; Carroll, F. I.; Burgess, J. P.; Wyrick, C. D.; Burch,
D. F. J. Label. Compd. Radiopharm. 2002, 45, 59–70.
6. Barth, F.; Casellas, P.; Congy, C.; Martinez, S.; Rinaldi, M.; Anne-
Archard, G.; Eur. Patent EP656354, 1995.
7. Kotagiri, V. K.; Suthrapu, S.; Reddy, J. M.; Rao, C. P.; Bollugoddu,
V.; Bhattacharya, A.; Bandichhor, R. Org. Process Res. Dev. 2007, 11,
910–912.
8. Lange, J. H. M.; Kruse, C. G. Drug Discovery Today 2005, 10, 693–
702.
9. Carruthers, W. Cycloadditions Reactions in Organic Synthesis;
Pergamon Press: New York, 1990.
10. Oh, L. M. Tetrahedron Lett. 2006, 47, 7943–7946.
11. White, W. A.; Weingarten, H. J. Org. Chem. 1967, 32, 213–214.
˚
Acknowledgments
12. Carlson, R.; Nilsson, A.; Stro¨mqvist, M. Acta Chem. Scand. Ser.
B—Org. Chem. Biochem. 1983, 37, 7–13.
13. Barth, F.; Martinez, S.; Rinaldi-Carmona, M., French Patent
FR2856683, 2004.
This work was supported by the Intramural Program of
the National Institutes of Health (NIMH) (Project # Z01-