Efficient synthesis of a selective Y5 receptor antagonist

Article abstract of DOI:10.1081/SCC-120004266

A selective Y₅ receptor antagonist, the hydrochloride of 2-methyl-4-pyrrolidinyl-6-[(E)-2-(3-trifluoromethylphenyl)-vinyl]pyridine, can be prepared in a 7-step synthesis.

Full text of DOI:10.1081/SCC-120004266

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EFFICIENT SYNTHESIS OF A SELECTIVE Y5 RECEPTOR
ANTAGONIST
Sébastien Guery a , Yveline Rival a & Camille G. Wermuth a
a Faculté de Pharmacie , Laboratoire de Pharmacochimie de la Communication Cellulaire ,
UMR 7081 CNRS/ULP , Université Louis Pasteur , 74 Route du Rhin, Illkirch, Cedex 67401,
France
b Université Louis Pasteur , Laboratoire de Pharmacochimie de la Communication Cellulaire,
UMR 7081 CNRS/ULP, Faculté de pharmacie, 74 Route du Rhin, Illkirch Cedex, 67401, France
Published online: 16 Aug 2006.
To cite this article: Sébastien Guery , Yveline Rival & Camille G. Wermuth (2002) EFFICIENT SYNTHESIS OF A SELECTIVE Y5
RECEPTOR ANTAGONIST, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 32:11, 1715-1719, DOI: 10.1081/SCC-120004266
To link to this article: http://dx.doi.org/10.1081/SCC-120004266
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SYNTHETIC COMMUNICATIONS, 32(11), 1715–1719 (2002)
EFFICIENT SYNTHESIS OF A
SELECTIVE Y5 RECEPTOR ANTAGONIST
*
Sebastien Guery, Yveline Rival, and
Camille G. Wermuth
Laboratoire de Pharmacochimie de la Communication
Cellulaire, UMR 7081 CNRS/ULP,
Universite Louis Pasteur, Faculte de pharmacie,
74 Route du Rhin, 67401 Illkirch Cedex, France
ABSTRACT
A
selective Y5 receptor antagonist, the hydrochloride
of 2-methyl-4-pyrrolidinyl-6-[(E)-2-(3-trifluoromethylphenyl)-
vinyl]pyridine, can be prepared in a 7-step synthesis.
Neuropeptide Y(NPY) is a 36 amino-acid peptide, which binds to 5
subtypes of receptors called Y1, Y2, Y4, Y5 and Y6,[1,2] and it seems to be
implicated in the physiological regulation of food intakes via the Y1 and Y5
receptors.[3–9] Particularly selective antagonists of these latter receptors
may lead structures for the design of anti-obesity drugs.[10] Some Y5
antagonists have been reported in the literature[10,11] but most of them
are inactive in vivo.[11] An exception is represented by the compound 8,
described in a patent from the Banyu Pharmaceutical Co.[10] (Scheme 1).
*Corresponding author. E-mail: Rival@pharma.u-strasbg.fr
1715
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1716
GUERY, RIVAL, AND WERMUTH
Reagents and conditions: (a) 1-(CH3)2SO4, 2-KCN, ꢀ8ꢁC (50%); (b) 90% H2SO4,
NaNO2, 91%; (c) 37% HCl, 100ꢁC, 2 h (80%); (d) Pyrrolidine, NH4Cl, 140ꢁC, 2 h;
(e) 1-SOCl2, 60ꢁC, 3 h; 2-Pyridine, CH2Cl2, H3C–NH–O–CH3, HCl (50%);
(f) DiBALH, THF, ꢀ78ꢁC (93%); (g) Trifluoromethylbenzylphosphonate,
CH3ONa, DMF, 7 h, r.t. (23%).
Scheme 1.
This compound is claimed to be active in vivo[10] and we wanted to use it
as a reference for the biologic testing of our own compounds. The
description of the synthesis of the reference compound 8 in the Banyu
patent is limited to the last step, a Wittig-Horner reaction between
6-methyl-4-pyrrolidinylpyridine-2-carboxaldehyde 7 and 3-trifluoromethyl-
benzyldiethylphosphonate.
In this paper, we describe the complete synthetic sequence leading to
compound 8 which may be useful to the pharmacologists working in the
field of NPY.
Our synthesis starts with the pyridinium N-oxide 1 which was con-
densed with potassium cyanide in a Reissert-Kaufmann reaction[12] to yield
the nitrile 2[16] which was hydrolyzed to the carboxylic acid 3.[12,17]
(Scheme 1). The N-pyrrolydinyl picolinic acid 5 was prepared starting
from 2-methyl-4-nitropicolinic acid 3 by means of two successive aromatic
nucleophilic substitutions.[13,18,19] The transformation of compound 5 in a
Weinreb amide 6, followed by reduction by means of DiBALH gave
compound 7.[13,20] The last step was a Wittig-Horner reaction between 7
and 3-trifluoromethylbenzyldiethylphosphonate; we performed it according
to the procedure in the Banyu patent.[10,14,21]
Despite the moderate yield of the last step, the present procedure
allows an efficient access to 2-methyl-4-pyrrolidinyl-6-[(E)-2-(3-trifluoro-
methylphenyl) vinyl] pyridine 8.

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SELECTIVE Y5 RECEPTOR ANTAGONIST
REFERENCES
1717
1. Ingenhaven, N.; Beck-Sickinger, A.G. Current Medicinal Chemistry
1999, 6, 1055–1066.
2. Blomqvist, A.G.; Herzog, H. Trends Neurosci. 1997, 20, 294–298.
3. Inui, A. TIPS 1999, 20, 43–46.
4. Marsh, D.J.; Hollopeter, G.; Kafer, K.E.; Palmiter, R.D. Nat. Med.
Chem. 1998, 4, 718–721.
5. Wyss, P.; Levens, N.; Stricker-Krongrad, A. Neuroreport 1998, 9,
2675–2677.
6. Gerald, C.; Walker, M.W.; Criscione, L. Nature 1996, 382, 168–171.
7. Bischoff, A.; Michel, M.C. TIPS 1999, 20, 104–106.
8. Zimanyi, I.A.; Fathi, Z.; Poindexter, G.S. Current Pharmaceutical
Design 1998, 4, 349–366.
9. Gehlert, D.R.; Hipskind, P.A. Exp. Opin. Invest. Drugs 1997, 6,
1827–1838.
10. Fukami, T.; Okamoto, O.; Fukuroda, T.; Kanatani, A.; Ihara, M.
Drugs Containing Aminopyridine Derivatives as the Active Ingredient;
Japan Patent, 1998; Banyu Pharmaceutical Co., Ltd[JP/JP], WO
98/40356, pp 1–71.
11. Kordik, C.P.; Reitz, A.B. J. Med. Chem. 1999, 42, 181–201.
12. Matsumara, E.; Masahiro, A.; Ohfuji, T. Bull. Chem. Soc. Jap. 1970,
43, 3210–3214.
13. Nahm, S.; Weinreb, S.M. Tetrahedron Lett. 1981, 22(39), 3815–3818.
14. Wadsworth, D.H.; Schupp, O.E.; Seus, E.J.; Ford, J.A. J. Org. Chem.
1965, 30, 680–685.
15. 2-Methyl-4-pyrrolidinyl-6-[(E)-2-(3-trifluoromethylphenyl)vinyl]pyridine
8. The mixture of 3-trifluoromethylbenzylphosphonate (1.57 g,
5.3 mmol, 1.2 eq.) and aldehyde 7 (840 mg, 4.42 mmol, 1 eq.) was
added dropwise to a ice-cooled solution of sodium methylate
(3.43 mg, 6.37 mmol, 1.44 eq.) in dry DMF (1.53 ml) and the mixture
was stirred for 9 h at room temperature. H2O (15 ml) was added and
the aqueous layer was extracted with Et2O (3 ꢂ 5 ml). The organic layer
was washed with a 10% citric acid solution and the combined aqueous
phases were rendered alkaline with K2CO3 and then extracted with
Et2O. After drying over Na2SO4, the organic layer was evaporated
under reduced pressure and the obtained crude compound was purified
by flash chromatography using EtOAc–MeOH: 9 : 1 with 2%(v/v)
triethylamine and 340 mg of 8 were obtained. The corresponding
hydrochloride was prepared by treating the free base dissolved in
Et2O with gaseous hydrogen chloride. The collected solid (180 mg)
was recrystallized in i-PrOH with Et2O. The global yield starting

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1718
GUERY, RIVAL, AND WERMUTH
from compound 7 is 23%. M.p. 220ꢁC (hydrochloride). Rf. 0.50
(AcOEt/MeOH 9 : 1). 1H NMR (CDCl3, 200 MHz): ꢀ 2.08 (quint,
J ¼ 3.30 Hz, 4H), 2.55(s, 3H), 3.39 (t, J ¼ 6.6 Hz, 4H), 6.22 (d,
J ¼ 1.9 Hz, 1H), 6.44 (d, J ¼ 1.9 Hz, 1H), 7.22 (d, J ¼ 16 Hz, 1H),
7.45–7.85 (m, 5H). 13C-RMN (CDCl3, 300 MHz): ꢀ ¼ 157.5, 153.5,
153.12, 137.94, 130.39, 129.26, 124.52, 123.61, 105.34, 103.68, 47.30,
25.45, 24.52. Anal. calcd for C19H19F3N2. HCl. 3 H2O: C, 59.69; H,
5.67, N, 7.33. Found: C, 59.73; H, 6.10; N, 7.26.
16. 6-Methyl-4-nitropyridine-2-carbonitrile 2. A mixture of 2-methyl-4-
nitropyridine N-oxide 1 (5 g; 32.5 mmol; 1 eq.) and dimethyl sulfate
(3.7 ml; 39 mmol; 1.2 eq.) was stirred at 70ꢁC for 1 h. The reaction
was allowed to cool to r.t. and after filtration, the mixture was con-
centrated under reduced pressure. The residue was diluted with H2O
(12.5 ml) and a solution of KCN (4.72 g) in H2O (25 ml) was added
dropwise at ꢀ8ꢁC. The mixture was allowed to warm to 0ꢁC. After
standing overnight, filtration and recrystallization in (i-Pr)2O gave
2.64 g of crystalline 2. Yield 50%. m.p. 76ꢁC (lit. 76.5–77.5ꢁC).
1H NMR (CDCl3, 200 MHz): ꢀ 2.80 (s, 3H), 8.12 (s, 1H), 8.24 (s, 1H).
17. 6-Methyl-4-nitropyridine-2-carboxylic acid 3. A solution of 6-methyl-
4-nitropyridine-2-carbonitrile 2 (2.92 g, 18 mmol, 1 eq.) in 90% H2SO4
(29.2 g) was heated for 2 h at 120ꢁC. After cooling to room tempera-
ture, a solution of NaNO2 (3.3 g) in H2O (5.82 ml) was added and the
reaction mixture was stirred for 1 h, heated at 80ꢁC for 1 h, then poured
over a mixture of H2O/ice (20 ml). The precipitate was removed by
filtration and 2.96 g of 3 were obtained as yellow crystals. Yield
91%. M.p. 127ꢁC (lit. 129ꢁC). H NMR (CDCl3, 300 MHz): ꢀ 2.83 (s,
1
3H), 8.18 (d, J ¼ 1.5 Hz, 1H), 8.73 (d, J ¼ 1.5 Hz, 1H).
18. 4-Chloro-6-methylpyridine-2-carboxylic acid 4.
A
solution of
6-methyl-4-nitropyridine-2-carboxylic acid 3 (2.96 g, 16.3 mmol, 1 eq.)
in 37% HCl (29.6 ml) was heated at 100ꢁC for 2 h. After evaporation
under reduced pressure, the residue was diluted with H2O and the
mixture was alkalinized with K2CO3 until pH ¼ 2. The solid material
was collected by filtration affording 2.2 g of compound 4. Yield 80%.
m.p. 123ꢁC (lit. 123–124ꢁC). 1H NMR (CDCl3, 200 MHz): ꢀ 2.63
(s, 3H), 4.51 (m, 1H), 7.45 (s, 1H), 8.04 (s, 1H).
19. N-methoxy-N,6-dimethyl-4-pyrrolidinylpyridin-2-carboxamide 5.
mixture of 4-chloro-6-methylpyridine-2-carboxylic acid
A
(2 g,
4
11.7 mmol, 1 eq.), pyrrolidine (1.93 ml, 23.3 mmol, 2 eq.), ammonium
chloride (11.7 mmol) in n-BuOH (42 ml) was refluxed for 16 h. The
solvent was removed by evaporation. The crude product 5 was
dissolved in SOCl2 (60 ml) and the reaction mixture was heated at
60ꢁC for 3 h. After cooling, SOCl2 was removed by distillation under

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SELECTIVE Y5 RECEPTOR ANTAGONIST
1719
reduced pressure giving a green oil. N-O-Dimethylhydroxylamine
hydrochloride (1.2 g, 12.8 mmol, 1.1 eq.) was added dropwise to a
stirred solution of the previous oil dissolved in CH2Cl2 (82 ml). The
reaction mixture was then cooled to 0ꢁC and pyridine (1.72 ml,
21.36 mmol, 2.2 eq.) was added. After stirring for 1 h, the solvent was
removed by evaporation. The residue was dissolved in water (20 ml)
and brine (10 ml) and extracted with EtOAc (3 ꢂ 5 ml). The organic
layer dried over Na2SO4 was evaporated under reduced pressure. A
yellow oil (1.5 g) of 6 was obtained after purification by flash chroma-
tography (EtOAc–MeOH: 9 : 1 with 2% (v) triethylamine). Yield 50%.
Rf. 0.23 (AcOEt/MeOH 9 : 1, TEA 2% v). 1H NMR (CDCl3,
300 MHz): ꢀ 2.01 (quint, J ¼ 3.35 Hz, 4H), 2.45 (s, 3H), 3.29–3.37 (m,
7H), 3.79 (s, 3H), 6.26 (d, J ¼ 2.2 Hz, 1H), 6.56 (m, 1H).
20. 6-Methyl-4-pyrrolidinylpyridin-2-carboxaldehyde 7. Argon was passed
for 20 min through a solution of 6 (1.2 g, 4.7 mmol, 1 eq.) in dry THF
(47.2 ml), a solution of 1 M DiBALH in THF (14.2 ml, 14.2 mmol,
3 eq.) was added dropwise under stirring to the reaction mixture cooled
until ꢀ78ꢁC. After 2 h, a solution of 5% HCl in EtOH (14 ml) was
added dropwise. The reaction mixture was allowed to warm to room
temperature and the solvents were removed under reduced pressure.
The residue was diluted with a saturated solution of K2CO3 and
extracted with EtOAc (3 ꢂ 5 ml). The organic layer was washed with
H2O (3 ꢂ 5 ml), dried over Na2SO4 and concentrated under reduced
pressure. The crude product was purified by chromatography on silica
gel eluting with a 9 : 2 (v/v) mixture of EtOAc–Heptane: 840 mg of 6
(yellow oil) were obtained. Yield 93%. Rf 0.20 (AcOEt/Heptane 9 : 2).
1H NMR (CDCl3, 200 MHz): ꢀ 2.04 (quint, J ¼ 3.30 Hz, 4H), 2.52
(s, 3H), 3.35 (t, J ¼ 4.5 Hz, 4H), 6.40 (d, J ¼ 2.5 Hz, 1H), 6.92
(d, J ¼ 2.5 Hz, 1H), 9.95 (s, 1H).
21. Cabares, J.; Mavoungou-Gomes, L. Bull. Soc. Chim. Fr. 1986, 3,
401–412.
Received in the Netherlands May 30, 2001

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