An efficient and cost-effective synthesis of 2-phenyl-3-aminopyridine

Article abstract of DOI:10.1021/op000227e

The synthesis of 2-phenyl-3-aminopyridine, a key intermediate in the preparation of 2-phenyl-3-aminopiperidine, from 2-chloro-3-aminopyridine is described using an imine as a protecting group for an aminopyridine. The in situ protection of 2-chloro-3-amin

Full text of DOI:10.1021/op000227e

Organic Process Research & Development 2001, 5, 254−256
Technical Notes
An Efficient and Cost-Effective Synthesis of 2-Phenyl-3-aminopyridine
Ste´phane Caron,* Steve S. Massett, David E. Bogle, Michael J. Castaldi, and Tamim F. Braish
Chemical Research and DeVelopment, Pfizer Global Research and DeVelopment, Groton, Connecticut 06340-8156
Abstract:
well as from 2-phenyl-3-aminopyridine (1).10 The literature
preparations of 1 included the low-yielding addition of phen-
yllithium to 3-aminopyridine11 and alternatively a nickel-
catalyzed coupling between a phenylzinc reagent and 2-chloro-
3-aminopyridine (2).12 Our work focused on a robust, cost-
effective, and efficient synthesis of 2-phenyl-3-aminopyridine
(1).
The synthesis of 2-phenyl-3-aminopyridine, a key intermediate
in the preparation of 2-phenyl-3-aminopiperidine, from 2-chloro-
3-aminopyridine is described using an imine as a protecting
group for an aminopyridine. The in situ protection of 2-chloro-
3-aminopyridine with benzaldehyde followed by Suzuki cou-
pling with phenylboronic acid and subsequent acid hydrolysis
provided the titled compound in a single, high-yielding step
from inexpensive and commercially available starting materials.
Discussion
Initial attempts at direct Suzuki coupling13 between
phenylboronic acid (3) and 2-chloro-3-aminopyridine (2)
proved to be unproductive. However, if the aminopyridine
was first protected as the acetamide (4),14 then the palladium-
mediated coupling proceeded efficiently with subsequent
cleavage of 5 using HCl. While this synthesis was straight-
forward, the use of the acetamide as a protecting group
resulted in a three-step process. However, it demonstrated
that Suzuki coupling of 2 could be performed with a suitable
protecting group on the aminopyridine (Scheme 1).
Introduction
3-Amino-2-phenyl-piperidine is an important pharma-
cophore present in potent non-peptidic NK1 receptor
antagonists1-4 such as CP-99,994 and GR203040 (Figure 1)
and has displayed utility as a chiral auxiliary for asymmetric
epoxidations.5
Scheme 1
Figure 1.
Syntheses of the piperidine moiety have been reported
starting from nitrobutyrate,6 2-chloro-3-nitropyridine,7-9 as
* Author for correspondence. E-mail stephane_caron@groton.pfizer.com;
telephone (860) 441-3103; fax (860) 441-3630.
(1) Desai, M. C.; Lefkowitz, S. L.; Thadeio, P. F.; Longo, K. P.; Snider, R.
M. J. Med. Chem. 1992, 35, 4911-4913.
(2) Ward, P.; Armour, D. R.; Bays, D. E.; Evans, B.; Giblin, G. M. P.; Heron,
N.; Hubbard, T.; Liang, K.; Middlemiss, D.; Mordaunt, J.; Naylor, A.; Pegg,
N. A.; Vinader, M. V.; Watson, S. P.; Countra, C.; Evans, D. C. J. Med.
Chem. 1995, 38, 4985-4992.
(3) Rosen, T. J.; Godek, D. M.; Gut, S.; Wint, L. (Pfizer Inc.). U.S. Patent
5,364,943, 1994.
(4) Congreve, M. S. Synlett 1996, 359-360.
(5) Bulman Page, P. C.; Rassias, G. A.; Bethell, D.; Schilling, M. B. J. Org.
Chem. 1998, 63, 2774-2777.
(6) Desai, M. C.; Thadeio, P. F.; Lefowitz, S. L. Tetrahedron Lett. 1993, 34,
5831-5834.
(7) Ali, N. M.; McKillop, A.; Mitchell, M. B.; Rebelo, R. A.; Wallbank, P. J.
Tetrahedron 1992, 48, 8117-8126.
The second protecting group considered was an imine.
The preparation of the benzophenone imine was very slow
(>3 days), whereas the reaction of 2-chloro-3-aminopyridine
(2) with benzaldehyde (6) was accomplished in high yield
overnight. The crude toluene solution was used directly for
the Suzuki coupling under standard conditions with PhB-
(OH)2 (3). The palladium-mediated coupling was very rapid
and proceeded in less than 30 min. Following an extractive,
acidic workup, a 90% yield of 1 was obtained (Scheme 2).
(8) Armour, D. R.; Chung, K. M. L.; Congreve, M.; Evans, B.; Guntrip, S.;
Hubbard, T.; Kay, C.; Middlemiss, D.; Mordaunt, J. E.; Pegg, N. A.;
Vinader, M. V.; Ward, P.; Watson, S. P. Bioorg. Med. Chem. Lett. 1996,
6, 1015-1020.
(10) Rosen, T. J. (Pfizer Inc.). U.S. Patent 5,686,615, 1997.
(11) Abramovich, R. A.; Notation, A. D. Can. J. Chem. 1960, 38, 1445-1448.
(12) Miller, J. A.; Farrell, R. P. Tetrahedron Lett. 1998, 39, 6441-6444.
(13) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(14) Mikami, M.; Shinkai, S. J. Chem. Soc., Chem. Commun. 1995, 153-154.
(9) Mitchell, M. B.; Wallbank, P. J. Tetrahedron Lett. 1991, 32, 2273-2276.
254
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10.1021/op000227e CCC: $20.00 © 2001 American Chemical Society and The Royal Society of Chemistry
Published on Web 02/07/2001

Scheme 2
and the solids were filtered to afford 42.4 g (62% yield) of
N-(2-chloro-pyridin-3-yl)-acetamide (4). Mp ) 81-83 °C.
1H NMR (400 MHz, CDCl3) δ 2.23 (s, 3), 7.21 (dd, 1, J )
8.1, 4.7), 7.67 (bs, 1), 8.06 (dd, 1, J ) 4.7, 1.3), 8.66 (d, 1,
J ) 7.9). 13C NMR (100 MHz, CDCl3) δ 24.93, 123.34,
129.06, 131.89, 143.81, 144.08, 168.79. The melting point
of 1 compared to the known data in the literature.16
N-(2-Phenyl-pyridin-3-yl)-acetamide Hydrochloride (5).
To a mixture of N-(2-chloro-pyridin-3-yl)-acetamide (4) (50,0
g, 29.3 mmol), PhB(OH)2 (3) (39.3 g, 32.2 mmol), Na2CO3
(49.7 g, 46.9 mmol), in toluene (400 mL), EtOH (100 mL),
and H2O (200 mL) was added Pd(PPh3)4 (1.02 g, 0.883
mmol). The reaction mixture was heated to reflux for 8 h
and cooled to room temperature, and the layers were
separated. The aqueous layer was extracted with EtOAc (500
mL), and the organic extracts were combined and concen-
trated to a yellow solid. The crude solid was dissolved in
MeOH (500 mL), and concentrated HCl was added (10 mL).
The solution was concentrated to a low volume, and THF
(500 mL) was added. The solid was triturated, filtered, and
dried to afford N-(2-phenyl-pyridin-3-yl)-acetamide hydro-
Since the imine formation was fast, we speculated that
the benzaldehyde imine (7) formation could be accomplished
in situ under the cross-coupling conditions. Indeed, treatment
of the 2 with benzaldehyde (6) (1.01 equiv), PhB(OH)2 (3)
(1.2 equiv), and PdCl2(PPh3)2 (0.37 mol %) in a mixture of
toluene and aqueous sodium carbonate (1.2 equiv) proved
to be acceptable for production of the imine 7 (Scheme 3).
Scheme 3
1
chloride (5) (62.5 g, 86%). Mp ) 262-263 °C. H NMR
Monitoring by HPLC confirmed that the reaction was
complete within 7 h. At the end of the reaction, aqueous
HCl was added to cleave imine 8 and to bring protonated 1
into the aqueous layer. After removal of the organic layer
that contained benzaldehyde, the acidic layer was neutralized
and extracted. The desired aniline was recovered from the
(300 MHz, DMSO-d6) δ 2.52 (s, 3), 6.30 (bs, 2), 7.64-7.72
(m, 6), 7.78 (dd, 1, J ) 1.2, 8.6), 8.06 (dd, 1, J ) 1.2, 5.2).
2-Phenyl-3-aminopyridine Hydrochloride (1). To a
solution of N-(2-phenyl-pyridin-3-yl)-acetamide hydrochlo-
ride (5) (61.9 g, 24.9 mmol) in THF (100 mL) was added
concentrated HCl (100 mL). The reaction mixture was heated
to reflux overnight and concentrated to a low volume. THF
was added (2000 mL), and the volume was reduced to about
1000 mL as product started precipitating. The mixture was
cooled to 0 °C and was granulated for 2 h. The solids were
filtered to afford 2-phenyl-3-aminopyridine hydrochloride (1)
15
organic extracts and isolated as a solid in 99% yield.
Conclusions
Overall, we have developed a process for the one-pot
synthesis of 2-phenyl-3-aminopyridine (1) that is operation-
ally simple, high-yielding, robust, and amenable to multi-
kilogram scale.
1
(46.2 g, 90%). Mp ) 226-227 °C. H NMR (300 MHz,
CDCl3) δ 6.35 (bs, 3), 7.61-7.74 (m, 6), 7.82 (dd, 1, J )
1.4, 8.6), 8.05 (dd, 1, J ) 1.5, 5.4). Anal. Calcd for C11H11-
ClN2: C, 63.93; H, 5.36; N, 13.55. Found: C,63.64; H, 5.20;
N, 13.49.
Experimental Section
General. Starting materials were obtained from com-
mercial suppliers and used without further purification. Thin-
layer chromatography was performed with EM Separations
Technology silica gel F254, HPLC was performed with a
Hewlett-Packard Series 1100 using a Zorbax SB-CN column
(4.6 × 25 mm) and 60/40 CH3CN/pH 3.2 aqueous buffer
mobile phase. Melting points were measured in open
2-Phenyl-3-aminopyridine (1). To 2-chloro-3-amino-
pyridine (2) (1.06 g, 8.24 mmol) in toluene (25 mL) was
added benzaldehyde (6) (0.878 g, 8.27 mmol). The reaction
mixture was stirred at reflux in a Dean-Stark apparatus until
GC/MS analysis of the reaction mixture no longer showed
starting material. The reaction mixture was cooled to room
temperature, and the toluene solution containing benzylidene-
(2-chloro-pyridin-3-yl)-amine (7) was added to a mixture of
PhB(OH)2 (3) (1.30 g, 10.7 mmol), Na2CO3 (2.66 g, 25.1
mmol), and Pd(PPh3)4 (47 mg, 0.38mol %) in water (10 mL).
The reaction mixture was heated to 100 °C for 30 min, cooled
to room temperature, and poured into 1 N aqueous NaOH
(10 mL). The aqueous layer was removed, and the toluene
layer was extracted with 1 N aqueous HCl (2 × 15 mL).
The aqueous layer was neutralized to pH 12 with 6 N
aqueous NaOH and extracted with MTBE (2 × 20 mL). The
MTBE extracts were dried over MgSO4, filtered, and
concentrated to afford 2-phenyl-3-aminopyridine (1) as a
solid which crystallized from iPr2O (1.26 g, 90% yield). Mp
1
capillary tubes and are uncorrected. H NMR (400 MHz)
and 13C NMR (100 MHz) were measured in CDCl3 unless
otherwise indicated.
N-(2-Chloro-pyridin-3-yl)-acetamide (4). To a solution
of 2-chloro-3-aminopyridine (2) (51.4 g, 400 mmol) in CH2-
Cl2 (800 mL) at 0 °C was added Et3N (31.0 mL, 440 mmol)
followed by AcCl (62.0 mL, 440 mmol). The reaction was
allowed to warm to room temperature and was stirred
overnight. The reaction mixture was poured into H2O (800
mL), and the layers were separated. The organic layer was
treated with Darco-G-60, heated to reflux, filtered over Celite,
and concentrated to an oil. The oil was crystallized in iPr2O,
(15) Several palladium catalysts were investigated and proved to be effective,
but PdCl2(PPh3)2 was selected because of its robustness under the reaction
conditions.
(16) Couture, A.; Grandclaudon, P. Heterocycles 1984, 22, 1383-1385.
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1
) 67-68 °C. H NMR (300 MHz, CDCl3) δ 3.88 (bs, 2),
layers were allowed to separate. The organic layer was
treated with 3 N HCl (540 mL). The organic layer containing
the benzaldehyde (6) was discarded, and the aqueous acidic
layer was diluted with MTBE (500 mL) and the pH adjusted
to about 12 with 50% aqueous NaOH. The organic layer
was concentrated to an oil which crystallized upon standing
and afforded 2-pheyl-3-aminopyridine (1) (130.4 g, 99%)
having spectroscopic data identical to the procedure described
above.
7.02-7.11 (m, 2). 7.28-7.53 (m, 3), 7.67-7.71 (m, 2),
8.13-8.16 (m, 1). 13C NMR (100 MHz, CDCl3) δ 122.57,
122.96, 128.14, 128.38, 128.72, 138.54, 139.86, 139.93,
144.93. The melting point of 1 compared to the known data
in the literature.11
2-Phenyl-3-aminopyridine (1). In a 5L flask was added
toluene (1.5L), 2-chloro-3-aminopyridine (2) (100 g, 0.778
mol), PhB(OH)2 (3) (114 g, 0.934 mol), and benzaldehyde
(6) (83.4 g, 0.786 mol). The mixture was stirred at room
temperature for 10 min, and trans-dichloro(triphenylphos-
phine)palladium (II) (2.0 g, 2.8 mmol) was added. The
mixture was stirred for 15 min, and a solution of Na2CO3
(99.0 g, 0.934 mol) in water (1.5 L) was added. The biphasic
mixture was heated to reflux followed by HPLC. After 6.5
h, the mixture was cooled to room temperature, and Celite
(2.0 g) was added.. The suspension was filtered, and the
Acknowledgment
The authors would like to thank Dr. Robert W. Dugger
for helpful suggestions.
Received for review November 17, 2000.
OP000227E
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