A highly convergent synthesis of 2-phenyl quinoline as dual antagonists for NK2 and NK3 receptors

Article abstract of DOI:10.1080/00397910500281234

A novel and highly convergent synthesis leading to 2-phenyl-quinolines has been developed. As demonstrated in the preparation of 6-fluoro-3-(3-oxo- piperazin-1-ylmethyl)-2-phenyl-quinoline-4-carboxylic acid [(S)-1-cyclohexyl- ethyl]-amide (8), the method

Full text of DOI:10.1080/00397910500281234

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A Highly Convergent Synthesis of 2‐Phenyl
Quinoline as Dual Antagonists for NK2 and
NK3 Receptors
Hongxing Yan a , Jeffrey K. Kerns a , Qi Jin a , Chongjie Zhu a , Mary S.
Barnette b , James F. Callahan a , Douglas W. P. Hay b , Larry J. Jolivette
c , Mark A. Luttmann b , Henry M. Sarau b , Keith W. Ward c , Katherine L.
Widdowson a & Zehong Wan a
a Department of Medicinal Chemistry, Respiratory & Inflammation Centre
of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, King of
Prussia, Pennsylvania, USA
b Department of COPD Biology, Respiratory & Inflammation Centre of
Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, King of
Prussia, Pennsylvania, USA
c Department of DMPK, Respiratory & Inflammation Centre of Excellence
for Drug Discovery, GlaxoSmithKline Pharmaceuticals, King of Prussia,
Pennsylvania, USA
Version of record first published: 20 Aug 2006.
To cite this article: Hongxing Yan, Jeffrey K. Kerns, Qi Jin, Chongjie Zhu, Mary S. Barnette, James F.
Callahan, Douglas W. P. Hay, Larry J. Jolivette, Mark A. Luttmann, Henry M. Sarau, Keith W. Ward, Katherine
L. Widdowson & Zehong Wan (2005): A Highly Convergent Synthesis of 2‐Phenyl Quinoline as Dual Antagonists
for NK2 and NK3 Receptors, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 35:24, 3105-3112
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Synthetic Communicationsw, 35: 3105–3112, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500281234
A Highly Convergent Synthesis of 2-Phenyl
Quinoline as Dual Antagonists for NK2
and NK3 Receptors
Hongxing Yan, Jeffrey K. Kerns, Qi Jin, and Chongjie Zhu
Department of Medicinal Chemistry, Respiratory & Inflammation Centre
of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals,
King of Prussia, Pennsylvania, USA
Mary S. Barnette
Department of COPD Biology, Respiratory & Inflammation Centre
of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals,
King of Prussia, Pennsylvania, USA
James F. Callahan
Department of Medicinal Chemistry, Respiratory & Inflammation Centre
of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals,
King of Prussia, Pennsylvania, USA
Douglas W. P. Hay
Department of COPD Biology, Respiratory & Inflammation Centre
of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals,
King of Prussia, Pennsylvania, USA
Larry J. Jolivette
Department of DMPK, Respiratory & Inflammation Centre of Excellence
for Drug Discovery, GlaxoSmithKline Pharmaceuticals,
King of Prussia, Pennsylvania, USA
Received in the USA June 30, 2005
Address correspondence to Zehong Wan, Department of Medicinal Chemistry,
Respiratory & Inflammation Centre of Excellence for Drug Discovery, GlaxoSmith-
Kline Pharmaceuticals, 709 Swedeland Road, P.O. Box 1539, King of Prussia, PA
19406, USA. E-mail: zehong_2_wan@gsk.com
3105

3106
H. Yan et al.
Mark A. Luttmann and Henry M. Sarau
Department of COPD Biology, Respiratory & Inflammation Centre
of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals,
King of Prussia, Pennsylvania, USA
Keith W. Ward
Department of DMPK, Respiratory & Inflammation Centre of Excellence
for Drug Discovery, GlaxoSmithKline Pharmaceuticals,
King of Prussia, Pennsylvania, USA
Katherine L. Widdowson and Zehong Wan
Department of Medicinal Chemistry, Respiratory & Inflammation Centre
of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals,
King of Prussia, Pennsylvania, USA
Abstract: A novel and highly convergent synthesis leading to 2-phenyl-quinolines has
been developed. As demonstrated in the preparation of 6-fluoro-3-(3-oxo-piperazin-1-
ylmethyl)-2-phenyl-quinoline-4-carboxylic acid [(S)-1-cyclohexyl-ethyl]-amide (8),
the method provides fascile access to this class of analogues via the common
intermediate 7.
Keywords: Array approach, convergent systhesis, quinoline, COPD, NK2, NK3
The mammalian tachykinins (or neurokinins), including substance P (SP),
neurokinin A (NKA), and neurokinin B (NKB), are a family of small
peptides widely distributed in the central and peripheral neverous system.[1]
They interact to different degrees with three G-protein-coupled receptors
known as NK1, NK2, and NK3 and have been proposed to play key roles in
a wide range of central nervous system (CNS) and peripheral disorders
including asthma and chronic obstructive pulmonary disease (COPD).[2]
Several research teams have published either selective[2] or nonselective[3]
antagonists of the NK1, NK2, and NK3 receptors for the treatment of these
conditions. The 2-phenyl-quinolines (I, Scheme 1) were disclosed previously
as combined NK2/NK3 receptor antagonists;[4] however, very limited vari-
ations at C2 of the template were explored. To further expand the structure
activity relationship (SAR) around this position, a large number of
analogues with aryl or heteroaryl groups (e.g., II: R1 ¼ aryl/heteroaryl) at
C2 were sought. This posed a challenge when using the previous synthetic
routes for this class of molecules because of the need to install the C2 substi-
tuents early in the syntheses and the lengthy synthetic steps leading to the
target compounds.[4] Fascile access to these analogues might be achieved
via a convergent approach (for reviews of convergent synthesis and array
approach, see Ref.[5]) where various substituents are introduced at C2 of a

Synthesis of 2-Phenyl Quinoline
3107
Scheme 1.
common intermediate (e.g., III) in the last step of a synthetic sequence. Our
long-standing interest in developing convergent syntheses for SAR studies
has prompted us to design a synthetic pathway meeting these requirements.[6a]
This article reports a novel and highly convergent synthesis furnishing
2-phenyl-quinolines II (e.g., II: R1 ¼ Ph).
Our approach started with the synthesis of the 2-chloro-quinoline 7
(Scheme 2), a key intermediate for generating various C2 analogues because
of its potential reactivity in transition-metal-mediated cross-coupling
reactions. The synthesis commenced with acid 1, which was readily
prepared from 5-fluoroisatin.[7] Treatment with oxalyl chloride completed
two conversions: quinolinone to 2-chloro-quinoline and acid to acid
chloride. The resultant acid chloride was reacted with (S)-1- cyclohexyl-ethyl-
amine to afford the amide 2. Our next goal was the installation of piperazin-2-
one through the displacement of 3-bromomethyl (or chloromethyl)-quinoline
(e.g., 3), a compound we thought could be prepared via reaction with N-bromo-
succinimide (NBS) (or N-chlorosuccinimide [NCS]). Much to our surprise, no
reaction was observed under either radical or photochemically initiated
Scheme 2.

3108
H. Yan et al.
conditions and only the starting material was isolated from the reaction. The
poor reactivity of this substrate may be related to the electron-withdrawing
nature of the C2 chloride and could be improved by converting to an
electron-donating group (e.g., –OMe) at the C2 position. For this purpose,
reaction of the 2-chloro-quinoline 2 with methanol provided the 2-methoxy-
quinoline 4. Radical bromination of 4 with NBS furnished the 3-bromo-
methyl-quinoline 5 in good yield. Subsequent treatment with oxalyl chloride
then reinstalled the chlorine at C2 along with the conversion of the C3 bromo-
methyl group to a C3 chloromethyl group, providing compound 6 presumably
through halogen exchange. Selective displacement of the C3 chloride with
piperazin-2-one then afforded the 2-chloro-quinoline 7.
With the key intermediate 7 in hand, we were ready to investigate the intro-
duction of C2 substituents. Phenylboronic acid was studied as a model system
to discover general reaction conditions for the desired transformation.
Microwave-assisted Suzuki cross-coupling reaction under Pd(PPh3)4
catalysis (Entry 1, Table 1), a condition suitable for a heterocyclic
chloride,[6b] was employed at first and furnished the desired product 8 in
modest yield (32%). A significant amount of the quinolinone 9 was
produced, the likely result of hydrolysis of the C2-chloride. (Compounds 9
and 10 were not isolated. Their structure was consistent with molecular
weight [LC-MS]). Cross-coupling reactions under anhydrous conditions did
not afford any of the side product 9 (Reactions were carried out under the
same conditions as entry 1 except solvent [dioxane] and base [K2CO3,
t-BuOK or n-BuLi]), however, diminished yields of the desired product 8
and recovered starting material 7 resulted even after prolonged heating. This
Table 1. Suzuki cross-coupling reactions of 7 with phenylboronic acid
Component relative ratioa
Yield of
Entry
Catalyst
Base
8
9
10
7
isolated 8
1
2
3
4
5
Pd(PPh3)4
POPd1
POPd2
POPd
K2CO3
K2CO3
K2CO3
K2CO3
n-BuLi
1.00
1.00
1.00
1.00
1.00
1.05
0.25
0.15
0.20
0.10
—
—
1.25
0.20
—
32%
15%
26%
44%
70%
0.25
0.15
0.20
0.10
POPd
—
aBased on HPLC measurements of the crude reaction mixture relative to 8 after
heated with a microwave for 15 min at 1508C.

Synthesis of 2-Phenyl Quinoline
3109
suggested the C2 chloride in 7 was not as reactive as that in the unsubstituted
2-chloro-quinoline, for which numerous cross-coupling reactions have been
reported (For recent examples of Suzuki cross-coupling reactions with aryl
boronic acids, see Ref.[8a–d], transition-metal-mediated cross-coupling
reactions with aryl Grinard reagents, see Ref.[8e–h], Stille cross-coupling
reactions with aryl Stille reagents, see Ref.[8i]). In light of recent reports[9]
that catalysts such as POPd, POPd1, and POPd2 have demonstrated superior
efficiency in the coupling reactions of deactivated aryl chlorides with aryl
boronic acids, we were interested in evaluating these catalysts for our trans-
formations (Entries 2–4, Table 1). (POPd, POPd1 and POPd2 were
purchased from Combiphos Catalysts, Princeton, NJ. POPd ¼ dihydrogen
dichlorobis[di-tert-butyl phosphinito-kP]palladate[2-], POPd1 ¼ dihydrogen
di-m-chlorotetraskis-[di-tert-butylphosphinito-kP]dipalladate[2-],
dihydrogen di-m-chlorodichlorobis[di-tert-butylphosphinito-kP]dipalladate
POPd2 ¼
[2-]). Experimental results showed that the desired product 8 had been formed
with all three catalysts along with two side products: 9 from hydrolysis and 10
arising via reduction of the C2 chloride. The reaction mediated by POPd
enjoyed the fastest rate and the best yield, which was further improved to 70%
when the catalyst was pretreated with n-BuLi (Entry 5, Table 1) (Pd[0] was
generated upon the treatment with a base, and we propose that it participates
in the catalytic cycle [see Ref. 10]. Pd[0] might be produced in situ more
rapidly and more efficiently when treated with n-BuLi, a method reported to
prepare Ni[0] in situ from NiCl2 L ([L ¼ dppf, 2PPh3][10]).
.
In summary, a novel and highly convergent synthesis of 2-phenyl-
quinoline as combined antagonists for the NK2 and NK3 receptors was
developed (e.g., 8). Noteworthy is the efficiency of the combination POPd/
n-BuLi for Suzuki cross-coupling reactions of a relatively unreactive
heteroaryl chloride.
EXPERIMENTAL
Commercially available reagents were purchased and used as supplied, unless
stated otherwise. Mass spectra were collected on an LCMS system using a
Sciex API 150EX instrument [1 ꢀ 40 mm Aquasil (C18) column, gradient
4.5%–90% acetonitrile–water (0.02% TFA) over 3.2 min, detection by
1
mass, UV at 214 nm, and evaporative light scattering]. H NMR (hereinafter
“NMR”) spectra were recorded at 400 MHz using a Bruker AM 400 spec-
trometer or a Bruker Avance 400. Multiplicities indicated are s ¼ singlet,
d ¼ doublet, t ¼ triplet, q ¼ quartet, and m ¼ multiplet, and br indicates a
broad signal. Flash chromatography was run on Merck silica gel 60
(230–400 mesh). Reverse phase preparative HPLC was run using (unless
otherwise stated) a 50 ꢀ 20-mm internal diameter YMC CombiPrep ODS-A
column at 20 mL/min with a 10-min gradient from 10% CH3CN to 90%
CH3CN in H2O and a 2-min hold at 90% CH3CN in H2O at the end of each

3110
H. Yan et al.
run. Microwave reactions were conducted in a Smith Creator manufactured by
Personal Chemistry.
2-Chloro-6-fluoro-3-methyl-quinoline-4-carboxylic acid [(S)-1-cyclohexyl-
ethyl]-amide (2). Oxalyl chloride (2.36 mL, 27.1 mmol) was added slowly to a
solution of 6-fluoro-2-oxo-1,2-dihydro-quinoline-4-carboxylic acid (2.0 g,
9.04 mmol) in CH2Cl2 (100 mL). The resultant mixture was stirred for 20 min
before DMF (2.0 mL) was added. After stirring for 60 min, the reaction mixture
was concentrated, CH2Cl2 (2 ꢀ 50 mL) was added, and the solvent was
removed under reduced pressure to provide a brownish liquid residue. This was
dissolved in THF (200 mL), and the solution was then mixed with Et3N
(2.54 mL, 18.1 mmol) and (S)-cyclohexyl-ethyl-amine (1.99 mL, 13.4 mmol).
After stirring for 30 min, all solvents were removed under reduced pressure and
the residue was mixed with H2O (50 mL). The mixture was extracted with
EtOAc (2 ꢀ 100 mL) and the combined organic phases were washed with brine
(100 mL), dried over MgSO4, filtered, and concentrated. Flash column chromato-
graphy (EtOAc–hexane, 1 : 1) then afforded 2.05 g of the title compound (65%).
1
Mp 196–1978C; LC-MS (ES) m/z 349 (M þ H)þ; H NMR (CDCl3) d 1.18
(m, 6H), 1.32 (d, J ¼ 6.7 Hz, 3H), 1.51 (m, 1H), 1.80 (m, 4H), 2.53 (s, 3H),
4.24 (m, 1H), 5.83 (s, br, 1H), 7.39 (m, 1H), 7.47 (m, 1H), 7.98 (m, 1H).
6-Fluoro-2-methoxy-3-methyl-quinoline-4-carboxylic acid [(S)-1-cyclohexyl-
ethyl]-amide (4). A solution of 2 (0.82 g, 2.35 mmol) in MeOH (16 mL) was
mixed with NaH (0.169 g, 60% dispersion in mineral oil, 4.22 mmol). The
mixture was heated at 1508C with microwave irradiation for 30 min. After
removing all solvents under reduced pressure, the residue was dissolved in
EtOAc (40 mL) and washed with H2O (2 ꢀ 20 mL), followed by brine
(30 mL). The organic phases were dried over MgSO4, filtered, and concentrated.
Flash column chromatography (EtOAc–hexane, 1 : 2) then afforded 0.73 g of the
1
title compound (90%). Mp 143–1448C; LC-MS (ES) m/z 345 (M þ H)þ; H
NMR (CDCl3) d 1.09 (m, 6H), 1.21 (d, J ¼ 6.7 Hz, 3H), 1.41 (m, 1H), 1.76
(m, 4H), 2.20 (s, 3H), 4.06 (s, 3H), 4.10 (m, 1H), 6.18 (s, br, 1H), 7.20
(m, 1H), 7.28 (m, 1H), 7.74 (m, 1H).
6-Fluoro-2-methoxy-3-bromomethyl-quinoline-4-carboxylic acid [(S)-1-
cyclohexyl-ethyl]-amide (5). A solution of 4 (0.72 g, 2.09mmol) in CCl4
(72mL) was mixed with NBS (0.74 g, 4.18mmol) and dibenzoyl peroxide
(0.076 g, 0.31mmol). The resultant mixture was heated at reflux for 3–5 h,
filtered, and concentrated. The resulting residue was dissolved in CH2Cl2
(50mL), and washed with H2O (30mL) and brine (30mL). The organic phase
was dried over MgSO4, filtered, and concentrated. Flash column chromatography
(EtOAc–hexane, 1 : 3) then afforded 0.42g of the title compound (47%). Mp
1
157–158.58C; LC-MS (ES) m/z 423 (M þ H)þ; H NMR (CDCl3) d 1.18
(m, 6H), 1.33 (d, J ¼ 6.7 Hz, 3H), 1.51 (m, 1H), 1.86 (m, 4H), 4.17 (s, 3H),
4.32 (m, 1H), 4.64 (br, 2H), 6.12 (s, br, 1H), 7.42 (m, 2H), 7.84 (m, 1H).

Synthesis of 2-Phenyl Quinoline
3111
2-Chloro-6-fluoro-3-chloromethyl-quinoline-4-carboxylic acid [(S)-1-
cyclohexyl-ethyl]-amide (6). A solution of 5 (1.0 g, 2.36 mmol) in CHCl3
(50 mL) was mixed with oxalyl chloride (2.06 mL, 23.6 mmol) and DMF
(1.0 mL). The mixture was stirred at 608C for 1 h and upon cooling was
washed with H2O (20 mL) and brine (20 mL). The organic phases were
collected, dried over MgSO4, filtered, and concentrated. Flash column chroma-
tography (EtOAc–hexane, 1 : 2.5) then afforded 0.73 g of the title compound
(80%). Mp 196–196.58C; LC-MS (ES) m/z 383 (M þ H)þ; 1H NMR
(CDCl3) d 1.11 (m, 6H), 1.27 (d, J ¼ 6.8 Hz, 3H), 1.46 (m, 1H), 1.75
(m, 4H), 4.15 (m, 1H), 4.70 (br, 2H), 6.43 (s, br, 1H), 7.35 (m, 1H), 7.49
(m, 1H), 7.94 (m, 1H).
2-Chloro-6-fluoro-3-(3-oxo-piperazin-1-ylmethyl)-quinoline-4-carboxylic
acid [(S)-1-cyclohexyl-ethyl]-amide (7). A solution of 6 (1.0 g, 2.61 mmol) in
CH2Cl2 (100 mL) and MeCN (10 mL) was mixed with Et3N (0.77 mL) and
piperazin-2-one (0.29 g, 2.89 mmol). The resultant mixture was heated to
reflux for 20 h. All solvents were then removed under reduced pressure and
the resulting residue was dissolved in EtOAc (100 mL) and washed with
H2O (50 mL) and brine (50 mL). The organic phase was collected, dried
over MgSO4, filtered, and concentrated. Flash column chromatography
(EtOAc) then afforded 0.59 g of the title compound (50%). Mp 132–
133.58C; LC-MS (ES) m/z 447 (M þ H)þ; 1H NMR (CDCl3) d 1.10
(m, 6H), 1.29 (d, J ¼ 6.8 Hz, 3H), 1.47 (m, 1H), 1.72 (m, 4H), 2.62 (s, 2H),
3.30 (s, 4H), 3.90 (m, 2H), 4.12 (m, 1H), 7.19 (s, br, 1H), 7.41 (s, br, 1H),
7.51 (m, 2H), 7.97 (m, 1H).
6-Fluoro-2-phenyl-3-(3-oxo-piperazin-1-ylmethyl)-quinoline-4-car-
boxylic acid [(S)-1-cyclohexyl-ethyl]-amide (8). A solution of POPd
(1.2 mg, 0.0022 mmol) in dioxane (1.0 mL) was treated with n-BuLi
(0.028 mL, 1.6 M in THF, 0.045 mmol) for 5 min. H2O (0.33 mL), K2CO3
(0.025 g, 0.18 mmol), 7 (20 mg, 0.045 mmol), and phenyl boronic acid
(0.011 g, 0.090 mmol) were then added to the reaction mixture. The
resultant mixture was heated with microwave irradiation at 1708C for
30 min. All solvents were then removed under reduced pressure. Reverse
phase preparative HPLC then afforded 0.016 g of the title compound (73%).
Mp 2308C; LC-MS (ES) m/z 489 (M þ H)þ; 1H NMR (CDCl3) d 1.12
(m, 6H), 1.30 (d, J ¼ 6.7 Hz, 3H), 1.49 (m, 1H), 1.75 (m, 4H), 2.45
(m, 2H), 2.95 (m, 2H), 3.15 (m, 2H), 3.82 (s, 2H), 4.25 (m, 1H), 5.79
(s, 1H), 6.88 (s, br,1H), 7.54 (m, 5H), 7.66 (m, 2H), 8.16 (m, 1H).
ACKNOWLEDGMENTS
Helpful discussions with Michael Palovich during the preparation of this
manuscript are acknowledged.

3112
H. Yan et al.
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