CRF ligands via Suzuki and Negishi couplings of 3-pyridyl boronic acids or halides with 2-benzyloxy-4-chloro-3-nitropyridine.

Article abstract of DOI:10.1016/S0960-894X(02)00835-1

A series of imidazo[4,5-b]pyridines with a 7-(3-pyridyl) substituent is described as high affinity CRF receptor ligands. Individual analogues were synthesized from key intermediates obtained via palladium-catalyzed coupling of 3-pyridyl zinc or boronic acid organometallic intermediates with 2-benzyloxy-4-chloro-3-nitropyridine 12.

Full text of DOI:10.1016/S0960-894X(02)00835-1

Bioorganic & Medicinal Chemistry Letters 13 (2003) 289–291
CRF Ligands Via Suzuki and Negishi Couplings of
3-Pyridyl Boronic Acids or Halides with
2-Benzyloxy-4-chloro-3-nitropyridine
Argyrios G. Arvanitis,a,* Charles R. Arnold,a Lawrence W. Fitzgerald,b,y
William E. Frietze,a Richard E. Olson,a Paul J. Gilligana and David W. Robertsona,y
aDiscovery Chemistry-Wilmington, Bristol-Myers Squibb Company, Experimental Station, Wilmington, DE 19880, USA
bCNS Diseases Research, Bristol-Myers Squibb Company, Experimental Station, Wilmington, DE 19880, USA
Received 14 June 2002; accepted 17 September 2002
Abstract—A series of imidazo[4,5-b]pyridines with a 7-(3-pyridyl) substituent is described as high affinity CRF receptor ligands.
Individual analogues were synthesized from key intermediates obtained via palladium-catalyzed coupling of 3-pyridyl zinc or
boronic acid organometallic intermediates with 2-benzyloxy-4-chloro-3-nitropyridine 12.
# 2002 Elsevier Science Ltd. All rights reserved.
In a previous communication we described a 7-phenyl-
imidazo[4,5-b]pyridine series as potent CRF receptor
ligands.1 Several of these compounds had high affinity
(Kiꢀ1 nM) for the rat CRF receptor, as well as good
pharmacokinetic parameters. In general, these compounds
were rather lipophilic with limited water solubility, and
introduction of a pyridine ring in the place of the phenyl
substituent was pursued to improve these properties.
A 3-pyridyl ring can be accommodated in that position
without loss of affinity, as has been demonstrated in
the corresponding purine series, where the phenyl and
3-pyridyl analogues were equipotent (Fig. 1, compounds
II and III).2
Figure 1. Activity of an imidazo[4,5-b]pyridine (in nM) compared to
purines with and without a 3-pyridyl.
In the case of 3-iodo-6-methoxy-2-trifluoro-methyl-
pyridine 10,4 attempts to effect Li–I exchange, followed
by ZnCl2, were unsuccessful under standard conditions
(nBuLi, sBuLi, and tBuLi), presumably because of the
instability of the lithiated species that was generated.
Similar attempts with the corresponding bromide were
also unsuccessful. However, treatment of the iodide 10
with commercial Rieke Zn1, followed by Pd(PPh3)4
catalyzed coupling to 12 afforded 1c in good yield.5
Negishi or Rieke Zn1 conditions were not successful in
coupling the 5-bromo- or 5-iodo-2-methoxy-4-methyl
pyridine with 12.6 5-Bromo-2-methoxy-4-methyl pyri-
dine 8 was converted to the corresponding 5-boronic
acid 11 by treatment with nBuLi, followed by isopropyl
borate,7 then acidic aqueous workup. Compound 11
was coupled with 12, under Suzuki coupling conditions8
to give 1a.
In order to synthesize and evaluate these analogues of I
we needed to develop a synthesis for the new pyridyl key
4-(3-pyridyl)pyridine intermediates 1 which is described
in Scheme 1. Because of the reactivity of 2-halo pyri-
dines toward nucleophilic substitution we decided to
introduce (2-methyl-6-methoxy) and (2-trifluoromethyl-
6-methoxy)-3-pyridyl substituents as phenyl replacements.
3-Bromo-6-methoxy-2-methylpyridine 9 was coupled
with 12 under Negishi coupling conditions3 to give 1b.
*Corresponding author. Tel.: +1-302-467-5804; fax: +1-302-467-
6705; e-mail: argyrios.arvanitis@bms.com
yPresent address: Pharmacia.
0960-894X/03/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00835-1

290
A. G. Arvanitis et al. / Bioorg. Med. Chem. Lett. 13 (2003) 289–291
ꢂ
.
Scheme 1. (a) B(OiPr)3, nBuLi, ꢁ90 C; HCl; (b) 2-BzlO-4-Cl-3-NO2-pyridine (12), Pd(PPh3)2Cl2, Ba(OH)2 8H2O, DME/water, reflux 18 h;
(c) nBuLi, THF, ꢁ78 ꢂC; ZnCl2; (d) 12, reflux; (e) Rieke Zn1, THF, 12, 25 ꢂC; Pd(PPh3)4, reflux.
Scheme 2. (a) TFA, 25 ꢂC, 2 h; (b) POCl3, reflux, 4 h; (c) RNH2, MeCN, 80 ꢂC sealed vial, 48 h; (d) Na2S2O4, NH4OH, dioxane/water, 25 ꢂC, 18 h;
(e) EtCO2H, reflux, 48 h; (f) EtCO2H, EtC(OEt)3, reflux, 18 h; (g) EtCO2H, toluene, reflux, 18 h.
The general synthetic route for the synthesis of the tar-
get analogues is described in Scheme 2. The key inter-
mediates 2-benzyloxy-3-nitro-4-(3-pyridyl)pyridines 1
were deprotected in TFA to give the pyridones 2, which
were converted to the corresponding chloropyridines 3
in refluxing POCl3. In one case, the formation of
dichloropyridine 4 was observed as a contaminant due
to cleavage of the methyl ether and subsequent conver-
sion of the pyridone to the chloropyridine. Intermediates
3 were reacted with the appropriate primary branched
amines to give compounds 5, which were reduced with
Na2S2O4 and cyclized to the imidazo[4,5-b]pyridines 7.
Table 1. Biological data of 30-pyridyl analoguesb
a
Compd
R1
R2
R3
R4
Ki
(nM)
7a
7b
7c
7d
7e
7f9
7g10
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
–CH(Me)Pr
–CH(Me)Et
–CH(cPr)Et
–CH(cBu)Me
–CH(C2H4OMe)Et
–CH(Me)Pr
–CH(Me)Pr
–CH(Me)Pr
–CH(cPr)Et
–CH(Me)Pr
–CH(cPr)Me
–CH(cBu)Me
–CH(Me)Et
–CH(cPr)Et
–CH(Me)Pr
–CH(cPr)Et
–CH(Me)Pr
–CH(Me)Pr
OMe
OMe
OMe
OMe
OMe
OH
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
0.6
0.7
0.7
0.8
Binding affinities of various analogues synthesized are
listed in Table 1. Data on Table 1 indicate that several
analogues possess high affinity. Generally analogues
with the 20-trifluoromethyl group (7a–7e) are more potent
than the corresponding analogues with a 20-methyl group
(7i–7m). O-Demethylation led to diminished affinity (7f
and 7q) which was not recovered with introduction of a
large substituent (7g). The affinity could be increased by
reduction of the ester functionality to the corresponding
alcohol (7h). Generally affinity of the 20-methyl ana-
logues (7i–7m) seemed to be more sensitive to the alkyl
substitution (R1) than the 20-trifluoromethyl analogues
and the 1-cyclopropylpropyl chain was optimal (7i). On
the 60-position the methoxy substituent was optimal, since
replacing it with chloro- or N,N-dimethyamino led to
compounds of lower affinity (7n and 7p, respectively).
1.6
602
1045
10.1
0.7
1.1
2.0
2.1
9.2
3.3
6.6
OCH2CO2Et
OC2H4OH
OMe
OMe
OMe
OMe
OMe
Cl
Cl
NMe2
OH
OMe
7.5
>10,000
17.1
a-helical CRF9-41
7.6
aRacemic mixtures unless otherwise indicated.
bValues are means of two or more experiments. Receptor binding affinity for all
compounds was determined using rat cortical homogenates.

A. G. Arvanitis et al. / Bioorg. Med. Chem. Lett. 13 (2003) 289–291
291
Finally the 40-methyl analogue (7r) had significantly lower
affinity than the corresponding 20-methyl analogue (7j).
The commercially available 2-chloro-6-methoxy-3-nitropyr-
idine 13 (14.83 g, 78.06 mmol) was heated with CuI (18.74 g,
95.23 mmol), KF (5.51 g, 95.25 mmol) and ClF2CO2Me (18.72
mL, 181.48 mmol) in 74 mL DMF at 125–130 ꢂC for 5 h. After
cooling it was poured into a 1:9 mixture of NH4OH/NH4Cl (300
mL), stirred until homogeneous and extracted with EtOAc
(3ꢃ250 mL). The organic extracts were washed with brine, dried
and stripped in vacuo to give 14. These reaction conditions have
been employed for the conversion of aryl bromides and iodides to
CF3 groups (Su, D.-B.; Duan, J.-X.; Chen, Q.-Y. Tetrahedron
Lett., 1991, 32, 7689). To our knowledge, these conditions have
not been previously reported in the literature for the conversion of
a 2-Cl–3-NO2 pyridine to the 2-CF3–NO2 pyridine.
In summary, a series of 7-(3-pyridyl)imidazo[4,5-b]pyri-
dines was explored and individual compounds were
identified with high affinity for the rat CRF receptor.
Physical and biological data will be described in sub-
sequent publications.
Acknowledgements
The nitro group was reduced with Na2S2O4 and the corre-
sponding amine was converted to the iodide 15 under standard
conditions in 45% yield after column chromatography.
5. The iodide 13 (2.0 g, 6.6 mmol) was dissolved in dry THF
(11 mL) and a suspension of Rieke Zn1 in THF (9 mL, 6.86
mmol) was added. The mixture was stirred vigorously for 20
min, allowed to settle for 5 min and the supernatant was
transferred into a dry flask containing Pd(PPh3)4 (202 mg,
0.176 mmol) and 12 (858 mg, 3.36 mmol) and heated to reflux
for 24 h. The mixture was filtered through Celite, extracted
with EtOAc and the organic solution was dried and stripped in
vacuo. The product was purified by silica gel chromatography
(15% EtOAc/hexanes eluent), and crystallized from hexanes,
1.15 g, 56% yield. For other zinc-mediated couplings of 3-
iodopyridines, see: Sakamoto, T.; Kondo, Y.; Murata, N.;
Yamanaka, H. Tetrahedron Lett. 1992, 33, 5373. Sakamoto,
T.; Kondo, Y.; Murata, N.; Yamanaka, H. Tetrahedron 1993,
49, 7913.
The authors wish to thank Anne Marshall, Sue Keim,
Deborah Conklin, and Carol Krause for providing pri-
mary screen data.
References and Notes
1. Arvantis, A. G.; Rescinito, J. T.; Arnold, C. R.; Wilde,
R. G.; Cain, G. A.; Sun, J.-H.; Yan, J.-S.; Teleha, C. A.;
Fitzgerald, L. W.; McElroy, J.; Zaczek, R.; Hartig, P. R.;
Grossman, S.; Arneric, S. P.; Giligan, P. J.; Olson, R. E.;
Robertson, D. W. Bioorg. Med. Chem. Lett. 2002, 12 Update
BMCL 6255.
2. Wilde, R. G.; Klaczkiewicz, J. D.; Carter, K. L.; Gilligan,
P. J.; Olson, R. E.; Frietze, W. E.; Buckner, W. H.; Beck, J. P.;
Curry, M. A.; Robertson, D. W.; Sun, J. H.; Arneric, S. P.;
Hartig, P. R.; Fitzgerald, L. W.; Marshall, W. J. Abstracts of
Papers, 219th National Meeting of the American Chemical
Society: San Francisco, CA, 26–30 March, 2000.
6. Gray, M. A.; Konopski, L.; Langlois, Y. Synth. Commun.
1994, 24, 1367.
3. To 5-bromo-2-methoxy-6-methylpyridine (6.0 g, 29.7 mmol)
in 100 mL dry THF (ꢁ78 ꢂC) was added n-BuLi (1.6M/hex-
anes, 20.4 mL, 32.7 mmol) dropwise, via addition funnel. The
reaction was stirred 30 min and then ZnCl2 (0.5 M/THF, 59.4
mL, 29.7 mmol) was added dropwise, via addition funnel. The
reaction was warmed to 0 ꢂC, and tetrakis(triphenylphos-
phine)palladium(0) (172 mg, 0.149 mmol) and 2-beznyloxy-4-
chloro-3-nitropyridine (3.93 g, 14.85 mmol) were added. The
reaction was then heated at reflux for 5 h, after which time it
was concentrated in vacuo. The crude product was partitioned
between ethyl acetate and 1 M EDTA disodium (aq). The
ethyl acetate was washed with brine, dried and concentrated.
The residue was chromatographed on silica gel using ethyl
acetate/hexane (1:4) as eluent. 4.28 g, 12.1 mmol, 82% yield.
4. The 3-iodo-6-methoxy-2-trifluoromethylpyridine was syn-
thesized by the following scheme.
7. To 5-bromo-2-methoxy-4-methylpyridine (3.5 g, 17.3
mmol) and tri-isopropylborate (5.0 mL, 21.7 mmol) in 50 mL
dry THF (ꢁ100 ꢂC) was added n-BuLi (1.6 M/hexanes, 11.9
mL, 19.0 mmol) dropwise. The reaction was stirred at ꢁ100 ꢂC
for 1.5 h, warmed slowly to room temperature (1 h), and stir-
red 18 h. To the reaction was then added 1 N HCl and the
reaction stirred for 1 h. The pH was adjusted to 9 with NaOH,
and the mixture was extracted with ethyl acetate and ether.
The pH of the aqueous layer was then adjusted to 7, and again
extracted with ethyl acetate. All the extracts when con-
centrated contained the desired product. 2.7 g, 93% yield.
8. 2-Benzyloxy-4-chloro-3-nitropyridine (198 mg, 0.749
mmol), the pyridyl boronic acid (150 mg, 0.898 mmol), bis(tri-
phenylphosphine)palladium(II) chloride (26 mg, 0.037 mmol),
ethylene glycol dimethyl ether (2.5 mL), water (2.5 mL), and
barium hydroxide octahydrate (282 mg, 0.898 mmol) were
combined, degassed under vacuum, and heated at reflux 18 h.
To the cooled reaction was added water, which was extracted
with ethyl acetate. The ethyl acetate was washed with brine,
dried and concentrated. the residue was chromatographed on
silica gel using ethyl acetate/hexane (1:4) as eluent, yielding
105 mg, 40% yield.
9. Synthesized from 7a by treatment with 48% HBr at 110 ꢂC
for 16 h.
(a) ClCF2CO2Me, CuI, KF, DMF 130 ꢂC; (b) Na2S2O4,
NH4OH, dioxane/water, 25 ꢂC, 48 h; (c) NaNO2, HCl; KI,
water/cyclohexane.
10. Synthesized from 7f by treatment with Ag2CO3/
BrCH2CO2Et/C6H6. The regiochemistry of the 7g was estab-
lished by NOE experiments.