2942
T. Honda et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2939–2943
H. S.; Fukazawa, H.; Shibuya, M.; Uehara, Y. Bioorg.
Med. Chem. Lett. 2006, 5, 5127.
compounds V–IX of 4-pyridylmethyl derivatives 5–9
suggests that the major conformations of the active
derivatives 5–7, apparently shaped pseudobicyclic rings
through intramolecular hydrogen bonding/S–O non-
bonded interaction, were similar to each other, and
thus to PTK787 2. This conformation was found in
the crystal of 1 monohydrate, in which an intramolec-
ular nonbonded S–O interaction was indicated. X-ray
crystallography of an inactive 9 crystal revealed that
the conformation was very different from that of 1.
An intramolecular nonbonded interaction, such as
hydrogen bonding or S–O interaction, is a critical
structural property for compounds in this class for
the inhibition of KDR (Table 2).
8. Furet, P.; Bold, G.; Hofmann, F.; Manley, P.; Meyer, T.;
Altmann, K.-H. Bioorg. Med. Chem. Lett. 2003, 13, 2967.
9. Santen Pharmaceutical. Co. Ltd Patent WO04/78723.
10. Synthesis of 10: To the mixture of methyl salicylate
(9.48 g, 62.2 mmol), 4-chloropyridine hydrochloride
(10.2 g, 62.2 mmol), and N,N-dimethylformamide
(100 ml), potassium carbonate (17.3 g, 125 mmol) was
added at 4 °C. The reaction mixture was stirred at rt over
night and was poured into ice water. The extract with
AcOEt (250 ml) was washed with saturated NaCl aq and
dried over anhydrous Na2SO4. The solvent was evapo-
rated and the residue was purified by silica gel column
chromatography (Hexane–AcOEt) to give the desired
alkylated product 11 (7.34 g) as a colorless solid in 49%
yield. To the solution of the above product (8.75 g,
36.0 mmol) in THF (60 ml), 1.0 M NaOH aq (108 ml,
108 mmol) was added at 4 °C and the mixture was stirred
at rt for 2 h. After the addition of 1.0 M HCl aq (100 ml,
100 mmol) to the mixture, the insoluble material was
filtered out and the filtrate was concentrated in vacuo.
Carboxylic acid 10 (6.87 g) was obtained as a colorless
solid in 83% yield.
Acknowledgments
We greatly thank Shouhei Katao of Nara Institute of
Science and Technology for X-ray crystallographic
analyses of compounds 1 (monohydrate) and 9. Also,
we thank Dr. Ken-ichi Fujimura and Dr. Koushi Fujis-
awa of the Research and Development Center at San-
ten Pharmaceutical Co. Ltd for their helpful
suggestions.
Synthesis of 8: To the mixture of 10 (1.00 g, 4.36 mmol),
p-chloroaniline (612 mg, 4.80 mmol), N,N-diisopropylethy-
amine (1.69 g, 13.1 mmol), and N,N-dimethylformamide
(30 ml), 1-[bis(dimethylamino)methylene]-5-chloro-1H-
benzotriazolium-3-oxidehexafluorophosphate (HCTU,
3.61 g, 8.72 mmol) was added at 4 °C. The reaction
mixture was stirred at rt over night. The mixture was
diluted with AcOEt (40 ml), and then 0.1 M NaOH aq
(60 ml, 6.0 mmol) was added to it. The resulting colorless
solid was filtered and dried in vacuo. Anilide 8 (963 mg)
was obtained as a colorless powder in 65% yield.
Supplementary data
Supplementary data associated with this article can be
Synthesis of 9: After refluxing the mixture of 8 (501 mg,
(660 mg,
1.48 mmol),
phosphorous
pentasulfide
1.48 mmol), and chlorobenzene (40 ml) for 2 h, the mix-
ture was cooled to rt and diluted with N,N-dimethylform-
amide (40 ml). Saturated NaHSO4 aq (100 ml) was added
to the mixture. The AcOEt layer of the mixture was dried
over anhydrous Na2SO4, and then the solvent was
removed by evaporation. The residue was purified by
NH silica gel column chromatography (Hexane–AcOEt)
to give thioamide 9 (57.5 mg) as a yellow solid in 11%
yield.
References and notes
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