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stirred for 30 min turning a deep golden color. This catalyst
solution was added to the reaction solution without exposure
to air. Reaction solution was heated to 60 8C for 6 h. As
completion neared, product began to precipitate out, even at
60 8C. Reaction should be assayed after 4 h, or if reaction
becomes thick with product precipitate before that time.
When boronic acid was consumed, reaction was allowed to
cool to room temperature and poured into 55 L water to
complete product precipitation. This gray slurry was filtered
and solids were collected. Filter cake was washed with
another 55 L water, then dried under partial vacuum at
40–50 8C overnight, until constant weight, to give 1.51 kg,
80% yield. NMR 1H d: 1.72 (t, JZ7.1 Hz, 3H), 4.41 (q, JZ
7.1 Hz, 2H), 7.45 (dd, JZ7.6, 4.4 Hz, 1H), 7.47 (d, JZ
8.8 Hz, 1H), 7.57(dt, JZ6.4, 2.0 Hz, 1H), 7.60 (dd, JZ8.4,
2.0 Hz, 1H), 7.65–7.68 (m, 1H), 7.71–7.77 (m, 2H), 8.53 (d,
JZ2.0 Hz, 1H), 8.64 (dd, JZ4.4, 2.0 Hz, 1H), 8.73 (s, 1H),
8.84 (dd, JZ8.0, 2.0 Hz, 1H). NMR 13C d: 14.3, 27.3, 61.2,
71.5, 113.0, 121.5, 122.8, 123.2, 126.13, 126.14, 127.6,
128.1, 130.8, 136.4, 136.9, 137.0, 138.8, 141.2, 149.1,
149.9, 152.5, 153.8, 164.8, 174.6. Hi-Res MS calcd for
C25H23N3O5: 446.1716 (MCH). Found: 446.1708 (MCH).
until constant weight to give 1.24 kg white solids, 82%
yield. The white solids were suspended in 60 L dry ethanol
in a 100 L cylindrical flask. The mixture was heated to
reflux, then allowed to cool to room temperature. The solids
were collected by filtration, washed with 5 L ethanol, and
dried in a vacuum oven at 40 8C under a nitrogen stream
until constant weight to give 1.20 kg white solids, 96%
recovery. Mp 271 8C. NMR 1H d: 0.66–0.70 (m, 2H), 0.84–
0.89 (m, 2H), 1.72 (s, 6H), 2.97–2.03 (m, 1H), 7.45–7.60
(overlapping multiplets, 4H), 7.64 (s, 1H), 7.72–7.76 (m,
2H), 8.53 (d, JZ4.3 Hz, 1H), 8.83 (d, JZ8.0 Hz, 1H), 9.05
(s, 1H), 9.76 (s, 1H). NMR 13C d: 6.5, 22.4, 27.3, 71.5,
113.5, 121.4, 122.1, 122.7, 126.11, 126.14, 127.7, 128.0,
130.7, 136.3, 136.5, 136.9, 138.8, 141.2, 148.0, 149.8,
153.0, 153.7, 165.1, 177.1. Anal. calcd for C26H24N4O4$1/2
EtOH (hemi-ethanol adduct): C, 67.63; H, 5.68; N, 11.68.
Found: C, 67.69; H, 5.28; N, 12.16.
Acknowledgements
We thank Tom Novak for his expertise in high resolution
mass spectrometry, and Andy Newell and Tony Houck for
their assistance with high pressure equipment.
2.1.6. 1-{3-[6-(1-Hydroxy-1-methylethyl)-1-oxidopyri-
din-3-yl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-
carboxylate (16). A 72 L round bottom flask was flushed
with nitrogen, fitted with thermocouple, overhead stir
paddle, and addition funnel. The flask was charged with
ester compound 0.96 kg (2.15 mol), THF 10 L, and
methanol 10 L, followed by 2 N aqueous sodium hydroxide
10 L. Reaction was allowed to stir overnight at room
temperature. Reaction was adjusted to pH 8 by addition of
1.4 L concentrated hydrochloric acid. Darco G-60 0.96 kg
(100 wt%) was added and resulting mixture was allowed to
stir for 2 h. The mixture was filtered through Solka Floc to
remove Darco resin. Concentrated hydrochloric acid was
added to the filtrate to adjust to pH 3. White precipitate was
collected by filtration. The filter cake was dried in a vacuum
oven at 40–50 8C under nitrogen stream until constant
weight to give 0.65 kg white solids, 72% yield. Mp 163 8C.
References and notes
1. (a) Souness, J. E.; Foster, M. Drugs 1998, 1, 541–553. (b)
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3. For a review, see: (a) Stanforth, S. P. In Comprehensive
Heterocyclic Chemistry II, 527; Elsevier Science: New York,
1996; pp 527–559. (b) Jacquet, J-P. ; Bouzard, D.; Di Cesare,
P.; Dolnic, N.; Massoudi, M.; Remuzon, P. Heterocycles 1992,
3412, 2301. (c) Jacquet, J.-P.; Bouzard, D.; Di Cesare, P.;
Dolnic, N.; Massoudi, M.; Remuzon, P. Heterocycles 1992,
3412, 2301. (d) Chu, D. T. W.; Fernandes, P. B.; Claiborne,
A. K.; Gracey, E. H.; Pernet, A. G. J. Med. Chem. 1986, 29,
2363. (e) Yoon, S. J.; Chung, Y. H.; Lee, C. W.; Oh, Y. S.;
Choi, D. R.; Kim, N. D.; Lim, J. K.; Jin, Y. H.; Lee, D. K.; Lee,
W. Y. J. Heterocycl. Chem. 1997, 34, 1021. (f) Chu, D. T. W.;
Claiborne, A. K. J. Heterocycl. Chem. 1990, 27, 1191.
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J.; Reider, P. J. Tetrahedron Lett. 2000, 41, 4335–4338.
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6. Song, J. J.; Yee, N. K. J. Org. Chem. 2001, 66, 605–608.
7. (a) Head, R. A.; Ibbotson, A. Tetrahedron Lett. 1984, 25,
5939–5942. (b) Scalone, M.; Vogt, P. EP 385210 A2, 1990. (c)
Najiba, D.; Carpentier, J.-F.; Castanet, Y.; Biot, C.; Brocard,
J.; Mortreux, A. Tetrahedron Lett. 1999, 40, 3719–3722.
8. (a) Bessard, Y.; Crettaz, R. Heterocycles 1999, 51, 2589–2602.
(b) Beller, M.; Magerlein, W.; Indolese, A.; Fischer, C.
Synthesis 2001, 1098–1109. (c) Albaneze-Walker, J.; Bazaral,
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1
NMR H (DMSO-d6) d: 1.59 (s, 6H), 7.70–7.74 (m, 4H),
7.85 (dd, JZ8.4, 1.8 Hz, 1H), 7.97–8.00 (m, 1H), 8.11 (br s,
1H), 8.75 (d, JZ1.8 Hz, 1H), 8.80 (dd,, JZ8.0, 1.9 Hz, 1H),
8.87 (dd, JZ4.5, 1.9 Hz, 1H), 9.03 (s, 1H). NMR 13C
(DMSO-d6) d: 27.1, 71.5, 109.4, 120.7, 123.1, 123.8, 126.0,
126.0, 128.2, 128.8, 130.4, 135.9, 136.0, 136.5, 138.6,
141.0, 150.4, 150.8, 154.2, 154.9, 165.5, 179.2. Anal. calcd
for C23H19N3O5.2H2O (dihydrate): C, 60.92; H, 5.11; N,
9.27. Found: C, 60.61; H, 4.74; N, 9.11.
2.1.7. Cyclopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-1-
oxidopyridin-3-yl]phenyl}-1,4-dihydro[1,8]naphthyri-
din-4-one-3-carboxamide (1). A 100 L cylindrical flask
was flushed with nitrogen, fitted with an addition funnel.
The flask was charged with the naphthyridone acid
derivative followed by DMF 28 L and carbonyldiimidazole
1.4 kg (4.9 mol). Reaction was allowed to stir until acid was
consumed. Cyclopropylamine 5.9 L (48.9 mol) was added
and reaction stirred overnight. Water was added to milky
reaction mixture and temperature was noted to rise to 38 8C.
The mixture was allowed to cool to room temperature, then
filtered and washed with ethanol 20 L to collect white
solids. The filter cake was dried under a nitrogen stream
9. Caron, S.; Do, N. M.; Sieser, J. E. Tetrahedron Lett. 2000, 41,
2299–2302.
10. Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002,
124, 6343–6348.