solution (47 °C) of potassium hydroxide (158.2 g, 2.39 mol) in
methanol (1.343 kg) at 16-19 °C. The resulting pale-yellow
solution was warmed slowly to 65 °C over 1.5 h and maintained
at this temperature for 2 h. The mixture was cooled to 35 ( 3
°C and concentrated at this temperature to a hazy, viscous oil.
Heptane (926 g) and water (2.5 kg) were added and stirred for
15 min (pH ≈ 8.5). The pH of the mixture was adjusted to pH
10.5 by adding potassium carbonate (20 g) and water (100 g),
the aqueous layer was separated, and the organic layer contain-
ing the starting material 16 was washed with water (100 g) and
saved for recycling. The combined aqueous layers were
extracted with heptane (686 g), and the aqueous layer was
saturated with sodium chloride (250 g), followed by the addition
2.34 kg of tert-butyl methyl ether. The pH of the mixture was
adjusted to 5.5 by adding conc. hydrochloric acid (209 g) in
water (174 g), and the aqueous layer was separated. The organic
layer was washed with water (100 g) and concentrated at 50-71
°C under atmospheric pressure to give a viscous oil. Addition
of heptane (997 g) to the oil at 60 °C, and holding at 54 °C or
1 h, then cooling to 9 ( 3 °C over 1.5 h, followed by filtration
and drying at 60 °C (15 mbar) gave 299 g of 17 as a white
solid (a trans/cis 36/64 mixture) in 67% yield with 98.4% purity
(300 MHz, CDCl3) δ 26.32, 26.98, 27.63, 41.40, 44.71, 48.51,
49.79, 124.31, 130.26, 140.42, 145.29, 147.75, 164.02, 180.42,
208.75.
4-(8-Oxo-7,8-dihydro[1,7]naphthyridin-6-yl)cyclohexane-
carboxylic Acid (19). A mixture of 18 (0.136 kg, 0.393 mol),
ammonium acetate (303 g, 3.93 mol), and acetic acid (275 g)
was stirred until it became a thick homogeneous slurry. The
mixture was heated to 108 ( 3 °C over 40 min and stirred at
this temperature for another 12 h. The mixture was cooled to
50 °C, water (1.5 L) was added, and the mixture was cooled to
10 °C. After 1.5 h, the precipitated solids were collected by
filtration, washed with a chilled (10 ( 5 °C) mixture of water
(600 mL) and methanol (76 mL), and was dried under vacuum
(60 ( 5 °C, 25 mbar) for 14 h to afford 19 86.3 g (81% yield)
as an off-white powder and about a 93:7 mixture of the trans-
and cis-isomers (99% by HPLC); mp > 270 °C; m/z (M + 1)
273; 1H NMR (300 MHz, DMSO-d6) δ 1.34-1.54 (m, 4 H),
1.91-1.99 (m, 4 H), 2.30-2.45 (m, 1 H), 2.50-2.52 (m, 2
H); 6.33 (s, 1 H), 7.60-7.64 (m, 1 H), 8.01-8.04 (m, 1 H),
8.68-8.69 (m, 1 H), 11.47 (br s, 1 H); 13C NMR (300 MHz,
DMSO-d6) δ 25.31, 28.88, 30.56, 42.24, 98.86, 127.09, 134.79,
134.83, 140.92, 148.18, 148.54, 161.63, 176.93.
4-(8-Chloro[1,7]naphthyridin-6-yl)cyclohexanecarboxy-
lic Acid (20). A suspension of 19 (70.9 g, 0.257 mol), toluene
(770 mL), and phosphorus oxychloride (247 mL, 2.671 mol)
was heated to about 106 °C over 1 h, refluxed gently at 108 (
3 °C for 6.5 h to give a dark homogeneous mixture. The reaction
was cooled to 20 ( 3 °C over 30 min, and poured slowly into
cold (about 2 °C) water (3.03 L). The temperature was
maintained at 5 ( 3 °C for 1 h. The flask was rinsed once with
toluene (350 mL), and the rinse solution was combined with
the cooled reaction mixture. The combined mixture was stirred
at 5 ( 3 °C for 1.5 h. A solution of sodium hydroxide (413 g)
in water (413 mL) was added over 30-60 min while maintain-
ing the temperature at 5 ( 3 °C to adjust the pH of the mixture
to 3.1 ( 0.2 (end volume ∼4.7 L). The suspension was warmed
to 7 ( 3 °C over 10 min, and the solids were collected by
filtration, washed twice with water (2 × 250 mL). The solids
were dried (50 °C, 15 mbar) for 18 h to give 20 (71.1 g, 93%
yield) as a 81:19 mixture of the trans- and cis-isomers;: mp
213-214 °C (with decomposition); m/z (M + 1) 291; 1H NMR
(300 MHz, CDCl3) δ 1.59-1.78 (m, 4 H), 2.05-2.25 (m, 4
H), 2.30-2.40 (m, 1 H), 2.65-2.90 (m, 1 H), 7.35 (s, 1 H),
7.55-7.59 (m, 1 H), 8.07 (d, J ) 1.5 Hz, 1 H), 9.02 (d, J )
1.68 Hz, 1 H), 11.02 (br s,1 H); 13C NMR (300 MHz, CDCl3)
δ 25.82, 27.96, 30.54, 41.39, 114.91, 124.78, 132.66, 134.18,
138.15, 150.74, 151.48, 158.24, 180.13.
1
by HPLC; mp: 85-87 °C; H NMR (300 MHz, CDCl3) δ
1.43-1.51 (m, 4 H), 2.08-2.10 (m, 4 H), 2.2-2.37 (m, 2 H),
3.67-3.68 (s, 3 H), 4.60-5.20 (br, 1 H).
4-[2-(2-tert-Butylcarbamoylpyridin-3-yl)acetyl]cyclohex-
anecarboxylic Acid (18). To a solution of THF (1.9 L) and
diisopropylamine (1.25 mol, 126.5 g) at -40 to -50 °C
n-hexyllithium in hexane (4.54 equiv, 2.27 mol, 645 g) was
added slowly over 30-40 min. 3-Methyl-pyridine-2-carboxylic
acid tert-butylamide (15, 0.5 mol, 96 g) in THF (300 mL) was
added while maintaining the temperature at -40 to -50 °C
over 30 min. The mixture was stirred for another 30 min and
warmed to 0-3 °C. A solution of cyclohexane-1,4-dicarboxylic
acid monomethyl ester (17, 0.644 mol, 120 g) in THF (300
mL) was added over 7-10 min. During the addition, the internal
temperature rose from about 3 °C to about 36 °C (vigorous
stirring is necessary as solids tend to separate at this stage).
Stirring was continued at this temperature for 1.5 h and then
cooled to -5 to -20 °C. Water (1.25 L) was added slowly,
and the mixture was warmed to 10-20 °C. The layers were
separated, the aqueous layer was extracted with tert-butyl methyl
ether (500 mL), and the aqueous solution was held at 20 °C
for at 8 h. Aqueous hydrochloric acid (5 N HCl, 365 mL) was
added at 10 ( 3 °C to adjust the pH to 5.8 ( 0.2. The mixture
was stirred at this pH for 30 min or until solid formation was
observed. Aqueous 6 N HCl was added slowly to reach a pH
of 5.0. The suspension was stirred at 0-5 °C for 1 h, and the
solids were collected by filtration. The solids were washed with
water (300 mL) and dried at 50 °C (25 mbar) for 14 h to give
18 (139 g, 80% yield) as an off-white powder and about a 95:5
mixture of the trans- and cis-isomers by NMR (98% by HPLC,
trans + cis); mp ≈ 160 °C; m/z (M + 1) 347; 1H NMR (300
MHz, CDCl3) δ 1.12-1.47 (m, 4 H), 1.35 (s, 9 H), 2.03-2.08
(m, 4 H), 2.20-2.25 (m, 1 H), 2.51-2.58 (m, 1 H), 4.28 (s, 2
H), 7.24-7.26 (m, 1 H), 7.40 (d, J ) 1.7 Hz, 1 H), 7.87 (b s,
1 H), 8.35 (d, J ) 1.8 Hz, 1 H), 10.5 (br s, 1 H); 13C NMR
4-[8-(3-Fluorophenyl)[1,7]naphthyridin-6-yl]cyclohexane-
carboxylic Acid (Crude 1). A solution of water (400 mL), potas-
sium carbonate (0.499 mol, 69 g), 4-(8-chloro[1,7]naphthyridin-
6-yl)cyclohexanecarboxylic acid (20, 0.2 mol, 58.2 g), 3-
fluorophenylbronic acid (7, 0.24 mol, 33.6 g), and palla-
dium(I) tri-tert-butylphosphine bromide dimer (0.809 mmol,
629 mg) was heated to 83 ( 3 °C and maintained at this
temperature for 2 h. The reaction was monitored by HPLC.
After the completion of the reaction, water (400 mL) was
added, and the mixture was extracted with tert-butylmethyl
ether (3 × 240 mL). Hydrochloric acid (700 mL, 37%) was
888
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Vol. 14, No. 4, 2010 / Organic Process Research & Development