°
C, and aged for a further 60 min. The product was collected
(q, J ) 7.2 Hz, 2H), 1.26 (t, J ) 7.2 Hz, 3H); 13C NMR
(CD Cl , δ) 167.48, 153.71 (t, J ) 29 Hz), 152.02, 151.71,
by filtration, washed with toluene (17 L), and dried in vacuo
2
2
at 40 °C. Ethyl-3-hydroxypyrazin-(1H)-2-one-1-acetate (4,
149.90, 137.83, 125.77, 122.15, 120.09, 119.71 (t, J ) 243
1
0.66 kg) was obtained as a white crystalline solid in 75%
Hz), 118.15, 62.49, 50.29, 45.79 (t, J ) 29 Hz), 14.41; MS
+
yield, 94% pure, containing 6% of the free acid.
m/z 339.4 (M + H ). Anal. Calcd for C15
H F N
16 2 4
O
3
: C,
Recrystallization. The crude ethyl pyrazinone acetate (4,
0.65 kg; 53.7 mol) was slurried in absolute ethanol (106
53.25; H, 4.77; F, 11.23; N, 16.56. Found: C, 53.08; H, 4.70;
F, 11.27; N, 16.54.
1
L), and concentrated sulfuric acid (146 mL; 2.69 mol) was
added. The mixture was heated to reflux temperature, and
ethanol (53 L) was removed by distillation at atmospheric
pressure. Absolute ethanol (53 L) was added, and distillation
continued until a further 74 L of solvent had been distilled.
The batch was allowed to cool to 45 °C, and ethyl acetate
Ethyl 2-{3-[(2,2-Difluoro-2-(2-pyridyl)ethyl)amino]-6-
chloro-2-oxohydro-pyrazinyl}acetate (29). Ethyl 2-{3-
1
[(2,2-difluoro-2-(2-pyridyl)ethyl)amino]-2-oxohydro-
pyrazinyl}acetate (28, 3.22 kg; 9.53 mol) was slurried in
acetonitrile (16.15 L) and heated to 70 °C. A solution of
N-chlorosuccinimide (1.30 kg, 9.75 mol) in acetonitrile
(16.15 L) was added over 15 min. The solution was stirred
and heated at 70 °C for 1.25 h. The reaction mixture was
cooled to 25 °C, and water (73 L) was added to precipitate
the product. The batch was cooled to 5 °C and aged for 1 h,
and the product was collected by filtration. The product was
washed with water (81 L) and dried in vacuo at 45 °C. Ethyl
2-{3-[(2,2-difluoro-2-(2-pyridyl)ethyl)amino]-6-chloro-2-
oxohydro-pyrazinyl}acetate (29, 3.21 kg) was isolated as a
(64 L) was added over 30 min. The batch was cooled to 5
°C and aged for 1 h. The product was collected by filtration,
washed with cold (5 °C) ethanol/ethyl acetate (1:2, 33 L),
and dried in vacuo at 45 °C. Ethyl-3-hydroxypyrazin-(1H)-
2
-one-1-acetate (4, 9.53 kg) was obtained in 88% recovery,
1
>
99% pure, containing <0.2% free acid. Mp 132-4 °C. H
NMR (CD OD, δ) 6.53 (d, J ) 5.9 Hz, 1H), 6.40 (d, J )
.9 Hz, 1H), 4.60 (s, 2H), 4.23 (q, J ) 7.1 Hz, 2H), 1.28 (t,
3
5
13
J ) 7.1 Hz, 3H); C NMR (CD
3
OD, δ) 169.04, 158.97.
crystalline off-white solid in 90% yield, 97.5% pure. Mp
1
1
58.09, 116.09, 110.53, 63.07, 50.92, 14.55; MS m/z 197.1
101-2 °C; H NMR (CD
2
Cl
2
, δ) 8.67 (dq, J ) 0.8, 4.8 Hz,
-
(M - H ). Anal. Calcd for C
H
8 10
N
2
O
4
: C, 48.48; H, 5.09;
1H), 7.85 (td, J ) 1.8, 7.9 Hz, 1H), 7.68 (dt, J ) 1.1, 7.8
Hz, 1H), 7.42 (ddd, J ) 0.8, 4.9, 7.8 Hz, 1H), 6.93 (s, 1H),
6.48 (br t, J ) 6.2 Hz, 1H), 4.86 (s, 2H), 4.34 (dt, J ) 6.5,
14.2 Hz, 2H), 4.22 (q, J ) 7.2 Hz, 2H), 1.27 (t, J ) 7.2 Hz,
N, 14.14. Found: C, 48.35; H, 5.01; N, 14.10.
Ethyl 2-{3-[(2,2-Difluoro-2-(2-pyridyl)ethyl)amino]-2-
1
oxohydro-pyrazinyl}acetate (28). To a stirred mixture of
1
3
DMF (7.5 mL) and acetonitrile (0.075 L) in isopropyl acetate
2 2
3H); C NMR (CD Cl , δ) 167.11, 153.63 (t, J ) 28 Hz),
(
0.105 L) was added ethyl pyrazinone ester (4, 0.03 kg; 151
153.06, 152.36, 149.90, 137.89, 125.85, 121.00 (t, J ) 4
Hz), 120.82, 119.58 (t, J ) 244 Hz), 118.48, 62.65, 46.77,
44.82 (t, J ) 29 Hz), 14.41; MS m/z 373.3 (M + H ). Anal.
mmol). Oxalyl chloride (0.0215 kg; 166 mmol) was added
over 30 min, and the temperature was gradually raised to
+
35-40 °C. The solution was aged at 40 °C for 2 h, cooled
2 4
Calcd for C15H15ClF N O: C, 48.33; H, 4.06; Cl, 9.51; F,
to 20 °C, and diluted with isopropyl acetate (0.165 L). The
reaction was quenched with 15% sodium chloride solution
10.19; N, 15.03. Found: C, 48.60; H, 4.09; Cl, 9.32; F, 10.19;
N, 14.78.
(
0.15 L), and the phases were separated. The organic layer
2-{3-[(2,2-Difluoro-2-(2-pyridyl)ethyl)amino]-6-chloro-
2-oxohydropyrazinyl}-N-[(3-fluoro(2-pyridyl))methyl]-
acetamide (1). Ethyl 2-{3-[(2,2-difluoro-2-(2-pyridyl)ethyl)-
was washed with 15% sodium chloride solution (0.075 L).
The organic layer was concentrated under reduced pressure
to ca. 90 mL and flushed with acetonitrile (2 × 0.15 L).
The mixture was diluted with acetonitrile to give a final
volume of 240 mL. The assay yield of 26 was 31.5 g (96%).
To the above solution were added 2,2-difluoro-2-(2-
pyridyl)ethylamine‚BSA salt (3, 0.051 kg; 153 mmol) and
N,N-diisopropylethylamine (0.020 kg; 153 mmol). Sodium
iodide (0.044 kg; 291 mmol) was added, and the mixture
was stirred and heated at reflux for 30 h. The reaction mixture
was cooled to 20 °C, and water (0.378 L) added over 20
min. Aqueous potassium hydrogencarbonate solution (2 M,
1
amino]-6-chloro-2-oxohydro-pyrazinyl}acetate (29, 4.12 kg;
11.06 mol) was dissolved in THF (41.2 L), treated with
Darco G60 (206 g), and stirred at ambient temperature for
30 min. The mixture was filtered through Hyflo, and the
filtered solution was diluted with THF (61.0 L). 1 M KOH
(27.14 L; 27.14 mol) solution was added, and the two-phase
mixture was stirred at 40 °C for 2.25 h. HOBt (0.74 kg;
5.48 mol) and 2-amino-3-fluoropyridine‚2HCl (2, 2.65 kg;
13.3 mol) were added, and a solution of EDC‚HCl (2.70 kg;
14.08 mol) in water (9.6 L) was added over 1.5 h. The
mixture was stirred at 40 °C for 1.75 h. The batch was filtered
(1 µm cartridge, Whatman Polycap 36HD), and the equip-
ment was rinsed with water (9.6 L) and THF (9.6 L). The
mixture was cooled to 25 °C, and crystallization was
completed by the addition of water (138.0 L). The batch was
stirred at 20 °C for 2 h. The product was collected by
filtration, washed with (2 × 13.5 L), and dried in vacuo at
40 °C. The thrombin inhibitor (1, 4.53 kg) was obtained in
91% yield, >99% pure.
0
.073 L; 146 mmol) was added, and the slurry was cooled
to 5 °C and stirred for 1 h. The product was collected by
filtration, washed with acetonitrile/water (10:90, 0.36 L). and
dried in vacuo at 40 °C. Ethyl 2-{3-[(2,2-difluoro-2-(2-
pyridyl)ethyl)amino]-2-oxohydro-pyrazinyl}acetate (28, 0.044
kg) was obtained as a white crystalline solid in 85.0% yield,
>
1
99% pure from 4. Mp 105-6 °C. H NMR (CD
2
Cl
2
, δ)
8
1
.66 (dq, J ) 0.8, 4.9 Hz, 1H), 7.84 (td, J ) 1.8, 8.0 Hz,
H), 7.68 (dt, J ) 8.0, 1.11 Hz, 1H), 7.41 (m, 1H), 6.82 (d,
J ) 4.8 Hz, 1H), 6.51 (bt, J ) 5.9 Hz, 1H), 6.45 (d, J ) 4.6
Hz, 1H), 4.52 (s, 2H), 4.36 (dt, J ) 6.5, 14.3 Hz, 2H), 4.21
Recrystallization. Compound 1 (4.53 kg) was slurried
in absolute ethanol (156 L), and the batch was heated to 80
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