2:1 mixture of rotomers), 2.01–2.21 (m, 1H), 2.50–2.59 (m,
1H), 3.53–3.74 (m, 2H), 4.57–4.63 (m, 1H), 5.23–5.40 (m, 1H),
7.70, 7.73 (two dd, J ) 7.6, 3.8 Hz, 1H, 2:1 mixture of
rotomers), 8.31, 8.35 (two d, J ) 7.6 Hz, 1H, 2:1 mixture of
rotomers), 8.98–8.99 (m, 1H), 11.31, 11.39 (two singlets, 1H,
2:1 mixture of rotomers); 13C NMR (CDCl3) δ (ppm) 172.4,
171.8, 162.2, 155.3, 153.4, 152.9, 148.6, 128.6, 128.4, 118.1,
118.0, 93.0, 92.3, 91.8, 91.2, 79.4, 79.2, 58.5, 58.3, 53.6, 53.5,
53.2, 53.1, 37.3, 37.1, 36.6, 36.4, 28.0, 27.8 (mixture of
rotomers). HR-MS calculated for C14H19FN4O3, 310.1441;
found, 310.1452 [M]+.
(2S,4R)-4-Fluoro-N-3-pyridazinyl-2-pyrrolidinecarboxa-
mide Dihydrochloride (13). A 1-L, 4-necked round-bottomed
flask was charged with (2S,4R)-1-pyrrolidine-carboxylic acid
4-fluoro-[(3-pyridazinylamino)carbonyl]-1,1-dimethylethyl ester
(23, 5.10 kg, 16.4 mol) and acetonitrile (36 kg). The suspension
was stirred under nitrogen at 21 ( 3 °C and concentrated
hydrochloric acid (7.39 kg, 74.0 mol) was added over a
period of 30 min while maintaining the internal temper-
ature at 21 ( 3 °C. The mixture was stirred at this
temperature for an additional 6 h and was cooled to 0 (
5 °C over 20 min. The resulting suspension was stirred at
this temperature for an additional 1 h. The solid was
collected by filtration over a Büchner funnel, washed with
acetonitrile (2 × 3 kg), and dried under reduced pressure
(20 mbar) at 45 °C for 24 h until LOD < 1% to give 4.49
kg (96.5% yield) of (2S,4R)-4-fluoro-N-3-pyridazinyl-2-
pyrrolidinecarboxamide dihydrochloride (13) as an off-
white solid: mp 232–234 °C. 1H NMR (CDCl3, 500 MHz)
δ (ppm) 2.20–2.37 (m, 1H), 2.79–2.88 (m, 1H), 3.50–3.68
(m, 2H), 4.73 (br s, 1H), 5.52 (dt, J ) 43.7, 2.9 Hz, 1H),
7.93 (dd, J ) 7.6, 4.1 Hz, 1H), 8.40 (d, J ) 7.6 Hz, 1H),
9.14 (dd, J ) 4.1, 1.3 Hz, 1H), 9.22 (br s, 1H), 11.15 (s,
1H), 12.07 (s, 1H), 12.50 (br s, 1H); 13C NMR (CDCl3) δ
(ppm) 167.4, 155.0, 148.3, 129.9, 120.4, 92.5 (d, J ) 175.6
Hz), 58.5, 51.6 (d, J ) 24.2 Hz), 36.5 (d, J ) 20.9 Hz).
HR-MS calculated for C9H11FN4O, 210.0917; found,
210.0927 [M]+.
1-[(2R)-3-Cyclobutyl-2-[(formylhydroxyamino)methyl]-
1-oxopropyl]-4-fluoro-N-3-pyridazinyl-(2S,4R)-2-pyrrolidi-
necarboxamide (1). A 200-L reactor was charged with R-[(formyl-
(phenylmethoxy)amino]-(RR)-cyclobutanepropanoic acid di-
cyclohexylamine salt (20, 7.96 g, 17.0 mol) and toluene (55
kg). The suspension was stirred at 20–25 °C, and a solution of
citric acid (6.6 kg) in water (60 kg) was added over the
period 10 min while maintaining the internal temperature
at 20–25 °C. The mixture was stirred vigorously for 20
min, and the upper organic layer was separated. The
organic layer was washed with water (2 × 19 kg) and
concentrated under reduced pressure (58–50 mbar) at an
internal temperature 29–35 °C to a batch volume of ∼9
L. The solution was diluted with N,N-dimethylformamide
(35.3 kg). 1-Methylimidazole (5.0 kg, 60.7 mol) was
added. The resulting solution was cooled to -12 ( 3 °C
over 15 min, and methanesulfonyl chloride (1.84 g, 16.0
mol) was added over a period of 1 h while maintaining
the internal temperature at -12 ( 3 °C. The mixture was
stirred at -12 ( 3 °C for 30 min, and (2S,4R)-4-fluoro-
N-3-pyridazinyl-2-pyrrolidinecarboxamide dihydrochloride
(13, 4.31 kg, 15.2 mol) was added over a period of 1 h in
10 equal portions while maintaining the internal temper-
ature at -12 ( 3 °C. The reaction mixture was warmed
to 20 ( 5 °C over 1 h and stirred for an additional 6 h.
The mixture was cooled to 0 ( 5 °C over 20 min, and
15% aqueous sodium chloride solution (86 kg) was added
over 20 min while maintaining the internal temperature
at 0 ( 8 °C. Then isopropyl acetate (58 kg) was added to
the mixture. The mixture was warmed to 20 ( 5 °C over
20 min and stirred for an additional 30 min. The organic
layer was separated. The aqueous layer was extracted with
isopropyl acetate (58 kg). The combined organic layer was
washed with water (45 kg), saturated sodium bicarbonate
solution (46 kg), and water (2 × 45 kg). The organic layer
was concentrated under reduced pressure (74–69 mbar)
at 25–27 °C to a batch volume of ∼12 L. The batch was
diluted with ethyl alcohol (200 proof, 19 kg) to afford ∼35
L of 1-[(2R)-3-cyclobutyl-2-[[formyl(phenylmethoxy)amino]-
1-oxopropyl]-4-fluoro-N-3-pyridazinyl-(2S,4R)-2-pyrrolidi-
necarboxamide (24) in ethanol/isopropyl acetate. To this
solution was added 10% Pd/C (50% wet, 1.07 kg) and
ammonium formate (0.86 kg, 13.6 mol). The mixture was
heated to 60 ( 5 °C over 0.5 h and stirred for an additional
0.5 h. It was cooled to 20 ( 5 °C over a period 20 min and
filtered over a pad of Celite (1.6 kg). The Celite pad was
washed with ethanol (200 proof, 2 × 2.5 kg). The filtrate
was transferred to a 200-L reactor, and activated charcoal
(Pica P1400, 0.67 kg) was added. The mixture was heated
to 35 ( 5 °C over 15 min and stirred for an additional 4 h.
The mixture was cooled to 20 ( 5 °C over a period 20 min
and filtered over a pad of Celite (1.6 kg). The Celite pad
was washed with ethanol (200 proof, 2 × 3.8 kg), and the
filtrate was concentrated under reduced pressure (80–77
mbar) at 25–27 °C to a batch volume of ∼7.5 L. The batch
was heated to 35 ( 3 °C over 15 min, and isopropyl acetate
(84 kg) was added over a period of 1 h while maintaining
the internal temperature at 35 ( 3 °C. The mixture was
seeded with pure 1 (2.4 g) at this temperature. The mixture
was cooled to 20 ( 5 °C over a period of 1 h and stirred
for an additional 68 h. The solid was collected by filtration
over a Büchner funnel, washed with cold isopropyl acetate
(∼5 °C, 2 × 3.5 kg), and dried under reduced pressure
(20 mbar) at 45 °C for 12 h until LOD < 1% to afford
3.1 kg (60.1% yield) of 1-[(2R)-3-cyclobutyl-2-[(formyl-
hydroxyamino)methyl]-1-oxopropyl]-4-fluoro-N-3-pyridazi-
nyl-(2S,4R)-2-pyrrolidinecarboxamide (1) as a white solid:
1
mp 154–156 °C. H NMR (CDCl3, 500 MHz) δ (ppm)
1.41–2.42 (m, 10H), 2.45–2.95 (m, 2H), 3.25–3.87 (m,
4H), 3.92–4.09 (m, 1H), 4.70–4.75, 4.90–4.92 (m, 1H,
mixture of four rotomers), 5.30–5.50 (m, 1H, mixture of
four rotomers), 7.65–7.73 (m, 1H, mixture of four
rotomers), 7.80, 7.84, 8.15, 8.23 (four singlets, 1H, mixture
of four rotomers in 7:1:1:5 ratio), 8.28–8.35 (m, 1H,
mixture of four rotomers), 8.98–9.00 (m, 1H, mixture of
four rotomers), 9.31, 9.74, 9.75, 10.10 (four singlets, 1H,
mixture of four rotomers in 1:7:1:5 ratio), 11.31, 11.52,
11.5 (three singlets, 1H, mixture of four rotomers); 13C
190
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Vol. 12, No. 2, 2008 / Organic Process Research & Development