Experimental Section
filtered through Celite and concentrated. The residue was
dried in vacuo to provide 4 (97.4 g, 97%). 1H NMR (DMSO-
d6) δ 7.61 (s, 1H), 7.61 (d, J ) 5, 1H), 6.64 (d, J ) 5, 1H),
5.76 (s, 1H), 4.51 (s, 2H), 2.36, (m, 1H), 0.72 (m, 2H), 0.40
(m, 2H).
General Procedures. Proton and carbon NMR spectra
were recorded at 500 and 125 MHz, respectively, unless
otherwise noted. Chemical shifts are reported in ppm
downfield from TMS and coupling constants in Hertz using
residual protonated solvent as the reference. Unless otherwise
noted, infrared spectra were taken as KBr pellets. All reagents
were obtained from a commercial supplier and were used
without further purification. Unless otherwise stated, all
reactions were run under nitrogen, and products were dried
in a vacuum oven. When applicable, all solvents were
removed under vacuum using a rotary evaporator.
Ethyl 4-(cyclopropylamino)pyridin-3-ylcarbamate(15).
To a solution of 4 (36.0 g, 0.240 mol) in CH3CN (480 mL)
was added ethyl chloroformate (46.0 mL, 0.480 mol)
dropwise at room temperature. The resulting mixture was
heated at 75 °C for 15h. The mixture was cooled to room
temperature, filtered, and dried in vacuo to provide 15 (47.8
1
g, 77%). H NMR (DMSO-d6) δ 9.32 (broad singlet, 1H),
4-Hydroxy-3-nitropyridine (11). A round-bottomed flask
was charged with H2SO4 (155 mL) and cooled to 0 °C.
4-Hydroxypyridine (10, 25.0 g, 0.263 mol) was added in
portions followed by SLOW addition of KNO3 (53.0 g, 0.526
mol) via a solid addition funnel.10 The resulting mixture was
heated to 100 °C for 1 h and then cooled to 0 °C and poured
onto ice water (100 mL). The mixture was neutralized (pH
) 6.5) with NH4OH (220 mL) at 0 °C. The precipitate was
8.48 (s, 1H), 8.44 (s, 1H), 8.23 (d, J ) 7, 1H), 7.20 (d, J )
7, 1H), 4.13 (q, J1 ) 7, J2 ) 14, 2H), 2.68 (m, 1H), 1.23 (t,
J ) 7, 3H), 0.89 (m, 2H),0.64 (m, 2H).
1-Cyclopropyl-1,3-dihydroimidazo[4,5-c]pyridin-2-
one Hydrochloride (5a). KOtBu (1.0 N in THF, 730 mL,
0.730 mol) was added dropwise to a suspension of 15 (47.0
g, 0.182 mol) in THF (365 mL) at 0 °C. The reaction mixture
was warmed to room temperature, stirred for 15 h, and then
cooled to 0 °C. HCl (4.0 N in 1,4-dioxane, 180 mL, 0.720
mol) was added dropwise. The precipitate was collected by
filtration and redissolved in MeOH (1.8 L) at 50 °C. The
solution was cooled to room temperature and the insoluble
salts were removed by filtration. The mother liquor was
concentrated and the residue was triturated with MeOH (700
mL). The solid was filtered and dried in vacuo to provide
5a (34.9 g, 91%). 1H NMR (CDCl3) δ 8.48 (s, 1H), 8.47 (s,
1H), 7.65 (d, J ) 7, 1H), 3.02 (m, 1H), 1.08 (m, 2H), 0.92
(m, 2H).
1
filtered and dried in vacuo to provide 11 (36.0 g, 98%). H
NMR (DMSO-d6) δ 8.78 (s, 1H), 7.77 (d, J ) 7, 1H), 6.47
(d, J ) 7, 1H).
4-Methoxy-3-nitropyridine (2a). A three-necked flask
(equipped with mechanical stirrer) was charged with 4-
hydroxy-3-nitropyridine (11, 100.0 g, 0.714 mol) and 1,2-
dichloroethane (571 mL) and heated to 80 °C. POCl3 (80.0
mL, 0.856 mol) was added dropwise at such a rate to
maintain the temperature around 80 °C. Upon completion
of addition, the reaction was heated at 85 °C for 4 h and
cooled to 0 °C, and then MeOH (396 mL) was added
dropwise. The mixture was heated at 65 °C for 1 h and then
cooled to 0 °C. The precipitate was filtered and dried in
1-Cyclopropyl-1,3-dihydroimidazo[4,5-c]pyridin-2-
one (5b). To a solution of 4 (20.0 g, 0.134 mol) in CH3CN
(268 mL) at 0 °C was added CDI (22.8 mL, 0.141 mol),
and the resulting mixture was warmed to room temperature
over 1 h. The precipitate was collected by filtration and dried
1
vacuo to provide 2a (104 g, 76%). H NMR (DMSO-d6) δ
9.12 (s, 1H), 8.78 (d, J ) 6, 1H), 7.59 (d, J ) 6, 1H), 4.07
(s, 3H).
1
in vacuo to give 5b (16.9 g, 72%). H NMR (DMSO-d6) δ
N-Cyclopropyl-3-nitropyridin-4-amine (3). A round-
bottomed flask was charged with 3-nitro-4-ethoxypyridine
hydrochloride (2b, 70.6 g, and 0.345 mol), absolute EtOH
(250 mL), i-Pr2NEt (125 mL, 0.718 mol) and cyclopropyl-
amine (50.0 g, 0.876 mol). The resulting solution was
refluxed for 3 h. The reaction was cooled to 0 °C, and the
solid was collected by filtration. The filter cake was washed
with cold ethanol (absolute, 2 × 30 mL) to give 3 (52.4 g,
85%). The mother liquor was concentrated and partitioned
between water (200 mL) and ethyl acetate (200 mL). The
aqueous layer was extracted with ethyl acetate (2 × 100 mL),
dried over MgSO4, filtered, and concentrated to give a second
11.01 (s, 1H), 8.17 (d, J ) 5, 1H), 8.15 (singlet, 1H), 7.17
(d, J ) 5, 1H), 2.88 (m, 1H), 1.00 (m, 2H), 0.85 (m, 2H).
13C NMR (DMSO-d6) δ 154.15, 142.12, 137.38, 129.24,
125.76, 103.88, 22.27, 5.60. Anal. Calcd for C9H9N3O: C
61.70, H 5.18, N 23.99; found: C 61.51, H 5.10, N 23.94.
KF < 0.1%
2,2-Dimethylpropionic Acid, 4-Iodobutyl Ester (16). A
suspension of sodium iodide (61.7 g, 0.412 mol) in CH3CN
(100 mL) was cooled to ∼2 °C, and THF (28.6 mL, 0.352
mol) was added, followed by the addition of a solution of
trimethylacetyl chloride (42.8 mL, 0.348 mol) in CH3CN (60
mL) at a rate to keep the internal temperature below 10 °C.
The mixture was stirred at 10 °C for 2 h and then warmed
to room temperature and stirred for 15 h. tert-Butyl methyl
ether (450 mL) was added followed by 1 N sodium
thiosulfate (275 mL). After 30 min the layers were separated,
and the organic layer was washed with water (325 mL) and
half-saturated aqueous brine (275 mL). The organic layer
was dried over magnesium sulfate, filtered, and concentrated
to yield 16 (93.5 g, 94%). IR (KBr) 1725 (CdO) (cm-1);
1H NMR (DMSO-d6) δ 4.03 (t, J ) 6, 2H), 3.31 (t, J ) 7,
2H), 1.81 (m, 2H), 1.66 (m, 2H), 1.14 (s, 9).
1
crop of product (10.7 g, 15% (slightly impure)). H NMR
(CDCl3) δ 9.20 (s, 1H), 8.34 (d, J ) 6, 1H), 8.19 (broad
singlet, 1H), 7.15 (d, J ) 6, 1H), 2.62 (m, 1H), 0.99 (m,
2H), 0.71 (m, 2H).
N4-Cyclopropylpyridine-3,4-diamine (4). A suspension
of 4-(N-cyclopropyl)amino-3-nitropyridine (2, 120 g, 0.670
mol) and 10% Pd/C (50% water; 24 g) in EtOH (1 L) was
hydrogenated at 50 psi H2 for 4 h. The suspension was
(10) Rapid addition of KNO3 results in a dangerous exotherm and severe off-
gassing.
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