offered additional access to urea 3 in high yield and purity
without evidence of a symmetrical urea byproduct. All of
the intermediates and final target were isolated cleanly in
high yield without a need for chromatographic purification.
mmol, 78% based on 683.45 mmol of acid chloride remain-
ing in the filtrate) as a white solid. Mp ) 108-112 °C. H
1
NMR (DMSO-d6, 300 MHz): δ 3.88 (s, 3H, -CO2CH3);
7.82 (dd, J ) 2.2, 5.5 Hz, 1H, aromatic); 8.08 (d, J ) 2.2
Hz, 1H, aromatic); 8.68 (d, J ) 5.5 Hz, 1H, aromatic); 10.68
(br s, 1H, -NHCl). Mass spectrum (HPLC/ES): m/e ) 172
(M + 1). Anal. Calcd for C7H7NClO2‚HCl: C, 40.41; H,
3.39; N, 6.73. Found: C, 40.34; H, 3.40; N, 6.61.
Experimental Section
General. All NMR analyses were performed on a GE
300-MHz instrument using hexadeuterated dimethyl sulfox-
ide. Mass spectra were obtained from a Kratos Concept mass
spectrometer. All solvents and reagents were purchased from
EM Science, Lancaster, or Aldrich Chemicals and used
without further purification. Elemental analyses were ob-
tained from Robertson Microlit Labs. HPLC purities were
determined with a Perkin-Elmer Pecosphere 3 × 3C C-18
reversed-phase column (0.46 × 3.3 cm) used in conjunction
with a Sedere Sedex model 55 evaporative light scattering
(ELS) detector. Eluent gradients ranged from 10 to 90%
acetonitrile/0.1% TFA in water; λ ) 254 nm.
Synthesis of 4-Chloropyridine-2-carbonyl Chloride
Hydrochloride (5). Anhydrous N,N-dimethylformamide (6
mL) was slowly added to thionyl chloride (180 mL) at a
temperature range of 40-50 °C under argon. The solution
was stirred in that temperature range for 10 min prior to
portionwise addition of picolinic acid (4, 60.00 g, 487.37
mmol) over a 30-min period. The initial green color went to
orange and then to purple. The solution was heated to 72
°C, and vigorous SO2 evolution was observed. A yellow solid
precipitated after 16 h. The mixture was then cooled to room
temperature, diluted with toluene (500 mL), and concentrated
to 200 mL. This process was repeated two additional times
before the contents were concentrated to near dryness. The
mixture was filtered, washed with toluene (50 mL), and dried
under high vacuum for 4 h to afford 5 (92.00 g, 433.02 mmol,
89%) as an off-white solid. The integrity of this material
was verified through its subsequent reaction with methanol
or methylamine, which led to pure intermediates.
Synthesis of Methyl 4-Chloropyridine-2-carboxylate
Hydrodrochloride (6). Anhydrous N,N-dimethylformamide
(10 mL) was slowly added to thionyl chloride (300 mL) at
a temperature range of 40-48 °C under argon. The solution
was stirred in that temperature range for 10 min prior to
portionwise addition of picolinic acid (4, 100.00 g, 812.28
mmol) over a 30-min period. The initial green color went to
orange and then to purple. The solution was heated to 72
°C and vigorous SO2 evolution was observed. A yellow solid
precipitated after 16 h. The mixture was then cooled to room
temperature, diluted with toluene (500 mL), and concentrated
to 200 mL. This process was repeated two additional times
before the contents were concentrated to near dryness. The
mixture was filtered, washed with toluene (50 mL), and dried
under high vacuum for 4 h to afford 5 (27.24 g, 128.21
mmol) as an off-white solid. The red filtrate was added to
methanol (200 mL) at a rate that kept the internal temperature
of the mixture below 55 °C. The contents were stirred at
room temperature for 45 min, cooled to 5 °C, and treated
with dropwise addition of diethyl ether (200 mL). The
material was filtered, washed with ether (200 mL), and dried
under high vacuum at 35 °C to provide 6 (110.23 g, 529.85
Synthesis of (4-Chloro(2-pyridyl))-N-methylcarboxa-
mide (7) from 6. A suspension of 6 (89.00 g, 427.80 mmol)
in methanol (75 mL) was cooled to 0 °C under argon and
slowly treated with 2.0 M methylamine in tetrahydrofuran
(1000 mL) at a rate that kept the internal temperature below
5 °C. The mixture was stirred at 3 °C for 5 h and
concentrated, and the contents were suspended in ethyl
acetate (1000 mL) and filtered. The filtrate was washed with
brine (500 mL), dried over sodium sulfate, and concentrated
to afford 7 (71.15 g, 417.06 mmol, 97%) as pale-yellow
crystals (crystallization occurred during the rotary evapora-
1
tion process). Mp ) 41-43 °C. H NMR (DMSO-d6, 300
MHz): δ 2.81 (s, 3H, -NHCH3); 7.74 (dd, J ) 2.2, 5.1 Hz,
1H, aromatic); 8.00 (d, J ) 2.2, 1H, aromatic); 8.61 (d, J )
5.1 Hz, 1H, aromatic); 8.85 (br d, 1H, -NHCH3). Mass
spectrum (CI+): m/e ) 171 (M + 1). Anal. Calcd for
C7H7N2ClO: C, 49.28; H, 4.14; N, 16.42. Found: C, 49.25;
H, 4.22; N, 16.42.
Synthesis of (4-Chloro(2-pyridyl))-N-methylcarboxa-
mide (7) from 5. Acid chloride 5 (7.00 g, 32.95 mmol) was
added portionwise to 2.0 M methylamine in tetrahydrofuran
(100 mL) and methanol (20 mL) at 0 °C under argon. The
mixture was stirred at 3 °C for 4 h, concentrated to near
dryness, and dissolved in ethyl acetate (100 mL). The
organics were washed with brine (2 × 100 mL), dried over
sodium sulfate, and concentrated to provide 7 (4.95 g, 29.02
mmol, 88%) as a yellow, crystalline solid. Mp ) 37-40
°C. NMR data supported product structure (see above
experimental data).
Synthesis of [4-(4-Aminophenoxy)(2-pyridyl)]-N-
methylcarboxamide (9). A solution of 4-aminophenol (9.60
g, 87.98 mmol) in dry N,N-dimethylformamide (150 mL)
was treated with potassium tert-butoxide (10.29 g, 91.69
mmol), and the reddish-brown mixture was stirred at room
temperature for 2 h. The contents were treated with 7 (15.00
g, 87.92 mmol) and potassium carbonate (6.50 g, 47.03
mmol) and then heated to 80 °C under argon for 6 h. The
mixture was cooled to room temperature and poured into
ethyl acetate (500 mL) and brine (500 mL). The layers were
separated, and the aqueous phase was back-extracted with
ethyl acetate (300 mL). The combined organics were washed
with brine (4 × 1000 mL), dried over sodium sulfate, and
concentrated to afford 9 (18.62 g, 76.54 mmol, 87%) as a
1
light-brown solid after vacuum-drying at 35 °C for 3 h. H
NMR (DMSO-d6, 300 MHz): δ 2.77 (d, J ) 4.8 Hz, 3H,
-NHCH3); 5.17 (br s, 2H, -NH2); 6.64, 6.86 (AA′BB′
quartet, J ) 8.4 Hz, 4H, aromatic); 7.06 (dd, J ) 2.5, 5.5
Hz, 1H, aromatic); 7.33 (d, J ) 2.5 Hz, 1H, aromatic); 8.44
(d, J ) 5.5 Hz, 1H, aromatic); 8.73 (br d, 1H, -NHCH3).
780
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Vol. 6, No. 6, 2002 / Organic Process Research & Development