19.50, 15.86. Anal. calcd for C7H8N2O3: C, 50.00; H, 4.79; N,
16.66. Found: C, 50.01; H, 4.59; N, 16.75.
0.48-0.53 (m, 3H), 0.33-0.37 (m, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 71.66, 58.29, 55.12, 10.92, 3.96, 3.51. HRMS
(ES-MS) Calcd for C6H14NO: 116.1075; HRMS found [M +
H]+: 116.1069.
2-(Difluoromethoxy)-3,6-dimethyl-5-nitropyridine (9). To
a suspension of 8 (640 g, 3.77 mol) in MeCN (19.5 L) was
added NaH (310 g, 7.75 mol; 60% in mineral oil). After stirring
at 20-25 °C for 1.5 h, 2,2-difluoro-2-(fluorosulfonyl)acetic acid
(1.0 L, 9.39 mol) was added dropwise over 2 h at E40 °C.
After 1 h, the reaction was quenched by the slow addition of
water (340 mL). The mixture was filtered through Celite, and
then the solvent was switched to heptane and the volume
adjusted to 9 L. The mixture was cooled to -14 °C, resulting
in a slurry. The slurry was filtered, and then the mother liquor
was concentrated and cooled to -14 °C, resulting in a second
crop. Both crops were air-dried to provide 703 g of 9 as yellow
crystals (99.3% HPLC area purity, 86% yield). Mp 48-49 °C;
1H NMR (500 MHz, CDCl3) δ 8.23 (s, 1 H), 7.56 (t, J ) 72.4
Hz, 1 H), 2.77 (s, 3 H), 2.32 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 158.1, 151.1, 141.9, 137.1, 120.0, 113.8 (t, J ) 257.6
Hz), 23.7, 14.8; 19F NMR (376.5 MHz, CDCl3) δ -89.8. Anal.
calcd for C8H8N2O3F2: C, 44.04; H, 3.69; N, 12.84. Found: C,
43.78; H, 3.55; N, 12.58.
2-(1-Cyclopropyl-2-methoxyethylamino)acetonitrile Hy-
drochloride (rac-12). A mixture of rac-11 (650 g, 4.29 mol),
potassium iodide (783 g, 4.72 mol), potasium carbonate (1480
g, 4.87 mol), MeCN (9.8 L), and chloroacetonitrile (275 mL,
4.34 mol) was heated to 50 °C for 3 h, cooled to 25 °C, and
diluted with MTBE (8.0 L). The heterogeneous slurry was
filtered to remove the inorganic solids, and then the solvent
was switched to 2-propanol. The mixture was concentrated to
∼3.25 L under vacuum (115 Torr), then the batch was cooled
to E10 °C, and 4-5 M HCl in 2-propanol (2.0 L) was added
dropwise at E20 °C. The mixture was concentrated to ∼3.25
L and then cooled to 20-25 °C, resulting in a slurry which
was aged for 15 min. MTBE (6.5 L) was then charged, and the
slurry was aged for 15 h and filtered, and the cake was washed
with MTBE (2.0 L) and dried under vacuum at 50 °C to afford
570 g of rac-12 as an off-white solid (70% yield). Mp )
113-115 °C; 1H NMR (400 MHz, CDCl3) δ 10.57 (bs, 2H),
4.44 (d, A of AB, JAB ) 16.4 Hz, 1H), 4.37 (d, B of AB, JAB
6-(Difluoromethoxy)-2,5-dimethylpyridin-3-amine (3). To
a solution of 9 (400 g, 1.82 mol) in methanol (4 L) was added
10% palladium hydroxide (72 g, 103 mmol), and the resulting
suspension was hydrogenated in a 5-L Buchi reactor under 40
psi H2 at 25 °C for 4 h. The reaction mixture was filtered
through a polypropylene 0.5-µm filter cartridge. The solvent
was switched to hexane (1.6 L) and the solution cooled to -15
°C, resulting in a slurry which was filtered, and the cake was
air-dried to furnish 328 g of 3 (99.8% HPLC area purity, 96%
yield). Mp 40-42 °C; 1H NMR (500 MHz, CDCl3) δ 7.33 (t,
J ) 74.0 Hz, 1 H), 6.86 (s, 1 H), 2.27 (s, 3 H), 2.15 (s, 3 H);
13C NMR (125 MHz, CDCl3) δ 149.8, 137.9, 137.5, 127.8,
119.4, 115.3 (t, J ) 253.1 Hz), 19.4, 15.0; 19F NMR (376.5
MHz, CDCl3) δ -86.9; Anal. calcd for C8H10N2OF2: C, 51.12,
H, 5.38, N, 14.86. Found: C, 51.17, H, 5.29, N, 14.87.
1-Cyclopropyl-2-methoxyethanamine Hydrochloride (rac-
11). A mixture of magnesium turnings (205 g, 8.44 mol) and
THF (3.0 L) was cooled to 5 °C, and then a premixed solution
of cyclopropyl bromide (1.62 kg, 13.4 mol) in THF (2.5 L)
was slowly added. The reaction mixture was cooled to 15 °C,
10 (500 g, 7.03 mol) was charged slowly followed by lithium
aluminum hydride (1 M in THF) (3.79 kg, 4.21 mol) at 25 °C.
The reaction mixture was then heated to reflux (67 °C) for 12 h
and then cooled to 20 °C. The reaction mixture was then added
slowly to a solution of Rochelle salt (3.81 kg, 13.5 mol) in
water (8.9 L) at 5-10 °C. IPAc (6 L) was added; then the
phases were separated, and the rich organic layer was decanted.
The aqueous layer was back extracted with 1:1 IPAc/THF (4
× 8 L), and the combined organic layers were concentrated
under vacuum and then cooled to 10 °C. Methanol (338 g, 10.6
mol) was slowly added and then trimethylsilyl chloride (765
g, 7.04 mol), resulting in a slurry. The slurry was filtered, and
the wet cake was washed with IPAc (3 L) and dried under
vacuum at ambient temperature to afford 555 g of rac-11
(97-99% GC area purity of free base, 52% yield). Mp ) 112
°C; 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 3H), 3.54-3.6
(m, 2H), 3.31 (s, 3H), 2.54-2.44 (m, 1H), 0.95-1.02 (m, 1H),
) 16.4 Hz, 1H), 3.97 (dd, A of ABX, JAB ) 10.9 Hz, JAX
)
7.8 Hz, 1H), 3.82 (dd, B of ABX, JAB ) 11.0 Hz, JBX ) 3.0
Hz, 1H), 3.44 (s, 3H), 2.80 (ddd, J ) 10.5, 8.0, 2.8 Hz, 1H),
1.30-1.21 (m, 1H), 0.93-0.86 (m, 1H), 0.83-0.73 (m, 2H),
0.44-0.38 (m, 1H); 13C NMR (100 MHz CDCl3) δ 112.80,
71.93, 63.59, 59.23, 33.29, 9.18, 5.51, 3.93. HRMS Calcd for
C8H15N2O, 155.1184; HRMS found [M+]+: 155.1179 (for the
free base).
3,5-Dichloro-1-(1-cyclopropyl-2-methoxyethyl)pyrazin-
2(1H)-one (rac-4). A solution of rac-12 (800 g, 4.20 mol), THF
(4.0 L), and DCM (4.0 L) was cooled to 0 °C, and oxalyl
chloride (1090 mL, 12.6 mol) was added over 30 min at <10
°C. The mixture was warmed to 20 °C and aged for 15 h and
then was added slowly to a saturated KH2PO4 solution (8.0 L)
at 0 °C over 30 min at E20 °C. The mixture was agitated for
1 h, then the product rich lower organic phase was removed.
The aqueous phase was extracted with DCM (2.4 L), and the
organic phases were combined. The solvent was switched to
IPA under reduced pressure, and the volume was adjusted to
∼4.0 L, resulting in a slurry. Water (8.0 L) was added, and
then the slurry was aged for 15 h and filtered; then the cake
was washed with 4:1 water/IPA solution (2.5 L) and dried under
vacuum at 50 °C to provide 810 g of rac-4 as a beige solid
1
(99.7% HPLC area purity, 73% yield). Mp ) 95-98 °C; H
NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 4.11 (dt, J ) 10.0,
3.6 Hz, 1H), 3.74 (dd, A of ABX, JAB ) 10.5 Hz, JAX ) 4.5
Hz 1H), 3.64 (dd, B of ABX, JAB ) 10.4 Hz, JBX ) 3.1 Hz
1H), 3.33 (s, 3H), 1.45-1.36 (m, 1H), 0.85-0.77 (m, 1H),
0.67-0.60 (m, 1H), 0.52 (dq, J ) 9.9, 4.8 Hz, 1H), 0.30 (dq,
J ) 10.7, 5.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 151.80,
146.38, 125.65, 123.57, 72.03, 63.57, 59.27, 11.17, 6.24, 4.00;
Anal. calcd for C10H12N2O2Cl2: C, 45.64; H, 4.59; N, 10.64;
Cl, 26.94. Found: C, 45.78; H, 4.35; N, 10.52; Cl, 26.86; HRMS
calcd for C10H13Cl2N2O2: 263.0354; HRMS found [M + H]+:
263.0358.
1226
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Vol. 14, No. 5, 2010 / Organic Process Research & Development