Yasuda et al.
0.01 % vol TFA in MeOH; 1.0 mL/min; 13.9 min (desired
enantiomer) and 17.4 min (undesired).
t et r a h yd r o-1,8-n a p h t h yr id in -2-yl)p r op yl]-2,3-d ih yd r o-
1H-im id a zol-1-yl}p r op a n oic Acid (36). To a solution of 35
and iPAc (140 mg/mL, 220 mL, 30.8 g, 62.4 mmol) was added
3.06 M sulfuric acid (150 mL). The aqueous layer was
separated and stirred at 40 °C for 3 h. The mixture was cooled
to 10 °C. The pH of the solution was adjusted to about 2 with
50 wt % NaOH. To the solution was added SP207 resin30 (310
mL). The pH of the suspension was adjusted to 5.9 with 50 wt
% NaOH and stirred at room temperature for 4 h. The
suspension was filtered, and the resin was washed with water
(930 mL) and then with 70 v/v % acetone-water (1.5 L). The
fractions containing 36 were combined and concentrated to
remove acetone. The resulting suspension was cooled to 5 °C.
Crystals were collected by filtration, washed with cold water
(20 mL), and dried at 30 °C under vacuum to provide 36 (23.5
g, 86%) as crystals. Recrystallization from aqueous iPA gave
a thermodynamically more stable crystal form: mp 123 °C;
1H NMR (400 MHz, CD3OD) δ 8.16 (d, J ) 2.6 Hz, 1H), 7.73
(dd, J ) 8.6, 2.6 Hz, 1H), 7.45 (d, J ) 7.4 Hz, 1H), 6.81 (d, J
) 8.6 Hz, 1H), 6.54 (d, J ) 3.1 Hz, 1H), 6.53 (d, J ) 7.4 Hz,
1H), 6.50 (d, J ) 3.1 Hz, 1H), 5.70 (dd, J ) 11.6, 4.2 Hz, 1H),
3.90 (s, 3H), 3.76 (ddd, J ) 14.0, 9.7, 4.3 Hz, 1H), 3.51 (dt, J
) 14.0, 5.0 Hz, 1H), 3.46 (m, 2H), 2.99 (dd, J ) 14.0, 11.6 Hz,
1H), 2.85 (dd, J ) 14.0, 4.2 Hz, 1H), 2.77 (t, J ) 6.2 Hz, 2H),
2.70 (ddd, J ) 13.5, 7.5, 5.3 Hz, 1H), 2.50 (dt, J ) 15.3, 8.2
Hz, 1H), 2.14-1.87 (m, 4H); 13C NMR (101 MHz, CD3OD) δ
177.6, 163.9, 153.8, 152.2, 148.8, 145.0, 140.1, 137.9, 128.6,
118.2, 111.1, 110.4, 109.5, 108.6, 52.7, 52.1, 41.5, 40.8, 40.3,
28.9, 28.1, 25.1, 19.4. Anal. Calcd for C23H27N5O4‚0.5 H2O: C,
61.87; H, 6.30; N, 15.64. Found C, 61.76; H, 6.12; N, 15.71.
KF 1.97%.
(3S)-3-(6-Met h oxyp yr id in -3-yl)-3-{2-oxo-3-[3-(5,6,7,8-
tetr a h yd r o-1,8-n a p h th yr id in -2-yl)p r op yl]im id a zolid in -1-
yl}p r op ion ic Acid (1). A suspension of 36 (105 g, 240 mmol),
water (247 mL), 5 M NaOH (84 mL), and 20 wt % Pd(OH)2/C
(21 g) was hydrogenated at 120 psi of hydrogen at 80 °C for
18 h. The pH was adjusted to 9.0 with concentrated HCl, and
the catalyst was removed by filtration through a pad of Solka
Flok (13 g). The filter cake was rinsed with water (200 mL),
and the combined filtrate was adjusted to pH 6.4 with
concentrated HCl. The solution was seeded and stirred at 0
°C for 1 h. The resulting crystals were collected by filtration
and dried under nitrogen to provided 1 as a hemihydrate (84.5
g, 80%): mp 122 °C; 1H NMR (500 MHz, CD3OD) δ 8.08 (d, J
) 2.4 Hz, 1H), 7.66 (dd, J ) 8.7, 2.4 Hz, 1H), 7.45 (d, J ) 7.2
Hz, 1H), 6.79 (d, J ) 8.7 Hz, 1H), 6.53 (d, J ) 7.2 Hz, 1H),
5.48 (dd, J ) 12.3, 3.6 Hz, 1H), 3.89 (s, 3H), 3.64 (q, J ) 9.2
Hz, 2H), 3.50 (m, 1H), 3.45 (m, 2H), 3.34 (ddd, J ) 14.1, 12.1,
3.9 Hz, 1H), 3.16 (q, J ) 9.1 Hz, 1H), 2.98 (m, 1H), 2.97 (t, J
) 12.3 Hz, 1H), 2.81 (dt, J ) 14.1, 4.0 Hz, 1H), 2.75 (m, 3H),
2.65 (ddd, J ) 14.4, 11.2, 5.0 Hz, 1H), 2.55 (dd, J ) 12.3, 3.4
Hz, 1H), 2.06 (m, 1H), 1.92 (m, 2H), 1.82 (m, 1H); 13C NMR
(125.7 MHz, CD3OD) δ 180.7, 165.1, 162.6, 153.3, 150.2, 146.6,
141.4, 139.7, 130.0, 119.6, 111.6, 110.7, 54.1, 53.1, 42.2, 41.6,
41.0, 38.7, 38.6, 29.1, 27.9, 26.6, 20.7. Anal. Calcd for
ter t-Bu t yl (3S)-3-[(2,2-Dim et h oxyet h yl)a m in o]-3-(6-
m eth oxyp yr id in -3-yl)p r op a n oa te (32). To a solution of 31
(100 g, 239 mmol) and dimethoxyacetaldehyde (60 wt % in
water, 39.3 mL, 261 mmol) and THF (400 mL) was added a
suspension of sodium triacetoxyborohydride (95 wt %, 79 g,
354 mol) and THF (200 mL) over 1 h, maintaining the reaction
temperature below 10 °C. The residual sodium triacetoxyboro-
hydride was rinsed into the reaction mixture with THF (40
mL). The mixture was stirred at 5-10 °C for 30 min and then
at room temperature for 30 min. After the mixture was cooled
to below 10 °C, aqueous Na2CO3 (10 wt %, 120 mL) was added
maintaining the temperature below 10 °C. The mixture was
extracted with EtOAc (750 mL), and the organic phase was
washed with saturated aqueous NaHCO3 (600 mL) and water
(500 mL) and concentrated in vacuo to give crude 32 (88.4 g,
83.9 wt %, 92.2%). An analytical sample was prepared by silica
gel column chromatography: 1H NMR (400 MHz, CDCl3) δ
8.08 (d, J ) 2.4 Hz, 1H), 7.61 (dd, J ) 8.4, 2.4 Hz, 1H), 6.73
(d, J ) 8.4 Hz, 1H), 4.41 (t, J ) 5.6 Hz, 1H), 4.00 (dd, J ) 8.2,
6.0 Hz, 1H), 3.93 (s, 3H), 3.35 (s, 3H), 3.31 (s, 3H), 2.67 (dd, J
) 15.3, 8.2 Hz, 1H), 2.60 (dd, J ) 12.0, 5.6 Hz, 1H), 2.51 (dd,
J ) 12.0, 5.6 Hz, 1H), 2.49 (dd, J ) 15.3, 6.0 Hz, 1H), 1.40 (s
9H); 13C NMR (101 MHz, CDCl3) δ 170.6, 163.8, 145.9, 137.4,
130.4, 110.9, 103.5, 80.9, 56.9, 53.71, 53.68, 53.4, 48.6, 43.8,
28.0.
ter t-Bu tyl (3S)-3-(6-Meth oxyp yr id in -3-yl)-3-{2-oxo-3-[3-
(5,6,7,8-tetr a h yd r o-1,8-n a p h th yr id in -2-yl)p r op yl]-2,3-d i-
h yd r o-1H-im id a zol-1-yl}p r op a n oa te (35). A solution of 24
(10.4 g, 35 mmol) and 6 M HCl (18 mL) was stirred at 35 °C
for 1.5 h. The pH of the reaction mixture was adjusted at 7
with 50 wt % NaOH. After addition of sec-butanol (35 mL),
the pH of the aqueous layer was adjusted at 11.5 with 50 wt
% NaOH. The organic layer was separated, washed with
saturated aqueous NaCl (10 mL), and concentrated in vacuo
to remove water to yield a dry solution of amine 2 (35 mmol)
and sec-butanol.
A solution of 32 (10 g as pure, 29 mmol), triethylamine (5.5
mL, 40 mmol), and THF (45 mL) was added to a cold solution
of bis(trichloromethyl)carbonate (3.51 g, 12 mmol) and THF
(75 mL) over 30 min, maintaining the temperature below 0
°C. The mixture was stirred for 2 h at room temperature to
yield chlorocarbamate 33. The solution of 2, prepared above,
and triethylamine (5.5 mL, 40 mmol) was added to the reaction
mixture containing 33. The resulting mixture was stirred at
45 °C for 3 h. To the mixture was added water (20 mL). The
phases were separated, and the organic layer, which contained
urea 34, was retained. To the organic layer was added 2 M
sulfuric acid (40 mL), and the mixture was stirred for 18 h at
room temperature. To the mixture was added iPAc (50 mL).
The organic layer was separated and extracted with 2 M
sulfuric acid (20 mL). The aqueous layers were combined and
extracted with iPAc (50 mL). iPAc (80 mL) was added to the
aqueous phase, and the two-phase mixture was cooled to 0 °C.
The pH was adjusted to 8.3 by addition of 5 M NaOH (∼40
mL). The organic layer was separated and washed with water
(3 × 45 mL). The solution containing 35 (12.0 g, 84%) was used
for the next step without further purification. An analytical
sample was prepared by silica gel column chromatography:
1H NMR (250 MHz, CDCl3) δ 8.05 (d, J ) 2.5 Hz, 1H), 7.53
(dd, J ) 8.6, 2.5 Hz, 1H), 6.95 (d, J ) 7.3 Hz, 1H), 6.63 (d, J
) 8.6 Hz, 1H), 6.25 (d, J ) 7.3 Hz, 1H), 6.16 (d, J ) 3.0 Hz,
1H), 6.12 (d, J ) 3.0 Hz, 1H), 5.53 (t, J ) 8.1 Hz, 1H), 4.90
(bs, 1H), 3.82 (s, 3H), 3.54 (t, J ) 7.1 Hz, 2H), 3.32-3.23 (m,
2H), 3.04 (dd, J ) 15.5, 8.3 Hz, 1H), 2.90 (dd, J ) 15.5, 7.9
Hz, 1H), 2.59 (t, J ) 6.3 Hz, 2H), 2.46 (t, J ) 7.5 Hz, 2H), 1.93
(m, 2H), 1.80 (m, 2H), 1.27 (s, 9H); 13C NMR (62.9 MHz, CDCl3)
δ 168.6, 163.6, 156.6, 155.5, 152.1, 145.1, 137.6, 136.5, 127.6,
113.2, 111.1, 110.8, 110.7, 107.4, 81.1, 53.3, 51.2, 42.8, 41.3,
39.6, 34.4, 29.1, 27.6, 26.1, 21.2.
C
23H29N5O4: C, 62.85; H, 6.65; N, 15.94. Found C, 62.51; H,
6.76; N, 16.04. Chiral HPLC analysis: Chiralpack AD (4.6 ×
250 mm); 0.045 % vol TFA and 0.023 % vol diethylamine in
hexanes, EtOH, and MeOH (14:3:3); 1.0 mL/min; 7.3 min
(undesired enantiomer) and 8.9 min (desired).
Ack n ow led gm en t. The authors greatly acknowl-
edge Mr. Robert A. Reamer and Ms. Lisa DiMichele for
NMR support.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
of 7, a mixture of 8 and 9, 16, 19-21, 23, 32, and 35 and 13C
NMR of 7, a mixture of 8 and 9, 16, 19-21, 32, and 35. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O030297U
(3S)-3-(6-Met h oxyp yr id in -3-yl)-3-{2-oxo-3-[3-(5,6,7,8-
(30) Trademark by Mitsubishi Chemical.
1966 J . Org. Chem., Vol. 69, No. 6, 2004