∼0.5% of methyl ester from 2, <0.5% bis-acylated impurity,
>97.5% wt/wt % assay).
(1 × 4 L). The organic phase was separated, dried (Na2SO4,
2.5 kg), and filtered, and the solvent was removed in Vacuo to
yield crude amidine 1 as a solid (1.8 kg, 93.5 area % by HPLC).
The solid was dissolved in acetonitrile (9 L) while heating to
35-40 °C. After 1/2 h, seed crystals were added, and a thick,
white slurry formed. The mixture was cooled to -10 to -15
°C in an ice/acetone bath and stirred for 1-2 h. The slurry was
filtered, and the resulting solid was rinsed with cold acetonitrile
(2 × 0.5 L) and dried in Vacuo to provide amidine 1 as a partial
CH3CN solvate (1.10 kg, 77%, 98.6 area % by HPLC). Three
CH3CN solvate lots (2.86 kg) were combined and dissolved in
21.8 L of methanol. The solution was passed through a 0.45
µm carbon impregnated filter, and the tank and filter were rinsed
with 24 L of methanol. To the solution was added 5.7 kg of
H2O over 35 min followed by 15 g of seed crystals. After 20
min, 1.15 kg of H2O was added followed by 15 g of seed
crystals. After 1 h, 1.15 kg of H2O was added over 30 min
followed by 15 g of seed crystals. After 10 min, 3.4 kg of H2O
was added over 1 h, and the slurry was stirred at rt for 1 h and
at 0 °C for 45 min. The solid was collected by filtration, rinsed
with a cold solution of 11.4 L of methanol and 2.9 L of H2O,
and dried under vacuum at 50 °C for 24 h. The solid was
equilibrated in air for 4 h to afford amidine 1 as a white solid
(hemihydrate), 2.19 kg, 76% recovery (typical laboratory
recovery is 87%, but the wash of the carbon impregnated filter
was inadequate on scale), 99.3 area % by HPLC, 99.5 wt/wt
% assay. [R]D +105.2 (MeOH, c ) 1.0). IR (CHCl3, cm-1):
3489, 1643, 1606, 1600, 1509, 1482. 1H NMR (CDCl3): δ 7.90
(d, 2, J ) 8.6), 7.69 (d, 2, J ) 8.6), 7.63 (d, 2, J ) 8.2), 7.48
(t, 2, J ) 8.2, 7,6), 7.41 (d, 1, J ) 7.3), 7.24 (dd, 2, J ) 8.5,
5.2), 7.14 (d, 1, J ) 7.9), 7.04, (t, 2, J ) 8.7), 6.72-6.63 (m,
3), 5.31 (t, 1, J ) 5.6), 4.84 (br s, 1), 4.64 (dd, 2, J ) 21.4,
15.6), 4.54 (dd, 1, J ) 14.0, 7.9), 3.32 (dd, 1, J ) 15.6, 7.9),
3.01 (s, 3), 2.95 (dd, 1, J ) 15.7, 8.0), 1.97 (s, 3). 13C NMR
(CDCl3): δ 15.3, 36.2, 38.3, 52.6, 65.2, 82.7, 115.7, 115.8,
116.7, 123.2, 125.9, 127.5, 127.6, 127.9, 128.4, 128.9, 129.2,
132.2, 133.8, 134.2, 139.7, 140.0, 145.1, 151.8, 157.6, 163.2,
169.7. MS (m/z): 508.2 (M + 1). EA calcd for C32H30N3O2 ·1/2
H2O: C, 74.40; H, 6.05; N, 8.13. Found: C, 74.50; H, 5.93; N,
8.17.
N-[(1R,2R)-6-Amino-2,3-dihydro-2-hydroxy-1H-inden-1-
yl]-[1,1′-biphenyl]-4-carboxamide (4). Kilolab Procedure.
Pd/C 10 wt % (50% H2O wet, 0.176 kg) was wetted with
DMF (4 L), and the slurry was charged to a 10-gal
autoclave. Amide 13 (1.7 kg) was added, followed by
DMF (13.6 L). The autoclave was sealed, purged with
nitrogen, and then pressurized to 50 psi of H2. After 19 h,
the mixture was filtered; 5 L of the DMF solution was
added to H2O (10 L), and the slurry stirred for 2 h. This
operation was repeated twice to work up the entire reaction
volume. The slurries were filtered together, and the
resulting filter cake was washed with H2O (3 × 7 L). The
filter cake was dried in Vacuo to afford aniline 4 (1.42
kg, 87.7%) as a white solid (97.2 wt/wt % assay). IR (KBr,
cm-1): 3584, 3364, 3277, 1632, 1543, 1326, 1073, 743.
1H NMR (DMSO-d6): δ 8.72 (d, 1, J ) 9.0), 8.03-8.05
(m, 2), 7.72-7.79 (m, 4), 7.46-7.51 (m, 2), 7.39 (t, 1, J
) 7.5), 6.82 (d, 1, J ) 8.4), 6.39 (d, 1, J ) 8.1), 6.34 (s,
1), 5.19-5.26 (m, 2), 4.88 (br s, 2), 4.32-4.42 (m, 1),
2.97 (dd, 1, J ) 14.7, 7.2), 2.57 (dd, 1, J ) 14.7, 8.1);
13C NMR (DMSO-d6): δ 20.8, 61.5, 77.8, 109.1, 113.4,
124.6, 126.0, 126.2, 126.8, 127.9, 128.0, 128.9, 133.3,
139.1, 142.5, 147.6, 166.0. HRMS calcd for C22H20N2O2:
344.1525; Found: 344.1525. EA calcd for C22H20N2O2:
C, 76.72; H, 5.85; N, 8.13. Found: C, 76.51; H, 5.84; N,
8.10.
Pilot-Plant Procedure. To 205 L of MeOH were added 15
kg of amide 13, 5.4 kg of concd HCl, and 4.5 kg of 10% Pd/C
(40% H2O wet) slurried in 20 L of MeOH. The catalyst portable
tank was rinsed with 10 L of MeOH (2×). After purging with
nitrogen, the reaction mixture was subjected to 60 psi of H2 at
30 °C for 3 d. The catalyst was removed by filtration over
diatomaceous earth, and the cake was rinsed with 150 L of
MeOH. The mixture was concentrated to 300 L by vacuum
distillation, and 300 L of 0.2 N NaOH was added at 50-60
°C. After cooling to rt, the solid was collected by filtration and
washed with 110 L of 1:1 H2O/MeOH followed by 110 L of
H2O. The solid was dried at 50 °C under vacuum to afford
12.9 kg (93%) of aniline 4. To 25 kg of aniline 4 prepared in
this manner was added 1000 L of CH3CN, and the slurry was
heated at 70 °C for 24 h. After cooling to room temperature,
the solids were collected by filtration and rinsed with 75 L of
CH3CN. The solid was dried at 50 °C under vacuum to afford
22.3 kg (90% recovery) of aniline 4 (98.8 area %, 100.4 wt/wt
% assay).
Amidine 1. Improved Process Laboratory Procedure. To
a slurry of aniline 4 (10.04 g, 29.2 mmol), K2CO3 (2.01 g, 14.6
mmol, 0.5 equiv), and DMAP (0.356 g, 2.92 mmol, 0.1 equiv)
in THF (100 mL) under nitrogen at ambient temperature was
added thioimidate 20 (9.89 g, 29.2 mmol, 1.0 equiv). After
stirring overnight, K2CO3 (14 g, 101 mmol, 3.5 equiv) was
added. After 6 h, the solids were removed by filtration and the
filtrate was concentrated in Vacuo. The resulting tan foam (18
g) was dissolved in CH3CN (100 mL), and a thick, white slurry
resulted within 10 min. The slurry was stirred 2 h at ambient
temperature, then 2 h in an ice/H2O bath. The crystals were
collected by filtration, washed with cold CH3CN (2 × 10 mL),
and dried overnight in Vacuo at 50 °C to afford 12.47 g (84%)
of amidine 1 as a partial CH3CN solvate (99.1 area % by
HPLC). The hemihydrate was formed using the procedure
above.
N-[(1R,2R)-6-[[1-[[(4-Fluorophenyl)methyl]methylamino]-
ethylidene]amino]-2,3-dihydro-2-hydroxy-1H-inden-1-yl]-
[1,1′-biphenyl]-4-carboxamide, Hemihydrate (1). Kilolab
Procedure. To a slurry of aniline 4 (0.969 kg, 2.8 mol) in THF
(9.7 L) at rt was added thioimidate 20 (0.954 kg, 2.8 mol) and
DMAP (34.5 g, 0.28 mol). When HPLC indicated that thio-
imidate 20 was <2 area % (20-24 h), the mixture was
transferred to a rotary evaporator, and the solvent was removed
in Vacuo. The resulting foam was dissolved in CH2Cl2 (12.5
L), and the organic phase was washed with 1.0 N HCl(aq) (1 ×
4 and 1 × 3 L), 1.0 M NaOH(aq) (1 × 2.44 L) and sat. NaCl(aq)
N-(4-Fluorobenzyl)-N-methylacetamide (5). To 224 g
(134 g corrected for mineral oil, 5.55 mol, 1.2 equiv)
206
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Vol. 13, No. 2, 2009 / Organic Process Research & Development