mol) and THF (55 gal). The slurry was heated to 50 °C, at
which point the mixture was heated another 2 h until a
homogeneous solution was observed. To the heated solution
was added a solution of 17 (theor. 111.6 mol, in MTBE, 40
gal total volume, from previous step) at such a rate that the
internal temperature was maintained above 47 °C. The stirred
mixture was seeded with 19 in a slurry of MTBE (0.5 gal)
immediately after complete addition of the MTBE/17 solu-
tion. After seeding, another portion of MTBE (73 gal) was
charged. After the second MTBE addition was complete,
heating was discontinued and the mixture gradually cooled
to room temperature over 2 h. The mixture was stirred for 8
h at 23 °C. The mixture was filtered, and the solids were
rinsed with 1:1 MTBE/THF (18 gal). The filter was blown
down with nitrogen for 1 h, and then the solids were removed
from the filter and used directly in the subsequent recrys-
tallization.
Recrystallization of 19. A 200-gal reactor was charged
with 19 (wet cake from above) and isopropyl alcohol (IPA,
153 gal). The slurry was stirred and heated over 2 h to reach
80 °C. After 45 min at 80 °C, the solids were completely
dissolved. The solution was seeded with 19 in a slurry of
IPA (0.25 gal), and the stirred mixture was cooled to room
temperature over 2 h and granulated for 6 h. The mixture
was then filtered, and the solids were rinsed with IPA (6
gal). The solids were dried at 50 °C for 4 days to provide
19.8 kg (38%) of 19 as a white crystalline solid. Chiral HPLC
analysis of the acid showed product with >99% ee. 1H NMR
(300 MHz, d6-DMSO) δ 1.36-1.62 (m, 8), 1.62-1.74 (m,
2), 1.70 (s, 6), 1.90-2.04 (m, 1), 2.17 (d, 1, J ) 15.3), 2.23
(d, 1, J ) 15.3), 2.58-2.68 (m, 2), 2.89 (dd, 1, J ) 3.3,
16.2), 3.07 (dd, 1, J ) 5.8, 16.2), 4.39 (d, 1, J ) 5.5), 4.52
(dt, 1, J ) 3.3, 5.6), 7.03-7.47 (m, 7); 13C NMR (75 MHz,
d6-DMSO) δ 26.4, 27.0 (d, J ) 16.0), 27.5 (d, J ) 1.0),
30.4, 33.9, 40.0, 41.9, 43.9, 48.5, 58.3, 72.1, 73.3, 116.9 (d,
J ) 21.0), 124.6, 125.4, 125.5, 125.6, 125.8 (d, J ) 6.0),
127.4, 127.7 (d, J ) 4.0), 129.1, 141.0, 142.2, 147.4 (d, J )
8.0), 160.8 (d, J ) 247), 177.4. Anal. Calcd for C29H37-
FN2O4: C, 70.14; H, 7.51; N, 5.64. Found: C, 70.10; H,
7.46; N, 5.64
(R)-5-(4-(2-Cyanopropan-2-yl)-3-fluorophenyl)-3-cyclo-
pentyl-3-hydroxypentanoic Acid (20). A 200-gal reactor
was charged with 19 (19.8 kg, 39.9 mol) and MTBE (58
gal). The mixture was stirred at room temperature, and
aqueous citric acid (10 kg citric acid in 26 gal H2O) solution
was added. After stirring for 3 h, the mixture was allowed
to settle for 30 min, and the lower aqueous layer was
removed. The organic phase was washed with water (2 gal),
mixed well, and separated. The organic solution was
transferred to a clean reactor, and the solution was distilled
under atmospheric pressure to 15 gal, removing water
azeotropically. An aliquot was removed and showed 0.63%
water by K-F titration. This solution of 20 was used directly
in the next step. 1H NMR (300 MHz, CD3OD) δ 1.50-1.76
(m, 7), 1.79 (s, 6), 1.92 (m, 2), 2.18 (m, 1), 2.61 (q, 2, J )
14), 2.76 (t, 2, J ) 8.0), 4.92 (s, 3), 7.08 (m, 2), 7.41 (t, 1,
J ) 8.3); 13C NMR (75 MHz, CD3OD) δ 27.5 (d, J ) 8.3),
28.0, 28.3, 28.5 (d, J ) 2.2), 31.6, 36.2, 42.4, 43.4, 76.0,
118.2 (d, J ) 23), 125.7, 126.5 (d, J ) 2.7), 127.3 (d, J )
12), 128.7 (d, J ) 3.8), 148.2 (d, J ) 7.7), 162.7 (d, J )
248), 176.3.
(R)-Ethyl 7-(4-(2-cyanopropan-2-yl)-3-fluorophenyl)-
5-cyclopentyl-5-hydroxy-3-oxoheptanoate (24). A 100-gal
reactor was charged with CDI (9.70 kg, 59.8 mol), DMAP
(244 g, 2.00 mol), and MTBE (6 gal). An MTBE solution
of 20 (13.85 kg, 39.87 mol, ∼15 gal) was added to the stirred
mixture over a 30-min period. The line was rinsed with THF
(2 gal), and the mixture was stirred for 75 min to complete
formation of the acylimidazole intermediate. A separate 200-
gal tank was charged with ethyl magnesium malonate (17.1
kg, 59.66 mol) and THF (9 gal). The stirred mixture was
heated to 46 °C, and the acylimidazole solution was slowly
added to the ethyl magnesium malonate mixture. Stirring was
continued at 48 °C for 2 h. The solution was cooled to room
temperature and charged with IPE (18 gal) and 1 M HCl
(32 gal), the mixture was stirred well, and the phases were
separated. The organic phase was washed with H2O (1 gal),
the phases were separated, and the organic layer was distilled
to 12 gal to remove water (K-F titration )0.18%). The
1
solution of 24 was used directly in the next step. H NMR
(300 MHz, CDCl3) δ 1.29 (t, 3, J ) 7.2), 1.40-1.55 (m, 3),
1.57-1.72 (m, 6), 1.86 (m, 6), 2.12 (m, 1), 2.65 (m, 2), 2.82
(d, 1, J ) 5.1), 3.66 (m, 2), 3.76 (m, 3), 4.22 (q, 2, J ) 7.2),
6.97 (m, 2), 7.38 (app. t, 1, J ) 8.1); 13C NMR (75 MHz,
CDCl3) δ 14.0, 25.7 (d, J ) 2.0), 26.5 (d, J ) 24), 27.1 (d,
J ) 3.0), 29.7, 34.8 (d, J ) 2.0), 39.9, 47.4, 48.3, 50.8, 61.6,
74.9, 117.0 (d, J ) 23), 124.1, 124.7 (d, J ) 3.0), 125.6 (d,
J ) 11.0), 127.4 (d, J ) 5.0), 145.4 (d, J ) 8.0), 160.9 (d,
J ) 250), 167.4, 172.9, 176.0.
(R)-2-(4-(2-(2-Cyclopentyl-4-hydroxy-6-oxo-3,6-dihy-
dro-2H-pyran-2-yl)ethyl)-2-fluorophenyl)-2-methylpropane-
nitrile (10). A 200-gal reactor was charged with K2CO3 (8.3
kg, 60 mol), MeOH (9 gal), and the solution of 24 (16.64
kg, 39.87 mol) from the previous experiment. The mixture
was heated to 50 °C for 4 h. The solution was cooled to
room temperature and charged with IPE (4 gal) and water
(18 gal). The mixture was stirred, and the phases were
separated. The product-containing aqueous phase was ex-
tracted with IPE (2 gal). The layers were separated, and the
aqueous phase was added back to the reactor. To the aqueous
phase was added 2-methyl-THF (27 gal), MTBE (9 gal), and
1 M HCl (∼28.5 gal) until the pH of the aqueous phase was
∼3.5. The phases were mixed well, and the aqueous phase
was removed. The organic phase was washed with saturated
aqueous NaCl (2 gal) and then concentrated by distillation
to ∼14 gal. The temperature was adjusted to 52 °C, and
heptane (4 gal) was added at such a rate that the internal
temperature was kept above 50 °C. The solution was then
seeded with solid 10 (5 g), followed by the addition of
heptane (22 gal). The heating was continued for 1 h, and
then the stirred mixture was allowed to gradually cool to
room temperature. After stirring for 60 min at room
temperature, the mixture was filtered, and the solids were
rinsed with 1:1 IPE/heptane (6 gal). The solids were dried
at 50 °C for 4 days to provide 9.1 kg (61% from 19) of 10
1
as granular crystals. H NMR (300 MHz, CDCl3) δ 1.46-
820
•
Vol. 10, No. 4, 2006 / Organic Process Research & Development