Organic Process Research & Development
Article
five equal portions at −10 to 0 °C. The resulting slurry was
held at 0 °C for 7 h, diluted with MTBE (74 L), and held for
1 h before passing through a Celite-packed Nutsche filter. The
filter cake was washed four times with MTBE (30 L per wash),
and the combined filtrates were washed three times with water
(240 L per wash). The organic layer was separated, con-
centrated to 30−40 L (30 °C, 0.2 bar), and diluted with toluene
(48 L) to obtain 20.6 kg of imidazolyl ester 9 (containing 4%
regioisomer 10; 90% combined yield) as a ∼30 wt% solution in
toluene (75.9 kg total solution) that was telescoped directly into
ester hydrolysis. An analytical sample of 9 was purified by silica
gel chromatography (25% EtOAc/hexanes) as a pale yellow oil
with physical and analytical data matching those reported above.
(S)-3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-
1-yl)propanoic Acid (2). Acid-Catalyzed Hydrolysis. A
stirred, biphasic mixture of ester 9 (5.62 kg of 9 + 10, 18.6
mol of 9 corrected for 4% 10) in toluene (6 L) and 6 M
aqueous HCl (34 L) was heated at 90 °C for 5 h and cooled to
20 °C. The phases were separated, and the aqueous layer was
held at <40 °C while charging with 50% aqueous NaOH (10 L).
The mixture was adjusted to pH 3 with the addition of 6 M aq
HCl or 6 M aq NaOH as necessary at <30 °C. The resulting
suspension was mixed at 5 °C for 12 h while readjusting to pH
3 as necessary. The solids were extracted into EtOAc (56 L),
and the organic layer was dried over Na2SO4 (11 kg) and
passed through a Celite-packed Nutsche filter. The filter cake
was rinsed with EtOAc (56 L), and the combined filtrates were
concentrated to 12 L (50 °C, 0.1 bar). The solution was diluted
with EtOAc (11 L) and distilled at 78 °C at constant volume
with the continuous addition of EtOAc (45 L). The solution
was concentrated to 18 L, cooled to 25 °C, and diluted with
heptane (39 L) to precipitate solids. The mixture was heated at
65 °C for 1 h to redissolve the solids and cooled to 15 °C over
2 h. The recrystallized solids were mixed at 15 °C for 12 h,
collected on a Nutsche filter, rinsed with heptane (10 L), and
dried at 45 °C under vacuum with N2 sweep to obtain 3.53 kg
while adjusting to pH 3 with the addition of 12% aqueous HCl
(56.4 kg). The mixture was held at 20 °C for 30 min, and
the organic layer was washed twice with 0.01 M aqueous HCl
(84 L per wash). The organic layer was concentrated to 120−150 L
(40 °C, 0.2 bar), diluted with heptane (310 L), and re-
concentrated to 300−350 L (40 °C, 0.2 bar). The mixture was
cooled to 20 °C and passed through a Nutsche filter. The filter
cake was rinsed with heptane (42 L) and dried under vacuum at
40 °C to provide 42.2 kg of acid 2 (78% yield) as a white solid
with physical and analytical data matching those reported above.
(S)-Benzyl 6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-
imidazol-1-yl)propanamido)nicotinate (11). A stirred mix-
ture of acid 2 (22.00 kg, 79.64 mol), amine 3 (20.00 kg, 87.62
mol, 1.1 equiv), pyridine (22 L, 270 mol, 1.0 vol), MeCN (110 L),
and EtOAc (57 L) was charged with T3P solution (50 wt%
MeCN, 101 kg, 104 L, 159 mol, 2.0 equiv) at −5 °C. The re-
sulting homogeneous solution was held at 0 °C for 20 h as fine
solids precipitated. A solution of 0.5 M aqueous HCl (67 L)
was added over 30 min at <10 °C, and the resulting suspension
was mixed at 20 °C for 16 h and passed through a filter drier.
The cake was rinsed under continuous agitation with three
charges of water (110 L per charge) and dried at 50 °C with N2
sweep to obtain 34.08 kg of amide 11 (88% yield) as a white
1
solid: mp 170−171 °C; H NMR (400 MHz, d6-DMSO) δ
11.55 (s, 1H); 8.91 (dd, J = 0.4, 2.4 Hz, 1H), 8.34 (dd, J = 2.4,
8.8 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.97−7.99 (m, 2H),
7.46−7.50 (m, 2H), 7.34−7.44 (m, 3H), 5.36 (s, 2H), 5.26 (dd,
J = 5.2, 10.4 Hz, 1H), 2.20 (ddd, J = 6.0, 10.4, 14.0 Hz, 1H),
2.10 (ddd, J = 5.2, 8.8, 14.0 Hz, 1H), 1.27−1.69 (m, 8H), 1.02−
1.12 (m, 1H); 13C NMR (100 MHz, d6-DMSO) δ 168.9, 164.1,
154.7, 149.6, 139.7, 138.9, 135.9, 130.0 (q, JCF = 38 Hz), 128.5,
128.2, 128.1, 122.1 (q, JCF = 265 Hz), 121.5, 120.1 (q, JCF = 4
Hz), 113.0, 66.3, 60.0, 37.5, 36.2, 32.0, 30.8, 24.6, 24.4; 19F NMR
(376 MHz, d6-DMSO) δ −60.7. HRMS-ESI m/z: [M + H]+
calcd for C25H25F3N4O3, 487.1952; found, 487.1955. Achiral
HPLC: rt 5.9 min. Chiral HPLC: rt 6.0 min (11), 7.0 min (ent-11).
(S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imida-
zol-1-yl)propanamido)nicotinic Acid (1). Pressure Hydro-
genation. A stirred mixture of benzyl ester 11 (4.28 kg, 8.80
mol), 10% Pd/C (0.22 kg, 5 wt% relative to 11), and IPA
(26 L) under 50 psig of H2 was held in a pressure reactor at
25 °C for 24 h. The reactor was vented and purged with N2,
and the reactor contents were passed through a Celite-packed
Nutsche filter and rinsed with IPA (8 L). The filtrate was
diluted with heptane (40 L), held at 25 °C for 30 min, and
passed through another Celite-packed Nutsche filter with 1:1
v/v IPA/heptane rinse (6 L). The filtrates were stirred over Si-
Thiol (0.35 kg) at 25 °C for 4 h, passed through a speck-free
filter, and concentrated to 9 L (35−45 °C; 0.1 bar). The
solution was diluted with heptane (8 L), cooled to 20 °C over
2 h, and held at 20 °C for 12 h. The mixture was diluted with
additional heptane (40 L) over 1 h, cooled to 15 °C, and held
at 15 °C for 12 h. The suspension was passed through a Nutsche
filter, and the filter cake was rinsed with 9:1 v/v heptane/IPA (8 L)
and dried at 45 °C under vacuum with N2 sweep to obtain 3.12 kg
of 1 (89% yield) as a white solid: mp 187−189 °C; 1H NMR (400
MHz, d6-DMSO) δ 13.23 (s, 1H), 11.49 (s, 1H), 8.86 (dd, J = 0.4,
2.4 Hz, 1H), 8.27 (dd, J = 2.4, 8.8 Hz, 1H), 8.13 (d, J = 8.8 Hz,
1H), 7.97−7.99 (m, 2H), 5.27 (dd, J = 5.6, 10.0 Hz, 1H), 2.20
(ddd, J = 6.0, 10.0, 14.0, 1H), 2.10 (ddd, J = 5.6, 8.4, 14.0, 1H),
1.27−1.69 (m, 8H), 1.03−1.12 (m, 1H); 13C NMR (100 MHz, d6-
1
of acid 2 (69% yield) as a white solid: mp 160−161 °C; H
NMR (400 MHz, d6-DMSO) δ 13.42 (br s, 1H), 7.95−7.97 (m,
2H), 5.06 (dd, J = 4.4, 11.2 Hz, 1H), 2.20 (ddd, J = 5.2, 11.2,
14.0 Hz, 1H), 2.02 (ddd, J = 4.4, 9.2, 14.0 Hz, 1H), 1.69−1.76
(m, 1H), 1.49−1.61 (m, 3H), 1.36−1.47 (m, 3H), 1.09−1.18
(m, 1H), 1.01−1.08 (m, 1H); 13C NMR (100 MHz, d6-DMSO)
δ 171.3, 139.2, 129.9 (q, JCF = 37 Hz), 122.1 (q, JCF = 265 Hz),
120.2 (q, JCF = 4 Hz), 59.0, 37.4, 36.4, 31.9, 31.3, 24.6, 24.3; 19F
NMR (376 MHz, d6-DMSO) δ −60.7. HRMS-ESI m/z: [M +
H]+ calcd for C12H15F3N2O2, 277.1158; found, 277.1160. Achiral
HPLC: rt 4.4 min. Chiral SFC: rt 4.6 min (2), 2.0 min (ent-2).
Base-Catalyzed Hydrolysis. A solution of ester 9 (58.9 kg of
9 + 10, 195 mol of 9 corrected for 4% 10) in toluene (140 L)
was added to a stirred solution of NaOH (24.4 kg, 610 mol, 3.1
equiv) in water (790 L) over 4 h at 15−20 °C. The biphasic
mixture was held at 20 °C for 2 h and adjusted to pH 3 with
conc HCl (45 L) at 15−20 °C. The resulting suspension was
mixed at 20 °C for 30 min and passed through a Nutsche filter,
and the filter cake was rinsed sequentially with toluene (90 L)
and 0.01 M aqueous HCl (40 L). The filtered solids were dried
under vacuum at 45 °C, dissolved in MTBE (510 L) and
acetone (55 L), and charged with a solution of (R)-(+)-α-
methylbenzylamine (25.9 kg, 214 mol, 1.1 equiv) in MTBE (68 L)
at 15−25 °C. The resulting suspension was mixed at 20 °C for
3 h and passed through a Nutsche filter, and the filter cake was
rinsed with MTBE (290 L). The filtered solids were redissolved
in MTBE (320 L) and water (450 L) and held at 15−20 °C
DMSO) δ 168.8, 165.7, 154.3, 149.7, 139.6, 138.8, 129.9 (q, JCF
=
38 Hz), 122.6, 122.0 (q, JCF = 265 Hz), 120.0 (q, JCF = 4 Hz),
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dx.doi.org/10.1021/op300194c | Org. Process Res. Dev. 2012, 16, 1635−1645