Suzuki-Miyaura Approach to JNJ-26076713
with NaHCO3 (2 × 2 L) and 0.5 M NaOH (2 × 2 L). The combined
aqueous phases were extracted with EtOAc (1 L) and the combined
organic extracts were dried over Na2SO4, filtered, and concentrated
under reduced pressure affording crude 5a (200 g) as a brown oil.
Purification by chromatography on silica gel (1 kg, 70-230 mesh,
gradient elution with 4 L of hexanes, 4 L of 10% EtOAc/hexanes,
2 L of 40% EtOAc/hexanes, and 100% EtOAc) afforded a dark
brown oily solid. The oily solid was triturated with hexanes (150
mL) and collected by filtration affording R,â-unsaturated ester 5a,
which was 96% pure by HPLC analysis (139.1 g, 67%, mp 119-
124 °C). NMR analysis indicated lower purity in the aromatic region
(15% impurity). The olefin 5a was the Z-isomer as determined by
NOE studies (Z-isomer vinyl proton resonance at 6.05 ppm,
(rinsing plug); injection amount: 4 g/ 250 mL of eluent; capacity:
3.5 runs/h (14 g/h)]. Compound 6, Fr-4 (65 g; 20% yield; 96.1%
pure by chiral HPLC; 0.68, 1.87, 1.35% of Fr-1, -2, and -3,
respectively) was isolated. Samples of the other fractions were also
obtained in similar purity,8b but no attempt was made to maximize
the quantity of them in this purification. Chiral HPLC Method A:
Chiralpak AD (5 µm, 150 mm × 4.6 mm); isocratic ethanol;
ambient; flow rate: 1.0 mL/min; UV detection: 254 nm; retention
times: 6, Fr-1, 5.5 min; 6, Fr-2, 6.0 min; 6, Fr-3, 7.5 min; 6, Fr-4,
8.5 min.
(3S,3′S)-4-Piperidin-4-yl-3-(1,2,3,4-tetrahydroquinolin-3-yl)-
butyric Acid Methyl Ester (10). A 3-L, 3-necked, round-bottomed
flask, equipped with magnetic stirrer and argon inlet, was charged
with compound Fr-4-(2S,3′S)-6 (55.22 g, 133 mmol), methoxy-
benzene (1.44 mL, 13.3 mmol), and 1,4-dioxane (880 mL). This
solution was treated with 4 M HCl gas in dioxane (883 mL, 3.53
mol) to give a clear solution that became hazy and deposited a
thick red oil that was difficult to stir. A spatula was used to loosen
the red oil. After 4 h, additional 4 M HCl/dioxane (90 mL, 0.36
mol) was added and the reaction was stirred for an additional 7 h
until complete by LC/MS. The solvent was removed in vacuo at
45 °C to afford a solid that was triturated with ethyl ether (1 L),
collected by filtration, and washed with ethyl ether (0.5-1 L). The
isolated light pink solid was dried in a vacuum oven (55-60 °C)
for 6 h to give 10 as the bis-hydrochloride salt (50.87 g, 98%). 1H
NMR (300 MHz, DMSO-d6) δ 7.2-6.8 (m, 4H), 3.58 (s, 3H),
3.33-3.21 (m, 3H), 3.0-2.4 (m, 6H), 2.33-2.26 (m, 1H), 2.04
(m, 2H), 1.82-1.76 (m, 2H), 1.59 (m, 1H), 1.4-1.1 (m, 4H). HPLC
Method B: >99% area; retention time: 4.85 min; Thermo
Betabasic-C-18, 4.6 × 150 mm2; ambient; H2O:MeCN 95:5 to 5:95
in 12 min, H2O and acetonitrile buffered with 0.1% TFA; flow
rate: 1.5 mL min-1; UV detection: 210 nm, 254 nm; LC/MS (ES+)
m/z 317.3 (M + 1). Anal. Calcd for C19H28N2O2‚2HCl‚0.35H2O‚
0.60C4H10O: C, 57.30; H, 7.98; N, 6.24; Cl, 15.81. Found: C,
56.94; H, 8.13; N, 6.70; Cl, 15.77. Karl Fisher Titration Calcd:
1.41%. Found: 1.39% (w/w).
1
E-isomer at 6.28 ppm). H NMR (300 MHz, CDCl3) δ 8.71 (d, J
) 2.2 Hz, 1H), 8.10 (d, J ) 8.4 Hz, 1H), 7.96 (d, J ) 2.2 Hz, 1H),
7.81 (d, J ) 8.4 Hz, 1H), 7.72 (td, J ) 7.0, 1.3 Hz, 1H), 7.56 (td,
J ) 7.0, 1.3 Hz, 1H), 6.05 (s, 1H), 4.01 (br s, 2H), 3.47 (s, 3H),
2.59 (br s, 2H), 2.51 (d, J ) 7.0 Hz, 2H), 1.70-1.60 (m, 2H), 1.42
(s, 10 H), 1.20-1.03 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 165.9,
154.9, 154.2, 150.0, 147.7, 133.8, 132.7, 130.0, 129.6, 128.2, 127.6,
127.1, 120.3, 79.6, 51.5, 47.7, 44.0 (br), 34.0, 32.1, 28.6. HPLC
Method A: retention time: 11.21 min; LC/MS (ES+) m/z 411.2
(M + 1). Anal. Calcd for C24H30N2O4: C, 70.22; H, 7.37; N, 6.82.
Found: C, 69.87; H, 7.56; N, 6.58. Palladium: 170 ppm by ICP.
4-[3-Methoxycarbonyl-2-(1,2,3,4-tetrahydroquinolin-3-yl)pro-
pyl]piperidine-1-carboxylic Acid tert-Butyl Ester (6). To a 5-L,
6-necked pressure vessel equipped with a pressure relief valve,
pressure gauge, large stirring bar, blast shield, and quick connect
gas inlet was charged 10% Pd/C (112.5 g, Degussa type-50% water
wet), which was vacuum/N2 degassed, followed by addition of a
solution of (Z)-5a (150 g, 0.365 mol) in methanol (3.4 L). The
mixture was pressurized with H2 at 50 psig and stirred at ambient
temperature for 24 h. The hydrogen pressure was adjusted back up
to 50 psig as needed. The reaction was judged complete by TLC
(30% EtOAc in hexanes) by disappearance of (Z)-5a. The reaction
mixture was filtered through 150 g of Celite in a glass-fritted filter,
and rinsed with additional methanol (6 L). The methanol filtrate
was then concentrated under reduced pressure, affording an orange-
red gum. The gum was purified by chromatography on silica gel
(3.0 kg, 230-400 mesh, gradient elution with 20 L hexanes, 20 L
of 10% EtOAc/hexanes, 20 L of 20% EtOAc/hexanes, and then 20
L of 30% EtOAc/hexanes). This afforded racemic 6 (76.0 g, 51%)
(3-S,3′-S)-4-[1-(3-5,6,7,8-Tetrahydro[1,8]naphthyridin-2-yl-
propionyl)piperidin-4-yl]-3-(1,2,3,4-tetrahydroquinolin-3-yl)bu-
tyric Acid Methyl Ester (12). A 2000-mL, round-bottomed flask,
equipped with magnetic stirrer and argon inlet, was charged with
a slurry/solution of piperidine (3S,3′S)-10 (29.5 g, 75.8 mmol), acid
11 (20.23 g, 83.3 mmol, Adesis Inc., New Castle, DE), 1-hydroxy-
benzotriazole hydrate (5.89 g, 37.9 mmol), and dimethylformamide
(295 mL). This solution was purged with an argon stream (15-20
min) and chilled in an ice bath. To the reaction was added 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI,
15.98 g, 83.3 mmol) in one portion and diisopropylethylamine
(39.64 mL, 227 mmol) in a dropwise fashion. The reaction was
stirred for 60 min, removed from the ice/water bath, and stirred at
rt for 17 h. The reaction was complete by LC/MS and was poured
into saturated sodium bicarbonate (3 L). The reaction mixture was
extracted with ethyl acetate (4 × 750 mL) and the combined organic
phases were washed with saturated ammonium chloride (2 × 500
mL) and brine (3 × 500 mL), dried (MgSO4 and Na2SO4), and
concentrated to give crude amide product (35.4 g). This was
dissolved in dichloromethane and loaded onto an Analogix column
(2 runs; SiO2, 220 g) and eluted (linear gradient, dichloromethane
to 1:6:3:90 NH4OH/i-PrOH/EtOH/dichloromethane) to give crude
12 (4.1 g), followed by pure 12 (31.7 g). The mixed fractions were
dissolved in dichloromethane and loaded onto an Isco column (SiO2;
120 g) and eluted (linear gradient, dichloromethane to 1.5:6:3:89.5
NH4OH/i-PrOH/EtOH/dichloromethane) to give additional product
(2.7 g). After combining and concentrating from chloroform, the
1
as an orange gum. H NMR (300 MHz, CDCl3) δ 6.95 (m, 2H),
6.61 (t, J ) 7.2 Hz, 1H), 6.46 (d, J ) 8.4 Hz, 1H), 4.05 (m, 2H),
3.84 (br s, 1H), 3.66 (s, 3H), 3.24 (d, J ) 10.5 Hz, 1H), 2.99 (td,
J ) 10.5, 3.0 Hz, 1H), 2.78-2.55 (m, 5H), 2.46-2.21 (m, 2H),
2.20-1.90 (m, 2H), 1.66 (m, 2H), 1.45 (s, 9H), 1.40-1.00 (m,
4H). HPLC Method A with UV detection at 254 nm: retention
time: 11.57 min; purity: 85%; LC/MS (ES+) m/z 417.4 (M + 1).
Isolation of Fr-4, (2-S,3′-S)-4-[3-Methoxycarbonyl-2-(1′,2′,3′,4′-
tetrahydroquinolin-3′-yl)propyl]piperidine-1-carboxylic Acid
tert-Butyl Ester (6). Racemic 6 (323 g, 0.775 mol) was purified
by sequential chiral chromatography. In this paper, the isomer
numbering is based on Chiralpak AD elution order (Fr-4, last
eluting). Previously, the Chiralcel OD column was used for
numbering, thereby reversing the order of Fr-2 (c) and Fr-3 (b).8b
Crude 6 was a 1/1/1/1 ratio of Fr-1, -2, -3, and -4. Compound 6,
Fr-1 and Fr-3 were separated from 6, Fr-2 and Fr-4 by using a
Chiralcel OD column [110 mm i.d. dynamic axial compression
(DAC) column filled with 2000 g of 20 µm Chiralcel OD (Daicel);
temperature of eluent: 28 °C; column wall temperature: 30 °C;
eluent: methanol; flow rate: 750 mL/min]. The sample was
prepared by dissolving 5.8 g of 6 in 200 mL of the eluent (29 mg/
mL) and injected at a rate of 3.6 runs per hour (20.9 g of 6/h). The
purification was complete after 15 h of continuous chromatography
(56 injections). Compound 6, Fr-2 was separated from 6, Fr-4 by
using a Chiralpak AD column [110 mm i.d. DAC filled with 2000
g of Chiralpak AD; temperature of eluent: 38 °C; temperature of
column wall: 40 °C; eluent: acetonitrile (750 mL/min), ethanol
1
total yield of 12 was 34.4 g (83%). H NMR (300 MHz, DMSO-
d6) δ 7.00 (m, 1H), 6.84-6.80 (m, 2H), 6.42-6.38 (m, 2H), 6.28-
6.23 (m, 2H), 5.60 (br s, 1H), 4.35 (br d, J ) 13 Hz, 1H), 3.82 (br
d, J ) 13 Hz, 1H), 3.59 (s, 3H), 3.3-3.1 (m, 3H), 3.0-2.8 (m,
2H), 2.7-2.4 (m, 10H), 2.29-2.27 (m, 1H), 1.98 (m, 1H), 1.8-
1.4 (m, 6H), 1.30 (m, 1H), 1.14 (m, 1H), 0.88 (m, 2H). HPLC
J. Org. Chem, Vol. 73, No. 6, 2008 2307