Large-Scale Synthesis of BILN 2061
(19.0 g, 43.2 mmol), and diisopropylethylamine (7.5 mL) in
dichloromethane (80 mL) was added over 20 min. Additional
diisopropylethylamine (3.5 mL) was added, and the reaction was
stirred at rt for 1.5 h, at which point the reaction was complete.
The mixture was concentrated, and the residue was diluted with
toluene (100 mL) and MTBE (200 mL). The organic layer was
washed with half-saturated NaHCO3 to remove HOBT and with
water to remove tetramethylurea. The organic layer was concen-
trated, and the residue was stripped from toluene (160 mL) to give
the crude product 11 (27.3 g by HPLC assay, 95%) as a thick oil;
(1S,4R,6S,7Z,14S,18S)-18-(4-Bromo-benzenesulfonyloxy)-14-
cyclopentyloxycarbonylamino-2,15-dioxo-3,16-diaza-tricyclo-
[14.3.0.04,6]nonadec-7-ene-4-carboxylic Acid Methyl Ester (15).
A solution of brosyl chloride (6.90 g, 27.0 mmol) in CH2Cl2 (100
mL) was added to a solution of 13 (9.84 g by HPLC assay, 20.0
mmol), triethylamine (8.37 mL, 60 mmol), and DMAP (122 mg,
1.0 mmol) in toluene (30 mL) at ambient temperature. The reaction
mixture was stirred at ambient temperature overnight (15 h). HPLC
analysis indicated that the reaction was complete. The reaction
mixture was diluted with toluene (40 mL), washed with 0.5 N HCl
(94 mL) and 5% NaHCO3 (94 mL), and concentrated to give
crude 15 (13.24 g, 93% assay yield by HPLC). This crude
product was used directly for the next step. 1H NMR (CDCl3, 600
MHz): δ 7.82 (dd, J ) 8.6, 1.8 Hz, 2 H), 7.71 (dd, J ) 8.6, 1.9
Hz, 2 H), 6.91 (br s, 1 H), 5.50 (dt, J ) 10.9, 5.4 Hz, 1 H), 5.32
(br d, J ) 7.9 Hz, 1 H), 5.22-5.16 (m, 2 H), 5.06 (m, 1 H), 4.77
(dd, J ) 9.2, 1.8 Hz, 1 H), 4.53 (br t, J ) 6.3 Hz, 1 H), 4.24 (dd,
J ) 12.1, 5.6 Hz, 1 H), 3.84 (dd, J ) 12.1, 1.4 Hz, 1 H), 3.61 (s,
3 H), 2.65 (d, J ) 14.5 Hz, 1 H), 2.30-2.20 (m, 1 H), 2.16-2.08
(m, 2 H), 2.05-1.91 (m, 3 H), 1.90-1.76 (m, 2 H), 1.70-1.20
(m, 14 H). 13C NMR (CDCl3, 150 MHz): δ 172.8, 169.7, 169.6,
155.9, 135.4, 134.1, 132.6, 129.5, 129.4, 125.5, 79.0, 78.1, 58.4,
53.3, 52.4, 51.6, 41.1, 32.7, 32.1, 31.4, 28.0, 27.9, 25.8, 25.3, 23.6,
22.5, 22.4. HRMS calcd for C31H41BrN3O9S [M + H] 710.1747,
found 710.1741.
(1S,4R,6S,7Z,14S,18R)-14-Cyclopentyloxycarbonylamino-18-
[2-(2-isopropylamino-thiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-
2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-car-
boxylic Acid Methyl Ester (16). A suspension of brosylate 15
(13.24 g by HPLC assay, 18.64 mmol), 4 (5.88 g, 18.64 mmol),
and Cs2CO3 (7.89 g, 24.23 mmol) in NMP (47 mL) was heated to
50 °C and stirred at 50 °C for 24 h. HPLC analysis indicated that
the reaction was complete. After cooling to rt, EtOAc (200 mL)
was added, and the suspension was washed with 2.5% NaHCO3 (2
× 160 mL). NMP (80 mL) was added, and the organic layer was
washed with 2.5% NaHCO3 until all 4 was removed. The organic
layer was washed with 2% NaCl (200 mL) and concentrated to
give crude product 16 (12.3 g by HPLC assay, 84%).
The crude product 16 was dissolved with EtOAc (450 mL). The
solution was heated to 40 °C and treated with charcoal (6 g) for 3
h. The mixture was filtered, and the filtrate was concentrated until
the total weight was ∼85 g (∼80 mL EtOAc remained). The
solution was heated to 65 °C, and heptane (120 mL) was added
over 1 h.The solution then was stirred for an additional 30 min.
After the suspension was cooled to rt over 2 h, was stirred at rt for
4 h and at 4-5 °C for 1 h, the crystalline solids 16 (10.7 g, >99%
purity by HPLC) were collected by filtration. A full characterization
of this compound was reported in ref 4; mp 176 °C; [R]25D +53.3
(c ) 1.13, MeOH). 13C NMR (DMSO-d6, 100 MHz): δ 172.9,
171.7, 170.6, 167.7, 160.65, 159.5, 155.6, 154.0, 150.8, 150.7,
132.9, 126.5, 123.0, 117.1, 115.0, 106.8, 105.4, 98.3, 76.7, 76.1,
58.1, 55.3, 52.6, 52.0, 51.8, 46.6, 40.0, 33.3, 32.1, 31.5, 30.1, 27.2,
26.8, 25.9, 24.4, 23.1, 22.3, 21.3.
(1S,4R,6S,7Z,14S,18R)-14-Cyclopentyloxycarbonylamino-18-
[2-(2-isopropylamino-thiazol-4-yl)-7-methoxy-quinolin-4-yloxy]-
2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-car-
boxylic Acid (1). A solution of 16 (20.0 g, 25.3 mmol) in THF
(160 mL) was treated with a solution of LiOH-H2O (2.45 g, 102
mmol) in water (54 mL) at 40-45 °C, and the mixture was stirred
for 8 h at the same temperature. After complete conversion, the
mixture was cooled to rt, the aqueous layer was separated, ethanol
(54 mL) was added to the organic layer, and the pH was adjusted
to pH 5.5-5.7 by addition of 1 M HCl. The mixture was heated to
40-45 °C, and water (80 mL) was added slowly. After precipitation
started, additional water (80 mL) was added at 40-45 °C and the
suspension was cooled to rt and then stirred for 1 h at the same
temperature. After filtration, the precipitate was washed with water
(3 × 20 mL) and dried under vacuum at 35 °C. Yield: 17.7 g
(90%). A full characterization of this compound was reported in
[R]25 +6.8 (c 1.98, MeOH). 1H NMR (rotamers, CDCl3, 500
D
MHz): δ 8.25-8.15 (m, 4 H), 7.81 (s, 1 H), 5.72-5.69 (m, 2 H),
5.62-5.58 (m, 1 H), 5.22-5.09 (m, 4 H), 4.95-4.88 (m, 2 H),
4.81 (d, J ) 7.9 Hz, 1 H), 4.52-4.45 (m, 1 H), 4.25-4.15 (m, 1
H), 3.78 (d, J ) 12.0 Hz, 1 H), 3.55, 3.38 (2s, 3 H), 3.00 (d, J )
13.8 Hz, 1 H), 2.30-2.20 (m, 1 H), 2.03-1.25 (m, 21 H). 13C
NMR (rotamers, CDCl3, 125 MHz): δ 174.0, 170.3, 164.2, 156.3,
150.6, 138.5, 135.1, 133.5, 133.4, 131.1, 130.9, 123.4, 118.0, 114.6,
114.4, 78.1, 74.3, 72.7, 59.1, 53.2, 52.4, 52.0, 40.0, 33.8, 33.5, 33.4,
33.3, 32.8, 32.7, 31.2, 28.7, 28.6, 28.5, 25.1, 23.6, 23.0. HRMS
calcd for C34H45N4O10 [M + H] 668.3057, found 669.3132.
(1S,4R,6S,7Z,14S,18S)-14-Cyclopentyloxycarbonylamino-18-
(4-nitro-benzoyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]-
nonadec-7-ene-4-carboxylic Acid Methyl Ester (12). A solution
of 11 (668.7 g, 1.0 mol) in CH2Cl2 (100 L) was degassed by
bubbling nitrogen. Hoveyda catalyst 18 (30 g, 0.05 mol) was added
at rt. The reaction mixture was heated at reflux for 24 h, at which
point the HPLC analysis indicated that the reaction was complete.
The reaction mixture was cooled to 30 °C and 2-mercaptonicotinic
acid (155.2 g, 1.0 mol) was added followed by triethylamine (101.2
g, 1.0 mol). The mixture was stirred at 30 °C for 30 min and then
concentrated. The residue was diluted with toluene (25 L), and the
solution was stirred at 55 °C for 6 h. The solution was cooled to rt
and washed with 0.5 M NaHCO3 (2 × 25 L). Activated carbon
(0.5 kg) was added to the organic layer, and the mixture was stirred
at 35 °C overnight (15 h). The mixture was filtered and concentrated
to give crude product 12 (557.3 g by HPLC assay, 87%). This crude
product was used directly for the next step. 1H NMR (CDCl3, 500
MHz): δ 8.25 (AB d, J ) 8.6 Hz, 2 H), 8.22 (AB d, J ) 8.6 Hz,
2 H), 7.14 (s, 1 H), 5.63 (dd, J ) 5.3, 5.3 Hz, 1H), 5.47 (dt, J )
10.9, 4.9 Hz, 1 H), 5.38 (d, J ) 8.1 Hz, 1 H), 5.14 (t, J ) 9.0 Hz,
1 H), 5.08 (br s, 1 H), 5.01 (d, J ) 8.8 Hz, 1 H), 4.64 (br dd, J )
6.7, 6.7 Hz, 1 H), 4.37 (dd, J ) 12.2, 5.5 Hz, 1 H), 3.86 (d, J )
12.9 Hz, 1 H), 3.29 (s, 3 H), 2.98 (d, J ) 14.3 Hz, 1 H), 2.35-2.
22 (m, 2 H), 2.16 (q, J ) 3.9 Hz, 1 H), 2.02-1.58 (m, 12 H),
1.52-1.18 (m, 7 H). HRMS calcd for C32H41N4O10 [M + H]
641.2744, found 641.2824.
(1S,4R,6S,7Z,14S,18S)-14-Cyclopentyloxycarbonylamino-18-
hydroxy-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-
ene-4-carboxylic Acid Methyl Ester (13). A solution of 12 (48.74
g by HPLC assay, 76.1 mmol) in THF (300 mL) was stirred at -5
°C as a solution of LiOH-H2O (3.35 g, 79.9 mmol) in water (100
mL) was added over 2 h while the temperature was kept at -2 to
0 °C. After the reaction was stirred for another hour, HPLC analysis
indicated that the reaction was complete. The reaction was
neutralized with 1 N HCl (∼8 mL) at 0 °C until pH ) 7. The
reaction mixture was diluted with EtOAc (570 mL) and the organic
layers were washed with 5% NaHCO3 (2 × 250 mL) and 2% NaCl
(200 mL) and concentrated to give crude product 13 as an oil (33.26
g by HPLC assay, 89%). 1H NMR (CDCl3, 400 MHz): δ 7.38 (br
s, 1 H), 5.58 (dt, J ) 9.5, 9.5 Hz, 1 H), 5.35 (d, J ) 7.8 Hz, 1 H),
5.27 (t, J ) 9.4 Hz, 1 H), 5.00-5.18 (m, 2 H), 4.73 (d, J ) 9.3
Hz, 1 H), 4.42-4.50 (m, 2 H), 3.91 (dd, J ) 11.1, 4.3 Hz, 1 H),
3.75 (d, J ) 11.1 Hz, 1 H), 3.68 (s, 3 H), 2.43 (d, J ) 14.4 Hz, 1
H), 2.30-2.00 (m, 4 H), 1.90-1.20 (m, 18 H). 13C NMR (CDCl3,
100 MHz): δ 174.4, 173.1, 169.7, 155.8, 134.4, 125.5, 77.9, 71.2,
59.5, 57.4, 52.4, 51.7, 41.2, 34.6, 32.8, 32.7, 32.1, 28.8, 27.5, 26.3,
25.4, 23.9, 23.6, 22.2. HRMS calcd for C25H38N3O7 [M + H]
492.2709, found 492.2704.
J. Org. Chem, Vol. 71, No. 19, 2006 7143