ester (3), New Process Conditions. In a suitable reactor
charged with nitrogen, sodium hydride (60% in paraffin oil,
6.0 g, 0.15 mol) was mixed with THF (120 mL) to form a
suspension at 20-25 °C. tert-Butyl acetoacetate (23.7 g, 0.15
mol) was added within 30 min maintaining the temperature
at 20-25 °C and the mixture was further stirred for 15 min.
After cooling to 0 °C, butyllithium (1.6 M in hexane, 97.5
mL, 0.15 mol) was added within 60 min, maintaining the
temperature at 0 °C. The reaction mixture was stirred at this
temperature for a further 30-45 min. A solution of 4 (38.5
g, 0.125 mol) dissolved in THF (100 mL) was added to the
reaction mixture, maintaining the temperature at 0 °C. After
60 min stirring at 0 °C, the reaction mixture was quenched
with acetic acid (22.6 g, 0.38 mol) and then with water (43.5
mL).24 The reaction mixture was extracted twice with
saturated sodium chloride solution (100 mL) and once with
water (50 mL). After removal of the solvents at 30-50 °C
and 30 mbar pressure, the evaporation residue containing
57.5 g of 3 (98.8%) was diluted in THF (75 mL) and kept
at 0-5 °C (storage solution of 3).
1347, 1222, 1156, 1141, 1104, 1094, 1018, 968, 838, 743
(cm-1).
7-[3-(4-Fluorophenyl)-1-(1-methylethyl)-1H-indol-2-
yl]-3,5-dihydroxy-6-heptenoic Acid 1,1-Dimethylethylester
(2), New Process Conditions. In a suitable reactor charged
with nitrogen, sodium borohydride (6.13 g, 0.163 mol) was
added to THF (300 mL) at -78 °C. The suspension was
stirred at -78 °C during 15 min. A solution of diethyl-
methoxyborane in THF (50%, 12.5 g, 0.0625 mol) was added
within 15 min at -78 °C. A solution of 3 (57.5 g, 0.124
mol) in THF (75 mL) and methanol (100 mL) was added
within 2 h at -78 °C. At the end of the addition, the mixture
was stirred for 1 h at -78 °C. The reaction mixture was
quenched by transferring it to a mixture of isopropylacetate
(100 mL), sodium bicarbonate (13.7 g), and water (444 mL).
The reactor was rinsed with additional isopropylacetate (100
mL). The mixture was stirred vigorously during at least 60
min until no gas evolution was observed. After phase
separation, the organic phase was extracted twice with a
solution of sodium chloride (45.9 g) in water (162 mL). The
mixture was concentrated at 50 °C and 30 mbar.
The evaporation residue was suspended in isopropylac-
etate (504 mL) at 50 °C. A solution of hydrogen peroxide
35% (35.7 g, 0.36 mol) was added at 50 °C within 60 min
under efficient stirring. The reaction mixture was further
stirred during 2-3 h at 50 °C. The reaction mixture was
extracted first with a solution of sodium sulfite (16.1 g) in
water (207 mL) and then with water (4 × 207 mL) at 55
°C.
The reaction mixture was concentrated at 80 °C (jacket)
and 220-50 mbar pressure to a residual volume of 350 mL.
The mixture was heated to an internal temperature of 80-
85 °C to get a clear solution. After cooling down to 70 °C,
the mixture was seeded with a suspension of 2 in isopropy-
lacetate and further stirred at 70 °C during at least 1 h. The
suspension was cooled down within 8 h to -10 °C and
further stirred at -10 °C during 60 min. The resulting
suspension was filtered, and the filter cake washed with cold
isopropylacetate (30 mL). The filter cake was suspended in
isopropylacetate (200 mL) and heated up to 85 °C to get a
clear solution. The mixture was cooled to 70 °C, seeded at
70 °C, and aged at 70 °C for 1 h. The suspension was cooled
down within 7 h to 0 °C and further stirred at 0 °C during
60 min. The resulting suspension was filtered and the filter
cake washed twice with cold isopropylacetate (30 mL). The
filter cake was dried at 50 °C and 125 mbar pressure to give
46.8 g of pure 2 (yield ) 80% based on 4).
3-[3-(4-Fluorophenyl)-1-(1-methylethyl)-1H-indol-2-
yl]-2-propen-1-ol (7), via Reduction of 4 with Sodium
Borohydride. To a stirred mixture of 4 (30.8 g, 0.10 mol)
and methanol (100 mL) was added sodium borohydride (3.8
g, 0.10 mol) in portions at 20 °C over a period of 30 min.
The reaction mixture was stirred for 45 min at 20 °C and
then quenched by addition to water (200 mL). After addition
of tert-butylmethylether the phases were separated. The
aqueous phases were washed with tert-butylmethylether. The
combined organic phases were washed with water and dried
over sodium sulfate. The solvent was removed under
Formation of Compound 14. If the quench in the above-
described experiment is performed only with water, the
reaction mixture after the work-up consisted of 3 (10%), 14
(85%), and small amounts of 15 and 16. Compound 14 was
1
isolated by silica gel chromatography: H NMR (400 MHz,
DMSO-d6) δ 1.40 (s, 9 H), 1.63 (d, J ) 6.95 Hz, 6 H), 3.59
(s, 2 H), 4.90-5.04 (m, 1 H), 6.09 (d, J ) 15.35 Hz, 1 H),
6.41 (dd, J ) 15.57, 10.96 Hz, 1 H), 7.05 (t, J ) 7.23 Hz,
1 H), 7.20 (t, J ) 7.07 Hz, 1 H), 7.29 (t, J ) 8.87 Hz, 2 H),
7.32-7.49 (m, 5 H), 7.68 (d, J ) 8.46 Hz, 1 H); MS (ES+)
m/z 448 (MH+); IR (solid film): 3081, 3047, 2983, 2935,
1626, 1613, 1574, 1542, 1499, 1456, 1412, 1397, 1368, 1345,
1247, 1224, 1158, 1133, 997, 944, 839, 803, 749 (cm-1).
Thermal Stress Experiment with 3 Leading to 14, 15,
and 16. The thermal stability of compound 3 was studied
by heating a sample of the storage solution of 3 from the
aldol condensation (see above) at 50 °C. After 24 h, about
30% of 3 was degraded, and compounds 14, 15, and 16 were
formed as major by-products. 15 and 16 were isolated by
silica gel chromatography. 15: 1H NMR (400 MHz, DMSO-
d6) δ 1.59 (d, J ) 6.95 Hz, 6 H), 2.09 (s, 3 H), 2.41-2.56
(m, 2 H), 4.47-4.59 (m, 1 H), 4.80-4.95 (m, 1 H), 5.16 (d,
J ) 5.12 Hz, 1 H), 5.73 (dd, J ) 16.01, 5.15 Hz, 1 H), 6.66
(dd, J ) 16.01, 1.42 Hz, 1 H), 7.01 (t, J ) 7.45 Hz, 1 H),
7.13 (t, J ) 8.18 Hz, 1 H), 7.23 (t, J ) 8.91 Hz, 2 H), 7.40
(dd, J ) 8.31, 6.16 Hz, 3 H), 7.63 (d, J ) 8.27 Hz, 1 H);
MS (ES+) m/z 366 (MH+); IR (solid form): 3467, 3047,
2976, 2937, 2879, 1704, 1605, 1593, 1547, 1503, 1459, 1346,
1219, 1158, 1140, 1116, 1102, 975, 837, 748 (cm-1). 16:
1H NMR (400 MHz, DMSO-d6) δ 1.60 (d, J ) 6.88 Hz, 6
H), 2.36-2.56 (m, 2 H), 4.79-4.94 (m, 1 H), 4.97 (s, 1 H),
5.00-5.12 (m, 1 H), 5.77 (dd, J ) 16.11, 5.94 Hz, 1 H),
6.82 (dd, J ) 16.14, 1.04 Hz, 1 H), 7.03 (t, J ) 7.48 Hz, 1
H), 7.15 (t, J ) 7.14 Hz, 1 H), 7.24 (t, J ) 8.81 Hz, 2 H),
7.38-7.46 (m, 3 H), 7.65 (d, J ) 8.08 Hz, 1 H), 11.47 (s,
1 H); MS (ES+) m/z 392 (MH+); IR (solid form): 3050,
2970, 2932, 2874, 1889, 1646, 1545, 1501, 1457, 1419, 1371,
(24) To avoid the formation of 14, the pH must reach ca. 5 before water is added.
Vol. 11, No. 1, 2007 / Organic Process Research & Development
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