sodium bromide (2.5 g, 0.024 mol), tetrabutylammonium
bromide (0.5 g, 1.55 mmol), methanol (616 mL), acetic acid
(200 mL), water (49 mL), and ethyl acetate (1330 mL). The
mixture was stirred at room temperature until a homogeneous
solution formed (15 min) and then cooled to 0 °C. Sodium
hypochlorite solution (5.23%, 756 g, 0.531 mol) was added
over 1 h at 1-2 °C (exothermic), and the yellow suspension
was stirred at 1-2 °C for 0.5 h, then warmed slowly to 5
°C over 0.5 h to give a pale-yellow slurry. If a test for
hypochlorite (peroxide test paper) at this point was negative,
37 g of bleach was added and stirred at 4-5 °C for an
additional 30 min and then checked for excess hypochlorite
again. Aqueous sodium hydrosulfite (3.3%, 83 g, 0.0135 mol)
was added to afford a white suspension (negative test for
peroxide). Water (2113 mL) was added at 7-15 °C and the
mixture stirred at 14-15 °C for 5 min. The slurry was cooled
back to 10 °C and most of the clear bottom aqueous layer
removed. The remaining suspension was filtered and the cake
washed with a precooled (5 °C) mixture of water (200 mL)
and ethyl acetate (100 mL). The solid was dried at 60 °C
and 150 mbar for 16 h to afford 11 (149 g, 79.2%) as a
white solid. Purity: 96.6% 11; 1.0% (5â)-3,7-dioxocholan-
24-oic acid; 1.9% (5â,7R)-7-hydroxy-3-oxocholan-24-oic
acid (by HPLC peak area normalization); mp 196-198 °C.
(3r,5â)-6-Fluoro-3-hydroxy-7-oxocholan-24-oic acid
(13). A 5-L, four-necked flask equipped with a mechanical
stirrer was purged with nitrogen. Keto acid 11 (144.9 g, 0.371
mol), sodium iodide (278.0 g, 1.855 mol), toluene (750 mL),
acetonitrile (750 mL), and triethylamine (310 mL, 2.22 mol)
were charged. Chlorotrimethylsilane (235 mL, 1.85 mol) was
added over 15 min to the stirred suspension, causing the
temperature to rise to approximately 40 °C (from room
temperature). Stirring at 40 °C was continued for 30 min,
and then the reaction mixture was heated at 50 °C for 6 h.
The mixture was cooled to room temperature, and water
(1500 mL) was added while stirring vigorously. After stirring
for 3-5 min, the bottom aqueous layer was removed, and
the organic layer was washed with three portions of
phosphate buffer (pH 6, 0.2 M, 1541 g each) and brine (1800
g). Meanwhile, a 5-L round-bottomed flask equipped with a
mechanical stirrer was purged with nitrogen and charged with
Selectfluor (164.3 g, 0.464 mol) and acetonitrile (1500 mL).
The mixture was stirred vigorously at 20 °C for 1-1.5 h,
and then the solution of 13 was added over ca. 2 h while
cooling to maintain a temperature of 17-20 °C. Stirring was
continued at 20 °C for at least 6 h. While stirring vigorously,
solvent (1700 mL) was distilled off at a vacuum of 400 mbar.
Cold (rt) water (1500 mL) and heptane (500 mL) were added
to the hot reaction mixture, which was then cooled to 5 °C
over 1 h, stirred for 15-30 min, and filtered. The cake was
washed with acetonitrile/water (400 mL, 1:2.5) in two
portions, and dried at e50 °C and 150 mbar for 16 h to
obtain 13 (141.0 g, 0.345 mol, 93%). Purity: 96%, by HPLC
peak area normalization; ratio of R/â-isomers: 87/13; mp
m). 1H NMR (R-isomer, 300 MHz, CDCl3/CD3OD) 5.35 (1
H, dd, J ) 49.6, 6.4), 4.2 (2H, broad), 3.54 (1 H, m), 2.5-
0.85 (30 H, m), 0.68 (3 H, s). 13C NMR (R-isomer, 75 MHz,
CDCl3/CD3OD) 206.9 (d, 13.5 Hz), 176.8, 91.8 (d, J ) 191),
60.4, 54.5, 50.7 (d, J ) 15 Hz), 48.2, 47.5, 42.5, 42.4, 38.4,
35.7 (d, J ) 7 Hz), 35.0, 34.0, 30.8, 30.7, 29.4 (d, J ) 5
Hz), 28.9, 27.9, 24.1, 23.0, 21.4, 18.0, 11.7. 19F NMR (R-
isomer, CDCl3/CD3OD) -203.1 (d, J ) 50 Hz).
Methyl (3r,5â,6r)-3-Acetoxy-6-fluoro-7-oxocholan-24-
oate (14). Keto acid 13 (140.6 g) and methanol (650 mL)
were charged into an inerted, four-necked round-bottomed
flask equipped with a mechanical stirrer, and sodium
methoxide solution (25 wt %, 92.9 g) was added. The mixture
was heated at reflux for 3 h and cooled to 10 °C, and
chlorotrimethylsilane (66.3 g) was added over 15 min. The
mixture was heated at reflux for 3 h. After cooling to room
temperature, toluene (780 mL) and aqueous Na2HPO4
solution (3.8%, 811 g) were added and stirred for 5-10 min.
After removal of the aqueous bottom layer, the organic layer
was washed with brine (775 g) before toluene (600 mL) was
added. Solvent (950 mL) was distilled off at a pressure of
275 mbar. After cooling to room temperature, acetonitrile
(260 mL), triethylamine (65 mL), and 4-(N,N-dimethylami-
no)pyridine (880 mg) were added. The mixture was heated
to 60 °C, and acetic anhydride (37 mL) was added over 10-
20 min at a rate to keep the temperature of the reaction at
55-60 °C. The mixture was stirred at 55-60 °C for 3 h
and cooled to room temperature. Aqueous phosphoric acid
(3.45%, 813 g) was added, the mixture was heated to 60-
65 °C, stirred for 3-5 min, and the bottom aqueous layer
was removed at this temperature. The organic layer was
washed with water (680 mL) and brine (600 g); both phase
separations were performed at 60-65 °C. Solvent (460 mL)
was distilled off at a pressure of 275 mbar. Without cooling
the residue, toluene (150 mL) was added to the distillation
residue, and the mixture was heated to 70 °C. Heptane (900
mL) was added over 30 min at 70 °C. The mixture was
cooled to 5 °C over 90 min, stirred for 30 min, and filtered.
The filter cake was washed with toluene/heptane (ratio 1:2,
250 mL) and dried in a vacuum oven at 50 °C and 150 mbar
to obtain 14 (139.3 g, 0.300 mol, 87%). Purity: 98% (by
HPLC peak area normalization); 0.8-1% of desfluoro-17
(by HPLC and 1H NMR); mp 173-175 °C. 1H NMR
(CDCl3) 5.35 (1 H, dd, J ) 49.5, 6.4), 4.68 (1H, m), 3.67
(3H, s), 2.45-2.15 (5 H, m), 1.70-2.08 (10H, m), 0.85-
1.63 (18 H, m), 0.68 (3 H, s). 13C NMR (CDCl3) 205.45 (d,
13.5 Hz), 174.5, 170.2, 91.5 (d, J ) 192 Hz), 72.0, 54.6,
51.4, 50.6 (d, J ) 15 Hz), 48.3, 47.5, 42.55, 42.51, 38.5,
35.8 (d, J ) 7 Hz), 35.1, 33.8, 30.9, 30.8, 28.1, 26.1 (d, J )
6 Hz), 25.8, 24.3, 23.2, 21.5, 21.1, 18.2, 11.9. 19F NMR
(CDCl3) -203.2 (d, J ) 50 Hz).
Methyl (3r,5â,6r,7r)-3-Acetoxy-6-fluoro-7-hydroxy-
cholan-24-oate (15). A 1000-mL stirred pressure reactor was
charged with ketone 14 (50.0 g, 107.2 mmol), platinum(IV)
oxide (2.0 g, 8.8 mmol), and acetic acid (250 mL). The vessel
was closed and inerted with nitrogen. While stirring mod-
erately, the mixture was heated to 45 °C. Stirring was
stopped, and the headspace was purged with hydrogen at 40
1
225-235 °C dec. H NMR (isomeric mixture, 300 MHz,
CDCl3/ CD3OD) 5.35 (0.87 H, dd, J ) 49.6, 6.4), 4.26 (0.13
H, dd, J ) 52.0, 3.0), 3.54 (1 H, m), 3.00 (0.13 H, m), 2.52
(0.87 H, t, J ) 11.2 Hz), 2.42 (30 H, m), 0.8-0.68 (3 H,
668
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Vol. 6, No. 5, 2002 / Organic Process Research & Development