to room temperature, and the crystals were collected by
filtration. The filter cake was washed with cold 2-propanol
temperature probe and flushed with argon was charged the
chiral R-hydroxy acid 7 (20 g, 76.3 mmol, >99% ee), 1,2,4-
triazole (7.4 g, 106.8 mmol), and 150 mL of dichloromethane
in that order. The mixture was stirred at room temperature
until it became clear, and then it was cooled to 0 °C. The
N-sulfinyl compound 15 (23 g, 106.8 mmol) was charged
in one portion, and the mixture was stirred at 0 °C for 3 h;
the dichloromethane was distillatively replaced with heptane
at 35 °C. At this point solids precipitated from the solution.
The heptane was removed under reduced pressure, and the
residue was dissolved in a 2:1 mixture of heptane/MTBE,
washed with 5 × 70 mL of 3 N HCl, 2 × 50 mL of saturated
(
0 °C) followed by 3 × 40 mL of hexanes to give 40.7 g of
the chiral R-hydroxy acid as a salt (83% yield, (R/S) > 99:
).
1
To a slurry of 40.5 g of the preceding salt in 300 mL of
water cooled to 2 °C was added dropwise 150 mL of a 1 N
solution of NaOH (1.5 mol equiv) while the temperature was
maintained between 0 and 5 °C. The mixture was stirred
until it became clear and then extracted with 3 × 80 mL of
MTBE. The aqueous layer was acidified to pH of 2-3 with
6
N HCl and extracted with 3 × 150 mL of ethyl acetate.
The combined organics were washed with water and brine
and then dried over anhydrous MgSO . Removal of the
NaHCO
3
, and 1 × 50 mL of brine. The organic layer was
4
dried over anhydrous Na
2
SO , and the solvents were removed
4
solvents under reduced pressure gave 25.4 g (97% yield from
under reduced pressure to give 31 g of crude 16. This was
crystallized as follows.
the amine salt, (R/S) ) 100:0) of 7 as a white solid, mp
1
1
45-147 °C. H NMR (CDCl
3
): δ 1.27 (s, 12 H), 1.68 (s, 4
To a 500-mL three-necked flask equipped with a me-
chanical stirrer, gas inlet adapter, and temperature probe were
charged the crude ester (31 g) and 360 mL of cyclohexane.
The mixture was heated to 75 °C at which point it turned
clear; it was then cooled slowly to 35 °C and seeded with
an authentic sample of the ester 16. Crystallization com-
menced at this point. The reaction mixture was held at 37
H), 5.21 (s, 1 H), 7.18 (dd, J ) 8.4, 1.6 Hz; 1 H), 7.31 (d,
1
3
J ) 8.4 Hz, 1 H), 7.37 (d, J ) 1.6 Hz, 1 H). C NMR
(CDCl
3
): δ 31.7, 34.1, 34.3, 34.8, 34.9, 72.7, 123.5, 124.9,
1
27.1, 134.3, 145.5, 145.7, 178.4. Anal. Calcd for C16-
H
22
O
3
: C, 73.25; H, 8.45. Found: C, 73.05; H,8.36.
Preparation of N-Sulfinyl derivative (15). To a 500-
mL, three-necked flask equipped with a mechanical stirrer,
gas inlet adapter, addition funnel, and a temperature probe
were charged imidazole (17.7 g, 260 mmol) and 250 mL of
anhydrous methylene chloride. The mixture was cooled to
°
C for 3 h and then at room temperature (22 °C) for 10 h.
The crystals were collected by filtration, washed with
cyclohexane, and dried at 40 °C under reduced pressure for
3
h to give 24.2 g of 16 (77% yield, 99.7 area % pure, 99%
-
10 °C, and SOCl
while the internal temperature was maintained at ca. -10
C. The mixture was then warmed to 15 °C, stirred for 10
2
(4.75 mL, 65 mmol) was added dropwise
1
ee). H NMR (CDCl
3
, 500 MHz): δ 1.25-1.30 (overlapping
singlets, 12 H), 1.68 (s, 4 H), 3.51 (bd, J ) 2.6 Hz, 1 H),
°
3
1
1
.89 (s, 3 H), 5.17 (bd, J ) 2.1 Hz, 1 H), 7.22 (dd, J ) 8.4,
.6 Hz, 1 H), 7.33 (d, J ) 8.4 Hz, 1 H), 7.40 (d, J ) 1.6 Hz,
H), 7.75 (dd, J ) 11, 1.6 Hz, 1 H), 7.80 (d, J ) 11 Hz, 1
min, and filtered through an oven-dried glass funnel. The
solids were washed with 30 mL of dichloromethane, and
the filtrate was transferred to a 500-mL, three-necked flask
equipped with a mechanical stirrer, gas inlet adapter, addition
funnel, and a temperature probe, and cooled to ca. -10 °C.
13
H), 8.44 (m, 1 H), 8.86 (bd, J ) 2.1 Hz, 1 H); C NMR
CDCl , 500 MHz): δ 26.8, 31.6, 31.7, 31.8, 34.1, 34.3, 34.8,
4.9, 52.3, 75.0, 115.9 (d, J ) 20.3 Hz), 120.3, 123.5, 125.1,
(
3
3
1
1
1
2
Additional SOCl (4.75 mL, 65 mmol) was added dropwise
26.0, 126.1, 126.5, 127.4, 130.2 (d, J ) 10.1 Hz), 135.5,
45.8 (d, J ) 26.3 Hz), 151.7 (d, J ) 242.9 Hz), 165.8,
70.7; HRMS: Calcd for C24H28FNO : 414.2081 (M + H);
4
to the mixture, which was warmed to 15 °C and stirred for
an additional 10 min. This solution was transferred to an
addition funnel and added dropwise to a solution of the
aniline 11 in 130 mL of anhydrous dichloromethane and 30
mL of anhydrous THF cooled to -30 °C and contained in
a 500-mL three-necked flask equipped with a mechanical
stirrer, gas inlet adapter, and a temperature probe while the
temperature was maintained between -15 and -25 °C. The
mixture was then warmed to 15 °C and stirred for an hour.
The solids were removed by filtration and washed with 2 ×
Found: 414.2066
BMS-270394 (1). To a 1-L, three-necked flask equipped
with a mechanical stirrer, nitrogen inlet adapter, and tem-
perature probe was charged the ester 16 (15 g, 36.3 mmol,
9
9% ee). The flask was flushed thoroughly with nitrogen
and charged with 225 mL of acetonitrile (HPLC grade, Karl
Fisher e 0.1), and the mixture was stirred at room temper-
ature (22 °C) until a solution was obtained. Potassium
trimethylsilanolate (18.1 g, 126.29 mmol) was added in one
portion. After 5 h, the reaction mixture was cooled to 0-5
40 mL of dichloromethane. Argon was bubbled through the
filtrate for about a minute. The solvent was removed under
reduced pressure, and methylene chloride was distillatively
replaced with heptane, which was removed under reduced
°
C and quenched with a solution of acetic acid (15.3 mL,
2
53.9 mmol) in 15.3 mL of water, while the temperature
pressure; the residual yellowish solid was dried to give 27.8
1
g (99% yield) of 20. H NMR (CDCl
3
): δ 3.93 (s, 1 H),
was maintained between 1 and 5 °C. Ethyl acetate (225 mL)
was then added, and the mixture was warmed to room
temperature. The organic layer was collected and washed
with 2 × 100 mL of water and 1 × 100 mL of brine, and
dried over sodium sulfate. Removal of the solvents under
reduced pressure gave 15 g of the crude product 1 which
was then crystallized.
7
.80-7.90 (m, 2 H), 8.14 (dd, J ) 7.9, 7.9 Hz, 1 H).
HRMS: Calcd for C FNO S: 215.0052. Found: 215.0052
-Fluoro-4-[2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8-
H
8 6
3
3
tetrahydro-naphthalen-2-yl)acetylamino]benzoic Acid
Methyl Ester (16). To a 500-mL, three-necked flask
equipped with a mechanical stirrer, gas inlet adapter, and
Vol. 6, No. 5, 2002 / Organic Process Research & Development
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635