10% A-90% B. Rt: 11, 5.9 min; 17, 3.1 min; (R,S)-
diastereomer, 3.6 min.
3-[(4S)-(3-Fluorobenzyl)-2-oxo-oxazolidin-(5S)-yl]pro-
pionitrile 20. (5S)-(2-[1,3]Dioxan-2-yl-ethyl)-(4S)-(3-fluo-
robenzyl)oxazolidin-2-one 19 (19.2 g, 62.13 mmol) was
combined with hydroxylamine hydrochloride (5.61 g, 80.77
mmol) and p-toluenesulfonic acid (1.18 g, 6.43 mmol) in
ethanol (200 mL) and heated to reflux overnight. The reaction
was concentrated in vacuo, and the resulting oil was
partitioned between ethyl acetate and water. The layers were
separated, and the organic layer was washed with water and
brine and concentrated to an oil in vacuo. The oil was stirred
with IPE (80 mL) for 2 h during which time a solid formed.
The suspension was diluted with an equal volume of hexanes.
The solids were collected by filtration, washed with hexanes,
and dried in vacuo to yield the desired nitrile, 13.0 g, 90%.
mp 68.5-70 °C. [R]D: - 67.3 (c ) 1.0, MeOH). HPLC:
initial eluent, 70% A-30% B; final, 10% A-90% B. Rt:
19, 5.1 min; 20, 3.3 min; 21, 6.8 min.
1H NMR (CDCl3, 400 MHz): δ 7.30 (m, 1), 6.97 (m, 2),
6.91 (d, 1), 6.41 (s, 1), 4.36 (m, 1), 3.71 (m, 1), 2.95-2.82
(m, 2), 2.46 (t, 2), 1.93 (m, 1), 1.76 (m, 1). 13C NMR (CDCl3,
100 MHz): 164.5, 162.0, 158.4, 137.9, 131.0, 125.1, 118.7,
116.3, 114.7, 79.5, 58.8, 41.1, 30.7, 13.6. LCMS exact mass
measurement: calcd for C13H13N2O2F+Na+, 249.1039;
Measured, 249.1027.
[(2S)-(3-Fluorophenyl)-(1S)-(5-oxotetrahydrofuran-2-
yl)ethyl]carbamic Acid tert-Butyl Ester 1. 3-[(4S)-(3-
Fluorobenzyl)-2-oxo-oxazolidin-(5S)-yl]propionitrile 20 (10.7
g, 43.15 mmol) was dissolved in 50% aqueous ethanol (100
mL) with sodium hydroxide (6.9 g, 172 mmol), and the
solution was heated to reflux overnight. The reaction was
cooled to rt. The solution was concentrated in vacuo, more
water was added, and the solution was concentrated again
to remove ethanol. The final oil was diluted to 75 mL with
water. The aqueous solution was cooled in an ice bath, and
concentrated HCl was added to adjust the pH to 10. Tet-
rahydrofuran (50 mL) was added to the reaction, and di-
tert-butyl dicarbonate (12.22 g, 56 mmol) was added. The
pH was monitored, and additional sodium hydroxide pellets
were added to maintain a pH > 9.0. After stirring overnight,
the THF was evaporated in vacuo and the aqueous solution
was extracted with ethyl acetate twice. This was found to
contain excess di-tert-butyl dicarbonate. The aqueous layer
was acidified with acetic acid (10 mL) and extracted twice
with ethyl acetate. The combined ethyl acetate layers were
evaporated, and the solid residue was dissolved in toluene
(125 mL) and acetic acid (5 mL) and heated to reflux for 3
h. This was cooled and diluted with ethyl acetate (125 mL).
Water and excess sodium bicarbonate were added to neutral-
ize the acetic acid. The organic layer was evaporated in
vacuo. The desired lactone was isolated as a solid by slurring
in a mixture of isopropyl ether and hexanes (1:1); 12.58 g,
90.3% yield. Mp 108-108.5 °C. [R]D: - 26.1 (c ) 1.0,
MeOH). HPLC: initial eluent, 60% A-40% B; final, 10%
A-90% B. Rt: 1, 3.4 min; 20, 0.9 min; (R,S)-diastereomer,
3.1 min. HPLC: 99.8% desired diastereomer. Chiral
HPLC: Chiralpak AS. Mobile phase: 1000:30 hexane/eth-
anol. Flow rate: 1.5 mL/min. Detection: 210 nm. Rt: 1,
12.5 min; ent-1, 9.8 min.
1H NMR (CDCl3, 400 MHz): δ 7.22 (m, 2), 6.98 (d, 1),
6.94-6.86 (m, 2), 4.60 (m, 2), 4.15 (m, 2), 3.78 (m, 3), 3.61
(s, 1), 3.46 (s, 1), 2.91 (m, 1), 2.75 (m, 1), 2.16 (m, 1), 1.84-
1.55 (m, 4), 1.34 (s, 9). 13C NMR (CDCl3, 100 MHz): 164.2,
156.0, 129.9, 125.3, 116.5, 113.2, 102.1, 79.6, 73.7, 67.2,
56.3, 35.6, 32.1, 28.5, 27.9, 25.8.
Anal. Calcd for C20H30NO5F: C, 62.643; H, 7.885; N,
3.65. Found: C, 62.60; H, 8.00; N, 3.64.
Methanesulfonic Acid (2S)-tert-Butoxycarbonylamino-
1-(2-[1,3]dioxan-2-yl-ethyl)-(3R)-(3-fluorophenyl)propyl
Ester 18. [4-[1,3]Dioxan-2-yl-(1S)-(3-fluorobenzyl)-(2R)-
hydroxybutyl]carbamic acid tert-butyl ester 17 (30 g, 78.3
mmol) was added to pyridine (100 mL) under nitrogen.
Methanesulfonyl chloride (6.67 mL, 86 mmol) was added
dropwise over 35 min with a mild exotherm from 20 to 27
°C. The reaction mixture was stirred for 2.5 h at which time
TLC showed the conversion was complete. The reaction was
cooled to 15 °C in an ice water bath, and water (250 mL)
was added slowly with a slight initial exotherm. The resulting
slurry was stirred at 15 °C for 20 min, and the solids were
collected and washed with water. The solids were air-dried
and then slurried in isopropyl ether (275 mL) for 5 h. The
product was filtered and washed with IPE and dried. The
yield was 34 g, 94%. Mp 121-22 °C. [R]D: - 4.2 (c ) 1.0,
MeOH).
1H NMR (CDCl3, 400 MHz): δ 7.24 (m, 1), 6.98 (d, 1),
6.91 (m, 2), 4.86 (s, 1), 4.80 (d, 1), 4.10 (m, 3), 3.75 (t, 1),
3.07 (s, 3), 2.95 (dd, 1), 2.64 (m, 1), 2.05 (m, 1), 1.87-1.68
(m, 4), 1.32 (s, 9). 13C NMR (CDCl3, 100 MHz): 164.2,
161.8, 155.5, 140.1, 130.1, 125.0, 116.3, 113.7, 101.1, 84.4,
79.9, 67.1, 54.0, 38.9, 35.5, 31.0, 28.4, 25.9, 25.5. Anal.
Calcd for C21H32NO7FS: C, 54.647; H, 6.987; N, 3.035.
Found: C, 54.32; H, 7.08; N, 2.96.
5S-(2-[1,3]Dioxan-2-yl-ethyl)-(4S)-(3-fluorobenzyl)ox-
azolidin-2-one 19. Methanesulfonic acid (2S)-tert-butoxy-
carbonylamino-1-(2-[1,3]dioxan-2-yl-ethyl)-(3R)-(3-fluo-
rophenyl)propyl ester 18 (29 g, 62.0 mmol) was dissolved
in dry pyridine (50 mL) under nitrogen, and the mixture was
heated in an oil bath to 80 °C. After 2 h, the reaction solution
was cooled to rt, and ethyl acetate and water were added.
The layers were separated, and the aqueous layer was
extracted with ethyl acetate. The combined organic layers
were washed with 3 N HCl (2 × 300 mL), water, and brine.
The solution was dried over sodium sulfate. The solution
was filtered and evaporated in vacuo to provide the desired
product as an oil in quantitative yield, 20.1 g. This was
suitable for use in the next step. [R]D: - 47.7 (c ) 1.0,
MeOH). HPLC: initial eluent, 70% A-30% B; final, 10%
A-90% B. Rt: 19, 5.1 min; (R,S)-diastereomer, 5.5 min.
1H NMR (CDCl3, 400 MHz): δ 7.24 (m,1), 6.91 (m, 2),
6.84 (d, 1), 6.60 (s, 1), 4.45 (s, 1), 4.26 (s, 1), 3.98 (m, 2),
3.67 (m, 3), 2.78 (m, 2), 1.95 (m, 1), 1.71-1.53 (m, 4), 1.28
(d, 1). 13C NMR (CDCl3, 100 MHz): 164.3, 161.9, 159.4,
138.7, 130.6, 125.2, 116.3, 114.2, 101.3, 81.4, 67.0, 59.0,
41.2, 30.3, 29.0, 25.9. LCMS exact mass measurement: calcd
for C16H20NO4F+Na+, 332.1274; measured, 332.1262.
174
•
Vol. 8, No. 2, 2004 / Organic Process Research & Development