Two Oxazolidinone Antibacterial Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 3 677
(S)-N-[[3-[3-F lu or o-4-(N-1-p ip er a zin yl)p h en yl]-2-oxo-5-
portion was extracted with ethyl acetate (3 × 100 mL). The
combined organic portions were dried (Na2SO4) and concen-
trated to give 64.905 g of crude 2b as a yellow solid, which
was recrystallized from acetone and water to give 60.096 g
(98% yield) of 2b as a yellow solid, mp 111-112 °C. 1H NMR
(CDCl3, 300 MHz): δ 7.99 (ddd, J ) 9.0 Hz, J ′ ) 2.7 Hz, J ′′ )
1.2 Hz, 1H), 7.91 (dd, J ) 13.2 Hz, J ′ ) 2.7 Hz, 1H), 6.92 (t, J
) 9.0 Hz, 1H), 3.88 (m, 4H), 3.29 (m, 4H). 13C NMR (75.47
MHz, CDCl3): 49.52, 49.59, 66.23, 112.21 (d, J ) 26.11 Hz),
116.54 (d, J ) 3.6 Hz), 120.64 (d, J ) 2.6 Hz), 140.47 (d, J )
7.5 Hz), 145.13 (J ) 7.7 Hz), 152.75 (d, J ) 249.1 Hz). IR
(mineral oil mull, cm-1): 2925, 1604, 1517, 1496, 1330, 1245,
1124, 950. MS: m/ z 226 (89.6, M+), 168 (100), 138 (23.5), 122
(13.2). Exact mass: calcd for C10H11FN2O3, 226.0754; found,
226.0747. Anal. (C10H11FN2O3) C, H, N.
3-F lu or o-4-m or p h olin yla n ilin e, 3b. To a solution of
30.690 g (135.7 mmol) of 2b in 80 mL of tetrahydrofuran and
320 mL of methanol (320 mL) was added 34.064 g (540.2 mmol)
of ammonium formate. The flask was alternately evacuated
and filled with nitrogen (3×) and cooled to 0 °C; then 10%
palladium on carbon was added (0.791 g), and the system was
again evacuated and filled with nitrogen. After stirring for 2
h, the reaction mixture was filtered through a plug of diato-
maceous earth, which was then washed with tetrahydrofuran
(30 mL) and ethyl acetate (60 mL). The volume of the solution
was reduced to 300 mL; then water (250 mL) and ethyl acetate
(300 mL) were added and the phases separated, and the
aqueous portion was extracted with ethyl acetate (1 × 200 mL,
2 × 100 mL). The combined organic portions were washed
with saturated sodium chloride (150 mL), dried (MgSO4), and
evaporated to give 29.310 g of crude 3b as a yellow solid which
was immediately taken on “as is” in the next reaction. 1H
NMR (CDCl3, 300 MHz): δ 6.79 (m, 1H), 6.41 (overlapping m,
2H), 3.84 (m, 4H), 3.56 (br s, 2H), 2.96 (m, 4H). 13C NMR
(75.47 MHz, CDCl3): 51.70, 51.72, 67.01, 103.81 (d, J ) 23.7
Hz), 110.71 (d, J ) 2.5 Hz), 120.25 (d, J ) 3.9 Hz), 131.30 (d,
J ) 9.43 Hz), 143.22 (d, J ) 10.3 Hz), 156.69 (d, J ) 245.0
Hz).
N-Car boben zoxy-3-flu or o-4-m or ph olin ylan ilin e, 4b. To
a solution of 3b (29.310 g, crude, 135.7 mmol) in acetone (500
mL) and water (250 mL) at 0 °C were added 23.454 g (279.2
mmol) of sodium bicarbonate and then 20.0 mL (140.1 mmol)
of benzyl chloroformate over 6 min via syringe. The mixture
was stirred overnight and then poured onto 500 mL of ice and
1.2 L of water and the solid filtered and washed thoroughly
with water (3 × 250 mL) to give 41.500 g (93%) of 4b as a
cream-colored solid, which was recrystallized from acetone and
water to give 31.343 g (70%) of 4b, as cream-colored crystals,
mp 123-124 °C. Three additional crops of slightly less pure
material (9.89 g, 21%) were also collected. 1H NMR (CDCl3,
300 MHz): δ 7.35 (m, 6H), 6.93 (m, 3H), 5.16 (s, 2H), 3.85 (t,
J ) 4.5 Hz, 4H), 3.01 (t, J ) 4.5 Hz, 4H). IR (mineral oil mull,
cm-1): 3321, 2924, 1706, 1534, 1378, 1281, 1239, 1120. MS:
m/ z 330 (67.6, M+), 195 (98.1), 91 (100). Exact mass: calcd
oxa zolid in yl]m eth yl]a ceta m id e, Hyd r och lor id e, 10.
A
mixture of 15.660 g (33.32 mmol) of 9 and 2.250 g of 10%
palladium on carbon in 750 mL of methanol and 250 mL of
methylene chloride was stirred under hydrogen (balloon)
overnight. The mixture was then filtered through diatoma-
ceous earth. The filter cake was washed with 200 mL of 25%
methylene chloride in methanol followed by 100 mL of ethyl
acetate, and the filtrates were concentrated to give 12.040 g
of off-white solids. The solids were triturated with 200 mL of
10% methanol-ethyl acetate in a warm water bath for 30 min
and then cooled to 0 °C. The solids were collected to provide
11.696 g (94%) of 10 as a white solid, mp 214-217 °C. 1H
NMR (CDCl3 + MeOH-d4, 300 MHz): δ 7.45 (dd, J ) 14.2 Hz,
J ′ ) 2.5 Hz, 1H), 7.07 (dd, J ) 11.5 Hz, J ′ ) 9.6 Hz, 1H), 6.96
(t, J ) 9.1 Hz, 1H), 4.77 (m, 1H), 4.04 (t, J ) 9.1 Hz, 1H), 3.76
(dd, J ) 9.2 Hz, J ′ ) 6.7 Hz, 1H), 3.65 (dd, J ) 11.2 Hz, J ′ )
3.4 Hz, 1H), 3.57 (dd, J ) 14.6 Hz, J ′ ) 5.7 Hz, 1H), 3.20 (s,
8H), 2.01 (s, 3H). IR (mineral oil mull, cm-1): 1742, 1656,
1517, 1237. MS: m/ z 336 (62.4, M+), 294 (100), 250 (24.5), 56
(24.5), 29 (19.6). [R]20 -22° (c 0.948, DMSO).
D
(S)-N-[[3-[3-F lu or o-4-[N-1-[(4-ben zyloxy)a cetyl]p ip er -
a zin yl]p h en yl]-2-oxo-5-oxa zolid in yl]m eth yl]a ceta m id e,
11. To a suspension of 3.569 g (9.594 mmol) of 10 in 200 mL
of methylene chloride at 0 °C were added 3.0 mL (21.52 mmol)
of triethylamine and then 2.0 mL (12.67 mmol) of (benzyloxy)-
acetyl chloride, dropwise over 2 min. The mixture became
homogeneous, was stirred at 0 °C for 2 h and then at room
temperature for 2.5 h, and then washed with water (2 × 100
mL), and the combined aqueous layers were extracted with
methylene chloride (50 mL). Ethyl acetate (50 mL) was added
to the combined organic layers to provide a homogeneous
mixture, which was dried (MgSO4) and concentrated to provide
5.040 g (100%) of 11 as a white solid, mp 164-166 °C, which
was used in the next step without further purification. 1H
NMR (CDCl3, 300 MHz): δ 7.45 (dd, J ) 14.1 Hz, J ′ ) 2.6 Hz,
1H), 7.34 (m, 5H), 7.07 (dd, J ) 10.4 Hz, J ′ ) 8.8 Hz, 1H),
6.88 (t, J ) 9.1 Hz, 1H), 6.31 (t, br, J ) ca. 11 Hz, 1H), 4.76
(m, 1H), 4.62 (s, 2H), 4.23 (s, 2H), 4.01 (t, J ) 9.0 Hz, 1H),
3.75 (m, 3H), 3.62 (m, 4H), 3.01 (s, 4H), 2.02 (s, 3H). IR
(mineral oil mull, cm-1): 1757, 1673, 1643, 1521, 1227. MS:
m/ z 484 (86.2, M+), 440 (30.1), 306 (66.1), 91 (100), 56 (72).
(S)-N-[[3-[3-Flu or o-4-[N-1-(4-h ydr oxyacetyl)piper azin yl]-
ph en yl]-2-oxo-5-oxazolidin yl]m eth yl]acetam ide, U-100592.
A mixture of 29.04 g (60.0 mmol) of 11 and 8.114 g of 10%
palladium on carbon in 2 L of 33% (v/v) methylene chloride-
methanol was stirred under hydrogen (balloon) overnight,
filtered over diatomaceous earth, and concentrated under
reduced pressure to give a solid. This was purified by silica
gel chromatography (49 cm × 5 cm column) and eluted with a
methanol-methylene chloride gradient (1 L each, 3%, 5%, 7%,
9%, and 11% MeOH). The appropriate fractions were pooled
to provide a foamy solid, which was triturated with 10%
methanol-ethyl acetate to provide 19.239 g (81%) of U-100592
as a white solid, mp 175-176 °C. 1H NMR (CDCl3, 300
MHz): δ 7.47 (dd, J ) 14.1 Hz, J ′ ) 2.6 Hz, 1H), 7.07 (d, J )
ca. 9 Hz, 1H), 6.91 (t, J ) 9.1 Hz, 1H), 6.21 (t, br, 1H), 4.78
(m, 1H), 4.21 (d, 4.4 Hz, 2H), 4.02 (t, J ) 9.0 Hz, 2H), 3.84 (m,
2H), 3.74 (dd, J ) 9.1 Hz, J ′ ) 6.7 Hz, 1H), 3.63 (m, 2H), 3.45
(m, 2H), 3.06 (t, J ) 5.1 Hz, 4H), 2.02 (s, 3H). IR (mineral oil
mull, cm-1): 3453, 3295, 1730, 1647, 1520, 1239. MS: m/ z
394 (65.6), 350 (88.3), 306 (72.4), 266 (42.6), 56 (100). Exact
for C18H19FN2O3, 330.1380; found, 330.1373. Anal. (C18H19
FN2O3) C, H, N.
-
(R )-[N -3-(3-F lu o r o -4-m o r p h o lin y lp h e n y l)-2-o x o -5-
oxa zolid in yl]m eth a n ol, 5b. To a solution of 40.604 g (123.0
mmol) of 4b in tetrahydrofuran (500 mL) under nitrogen at
-78 °C was added n-butyllithium (77 mL, 1.6 M in hexane,
123.2 mmol) over 20 min via syringe. The solution was stirred
at -78 °C for 35 min; then a tetrahydrofuran solution (25 mL)
of (R)-glycidyl butyrate (17.8 mL, 125.7 mmol) was added in a
dropwise fashion via addition funnel, over 30 min. After
stirring at -78 °C for 1 h, the bath was removed and the
reaction mixture was stirred at room temperature overnight.
The reaction was then quenched with 20 mL of saturated
ammonium chloride, ethyl acetate (300 mL), saturated am-
monium chloride (400 mL), and water (300 mL) were added,
the phases were separated, and the aqueous portion was
extracted with ethyl acetate (3 × 300 mL). The combined
organic portions were washed with saturated sodium chloride,
dried (MgSO4), and evaporated to give 5b (60.725 g) as a yellow
solid; this was recrystallized from ethyl acetate and hexanes
to give 30.814 g (85%) of 5b as a light gray amorphous solid,
mp 112-114 °C. A second crop (2.431 g, 7%) of less pure
mass: calcd for C18H23FN4O5, 394.1652; found, 394.1651. [R]20
-21° (c 0.853, DMSO). Anal. (C18H23FN4O5) C, H,N.
D
3-F lu or o-4-m or p h olin yln itr oben zen e, 2b. To a solution
of 26.0 mL (297.2 mmol) of morpholine and 51.0 mL (293.0
mmol) of N,N-diisopropylethylamine in 150 mL of ethyl acetate
was added slowly 30.0 mL (271.0 mmol) of 3,4-difluoronitro-
benzene via an addition funnel. After the addition was ca.
two-thirds complete, the reaction mixture had warmed to >35
°C. The flask was cooled in an ice bath, the remaining 3,4-
difluoronitrobenzene added over the next 30 min, and mixture
gradually warmed to room temperature overnight. Methylene
chloride (100 mL), ethyl acetate (400 mL), and water (200 mL)
were added to the reaction mixture, which contained a yellow
precipitate. The phases were separated, and the aqueous