Carbon-carbon-linked (pyrazolylphenyl)oxazolidinones with antibacterial activity against multiple drug resistant gram-positive and fastidious gram-negative bacteria.

Article abstract of DOI:10.1016/S0968-0896(01)00233-4

In an effort to expand the spectrum of activity of the oxazolidinone class of antibacterial agents to include Gram-negative bacteria, a series of new carbon-carbon linked pyrazolylphenyl analogues has been prepared. The alpha-N-substituted methyl pyrazole

Full text of DOI:10.1016/S0968-0896(01)00233-4

Bioorganic & Medicinal Chemistry 9 (2001) 3243–3253
Carbon–Carbon-Linked (Pyrazolylphenyl)oxazolidinones with
Antibacterial Activity Against Multiple Drug Resistant
Gram-Positive and Fastidious Gram-Negative Bacteria
Chi Sing Lee,a Debra A. Allwine,a Michael R. Barbachyn,a Kevin C. Grega,a
Lester A. Dolak,b Charles W. Ford,c Randy M. Jensen,b Eric P. Seest,b
Judith C. Hamel,c Ronda D. Schaadt,c Douglas Stapert,c Betty H. Yagi,c
a,
Gary E. Zurenkoc andMichael J. Genin *
aCombinatorial and Medicinal Chemistry Research, Pharmacia Corporation, Kalamazoo, MI 49001, USA
bStructural Analytical and Medicinal Chemistry Research, Pharmacia Corporation, Kalamazoo, MI 49001, USA
cInfectious Diseases Research, Pharmacia Corporation, Kalamazoo, MI 49001, USA
Received2 May 2001; accepted18 June 2001
Abstract—In an effort to expand the spectrum of activity of the oxazolidinone class of antibacterial agents to include Gram-nega-
tive bacteria, a series of new carbon–carbon linkedpyrazolylphenyl analogues has been prepared. The a-N-substitutedmethyl
pyrazole (10a) in the C3-linkedseries exhibitedvery goodGram-positive activity with MICs ꢀ0.5–1 mg/mL andmoderate Gram-
negative activity with MICs=2–8 mg/mL against Haemophilus influenzae and Moraxella catarrhalis. This analogue was also found
to have potent in vivo activity with an ED50=1.9 mg/kg. b-Substitution at the C3-linkedpyrazole generally results in a loss of
activity. The C4-linkedpyrazoles are slightly more potent than their counterparts in the C3-linkedseries. Most of the analogues in
the C4-linkedseries exhibitedsimilar levels of activity in vitro, but lower levels of activity in vivo than 10a. In addition, incor-
poration of a thioamide moiety in selected C4-linked pyrazole analogues results in an enhancement of in vitro activity leading to
compounds several times more potent than eperezolid, linezolid and vancomycin. The thioamide of the N-cyanomethyl pyrazole
analogue (34) exhibitedan exceptional in vitro activity with MICs of ꢀ 0.06–0.25 mg/mL against Gram-positive pathogens andwith
MICs of 1 mg/mL against fastidious Gram-negative pathogens. # 2001 Elsevier Science Ltd. All rights reserved.
Introduction
drug-resistant Gram-positive bacterial pathogens.8 The
recently approvedoxazoliidnone linezolid( 1, PNU-
The number of life-threatening infections causedby
multi-drug-resistant Gram-positive pathogens has
reachedan alarming level in hospitals andthe commu-
nity.1À3 Several clinical reports in the UnitedStates and
worldwide have independently described the emergence
of vancomycin resistance in methicillin-resistant Staphy-
lococcus aureus (MRSA) isolates.4À7 Infections caused
by these organisms pose a serious challenge to the
medical community and the need for an effective ther-
apy has ledto a search for novel antibacterial agents.
100766) anda derivative eperezolid( 2) exhibit potent
activity against several important human pathogens
including MRSA9 and Staphylococcus epidermidis,9
vancomycin-resistant enterococci,10,11 andpenicillin-
andvancomycin-resistant streptococci. This new class
of antibiotics gives physicians a powerful new tool for
the treatment of infections causedby these organisms.
12
These compounds have been shown to inhibit bacterial
translation at the initiation phase of protein synthesis by
binding to the 50S ribosomal subunit.13À16 In recent
years there has been a significant effort placedon dis-
covering the exact molecular target within the ribosome
complex. A review by Shinabarger discusses the mechan-
ism of action of the oxazolidinones in more detail.17 It is
suggested that the oxazolidinones act by disrupting the
processing of N-formylmethionyl-tRNA by the ribosome.
The oxazolidinones are a totally synthetic class of anti-
bacterial agents effective against sensitive andmulti-
*Corresponding author. Tel.: +1-616-833-9869; fax: +1-616-833-
2516; e-mail: michael.j.genin@pharmacia.com
0968-0896/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00233-4

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C. S. Lee et al. / Bioorg. Med. Chem. 9 (2001) 3243–3253
Given that a large number of upper respiratory tract
infections including otitis media are caused by the fasti-
dious Gram-negative pathogens Haemophilus influenzae
and Moraxella catarrhalis, we have targetedthese
organisms in our efforts to expandthe spectrum of
antibacterial activity of the oxazolidinones. To this end
we have replacedthe morpholine ring moiety of line-
zolidwith various five-memberednitrogen-containing
heterocycles (azoles).18,19 From this effort, the nitrogen–
carbon linkedpyrazole derivatives were foundto have
very interesting activity profiles. In particular, the 3-
cyano derivative 3 (PNU-172576) has excellent in vitro
activity against a broadspectrum of Gram-positive
organisms with MICs ꢀ0.125–0.5 mg/mL as well as
goodactivity against fastidious Gram-negative bacteria
with MICs=2–4 mg/mL.19 This analogue also shows
very goodin vivo activity with an ED 50=1.2 mg/kg
against S. aureus in a mouse model.19 In light of these
observations, we exploredthe structure–activity rela-
tionships of carbon–carbon linkedpyrazole derivatives.
cury, compound 6 was treatedwith formic acidto give
ketone 7. Unfortunately, this sequence gave variable
results andthe yields were not reproducible. Thus, 5 was
treatedwith formic acidwhich resultedin the direct
formation of ketone 7 in goodyield. The ketone was
then condensed with N,N-dimethylformamide dimethy-
lacetal to give the key intermediate 8.
With 8 prepared, the vinylogous amide moiety was
converted to the pyrazole using hydrazine hydrate in
ethanol.21 This transformation gave the unsubstituted
C3-linkedpyrazole ( 9) in goodyield. The methyl ( 10),
hydroxyethyl (11) andcyanoethyl ( 12) derivatives were
also obtainedfrom 8 via treatment with the corre-
sponding substituted hydrazine. These conditions gave
mixtures of regioisomers with the a-isomers as the pri-
mary products. The isomers were separated on a chiral
HPLC column andthe regiochemistry was determined
via NMR (Table 1). Due to the close proximity of the a-
substituent to the phenyl hydrogen ortho to the pyrazole
ring, an interaction is observedbetween these two
groups in a difference NOE experiment.22 However, no
NOE is seen between the a-substituent andthe pyra-
zole-5-H. In the case of the b-isomers the opposite is
true. Irradiation of the b-substituent results in an NOE
with the pyrazole-5-H but not with the ortho-hydrogen
of the phenyl ring. In addition, the hydrogens (H-4 and
H-5) of the pyrazole are shifteddown fieldby 0.18–
0.22 ppm (H-4) and0.23–0.56 ppm (H-5), respectively,
in the b-isomers relative to the a-substitutedanalogues
(a-isomers: d H-4=6.34-6.41, H-5=7.46–7.56 ppm; b-
isomers: d H-4=6.55–6.61, H-5=7.76–7.90 ppm).
The b-N-substitutedpyrazole analogues 13–16 were
obtainedvia direct functionalization of pyrazole 9, also
shown in Scheme 1. Treatment of 9 with two equiva-
lents of sodium hydride followed by the addition of an
appropriate alkylating/acylating agent gave allyl (13),
cyanomethyl (14), methoxycarbonyl (15), andacetate
(16) derivatives. Formation of the b-isomers was
favored under these conditions.
N-substituted C4-linked pyrazole analogues. We initially
targetedthe synthesis of 22 as the key intermediate in
the C4-linkedpyrazole series. As shown in Scheme 2,
Stille coupling between trimethylstanane 17 andtrity-
lated4-iodopyrazole 19 using Pd2(dba)3 in NMP affor-
ded inconsistent yields of the desired coupling product
(21) along with inseparable side-products. Removal of
the trityl protecting group using trifluoroacetic acid
facilitatedthe purification process andgave pyrazole 22
in very poor yields. Addition of copper(I) catalyst did
not improve the yieldandusing Pd(OAc) 2, PPh3 and n-
BuLi to generate Pd(0) in situ did not afford any cou-
pling product. In addition, coupling between 17 and
iodide 20 also gave low yields of the desired product
(23).
Results and Discussion
Chemistry
N-Substituted C3-linked pyrazole analogues. The vinylo-
gous amide 8 was usedas a key intermediate in the
synthesis of the N-substitutedC3-linkedpyrazole oxa-
zolidinones (Scheme 1). Palladium mediated coupling of
the known iodophenyloxazolidionone derivative 420 and
trimethylsilylacetylene resultedin the formation of 5.
Initially, preparation of the acetyl intermediate 7 was
problematic. Removal of the trimethylsilyl group of 5
with potassium carbonate gave 6. The acetylene was
then treatedwith mercury oxide andNafion to afford
the ketone 7 in very poor yields. In an attempt to
improve this transformation andavoidthe use of mer-
In order to optimize the yield of 22, the utility of the
one-pot Suzuki coupling23 using pinacol diborane ester
to generate the arylboronic acidin situ was investigated.
The optimal conditions are shown in Scheme 2. Boronic
ester formation with iodide 19 proceeded smoothly with

C. S. Lee et al. / Bioorg. Med. Chem. 9 (2001) 3243–3253
3245
Scheme 1. Reagents: (a) TMSCCH, Pd(PPh3)2Cl2,CuI, Et3N, DMF, 45 ꢁC, 99%; (b) K2CO3, CH3OH, 60% (c) HgO, Nafion, H2O, CH2Cl2, reflux,
20% or formic acid, 85 ꢁC, 57%; (d) formic acid, 95 ꢁC, 69%; (e) Me2NCH(OMe)2, EtOH, reflux, 76%; (f) H2NNHR, EtOH reflux to yield62–97%
of 9, 10 (a/b=6:1), 11 (a/b=7:1), 12 (a/b=10:1); (g) NaH, DMF, 0 ꢁC then RBr or RCOCl to yield26–94% of 13 (a/b=1:8), 14b, 15b and 16b.
Table 1. Determination of the regiochemistry of a- and b-isomers of analogues 10–16
CompoundR
d H-4 (ppm)
a-isomer
d H-5 (ppm)
a-isomer
d H-4 (ppm)
b-isomer
d H-5 (ppm)
b-isomer
10
11
12
13
14
15
16
CH3
CH2CH2OH
CH2CH2CN
Allyl
CH2CN
CO2CH3
Ac
6.37
6.34
6.41
6.39
7.50
7.55
7.46
7.56
6.55
6.56
6.61
6.60
6.68
6.90
6.94
7.76
7.78
7.90
7.79
7.92
8.43
8.48
pinacol diborane ester, potassium acetate and
Pd(PPh3)4 in DMF at 100 ꢁC. Base hydrolysis followed
by coupling with iodide 4 afforded good yields of the
intermediate N-tritylatedpyrazole 21. Finally, removal
of the trityl protecting group using trifluoroacetic acid
afforded 22 in goodyield.
Gram-positive andfastidious Gram-negative bacterial
isolates. Minimum inhibitory concentration (MIC)
values were determined using agar dilution methodol-
ogy.24 Selectedanalogues were also testedfor in vivo
activity by a S. aureus infection model in mice.24 The
MIC andED 50 values are shown in Tables 2 and3.
Compound 22 was useful for the synthesis of substituted
C4-linkedanalogues 24–34 via alkylation conditions
shown in Scheme 3. The thioamides of four analogues
were also prepared. Thus, 22 and 27–29 were convertedto
the corresponding thioamides 31–34 using Lawesson’s
reagent in refluxing THF in moderate to good yields.
The C3-linkedunsubstitutedpyrazole analogue ( 9)
exhibitedsimilar levels of in vitro activity to that of
linezolid( 1) andeperezolid( 2). The Gram-positive
MICs are <0.5–4 mg/mL for 9 and1–4 mg/mL for line-
zolid(Table 2). Switching the connectivity of the pyra-
zole to the C4-linkedanalogue ( 22) ledto an improvement
in the in vitro activity against MRSA, E. faecalis and H.
influenzae (Table 3); however the compoundhas only
moderate in vivo activity (ED50=11.4 mg/kg).
Antibacterial activity
The oxazolidinone analogues prepared above were tes-
tedfor antibacterial activity in vitro against a panel of
The C3-linkedpyrazole series showedinteresting sub-

3246
C. S. Lee et al. / Bioorg. Med. Chem. 9 (2001) 3243–3253
stituent effects (Table 2). Changing the hydrogen at the
a-position of the pyrazole (9) to a methyl group (10a)
ledto enhancement of in vitro activity against all
organisms with the exception of S. pneumoniae. The
Gram-positive MICs are <0.5–1 mg/mL, andthe MICs
versus H. influenzae and M. catarrhalis are 8 mg/mL and
2 mg/mL, respectively. Moreover, 10a was also found
to be very potent in vivo with an ED50=1.9 mg/kg
which is comparable to that of linezolid(3.5 mg/kg).
It is interesting to note the drop in antibacterial
activity by simply moving the methyl group from the
a- to the b-position (10a vs 10b). The Gram-positive
MICs increase from <0.5–1 mg/mL for 10a to 2–
>64 mg/mL for 10b. This effect is quite profound
when considering S. pneumoniae and H. influenzae
where 10b was completely inactive at 64 mg/mL, and
10a has MICs of <0.5 mg/mL and8 mg/mL, respec-
tively, against these organisms. Replacement of the
methyl group with the hydroxyethyl (11a,b), cyanoethyl
(12a,b) or allyl (13a,b) moieties results in analogues
with poor to moderate Gram-positive activity and little
or no activity against the fastidious Gram-negative
organisms. The exception to this trendwas the cyano-
methyl derivative (14b), which has essentially the same
level of Gram-positive activity as linezolid; Gram-posi-
tive MICs of 14b are <0.5–4 mg/mL versus 1–4 mg/mL
for linezolid.
Scheme 2. Reagents: (a) (Me3Sn)2, PdCl2(PPh3)2, dioxane, reflux,
99%; (b) Trityl-Cl, Et3N, DMF, >90% or NaH, DMF; BrCH2CH2F,
80%; (c) 19 or 20, Pd2(dba)3, TFP, LiCl, NMP, 90 ꢁC (0–40%); (d)
Diboron pinacol ester, KOAc, Pd(PPh3)4, DMF, 100 ꢁC then 4,
Pd(PPh3)4, Na2CO3, 100 ꢁC; (e) TFA, CH2Cl2, 53–76% for steps dand
e to give 22.
Scheme 3. Reagents: (a) RBr or RCOCl, base, THF or acetone, reflux,
21–94%, or NaH, DMF, 0 ꢁC then CH3NCS, 43%; (b) Lawesson’s
reagent, THF, reflux, 32–94%.
Table 2. Antibacterial activity (MIC, mg/mL) of the N-substitutedC3-linkedpyrazolylphenyl oxazolidinones
h
i
CompoundR
S.a.a
S.a.b
S.e.c
S.p.d
E.f.e
H.inf.f
M.cat.g
ED50
Control ED50
9
10a
11a
12a
13a
10b
11b
12b
13b
14b
15b
16b
H
CH3
CH2CH2OH
CH2CH2CN
Allyl
4
1
16
16
8
8
16
4
8
2
8
4
4
<0.5
16
8
16
8
16
8
8
1
<0.5
<0.5
8
4
4
>64
4
2
4
<0.5
32
16
16
8
16
8
16
4
32
8
>64
>64
>64
>64
>64
>64
>64
32
8
2
<0.5
1.9(1.3–2.5)
3.5(2.8–4.8)l
8
4
4
2
8
2
2
1
2
2
64
32
64
16
32
32
32
8
CH3
CH2CH2OH
CH2CH2CN
Allyl
CH2CN
CO2CH3
Ac
2
<0.5
1
2
8
4
8
8
>64
64
32
16
1
Linezolid4
Eperezolid4
Vancomycin
2
1
0.5
1
0.5
4
16
16
8
5.6(2.9–8.5)
1.9(1.4–3.8)
>32
3.9(2.5–6.4)v
3.9(2.5–6.4)v
>32 3.9(2.5–6.4)
1
2
8
1
1
2
0.5
4
aMethicillin-susceptible S. aureus UC19213.
bMethicillin-resistant S. aureus UC112673.
cMethicillin-resistant Staphylococcus epidermidis UC112084.
dStreptococcus pneumoniae UC19912.
eEnterococcus faecalis UC19217.
fHaemophilus influenzae UC130063.
gMoraxella catarrhalis UC130610. Minimum inhibitory concentration (MIC): lowest concentration of drug (mg/mL) that inhibits visible growth of
the organism.
hED50 is the amount of drug required after oral administration (mg/kg/day) to cure 50% of infected mice subjected to a lethal systemic infection of
S. aureus. Numbers in parentheses are 95% confidence ranges. Data shown is from one experiment (n=36 mice/drug).
iv=vancomycin, e=eperezolid, l=linezolid as controls.

C. S. Lee et al. / Bioorg. Med. Chem. 9 (2001) 3243–3253
3247
Table 3. Antibacterial activity (MIC, mg/mL) of the N-substitutedC4-linkedpyrazolylphenyl oxazolidinones
S.a.a
S.a.b
S.e.c
S.p.d
E.f.e
H.inf.f
M.cat.g
ED50
Control ED50
h
i
CompoundR
X
22
23
24
25
26
27
28
29
30
31
32
33
H
O
O
O
O
O
O
O
O
O
S
2
2
2
8
4
1
4
2
1
1
2
2
4
4
1
4
1
1
0.5
0.5
1
0.25
0.5
0.5
2
0.5
0.25
1
0.25
0.25
0.125
0.125
0.25
<0.06
8
1
2
2
4
2
1
4
1
2
8
>16
16
>64
>16
8
64
8
>16
4
4
8
8
8
8
4
8
2
>16
1
0.5
1
1
11.4(0.0–22)
>20
2.5(1.5–4.1)l
6.0(3.9–9.7)e
CH2CH2F
Ac
Benzyl
Allyl
CH3
CH2CH3
CH2CN
(CS)NHMe
H
2
0.5
0.5
2
0.25
0.5
0.25
0.25
0.5
0.125
16
3.7(2.2–6.6)
2.5(1.5–4.1)l
0.5
0.5
1
0.5
0.25
1
0.25
4
0.5
0.25
0.5
0.25
5.6(2.9–8.5)
1.9(1.4–3.8)
>20
16(10.9–19)
3.4(2.3–5.3)l
4.5(2.9–7.3)l
CH3
S
S
S
8
16
1
CH2CH3
CH2CN
2
34
0.25
>17.5
5.0(4.4–5.5)l
Linezolid4
Eperezolid4
Vancomycin
1
0.5
1
3.9(2.5–6.4)v
3.9(2.5–6.4)v
>32
1
0.5
1
2
1
16
2
8
0.5
4
>32
3.9(2.5–6.4)
aMethicillin-susceptible S. aureus UC19213.
bMethicillin-resistant S. aureus UC112673.
cMethicillin-resistant Staphylococcus epidermidis UC112084.
dStreptococcus pneumoniae UC19912.
eEnterococcus faecalis UC19217.
fHaemophilus influenzae UC130063.
gMoraxella catarrhalis UC130610 or UC130607. Minimum inhibitory concentration (MIC): lowest concentration of drug (mg/mL) that inhibits
visible growth of the organism.
hED50 is the amount of drug required after oral administration (mg/kg/day) to cure 50% of infected mice subjected to a lethal systemic infection of
S. aureus. Numbers in parentheses are 95% confidence ranges. Data shown is from one experiment (n=36 mice/drug).
iv=vancomycin, e=eperezolid, l=linezolid as controls.
The substitutedC4-linkedpyrazole analogues are slightly
more potent than the a- or b-substitutedC3-linked
counterparts (Table 3). Again, the methyl andcyano-
methyl pyrazoles 27 and 29 in this series provedthe most
interesting. The methyl derivative 27 has Gram-positive
MICs of 0.25–1 mg/mL, slightly better than the 1–4 mg/
mL for linezolid. In addition, this congener has similar
in vivo activity with an ED50=3.7 mg/kg.
nately, all of these compounds have little or no in vivo
activity at the highest doses. The difference in in vivo
activity is striking when comparing the acetamide 27 to
the corresponding thioamide 32. The ED50 of the acet-
amide 27 is 3.7 mg/kg whereas the ED50 of the thioa-
mide 32 is 16 mg/kg. The unsubstitutedanalogue 31 and
the cyanomethyl congener 34 were both inactive at the
levels tested, ED50s=>20 mg/kg and >17.5 mg/kg,
respectively.
Of particular interest is the dramatic increase in anti-
bacterial activity seen when converting the acetamides
(22, 27–29) to the thioamides (31–34).25,26 This mod-
ification alters both the electronic character as well as
the lipophilicity of the molecules. In some cases the
thioamides display exceptional antibacterial activity and
are up to 8 times more potent than the corresponding
acetamide (Table 3). This increase, however, is not seen
for all compounds against all organisms. For example,
the unsubstitutedpyrazole 31 has a significant increase
of two dilutions in activity against only two strains, S.
aureus and M. catarrhalis. However, the cyanomethyl
analogue 34 is significantly more potent than its acet-
amide counterpart in five of the seven organisms, exhi-
biting Gram-positive MICsꢀ0.06–0.25 mg/mL versus
0.25–2 mg/mL for the acetamide counterpart 29. This
compoundalso has excellent activity against the fasti-
dious Gram-negative bacteria H. influenzae and M. cat-
arrhalis with MICs=1 mg/mL. Three thioamides (31, 32
and 34) were selectedfor in vivo evaluation. Unfortu-
Several years ago workers at Pharmacia reportedthat
deletion of the E. coli acrAB efflux pump confers sus-
ceptibility to oxazolidinones, thus it is likely that efflux
is playing a role in the spectrum of activity of these
molecules. However it is not clear what structural mod-
ifications will leadto compounds that are able to bypass
these efflux mechanisms. Furthermore, the goodGram-
negative activity of some of the analogues reportedhere
andelsewhere does not necessarily imply that they are
poor substrates for the pumps. It couldbe a matter of
potency or it may simply mean that they are better able
to cross the membrane andthe pumps are unable to
27,28
keep up with the rapidinflux of drug.
Conclusion
In summary, a series of new carbon–carbon-linkedpyr-
azole oxazolidinones have been prepared and tested for
antibacterial activity. The unsubstitutedC3- andC4-

3248
C. S. Lee et al. / Bioorg. Med. Chem. 9 (2001) 3243–3253
linkedpyrazoles ( 9 and 22) both exhibitedgoodin vitro
activity against Gram-positive pathogens (MICs=0.25–
4 mg/mL), but moderate to poor activity against Gram-
negative organisms (MICs=8–32 mg/mL). The analo-
gues in the C4-linkedseries were slightly more potent
than the corresponding C3-linked analogues. Substitu-
tion on the pyrazole generally ledto a loss of anti-
bacterial activity, except in the cases of the a-N-methyl
C3-linkedpyrazole ( 10a) andthe N-cyanomethyl C4-
linkedpyrazole ( 29) analogues. In addition, the activity
was increasedremarkably by incorporating the thioa-
mide moiety. The most active analogue, the thioamide
of the cyanomethylpyrazolylphenyloxazolidinone (34),
was foundto be several times more potent than line-
zolid, eperezolid and vancomycin for in vitro Gram-
positive activity. More importantly, this analogue was
also very potent against H. influenzae and M. catarrhalis
with MICs=1 mg/mL. Unfortunately, it was not active
in the in vivo mouse model at the highest doses tested.
N-{[(5S)-3-(4-Ethynyl-3-fluorophenyl)-2-oxo-1,3-oxazoli-
din-5-yl]methyl}acetamide (6). Potassium carbonate
(11.479 g, 83.05 mmol) was added to a methanol
(100 mL) solution of 5 (14.536 g, 41.71 mmol). After
stirring the reaction mixture for 45 min, the solvent was
evaporated. The residue was dissolved in methylene
chloride and water, the phases were separated, and the
aqueous portion was extractedwith methylene chloride.
The combinedorganic portions were rdied(MgSO
)
4
and evaporated. The crude material was purified on a
5.2Â30 cm medium pressure silica column with 35–80%
acetone/hexanes to give 8.7 g of improvedquality mate-
rial which was further purifiedon a secondmedium
pressure silica column (5.2Â36 cm) with 2–5% metha-
nol/methylene chloride to give 6.9 g (60%) of the desired
material as a white solid: mp 162.5–164 ꢁC; [a]D25=À36ꢁ
(c 0.95, DMSO); 1H NMR (400 MHz, CDCl3) d 2.03 (s,
3H), 3.29 (s, 1H), 3.64 (dt, J=15, 6 Hz, 1H), 3.70 (ddd,
J=15, 6, 3 Hz, 1H), 3.79 (dd, J=9, 7 Hz, 1H), 4.06 (t,
J=9 Hz, 1H), 4.81 (m, 1H), 6.14 (bt, J=7 Hz, 1H), 7.16
(dd, J=9, 2 Hz, 1H), 7.47 (t, J=8 Hz, 1H), 7.50 (dd,
J=11, 2 Hz, 1H); MS (+ESI) m/z 277 (M+H), anal.
calcdfor C 14H13FN2O3: C, 60.87; H, 4.74; N, 10.14;
found: C, 61.01; H, 4.88; N, 10.07.
Experimental
General
Melting points were determined on a Fisher–Johns or a
Thomas–Hoover apparatus andare uncorrecte.d 1H
NMR spectra were recorded on either a Bruker AM-300
or ARX-400 spectrometer. Chemical shifts are reported
in d units (ppm) relative to TMS as internal standard.
Mass spectra andcombustion analysis were obtainedby
the Structural, Analytical andMeidcinal Chemistry
Department of the Pharmacia Corporation. Unless
otherwise indicated all reactions were conducted in
commercially available anhydrous solvents under nitro-
gen atmosphere in oven- or flame-dried glassware.
Chromatography was carriedout on EM Science 230–
400 mesh ASTM silica gel. Elemental analysis were
within Æ0.4% of calculatedvalues. Biological assays
were performedas describedpreviously in ref 24.
N-{[(5S)-3-(4-Ethynyl-3-fluorophenyl)-2-oxo-1,3-oxazoli-
din-5-yl]methyl}acetamide (7). Formic acid(100 mL)
was added to a flask containing 5 (15.85 g, 45.49 mmol).
The solution was heatedat 95 ꢁC under nitrogen atmo-
sphere for 1.5 h. Then it was pouredonto ice and
sodium bicarbonate. Sodium bicarbonate was added
until the solution pH was 8. The reaction mixture was
then extractedwith CH 2Cl2. The combinedorganic
portions were dried (MgSO4) andevaporate.d The
crude material was purified on a 5.2Â36 cm medium
pressure silica column with 2–10% CH3OH/CH2Cl2 to
give 11.0 g (69%) of the desired material as a white
solid: mp 174–175 ꢁC; [a]2D5=À33ꢁ (c 1.00, DMSO); H
1
NMR (400 MHz, DMSO-d6) d 1.82 (s, 3H), 2.54 (d,
J=4 Hz, 3H), 3.42 (t, J=6 Hz, 2H), 3.78 (dd, J=9,
7 Hz, 1H), 4.16 (t, J=9 Hz, 1H), 4.76 (m, 1H), 7.43 (dd,
J=9, 2 Hz, 1H), 7.56 (dd, J=14, 2 Hz, 1H), 7.87 (t,
J=9 Hz, 1H), 8.22 (t, J=4 Hz, 1H); HRMS calcdfor
C14H15FN2O4 294.1016; found294.1016; anal. calcdfor
C14H15FN2O4: C, 57.14; H, 5.14; N, 9.52; found: C,
56.98; H, 5.20; N, 9.49.
N-[((5S)-3-{3-Fluoro-4-[2-(trimethylsilyl)ethynyl]phenyl}-
2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide (5). (Tri-
methylsilyl)acetylene (5.0 g, 50.91 mmol), copper iodide
(0.097 g, 0.51 mmol), andbistriphenylphosphine
dichloropalladium (0.594 g, 0.85 mmol) were added to a
solution of iodide 420 (15.871 g, 41.97 mmol) in N,N-
dimethylformamide (60 mL) and triethylamine (60 mL).
The reaction mixture was heatedat 45 ꢁC overnight
under nitrogen atmosphere. The solvents were evapo-
rated, and the resulting residue was purified on a
5.2Â37 cm medium pressure silica column with 35–50%
acetone/hexanes to give 14.5 g (99%) of the desired
product as an off-white solid: mp 139–140.5 ꢁC;
[a]2D5=À28ꢁ (c 0.88, DMSO); 1H NMR (400 MHz,
CDCl3) d 0.26 (s, 9 H), 2.02 (s, 3 H), 3.63 (dt, J=15,
6 Hz, 1H), 3.70 (ddd, J=15, 6, 3 Hz, 1H), 3.78 (dd,
J=9, 7 Hz, 1H), 4.05 (t, J=3 Hz, 1H), 4.79 (m, 1H),
6.13 (t, J=7 Hz, 1H), 7.14 (dd, J=9, 2 Hz, 1H), 7.43 (t,
J=8 Hz, 1H), 7.46 (dd, J=11, 2 Hz, 1H); MS (ÀESI) m/
z 347 (MÀH); Anal. calcdfor C 17H21FN2O3Si: C,
58.60; H, 6.07; N, 8.04; found: C, 58.45; H, 6.05; N,
7.97.
N-[((5S)-3-{4-[(E)-3-(Dimethylamino)-2-propenoyl]-3-
fluorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]aceta-
mide (8). An ethanol (180 mL) solution of ketone 7
(9.977 g, 33.90 mmol) and N,N-dimethylformamide
dimethyl acetal (25.0 mL, 181.90 mmol) was refluxed
under nitrogen atmosphere for 4 h. The mixture was
allowedto cool to room temperature as it stirredover-
night. The solvent was then evaporated, and the result-
ing residue was purified on a 5.2Â54 cm medium
pressure silica column with 2–5% CH3OH/CH2Cl2 to
give 8.3 g (70%) of the desired maꢁterial as a light orange
ꢁ
1
solid: mp 124–125.5 C; [a]2D5=18 (c 0.99, DMSO); H
NMR (400 MHz, CDCl3) d 2.01 (s, 3H), 2.91 (bs, 3H),
3.14 (bs, 3H), 3.65 (m, 2H), 3.79 (dd, J=9, 7 Hz, 1H),
4.05 (t, J=9 Hz, 1H), 4.79 (m, 1H), 5.65 (d, J=11 Hz,
1H), 6.64 (t, J=6 Hz, 1H), 7.14 (dd, J=9, 2 Hz, 1H),

C. S. Lee et al. / Bioorg. Med. Chem. 9 (2001) 3243–3253
3249
7.48 (dd, J=13, 2 Hz, 1H), 7.80 (m, 2H); MS (+ESI) m/
.
z 350 (M+H); anal. calcdfor C 17H20FN3O4 0.25H2O:
C, 57.70; H, 5.84; N, 11.87; found: C, 57.73; H, 5.73; N,
11.72.
silica column with 2–20% CH3OH/CH2Cl2 to give
0.100 g (85%) of the desired material as a mixture of
regioisomers. After HPLC purification, 0.084 g (72%) of
11a as a yellow solidand0.012 g (10%) of 11 b as a yel-
low solidwere obtained.
N-({(5S)-3-[3-Fluoro-4-(1H-pyrazol-3-yl)phenyl]-2-oxo-
1,3-oxazolidin-5-yl}methyl)-acetamide (9). Hydrazine
hydrate (1.0 mL, 20.61 mmol) was added to an ethanol
(100 mL) solution of 8 (1.75 g, 5.01 mmol). The reaction
mixture was stirredfor 2 days then the solvent was
evaporatedto give 1.548 g (97%) of 9 as a cream solid:
11a: mp 70–71 ꢁC; [a]2D5=À24ꢁ (c 0.46, DMSO); 1H
NMR (400 MHz, DMSO-d6) d 1.83 (s, 3H), 3.42 (m,
2H), 3.67 (dd, J=12, 6 Hz, 2H), 3.78 (dd, J=9, 6 Hz,
1H), 4.00 (t, J=6 Hz, 2H), 4.07 (dd, J=10, 5 Hz, 1H),
4.17 (t, J=9 Hz, 1H), 4.77 (m, 1H), 6.34 (d, J=1 Hz,
1H), 7.43 (dd, J=9, 2 Hz, 1H), 7.55 (m, 2H), 7.63 (dd,
J=13, 2 Hz, 1H), 8.23 (t, J=5 Hz, 1H); HR-MS(FAB)
calcdfor C 17H19FN4O4: 362.1390; found: 362.1395;
mp 208–209 ꢁC; [a]D25=À26ꢁ (c 0.54, DMSO); H NMR
1
(400 MHz, DMSO-d6) d 1.83 (s, 3H), 3.30 (bs, 1H), 3.42
(t, J=6 Hz, 2H), 3.77 (dd, J=9, 7 Hz, 1H), 4.15 (t,
J=9 Hz, 1H), 4.75 (m, 1H), 6.60 (dd, J=4, 2 Hz, 1H),
7.36 (d, J=7 Hz, 1H), 7.57 (d, J=14 Hz, 1H), 7.81 (bs,
1H), 7.96 (bs, 1H), 8.23 (t, J=5 Hz, 1H); HRMS (FAB)
calcdfor C 15H15FN4O3+H 319.1206; Found319.1197;
.
anal. calcdfor C 17H19FN4O4 0.25H2O: C, 55.66; H,
5.36; N, 15.27; found: C, 55.76; H, 5.59; N, 14.94. 11b:
mp: 110 ꢁC; H NMR (400 MHz, DMSO-d6) d 1.83 (s,
1
3H), 3.42 (t, J=5 Hz, 2H), 3.76 (m, 3H), 4.14 (t, J=9 Hz,
1H), 4.19 (t, J=6 Hz, 2H), 4.74 (m, 1H), 4.90 (t, J=5 Hz,
1H), 6.56 (dd, J=4, 2 Hz, 1H), 7.36 (dd, J=9, 2 Hz, 1H),
7.54 (dd, J=14, 2 Hz, 1H), 7.78 (d, J=2 Hz, 1H), 7.92 (t,
J=9 Hz, 1H), 8.22 (t, J=5 Hz, 1H); HR-MS (FAB)
calcdfor C 17H19FN4O4 362.1390; found362.1392.
.
anal. calcdfor C 15H15FN4O3 0.5H2O: C, 55.04; H, 4.93;
N, 17.12; Found: C, 54.87; H, 4.75; N, 16.78.
N-({(5S)-3-[3-Fluoro-4-(1-methyl-1H-pyrazol-5-yl)phenyl]-
2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (10ꢀ) and N-
({(5S)-3-[3-Fluoro-4-(1-methyl-1H-pyrazol-3-yl)phenyl]-2-
oxo-1,3-oxazolidin-5-yl}methyl)acetamide (10ꢁ). An etha-
nol (10 mL) solution of 8 (0.241 g, 0.69 mmol) and
methyl hydrazine (0.21 mL, 3.94 mmol) was stirred
overnight at room temperature under nitrogen atmo-
sphere. Then, the solvents were evaporated, and the
resulting residue was purified on a 2Â25.2 cm medium
pressure silica column with 2% CH3OH/CH2Cl2 to give
0.177 g (77%) of the desired material as a mixture of the
two regioisomers. After HPLC purification, 0.070 g
(31%) of 10a as a white solidand0.019 g (8%) of 10b as
N-[((5S)-3-{3-Fluoro-4-[1-(3-nitrilopropyl)-1H-pyrazol-5-
yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
(12ꢀ) and N-[((5S)-3-{3-Fluoro-4-[1-(3-nitrilopropyl)-1H
-pyrazol-3-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]a-
cetamide (12ꢁ). An ethanol (5 mL) solution of 8
(0.100 g, 0.29 mmol) and3-hyradzinopropanenitrile
(0.040 g, 0.47 mmol) was stirredunder nitrogen atmo-
sphere for 2 days. The reaction was not complete,
therefore, the mixture was refluxedfor 24 h, then more
3-hydrazinopropanenitrile (0.060 g, 0.70 mmol) was
added. After 4 h, the mixture was allowed to cool to
room temperature, the solvents were evaporated, and
the resulting residue was purified on a 3Â24 cm medium
pressure silica column with 2% methanol/methylene
chloride to give 0.078 g (73%) of the desired material as
a mixture of regioisomers. After HPLC purification,
0.060 g (57%) of 12a as a cream solidand0.006 g (6%)
of 12b as a tan solidwere obtained. 12a: mp: 183–
184 ꢁC; [a]2D5=À23ꢁ (c 0.44, DMSO); 1H NMR
(400 MHz, DMSO-d6) d 1.84 (s, 3H), 2.99 (t, J=6 Hz,
2H), 3.43 (t, J=6 Hz, 2H), 3.79 (dd, J=9, 6 Hz, 1H),
4.17 (t, J=9 Hz, 1H), 4.22 (t, J=6 Hz, 2H), 4.77 (m,
1H), 6.41 (d, J=2 Hz, 1H), 7.46 (m, 2H), 7.65 (m, 2H),
8.24 (t, J=6 Hz, 1H); HR-MS (FAB) calcdfor
C18H18FN5O3+H 372.1472; found372.1479; anal.
calcdfor C 18H18FN5O3: C, 58.22; H, 4.89; N, 18.86;
found: C, 58.00; H, 5.00; N, 18.57. 12b: mp 137–138 ꢁC;
1H NMR (400 MHz, DMSO-d6) d 1.83 (s, 3H), 3.11 (t,
J=6 Hz, 2H), 3.42 (t, J=5 Hz, 2H), 3.77 (dd, J=9,
7 Hz, 1H), 4.15 (t, J=9 Hz, 1H), 4.45 (t, J=6 Hz, 2H),
4.74 (m, 1H), 6.61 (dd, J=4, 2 Hz, 1H), 7.38 (dd, J=9,
2 Hz, 1H), 7.56 (dd, J=14, 2 Hz, 1H), 7.90 (d, J=2 Hz,
1H), 7.93 (t, J=9 Hz, 1H), 8.23 (t, J=6 Hz, 1H); HR-
MS (FAB) calcdfor C 18H18FN5O3+H 372.1472; found
372.1486.
a white solidwere obtained. 10a: mp 101–102 ꢁC; H
1
NMR (400 MHz, DMSO-d6) d 1.83 (s, 3H), 3.43 (t,
J=5 Hz, 2H), 3.72 (s, 3H), 3.78 (dd, J=9, 6 Hz, 1H),
4.17 (t, J=9 Hz, 1H), 4.76 (m, 1H), 6.37 (d, J=2 Hz,
1H), 7.44 (dd, J=9, 2 Hz, 1H), 7.50 (d, J=2 Hz, 1H),
7.51 (dd, J=8, 8 Hz, 1H), 7.64 (dd, J=13, 2 Hz, 1H),
8.23 (t, J=6 Hz, 1H); 367 (M+Cl), 663 (2MÀH); HR-
MS (FAB) calcdfor C 16H17FN4O3+H 333.1363; found
.
333.1330; anal. calcdfor C 16H17FN4O3 0.25H2O: C,
57.05; H, 5.24; N, 16.63; found: C, 57.16; H, 5.13; N,
1
16.43. 10b: H NMR (400 MHz, DMSO-d6) d 1.83 (s,
3H), 3.42 (t, J=6 Hz, 2H), 3.76 (dd, J=9, 7 Hz, 1H),
3.89 (s, 3H), 4.14 (t, J=9 Hz, 1H), 4.73 (m, 1H), 6.55
(dd, J=4, 2 Hz, 1H), 7.35 (dd, J=9, 2 Hz, 1H), 7.54 (dd,
J=14, 2 Hz, 1H), 7.76 (d, J=2 Hz, 1H), 7.91 (t,
J=9 Hz, 1H), 8.22 (t, J=6 Hz, 1H); HR-MS (FAB)
calcdfor C 16H17FN4O3 +H 333.1363; found333.1368.
N-[((5S)-3-{3-Fluoro-4-[1-(2-hydroxyethyl)-1H-pyrazol-5-
yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide
(11ꢀ) and N-[((5S)-3-{3-Fluoro-4-[1-(2-hydroxyethyl)-
1H-pyrazol-3-yl]phenyl}-2-oxo-1,3-oxazolidin-5-yl)methy-
l]acetamide (11ꢁ). 2-Hydroxyethylhydrazine (0.3 mL,
4.43 mmol) was added to an ethanol (5 mL) solution of
8 (0.113 g, 0.32 mmol). The reaction mixture was heated
at 105 ꢁC for 2 h under nitrogen atmosphere, then was
allowedto cool to room temperature as it stirredover-
night. The solvent was evaporated, and the resulting
residue was purified on a 3Â26 cm medium pressure
General procedure for the conversion of pyrazole 9 to
analogues 13–16. N,N-Dimethylformamide (8 mL) was
added to a flame-dried flask which contained 9 (1

3250
C. S. Lee et al. / Bioorg. Med. Chem. 9 (2001) 3243–3253
equiv). The solution was cooledto 0 ꢁC under nitrogen
atmosphere. Then sodium hydride (60%, 2 equiv) was
added. After stirring 20 min, the appropriate alkylating
agent (1.2 equiv) was added. The reaction mixture was
stirredfor 30 min, then water andCH 2Cl2 were added.
The phases were separated, and the aqueous portion
was extractedwith CH Cl2 andethyl acetate. The com-
2
binedorganic portions were dried(MgSO 4) andevapo-
rated. The resulting residue was purified as described.
[a]2D5=À26ꢁ (c 0.51, DMSO); 1H NMR (400 MHz,
DMSO-d6) d 1.83 (s, 3H), 3.43 (t, J=5 Hz, 2H), 3.79
(dd, J=9, 7 Hz, 1H), 4.01 (s, 3H), 4.16 (t, J=9 Hz, 1H),
4.76 (m, 1H), 6.89 (t, J=3 Hz, 1H), 7.44 (dd, J=9, 2 Hz,
1H), 7.62 (dd, J=14, 2 Hz, 1H), 7.99 (t, J=9 Hz, 1H),
8.23 (t, J=6 Hz, 1H), 8.43 (d, J=3 Hz, 1H); HR-MS
(FAB) calcdfor C 17H17FN4O5+H 402.1465; found
.
402.1470; anal. calcdfor C 17H17FN4O5 0.25H2O: C,
53.61; H, 4.63; N, 14.71; Found: C, 54.06; H, 4.51; N,
14.72.
N-({(5S)-3-[4-(1-Allyl-1H-pyrazol-5-yl)-3-fluorophenyl]-2-
oxo-1,3-oxazolidin-5-yl}methyl)acetamide (13ꢀ) and N-
({(5S)-3-[4-(1-Allyl-5-methyl-1H-pyrazol-3-yl)-3-fluorophe-
N-({(5S)-3-[4-(1-Acetyl-1H-pyrazol-3-yl)-3-fluorophe-
nyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (16ꢁ).
Acylation with acetyl chloride gave a residue that was
purifiedon a 3 Â25 cm medium pressure silica column
with 2–5% CH3OH/CH2Cl2 to give 0.052 g (46%) of
16b as a white solid: mp 181–183 ꢁC; [a]D25=À26ꢁ (c
nyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide
Alkylation with allyl bromide gave a residue that was
(13ꢁ).
purifiedon a 40 g Biotage column with 0–5% CH OH/
3
CH2Cl2 to give 0.073 g (28%) of monoallylatedmaterial
and0.172 g (61%) of bisallylatedmaterial. After HPLC
purification, 0.007 g (3%) of 13a as a yellow solid,
1
0.43, DMSO); H NMR (400 MHz, DMSO-d6) d 1.83
(s, 3H), 2.71 (s, 3H), 3.43 (t, J=5 Hz, 2H), 3.79 (dd,
J=9, 7 Hz, 1H), 4.17 (t, J=9 Hz, 1H), 4.76 (m, 1H),
6.94 (t, J=3 Hz, 1H), 7.45 (dd, J=9, 2 Hz, 1H), 7.62
(dd, J=14, 2 Hz, 1H), 8.03 (t, J=9 Hz, 1H), 8.24 (t,
J=6 Hz, 1H), 8.48 (d, J=3 Hz, 1H); HR-MS (FAB)
calcdfor C 17H17FN4O4+H 361.1312; found361.1310;
1
0.058 g (23%) of 13b as a cream solid. 13a: H NMR
(400 MHz, DMSO-d6) d 1.81 (s, 3 H), 3.42 (t, J=5 Hz,
2H), 3.78 (dd, J=9, 6 Hz, 1H), 4.16 (t, J=9 Hz, 1H),
4.64 (d, J=5 Hz, 2H), 4.75 (m, 1H), 4.77 (d, J=12 Hz,
1H), 5.05 (dd, J=11, 2 Hz, 1H), 5.88 (m, 1H), 6.39 (d,
J=1 Hz, 1H), 7.43 (m, 2H), 7.56 (d, J=2 Hz, 1H), 7.63
(dd, J=15, 2 Hz, 1H), 8.23 (t, J=6 Hz, 1H); HR-MS
(FAB) calcdfor C 18H19FN4O3+H 359.1519; found
359.1528. 13b: mp 144–146 ꢁC; [a]D25=À25ꢁ (c 0.58,
DMSO); 1H NMR (400 MHz, DMSO-d6) d 1.83 (s, 3H),
3.42 (t, J=5 Hz, 2H), 3.76 (dd, J=9, 7 Hz, 1H), 4.14 (t,
J=9 Hz, 1H), 4.75 (m, 1H), 4.81 (d, J=6 Hz, 2H), 5.20
(m, 2H), 6.10–6.00 (m, 1H), 6.60 (dd, J=4, 2 Hz, 1H),
7.35 (dd, J=9, 2 Hz, 1H), 7.55 (dd, J=14, 2 Hz, 1H),
7.79 (d, J=2 Hz, 1H), 7.91 (t, J=9 Hz, 1H), 8.23 (t,
.
anal. calcdfor C 17H17FN4O4 0.25H2O: C, 55.96; H,
4.83; N, 15.36; found: C, 55.99; H, 4.88; N, 15.06.
N-({(5S)-3-[3-fluoro-4-(trimethylstannyl)phenyl]-2-oxo-
1,3-oxazolidin-5-yl}methyl)acetamide (17). A solution of
iodide 4 (0.83 g, 2.2 mmol) in 1,4-dioxane (15 mL) was
treatedwith Pd 2Cl2(PPh3)2 (77 mg, 0.11 mmol) and
hexamethylditin (0.86 g, 2.6 mmol). The slurry was
heatedunder reflux for 2 h andthen concentratedin
vacuo. Chromatography (1–4% CH3OH in CH2Cl2) of
the residue afforded 17 (0.91 g, 2.2 mmol, 100%) as an
amber glassy solidwhich was usedas is.
J=6 Hz,
C18H19FN4O3+H 359.1519; found359.1524; anal.
1H);
HR-MS
(FAB)
calcdfor
.
calcdfor C 18H19FN4O3 0.25H2O: C, 59.58; H, 5.42; N,
15.44; found: C, 59.66; H, 5.42; N, 15.08.
1-(2-fluoroethyl)-4-iodo-1H-pyrazole (20). A solution of
4-iodo-1H-pyrazole (1.16 g, 6.00 mmol) in anhydrous
DMF (30 mL) was treatedwith NaH (264 mg of a 60%
dispersion in mineral oil, 6.60 mmol) and stirred at
ambient temperature for 20 min. The solution was then
N-[((5S)-3-{4-[1-(Cyanomethyl)-1H-pyrazol-3-yl]-3-fluoro-
phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide (14ꢁ).
Alkylation with bromoacetonitrile gave a residue that
was purifiedon a 3 Â24 cm medium pressure silica col-
umn with 2–5% CH3OH/CH2Cl2 to give 0.143 g of
material, which was a mixture of regioisomers. After
HPLC purification, 0.102 g (91%) of 14b as a white
treatedwith
1-bromo-2-fluoroethane
(0.50 mL,
6.6 mmol) andstirredat ambient temperature for 14 h.
The solution was diluted with distilled water (300 mL)
andextractedwith ethyl acetate (300 mL Â3). The com-
binedextracts were washedwith distilledwater, brine
anddriedover Na 2SO4. Filtration, concentration and
chromatography (5–15% ethyl acetate in hexanes)
afforded iodide 20 (1.15 g, 4.79 mmol, 80%) as a color-
less oil: 1H NMR (400 MHz, CDCl3) d 7.55 (s, 1H), 7.53
(s, 1H), 4.73 (dt, J=4, 73 Hz, 2H), 4.42 (dt, J=4, 27 Hz,
2H); MS (+ESI) m/z 240 (M+H); anal. calcdfor
C5H6FIN2: C, 25.02; H, 2.52; N, 11.67; found: C, 24.90;
H, 2.42; N, 11.56.
solid: mp 168–169 ꢁC; [a]2D5=À25ꢁ (c 0.47, DMSO); H
1
NMR (400 MHz, DMSO-d6) d 1.83 (s, 3H), 3.42 (t,
J=5 Hz, 2H), 3.78 (dd, J=9, 7 Hz, 1H), 4.15 (t,
J=9 Hz, 1H), 4.75 (m, 1H), 5.55 (s, 2H), 6.68 (dd, J=4,
2 Hz, 1H), 7.40 (dd, J=9, 2 Hz, 1H), 7.58 (dd, J=14,
2 Hz, 1H), 7.92 (t, J=9 Hz, 1H), 7.94 (d, J=2 Hz, 1H),
8.23 (t, J=6 Hz, 1H); HR-MS (FAB) calcdfor
C17H16FN5O3+H 358.1315; found358.1319; anal.
calcdfor C 17H16FN5O3: C, 57.14; H, 4.51; N, 19.60;
found: C, 56.81; H, 4.24; N, 19.21.
N-({(5S)-3-[3-fluoro-4-(1H-pyrazol-4-yl)phenyl]-2-oxo-
1,3-oxazolidin-5-yl}methyl)-acetamide (22). Stille Proto-
col: a solution of Pd2(dba)3 (0.17 g, 0.18 mmol) in NMP
(100 mL) was treatedwith TFP (0.17 g, 0.72 mmol) and
stirredat ambient temperature for 15 min. The solution
was treated with iodide 19 (3.14 g, 7.2 mmol) followed
by 17 (3.6 g, 7.2 mmol) andlithium chloried (1.53 g,
Methyl 3-(4-{(5S)-5-[(acetylamino)methyl]-2-oxo-1,3-ox-
azolidin-3-yl}-2-fluorophenyl)-1H-pyrazole-1-carboxylate
(15ꢁ). Acylation with methyl chloroformate gave a
residue that was purified on a 3Â24 cm medium pressure
silica column with 2–5% CH3OH/CH2Cl2 to give
0.101 g (85%) of 15b as a white solid: mp 184–185 ꢁC;

C. S. Lee et al. / Bioorg. Med. Chem. 9 (2001) 3243–3253
3251
36 mmol). The resulting mixture was stirredat 90 ꢁC for
24 h, then cooledto ambient temperature anddiluted
with distilled water (600 mL). The aqueous phase was
extractedwith ethyl acetate (700 mL Â3). The combined
extracts were washedwith distilledwater, brine and
dried over Na2SO4. Filtration, concentration and
chromatography (5% CH3OH in CH2Cl2) afforded
21 along with side-products. The mixture was dis-
solvedin CH 2Cl2 (20 mL) andtreatedwith tri-
fluruoacetic acid(10 mL). The solution was stirred
at ambient temperature for 30 min andthen con-
centrated in vacuo. The residue was dissolved in
CH2Cl2 (20 mLÂ2) andconcentratedto remove any
remaining acid. Then the residue was dissolved in
CH2Cl2 andtreatedwith triethylamine (1 mL). Con-
centration andchromatography (5% CH 3OH in
CH2Cl2) afforded 22 (0.91 g, 2.9 mmol, 40%) as a white
N-[((5S)-3-{3-fluoro-4-[1-(2-fluoroethyl)-1H-pyrazol-4-yl]-
phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide (23).
The aryl stannane 17 was dissolved in NMP (13 mL)
andtreatedwith pyrazole
20 (0.48 g, 2.0 mmol),
Pd2(dba)3 (92 mg, 0.10 mmol) andTFP (93 mg,
0.40 mmol). The resulting mixture was stirredat 95 ꢁC
for 14 h, then diluted with distilled water (100 mL) and
extractedwith ethyl acetate (100 mL Â3). The combined
extracts were treatedwith CH OH to dissolve any pre-
3
cipitate. The resulting solution was washedwith water,
brine anddriedover Na 2SO4. Filtration, concentration
andchromatography (1.5–4% CH 3OH in CH2Cl2)
afforded 23 (138 mg, 0.38 mmol, 19%) as a light pink
solid: mp 196–198 ꢁC; [a]2D5=À38ꢁ (c 0.98, DMF); H
1
NMR (400 MHz, CDCl3) d 7.89 (br s, 2H), 7.48–7.55
(m, 2H), 7.22 (dd, J=2, 9 Hz, 1H), 6.06 (br s, 1H), 4.81
(dt, J=2, 47 Hz, 2H) 4.80 (br s, 1H), 4.47 (dt, J=2,
26 Hz, 2H), 4.07 (t, J=9 Hz, 1H), 3.80 (dd, J=7, 9 Hz,
1H), 3.60–3.73 (m, 2H), 2.04 (s, 3H); HR-MS (EI) calcd
for C17H18F2N4O3 364.1347; found364.1345; anal.
calcdfor C 17H18F2N4O3: C, 56.04; H, 4.98; N, 15.38;
found: C, 54.60; H, 5.11; N, 14.73.
solid: mp 192–195 ꢁC; H NMR (400 MHz, DMSO-d6)
1
d 8.23 (br s, 1H), 7.83–8.15 (br m, 2H), 7.74 (t, J=9 Hz,
1H), 7.54 (d, J=14 Hz, 1H), 7.31 (d, J=9 Hz, 1H),
4.71–4.75 (m, 1H), 4.13 (t, J=9 Hz, 1H), 3.75 (dd, J=7,
9 Hz, 1H), 3.42 (t, J=5 Hz, 2H), 1.83 (s, 3H); MS
(+ESI) m/z 319 (M+H); anal. calcdfor C 15H15FN4O3:
C, 56.60; H, 4.75; N, 17.60; found: C, 56.35; H, 4.82; N,
17.45.
N-({(5S)-3-[4-(1-acetyl-1H-pyrazol-4-yl)-3-fluorophenyl]-
2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (24).
A
solution of 21 (1.18 g, 2.11 mmol) in CH2Cl2 (25 mL)
was treatedwith trifluoroacetic acid(2.0 mL, 26 mmol)
at 0 ꢁC. The solution was warmedto ambient tempera-
ture, stirredfor 2 h andthen concentratedin vacuo. The
residue was dissolved in CH2Cl2 andtreatedwith aqu-
eous NaOH (1.5 mL of a 1 N solution) with vigorous
stirring. The resulting precipitate was filtered, dried in
vacuo and dissolved in pyridine (20 mL). The solution
was treated with acetic anhydride (0.5 mL, 5 mmol) at
ambient temperature, stirredfor 1 h andconcentratedin
vacuo. Chromatography (1–4% CH3OH in CH2Cl2) of
the residue afforded 24 with remaining free pyrazole
(69 mg). The mixture was then resubmittedto the above
acetylation conditions, stirred for 16 h and concentrated
in vacuo. Chromatography (1–4% CH3OH in CH2Cl2)
of the residue afforded 24 (38 mg, 0.11 mmol, 5% for 2
N-({(5S)-3-[3-fluoro-4-(1H-pyrazol-4-yl)phenyl]-2-oxo-
trifluoroacetate
1,3-oxazolidin-5-yl}methyl)acetamide
(22). Suzuki Protocol: a solution of 19 (1.0 g, 2.3 mmol)
in dry DMF (10 mL) was treated with potassium acetate
(675 mg, 6.9 mmol), diboron pinacol ester (1.2 g,
4.7 mmol) andterakis(triphenylphosphine)palladium(0)
(130 mg, 0.11 mmol). The mixture was heatedunedr
reflux for 2 h, then cooledto ambient temperature and
treatedwith ioided
4 (870 mg, 2.3 mmol), terakis(tri-
phenylphosphine)palladium(0) (130 mg, 0.11 mmol) and
aqueous Na2CO3 (5.8 mL of a 2 M solution, 11.6 mmol).
The resulting mixture was stirredat 100 ꢁC overnight.
Then the solution was cooledto ambient temperature,
diluted with distilled water (20 mL) and treated with
10% aqueous HCl (10 mL). The aqueous phase was
extractedwith ethyl acetate (50 mL Â3). The combined
extracts were dried over Na2SO4, filteredandcon-
centratedin vacuo. Chromatography (0–10% methanol
in CH2Cl2) of the residue afforded 21 along with side-
products (1.414 g). The mixture was dissolved in CH2Cl2
(20 mL) andtreatedwith TFA (10 mL) slowly at ambi-
ent temperature. The solution was stirredat ambient
temperature for 2 h, then concentratedwith a stream of
N2 and dried in vacuo overnight. The residue was trea-
tedwith CHCl 3 (10 mL) andproduct (755 mg, 1.7 mmol,
76%) was collectedby vacuum filtration. A sample of
the product was treated with triethylamine and con-
ꢁ
1
steps) as an off-white solid: mp 230–231 C; H NMR
(400 MHz, DMF-d7) d 8.83 (s, 1H), 8.49 (s, 1H), 8.43–
8.46 (m, 1H), 8.10 (t, J=9 Hz, 1H), 7.85 (d, J=14 Hz,
1H), 7.58 (d, J=9 Hz, 1H), 5.02 (br s, 1H), 4.42 (t,
J=9 Hz, 1H), 4.09 (dd, J=7, 9 Hz, 1H), 3.73–3.76 (br s,
2H), 2.88 (s, 3H), 2.09 (s, 3H); HR-MS (FAB) calcdfor
C17H17FN4O4+H 361.1312; found361.1307; anal.
.
calcdfor C 17H17FN4O4 0.1 H2O: C, 56.38; H, 4.79; N,
15.47; found: C, 56.24; H, 4.49; N, 15.19.
General procedure for the conversion of pyrazole 22 to
analogues 25–29. A solution of 22 (1 equiv) in dry THF
centratedin vacuo. Chromatography (5% CH OH in
3
or acetone (5 mL) was treatedwith K CO3 or NaHCO3
2
CH2Cl2) of the residue afforded 22 as the free base: mp
(10–50 equiv) andan appropriate alkylating agent (10
equiv). The mixture was heatedunedr reflux over-
night, then cooledto ambient temperature andtrea-
tedwith distilledwater (10 mL). The aqueous phase
was extractedwith ethyl acetate (20 mL Â3). The
combinedextracts were driedover Na 2SO4, filteredand
concentratedin vacuo. Chromatography (2.5–5%
CH3OH in CH2Cl2) of the residue afforded the desired
products.
192–195 ꢁC, H NMR (400 MHz, DMSO-d6) d 8.23 (br
1
s, 1H), 7.83–8.15 (br m, 2H), 7.74 (t, J=9 Hz, 1H), 7.54
(d, J=14 Hz, 1H), 7.31 (d, J=9 Hz, 1H), 4.71–4.75 (m,
1H), 4.13 (t, J=9 Hz, 1H), 3.75 (dd, J=7, 9 Hz, 1H),
3.42 (t, J=5 Hz, 2H), 1.83 (s, 3H); MS (+ESI) m/z 319
(M+H); anal. calcdfor C 15H15FN4O3: C, 56.60; H,
4.75; N, 17.60; found: C, 56.35; H, 4.82; N, 17.45.

3252
C. S. Lee et al. / Bioorg. Med. Chem. 9 (2001) 3243–3253
N-({(5S)-3-[4-(1-benzyl-1H-pyrazol-4-yl)-3-fluorophe-
nyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (25).
4.14 (t, J=9 Hz, 1H), 3.76 (t, J=7 Hz, 1H), 3.42 (t,
J=5 Hz, 2H), 1.83 (s, 3H); HR-MS (EI) calcdfor
C17H16FN5O3 357.1237, found357.1233; anal. calcdfor
C17H16FN5O3 0.6H2O: C, 55.46; H, 4.71; N, 19.02;
found: C, 55.45; H, 4.84; N, 18.90.
Alkylation with benzyl bromide afforded 25 (0.16 g,
0.39 mmol, 90%) as a white solid: mp 169–170 ꢁC dec.;
[a]2D5=À20ꢁ (c 0.96, DMSO); 1H NMR (400 MHz,
CDCl3) d 7.89 (s, 1 H), 7.78 (d, J=2 Hz, 1H), 7.51 (dd,
J=9, 12 Hz, 1H), 7.49 (dd, J=3, 14 Hz, 1H), 7.29–7.39
(m, 5H), 7.20 (dd, J=2, 9 Hz, 1H), 5.93–6.00 (m, 1H),
5.36 (s, 2H), 4.76–4.83 (m, 1H), 4.07 (t, J=9 Hz, 1H),
3.79 (dd, J=7, 9 Hz, 1H), 3.73 (ddd, J=4, 7, 16 Hz,
1H), d 3.60–3.66 (m, 1H), 2.03 (s, 3H); HR-MS (FAB)
calcdfor C 22H21FN4O3+H 409.1676; found409.1682;
.
N-{[(5S)-3-(3-fluoro-4-{1-[(methylamino)carbothioyl]-1H
-pyrazol-4-yl}phenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}a-
cetamide (30). A solution of 22 (0.125 g, 0.39 mmol) in
dry DMF (5 mL) was treated with NaH (32 mg of a
60% dispersion in mineral oil, 0.80 mmol). The mixture
was stirredat ambient temperature for 15 min, then
treatedwith methyl thioisocyanate (58 mg, 0.79 mmol)
andstirredat ambient temperature for 5 h. The mixture
.
anal. calcdfor C 22H21FN4O3 0.35 H2O C, 63.71; H,
5.27; N, 13.51; found: C, 64.08; H, 5.36; N, 12.62.
was treatedwith saturatedaqueous NaHCO
(5 mL)
3
N-({(5S)-3-[4-(1-allyl-1H-pyrazol-4-yl)-3-fluorophenyl]-
2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (26). Alky-
lation with allyl bromide afforded 26 (0.24 g, 0.67 mmol,
22%) as a tan solid: mp 162–165 ꢁC; 1H NMR
(400 MHz, CDCl3) d 7.84 (s, 1H), 7.76 (d, J=2 Hz, 1H),
7.45–7.52 (m, 2H), 7.17 (dd, J=2, 9 Hz, 1H), 6.44 (br s,
1H), 6.01–6.11 (m, 1H), 5.31 (d, J=10 Hz, 1H), 5.27 (d,
J=17 Hz, 1H), 4.78 (m, 3H), 4.05 (t, J=9 Hz, 1H), 3.80
(dd, J=7, 9 Hz, 1H), 3.63–3.70 (m, 2H), 2.03 (s, 3H);
HR-MS (FAB) calcdfor anal. calcdfor
andextractedwith CH 2Cl2 (10 mLÂ3). The combined
extracts were dried over Na2SO4, filteredandcon-
centratedin vacuo. Chromatography (5% CH OH in
3
CH2Cl2) of the residue afforded 30 (67 mg, 0.17 mmol,
44%) as a white solid: mp=178–180 ꢁC; 1H NMR
(400 MHz, CDCl3) d 9.00 (br s, 1H), 8.97 (s, 2H), 7.50–
7.56 (m, 2H), 7.24 (dd, J=2, 11 Hz, 1H), 6.16 (br s, 1H),
4.82 (m, 1H), 4.08 (t, J=9 Hz, 1H), 3.82 (dd, J=7, 9 Hz,
1H), 3.65–3.75 (m, 2H), 3.34 (d, J=5 Hz, 3H), 2.04 (s,
3H); HR-MS (FAB) calcdfor C 17H18FN5O3S+H
392.1192; found392.1189.
C18H19FN4O3+H
.
359.1519;
found359.1529;
C18H19FN4O3 0.3 H2O: C, 59.43; H, 5.43; N, 15.40;
Found: C, 59.15; H, 5.33; N, 15.16.
General procedure for the conversion of acetamides 22
and 27–29 to thioamides 31–34. A solution of the start-
ing acetamide (1 equiv) in dry THF was treated with
Lawesson’s reagent (2.5 equiv) andrefluxedovernight.
After removal of THF in vacuo, the residue was chro-
N-({(5S)-3-[3-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phe-
nyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (27).
Alkylation with iodomethane afforded 27 (0.078 g,
0.23 mmol, 76%) as a white solid: mp 224–225 ꢁC; H
matographedon silica gel with 0–5% CH OH/CH2Cl2
3
1
NMR (400 MHz, CDCl3) d 7.82 (s, 1H), 7.75 (s, 1H),
7.48–7.52 (m, 2H), 7.20 (d, J=9 Hz, 1H), 6.07 (br s,
1H), 4.81 (br s, 1H), 4.07 (t, J=9 Hz, 1H), 3.96 (s, 3H),
3.80 (t, J=7 Hz, 1H), 3.66–3.77 (m, 2H), 2.04 (s, 3H);
MS (+ESI) m/z 333 (M+H); anal. calcdfor
C16H17FN4O3: C, 57.83; H, 5.16; N, 16.86; found: C,
57.69; H, 5.23; N, 16.63.
to afforded the indicated analogues.
N-({(5S)-3-[3-fluoro-4-(1H-pyrazol-4-yl)phenyl]-2-oxo-
1,3-oxazolidin-5-yl}methyl)ethanethioamide (31). Com-
pound 31 (97 mg, 0.29 mmol, 94%) was isolatedas a
white solid: mp 188–190 ꢁC (dec.); [a]2D5=8ꢁ (c 0.78,
DMSO); 1H NMR (400 MHz, DMSO-d6) d 10.34–10.38
(m, 1H), 8.12 (br s, 1H), 7.91 (br s, 1H), 7.75 (t,
J=9 Hz, 1H), 7.55 (dd, J=2, 14 Hz, 1H), 7.32 (dd,
J=2, 9 Hz, 1H), 4.91–4.98 (m, 1H), 4.18 (t, J=9 Hz,
1H), 3.92 (dd, J=4, 10 Hz, 2H), 3.85 (dd, J=7, 9 Hz,
1H), 2.44 (s, 3H); HR-MS (FAB) calcdfor
C15H15FN4O2S+H 335.0978; found335.0985; anal.
calcdfor C 15H15FN4O2S: C, 53.88; H, 4.52; N, 16.76;
found: C, 54.27; H, 5.02; N, 14.88; HPLC shows purity
of the product >95%.
N-({(5S)-3-[4-(1-ethyl-1H-pyrazol-4-yl)-3-fluorophenyl]-
2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (28). Alky-
lation with iodoethane afforded 28 (0.20 g, 0.58 mmol,
92%) as a white solid: mp 192–193 ꢁC; [a]D25=À25ꢁ (c
1
0.79, DMSO); H NMR (400 MHz, DMSO-d6) d 7.81
(s, 1H), 7.75 (d, J=2 Hz, 1H), 7.48 (dd, J=9,
12 Hz, 1H), 7.46 (dd, J=4, 15 Hz, 1H), 7.16 (dd,
J=2, 9 Hz, 1H), 6.54 (t, J=6 Hz, 1H), 4.76–4.83
(m, 1H), 4.20 (q, J=7 Hz, 2H), 4.05 (t, J=9 Hz, 1H),
3.80 (dd, J=7, 9 Hz, 1H), 3.61–3.72 (m, 2H), 2.03 (s,
3H), 1.52 (t, 3H); HR-MS (FAB) calcdfor
C17H19FN4O3+H 347.1519; found347.1523; anal.
calcdfor C 17H19FN4O3: C, 58.95; H, 5.53; N, 16.18;
found: C, 58.65; H, 5.58; N, 16.00.
N-({(5S)-3-[3-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]
-2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide (32).
Compound 32 (98 mg, 0.28 mmol, 58%) was isolatedas
a white solid: mp 175–176 ꢁC; [a]2D5=9ꢁ (c 0.82, DMSO);
1H NMR (400 MHz, DMSO-d6) d 10.34–10.38 (m, 1H),
8.09 (s, 1H), 7.85 (s, 1H), 7.72 (t, J=9 Hz, 1H), 7.55 (dd,
J=2, 14 Hz, 1H), 7.32 (dd, J=2, 9 Hz, 1H), 4.93–4.99
(m, 1H), 4.18 (t, J=9 Hz, 1H), 3.91 (dd, J=5, 10 Hz,
2H), 3.88 (s, 3H), 3.84 (dd, J=7, 9 Hz, 1H), 2.44 (s, 3H);
HR-MS (FAB) calcdfor C 16H17FN4O2S+H 349.1134;
found349.1141; anal. calcdfor C 16H17FN4O2S: C,
55.16; H, 4.92; N, 16.08; found: C, 55.08; H, 5.00; N,
15.93.
N-[((5S)-3-{4-[1-(cyanomethyl)-1H-pyrazol-4-yl]-3-fluoro-
phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide (29).
Alkylation with bromoacetonitrile afforded 29 (138 mg,
0.39 mmol, 82%) as a white solid: mp 130–132 ꢁC; H
1
NMR (400 MHz, DMSO-d6) d 8.20–8.25 (m, 2H), 8.06
(s, 1H), 7.76 (t, J=9 Hz, 1H), 2.57 (d, J=16 Hz, 1H),
7.35 (d, J=9 Hz, 1H), 5.53 (s, 2H), 4.70–4.78 (m, 1H),

C. S. Lee et al. / Bioorg. Med. Chem. 9 (2001) 3243–3253
3253
N-({(5S)-3-[4-(1-ethyl-1H-pyrazol-4-yl)-3-fluorophenyl]-
2-oxo-1,3-oxazolidin-5-yl}methyl)ethanethioamide (33).
Compound 33 (120 mg, 0.33 mmol, 72%) was isolated
as a white solid: mp 162–164 ꢁC; [a]D25=7ꢁ (c 0.78,
DMSO); 1H NMR (400 MHz, DMSO-d6) d 10.33–10.38
(m, 1H), 8.13 (s, 1H), 7.86 (s, 1H), 7.72 (t, J=9 Hz, 1H),
7.55 (dd, J=2, 14 Hz, 1H), 7.32 (dd, J=2, 9 Hz, 1H),
4.93–4.98 (m, 1H), 4.17 (m, 3H), 3.92 (dd, J=5, 10 Hz,
2H), 3.84 (dd, J=7, 9 Hz, 1H), 2.44 (s, 3H), 1.39 (t,
J=7 Hz, 3H); HR-MS (FAB) calcdfor C 17H19FN4O2S
+H 363.1291; found363.1293; anal. calcdfor
6. Sieradzki, K.; Roberts, R. B.; Haber, S. W.; Thomasz, A.
N. Engl. J. Med. 1999, 340, 517.
7. Waldvogel, F. A. N. Engl. J. Med. 1999, 340, 556.
8. Brickner, S. J. Curr. Pharm. Des 1996, 2, 175.
9. Brumfitt, W.; Hamilton-Miller, J. M. T. Drugs Exp. Clin.
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10. Low, D. E.; Willey, B. M.; McGeer, A. J. Am. J. Surg.
1995, 5A (Suppl.), 8S.
11. Spera, R. V., Jr.; Farber, B. F. Drugs 1994, 48, 678.
12. Appelbaum, P. C. Clin. Infect. Dis 1992, 15, 77.
13. Lin, A. H.; Murray, R. W.; Vidmar, T. J.; Marotti, K. R.
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.
14. Shinabarger, D. L.; Marotti, K. R.; Murray, R. W.; Lin,
A. H.; Melchior, E. P.; Swaney, S. M.; Dunyak, D. S.; Dem-
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C17H19FN4O2S 0.45 H2O: C, 55.11; H, 5.41; N, 15.12;
found: C, 55.42; H, 5.37; N, 14.73.
N-[((5S)-3-{4-[1-(cyanomethyl)-1H-pyrazol-4-yl]-3-fluoro-
phenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]ethanethioa-
mide (34). Compound 34 (74 mg, 0.20 mmol, 32%) was
isolatedas a pale yellow solid: mp 72–75 ꢁC; [a]D25=5ꢁ (c
0.71, DMSO); 1H NMR (400 MHz, DMSO-d6) d 10.33–
10.38 (m, 1H), 8.25 (s, 1H), 8.06 (s, 1H), 7.77 (t,
J=9 Hz, 1H), 7.58 (dd, J=2, 14 Hz, 1H), 7.36 (dd,
J=2, 9 Hz, 1H), 5.54 (s, 2H), 4.93–5.00 (m, 1H), 4.19 (t,
J=9 Hz, 1H), 3.91 (dd, J=4, 10 Hz, 2H), 3.85 (dd,
J=7, 9 Hz, 1H), 2.44 (s, 3H); HR-MS (FAB) calcdfor
C17H16FN5O2S+H 374.1087; found374.1086; anal.
15. Kaatz, G. W.; Seo, S. M. Antimicrob. Agents Chemother.
1996, 40, 799.
16. Zurenko, G. E.; Yagi, B. H.; Schaadt, R. D.; Allison,
J. W.; Kilburn, J. O.; Glickman, S. E.; Hutchinson, D. K.;
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M. R.; Emmert, D. E.; Garmon, S. A.; Graber, D. R.; Grega,
K. C.; Hester, J. B.; Hutchinson, D. K.; Morris, J.; Reischer,
R. J.; Ford, C. W.; Zurenko, G. E.; Hamel, J. C.; Schaadt,
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.
calcdfor C 17H16FN5O2S 0.5CH3OH: C, 53.98; H, 4.66;
N, 17.98; found: C, 54.09; H, 4.49; N, 17.82.
Acknowledgements
20. Park, C.-H.; Brittelli, D. R.; Wang, C. L.-J.; Marsh, F. D.;
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We thank the Structural, Analytical andMeidcinal
Chemistry Department of the Pharmacia Corporation
for mass spectral andcombustion analysis data andthe
Oxazolidinone Program Team for many helpful discus-
sions.
24. Brickner, S. J.; Hutchinson, D. K.; Barbachyn, M. R.;
Manninen, P. R.; Ulanowicz, D. A.; Garmon, S. A.; Grega,
K. C.; Hendges, S. K.; Toops, D. S.; Ford, C. W.; Zurenko,
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