Novel substituted (pyridin-3-yl)phenyloxazolidinones: Antibacterial agents with reduced activity against monoamine oxidase A and increased solubility

Article abstract of DOI:10.1021/jm070428+

Oxazolidinones represent a new and promising class of antibacterial agents. Current research in this area is mainly concentrated on improving the safety profile and the antibacterial spectrum. Oxazolidinones bearing a (pyridin-3-yl)phenyl moiety (e.g., 3) generally show improved antibacterial activity compared to linezolid but suffer from potent monoamine oxidase A (MAO-A) inhibition and low solubility. We now disclose the finding that new analogues of 3 with acyclic substituents on the pyridyl moiety exhibit excellent activity against Gram-positive pathogens, including linezolid-resistant Streptococcus pneumoniae. Generally, more bulky substituents yielded significantly reduced MAO-A inhibition relative to the unsubstituted compound 3. The MAO-A SAR can be rationalized on the basis of docking studies using a MAO-A/MAO-B homology model. Solubility was enhanced with incorporation of polar groups. One optimized analogue, compound 13, showed low clearance in the rat and efficacy against S. pneumoniae in a mouse pneumonia model.

Full text of DOI:10.1021/jm070428+

4868
J. Med. Chem. 2007, 50, 4868-4881
Novel Substituted (Pyridin-3-yl)phenyloxazolidinones: Antibacterial Agents with Reduced
Activity against Monoamine Oxidase A and Increased Solubility
Folkert Reck,* Fei Zhou, Charles J. Eyermann, Gunther Kern, Dan Carcanague, Georgine Ioannidis, Ruth Illingworth,
Grace Poon, and Michael B. Gravestock
AstraZeneca DiscoVery, AstraZeneca R&D Boston, 35 Gatehouse DriVe, Waltham, Massachusetts 02451
ReceiVed April 11, 2007
Oxazolidinones represent a new and promising class of antibacterial agents. Current research in this area is
mainly concentrated on improving the safety profile and the antibacterial spectrum. Oxazolidinones bearing
a (pyridin-3-yl)phenyl moiety (e.g., 3) generally show improved antibacterial activity compared to linezolid
but suffer from potent monoamine oxidase A (MAO-A) inhibition and low solubility. We now disclose the
finding that new analogues of 3 with acyclic substituents on the pyridyl moiety exhibit excellent activity
against Gram-positive pathogens, including linezolid-resistant Streptococcus pneumoniae. Generally, more
bulky substituents yielded significantly reduced MAO-A inhibition relative to the unsubstituted compound
3. The MAO-A SAR can be rationalized on the basis of docking studies using a MAO-A/MAO-B homology
model. Solubility was enhanced with incorporation of polar groups. One optimized analogue, compound
13, showed low clearance in the rat and efficacy against S. pneumoniae in a mouse pneumonia model.
Scheme 1a
Introduction
Oxazolidinones are a new class of antibacterial agent that
show good activity against Gram-positive bacteria. Oxazolidi-
nones target bacterial protein synthesis, probably by binding at
or near the peptidyltransferase center in actively translating
bacterial ribosomes.1-3 Linezolid was the first member of this
class to achieve FDAa approval. However, resistance against
linezolid has already started to develop in Enterococcus
faecium4-8 and, more alarmingly, in S. aureus, giving rise to
linezolid-resistant MRSA strains.9 A key concern with oxazo-
lidinones as a drug class has been inhibition of MAO, especially
type A (MAO-A), because of the structural similarity to MAO
inhibitors like toloxatone.10 Inhibition of MAO-A could poten-
tially lead to severe hypertensive crises as a result of ingesting
tyramine-containing food together with an oxazolidinone drug
(the “cheese effect”).11,12 It is therefore desirable to develop
novel oxazolidinones that have improved activity against
linezolid-resistant Gram-positive bacteria and show an improved
safety profile with regard to MAO-A inhibition.13 Pyridylphe-
nyloxazolidinones, exemplified by the triazole derivative 3,
display excellent activity against Gram-positive bacteria. How-
ever, unsubstituted pyridyl derivatives such as 3 suffer from
potent MAO-A inhibition (3: Ki < 0.3 µM) and cytochrome
P450 (CYP) inhibition (Ki ≈ 7 µM for 3 against both 2D6 and
3A4 isozymes). In addition, the low solubility of 3 is a problem
for iv formulation. We and others have addressed these issues
with varying success by appending yet another ring directly off
the pyridine unit in the 6-position.14-17 However, in our exper-
ience, this approach generally tends to confound problems with
slow dissolution rates because of increased crystallinity and low
solubility, and problems with formulation remain. Also, these
analogues with a flat and rodlike shape, consisting of four
conjoined rings, still generally retain potent MAO-A inhibition.
* To whom correspondence should be addressed. Phone: 781-839-4617.
Fax: 781-839-4630. E-mail: folkert.reck@astrazeneca.com.
a Abbreviations: MAO-A, monoamine oxidase A; MAO-B, monoamine
oxidase B; SAR, structure-activity relationship; FDA, Food and Drug
Administration; MRSA, methicillin-resistant Staphylococcus aureus; CyP450,
cytochrome P450 enzymes; MS (ESP), mass spectroscopy (electrospray);
APCI, atmospheric pressure chemical ionization.
a Reagents: (a) Na2CO3, Pd(PPh3)4, DMF, 75 °C; (b) HCl, dioxane, room
temp; (c) Na(BH4), THF, 0 °C; (d) H2, Pd/C, MeOH, room temp; (e) NaH,
MeI, DMF, 0 °C; (f) iprMgBr, THF, -20 °C to room temp.
10.1021/jm070428+ CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/28/2007

Substituted Oxazolidinones
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 20 4869
Scheme 2a
a Reagents: (a) NEt3, DMAP, Ac2O, CH2Cl2, room temp; (b) Ag triflate, I2, CHCl3/CH3CN, room temp; (c) K2CO3, MeOH/CH2Cl2, room temp; (d) NEt3,
MsCl, CH2Cl2, 0 °C to room temp; (e) NaN3, DMF, 75 °C; (f) bicyclo[2.2.1]hepta-2,5-diene, dioxane, 100 °C; (g) bis(pinacolato)diboron, KOAc, Pd(dppf)Cl2.
Scheme 3a
Scheme 5a
a Reagents: (a) MeMgBr, THF, 0 °C.
Scheme 6a
a Reagents: (a) 36, iprMgCl, THF, -10 °C, then 35, 10 °C.
Scheme 4a
a Reagents: (a) concentrated HCl, 80 °C, then morpholine, 85 °C.
25, 27), reduction of ketones to alcohols (7, 15, 21), and simple
deprotection reactions, were performed after coupling using
standard functional group manipulations. However, most trans-
formations were carried out at the pyridyl bromide stage rather
than after Suzuki coupling because of the low solubility of
oxazolidinone intermediates such as 4 and 28 in most organic
solvents. The boronic ester 2h was synthesized using a silver
triflate assisted iodination in the key step, as outlined in Scheme
2. Acylated pyridyl bromides 1a-d were prepared by reaction
of Weinreb amides 35a-d with the Grignard reagent prepared
from 5-bromo-2-iodopyridine (36) and isopropylmagnesium
chloride23 (Scheme 3). Imidazole derivatives 1i-n were obtained
by reaction of R-bromoketone 38 with imidazoles (Scheme 4).
Compound 38 was obtained from methyl ketone 3717,24 by
bromination with bromine/HBr. For the 2,5-dimethyl-1H-
imidazole derivative 1n, 2,4-dimethylimidazole was first pro-
tected on the less sterically hindered nitrogen with a trityl group
and then reacted with 38, followed by deprotection of the trityl
group. Amino alcohols 1e-g and 1,2-diol 1h were prepared by
nucleophilic substitution on 38 with an amine or, for 1h, with
sodium formate, followed by reduction of the R-aminoketone/
R-hydroxyketone intermediates with sodium borohydride in situ.
The ketone intermediates of 1e-h were unstable and could not
be isolated. Reaction of aldehyde 1o23,25 with methylmagnesium
bromide gave the chiral alcohols 1p and 1q (Scheme 5), which
were separated by chromatography on a chiral stationary phase.
The hydroxymethyl and 1-hydroxy-1-methylethylpyridyl bro-
mides needed for 22 and 30 were obtained via selective
monolithiation of 2,5-dibromopyridine.25 For 1s (Scheme 6),
ethyl 5-bromopyridine-2-carboxylate was reacted with the
a Reagents: (a) Br2, HBr, MeOH/HOAc, 0 °C to room temp; (b) amine,
THF, 0 °C, then NaBH4, MeOH; for 1h, HCOONa, EtOH, 50 °C, then
NaBH4, MeOH, 0 °C; (c) imidazole derivative, THF, 0 °C; (d) TrCl, NEt3,
CH2Cl2, room temp; (e) dioxane, 75 °C; (f) TFA/CH2Cl2, reflux.
We now report on our studies into the SAR of 6-acyclic-
substituted pyridylphenyloxazolidinones (researchers at RibX
have recently published patent applications in this area as
well18-20) that have led to new oxazolidinones with significantly
reduced MAO-A inhibition and improved solubility relative to
the lead 3 and with excellent Gram-positive activity, including
against linezolid-resistant strains.21,22
Chemistry
Pyridylphenyloxazolidinones were assembled by Suzuki
coupling of pyridyl bromides 1a-s (Schemes 3-6) with the
boronic ester 2h (Scheme 1). In some cases further modifica-
tions, including alkylations of alcohols to methoxy ethers (23,

4870 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 20
Reck et al.
Table 1. SAR of Alcohols and Ethers Compared to Unsubstituted Lead 3
a Methicillin-susceptible Staphylococcus aureus AP601055. b Penicillin-susceptible Streptococcus pneumoniae AP671401. c Linezolid-resistant (LinR)
Streptococcus pneumoniae.43 d Haemophilius influenzae ATCC51907. Minimum inhibitory concentration (MIC): lowest drug concentration that reduced
growth by 80% or more.32 e Solubilities were obtained by nephelometric analysis of test compounds diluted into the MAO-A assay mixture. f Human
plasma protein binding. ND: no data. g Monoamineoxidase A Ki.35
sodium salt of γ-butyrolactone to give the dihydrofuranone 1r,26
which was cleanly converted to the γ-chloride with HCl. Heating
of the chloride with morpholine gave 1s, together with the
7-bromo-1-oxo-1,2,3,4-tetrahydroquinolizinium salt.
Figure 1 illustrates the most favorable binding mode identified
for 3. Figure 2 shows the docking of the sterically more
demanding 13, indicating less favorable binding due to crowding
at the 6-position of the pyridyl moiety.
Molecular Modeling
Results and Discussion
Crystal structures for human mitochondrial monoamine
oxidase B (MAO-B) have been reported recently.27-29 A simple
homology model for MAO-A was built by substituting the
MAO-B substrate cavity residues Leu 171, Cys 172, Ile 199,
and Tyr 326 with the MAO-A residues Ile 180, Asn 181, Phe
208, and Ile 335, respectively. The accuracy of the model is
supported by the similarity of the active sites of MAO-A and
MAO-B.29 Docking studies of oxazolidinones using the homol-
ogy model of MAO-A were performed using the QXP/FLO
software.30 Residues in the substrate and entrance cavities were
allowed full conformational flexibility in the docking studies.
Oxazolidinones bearing a 6-substituted pyridylphenyl moiety
were submitted for evaluation of antibacterial activity. For
alcohols (Table 1), compounds bearing a substituent that is
relatively small and nonbasic (compounds 22, 24, 26, 31) retain
the excellent Gram-positive activity of the unsubstituted parent
3, including against linezolid-resistant strains. Moreover, com-
pounds 22 and 31 also show good activity against Haemophilus
influenzae. Substituents that are more sterically demanding or
basic yield reduced activity (7, 21, 29, 30, 32-34). Ethers
(compounds 23, 25, 27) were less active than the corresponding
alcohols. The presence of a base may reduce permeability

Substituted Oxazolidinones
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 20 4871
Table 2. SAR of Ketones
a Methicillin-susceptible Staphylococcus aureus AP601055. b Penicillin-susceptible Streptococcus pneumoniae AP671401. c Linezolid-resistant (LinR)
Streptococcus pneumoniae.43 d Haemophilius influenzae ATCC51907. Minimum inhibitory concentration (MIC): lowest drug concentration that reduced
growth by 80% or more.32 e Solubilities were obtained by nephelometric analysis of test compounds diluted into the MAO-A assay mixture. f Human
plasma protein binding. ND: no data. g Monoamineoxidase A Ki.35
through the bacterial membrane, especially for the more polar
alcohols. For ketones (Table 2) antibacterial activity was
generally excellent and similar to 3 except for the azetidine
analogue 6.
shown in Figures 1 and 2. The Lee and Richards molecular
surface in Figure 2 indicates that substitution of the pyridyl ring
in the 6-position is sterically crowded for larger and more rigid
substituents.
With regard to the undesired MAO-A inhibition, we observed
a correlation to substituent size, with rising Ki values observed
for compounds with greater steric bulk next to the alcohol (7,
21, 29) or ketone (20), relative to unbranched derivatives (4,
14- 15, 16, 18, 24, 26). Amino alcohols 21 and 32-34 had
no or weak MAO-A inhibition, which could be due to a
combination of increased steric bulk and basic group. The
MAO-A SAR of the oxazolidinones listed in Tables 1 and 2
can be largely rationalized on the basis of the docking model
The solubility of substituted compounds was generally en-
hanced relative to parent 3, especially when ionizable groups
were added. Human protein binding was low (<50%) for more
soluble compounds (14, 31, and 32) but higher for the less polar
ketones 10 and 13 (88% and 90%, respectively) (Tables 1 and
2).
A small substituent added to the pyridine ring in the 6-position
(compound 22) abolished moderate CYP 3A4 and 2D6 inhibi-
tion seen with compound 3 (Table 3). Potent CYP 3A4

4872 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 20
Reck et al.
Table 3. CYP450 Inhibition: Substitution Effects on Pyridine and
Imidazolea
Figure 1. Model of compound 3 docked into a MAO-A homology
model. The triazole ring is buried in an “aromatic cage” formed by
Y398, Y435, and the flavin cofactor. Note that the binding of 3 induces
a conformational change on Phe 199, the gatekeeper residue identified
by Binda27 that joins or separates the entrance and substrate cavities.
A Lee and Richards molecular surface is displayed to illustrate the
shape of the induced binding pocket. Residue numbers correspond to
those from the MAO-B X-ray structure.27,28
a CYP450 inhibition using recombinant human P450 enzymes.
Table 4. Pharmacokinetics of Alcohols and Ketones in the Rata
a Pharmacokinetic parameters following administration of 2 mg/kg
(compounds 10, 12, 13) or 10 mg/kg (compounds 11, 18, 20, 26, 31) iv
bolus injection. Oral bioavailability was assessed following a 10 mg/kg
dose.
Figure 2. Close-up view of the MAO-A binding pocket surrounding
the (pyridin-3yl)phenyl scaffold of 13. The Lee and Richards molecular
surface indicates that substitution of the pyridyl ring in the 6-position
is sterically crowded. Small flexible substituents at the 6-position are
better tolerated than larger and more rigid substituents. Compound 3
is >60 times more potent against MAO-A than 13.
major metabolites in rat. Ketones with less steric hindrance
around the keto group were unstable in vitro in rat microsomes
or showed high clearance in vivo (9, 11, 18). Imidazoles 9-11
exhibited the best properties overall with regard to microbiologi-
cal potency, reduced MAO-A inhibition, absence of CYP
inhibition, and acceptable solubility. However, high clearance
remained a problem. Metabolic studies for 11 in rat, dog, and
human microsomes identified one major metabolite in all species
with two mass units higher than the mass of the parent drug,
indicating reduction to the corresponding alcohol. The alcohol
inhibition was observed with the unsubstituted imidazole
analogue 8; however, the addition of alkyl groups (9, 11, 13)
on the imidazole ring removed that problem.31
The pharmacokinetics of selected compounds were deter-
mined in the rat (Table 4). The alcohols (26, 31) showed high
clearance and short half-lives, with glucuronidates identified as

Substituted Oxazolidinones
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 20 4873
Table 5. Exposure and Efficacy of Compound 13 Compared to Linezolid in a Mouse Pneumonia Modela
compound 13
linezolid
log of reduction in
CFU/lung vs
vehicle-treated control
log of reduction in
CFU/lung vs
vehicle-treated control
exposure
exposure
(AUC, g h-1 mL-1
)
(AUC, g h-1 mL-1
)
40 mg kg-1 day-1
80 mg kg-1 day-1
17.4
31.0
1.94
2.57
45.7
105
ND
3.89
a In vivo activity against S. pneumoniae 548 (ARC548, AstraZeneca culture collection).
confirmed by dialysis against 10 mM potassium phosphate, pH 7.4,
and subsequent MAO-A activity determination.
and the associated glururonidate were observed as metabolites
in rat plasma after iv dosing of 11. Since both enantiomeric
alcohols showed reduced antibacterial activity relative to 11
(data not shown), we tried to block this metabolism. We
hypothesized that metabolic lability of the ketone functionality
in the imidazole derivatives would be reduced in a 2,5-
disubstituted imidazole because of increased steric hindrance.
Indeed, 2,5-dimethylimidazole 13 showed lower clearance of
10 mL min-1 kg-1 in the rat, considered acceptable for further
pharmacodynamic studies. Oral bioavailability of 13 in the rat
was 73%. Compound 13 was orally active against Streptococcus
pneumoniae in a mouse pneumonia model at 40 mg kg-1 day-1
(Table 5), causing a ∼2 log reduction in viable counts in the
lung relative to the vehicle-treated control.
Ki values were fitted using the model for MAO-A previously
described.36
Plasma Protein Binding. Plasma protein binding was determined
using the Dianorm equilibrium dialysis chamber.
Compound (10 µM) was spiked in the plasma chamber (donor
side), and phosphate buffer was placed in the receiver side. The
unit was rotated at 37 °C for 16 h. Drug concentration was
determined for the plasma sample that represents the bound fraction
and for the buffer sample that represents the free fraction. LC/
MS-MS quantitative sample analysis was achieved using an Ace
C18 50 mm × 4.6 mm column (MacMod, PA) and electrospray
ionization MRM detection (PE Sciex API 4000 mass spectrometer,
Applied Biosystems CA). Plasma samples (50 µL) or the buffer
samples (100 µL) were treated with methanol (150 µL) containing
an internal standard (an oxazolidinone analogue) to precipitate the
protein. Concentration determination was based on a standard curve
(10 nM to 10 µM), and data were processed by the Analyst, version
1.4.1, software.
P450 Inhibition Assay. The IC50 of CYP3A4, CYP1A2,
CYP2D6, CYP2C9, and CYP2C19 was determined in 96-well
plates, at 0.2-20 µM , using recombinant human P450 enzymes.
The following chemicals were used as substrates: 7-methoxy-4-
trifluoromethylcoumarin (2C19), 7-methoxy-4-trifluoromethylcou-
marin (2C9), 7-methoxy-4-(aminomethyl)coumarin (2D6), 7-ben-
zyloxy-4-(trifluoromethyl)coumarin (3A4), and 3-cyano-7-ethoxy-
coumarin (1A2). Sample preparation and detection were performed
on a Tecan U.S. Genesis RSP200 robotic workstation and a Tecan
Safire monochromator fluorescence detector (Durham NC).
Microsomal Incubation. Study compounds (2 µM) were
incubated with rat, dog, or human liver microsomes (0.5 mg/mL
protein, BD Bioscience, MA) in the presence of NADPH (2 mM)
at 37 °C. Aliquots (25 µL) were withdrawn at 0, 5, 10, 20, and 30
min, mixed with methanol (100 µL) containing an oxazolidinone
internal standard, prior to sample analysis.
Conclusions
We report the synthesis and biological evaluation of novel
oxazolidinones with acyclic substituents in the 6-position of a
(pyridin-3yl)phenyl moiety. We found that compounds bearing
a relatively small alcohol or ketone substituent on the pyridine
were potent antibacterials with good activity against Gram-
positive pathogens, including linezolid-resistant strains. Many
of these analogues, especially the alcohol derivatives, had
significantly higher MAO-A Ki values than the unsubstituted
parent, a potential advantage in the search for oxazolidinones
with a better safety profile. The MAO-A SAR can largely be
rationalized by docking studies using a MAO-A/MAO-B
homology model. The incorporation of polar groups resulted
in significantly improved solubility for some compounds,
improving the potential for iv formulations.
Experimental Section
Metabolite Identification. Rat plasma samples were taken at
various time points after drug administration, or at 30 min after
microsomal incubations, and treated with methanol followed by
quantitative sample analysis as described for plasma protein binding.
Qualitative sample analysis was performed on an Ace C18 150
mm × 4.6 mm column, and metabolites detection was achieved
by full scan, precursor scan, MRM scan, and product ion scan.
Animals. Wistar Han rats for pharmacokinetic studies were
obtained from Charles River Laboratories (Raleigh, NC). CD-1 mice
were obtained from Charles River Laboratories (Kingston, NY).
All animals were housed and acclimated in the animal facility on
site before each study. All experimental procedures were conducted
in accordance with protocols approved by the Institutional Animal
Care and Use Committee.
Pharmacokinetic Studies. Pharmacokinetic properties of se-
lected compounds were studied in the rat. Groups of three Wistar
Han rats were administered test compound at a dose of 2 or 10
mg/kg by bolus injection into a cannulated jugular vein. Oral
bioavailability was determined following a 10 mg/kg dose given
by oral gavage. Serial 200 µL samples of whole blood were taken
at time intervals. The concentration of compound in plasma was
determined by LC-MS/MS, and pharmacokinetic parameters were
estimated using a noncompartmental model in WinNonLin (Phar-
sight).
Minimum Inhibitory Concentration Testing. Minimum inhibi-
tory concentrations were determined by broth microdilution ac-
cording to the Clinical and Laboratory Standards Institute guide-
lines.32 Compounds were dissolved in 100% DMSO and diluted to
2% DMSO (v/v) in culture medium from 64 to 0.06 µg/mL. Specific
culture media are as follows: for S. aureus, Mueller Hinton broth,
Difco catalog no. 275730; for H. influenzae, 2.2% (w/v) Mueller
Hinton broth, 0.5% (w/v) yeast extract (Difco, catalog no. 288620),
15 µg/mL hematin (Sigma, catalog no. H3281-5G), and 1.5 µg/
mL NAD (Sigma, catalog no. N6522-5G); for S. pneumoniae, 2.2%
(w/v) Mueller Hinton broth, 0.65% (v/v) lysed horse blood (Hema
Resource and Supply, catalog no.15-14-0100-28). Cultures were
incubated at 35 °C under aerobic conditions for S. aureus and in a
5% CO2 atmosphere for S. pneumoniae and H. influenzae. Microtiter
plates were read by spectrophotometry at 620 nm.
MAO-A Assay. Human liver MAO-A was expressed in yeast33
and purified according to Tan.34 The assay was carried out adapting
the method of Flaherty.35 Specific conditions were 100 µM substrate
4-(1-methyl-2-pyrryl)-1 methyl-1,2,3,6-tetrahydropyridine, 82 nM
human liver monoamine oxidase A34 (MAO-A concentration was
determined using the BioRad Protein assay reagent, catalog no. 500-
0006), 100 mM potassium phosphate buffer at pH 7.4 and 25 °C;
total substrate turnover was ∼10%. Inhibition was reversible and
competitive to the amine substrate. Reversibility of inhibition was

4874 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 20
Reck et al.
Exposure in CD-1 mice was determined for analysis of the
efficacy studies. Compound 13 was dosed by oral gavage to groups
of mice at 40 and 80 mg/kg. At timed intervals, groups of three
mice were sacrificed and whole blood samples collected by cardiac
puncture. Plasma samples were prepared and analyzed as described
above.
S. pneumoniae Lung Infection Model. Compound 13 and
linezolid were studied in a mouse lung infection model. Groups of
10 mice were infected with S. pneumoniae 548 (AstraZeneca culture
collection) at 1 × 105 cfu/lung via the intratracheal route. Treatment
with test compound or with vehicle alone was given by oral gavage
and commenced 18 h after infection. Efficacy was evaluated by
viable counts in the lung 24 h after the start of treatment. Mice
were sacrificed; lungs were removed aseptically and homogenized
and serial dilutions plated on Tryptic Soy agar plates supplemented
with 5% sheep blood.
1-(5-Bromopyridin-2-yl)-2-morpholin-4-ylethanol (1e). Com-
pound 38 (600 mg, 1.67 mmol) was suspended in dry THF (5 mL)
and cooled to 0 °C. Morpholine (0.58 mL, 6.7 mmol) was added,
and the mixture was vigorously stirred for 1 h at 0 °C. Sodium
borohydride (190 mg, 5 mmol) was added, followed by addition
of methanol (4 mL). The mixture was stirred for 30 min at 0 °C
and then acidified to pH < 2 with concentrated hydrochloric acid.
Solvent was removed under reduced pressure, and the pH was
adjusted to pH 10 with aqueous potassium hydroxide solution (1
M). The product was extracted with dichloromethane and dried over
sodium sulfate. Chromatography on silica gel with hexanes/acetone
(1:1) and then with acetone gave 388 mg (81%) of the product as
a pale-yellow solid. MS (ESP) m/z 287/289 (MH+). 1H NMR
(DMSO-d6) δ: 2.40-2.65 (m, 6H), 3.53 (dd, 4H), 4.73 (ddd, 1H),
5.37 (d, 1H), 7.47 (m, 1H), 8.02 (m, 1H), 8.59 (m, 1H).
1-(5-Bromopyridin-2-yl)-2-(dimethylamino)ethanol (1f). 38
(500 mg, 1.8 mmol) was dissolved in methanol (20 mL) and cooled
to -10 °C. Dimethylamine (0.9 mL, 2 M in THF) was added
dropwise, followed by addition of triethylamine (0.25 mL). After
30 min, more dimethylamine solution (0.25 mL) was added and
the mixture was stirred for 1.5 h at -10 to -5 °C. Sodium
borohydride (205 mg, 5.4 mmol) was added in portions, the reaction
mixture was stirred for another hour at -5 °C and then acidified
to pH < 2 with concentrated hydrochloric acid. Solvent was
removed under reduced pressure, and the pH was adjusted to pH
10 with aqueous potassium hydroxide solution (1 M). Chromatog-
raphy on a C-18 column (RediSep, Isco Inc.) with 0-5% aceto-
nitrile in water containing 0.1% TFA gave approximately 220 mg
of the TFA salt of the product (34%) together with the TFA salts
of dimethylamine and triethylamine. The product was used without
further purification. MS (ESP) m/z 245/247 (MH+). 1H NMR
(DMSO-d6) δ: 2.87-3.15 (m, 3H), 3.02 (s, 6H), 4.70 (m, 1H),
7.20 (d, 1H), 7.77 (dd, 1H), 8.29 (s, 1H), 9.53 (brs, 1H).
General Chemical Methods. All commercially available sol-
vents and reagents were used without further purification. All
moisture-sensitive reactions were carried out under a nitrogen
atmosphere in commercially available anhydrous solvents. Column
chromatography was performed on 230-400 mesh silica gel 60.
Aluminum-backed sheets of silica gel 60 F254 (EM Science) were
used for TLC. Melting points were obtained with a Mel-TempII
melting point apparatus from Laboratory Devices, Inc., and are
1
uncorrected. H NMR spectra were recorded at 300 or 500 MHz.
Chemical shifts are reported in ppm (δ) relative to solvent. Mass
spectroscopy was performed using a Micromass Quattro Micro mass
spectrometer (for ESP) and an Agilent 1100 MSD instrument (for
APCI). Elemental analyses were carried out by Quantitative
Technology, Inc., Whitehouse, NJ.
tert-Butyl 3-[(5-Bromopyridin-2-yl)carbonyl]azetidine-1-car-
boxylate (1a). A solution of 5-bromo-2-iodopyridine (1.09 g, 3.85
mmol) in THF (10 mL) was cooled to -10 °C and treated dropwise
with a solution of iprMgCl in THF (2 M, 1.83 mL, 3.66 mmol). It
was stirred for 30 min, and then a solution of 35a (466 mg, 1.9
mmol) was added via syringe. The reaction mixture was allowed
to warm to 10 °C over 2 h and was then poured into potassium
phosphate buffer (1 M, pH 7, 200 mL) under stirring. It was
extracted with ethyl acetate (150 mL) and dried over sodium sulfate.
Chromatography on silica gel with hexanes/ethyl acetate (7:1) gave
447 mg (69%) of the product as a colorless solid. MS (ESP) m/z
341/343 (MH+). 1H NMR (DMSO-d6) δ: 1.36 (s, 9H), 3.92-4.14
(m, 4H), 4.44 (m, 1H), 7.93 (d, 1H), 8.28 (dd, 1H), 8.84 (d, 1H).
1-(5-Bromopyridin-2-yl)-2-(isopropylamino)ethanol (1g). 38
(600 mg, 1.67 mmol) was reacted with isopropylamine (0.57 mL,
6.7 mmol) as described for 1f. Chromatography on a C-18 column
(RediSep, Isco Inc.) with 0-30% acetonitrile in water, containing
0.1% TFA, gave 241 mg of the TFA salt of the product (39%) as
1
a colorless oil. MS (ESP) m/z 259/261 (MH+). H NMR (MeOH-
d4) δ: 1.34 and 1.36 (2 × d, 6H), 3.22 (m, 1H), 3.38-3.55 (m,
2H), 4.98 (dd, 1H), 7.59 (d, 1H), 8.04 (dd, 1H), 8.64 (s, 1H).
1-(5-Bromopyridin-2-yl)ethane-1,2-diol (1h). 38 (700 mg, 2.51
mmol) and sodium formate (683 mg, 10.04 mmol) were mixed in
85% ethanol (5 mL) and heated to 50 °C for 3 h. It was cooled to
room temperature, and most of the solvent was evaporated under
reduced pressure. It was diluted with dichloromethane (50 mL) and
water (5 mL). The aqueous phase was extracted three times with
dichloromethane, and the combined organic phases were dried over
sodium sulfate. The solvent was removed under reduced pressure,
the residue was taken up in methanol (20 mL) and cooled to 0 °C.
Sodium borohydride (285 mg, 7.5 mmol) was added in portions,
and the mixture was stirred for 1 h at 0 °C. The pH was adjusted
to ∼pH 2 by addition of concentrated HCl, and the solvent was
removed under reduced pressure. The residue was taken up with
dichloromethane (100 mL) and saturated aqueous sodium hydrogen
carbonate solution (10 mL), and the aqueous phase was extracted
three times with dichloromethane. The combined organic phases
were dried over sodium sulfate. Chromatography on silica gel with
hexanes/acetone (2:1) gave 223 mg (41%) of the product as a
colorless solid. MS (ESP) m/z 218/220 (MH+). 1H NMR (DMSO-
d6) δ: 3.47 (m, 1H), 3.65 (m, 1H), 4.55 (m, 1H), 4.71 (ddd, 1H),
5.50 (dd, 1H), 7.45 (m, 1H), 8.01 (m, 1H), 8.59 (m, 1H).
1-(5-Bromopyridin-2-yl)-4-(4-methylpiperazin-1-yl)butan-1-
one (1b). 5-Bromo-2-iodopyridine (927 mg, 3.27 mmol) was reacted
with isopropylmagnesium chloride (2 M in THF, 1.64 mL, 3.27
mmol) and 35b (749 mg, 3.27 mmol) as described for 1a.
Chromatography on silica gel with dichloromethane/methanol (10:1
to 4:1) gave 582 mg (55%) of the product as a colorless oil. MS
1
(ESP) m/z 326.47/328.47 (MH+). H NMR (DMSO-d6) δ: 1.80
(tt, 2H), 2.04 (s, 3H), 2.02-2.35 (m, 10H), 3.07 (t, 2H), 7.87 (d,
1H), 8.25 (m, 1H), 8.85 (m, 1H).
Benzyl 4-[(5-Bromopyridin-2-yl)carbonyl]piperidine-1-car-
boxylate (1c). 5-Bromo-2-iodopyridine (490 mg, 1.73 mmol) was
reacted with isopropylmagnesium chloride (2 M in THF, 0.86 mL,
1.73 mmol) and 35c (529 mg, 1.73 mmol) as described for 1a.
Chromatography on silica gel with hexanes/ethyl acetate (5:1) gave
252 mg (36%) of the product as a colorless solid. MS (ESP) m/z
1
403/405 (MH+). H NMR (DMSO-d6) δ: 1.42 (m, 2H), 1.83 (m,
2H), 2.99 (m, 2H), 3.93 (m, 1H), 4.04 (m, 2H), 5.07 (s, 2H), 7.26-
7.40 (m, 5H), 7.90 (d, 1H), 8.28 (d, 1H), 8.88 (d, 1H).
tert-Butyl 4-[2-(5-Bromopyridin-2-yl)-2-oxoethyl]piperidine-
1-carboxylate (1d). 5-Bromo-2-iodopyridine (764 mg, 2.69 mmol)
was reacted with isopropylmagnesium chloride (2 M in THF, 1.35
mL, 2.63 mmol) and 35d (770 mg, 2.69 mmol) as described for
1a. Chromatography on silica gel with hexanes/ethyl acetate (7:1)
gave 591 mg (57%) of the product as a colorless solid. MS (ESP)
1-(5-Bromopyridin-2-yl)-2-(1H-imidazol-1-yl)ethanone (1i). 38
(440 mg, 1.22 mmol) was suspended in dry THF (5 mL) and cooled
to 0 °C. Imidazole (330 mg, 4.85 mmol) was added, and the mixture
was vigorously stirred for 1 h. The reaction mixture was diluted
with dichloromethane, washed with water, and dried over sodium
sulfate. Chromatography on silica gel with dichloromethane/
methanol (15:1) gave 197 mg of the product (61%) as an off-white
1
m/z 383/385 (MH+). H NMR (DMSO-d6) δ: 1.09 (m, 2H), 1.37
(s, 9H), 1.63 (m, 2H), 2.02 (m, 1H), 2.72 (m, 2H), 3.06 (m, 2H),
3.91 (m, 2H), 7.87 (d, 1H), 8.25 (dd, 1H), 8.85 (d, 1H).

Substituted Oxazolidinones
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 20 4875
1
solid. H NMR (DMSO-d6) δ: 5.77 (s, 2H), 6.91 (brs, 1H), 7.13
oxo-1,2,3,4-tetrahydroquinolizinium salt. Chromatography on silica
gel with hexanes/acetone (5:1), followed by chromatography on
RediSep C-18 with 5-20% acetonitrile in water (0.1% TFA) gave
190 mg of the trifluoroacetate (TFA) salt of the product (12%) as
a colorless oil. MS (ESP) m/z 313/315 (MH+). 1H NMR (DMSO-
d6) δ: 1.99 (m, 2H), 2.98-3.30 (m, 6H), 3.46 (m, 2H), 3.64 (t,
2H), 3.97 (m, 2H), 7.90 (m, 1H), 8.29 (m, 1H), 8.87 (m, 1H), 9.79
(brs, 1H).
(brs, 1H), 7.59 (s, 1H), 7.93 (dd, 1H), 8.34 (dd, 1H), 8.96 (dd,
1H).
1-(5-Bromopyridin-2-yl)-2-(2-methyl-1H-imidazol-1-yl)etha-
none (1j). 38 (650 mg, 1.8 mmol) and 2-methylimidazole (593 mg,
7.2 mmol) were reacted as described for 1i to give 336 mg of the
product (66%) as an off-white solid. MS (ESP) m/z 280/282 (MH+).
1H NMR (DMSO-d6) δ: 2.15 (s, 3H), 5.68 (s, 2H), 6.74 (d, 1H),
7.00 (d, 1H), 7.93 (d, 1H), 8.33 (dd, 1H), 8.96 (d, 1H).
1-(5-Bromopyridin-2-yl)-2-(2-ethyl-1H-imidazol-1-yl)etha-
none (1k). 38 (400 mg, 1.81 mmol) and 2-ethylimidazole (427 mg,
4.4 mmol) were reacted as described under 1i to give 237 mg of
the product as an off-white solid. MS (ESP) m/z 294/296 (MH+).
1-(5-Bromopyridin-2-yl)-2-(4-methyl-1H-imidazol-1-yl)etha-
none (1l). 38 (1.2 g, 3.3 mmol) and 4-methylimidazole (1.09 g,
13.3 mmol) were reacted as for 1i. Chromatography on silica gel
with acetone/hexanes (1:1 to 2:1) gave 170 mg of the product (18%)
as an off-white solid (rf ) 0.29, TLC; acetone/hexanes, 1:1; the
5-methylimidazole analogue was also formed, rf ) 0.21). MS (ESP)
Acetic Acid (5R)-3-(3-Fluorophenyl)-2-oxooxazolidin-5-ylm-
ethyl Ester (2b). (5R)-3-(3-Fluorophenyl)-5-hydroxymethyloxazo-
lidin-2-one, 2a37,38 (40 g, 0.189 mol), was suspended by stirring in
dry dichloromethane (400 mL) under nitrogen. Triethylamine (21
g, 0.208 mol) and 4-dimethylaminopyridine (0.6 g, 4.9 mmol) were
added, followed by dropwise addition of acetic anhydride (20.3 g,
0.199 mol) over 30 min, and stirring continued at ambient
temperature for 18 h. Saturated aqueous sodium bicarbonate (250
mL) was added and the organic phase was separated, washed with
2% sodium dihydrogen phosphate, dried (magnesium sulfate),
filtered, and evaporated to give the desired product (49.6 g) as an
oil. MS (ESP) m/z 254 (MH+). 1H NMR (CDCl3) δ: 2.02 (s, 3H),
3.84 (dd, 1H), 4.16 (t, 1H), 4.25 (dd, 1H), 4.32 (dd, 1H), 4.95 (m,
1H), 6.95 (td, 1H), 7.32 (d, 1H), 7.43 (t, 1H) , 7.51 (d, 1H).
Acetic Acid (5R)-3-(3-Fluoro-4-iodophenyl)-2-oxooxazolidin-
5-ylmethyl Ester (2c). 2b (15.2 g, 60 mmol) was dissolved in a
mixture of chloroform (100 mL) and acetonitrile (100 mL) under
nitrogen, and silver trifluoroacetate (16.96 g, 77 mmol) was added.
Iodine (18.07 g, 71 mmol) was added in portions over 30 min to
the vigorously stirred solution, and stirring continued at ambient
temperature for 18 h. Because reaction was not complete, a further
portion of silver trifluoroacetate (2.64 g, 12 mmol) was added and
stirring continued for 18 h. After filtration, the mixture was added
to sodium thiosulfate solution (3%, 200 mL) and dichloromethane
(200 mL), and the organic phase was separated, washed with sodium
thiosulfate (200 mL), saturated aqueous sodium bicarbonate (200
mL), and brine (200 mL), dried (magnesium sulfate), and filtered
and solvent evaporated. The crude product was suspended in
isohexane (100 mL) and sufficient diethyl ether added to dissolve
the brown impurity while stirring for 1 h. Filtration gave the desired
m/z 280/282 (MH+). H NMR (DMSO-d6) δ: 2.09 (s, 3H), 5.67
1
(s, 2H), 6.79 (s, 1H), 7.44 (s, 1H), 7.93 (d, 1H), 8.33 (dd, 1H),
8.94 (d, 1H). The assignment of the 4- and 5-methylimidazole
isomers was based on HMBC (heteronuclear multiple bond cor-
relation NMR- experiment).
1-(5-Bromopyridin-2-yl)-2-(2,4-dimethyl-1H-imidazol-1-yl)-
ethanone (1m). 38 (400 mg, 1.81 mmol) and 2,4-dimethylimidazole
(422 mg, 4.4 mmol) were reacted as described under 1i to give
210 mg of the product as an off-white solid. MS (ESP) m/z 294/
296 (MH+).
1-(5-Bromopyridin-2-yl)-2-(2,5-dimethyl-1H-imidazol-1-yl)-
ethanone (1n). 40 (4.75 g, 7.7 mmol) was dissolved in dichlo-
romethane (100 mL), and trifluoroacetic acid (15 mL) was added.
The mixture was heated at gentle reflux for 1.5 h. It was diluted
with dichloromethane (200 mL) and washed with potassium
phosphate buffer (pH 7, 1 M, ∼600 mL). The aqueous phase was
extracted three times with dichloromethane (3 × 100 mL), and the
combined organic phases were dried over sodium sulfate. Chro-
matography on silica gel with dichloromethane/methanol (20:1)
gave 1.94 g (77%) of the product as an off-white solid. MS (ESP)
1
product (24.3 g) as a cream solid. MS (ESP) m/z 380 (MH+). H
NMR (DMSO-d6) δ: 2.03 (s, 3H), 3.82 (dd, 1H), 4.15 (t, 1H),
4.24 (dd, 1H), 4.30 (dd, 1H), 4.94 (m, 1H), 7.19 (dd, 1H), 7.55
(dd, 1H), 7.84 (t, 1H).
m/z 294/296 (MH+). H NMR (DMSO-d6) δ: 1.98 (s, 3H), 2.12
(s, 3H), 5.57 (s, 2H), 6.49 (s, 1H), 7.93 (m, 1H), 8.35 (m, 1H),
8.98 (m, 1H).
1
(5R)-3-(3-Fluoro-4-iodophenyl)-5-hydroxymethyloxazolidin-
2-one (2d). 2c (30 g, 79 mmol) was treated with potassium
carbonate (16.4 g, 0.119 mmol) in a mixture of methanol (800 mL)
and dichloromethane (240 mL) at ambient temperature for 25 min,
then immediately neutralized by the addition of acetic acid (10 mL)
and water (500 mL). The precipitate was filtered, washed with
water, and dissolved in dichloromethane (1.2 L), and the solution
was washed with saturated sodium bicarbonate and dried (magne-
sium sulfate). Filtration and evaporation gave the desired product
(1R)-1-(5-Bromopyridin-2-yl)ethanol (1p) and (1S)-1-(5-Bro-
mopyridin-2-yl)ethanol (1q). 5-Bromopyridine-2-carbaldehyde
(1o)23,25 (1.0 g, 5.4 mmol) was dissolved in dry THF (25 mL) and
cooled to 0 °C. Methylmagnesium bromide (1.4 M in toluene/THF
(3:1), 4.6 mL, 6.45 mmol) was added dropwise under stirring. The
reaction mixture was diluted with ethyl acetate, washed with
potassium phosphate buffer (1 M, pH 7), and dried over sodium
sulfate. Chromatography on silica gel with hexanes/ethyl acetate
(2:1) gave 1.013 g (93%) of the racemic product as a colorless oil.
1
(23 g). MS (ESP) m/z 338 (MH+). H NMR (DMSO-d6) δ: 3.53
MS (ESP) m/z 202/204 (MH+). H NMR (DMSO-d6) δ: 1.33 (d,
1
(m, 1H), 3.67 (m, 1H), 3.82 (dd, 1H), 4.07 (t, 1H), 4.70 (m, 1H),
5.20 (t, 1H), 7.21 (dd, 1H), 7.57 (dd, 1H), 7.81 (t, 1H).
3H), 4.68 (m, 1H), 5.45 (d, 1H), 7.48 (d, 1H), 8.01 (dd, 1H), 8.57
(d, 1H). The racemic mixture of the two products was separated
on a Chiralpak AD column with 95% hexanes, 5% ethanol/methanol
(1:1). The first isomer to elute from the column had an optical
rotation of [R]2D0 -42.2 (c 1, ethanol) and was assigned the
S-configuration. Yield: 400 mg. The second isomer to elute showed
an optical rotation of [R]2D0 +38.3 (c 1, ethanol) and was assigned
the R-configuration. Yield: 430 mg.
[(5R)-3-(3-Fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]m-
ethyl Methanesulfonate (2e). 2d (25.0 g, 74.2 mmol) was stirred
in dichloromethane (250 mL) at 0 °C. Triethylamine (10.5 g, 104
mmol) was added followed by methanesulfonyl chloride (11.2 g,
89 mmol), and the mixture was stirred overnight, slowly warming
to room temperature. The yellow solution was diluted with sodium
bicarbonate, and the compound was extracted with dichloromethane
(3 × 250 mL). The organic layer was dried (magnesium sulfate),
filtered, and concentrated to give the desired product as a light-
yellow solid (30.3 g). MS (ESP) m/z 416 (MH+). 1H NMR (DMSO-
d6) δ: 3.24 (s, 3H), 3.82 (dd, 1H), 4.17 (t, 1H), 4.43-4.52 (m,
2H), 4.99-5.03 (m, 1H), 7.21 (dd, 1H), 7.55 (dd, 1H), 7.83 (t,
1H).
1-(5-Bromopyridin-2-yl)-4-morpholin-4-ylbutan-1-one (1s).
3-[(5-Bromopyridin-2-yl)carbonyl]dihydrofuran-2(3H)-one, 1r,26
sodium salt (1.05 g, 3.6 mmol) was heated in concentrated HCl (5
mL) for 1 h at 80 °C. The reaction mixture was cooled to room
temperature and poured into saturated aqueous sodium hydrogen
carbonate solution (100 mL). It was extracted with dichloromethane
(3 × 100 mL) and dried over sodium sulfate, and the solvent was
removed under reduced pressure. The crude 1-(5-bromopyridin-2-
yl)-4-chlorobutan-1-one intermediate was heated in morpholine (3
mL) at 85 °C for 3 h to give the product next to the 7-bromo-1-
(5R)-5-(Azidomethyl)-3-(3-fluoro-4-iodophenyl)-1,3-oxazoli-
din-2-one (2f). 2e (6.14 g, 14.7 mmol) was dissolved in N,N-
dimethylformamide (50 mL). Sodium azide (1.92 g, 29.6 mmol)
was added, and the mixture was stirred at 75 °C overnight. The

4876 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 20
Reck et al.
yellow mixture was poured into half-saturated sodium bicarbonate
and extracted using ethyl acetate. The organic layer was washed
three times with water, dried (magnesium sulfate), filtered, and
concentrated to give the title compound as a yellow solid (4.72 g).
4.30 (dd, 1H), 4.53 (m, 1H), 4.86 (d, 2H), 5.19 (m, 1H), 7.44 (dd,
1H), 7.60 (dd, 1H), 7.73 (dd, 1H), 7.77 (s, 1H), 8.10 (d, 1H), 8.18
(s, 1H), 8.20 (m, 1H), 8.88 (brs, 1H).
(5R)-3-{4-[6-(Azetidin-3-ylcarbonyl)pyridin-3-yl]-3-fluorophe-
nyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (6). A
solution of 5 (220 mg, 0.42 mmol) in dioxane (2 mL) was treated
under vigorous stirring with HCl (4 M in dioxane, 2 mL), and the
mixture was stirred at room temperature for 1 h. Solvent was
evaporated under reduced pressure. Chromatography was performed
on C-18 RP silica (using a RediSep cartridge) with 0-20%
acetonitrile (containing 0.1% TFA) in water. Fractions containing
product were pooled, and solvent was removed under reduced
pressure. The residue was taken up in isopropanol (20 mL), and
HCl (1 M in ether, 0.2 mL) was added under vigorous stirring.
The precipitated solid was collected by filtration and dried at room
temperature under reduced pressure to give 44 mg (23%) of the
hydrochloride salt of the product as a greenish solid, mp >90 °C
1
MS (ESP) m/z 363 (MH+). H NMR (DMSO-d6) δ: 3.72-3.82
(m, 3H), 4.14 (t, 1H), 4.89-4.94 (m, 1H), 7.22 (dd, 1H), 7.57 (dd,
1H), 7.83 (t, 1H).
(5R)-3-(3-Fluoro-4-iodophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-
1,3-oxazolidin-2-one (2g). 2f (30.3 g, 72.9 mmol) was stirred in
1,4-dioxane. Bicyclo[2.2.1]hepta-2,5-diene (40.3 g, 437 mmol) was
added, and the mixture was heated at 100 °C overnight. The
resulting brown mixture was filtered, and the desired product was
obtained as a light-brown solid (14.8 g). MS (ESP) m/z 389 (MH+).
1H NMR (DMSO-d6) δ: 3.90 (dd, 1H), 4.23 (t, 1H), 4.84 (d, 2H),
5.11-5.18 (m, 1H), 7.14 (dd, 1H), 7.49 (dd, 1H), 7.76 (s, 1H),
7.82 (t, 1H), 8.17 (s, 1H).
(5R)-3-[3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-
one (2h). 2g (2 g, 5.15 mmol), bis(pinacolato)diboron (2.62 g, 10.3
mmol), potassium acetate (2.5 g, 25.5 mmol), and 1,1′-[bis-
(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane
complex (0.38 g, 0.52 mmol) were suspended in DMSO (15 mL).
The mixture was heated at 80 °C for 40 min to give a clear black
solution. Ethyl acetate (150 mL) was added, and the mixture was
filtered through Celite, washed with saturated brine (2 × 100 mL),
dried over sodium sulfate, and evaporated. The dark residue was
purified by chromatography on silica gel with 40-100% ethyl
acetate in hexane, followed by 1-5% acetonitrile in ethyl acetate,
to give the product as a crystalline tan solid, 1.97 g (98%). (Note:
highly colored impurities elute ahead of product band, and extended
elution is required to obtain product). 1H NMR (DMSO-d6) δ: 1.28
(s, 12H), 3.91 (dd, 1H), 4.23 (t, 1H), 4.83 (d, 2H), 5.14 (m, 1H),
7.27 (dd, 1H), 7.37 (dd, 1H), 7.62 (t, 1H), 7.75 (s, 1H), 8.16 (s,
1H).
1
(dec). MS (ESP) m/z 423 (MH+). H NMR (DMSO-d6) δ: 3.97
(dd, 1H), 4.17-4.34 (m, 5H), 4.70 (m, 1H), 4.86 (d, 2H), 5.19 (m,
1H), 7.44 (m, 1H), 7.60 (m, 1H), 7.73 (dd, 1H), 7.77 (s, 1H), 8.11-
8.27 (m, 3H), 8.81 (m, 1H), 8.90 (brs, 1H), 9.22 (m, 1H). Anal.
(C21H19FN6O3) C, H, N.
(5R)-3-(4-{6-[Azetidin-3-yl(hydroxy)methyl]pyridin-3-yl}-3-
fluorophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-
one (7). 5 (245 mg, 0.47 mmol) was dissolved in THF (5 mL).
The mixture was cooled to 0 °C, and sodium borohydride (53 mg,
1.4 mmol) was added, followed by addition of methanol (2 mL).
After 2 h at 0 °C the mixture was quenched with potassium
phosphate buffer (pH 7, 1 M, 5 mL) and diluted with ethyl acetate
(100 mL), and the organic phase was dried over sodium sulfate
and concentrated to give the crude Boc-protected alcohol. This
alcohol was dissolved in 1,4-dioxane (5 mL), and HCl (4 M in
dioxane, 3 mL) was added under vigorous stirring. After 1 h, the
solvent was evaporated under reduced pressure and the residue was
codistilled twice with water and crystallized from water/isopropanol
to give 171 mg (79%) of the hydrochloride salt of the product as
(5R)-3-(3-Fluoro-4-pyridin-3-ylphenyl)-5-(1H-1,2,3-triazol-1-
ylmethyl)-1,3-oxazolidin-2-one (3). A mixture of 3-bromopyridine
(245 mg, 1.55 mmol), 2h (500 mg, 1.29 mmol), and sodium
carbonate (430 mg, 4.05 mmol) in N,N-dimethylformamide/water
(5 mL, 10:1) was degassed, and flushed with nitrogen, and tetrakis-
(triphenylphosphine)palladium(0) (75 mg, 0.065 mmol) was added.
The mixture was heated at 75 °C overnight and cooled to room
temperature, and the solvent was evaporated. Chromatography with
5% methanol in dichloromethane gave the product as an off-white
1
an off-white solid, mp >180 °C. MS (ESP) m/z 425 (MH+). H
NMR (DMSO-d6) δ: 3.27 (m, 1H), 3.70-4.70 (m, 7H), 4.86 (d,
2H), 4.96 (m, 1H), 5.19 (m, 1H), 7.41 (dd, 1H), 7.58 (dd, 1H),
7.67 (dd, 1H), 7.72-7.85 (m, 2H), 8.16-8.25 (m, 2H), 8.74 (brs,
1H), 8.90 (brs, 1H), 9.17 (brs, 1H). Anal. (C21H21FN6O3) C, H, N.
(5R)-3-{3-Fluoro-4-[6-(1H-imidazol-1-ylacetyl)pyridin-3-yl]-
phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (8).
1i (195 mg, 0.73 mmol), 2h (284 mg, 0.73 mmol), sodium carbonate
(233 mg, 2.2 mmol), and tetrakis(triphenylphosphine)palladium-
(0) (85 mg, 0.07 mmol) were reacted as described for 4. Chroma-
tography was done on silica gel with dichloromethane/methanol
(10:1). The free base thus obtained was dissolved in isopropanol/
dichloromethane (∼20 mL, 1:1). HCl in ether (1 mL, 1 M) was
added, and most of the dichloromethane was removed under reduced
pressure. The residue was collected by filtration and dried to give
189 mg (59%) of the hydrochloride salt of the product as a colorless
1
solid (220 mg). MS (ESP) m/z 340 (MH+). H NMR (DMSO-d6)
δ: 3.96 (m, 1H), 4.31 (dd, 1H), 4.86 (d, 2H), 5.18 (m, 1H), 7.40
(dd, 1H), 7.52 (m, 2H), 7.62 (t, 1H), 7.75 (s, 1H), 7.96 (d, 1H),
8.19 (s, 1H), 8.59 (s, 1H), 8.72 (s, 1H). Anal. (C17H14FN5O2) C,
H, N.
(5R)-3-[4-(6-Acetylpyridin-3-yl)-3-fluorophenyl]-5-(1H-1,2,3-
triazol-1-ylmethyl)-1,3-oxazolidin-2-one (4). 37 (2.47 g, 12.4
mmol),17,24 2h (4.0 g, 10.3 mmol), sodium carbonate (3.98 g, 37.5
mmol), and tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.03
mmol) were reacted as described for 3, but the mixture was heated
for 3 h. Chromatography on silica gel with hexanes/acetone (1:1)
to acetone and precipitation of the product from methanol/
dichloromethane (4:1, 50 mL) by removing most of the dichlo-
romethane under reduced pressure gave 1.98 g of product (50%)
as an off-white solid, mp >210 °C (dec). MS (ESP) m/z 382 (MH+).
1H NMR (DMSO-d6) δ: 2.66 (s, 3H), 3.96 (dd, 1H), 4.30 (dd,
1H), 4.86 (d, 2H), 5.19 (m, 1H), 7.43 (dd, 1H), 7.60 (dd, 1H), 7.72
(dd, 1H), 7.76 (s, 1H), 8.03 (d, 1H), 8.17 (m, 1H), 8.18 (s, 1H),
8.90 (s, 1H). Anal. (C19H16FN5O3) C, H, N.
tert-Butyl 3-[(5-{2-Fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-
1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}pyridin-2-yl)carbonyl]-
azetidine-1-carboxylate (5). 1a (447 mg, 1.31 mmol), 2h (509 mg,
1.31 mmol), sodium carbonate (416 mg, 3.93 mmol), and tetrakis-
(triphenylphosphine)palladium(0) (151 mg, 0.13 mmol) were
reacted as described for 4 but using 10 mL of solvent. Chroma-
tography on silica gel with hexanes/acetone (1:1) gave 500 mg
(73%) of product as a colorless hard foam. MS (ESP) m/z 523
(MH+). 1H NMR (DMSO-d6) δ: 1.37 (s, 9H), 3.93-4.18 (m, 5H),
1
solid, mp >230 °C (dec). MS (ESP) m/z 448 (MH+). H NMR
(DMSO-d6) δ: 3.97 (m, 1H), 4.31 (m, 1H), 4.86 (d, 2H), 5.20 (m,
1H), 6.12 (s, 2H), 7.45 (dd, 1H), 7.62 (dd, 1H), 7.70-7.82 (m,
5H), 8.11-8.20 (m, 2H), 8.29 (m, 1H), 9.05 (d, 1H), 14.62 (brs,
1H). Anal. (C22H18FN7O3) C, H, N.
(5R)-3-(3-Fluoro-4-{6-[(4-methyl-1H-imidazol-1-yl)acetyl]py-
ridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-
2-one (9). 1l (170 mg, 0.607 mmol), 2h (214 mg, 0.552 mmol),
sodium carbonate (175 mg, 1.65 mmol), and tetrakis(triphenylphos-
phine)palladium(0) (64 mg, 0.05 mmol) were reacted as described
under 8 to give 155 mg (56%) of product as the hydrochloride
salt, a colorless solid, mp >217 °C (dec). MS (ESP) m/z 462 (MH+).
1H NMR (DMSO-d6) δ: 2.32 (s, 3H), 3.97 (dd, 1H), 4.31 (dd,
1H), 4.87 (d, 2H), 5.20 (m, 1H), 6.06 (s, 2H), 7.40-7.49 (m, 2H),
7.62 (dd, 1H), 7.74-7.80 (m, 2H), 8.13 (d, 1H), 8.19 (s, 1H), 8.28
(m, 1H), 8.95 (s, 1H), 9.02 (brs, 1H), 14.57 (brs, 1H). Anal. (C23H20-
FN7O3) C, H, N.
(5R)-3-(4-{6-[(2,4-Dimethyl-1H-imidazol-1-yl)acetyl]pyridin-
3-yl}-3-fluorophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazo-

Substituted Oxazolidinones
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 20 4877
lidin-2-one (10). 1m (210 mg, 0.714 mmol), 2h (333 mg, 0.86
mmol), potassium carbonate (296 mg, 2.14 mmol), and tetrakis-
(triphenylphosphine)palladium(0) (46 mg, 0.04 mmol) were reacted
and the product was purified as described for 4 to give 105 mg of
the product as an off-white solid, mp 78 °C. MS (ESP) m/z 476
(52 mg, 1.38 mmol) was added, followed by addition of methanol
(5 mL). After 30 min, the reaction was quenched with HCl
(aqueous, 1 M, 5 mL), and the mixture was concentrated to dryness
under reduced pressure. This material was heterogeneous by LC,
with several peaks showing the desired product mass, indicating
the presence of boronic ester product complexes. The residue was
taken up in HCl (aqueous, 3 M, 5 mL), and the mixture was heated
at 65 °C for 45 min. A homogeneous product was obtained by LC-
MS. The reaction mixture was concentrated under reduced pressure,
and the residue was taken up in water (5 mL) and purified on a RP
(C-18) Redi Sep cartridge with 0-20% acetonitrile in water
containing 0.1% TFA. The fractions containing product were pooled
and concentrated under reduced pressure. The residue was taken
up in isopropanol (15 mL), and HCl (1 M in ether, 0.8 mL) was
added under vigorous stirring. The precipitate was collected by
filtration and dried under vacuum to give 100 mg (50%) of the bis
hydrochloride salt of the product as slightly yellow solid, mp
1
(MH+). H NMR (DMSO-d6) δ: 2.26 (s, 3H), 3.55 (s, 3H), 3.95
(m, 1H), 4.27 (m, 1H), 4.98 (m, 2H), 5.18-5.22 (m, 1H), 5.98 (s,
2H), 7.27 (m, 1H), 7.43-7.64 (m, 2H), 7.76 (m, 2H), 8.10 (m,
1H), 8.19 (m, 1H), 8.26-8.28 (m, 1H), 9.03 (s, 1H). Purity, >95%
by HPLC.
(5R)-3-(3-Fluoro-4-{6-[(2-methyl-1H-imidazol-1-yl)acetyl]py-
ridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-
2-one (11). 1j (336 mg, 1.2 mmol), 2h (388 mg, 1.0 mmol), sodium
carbonate (300 mg, 2.8 mmol), and tetrakis(triphenylphosphine)-
palladium(0) (115 mg, 0.1 mmol) were reacted as described for 8
to give 276 mg (55%) of product as the hydrochloride salt, a
colorless solid, mp >240 °C (dec). MS (ESP) m/z 462 (MH+). 1H
NMR (DMSO-d6) δ: 2.55 (s, 3H), 3.97 (m, 1H), 4.31 (m, 1H),
4.87 (d, 2H), 5.20 (m, 1H), 6.05 (s, 2H), 7.46 (dd, 1H), 7.57-7.65
(m, 3H), 7.72-7.80 (m, 2H), 8.13 (d, 1H), 8.19 (s, 1H), 8.27 (m,
1H), 9.03 (s, 1H), 14.48 (brs, 1H). Anal. (C23H20FN7O3) C, H, N.
(5R)-3-(4-{6-[(2-Ethyl-1H-imidazol-1-yl)acetyl]pyridin-3-yl}-
3-fluorophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-
2-one (12). 1k (237 mg, 0.806 mmol), 2h (376 mg, 0.97 mmol),
potassium carbonate (340 mg, 2.41 mmol), and tetrakis(triph-
enylphosphine)palladium(0) (46 mg, 0.04 mmol) were reacted and
the product was purified as described for 4, but it was heated at
80 °C for 30 min, to give 174 mg of the product as an off-white
solid, mp 77-79 °C. MS (ESP) m/z 476 (MH+). 1H NMR (DMSO-
d6) δ: 1.21 (m, 3H), 2.89-2.96 (m, 2H), 3.52 (m, 2H), 3.98-3.98
(m, 1H), 4.28 (m, 1H), 4.86 (s, 2H), 5.17-5.20 (m, 1H), 6.08 (s,
2H), 7.42-7.44 (dd, 1H), 7.57-7.72 (m, 1H), 7.76 (s, 1H), 7.98-
8.08 (m, 1H), 8.19 (s, 1H), 8.43-8.59 (m, 1H), 8.82 (m, 2H). Anal.
(C24H22FN7O3) C, H, N.
1
>212 °C (dec). MS (ESP) m/z 510 (MH+). H NMR (DMSO-d6)
δ: 1.76 (m, 4H), 2.45-3.75 (m, 11H), 2.79 (s, 3H), 3.95 (dd, 1H),
4.29 (dd, 1H), 4.67 (m, 1H), 4.86 (d, 2H), 5.19 (m, 1H), 7.39 (dd,
1H), 7.56 (dd, 1H), 7.60-7.66 (m, 2H), 7.77 (s, 1H), 8.02 (m, 1H),
8.18 (s, 1H), 8.67 (brs, 1H). Anal. (C26H32FN7O3) C, H, N.
(5R)-3-{3-Fluoro-4-[6-(4-morpholin-4-ylbutanoyl)pyridin-3-
yl]phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-
one (16). 1s, TFA salt (190 mg, 0.44 mmol), 2h (173 mg, 0.44
mmol), sodium carbonate (141 mg, 1.33 mmol), and tetrakis-
(triphenylphosphine)palladium(0) (51 mg, 0.044 mmol) were
reacted as described for 8 to give 119 mg of the hydrochloride salt
of the product (54%) as a colorless solid, mp >240 °C (dec). MS
1
(ESP) m/z 495 (MH+). H NMR (DMSO-d6) δ: 2.00-2.12 (m,
2H), 3.00-4.02 (m, 13H), 4.30 (m, 1H), 4.86 (m, 2H), 5.19 (m,
1H), 7.43 (m, 1H), 7.60 (m, 1H), 7.68-7.78 (m, 2H), 8.05 (m,
1H), 8.16-8.22 (m, 2H), 8.91 (s, 1H), 10.57 (s, 1H). Anal. (C25H27-
FN6O4) C, H, N.
tert-Butyl 4-[2-(5-{2-Fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-
1-ylmethyl)-1,3-oxazolidin-3-yl]phenyl}pyridin-2-yl)-2-oxoethyl]-
piperidine-1-carboxylate (17). 1d (590 mg, 1.54 mmol), 2h (598
mg, 1.54 mmol), sodium carbonate (490 mg, 4.6 mmol), and
tetrakis(triphenylphosphine)palladium(0) (178 mg, 0.154 mmol)
were reacted as described for 4. Chromatography on silica gel with
hexanes/acetone (2:1) gave 691 mg (79%) of product as a colorless
solid, mp >140 °C. MS (ESP) m/z 565 (MH+). 1H NMR (DMSO-
d6) δ: 1.11 (m, 2H), 1.38 (s, 9H), 1.66 (m, 2H), 2.07 (m, 1H),
2.72 (m, 2H), 3.13 (m, 2H), 3.84-4.00 (m, 3H), 4.30 (dd, 1H),
4.86 (d, 2H), 5.19 (m, 1H), 7.43 (dd, 1H), 7.60 (dd, 1H), 7.72 (dd,
1H), 7.77 (s, 1H), 8.05 (d, 1H), 8.15-8.21 (m, 1H), 8.18 (s, 1H),
8.90 (brs, 1H).
(5R)-3-(4-{6-[(2,5-Dimethyl-1H-imidazol-1-yl)acetyl]pyridin-
3-yl}-3-fluorophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazo-
lidin-2-one (13). 1n (985 mg, 3.35 mmol), 2h (1.30 g, 3.35 mmol),
sodium carbonate (887 mg, 8.37 mmol), and tetrakis(triphenylphos-
phine)palladium(0) (387 mg, 0.35 mmol) were reacted as described
for 4 but using 15 mL of solvent and heating at 75 °C for 6 h.
Chromatography on silica gel with dichloromethane/methanol (10:1
to 8:1), followed by crystallization from ethanol, gave 658 mg
(41%) of product as colorless needles, mp 112-115 °C. MS (ESP)
1
m/z 476 (MH+). H NMR (DMSO-d6) δ: 2.01 (s, 3H), 2.15 (s,
3H), 3.97 (dd, 1H), 4.31 (dd, 1H), 4.86 (d, 2H), 5.19 (m, 1H), 5.64
(s, 2H), 6.51 (s, 1H), 7.46 (dd, 1H), 7.62 (dd, 1H), 7.75 (dd, 1H),
7.77 (s, 1H), 8.10 (d, 1H), 8.19 (s, 1H), 8.25 (m, 1H), 8.99 (brs,
1H). Anal. (C24H22FN7O3) C, H, N.
(5R)-3-{3-Fluoro-4-[6-(piperidin-4-ylacetyl)pyridin-3-yl]phe-
nyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (18). A
solution of 17 (630 mg, 1.12 mmol) in dioxane (5 mL) was treated
under vigorous stirring with a solution of HCl in dioxane (4 M, 5
mL). The mixture was stirred overnight at room temperature and
solvent was removed under reduced pressure and the residue
recrystallized from water/isopropanol (33 mL, 1:10) to give 409
mg (73%) of product as the hydrochloride salt, a colorless solid,
mp >196 °C (dec). MS (ESP) m/z 465 (MH+). 1H NMR (DMSO-
d6) δ: 1.45 (m, 2H), 1.83 (m, 2H), 2.19 (m, 1H), 2.88 (m, 2H),
3.16-3.26 (m, 4H), 3.97 (dd, 1H), 4.30 (dd, 1H), 4.87 (d, 2H),
5.20 (m, 1H), 7.43 (dd, 1H), 7.60 (dd, 1H), 7.72 (dd, 1H), 7.77 (s,
1H), 8.05 (d, 1H), 8.16-8.21 (m, 1H), 8.19 (s, 1H), 8.70 (m, 1H),
8.87-8.98 (m, 1H), 8.90 (brs, 1H). Anal. (C24H25FN6O3) C, H, N.
Benzyl 4-[(5-{2-Fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-
ylmethyl)-1,3-oxazolidin-3-yl]phenyl}pyridin-2-yl)carbonyl]pi-
peridine-1-carboxylate (19). 1c (250 mg, 0.62 mmol), 2h (241
mg, 0.62 mmol), sodium carbonate (197 mg, 1.86 mmol), and
tetrakis(triphenylphosphine)palladium(0) (72 mg, 0.06 mmol) were
reacted as described for 4. Chromatography on silica gel with
hexanes/acetone (1:1) gave 339 mg (93%) of product as a slightly
(5R)-3-(3-Fluoro-4-{6-[4-(4-methylpiperazin-1-yl)butanoyl]-
pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazo-
lidin-2-one (14). 1b (580 mg, 1.8 mmol), 2h (690 mg, 1.8 mmol),
sodium carbonate (377 mg, 3.55 mmol), and tetrakis(triphenylphos-
phine)palladium(0) (205 mg, 0.18 mmol) were reacted as described
for 4 but using 10 mL of solvent. Chromatography on silica gel
with dichloromethane/methanol (5:1 to 3:1) gave 510 mg (57%)
of product as a colorless hard foam. The free base of the product
(310 mg, 0.61 mmol) was taken up in isopropanol (10 mL). HCl
(1 M in ether, 2 mL) was added under vigorous stirring. After the
mixture was stirred for 15 min, solvent was removed under reduced
pressure and the residue was crystallized from water/isopropanol
(∼30 mL, 1:15) to give 261 mg of the bis HCl salt of the product
1
as a colorless solid, mp >240 °C. MS (ESP) m/z 508 (MH+). H
NMR (DMSO-d6) δ: 2.09 (m, 2H), 2.82 (s, 3H), 3.13-3.88 (m,
12H), 3.97 (dd, 1H), 4.30 (dd, 1H), 4.86 (d, 2H), 5.19 (m, 1H),
7.43 (m, 1H), 7.60 (m, 1H), 7.73 (dd, 1H), 7.77 (s, 1H), 8.06 (d,
1H), 8.15-8.23 (m, 2H), 8.91 (brs, 1H). Anal. (C26H30FN7O3) C,
H, N.
(5R)-3-(3-Fluoro-4-{6-[1-hydroxy-4-(4-methylpiperazin-1-yl)-
butyl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-
oxazolidin-2-one (15). 14, bis hydrochloride salt (200 mg, 0.34
mmol), in THF (5 mL) was cooled to 0 °C. Sodium borohydride
1
yellow hard foam. MS (ESP) m/z 585 (MH+). H NMR (DMSO-
d6) δ: 1.47 (m, 2H), 1.87 (m, 2H), 3.01 (m, 2H), 3.93-4.12 (m,
4H), 4.30 (dd, 1H), 4.86 (d, 2H), 5.08 (s, 2H), 5.19 (m, 1H), 7.28-

4878 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 20
Reck et al.
7.46 (m, 6H), 7.60 (dd, 1H), 7.73 (dd, 1H), 7.77 (s, 1H), 8.06 (d,
1H), 8.15-8.23 (m, 2H), 8.93 (brs, 1H).
NMR (DMSO-d6) δ: 1.39 (d, 3H), 3.95 (dd, 1H), 4.29 (dd, 1H),
4.76 (m, 1H), 4.85 (d, 2H), 5.18 (m, 1H), 5.42 (d, 1H), 7.38 (dd,
1H), 7.52-7.66 (m, 3H), 7.77 (s, 1H), 7.95 (m, 1H), 8.18 (s, 1H),
8.63 (s, 1H). Purity, >98% by HPLC.
(5R)-3-{3-Fluoro-4-[6-(piperidin-4-ylcarbonyl)pyridin-3-yl]-
phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (20)
and (5R)-3-(3-Fluoro-4-{6-[hydroxy(piperidin-4-yl)methyl]py-
ridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-
2-one (21). 19 (305 mg, 0.52 mmol) was hydrogenated on Pd/C
(10%, wet) in methanol (10 mL, containing a few drops of acetic
acid) at room temperature and normal pressure for 2 h. It was
filtered through a 0.45 µm membrane, and solvent was removed
under reduced pressure. Chromatography was performed on C-18
RP silica (using a RediSep cartridge) with 0-20% acetonitrile
(containing 0.1% TFA) in water to give the free bases of 20 and
21. Fractions containing 20 and 21 were separately pooled, and
solvent was removed under reduced pressure. The residues were
taken up in isopropanol (20 mL) and HCl (1 M in ether, 0.5 mL)
was added under vigorous stirring. It was diluted with hexanes (10
mL) and the solids were collected by filtration and dried at 50 °C
under reduced pressure to give 71 mg (28%) of the hydrochloride
salt of 20 as a colorless solid, mp >275 °C (dec), and 44 mg (17%)
of the hydrochloride salt of 21 as a colorless solid, mp >185 °C
(dec).
(5R)-3-(3-Fluoro-4-{6-[(1R)-1-methoxyethyl]pyridin-3-yl}-
phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (25).
24 (300 mg, 0.78 mmol) was dissolved in dry DMF (3 mL) and
cooled to 0 °C. Sodium hydride (60% in mineral oil, 35 mg, 0.86
mmol) was added, and the mixture was stirred for 10 min. Then
methyl iodide (0.058 mL, 0.94 mmol) was added. After 1.5 h the
reaction was quenched with acetic acid (1 drop) and solvent was
evaporated under reduced pressure. Chromatography on silica gel
with hexanes/acetone (1:1) and crystallization from ethanol/hexanes
gave 138 mg (44%) of the product as colorless solid, mp 150 °C.
MS (ESP) m/z 398 (MH+). 1H NMR (DMSO-d6) δ: 1.39 (d, 3H),
3.23 (s, 3H), 3.95 (dd, 1H), 4.29 (dd, 1H), 4.42 (m, 1H), 4.85 (d,
2H), 5.18 (m, 1H), 7.39 (dd, 1H), 7.50 (d, 1H), 7.57 (dd, 1H), 7.64
(dd, 1H), 7.77 (s, 1H), 7.99 (m, 1H), 8.18 (s, 1H), 8.68 (s, 1H).
Anal. (C20H20FN5O3) C, H, N.
(5R)-3-(3-Fluoro-4-{6-[(1S)-1-hydroxyethyl]pyridin-3-yl}-
phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (26).
1r (400 mg, 1.98 mmol), 2h (769 mg, 1.98 mmol), sodium
carbonate (630 mg, 5.9 mmol), and tetrakis(triphenylphosphine)-
palladium(0) (228 mg, 0.198 mmol) were reacted as described for
24 to give 287 mg (38%) of the product as a colorless solid, mp
183 °C. MS (ESP) m/z 384 (MH+). 1H NMR (DMSO-d6) δ: 1.39
(d, 3H), 3.95 (dd, 1H), 4.29 (dd, 1H), 4.76 (m, 1H), 4.85 (d, 2H),
5.18 (m, 1H), 5.42 (d, 1H), 7.38 (dd, 1H), 7.52-7.66 (m, 3H),
7.77 (s, 1H), 7.95 (m, 1H), 8.18 (s, 1H), 8.63 (s, 1H). Anal. (C19H18-
FN5O3‚0.05CH2Cl2) C, H, N. H: calcd, 4.71; found, 4.27.
(5R)-3-(3-Fluoro-4-{6-[(1S)-1-methoxyethyl]pyridin-3-yl}-
phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (27).
26 (220 mg, 0.57 mmol), sodium hydride (60% in mineral oil, 25
mg, 0.63 mmol), and methyl iodide (0.043 mL, 0.69 mmol) were
reacted following the procedure described for 25 to give 112 mg
(49%) of the product as colorless solid, mp 160 °C. MS (ESP) m/z
1
20: MS (ESP) m/z 451 (MH+). H NMR (DMSO-d6) δ: 1.79
(m, 2H), 2.04 (m, 2H), 3.10 (m, 2H), 3.97 (dd, 1H), 4.12 (m, 1H),
4.30 (dd, 1H), 4.86 (d, 2H), 5.19 (m, 1H), 7.44 (dd, 1H), 7.60 (dd,
1H), 7.73 (dd, 1H), 7.77 (s, 1H), 8.07 (d, 1H), 8.18 (s, 1H), 8.21
(m, 1H), 8.50 (m, 1H), 8.76 (m, 1H), 8.92 (brs, 1H). An additional
2H signal is either under the solvent or under the HDO signal. Anal.
(C23H23FN6O3) C, H, N.
1
21: MS (ESP) m/z 453 (MH+). H NMR (DMSO-d6) δ: 1.60
(m, 4H), 2.05 (m, 1H), 2.78 (m, 2H), 3.23 (m, 2H), 3.40-3.75 (m,
1H, under HDO peak), 3.97 (dd, 1H), 4.29 (dd, 1H), 4.61 (d, 1H),
4.86 (d, 2H), 5.19 (m, 1H), 7.41 (dd, 1H), 7.58 (dd, 1H), 7.67 (dd,
1H), 7.68-7.72 (m, 1H), 7.77 (s, 1H), 8.15-8.21 (m, 2H), 8.38
(m, 1H), 8.72-8.83 (m, 2H). Anal. (C23H25FN6O3) C, H, N.
(5R)-3-{3-Fluoro-4-[6-(hydroxymethyl)pyridin-3-yl]phenyl}-
5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (22). (5-
Bromopyridin-2-yl)methanol25 (200 mg, 1.06 mmol), 2h (413 mg,
1.06 mmol), sodium carbonate (450 mg, 4.25 mmol), and tetrakis-
(triphenylphosphine)palladium(0) (122 mg, 0.106 mmol) were
reacted as described for 4. Chromatography on silica gel with
dichloromethane/methanol (10:1) and precipitation from hot metha-
nol with hexanes gave 191 mg (49%) of the product as a colorless
1
398 (MH+). H NMR (DMSO-d6) δ: 1.39 (d, 3H), 3.23 (s, 3H),
3.95 (dd, 1H), 4.29 (dd, 1H), 4.42 (m, 1H), 4.85 (d, 2H), 5.18 (m,
1H), 7.39 (dd, 1H), 7.50 (d, 1H), 7.57 (dd, 1H), 7.64 (dd, 1H),
7.77 (s, 1H), 7.99 (m, 1H), 8.18 (s, 1H), 8.68 (s, 1H). Anal. (C20H20-
FN5O3) C, H, N.
5-{2-Fluoro-4-[(5R)-2-oxo-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-
oxazolidin-3-yl]phenyl}pyridine-2-carbaldehyde (28). 1o23,25 (450
mg, 2.42 mmol), 2h (939 mg, 2.42 mmol), sodium carbonate (769
mg, 7.26 mmol), and tetrakis(triphenylphosphine)palladium(0) (280
mg, 0.24 mmol) were reacted as described for 3 but with 10 mL of
solvent and 10 h of heating at 70 °C. Chromatography on silica
gel with hexanes/acetone (1:1) gave 535 mg (60%) of the product
as a colorless solid, mp >180 °C (dec). MS (ESP) m/z 368 (MH+).
1H NMR (DMSO-d6) δ: 3.97 (dd, 1H), 4.30 (dd, 1H), 4.86 (d,
2H), 5.19 (m, 1H), 7.45 (dd, 1H), 7.61 (dd, 1H), 7.75 (dd, 1H),
7.77 (s, 1H), 8.02 (d, 1H), 8.18 (s, 1H), 8.23 (d, 1H), 9.01 (s, 1H),
10.02 (s, 1H).
1
solid, mp 177 °C. MS (ESP) m/z 370 (MH+). H NMR (DMSO-
d6) δ: 3.95 (dd, 1H), 4.29 (dd, 1H), 4.60 (d, 2H), 4.86 (d, 2H),
5.18 (m, 1H), 5.48 (t, 1H), 7.39 (m, 1H), 7.52-7.66 (m, 3H), 7.77
(s, 1H), 7.96 (m, 1H), 8.18 (s, 1H), 8.64 (s, 1H). Anal. (C18H16-
FN5O3) C, H, N.
(5R)-3-{3-Fluoro-4-[6-(methoxymethyl)pyridin-3-yl]phenyl}-
5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (23). 22 (150
mg, 0.41 mmol) and iodomethane (116 mg, 0.82 mmol) were mixed
in dry DMF (3 mL) and cooled to 0 °C. Sodium hydride (14.6 mg,
0.61 mmol) was added, and the reaction mixture was slowly warmed
to room temperature overnight. The reaction was quenched with a
few drops of water and extracted with dichloromethane. The organic
phase was dried over anhydrous magnesium sulfate, concentrated,
and purified by chromatography on silica gel with 5% methanol in
dichloromethane to give the product as a colorless solid (31 mg,
(5R)-3-{3-Fluoro-4-[6-(1-hydroxy-2-methylpropyl)pyridin-3-
yl]phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-
one (29). To a solution of 28 (150 mg, 0.37 mmol) in dry THF (10
mL) was added dropwise at -20 °C isopropylmagnesium bromide
(1 M in THF, 0.74 mL, 0.74 mmol). The reaction mixture was
allowed to reach room temperature over 2 h and was stirred
overnight. It was quenched with a few drops of water, diluted with
ethyl acetate (15 mL), washed with HCl (aqueous, 5%, 10 mL)
and with brine (10 mL), and dried over sodium sulfate. Chroma-
tography on silica gel with dichloromethane/acetone (1:1) gave 31
mg of the product as a colorless solid, mp 156-157 °C. MS (ESP)
1
20%). MS (ESP) m/z 384 (MH+). H NMR (CDCl3) δ: 3.50 (s,
3H), 3.97 (dd, 1H), 4.17 (t, 1H), 4.60 (s, 2H), 4.80 (d, 2H), 5.05
(m, 1H), 7.17 (d, 1H), 7.38-7.50 (m, 3H), 7.70 (s, 1H), 7.81 (s,
1H), 7.82 (d, 1H), 8.70 (s, 1H). Anal. (C19H18FN5O3) C, H, N.
(5R)-3-(3-Fluoro-4-{6-[(1R)-1-hydroxyethyl]pyridin-3-yl}-
phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (24).
1p (430 mg, 2.13 mmol), 2h (826 mg, 2.13 mmol), sodium
carbonate (677 mg, 6.4 mmol), and tetrakis(triphenylphosphine)-
palladium(0) (246 mg, 0.213 mmol) were reacted as described for
3 but heating at 70 °C for 4 h in 10 mL of solvent. Chromatography
on silica gel with dichloromethane/methanol (12:1) and crystal-
lization from ethanol/hexanes gave 421 mg (52%) of the product
1
m/z 412 (MH+). H NMR (DMSO-d6) δ: 0.80 (d, 3H), 0.88 (d,
3H), 2.05 (m, 1H), 3.95 (m, 1H), 4.27 (dd, 1H), 4.37 (m, 1H),
4.82 (d, 2H), 5.17 (m, 1H), 5.27 (d, 1H), 7.41 (m, 1H), 7.50∼7.68
(m, 3H), 7.78 (s, 1H), 7.95 (d, 1H), 8.19 (s, 1H), 8.65 (s, 1H).
Anal. (C21H22FN5O3) C, H, N.
(5R)-3-{3-Fluoro-4-[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]-
phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (30).
1
as a colorless solid, mp 190 °C. MS (ESP) m/z 384 (MH+). H

Substituted Oxazolidinones
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 20 4879
2-(5-Bromopyridin-2-yl)propan-2-ol25 (500 mg, 2.31 mmol), 2h
(900 mg, 2.32 mmol), sodium carbonate (740 mg, 7 mmol), and
tetrakis(triphenylphosphine)palladium(0) (268 mg, 0.232 mmol)
were reacted as described for 3 but heating at 70 °C for 7.5 h in 10
mL of solvent. Chromatography on silica gel first with dichlo-
romethane/methanol (17:1) and then with dichloromethane/DMF
(20:1) and precipitation from dichloromethane/DMF (20:1, 20 mL)
with hexanes gave 247 mg (27%) of the product as a colorless
oxazolidinyl)phosphinic chloride (0.633 g, 2.48 mmol) in DMF (4
mL) was added N,O-dimethylhydroxylamine hydrochloride (339
mg, 3.48 mmol), followed by diisopropylethylamine (1.3 mL, 7.45
mmol). The reaction was exothermic, and the mixture was allowed
to cool to room temperature and was stirred for 2 h. Excess base
was removed under reduced pressure, and the residue was diluted
with ethyl acetate (100 mL), washed with potassium phosphate
buffer (1 M, pH 7, 2 × 100 mL) and with water (2 × 100 mL),
and dried over sodium sulfate. Chromatography on silica gel with
hexanes/acetone (3:1) gave 470 mg (77%) of the product as a
colorless solid. MS (ESP) m/z 267 (MNa+). 1H NMR (DMSO-d6)
δ: 1.36 (s, 9H), 3.10 (s, 3H), 3.61 (s, 3H), 3.68 (m, 1H), 3.83-
4.00 (m, 4H).
1
solid, mp 180 °C. MS (ESP) m/z 398 (MH+). H NMR (DMSO-
d6) δ: 1.46 (s, 6H), 3.95 (dd, 1H), 4.29 (dd, 1H), 4.85 (d, 2H),
5.18 (m, 1H), 5.27 (s, 1H), 7.38 (dd, 1H), 7.55 (dd, 1H), 7.62 (dd,
1H), 7.73 (d, 1H), 7.76 (s, 1H), 7.92 (m, 1H), 8.18 (s, 1H), 8.64 (s,
1H). Anal. (C20H20FN5O3) C, H, N.
(5R)-3-{4-[6-(1,2-Dihydroxyethyl)pyridin-3-yl]-3-fluorophe-
nyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (31). 1h
(323 mg, 1.48 mmol), 2h (575 mg, 1.48 mmol), sodium carbonate
(471 mg, 4.44 mmol), and tetrakis(triphenylphosphine)palladium-
(0) (171 mg, 0.148 mmol) were reacted as described for 4.
Chromatography on silica gel with dichloromethane/methanol (5:
1) and crystallization from ethanol/hexanes gave 388 mg of the
product (66%) as a colorless solid, mp 175 °C. MS (ESP) m/z 400
(MH+). 1H NMR (DMSO-d6) δ: 3.52 (m, 1H), 3.71 (m, 1H), 3.95
(m, 1H), 4.28 (dd, 1H), 4.63 (m, 1H), 4.73 (m, 1H), 4.85 (d, 2H),
5.18 (m, 1H), 5.45 (m, 1H), 7.39 (m, 1H), 7.53-7.64 (m, 3H),
7.76 (s, 1H), 7.94 (m, 1H), 8.17 (s, 1H), 8.64 (s, 1H). Anal. (C19H18-
FN5O4) C, H, N.
(5R)-3-{3-Fluoro-4-[6-(1-hydroxy-2-morpholin-4-ylethyl)py-
ridin-3-yl]phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-
2-one (32). 1e (388 mg, 1.35 mmol), 2h (525 mg, 1.35 mmol),
sodium carbonate (430 mg, 4.05 mmol), and tetrakis(triphenylphos-
phine)palladium(0) (156 mg, 0.135 mmol) were reacted as described
for 4. Chromatography was done on silica gel with dichloromethane/
methanol (10:1). The hydrochloride salt was prepared as described
for 8 to give 507 mg of the hydrochloride salt of the product (74%)
as a colorless solid, mp >194 °C (dec). MS (ESP) m/z 469 (MH+).
1H NMR (DMSO-d6) δ: 3.00-4.20 (m, 11H), 4.29 (dd, 1H), 4.86
(d, 2H), 5.14-5.40 (m, 2H), 6.61 (brs, 1H), 7.40 (m, 1H), 7.52-
7.75 (m, 3H), 7.77 (s, 1H), 8.05 (d, 1H), 8.19 (s, 1H), 8.71 (s, 1H),
10.58 (brs, 1H). Anal. (C23H25FN6O4) C, H, N.
(5R)-3-(3-Fluoro-4-{6-[1-hydroxy-2-(isopropylamino)ethyl]py-
ridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-
2-one (33). 1g, TFA salt (241 mg, 0.65 mmol), 2h (361 mg, 0.93
mmol), sodium carbonate (296 mg, 2.79 mmol), and tetrakis-
(triphenylphosphine)palladium(0) (108 mg, 0.093 mmol) were
reacted as described for 4. Chromatography on silica gel with
acetonitrile/water (6:1) and then with dichloromethane/methanol
(5:1), followed by precipitation of the hydrochloride salt as
described for 8, gave 193 mg of the hydrochloride salt of the product
(63%) as a colorless solid, mp >170 °C (dec). MS (ESP) m/z 441
(MH+). 1H NMR (DMSO-d6) δ: 1.27 (m, 6H), 3.12 (m, 1H), 3.37
(m, 2H), 3.96 (m, 1H), 4.30 (dd, 1H), 4.86 (d, 2H), 5.11-5.22 (m,
3H), 7.40 (m, 1H), 7.53-7.75 (m, 3H), 7.77 (s, 1H), 8.13 (d, 1H),
8.20 (s, 1H), 8.67 (brs, 1H), 8.75 (s, 1H), 9.15 (brs, 1H). Anal.
(C22H25FN6O3) C, H, N.
N-Methoxy-N-methyl-4-(4-methylpiperazin-1-yl)butana-
mide (35b). 4-Chloro-N-methoxy-N-methylbutyramide39 (1 g, 6.04
mmol) and 1-methylpiperazine (1.2 g, 12 mmol) were mixed in
DMSO (2 mL) and heated to 80 °C for 3 h. The reaction was
quenched with saturated aqueous sodium hydrogen carbonate
solution (∼100 mL), extracted with dichloromethane (3 × 100 mL),
and dried over sodium sulfate. Chromatography on silica gel with
dichloromethane/methanol (18:1 to 3:1) gave 749 mg (54%) of the
1
product as a slightly yellow oil. MS (ESP) m/z 230 (MH+). H
NMR (DMSO-d6) δ: 1.63 (tt, 2H), 2.13 (s, 3H), 2.10-2.45 (m,
10H), 3.07 (s, 3H), 3.38 (m, 2H), 3.64 (s, 3H).
Benzyl 4-{[Methoxy(methyl)amino]carbonyl}piperidine-1-
carboxylate (35c).40 A mixture of benzyl 4-(chlorocarbonyl)-
piperidine-1-carboxylate (1 g, 3.55 mmol) and N,O-dimethylhy-
droxylamine hydrochloride (346 mg, 3.55 mmol) in dichloromethane
(20 mL) was cooled to -20 °C, and pyridine (1.15 mL, 14.2 mmol)
was added. The reaction mixture was allowed to reach room
temperature over 30 min and was stirred for another hour. It was
diluted with dichloromethane (100 mL), washed with potassium
phosphate buffer (1 M, pH 7, 3 × 100 mL), and dried over sodium
sulfate. Chromatography on silica gel with hexanes/ethyl acetate
(1:1 to 0:1) gave 650 mg (60%) of the product as a colorless oil.
MS (ESP) m/z 307 (MH+). 1H NMR (DMSO-d6) δ: 1.40 (m, 2H),
1.66 (m, 2H), 2.80-2.99 (m, 3H), 3.08 (s, 3H), 3.67 (s, 3H), 4.01
(m, 2H), 5.06 (s, 2H), 7.26-7.45 (m, 5H).
tert-Butyl 4-{2-[Methoxy(methyl)amino]-2-oxoethyl}piperidine-
1-carboxylate (35d).41,42 To a solution of Boc-(4-carboxymethyl)-
piperidine (1 g, 4.11 mmol) and bis(2-oxo-3-oxazolidinyl)-
phosphinic chloride (1.05 g, 4.11 mmol) in DMF (4 mL) was added
N,O-dimethylhydroxylamine hydrochloride (561 mg, 5.57 mmol),
followed by diisopropylethylamine (2.15 mL, 12.3 mmol). It was
stirred for 30 min, diluted with ethyl acetate (100 mL), washed
with water (2 × 50 mL), and dried over sodium sulfate. Chroma-
tography on silica gel with hexanes/ethyl acetate (2:1 to 1:2) gave
770 mg (65%) of the product as a colorless oil. MS (ESP) m/z 187
1
(M - BocH+). H NMR (DMSO-d6) δ: 1.02 (m, 2H), 1.37 (s,
9H), 1.61 (m, 2H), 1.85 (m, 1H), 2.29 (m, 2H), 2.68 (m, 2H), 3.06
(s, 3H), 3.62 (s, 3H), 3.89 (m, 2H).
1-(5-Bromopyridin-2-yl)ethanone (37).17,24 5-Bromo-2-cyan-
opyridine (8 g, 43.7 mmol) was dissolved in dry THF (200 mL)
and cooled to -20 °C. Methylmagnesium bromide (43.7 mL, 3
M) was added dropwise, and the temperature was held between
-20 and -10 °C for 3 h. The reaction mixture was cooled to -40
°C, and concentrated HCl (4.5 mL) in water (15 mL) was added
dropwise. It was stirred for 10 min at -35 °C and then poured into
potassium phosphate buffer (300 mL, 1 M, pH 7), under stirring.
Ethyl acetate (300 mL) was added, and the organic phase was dried
over sodium sulfate. Upon concentration at room temperature under
reduced pressure to ∼50 mL the product crystallized, 2.4 g, mp
112 °C. The mother liquor was further concentrated and chromato-
graphed on silica gel with dichloromethane/ethyl acetate (100:1)
to give another 3.25 g of product (65% combined yield). 1H NMR
(DMSO-d6) δ: 2.60 (s, 3H), 7.88 (dd, 1H), 8.25 (dd, 1H), 8.86 (d,
1H).
(5R)-3-(4-{6-[2-(Dimethylamino)-1-hydroxyethyl]pyridin-3-
yl}-3-fluorophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazoli-
din-2-one (34). 1f, TFA salt (200 mg, 0.56 mmol), 2h (216 mg,
0.56 mmol), sodium carbonate (177 mg, 1.67 mmol), and tetrakis-
(triphenylphosphine)palladium(0) (64 mg, 0.056 mmol) were
reacted as described for 3. Chromatography on silica gel with
acetonitrile/water (5:1) and precipitation from ethanol by addition
of HCl in ether (1 M, ∼0.7 mL) gave 125 mg (48%) of the
hydrochloride salt of the product as a colorless solid, mp >115 °C
1
(dec). MS (ESP) m/z 427 (MH+). H NMR (DMSO-d6) δ: 2.88
(s, 6H), 3.25-3.75 (m, 3H), 3.96 (m, 1H), 4.29 (dd, 1H), 4.86 (d,
2H), 5.12-5.20 (m, 2H), 7.39 (m, 1H), 7.52-7.75 (m, 3H), 7.75
(s, 1H), 8.05 (d, 1H), 8.20 (s, 1H), 8.69 (s, 1H), 10.20 (brs, 1H).
Anal. (C21H23FN6O3) C, H, N.
2-Bromo-1-(5-bromopyridin-2-yl)ethanone (38). 37 (5.65 g,
28.2 mmol) was dissolved in methanol/acetic acid (50 mL + 70
mL) and cooled to 0 °C, and 30% HBr in acetic acid (8 mL) was
added. Bromine (1.45 mL, 28.3 mmol) in acetic acid (10 mL) was
tert-Butyl 3-{[Methoxy(methyl)amino]carbonyl}azetidine-1-
carboxylate (35a). To a solution of 1-(tert-butoxycarbonyl)-
azetidine-3-carboxylic acid (0.5 g, 2.48 mmol) and bis(2-oxo-3-

4880 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 20
Reck et al.
(3) Xiong, L.; Kloss, P.; Douthwaite, S.; Andersen, N. M.; Swaney, S.;
Shinabarger, D. L.; Mankin, A. S. Oxazolidinone resistance mutations
in 23S rRNA of Escherichia coli reveal the central region of domain
V as the primary site of drug action. J. Bacteriol. 2000, 182, 5325-
5331.
(4) Auckland, C.; Teare, L.; Cooke, F.; Kaufmann, M. E.; Warner, M.;
Jones, G.; Bamford, K.; Ayles, H.; Johnson, A. P. Linezolid-resistant
Enterococci: report of the first isolates in the United Kingdom. J.
Antimicrob. Chemother. 2002, 50, 743-746.
added dropwise, and the reaction mixture was allowed to reach
room temperature and then was heated to 70 °C for 1 h. It was
cooled to ∼50 °C. More bromine (0.4 mL) in acetic acid (5 mL)
and methanol (15 mL) was added, and the mixture was heated to
70 °C for another 30 min. The reaction mixture was concentrated
to dryness under reduced pressure and the residue was crystallized
from isopropanol to give 3.45 g (34%) of the crude hydrobromide
salt of the product as a pale-yellow solid. MS (ESP) m/z 278/280/
(5) Potoski, B. A.; Mangino, J. E.; Goff, D. A. Clinical failures of
linezolid and implications for the clinical microbiology laboratory.
Emerging Infect. Dis. 2002, 8, 1519-1520.
1
282 (MH+). H NMR (DMSO-d6) δ: 4.96 (s, 2H), 7.93 (m, 1H),
8.29 (m, 1H), 8.87 (m, 1H), 9.19 (brs, 1H).
2,4-Dimethyl-1-trityl-1H-imidazole (39). A solution of trityl
chloride (15 g, 55 mmol) in dichloromethane (50 mL) was added
dropwise over 45 min to a solution of 2,4-dimethylimidazole (5 g,
52 mmol) in a mixture of dichloromethane (100 mL) and triethy-
lamine (11.3 mL, 81 mmol) at room temperature. The mixture was
stirred overnight, then quenched with methanol (4 mL) and stirred
for additional 30 min. The solvent was evaporated, and the residue
was taken up in toluene (600 mL), washed with potassium
phosphate buffer (pH 7, 1M, 2 × 200 mL) and with water (200
mL). The organic phase was diluted with dichloromethane (200
mL), dried over sodium sulfate, and concentrated under reduced
pressure to ∼100 mL. Hexanes (100 mL) were added and the
precipitate was collected by filtration and washed with hexanes (2
× 50 mL) to give 14.76 g (84%) of the product as a colorless solid.
1H NMR (CDCl3) δ: 1.62 (s, 3H), 2.16 (s, 3H), 6.40 (s, 1H), 7.10-
7.40 (m, 15H).
1-[2-(5-Bromopyridin-2-yl)-2-oxoethyl]-2,5-dimethyl-3-trityl-
1H-imidazol-3-ium bromide (40). A mixture of 39 (4.5 g, 13.4
mmol), 38 (free base) (2.5 g, 9 mmol) (the free base was generated
from the hydrobromide salt by treating a suspension of the
hydrobromide salt of 38 in ethyl acetate with potassium phosphate
buffer (pH 7, 1 M), washing the organic phase with water and
drying over sodium sulfate), and 2,6-di-tert-butylpyridine (3 mL,
13.35 mmol) was heated in 1,4-dioxane (50 mL) at 75 °C for 30
min. The reaction mixture was allowed to cool to room temperature
and the precipitate was collected by filtration and washed with
hexanes (2 × 50 mL) to give 4.75 g (86%) of the product as an
off-white solid, mp >150 °C (dec). MS (ESP) m/z 536/538 (M+).
1H NMR (DMSO-d6) δ: 1.82 (s, 3H), 2.21 (s, 3H), 5.95 (s, 2H),
7.07 (s, 1H), 7.12-7.18 (m, 6H), 7.44-7.65 (m, 9H), 7.98 (m,
1H), 8.36 (m, 1H), 8.98 (m, 1H).
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Acknowledgment. The authors thank Dr. Camil Joubran,
Analytical Chemistry Department of AstraZeneca R&D Boston,
for performing NOE- and HMBC NMR experiments; Organix,
Inc., Woburn, Massachusetts, for the synthesis of some inter-
mediates; Adam Mondello and Jeanette Jones, Microbiology
Department, AstraZeneca R&D Boston, for the determination
of MICs; Lena Grosser, Joanna Bryant, and Sussie Hopkins,
Pharmacology Department, AstraZeneca R&D Boston, for
pharmacokinetic and efficacy studies; and Elaina Zverina,
Biochemistry Department, AstraZeneca R&D Boston, for the
determination of MAO-A Ki values.
Supporting Information Available: Elemental analysis results.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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