Novel tetrahydro-thieno pyridyl oxazolidinone: An antibacterial agent

Article abstract of DOI:10.1016/j.bmc.2004.07.019

We have synthesized and evaluated antibacterial activity of a number of 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine substituted oxazolidinones against several Gram-positive pathogens. Effect of various substituents on 5-position of the oxazolidinone ring has been studied. Synthesis of a number of 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine substituted oxazolidinones have been reported. They have been screened against a panel of Gram-positive pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis. A SAR has been developed. Compound 15 showed comparable activity (MIC) to linezolid and superior to eperezolid.

Full text of DOI:10.1016/j.bmc.2004.07.019

Bioorganic & Medicinal Chemistry 12 (2004) 4557–4564
Novel tetrahydro-thieno pyridyl oxazolidinone:
an antibacterial agentq
Braj Bhushan Lohray,* Vidya Bhushan Lohray, Brijesh Kumar Srivastava,
Prashant B. Kapadnis and Purvi Pandya
Zydus Research Centre, Cadila Healthcare Ltd, Sarkhej-Bavla N. H.8 A, Moraiya, Ahmedabad 382210, India
Received 3 June 2004; revised 6 July 2004; accepted 7 July 2004
Abstract—Synthesis of a number of 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine substituted oxazolidinones have been reported. They
have been screened against a panel of Gram-positive pathogens including methicillin-resistant Staphylococcus aureus and vanco-
mycin-resistant Enterococcus faecalis. A SAR has been developed. Compound 15 showed comparable activity (MIC) to linezolid
and superior to eperezolid.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
patients receiving prolonged treatment has been
reported.4
Despite a number of antibiotics available for the treat-
ment of bacterial infections, emergence of multi-drug
resistant organism has posed a great challenge to the sci-
entists. The latest addition to the armory for treating
antibacterial infections has been oxazolidinone, linezolid
1 (Fig. 1) by Pharmacia and UpJohn, based on the lead
molecule DuP 721 2 (Fig. 1) discovered at DuPont in
1987.1 Linezolid (Zyvox)2 was launched as the only drug
of choice, for the treatment of infections associated with
vancomycin-resistant Enterococcus faecium including
blood stream infections, hospital acquired pneumonia
and methicillin-resistant Staphylococcus aureus.3 How-
ever, toxicity as well as emergence of resistance in some
A number of attempts have been made by various re-
search groups to obtain potent and safer analogues
without much success.5 There appears to be a need for
second generation oxazolidinone with improved drug
efficacy and better toxicity profile. We have also recently
reported some of our interesting findings of oxazolidi-
nones.6,7 Recently, Paget et al.8 reported 6:5 fused ring
pyrrolopyridine substituted oxazolidinones, in which 3
and 4 (Fig. 2) have been shown to have 2–4-fold better
antibacterial (MIC) activity to linezolid and similar to
linezolid against Staphylococcus aureus in in vivo experi-
ment.8
In the present article, we would like to disclose a few ox-
azolidinones 11–21 (Fig. 3) having 4,5,6,7-tetrahydro-
thieno[3,2-c]pyridine ring systems and their antibacterial
activity.
O
O
O
O
O
N
O
N
N
NHAc
NHAc
F
2
1
2. Chemistry
DuP-721
Linezolid
Figure 1.
The syntheses of compounds have been outlined in
Scheme 1. 4,5,6,7-Tetrahydro-thieno[3,2-c]pyridine 5
and its derivatives were synthesized by methods de-
scribed in the literature.9 Reaction of 5 with 3,4-difluoro-
nitrobenzene 6 was carried out under basic conditions
leading to the nucleophilic substitution at 4-position to
yield a nitro compound 7 (Scheme 1).
Keywords: Oxazolidinone; 4,5,6,7-Tetrahydro-thieno[3,2-c]pyridine;
Linezolid; In vitro activity.
q ZRC Communication No 124.
*
Corresponding author. Tel.: +91-02717-250802; fax: +91-02717-
250606; e-mail: braj.lohray@zyduscadila.com
0968-0896/$ - see front matter ꢀ 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.07.019

4558
B. B. Lohray et al. / Bioorg. Med. Chem. 12 (2004) 4557–4564
O
O
O
O
N
N
N
N
N
NHAc
NHAc
N
F
F
3
4
Figure 2.
tetrahydro-thienopyridine ring did not show any
improvement in antibacterial activity, such as 7-methyl
(12) or 4-methyl (16) were inferior to linezolid. When
the methyl group of acetamide side chain of compound
11 was replaced by a cyclopropyl group to give com-
pound 13, inferior antibacterial activity was observed,
when compared to compound 11. Recently, it has been
shown in several studies that replacement of acetamide
side chain with thioacetamide, thiourea or carbamate
lead to improvement in their antibacterial potential.10–12
Thus, we synthesized thioamide 14, thiourea 15 and
16, urea 17, thiocarbamate derivative 18 and dithio-
carbamate derivative 19 and evaluated their antibacte-
rial activity in panel of Gram-positive strains. The
thioacetamide derivative 14 showed an improved anti-
bacterial activity as compared to compounds 11, 12
and 13, however, it remains inferior to linezolid and epe-
rezolid in MIC value. Thiourea derivatives 15 was
equally potent and showed comparable antibacterial
activity to linezolid and eperezolid; however, methyl
substituted analogue 16 was relatively inferior. When
ꢀSꢁ atom of thiourea of compound 15 is replaced by
ꢀOꢁ atom to furnish urea derivative 17 a dramatic de-
crease in the antibacterial activity was observed. Based
on the result of 15 and 16, we envisioned that introduc-
tion of one more ꢀSꢁ atom in the compound 15 will give
superior compound 19, however, it was much inferior to
15 and 16. Interestingly, substitution of –NH of aceta-
mide, thioacetamide or thiourea with a methyl group,
which led to the formation of compounds 20 and 21
O
R
N
4
7
3
O
5
6
N
2
R1
S
F
1
11-21
Figure 3.
The nitro group of compound 7 was then reduced by hy-
drazine/Raney-Ni at 30ꢁC to afford amino compound
which was protected by carboxybenzyloyl group to fur-
nish compound 8. Reaction of 8 with n-BuLi followed
by reaction with (R)-glycidyl butyrate lead to the forma-
tion of oxazolidinone alcohol 9a. Alcohol 9a was then
converted into azide 9c or methylamino derivative 9d
via mesylated intermediate 9b by standard method.3,10,11
The azide 9c or amine 9d can be converted into various
substituted oxazolidinones 11–21 as shown in Scheme 1.
3. Results and discussion
The results of in vitro antibacterial activities (MIC)
against various bacterial strains are summarized in
Table 1. Tetrahydro-thienopyridine substitution at
4-position of the phenyl ring gave compound 11, which
showed antibacterial activities. Any substitution of the
b, c
S
a
NH
S
+
N
NH
O
F
NO2
N
NO2
O
S
F
7
F
F
8
5
6
Ph
d
O
O
g
O
O
S
S
N
N
N
N
NHR'
R
F
F
10: R' = H
h
k
9
11: R' = COMe
i
j
l
13: R' = COcyclopropyl
14: R' = CSMe
15: R' = CSNH2
17: R' = CONH2
18: R' = CSOMe
19: R' = CSSMe
9a: R = OH
e
9b: R = OMs
9c: R = N3
f
o
9d: R = NHCH3
p
q
m
n
20: R = NCH3COCH3
21: R = NCH3CSNHCH3
Scheme 1. Reagents and conditions: (a) acetonitrile, 75–78ꢁC, 2h. (b) Raney-Nickel, NH2NH2ÆH2O, 28–30ꢁC, 1h. (c) Benzyl chloroformate (50% in
toluene), 10% Na2CO3, acetone, 27–30ꢁC, 18h. (d) n-BuLi (1.6M in hexane), (R)-glycidyl butyrate, THF, À78ꢁC, 3h. (e) MeSO2Cl, TEA, CH2Cl2,
0–5ꢁC, 3h. (f) NaN3, DMF, 70–75ꢁC, 2h. (g) P(Ph)3, NH4OH, MeOH, 1,4-dioxane, 25–27ꢁC, 2h. (h) Ac2O, pyridine, 25–27ꢁC, 30min. (i)
Cyclopropanoic acid, HOBt–H2O, EDC–HCl, TEA, CH2Cl2, 26–28ꢁC, 30min. (j) Lawessonꢁs reagent, 1,4-dioxzane, 95–100ꢁC, 4h. (k) CS2, TEA,
THF, Ethyl chloroformate, 30% NH3 in MeOH, 26–28ꢁC, 2h. (l) Hg(OAc)2, CH2Cl2, 38–40ꢁC, 3h. (m) NaH (60% in oil), MeOH, 0–5ꢁC, 3h. (n)
CS2, TEA, MeI, THF, 0–5ꢁC, 4h. (o) 40% methyl amine in methanol, 60–65 ꢁC, 24h. (p) Pyridine, Ac2O, 25–28ꢁC, 1.5h. (q) TEA, MeNCS, CH2Cl2,
26–28ꢁC, 2h.

B. B. Lohray et al. / Bioorg. Med. Chem. 12 (2004) 4557–4564
4559
Table 1. MIC (minimum inhibitory concentration in microgram per litre) values of new oxazolidinones in various Gram-positive bacteria
O
R
N
4
7
3
O
5
6
N
2
R1
S
F
1
11 - 21
Compd
R
H
R1
B.p.
4–8
B.c.
S.p.
1–2
S.e.
E.f. 1
4–8
E.f. 2
8–16
S.a. 1
4–8
S.a. 2
8–16
S.a. 3
8–16
S.a. 4
H
N
Me
Me
11
8–16
8–16
4–8
8–16
ND
O
O
H
N
12
13
14
15
16
17
18
19
20
21
7-CH3
H
ND
8–16
1–2
ND
>16
>16
8–16
1–2
ND
>16
>16
>16
ND
H
N
8–16–8 2–448–16
>16
>16
>16
O
S
S
S
O
S
S
H
N
Me
H
>16
1–2
1–2
0.5–1
>16
2–4 2–42–48–16
2–42–42–4
H
N
NH2
NH2
NH2
OMe
SMe
Me
H
1–2
2–4 1–2
2–41–2
0.5–1.0
H
N
4-CH3
H
2–42–41–2
1–2
2–4 2–4 2–4 2––84 4 8–16
H
N
8–16
1–2
8–16
1–2
4–8
8–16
1–2
8–16
>16
8–16
4–8
>16
4–8
>16
>16
8–16
>16
>16
>16
>16
>16
H
N
H
>16
0.5–1
2–41–2
>16
0.5–1
>16
>16
H
N
H
>16
>16
ND
>16
>16
>16
>16
>16
Me
N
H
>16
>16
>16
>16
O
Me
N
NHMe
H
64ND
>6432
0.5–1
ND
>64 ND
ND
ND
S
Linezolid
Eperezolid
1–2
1–2
2–40.25–0.5
1–2 0.5–1
1–2
2–42–41–2
1–2
1–2
2–4 2–42–42–4
2–42–42–4
B.p. = Bacillus pumilus MTCC 1607, B.c. = Bacillus cereus MTCC 430, S.p. = Streptococcus pyogenes MTCC 442, S.e. = Staphylococcus epidermidis
MTCC 155, E.f. 1 = Enterococcus faecalis MTCC 439, E.f. 2 = Enterococcus faecalis ATCC 14506, S.a. 1 = Staphylococcus aureus MTCC 96, S.a.
2 = Staphylococcus aureus ATCC 14154, S.a. 3 = Staphylococcus aureus, ATCC 25923, S.a. 4= Staphylococcus aureus ATCC 29213, ND = not done.
were totally devoid of any activity suggesting the impor-
tance of NH group in the side chain for their antibacte-
rial activity.
ity of a compound can be achieved with appropriate
combination of heterocyclic moiety at 4-position of aro-
matic ring as well as appropriate modification of acet-
amide side chain. The compound 15 is showing promis-
ing results, and studies to establish its safety are being
planned for its further development.
4. Conclusion
In summary, unsubstituted tetrahydro-thienopyridine
substitution at p-position of the aromatic ring in oxazo-
lidinone skeleton furnishes active antibacterial com-
pound 11, however, best antibacterial activity can be
obtained with thiourea as side chain, compound 15.
Thus, it appears that most potential antibacterial activ-
5. In vitro MIC
The in vitro (MIC) antibacterial activity of the
compounds against Gram-positive (Bacillus pumilus,
Bacillus cereus, Staphylococcus aureus, Staphylococcus

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B. B. Lohray et al. / Bioorg. Med. Chem. 12 (2004) 4557–4564
epidermidis, Enterococcus faecalis) bacteria was tested as
growth inhibition with the use of microdilution broth
method according to NCCLS.13 Compounds were dis-
solved in concentrated DMSO and water was added to
get stock solution in 80% DMSO. The working solution
was prepared by diluting the stock solution 1:10 times in
4–8% DMSO in water or medium, and the dissolved
compounds were evaluated in the concentrations of
0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 32 and 64lg/mL.
The reaction was warmed to 26–28ꢁC and stirred at this
temperature for 18h. The completion of reaction was
checked by TLC using mobile phase CHCl3–MeOH
(9:1). The solvent was evaporated on a rotatory evapo-
rator under reduced pressure to afford oil. Water
(75mL) was added to oil, and extracted with ethyl ace-
tate (3 · 75mL). The organic layer was treated with acti-
vated charcoal (1g), warmed for 10min at temperature
45–50ꢁC and filtered through hy-flow. The solvents were
evaporated on a rotatory evaporator under reduced
pressure to afford an oil. The oil was triturated with hex-
ane (10mL) to give the title compound 8 as an off-white
solid (1.3g, 47%) (99.1% purity in HPLC). Mp 100–
103ꢁC. 1H NMR (CDCl3): d 7.39 (m, 5H), 7.12 (d,
1H, J = 5.1Hz), 6.81 (d, 1H, J = 5.1Hz), 6.61 (m, 2H),
6.57 (s, 1H), 5.19 (s, 2H), 4.18 (s, 2H), 3.43 (t, 2H,
J = 5.64Hz), 2.95 (t, 2H, J = 5.52Hz). IR (KBr): 3330,
2922, 2777, 1697, 1587, 1527, 1456, 1417, 1375, 1301,
1217, 1072, 711cmÀ1. ESI-MS: 383.0 (M+H)+.
6. Experimental
1H spectral data are recorded using a 300MHz 1H
NMR spectrometer (M-300) and reported in d scale,
using tetramethyl silane as the internal standard. IR
spectra are recorded on FTIR 8300 Shimadzu in KBr
pellets. Mass spectra are recorded on a Perkin Elmer
Sciex API 3000. HPLC of the pure compounds are done
at kmax 220nm using column ODS C-18, 150mm ·
4.6mm · 4l on AGILENT 1100 series. Melting points
are taken on scientific melting point apparatus and are
uncorrected. 25 DC-Alufolien 20 · 20cm kieselgel 60
F254 Merck plates were used for TLC unless specified.
6.3. [4-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-yl)-3-
fluoro-phenyl]-2-oxo-5-oxazolidinyl methanol (9a)
To a solution of compound 8 (3.5g, 9.16mmol) in
freshly distilled THF (40mL) at À78ꢁC under nitrogen
atmosphere was added dropwise, n-BuLi (1.6M in hex-
ane, 11.1mL, 9.3mmol) and mixture was stirred for
1.5h. To this (R)-glycidyl butyrate (1.34mL, 9.4mmol)
was added at À78ꢁC and stirred for 1h. The reaction
mixture was warmed to 27–28ꢁC and stirred for 3.5h.
The completion of reaction was checked by TLC using
mobile phase CHCl3–MeOH (9:1). Saturated aqueous
solution of ammonium chloride (5g) was added to the
reaction mixture followed by ethyl acetate (50mL) and
water (5mL). The layers were separated and aqueous
layer was extracted with ethyl acetate (3 · 25mL). The
organic layers were combined and dried over anhydrous
Na2SO4. The solvents were evaporated on a rotatory
evaporator under reduced pressure to afford a solid.
The solid was further taken in ethyl acetate (10mL)
and warmed on a water bath at 50–55ꢁC for 30min.
The solid was filtered to give compound 9a as a white
solid (1.3g, 41%) (94% purity in HPLC). Mp = 158–
6.1. Pyridin-5-(2-fluoro-4-nitro-phenyl)4,5,6,7-tetra-
hydro-thieno[3,2-c]pyridine (7)
A solution of 3,4-difluorobenzene 6 (2.28g, 143.0mmol)
in acetonitrile (30mL) was added to 4,5,6,7-tetrahydro-
thieno[3,2-c]pyridine 5 (5.0g, 35.0mmol) and heated at
temperature 75–78ꢁC for 2h. The reaction mixture
was cooled to temperature 27–28ꢁC and solvents were
removed under reduced pressure to afford a crude oil.
Water (100mL) was added to this and extracted with
ethyl acetate (3 · 100mL). The combined organic layer
was washed with saturated sodium chloride solution
(100mL) and dried over anhydrous Na2SO4. The sol-
vents were removed on a rotatory evaporator under re-
duced pressure to afford compound 7 as a yellow solid
(3.99g, 100%) (99.0% purity by HPLC). Mp 135ꢁC.
1H NMR (CDCl3): d 8.00 (m, 2H), 7.17 (d, 1H,
J = 5.13Hz), 6.95 (t, 1H, J = 8.64Hz), 4.43 (s, 2H),
3.70 (t, 2H, J = 5.58Hz), 3.00 (t, 2H, J = 5.52Hz); IR
(KBr): 3107, 2891, 2821, 2337, 1604, 1498, 1454, 1330,
1265, 1207, 1047cmÀ1. ESI-MS: 279 (M+H)+.
1
160ꢁC. H NMR (CDCl3): d 7.43 (dd, 1H, J = 2.55Hz,
11.6Hz), 7.13 (m, 2H), 6.98 (t, 2H, J = 9.18Hz), 6.81
(d, 1H, J = 5.13Hz), 4.74 (m, 1H), 4.21 (s, 2H), 4.00
(m, 3H), 3.77 (dd, 2H, J = 4.0Hz, 8.58Hz), 3.46 (t,
2H, J = 5.64Hz), 3.11 (s, 3H), 2.96 (t, 2H, J =
5.49Hz). IR (KBr): 3431, 2900, 2823, 1732, 1631,
1569, 1517, 1479, 1423, 1325, 1224, 1193, 1101, 991,
937, 831, 804, 752cmÀ1. ESI-MS: 349.0 (M+H)+, 371
(M+Na)+, 387 (M+K)+.
6.2. [4-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-yl)-3-
fluorophenyl]-carbamic acid benzyl ester (8)
To a solution of compound 7 (2g, 7.19mmol) in MeOH
(15mL) was added Raney-Nickel (2.5g) followed by hy-
drazine hydrate 99% (3mL) dropwise over a period of
5min. The mixture was stirred at 28–30ꢁC for 1h. The
completion of reaction was checked by TLC using mo-
bile phase CHCl3–MeOH (9:1). The reaction mixture
was filtered through celite and the celite bed was washed
with MeOH (15mL). The filtrate was concentrated on a
rotatory evaporator under reduced pressure to afford a
yellow solid. The solid was dissolved in acetone
(20mL) and treated with 10% Na2CO3 (aq) solution
(5mL) dropwise and cooled to 0–5ꢁC. To this benzyl
chloroformate (5mL) was added dropwise at 0–5ꢁC.
6.4. [4-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-yl)-3-
fluoro-phenyl]-2-oxo-5-oxazolidinyl methyl methane sulfo-
nate (9b)
To the solution of compound 9b (1g, 2.87mmol) and tri-
ethylamine (0.78mL) in dichloromethane at 0–5ꢁC was
added methane sulfonyl chloride (0.3mL) dropwise
within 2min. The mixture was stirred at 0–5ꢁC for 3h
and the completion of reaction was checked by TLC
using mobile phase CHCl3–MeOH (9:1). The reaction

B. B. Lohray et al. / Bioorg. Med. Chem. 12 (2004) 4557–4564
4561
mixture was diluted with water (50mL) and the aqueous
layer was extracted with dichloromethane (2 · 20mL).
The organic layers were combined, dried over anhy-
drous Na2SO4 and the solvents were evaporated on a
rotatory evaporator under reduced pressure to afford a
crude solid product. The solid was crystallized from
acetonitrile (10mL) and water (20mL) to get 9b as a
white solid. (1.03g, 84%) (93% purity in HPLC). Mp
140–144ꢁC. 1H NMR (CDCl3): d 7.45 (dd, 1H,
J = 2.55Hz, 11.5Hz), 7.00 (m, 2H), 6.99 (t, 2H,
J = 9.12Hz), 6.82 (d, 1H, J = 5.13Hz), 4.45 (m, 2H),
4.31(m, 1H), 4.21(s, 2H), 4.09 (t, 1H, J = 9.12Hz),
3.93 (m, 1H), 3.47 (t, 2H, J = 5.64Hz), 2.97 (t, 2H,
J = 5.55Hz). IR (KBr): 1743, 1517, 1419, 1365, 1172,
997cmÀ1. ESI-MS: 427.2 (M+H)+, 465 (M+K)+.
J = 4.62Hz), 3.13 (dd, 1H, J = 4.02Hz, J = 9.60Hz),
2.94(m, 3H). IR (KBr): 3392, 2823, 1732, 1517, 1421,
1325, 1222, 1193, 864, 804, 752cmÀ1
.
6.7. 1-{3-[4-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-yl)-3-
fluoro-phenyl]-2-oxo-oxazolidin-5-yl-methyl}-acetamide
(11)
Compound 10 (0.25g, 0.72mmol) in dry pyridine
(0.4mL) was treated with acetic anhydride (0.71mL)
and the mixture was stirred at 25–27ꢁC for 1.5h. The
completion of reaction was checked by TLC using mo-
bile phase CHCl3–MeOH (9:1). The reaction mixture
was poured into chilled water (40mL) and extracted
with ethyl acetate (3 · 50mL). The organic layers were
combined, dried over anhydrous Na2SO4 and the sol-
vents were evaporated on a rotatory evaporator under
reduced pressure to afford compound 11 as a white solid
(0.217g, 77%) (94% purity in HPLC). Mp 135–140ꢁC.
1H NMR (CDCl3): d 7.47 (dd, 1H, J = 2.46Hz,
11.64Hz), 7.13 (d, 1H, J = 5.13Hz), 7.04(dd, 1H,
J = 2.22Hz, 6.60Hz), 6.97 (t, 1H, J = 8.91Hz), 6.82 (d,
1H, J = 5.13Hz), 5.92 (s, 1H), 4.75 (s, 1H), 4.21(s,
2H), 4.05 (t, 1H, J = 9.0Hz), 3.74(m, 2H), 3.59 (m,
1H), 3.47 (t, 2H, J = 5.64Hz), 2.96 (t, 2H,
J = 5.49Hz), 2.02 (s, 3H). IR (KBr): 3093, 2923, 2815,
1741, 1641, 1517, 1431, 1328, 1228, 1132, 1014, 850,
815, 756cmÀ1. ESI-MS: 390 (M+H)+, 428 (M+K)+.
6.5. [4-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-yl)-3-
fluoro-phenyl]-2-oxo-5-oxazolidinylmethyl azide (9c)
Compound 9b (0.9g, 2.11mmol) in dimethyl formamide
(17mL) was treated with NaN3 (0.520g, 8.0mmol) and
heated to 70–75ꢁC with stirring for 2h. The completion
of reaction was checked by TLC using mobile phase
CHCl3–MeOH (8.5:1.5). The heat source was removed
and the reaction mixture was cooled to 25–26ꢁC. The
reaction mixture was diluted with water (50mL) and
extracted with ethyl acetate (3 · 25mL). The organic
layers were combined, dried over anhydrous Na2SO4
and the solvents were evaporated on a rotatory evapora-
tor under reduced pressure to afford oil. The oil was
triturated with CHCl3–IPE (1:2) to give compound 9c
as white solid (0.5g, 41%) (95% purity in HPLC). Mp
158–160ꢁC. 1H NMR (CDCl3): d 7.47 (dd, 1H,
J = 2.58Hz, 11.55Hz), 7.13 (m, 2H), 6.99 (t, 1H,
J = 9Hz), 6.82 (d, 1H, J = 5.13Hz), 4.78 (m, 1H), 4.21
(s, 2H), 4.05 (t, 1H, J = 8.91Hz), 3.83 (m, 1H), 3.69
(m, 2H), 3.57 (t, 2H, J = 5.61Hz), 2.96 (t, 2H,
J = 5.58Hz). IR (KBr): 2119, 1733, 1517, 1419, 1326
6.8. N-{3-[3-Fluoro-4-(7-methyl-6,7-dihydro-4H-thieno-
[3,2-c]pyridin-5-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-
acetamide (12)
The title compound was synthesized by a procedure
identical to the procedure described for the synthesis
of compound 11.
1
Yield: 27% (87% purity in HPLC). Mp 102–106ꢁC. H
+
1193, 1168cmÀ1. ESI-MS: 374(M+H) , 411 (M+K)+.
NMR (CDCl3): d 7.46 (dd, 1H, J = 16.50Hz), 7.14(d,
1H, J = 5.13Hz), 7.07 (dd, 1H, J = 10.11Hz), 6.82 (d,
1H, J = 5.13Hz), 6.02 (br s, 1H), 4.77 (br s, 1H), 4.31
(m, 1H), 4.03 (t, 1H, J = 6.0Hz,), 4.01 (m, 2H), 3.77
(m, 2H), 3.59 (m, 1H), 3.18 (m, 1H), 2.67 (m, 1H),
2.02 (s, 3H), 1.14(m, 3H). IR (KBr): 3093, 2923, 2815,
1741, 1641, 1517, 1431, 1328, 1228, 1132, 1014, 850,
815, 756cmÀ1. ESI-MS: 404.2 (M+H)+.
6.6. 3-[4-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-yl)-3-
fluoro-phenyl]-5-methyloxazolidin methylamine (10)
Compound 9c (1.77g, 4.7mmol) in dioxane (20mL) and
methanol (4mL) was treated with triphenyl phosphine
(2.47g, 9.4mmol) and stirred at 25–27ꢁC for 1h. The
completion of the reaction was checked by TLC using
mobile phase CHCl3–MeOH (8.5:1.5). The solvents
were evaporated on a rotatory evaporator under re-
duced pressure to afford a brown gummy compound.
The compound was taken in diisopropyl ether (10mL)
and heated on a warm water bath at 65–70ꢁC for
15min. The solvent was decanted and this operation
was done 2–3 times. The crude compound was purified
by column chromatography over silica gel (100–230
mesh) using 0–25% ethyl acetate as eluant. The required
fractions were collected and the solvents were removed
on a rotatory evaporator to give compound 10 as a pale
6.9. Cyclopropanecarboxylic acid {3-[4-(6,7-dihydro-4H-
thieno[3,2-c]pyridin-5-yl)-3-fluoro-phenyl]-2-oxo-oxazoli-
din-5-yl-methyl}-amide (13)
A solution of cyclopropanecarboxylic acid (0.123g,
1.43mmol) in 25mL of dichloromethane was treated
with compound 10 (0.5g, 1.44mmol), 1-hydroxybenzo-
triazole hydrate (0.510g, 3.86mmol), 1-(3-dimethylam-
inopropyl)-3-ethylcarbodiimide hydrochloride (0.522g,
2.73mmol) and triethylamine (0.1mL, 1.35mmol) in di-
chloromethane (25mL). The reaction mixture was stir-
red at 26–28ꢁC for 30min. The completion of reaction
was checked by TLC using mobile phase CHCl3–MeOH
(9:1). The reaction mixture was diluted with water
(100mL) and extracted with dichloromethane (3 ·
25mL). The organic layer was separated, dried over
1
yellow solid. (0.986g, 61%) (99% purity in HPLC). H
NMR (CDCl3): d 7.48 (dd, 1H, J = 2.52Hz, 11.7Hz),
7.12 (t, 2H, J = 5.10Hz), 6.98 (t, 1H, J = 9.0Hz), 6.81
(d, 1H, J = 5.16Hz), 4.71 (m, 1H), 4.21 (s, 2H), 4.00
(t, 1H, J = 9.1Hz), 3.82 (m, 1H), 3.46 (t, 2H,

4562
B. B. Lohray et al. / Bioorg. Med. Chem. 12 (2004) 4557–4564
anhydrous Na2SO4 and the solvents were evaporated on
a rotatory evaporator under reduced pressure to afford
compound 13 as a solid (0.476g, 80%) (99% purity in
HPLC). Mp 185ꢁC. 1H NMR (CDCl3): d 7.46 (dd,
1H, J = 2.33Hz, 11.69Hz), 7.13 (d, 1H, J = 5.13Hz),
7.04(m, 2H), 6.82 (d, 1H, J = 5.13Hz), 6.00 (m, 1H),
4.76 (m, 1H), 4.31 (m, 1H), 4.05 (m, 3H), 3.71 (m,
3H), 3.18 (d, 1H, J = 4.92Hz), 2.65 (m, 1H), 2.02 (s,
3H), 1.25 (s, 1H), 1.10 (m, 3H). IR (KBr): 3344, 1733,
1670, 1515, 1427, 1328, 1224, 1193, 1163, 1058, 906,
871, 744cmÀ1. ESI-MS: 416.2 (M+H)+, 454.2 (M+K)+.
with diisopropyl ether (15mL) to afford compound 15
as an off white solid (0.140g, 44%) (97% purity in
HPLC). Mp 80–85ꢁC. 1H NMR (CDCl3): d 8.01 (s,
1H), 7.46 (dd, 1H, J = 2.14Hz, 11.85Hz), 7.14 (d, 1H,
J = 5.07Hz), 7.03 (m, 2H), 6.82 (d, 1H, J = 5.08Hz),
4.98 (m, 1H), 4.21 (m, 3H), 4.03 (t, 2H, J = 8.93Hz),
3.81 (m, 1H), 3.47 (t, 2H, J = 5.55Hz), 2.98 (d, 2H,
J = 5.17Hz), 2.61 (s, 3H). IR (KBr): 3458, 3317, 1743,
1602, 1577, 1326, 1228cmÀ1. ESI-MS: 407 (M+H)+,
445 (M+K)+.
6.12. {3-[3-Fluoro-4-(4-methyl-6,7-dihydro-4H-thieno-
[3,2-c]pyridin-5-yl)-phenyl]-2-oxo-oxazolidin-5-yl-
methyl}-thiourea (16)
6.10. N-{3-[4-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-yl)-
3-fluoro-phenyl]-2-oxo-oxazolidin-5-yl-methyl}thioaceta-
mide (14)
The title compound was synthesized by a procedure
identical to the procedure described for the synthesis
of compound 15.
Compound 11 (0.250g, 0.64mmol) was treated with
Lawessonꢁs reagent (0.259g, 0.16mmol) in 1,4-dioxane
(6mL) under an atmosphere of nitrogen. The reaction
mixture was refluxed at 95–100ꢁC for 4h. The comple-
tion of reaction was checked by TLC using mobile phase
CHCl3–MeOH (9:1). The solvents were evaporated on a
rotatory evaporator under reduced pressure to afford
the crude product. The crude product was triturated
with diisopropyl ether (10mL) and the solid was filtered,
which was further purified by column chromatography
using silica gel (100–230 mesh) and 0–25% ethyl acetate
in hexane as eluant. The required fractions were pooled
and the solvents were evaporated on a rotatory evapora-
tor to give compound 14 as a yellow solid (190mg, 73%)
(91% purity in HPLC). Mp 162–164ꢁC. 1H NMR
(CDCl3): d 7.47 (dd, 1H, J = 2.04Hz, 12.03Hz), 7.14
(d, 1H, J = 4.98Hz), 7.06 (m, 1H), 6.96 (t, 1H, J =
9.03Hz), 6.82 (d, 1H, J = 4.98Hz), 6.36 (s, 1H), 4.76
(s, 1H), 4.20 (s, 2H), 4.03 (t, 1H, J = 8.88Hz), 3.79
(t,1H, J = 8.87Hz), 3.70 (d, 2H, J = 5.25Hz), 3.46 (t,
2H, J = 5.37Hz), 2.96 (s, 2H), 2.62 (s, 2H). IR (KBr):
1745, 1569, 1517,1226, 1118cmÀ1. ESI-MS: 406.2
(M+H)+.
Yield: 61% (95.2% purity in HPLC). Mp 118–120ꢁC. 1H
NMR (DMSO-d6): d 8.11(s, 1H), 7.52 (dd, 1H,
J = 2.01Hz, 12.01Hz), 7.14(d, 1H, J = 5.0Hz), 7.03
(m, 2H), 6.82 (d, 1H, J = 5.05Hz), 5.20 (s, 2H), 4.86
(d 1H, J = 3.02Hz), 4.19 (s, 2H), 4.01 (m, 4H), 3.46
(t, 2H, J = 5.36Hz), 2.96 (s, 2H), 2.49 (s, 2H). IR
(KBr): 3313, 2925, 2854, 1735, 1618, 1514, 852,
748cmÀ1. ESI-MS: 421 (M+H)+, 459 (M+K)+.
6.13. N-{3-[4-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-yl)-
3-fluoro-phenyl]-2-oxo-oxazolidin-5-yl-methyl}urea (17)
Compound 15 (0.250g, 0.61mmol) was treated with
Hg(OAc)2 (0.197g, 0.61mmol) in dichloromethane
(15mL) and refluxed at 38–40 ꢁC for 2h. The comple-
tion of reaction was checked by TLC using mobile phase
CHCl3–MeOH (9:1). The reaction mass was cooled to
26–28ꢁC, with the formation of solid residue. The solid
formed was filtered over buchner funnel and the filtrate
was diluted with water (50mL), extracted with 3 · 20mL
of dichloromethane. Organic layer was separated, dried
over anhydrous Na2SO4 and solvents were removed on
a rotatory evaporator to afford crude solid. The Crude
product was purified through column chromatography
using silica gel (100–230 mesh) and 0–10% methanol in
chloroform as eluant. The required fractions were col-
lected and solvents were removed under reduced pres-
sure to give title compound 17 as white solid (0.03 g,
12%) (98% purity in HPLC). Mp 138ꢁC (with decompo-
6.11. N-{3-[4-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-yl)-
3-fluoro-phenyl]-2-oxo-oxazolidin-5-yl-methyl}thiourea
(15)
Compound 10 (1g, 2.88mmol) in tetrahydrofuran
(50mL) was treated with CS2 (0.18mL, 2.916mmol)
and triethylamine (0.4mL, 0.114mmol) and stirred at
26–28ꢁC for 5h. Ethyl chloroformate (0.26mL,
2.68mmol) was added and further stirred at 26–28ꢁC
for 2h. The completion of reaction was checked by
TLC using mobile phase CHCl3–MeOH (8.5:1.5). The
reaction mixture was diluted with water (50mL) and ex-
tracted with ethyl acetate (3 · 25mL). The organic lay-
ers were combined, dried over anhydrous Na2SO4 and
the solvents were evaporated on a rotator evaporator
under reduced pressure to afford 3-[4-(6,7-dihydro-4H-
thieno[3,2-c]pyridin-5-yl)-3-fluoro-phenyl]-5-isothiocy-
anatomethyl-oxazolidin-2-one as an oil. The oil (0.3g,
0.7mmol) was taken in methanol (10mL) and the solu-
tion was treated with 30% NH3 in methanol (10mL) and
stirred at 26–28ꢁC for 2h. The completion of reaction
was checked by TLC using mobile phase CHCl3–MeOH
(8.5:1.5). The solid separated out was filtered, washed
1
sition). H NMR (CDCl3): d 7.57 (s, 1H), 7.34(dd, 1H,
J = 1.95Hz, 1.7Hz), 7.12 (d, 1H, J = 5.13Hz), 6.99 (m,
2H), 6.80 (dd, 1H, J = 1.32Hz, 3.81Hz), 6.18 (s, 2H),
4.82 (m, 1H), 4.65 (q, 1H, J = 6.6Hz), 4.35 (s, 1H),
4.07 (m, 3H), 3.92 (m, 1H), 3.48 (q, 2H, J = 4.14Hz),
2.84(m, 2H), 2.34(m, 2H). IR (KBr): 3392, 1728,
1654, 1517, 1228, 1191cmÀ1. ESI-MS: 391.1 (M+H)+,
429.2 (M+K)+.
6.14. N-{3-[4-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-yl)-
3-fluoro-phenyl]-2-oxo-oxazolidin-5-yl-methyl}thiocarba-
mate (18)
Compound 10 (0.5g, 1.44mmol) in tetrahydrofuran
(5mL) was treated with CS2 (0.1mL, 1.62mmol) and tri-

B. B. Lohray et al. / Bioorg. Med. Chem. 12 (2004) 4557–4564
4563
ethylamine (0.2mL, 1.427mmol), stirred at 26–28ꢁC for
2h. Ethyl chloroformate (0.26mL, 2.68mmol) was added
and further stirred at 26–28ꢁC for 2h. The completion of
reaction was checked by TLC using mobile phase
CHCl3–MeOH (8.5:1.5). The reaction mixture was di-
luted with water (100mL) and extracted with ethyl ace-
tate (3 · 50mL). The organic layers were combined,
dried over anhydrous Na2SO4 and the solvents were
evaporated on a rotatory evaporator under reduced pres-
sure to afford 3-[4-(6,7-dihydro-4H-thieno[3,2-c]pyridin-
5-yl)-3-fluoro-phenyl]-5-isothiocyanatomethyl-oxazoli-
din-2-one as an oil. To this oil, methanol (10mL) was
added and treated with NaH (100mg) at 0–5ꢁC. The
reaction mixture was stirred at 0–5ꢁC for 1h and then
brought to 26–28ꢁC and stirred for 2h. The completion
of reaction was checked by TLC using mobile phase
CHCl3–MeOH (9:1). The reaction mixture was quenched
with ice and the solid separated out was filtered and dried
to give a yellow crude product as granules (0.90g). The
crude product was taken in ethyl acetate (10mL) and
heated on warm water bath at 45–50ꢁC for 10min. The
solid was filtered to give yellow solid (0.350g, 31.2%).
The solid was further purified by column chromatogra-
phy using silica gel (100–230 mesh) and eluant 0–25%
ethyl acetate in hexane. The required fractions were
mixed and the solvents were removed on a rotatory evap-
orator to afford compound 18 as white crystalline solid
(0.200g, 17.8%) (99% purity in HPLC). Mp 160–
1H, J = 5.16Hz), 6.74 (s, 1H), 4.95 (m, 1H), 4.20 (s,
2H), 4.08 (m, 5H), 3.85 (m, 1H), 3.46 (t, 2H,
J = 5.61Hz,), 2.96 (t, 2H, J = 4.3Hz). IR (KBr): 3236,
1733, 1514, 1423, 1190 and 1056cmÀ1. ESI-MS: 438.1
(M+H)+, 476.2 (M+K)+.
6.16. 1-{3-[4-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-yl)-
3-fluoro-phenyl]-2-oxo-oxazolidin-5-yl-methyl}-N-methyl-
acetamide (20)
Compound 9b (2.24g, 5.25mmol) was treated with
methyl amine in methanol (12mL) and refluxed at 60–
65ꢁC for 24h. The completion of reaction was checked
by TLC using mobile phase CHCl3–MeOH (9:1). The
reaction mixture was diluted with water (50mL) and
the aqueous layer was extracted with chloroform
(2 · 25mL). The organic layers were combined, dried
over anhydrous Na2SO4 and the solvents were evapo-
rated on a rotatory evaporator under reduced pressure
to afford compound 9d which was further used in the
synthesis of title compound. Thus, compound 9d
(0.90g, 2.5mmol) in dry pyridine (1.9mL) was treated
with acetic anhydride (3.3mL) and mixture was stirred
at 25–28ꢁC for 1.5h. The completion of reaction was
checked by TLC using mobile phase CHCl3–MeOH
(9:1). The reaction mixture was poured into chilled
water (40mL) and extracted with ethyl acetate
(3 · 50mL). The organic layers were combined, dried
over anhydrous Na2SO4 and the solvents were evapo-
rated on a rotatory evaporator under reduced pressure
to afford compound 20 as a white solid (0.841g, 84%)
(98% purity in HPLC). Mp 114–116ꢁC. 1H NMR
(CDCl3): d 7.46 (dd, 1H, J = 2.49Hz, 11.58Hz), 7.26
(m, 1H), 7.13 (d, 1H, J = 5.16Hz), 7.05 (dd, 1H,
J = 2.19Hz, 6.72Hz), 6.95 (t, 1H, J = 9.09Hz), 6.82 (d,
1H, J = 5.13Hz), 4.95 (m, 1H), 4.45 (m, 1H), 4.21 (s,
2H), 4.07 (m, 2H), 3.80 (m, 1H), 3.47 (t, 2H,
J = 5.6Hz), 2.96 (t, 2H, J = 5.58Hz), 2.65 (m, 3H). IR
(KBr): 3093, 2923, 2815, 1741, 1641, 1517, 1431, 1328,
1228, 1132, 1014, 850, 815, 756cmÀ1. ESI-MS: 404.3
(M+H)+, 442 (M+K)+.
1
165ꢁC. H NMR (CDCl3): d 7.46 (dd, 1H, J = 2.34Hz,
11.76Hz), 7.13 (d, 1H, J = 5.1Hz), 7.01 (m, 2H), 6.96
(t, 1H, J = 8.73Hz), 6.82 (d, 1H, J = 5.16Hz), 6.49 (m,
2H), 4.75 (m,1H), 4.20 (s, 2H), 4.05 (t, 1H,
J = 8.97Hz), 3.85 (m, 1H), 3.53 (t, 2H, J = 3.93Hz),
2.96 (t, 2H, J = 5.61Hz). ESI-MS: 422.1 (M+H)+.
6.15. 3-[4-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-yl)-3-
fluoro-phenyl]-2-oxo-oxazolidin-5-yl-methyl}thiocarba-
mic acid methyl ester (19)
Compound 10 (0.5g, 1.44mmol) in freshly distilled
tetrahydrofuran (10mL) was treated with CS2
(0.16mL) and triethylamine (0.2mL). The reaction mix-
ture was stirred at 0–5ꢁC for 4h. The completion of
reaction was checked by TLC using mobile phase EtO-
Ac–hexane (8:2). Methyl iodide (0.1mL) was added to
the reaction mixture at 0ꢁC and maintained at 0ꢁC for
30min. The reaction mixture was warmed to 26–28ꢁC
by removing ice bath and stirred at this temperature
for 2h. The completion of reaction was checked by
TLC using mobile phase EtOAc–hexane (8:2). The reac-
tion mixture was diluted with water (20mL) and ex-
tracted with ethyl acetate (3 · 20mL). The organic
layers were combined, dried over anhydrous Na2SO4
and the solvents were evaporated on a rotatory evapora-
tor under reduced pressure to afford a brown oil (0.4g).
This crude product was chromatographed over silica gel
(100–230 mesh) using eluant 0–25% ethyl acetate in hex-
ane. The required fractions were pooled and the solvents
were evaporated to give the title compound as a white
solid (0.055g, 8.4%) (96% purity in HPLC). Mp 174–
6.17. 1-{3-[4-(6,7-Dihydro-4H-thieno[3,2-c]pyridin-5-yl)-
3-fluoro-phenyl]-2-oxo-5-oxazolidinyl methyl}1,3-dimeth-
yl thiourea (21)
Compound 9d (0.70g, 1.9mmol) was treated with tri-
ethyl amine (0.57mL) and MeNCS (0.388g, 5.3mmol)
in dichloromethane (10mL). The reaction mixture was
stirred at 26–28ꢁC for 2h. The reaction mixture was
diluted with water (40mL) and the aqueous layer
was extracted with dichloromethane (2 · 20mL). The
organic layers were combined, dried over anhydrous
Na2SO4 and the solvents were evaporated on a rotatory
evaporator to afford compound (21) as a white solid
1
(0.5g, 59%) (95% purity in HPLC). Mp 90–92ꢁC. H
NMR (CDCl3): d 7.47 (dd, 1H, J = 2.49Hz, 11.7Hz),
7.13 (d, 1H, J = 5.13Hz), 7.06 (m, 1H), 6.97 (t, 1H,
J = 9.12Hz), 6.82 (d, 1H, J = 5.13Hz), 4.87 (m, 1H),
4.20 (s, 2H), 4.02 (t, 1H, J = 9.0Hz), 3.99 (m, 1H),
3.75 (m, 1H), 3.48 (m, 3H), 3.18 (s, 2H), 2.98 (t, 2H,
J = 5.31Hz), 2.12 (s, 3H). IR (KBr): 3356, 1747, 1515,
1327, 1224, 1055, 750cmÀ1. ESI-MS: 435.2 (M+H)+.
1
176ꢁC. H NMR (CDCl3): d 7.47 (dd, 1H, J = 2.37Hz,
11.76Hz), 7.13 (d, 1H J = 5.13Hz), 7.07 (dd, 1H,
J = 2.19Hz, 6.63Hz), 6.97 (t, 1H, J = 9.09Hz), 6.82 (d,

4564
B. B. Lohray et al. / Bioorg. Med. Chem. 12 (2004) 4557–4564
5. (a) Hutchinson, D. Curr. Top. Med. Chem. 2003, 3, 1021,
Acknowledgements
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6. Lohray, B. B.; Lohray, V. B.; Srivastava, B. K.; Gupta, S.;
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Med. Chem. Lett. 2004, 14, 3139.
We thank Mr. Pankaj R. Patel, CMD and the manage-
ment of Zydus Group for encouragement and Mr. Sunil
Gupta, Mr. Manish Solanki, Mr. Vijay Takale of the
chemistry department of Zydus Research Centre for sci-
entific contributions, Mr. Binu Philip for preparation of
the manuscript and the analytical department for sup-
port.
7. Gandhi, N.; Srivastava, B. K.; Lohray, V. B.; Lohray,
B. B. Tetrahedron Lett. 2004, 45, 6269.
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