B. Das et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4261–4267
4267
9. Brighty, K. E.; Castaldi, M. J. Synlett 1996, 1097.
10. Brighty, K. E. US 5164402.
11. Synthesis of compound 2: To a solution of (S)-N-[[3-[3-
fluoro-4-(N-4-tert-butoxycarbonyl-piperazin-1-yl)phenyl]-
(t, 1H, phenyl–H), 6.51 (d, 1H, furyl–H), 6.11 (t, 1H,
–NHCO–), 4.77 (m, 1H, oxazolidinone ring C5–H), 4.01
(t, 1H), 3.85–3.45 (m, 5H), 3.09 (m, 4H, piperazine–H),
2.72 (m, 4H, piperazine–H), 2.02 (s, 3H, –COCH3). MS
m/z (rel. int.): 462.1 [(M+H)+, 100%], 484 [(M+Na)+,
25%], 500.2 [(M+K)+, 20%]. HPLC purity: 98%. Com-
pound 39 (3.6 kg, 7.81 mol) was dissolved in abs ethanol
(53.8 L) by heating to 60 °C. The resulting solution was
cooled to 45 °C and ethanolic hydrochloride (1.48 L,
7.9 N) was added dropwise in 10 min. The mixture was
then cooled to 10 °C and stirred for 4 h and the
precipitate formed was filtered and washed with ethanol
and dried to obtain (S)-N-[[3-[3-fluoro-4-[N-4-(5-nitro-2-
furylmethyl)-piperazin-1-yl]phenyl]-2-oxo-5-oxazolidinyl]-
methyl]acetamide hydrochloride (7, 3.2 kg, yield from 39:
82%, yield from 28a: 55%). Mp: 207–209 °C. 1H NMR
(DMSO, 300 MHz): d 8.30 (t, 1H, –NHCO–), 7.75 (d,
J = 3.3 Hz, 1H, furyl–H), 7.52 (dd, 1H, phenyl–H), 7.3–
7.0 (m, 3H, phenyl–H, furyl–H), 4.70 (m, 1H, oxazolid-
inone ring C5–H), 4.63 (s, 2H), 4.08 (t, J = 8.8 Hz, 1H,
–CH2–), 3.73 (t, J = 7.5 Hz, 1H), 3.43 (br m, piperazine–
H merged with H2O in DMSO), 1.83 (s, 3H, –COCH3).
HPLC purity: 98%. Anal. Calcd for C21H25ClN5O6Æ0.5-
H2O: C, 50.76; H, 5.48; N, 14.09. Anal. Found: C, 50.83;
H, 5.17; N, 13.83.
2-oxo-5-oxazolidinyl]methyl]acetamide
(28a,
0.3 g,
0.69 mmol) in dichloromethane (4 mL) cooled to 5 °C,
trifluoroacetic acid (1 mL) was added and stirred for 2 h,
while allowing the reaction mixture to warm to rt. The
reaction mixture was evaporated in vacuo and the residue
dissolved in DMF (5 mL). To the resulting mixture,
potassium carbonate (0.4 g, 2.89 mmol) added and stirred
at rt for 10 min. Then, 5-chloromethyl-2-furaldehyde19
(0.3 g, 2.1 mmol) was added and stirred for 1 h. The
reaction mixture was filtered over Celite and the filtrate
evaporated in vacuo. The residue was purified by column
chromatography (1–5% methanol in chloroform) to obtain
(S)-N-[[3-[3-fluoro-4-[N-4-(5-formyl-2-furylmethyl)-pipera-
zin-1-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (2,
0.1 g, yield 32%) as a sticky solid. 1H NMR (CDCl3,
300 MHz): d 9.62 (s, 1H, –CHO), 7.41 (dd, J = 2.2 Hz,
14.3 Hz, 1H, phenyl-H), 7.21 (d, J = 3.4 Hz, 1H, furyl-H),
7.06 (app d, J = 8.3 Hz, 1H, phenyl-H), 6.92 (t, J = 9.0 Hz,
1H, phenyl-H), 6.48 (d, J = 3.3 Hz, 1H, furyl-H), 6.08 (t,
1H, –NHCO–), 4.75 (m, 1H, oxazolidinone ring C5–H),
4.0 (t, J = 9.0 Hz, 1H), 3.80–3.55 (m, 6 H), 3.10 (m, 4H,
piperazine–H), 2.72 (m, 4H, piperazine–H), 2.01 (s, 3H,
–COCH3). HPLC purity: 90.69%.
13. Yamada, H.; Munesada, K.; Taniguchi, M. WO 95/21706.
14. Mehta, A.; Arora, S. K.; Das, B.; Ray, A.; Rudra, S.;
Rattan, A. WO 03/007870.
15. Mehta, A.; Arora, S. K.; Das, B.; Ray, A.; Rudra, S.;
Rattan, A. WO 02/06278.
16. Rattan, A. Drugs Future 2003, 28, 1070.
12. Synthesis of compound 7: (S)-N-[[3-[3-Fluoro-4-(N-4-tert-
butoxycarbonyl-piperazin-1-yl)phenyl]-2-oxo-5-oxa-zolid-
inyl]-methyl]acetamide (28a, 3.65 kg, 8.37 mol) was dis-
solved in dichloromethane (30.86 L) and cooled to 5 °C.
To it trifluoroacetic acid (6.17 L) added dropwise and
stirred for 14 h allowing the reaction mixture to warm to
rt. The reaction mixture was evaporated in vacuo and the
residue dissolved in tetrahydrofuran (58 L) followed by
17. The effect of RBx 7644 on whole cell macromolecular
synthesis in anaerobes was examined recently. In each case
a specific inhibitor with a known mechanism of action was
included as a positive control (Trovafloxacin and Metro-
nidazole for DNA and linezolid for protein). The results
indicate that the compound is inhibitory towards protein
synthesis but no effect was observed towards DNA
synthesis with 1X and 4XMIC upto 6 h. However, the
effect of RBx 7644 on SOS response and ability to act as a
substrate for nitroreductase enzymes from Gram-negative
bacteria was not investigated.
18. RBx 7644 (7) had MIC of 2 lg/mL when tested against
Acr AB pump deficient and Tol C pump deficient strains,
but the MIC was P16 lg/mL when tested against wild
type Escherichia coli strains. It is possible that the excellent
activity of RBx 7644 against anaerobes is because it is not
effluxed out.
˚
addition of molecular sieves 4 A (4.2 kg). To the resulting
mixture 5-nitro-2-furaldehyde (1.5 kg, 10.77 mol) was
added followed by sodium triacetoxyborohydride
(5.32 kg, 25.1 mol) and stirred for 14 h. The reaction
mixture was filtered over Celite and filtrate evaporated in
vacuo. The residue was dissolved in ethylacetate (85.6 L)
and washed with satd sodium bicarbonate solution (36 L)
and water (36 L). The organic layer was dried over anhyd
sodium sulfate (3 kg) and evaporated in vacuo. The crude
residue was purified by column chromatography (1–3%
methanol in ethylacetate) to obtain (S)-N-[[3-[3-fluoro-4-
[N-4-(5-nitro-2-furylmethyl)-piperazin-1-yl]phenyl]-2-oxo-
5-oxa-zolidinyl]methyl]acetamide (39, 2.6 kg, yield 67%).
1
Mp: 136 °C. H NMR (CDCl3): d 7.42 (dd, 1H, phenyl–
H), 7.29 (m, 2H, furyl–H), 7.07 (d, 1H, phenyl–H), 6.92
19. Chakraborty, T. K.; Tapadar, S.; Kumar, S. K. Tetrahe-
dron Lett. 2002, 43, 1317.