K.S. Lee et al. / European Journal of Medicinal Chemistry 41 (2006) 1347–1351
1351
K2CO3 (0.07 g, 0.6 mmol) at r.t. The reaction mixture was
added dropwise to a solution of 13 (0.40 g, 0.5 mmol) in
DMF (3 ml) and stirred for 2 h. The reaction mixture was fil-
tered, and then the filtrate was treated with water and ethyl
acetate. The organic layer was dried over anhydrous Na2SO4,
concentrated in vacuo. The residue was purified by silica gel
column chromatography (n-hexane/ethyl acetate = 1:3) to give
Calcd. for C19H26N6NaO4S2 (M + Na)+ 489.1355, Found
489.1350. 1d: Yield 16%; H NMR (D2O) δ 4.11–4.17 (m,
3H), 3.90 (m, 1H), 3.73 (m, 1H), 3.57 (m, 1H), 3.24–3.38
(m, 4H), 2.65 (m, 1H), 1.58 (m, 1H), 1.20 (d, J = 6.4 Hz, 3H),
1.12 (d, J = 7.2 Hz, 3H); FABHRMS m/z Calcd. for
C19H27N6O5S2 (M + H)+ 483.1484, Found 483.1478.
1
1
the title compound 14. 14a: Yield 56%; H NMR (CDCl3) δ
4.2. Measurement of in vitro antibacterial activity
8.20 (d, J = 8.7 Hz, 4H), 7.93 (d, J = 5.7 Hz, 1H), 7.64 (d,
J = 8.7 Hz, 2H), 7.25 (d, J = 8.7 Hz, 2H), 6.11 (d,
J = 5.7 Hz, 1H), 5.11–5.50 (m, 4H), 3.99–4.30 (m, 4H),
3.25–3.35 (m, 6H), 2.50 (m, 1H), 1.89 (m, 1H), 1.36 (d,
The in vitro antibacterial activity is given as minimum inhi-
bitory concentration (MIC) in μg/ml as determined by an agar
dilution method using Mueller–Hinton Broth. The culture
grown at 37 °C for 18 h was diluted to 107 CFU/ml, and about
104 CFU/ml was spotted onto the agar plates containing serial
twofold dilutions of antibiotics with a MIC-2000 multipin
inoculator. The plates were incubated at 37 °C for 18 h.
1
J = 5.8 Hz, 3H), 1.24 (d, J = 6.9 Hz, 3H). 14b: Yield 71%; H
NMR (CDCl3) δ 8.19 (d, J = 8.7 Hz, 4H), 7.63 (d, J = 8.7 Hz,
2H), 7.50 (d, J = 8.7 Hz, 2H), 6.05 (s, 1H), 5.20–5.50 (m, 4H),
3.90–4.25 (m, 5H), 3.26–3.65 (m, 5H), 2.55 (m, 1H), 2.20 (m,
1H), 1.33 (d, J = 6.1 Hz, 3H), 1.22 (d, J = 7.2 Hz, 3H). 14c:
1
Yield 42%; H NMR (CDCl3) δ 8.20 (d, J = 8.6 Hz, 4H), 7.63
4.3. Determination of susceptibility to renal DHP-I
(d, J = 8.6 Hz, 2H), 7.55 (d, J = 8.6 Hz, 2H), 5.23–5.49 (m,
5H), 4.24–4.41 (m, 3H), 4.12 (m, 1H), 3.27–3.68 (m, 6H),
2.55 (m, 1H), 2.05 (m, 1H), 1.36, (d, J = 6.2 Hz, 3H), 1.24 (d,
J = 6.9 Hz, 3H). 14d: Yield 42%; 1H NMR (CDCl3) δ
8.21–8.26 (m, 4H), 7.66 (d, J = 8.6 Hz, 2H), 7.53 (d,
J = 8.6 Hz, 2H), 5.22–5.53 (m, 4H), 4.26–4.30 (m, 2H),
4.03–4.12 (m, 2H), 3.55–3.77 (m, 3H), 3.28–3.40 (m, 3H),
2.55 (m, 1H), 1.76 (m, 1H), 1.36 (d, J = 6.2 Hz, 3H), 1.30 (d,
J = 7.2 Hz, 3H).
Stability of carbapenems to hydrolysis by DHP-I was deter-
mined using partially purified porcine renal DHP-I. The carba-
penems (50 μg/ml solution in 50 mM MOPS at pH 7.0) was
challenged with DHP-I at 30 °C. Rates of hydrolysis were
monitored on a spectrophotometer at time course between 0,
0.5, 1, 2, and 4 h. The stability was expressed as relative half
life of hydrolysis, taking that of meropenem as 1.0.
Acknowledgements
4.1.12. General procedure for the synthesis of (1R,5S,6S)-2-
[(3S,5S)-5-(aminosubstituted pyrimidinyl-2-thiomethyl)
pyrrolidin-3-ylthio]-6-[(1R)-1-hydroxyethyl]-1-
We are grateful to the Ministry of Science and Technology
(MOST) of Korea for financial support.
methylcarbapen-2-em-3-carboxylic acids (1a–d)
The appropriate compound 14 (0.3 mmol) and 10% Pd/C
(0.25 g) were suspended in a mixed solution (10 ml) of THF/
EtOH (10:1), and the reaction mixture was hydrogenated at
50–60 psi at r.t. for 2 h. The mixture was filtered through celite
pad, and then the filtrate was washed with ethyl acetate. The
aqueous layer was lyophilized to give residue, which was pur-
ified on a Diaion HP-20 column by eluting with 3% THF in
water to give the title carbapenem 1 as a white amorphous
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1H), 6.23 (d, J = 6.1 Hz, 1H), 4.08–4.15 (m, 2H), 3.87–3.91
(m, 2H), 3.19–3.48 (m, 6H), 2.64 (m, 1H), 1.73 (m, 1H), 1.17
(d, J = 6.3 Hz, 3H), 1.09 (d, J = 7.1 Hz, 3H); FABHRMS m/z
Calcd. for C19H26N5O4S2 (M + H)+ 452.1426, Found
452.1424. 1b: Yield 17%; 1H NMR (D2O) δ 5.93 (s, 1H)
4.13–4.63 (m, 2H), 3.93–3.95 (m, 2H), 3.27–3.56 (m, 6H),
2.69 (m, 1H), 1.82 (m, 1H), 1.22 (d, J = 6.4 Hz, 3H), 1.14 (d,
J = 7.2 Hz, 3H); FABHRMS m/z Calcd. for C19H27N6O4S2 (M
1
+ H)+ 467.1535, Found 467.1526. 1c: Yield 13%; H NMR
(D2O) δ 5.47 (s, 1H), 4.12–4.19 (m, 2H), 3.90–3.92 (m, 2H),
3.25–3.41 (m, 5H), 2.67 (m, 1H), 1.79 (m, 1H), 1.22 (d,
J = 6.3 Hz, 3H), 1.44 (d, J = 7.1 Hz, 3H); FABHRMS m/z
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