C.-H. Oh et al. / European Journal of Medicinal Chemistry 37 (2002) 743ꢀ
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3.37. p-Nitrobenzyl (1R,5S,6S)-6-[(1R)-
hydroxyethyl]-3-[5-(4-ethoxycarbonyllthiazole-2-yl)-1-
(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio]-1-
methylcarbapen-2-em-3-carboxylate (27a)
HRMS (FAB): Calc. for C18H24N3O5S2: 426.1157.
Found [Mꢄ
H]ꢄ: 426.1162%.
Compound 28c: Yield: 41.2%. UV: lmax 298 nm. M.p.
115ꢀ
123 8C (dec.). 1H-NMR (D2O): d 1.08 (d, 3H, Jꢁ
7.1 Hz), 1.22 (d, 3H, Jꢁ 6.0 Hz), 2.23 (m, 1H), 2.89 (m,
1H), 3.11 (bs, 2H), 3.53 (dd, 1H, Jꢁ 6.0 Hz), 3.85 (m,
1H), 4.01 (bs, 2H), 4.55 (m, 1H), 5.15 (t, 1H, Jꢁ 8.1
Hz), 8.11 (s, 1H). IR (KBr): 3480 (OH), 3260 (NH),
1670 (CÄ HRMS (FAB): Calc. for
O) cmꢂ1
C18H23N4O5S2: 439.1110. Found [Mꢄ
H]ꢄ: 439.1104%.
Compound 28d: Yield: 37.9%. UV: lmax 298 nm. M.p.
132ꢀ
142 8C (dec.). 1H-NMR (D2O): d 1.05 (d, 3H, Jꢁ
6.7 Hz), 1.15 (d, 3H, Jꢁ 6.0 Hz), 1.96 (bs, 1H), 2.79 (m,
1H), 2.98 (bs, 1H), 3.22ꢀ3.29 (bs, 2H), 3.57 (q, 1H, Jꢁ
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A solution of p-nitrobenzyl (1R,5S,6S)-3-(diphenyl-
phosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarba-
pen-2-em-3-carboxylate (26, 0.54 g, 0.91 mmol) in
CH3CN (50 mL) was cooled to 0 8C under N2. To
this solution was added diisopropylethylamine (0.13 g,
1.0 mmol) and a solution of the mercapto compound
25a (0.40 g, 0.91 mmol) in CH3CN (10 mL). After
stirring for 2 h, the mixture was diluted with EtOAc,
washed with 10% NaHCO3, brine, and dried over
anhydrous MgSO4. Evaporation in vacuo gave a
foam, which was purified by silica gel chromatography
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5.9 Hz), 3.82 (m, 1H), 4.11 (m, 2H), 4.23 (s, 2H), 4.44
(bs, 1H), 7.59 (s, 1H). IR (KBr): 3540 (OH, NH2), 3270
1
to give 27a as a yellow foam solid. Yield: 79.3%. H-
(NH), 1705, 1665 (CÄ
C18H25N4O4S2: 425.1317. Found [Mꢄ
Compound 28e: Yield: 34.5%. UV: lmax 296 nm. M.p.
133ꢀ
134 8C (dec.). 1H-NMR (D2O): d 1.07 (d, 3H, Jꢁ
6.7 Hz), 1.18 (d, 3H, Jꢁ 6.0 Hz), 1.90 (m, 1H), 2.79ꢀ
2.88 (m, 1H), 3.01 (s, 3H), 3.13 (dd, 1H, Jꢁ 4.1 Hz),
3.32ꢀ3.38 (bs, 2H), 3.57 (q, 1H, Jꢁ 5.9 Hz), 3.85 (m,
1H), 4.11ꢀ4.20 (m, 2H), 4.23 (s, 2H), 4.48 (bs, 1H), 7.51
(s, 1H). IR (KBr): 3510 (OH), 3300 (NH), 1710, 1690
(CÄO), 1220 (SÄ
O) cmꢂ1. HRMS (FAB): Calc. for
C19H27N4O6S3: 503.1093. Found [Mꢄ
H]ꢄ: 503.1099%.
Compound 28f: Yield: 23.8%. UV: lmax 298 nm. M.p.
156ꢀ
160 8C (dec.). 1H-NMR (D2O): d 1.09 (d, 3H, Jꢁ
6.5 Hz), 1.16 (d, 3H, Jꢁ 6.0 Hz), 2.21 (m, 1H), 2.98 (m,
1H), 3.57ꢀ3.76 (m, 3H), 3.82 (m, 2H), 4.09ꢀ4.23 (m,
3H), 4.44 (bs, 1H), 5.10 (t, 1H, Jꢁ 6.6 Hz), 7.49 (s, 1H).
IR (KBr): 3510 (OH), 3270 (NH), 2210 (CÄN), 1710,
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O) cmꢂ1. HRMS (FAB): Calc. for
NMR (CDCl3): d 1.25 (d, 3H, Jꢁ
(dd, 6H, Jꢁ 6.6 Hz), 1.98 (bs, 1H), 2.14 (m, 1H), 2.46
(m, 1H), 2.95 (m, 2H), 3.45 (d, 2H, Jꢁ 9.6 Hz), 4.01ꢀ
4.18 (m, 4H), 4.43 (bs, 1H), 5.11ꢀ5.55 (m, 2H), 7.09 (s,
1H), 7.23 (d, 2H, Jꢁ 7.3 Hz), 7.45 (d, 2H, Jꢁ 7.3 Hz),
8.21 (d, 4H, Jꢁ 7.3 Hz). IR (KBr): 3410 (OH), 3230
(NH), 1720, 1705, 1660 (CÄ
O) cmꢂ1
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6.6 Hz), 1.31ꢀ
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1.37
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H]ꢄ: 425.1316%.
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3.38. (1R,5S,6S)-6-[(1R)-Hydroxyethyl]-3-[5-(4-
ethoxycarbonylthiazole-2-yl)pyrrolidin-3-ylthio]-1-
methylcarbapen-2-em-3-carboxylic acid (28a)
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Compound 27a (0.24 g, 0.06 mmol) and 0.1 g of Pdꢀ
/C
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(10%) were dissolved in THFꢀphosphate buffer (pH 7)
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(1:1, 10 mL each). The mixture was hydrogenated at 50
psi for 1 h. The solution was filtered through celite and
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1680 (CÄ
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O) cmꢂ1
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HRMS (FAB): Calc. for
washed with water (2ꢃ/10 mL). The combined filtrate
C19H23N4O4S2: 435.1161. Found [Mꢄ
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H]ꢄ: 435.1154%.
1
Compound 28g: Yield: 40.1%. UV: lmax 298 nm. H-
was washed with ethyl ether (2ꢃ/20 mL) and lyophilised
to give a yellow powder which was purified on a Diaion
HP-20 column, eluting with 2% THF in water. Fractions
having UV absorption at 298 nm were collected and
lyophilised again to give the title compound 27a as a
white powder. Yield: 47.9%. UV: lmax 298 nm. M.p.
NMR (D2O): d 1.08 (d, 3H, Jꢁ
Jꢁ 7.0 Hz), 2.16 (m, 1H), 2.93 (m, 1H), 3.23ꢀ
2H), 3.65 (m, 1H), 3.85 (s, 2H), 4.01 (bs, 1H), 4.25 (bs,
2H), 4.55 (bs, 1H), 5.01 (t, 1H, Jꢁ 8.3 Hz), 7.38 (s, 1H).
IR (KBr): 3480 (OH), 3260 (NH), 1730, 1690, 1670 (CÄ
O) cmꢂ1. HRMS (FAB): Calc. for C19H25N4O5S2:
453.1266. Found [Mꢄ
H]ꢄ: 453.1278%.
Compound 28h: Yield: 32.9%. UV: lmax 298 nm. M.p.
155ꢀ
159 8C (dec.). 1H-NMR (D2O): d 1.16 (d, 3H, Jꢁ
7.2 Hz), 1.21 (d, 3H, Jꢁ 6.4 Hz), 2.14 (m, 1H), 2.86 (m,
1H), 2.96 (t, 2H, Jꢁ 6.4 Hz), 3.21ꢀ3.39 (m, 3H), 3.59
(dd, 1H, Jꢁ 5.4 and 5.8 Hz), 3.76 (t, 2H, Jꢁ 6.4 Hz),
3.90 (bs, 1H), 4.10 (m, 1H), 4.43 (m, 1H), 4.95 (t, 1H,
Jꢁ 6.6 Hz), 7.24 (s, 1H). IR (KBr): 3500 (OH), 3320
(NH), 1710, 1690 (CÄ
O) cmꢂ1. HRMS (FAB): Calc. for
C19H26N3O5S2: 440.1314. Found [Mꢄ
H]ꢄ: 440.1315%.
Compound 28i: Yield: 29.8%. UV: lmax 298 nm. M.p.
127ꢀ
130 8C (dec.). 1H-NMR (D2O): d 1.12 (d, 3H, Jꢁ
7.2 Hz), 1.21 (d, 3H, Jꢁ 6.4 Hz), 2.24 (s, 3H), 2.46 (m,
1H), 2.66 (m, 1H), 3.11ꢀ3.39 (m, 3H), 3.59 (dd, 1H, Jꢁ
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7.8 Hz), 1.22 (d, 3H,
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3.43 (m,
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145ꢀ
6.5 Hz), 1.15 (d, 3H, Jꢁ
Hz), 2.04 (bs, 1H), 2.86 (m, 1H), 3.01ꢀ
3.53 (bs, 2H), 3.70 (bs, 1H), 4.10 (m, 2H), 4.15 (q, 2H,
Jꢁ 6.1 Hz), 4.51 (bs, 1H), 7.11 (s, 1H). IR (KBr): 3470
(OH), 3230 (NH), 1710, 1690, 1660 (CÄ
O) cmꢂ1
HRMS (FAB): Calc. for C20H26N3O6S2: 468.1263.
Found [Mꢄ
H]ꢄ: 468.1272%.
Compound 28b: Yield: 35.0%. UV: lmax 298. M.p.
145ꢀ
151 8C (dec.). 1H-NMR (D2O): d 1.16 (d, 3H, Jꢁ
6.4 Hz), 1.21 (d, 3H, Jꢁ 6.4 Hz), 2.14 (m, 1H), 2.86 (m,
1H), 2.75 (m, 2H), 3.01ꢀ3.13 (bs, 2H), 3.53 (dd, 1H, Jꢁ
5.4 and 5.8 Hz), 3.97 (bs, 1H), 4.10 (m, 2H), 4.43 (m,
1H), 4.91 (t, 1H, Jꢁ 6.6 Hz), 7.11 (s, 1H). IR (KBr):
3510 (OH), 3300 (NH), 2990, 1710, 1690 (CÄ
O) cmꢂ1
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150 8C (dec.). 1H-NMR (D2O): d 1.06 (d, 3H, Jꢁ
5.7 Hz), 1.29 (t, 3H, Jꢁ 6.1
3.13 (bs, 2H),
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