SAR of (Lactamylvinyl)cephalosporins
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 9 1869
150 °C; 1H-NMR (DMSO-d6) δ 1.48 (s, 9 H), 2.50 (m, 1 H), 2.76
(m, 1 H), 3.64 (m, 1 H), 4.04 (m, 1 H), 5.90 (m, 1 H), 7.18 (d,
2 H, J ) 8 Hz), 7.40 (d, 2 H, J ) 8 Hz), 7.7-8.0 (m, 15 H); IR
(KBr) 1756, 1690 cm-1. Anal. (C33H33BrNO4P) C, H, N.
(E)-(2R,6R,7R)-7-[(ter t-Bu t oxyca r b on yl)a m in o]-3-[[1-
[4-[(ter t-bu toxyca r bon yl)oxy]p h en yl]-2-oxop yr r olid in -3-
yliden e]m eth yl]-8-oxo-5-th ia-1-azabicyclo[4.2.0]oct-3-en e-
2-ca r boxylic Acid Ben zh yd r yl Ester (6j). A mixture of
12.11 g (24.49 mmol) of 1615 and 17.17 g (27.77 mmol) of 5j in
250 mL of 1,2-dichloroethane:1,2-epoxybutane (1:1) was re-
fluxed for 3.5 h. The solution was evaporated and the residue
purified by silica gel column chromatography (CH2Cl2:EtOAc
) 9:1) affording 9.81 g (53%) of 6j: 1H-NMR (CDCl3) δ 1.46
(s, 9 H), 1.57 (s, 9 H), 2.83 (m, 2 H), 3.61 (t, 2 H), 5.26 (d, 1 H,
J ) 5 Hz), 5.28 (br s, 2 H), 5.33 (br m, 1 H), 6.61 (s, 1 H), 6.87
(s, 1 H), 6.99 (s, 1 H), 7.20 (m, 13 H), 7.73 (d, 2 H, J ) 8 Hz);
IR (KBr) 1781, 1750, 1691 cm-1; MS (ISP) 754.5 (M + H)+.
(E)-(5R,6R,7R)- a n d -(5S,6R,7R)-7-[(ter t-Bu toxyca r bo-
n yl)a m in o]-3-[[1-[4-[(ter t-bu toxyca r bon yl)oxy]p h en yl]-2-
o x o p y r r o lid in -3-y lid e n e ]m e t h y l]-5,8-d io x o -5-t h ia -1-
a za bicyclo[4.2.0]oct-2-en e-2-ca r boxylic Acid Ben zh yd r yl
Ester (7j). A solution of 3.27 g (15 mmol) of 80-90%
m-chloroperbenzoic acid in 60 mL of CH2Cl2 was added at 4
°C to a solution of 11.3 g (15 mmol) of 6j in 120 mL of CH2Cl2.
After 1 h, the reaction mixture was washed successively with
cold 10% aqueous Na2S2O3, 5% aqueous NaHCO3, and water.
After drying the organic layer over MgSO4, the solvent was
removed and the residue was purified by flash silica gel column
chromatography (EtOAc:hexane ) 3:2) affording 10.59 g
(91.7%) of 7j as a yellow foam: 1H-NMR (CDCl3, 2:1 mixture
of diastereomers) δ 1.47 (s, 9 H), 1.57 (s, 9 H), 2.30-3.0 (m, 2
H), 3.16 (d, major isomer, 1 H, J ) 18 Hz), 3.4-3.8 (m, 3 H),
3.94 (d, major isomer, 1 H, J ) 18 Hz), 4.50 (d, minor isomer,
1 H, J ) 18 Hz), 4.47 (br d, major isomer, 1 H, J ) 5 Hz), 4.58
(d, minor isomer, 1 H, J ) 5 Hz), 5.45 (m, minor isomer, 2 H),
5.81 (m, major isomer, 2 H), 7.03 (s, minor isomer, 1 H), 7.05
(s, major isomer, 1 H), 7.1-7.5 (m, 12 H), 7.71 (m, 3 H); IR
(KBr) 1799, 1757, 1723 cm-1; MS (ISP) 770.5 (M + H)+.
(E)-(6R,7R)-7-[(ter t-Bu t oxyca r b on yl)a m in o]-3-[[1-[4-
[(ter t-b u t oxyca r b on yl)oxy]p h en yl]-2-oxop yr r olid in -3-
yliden e]m eth yl]-8-oxo-5-th ia-1-azabicyclo[4.2.0]oct-2-en e-
2-ca r boxylic Acid Ben zh yd r yl Ester (8j). A solution of 5.1
mL of phosphorus tribromide in 15 mL of CH2Cl2 was added
at -30 °C to a solution of 10.45 g (13.57 mmol) of 7j in 120
mL of CH2Cl2, 12.1 mL of N-methylacetamide, and 12.8 mL
of DMF. The mixture was stirred for 1 h at -30 °C and then
poured into a stirred solution of 20 g of NaHCO3 in 250 mL of
ice-water. The organic phase was separated, washed with
water, dried over MgSO4, and concentrated in vacuo. The
residue was stirred with hexane and the solid material
collected by filtration to give 8j (9.85 g, 96.3%): 1H-NMR
(CDCl3) δ 1.48 (s, 9 H), 1.57 (s, 9 H), 2.36 (m, 1 H), 2.69 (m, 1
H), 3.44 (m, 1 H), 3.56 (s, 2 H), 3.66 (m, 1 H), 5.02 (d, 1 H, J
) 5 Hz), 5.35 (br d, 1 H), 5.69 (m, 1 H), 7.03 (s, 1 H), 7.1-7.4
(m, 12 H), 7.71 (m, 2 H); IR (KBr) 1787, 1758, 1722 cm-1; MS
(ISP) 754.5 (M + H+).
dissolved in 150 mL of EtOAc and washed twice with 25 mL
of water. The organic phase was concentrated to about one-
third of its volume, upon which the product started to
crystallize. It was collected by filtration, washed with EtOAc
and Et2O, and dried to yield 1.12 g of the trityl-protected
product as yellow crystals: 1H-NMR (DMSO-d6) δ 3.16 (m, 2
H), 3.82 (t, 2 H), 3.98 (br s, 2 H), 5.30 (d, 1 H, J ) 5 Hz), 6.03
(dd, 2 H, J ) 5, 7 Hz), 6.62 (s, 1 H), 6.78 (d, 2 H, J ) 8 Hz),
7.32 (m, 18 H), 7.56 (d, 2 H), 9.43 (s, 1 H), 9.96 (d, 1 H, J ) 7
Hz), 13.88 (br s, 1 H); IR (KBr) 1784, 1679 cm-1; MS (ISP)
799.4 (M + H)+.
This material (1.1 g, 1.38 mmol) was added portionwise to
10 mL of ice-cold trifluoroacetic acid, the temperature being
kept below 5 °C. Triethylsilane (0.4 mL) was added dropwise
during 20 min resulting in a beige suspension which was
poured into 100 mL of Et2O. This mixture was stirred for 30
min, and the solid was collected by filtration and crystallized
from 15 mL of 90% aqueous acetone (552.5 mg of 10j, 72%,
yellow crystals): 1H-NMR (DMSO-d6) δ 3.12 (m, 2 H), 3.82 (t,
2 H), 3.92 (br s, 2 H), 5.20 (d, 1 H, J ) 5 Hz), 5.83 (dd, 2 H, J
) 5, 7 Hz), 6.67 (s, 1 H), 6.78 (d, 2 H, J ) 8 Hz), 7.14 (s, 2 H),
7.35 (s, 1 H, d, 2 H), 7.55 (d, 2 H, J ) 8 Hz), 9.42 (s, 1 H), 9.53
(d, 1 H, J ) 7 Hz), 11.50 (s, 1 H), 14.84 (br s, 1 H); IR (KBr)
1774, 1667 cm-1
(C23H20N6O7S2) C, H, N, S.
; MS (ISP) 557.4 (M +
H)+. Anal.
Compounds 10a -i,k -q and 19 were obtained using meth-
ods similar to those used for 10j. Compounds 11-15 were
synthesized by reacting 9a with the appropriate (aminothi-
azolyl)(alkoxyimino)acetic acid benzothiazole thioesters 18a -
e17 in DMF at room temperature. The mixtures obtained were
concentrated in vacuo and triturated with 50 mL of EtOAc:
water (1:1). The solid materials were collected by filtration
to yield 11-15. The sodium salts 11, 12, and 19 were obtained
by suspending the corresponding acids in water/acetone and
adjusting the pH to 6.5-7 with 1 N NaOH. Purification was
performed by reversed phase chromatography, using water
with a gradient of acetonitrile as eluent.
1-P h en yla zetid in e-2,3-d ion e (22). Through a solution of
800 mg (5 mmol) of 2120 in 50 mL of ethyl acetate, cooled to
-70 °C, was passed ozone for 15 min. Then 0.5 mL of dimethyl
sulfide was added, and the solution was stirred for 1.5 h at
-70 °C. The temperature was raised to 0 °C, and 25 mL of
water was added. After 5 min the organic phase was sepa-
rated, extracted with 50 mL Na2S2O3 and FeSO4 solutions, and
then dried over MgSO4. The solvent was evaporated and the
residue purified by silica gel column chromatography (benzene)
affording 114 mg (14.5%) of 22 as colorless crystals: mp 115-
117°C; 1H-NMR (CDCl3) δ 4.34 (s, NCH2, 2 H), 7.27 (m, 1 H),
7.50 (m, 4 H); IR (KBr) 1822, 1757 cm-1; MS (EI) 161 (M).
Anal. (C9H7NO2) C, H, N.
Wittig Rea ction Lea d in g to 23 a n d 24. A suspension of
114 mg (0.708 mmol) of 22 in 15 mL of 1,2-epoxybutane and
695 mg (0.80 mmol) of 2919 was stirred at room temperature
for 1.5 h. The dark-brown solution was then evaporated and
the product mixture separated by silica gel column chroma-
tography (hexane:EtOAc ) 4:1, 3:1, 2:1).
(Z)-(6R,7R)-7-[(ter t-Bu t oxyca r b on yl)a m in o]-8-oxo-3-
[(2-oxo-1-p h e n yla ze t id in -3-ylid e n e )m e t h yl]-5-t h ia -1-
a za bicyclo[4.2.0]oct-2-en e-2-ca r boxylic Acid Ben zh yd r yl
Ester (23). 23 eluted first: yield, 140 mg (32%) of yellow
crystals; 1H-NMR (CDCl3) δ 1.47 (s, 9 H), 3.78 (d, 1 H, J )
17.5 Hz), 3.99 (dd, 2 H), 4.44 (d, 1 H, J ) 17.5 Hz), 5.03 (d, 1
H, J ) 5 Hz), 5.26 (br d, 1 H), 5.71 (br q, 1 H), 6.75 (s, 1 H),
6.99 (s, 1 H), 7.15 (m, 1 H), 7.37 (m, 14 H); IR (KBr) 1788,
1727 cm-1; MS (ISP) 624.4 (M + H)+.
(E)-(6R,7R)-7-Am in o-3-[[1-(4-h yd r oxyp h en yl)-2-oxo-
p yr r olid in -3-ylid en e]m eth yl]-8-oxo-5-th ia -1-a za bicyclo-
[4.2.0]oct-2-en e-2-ca r boxylic Acid Tr iflu or oa ceta te (9j).
Trifluoroacetic acid (50 mL) was added at 0 °C to a solution of
9.78 g (12.97 mmol) of 8j in 100 mL of CH2Cl2 and 10 mL of
anisole. After 2 h at room temperature, the mixture was
concentrated and poured into Et2O. The resulting solid was
collected by filtration and washed with Et2O and hexane
affording 9j (5.12 g, 96.2%): 1H-NMR (DMSO-d6) δ 3.13 (m, 2
H), 3.82 (t, 2 H), 3.95 (br s, 2 H), 4.98 (d, 1 H, J ) 5 Hz), 5.11
(d, 2 H, J ) 5 Hz), 6.77 (d, 2 H, J ) 8 Hz), 7.35 (s, 1 H), 7.55
The second eluate (163 mg) consisted of two products that
were separated by another silica gel column chromatography
(CH2Cl2:EtOAc ) 96:4) affording 82 mg (18%) of (E)-(6R,7R)-
7-[(tert-butoxycarbonyl)amino]-8-oxo-3-[(2-oxo-1-phenylazeti-
din-3-ylidene)methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid benzhydryl ester (24) as a yellow foam: 1H-
NMR (CDCl3) δ 1.47 (s, 9 H), 3.57 (dd, 2 H, J ) 17.5 Hz), 4.26
(d, 1 H, J ) 9 Hz), 4.37 (d, 1 H, J ) 9 Hz), 5.01 (d, 1 H, J )
5 Hz), 5.34 (br d, 1 H), 5.73 (br q, 1 H), 7.01 (s, 1 H), 7.13 (m,
(d, 2 H, J ) 8 Hz), 9.44 (s, 1 H); IR (KBr) 1778, 1676 cm-1
;
MS (ISP) 388.4 (M + H)+.
(6R,7R)-7-[(Z)-[2-(2-Am in oth ia zol-4-yl)-2-(h yd r oxyim i-
n o)a cetyl]a m in o]-3-[(E)-[1-(4-h yd r oxyp h en yl)-2-oxop yr -
r olidin -3-ylidin e]m eth yl]-8-oxo-5-th ia-1-azabicyclo[4.2.0]-
oct-2-en e-2-ca r boxylic Acid (10j). The activated ester 1716
(1.4 g, 2.56 mmol) was added to a stirred suspension of 820
mg (2 mmol) of 9j in 30 mL of DMF. After 20 h at room
temperature, the mixture was concentrated and the residue
1 H), 7.34 (m, 13 H), 7.46 (m, 2 H); IR (KBr) 1790, 1727 cm-1
;
MS (ISP) 624.5 (M + H)+.