1752 Reddy et al.
Asian J. Chem.
were recorded in the solid state as KBr pellet using a Perkin-
Elmer FT-IR spectrophotometer. Mass spectrum was recorded
by using a Perkin-Elmer PE SCIEX-API 2000, equipped with
ESI source used online with a HPLC system after the ultraviolet
(UV) detector.
ature and stirred the reaction mass for about 30 min. This
solution is cooled to -20 ºC and added above prepared toluene
solution of 1-iodoethyl methyl carbonate in 30 min at -20 to -15
ºC. Further, stirred the reaction mass for 2h at -20 to -15 ºC to
complete the esterification reaction.After completion of reaction
by HPLC, poured the reaction mass into mixture of water (800
mL) and cyclohexane (400 mL) at 20-25 ºC to precipitate the
product. Adjusted pH of the slurry mass to 6.0 with aqueous
sodium bicarbonate solution and isolated the product by filtra-
tion. Wet material after washing with water dried at 45-50 ºC
to obtain 20.5 g (82%) of white coloured methyl analogue of
Synthesis of 1-(ethoxycarbonyloxy)ethyl (6R,7R)-7-
[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-
3-methoxymethyl-3-cephem-4-carboxylate (ethyl analogue
of cefpodoxime proxetil) (10): To a suspension of sodium
iodide (10.26 g, 68.4 mmol) in toluene (50 mL), added 18-
crown-6 (0.2 g, 2% w/w) followed by 1-chloroethyl ethyl
carbonate (10 g. 65.14 mmol) at room temperature. The susp-
ension was heated to 105-110 ºC and stirred for 2h to complete
the reaction. Cooled the reaction mass to 0-5 ºC and filtered
the unreacted sodium iodide and sodium chloride byproducts.
Toluene filtrate containing 1-iodoethyl ethyl carbonate is
washed with 1% aqueous sodium thiosulfate and used as such
in the further process.
cefpodoxime proxetil. HPLC purity : 96.72%; IR (KBr, νmax
,
cm-1): 3438, 3340, 2940, 2824, 1769, 1677, 1619, 1535, 1445,
1379, 1280, 1220, 1181, 1077, 1055, 787, 742, 691; 1H NMR
(DMSO-d6, 500 MHz): 1.491-1.502 (d, J = 5.5 Hz, 3H), 3.212
(s, 3H), 3.645-3.552 ( m, 2H), 3.746 (s, 3H), 3.833 (s, 3H),
4.178-4.122 (m, 2H), 5.197-5.170 (m, 1H), 5.837-5.790 (m,
1H), 6.893-6.739 (m, 1H), 7.204 (brs, 2H), 9.619-9.593 (m,
1H). MS m/z: 530.1 [(M+H)+].
To a solution of cefpodoxime acid (20 g, 46.83 mmol) in
N,N-dimethylacetamide (100 mL), added 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU,6.90 g, 45.39 mmol) at room temp-
erature and stirred the reaction mass for about 30 min. This
solution is cooled to -20 ºC and added above prepared toluene
solution of 1-iodoethyl ethyl carbonate in 30 min at -20 to -15
ºC. Further, stirred the reaction mass for 2 h at -20 to -15 ºC to
complete the esterification reaction. After completion of
reaction by HPLC, poured the reaction mass into mixture of
water (800 mL) and cyclohexane (400 mL) at 20-25 ºC to
precipitate the product. Adjusted pH of the slurry mass to 6.0
with aqueous Na2CO3 solution and isolated the product by
filtration. Wet material after washing with water dried at 45-50
ºC to obtain 20 g (79%) of white colored ethyl analogue of
cefpodoxime proxetil. HPLC purity: 99.15%; IR (KBr pellet,
cm-1): 3436, 3332, 3211, 2987, 2939, 2823, 1778, 1769, 1681,
1620, 1537, 1447, 1374, 1349, 1301, 1270, 1219, 1181, 1149,
Synthesis of 1-(isopropoxycarbonyloxy)ethyl (6R,7R)-
7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)aceta-
mido]-3-methoxymethyl-3-cephem-4-carboxylate (propyl
analogue of cefpodoxime proxetil) (18): To a suspension of
sodium iodide (21.7 g, 144.6 mmol) in toluene (250 mL),
added 18-crown-6 (0.5 g, 2% w/w) followed by 1-chloropropyl
isopropyl carbonate (25 g, 137.7 mmol) at room temperature.
The suspension was heated to 105-110 ºC and stirred for 2 h
to complete the reaction. Cooled the reaction mass to 0-5 ºC
and filtered the unreacted sodium iodide and sodium chloride
byproducts. Toluene filtrate containing 1-iodoethyl ethyl carbonate
is washed with 1% aqueous sodium thiosulfate and used as
such in the further process.
To a solution of cefpodoxime acid (50 g, 117 mmol) in N,N-
dimethylacetamide (250 mL), added 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU, 17.26 g, 113.5 mmol) at room temperature
and stirred the reaction mass for about 30 min. This solution
is cooled to -20 ºC and added above prepared toluene solution
of 1-iodopropyl isopropyl carbonate in 30 min at -20 to -15 ºC.
Further, stirred the reaction mass for 2h at -20 to -15 ºC to
complete the esterification reaction.After completion of reaction
by HPLC, poured the reaction mass into mixture of water (2000
mL) and cyclohexane (1000 mL) at 20-25 ºC to precipitate the
product. Adjusted pH of the slurry mass to 6.0 with aqueous
sodium bicarbonate solution and isolated the product by
filtration. Wet material after washing with water dried at 45-50
ºC to obtain 52 g (78%) of white colored propyl analogue of
1
1130, 1076, 1055, 786, 740, 691; H NMR (DMSO-d6, 500
MHz): 1.246-1.205 ( t, J = 7.0, 6.5 Hz, 3H), 1.504-1.488 (d, J
= 3.0 Hz, 3H), 3.207 (s, 3H) , 3.645-3.550 ( m, 2H), 3.833 (s,
3H), 4.195-4.144 (m, 4H), 5.198-5.171 (m, 1H), 5.847-5.793
(m,1H), 6.870-6.725 (m, 2H), 7.206 (brs, 2H), 9.620-9.593
(m, 1H). MS m/z: 544.1 [(M+H)+].
Synthesis of 1-(methoxycarbonyloxy)ethyl (6R,7R)-7-
[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-
3-methoxymethyl-3-cephem-4-carboxylate (methyl analogue
of cefpodoxime proxetil) (13): To a suspension of sodium
iodide (11.29 g, 75.26 mmol) in toluene (50 mL), added 18-
crown-6 (0.2 g, 2% w/w) followed by 1-chloroethyl methyl
carbonate (10 g. 71.68 mmol) at room temperature. The suspen-
sion was heated to 105-110 ºC and stirred for 2 h to complete
the reaction. Cooled the reaction mass to 0-5 ºC and filtered
the unreacted sodium iodide and sodium chloride byproducts.
Toluene filtrate containing 1-iodoethyl methyl carbonate is
washed with 1% aqueous sodium thiosulfate and used as such in
the further process.
cefpodoxime proxetil. HPLC purity: 96.27%; IR (KBr, νmax
,
cm-1): 3742, 3110, 2984, 2939, 2823, 1760, 1680, 1617, 1535,
1465, 1453, 1376, 1350, 1275, 1219, 1182, 1147, 1099, 1076,
788, 741, 692; 1H NMR (DMSO-d6, 500 MHz): 0.913-0.873
(t, J = 7.5, 12.5 Hz, 3H), 1.234-1.206 (d, J = 3.0 Hz, 3H), 1.776-
1.761 (m, 2H), 3.128 (s, 3H) , 3.323 (m, 2H), 3.587 (s, 3H),
4.104 (s, 2H), 4.752 (s, 2H), 5.170-5.142 (m, 1H), 5.782 (m,
1H), 6.749 (m, 2H), 7.178 (brs, 2H), 9.569-9.553 (d, J = 8.0 Hz,
1H). MS m/z: 558.1 [(M+H)+].
To a solution of cefpodoxime acid (20 g, 46.83 mmol) in
N,N-dimethylacetamide (100 mL), added 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU, 6.90 g, 45.39 mmol) at room temper-
Synthesis of 1-(Propoxycarbonyloxy)ethyl (6R,7R)-7-
[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-