Field of the Invention
The present invention provides a process for the preparation of 7-amino-3-(4-
methylthiazol-5-yl) vinyl-3-cephem-4-carboxyIic acid [7-ATCA]; an intermediate used in
the synthesis of cefditoren pivoxil. Further, this invention provides an improved process for
preparing crystalline cefditoren pivoxil employing the 7-amino-3-(4-methylthiazol-5-yl)
vinyl-3-cephem-4-carboxylic acid [7-ATCA] as an intermediate.
Background of the Invention
Cefditoren is disclosed first in the patent US 4,839,350 for its wide antimicrobial
spectrum and chemically known as (+)-(6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-
methoxyiminoacetamido]-3-[(Z-)-2-(4-methylthiazol-5-yl)ethenyl]-8-oxo-5-thia-l-
azabicyclo[4.2.0]oct-2-e- ne-2-carboxylic acid having the formula as mentioned below,

Cefditoren pivoxil is a prodrug of cefditoren, in which a pivaloyloxymethyl group has
been attached by an ester bond to a carboxylic acid at the 4-position for improved oral
absorption of cefditoren.
The patent US 5,233,035 assigned to Yamanouchi Pharmaceutical Company Limited,
describes the preparation of p-methoxybenzyl-7-(phenylacetamido-3-(4-methylthiazole-
5-yl)-vinyl-3-cephem-4-carboxylate involving the steps of: reacting p-methoxybenzyl-7-
phenylacetamido-3-chloromethyl-3-cephem-4-carboxylate with triphenylphosphine in the
presence of sodium iodide in dimethyl formamide; followed by the reaction of the
obtained product with 5-formyl-4-methylthiazole in methylene chloride. The obtained p-
methoxybenzyl-7-(phenylacetamido-3-(4-methylthiazole-5-yl)-vinyl-3-cephem-4-
carboxylate was then purified by silica gel column chromatography eluted with
chloroform. This process is associated with problems such as poor yield and quality with
high percentage of E isomer content.
The patent application WO 20053141 assigned to Orchid Pharmaceutical Chemicals
Limited, India describes the preparation of Wittig salt by reacting p-methoxybenzyl-7-
phenylacetamido-3-chloromethyl-3-cephem-4-carboxylate with triphenyl phosphine in
the presence of sodium iodide in tetrahedron and water.
The patent application US 20040087786 assigned to Orchid Pharmaceutical Company
Limited, India describes the preparation of Wittig salt by reacting p-methoxybenzyl-7-
phenylacetamido-3-chloromethyl-3-cephem-4-carboxylate with triphenyl phosphine in
the presence of sodium iodide in dichloromethane and water.
The patent US 6,288,233 discloses a process for the preparation of cefditoren by
condensing Wittig salt of cephem moiety with thiazole-5-carbaldehyde in a mixture of
chlorinated hydrocarbon and lower alkanol medium.
Summary of the Invention
The primary objective of the present invention is to provide a process for the preparation
of 7-amino-3-(4-methylthiazol-5-yl)-vinyl-3-cephem-4-carboxylic acid having a purity of
more than 99.0%.
An aspect of the invention is to provide a process for the preparation of p-
methoxybenzyl-7-amino-3(Z)-(4-methylthiazol-5-yl)-3-cephem-4-carboxylate having
purity more than 98.0%.
Another aspect of the invention is to provide a process for the depletion of p-
methoxybenzyl-7-(4-phenylacetamido-3-[(E)-2-(4-methyl-thiazole-5-yl)-vinyl]-3-cephem
-4-carboxylate in Z/E mixtures of p-methoxybenzyl-7-(4-phenylacetamido-3-[2-(4-
methyl-thiazole-5-yl)vinyl]-3-cephem-4-carboxylate.
A further aspect of the invention is to provide an improved process for crystallization of
cefditoren pivoxil having purity more than 98.5%.
Detailed description of the invention
The present invention provides an improved process for the preparation of cefditoren
pivoxil including the steps as depicted below,

Wherein the improvement of said process is characterized as the following:
(i) reacting p-methoxybenzyl-7-phenylacetamido-3-chloromethyl-3-cephem
carboxylate (1) with triphenylphosphine in the presence of a mixture of
sodium bromide and sodium iodide in dichloromethane and water to obtain p-
methoxybenzyl-7-(phenylacetamido)-3-
[(triphenylphosphoranylidene)methyl]-3-cephem-4-carboxylate (2);
(ii) reacting p-methoxybenzyl-7-(phenylacetamido)-3-
[(triphenylphosphoranylidene)methyl]-3-cephem-4-carboxylate (2) with 4-
methylthiazole-5-carbaldehyde in a mixture of solvents selected from the
group consisting of (a) dichloromethane and isopropanol; and (b) toluene and
isopropanol; to obtain p-methoxybenzyl-7-(phenylacetamido-3-(4-
methylthiazole-5-yl)-vinyl-3-cephem-4-carboxylate (3);
(iii) de-esterification of p-methoxybenzyl-7-amino-3-(4-methylthiazol-5-yl)-
vinyl-3-cephem-4-carboxylate (4) by an acid selected from the group of
trifluoroacetic acid, aqueous hydrochloric acid and aqueous hydrobromic acid
to form 7-amino-3-(4-methylthiazol-5-yl)-vinyl-3-cephem-4-carboxylic acid
(5); and
(iv) Crystallizing the cefditoren pivoxil in ethyl acetate to get pure crystalline
cefditoren pivoxil.
One embodiment of the invention provides an improved process for the preparation of
cefditoren involving the steps of:
(i) reacting p-methoxybenzyl-7-phenylacetamido-3-chloromethyl-3-cephem
carboxylate (1) with triphenylphosphine in the presence of a mixture of
sodium bromide and sodium iodide in dichloromethane and water to obtain p-
methoxybenzyl-7-(phenylacetamido)-3-
[(triphenylphosphoranylidene)methyl]-3-cephem-4-carboxylate (2);
(ii) reacting p-methoxybenzyl-7-(phenylacetamido)-3-
[(triphenylphosphoranylidene)methyl]-3-cephem-4-carboxylate (2) with 4-
methylthiazole-5-carbaldehyde in a mixture of solvents selected from the
group consisting of (a) dichloromethane and isopropanol; and (b) toluene and
isopropanol; to obtain p-methoxybenzyl-7-(phenylacetamido-3-(4-
methylthiazole-5-yl)-vinyl-3-cephem-4-carboxylate (3);
(iii) optionally recrystallizing the obtained p-methoxybenzyl-7-(phenylacetamido-
3-(4-methylthiazole-5-yl)-vinyl-3-cephem-4-carboxylate (3) in a mixture of
toluene and methanol;
(iv) reacting p-methoxybenzyl-7-(phenylacetamido-3-(4-methylthiazole-5-yl)-
vinyl-3-cephem-4-carboxylate (3) with trimethylsilyl chloride in
dichloromethane, followed by addition of N,N-dimethylaniline and
phosphorous pentachloride to obtain p-methoxybenzyl-7-amino-3(Z)-(4-
methylthiazol-5-yl)-3-cephem-4-carboxylate (4);
(v) de-esterification of p-methoxybenzyl-7-amino-3-(4-methylthiazol-5-yl)-vinyl-
3-cephem-4-carboxylate (4) by an acid selected from the group of
trifluoroacetic acid, aqueous hydrochloric acid and aqueous hydrobromic acid
to form 7-amino-3-(4-methylthiazol-5-yl)-vinyl-3-cephem-4-carboxylic acid
(5);
(vi) reacting 7-amino-3-(4-methylthiazol-5-yl)-vinyl-3-cephem-4-carboxylic acid
(5) with benzothiazol-2-yl-(Z)-2-methoxy-imino-2-(2-aminothiazole-4-yl)-
thioacetate to obtain cefditoren (6) in the presence of triethylamine in a
mixture of tetrahydrofuran and water;
(vii) treating the obtained cefditoren with sodium-2-ethylhexanoate in acetone to
get cefditoren sodium; and
(viii) reacting cefditoren sodium with iodomethylpivalate in the presence of sodium
carbonate in dimethylformamide to get cefditoren pivoxil;
(ix) crystallizing the cefditoren pivoxil in ethyl acetate to get pure crystalline
cefditoren.
Another embodiment of the invention provides an improved process for the preparation
of 7-amino-3-(4-methylthiazol-5-yl)-vinyl-3-cephem-4-carboxylic acid having a purity of
about 99.0% involving the steps of:
(i) reacting p-methoxybenzyl-7-phenylacetamido-3-chloromethyl-3-cephem
carboxylate (1) with triphenylphosphine in the presence of a mixture of
sodium bromide and sodium iodide in dichloromethane and water to obtain p-
methoxybenzyl-7-(phenylacetamido)-3-
[(triphenylphosphorany!idene)methyl]-3-cephem-4-carboxylate (2);
(ii) reacting p-methoxybenzyl-7-(phenylacetamido)-3-
[(triphenylphosphoranylidene)methyl]-3-cephem-4-carboxylate (2) with 4-
methylthiazole-5-carbaldehyde in a mixture of solvents selected from the
group consisting of (a) dichloromethane and isopropanol; and (b) toluene and
isopropanol; to obtain p-methoxybenzyl-7-(phenylacetamido-3-(4-
methylthiazole-5-yl)-vinyl-3-cephem-4-carboxylate (3);
(iii) optionally recrystallizing the obtained p-methoxybenzyl-7-(phenylacetamido-
3-(4-methylthiazole-5-yl)-vinyl-3-cephem-4-carboxylate (3) in a mixture of
toluene and methanol;
(iv) reacting p-methoxybenzyl-7-(phenylacetamido-3-(4-methylthiazole-5-yl)-
vinyl-3-cephem-4-carboxylate (3) with trimethylsilyl chloride in
dichloromethane, followed by addition of N,N-dimethylaniline and
phosphorous pentachloride to obtain p-methoxybenzyl-7-amino-3(Z)-(4-
methylthiazol-5-yl)-3-cephem-4-carboxylate (4); and
(v) de-esterification of p-methoxybenzyl-7-amino-3-(4-methylthiazol-5-yl)-
vinyl-3-cephem-4-carboxylate (4) by an acid selected from the group of
trifluoroacetic acid, aqueous hydrochloric acid and aqueous hydrobromic acid
to form 7-amino-3-(4-methylthiazol-5-yl)-vinyl-3-cephem-4-carboxylic acid
(5).
Still another embodiment of the present invention to provide the process for the depletion
of p-methoxybenzyl-7-(4-phenylacetamido-3-[(E)-2-(4-methyl-thiazole-5-yl)-vinyl]-3-
cephem-4-carboxylate in Z/E mixture of p-methoxybenzyl-7-(4-phenylacetamido-3-[2-
(4-methyl-thiazole-5-yl)vinyl]-3-cephem-4-carboxylate involving the steps of:
suspending Z/E mixture of p-methoxybenzyl-7-(4-phenylacetamido-3-[2-(4-methyl-
thiazole-5-yl)vinyl]-3-cephem-4-carboxylate in toluene; optionally separating the
undissolved particles by filtration; and adding methanol to the clear solution to get pure
p-methoxybenzyl-7-(phenylacetmido-3-(4-methylthiazol-5-yl)-vinyl-3-cepham-4-
carboxylate with enriched Z-isomer.
Yet another embodiment of the present invention is to provide a process for the
preparation of p-methoxybenzyl-7-amino-3(Z)-(4-methylthiazol-5-yl)-3-cephem-4-
carboxylate involving the step of: adding trimethylsilyl chloride to a dichloromethane
solution of p-methoxybenzyl-7-(phenylacetamido-3-(4-methylthiazole-5-yl)-vinyl-3-
cepham-4-carboxylate; adding N,N-dimethylaniline and phosphorous pentachloride to
the reaction mixture; adding methanol to the reaction mixture; isolating solid formed;
dissolving the isolated solid in dichloromethane; distilling the dichloromethane solution
in vacuum; adding methanol to the residue; and isolating crystalline p-methoxybenzyl-7-
amino-3(Z)-(4-methylthiazol-5-yl)-3-cephem-4-carboxylate.
Still another embodiment of the present invention is to provide a process for the
preparation of cefditoren sodium involving the steps of: reacting 7-amino-3-(4-
methylthiazol-5-yl)-vinyl-3-cephem-4-carboxylic acid with benzothiazol-2-yl-(Z)-2-
methoxyimino-2-(2-aminothiazol-4-yl)-thioacetate in the mixture of tetrahydrofuran and
water in the presence of triethylamine to get cefditoren triethylamine; treating the
obtained cefditoren triethylamine with 2-ethylhexanoate in acetone to give cefditoren
sodium.
Yet another embodiment of the present invention is to provide a process for the
preparation of cefditoren pivoxil involving the steps of treating cefditoren sodium with
iodomethylpivalate in the presence of sodium bicarbonate in dimethylformamide.
Still another embodiment of the present invention is to provide a process for the
crystallization of cefditoren pivoxil involving the step of: distillation of dichloromethane
solution under vacuum at 25 to 35 degree C; and followed by the addition of ethyl
acetate.
Yet another embodiment of the present invention provides an improved de-esterification
process for p-methoxybenzyl-7-amino-3-(4-methylthiazol-5-yl)-vinyl-3-cephem-4-
carboxylate by an acid selected from the group of trifluoroacetic acid, aqueous
hydrochloric acid and aqueous hydrobromic acid to form 7-amino-3-(4-methylthiazol-5-
yl)-vinyl-3-cephem-4-carboxylic acid.
Example -1
Preparation of p-methoxybenzyl-7-(phenylacetamido-3-(4-methylthiazole-5-yl)
vinyl-3-cephem -4-carboxylate
In a mixture of dichloromethane (600ml) and water (400ml), p-methoxybenzyl 7-
phenylacetamido -3-chloromethyl -3- cephem -4- carboxylate [GCLE] (100g) and a mixture
of sodium bromide (21.0g) and sodium iodide (4.0g) were added followed by the addition of
triphenylphosphine (56.0g). The resultant mixture was stirred at a temperature of 28-32°C for
3-4 hours. The dichloromethane layer of the reaction mixture containing formed p-
methoxybenzyl 7-(phenylacetamido)-3-triphenylphosphonium-methyl-3-cephem-4-carboxyl
iodide was separated and cooled.
To the cold dichloromethane layer cold aqueous sodium hydroxide solution (8.2g in 500ml
water) was added and stirred for 1 hour. The dichloromethane layer containing formed p-
methoxybenzyl-7-(phenylacetamido)-3 - [(triphenylphosphoranylidene) methyl] -3 -cephem-4-
carboxylate was separated from the resulting reaction mixture and the aqueous layer was then
extracted with dichloromethane (100ml). The combined organic layer washed with 20%
sodium chloride solution, cooled to 15 ± 5°C and n-propanol (350ml) was added.
To the resulted solution 4- methylthiazole-5-carbaldehyde (32.6g) was added and stirred for
15 hours at temperature of 15 ± 5°C. After completion of the reaction, sodiumbisulphite
solution was added to the reaction mixture. The dichloromethane layer was separated,
washed with 20% sodium chloride solution and distilled under vacuum to get residue.
Methanol (500ml) was added to the residue and stirred for 60 min at a temperature of 0-5°C.
The solid formed was separated by filtration to give p-methoxybenzyl-7-(phenylacetamido-3-
(4-methylthiazole-5-yl)vinyl-3-cephem-4-carboxylate crude (85.0g) with HPLC purity above
85% Z-isomer.
Example-2
Purification of p-methoxybenzyl-7-(phenylacetamido-3-(4-methylthiazole-5-yl)-vinyl-3-
cephem-4-carboxylate
The crude p-methoxybenzyl-7-(phenylacetamido-3 -(4-methylthiazoIe-5 -yl)-vinyl-3 -cephem-
4-carboxylate (100.0g) with purity [77.4%, Z-isomer and 14.23%, E-isomer] was suspended
in toluene (300ml) and stir for 30 min at 30-35°C. Undissolved solid was separated by
filtration and washed with toluene (50.0ml). Methanol (500ml) was added to the filtrate and
stirred at 25-30°C for 60min. The solid formed was filtered, washed with methanol (200ml)
and dried under vacuum at 45-50°C to get pure p- methoxybenzyl 7-( phenylacetamido-3-(4-
methylthiazole-5-yl)-vinyl-3-cephem-4-carboxylate (65.0g) with enriched Z-isomer above
98.0% and E-isomer less than 1.0% by HPLC purity .
Example-3
Preparation of p-methoxybenzyl-7-(phenyIacetamido-3-(4-methylthiazole-5-yl)
vinyl-3-cephem -4-carboxylate
In a mixture of dichloromethane (600ml) and water (400ml), p-methoxybenzyl-7-
phenylacetamido-3-chloromethyl-3-cephem-4-carboxlate [GCLE] (100g) and a mixture of
sodium bromide (21.0g) and sodium iodide (4.0g) were added, followed by the addition of
triphenylphosphine (56.0g). The resultant mixture was stirred at a temperature of 28-32°C for
3-4 hours. The dichloromethane layer of the reaction mixture containing formed p-
methoxybenzyl-7-(phenylacetamido)-3-triphenylphosphonium-methyl-3-cephem-4-carboxyl
iodide was separated and cooled.
To the cold dichloromethane layer cold aqueous sodium hydroxide solution (8.2 g in 500 ml
water) was added and stirred for 1 hour. The dichloromethane layer containing formed p-
methoxybenzyl-7-(phenylacetamido)-3-[(triphenylphosphoranylidene)-methyl]-3-cephem-4-
carboxylate was separated from the resulting reaction mixture and the aqueous layer was
extracted with dichloromethane (100ml). The combined organic layer was washed with 20%)
sodium chloride solution and distilled under vacuum at 30-35°C to get residue. The toluene
(500ml) was added to the residue, cooled to 15 ± 5°C and n-propanol (50ml) was added.
To the resulted solution 4-methylthiazole-5-carbaldehyde (32.6g) was added and stirred for
15 hours at temperature of 15 ± 5°C. After completion of the reaction, sodiumbisulphite
solution was added to the reaction mixture. The dichloromethane layer was separated,
washed with 20% sodium chloride solution and distilled under vacuum to get residue. To the
residue methanol (500 ml) was added and stirred for 60 min at 0-5°C. The solid formed was
separated by filtration to give p- methoxybenzyl-7-( phenylacetamido-3-(4-methylthiazole-
5-yl) vinyl-3-cephem -4-carboxylate crude (70.0g) with HPLC purity above 87 % Z-isomer
and E- isomer less than 10%.
Example-4
Preparation of p-methoxybenzyl-7-amino-3(Z)-(4-methylthiazol-5-yl)-3-cephem-4-
carboxylate
To a solution of p-methoxybenzyl-7-(phenylacetamido-3-(4-methylthiazole-5-yl)-vinyl-3-
cephem-4-carboxylate (100.0g) with purity [85.74%, Z- isomer and 10.53%, E- isomer] in
dichloromethane (800ml), trimethylsilyl chloride (10.0ml) was added at 0-5°C. The
solution was cooled to -50 to -55°C, followed by the addition of N, N-dimethylaniline
(53.8g) and phosphorus pentachloride (74.0g). The reaction mixture was stirred at -35 to -
45°C for 2.0 hours. To the reaction mixture methanol (200 ml) was added and continuously
stirred for 2.0 hours at -20 to -30°C. After completion of the reaction, pre-cooled 20%
sodium chloride solution was added to the reaction mixture and stirred for 30 min at 5-
10°C and the aqueous layer was separated. To the aqueous layer dichloromethane was
added, pH was adjusted to 3.5 by sodium hydroxide solution and separated the
dichloromethane layer. The dichloromethane layer was distilled in vacuum to a residue.
The residue was dissolved in methanol to give p-methoxybenzyl-7-amino-3(Z)-(4-
methylthiazol-5-yl)-3-cephem-4-carboxylate. The solid was dissolved in dichloromethane
(200ml), treated with carbon, filtered and distilled under vacuum at 35-40°C to get a
residue. To the residue methanol (200ml) was added and stirred at 25-30 °C for 60 minutes
to get crystalline solid. The solid formed was filtered at 5-10°C to give p-methoxybenzyl-7-
amino-3(Z)-(4-methylthiazol-5-yl)-3-cephem-4-carboxylate (48.0g) with HPLC purity Z-
isomer enriched above 98% and E-isomer less than 1.0%.
Example-5
Preparation of p-methoxybenzyl-7-amino-3(Z)-(4-methylthiazol-5-yl)-3-cephem-4-
carboxylate
To a solution of p-methoxybenzyl-7-(phenylacetamido-3-(4-methylthiazole-5-yl)-vinyl-3-
cephem-4-carboxylate (100.0g) in dichloromethane (800ml), trimethylsilyl chloride (10.0
ml) was added at 0-5°C. The solution was cooled to -50 to -55°C, followed by the addition
of N, N-dimethylaniline (53.8g) and phosphorus pentachloride (74.0g). The reaction
mixture was stirred at -35 to -45°C, for 2.0 hours. To the reaction mixture methanol (200
ml) was added and continuously stirred for 2.0 hours at -20 to -30°C. After completion of
the reaction, the reaction mixture was added into pre-cooled 20% sodium chloride solution
and stirred for 30 min at 5-10°C and the aqueous layer was separated. To the aqueous layer
dichloromethane was added, pH was adjusted to 3.5 by sodium hydroxide solution and
separated the dichloromethane layer. The dichloromethane layer was distilled in vacuum to
a residue. The residue was dissolved in isopropyl alcohol to give the solid p-
methoxybenzyl-7-amino-3(Z)-(4-methylthiazol-5-yl)-3-cephem-4-carboxylate. This solid
was dissolved in dichloromethane (200 ml) and treated with carbon, filtered and distilled
under vacuum at 35-40°C to which methanol (200ml) was added stirred at 25-30°C for 60
min get a solid. The solid was separated by filtration at 5-10°C gives p-methoxybenzyl-7-
amino-3(Z)-(4-methylthiazol-5-yl)-3-cephem-4-carboxylate (44.0 g) with HPLC purity Z-
isomer enriched 97% and E-isomer 1.57%.
Example-6
Preparation of 7-amino-3-(4-methylthiazol-5-yl) vinyl-3-cephem-4-carboxylic acid [7-
ATCA]
To a solution of p-methoxybenzyl-7-amino-3(Z)-(4-methylthiazol-5-yl)-3-cephem-4-
carboxylate (100.0 g) in dichloromethane (400 ml) trifluoroacetic acid (180 ml) was added
at 5-10°C. The reaction mixture was stirred at 5 to 10°C, for 3.0 hours. After completion of
reaction pre cooled DM water was added into the reaction mixture and stirred at 5-10°C for
30 min. The aqueous layer separated and was subjected to pH adjustment to 7.5 - 8.5 with
aqueous ammonia solution, treated with carbon, filtered and adjusted the pH 3.0-3.5 with
dilute hydrochloric acid to get a crystalline solid. The solid was filtered and washed with
water and then acetone to get 7-amino-3-(4-methylthiazol-5-yl) vinyl-3-cephem-4-
carboxylic acid ( 64.0 g) with HPLC purity Z-isomer enriched above 99%and E- isomer
less than 0.5%.
Example - 7
Preparation of 7-amino-3-(4-methylthiazol-5-yl) vinyl-3-cephem-4-carboxylic acid [7-
ATCA]
To a solution of p-methoxybenzyl-7-amino-3(Z)-(4-methylthiazol-5-yl)-3-cephena-4-
carboxylate (100.0g) in aqueous hydrochloric acid (500ml) was stirred at 15 to 20°C, for
3.0 hours. After completion of the reaction dichloromethane (300ml) was added into the
reaction mixture and stirred at 15-20°C for 30 min. The aqueous layer separated and was
subjected to pH adjustment to 7.5 - 8.5 with aqueous ammonia solution, treated with
carbon, filtered and adjusted the pH 3.0-3.5 with dilute hydrochloric acid to crystalline
solid .The solid filtered and washed with water and with acetone to get 7-amino-3-(4-
methylthiazol-5-yl)-vinyl-3-cephem-4-carboxylic acid (60.0g) with HPLC purity Z-isomer
enriched above 99%and E- isomer less than 0.5%.
Example-8
Preparation of 7-amino-3-(4-methylthiazol-5-yl) vinyl-3-cephem-4-carboxylic acid [7-
ATCA]
To a solution of p-methoxybenzyl-7-amino-3(Z)-(4-methylthiazol-5-yl)-3-cephem-4-
carboxylate (100.0g) in aqueous hydrobromic acid (300 ml) was stirred at 15 to 20°C, for
3.0 hours. After completion of reaction dichloromethane (300ml) was added into the
reaction mixture and stirred at 15-20°C for 30 min. The aqueous layer separated and was
subjected to pH adjustment to 7.5 - 8.5 with aqueous ammonia solution, treated with
carbon, filtered and adjusted the pH 3.0-3.5 with dilute hydrochloric acid to crystalline
solid. The solid filtered and washed with water and with acetone to get 7-amino-3-(4-
methylthiazol-5-yl)-vinyl-3-cephem-4-carboxylic acid (64.0g) with HPLC purity Z-isomer
enriched above 98%and E- isomer less than 0.5%.
Example-9
(A) Preparation of cefditoren sodium
To a mixture of 7-amino-3-(4-methylthiazol-5-yl)-vinyl-3-cephem-4-carboxylic acid [7-
ATCA] (100g), triethylamine (40.67ml) and a mixture of tetrahydrofuran (400 ml) and
DM Water(200 ml) benzothiazol-2-yl-(Z)-2-methoxyimino-2-(2-aminothiazol-4-yl)-
thioacetate [MAEM] (124.46 g) was added at 5°C to 10°C to give cefditoren
triethylamine salt. The cefditoren triethylamine salt was washed with dichloromethane,
treated with sodium 2- ethylhexanoate (66.73 g) in acetone (1500 ml) and stirred at 10-
15°C for 60 min. The formed solid was separated by filtration to get crystalline cefditoren
sodium (155.0 g) with HPLC purity 99.32 %.
(B) Preparation of cefditoren pivoxil crude
To a solution of Cefditoren sodium (100 g) in dimethylformamide (600ml),
iodomethylpivalate (55.0 g) and sodium bicarbonate was added at -30°C to -35°C. After
completion of the reaction, the reaction mixture was added to a mixture of ethyl acetate
and DM water; and the ethyl acetate layer separated. The cefditoren pivoxil in the ethyl
acetate was extracted into DM water by adjusting the pH 0.5-0.8 with hydrochloric acid
to give cefditoren pivoxil hydrochloride. This cefditoren pivoxil hydrochloride is
converted into free cefditoren pivoxil by adjusting the pH 6.0-6.5 with sodium
bicarbonate solution. The cefditoren pivoxil in the aqueous solution was extracted with
dichloromethane. The dichloromethane extract was distilled under vacuum at 20°C-35°C
to get a residue. The ethyl acetate (400ml) was added to the residue and stirred at 20-25
°C for 60 min and then at 5-10 °C for 60 min to give solid cefditoren pivoxil (92.0g)
with HPLC purity 99.23%.
We Claim:
1) An improved process for preparing cefditoren pivoxil, wherein the improvement of the
said process is characterized as the following:
(i) reacting p-methoxybenzyl-7-phenylacetamido-3-chloromethyl-3-cephem
carboxylate with triphenylphosphine in the presence of a mixture of sodium
bromide and sodium iodide in dichloromethane and water to obtain p-
methoxybenzyl-7-(phenylacetamido)-3-
[(triphenylphosphoranylidene)methyl]-3-cephem-4-carboxylate;
(ii) reacting p-methoxybenzyl-7-(phenylacetamido)-3-
[(triphenylphosphoranylidene)methyl]-3-cephem-4-carboxylate with 4-
methylthiazole-5-carbaldehyde in a mixture of solvents selected from the
group consisting of (a) dichloromethane and isopropanol; and (b) toluene and
isopropanol; to obtain p-methoxybenzyl-7-(phenylacetamido-3-(4-
methylthiazole-5-yl)-vinyl-3-cephem-4-carboxylate;
(iii) de-esterification of p-methoxybenzyl-7-amino-3-(4-methylthiazol-5-yl)-vinyl-
3-cephem-4-carboxylate by an acid selected from the group of trifluoroacetic
acid, aqueous hydrochloric acid and aqueous hydrobromic acid to form 7-
amino-3-(4-methylthiazol-5-yl)-vinyl-3-cephem-4-carboxylic acid; and
(iv) Crystallizing the cefditoren pivoxil in ethyl acetate to get pure crystalline
cefditoren pivoxil.
2. An improved process for the preparation of cefditoren involving the steps of:
(i) reacting p-methoxybenzyl-7-phenylacetamido-3-chloromethyl-3-cephem
carboxylate with triphenylphosphine in the presence of a mixture of sodium
bromide and sodium iodide in dichloromethane and water to obtain p-
methoxybenzyl-7-(phenylacetamido)-3-
[(triphenylphosphoranylidene)methyl]-3-cephem-4-carboxylate;
(ii) reacting p-methoxybenzyI-7-(phenylacetamido)-3-
[(triphenylphosphoranylidene)methyI]-3-cephem-4-carboxylate with 4-
methylthiazole-5-carbaldehyde in a mixture of solvents selected from the
group consisting of (a) dichloromethane and isopropanol; and (b) toluene and
isopropanol; to obtain p-methoxybenzyl-7-(phenylacetamido-3-(4-
methylthiazole-5-yl)-vinyl-3-cephem-4-carboxylate;
(iii) optionally recrystallizing the obtained p-methoxybenzyl-7-(phenylacetamido-
3-(4-methylthiazole-5-yl)-vinyl-3-cephem-4-carboxylate in a mixture of
toluene and methanol;
(iv) reacting p-methoxybenzyl-7-(phenylacetamido-3-(4-methylthiazole-5-yl)-
vinyl-3-cephem-4-carboxylate with trimethylsilyl chloride in
dichloromethane, followed by addition of N,N-dimethylaniline and
phosphorous pentachloride to obtain p-methoxybenzyl-7-amino-3(Z)-(4-
methylthiazol-5-yl)-3-cephem-4-carboxylate;
(v) de-esterification of p-methoxybenzyl-7-amino-3-(4-methylthiazol-5-yl)-vinyl-
3-cephem-4-carboxylate by an acid selected from the group of trifluoroacetic
acid, aqueous hydrochloric acid and aqueous hydrobromic acid to form 7-
amino-3-(4-methylthiazol-5-yl)-vinyl-3-cephem-4-carboxylic acid;
(vi) reacting 7-amino-3-(4-methylthiazol-5-yl)-vinyl-3-cephem-4-carboxylic acid
with benzothiazol-2-yl-(Z)-2-methoxy-imino-2-(2-aminothiazole-4-yl)-
thioacetate to obtain cefditoren in the presence of triethylamine in a mixture of
tetrahydrofuran and water;
(vii) treating the obtained cefditoren with sodium-2-ethylhexanoate in acetone to
get cefditoren sodium; and
(viii) reacting cefditoren sodium with iodomethylpivalate in the presence of sodium
carbonate in dimethylformamide to get cefditoren pivoxil;
(ix) crystallizing the cefditoren pivoxil in ethylacetate to get pure crystalline
cefditoren.
3) An improved process for the preparation of 7-amino-3-(4-methylthiazol-5-yl)-vinyI-3-
cephem-4-carboxylic acid having a purity of about 99.0% involving the steps of:
(i) reacting p-methoxybenzyl-7-phenylacetamido-3-chloromethyl-3-cephem
carboxylate (1) with triphenylphosphine in the presence of a mixture of
sodium bromide and sodium iodide in dichloromethane and water to obtain p-
methoxybenzyl-7-(phenylacetamido)-3-
[(triphenylphosphoranylidene)methyl]-3-cephem-4-carboxylate;
(ii) reacting p-methoxybenzyl-7-(phenylacetamido)-3-
[(triphenylphosphoranylidene)methyl]-3-cephem-4-carboxylate with 4-
methylthiazole-5-carbaldehyde in a mixture of solvents selected from the
group consisting of (a) dicloromethane and isopropanol; and (b) toluene and
isopropanol; to obtain p-methoxybenzyl-7-(phenylacetamido-3-(4-
methylthiazole-5-yl)-vinyl-3-cephem-4-carboxylate;
(iii) optionally recrystallizing the obtained p-methoxybenzyl-7-(phenylacetamido-
3-(4-methylthiazole-5-yl)-vinyl-3-cephem-4-carboxylate in a mixture of
toluene and methanol;
(iv) reacting p-methoxybenzyl-7-(phenylacetamido-3-(4-methylthiazole-5-yl)-
vinyl-3-cephem-4-carboxylate with trimethylsilyl chloride in
dichloromethane, followed by addition of N,N-dimethylaniline and
phosphorous pentachloride to obtain p-methoxybenzyl-7-amino-3(Z)-(4-
methylthiazol-5-yl)-3-cephem-4-carboxylate; and
(v) de-esterification of p-methoxybenzyl-7-amino-3-(4-methylthiazol-5-yl)-vinyl-
3-cephem-4-carboxylate by an acid selected from the group of trifluoroacetic
acid, aqueous hydrochloric acid and aqueous hydrobromic acid to form 7-
amino-3-(4-methylthiazol-5-yl)-vinyl-3-cephem-4-carboxylic acid.
4. The process for the depletion of p-methoxybenzyl-7-(4-phenylacetamido-3-[(E)-2-(4-
methyl-thiazole-5-yl)-vinyl]-3-cephem-4-carboxylate in Z/E mixture of p-
methoxybenzyl-7-(4-phenylacetamido-3-[2-(4-methyl-thiazole-5-yl)vinyl]-3-cephem-4-
carboxylate involving the steps of: suspending Z/E mixture of p-methoxybenzyl-7-(4-
phenylacetamido-3-[2-(4-methyl-thiazole-5-yl)vinyl]-3-cephem-4-carboxylate in toluene;
optionally separating the undissolved particles by filtration; and adding methanol to the
clear solution to get pure p-methoxybenzyl-7-(phenylacetmido-3-(4-methylthiazol-5-yl)-
vinyl-3-cepham-4-carboxylate with enriched Z-isomer.
5. A process for the preparation of p-methoxybenzyl-7-amino-3(Z)-(4-methylthiazol-5-
yl)-3-cephem-4-carboxylate involving the step of: adding trimethylsilyl chloride to a
dichloromethane solution of p-methoxybenzyl-7-(phenylacetamido-3-(4-methylthiazole-
5-yl)-vinyl-3-cepham-4-carboxylate; adding N,N-dimethyIaniline and phosphorous
pentachloride to the reaction mixture; adding methanol to the reaction mixture; isolating
solid formed; dissolving the isolated solid in dichloromethane; distilling the
dichloromethane solution in vacuum; adding methanol to the residue; and isolating
crystalline p-methoxybenzyl-7-amino-3(Z)-(4-methylthiazol-5-yl)-3-cephem-4-
carboxylate.
6. A process for the preparation of cefditoren sodium involving the steps of: reacting 7-
amino-3-(4-methylthiazol-5-yl)-vinyl-3-cephem-4-carboxylic acid with benzothiazol-2-
yl-(Z)-2-methoxyimino-2-(2-aminothiazol-4-yl)-thioacetate in the mixture of
tetrahydrofuran and water in the presence of triethylamine to get cefditoren triethylamine;
treating the obtained cefditoren triethylamine with 2-ethylhexanoate in acetone to give
cefditoren sodium.
7. A process for the preparation of cefditoren pivoxil involving the steps of treating
cefditoren sodium with iodomethylpivalate in the presence of sodium bicarbonate in
dimethylformamide.
8. A process for the crystallization of cefditoren pivoxil involving the step of: distillation
of dichloromethane solution under vacuum at 25 to 35 degree C; and followed by the
addition of ethyl acetate.
9. An improved de-esterification process for p-methoxybenzyl-7-amino-3-(4-
methylthiazol-5-yl)-vinyl-3-cephem-4-carboxylate by an acid selected from the group of
trifluoroacetic acid, aqueous hydrochloric acid and aqueous hydrobromic acid to form 7-
amino-3-(4-methylthiazol-5-yl)-vinyl-3-cephem-4-carboxylic acid.

An improved process for the preparation of 7-amino-3-(4-methylthiazol-5-yl) vinyl-3-
cephem-4-carboxylic acid [7-ATCA]; an intermediate used in the synthesis of cefditoren
pivoxil with a high purity.