The present invention relates to an improved process for the preparation of cephem esters.
Cephem esters having a physiologically labile group are used as prodrugs for oral administration of cephalosporin antibiotics. Preparation of cephem esters from the corresponding cephem free acid or salts thereof results in formation of undesired Δ2 -isomer of the cephem ester of Formula A, as shown in the accompanied drawings, along with the Δ3 - isomer of Formula B, as shown in the accompanied drawings, which is the desired cephem ester. The Δ2- isomer is formed as a result of Δ3 - Δ2 isomerization under basic conditions. Basic conditions are necessary for the esterification reaction to go to completion. Removal of the Δ2 -isomer from the cephem ester is difficult due to the similar structures of Δ2 and Δ3-isomers and also entails decrease in yield.
Several processes have been reported to overcome this problem in the synthesis of cephem esters by minimizing isomerization. J. Org. Chem. 1986, 51, 4723 and J. antibiotics, 1991, 44 (2), 200 give preparation of cephem esters wherein dioxane is added as a cosolvent to lower the polarity of the reaction medium and thus decrease the basicity of the cephem carboxylate, which is believed to be responsible for the isomerization.
US Patent No. 5,498,787 teaches the use of quaternary ammonium or quaternary phosphonium salts as catalysts for eliminating the formation of Δ2 -isomer of cephem esters. PCT patent application WO 02/16372 uses crown ether catalysts to achieve similar results for preparation cefuroxime axetil.
The addition of a polarity lowering cosolvent like dioxane often results in sluggish and incomplete reactions thus lowering the ' yield. Also crown ether / quaternary ammonium or phosphonium salts are expensive and are not preferred at a commercial scale.

The present invention provides an inexpensive and efficient process for preparing cephem esters while minimizing the concomitant formation of the corresponding A2-isomer.
The present invention provides a process for preparation of cephem ester of formula
I, as shown in the accompanied drawings, wherein
R is cyano, phenyl, cyclohexadienyl, heterocyclyl, heterocyclylthio, or a
heterocyclylamido group, wherein the phenyl or the heterocyclic ring may be further
substituted by an alkyl, hydroxy, amino, aminoalkyl, halo or a carboxyalkyl group;
A is selected from the mono or disubstituted methylene groups as shown in Sheet 5
of the accompanied drawings, wherein RI is alkyl, alkoxyalkyl or carboxyalkyl;
R' is hydrogen, alkyl, alkenyl, alkynyl, alkoxymethyl, alkylthiomethyl,
alkanoyloxymethyl, carbamoyloxymethyl, or a heterocyclylthiomethyl group, wherein
the heterocyclic ring may be further substituted by hydroxy, alkyl, carboxyalkyl,
sulfonylalkyl or carbamoyl; and
R" is alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, alkoxyalkyl, alkanoyloxyalkyl or
alkoxycarbonyloxyalkyl,
which comprises reacting a compound of Formula II, as shown in the accompanied
drawings, wherein R and R' are as defined above for the compound of formula I, with
a compound of Formula R" X, wherein X is a halogen and R" is as defined above for
the compound of formula I, in the presence of an amine, an inorganic base and a
phosphate buffer to obtain the compound of Formula I.
The heterocyclyl group is a 5 or 6 membered heterocyclic ring containing upto four hetero atoms independently selected from the group consisting of nitrogen, oxygen and sulfur.
Examples of R include 4-hydroxyphenyl, 2-aminomethylphenyl, 2-amino-4-thiazolyl, 2-furanyl, 2-thienyl, 4-pyridinyl, 1H-tetrazolyl, 5-amino-1,2,4-thiadiazol-3-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 5-carboxy-1H-imidazol-4-yl, 4-hydroxy-6-methyl-3-pyridinyl, 3,5-dichloro-4oxo-1(4H)-pyridinyl, and 4-ethyl-2,3-dioxo-1-piperazinyl.

Examples of R' include methyl, 2-(4-rnethyl-5-thiazolyl)ethenyl, acetoxymethyl, methoxymethyl, chloro, 1-methyl-1H-tetrazol-5-ylthio, 1H-1,2,3-triazol-4-ylthio, 5-methyl-1,3,4-thiadiazol-2-yl, 1,2,3-thiadiazol-5-ylthio and 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3-ylthio.
Examples of R" include 1-acetoxyethyl, pivaloyl, pivaloyloxymethyl, 1-(isopropoxycabonyloxy)ethyl and 1-(cyclohexyloxycabonyloxy)ethyl.
Halogen X in R"X is selected from the group consisting of chloro, bromo and iodo.
The reaction is carried out in the presence of an amine. Suitable amines include triethylamine, tributylamine, N, N-dimethylaniline, dicyclohexylamine, pyridine, N-methylpiperidine N-methyl pyrrolidine, N-methyl morpholine, collidine, lutidine, picoline, quinoline, isoquinoline, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and mixture(s) thereof.
Suitable inorganic bases which may be used in the process include sodium carbonate, potassium carbonate and sodium bicarbonate.
Suitable phosphate buffers which may be used in the process include disodium hydrogenphosphate, dipotassium hydrogenphosphate and sodium hydrogen phosphate.
Preferably 0.5 to 2.5 molar equivalents of the phosphate buffer is used with respect to the inorganic base.
The reaction is performed in the presence of a solvent which is inert under the
reaction conditions. Suitable solvents include dimethylformamide,
dimethylacetamide, dimethylsulphoxide, hexamethylphosphoric triamide, tetrahydrofuran, dichloromethane, ethylacetate, acetonitrile and mixture(s) thereof.
The reaction is preferably conducted at ambient temperature or with cooling and most preferably at-10 to 0°C.

The process of the present invention consistently gives cephem esters in high yield and purity.
In the following section one preferred embodiment is described by way of example to illustrate the process of this invention. However, it is not intended in any way to limit the scope of the present invention.
EXAMPLE Preparation of cefpodoxime proxetil
(6R.7R) 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-(rnethoxymethyl)3-cephem-4-carboxylic acid (cefpodoxime acid, 10.Og) was dissolved in N, N-dimethylacetamide (35ml ) and the mixture was cooled to -10°C. A mixture of pulverized disodium hydrogenphosphate(0.8g) and pulverized sodium carbonate(0.5g) was added. 1,8-diazabicylco[5.4.0]undec-7-ene(DBU, 3.35g) was then added slowly followed by addition of 1,-iodoethyl isopropylcarbonate (6.2g) at -10 to -5°C in 10 minutes. The reaction mixture was stirred for about 2 hours at the same temperature and progress of the reaction was monitored by HPLC. Qualitative analysis after 2 hours showed 92.12% cefpodoxime proxetil, 0.56% corresponding Δ2-isomer, and 2.29% cefpodoxime acid.
The reaction mixture was poured into ethylacetate (300ml) followed by addition of water (300ml). The organic layer was separated and then washed successively with aqueous hydrochloric acid, aqueous sodium, thiosulphate and finally with aqueous sodium chloride. The ethyl acetate layer obtained above was concentrated to about 40 ml at 30-35°C under reduced pressure and added to cyclohexane (300ml) under stirring at 25°C during about 30 minutes. The precipitated solid was then filtered and washed with cyclohexane. The wet product was added to methanol (40ml) at
i V *
room temperature to obtain a solution and was concentrated at 30-35°C under reduced pressure to about 30ml. It was then added to water (180ml) in 15 minutes at 20-25°C to obtain a solid which was filtered and washed with a cold mixture of methanol and water (1:6 v/v, 20ml). The filtered solid was dried to obtain 10'.5g of

1 -(isopropoxycabonyloxy)ethyl (6R.7R) 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-(methoxymethyl)3-cephem-4-carboxylate i.e. cefpodoxime proxetil (Yield 80.5%, Assay : 98%, Qualitative HPLC cefpodoxime proxetil: 99%, corresponding Δ2-isomer: 0.5%).
Comparative Example Preparation of cefpodoxime proxetil
(6R.7R) 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-(methoxymethyl)3-cephem-4-carboxylic acid (cefpodoxime acid, 10.Og) was dissolved in N, N-dimethylacetamide (35ml ) and the mixture was cooled to -10°C. 1,8-diazabicylco[5.4.0]undec-7-ene(DBU, 3.35g) was then added slowly followed by addition of 1-iodoethyl isopropylcarbonate (6.2g) at -10 to -5°C in 10 minutes. The reaction mixture was stirred for about 2 hours at the same temperature and progress of the reaction was monitored by HPLC. Qualitative analysis after 2 hours showed 65.22% cefpodoxime proxetil, 8.2% corresponding Δ2 -isomer, and 13.9% cefpodoxime acid.

WE CLAIM:
1. A process for the preparation of a compound of Formula I, as shown in the
accompanied drawings, wherein
R is cyano, phenyl, cyclohexadienyl, heterocyclyl, heterocyclylthio, or a
heterocyclylamido group, wherein the phenyl or the heterocyclic ring may be
further substituted by an alkyl, hydroxy, arnino, aminoal'kyl, halo or a
carboxyalkyl group;
A is selected from the mono or disubstituted methylene groups as shown in
Sheet No. 5 of the accompanied drawings, wherein R1 is alkyl, alkoxyalkyl or
carboxyalkyl;
R' is' hydrogen, alkyl, alkenyl, alkynyl, alkoxymethyl, alkylthiomethyl,
alkanoyloxymethyl, carbamoyloxymethyl, or a heterocyclylthiomethyl group,
wherein the heterocyclic ring may be further substituted by hydroxy, alkyl,
carboxyalkyl, sulfonylalkyl orcarbamoyl; and
R" is alkyl, alkenyl, alkynyl, aryl, arylalkyl; alkylaryl, alkoxyalkyl, alkanoyloxyalkyl
or alkoxycarboxylalkyl,
which comprises reacting a compound of Formula II, as shown in the
accompanied drawings, wherein R and R' are as defined above for the
compound of formula I, with a compound of. Formula R" X, wherein X is a halogen
and R" is defined above for the compound of formula I, in the presence of an
amine, an inorganic base and a phosphate buffer to obtain the compound of
Formula I.
2. The process according to claim 1, wherein R in the compound of Formula I is
selected from the group consisting of 4-hydroxyphenyl, 2-aminomethylphenyl, 2-
amino-4-thiazoyl, 2-furanyl, 2-thienyl, 4-pyridinyl, 1H-tetrazolyl, 5-amino-1,2,4-
thiadiazol-3-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 5-carboxy-1H-irnidazol-4-yl, 4-
hydroxy-6-methyl-3-pyridinyl, 3,5-dichloro-4-oxo-1(4H)-pyridinyl, and 4-ethyl-2,3-
dioxo-1-piperazinyl.
3. The process according to claim 1, wherein R' in the compound of Formula I is
selected from the group consisting of methyl, 2-(4-methyl-5-thiazolyl)ethenyl,
acetoxymethyl, methoxymethyl, chloro, 1-methyl-1H-tetrazol-5-ylthio, 1H-1,2,3-

triazol-4-ylthio5-methyl-1,3,4-thiadiazol-2-yl, 1,2,3, -thiadiazol-5-ylthio and 1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3-ylthio.
4. The process according to claim 1, wherein R" in the compound of Formula I is
selected from the group consisting of 1-acetoxyethyl, pivaloyl, pivaloyloxymethyl,
1-(isopropoxycabonyloxy)ethyl and 1-(cyclohexyloxycabonyloxy)ethyl.
5. The process according to claim 1, wherein halogen X in R"X is selected from the
group consisting of chloro, bromo and iodo.
6. The process according to claim 1, wherein the amine is selected from the group
consisting of triethylamine, tributylamine, N, N-dimethylaniline, cycloexylamine,
pyridine, N-methylpiperidine N-methyl pyrrotidine, N-methyl morpholine, collidine,
lutidine, picoline, quinoline, isoquinoline, 1,8-diazabicyclo [5.4.0] undec-7-ene
(DBU) and mixture(s) thereof.
7. The process according to claim 1, wherein the inorganic base is selected from
the group consisting of potassium carbonate, sodium carbonate and sodium
bicarbonate.
8. The process according to claim 1, wherein the phosphate buffer is selected from
the group consisting of disodium hydrogenphosphate, dipotassium
hydrogenphosphate and sodium hydrogen phosphate.
9. The process according to claim 1, wherein 0.5 to 2.5 molar equivalents of the
phosphate buffer is used with respect to the inorganic base.
10.The process according to claim 1, wherein the reaction is performed in the presence of a solvent selected from the group consisting of dimethylformamide, dimethylacetamide, dimethylsulphoxide, tetrahydrofuran, dichloromethane, ethylacetate, acetonitrile and mixture(s) thereof.
11.The process according to claim 1, wherein the reaction is performed at ambient temperature or with cooling.

12.The process according to claim 1, wherein the reaction is performed at -10 to 0°C.
13.The process according to any of claims 1 to 12, wherein the compound of Formula I is cefpodoxime proxetil of Formula III, as shown in the accompanied drawings.
14.The process for the preparation of a compound of Formula I, as herein described and illustrated by the examples herein.