Field of the invention
The present invention is in the field of chemistry and more particularly the present invention relates to the preparation of 1-iodoethylisopropylcarbonate of formula (I) from 1-chloroethylisopropylcarbonate of formula (II) in an organic solvent using sodium halide preferably sodium bromide or sodium iodide in the absence of crown ether in a very simple, efficient and substantially advantageous process. The said compound of formula (I) is a very useful intermediate for the preparation of cefpodoxime proxetil of formula (III), which is a valuable antibiotic.
(Formula Removed)
Cefpodoxime proxetil of formula (III), is chemically known as (R,S)-l-(isopropoxycarbonyloxy) ethyl-(+)-(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-((Z)-methoxyimino) acetamido]-3-methoxymethyl-8-oxo-5-thia-l-azabicyclo [4,2,0] oct-2-en-2-carboxylate, is a cephalosporin ester pro-drug which, when orally administered, converts to cefpodoxime, an antibacterial agent, through rapid hydrolysis by esterases present on the intestinal wall. Cefpodoxime exhibits a wide range of antibacterial activity

against gram positive and negative bacteria such as staphylococcus aureus, streptococcus aureus, E. coli, klebsiella pneumonia and proteuse vulgaris, and also a high degree of 6-lactamase stability.

(Formula Removed)
Cefpodoxime proxetil of formula (III) is known from the patents US 4,486,425 and 4,716,158 which disclose its many processes, but these processes are not very suitable at industrial scale. The cefpodoxime proxetil of formula (III) is a A isomer prepared by various methods.
Hideo Nakao and Koich Huzimoto et al. reported a method of preparing cefpodoxime proxetil by reacting cefpodoxime with iodoalkylcarbonate in the presence of a base such as dicyclohexylamine (J. Antibiot., 1987, 40, 370). But the product obtained by this method is contaminated by about 3 % weight of the A2 isomer of formula (IV) formed as a by-product. Due to the structural similarity, it is very difficult to separate the undesired by-product from the A isomer. The conversion of the A isomer to the A isomer has been attempted and reported in related art, but this process requires a series of reactions, and thus is not economically feasible.
(Formula Removed)


According to the process disclosed in J. Antibiot., 1987, 40, 370, the preparation of 1-iodoethylisopropylcarbonate of formula (I) from 1-chloroethylisopropylcarbonate of formula (II) in benzene using sodium iodide in the presence of crown ether. This main draw back of this reported process is a prolonged time cycle (overnight) at a high temperature (reflux). Because of these observations, the present inventors are motivated to do the same reaction in a substantially better way, which ultimately resulted in a highly pure cefpodoxime proxetil of formula (III), which is substantially free from A isomer of formula (IV), as well as other related impurities..
According to the process disclosed in Farmaco 58 (2003) 363-369 the preparation of 1-iodoethylisopropylcarbonate of formula (I) from 1-chloroethylisopropylcarbonate of formula (II) in benzene using sodium iodide involves the presence of crown ether. The main draw back is same as discussed with reference to J. Antibiot., 1987, 40, 370.
US Patent No. 5, 498,787 discloses a method of preparing cefpodoxime proxetil from a cefpodoxime salt using a quaternary ammonium salt phase transfer catalyst, e. g., tetrabutylammonium hydrogensulfate in an amount ranging from 35 to 120 mole % based on cefpodoxime. The method can effectively inhibit the formation of the A2 isomer, but has problems in that the yield of the desired products is very low in the range of 50 to 60%, and the use of expensive quaternary ammonium salts is required.
According to the disclosure of patent US 6,639,068 (henceforth '068) cefpodoxime proxetil can be prepared by a simple process comprising the step of reacting a cefpodoxime salt with 1-iodoethylisopropylcarbonate in an organic solvent in the presence of a crown ether. Since the proposed inventors are not using this methodology of preparation of cefpodoxime proxetil, hence not obvious. Moreover the proposed inventors are neither using the crown ether in this reaction nor in the said invention as well
It has now been found that the preparation of 1-iodoethylisopropylcarbonate of formula (I) from 1 -chloroethylisopropylcarbonate of formula (II) in an organic solvent


using sodium halide preferably sodium bromide or sodium iodide in the absence of crown ether is possible and the use of the resultant 1-iodoefhylisopropylcarbonate of formula (I) in the synthesis of cefpodoxime proxetil of formula (I) is extremely successful and free from A2 isomer of formula (IV) and related impurities. The absence of crown ether makes the approach of present inventors unique, distinct, remarkable and advantageous, which makes the process over all very successful at industrial and commercial level. The use of this improved approach is extremely useful for the preparation of high purity cefpodoxime proxetil of formula (III).
As discussed above none of the prior art references disclosed or claimed the preparation of 1-iodoethylisopropylcarbonate of formula (I) from 1-chloroethylisopropylcarbonate of formula (II) in an organic solvent using sodium halide preferably sodium bromide or sodium iodide in the absence of crown ether, hence we focused our research to develop an improved and efficient process for the preparation of a compound of formula (I), which may be ultimately resulting in good quality of cefpodoxime proxetil of formula (III).
Objective of the invention
The main object of the present invention is to provide a process for the preparation of a compound of formula (I), which is very simple, economical, user-friendly and commercially viable
Another objective of the present invention is to provide a process for the preparation of a compound of formula (I), which would be easy to implement on commercial scale, and to avoid excessive use of reagent(s) and organic solvent(s) and to avoid hazardous and risky solvents, which makes the present invention more safe and eco-friendly as well.


Yet another objective of the present invention is to provide a process for the preparation of a compound of formula (I) in shorter time with less exposure to high temperature so that the same can be utilized for the preparation of a compound of formula (III) in greater yield with higher chemical purity and to avoid the byproduct formation.
Summary of the invention
Accordingly, the present invention provides a process for the preparation of 1-iodoethylisopropylcarbonate of formula (I), comprising the steps of:

(Formula Removed)
(i) adding sodium halide in an organic solvent;
(ii) optionally removing water from reaction mixture as obtained from step (i);
(iii) reacting 1-chloroethylisopropylcarbonate of formula (II) with the reaction mixture
as obtained from step (i) at reflux temperature in the absence of crown ether; (iv) adding water to the reaction mixture as obtained from step (iii); (v) separating the organic layer from aqueous layer;
(vi) optionally treating the organic layer with sodium thiosulphate solution; (vii) optionally washing the organic layer with sodium chloride solution; (viii) optionally charcolizing the organic layer; and (ix) filtering and concentrating the organic layer to get 1-iodoethylisopropylcarbonate
of formula (I).

The above process is illustrated in the following synthetic scheme:

(Formula Removed)
Accordingly in an embodiment of the present invention, the said sodium halide is preferably sodium bromide or sodium iodide, more preferably sodium iodide.
In another embodiment of the present invention, the said organic solvent may be selected from hydrocarbon or amide or mixture thereof, preferably N,N-dimethylacetamide and toluene.
In another embodiment of the present invention, all the steps are preferably performed at a temperature in the range of (-) 10°C to reflux temperature of the solvent used.
In yet another embodiment of the present invention, process for preparation of a compound of formula (I) may also be extended further in the making of cephalosporin antibiotics such as cefpodoxime proxetil of formula (III) by conventional methods.
In the present invention starting material(s) for the preparation of a compound of formula (I), were prepared according to the known processes in the prior art.
The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.


Example (1) Preparation of l-iodoethylisopropylcarbonate
Sodium iodide (27g) was added to a mixture of toluene (150mL) and N, N-dimethylacetamide (15mL) at room temperature. The reaction mixture was stirred under reflux for 2hours for azeotropic removal of water. 1-Chloroethyl isopropyl carbonate (30.0 gm) is added to this at 102 to l05°C and the reaction mixture is maintained at the same temperature for 2hours and 30minutes. The reaction mixture was washed with 100 mL of water, 5% sodium thiosulphate solution (100 mL) followed by 20% sodium chloride solution. The washed organic layer is stirred with charcoal, filtered, and concentrated to one fifth of its original volume under reduced pressure to obtain 1-Iodomethyl isopropyl carbonate at a purity of more than 88%.
Example (2) Preparation of l-(isopropoxycarbonyloxy) ethyl (6R,7R)-7-[2-(2-amino-4-thiazolyl)-(Z)-2-(methoxvimino)acetamidol-3-methoxvmethyl-3-cephem-4-carboxylate (Cefpodoxime Proxetil)
l,8-Diazabicycloundec-7-ene (19gm) is added to a solution of cefpodoxime acid (55gm) in N,N -dimethylacetamide (275mT), at 0 to (-) 5°C. 1-iodoethyl isopropyl carbonate prepared as in the above example is added into the reaction mixture at (-) 8 to (-) 10°C under vigorous stirring. The mixture is stirred for 45 to 50 min at the same temperature and ethyl acetate (525mL) is added. The reaction mixture is then washed successively with water and brine and then stirred with charcoal. It's filtered and the filtrate is concentrated completely under reduced pressure. Methanol is added to the final residue and distilled off completely under reduced pressure to ensure thorough concentration. Methanol (160 mL) is further added and stirred for 15 minutes at 25 to 35°C to get a clear solution. The resultant clear solution was added into water (1500 mL) at 30 to 32°C while maintaining the reaction mass pH at 3.5 to 4.0, by simultaneous addition of 5% aqueous ammonia solution to complete the crystallization. The product slurry is filtered and washed with water and dried under reduced pressure at 45 to 50°C


for 8 to 10 hours to give Cefpodoxime proxetil with yield 60g at HPLC purity of more than 97%), with A2 impurity at not more than 0.60%.

We claim:
(1) An improved process for the preparation of 1-iodoethylisopropylcarbonate of formula (I), comprising the steps of:
(Formula Removed)
(i) adding sodium halide in an organic solvent;
(ii) optionally removing water from reaction mixture as obtained from step (i); (iii) reacting 1 -chloroethylisopropylcarbonate of formula (II) with the reaction mixture as obtained from step (i) at reflux temperature in the absence of crown ether;
(Formula Removed)
(iv) adding water to the reaction mixture as obtained from step (iii);
(v) separating the organic layer from aqueous layer;
(vi) optionally treating the organic layer with sodium thiosulphate solution;
(vii) optionally washing the organic layer with sodium chloride solution;
(viii) optionally charcolizing the organic layer; and
(ix) filtering and concentrating the organic layer to get 1-iodoethylisopropylcarbonate
of formula (I).
(2) A process according to claim 1, wherein the said sodium halide is preferably sodium bromide or sodium iodide, most preferably sodium iodide.

(3) A process according to claim 1, wherein the said organic solvent may be selected from hydrocarbon or amide or mixture thereof, preferably N, N-dimethylacetamide and toluene.
(4) A process according to claim 1, wherein all the steps are preferably performed at a temperature in the range of (-) 10°C to reflux temperature of the solvent used.
(5) An improved process for the preparation of 1 -iodoethylisopropylcarbonate of formula (I) by reacting 1 -chloroethylisopropylcarbonate of formula (II) with sodium iodide in a mixture of N, N-dimethylacetamide and toluene in the absence of crown ether.
(Formula Removed)