PROCESS FOR PREPARING AMORPHOUS CEFDITOREN PIVOXIL

Field of the Invention
The present invention relates to a process for preparing amorphous form of cefditoren pivoxil.

Background of the Invention
Cefditoren pivoxil, chemically known as [6R-[3(Z),6a,7b(Z)]]-7[[(2-amino-4-thiazolyl) (methoxyimino)acetyl]amino]-3-[2-(4-methyl-5-thiazolyl)ethenyl]-8-oxo-5-thia-l-aza bicyclo[4.2.0]oct-2-ene-carboxylic acid, pivaloyloxymethyl ester of formula I, is a third generation cephalosporin derivative belonging to the class of 3-(2-substitutedvinyl) cephalosporin, which was first developed by Meiji Seika of Japan. Cefditoren pivoxil is highly active, not only against a variety of gram-positive and gram-negative bacteria, but also against some resistant strains of bacteria.

Formula I
A compound of formula I was first claimed in US 4,839,350. This patent further discloses a process for preparation of claimed compound thereof as well as its therapeutic use as antibacterial. In addition, the patent describes a process for preparing amorphous form of cefditoren pivoxil wherein the process is giving more than 20% of unwanted E-isomer, which is then separated by means of column chromatography. The purity of cefditoren pivoxil obtained is described as being typically around 94.0% to 95.5% when analyzed by HPLC.

US 6,294, 669 discloses a crystalline form of cefditoren pivoxil and process for preparing the same wherein the crystalline form is having a purity of about 97 to 98%, typically 97.7%. The disclosed process for converting amorphous cefditoren pivoxil to the crystalline substance is believed to be very complicated, requiring eight steps that include dissolution, concentration, and addition of two or three different solvents in different steps.

Thus, the conversion of amorphous form to crystalline form may be time consuming, low yielding and difficult to scale up to commercial levels.

Japanese Patent Application No. 2001-131071A2 discloses a process for preparing amorphous cefditoren pivoxil by precipitation, spray-drying, and freeze-drying. It further discloses a process of converting crystalline cefditoren pivoxil to amorphous cefditoren pivoxil by milling. This process provides a product that has purity in the range of 93 to 98%.

PCT application WO 2005/044824 describes several processes for preparation of highly pure amorphous as well as crystalline cefditoren pivoxil. One of the processes employs higher amount of water miscible solvent after dissolving the crystalline cefditoren pivoxil in acid to get an amorphous cefditoren pivoxil.

PCT application WO2006/024900 describes a process for preparation of amorphous cefditoren pivoxil which comprises use of water immiscible solvent after dissolving the crystalline cefditoren pivoxil in organic solvent followed by precipitation by means of antisolvent or evaporation of water immiscible organic solvent.

The prior art processes disclosed above have one or more of the disadvantages such as the use of very large volumes of a solvent that by their toxicity and possibility of explosive may render the process not commercially feasible. Precipitation of the product dissolved in solvent requires very elaborate experimental set up in the laboratory (filtration of the solution of the product prior to its spray drying, high rate of stirring, exact rate of addition, continuous froth collection, the necessity to harvest the product immediately) which renders the reaction arduous and difficult to manage in a large scale manufacturing environment. In fact, even under a manageable laboratory environment, only a substantially amorphous product could be obtained.

Hence, there remains a need for a simple, cost-effective process for producing highly pure amorphous form of cefditoren pivoxil, wherein the process by is easily scalable for commercial level production.

Object and Summary of the Invention
The object of the present invention is to provide a process for producing cefditoren pivoxil which is convenient and efficient.

It is another object of the present invention to provide a simple, cost-effective process for producing highly pure amorphous cefditoren pivoxil.

It is another object of the present invention to provide a process for producing amorphous cefditoren pivoxil with high purity and yield at large scale industrial production.

It is yet another object of the present invention to provide an easy and ecofriendly process for preparation of highly pure amorphous cefditoren pivoxil employing less quantity of solvents.

The above and other objects of the present invention are attained according to following preferred embodiments of the present invention. However the scope of the invention is not restricted to the particular embodiments discussed herein after.

In accordance with the present invention there is provided a process for preparing amorphous cefditoren pivoxil comprises of dissolving crude cefditoren pivoxil in water followed by acidification, subsequently treating the resultant solution with a first organic solvent until complete dissolution of cefditoren pivoxil followed by treatment with base, precipitating the resultant solid from the organic layer and isolating the amorphous cefditoren pivoxil.

In accordance with other embodiment of the present invention, the acidification is performed employing an acid selected from inorganic or organic acid in an amount to maintain pH in the range of 0.1 to 1.

In accordance with other embodiment of the present invention, wherein the treatment with base is performed employing a base is selected from organic or inorganic base, to adjust pH in the range of 5.5 to 7.5.

In accordance with another embodiment of the present invention the cefditoren pivoxil produced is having purity greater than 98.5%.

Detailed description of the Invention
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.

The present invention discloses a process for large scale production of amorphous cefditoren pivoxil by a simple and economic process.

In accordance with the invention crude cefditoren pivoxil is dissolved in water followed by acidification. The acidic solution is further treated with a first organic solvent for complete dissolution of cefditoren pivoxil. The resultant solution is treated with a base and the layers so formed are separated and solid precipitated from an organic layer which is further isolated and dried under vacuum.

Embodiments of the process of the present invention may include one or more of the following features. An acid employed for the acidification is selected from an inorganic or organic acid wherein the inorganic acids are selected from group consisting of but not limited to hydrogen chloride, hydrogen iodide, hydrogen bromide, and the like and the organic acids are selected from the group consisting of but not limited to oxalic acid, tartaric acid, succinic acid, fumaric acid, salicylic acid, malonic acid, maleic acid, napthanoic acid, acetic acid and the like. The acid employed herewith is in an amount sufficient to adjust pH of 0.1 to 1.0, preferably 0.2 to 0.8.

According to the invention, the first organic solvent may be an alcohol, a ketone, an ester, a chlorinated hydrocarbon or a mixture thereof. The alcohol may be one or more of butanol, pentanol and hexanol or a mixture thereof. The ester may be one or more of ethyl formate, methyl acetate, ethyl acetate, isobutyl acetate, butyl acetate or a mixture thereof. The ketone may be one or more of acetone, methyl ethyl ketone, diisobutyl ketone, methyl isobutyl ketone or a mixture thereof. The glycol may be one or more of propylene glycol, ethylene glycol or a mixture thereof. The chlorinated hydrocarbon may be one or more of methylene chloride, ethylene chloride, chloroform or a mixture thereof.

According to the invention, the base used herein is selected from the group consisting of but not limited to organic or inorganic base, in an amount sufficient to adjust pH of 5.5 to 7.5, preferably 6.0 to 7.0 and more preferably 6.0-6.5. Organic base used herein is selected from the group consisting of but not limited to triethyl amine, diisopropyl amine, diisopropyl ethyl amine, N-methylpyrrolidone etc. Inorganic base used herein is selected from the group consisting of alkali metal, alkaline earth metal hydroxide, carbonate, hydroxy carbonate such as for example, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, calcium carbonate, magnesium carbonate, magnesium hydroxide and the like.

According to the invention, isolation of an amorphous cefditoren pivoxil is carried out either by removing the first organic solvent by spray-drying, freeze drying, distillation, or alternately by adding the second organic solvent to the first organic solvent in an amount sufficient to precipitate the cefditoren pivoxil from the solution, which is filtered by using the known techniques such as filtration under reduced pressure or under atmospheric pressure. The second organic solvent, employed for precipitation, may be alkyl ether, a hydrocarbon or a mixture thereof.

Crude cefditoren pivoxil used herein is prepared by the process disclosed in the literature and consists of either crystalline or mixture of crystalline and amorphous cefditoren pivoxil.

In accordance with the present invention, the amorphous cefditoren pivoxil so produced by a process of the invention is having purity greater than 98.5%.

In the following section preferred embodiments are described by way of examples to illustrate the process of the invention. However, these are not intended in any way to limit the scope of the present invention.

Example 1
Crude cefditoren pivoxil (100 gm) was dissolved in water at ambient temperature, solution cooled to 5-10 °C and pH of the solution was adjusted to 0.4 to 0.6 by adding hydrochloride solution. The resultant solution was treated with dichloromethane (1000ml) for complete dissolution of cefditoren pivoxil followed by basifying with 8% solution of sodium bi-carbonate. The layers so formed were separated and compound extracted to organic layer. The organic layer was subjected to spray drying to obtain an amorphous cefditoren pivoxil, which was further dried in vacuum oven at 40-45 ºC. The purity of amorphous cefditoren pivoxil so obtained is having purity greater than 98.5%.

Example 2
Crude cefditoren pivoxil (100 gm) was dissolved in water at ambient temperature and solution cooled to 5-10 °C followed by adjusting the pH of the solution to 0.4 to 0.6 by adding hydrochloride solution. The resultant solution was treated with dichloromethane (1000ml) for complete dissolution of cefditoren pivoxil. The solution is basified with 8% solution of sodium bi-carbonate. The layers so formed were separated and compound was extracted to organic layer. The organic layer was subjected to precipitation by means of cyclohexane (250 ml). The precipitate so obtained was filtered and dried to obtain an amorphous cefditoren pivoxil.

While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope and spirit of this invention.

We Claim:
1. A process for preparing amorphous cefditoren pivoxil comprising:
dissolving crude cefditoren pivoxil in water followed by acidification;
treating the resultant solution with a first organic solvent until complete dissolution of cefditoren pivoxil followed by a treatment with base;
precipitating the resultant solid from the organic layer and
isolating the amorphous cefditoren pivoxil.

2. The process according to claim 1, wherein the acidification is performed employing an acid selected from inorganic or organic acid in an amount to maintain pH in the range of 0.1 to 1.

3. The process according to claim 2, wherein the acidification is performed employing an acid selected from inorganic or organic acid in an amount to maintain pH in the range of 0.2 to 0.8.

4. The process according to claim 2, wherein the inorganic acid is selected from group consisting of hydrogen chloride, hydrogen iodide and hydrogen bromide and wherein the organic acid is selected from a group consisting of oxalic acid, tartaric acid, succinic acid, fumaric acid, salicylic acid, malonic acid, maleic acid, napthanoic acid and acetic acid.

5. The process according to claim 1, wherein the first organic solvent is selected from group consisting of alcohol, ketone, ester and chlorinated hydrocarbon or a mixture thereof.

6. The process according to claim 5, wherein the first organic solvent is selected from a group consisting of butanol, pentanol, hexanol ethyl formate, methyl acetate, ethyl acetate, isobutyl acetate, butyl acetate, acetone, methyl ethyl ketone, diisobutyl ketone, methyl isobutyl ketone, propylene glycol, ethylene glycol, methylene chloride, ethylene chloride, and chloroform or a mixture thereof.

7. The process according to claim 1, the base is selected from organic or inorganic base, to adjust pH in the range of 5.5 to 7.5.

8. The process according to claim 1, the base is selected from organic or inorganic base, to adjust pH in the range of 6.0 to 6.5

9. The process according to claim 8, wherein the organic base is triethyl amine, diisopropyl amine, diisopropyl ethyl amine and N-methylpyrrolidone; and inorganic base is sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, calcium carbonate, magnesium carbonate, magnesium hydroxide.

10. The process according to claim 1, wherein the resultant cefditoren pivoxil is having a purity greater than 98.5% .

Dated this the 17th day of February, 2011.
MANISHA SINGH NAIR
Agent for the Applicant [IN/PA –740]
LEX ORBIS IP PRACTICE

PROCESS FOR PREPARING AMORPHOUS CEFDITOREN PIVOXIL

Abstract of the Invention
Disclosed herein is a process for preparing highly pure amorphous cefditoren pivoxil from crude cefditoren pivoxil.