WO2008132574A1

WO2008132574A1 - Purification of cefuroxime acid

Info

Publication number: WO2008132574A1
Application number: PCT/IB2008/000983
Authority: WO
Inventors: Rishi Pratap Singh; Vidya Bhushan Tiwari; Kishore Kumar Khemani; Parven Kumar Luthra
Original assignee: Parabolic Drugs Limited
Priority date: 2007-04-27
Filing date: 2008-04-22
Publication date: 2008-11-06

Abstract

The present invention relates to a process for the purification of cefuroxime acid {(6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxy-iminoacetamido] ceph-3-em-4-carboxylic acid} of formula (I).

Description

"PURIFICATION OF CEFUROXIME ACID"

Field of the Invention: The present invention is in the field of chemistry and more particularly the invention deals with the process for the purification of cefuroxime acid {(6R, 7R)-3- carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxy-iminoacetamido] ceph-3-em-4- carboxylic acid} of general formula (I).

(I)

Background of the Invention:

Cefuroxime acid is a key intermediate for the industrial synthesis of cefuroxime sodium (for the injection administration) and cefuroxime axetil (for the oral administration). These compounds have a valuable broad spebtrum and having activity against wide range of gram-positive and gram-negative microorganisms. Their effectiveness is advantageously combined with remarkable resistance to β-lactamases.

Cefuroxime can be prepared by condensation of 3-hydroxymethyl-7-amino cephalosporanic acid with (fur-2-yl)-2-methoxyimino. acetic acid to produce (6R,7R)-7- [(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid followed by carbamoylation of resulting acid with isocyanate of formula RNCO wherein R is a labile substituent to get (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2~ yl)-2-methoxyimino acetamido] ceph-3-em-4-carboxylic acid (cefuroxime acid).

In prior art pure crystalline cefuroxime axetil is obtained by cefuroxime sodium from either 3-hydroxy cefuroxime or cefuroxime. Therefore, the said process involves an additional step of preparing sodium cefuroxime and therefore it is not economical. If purification of cefuroxime axetil or cefuroxime sodium is done without purifying cefuroxime then the yield of the final product will be low. Purify the compound on penultimate stage is more economical rather than on the final stage.

Hence, there is unmet need to develop a simple and environment friendly process for the purification of cefuroxime acid, which is convenient to perform on a commercial scale, operationally safe and provide the product in pure form.

Objects of the Invention:

An object of the present invention is to provide a simple and environment friendly process for the purification of cefuroxime acid of formula (I) with good yield, high purity and color absorbance of less than 0.1 at 410 nm.

Summary of the Invention:

The present invention provides process for the process for the purification of cefuroxime acid {(6R, 7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxy- iminoacetamido] ceph-3-em-4-carboxylic acid} of general formula (I).

DETAILED DISCRIPTION OF THE INVENTION

Accordingly, the present invention provides a simple and environment friendly process for the preparation of cefuroxime acid of formula (I) with high purity and improved color. Cefuroxime acid with color absorbance of less than 0.1 at 410nm is useful for manufacturing of cefuroxime axetil having acceptable quality in terms of purity and color. The spray drying process for making amorphous cefuroxime axetil always result in the enhancement of color hence it is utmost important to control the color of cefuroxime acid to get acceptable quality of amorphous cefuroxime axetil.

The process for purification of cefuroxime acid of formula (I),

(I) Which comprises the steps of:

(i) dissolving impure cefuroxime acid of formula (I) in a mixture of water and polar aprotic solvent, (ii) adjusting the pH of the mixture in the range 6.0 to 7.0 by adding a base to get a clear solution,

(iii) treating the solution with activated charcoal followed by filtration, (iv) adjusting the pH of the filtrate to 3.5-3.6 by adding dilute acid and; (v) isolating the precipitated product by adjusting pH 1.5-2.5 by adding dilute acid at a temperature range 0 to 5⁰C.

Moreover, the acid product can easily be converted into the corresponding pharmaceutically acceptable salt or ester, preferably into cefuroxime salt and cefuroxime axetil, by using conventional techniques known to those skilled in the art.

For purposes of this invention, polar aprotic solvent is selected from the group of acetonitrile, dioxane, tetrahydrofuran, alcohol or acetone.

Base used in this invention is selected from the group of alkali/alkaline earth metal hydroxides like sodium hydroxide, potassium hydroxide.

Preferably, dissolution is carried out in the temperature range of 0 to 5°C. The above solution is then charcoalised with activated carbon followed by filtration. Preferably, the charcoalisation is carried out in the temperature range of 0 to 5⁰C.

Finally, the acid used for adjusting pH from 1.5-2.5 is selected from the group of hydrochloric acid or sulphuric acid, more preferable pH to isolate the cefuroxime acid of formula (I) in pure form having color absorbance less than 0.1 at 410 nm and purity more than 99.0% in the range of 2.0±0.05 at a temperature in the range of 0 to 5⁰C .

The invention is illustrated by the following examples which are only meant to illustrate the invention and not act as limitations. All embodiments apparent to a process their in the art are deemed to fall within the scope of the present invention. Examples

Example- 1

Crude cefuroxime acid [(10.0 g), purity: 98.73%, Color absorbance: 2.263] was added to the mixture of water (130 ml) and ACN (30 ml) at 25-30⁰C. The pH of the solution was adjusted to 6.0 to 7.0 by adding 10 % sodium hydroxide solution and was stirred for 60 minutes at 0 to 5°C to get the clear solution. Activated charcoal was added and stirred for 30 minutes at 0 to 5⁰C. The solution was filtered and washed with 10 ml of water. The pH of the filtrate was adjusted to 3.5 to 3.6 by adding 5% HCl and was stirred for 30 minutes at 0 to 5⁰C. Finally, the. pH was adjusted to 1.5 to 2.1 by adding 5% HCl solution and was stirred for 60 minutes at 0 to 5°C. The product was filtered and washed with a mixture of ACN and water. The product was dried to get cefuroxime acid (6.0 g) in pure form. HPLC purity: 99.50 %, Color absorbance: 0.04.

Example 2-9

The reaction was conducted in the similar manner as explained in example 1 by using different solvents. Results are given in Table 1. '

Table: 1

Abbreviations

ACN : Acetonitrile

HCl : Hydrochloric acid

IPA : Isopropyl alcohol

THF : Tetrahydrofuran

MDC : Dichloromethane

Claims

We Claim:

1) A process for the purification of cefuroxime acid of general formula (I)

comprising the steps of:

(i) dissolving impure cefuroxime acid of formula (I) in a mixture of water and polar aprotic solvent (ii) adjusting the pH of the mixture in the range of 6.0 to 7.0 by adding a base to get a clear solution,

(ii) treating the solution with activated charcoal followed by filtration, (iii) adjusting the pH of the filtrate to 3.5 to 3.6 by adding dilute acid and; (iv) isolating the precipitated product by adjusting pH 1.5-2.5 by adding dilute acid at a temperature range 0 to 5⁰C.

2) The process as claimed in claim 1, wherein the polar aprotic solvent used in step (i) is selected from the group of acetonitrile, Tetrahydrofuran, acetone, dioxane or mixture thereof.

3) The process as claimed in claim 2, wherein the preferred polar aprotic solvent is acetonitrile.

4) The process as claimed in claim I₅ wherein said base used in step (ii) is selected from alkali or alkaline earth metal hydroxides like sodium hydroxide, potassium hydroxide.

5) The process as claimed in claim 4, wherein the preferred base is sodium hydroxide. • .

6) The process as claimed in claim 1, wherein the acid used in step (iv)is selected from the group of hydrochloric acid or sulphuric acid. 7) The process as claimed in claim 1, wherein the said pure cefuroxime acid having the color absorbance less than 0.1 at 410 nm. 8) Cefuroxime acid having the color absorbance less than 0.1 at 410 nm.