GB2330140A

GB2330140A - Cefixim preparation

Info

Publication number: GB2330140A
Application number: GB9821966A
Authority: GB
Inventors: Anuja Chauhan Sisodia; Debashis Das; Anil Kumar Sharma; Arun Malhotra; Baldev Raj
Original assignee: J K IND Ltd
Current assignee: J K IND Ltd
Priority date: 1997-10-08
Filing date: 1998-10-08
Publication date: 1999-04-14
Also published as: GB9821966D0; PT102061B; ES2155350A1; DE19846448A1; ES2155350B1; PT102061A

Abstract

Cefixim of formula I is prepared by reacting an ester of formula II for 1.5 - 2 hours with an inorganic base in a mixture of dimethylformamide (DMF) and water, isolating the cefixim of required purity by acidifying the resulting reaction mixture and drying.

Description

2330140

DESCRIPTION PROCESS FOR THE PREPARATION OF ORALLY ACTIVE CEPHALOSPORIN ANTIBIOTIC-CEFIXIM

This invention relates to a process for the preparation of orally active cephalosporin Antibiotic-Cefixim.

BACKGROUND

The first of a new series of cephalosporins which exhibit most of the properties desirable in a compount to be used for empiric therapy was Cefotaxime, a methoxy iminocephalosporin bearing a 2-iminotiazol-4-ylgroup, which was swiftly followed by a number of very similar methoximes with different 3-substituents Ue Ceftizoxime, Cefinenoxime, Ceftriaxone and Ceftazidime compound (Am.J.Med. (1985), Suppl 2A,14.; Am.J. Med.(1985, ) Suppl 2A,21; Clin.Pharm.(1987),6,59.; Recent Advances in the Chemistry of P-Lactam Antibiotics, Special publication No. 52, The Royal Society of Chemistry, London, July 1984,p.1).

Most of the aminothiazolyl cephalosporins are not absorbed from the GI tract and are not orall active. Cefixim is one such exception having carbox.ymethoxime group with small lipophillic 3-substituents. In the synthesis of CefiXim, 3-acetoxy group of 7-ACA is transformed via a 3phosphonium salt and by Wittia reaction to a vinyl intermediate, which is then converted into Cefixim of formula I by standard procedure as described in J.Antibiotics (1985), 38, 1738. The said standard process comprises of the following steps:

- hvdrolvsis of methA ester of formtila II with inorganic base in aoueotis solution at 40 degree C for 7 hours. adjusting the pH of the resulting solution to 6.0 with 10% Hcl and subjecting it to column chromatography on Diaion HP-20 for punification; eluting the column with water and acidifying the fraction containing the desired compound (Cefixim) to pH 2.1 with 10% Hcl; stirrina the resultina solution for one hour and collecting the precipitate of Cefixim by filtration.

The product yield in this process is 41%. This process suffers from the following drawbacks:

- The reaction is carried out at an elevated temperature, viz., 40 degree C and is completed in 7 hours. TIfis leads to the formation of many undesirable impurities, and thereby decrease the purity of the final product in the solution.

To get the desired purity of the final product, the said solution is subjec ted to column chromatography on Diaion HP -20 (Resin).

The purification technique involve the use of column chromatography using Diaion HP-20 which is expensive and industrially uneconomical.

In US Patent 440924, Cefixim is obtained by hydrolysing tertiary butyl ester along with other protected substituents such as benzhydral and formamide by usina trifluoroacetic acid. This process involves more number of complicated steps.

The obejcts of this invention are: To reduc.- the reaction time by increasing the speed of the reaction. To decrease the reaction temperature. To overcome the formation of undesirable impurities and increase the yield.

To eliminate the use of expensive uneconomical puidfication technique and thereby decrease the production cost. To reduce the number of complicated steps in the process.

H.N S C - CONH 0 OCH: tOOH 1 COOH H:N S S C - CON-H 0 OCH2 COOR 1 CO0CH3 (E) To achieve the aforesaid objectives this invention provides a process of preparing orally active cephalosporin antibiotic Cefixim of formula I comprising:

- reacting ester of formula U with inorganic base in a mixture of dimethyl formamide (DNE) and water at ambient temperature for a period of P1/2 to 2 hours; - isolating Cefixim of required purity by acidifying the resulting reaction mixture and drying.

The ester of formula U preferably a methyl ester and inorganic base is preferably alkali carbonate. The ambient temperature during the reaction is preferably between 10 to 25 degree C. The DNT: water is in the ratio; 1:4 and the isolation of Cefixim is carried out by using 1011/0 HC 1.

In this method DNIF not only acts as a solvent but also acts as a catalyst. It is well knos,,-n that the lone pair of electrons at nitrogen atom of DMF coordinates and thus solvates the K ion, thereby facilitating easy av.allability of C03:-. ions responsible for the hydrolysis of the ester gloup.

The invention will now be described with reference to the following examples:

EXAMPLES I:-

To ester of formula H (500 ing, 1.07 mmol) in DNT was added K2C03 (740 mg, 5.36 mmol) dissolved in water. Reaction rniixture was stirred at degree C. After the reaction was completed (2 hours as shown by 1HPLC monitoring), the product (Cefixim) was isolated by acidifying the reaction mixture to pH = 2.1 using 10% HCL The resulting solid was collected by filtration and dried to afford 3)44 me, of the compound of formula I. Tests were cQnducted on this compound of formula I by standard methods and the results found were as follows:

Purity (HPLC) = 98.5%, [a]" D = -78.760; IR (Kbr): 1770, 1668 cml; H NMR (DMSO-d,6): 3 3.54 -3.87 (2H, q, J = 17.61 Hz); 4.61 (214, s); 5.21 (IH, d, J =4.81 Hz); 5.32 (IH, d, J = 11.37 Hz); 5.6 (1 H, d, J = 17.45 Hz); 5.81 (1 H, dd, J = 4.81 Hz, 8.16 Hz); 6.81 (1 R s); 6.91 (1 R dd, J = 11. 31 Hz, 17.51 Hz); 7.2 9 (2H, bs, D20 exchangeable); 9.61 (1 H, d, J = 8.2 11-Tz. D20 exchangeable).

EXANIPLE 2:- To ester formula 11 (500 me, 1.07 rrun(-,1) in DIkT was added INTa2C03 (583 mg, 5.5 nirnol) dissolved in water. Reaction mixture ".as stirred at 25 deQree C. After the reaction was completed (1 hr 50 min. as shown by HPLC monitoring), the product (Cefixim) was isolated by acidiMna, the reac- z - 5 tion mixture to pH - 2.1 using 10% HC 1. The resulting solid was collected by filtration and dried to afford 305 mg of the compound of formula 1. Tests were conducted on this compound of formula 1 by standard methods. The results found were as Mows:

Purity "LC) = 97.3%, [CC12' D= -77.920; IR (Kbr): 1770, 1669 cm71; H (DMSO-&): 3 3.51 - 3.86 (2H, q, J = 17.58 Hz); 4.58 (2H,s) 5.20 (11- d, J = 4.78 Hz); 5.31 (IH, d, J = 11.32 Hz); 5.6 (IH, d, J = 17. 39 Hz); 5.81 (IH, dd, J = 4,78 Hz, 8.03 Hz); 6.81 (IH, s), 6.9 (IH, dd, J = 11.32 Hz, 17.41 Hz); 7.25 (2H, bs, D20 exchangeable); 9.60 (1 H, d, J = 8.11 Hz, D20 exchangeable).

Claims

I. A process of preparing orally active cephalosporin antibiotic-Cefixim of formula 1 comprising:

reacting ester of formula 11 with inorganic base in a mixture of dimethylformarnide (DNE) and water at ambient temperature for a period of 1- 1/2 to 2 hours; - isolating the Cefixim of required purity by acidifying the resulting reaction mixture and drying.
2. A process as claimed in claim 1 wherein the said ester of formula H is preferably methyl ester.
3. A process as claimed in claim 1 wherein the inorganic base is alkali carbonate.
4. A process as claimed in claim 3 wherein the alkali carbonate is Potassium/Sodium Carbonate.
5. A process as claimed in claim 1 whereim the DW and water are in the rati o 1: 4.
6. A process as claimed in claim 1 wherelm the ambient temperature during the reaction is between 10-25 de!zree C.
7. A process as claimed in claim 1 whereim the acidification of the resulting reaction rnixture for isolation of Cefixim is carried out by 101,0' HC 1 to pH 27. 1.
8. A process as claimed in claim 1 substantially as hereinbefore described in Example 1 or Example 2.
9. An oral pharmaceutical composition comprising an orally active caphalosprin antibiotic-Cefixim when prepared by the process as claimed in any one of the preceding claims.