GB2330141A

GB2330141A - Preparation of orally active cephalosporin antibiotic-cefixim

Info

Publication number: GB2330141A
Application number: GB9821967A
Authority: GB
Inventors: Anil Kumar Sharma; Arun Malhotra; Baldev Raj; Anuja Chauhan Sisodia; Debashis Das
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: DE19846449A1; PT102062A; GB9821967D0; PT102062B; ES2155349B1; ES2155349A1

Abstract

A process for the preparation of an orally active cephalosporin antibiotic-cefixim, of formula I in which an ester of formula II is reacted for 30 - 90 minutes at room temperature in an organic solvent with an aqueous solution of inorganic base in presence of a phase transfer catalyst, thus allowing that resultant mixture settles till separation of the aqueous and organic phases, isolating the cefixim of required purity from the aqueous layer by acidifying said aqueous layer by acidifying said aqueous layer.

Description

DESCRIPTION PROCESS FOR THE PREPARATION OF ORALLY

ACTIVE CEPRALOSPORIN ANTIBIOTIC-CEFIXIM 2330141 This invention relates to a process for the preparation of orally active cephalosporin Andblotic-Cefixim.

BACKGROUND

The first of a new series of cephalosporins which exhibit most of the properties desirable mi a compound to be used for empiric therapy was Cefotaxime, a methoxy iminocephalosporin bearing a 2-iminothiazol4-ylorotip, which was sWiftly followed by a number of very similar methoximes wili different -3-substituents like Ceftizoxime, Cef:meno.xime, Ceftriaxone and Ceftazidime compound (Am.J.Med. (1985), Suppl 2A,14.; Am. 1Med(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 arnffiothiazolyl cephalosporins are not absorbed from the G1 tract and are not orally active. Cefixim is one such exception having carboxy-methoxine 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 Wittig reaction to a vinyl intermediate, which is then converted into Cefixim. of formula I by standard procedure as described in.J.Antibioties (1985), 38, 1738. The said standard process comprises of the folio"-ine, s.cps:

, L 2 hydrolysis of methyl ester of formula II with inorganic base in aqueous solution at 40 degree C for 7 hours; adjusting the pH of the resulting solution to 6.0 with 10% HC 1 and subjecting it to column chromatography on Diaion EP-20 for purification; elutina the column with water and acidifying the fraction containing the desired compound (CefLxim) to pH 2. 1 with 10% HC 1; stirring the resulting solution for one hour andcoIlecting 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. This 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 subjected to column chromatography on Diaion HP -20 (Resin). lle purification technique involve the use of column chromatography using Dialon HP -20 which is expensive and industrially uneconomicad.

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

The objects of this invention are:

- To reduce the reaction time by increasing the speed of the reaction.

3 To decrease the reaction temperature. To overcome the formation of undesirable u'npunties are increase me yield. To eliminate the use of expensive uneconomical purification technique and thereby decrease the production cost. To reduce the number of complicated steps in the process.

H,N Y1 S 1 S N 1 C -CO 0 OCH, COOH 1 COOH (1) H,'N' S S OCH: COOH 1 COOCH, (II) 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 in organic solvent with aqueous solution of inorganic base in the presence of phase transfer catalyst at ambient temperature for a period of 30-90 minutes; allowina the resulting mixture to settle till the aqueous and organic layers separate; isolating Cefixin of required purity from aqueous layer by acidif-ing the said aqueous layer.

The ester of formula II, is a methyl ester and the oresnic solvent is a halogenated aliphatic hydrocarbon preferably methylene chloride. The weak increanic base used in the process is alkali carbonate prIeferably KC03. The ambient temperature during the reaction is preferably between 10 to 25 0 4 degree C and the acidification of the said aqueous layer is carried out by 10% HC 1 to pH 2. 1. Phase transfer catalyst improves the reaction condition as well as the quality of the final product without using purification techniques. The phase transfer catalyst used in the process is quaternary ammionium salt(s) of general formula R4NX-, where, and X n-butyl (CH3(CH2)31 n-pentyl (CH3(CH2)4_) n-hexyl (CH3(CH2)s Cl-, Br-, Ior OH- The said quaternary ammonium salt is tetraalkylammonium, halide or hydroxide. The cation contains large alkyl groups which confer upon its solubility Mi organic sol,,,,-ents. The anion is a halide or a hydroxide group, which is soluble in water. Such a cation will transport the anion (hydroxide ion) as its counter ion into organic phase from aqueous phase. This greatly facilitates the reaction which otherwise would occur only at the interphase The invention will now be described with reference to the following examples:

EXAMPLE l:-

K2C03066 mg, 1.2mmol) dissolved in water was added to a stH"Ted solution of the ester of formula 11 (500 rrig, 1.07 mmol) and tetrabutylammonium bromide (3.2 rrig, 0.01 mmol) in CH2C], at 20 deeree C. The reaction was complete in 40 min. (HPLC monitoring. The pH of the aq. layer after separation mas adjusted to 2.1 by 1001/o THIC1 to yield 2286 mg of Cefixhn of formula 1. Tests were conducted on this compound of formula I by standard methods and the results found were as follows: Purity (HPLC) = 98.5%, [(X]25 D = -78.760; IR (Kbr): 1771, 1669 cm71; 'H NMR (DMSO-&): 3 3.55-3.88(2RqJ = 17.66 Hz); 4.6 (2H,s); 5.21 (1 H,dJ = 4.719 Hz); 5.32 (1 H,dJ = 11.339 Hz); 5.6 (1H,dJ = 17.47 Hz); 5.81 (IH ddJ = 4.78 Hz, 8.18 Hz); 6.81 (1 H,s); 6.91 (1 H,ddj = 11 17 Hz, 17.52 Hz); 7.29 (2H,bs, D20 exchangeable); 9.61 (1 H,dJ = 8.2 Hz, D,0 exchangeable).

EXAMPLE 2:-

K2C03 (166mg, 1.2mmol) dissolved in water was added to a stirred solution of the ester of formula H (500 mg, 1.07 mmol) and tetrahexylammonium chloride (3.9 mg, 0.01 mmol) in CH2C12 at 20 degree C. The reaction was complete in 75 min. (HPLC monitoring). The pH of the aq. layer after separation was adjusted to 2.1 -by 10% HCI to yield 297 mg of Cefixim for formula I. Tests were conducted on this compound of formula I by standards methods and results found were as follows:

Purity l-IPLC) = 98.70/o; [Ctf'D= -79.520; IR (KBr) = 1769, 1670 cm-l; 'H (DMSO-d6): 3 3.54-3.88(2H,qJ = 17.5 Hz); 4.59 (2H,s); 5.21 (1 H,dJ = 4.76 Hz); 5.32 (1H,dJ =1 7.36 Hz); 5.6 (1H,dJ---17.48 Hz); 7.30 CM,bs, D-O exchangeable); 9.60 (1 H,dJ = 8.15 Hz, D20exhangeable).

6

Claims

C L A IM S

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

reacting ester of formula H in organic solvenewrith aqueous solution of inorganic base in the presence of a phase transfer catalyst at ambient temperature for a period of 30-90 minutes; allowing the resulting mixture to settle till the aqueous and organic layers separate; isolating the Cefixim of required purity from aqueous layer by acidifyffig the said aqueous layer.

2. A process as claimed in claim 1 wherein the said ester of formula II is a methyl ester.

3. A process as claimed in claim 1 wherein the weak inorganic base is alkali carbonate preferably K2C03.

4. A process as claimed in claim 1 wherein the organic solvent is a halogenated aliphatic hydrocarbon.

5. A process as claimed in claun 4 wherein the said halogenated aliphatic hydrocarbon is methylene chloride.

6. A process as claimed in claim 1 wherein the ambient temperature during the r%-.actior, is bet,.e--n 10-25 degree C.

7 7. A process as claimed in claim 1 wherein acidification of the aqueous layer is carried out by 10% HC 1 to pH 2. 1.

8. A process a claimed in claim 1 wherein the said phase transfer catalyst is quaternary ammonlum salts of geneal formula R4INT' X," where, R n-butyl. (CH3(CH2)31 n-pentyl (CH3(CH2)4), n-hexyl (CH3(CH2)s'), Cl-, Br-, P or Off.

and X

9. A process as claimed in claim 8 wherein the phase transfer catalyst is tetrabuty.lammoniwn bromide or tetrahexylarnmoniurn chloride.

10. A process as claimed in claim 1 substantially as described in Example 1 or Example 2.

11. An oral pharmaceutical composition comprising an orally active cephalosporin antibiotic - cefixim when prepared by a process as claimed in any one of the preceding claims.