Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF CEFPHALOSPHORIN ANTIBIOTIC

Abstract The present invention relates to an improved process for the preparation of a cephalosporin antibiotic. More particularly, the present invention relates to an improved process for the preparation of Cefpodoxime acid of the formula (I).
Full Text

Field of the Invention
The present invention relates to an improved process for the preparation of cephalosporin antibiotic. The present invention more particularly relates to a process for the preparation of Cefpodoxime acid of the formula (I).

Background of the Invention
Cefpodoxime is a third generation cephalosporin antibiotic for oral administration and has a broader antibacterial spectrum over the general gram positive and gram negative bacteria, especially against Streptococci, than other antibiotics for oral administration which is administered as Cefpodoxime proxetil. The activity is primarily due to the Cefpodoxime acid, which is generated, easity in vivo by the hydrolysis of the proxetil.
WO 00/63214 discloses a process for the preparation of cephalosporin of general formula (VIII) by condensation of carboxy ester intermediate with silylatcd


or together with the COO- group to which RE is attached is an ester. This paitent publication always involves condensation of desilylated compound of fonnula (II) with silyl thiourea.

carboxylic acid salt; X is halogen. The process comprises reacting the compound of formula (IX) with compound of formula (III) and desilylating the compound of formula (X) and cyclizing the desilylated compound with thiourea to produce Cefpodoxime acid of formula (XII). This invention always involves de-silylation and isolation of compound of formula (X). Also this invention is exemplified only with silyl-protected compound of formula (IX).
The present process avoids the use of silylation step and hence does not involve the isolation of compound of formula (X), thereby reduces the eosi oi^ production and also makes the process simple and easy to implement in commercial scale.


wherein X represents a halogen atom, R3 represents -CH2R5 (R5 is hydrogen atom or the residue of a nucleophilic compound), a halogen atom, an alkoxyl group, rhiol group, amino group etc., -COOR4 represents a carboxylic group which may be esterified, and R6 represents an alkyl group and also a process for preparing a 7-| 2-(2-aminothiazol-4-yl)-2-(syn)-alkoxyiminoacetamido]cephalosporin derivatives of the formula (XIV)


During our continued research to find an alternative process we found a process, which is cost effective, commercially viable, eco-friendly, as it docs not involve silylation process, and yield product with good quality and quantity.
Objective of the Invention
The primary objective of the invention is to provide a new method tor the preparation of Cefpodoxime acid of the formula (I), which would be easy lo implement in commercial scales.
Another objective of the present invention is to provide an improved process for the preparation of cephalosporin antibiotic of the formula (I) in high purity and yield.
Another objective of the present invention is to provide a simple process tor producing cephalosporin antibiotic of the formula (I), which avoids the use ot silylation and desilylation, thereby reducing the cost of production and increasing the productivity.
Yet another objective of the present invention is to provide a purification process for the compound of formula (I).


i) preparing solution A by dissolving AMCA of formula (II) using water in ihc
presence of base,
ii) preparing solution B by treating chloro acid of formula (III) in an polar
organic solvent with activating agent consisting of POCI3, SOCI2, PCI
chloride,
iii) condensing solution A and B by maintaining the pH in the range 5.0-It).0
using an inorganic base to produce compound of formula (IV),
iv) cyclizing the compound of formula (IV) with thiourea in the presence of
solvent and salt of organic or inorganic base at a temperature in the range of 50 lo
+50 °C and isolating compound of formula (I),
v) dissolving the compound of formula (I) in an organic acid
vi) adding a solvent, and
vii) adjusting pH using base to produce pure Cefpodoxime of formula (I)
In yet another embodiment of the present invention is to provide a proeess lor
purification of compound of formula (I). The said process comprising the steps o(;
a) dissolving the compound of formula (I) in an organic acid
b) adding a solvent, and
c) adjusting pH using base to produce pure Cefpodoxime of formula (I) The reaction is shown in scheme I given below:


In an embodiment of the present invention, the groups represented by Y is a group that activates the carboxylic acid preferably halogen such as chloro, bromo, iodo, and the activation agent used is selected from POCI3, SOCI2, PCI5, oxalyl chloride, diphenyl chorophosphoridate, dialkyl chorophosphoridate, mercapto benzothiazole or biS-(2-oxo-oxazolidinyl) phosphonic chloride preferably POCI3.
In another embodiment of the present invention base used in step (i) is selected from sodium bicarbonate, sodium carbonate and the like.
In another embodiment of the present invention, the polar organic solvent used in step (ii) is such as dimethyl formamide, dimethyl acetamide (DMAc), and the like.
In still another embodiment of the present invention, inorganic base used in step (iii) is selected from ammonia, and sodium bicarbonate
In yet another embodiment of the present invention, the organic or inorganic base used in step (iv) is selected from ammonia, sodium acetate, and sodium bicarbonate

In an embodiment of the present invention, the compound of formula (I) obtained is a syn-isomer.
In another embodiment of the present invention, the invention is carried out without isolation of compound of formula (IV), which makes the process commercially viable and cost effective.
In another embodiment of the present invention the organic acid used in step (v or a) is such as acetic acid, formic acid and the like.
In yet another embodiment of the present invention the solvent used in step (v or a) is such acetone, methanol, THF, DMF, water and the like or mixtures thereof
In still another embodiment of the present invention the reaction carried out in situ manner from step (ii) to (iv).
In yet another embodiment of the present invention the Cefpodoxime obtained from step (iv) can be used as such or optionally purified by performing the steps of (v) to (vii).
In still another embodiment of the present invention the purification technique given in step (a) to (b) can be employed to Cefpodoxime which is prepared by the process given in prior art or the process given in the present invention. Generally Cefpodoxime obtained by open chain process suffers from the quality in terms of color and purity, and by applying this purification steps yields compounds of formula (I) in good purity and color.
In one more embodiment of the present invention the Cefjpodoxime of formula (I) obtained from the present invention can be further purified if required by utilizing the acid base technique.
In yet another embodiment of the present invention the process given in the present invention can be extended without any difficulties to similar type of

cephalosporin having aminothiazole substituent at 7th position of cephem such as ceftriaxone, cefotaxime, cefepime, etc...
In still another embodiment of the present invention the compound of formula (I) is further converted into salts or esters by the process known in literature.
The process is environmental friendly because, the present inventions do not involve hazardous silylating agent and its by-product.
The present invention is provided by the example given below, which is provided by way of illustration only and should not be considered to limit the scope of the invention.
Example 1
Preparation of (+)-(6R,7R)-7-[2-(2-Aminothiazol-4-yl)-(Z)-2-
methoxyiminoacetamido]-3-methoxymethyl- 3-cephem-4-carboxylic acid (Cefpodoxime acid)
Preparation of solution A
To AMCA (100 g) in water, sodium bicarbonate solution (68.75 g in 800 ml) was
added slowly and stirred to get clear solution.
Preparation of solution B
To DMAc (150 ml) chloroacid (4-chloro-2(Z)-methoxyimino-3-oxo-butyric acid) (85 g) was added and stirred to get a clear solution. The solution was cooled to -15 °C and POCI3 (72 g) was added and stirred at -10 °C. Condensation
To precooled solution A, solution B was added at -10 °C by maintaining pH of 6.4 - 6.6 using aqueous ammonia and stirred for 30 minutes at 2°C. To the reaction mixture thiourea (72 g in 625 ml) solution was added and stirred for 3 hr at 2 °C was added by maintaining pH 6.4 - 6.6 using aqueous ammonia.

To the reaction mixture EDTA, hydro, and carbon were added and stirred for 10
minutes. Carbon was filtered and the pH of clear filtrate was adjusted to 2.75 - 2.85
using 10% sulphuric acid solution. The solid obtained was filtered and washed with
water. The wet solid is taken for purification.
Wet Weight of the product : 130 - 150 g
Water content : 10 - 20%
Purification -I of Cefpodoxime acid:
To formic acid (100 ml), Cefpodoxime acid (140 g; 10% m/c) obtained according to the process given in example-1 was added, stirred to get suspension. To the suspension water was added followed by addition of acetone (300 ml). The pH of reaction mixture was adjusted to 2.8 using dilute ammonia solution. The solid obtained was filtered, washed with water and the wet solid was taken for further purification.
Wet Weight of the product : 125 - 130 g
Water content : 7-15%
Purification - II of Cefpodoxime acid;
To water (1500 ml), Cefpodoxime acid (125 - 130 g; 7 - 15% m/c) obtained
according to the process given in purification-1 followed by triethylamine was
added slowly and stirred to get clear solution. The clear solution was subjected to
carbon treatment followed by filtration. To the filtrate, water (300ml) was added.
The pH was adjusted to 2.8 using dilute sulphuric acid. The soUd obtained was
filtered and washed with water, followed by acetone wash. The wet product was
dried under vacuum to get pure Cefpodoxime acid.
Dry weight of the product : 100 - 110 g
Water content : less than L0%









We claim:
1) An improved process for the preparation Cefjpodoxime of formula (I), which
comprising the steps of:
i) preparing solution A by dissolving AMCA of formula (II) using water in the presence of base,

ii) preparing solution B by treating chloro acid of formula (III) in an polar organic solvent with an activating agent consisting of POCl3, SOCI2, PCI5, oxalyl chloride,

iii) condensing solution A and B by maintaining the pH in the range 5.0-10.0 using an inorganic base to produce compound of formula (IV),


iv) cyclizing the compound of formula (IV) with thiourea in the presence of solvent and organic or inorganic base at a temperature in the range of-50 to +50 °C and isolating compound of formula (I),
v) dissolving the compound of formula (I) in an organic acid
vi) adding a solvent, and
vii) adjusting pH using base to produce pure Cefpodoxime of formula (I).
2. An improved process for the preparation Cefpodoxime of formula (I), which
comprising the steps of:
i. preparing solution A by dissolving AMCA of formula (II) using water in the
presence of base, ii. preparing solution B by treating chloro acid of formula (III) in an polar
organic solvent an activating agent consisting of POCI3, SOCI, PCI5, oxalyl
chloride, iii. condensing solution A and B by maintaining the pH in the range 5.0-10.0
using an inorganic base to produce compound of formula (IV), and iv. cyclizing the compound of formula (IV) with thiourea in the presence of
solvent and organic or inorganic base at a temperature in the range of-50 to
+50 °C and isolating compound of formula (I).
3. A process for the purification of compound of formula (I), which comprising the
steps of;
a) dissolving the compound of formula (I) in an organic acid,
b) adding a solvent, and
c) adjusting pH using base to produce pure Cefpodoxime of formula (I).

4. The process as claimed in claim 1 or 2, wherein the polar organic solvent used in step (ii) is selected from dimethyl formamide or dimethyl acetamide.
5. The process as claimed in claim 1 or 2, wherein the inorganic base used in step (iii) is selected from ammonia, and sodium bicarbonate.

6. The process as claimed in claim 1 or 2, wherein the organic or inorganic base used in step (iv) is selected from ammonia, sodium acetate, and sodium bicarbonate.
7. The process as claimed in claim 1 or 3, wherein the organic acid used in step (v) or (a) is selected from acetic acid, or formic acid.
8. The process as claimed in claim 1 or 3, wherein the solvent used in step (vi) or (b) is selected from acetone, methanol, THF, DMF, water or mixtures thereof.


Documents:

052-che-2005-abstract.pdf

052-che-2005-claims.pdf

052-che-2005-correspondnece-others.pdf

052-che-2005-description(complete).pdf

052-che-2005-description(provisional).pdf

052-che-2005-form 1.pdf

052-che-2005-form 5.pdf

52-CHE-2005 AMENDED PAGES OF SPECIFICATION 15-06-2011.pdf

52-CHE-2005 AMENDED CLAIMS 15-06-2011.pdf

52-CHE-2005 EXAMINATION REPORT REPLY RECEIVED 15-06-2011.pdf

52-CHE-2005 FORM-13 29-06-2011.pdf

52-CHE-2005 FORM-18.pdf


Patent Number 249382
Indian Patent Application Number 52/CHE/2005
PG Journal Number 42/2011
Publication Date 21-Oct-2011
Grant Date 18-Oct-2011
Date of Filing 24-Jan-2005
Name of Patentee ORCHID CHEMICALS & PHARMACEUTICALS LTD,
Applicant Address ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI.
Inventors:
# Inventor's Name Inventor's Address
1 THAMBIDURAI MARAPPA GOUNDAR ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600 119
2 SELVARAJ SUBRAMANIAM ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600 119
3 PRABHAT KUMAR SAHOO ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600 119
4 GEEDI SREEDHAR ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600 119
PCT International Classification Number C07D 501/06
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA