FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
PROCESS FOR PREPARATION OF CEFDINIR USING IMIDAZOLE SALT INTERMEDIATE.
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai - 400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides a simple process for preparation of crystalline cefdinir using imidazole salt intermediate.
The following specification particularly describes the invention and the manner in which it is to be performed.
The present invention provides a simple process for preparation of crystalline cefdinir using imidazole salt intermediate.
[(-)6R,7R]-7-((Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido)-3-vinyl-8-oxo -5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid commonly termed as cefdinir of Formula I is third generation semi-synthetic cephalosporin for oral use, characterized by broad antibacterial spectrum against gram-positive and gram-negative bacteria. In particular cefdinir shows excellent antibacterial activity against Streptococci and Staphylococci.
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US Patent No. 4,559,334 provides a process for preparation of cefdinir in amorphous form by lyophilization. The amorphous form produced in turn is highly hygroscopic and therefore very difficult to formulate.
US Patent No. 4,935,507 provides a crystalline Form A of cefdinir and process for preparation thereof. Form A of cefdinir is reported to be having specific X-Ray diffraction (XRD) pattern.
US Application No. 20030204082 provides crystalline form of cefdinir having a specific XRD pattern.
US Application No. 20040210049 provides crystalline acid addition salts of cefdinir specifically sulphate and mesylate salt.
US Application No. 20040242556 provides crystalline form of cefdinir designated as Form B having a specific XRD pattern. Said form B is prepared from crystalline form A by first forming the trifluoroacetic acid salt followed by basification with ammonia.
US Patent No. 6,350,869 (PCT Application No. WO 98/45299) describes a process for preparation of crystalline dicyclohexylamine (DCHA) salt of cefdinir and monohydrate form of cefdinir. However, characterization data of the crystalline salt or monohydrate form of cefdinir is not provided in the '869 Patent.
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Several PCT Applications detail crystalline salts of cefdinir which are either useful as intermediates in preparation of cefdinir or can be used as broad-spectrum antimicrobials. WO 02/98884 (crystalline sulphate, tosylate and mesylate salt of cefdinir); WO 04/16623 (crystalline salts of acetyloximino cefdinir / methylcarbonyloxyimino cefdinir) and WO 04/56835 (crystalline phosphate salts).
PCT Application No WO 03/50124 describes crystalline cefdinir potassium monohydrate and process for preparation thereof. The application further details utilization of the potassium salt of cefdinir in monohydrate form as potential antimicrobial agent.
Indian Patent Application No. 1508/Del/2004 describes a crystalline Form B of cefdinir having a specific XRD, DSC and FTIR spectrum, which is essentially different from the one provided by US Application No 20040242556.
The present inventors have embarked upon a simple process for preparation of crystalline cefdinir using imidazole salt intermediate.
In one aspect of the present invention there is provided a process for preparation of crystalline cefdinir having XRD pattern as depicted in Figure 1 wherein the said process comprises of

Formula II
b) acidifying the solution under cooling,
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a) dissolving imidazole salt intermediate of fomula II in a suitable solvent,

c) isolating crystalline cefdinir having XRD pattern as depicted in Figure 1 from the reaction mixture obtained thereof.
Cefdinir imidazole salt is suspended in water and the resultant clear mixture is cooled to 0-15°C. The pH of the clear solution is then adjusted using an acid in the range of 1.0 to 3.0. The acid is selected from inorganic or organic acid. The resultant mass is stirred at 0 to 30°C for 5 to 30 hours and the precipitated solids are filtered, washed with water. The product obtained is dried at room temperature to yield crystalline cefdinir.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example 1 Preparation of Cefdinir
Cefdinir imidazole intermediate salt (10 g) was dissolved in de-mineralized water
(300 ml) and cooled to 0-5°C after charcolazition. Dilute hydrochloric acid was
added to adjust the pH of the solution in the range of 2.2-3.0. The reaction
mixture was stirred for about 3 hours at the same temperature. The separated
solids were filtered, washed with de-mineralized water and dried to obtain title
compound
Yield: 6.2 g,
Moisture Content: 6.41% w/w.
Purity: 99.31% w/w by HPLC.
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WE CLAIM:
1. A process for preparation of crystalline cefdinir having XRD pattern as
depicted in Figure 1 wherein the said process comprises of
a) dissolving imidazole salt intermediate of formula II in a suitable solvent,

Formula II
b) acidifying the solution under cooling,
c) isolating crystalline cefdinir having XRD pattern as depicted in Figure 1 from the reaction mixture obtained thereof.

2. The process according to claim 1 wherein acidification is carried out using inorganic or organic acid.
3. A process according to claim 2 wherein the acid is hydrochloric acid.
4. A process according to claim 1 wherein the cooling is carried out at 0-15°C.
5. A process according to claim 1 wherein the solvent is water.
6. A process according to claim 1 wherein crystalline cefdinir so obtained having
moisture content of about 3 to 8% w/w.
7. A process according to claim 1 wherein crystalline cefdinir so obtained having
purity 99% w/w or more by HPLC.
Dated this7nt day of June, 2006
For Wockhardt Limited
(Yatendra Kumar) Authorized Signatory
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