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:
AN IMPROVED PROCESS FOR PREPARATION OF CEFDINIR
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
An improved process for preparation of crystalline cefdinir using O-Acetyl HATA TEA salt intermediate.
The following specification particularly describes the invention and the manner in which it is to be performed.
An improved process for preparation of cefdinir using O-Acetyl HATA TEA 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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Formula I
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 (hereinafter designated as Form R) 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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US Application No. 20040034233 provides a process for preparation of anhydride of aminothiazole derivative.
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 ester of 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.
Cefdinir can be prepared by using 2-(2Aminothiazole-4-yl)-2-(methyl carbonyloxyimino)-acetic acid (herein after refered as O-Acetyl HATA) as starting material by methods known in the art. However, O-Acetyl HATA is associated with the problems of drying (moisture content of 13 % w/w or more). The removal of water by refluxing the product having high moisture content with organic solvent and then drying or by azeotropic distillation is costly and time consuming at industrial scale.
The present inventors have embarked upon a simple salt formation process for preparation of crystalline cefdinir using O-Acetyl HATA, wherein the said problems can be solved.
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In one aspect of the present invention there is provided a process for preparation of crystalline cefdinir wherein the said process comprises of
a) Treating a solution of O-Acetyl HATA of formula II in a suitable solvent with triethylamine,

Formula II
b) isolating O-Acetyl HATA TEA salt of formula III from the reaction mixture obtained thereof,

Formula III
c) converting O-Acetyl HATA TEA salt to its active ester,
d) reacting 7-amino-3-vinyl-3-cephem-4-carboxylic acid (7-AVCA ) with the active ester of O-Acetyl HATA
e) de-protecting the acetyl cefdinir formed,
f) isolating crude cefdinir from the reaction mass thereof.
The O-Acetyl HATA TEA salt intermediate so obtained having low moisture content (moisture content of 1 % w/w or less) provides a cost effective means to prepare cefdinir.
The title intermediate is converted to cefdinir by any process know in art, which may optionally include its conversion to its active-ester form, which is further
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coupled with 7 AVCA in presence of bis(triethylsilyl)acetamide and dimethylacetamide and isolation of crude cefdinir after subsequent deprotection.
Another aspect of the present invention provides triethylamine (TEA) salt of 0-acetyl HATA. The TEA salt of O-acetyl HATA has moisture content 5% or less.
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 O-Acetyl HATA TEA salt intermediate
O-Acetyl HATA (1130 gm) was suspended in acetone (10 L) under stirring. The reaction mass was basified using triethyl amine (700 gm) at ambient temperature. Filtered and washed with acetone after prolong stirring. Dried at 40 to 45°C to get the syn -2-(2-Aminothiazol-4-yl)-2-(methylcarbonyloxyimino)-acetic acid triethyl amine salt (O-Acetyl HATA TEA salt) (1250 gm).
Moisture Content: 0.83% HPLC purity: 99.78%
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WE CLAIM:
1. A process for preparation of crystalline cefdinir wherein the said process
comprises of
a) Treating a solution of O-Acetyl HATA of formula II in a suitable solvent
with triethylamine,

Formula II
b) isolating O-Acetyl HATA TEA salt of formula III from the reaction mixture
obtained thereof,

Formula III
c) converting O-Acetyl HATA TEA salt to its active ester,
d) reacting 7-amino-3-vinyl-3-cephem-4-carboxylic acid (7-AVCA ) with the active ester of O-Acetyl HATA
e) de-protecting the acetyl cefdinir formed,
f) isolating crude cefdinir from the reaction mass thereof.

2. A process for according to claim 1(a), wherein the suitable solvent is acetone.
3. A process for according to claim 1, wherein the O-Acetyl HATA TEA salt so obtained has moisture content of 1% w/w or less.
4. Triethylamine (TEA) salt of O-acetyl HATA.
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5. The TEA salt of O-acetyl HATA having moisture content 1% or less.
6. A compound of Formula III as an intermediate in synthesis of cefdinir or salt
thereof.
Dated this 7nt day of June, 2006
For Wockhardt Limited
(Yatendra Kumar) Authorized Signatory
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