F0RM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - PROCESS FOR PREPARING INTERMEDIATES
USEFUL IN SYNTHESIS OF CIIEPHALOSPRIN

2. Applicant(s)
(a) NAME :
(b) NATIONALITY
(c) ADDRESS :

ALEMBIC LIMITED
An Indian Company.
Alembic Campus, Alembic Road, Vadodara - 390 003, Gujarat, India.

3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION:

This invention relates to an improved process for preparing a compound of formula (I), wherein X is HI, HCl or H2SO4 and is useful as an intermediate for the synthesis of cephalosporin antibiotics.
COO Formula (I)
X.H2Nx s^
BACKGROUND OF THE INVENTION AND PRIOR ART:
Cephalosporin antibiotics are used widely for the treatment of bacterial infections. Cefepime of formula (A) belongs to fourth generation of Cephalosporin due to its intrinsic antimicrobial properties. It possesses extended spectrum of activity for gram negative and gram positive organisms in comparison to other generations of Cephalosporins. Also it has minimal beta-lactamase activity due to rapid periplasmic penetration and high penicillin-binding protein (PBP) access.
N-OCH3

Formula (A)

COO

Cefepime of formula (A) is first disclosed in US Patent No. 4,406,899. US Patent No. 4,754,031 discloses a process for its preparation.
US Patent No. 4,659,812 and US Patent No. 4,714,760 discloses novel intermediate and its crystalline salts of formula (I) and its use for preparation of Cefepime, which does not require carboxyl group deblocking on conversion to N-acylated compounds and thus offer an efficiency in acylating agent use. Also these intermediates are stable and can be
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stored for a longer period without degradation and converted to desired compound as and when required.
US Patent No. 4,868,294 discloses the process for preparing novel intermediate and its crystalline salts of formula (I) substantially free from 2 isomer. It involves conversion of 7-amino cephalosporinic acid (7-ACA) of formula (V) into it silyl derivative, which is condensed with silyl protected N-methyl pyrrolidine in 1,1,2-trichlorotrifluoroethane (Freon TF) or 1,1,1-trichlorotrifluorethane, and subsequently disilylation with lower alkanol, followed by acidification to give salt. However, the use of Freon TF as solvent is avoidable at plant scale considering the health and safety related requirement.
US Patent No. 5,594,131 discloses the use of Freon C5.8 cycloalkane optionally substituted by one or two (lower) alkyl in place of Freon TF type of solvents. The subsequent disilylation is carried out in alkanol and it is converted to salt on acidification. However, this method is not high yielding (ranging from 27% to 59%) and the purity of product obtained is in the range of 91% to 97%.
The inventors of the present invention have surprisingly found that the desilylation of compound of formula (II) to prepare compound of formula (I) can be conveniently carried out in presence of an acid optionally in presence of solvent selected from group comprising of C3-6 ketone, C1-6 nitrile or C4-10 ether. It is particularly found according to the present invention that the use of an acid optionally in presence of solvent selected from group comprising of C3-6 ketone, C1-6 nitrile or C4-10 ether for desilylation results in increased yield and purity of the compound of formula (I) as compared to the prior art process making use of alkanol for desilylation. It is further found that the addition of acid separately may be done away with if the acid is incorporated at the desilylation step which helps direct formation of salt.
OBJECT OF THE INVENTION:
Accordingly it is the primary object of the present invention to provide an improved process for preparing cephalosporin intermediate of formula (I), which shows an increase in purity and yield of the product.
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Hence it is object of the invention to provide a method which produces compound of formula (I) with high purity and useful for the synthesis of broad spectrum cephalosporin antibiotics.
Therefore it is object of the present invention to provide compound of formula (I), having high purity such that it can easily be converted to broad spectrum cephalosporin antibiotics without blocking or de-blocking steps.
SUMMARY OF THE INVENTION:
Thus according to the present invention there is provided a method of preparation of compound of formula (I), wherein X is HI, HC1 or H2SO4, having high purity, comprising
(a) preparing compound of formula (IV) by treating compound of formula (V) in C5-
8 cycloalkane optionally substituted by one or two (lower) alkyl with
hexamethyldisilazane and catalytic amount of trimethyliodosilane,
H2N s (H3C)3SiHN
^s
O
O