Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF CEFADROXIL

Abstract A process for the preparation of cefadroxil having water content in the range of 4-5 %, which comprises: i) silylating the 7-ADCA with trimethyl silyl chloride and hexamethyl disilazane in the presence of an organic solvent to obtain silylated derivative of 7-ADCA at a temperature in the range of 30 °C to reflux temperature of the solvent, ii) condensing the mixed anhydride with the solution of silylated derivative of 7-ADCA obtained in step (i) above to produce a compound of formula (VII), iii) hydrolyzing the compound of formula (VII) using dil. acid, iv) separating the aqueous layer from organic layer, v) adding DMF to the aqueous layer, vi) adjusting the pH of the solution to 4-6 to obtain DMF solvate, vii) desolvating the cefadroxil DMF solvate in water heated at 30 - 70 °C for a period of 1 to 4 h, viii) cooling the solution to 0 to 10 °C and isolating the product formed.
Full Text

Field of the Invention
The present invention relates to an improved process for the preparation of cefadroxil of the formula (I). More, particularly, the present invention relates to an improved process for the preparation of cefadroxil having water content in the range of 4-5 %.

Cefadroxil is chemically known as 7-[D-a-amino-a-(p-hydroxyphenyl)acetamido]-3-methyl-3-cephem»4-carboxylic acid. It is a well-known antibiotic substance having antibacterial activity and is disclosed in US Patent No. 3,489,752. US patent No. 3,985,741 discloses preparation of cefadroxil by acylation of 7-aminodesacetoxycephalosporanic acid (7-ADCA) with the mixed anhydride of D-(-)-a-(p-hydroxyphenyl)glycine.
US patent No. 4,504,657 claims a different form of cefadroxil that is the crystalline form of cefadroxil, known as cefadroxil monohydrate having a well-defined X-ray diffraction pattern. This crystalline cefadroxil monohydrate is
obtained by acylation of silylated 7-ADCA acid with D(-)a-amino-a-(p-hydroxyphenyl)acetyl chloride hydrochloride.
US patent No. 4,962,195 discloses yet another novel crystalline cefadroxil having water content of about 3% and characterized by distinct X-ray diffraction properties. This novel cefadroxil is called "cefadroxil hemihydrate" and is shown to be more stable than crystalline cefadroxil monohydrate.
US patent Nos. 4,962,195 and 5,023,331 discloses a method of producing cefadroxil hemihydrate by adding to an aqueous solution containing cefadroxil prepared from 7-aminodesacetoxycephalosporanic acid, a solvent selected from the group consisting of dimethylacetamide, monomethylformamide or N-methyl-

2-pyrrolidone at a controlled pH (5.5 to 6.0) to give the corresponding cefadroxil solvate which precipitates and is filtered off. After the cefadroxil solvate is dried, it is slurred with a mixture of methanol-isopropyl alcohol 30:70 to 50:50 by volume at a temperature in the range of 45°C to 55 °C, to give crystalline cefadroxil hemihydrate which is isolated by filtration.
Both these patents report that the use of the cefadroxil solvates of dimethylacetamide, of N-methyl-2-pyrrolidone and of monomethylformamide is critical for the preparation of crystalline cefadroxil hemihydrate and that it was impossible to obtain the desired crystalline cefadroxil hemihydrate from the known cefadroxil dimethyl formamide solvate (U.S. Pat. Nos. 3,985,741, 4,504,657 and U.S. Pat. No. RE 31,730). It always resulted in the isolation of the known crystalline cefadroxil monohydrate due to the fact that the cefadroxil dimethyl formamide solvate has a K.F. value of 1.8% or more.
US patent No. 4,358,588 discloses a process for the preparation of cefadroxil comprising silylating 7-ADCA with silylating agent selected from trimethylchlorosilane and treating the resulting silylated ADCA with an equimolar amount of mixed anhydride in the presence of inert anhydrous, organic solvent.
US patent No. 5,998,610 discloses a process for the silylation of 7-amino-desacetoxy-cephalosporanic acid by silylation in certain carboxylic acid esters and its use in the production of 6-alpha-aminoacyl-penicillins and 7-alpha-aminoacyl-desacetoxy-cephalosporins.
US patent No. 6,337,396 discloses a method of producing crystalline cefadroxil hemihydrate, from cefadroxil dimethyl formamide solvate which comprises slurrying cefadroxil dimethyl formamide solvate with a mixture of a lower alkanol and water, at a temperature in the range of about 40 °C to 50 °C and isolating the crystalline cefadroxil hemihydrate from the reaction mixture.
US patent No. 5,329,001 disclose a method oT producing crystalline cefadroxil having a water content from about 0.8 % to about 3.9 %.

Objective of the Invention
The primary objective of the invention is to provide a new method for the preparation of cefadroxil of the formula (I), having water content in the range of of 4-5 %.
Summary of the Invention
Accordingly, the present invention provides an improved process for the preparation of cefadroxil of the formula (I)

having water content in the range of 4-5 %, which comprises: i) silylating the 7-amino desacetoxy cephalosporanic acid (7-ADCA) of the formula (II) with trimethyl silyl chloride and hexamethyl disilazane (HMDS) in the presence of an organic solvent to obtain silylated derivative of 7-amino desacetoxy cephalosporanic acid (7-ADCA) of the formula (III) wherein Ri represents methyl group at a temperature in the range of 30 °C to reflux temperature of the solvent,
ii) condensing the mixed anhydride of the formula (VI) prepared from Dane salt of formula (IV) where R3 represents methyl, ethyl or isopropyl and M is sodium or potassium and chloroformate of formula (V) where R2 represents alkyl, phenyl, benzyl or cycloalkyl in the presence of mixture of solvents and a catalyst, with the solution of silylated derivative of 7-amino desacetoxy cephalosporanic acid (7-ADCA) of the formula (III) obtained in step (i) above to produce a compound of formula (VII), where Ri and R3 are as defined above, iii) hydrolyzing the compound of formula (VII) usin£ dil. acid, iv) separating the aqueous layer from organic layer,

v) adding DMF to the aqueous layer,
vi) adjusting the pH of the solution to 4-6 to obtain DMFsolvate,
vii) desolvating the cefadroxil DMF solvate in water heated at 30 - 70 °C for
a period of 1 to 4 h,
viii) cooling the solution to 0 to 10 °C and isolating the product formed.
The process is shown in Scheme-1 below:

In yet another embodiment of the present invention the silylation in step (i) is carried out in the presence of solvents such as halogenated hydrocarbons, ethyl acetate, tetrahydrofuran, acetonitrile, N,N-Dimethylformamide and the like or mixtures thereof.
In yet another embodiment of the present invention the solvents used for preparing mixed anhydride may be selected from MDC/dimethyl acetamide, EDC/dimethyl acetamide, MDC/DMF, EDC/DMF and the like and catalyst such as N-methyl morpholine.

In yet another embodiment of the present invention the acid used for hydrolysis may be selected from HC1, H2S04 and the like. ■
In yet another embodiment of the present invention the pH is adjusted using ammonia.
The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention.
Example 1
Preparation of 7-[D-a-amino-a-(p-hydroxyphenyl)acetamido]-3-methyl-3-
cephem-4-carboxylic acid
7-Amino desacetoxy cephalosporanic acid (100 gm) was taken in methylene chloride (275 ml), trimethyl silyl chloride (35.6 g) and hexamethyl disilazane (51 g) were added. The reaction mass was stirred for 120 - 130 minutes at 38 -46 °C to get silylated derivative of 7-aminodesacetoxy cephalosporanic acid, which was condensed with the mixed anhydride of D(-) a 4-hydroxyphenyl phenyl glycine Dane salt methyl, potassium, obtained by reaction of D(-) a 4-hydroxyphenyl glycine Dane Salt methyl, potassium (152 g) with methyl chloroformate (48 g) in a mixture of dichloromethane (530 ml) and N,N-dimethylacetamide (170 g), in presence of catalytic N-methyl morpholine (1.4 g) at -44 to -40 °C for 90-100 minutes. After completion of reaction, the reaction mass was subjected to hydrolysis in dilute hydrochloric acid (325 ml, 6.2 % aqueous hydrochloric acid). Aqueous layer was separated from the organic layer and to this N,N-dimethylformamide (1050 ml) was added. pH of the solution was adjusted to 5.6 - 6.0 with dilute ammonia (80 ml) at 24 - 32 °C to get cefadroxil DMF solvate, which was filtered and washed with aqueous DMF (100 ml) followed by acetone wash (400 ml). Cefadroxil DMF solvate was desolvated in purified water (300 ml) at 38 - 54°C for 90 - 120 minutes. The

product slurry was cooled to 10°C and filtered, washed with acetone (250 ml) and dried to get cefadroxil monohydrate (157-162 g), water content 4.7%.





We claim :
1. A process for the preparation of cefadroxil of the formula (I)

having water content in the range of 4-5 %, which comprises:
i) silylating the 7-amino desacetoxy cephalosporanic acid (7-ADCA) of the
formula (II)
with trimethyl silyl chloride and hexamethyl disilazane (HMDS) in the presence of an organic solvent to obtain silylated derivative of 7-amino desacetoxy cephalosporanic acid (7-ADCA) of the formula (III)

wherein Ri represents methyl group at a temperature in the range of 30 °C to
reflux temperature of the solvent,
ii) condensing the mixed anhydride of the formula (VI)

wherein R2 represents, alkyl,-phenyl, benzyl or cycloalkyl; R3 represents methyl, ethyl or isopropyl with the solution of silylated derivative of 7-amino desacetoxy cephalosporanic acid (7-ADCA) of the formula (III) obtained in step (i) above to produce a compound of formula (VII),


where R1 and R3 are as defined above,
iii) hydrolyzing the compound of formula (VII) using dil. acid,
iv) separating the aqueous layer from organic layer,
v) adding DMF to the aqueous layer,
vi) adjusting the pH of the solution to 4-6 to obtain DMF solvate,
vii) desolvating the cefadroxil DMF solvate in water heated at 30 - 70 °C for
a period of 1 to 4 h,
viii) cooling the solution to 0 to 10 °C and isolating the product formed.
2. The process as claimed in claim 1, the solvent used in step (i) is selected from halogenated hydrocarbons, ethyl acetate, tetrahydrofuran, acetonitrile, N,N-dimethylformamide or mixtures thereof
3. The process as claimed in claim 1, wherein the solvents used for preparing mixed anhydride are selected from MDC/dimethyl acetamide, EDC/dimethyl acetamide, EDC/DMF or MDC/DMF.
4. The process as claimed in claim 1, wherein the acid used in step (iii) is selected from HC1 or H2SO4.
5. The process as claimed in claim 1, wherein the pH is adjusted using ammonia.


Documents:

760-mas-2002 - abstract.pdf

760-mas-2002 - claims.pdf

760-mas-2002 - correspondence others.pdf

760-mas-2002 - correspondence po.pdf

760-mas-2002 - description complete.pdf

760-mas-2002 - form 1.pdf

760-mas-2002 - form 3.pdf

760-mas-2002 - form 5.pdf

760-mas-2002 - other documents.pdf

760-mas-2002 - pct.pdf


Patent Number 194930
Indian Patent Application Number 760/MAS/2002
PG Journal Number 30/2009
Publication Date 24-Jul-2009
Grant Date 05-Jan-2006
Date of Filing 16-Oct-2002
Name of Patentee M/S. ORCHID CHEMICALS & PHARMACEUTICALS LTD.,
Applicant Address ORCHID TOWERS, 313, VALLUVAR KOTTAM HIGH ROAD NUNGAMBAKKAM, CHENNAI-600034
Inventors:
# Inventor's Name Inventor's Address
1 PRAMOD NARAYAN DESHPANDE 5-TEMPLE GLADE APARTMENTS, 41-D, BEACH ROAD, KALAKSHETRA COLONEY, BESANT NAGAR, CHENNAI-600090 TAMILNADU
2 GAUTAM KUMAR DAS GEETHA APARTMENTS, 33, RUKMINI ROAD, KALAKSHETRA COLONY, BESANTNAGAR CHENNAI-600090 TAMILNADU
3 RAJENDRA JANARDAN SARANGDHAR PLOT NO.8 (OLD)/NEW NO.19 ELEGANT APARTMENTS DR. VASUDAVE NAGAR EXTENSION, THIRUVANMIYUR CHENNAI
4 PETER XAVIER THARIAL V-107, KOVAIPUDUR, COIMBATORE-641042 TAMILNADU INDIA
PCT International Classification Number A61K31/545
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA