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Method for manufacture of ceftriaxone sodium

a technology of ceftriaxone and sodium ceftriaxone, which is applied in the field of improved methods for manufacturing of ceftriaxone sodium, can solve the problems of inconsequential changes in parameters and solvents, no bearing on the course of reaction, and increase the overall cost of coupling reaction, etc., and achieves high yield and purity.

Inactive Publication Date: 2005-03-17
LUPIN LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

In one aspect of the present invention, there is provided an improved one-pot process for preparation of ceftriaxone of formula (I), in high yield and purity,

Problems solved by technology

However, this method increases the overall cost of the coupling reaction since it involves the use of expensive triphenyl phosphine.
This method, however, utilizes expensive triphenyl phosphine for preparation of the activated ester.
The method however, suffers from a drawback in that the amide forming reaction, utilizing the said activated reactive derivative can be effected in only specific solvents like benzene and toluene.
However, both the methods function the same way giving substantially the same result, thereby indicating that the change in parameters and solvents are inconsequential and have no bearing in the course of the reaction.
Further, replication of the methods described in other prior art methods, mentioned hereinbefore also were found to afford the product in unsatisfactory yields and quality, rendering them less cost-effective.

Method used

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  • Method for manufacture of ceftriaxone sodium
  • Method for manufacture of ceftriaxone sodium
  • Method for manufacture of ceftriaxone sodium

Examples

Experimental program
Comparison scheme
Effect test

reference example — 1

REFERENCE EXAMPLE—1

Preparation of ceftriaxone sodium (II) as Per the Method Described in Example—2 of U.S. Pat. No. 6,552,186 B2

Step—1: Preparation of (N,O)-bis trialkylsilyl 7-amino-3-[2,5-dihydro-6-hydroxy-2-methyl5-oxo-as-triazin-3-yl]-3-cephem-4-carboxylic acid (III)

50 gm (0.135 moles) of 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl)}-3-cephem-4-carboxylic acid was suspended in dichloromethane (500 ml). An additional amount of 1000 ml of dichloromethane was added to the suspension and distilled out to effect azeotropic removal of water. To the suspension was added Bis silyl acetamide (109.70 gm; 0.540 moles) at 25° C. to 30° C. and the mixture agitated under an atmosphere of nitrogen for 2 hours. The solution of (N,O)-bis trialkylsilyl 7-amino-3-[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl]-3-cephem-4-carboxylic acid (III) thus obtained was cooled to −10° C.

Step—2: Preparation of 4-bromo-2-methoxyimino-3-oxo Yutyric acid chloride (IV...

example — 2

EXAMPLE—2

Preparation of ceftriaxone sodium (II) as Per the Method of the Present Invention Utilizing 4-halo-2-methoxyimino-3-oxo butyric acid (IV) having a Purity of 87% in the Absence of an Acid Scavenger

Step—1: Preparation of (N,O)-bis trialkylsilyl 7-amino-3-[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3 yl]-3-cephem-4-carboxylic acid (III)

A suspension of 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3yl)thio]methyl)}-3-cephem-4-carboxylic acid (100 gm; 0.270 moles) and dichloromethane (2700 ml) was heated to reflux and 2000 ml of dichloromethane was distilled out till moisture content of the reaction mixture is below 0.06%. The reaction mixture was cooled to room temperature. To this was added 74.0 gm (0.458 moles) of hexamethyldisilazane and trimethylchlorosilane (10.8 gm; 0.0095 moles) and the mixture refluxed for 8 hours. The solution containing (N,O)-bis trialkylsilyl 7-amino-3-[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl]-3-cephem-4-carboxylic...

example — 3

EXAMPLE—3

Preparation of ceftriaxone sodium (II) as Per the Method of the Present Invention Utilizing 4-halo-2-methoxyimino-3-oxo butyric acid (IV) having a Purity of 97% and Prepared as the Method Disclosed in WO03 / 045899 in the Absence of an Acid Scavenger

Step—1: Preparation of (N,O)-bis trialkylsilyl 7-amino-3-[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3 yl]-3-cephem-4-carboxylic acid (III)

A suspension of 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl)}-3-cephem-4-carboxylic acid (100 gm; 0.270 moles) and dichloromethane (2700 ml) was heated to reflux and 2000 ml of dichloromethane was distilled out till moisture content of the reaction mixture is below 0.06%. The reaction mixture was cooled to room temperature. To this was added 74.0 gm (0.458 moles) of hexamethyldisilazane and trimethylchlorosilane (10.8 gm; 0.0095 moles) and the mixture refluxed for 8 hours. The solution containing (N,O)-bis trialkylsilyl 7-amino-3-[2,5-dihydro-6-hydroxy-...

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Abstract

An improved process for preparation of ceftriaxone sodium of formula (II), is disclosed.

Description

FIELD OF THE INVENTION The present invention relates to an improved method for manufacture of ceftriaxone sodium of high purity, high stability and low absorbance, rendering it highly amenable for formulation into a suitable dosage form. BACKGROUND OF THE INVENTION [6R-[6α, 7β(Z)]]-7-[[(2-Amino-4-thiazolyl)(methoxyimino)acetyl]amino]-8-oxo-3-[[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3-yl)thio]methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid or (6R, 7R)-7-[2-(2-amino-4-thiazolyl)glyoxylamido]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, generically known as ceftriaxone of formula (I) is a third generation cephalosporin antibiotic for parenteral administration. It is commercially sold as the disodium hemiheptahydrate salt of formula (II), commonly referred to as ceftriaxone sodium, under the brand names Rocefin® and Rocephin(e)®. Ceftriaxone sodium is the largest-sellin...

Claims

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Application Information

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IPC IPC(8): C07D501/00C07D501/14
CPCC07D501/00
Inventor DATTA, DEBASHISHDANTU, MURALIKRISHNASHARMA, POLLEPEDDI LAKSHMI NARAYANAMISHRA, BRIJKISHORE
Owner LUPIN LTD
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