WO2005105813A1 - Improved process for the manufacture of ceftriaxone sodium - Google Patents

Improved process for the manufacture of ceftriaxone sodium Download PDF

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Publication number
WO2005105813A1
WO2005105813A1 PCT/IB2004/001692 IB2004001692W WO2005105813A1 WO 2005105813 A1 WO2005105813 A1 WO 2005105813A1 IB 2004001692 W IB2004001692 W IB 2004001692W WO 2005105813 A1 WO2005105813 A1 WO 2005105813A1
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Prior art keywords
oxo
methyl
syn
thiazolyl
dihydro
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PCT/IB2004/001692
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French (fr)
Inventor
Siddiqui Mohammed Jaweed Mukarram
Pankaj Kumar Naithani
Manish Purohit
Rajkumar Udhavrao Pokalwar
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Wockhardt Limited
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Priority to PCT/IB2004/001692 priority Critical patent/WO2005105813A1/en
Publication of WO2005105813A1 publication Critical patent/WO2005105813A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

  • the present invention relates to an improved process for the production of Ceftriaxone disodium hemiheptahydrate, i.e., (6,R,7R)-7-[2-(2-amino-4-thiazoryl)-2-syn- methoxyimino)acetamido] -3 - [ [2,5-dihydro-6-hydroxy-2-methyl-5 -oxo-as-triazin-3 - yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid disodium hemiheptahydrate.
  • Ceftriaxone comprises the reaction of 2-(2- chloroacetamido-4-thiazolyl)-2-syn-methoxyiminoacetyl chloride with (7R)-7-amino-3- deacetoxy-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)-thio]cephalosporonic acid (7-ACT) in water and in the presence of a base. Amino protected Ceftriaxone is subsequently deprotected by thiourea in water to obtain Ceftriaxone.
  • the later is converted to Ceftriaxone disodium hemiheptahydrate with sodium-2-ethylhexanoate in a mixture of acetone and water.
  • the product thus obtained is of high purity (above 99.5%) and having no single unknown impurity more than 0.1%.
  • Ceftriaxone sodium hemiheptahydrate i.e. (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z- methoxyimino)acetamido]-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3- yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid disodium hemiheptahydrate (Ceftriaxone sodium hemiheptahydrate) is a semi synthetic antibiotic of third generation and used for parenteral application in the treatment of acute and chronic infection like urinary track infection, respiratory infection, etc. This molecule was invented by Hoffman La Roche Inc. and was disclosed in US Patent No. 4,327,210.
  • the obtained product is further treated exhaustively, e.g., dissolution of crude precipitate of N-protected Ceftriaxone in acetone, filtration of unwanted solid material, charcoalization of filtrate, addition of ethyl acetate and concentration, filtration of unwanted black resin, azetropic distillation of filtrate with benzene, filtration of precipitated solid, drying, dissolution of dry material in acetone, filtration of unwanted and undissolved material, concentration of the filtrate, addition of acetone to the residue, filtration of unwanted, undissolved material, addition of ethyl acetate to the filtrate and concentration & filtration of the product.
  • the N-protected Ceftriaxone acid is subjected to deprotection in aqueous medium in presence of thiourea at pH between 6.8 to 7.0 at ambient temperature followed by overnight cooling.
  • Ceftriaxone acid is precipitated by adjusting pH of the reaction mass to 2.0 using formic acid.
  • the precipitated product is filtered and dried to get solid mass.
  • the Ceftriaxone acid is converted to Ceftriaxone disodium in acetone-water solvent system using sodium-2- ethyl hexanoate solution in acetone as a source of sodium.
  • the product is isolated by addition of acetone to the reaction mass followed by filtration of precipitated brown resin. Acetone is further added to the filtrate and kept at low temperature and the solid obtained is filtered.
  • the above said process is too cumbersome to be adopted at industrial scale as it needs a number of steps for isolation.
  • US Patent No. 47,67,852 discloses method for the preparation of Ceftriaxone that comprises silylation of 7-ACT (7-Amino-3-(2,5-dihydro-Z-methyl-6-hydroxy-5-oxo-as- triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid) using N,O-bis(trimethylsilyl) acetamide and reacting it with an active ester (MAEM i.e. Z-(2-Aminothiazol-4-yl)-Z-syn- methoxyimino acetic acid 2-benzothiazolyl thioester) in DCM.
  • MAEM active ester
  • the main disadvantage of the above described process is use of costly silylating agent for silylation.
  • Use of active ester MAEM is disclosed in several other literatures but due to lower reactivity its reaction with 7- ACT takes longer time for completion and also a by-product of this reaction is the toxic compound 2-mercapto
  • the present invention relates to an industrially scalable method for the manufacture and isolation of substantially pure Ceftiraxone disodium hemiheptahydrate, i.e. (6,R,7R)-7-[2-(2- amino-4-thiazolyl)-2-syn-methoxyimino)acetamido]-3-[[2,5-dihydro-6-hydroxy-2-methyl-5- oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid disodium hemiheptahydrate having the chemical Formula VI VI
  • a high yielding process for the production of Ceftriaxone disodium hemiheptahydrate.
  • the process comprises the reaction of 2-(2- chloroacetamidothiazol-4-yl)-2-syn-methoxyiminoacetyl chloride with (7R)-7-amino-3- deacetoxy-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]cephalosporonic acid (7-ACT) in water or aqueous isopropyl alcohol to yield the amino protected Ceftrioxane.
  • the chloroacetyl group is removed conventionally using thiourea and a mild base in a mixture of water and isopropyl alcohol.
  • the pH of the reaction mixture is brought up to about 2.0 to get the precipitate of Ceftriaxone in good purity.
  • the later is converted to Ceftriaxone disodium hemiheptahydrate by reacting sodium-2-ethylhexanoate in a mixture of acetone and water.
  • the present invention provides a simple, efficient and scalable method for the production of a cephalosporin, e.g., Ceftiraxone disodium hemiheptahydrate, i.e. (6,R,7R)-7- [2-(2-amino-4-thiazolyl)-2-syn-methoxyimino)acetamido]-3-[[2,5-dihydro-6-hydroxy-2- methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]-oct-2-ene-2- carboxylic acid disodium hemiheptahydrate.
  • the process of the invention involves cheaper and easily available raw materials, shorter reaction timings, simple reaction work-up procedures and isolation of the product in high purity (purity by HPLC above 99%).
  • the process of the present invention comprises the preparation of acid chloride of 2- (2-Chloroacetamido-4-thiazolyl)-2-syn-methoxyimino acetic acid.
  • the carboxy function of 2-(2-Chloroacetamido-4-thiazolyl)-2-syn-methoxyimino acetic acid (Formula I)
  • Orgamc layer contains the desired product which is used for the next step without any further work-up or purification step.
  • the deprotection step is carried out in water or a mixture of water and alcohol selected from methanol, ethanol or isopropyl alcohol, more particularly a mixture of water and isopropanol is preferred as solvent.
  • the removal of chloroacetyl function from compound having formula III comprises in the presence of thiourea at pH between about 5.0 to about 8.0, more preferably between about 6.5 to about 7.5.
  • the base used for the pH adjustment is aqueous sodium bicarbonate solution and the reaction is carried out in a temperature range of 10°C to 40°C, preferably between about 20°C to 30°C. Deprotection usually completes in 6 to 8 hours.
  • Ceftriaxone acid is finally converted to Ceftriaxone disodium hemiheptahydrate having Formula VI a VI
  • Ceftriaxone acid is finally converted to Ceftriaxone disodium hemiheptahydrate in acetone- water solvent system using sodium-2-ethylhexanoate solution in acetone.
  • the product is precipitated by adding acetone to the reaction mass.
  • the product thus formed is of high purity (above 99.5%) and having no unknown impurities above 0.1 %.
  • Example 1 The wet material obtained in Example 1 is suspended in a mixture of water (1.0 Ltr) and isopropyl alcohol (2.0 Ltr). Thiourea (275 g) is added to the reaction mixture and pH of the reaction mixture is adjusted to 7.0 using aqueous sodium bicarbonate solution. The reaction mixture is stirred at room temperature for 8 hours at a pH around 7.0. After completion of reaction (by HPLC monitoring), its pH is brought to around 2.0 by adding dilute HCl. The precipitated solid is filtered, washed with water and submitted wet for sodium salt preparation.
  • Thiourea 275 g
  • pH of the reaction mixture is adjusted to 7.0 using aqueous sodium bicarbonate solution.
  • the reaction mixture is stirred at room temperature for 8 hours at a pH around 7.0. After completion of reaction (by HPLC monitoring), its pH is brought to around 2.0 by adding dilute HCl.
  • the precipitated solid is filtered, washed with water and submitted wet for sodium salt preparation.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

A process for the production of (6R,7R)-7-[2-(2-Amino-4-thiazolyl)-2-syn­methoxyimino)acetamido]-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3­yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid (Ceftriaxone acid) in water is discussed. The synthesis is effected by condensing (7R)-7-Amino-3­deacetoxy-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]cephalosporanic acid (7-ACT) with 2-(2-chloroacetamido-4-thiazolyl)-2-syn-methoxyiminoacetyl chloride followed be deblocking amino function. Finally, (6R,7R)-7-[2-(2-Amino-4-thiazolyl)-2-syn­methoxyimino)acetamido]-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3­yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid (Ceftriaxone acid) is converted into Ceftriaxone disodium hemiheptahydrate in aqueous acetone using sodium-2-ethylhexanoate as sodium source. Isolation steps at every stage are quite short. The purity of the final product is obtained in more than 99 % by HPLC profile.

Description

IMPROVED PROCESS FOR THE MANUFACTURE OF CEFTRIAXONE SODIUM
FIELD OF THE INVENTION
The present invention relates to an improved process for the production of Ceftriaxone disodium hemiheptahydrate, i.e., (6,R,7R)-7-[2-(2-amino-4-thiazoryl)-2-syn- methoxyimino)acetamido] -3 - [ [2,5-dihydro-6-hydroxy-2-methyl-5 -oxo-as-triazin-3 - yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid disodium hemiheptahydrate. The synthesis of Ceftriaxone comprises the reaction of 2-(2- chloroacetamido-4-thiazolyl)-2-syn-methoxyiminoacetyl chloride with (7R)-7-amino-3- deacetoxy-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)-thio]cephalosporonic acid (7-ACT) in water and in the presence of a base. Amino protected Ceftriaxone is subsequently deprotected by thiourea in water to obtain Ceftriaxone. The later is converted to Ceftriaxone disodium hemiheptahydrate with sodium-2-ethylhexanoate in a mixture of acetone and water. The product thus obtained is of high purity (above 99.5%) and having no single unknown impurity more than 0.1%.
BACKGROUND OF THE INVENTION
Ceftriaxone sodium hemiheptahydrate i.e. (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z- methoxyimino)acetamido]-3-[[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3- yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid disodium hemiheptahydrate (Ceftriaxone sodium hemiheptahydrate) is a semi synthetic antibiotic of third generation and used for parenteral application in the treatment of acute and chronic infection like urinary track infection, respiratory infection, etc. This molecule was invented by Hoffman La Roche Inc. and was disclosed in US Patent No. 4,327,210.
The process described in above US patent comprises the preparation of acid chloride of 2-(2-Chloroacetamido-4-thiazolyl)-2-(Z-methoxyimino)acetic acid in dichloromethane using Phosphorous pentachloride. After the acid chloride is formed, the dichloromethane is evaporated and the residue is washed twice with n-heptane and finally residual acid chloride is dissolved in tetrahydrofuran. The acid chloride thus formed is treated with 7-ACT i.e. (7R)-7-amino-3-desacetoxy-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]- Cephalosporanic acid in tetrahydrofuran- water solvent system in presence of 2 N sodium hydroxide solution. N-protected Ceftriaxone acid is isolated after a complex reaction work-up that comprises the removal of tetr-ώydrofuran under vacuum, acidification of the reaction mass with sulfuric acid followed by filtration to get the crude precipitate. The obtained product is further treated exhaustively, e.g., dissolution of crude precipitate of N-protected Ceftriaxone in acetone, filtration of unwanted solid material, charcoalization of filtrate, addition of ethyl acetate and concentration, filtration of unwanted black resin, azetropic distillation of filtrate with benzene, filtration of precipitated solid, drying, dissolution of dry material in acetone, filtration of unwanted and undissolved material, concentration of the filtrate, addition of acetone to the residue, filtration of unwanted, undissolved material, addition of ethyl acetate to the filtrate and concentration & filtration of the product.
The N-protected Ceftriaxone acid is subjected to deprotection in aqueous medium in presence of thiourea at pH between 6.8 to 7.0 at ambient temperature followed by overnight cooling. Ceftriaxone acid is precipitated by adjusting pH of the reaction mass to 2.0 using formic acid. The precipitated product is filtered and dried to get solid mass. The Ceftriaxone acid is converted to Ceftriaxone disodium in acetone-water solvent system using sodium-2- ethyl hexanoate solution in acetone as a source of sodium. The product is isolated by addition of acetone to the reaction mass followed by filtration of precipitated brown resin. Acetone is further added to the filtrate and kept at low temperature and the solid obtained is filtered. The above said process is too cumbersome to be adopted at industrial scale as it needs a number of steps for isolation.
US Patent No. 47,67,852 discloses method for the preparation of Ceftriaxone that comprises silylation of 7-ACT (7-Amino-3-(2,5-dihydro-Z-methyl-6-hydroxy-5-oxo-as- triazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid) using N,O-bis(trimethylsilyl) acetamide and reacting it with an active ester (MAEM i.e. Z-(2-Aminothiazol-4-yl)-Z-syn- methoxyimino acetic acid 2-benzothiazolyl thioester) in DCM. The main disadvantage of the above described process is use of costly silylating agent for silylation. Use of active ester MAEM is disclosed in several other literatures but due to lower reactivity its reaction with 7- ACT takes longer time for completion and also a by-product of this reaction is the toxic compound 2-mercaptobenzothiazole.
SUMMARY OF THE INVENTION
The present invention relates to an industrially scalable method for the manufacture and isolation of substantially pure Ceftiraxone disodium hemiheptahydrate, i.e. (6,R,7R)-7-[2-(2- amino-4-thiazolyl)-2-syn-methoxyimino)acetamido]-3-[[2,5-dihydro-6-hydroxy-2-methyl-5- oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid disodium hemiheptahydrate having the chemical Formula VI VI
Figure imgf000004_0001
3.5 H20
In the first embodiment a high yielding process is provided for the production of Ceftriaxone disodium hemiheptahydrate. The process comprises the reaction of 2-(2- chloroacetamidothiazol-4-yl)-2-syn-methoxyiminoacetyl chloride with (7R)-7-amino-3- deacetoxy-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]cephalosporonic acid (7-ACT) in water or aqueous isopropyl alcohol to yield the amino protected Ceftrioxane. The chloroacetyl group is removed conventionally using thiourea and a mild base in a mixture of water and isopropyl alcohol. The pH of the reaction mixture is brought up to about 2.0 to get the precipitate of Ceftriaxone in good purity. The later is converted to Ceftriaxone disodium hemiheptahydrate by reacting sodium-2-ethylhexanoate in a mixture of acetone and water. Finally, (6,R,7R)-7-[2-(2-amino-4-thiazolyl)-2-syn-methoxyimino)acetamido]-3-[[2,5- dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-l- azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid disodium hemiheptahydrate is obtained in more than 99% HPLC purity without any unknown impurity more than 0.1 %. DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a simple, efficient and scalable method for the production of a cephalosporin, e.g., Ceftiraxone disodium hemiheptahydrate, i.e. (6,R,7R)-7- [2-(2-amino-4-thiazolyl)-2-syn-methoxyimino)acetamido]-3-[[2,5-dihydro-6-hydroxy-2- methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]-oct-2-ene-2- carboxylic acid disodium hemiheptahydrate. The process of the invention involves cheaper and easily available raw materials, shorter reaction timings, simple reaction work-up procedures and isolation of the product in high purity (purity by HPLC above 99%).
The process of the present invention comprises the preparation of acid chloride of 2- (2-Chloroacetamido-4-thiazolyl)-2-syn-methoxyimino acetic acid. The carboxy function of 2-(2-Chloroacetamido-4-thiazolyl)-2-syn-methoxyimino acetic acid (Formula I)
Formula I
Figure imgf000005_0001
is activated with phosporous pentachloride in a mixture of dichloromethane and dimethylacetamide between about -10°C to 25 °C, more preferably between about -5 to about 10°C. The acetylation is completed between about 30 min to about 3 hours. 2-(2- Chloroacetamido-4-thiazolyl)-2-syn-methoxyimino acetyl chloride (Formula II)
Formula II
Figure imgf000005_0002
is obtained after quenching the reaction with water and extracting with dichloromethane. Orgamc layer contains the desired product which is used for the next step without any further work-up or purification step.
The synthesis of (6R, 7R)-7-[2-[2-(2-Chloroacetamido)-4-thiazolyl]-2-syn-methoxy- imino)acetamido)-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8- oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (N-Protected Ceftriaxone acid, Formula III)
Formula III
Figure imgf000006_0001
is suitably carried out by acylating (7R)-7-amino-3-deacetoxy-3-[(2,5-dihydro-6-hydroxy-2- methyl-5-oxo-as-triazin-3-yl)thio]cephalosporonic acid (7-ACT) (Formula IN)
Formula IV
Figure imgf000006_0002
with 2-(2-Chloroacetamido-4-thiazolyl)-2-syn-methoxyimino acetyl chloride (Formula II) in water or aqueous isopropanol in presence of a base. Suitable base for this reaction include aliphatic amine more preferably triethylamine or aqueous sodium hydroxide. Temperature of the acylation reaction is maintained between about -10 to about 30°C more particularly between about -5 to 10°C. Acylation process of this reaction is rapid and completes in about 30 minutes to 1 hour. Once acylation reaction is over, pH of the reaction solution is adjusted between about 2.0 to 4.0, more particularly around 3.0 by adding dilute hydrochloric acid. At the above said pH of the reaction mixture Ν-protected Ceftriaxone acid (Formula πi) is precipitated out which is washed with water and found sufficiently pure for the deprotection of amino function.
In the next embodiment, amino group of (6R, 7R)-7-[2-[2-(2-Chloroacetamido)-4- tmazolyl]-2-syn-methoxyimino)acetamido)-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as- triazin-3-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (N- Protected Ceftriaxone Acid, Formula III) is deprotected. The deprotection step is carried out in water or a mixture of water and alcohol selected from methanol, ethanol or isopropyl alcohol, more particularly a mixture of water and isopropanol is preferred as solvent. The removal of chloroacetyl function from compound having formula III comprises in the presence of thiourea at pH between about 5.0 to about 8.0, more preferably between about 6.5 to about 7.5. The base used for the pH adjustment is aqueous sodium bicarbonate solution and the reaction is carried out in a temperature range of 10°C to 40°C, preferably between about 20°C to 30°C. Deprotection usually completes in 6 to 8 hours. After complete deprotection, pH of the reaction mixture is adjusted about 2.0 to about 4.0 for the precipitation of (6,R,7R)-7-[2-(2-amino-4-thiazolyl)-2-syn-methoxyimino)acetamido]-3- [[2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-l- azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid (Ceftriaxone acid) having formula V
Formula V
Figure imgf000007_0001
Ceftriaxone acid is finally converted to Ceftriaxone disodium hemiheptahydrate having Formula VI a VI
Figure imgf000007_0002
Ceftriaxone acid is finally converted to Ceftriaxone disodium hemiheptahydrate in acetone- water solvent system using sodium-2-ethylhexanoate solution in acetone. The product is precipitated by adding acetone to the reaction mass. The product thus formed is of high purity (above 99.5%) and having no unknown impurities above 0.1 %.
Examples The following example illustrate the invention, but is not limiting thereof,
EXAMPLE 1
(6R, 7R)-7-[2-[2Y2-Chloroacetamido)-4-thiazolylJ-2-syn-methoxyimino)acetamido)-3-[[(2,
5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]met
[4.2.0] oct-2~ene-2-carboxylic acid (N-Protected Ceftriaxone acid)
Stage I: 2-C2-Chloroacetamido4-thiazolvl)-2-svn-methoxviminoacetyl chloride
To a cooled suspension of phosphorous pentachloride (400 g) in dichloromethane (3 Ltr) is added Dimethyl acetamide (300 ml). After the addition, 2-(2-Chloroacetamido-4- thiazolyl)-2-syn-methoxyimino acetic acid (500 g) is added and the reaction is stirred at 0 to 5°C 'for 30 minutes. Chilled water is added to the reaction mixture and layers are separated. The organic layer contains the desired acid chloride, i.e., 2-(2-Chloroacetamido4-thiazolyl)- 2-syn-methoxyiminoacetyl chloride.
Stage II; (6R, 7R)-7-[2-[2γ2~Chloroacetamido)-4-thiazolyl]-2-syn-methoxyimino)aceta- mido)-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8- oxo-5-thia-l-azabicyclo[4.2.0] oct-2-ene-2-carboxylic acid (N-Protected Ceftriaxone acid)
(7R)-7-Amino-3-deacetoxy-3-[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3- yl)thio]cephalosporanic acid (7-ACT) (500 g) is suspended in water (2.50 Ltr) and triethylamine (400 g) is added to it under stirring whereupon a clear solution is formed. To the clear solution isopropyl alcohol (1.5 Ltr) is added. The reaction mixture is cooled to 0°C and to it organic layer containing acid chloride (as prepared above in stage I) is added during 30 to 45 minutes. The pH of the reaction mass is continuously adjusted to around 8 using triethylamine for 1 hour and after completion of reaction (by HPLC monitoring), the layers are separated. Aqueous layer is acidified using dilute HCl by adjusting the pH around 3.0 and the precipitated solid is filtered, washed with water and taken wet for the next stage. HPLC Purity = Above 95%.
EXAMPLE 2
(6R, 7R)-7-[2-(2-Amino-4-thiazolyl)-2-syn-methoxyimino)acetamido]-3-[[2, 5-dihydro-6- hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]-oct-2- ene-2-carboxylic acid (Ceftriaxone acid)
The wet material obtained in Example 1 is suspended in a mixture of water (1.0 Ltr) and isopropyl alcohol (2.0 Ltr). Thiourea (275 g) is added to the reaction mixture and pH of the reaction mixture is adjusted to 7.0 using aqueous sodium bicarbonate solution. The reaction mixture is stirred at room temperature for 8 hours at a pH around 7.0. After completion of reaction (by HPLC monitoring), its pH is brought to around 2.0 by adding dilute HCl. The precipitated solid is filtered, washed with water and submitted wet for sodium salt preparation.
EXAMPLE 3
(6R, 7R)-7-[2Y2-amino-4-thiazolyl)-2-syn-methoxyimino)acetamido]-3-[[2, 5-dihydro-6- hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]-oct-2- ene-2-carboxylic acid disodium hemiheptahydrate (Ceftriaxone disodium hemiheptahydrate)
A solution of sodium-2-ethyl hexanoate (390 g) in acetone (2.0 Ltr) is added to the wet Ceftriaxone acid obtained in Example 2 is suspended in a mixture of acetone and water. The reaction mixture is charcoalized and filtered. To the clear filtrate is added acetone whereupon the product precipitated. The precipitated solid is filtered, washed with acetone and dried to get 515 g of Ceftriaxone disodium hemiheptahydrate. HPLC purity = Above 99.5%.

Claims

We Claim
1 A process for manufacturing a compound of Formula (VI)
VI
Figure imgf000010_0001
. 3.5 H20 the said method comprising: (a) contacting a compound of the Formula IN
Formula IV
Figure imgf000010_0002
with 2-(2-Chloroacetamido-4-thiazolyl)-2-syn-methoxyiminoacetyl chloride in suitable solvent and a base for a sufficient time to form (6R, 7R)-7-[2-[2-(2-Chloroacetamido)-4- thiazolyl] -2-syn-methoxyimino)acetamido)-3 -[ [(2, 5 -dihydro-6-hydroxy-2-methyl-5 -oxo- as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
(b) isolation of (6R, 7R)-7-[2-[2-(2-Chloroacetamido)-4-thiazolyl]-2-syn-methoxyimino) acetamido)-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8- oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
(c) converting (6R, 7R)-7-[2-[2-(2-Chloroacetamido-4-thiazolyl]-2-syn-methoxyimino)- acetamido)-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8- oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid into (6R, 7R)-7-[2-[2-(2- Amino-4-thiazolyl]-2-syn-methoxyimino)acetamido)-3-[[(2,5-dihydro-6-hydroxy-2- methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid in presence of suitable solvent system and a deblocking agent. (d) isolation of (6R, 7R)-7-[2-[2-(2-Amino-4-thiazolyl]-2-syn-methoxyimino)acetamido)-3- [[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-1xiazin-3-yl)thio]methyl]-8-oxo-5-thia-l- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
(e) Conversion and isolation of step 1(d) product into Ceftriaxone disodium hemiheptahydrate.
2 The process of claim 1, wherein step (a) is carried out in water or aqueous alcohol.
3 The process of claim 2, wherein said alcohol is isopropyl alcohol.
4 The process of claim 3, wherein volume ratio of water and alcohol is between about 1 : 1 to about 1:3.
5 The process of claim 4, wherein more particularly volume ratio of water and alcohol is between about 1 : 1 to about 1 :2.
6 The process of claim 1, wherein (7R)-7-Amino-3-deacetoxy-3-[(2,5-dihydro-6-hydroxy- 2-methyl-5-oxo-as-triazin-3-yl)thio]cephalosporanic acid in step (a) is dissolved in water and an aliphatic amine prior to addition of 2-(2-Chlooroacetamido-4-thiazolyl)-2-syn- methoxyiminoacetyl chloride.
7 The process of claim 6, wherein aliphatic amine is triethylamine.
8 The process of claim 1 , wherein 2-(2-Chloroacetamido-4-thiazolyl)-2-syn-methoxy- iminoacetyl chloride is dissolved in dichloromethane in step (a) prior to its addition.
9 The process of claim 8, wherein 2-(2-Chloroacetamido-4-thiazolyl)-2-syn-methoxyimino -acetyl chloride solution is used for acylation after extraction without additional purification.
10 The process of claim 1, wherein the contact time for step (a) is about 20 minutes to about 1 hour.
11 The process of claim 1 , wherein the contact temperature for step (a) is between about -5 to about 10°C.
12 The process of claim 1, wherein pH of the reaction mixture in step (a) is around 8.
13 The process of claim 1, wherein aqueous and organic layers are separated in step (b) after the reaction is over.
14 The process of claim 13, wherein pH of the aqueous layer in step (b) is adjusted about 3 using dilute hydrochloric acid.
15 The process of claim 13 & 14, wherein the precipitated solid is filtered and washed with water. 16 The process of claim 1 (a) and (b), wherein HPLC purity of the (6R, 7R)-7-[2-[2-(2- Chloroacetamido)-4-thiazolyl]-2-syn-methoxyimino)acetamido)-3-[[(2,5-dihydro-6- hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo- [4.2.0]oct-2-ene-2-carboxylic acid is obtained in more than 95 %.
17 The process of claim 1 , wherein (6R, 7R)-7-[2-[2-(2-Chloroacetamido)-4-thiazolyl]-2- syn-methoxyinιino)acetamido)-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3- yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo- [4.2.0]oct-2-ene-2-carboxylic acid is deprotected in step (c) in aqueous isopropyl alcohol and thiourea.
18 The process of claim 1 , wherein (6R, 7R)-7-[2-[2-(2-Chloroacetamido)-4-thiazolyl]-2- syn-methoxyimino)acetamido)-3 - [ [(2,5 -dihydro-6-hydroxy-2-methyl-5 -oxo-as-triazin-3 - yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo- [4.2.0]oct-2-ene-2-carboxylic acid is converted to (6R, 7R)-7-[2-[2-(2-Chloroacetamido)-4-thiazolyl]-2-syn- methoxyimino)acetamido)-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3- yl)thio]methyl]-8-oxo-5-thia-l-azabicyclo- [4.2.0]oct-2-ene-2-carboxylic acid disodium hemiheptahydrate by reacting sodium-2-ethylhexanoate in acetone and drying the filtered precipitate.
19 A process for the manufacturing
Figure imgf000012_0001
the said method comprising:
(a) contacting 2-(2-Chloroacetylthiazolyl-4-yl-2-syn-methoxyiminoacetic acid with phosphorous pentachloride in suitable solvent at low temperature.
(b) isolation of 2-(2-Chloroacetylthiazolyl-4-yl-2-syn-methoxyiminoacetyl chloride.
20 The process of claim 19, wherein step (a) is carried out in a mixture of dichloromethane and dimethyl acetamide. The process of claim 19, wherein phosphorous pentachloride is mixed with dichloromethane and dimethyl acetamide in step (a) before adding to 2-(2-Chloroacetyl-4- thiazolyl-2-syn-methoxyimino acetic acid . The process of claim 19, wherein contact temperature in step (a) is between about -5°C to about 10°C. The process of claim 19, wherein contact time in step (a) is between about 15 min to about 1 hour. The process of claim 19, wherein 2-(2-Chloroacetylthiazolyl-4-yl-2-syn- methoxyiminoacetyl chloride is filtered and washed with isopropyl ether in step (b) to get solid mass. The process of claim 24, wherein isolated product is used without further purification. The process of claim 1, wherein Ceftriaxone disodium hemiheptahydrate isolated is more than 99.5 % pure by HPLC analysis. The process of claim 1 , wherein no unknown impurity is found above 0.1 % by HPLC analysis.
PCT/IB2004/001692 2004-04-28 2004-04-28 Improved process for the manufacture of ceftriaxone sodium WO2005105813A1 (en)

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