AN INTERMEDIATE OF CEFOPERAZONE SODIUM
INTRODUCTION
Aspects of the present application relates to process for the preparation of N,N-dimethylacetamide adduct of (6R,7R)-7-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-(p-hydroxyphenyl)-acetamido]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (i.e. N,N-dimethylacetamide adduct of cefoperazone acid) represented by the Formula I,
(Formula Removed)
which is an intermediate employed for the preparation of cefoperazone acid represented by the Formula II
(Formula Removed)
The drug compound having the adopted name "cefoperazone sodium" has a chemical name sodium (6R,7R)-7-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-(p-hydroxyphenyl)-acetamido]-3-[[(1-methyl-1H-
tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, and is represented by structural Formula III.
(Formula Removed)
Cefoperazone sodium sterile (marketed in US market as CEFOBID®), is a semi-synthetic broad spectrum cephalosporin antibiotic for intravenous or intramuscular administration.
US 4,410,522 claims sodium (6R,7R)-7-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-(p-hydroxyphenyl)-acetamido]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (i.e. cefoperazone sodium of formula III). This patent also discloses various processes for the preparation of cefoperazone sodium.
US 4,237,280 claims N,N-dimethylacetamide adduct of (6R,7R)-7-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-(p-hydroxyphenyl)-acetamido]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (i.e. N,N-dimethylacetamide adduct of Formula I).
US Patent Number 4,304,909 claims the process for producing N,N-dimethylacetamide adduct of cefoperazone of Formula I which comprises acylating 7-amino-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-A3-cephem-4-carboxylic acid hydrochloride (i.e. 7-ACMT hydrochloride of Formula IV), with D(-)-a-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-a-(4-hydroxyphenyl) acetyl chloride (i.e. acid chloride of OH-EPCP of Formula V) under anhydrous conditions in the presence of N,N-dimethylacetamide as a solvent to produce a solution of acylated product and recovering the N,N-dimethylacetamide adduct of cefoperazone acid of Formula I as a precipitate from the solution (Scheme I).
(Scheme Removed)
US 4,304,909 also claims a process for producing purified cefoperazone acid of Formula II, which comprises dissolving the compound represented by the formula (II) associated with the by-products of its prior syntheses in dimethylacetaminde and thereafter precipitating from said solution the N,N-dimethylacetamide adduct of cefoperazone of Formula I, and then treating the N,N/-dimethylacetamide adduct of cefoperazone acid of the Formula I with a solvent to liberate purified cefoperazone acid of Formula II.
The prior art methods for the preparation of N,N-dimethylacetamide adduct of cefoperazone acid of Formula I employ expensive silylating agents such as trimethylchlorosilane.
There still remains a need to provide the efficient and improved process for the preparation of highly pure cefoperazone which is simple, cost-effective, commercially viable, sustainable, eco-friendly, and to avoid multiple steps.
The main object of the present application is to provide a process for the preparation of N,N-dimethylacetamide adduct of cefoperazone acid of Formula I, which is simple, economical, user-friendly and commercially viable.
Another objective of the present application is to provide process for the preparation of N,N-dimethylacetamide adduct of cefoperazone acid of Formula I with high purity which can be advantageously used in the preparation of cefoperazone with high purity substantially free of impurities.
Another objective of the present application is to provide a process for the preparation of N,N-dimethylacetamide adduct of cefoperazone acid of Formula I, which would be easy to implement on commercial scale, and to avoid excessive use of reagent(s) and organic solvent(s) and to avoid hazardous and risky solvents, thus making the present process more safe.
SUMMARY
In an aspect, the present application includes a process for the preparation of N,N-dimethylacetamide adduct of cefoperazone represented by the Formula I,
(Formula Removed)
the embodiments comprising one or more of the following steps, individually or in the sequence recited:
i) reacting the compound represented by the Formula VI
(Formula Removed)
with an amine in a suitable solvent;
ii) condensing amine salt of Formula VI of step i) with the compound represented by the Formula V
(Formula Removed)
in a mixture of N,N-dimethylacetamide and a suitable solvent;
iii) adding water to the reaction mixture of step ii);
iv) separating the organic layer from solution of step iii);
v) concentrating the organic layer of step iv);
vi) adding alcohol to the residue of step v) at a suitable temperature;
vii) isolating N,N-dimethylacetamide adduct of cefoperazone represented by
the Formula I; and viii) optionally, converting N,N-dimethylacetamide adduct of cefoperazone
represented by the Formula I of step vii) to cefoperazone acid represented
by the Formula II
(Formula Removed)
or cefoperazone sodium represented by the Formula III
(Formula Removed)
DETAILED DESCRIPTION
All temperatures are in degrees Celsius unless specified otherwise. All measurements made are at about 25°C and about atmospheric pressure, and all percentages and ratios used herein are by weight of the total composition, unless otherwise designated.
As used herein, "comprising" means the elements recited, or their equivalent in structure or function, plus any other element or elements that are not recited. The terms "having" and "including" are also to be construed in the same manner. All ranges recited herein include the endpoints, including those that recite a range "between" two values. Terms such as "about," "generally," "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute term or value. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those having skill in the art. This includes the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
In an aspect, the present application includes a process for the preparation of N,N-dimethylacetamide adduct of cefoperazone acid represented by the Formula I,
(Formula Removed)
the embodiments comprising one or more of the following steps, individually or in the sequence recited:
i) reacting the compound represented by the Formula VI
(Formula Removed)
with an amine in a suitable solvent;
ii) condensing amine salt of Formula VI of step i) with the compound represented by the Formula V
(Formula Removed)
in a mixture of N,N-dimethylacetamide and a suitable solvent;
iii) adding water to the reaction mixture of step ii);
iv) separating the organic layer from solution of step iii);
v) concentrating the organic layer of step iv);
vi) adding alcohol to the residue of step v) at a suitable temperature;
vii) isolating N,N-dimethylacetamide adduct of cefoperazone represented by
the Formula I; and viii) optionally, converting N,N-dimethylacetamide adduct of cefoperazone
represented by the Formula I of step vii) to cefoperazone acid represented
by the Formula II
(Formula Removed)
or cefoperazone sodium represented by the Formula III
(Formula Removed)
7-amino-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-3-cephem-4-carboxylic acid (i.e.7-ACMT of Formula VI) and D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-a-(4-hydroxyphenyl) acetyl chloride (i.e. Acid chloride of OH-EPCP of Formula V) may be prepared using any processes known in the art.
An amine in step i) includes, but are not limited to: aliphatic, cyclic and aromatic amines such as methylamine; dimethylamine; diethylamine; triethylamine; trimethylamine; ethanolamine; methylethanolamine; diisopropylamine; dicyclohexylamine; N-tert-butylcyclohexylamine; pyridine; piperidine; N-methylpiperidine; N-ethylpiperidine; diphenylamine; 1,4-dimethylpiperazine; N,N-dibenzylethylenediamine; 4-dimethylaminopyridine; 1,5-Diazabicyclo[4.3.0]non-5-ene (DBN); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and the like, and any mixtures thereof. Preferably, an amine in step i) is diethylamine.
Suitable solvents in step i) and step ii) include, but are not limited to: halogenated organic solvents such as methylene dichloride and the like.
Suitable temperatures that may be employed in step i) are less than about 20°C, or less than about 0°C, or less than about -20°C, or less than about -40°C, or any other suitable temperatures.
Suitable times for maintaining the solution of the step i) depend on the temperature and other conditions, and may be generally less than about 10 hours, or less than about 5 hours, or less than about 2 hours, or less than about 1 hour, or any other suitable times. Longer times are also suitable.
Suitable temperatures that may be employed in step ii) are less than about 20°C, or less than about 0°C, or less than about -20°C, or less than about -40°C, or any other suitable temperatures.
Suitable times for maintaining the solution of the step ii) depend on the temperature and other conditions, and may be generally less than about 10 hours, or less than about 5 hours, or less than about 2 hours, or less than about 1 hour, or any other suitable times. Longer times are also suitable.
Suitable solvents in step vi) include, but are not limited to: alcohol such as methanol, ethanol, propanol, butanol, isopropanol and the like, and any mixtures thereof. Preferably, suitable solvents in step vi) is methanol.

Suitable temperatures that may be employed in step vi) are not less than about 25°C. Preferably, temperatures that may be employed in step vi) are in the range of 25°C. to 60°C; and more preferably in the range of 25°C. to 35°C.
Optionally, N,N-dimethylacetamide adduct of cefoperazone of Formula I of step vii) can be converted into cefoperazone acid of Formula II or cefoperazone sodium of Formula III.
All aspects of the present application such as base, temperature, reaction conditions should be strictly followed to avoid the preparation of impurities. The use of methanol for isolation in step vi) of present process plays a vital role in getting N,N-dimethylacetamide adduct of cefoperazone of Formula I with higher purity and keeps impurities under limit.
Certain aspects and embodiments of the present application are described in further details by the examples below, which are provided only for the purpose of illustration and are not intended to limit the scope of the application in any manner.
The following abbreviations are used:
N,N-dimethylacetamide adduct of cefoperazone acid: N,N-dimethylacetamide adduct of (6R,7R)-7-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-(p-hydroxyphenyl)-acetamido]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid represented by the Formula I
7-ACMT: 7-amino-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-3-cephem-4-carboxylic acid represented by the Formula VI.
Acid chloride of OH-EPCP: D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-a-(4-hydroxyphenyl) acetyl chloride represented by the Formula V.
EXAMPLE 1: Preparation of 7-amino-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-3-cephem-4-carboxylic acid (7-ACMT)
7-aminocephalosporanic acid (75 g, 0.276 mol) and 1-methyl-1 H-1,2,3,4-tetrazole-5-thiol (32.3 g, 0.276 mol) are added to a mixture of acetonitrile (525 mL) and BF3 (29.5 g, 0.338 mol) at 0°C. to 5°C. under vigorous stirring. The temperature of the reaction mass is raised to 25°C. to 30°C. and stirred for 30 minutes. After completion of the reaction, chilled water (1500 mL) is added to the reaction mass at 20°C. to 30°C. and stirred. The pH of the reaction mass is adjusted to 1.8-2.0 with 20% sodium carbonate solution at a temperature of 20°C. to 25°C. to give white coloured precipitated material. The reaction mass is further stirred for 1.0 hour at 20°C. to 25°C. for complete precipitation. The solid is filtered and washed with water (375 mL) followed by acetone (375 mL). The filtered solid is dried at 40°C. to 45°C. in hot air oven to afford 83.0 g of 7-amino-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-3-cephem-4-carboxylic acid (7-ACMT). (HPLC purity: 98.75%; moisture content: 2.5%).
EXAMPLE 2: Preparation of D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-a-(4-hydroxyphenyl) acetyl chloride (Acid chloride of OH-EPCP)
To a mixture of D(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-a-(4-hydroxyphenyl) acetic acid (73.0 g; 0.218 mol) in N,N-dimethylacetamide (240 mL) and dichloromethane (120 mL), phosphorus oxychloride (36.5 g, 0.238 mol) is added slowly over a period of 30 minutes at -40°C. to -45°C. After completion of the reaction, the temperature of reaction mass is raised to -18°C. and stirred for 1.0 hour at a same temperature to obtain D(-)-a-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-a-(4-hydroxyphenyl) acetyl chloride (Acid chloride of OH-EPCP). (HPLC Purity: 94.99%). This acid chloride is cooled to -40°C and is used in the next step without isolation.
EXAMPLE 3: Preparation of N,N-dimethylacetamide adduct of cefoperazone acid
Diethylamine (16.0 g; 0.219 mol) is added to a mixture of 7-amino-3-[5-(1-methyl-1,2,3,4-tetrazolyl)thiomethyl]-3-cephem-4-carboxylic acid (7-ACMT) (60.0 g; 0.183 mol) in dichloromethane (240 mL) at a temperature of 0°C. to 5°C. and
stirred for 60 minutes to get clear solution of diethyl amine salt of 7-ACMT . The diethylamine salt of 7-ACMT solution is cooled to -40°C. under nitrogen atmosphere and is poured into above prepared D(-)-a-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-a-(4-hydroxyphenyl) acetyl chloride solution. The reaction mass is stirred for 2.0 hours at -18°C. to -20°C. After completion of the reaction, water (240 mL) is added to the reaction mass and stirred for 20 minutes at 0°C. to 10°C. The organic layer is separated from the aqueous layer. The solvent is distilled off completely under vacuum to get thick residue. Methanol (600 mL) is added to the residue, stirred for 3 hours to 4 hours at a temperature of 30°C. to 32°C. for complete precipitation. The solid is filtered off, washed with methanol (180 mL) to give 84.0 g of N,N-dimethylacetamide adduct of cefoperazone acid.(HPLC Purity : 99.17%; N,N-dimethylacetamide content: 1.5%).
EXAMPLE 4: Preparation of cefoperazone sodium crude
N,N-dimethylacetamide adduct of cefoperazone acid(120.0 g; 0.164 mol) is dissolved in aqueous acetone [water: acetone (30 mL:360 mL)] at 20°C. to 30°C. Activated charcoal (1.20 g) is added to the clear solution and stirred for 5 minutes. The solution is filtered through celite bed and the bed is washed with 12.0 mL of aqueous acetone [water: acetone (3.60 mL: 8.4 mL)]. The pH of the combined filtrate is adjusted to 5.6-5.7 with 6.0% sodium bicarbonate solution (13.10 g, 0.156 mol). Acetone (960 mL) is added slowly to the reaction mixture in 30 minutes at a temperature of 20°C. to 25°C. and stirred for 2 hours to obtain hazy material. Acetone (2880 mL) is added to the above mass in 1.5 hours at a temperature of 20°C. to 25°C. and stirred for 1.0 hour for complete precipitation. The solid is filtered and the cake is washed with acetone (600 mL). The wet solid is semi dried at 25°C for 2 hours to get 180 g of crude cefoperazone sodium.
EXAMPLE 5: Preparation of cefoperazone acid
The crude cefoperazone sodium of example-4 is dissolved in water (2250 mL) at 20°C. to 25°C. Activated charcoal (1.20 g) is added to the clear solution and stirred for 5 minutes at 20°C. to 25°C.The solution is filtered through celite bed and the bed is washed with 60 mL of water. To the combined filtrate,
acetonitrile (750 mL) is added, stirred for 5 minutes to get homogeneous solution. The pH of the reaction mass is adjusted to pH 1.8-2.0 by adding dilute hydrochloric acid slowly to the solution at 20°C. to 25°C. to get the precipitated material and stirred for 60 minutes. The solid is filtered and the cake is washed with aqueous acetonitrile [450 mL: 150 ml_(water:acetonitrile)] to give 89.0 g of cefoperazone acid. (HPLC purity: 99.61%)
EXAMPLE 6: Preparation of cefoperazone sodium
Cefoperazone acid (45 g; 0.070 mol) is dissolved in aqueous acetone [water: acetone (12 mL: 135 mL)] at 20°C. to 25°C Activated charcoal (0.20 g) is added to the clear solution and stirred for 5 minutes at 20°C. to 25°C. The clear solution is filtered through celite bed and the bed is washed with aqueous acetone [water: acetone (5.5 mL: 16.5 mL)]. The pH of the reaction mass is adjusted to 5.6 to 5.7 with dilute sodium bicarbonate solution [5.55 g (0.066 mol) in 90 mL of water] at 20°C. to 25°C. Acetone (360 mL) is added slowly to the reaction mixture in 30 minutes at a temperature of 20°C. to 25°C. and stirred for 2 hours to obtain hazy material. Acetone (1080 mL) is added to the above mass in 1.5 hours at a temperature of 20°C. to 25°C. and stirred for 1.0 hour for complete precipitation. The precipitated solid is filtered and the cake is washed with acetone (225 mL). The wet solid is dried under vacuum at a temperature of 45°C. to 50°C to get 38 g of cefoperazone sodium. (HPLC purity: 99.63%; moisture content: not more than 5.0%).

We Claim:
1. A process for the preparation of N,N-dimethylacetamide adduct of cefoperazone acid represented by the Formula I,
(Formula Removed)
comprising one or more of the following steps, individually or in the sequence recited:
i) reacting the compound represented by the Formula VI
(Formula Removed)
with an amine in a suitable solvent;
ii) condensing amine salt of Formula VI of step i) with the compound represented by the Formula V
(Formula Removed)
in a mixture of N,N-dimethylacetamide and a suitable solvent;
iii) adding water to the reaction mixture of step ii);
iv) separating the organic layer from solution of step iii);
iv) concentrating the organic layer of step iv);
v) adding alcohol to the residue of step v) at a suitable temperature;
vi) isolating N,N-dimethylacetamide adduct of cefoperazone represented by the Formula I.
2. The process according to claim 1, wherein amine in step i) is selected from the group consisting of methylamine, dimethylamine, diethylamine, triethylamine, trimethylamine, ethanolamine , methylethanolamine, diisopropylamine, dicyclohexylamine, N-tert-butylcyclohexylamine, pyridine, piperidine, N-methylpiperidine, N-ethylpiperidine, diphenylamine, 1,4-dimethylpiperazine, N,N-dibenzylethylenediamine, 4-dimethylaminopyridine, 1,5-Diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and any mixtures thereof.
3. The process according to claim 1, wherein amine in step i) is diethylamine.
4. The process according to claim 1, wherein suitable solvent in steps i) and ii) is a halogenated organic solvent, preferably methylene dichloride.
5. The process according to claim 1, wherein alcohol in step vi) is selected from the group consisting of methanol, ethanol, propanol, butanol, isopropanol, and any mixtures thereof.
6. The process according to claim 1, wherein alcohol in step vi) is methanol.
7. The process according to claim 1, wherein suitable temperatures employed in
step vi) are not less than about 25°C.
8. The process according to claim 1, wherein suitable temperatures employed in
step vi) are in the range of 25°C. to 35°C.
9. A process for the preparation of cefoperazone acid represented by the Formula
II
(Formula Removed)
or cefoperazone sodium represented by the Formula III
(Formula Removed)
comprising one or more of the following steps, individually or in the sequence recited:
i) reacting the compound represented by the Formula VI
(Formula Removed)
with an amine in a suitable solvent;
ii) condensing amine salt of Formula VI of step i) with the compound represented by the Formula V
(Formula Removed)
in a mixture of N,N-dimethylacetamide and a suitable solvent;
iii) adding water to the reaction mixture of step ii);
iv) separating the organic layer from solution of step iii);
iv) concentrating the organic layer of step iv);
vi) adding alcohol to the residue of step v) at a suitable temperature; vii) isolating N,N-dimethylacetamide adduct of cefoperazone acid represented by the Formula I
(Formula Removed)
viii) converting N,N-dimethylacetamide adduct of cefoperazone represented by the Formula I of step vii) to cefoperazone acid represented by the Formula II
(Formula Removed)
or cefoperazone sodium represented by the Formula III
(Formula Removed)