PROCESS FOR THE PURIFICATION OF CEFDITOREN SODIUM
INTRODUCTION
Aspects of the present application relates to process for the purification of cefditoren sodium.
The drug compound having the adopted name "cefditoren" has a chemical name (-)-(6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl) ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, and is represented by structural Formula I.
(Structure Removed)
Cefditoren pivoxil, represented by Formula II, is chemically known as(-)-(6R,7R)-2,2-dimethylpropionyloxymethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl) ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, and is represented by Formula II.
(Formula Removed)
Cefditoren pivoxil (marketed in US market as SPECTRACEF®), a third generation semi-synthetic cephalosporin antibiotic for oral
administration is a prodrug which is hydrolyzed by esterases during absorption, and the drug is distributed in the circulating blood as active cefditoren.
US Patent Number US 4,839,350 claims 7-[2-methoxyimino-2-(2-amino-thiazol-4-yl) acetamido]-3-[2-(4-methylthiazol -5-yl) vinyl]-3-cephem-4-carboxylic acid (syn-isomer, cis-isomer) sodium salt (i.e. cefditoren sodium of Formula III). This patent also discloses various processes for the preparation of Cefditoren.
(Formula Removed)
Journal of Antibiotics, XLIII (8), 1047-1050 (1990) and Chem. Pharm. Bull., 39 (9), 2433-2436 (1991) discloses a process for the preparation of 4-methoxybenzyl ester of 7-phenylacetamido-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid of Formula IV in the form of a mixture of the Z-isomer (cis-isomer) and E-isomer (trans-isomer) at a mix ratio of 4.7:1.,
(Formula Removed)
which may be further employed for the preparation of cefditoren.
U.S. Patent Number US 5,616,703 discloses a process for depleting the E-isomer of a mixture of Z- and E-isomers of the compound of the Formula (V),
(Formula Removed)
which comprises; a) subjecting a mixture of Z- and E-isomers of the compound of Formula (V) in amine salt form to crystallization and converting the crystallized product into a mixture of Z- and E-isomers of the compound of Formula (V) enhanced with Z- isomer or to pure Z-isomer, or b) subjecting a mixture of Z- and E-isomers of the compound of formula (V) to adsorption chromatography.
U.S. Patent Number US 6,288,223 discloses a process for the production of the Z-isomer of a 7-N-unsubstituted or substituted-amino-3-[2-(4-substituted or unsubstituted-thiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid or an ester thereof, in a mixed solvent consisting of one or more chlorinated hydrocarbon solvent(s) and one or more lower alkanol(s) mixed at a mix ratio (by volume) in a range of from 1:3 to 1:0.25.
PCT application WO2005100369 claims a process for depleting E-isomer by treating the cefditoren acid with amine followed by adding sodium-2-ethyl hexanoate to yield cefditoren sodium with reduced E-isomer content.
PCT application WO2007054777 claims a process for the depletion of E-isomer of cefditoren sodium of Formula III, in a mixture of (Z/E)-isomers, which comprises the steps of (i) dissolving cefditoren sodium
containing 0.4-20% of E-isomer in a solvent using an acid, (ii) adding sodium salt of weak acid, and (iii) isolating cefditoren sodium.
There still remains a need to provide an improved process for depletion of the E-isomer from a mixture of Z- and E-isomers of cefditoren sodium to get pure cefditoren sodium enriched with Z-isomers of cefditoren sodium, 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 depletion of E-isomer of cefditoren sodium of Formula III, which is simple, economical, user-friendly and commercially viable.
Another objective of the present application is to provide a process for the depletion of E-isomer of cefditoren sodium of Formula III, 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 invention more safe and eco-friendly as well.
Yet another objective of the present application is to provide a process for the depletion of E-isomer of cefditoren sodium of Formula III in shorter time with less exposure to high temperature so that the same can be utilized for the preparation of a compound of Formula II in greater yield with higher chemical purity.
SUMMARY
In an aspect, the present application includes a process for the purification of cefditoren sodium of Formula III,
(Formula Removed)
by depleting the E-isomer content in a mixture of Z- and E-isomers of the compound of Formula VI,
(Formula Removed)
the embodiments comprising one or more of the following steps, individually or in the sequence recited:
(i) preparing a solution of a mixture of Z- and E-isomer of compound
of Formula VI in a suitable solvent;
(ii) adding a suitable inorganic salt to the solution of step (i); (iii) isolating Z-isomer enriched mixture of Z- and E-isomer of
compound of Formula VI; and (iv) optionally, converting Z-isomer enriched mixture of Z- and E-
isomer of compound of Formula VI of step (iii) to cefditoren pivoxil
of formula II.
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.
The term "enriched" should be understood to mean that the products obtainable in accordance with the process of present application have a higher content of one isomer, relative to the isomeric content of same isomer in a mixture before treating the same.
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 purification of cefditoren sodium of Formula III,
(Formula Removed)
by depleting the E-isomer content in a mixture of Z- and E-isomers of the compound of Formula VI,
(Formula Removed)
the embodiments comprising one or more of the following steps, individually or in the sequence recited:
(i) preparing a solution of a mixture of Z- and E-isomer of compound
of Formula VI in a suitable solvent;
(ii) adding a suitable inorganic salt to the solution of step (i); (iii) isolating Z-isomer enriched mixture of Z- and E-isomer of
compound of Formula VI; and (iv) optionally, converting Z-isomer enriched mixture of Z- and E-
isomer of compound of Formula VI of step (iii) to cefditoren pivoxil
of formula II.
(Formula Removed)
7-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylic acid-p-methoxybenzyl ester (GCLE), p-Methoxybenzyl-7-phenylacetamido-3-(4-methylthiozol-5-yl) vinyl-3-cephem-4-carboxylate (MTNE), 7-Amino-3-(4-methylthiazol-5-yl) vinyl-3-cephem-4-carboxylic acid (MTCA), and the compound of Formula VI may be prepared using any processes known in the art.
Step i) involves preparing a solution of a mixture of Z- and E-isomer of compound of Formula VI in a suitable solvent.
The mixture of Z- and E-isomer of compound of Formula VI in step i) may contain E-isomer of compound of Formula VI in amounts more than about 0.70% by weight.
Suitable solvents in step i) include, but are not limited to: polar protic solvents, such as, water, alcohols, e.g., methanol, ethanol, isopropanol, n-propanol, n-butanol, 2-butanol, and the like, and any mixtures thereof.
Suitable temperatures that may be employed for maintaining the solution of the step i) are less than about 100°C, or less than about 80°C, or less than about 60°C, or less than about 40°C, or less than about 20°C, or less than about 0°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 30 hours, or less than about 20 hours, or 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 also are suitable.
Step ii) involves adding a suitable inorganic salt to the solution of step (i).
Suitable inorganic salt in step ii) include, but are not limited to: halides and sulphates of alkali metals and alkaline earth metals, such as, sodium chloride, magnesium chloride, potassium chloride, sodium sulphate, magnesium sulphate, potassium sulphate, and the like, and any mixtures thereof.
Suitable temperatures that may be employed for maintaining the solution of the step ii) are less than about 100°C, or less than about 80°C, or less than about 60°C, or less than about 40°C, or less than about 20°C, or less than about 0°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 30 hours, or less than about 20 hours, or 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 also are suitable.
Optionally, the mixture obtained from step ii) may be directly employed for the preparation of a compound of Formula II, without further isolation or conventional work-up.
Step iii) involves isolating Z-isomer enriched mixture of Z- and E-isomer of compound of Formula VI.
The resulting Z-isomer enriched mixture of Z- and E-isomer of compound of Formula VI in step iii) may contain E-isomer of compound of Formula VI in amounts less than about 0.70% by weight.
The resulting Z-isomer enriched mixture of Z- and E-isomer of compound of Formula VI may be recovered using any methods known in the art. For example, it may be isolated by a method that includes but is not limited to: filtration by gravity or suction, centrifugation, slow evaporation, and the like. The resulting Z-isomer enriched mixture of Z-and E-isomer of compound of Formula VI may also be recovered from the mother liquors obtained by conventional processes, e.g., removal of solvent, cooling, concentrating the mass, combining with an anti-solvent, extraction with a solvent, and the like. Stirring or other alternate methods
such as shaking, agitation and the like may also be employed for isolation.
The resulting Z-isomer enriched mixture of Z- and E-isomer of compound of Formula VI in step iii) may be further purified one or more times using any suitable techniques. For example, it may be purified by precipitation, slurrying in a suitable solvent, or any other suitable techniques. Precipitation may be achieved by crystallization, such as by cooling a solution, concentrating a solution, or by combining an anti-solvent with a solution of the product, or any other suitable methods.
If desired, the isolated solid of step iii) may optionally be further washed with a suitable solvent. Suitable solvents include, but are not limited to: water miscible solvents, such as, acetone, ethyl acetate, alcohols e.g., methanol, ethanol, isopropanol, n-propanol, n-butanol, 2-butanol, and the like, and any mixtures thereof.
The wet cake obtained in step iii) may optionally be further dried. Drying may be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, rotary dryer, cone dryer, rotary cone dryer, and the like. Drying may be carried out at temperatures less than about 100°C, or less than about 60°C, or less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve the desired quality of the product, such as, for example, about 1 to about 15 hours, or longer.
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.
EXAMPLES 1: Preparation of p-Methoxybenzyl-7-phenylacetamido-3-(4-methylthiozol-5-yl) vinyl-3-cephem-4-carboxylate (MTNE).
To a mixture of N, N-Dimethyl formamide (5 Kg) and 7-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylic acid-p-methoxybenzyl ester (GCLE) (5 Kg), sodium bromide (1.15 Kg) and triphenylphosphine (3.35 Kg) are added. The reaction mixture is stirred at 30°C. to 32°C. till the reaction is complete. A mixture of dichloromethane (30 L) and water (15 L) is charged to the reaction mixture at 25°C. to 30°C. and stirred for 10 minutes to 15 minutes at the same temperature. Organic layer is separated from aqueous layer; organic layer is concentrated to its one third volume under vacuum. Tetrahydrofuran (25 L), DM water (25 L) and sodium bicarbonate (2.6 Kg) are added to the concentrated material and stirred for 10 minutes to 15 minutes to get uniform solution. 4-Methyl-5-formyl-1, 3-thiazole (FMT) (1.65 Kg) is added to the clear solution and stirred for 12 hours to 18 hours at 10°C. to 15°C. until completion of the reaction. Excess FMT traces are removed by giving sodium bisulphite wash to the organic layer. The organic layer is completely distilled off under vacuum at 50°C. to 55°C. to afford 11.87 Kg of the MTNE residue (HPLC purity: 79.54 %; Anti Isomer (E-isomer): 7.79 %).
EXAMPLES 2: Preparation of 7-Amino-3-(4-methylthiazol-5-yl) vinyl-3-cephem-4-carboxylic acid (MTCA)
To the p-Methoxybenzyl-7-phenylacetamido-3-(4-methylthiazol-5-yl) vinyl-3-cephem-4-carboxylate (MTNE) residue of example-1, phenol (22.5 Kg) is charged at 55°C. The reaction mixture is stirred for 8 hours till completion of reaction. After completion of the reaction, a mixture of n-butyl acetate and water are added to the reaction, stirred and layers are separated. To the resulted 7-phenylacetamido-3-(4-methylthiazol-5-yl) vinyl-3-cephem-4-carboxylic acid (MTNA), 5 % sodium bicarbonate
solution is added, stirred and layers are separated. The aqueous layer is washed with n-butyl acetate. Pen-G amidase (5 Kg) is added to the aqueous layer and stirred at 25°C. to 30°C, while maintaining pH at 7.5-8.5 with aqueous ammonia till completion of reaction after which, the enzyme is filtered and washed with water. The pH of the clear filtrate is adjusted to 5.5-6.0 with dilute hydrochloric acid at 10°C. Clear solution is stirred with charcoal, filtered through celite bed; and the bed is washed with water after filtration. Methanol (50 L) is added to the clear solution, pH is adjusted to 3.0-3.2 with dilute hydrochloric acid. The resulting precipitated yellow colored solid is filtered off, and washed with water followed by acetone to afford 1.25 Kg of the title compound. (HPLC Purity: 86.83%; Anti Isomer (E-isomer): 5.10%).
EXAMPLES 3: Preparation of cefditoren sodium
To a mixture of water (4 L) and acetone (10 L), MTCA (1 Kg), sodium-2-ethyl hexanoate (1.56 Kg) and methanol (1 L) are added. 2-mercaptobenzothiazolyl (Z)-2(2-aminothiazol-4-yl)-2-methoxyimino acetate (MAEM) (1.3Kg) is added to the clear solution at 10°C. to 15°C; and stirred till completion of reaction. After completion of reaction, acetone (35 L) is added to the reaction mixture and the precipitated solid is filtered and washed with acetone and dried under vacuum to give 1.35 Kg of crude cefditoren sodium (HPLC Purity: 89.37 %; Anti Isomer (E-isomer): 2.55 %).
EXAMPLES 4: Preparation of cefditoren sodium
To a solvent mixture of water (25.0 mL) and acetonitrile (125.0 mL), MTCA (25.0 g), 2-mercaptobenzothiazolyl (Z)-2(2-aminothiazol-4-yl)-2-methoxyimino acetate (MAEM) (29.8 g) and triethylamine (8.6 g) are added at 5°C. to 10°C. After completion of reaction, sodium-2-ethyl hexanoate (31.2 g) is added to the reaction mass and stirred for 2hrs at
10°C. to 15°C. for complete precipitation. The precipitated mass is filtered, washed with acetonitrile (75.0 mL) and dried under vacuum to give 41.0 g of crude cefditoren sodium (HPLC Purity: 95.98 %; Anti Isomer (E-isomer): 0.78 %).
EXAMPLES 5: Purification of cefditoren sodium (Depletion of E-isomer from mixture of Z- and E-isomers of the cefditoren sodium)
Crude cefditoren sodium (E-isomer content: 0.78 %) (41.0 g) is suspended in a mixture of water (1435.0 mL) and sodium metabisulfite (0.7 g) and heated to 35°C. to 40°C. to get a clear solution. Isopropyl alcohol (61.5 mL) and sodium chloride (215.0 g) are added to the clear solution at 30°C. to 35°C. and stirred for 1.0 hour for complete precipitation. The precipitated solid is filtered, and washed twice with acetone (2 x 50 mL) to give 36.0 g of cefditoren sodium (HPLC Purity: 98.87 %; Anti Isomer (E-isomer): 0.44 %).
EXAMPLES 6: Purification of cefditoren sodium (Depletion of E-isomer from mixture of Z- and E-isomers of the cefditoren sodium)
Crude cefditoren sodium (E-isomer content: 0.44 %) (35.0 g) is suspended in a mixture of water (2870.0 mL) and sodium metabisulfite (0.7g) and stirred for 10 minutes at 35°C. to 40°C. Isopropyl alcohol (41.0 mL) and sodium chloride (345.0 g) are added to the reaction mixture at 30°C. to 35°C. and stirred for 1.0 hour for complete precipitation. The precipitated solid is filtered, washed thrice with acetone (3 x 50 mL) to afford 37.0g of cefditoren sodium (HPLC Purity: 99.50 %; Anti Isomer (E-isomer): 0.28%).
EXAMPLES 7: Purification of cefditoren sodium (Depletion of E-isomer from mixture of Z- and E-isomers of the cefditoren sodium)
Crude cefditoren sodium (E-isomer content: 2.55 %) (1.3 Kg) is suspended in a mixture of water (26 L) and sodium metabisulfite (26 g) and heated to 45°C. to 50°C. to get a clear solution. Sodium chloride (5.2 Kg) is added to the clear solution at 30°C. and stirred for 1.0 hour for complete precipitation. The precipitated solid is filtered, washed twice with acetone (2 x 2 L) to give 1.7 Kg of wet cefditoren sodium (HPLC Purity: 96.38 %; Anti Isomer (E-isomer): 1.46 %).
EXAMPLES 8: Purification of cefditoren sodium (Depletion of E-isomer from mixture of Z- and E-isomers of the cefditoren sodium)
Wet cefditoren sodium (E-isomer content: 1.46%) (1.7 Kg) of example-7 is further suspended in a mixture of water (20 L) and sodium metabisulfite (26 g) and heated to 45°C. and sttired for 10 minutes. Isopropyl alcohol (2 L) and sodium chloride (1.9 Kg) are charged to the reaction mixture at 30°C. and stirred for 1.0 hour for complete precipitation. The precipitated solid is filtered, washed twice with acetone (2 x 2 L) to afford 1.0 Kg of wet cefditoren sodium (HPLC Purity: 98.45 %; Anti Isomer (E-isomer): 0.70 %).
EXAMPLES 6: Preparation of cefditoren pivoxil
To N, N-Dimethylacetamide (240 mL), Cefditoren Sodium (30 g) is added at 30°C. and heated to 38°C. to 40°C. to get a clear solution. The reaction mass is cooled to (-) 18°C. to (-) 20°C, and iodomethyl pivalate (13.8 g) is charged in a single lot to the reaction mass and stirred for 30 minutes at the same temperature. The reaction mass is poured into a chilled mixture of ethylacetate (900 mL) and water (450 mL). Organic layer is separated from the aqueous layer. To the separated organic layer, 300 mL of water and dilute hydrochloric acid (1:1; 60 mL) are added slowly at 0°C. to 5°C. and stirred for 15 minutes. Chilled water (150 mL) is charged to the separated organic layer, stirred for 5 minutes, and the
layers are left to settle for 5 minutes at 0°C. to 5°C. The organic layer is separated from the aqueous layer. Chilled water (150 mL) is charged to the organic layer, stirred for 5 minutes, settled and layers are separated. Ethylacetate (750 mL) is charged to the combined aqueous layer; pH is adjusted to 6.5-7.0 with dilute potassium carbonate at 0°C. to 5°C. The aqueous layer is separated from the organic layer. Organic layer is washed with brine solution (300 mL). The washed organic layer is stirred with charcoal; filtered through celite bed. Bed is washed with ethylacetate (30 mL). Filtrate solution is dispersed into chilled isopropyl ether (3.7 L) under vigorous stirring to get a pale yellow colored solid. The pale yellow colored solid obtained is washed with isopropyl ether (30 mL). Wet material is dried under vacuum to give 20 g of amorphous cefditoren pivoxil (HPLC purity-98.41 %; Anti Isomer (E-isomer): 0.62 %).

We claim:
1. A process for the purification of cefditoren sodium of Formula III,
(Formula Removed)
by depleting the E-isomer content in a mixture of Z- and E-isomers of the compound of Formula VI,
(Formula Removed)
comprising the steps of:
(i) preparing a solution of a mixture of Z- and E-isomer of compound
of Formula VI in a suitable solvent; and
(ii) adding a suitable inorganic salt to the solution of step (i).
2. A process for the purification of cefditoren sodium of Formula III,
(Formula Removed)
by depleting the E-isomer content in a mixture of Z- and E-isomers of the compound of Formula VI,
(Formula Removed)
comprising the steps of:
(iii) preparing a solution of a mixture of Z- and E-isomer of compound
of Formula VI in a suitable solvent; (iv) adding a suitable inorganic salt to the solution of step (i); (v) isolating Z-isomer enriched mixture of Z- and E-isomer of
compound of Formula VI; and (vi) optionally, converting Z-isomer enriched mixture of Z- and E-
isomer of compound of Formula VI of step (iii) to cefditoren pivoxil
of formula II.
3. The process according to claim 1 and 2, wherein suitable solvent is
polar protic solvent.
4. The process according to claim 3, wherein polar protic solvent is water
and alcohol or mixture thereof.
5. The process according to claim 4, wherein alcohol is selected from the
group consisting of methanol, ethanol, isopropanol, n-propanol, n-
butanol, 2-butanol, and the like, or any mixtures thereof.
6. The process according to claim 1 and 2, wherein suitable inorganic salt
is halides and sulphates of alkali metals and alkaline earth metals.
7. The process according to claim 6, wherein suitable inorganic salt is
selected from the group consisting of sodium chloride, magnesium
chloride, potassium chloride, sodium sulphate, magnesium sulphate,
potassium sulphate, and the like, and any mixtures thereof.
8. The process according to claim 1 and 2, wherein mixture of Z- and E-isomer of compound of Formula VI comprises E-isomer of compound of Formula VI in amounts more than about 0.70% by weight.
9. The process as claimed in claim 1 and 2, further comprising converting Z-isomer enriched mixture of Z- and E-isomer of compound of Formula VI into cefditoren pivoxil of Formula II.
(Formula Removed)