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WO2010097675A1 - An improved preparation process for cefpodoxime proxetil - Google Patents

An improved preparation process for cefpodoxime proxetil Download PDF

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Publication number
WO2010097675A1
WO2010097675A1 PCT/IB2010/000330 IB2010000330W WO2010097675A1 WO 2010097675 A1 WO2010097675 A1 WO 2010097675A1 IB 2010000330 W IB2010000330 W IB 2010000330W WO 2010097675 A1 WO2010097675 A1 WO 2010097675A1
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Prior art keywords
minutes
undec
ene
diazabicyclo
acetate
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French (fr)
Inventor
Rajendra Kumar Dubey
Sandeep Singh
Manish Dhanuka
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Dhanuka Laboratories Ltd
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Dhanuka Laboratories Ltd
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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
    • C07D501/02—Preparation
    • C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents

Definitions

  • the present invention relates to an improved process for the preparation of cefpodoxime proxetil from cefpodoxime acid.
  • cefpodoxime proxetil is l-isopropoxycarbonyloxyethyl(6R,7R)-7-[2-(2- aminothiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-(methoxymethyl)-3-cephem-4- carboxylate of Formula 1 and is disclosed in U.S. Patent No. 4, 486,425.
  • Cefpodoxime proxetil is one of the limited class of third generation cephalosporin derivatives which can be administered orally as it is readily adsorbed through the digestive tract and which is then readily hydrolyzed and converted in vivo to the corresponding carboxylic acid which, in turn, shows outstanding antibacterial activity against both gram-positive and gram-negative bacteria.
  • Pharmaceutical compounds are required in highly pure form because of the fear of unknown and potentially harmful effects of impurities. For purposes of patients' safety, it is highly desirable to limit the amount of impurities present in any medicament administered to a patient. This is achieved by either devising a process for or by additional purification steps like chromatography or recrystallization etc. The purity of intermediates and raw materials is essential for obtaining the target pharmaceutical compounds in high yield and purity.
  • WO 2004/060896Ai teaches a process for the preparation of Cefpodoxime proxetil free of impurities having a isomeric ratio ranging between 0.5 - 0.6.
  • US 2006/0009639Ai describes an improved process of the preparation of
  • Cefpodoxime proxetil having purity of 99.22% (HPLC) and ⁇ 3 -isomer of 0.36%.
  • Cefpodoxime proxetil having an assay upto98%.
  • Cefpodoxime proxetil prepared using various prior art processes have yields ranging from 42% - 92% ,HPLC purity 92% - 99.22%, assay up to 98% and R/R+S ratio ranging between 0 .51 to 0.54, more particularly when Diisopropyl ethylamine, Tetramethyl Guanidine is used as a base in the preparation, yield of the product ranged from 81% to 92%.
  • few of the processes described in the prior art did not reveal important parameters viz. R/R+S ratio or assay of the product Cefpodoxime proxetil obtained to establish its conformity with pharmacopial grade for establishing its commercial utility.
  • the present invention has met such need by providing a process for the preparation of cefpodoxime proxetil having enhanced assay and yield.
  • the present invention relates to processes for the preparation of cefpodoxime proxetil (I) by reacting cefpodoxime acid (II) with 1-iodoethylisopropyl corbonate (III) in presence of mixture of organic and inorganic bases, followed by workup to yield crude cefpodoxime proxetil, which is subsequently converted into its methane sulfonate salt followed by basifying the salt thus obtained up to pH 4.5 to yield cefpodoxime proxetil (I) having enhanced yield and assay .
  • An embodiment of present invention provides a process wherein in step (b) the temperature preferably ranges between -10 0 C to -15°C
  • step (b) organic base used is selected from a group consisting of tetramethyl guanidine(TMG) and 1, 8- diazabicyclo-undec-7-ene(DBU)
  • step (b) inorganic base used is selected from a group consisting of sodium acetate, sodium carbonate, potassium acetate, potassium carbonate, calcium acetate and calcium carbonate .
  • Still another embodiment of the present invention provides a process wherein in step(b) the mixture of base used is selected from a group of tetramethyl guanidine-sodium acetate, tetramethyl guanidine- sodium carbonate, tetramethyl guanidine- potassium acetate, tetramethyl guanidine- potassium carbonate, tetramethyl guanidine- calcium acetate, tetramethyl guanidine- calcium carbonate,, 1 ,8- diazabicyclo-undec-7-ene- sodium acetate, 1 ,8 diazabicyclo-undec-7-ene - sodium carbonate, 1,8- diazabicyclo-undec-7-ene - potassium acetate, 1,8- diazabicyclo-undec- 7-ene - potassium Carbonate, 1,8- diazabicyclo-undec-7-ene - calcium acetate and 1 ,8- diazabicyclo-undec-7-ene
  • An embodiment of the present invention provides a process wherein most preferred mixture of base used is 1,8- diazabicyclo-undec-7-ene-sodium acetate
  • Another embodiment of the present invention provides a process wherein the molar ratio of 1, 8- diazabicyclo-undec-7-ene-sodium acetate and tetramethyl guanidine- sodium acetate ranges from 0.9:.0.15 to 0.75:.30.
  • the process of present invention has provided an exemplified results by obtaining cefpodoxime proxetil product having an enhanced yield and assay up to 99.25% with concomitant control in the formation of ⁇ 3 impurity to less than 0.3%, which could not be achieved by adapting any of the prior art processes described.
  • Cefpodoxime acid was prepared as per the procedure described in US patent document no.4,486,425.
  • Cefpodoxime acid (40.0 gm; 0.0936 moles) was dissolved in dimethylacetamide (200 ml) and cooled to -10° C. (12.10 g ; 0.0796 moles) of l ,8-diazabicyclo[5,4,0]undec-7- ene was added drop wise maintaining the temperature in the range of -10 to -15° C in 10 minutes , stirred for 5 minutes. Anhydrous sodium acetate((1.54 g; 0.0188 moles) was added and stirred for 10 minutes., followed by addition of 1-iodoethylisopropyl carbonate(26.58 gm; 0.1030 moles) at -10 to -15°C over a period of 10 minutes.
  • reaction mixture was stirred for further 30 minutes
  • the reaction mixture was worked up by adding hydrochloric acid (4 ml) in (40 ml) water maintaining the temperature in the range of -15 0 C to +1O 0 C. followed by adding solution of (8.0 gm) of sodium thiosulphate in (800 ml) water and ethyl acetate (400ml).
  • the aqueous and organic layers were separated.
  • Aqueous layer is again extracted with ethyl acetate (200 ml). Combined both ethyl acetate layer and washed with 10% brine solution (300 ml x 3) at 10 0 C.
  • Organic layer was treated with activated carbon (8.0 gm) and sodium dithionite (2.0 gm) for 60 minutes and filtered.
  • the organic layer was concentrated under vacuum at 25°C.up to (140 ml) and cooled to 10 0 C.
  • the solution of crude cefpodoxime proxetil in ethyl acetate was treated with a solution of methanesulfonic acid (12.0 gm 0.125 moles) in water (400 ml) and stir for 15 minutes at 15°C, cyclohexane (100 ml) was added to the reaction mixture and stirred for 15 minutes.
  • the organic and aqueous layer was separated. The aqueous layer was de-gas under vacuum for 30 minutes at 25°C.
  • Cefpodoxime acid (10.0 g; 0.0234 moles) was dissolved in dimethylacetamide (50 ml) and cooled to -10° C.
  • Anhydrous sodium acetate (2.020 g ; 0.0246 moles) was added at 30 0 C to35°C. stirred for 10 minutes.
  • 1-iodoethylisopropyl carbonate (6.64 g; 0.0257 moles) was added at -10 to -15°C within 10 minutes. The reaction mixture was stirred for further 30 minutes and worked up as per example no.
  • EXAMPLE (5) Cefpodoxime acid (20.0 gm; 0.0468 moles) was dissolved in dimethylacetamide (100 ml) and cooled to -10° C. (6.05 g ; 0.0398 moles) of l,8-diazabicyclo[5,4,0]undec-7- ene was added drop wise over -10 0 C to -15°C in 10 minutes . Stirred for 5 minutes. Anhydrous sodium acetate(0.768g; 0.00936 moles) was added and stirred for 10 minutes. 1-iodoethylisopropyl carbonate(13.29gm; 0.0515 moles) was added at -10 to - 15°C within 10 minutes.
  • reaction mixture was stirred for further 30 minutes and hydrochloric acid (2 ml) in (20 ml) was added was added at -15°C to +10 0 C.
  • a solution of sodium thiosulphate (4.0 gm) in (400 ml) water was added followed by ethyl acetate (200ml) at 10 0 C.
  • the aqueous and organic layers were separated.
  • Aqueous layer is again extracted with ethyl acetate (100 ml). Combined ethyl acetate layer and washed with 10% brine solution (150 ml x 3) at 10 0 C.
  • Washed organic layer was treated with activated carbon (4.0 gm) and sodium dithionite (1.0 gm) for 60 minutes and filtered.
  • EXAMPLE (6) Cefpodoxime acid (20.0 gm; 0.0468 moles) was dissolved in dimethylacetamide (100 ml) and cooled to -10° C. (6.05 g ; 0.0398 moles) of l,8-diazabicyclo[5,4,0]undec-7- ene was added drop wise over -10 to -15° C over a period of 10 minutes . Stirred for 5 minutes. Anhydrous sodium acetate(0.768 g; 0.00936 moles) was added and stirred for 10 minutes.1-iodoethylisopropyl carbonate( 13.29 gm; 0.0515 moles) was added at - 10 0 C to -15°C within 15 minutes.
  • reaction mixture was stirred for further 30 minutes and hydrochloric acid (2.0 ml )in (20 ml) water was added maintaining the temperature between -15°C to +10 0 C.
  • hydrochloric acid 2.0 ml )in (20 ml) water was added maintaining the temperature between -15°C to +10 0 C.
  • the aqueous and organic layers were separated. Aqueous layer was again extracted with ethyl acetate (100 ml). Combined ethyl acetate layer washed with 10% brine solution (150 ml x 3) at 10 0 C. Washed ethyl acetate layer was treated with activated carbon (4.0 gm) and sodium dithionite (1.0 gm) for 60 minutes and filtered.
  • EXAMPLE (7) Cefpodoxime acid (30.0 gm; 0.07025 moles) was dissolved in dimethylacetamide (150 ml) and cooled to -10° C. Tetramethyl guanidine (7.92gm, 0.0688mols) was added drop wise over -10 to -15° C in 10 minutes . Stirred for 5 minutes. 1 -iodoethylisopropyl carbonate( 19.94 gm; 0.07728 moles) was added at -10 to -15°C within 10 minutes. The reaction mixture was stirred for further 30 minutes and hydrochloric acid (3.0 ml) in (30 ml) water was added at -15°C to +10 0 C.
  • Cefpodoxime acid (20.0 gm; 0.0468 moles) was dissolved in dimethylacetamide (100 ml) and cooled to -10° C.
  • Tetramethyl guanidine ( 5.28gm,0.0459mols) was added drop wise at a temperature ranging between -10 0 C to -15° C in 10 minutes Stirred for 5 minutes.
  • 1-iodoethylisopropyl carbonate (13.29gm; 0.0515 moles) was added at -10 0 C to -15°C within 15 minutes.
  • the reaction mixture was stirred for further 30 minutes and hydrochloric acid (2.0 ml)in (20 ml) water was added at -15°C to +10 0 C.
  • Cefpodoxime acid (20.0 gm; 0.0468 moles) was dissolved in dimethylacetamide (100 ml) and cooled to -10° C. (4.58 gm, 0.0398moles) of tetramethyl guanidine as added drop wise maintaining the temperature in the range of -10 0 C to -15°C in 10 minutes , stirred for 5 minutes.
  • Anhydrous sodium acetate((0.768 g; 0.00936 moles) was added and stirred for 10 minutes., followed by addition of 1-iodoethylisopropyl carbonate( 13.29 gm; 0.0515 moles) at -10°C to -15 0 C over a period of 15 minutes.
  • reaction mixture was stirred for further 30 minutes
  • the reaction mixture was worked up by adding hydrochloric acid (2 ml ) in (20 ml) water maintaining the temperature in the range of -15°C to +10 0 C. followed by adding solution of (4.0 gm) of sodium thiosulphate in water (400 ml) and ethyl acetate (200ml).
  • the aqueous and organic layers were separated.
  • Aqueous layer is again extracted with ethyl acetate ( 100 ml). Combined both ethyl acetate layer and washed with 10% brine solution (150 ml x 3) at 10 0 C.
  • Organic layer was treated with activated carbon (4.0 gm) and sodium dithionite (1.0 gm) for 60 minutes and filtered.
  • the organic layer was concentrated under vacuum at 25°C.up to volume (70 ml) and cooled to 10 0 C.
  • the solution of crude cefpodoxime proxetil in ethyl acetate was treated with a solution of methanesulfonic acid (6.0 gm 0.0625 moles) in water (200 ml) and stir for 15 minutes at 15°C, cyclohexane (50 ml) was added to the reaction mixture and stirred for 15 minutes.
  • the organic and aqueous layer was separated. The aqueous layer was de-gas under vacuum for 30 minutes at 25°C.
  • Cefpodoxime acid (20.0 gm; 0.0468 moles) was dissolved in dimethylacetamide (100 ml) and cooled to -10° C. (6.62 g ; 0.0435 moles) of l,8-diazabicyclo[5,4,0]undec-7- ene was added drop wise over -10 0 C to -15 0 C in 10 minutes . Stirred for 10 minutes. 1 - iodoethylisopropyl carbonate(1 1.70gm; 0.0453 moles) was added at -10 to - 15°C within 10 minutes.
  • reaction mixture was stirred for further 30 minutes and hydrochloric acid (1 ml) in (10 ml) was added was added at -15°C to +10°C.
  • a solution of sodium thiosulphate (2.0 gm) in (200 ml) water was added followed by ethyl acetate (100ml) at 10 0 C.
  • the aqueous and organic layers were separated.
  • Aqueous layer is again extracted with ethyl acetate (50 ml). Combined ethyl acetate layer and washed with 10% brine solution (75 ml x 3) at 10 0 C.
  • Washed organic layer was treated with activated carbon (2.0 gm) and sodium dithionite (0.5 gm) for 60 minutes and filtered.
  • the organic layer was concentrated under vacuum at 25°C.up to (35 ml) and cooled to 10 0 C.
  • the solution of crude cefpodoxime proxetil in ethyl acetate was treated with a solution of methanesulfonic acid (3.0 gm 0.03125 moles) in water (100 ml) and stir for 15 minutes at 15°C, cyclohexane (25 ml) was added to the reaction mixture and stirred for 15 minutes.
  • the organic and aqueous layer was separated. The aqueous layer was de-gas under vacuum for 30 minutes at 25°C.
  • Cefpodoxime acid (10.0 gm; 0.0234 moles) was dissolved in dimethylacetamide (50 ml) and cooled to -10° C. (3.56 g ; 0.0234 moles) of l,8-diazabicyclo[5,4,0]undec-7- ene was added drop wise over -10 0 C to -15°C in 10 minutes . Stirred for 10 minutes.
  • 1- iodoethylisopropyl carbonate (16.34 gm; 0.0245 moles) was added at -10 to -15 0 C within 10 minutes.
  • reaction mixture was stirred for further 30 minutes and hydrochloric acid (1 ml) in (10 ml) was added was added at -15°C to +10 0 C.
  • a solution of sodium thiosulphate (2.0 gm) in (200 ml) water was added followed by ethyl acetate (100ml) at 10 0 C.
  • the aqueous and organic layers were separated.
  • Aqueous layer is again extracted with ethyl acetate (50 ml). Combined ethyl acetate layer and washed with 10% brine solution (75 ml x 3) at 1O 0 C.
  • Washed organic layer was treated with activated carbon (2.0 gm) and sodium dithionite (0.5 gm) for 60 minutes and filtered.
  • the organic layer was concentrated under vacuum at 25°C.up to (35 ml) and cooled to 10 0 C.
  • the solution of crude cefpodoxime proxetil in ethyl acetate was treated with a solution of methanesulfonic acid (3.0 gm 0.03125 moles) in water (100 ml) and stir for 15 minutes at 15°C, cyclohexane (25 ml) was added to the reaction mixture and stirred for 15 minutes.
  • the organic and aqueous layer was separated. The aqueous layer was de-gas under vacuum for 30 minutes at 25°C.

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

Abstract

The present invention relates to an improved process for the preparation of cefpodoxime proxetil of formula (I) from cefpodoxime acid (II) by reacting 1 -iodoethyl isopropyl carbonate (III) in an aprotic solvent in presence of a mixture comprising of organic and inorganic base at a temperature ranging from 0° to -20°C for a time period of 10 minutes to 60 minutes More particularly, the invention provides a process, wherein the cefpodoxime proxetil obtained has Δ3 isomer impurity less than 0.3% and R/R+S ratio ranging between 0.5 to 0.6 with an enhanced yield and assay.

Description

AN IMPROVED PREPARATION PROCESS FOR CEFPODOXIME PROXETIL
Field of Invention:
The present invention relates to an improved process for the preparation of cefpodoxime proxetil from cefpodoxime acid.
Background Of The Invention: Chemically, cefpodoxime proxetil is l-isopropoxycarbonyloxyethyl(6R,7R)-7-[2-(2- aminothiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-(methoxymethyl)-3-cephem-4- carboxylate of Formula 1 and is disclosed in U.S. Patent No. 4, 486,425.
Figure imgf000002_0001
(I)
Cefpodoxime proxetil is one of the limited class of third generation cephalosporin derivatives which can be administered orally as it is readily adsorbed through the digestive tract and which is then readily hydrolyzed and converted in vivo to the corresponding carboxylic acid which, in turn, shows outstanding antibacterial activity against both gram-positive and gram-negative bacteria.
Pharmaceutical compounds are required in highly pure form because of the fear of unknown and potentially harmful effects of impurities. For purposes of patients' safety, it is highly desirable to limit the amount of impurities present in any medicament administered to a patient. This is achieved by either devising a process for or by additional purification steps like chromatography or recrystallization etc. The purity of intermediates and raw materials is essential for obtaining the target pharmaceutical compounds in high yield and purity.
Prior art of the Invention:
US 6,639,068Bi, relates to a method of preparing Cefpodoxime proxetil having purity up to 99% (HPLC)
WO 2004/060896Ai, teaches a process for the preparation of Cefpodoxime proxetil free of impurities having a isomeric ratio ranging between 0.5 - 0.6. US 2006/0009639Ai, describes an improved process of the preparation of
Cefpodoxime proxetil having purity of 99.22% (HPLC) and Δ3-isomer of 0.36%.
US 7045,618B2, teaches an improved and cost effective process for the preparation of
Cefpodoxime proxetil having an assay upto98%. '
US2006/0293296Ai, describes a process for the preparation of Cefpodoxime proxetil confirming to pharmacopial specification.
The methods described in the prior art for the preparation of Cefpodoxime proxetil is associated with several limitations enumerated below:
1) Blocking and deblocking of functional groups.
2) Chromatographic separation techniques. 3) Mixture of solvents for crystallization.
4) Several crystallization steps.
5) Obtaining the diasteroisomers R and S ratio to conform pharmacopial requirement.
It has been observed that Cefpodoxime proxetil prepared using various prior art processes (Refer Table-I) have yields ranging from 42% - 92% ,HPLC purity 92% - 99.22%, assay up to 98% and R/R+S ratio ranging between 0 .51 to 0.54, more particularly when Diisopropyl ethylamine, Tetramethyl Guanidine is used as a base in the preparation, yield of the product ranged from 81% to 92%. However, few of the processes described in the prior art did not reveal important parameters viz. R/R+S ratio or assay of the product Cefpodoxime proxetil obtained to establish its conformity with pharmacopial grade for establishing its commercial utility. Table - I
Data of Cefpodoxime Proxetil obtained by prior art processes
Figure imgf000004_0001
Therefore, it is a long awaited solution to obtain Cefpodoxime proxetil having enhanced yield and assay complying with the acceptable diasteroisomers R /R+S ratio and also controlling Δ3 impurity as low as possible.
The present invention has met such need by providing a process for the preparation of cefpodoxime proxetil having enhanced assay and yield.
Applicant has now prepared Cefpodoxime proxetil using various bases in their present work and the results are enumerated in Table II. Applicant finds that surprising results have been achieved by them using preferably a mixture inorganic and organic base in the process to obtain crude Cefpodoxime proxetil, followed by its purification by converting into its methane sulphonate salt and basifying the salt thus obtained to a pH4.5 yielding Cefpodoxime proxetil having enhanced yield.and assay Table II
Comparative Data of Cefpodoxime Proxetil obtained by Applicant using various bases
Figure imgf000005_0001
Summary of the Invention:
The present invention relates to processes for the preparation of cefpodoxime proxetil (I) by reacting cefpodoxime acid (II) with 1-iodoethylisopropyl corbonate (III) in presence of mixture of organic and inorganic bases, followed by workup to yield crude cefpodoxime proxetil, which is subsequently converted into its methane sulfonate salt followed by basifying the salt thus obtained up to pH 4.5 to yield cefpodoxime proxetil (I) having enhanced yield and assay .
Detailed description of the Invention:
In accordance with the present invention, provides an improved process for the preparation of cefpodoxime proxetil of formula (I)
Figure imgf000006_0001
(I)
the said process comprising steps of: a) preparing cefpodoxime acid (II) as described in the patent document US 4,486,425,
Figure imgf000006_0002
(H)
b) reacting cefpodoxime acid of step (a) with 1 - iodoethylisopropylcarbonate of formula (III)-
Figure imgf000006_0003
(III) in an aprotic solvent in presence of mixture of organic base and inorganic base at a temperature ranging from 00C to -2O0C for a time period of 10 minutes, to 60 minutes, working up the reaction mixture of the step (b) at a temperature ranging between -150C to +1O0C by the addition of aqueous HCl followed aqueous sodium thiosulfate and ethyl acetate, separating aqueous and organic layers, d) extracting once more aqueous layer with ethyl acetate and separating layers e) combining ethyl acetate layer of steps (c) and (d) , washing with 10 % aqueous brine solution, treating the washed ethyl acetate layer by stirring with activated charcoal and sodium dithionite for a period of 60 minutes., f) filtering step(e) solution to obtain crude cefpodoxime proxetil solution, g) purifying crude cefpodoxime proxetil of step (f) by converting into its methanesulfonate salt, basifying the salt thus obtained up to pH 4.5 to yield cefpodoxime proxetil having enhanced yield and assay.
An embodiment of present invention provides a process wherein in step (b) the temperature preferably ranges between -100C to -15°C
Another embodiment of the present invention provides a process wherein in step (b) organic base used is selected from a group consisting of tetramethyl guanidine(TMG) and 1, 8- diazabicyclo-undec-7-ene(DBU) Yet another embodiment of the invention provides a process wherein in step (b) inorganic base used is selected from a group consisting of sodium acetate, sodium carbonate, potassium acetate, potassium carbonate, calcium acetate and calcium carbonate . Still another embodiment of the present invention provides a process wherein in step(b) the mixture of base used is selected from a group of tetramethyl guanidine-sodium acetate, tetramethyl guanidine- sodium carbonate, tetramethyl guanidine- potassium acetate, tetramethyl guanidine- potassium carbonate, tetramethyl guanidine- calcium acetate, tetramethyl guanidine- calcium carbonate,, 1 ,8- diazabicyclo-undec-7-ene- sodium acetate, 1 ,8 diazabicyclo-undec-7-ene - sodium carbonate, 1,8- diazabicyclo-undec-7-ene - potassium acetate, 1,8- diazabicyclo-undec- 7-ene - potassium Carbonate, 1,8- diazabicyclo-undec-7-ene - calcium acetate and 1 ,8- diazabicyclo-undec-7-ene - calcium carbonate. Still yet another embodiment of the present invention provides a process wherein the preferred mixture of base used is tetramethyl guanidine-sodium acetate and 1 ,8- diazabicyclo-undec-7-ene- sodium acetate.
An embodiment of the present invention provides a process wherein most preferred mixture of base used is 1,8- diazabicyclo-undec-7-ene-sodium acetate
Another embodiment of the present invention provides a process wherein the molar ratio of 1, 8- diazabicyclo-undec-7-ene-sodium acetate and tetramethyl guanidine- sodium acetate ranges from 0.9:.0.15 to 0.75:.30.
The process of present invention has provided an exemplified results by obtaining cefpodoxime proxetil product having an enhanced yield and assay up to 99.25% with concomitant control in the formation of Δ3 impurity to less than 0.3%, which could not be achieved by adapting any of the prior art processes described.
The following examples illustrate particular methods for preparing cefpodoxime proxetil in accordance with this invention. The examples are only illustrative and should not be construed to limit the scope of the invention as it is defined by the appended claims.
EXAMPLES
EXAMPLE (1)
Cefpodoxime acid was prepared as per the procedure described in US patent document no.4,486,425.
EXAMPLE (2)
Cefpodoxime acid (40.0 gm; 0.0936 moles) was dissolved in dimethylacetamide (200 ml) and cooled to -10° C. (12.10 g ; 0.0796 moles) of l ,8-diazabicyclo[5,4,0]undec-7- ene was added drop wise maintaining the temperature in the range of -10 to -15° C in 10 minutes , stirred for 5 minutes. Anhydrous sodium acetate((1.54 g; 0.0188 moles) was added and stirred for 10 minutes., followed by addition of 1-iodoethylisopropyl carbonate(26.58 gm; 0.1030 moles) at -10 to -15°C over a period of 10 minutes. The reaction mixture was stirred for further 30 minutes The reaction mixture was worked up by adding hydrochloric acid (4 ml) in (40 ml) water maintaining the temperature in the range of -150C to +1O0C. followed by adding solution of (8.0 gm) of sodium thiosulphate in (800 ml) water and ethyl acetate (400ml). The aqueous and organic layers were separated. Aqueous layer is again extracted with ethyl acetate (200 ml). Combined both ethyl acetate layer and washed with 10% brine solution (300 ml x 3) at 100C. Organic layer was treated with activated carbon (8.0 gm) and sodium dithionite (2.0 gm) for 60 minutes and filtered.
The organic layer was concentrated under vacuum at 25°C.up to (140 ml) and cooled to 100C. The solution of crude cefpodoxime proxetil in ethyl acetate was treated with a solution of methanesulfonic acid (12.0 gm 0.125 moles) in water (400 ml) and stir for 15 minutes at 15°C, cyclohexane (100 ml) was added to the reaction mixture and stirred for 15 minutes. The organic and aqueous layer was separated. The aqueous layer was de-gas under vacuum for 30 minutes at 25°C. Methanol (160 ml) was added in the aqueous layer at 25°C, followed by addition of water (800 ml) stirred for 10 minutes and neutralized by 2.3% ammonia solution up to pH 4.5. The precipitated solid was filtered and washed with water (200ml x 3). The solid was filtered and dried under vacuum at 40°C.to give (48.8gm) of pure cefpodoxime proxetil having an isomeric ratio of (R/R+S)=0.51, 99.25%(assay), 99.46%(HPLC purity) and Δ3 -isomer 0.25%..
EXAMPLE (3) Cefpodoxime acid (10.0 g; 0.0234 moles) was dissolved in dimethylacetamide (50 ml) and cooled to -10° C. (3.73g ; 0.0245 moles) of l,8-diazabicyclo[5,4,0]undec-7-ene was added drop wise over -10 to -15° C in 10 minutes . stirred for 10 minutes. (6.64 g; 0.0257 moles) of 1-iodoethylisopropyl carbonate was added at -10 to -15°C within 10 minutes. The reaction mixture was stirred for further 30 minutes and worked up as per example(2).to get cefpodoxime poxetil lO.Ogm having an isomeric ratio of (R/R+S)=O.5O3, 92.17%(assay), 90.68%(HPLC purity) and Δ3 -isomer9.07% .
EXAMPLE (4)
Cefpodoxime acid (10.0 g; 0.0234 moles) was dissolved in dimethylacetamide (50 ml) and cooled to -10° C. Anhydrous sodium acetate(2.020 g ; 0.0246 moles) was added at 300C to35°C. stirred for 10 minutes. 1-iodoethylisopropyl carbonate (6.64 g; 0.0257 moles) was added at -10 to -15°C within 10 minutes. The reaction mixture was stirred for further 30 minutes and worked up as per example no. (2) to yield cefpodoxime proxetil (8.0gm) having an isomeric ratio of (R/R+S)=0.48, 96.34%( assay), 98.45%(HPLC purity) and Δ3 -isomerθ.31%.
EXAMPLE (5) Cefpodoxime acid (20.0 gm; 0.0468 moles) was dissolved in dimethylacetamide (100 ml) and cooled to -10° C. (6.05 g ; 0.0398 moles) of l,8-diazabicyclo[5,4,0]undec-7- ene was added drop wise over -100C to -15°C in 10 minutes . Stirred for 5 minutes. Anhydrous sodium acetate(0.768g; 0.00936 moles) was added and stirred for 10 minutes. 1-iodoethylisopropyl carbonate(13.29gm; 0.0515 moles) was added at -10 to - 15°C within 10 minutes. The reaction mixture was stirred for further 30 minutes and hydrochloric acid (2 ml) in (20 ml) was added was added at -15°C to +100C. A solution of sodium thiosulphate (4.0 gm) in (400 ml) water was added followed by ethyl acetate (200ml) at 100C. The aqueous and organic layers were separated. Aqueous layer is again extracted with ethyl acetate (100 ml). Combined ethyl acetate layer and washed with 10% brine solution (150 ml x 3) at 100C. Washed organic layer was treated with activated carbon (4.0 gm) and sodium dithionite (1.0 gm) for 60 minutes and filtered.
Divided ethyl acetate solution into two equal parts.
5A) Distilled off ethyl acetate to concentrate up to volume of (50ml) and charged this concentrated ethyl acetate solution on to cyclohexane (300ml) for crystallisation . Stir and filter to get crude cefpodoxime proxetil.
Dissolved crude cefpodoxime proxetil in methanol (40ml), added hydrochloric acid (3.25gm, 0.089mols) stirred and charged water (300ml) followed by addition of 2.3%ammonia solution to adjust the pH 4.5. Stirred to crystallize, filtered and washed with water((50ml x 3). The solid was filtered and dried under vacuum at 40°C.to get the pure cefpodoxime proxetil.(9.80gm), having an isomeric ratio of (R/R+S)=0.503, 97.40%( assay), 99.05%( HPLC purity) and Δ3 -isomer 0.30%.
5B) Distilled off ethyl acetate under vacuum to obtain a residue and ,charged methanol (40ml) to dissolve, added hydrochloric acid(3.25gm,0.089mols) stirred and charged water(300ml) followed by addition of 2.3%ammonia solution to adjust the pH 4.5. Stirred to crystallize, , filtered and washed with water (50ml x 3). The solid was filtered and dried under vacuum at 40°C.to get the pure cefpodoxime proxetil (l l .Ogm) having an isomeric ratio of (R/R+S)=0.505, 95.69%( assay), 99.32%HPLC purity) and Δ3 -isomerθ.27%
EXAMPLE (6) Cefpodoxime acid (20.0 gm; 0.0468 moles) was dissolved in dimethylacetamide (100 ml) and cooled to -10° C. (6.05 g ; 0.0398 moles) of l,8-diazabicyclo[5,4,0]undec-7- ene was added drop wise over -10 to -15° C over a period of 10 minutes . Stirred for 5 minutes. Anhydrous sodium acetate(0.768 g; 0.00936 moles) was added and stirred for 10 minutes.1-iodoethylisopropyl carbonate( 13.29 gm; 0.0515 moles) was added at - 100C to -15°C within 15 minutes. The reaction mixture was stirred for further 30 minutes and hydrochloric acid (2.0 ml )in (20 ml) water was added maintaining the temperature between -15°C to +100C. A solution of sodium thiosulphate(4.0 gm) in (400 ml) water was added , followed by ethyl acetate (200ml) at 100C. The aqueous and organic layers were separated. Aqueous layer was again extracted with ethyl acetate (100 ml). Combined ethyl acetate layer washed with 10% brine solution (150 ml x 3) at 100C. Washed ethyl acetate layer was treated with activated carbon (4.0 gm) and sodium dithionite (1.0 gm) for 60 minutes and filtered.
Divided ethyl acetate layer in to two equal parts. 6A) Distilled off ethyl acetate under vacuum to concentrate up to (50ml) and charged this concentrated ethyl acetate solution on to cyclohexane (300ml) for crystallization. Stirred and filtered to obtain crude cefpodoxime proxetil.
Dissolved the above crude cefpodoxime proxetil in ethyl acetate(25ml) and treated with a solution of methanesulfonic acid (3.0 gm 0.089 moles) in water (100 ml) and stirred for 15 minutes at 15°C, cyclohexane (20 ml) was added to the reaction mixture and stirred for 15 minutes. The organic and aqueous layer was separated. The aqueous
( layer was de-gas under vacuum for 30 minutes at 25°C. Methanol (40 ml) was added in the aqueous layer at 250C, stirred for 10 minutes followed by addition of water (300ml) and neutralized by 2.3% ammonia solution till pH 4.5 The precipitated solid was filtered and washed with water (50ml x 3s). The solid was dried under vacuum at 40°C.to get cefpodoxime proxetil (8.40gm) having an isomeric ratio of (R/R+S)=0.51 , 98.43%(assay), 99.63%( HPLC purity) and Δ3 -isomer 0.26%. 6B) Distilled off ethyl acetate under vacuum to obtain a residue and charged methanol (40ml) to dissolve, added methanesulfonic acid (3.0gm,0.0312mols) stirred and charged water (300ml) and neutralized by 2.3% ammonia solution up to pH 4.5. The precipitated solid was stirred, filtered and washed with water(50ml x 3). The solid was filtered and dried under vacuum at 400C. to get pure cefpodoxime proxetil (l l .Ogm) having an isomeric ratio of (R/R+S)=0.508, 94.90%( assay), 96.94%(HPLC purity) and Δ3 -isomer 0.23%.
EXAMPLE (7) Cefpodoxime acid (30.0 gm; 0.07025 moles) was dissolved in dimethylacetamide (150 ml) and cooled to -10° C. Tetramethyl guanidine (7.92gm, 0.0688mols) was added drop wise over -10 to -15° C in 10 minutes . Stirred for 5 minutes. 1 -iodoethylisopropyl carbonate( 19.94 gm; 0.07728 moles) was added at -10 to -15°C within 10 minutes. The reaction mixture was stirred for further 30 minutes and hydrochloric acid (3.0 ml) in (30 ml) water was added at -15°C to +100C. A solution of sodium thiosulphate (6.0 gm) in water (600 ml) was added followed by ethyl acetate (300ml) at 100C. The aqueous and organic layers were separated. Aqueous layer is again extracted with ethyl acetate (150 ml). Combined both ethyl acetate and washed with 10% brine solution (225 ml x 3) at 100C. Washed organic layer was treated with activated carbon (6.0 gm) and sodium dithionite (1.5 gm) for 60 minutes and filtered.
Divided ethyl acetate solution into three equal parts.
7A) Distilled off ethyl acetate under vacuum to concentrate up to (50ml) and charged this concentrated ethyl acetate solution on to cyclohexane (300ml) for crystallisation . Stirred and filtered to obtain crude cefpodoxime proxetil.
Dissolved crude cefpodoxime proxetil in methanol (40ml), added hydrochloric acid (3.25gm,0.0890mols) Stirred and charged water (300ml) for crystallization up to pH 4.5 by addition of 2.3% ammonia solution..Filtered solid and washed with water(50ml x 3). The solid was filtered and dried under vacuum at 400C. to yield pure cefpodoxime proxetil.(10.2gm) having an isomeric ratio of (R/R+S)=O.5O3, 96.73%(assay), 99.28%HPLC purity) and Δ3 -isomerθ.54%.
7B) The organic layer was concentrated to (35ml) under vacuum at 25°C.and cooled to 100C. The solution of impure cefpodoxime proxetil in ethyl acetate was treated with a solution of methanesulfonic acid (3.0 gm 0.03125 moles) in water (100 ml) and stirred for 10 minutes at 15°C, cyclohexane (25 ml) was added to the reaction mixture and stirred for 15 minutes. The organic and aqueous layer was separated. The aqueous layer was de-gas under vacuum for 30 minutes at 25°C. Methanol (40 ml) was added in the aqueous layer at 25°C, stirred for 10 minutes, added water (200ml) and neutralized with 2.3% ammonia solution till pH 4.5 is attained. The precipitated solid was filtered and washed with water (50ml x 3) . The solid was dried under vacuum at 40°C.to yield pure cefpodoxime proxetil(lθ.θgm) having an isomeric ratio of (R/R+S)=0.502, 97.25%(assay), 99.21%( HPLC purity) and Δ3 -isomer 0.56%.
7C) Distilled off ethyl acetate under vacuum to obtain a residue and, charged methanol (40ml) to dissolve, added hydrochloric acid( 3.25gm,0.089mols ) stirred and charged water(300ml) followed by addition of 2.3% ammonia solution to adjust the pH to 4.5 Filtered the solid, washed with water(50ml x 3). The solid was filtered and dried under vacuum at 400C. to obtain pure cefpodoxime proxetil (l l .Ogm). having an isomeric ratio of (R/R+S)=0.503, 95.43%(.assay), 99.0%(HPLC purity) and Δ3 -isomer 0.52%.
EXAMPLE (8) Cefpodoxime acid (20.0 gm; 0.0468 moles) was dissolved in dimethylacetamide (100.0ml) and cooled to -10° C. Tetramethyl guanidine(5.65gm,0.0491 mols) was added drop wise at a temperature ranging between -10 to -15° C in 10 minutes . Stirred for 5 minutes. . of 1-iodoethylisopropyl carbonate( 13.29 gm; 0.0515 moles) was added at - 10 to -15°C within 15 minutes. The reaction mixture was stirred for further 30 minutes and hydrochloric acid (2.0ml) in (20 ml) water was added at -15°C to +10°C. A solution of (4.0 gm) of sodium thiosulphate in water (400 ml) was added followed by ethyl acetate (200ml) at 100C. The aqueous and organic layers were separated. Aqueous layer is again extracted with ethyl acetate (100 ml). Combined ethyl acetate layer was washed with 10% brine solution (150 ml x 3) at 100C. Washed organic layer was treated with activated carbon (4.0 gm) and sodium dithionite (1.0 gm) for 60 minutes and filtered. Divided ethyl acetate solution into two equal parts.
8A) Distilled off ethyl acetate under vacuum to concentrate up to volume of (50. ml) and charged this concentrated ethyl acetate solution on to cyclohexane (300ml) for crystallisation .Stirred and filtered solid to obtain crude cefpodoxime proxetil. Dissolved the above crude cefpodoxime proxetil in ethyl acetate(25ml) and treated with a solution of methanesulfonic acid (3.0 gm 0.03125 moles) in water (100 ml) and stirred for 15 minutes at 15°C, cyclohexane (20 ml) was added to the mixture and stirred for 15 minutes. The organic and aqueous layer was separated. The aqueous layer was de-gas under vacuum for 30 minutes at 25°C. Methanol (40 ml) was added in the aqueous layer at 25°C, stirred for 10 minutes followed by addition of water (200ml) and adjusted to pH 4.5 by addition of 2.3% ammonia solution. The precipitated solid was filtered and washed with water (50ml x 3). The solid was dried under vacuum at 40°C.to give pure cefpodoxime proxetil(lθ.θgm) having an isomeric ratio of (R/R+S)=0.498, 91.12%(assay), 92.92%(HPLC purity) and Δ3 -isomer6.46%
8B) Distilled off ethyl acetate under vacuum to obtain a residue and charged methanol (40ml) to dissolve, added hydrochloric acid ( 3.25gm,0.0890mols), stirred and charged water(300ml) and adjusted to pH 4.5 by addition of 2.3% ammonia solution. Filtered solid and washed with water (50ml x 3). The solid was filtered and dried under vacuum at 400C. to yield pure cefpodoxime(1 1.4gm) having an isomeric ratio of (R/R+S)=0.503, 87.20%(assay),92.63%9 HPLC purity) and Δ3 -isomer 6.26%.
EXAMPLE (9)
Cefpodoxime acid (20.0 gm; 0.0468 moles) was dissolved in dimethylacetamide (100 ml) and cooled to -10° C. Tetramethyl guanidine( 5.28gm,0.0459mols) was added drop wise at a temperature ranging between -100C to -15° C in 10 minutes Stirred for 5 minutes.. 1-iodoethylisopropyl carbonate(13.29gm; 0.0515 moles) was added at -100C to -15°C within 15 minutes. The reaction mixture was stirred for further 30 minutes and hydrochloric acid (2.0 ml)in (20 ml) water was added at -15°C to +100C. A solution of (4.0 gm) of sodium thiosulphate in water (400 ml) was added, followed by ethyl acetate (200ml) at 100C. The aqueous and organic layers were separated. Aqueous layer is again extracted with ethyl acetate (100 ml). Combined ethyl acetate layer and washed with 10% brine solution (150 ml x 3) at 100C. Washed organic layer was treated with activated carbon (4.0 gm) and sodium dithionite (1.0 gm) for 60 minutes and filtered.
Divided ethyl acetate solution into two equal parts. 9A) Distilled off ethyl acetate under vacuum to reduce the volume to (50 ml) and charged this concentrated ethyl acetate solution on to cyclohexane (300ml) for crystallisation . Stirred and filtered to obtain crude cefpodoxime proxetil. Dissolved the above crude cefpodoxime proxetil in ethyl acetate (25ml) and treated with a solution of methanesulfonic acid (3.0 gm 0.03125 moles) in water (100 ml) and stirred for 15 minutes at 15°C, cyclohexane (20 ml) was added to the mixture and stirred for 15 minutes. The organic and aqueous layer was separated. The aqueous layer was de-gas under vacuum for 30 minutes at 25°C. Methanol (40 ml) was added to the aqueous layer at 25°C, stirred for 10 minutes followed by addition of water (200ml) and neutralized by 2.3% ammonia solution till pH 4.5. The precipitated solid was filtered and washed with water (50ml x 3 ). The solid was dried under vacuum at 400C. to yield cefpodoxime proxetil (8.6gm) having an isomeric ratio of (R/R+S)=0.508, 97.78%(assay),98.88%( HPLC purity) and Δ3 -isomerθ.63%.
9B) Distilled off ethyl acetate under vacuum to obtain a residue and charged methanol (40ml) to dissolve, added mehanesulfonic acid ( 3.0gm,0.03125mols) Stirred and charged water(300ml) and neutralized by 2.3% ammonia solution till pH 4.5. Filtered solid and washed with water(50ml x 3) and dried under vacuum to yield pure cefpodoxime proxetil (l l .Ogm) having an isomeric ratio of (R/R+S)=0.507, 95.95%(assay),98.32%( HPLC. purity) and Δ3 -isomerθ.53%.
EXAMPLE (10)
Cefpodoxime acid (20.0 gm; 0.0468 moles) was dissolved in dimethylacetamide (100 ml) and cooled to -10° C. (4.58 gm, 0.0398moles) of tetramethyl guanidine as added drop wise maintaining the temperature in the range of -100C to -15°C in 10 minutes , stirred for 5 minutes. Anhydrous sodium acetate((0.768 g; 0.00936 moles) was added and stirred for 10 minutes., followed by addition of 1-iodoethylisopropyl carbonate( 13.29 gm; 0.0515 moles) at -10°C to -150C over a period of 15 minutes. The reaction mixture was stirred for further 30 minutes The reaction mixture was worked up by adding hydrochloric acid (2 ml ) in (20 ml) water maintaining the temperature in the range of -15°C to +100C. followed by adding solution of (4.0 gm) of sodium thiosulphate in water (400 ml) and ethyl acetate (200ml). The aqueous and organic layers were separated. Aqueous layer is again extracted with ethyl acetate ( 100 ml). Combined both ethyl acetate layer and washed with 10% brine solution (150 ml x 3) at 100C. Organic layer was treated with activated carbon (4.0 gm) and sodium dithionite (1.0 gm) for 60 minutes and filtered.
The organic layer was concentrated under vacuum at 25°C.up to volume (70 ml) and cooled to 100C. The solution of crude cefpodoxime proxetil in ethyl acetate was treated with a solution of methanesulfonic acid (6.0 gm 0.0625 moles) in water (200 ml) and stir for 15 minutes at 15°C, cyclohexane (50 ml) was added to the reaction mixture and stirred for 15 minutes. The organic and aqueous layer was separated. The aqueous layer was de-gas under vacuum for 30 minutes at 25°C. Methanol (80 ml) was added in the aqueous layer at 25°C, stirred for 10 minutes, followed by addition of water (400ml) and neutralized by 2.3% ammonia solution till pH 4.5. The precipitated solid was filtered and washed with water (200ml x 3 ). The solid dried under vacuum at 40°C.to yield pure cefpodoxime proxetil (24.0 gm) having an isomeric ratio of (R/R+S)=O.5O5, 99.00% ( assay), 99.40% ( HPLC purity) and Δ3 -isomer 0.34%.
EXAMPLE (11)
Cefpodoxime acid (20.0 gm; 0.0468 moles) was dissolved in dimethylacetamide (100 ml) and cooled to -10° C. (6.62 g ; 0.0435 moles) of l,8-diazabicyclo[5,4,0]undec-7- ene was added drop wise over -100C to -150C in 10 minutes . Stirred for 10 minutes. 1 - iodoethylisopropyl carbonate(1 1.70gm; 0.0453 moles) was added at -10 to - 15°C within 10 minutes. The reaction mixture was stirred for further 30 minutes and hydrochloric acid (2 ml) in (20 ml) was added was added at -15°C to +100C. A solution of sodium thiosulphate (4.0 gm) in (400 ml) water was added followed by ethyl acetate (200ml) at 100C. The aqueous and organic layers were separated. Aqueous layer is again extracted with ethyl acetate (100 ml). Combined ethyl acetate layer and washed with 10% brine solution (150 ml x 3) at 100C. Washed organic layer was treated with activated carbon (4.0 gm) and sodium dithionite (1.0 gm) for 60 minutes and filtered. Divided ethyl acetate solution into two equal parts.
HA) Distilled off ethyl acetate under vacuum to concentrate up to (40ml) and charged this concentrated ethyl acetate solution on to cyclohexane (300ml) for crystallisation . Stirred and filtered to obtain crude cefpodoxime proxetil. Dissolved crude cefpodoxime proxetil in methanol (40ml),and reduce the volume up to (30ml). It was than added to water (180ml) in 30 minutes at 25C.to obtained solid .Filtered and washed with water(50ml x 3). The solid was filtered and dried under vacuum at 400C. to yield pure cefpodoxime proxetil.(9.0 gm) having an isomeric ratio of (R/R+S)=0.506, 96.99% (assay), 98.79% (HPLC purity) and Δ3 -isomer 0.24
HB) The organic layer was concentrated under vacuum at 25°C.up to (35 ml) and cooled to 100C. The solution of crude cefpodoxime proxetil in ethyl acetate was treated with a solution of methanesulfonic acid (3.0 gm 0.0312 moles) in water (100 ml) and stir for 15 minutes at 15°C, cyclohexane (25 ml) was added to the reaction mixture and stirred for 15 minutes. The organic and aqueous layer was separated. The aqueous layer was degassed under vacuum for 30 minutes at 25°C. Methanol (40 ml) was added in the aqueous layer at 25°C, followed by addition of water (200 ml) stirred for 10 minutes and neutralized by 2.3% ammonia solution up to pH 4.5. The precipitated solid was filtered and washed with water (50ml x 3). The solid was filtered and dried under vacuum at 40°C.to give (8.60gm) of pure cefpodoxime proxetil having an isomeric ratio of (R/R+S)=O.5O5, 98.00% (assay), 99.61% (HPLC purity) and Δ3 - isomer 0.20 %..
EXAMPLE (12) Cefpodoxime acid (10.0 gm; 0.0234 moles) was dissolved in dimethylacetamide (50 ml) and cooled to -10° C. (3.45 g ; 0.02269 moles) of l,8-diazabicyclo[5,4,0]undec-7- ene was added drop wise over -100C to -15°C in 10 minutes .Stirred for 10 minutes. 1 - iodoethylisopropyl carbonate(6.04 gm; 0.02234 moles) was added at -10 to -15°C within 10 minutes. The reaction mixture was stirred for further 30 minutes and hydrochloric acid (1 ml) in (10 ml) was added was added at -15°C to +10°C. A solution of sodium thiosulphate (2.0 gm) in (200 ml) water was added followed by ethyl acetate (100ml) at 100C. The aqueous and organic layers were separated. Aqueous layer is again extracted with ethyl acetate (50 ml). Combined ethyl acetate layer and washed with 10% brine solution (75 ml x 3) at 100C. Washed organic layer was treated with activated carbon (2.0 gm) and sodium dithionite (0.5 gm) for 60 minutes and filtered.
The organic layer was concentrated under vacuum at 25°C.up to (35 ml) and cooled to 100C. The solution of crude cefpodoxime proxetil in ethyl acetate was treated with a solution of methanesulfonic acid (3.0 gm 0.03125 moles) in water (100 ml) and stir for 15 minutes at 15°C, cyclohexane (25 ml) was added to the reaction mixture and stirred for 15 minutes. The organic and aqueous layer was separated. The aqueous layer was de-gas under vacuum for 30 minutes at 25°C. Methanol (40 ml) was added in the aqueous layer at 25°C, followed by addition of water (200 ml) stirred for 10 minutes and neutralized by 2.3% ammonia solution up to pH 4.5. The precipitated solid was filtered and washed with water (50ml x 3). The solid was filtered and dried under vacuum at 40°C.to give (lO.όOgm) of pure cefpodoxime proxetil having an isomeric ratio of (R/R+S)=0.510, 97.67% (assay), 99.55% (HPLC purity) and Δ3 -isomer 0.29%..
EXAMPLE (13)
Cefpodoxime acid (10.0 gm; 0.0234 moles) was dissolved in dimethylacetamide (50 ml) and cooled to -10° C. (3.56 g ; 0.0234 moles) of l,8-diazabicyclo[5,4,0]undec-7- ene was added drop wise over -100C to -15°C in 10 minutes . Stirred for 10 minutes. 1- iodoethylisopropyl carbonate(6.34 gm; 0.0245 moles) was added at -10 to -150C within 10 minutes. The reaction mixture was stirred for further 30 minutes and hydrochloric acid (1 ml) in (10 ml) was added was added at -15°C to +100C. A solution of sodium thiosulphate (2.0 gm) in (200 ml) water was added followed by ethyl acetate (100ml) at 100C. The aqueous and organic layers were separated. Aqueous layer is again extracted with ethyl acetate (50 ml). Combined ethyl acetate layer and washed with 10% brine solution (75 ml x 3) at 1O0C. Washed organic layer was treated with activated carbon (2.0 gm) and sodium dithionite (0.5 gm) for 60 minutes and filtered.
The organic layer was concentrated under vacuum at 25°C.up to (35 ml) and cooled to 100C. The solution of crude cefpodoxime proxetil in ethyl acetate was treated with a solution of methanesulfonic acid (3.0 gm 0.03125 moles) in water (100 ml) and stir for 15 minutes at 15°C, cyclohexane (25 ml) was added to the reaction mixture and stirred for 15 minutes. The organic and aqueous layer was separated. The aqueous layer was de-gas under vacuum for 30 minutes at 25°C. Methanol (40 ml) was added in the aqueous layer at 25°C, followed by addition of water (200 ml) stirred for 10 minutes and neutralized by 2.3% ammonia solution up to pH 4.5. The precipitated solid was filtered and washed with water (50ml x 3). The solid was filtered and dried under vacuum at 40°C.to give (1 1.20gm) of pure cefpodoxime proxetil having an isomeric ratio of (R/R+S)=0.506, 96.69% (assay), 98.37%(HPLC purity) and Δ3 -isomer 1.37%..

Claims

Claims:
1. An improved process for the preparation of cefpodoxime proxetil of formula (I)
Figure imgf000020_0001
, (I)
the said process comprising steps of:: a) preparing cefpodoxime acid (II) as described in the prior art document US 4,486,425,
Figure imgf000020_0002
(H)
b) reacting cefpodoxime acid of step (a) withl- iodoethylisopropylcarbonate of formula (III)-
Figure imgf000021_0001
(III) in an aprotic solvent in presence of mixture of organic base and inorganic base at a temperature ranging from 0° to -2O0C for a time period of 10 mts. to 60 mts,
c) working up the reaction mixture of the step (b) at a temperature at the ranging between -150C to + 1O0C by the addition of aqueous hydrochloric acid, followed by aqueous sodium thiosulfate and ethylacetate , separating aqueous and organic layers, d) extracting once more aqueous layer of step (c) with ethylacetate and separating layers, e) combining ethyl acetate layer of steps (c) and (d) , washing with 10 % aqueous brine solution, treating the washed ethyl acetate layer by stirring with activated charcoal and sodium dithionite for a period of 60 minute, f) filtered step (e) solution to obtain crude cefpodoxime proxetil solution, and g) purifying crude cefpodoxime proxetil of step (f) by converting into its methanesulfonate salt, treating the salt with a base to adjust the pH to 4.5 to obtain pure cefpodoxime proxetil having enhanced yield and assay.
The process of claim 1, wherein in step (b) the temperature preferably range between -100C to -150C
The process of claim 1, wherein in step (b) organic base used is selected from a group consisting of tetramethyl guanidine andl, 8- diazabicyclo-undec-7-ene
The process of claim 1, wherein in step (b) inorganic base used is selected from a group consisting of sodium acetate, sodium carbonate potassium acetate, potassium carbonate, calcium acetate and calcium carbonate .
5. The process of claim 1, wherein in step b) the mixture of base used is selected from a group consisting of tetramethyl guanidine-sodium acetate, tetramethyl guanidine- sodium carbonate, tetramethyl guanidine- potassium acetate, tetramethyl guanidine- potassium carbonate, tetramethyl guanidine- calcium acetate, tetramethyl guanidine- calcium carbonate,, l,8-diazabicyclo-undec-7- ene-sodium acetate, 1,8- diazabicyclo-undec-7-ene sodium carbonate, 1 , 8- diazabicyclo-undec-7-ene - potassium acetate, 1, 8- diazabicyclo-undec-7-ene - potassium carbonate, 1, 8- diazabicyclo-undec-7-ene- calcium acetate and 1 , 8- diazabicyclo-undec-7-ene- calcium carbonate,
6. The process of claim 3, wherein the preferred mixture of base is selected from a group consisting of tetramethyl guanidine-sodium acetate and 1 , 8- diazabicyclo-undec-7-ene - sodium acetate.
7. The process of claim 3, wherein the most preferred mixture of base is 1, 8- diazabicyclo-undec-7-ene - sodium acetate.
8. The process of claim 6, wherein the mole ratio of 1, 8- diisabicyclo-undec-7- ene-: sodium acetate and tetramethyl guanidine-sodium acetate ranges from 0.9:.0.15 to 0.75:.30
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