WO2000068234A2 - Process for the preparation of cefpodoxime acid - Google Patents

Process for the preparation of cefpodoxime acid Download PDF

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Publication number
WO2000068234A2
WO2000068234A2 PCT/IB2000/000585 IB0000585W WO0068234A2 WO 2000068234 A2 WO2000068234 A2 WO 2000068234A2 IB 0000585 W IB0000585 W IB 0000585W WO 0068234 A2 WO0068234 A2 WO 0068234A2
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Prior art keywords
formula
acid
cefpodoxime
organic solvent
preparation
Prior art date
Application number
PCT/IB2000/000585
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French (fr)
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WO2000068234A3 (en
Inventor
Yatendra Kumar
Rakesh Kumar Arora
Kaptan Singh
Hashim Nizar
Shantanu De
Jag Mohan Khanna
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Ranbaxy Laboratories Limited
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Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Priority to EP00969048A priority Critical patent/EP1178992A2/en
Priority to AU72243/00A priority patent/AU7224300A/en
Publication of WO2000068234A2 publication Critical patent/WO2000068234A2/en
Publication of WO2000068234A3 publication Critical patent/WO2000068234A3/en
Priority to HK02105883.7A priority patent/HK1044761A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a new process for the preparation of cefpodoxime acid, an antibiotic belonging to cephalosporin class of compounds. More specifically, the present invention relates to the preparation of cefpodoxime acid of high purity and yield.
  • cefpodoxime acid prepared according to the process of the present invention can be converted into its prodrug, cefpodoxime proxetil, by methods known in the art.
  • Cefpodoxime proxetil is chemically an isopropyloxy carbonyl oxyethyl (proxetil) ester of cefpodoxime. It is a potent antibiotic and is of great therapeutic interest in the treatment of acute bronchitis, exacerbations, pneumonia, sinusitis, recurrence of chronic tonsillitis, pharyngitis, and acute otitis media.
  • the present invention provides a process for the preparation of Cefpodoxime acid having the Formula I
  • MAEM 3-methoxymethyl-7-aminocephalosporanic acid
  • 7AMCA in the presence of an organic solvent and an organic base as herein described and optionally in the presence of water, washing with a water-immiscible solvent as herein described, precipitating the product by adjusting the pH to an acidic pH, isolating and drying the product having the Formula I.
  • the reaction between MAEM and 7AMCA is carried out at a temperature ranging from -5°C to about ambient temperature for about 2 to 12 hours.
  • the organic solvent used is selected from tetrahydrofuran, N, N-dimethylaceta- mide, N,N-dimethylformamide, chlorinated hydrocarbons, ketones or a mixture thereof.
  • the reaction is carried out in tetrahydrofuran in the presence of water.
  • the reaction is carried out in the presence of organic bases such as triethylamine, N-methylpiperidine, pyridine, 1 ,8-diazabicycloundecene, 4-dimeth- ylaminopyridine, or a mixture thereof.
  • the water-immiscible solvent used is chlorinated hydrocarbon, aromatic hydrocarbon or ketones.
  • cefpodoxime acid having the Formula I prepared according to the process of the present invention is a syn-isomer of this compound.
  • the present invention provides a method by which the syn-isomer of cefpodoxime acid is obtained in high purity and good yields without the necessity for protecting the amino group of acylating agent.
  • Aqueous layer was separated and washed with methylene chloride.
  • the aqueous layer was acidified to pH 2.75 with aqueous hydrochloric acid and the separated product was filtered. It was washed with water and dried under reduced pressure to yield 6.65gm (76%) of Cefpodoxime acid of 95.7% purity (HPLC).

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

Abstract

A new process is described for the preparation of cefpodoxime acid, which may then be converted into cefpodoxime proxetil by methods known in the art.

Description

PROCESS FOR THE PREPARATION OF CEFPODOXIME ACID
FIELD OF THE INVENTION
The present invention relates to a new process for the preparation of cefpodoxime acid, an antibiotic belonging to cephalosporin class of compounds. More specifically, the present invention relates to the preparation of cefpodoxime acid of high purity and yield.
The cefpodoxime acid prepared according to the process of the present invention can be converted into its prodrug, cefpodoxime proxetil, by methods known in the art. Cefpodoxime proxetil is chemically an isopropyloxy carbonyl oxyethyl (proxetil) ester of cefpodoxime. It is a potent antibiotic and is of great therapeutic interest in the treatment of acute bronchitis, exacerbations, pneumonia, sinusitis, recurrence of chronic tonsillitis, pharyngitis, and acute otitis media.
BACKGROUND OF THE INVENTION
The process known for the preparation of cefpodoxime acid in the literature (Journal of Antibiotics, Vol. 40, p-370, 1987) involves conversion of 7-[2-(2- chloroacetyl amino thiazol-4-yl)-(Z)-2-(2- methoxyimino acetamido]-3-acetoxy- methyl-3-cephem-4-carboxylic acid into the corresponding 3-methoxymethyl derivative, which on deprotection at the 2-aminothiazolyl ring gives cefpodoxime acid. Esterification of the acid with iodides affords the corresponding esters. The process involves additional steps of protection and deprotection of the amino group resulting in lower yields. SUMMARY OF THE INVENTION
It is an object of the present invention to provide an efficient process for the preparation of cefpodoxime acid of high purity and yield, and is economical from a commercial point of view.
It is a further object of the present invention to provide a process which requires fewer steps and eliminates the use of additional protection and deprotection steps.
Accordingly, the present invention provides a process for the preparation of Cefpodoxime acid having the Formula I
Figure imgf000004_0001
FORMULA I
comprising reacting 2-[2-aminothiazol-4-yl]-2-syn-methoxyimino acetic acid-2- benzothiazolyl thioester of Formula II
Figure imgf000005_0001
FORMULA π
(referred as MAEM) with 3-methoxymethyl-7-aminocephalosporanic acid of Formula III
Figure imgf000005_0002
FORMULA m
(referred as 7AMCA), in the presence of an organic solvent and an organic base as herein described and optionally in the presence of water, washing with a water-immiscible solvent as herein described, precipitating the product by adjusting the pH to an acidic pH, isolating and drying the product having the Formula I.
Preferably the reaction between MAEM and 7AMCA is carried out at a temperature ranging from -5°C to about ambient temperature for about 2 to 12 hours. The organic solvent used is selected from tetrahydrofuran, N, N-dimethylaceta- mide, N,N-dimethylformamide, chlorinated hydrocarbons, ketones or a mixture thereof. Preferably, the reaction is carried out in tetrahydrofuran in the presence of water. The reaction is carried out in the presence of organic bases such as triethylamine, N-methylpiperidine, pyridine, 1 ,8-diazabicycloundecene, 4-dimeth- ylaminopyridine, or a mixture thereof.
The water-immiscible solvent used is chlorinated hydrocarbon, aromatic hydrocarbon or ketones.
The cefpodoxime acid having the Formula I prepared according to the process of the present invention is a syn-isomer of this compound.
The present invention provides a method by which the syn-isomer of cefpodoxime acid is obtained in high purity and good yields without the necessity for protecting the amino group of acylating agent.
The present invention is further illustrated by the following examples :
DETAILED DESCRIPTION OF THE INVENTION
EXAMPLE 1
Preparation of 7-[(Z)-2-(2-Amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3- methoxy-methyl-3-cephem-4-carboxylic acid.
To a stirred mixture of 2-benzothiazolyl(Z)-2-(aminothiazol-4-yl) methoxyimino- thioacetate (7.89g)and 7-amino-3-methoxymethyl-3-cephem-4-carboxyIic acid (5.0g) in tetrahydrofuran and water was added triethylamine (2.58g) in tetra- hydrofuran-water at 2-3-C. The reaction mixture was stirred at 2-3QC for 4 hours. After completion of the reaction, it was washed with methylene chloride. The aqueous layer was separated and its pH was adjusted to 2.75 with aqueous hydrochloric acid. The product thus separated was filtered, washed with water and isopropanol. The product was dried under reduced pressure to yield 6.65 gm (76%) of Cefpodoxime acid of 95.56% purity (HPLC).
EXAMPLE 2
Preparation of 7-[(Z)-2-(2-Amino-4-thiazolyl)-(2-methoxyimino)acetamido]-3- methoxy-methyl-3-cephem-4-carboxylic acid.
To a stirred mixture of 2-benzothiazolyl(Z)-2-(aminothiazol-4-yl)methoxyimino- thioacetate (8.6g) and 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid (5.0g) in methylene chloride (75ml) was added triethylamine (7.24g) at 2-39C. The reaction mixture was stirred at 2-3QC for 3 hr. and water was added. The aqueous layer was separated and washed with methylene chloride. It was acidi- tied to pH 2.70 with aqueous hydrochloric acid. The product thus separated was filtered, washed and dried under reduced pressure to yield 6.2gm (70.8%) of Cefpodoxime acid of 94.30% purity (HPLC).
EXAMPLE 3
Preparation of 7-[(Z)-2-(2-Amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3- methoxy-methyl-3-cephem-4-carboxylic acid.
To a stirred mixture of 2-benzothiazolyl(Z)-2-(aminothiazolyl-4-yl)methoxyimino- thioacetate (7.89g) and 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid in acetone and water, was added triethylamine (2.06g). The reaction mixture was stirred at 5-7sC for 6 hrs. After completion of the reaction, it was washed with methylene chloride and aqueous layer was separated. The aqueous layer was acidified to pH 2.75 with aqueous hydrochloric acid. The product thus separated was filtered and washed with water and acetone. It was dried under reduced pressure at 45QC to afford 5.8gm (66%) of Cefpodoxime acid of 91.8% purity (HPLC).
EXAMPLE 4
Preparation of 7-[(Z)-2-(2-Amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3- methoxy-methyl-3-cephem-4-carboxylic acid.
To a mixture of N,N-dimethylformamide and water, were added at 0-5QC, 7- amino-3-methoxymethyl-3-cephem-4-carboxylic acid (5.0g), 2-benzothiazolyl(Z)-
(2-aminothiazol-4-yl)methoxyiminothioacetate (8.6g) and triethylamine (2.89g).
The resulting mixture was stirred at 10-15SC for 6 hrs. After completion of the reaction, the pH of the reaction was adjusted to 6.5 and stirred with methylene chloride (50ml). The aqueous layer was separated and acidified to pH 2.75 with aqueous hydrochloric acid. The product thus separated was filtered, washed with water and isopropanol, and dried under reduced pressure at 40QC to yield 4.9gm (56%) of Cefpodoxime acid of 94.92% purity (HPLC).
EXAMPLE 5
Preparation of 7-[(Z)-2-(2-Amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3- methoxy-methyI-3-cephem-4-carboxylic acid.
To a stirred mixture of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid (5.0g) in water (75ml) was added triethylamine (2.0 gm) at 2-5sC. To this was added a solution of 2-benzothiazolyl-(Z)-2-(aminothiazol-4-yl)methoxyiminothio- acetate (7.88gm) in dimethylacetamide at 2-5-C. The resultant mixture was stirred at 20-25sC for 12 hrs. After completion of the reaction, the reaction mixture was washed with methylene chloride. The aqueous layer was separated and pH was adjusted to 2.7 with aqueous hydrochloric acid. The solid thus separated was filtered and washed with cold water. The product was dried under reduced pressure at 40-45QC to yield 5.5gm (62%) of Cefpodoxime acid of 93.38% purity (HPLC).
EXAMPLE 6
Preparation of 7-[(Z)-2-(2-Amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3- methoxy-methyl-3-cephem-4-carboxylic acid] (Via in situ-generated MAEM):
A slurry containing triphenylphosphine (8.22g) and mercaptobenzothiazole disulphide (10.04g) in methylene chloride was stirred at 28-30QC for 1 hr. 2- (Aminothiazole-4-yl)- methoxyimino acetic acid (4.84g) and triethylamine (2.61 g) were added at 09C and stirred at 0-25C for 1 hr. 7-Amino-3-methoxymethyl-3- cephem-4-carboxylic acid (5.0g) and triethylamine (3.2g) were added and the resulting reaction mixture and further stirred for 2 hrs. After completion of the reaction, water was added and stirred for 10 min. Aqueous layer was separated and washed with methylene chloride. The aqueous layer was acidified to pH 2.75 with aqueous hydrochloric acid and the separated product was filtered. It was washed with water and dried under reduced pressure to yield 6.65gm (76%) of Cefpodoxime acid of 95.7% purity (HPLC).

Claims

LAIM :
A process for the preparation of cefpodoxime acid having the Formula I
Figure imgf000011_0001
FORMULA I
which comprises reacting 2-[2-aminothiazol-4yl]-2-syn-methoxyiminoacetic acid -2-benzothiazolyl thioester of Formula II,
Figure imgf000011_0002
FORMULA π
with 3-methoxymethyl-7-aminocephalosporanic acid of Formula III,
Figure imgf000011_0003
FORMULA ffl in the presence of an organic solvent and an organic base, precipitating the product by adjusting the pH to an acidic pH, isolating and drying the product having the Formula I.
2. The process of claim 1 , wherein after the reaction in the presence of an organic solvent and an organic base, before precipitation, the product is washed with a water-immiscible solvent.
3. The process of claim 1 , wherein cefpodoxime acid having the Formula I is a syn-isomer.
4. The process of claim 1 , wherein the organic solvent used is tetrahydrofuran, N,N-dimethylacetamide, N,N-dimethylformamide, chlorinated hydrocarbons, ketones or mixtures thereof.
5. The process of claim 4, wherein the organic solvent is methylene chloride.
6. The process of claim 1 , wherein the organic base is triethylamine, pyridine, N-methylpiperidine, 1 , 8-diazabicycloundecene, 4- dimethylaminopyridine or mixtures thereof.
7. The process of claim 1 , wherein the said reaction is carried out at a temperature in the range of -5QC to about ambient temperature for about 2 to 12 hours.
8. The process of claim 2, wherein the water-immiscible organic solvent is chlorinated hydrocarbon, aromatic hydrocarbon or ketones.
PCT/IB2000/000585 1999-05-07 2000-05-05 Process for the preparation of cefpodoxime acid WO2000068234A2 (en)

Priority Applications (3)

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EP00969048A EP1178992A2 (en) 1999-05-07 2000-05-05 Process for the preparation of cefpodoxime acid
AU72243/00A AU7224300A (en) 1999-05-07 2000-05-05 Process for the preparation of cefpodoxime acid
HK02105883.7A HK1044761A1 (en) 1999-05-07 2002-08-12 Process for the preparation of cefpodoxime acid

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US30701099A 1999-05-07 1999-05-07
US09/307,010 1999-05-07

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004037833A1 (en) * 2002-10-24 2004-05-06 Orchid Chemicals & Pharmaceuticals Ltd Process for the preparation of cephalosporin antibiotics
WO2011077217A1 (en) * 2009-12-21 2011-06-30 Nectar Lifesciences Ltd. An improved process for the preparation of cefpodoxime acid
CN106046024A (en) * 2016-06-30 2016-10-26 齐鲁动物保健品有限公司 Preparation method of cefpodoxime proxetil
CN111320514A (en) * 2020-04-03 2020-06-23 南京昊绿生物科技有限公司 Synthesis method of cefpodoxime D3

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0034536B1 (en) * 1980-02-18 1984-12-27 Roussel-Uclaf Oxime derivatives of 3-alkyloxy- or 3-alkylthiomethyl 7-amino-thiazolylacetamido cephalosporanic acid, their preparation, their use as medicaments and compositions containing them
EP0531875A2 (en) * 1991-09-07 1993-03-17 Hoechst Aktiengesellschaft Diastereomers of the 3-cephem-4-carboxylic acid-1-(-isopropoxycarbonyloxy)ethylester and process for their preparation

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DE3165922D1 (en) 1980-03-28 1984-10-18 Biochemie Gmbh New process for the production of cephalosporin antibiotics, and novel intermediates used in such process and their production
JPS60260583A (en) * 1985-05-14 1985-12-23 Sankyo Co Ltd Preparation of cephalosporin derivative
JPS60260584A (en) * 1985-05-14 1985-12-23 Sankyo Co Ltd Cephalosporin derivative and its preparation
TW538045B (en) 1997-01-16 2003-06-21 Biochemie Gmbh Process for purifying cefixime

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
EP0034536B1 (en) * 1980-02-18 1984-12-27 Roussel-Uclaf Oxime derivatives of 3-alkyloxy- or 3-alkylthiomethyl 7-amino-thiazolylacetamido cephalosporanic acid, their preparation, their use as medicaments and compositions containing them
US4992431A (en) * 1980-02-18 1991-02-12 Rousseluclaf Cephalosporins
EP0531875A2 (en) * 1991-09-07 1993-03-17 Hoechst Aktiengesellschaft Diastereomers of the 3-cephem-4-carboxylic acid-1-(-isopropoxycarbonyloxy)ethylester and process for their preparation

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 108, no. 5, 1 February 1988 (1988-02-01) Columbus, Ohio, US; abstract no. 55704m, FUJIMOTO K ET AL: "Studies on orally active cephalosporin esters" page 687; column 2; XP002901354 cited in the application & J. ANTIBIOT., vol. 40, no. 3, 1987, pages 370-384, *
PATENT ABSTRACTS OF JAPAN vol. 010, no. 136 (C-347), 20 May 1986 (1986-05-20) & JP 60 260583 A (SANKYO KK), 23 December 1985 (1985-12-23) *
PATENT ABSTRACTS OF JAPAN vol. 010, no. 136 (C-347), 20 May 1986 (1986-05-20) & JP 60 260584 A (SANKYO KK), 23 December 1985 (1985-12-23) *
See also references of EP1178992A2 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004037833A1 (en) * 2002-10-24 2004-05-06 Orchid Chemicals & Pharmaceuticals Ltd Process for the preparation of cephalosporin antibiotics
WO2011077217A1 (en) * 2009-12-21 2011-06-30 Nectar Lifesciences Ltd. An improved process for the preparation of cefpodoxime acid
CN106046024A (en) * 2016-06-30 2016-10-26 齐鲁动物保健品有限公司 Preparation method of cefpodoxime proxetil
CN111320514A (en) * 2020-04-03 2020-06-23 南京昊绿生物科技有限公司 Synthesis method of cefpodoxime D3

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WO2000068234A3 (en) 2001-02-08
AU7224300A (en) 2000-11-21
EP1178992A2 (en) 2002-02-13

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