WO2000068234A2 - Process for the preparation of cefpodoxime acid - Google Patents
Process for the preparation of cefpodoxime acid Download PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- acid
- cefpodoxime
- organic solvent
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
Classifications
-
- 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).
Landscapes
- 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
FORMULA I
comprising reacting 2-[2-aminothiazol-4-yl]-2-syn-methoxyimino acetic acid-2- benzothiazolyl thioester of Formula II
FORMULA π
(referred as MAEM) with 3-methoxymethyl-7-aminocephalosporanic acid of Formula III
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
FORMULA I
which comprises reacting 2-[2-aminothiazol-4yl]-2-syn-methoxyiminoacetic acid -2-benzothiazolyl thioester of Formula II,
FORMULA π
with 3-methoxymethyl-7-aminocephalosporanic acid of Formula III,
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.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU72243/00A AU7224300A (en) | 1999-05-07 | 2000-05-05 | Process for the preparation of cefpodoxime acid |
| EP00969048A EP1178992A2 (en) | 1999-05-07 | 2000-05-05 | Process for the preparation of cefpodoxime acid |
| HK02105883.7A HK1044761A1 (en) | 1999-05-07 | 2000-05-05 | Process for the preparation of cefpodoxime acid |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US30701099A | 1999-05-07 | 1999-05-07 | |
| US09/307,010 | 1999-05-07 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2000068234A2 true WO2000068234A2 (en) | 2000-11-16 |
| WO2000068234A3 WO2000068234A3 (en) | 2001-02-08 |
Family
ID=23187851
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2000/000585 Ceased WO2000068234A2 (en) | 1999-05-07 | 2000-05-05 | Process for the preparation of cefpodoxime acid |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1178992A2 (en) |
| AU (1) | AU7224300A (en) |
| HK (1) | HK1044761A1 (en) |
| WO (1) | WO2000068234A2 (en) |
Cited By (5)
| 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 |
| CN116003438A (en) * | 2022-12-28 | 2023-04-25 | 广药白云山化学制药(珠海)有限公司 | Preparation method of cephalosporin intermediate |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2476087A1 (en) * | 1980-02-18 | 1981-08-21 | Roussel Uclaf | NOVEL OXIMES DERIVED FROM 3-ALKYLOXY OR 3-ALKYL-THIOMETHYL 7-AMINO THIAZOLYL ACETAMIDO CEPHALOSPORANIC ACID, PROCESS FOR PREPARING THEM AND THEIR APPLICATION AS MEDICAMENTS |
| 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 |
| JPS60260584A (en) * | 1985-05-14 | 1985-12-23 | Sankyo Co Ltd | Cephalosporin derivative and its preparation |
| JPS60260583A (en) * | 1985-05-14 | 1985-12-23 | Sankyo Co Ltd | Preparation of cephalosporin derivative |
| ES2215161T3 (en) * | 1991-09-07 | 2004-10-01 | Aventis Pharma Deutschland Gmbh | DIASTEREOISOMERO DEL ESTER 1- (ISOPROPOXICARBONILOXI) -THETIC ACID 3-CEFEM-4-CARBOXILICO AND PROCEDURE FOR PREPARATION. |
| TW538045B (en) | 1997-01-16 | 2003-06-21 | Biochemie Gmbh | Process for purifying cefixime |
-
2000
- 2000-05-05 WO PCT/IB2000/000585 patent/WO2000068234A2/en not_active Ceased
- 2000-05-05 AU AU72243/00A patent/AU7224300A/en not_active Abandoned
- 2000-05-05 EP EP00969048A patent/EP1178992A2/en not_active Withdrawn
- 2000-05-05 HK HK02105883.7A patent/HK1044761A1/en unknown
Cited By (6)
| 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 |
| CN116003438A (en) * | 2022-12-28 | 2023-04-25 | 广药白云山化学制药(珠海)有限公司 | Preparation method of cephalosporin intermediate |
| CN116003438B (en) * | 2022-12-28 | 2025-09-05 | 广药白云山化学制药(珠海)有限公司 | A preparation method of cephalosporin intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| HK1044761A1 (en) | 2002-11-01 |
| WO2000068234A3 (en) | 2001-02-08 |
| EP1178992A2 (en) | 2002-02-13 |
| AU7224300A (en) | 2000-11-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6388070B1 (en) | Thioester derivatives of thiazolyl acetic acid and their use in the preparation of cephalosporin compounds | |
| US7405294B2 (en) | Intermediate cefdinir salts | |
| EP0399094A2 (en) | Improved process for the preparation of ceftriaxone | |
| EP0842937A2 (en) | Process for the preparation of the cephalosporin derivatives cefotaxime and ceftriaxone | |
| EP1863822B1 (en) | An improved process for the preparation of cefixime | |
| CN1134447C (en) | Process for purification of cephalosporin derivative | |
| US5869649A (en) | Process for producing cephalosporin antibiotics | |
| WO2011077217A1 (en) | An improved process for the preparation of cefpodoxime acid | |
| EP1178992A2 (en) | Process for the preparation of cefpodoxime acid | |
| US7045618B2 (en) | Cefpodixime proxetil | |
| AU690482B2 (en) | Process for producing cephalosporin antibiotics | |
| KR100342600B1 (en) | New Thiazole compounds and their preparations | |
| WO2001034611A1 (en) | Method of preparing highly pure cefpodoxime proxetil | |
| WO2003059908A1 (en) | Novel thioester derivatives and process for preparation of cephalosporin | |
| US5527906A (en) | Process for the preparation of ceftriaxon disodium salt hemiheptahydrate | |
| US6214997B1 (en) | Process for the preparation of crystalline (Z)-2-(2-tert.-butoxycarbonylprop-2-oxyimino)-2-(2-triphenylmethylaminothiazol-4-yl) acetic acid in association with N,N-dimethylformamide | |
| EP0948491B1 (en) | Aminothiazole derivatives useful in the preparation of beta-lactam antibiotics | |
| EP1704153A2 (en) | Improved process for the production of cefotaxime sodium | |
| WO2005040175A2 (en) | Process for the preparation of cephem carboxylic acids | |
| WO2005105813A1 (en) | Improved process for the manufacture of ceftriaxone sodium | |
| DE69702463T2 (en) | Process for the preparation of cephalosporin derivatives and intermediates | |
| US5138049A (en) | Cephalosporin derivative | |
| KR0176014B1 (en) | Method for producing cephalosporin derivatives | |
| KR20000074087A (en) | A method for preparing of cephalosporin derivatives | |
| JPS5984890A (en) | Cephalosporin compound for oral administration |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| AK | Designated states |
Kind code of ref document: A3 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| WWE | Wipo information: entry into national phase |
Ref document number: 2000969048 Country of ref document: EP |
|
| WWP | Wipo information: published in national office |
Ref document number: 2000969048 Country of ref document: EP |
|
| REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
| WWW | Wipo information: withdrawn in national office |
Ref document number: 2000969048 Country of ref document: EP |
|
| NENP | Non-entry into the national phase |
Ref country code: JP |