DE19846449A1 - Process for the preparation of orally active cephalosporin antibiotic cefixime - Google Patents
Process for the preparation of orally active cephalosporin antibiotic cefiximeInfo
- Publication number
- DE19846449A1 DE19846449A1 DE19846449A DE19846449A DE19846449A1 DE 19846449 A1 DE19846449 A1 DE 19846449A1 DE 19846449 A DE19846449 A DE 19846449A DE 19846449 A DE19846449 A DE 19846449A DE 19846449 A1 DE19846449 A1 DE 19846449A1
- Authority
- DE
- Germany
- Prior art keywords
- formula
- cefixime
- phase transfer
- transfer catalyst
- ester
- 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.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims description 20
- 229960002129 cefixime Drugs 0.000 title claims description 14
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 title claims description 14
- 229940124587 cephalosporin Drugs 0.000 title claims description 7
- 229930186147 Cephalosporin Natural products 0.000 title claims description 6
- 150000001780 cephalosporins Chemical class 0.000 title claims description 5
- 230000003115 biocidal effect Effects 0.000 title claims description 4
- 238000002360 preparation method Methods 0.000 title claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 239000003444 phase transfer catalyst Substances 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 6
- 239000010410 layer Substances 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- -1 hydrocarbon methylene chloride Chemical class 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 150000004702 methyl esters Chemical class 0.000 claims description 3
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000012044 organic layer Substances 0.000 claims description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 2
- ODTSDWCGLRVBHJ-UHFFFAOYSA-M tetrahexylazanium;chloride Chemical compound [Cl-].CCCCCC[N+](CCCCCC)(CCCCCC)CCCCCC ODTSDWCGLRVBHJ-UHFFFAOYSA-M 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims 1
- 229930195733 hydrocarbon Natural products 0.000 claims 1
- 239000000243 solution Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000004140 cleaning Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000010561 standard procedure Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 150000001450 anions Chemical class 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 1
- 241000158147 Sator Species 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- HJJDBAOLQAWBMH-YCRCPZNHSA-N cefmenoxime Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NN=NN1C HJJDBAOLQAWBMH-YCRCPZNHSA-N 0.000 description 1
- 229960003791 cefmenoxime Drugs 0.000 description 1
- GPRBEKHLDVQUJE-VINNURBNSA-N cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-VINNURBNSA-N 0.000 description 1
- 229960000484 ceftazidime Drugs 0.000 description 1
- ORFOPKXBNMVMKC-DWVKKRMSSA-N ceftazidime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 ORFOPKXBNMVMKC-DWVKKRMSSA-N 0.000 description 1
- 229960001991 ceftizoxime Drugs 0.000 description 1
- NNULBSISHYWZJU-LLKWHZGFSA-N ceftizoxime Chemical compound N([C@@H]1C(N2C(=CCS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 NNULBSISHYWZJU-LLKWHZGFSA-N 0.000 description 1
- 229960004755 ceftriaxone Drugs 0.000 description 1
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- VUQZKDREOOPLMD-UHFFFAOYSA-N formamide;2,2,2-trifluoroacetic acid Chemical compound NC=O.OC(=O)C(F)(F)F VUQZKDREOOPLMD-UHFFFAOYSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000016507 interphase Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Cephalosporin Compounds (AREA)
Description
Die Erfindung betrifft ein Verfahren zur Herstellung von oral aktivem Cephalosporin-Antibiotikum Cefixim.The invention relates to a method for producing orally active cephalosporin antibiotic cefixime.
Das erste einer neuen Reihe von Cephalosporinen, die die mei sten der für eine Verbindung zur Verwendung in einer empiri schen Therapie erwünschten Eigenschaften aufweisen, war Cefotaxim, ein Methoxyimino-Cephalosporin mit einer 2-Imino thiazol-4-yl-Gruppe, dem bald eine Reihe von sehr ähnlichen Methoximen mit unterschiedlichen 3-Substituenten, wie Ceftizoxim, Cefmenoxim, Ceftriaxon und Ceftazidim, folgten. (Am. J. Med. (1985), Suppl. 2A, 14.; Am. J. Med. (1985), Suppl. 2A, 21; Clin Pharm. (1987), 6, 59.; Recent Advances in the Chemistry of β-Lactam Antibiotics, Special publication No. 52, The Royal Society of Chemistry, London, July 1984, S. 1). The first of a new series of cephalosporins that the mei most for a connection for use in an empiri therapy desired properties was Cefotaxim, a methoxyimino-cephalosporin with a 2-imino thiazol-4-yl group, to which soon a number of very similar Methoximes with different 3-substituents, such as Ceftizoxime, cefmenoxime, ceftriaxone and ceftazidime followed. (Am. J. Med. (1985), Suppl. 2A, 14 .; Am. J. Med. (1985), Suppl. 2A, 21; Clin Pharm. (1987), 6, 59 .; Recent advances in the Chemistry of β-Lactam Antibiotics, Special publication No. 52, The Royal Society of Chemistry, London, July 1984, p. 1).
Die meisten Aminothiazolyl-Cephalosporine werden nicht aus dem
Verdauungstrakt (Gastrointestinaltrakt) absorbiert und sind
nicht oral aktiv. Cefixim ist eine solche Ausnahme mit einer
Carboxymethoxim-Gruppe mit kleinen lipophilen 3-Substituenten.
Bei der Synthese von Cefixim wird die 3-Acetoxy-Gruppe von 7-
ACA über ein 3-Phosphoniumsalz und nach der Wittig-Reaktion in
ein Vinyl-Intermediat umgewandelt, das anschließend nach einem
Standardverfahren, wie in J. Antibiotics (1985), 38, 1738,
beschrieben, in Cefixim der Formel I umgewandelt wird. Dieses
Standardverfahren weist die folgenden Schritte auf:
Most aminothiazolyl cephalosporins are not absorbed from the digestive tract (gastrointestinal tract) and are not orally active. Cefixime is one such exception with a carboxymethoxime group with small lipophilic 3 substituents. In the synthesis of cefixime, the 3-acetoxy group of 7-ACA is converted via a 3-phosphonium salt and after the Wittig reaction into a vinyl intermediate, which is then processed using a standard procedure as described in J. Antibiotics (1985), 38 , 1738, is converted to cefixime of formula I. This standard procedure has the following steps:
- - Hydrolyse des Methylesters der Formel II mit einer an organischen Base in einer wäßrigen Lösung bei 40°C über 7 Stunden- Hydrolysis of the methyl ester of formula II with an organic base in an aqueous solution at 40 ° C above 7 Hours
- - Einstellen des pH-Werts der erhaltenen Lösung auf 6,0 mit 10% HCl und Durchführen einer Säulenchromatographie auf Diaion HP-20 zur Reinigung;- Adjust the pH of the solution obtained to 6.0 with 10% HCl and perform column chromatography Diaion HP-20 for cleaning;
- - Elution der Säule mit Wasser und Ansäuern der die gewün schte Verbindung (Cefixim) enthaltenden Fraktion mit 10% HCl auf pH 2,1;- Elution of the column with water and acidification of the desired Most compound (cefixime) containing fraction with 10% HCl to pH 2.1;
- - Rühren der erhaltenen Lösung über 1 Stunde und Sammeln des Cefixim-Niederschlags durch Filtration.- Stir the solution obtained for 1 hour and collect of the cefixime precipitate by filtration.
Die Produktausbeute bei diesem Verfahren beträgt 41%. Dieses
Verfahren weist die folgenden Nachteile auf:
The product yield in this process is 41%. This method has the following disadvantages:
- - Die Reaktion wird bei erhöhter Temperatur, d. h. bei 40°C, durchgeführt, und ist nach 7 Stunden abgeschlossen. Dies führt zur Bildung vieler unerwünschter Verunreinigungen, wodurch die Reinheit des Endprodukts in der Lösung herab gesetzt wird.- The reaction is carried out at elevated temperature, i.e. H. at 40 ° C, performed, and is completed after 7 hours. This leads to the formation of many undesirable impurities, which lowers the purity of the final product in the solution is set.
- - Um die gewünschte Reinheit des Endprodukts zu erzielen, wird die Lösung einer Säulenchromatographie auf Diaion HP-20 (Harz) unterworfen.- To achieve the desired purity of the end product, is the solution of a column chromatography on diaion Subjected to HP-20 (resin).
- - Das Reinigungsverfahren umfaßt die Verwendung von Säulen chromatographie mit Diaion HP-20, die teuer und in indu strieller Hinsicht unökonomisch ist.- The cleaning process involves the use of columns chromatography with Diaion HP-20, which is expensive and in indu is economically uneconomical.
Gemäß der US-Patentschrift 440,924 wird Cefixim erhalten, in dem ein tertiärer Butylester zusammen mit anderen geschützten Substituenten wie Benzhydral und Formamid mittels Trifluoressigsäure hydrolysiert wird. Das Verfahren umfaßt eine erhöhte Anzahl komplizierter Schritte.According to U.S. Patent 440,924, cefixime is obtained in which is a tertiary butyl ester protected together with others Substituents such as benzhydral and formamide Trifluoroacetic acid is hydrolyzed. The process includes an increased number of complicated steps.
Die erfindungsgemäßen Ziele sind:
The goals of the invention are:
- - Die Reaktionszeit durch Erhöhen der Reaktionsgeschwindig keit zu verringern.- The reaction time by increasing the reaction speed decrease.
- - Die Reaktionstemperatur herabzusetzen.- to lower the reaction temperature.
- - Die Bildung unerwünschter Verunreinigungen auszuschalten und die Ausbeute zu erhöhen.- Eliminate the formation of unwanted contaminants and increase the yield.
- - Die Verwendung kostspieliger, unökonomischer Reinigungs verfahren auszuschalten und dadurch die Produktionskosten zu senken.- The use of expensive, uneconomical cleaning switch off process and thereby the production costs to lower.
- - Die Anzahl komplizierter Verfahrensschritte zu reduzie ren.- To reduce the number of complicated process steps ren.
Um die vorstehenden Ziele zu erreichen, stellt die Erfindung
ein Verfahren zur Herstellung von oral aktivem Cephalosporin-
Antibiotikum Cefixim der Formel I bereit, umfassend:
To achieve the above objectives, the invention provides a process for the preparation of orally active cephalosporin antibiotic cefixime of formula I, comprising:
- - Umsetzung des Esters der Formel II in einem organischen Lösungsmittel mit einer wäßrigen Lösung einer anorgan ischen Base in Anwesenheit eines Phasentransfer-Kataly sators (phase transfer catalyst) bei Raumtemperatur über eine Zeitspanne von 30 bis 90 Minuten;- Implementation of the ester of formula II in an organic Solvent with an aqueous solution of an inorganic base in the presence of a phase transfer catalyst sators (phase transfer catalyst) at room temperature a period of 30 to 90 minutes;
- - Absetzenlassen des erhaltenen Gemisches, bis sich die wäßrige und die organische Schicht getrennt haben;- Allow the mixture obtained to settle until the have separated aqueous and organic layers;
- - Isolieren von Cefixim mit der gewünschten Reinheit aus der wäßrigen Schicht durch Ansäuern derselben.- Isolate cefixime with the desired purity the aqueous layer by acidifying the same.
Der Ester der Formel II ist vorzugsweise ein Methylester, und
das organische Lösungsmittel ist ein halogenierter aliphati
scher Kohlenwasserstoff, vorzugsweise Methylenchlorid. Die in
dem Verfahren verwendete schwache anorganische Base ist ein
Alkalicarbonat, vorzugsweise K2CO3. Die Raumtemperatur während
der Reaktion liegt vorzugsweise zwischen 10 und 25°C, und die
Ansäuerung der wäßrigen Schicht wird mit 10% HCl auf einen pH-
Wert von 2,1 durchgeführt. Der Phasentransfer-Katalysator ver
bessert die Reaktionsbedingungen sowie die Qualität des End
produkts ohne den Einsatz von Reinigungsverfahren. Der in dem
Verfahren verwendete Phasentransfer-Katalysator stellt ein oder
mehrere quaternäre Ammoniumsalze der allgemeinen Formel R4N⁺X⁻
dar,
worin
R = n-Butyl (CH3(CH2)3-),
= n-Pentyl (CH3(CH2)4-),
= n-Hexyl (CH3(CH2)5-),
und X = Cl⁻, Br⁻, I⁻ oder OH⁻.
The ester of formula II is preferably a methyl ester and the organic solvent is a halogenated aliphatic hydrocarbon, preferably methylene chloride. The weak inorganic base used in the process is an alkali carbonate, preferably K 2 CO 3 . The room temperature during the reaction is preferably between 10 and 25 ° C, and the acidification of the aqueous layer is carried out with 10% HCl to a pH of 2.1. The phase transfer catalyst improves the reaction conditions and the quality of the end product without the use of cleaning processes. The phase transfer catalyst used in the process represents one or more quaternary ammonium salts of the general formula R 4 N⁺X⁻, wherein
R = n-butyl (CH 3 (CH 2 ) 3 -),
= n-pentyl (CH 3 (CH 2 ) 4 -),
= n-hexyl (CH 3 (CH 2 ) 5 -),
and X = Cl⁻, Br⁻, I⁻ or OH⁻.
Das quaternäre Ammoniumsalz ist ein Tetraalkylammoniumhaloge nid oder -hydroxid. Das Kation enthält lange Alkylgruppen, die eine Löslichkeit in organischen Lösungsmitteln verleihen. Das Anion ist eine Halogenid- oder eine Hydroxidgruppe, die wasserlöslich ist. Ein solches Kation transportiert das Anion (Hydroxidion) als Gegenion aus der wäßrigen Phase in die organische Phase. Dies erleichtert die Reaktion, die andern falls nur an der Interphase auftreten würde, erheblich.The quaternary ammonium salt is a tetraalkylammonium halogen nid or hydroxide. The cation contains long alkyl groups that impart solubility in organic solvents. The Anion is a halide or a hydroxide group that is water soluble. Such a cation transports the anion (Hydroxide ion) as a counter ion from the aqueous phase into the organic phase. This eases the reaction, the others if it only occurred at the interphase, considerable.
Die Erfindung wird nun unter Bezug auf die nachfolgenden Bei spiele beschrieben:The invention will now be described with reference to the following games described:
In Wasser gelöstes K2CO3 (166 mg, 1,2 mmol) wurde zu einer
gerührten Lösung aus einem Ester der Formel II (500 mg, 1,07
mmol) und Tetrabutylammoniumbromid (3,2 mg, 0,01 mmol) in
CH2Cl2 bei 20°C zugegeben. Die Reaktion war nach 40 Minuten
beendet (HPLC-Überwachung). Der pH-Wert der wäßrigen Schicht
nach der Trennung wurde mit 10% HCl auf 2,1 eingestellt, wo
durch 286 mg Cefixim der Formel I erhalten wurden. Es wurden
Versuche mit dieser Verbindung der Formel I nach Standard
verfahren durchgeführt, wobei die nachstehenden Ergebnisse
erhalten wurden:
Reinheit (HPLC) = 98,5%, [α] 25|D = -78,76°;
IR (Kbr): 1771, 1669 cm-1;
1H-NMR (DMSO-d6): δ 3,55-3,88 (2H, g, J = 17,66 Hz); 4,6
(2H, s); 5,21 (1H, d, J = 4,79 Hz); 5,32 (1H, d, J = 11,39
Hz); 5,6 (1H, d, J = 17,47 Hz); 5,81 (1H, dd, J = 4,78 Hz,
8,18 Hz); 6,81 (1H, s); 6,91 (1H, dd, J = 11,27 Hz, 17,52
Hz); 7,29 (2H, bs, D2O austauschbar);
9,61 (1H, d, J = 8,2 Hz, D2O austauschbar).K 2 CO 3 (166 mg, 1.2 mmol) dissolved in water became a stirred solution of an ester of the formula II (500 mg, 1.07 mmol) and tetrabutylammonium bromide (3.2 mg, 0.01 mmol) in CH 2 Cl 2 added at 20 ° C. The reaction was complete after 40 minutes (HPLC monitoring). The pH of the aqueous layer after the separation was adjusted to 2.1 with 10% HCl, where 286 mg of cefixime of the formula I were obtained. Experiments were carried out on this compound of formula I according to the standard procedure, the following results being obtained:
Purity (HPLC) = 98.5%, [α] 25 | D = -78.76 °;
IR (Kbr): 1771, 1669 cm -1 ;
1 H NMR (DMSO-d 6 ): δ 3.55-3.88 (2H, g, J = 17.66 Hz); 4.6 (2H, s); 5.21 (1H, d, J = 4.79 Hz); 5.32 (1H, d, J = 11.39 Hz); 5.6 (1H, d, J = 17.47 Hz); 5.81 (1H, dd, J = 4.78 Hz, 8.18 Hz); 6.81 (1H, s); 6.91 (1H, dd, J = 11.27 Hz, 17.52 Hz); 7.29 (2H, bs, D 2 O interchangeable); 9.61 (1H, d, J = 8.2 Hz, D 2 O interchangeable).
In Wasser gelöstes K2CO3 (166 mg, 1,2 mmol) wurde zu einer
gerührten Lösung aus einem Ester der Formel II (500 mg, 1,07
mmol) und Tetrahexylammoniumchlorid (3,9 mg, 0,01 mmol) in
CH2Cl2 bei 20°C zugegeben. Die Reaktion war nach 75 Minuten
beendet (HPLC-Überwachung). Der pH-Wert der wäßrigen Schicht
nach der Trennung wurde mit 10% HCl auf 2,1 eingestellt, wo
durch 297 mg Cefixim der Formel I erhalten wurden. Es wurden
Versuche mit dieser Verbindung der Formel I nach Standard
verfahren durchgeführt, wobei die nachstehenden Ergebnisse
erhalten wurden:
Reinheit (HPLC) = 98,7%, [α] 25|D = -79,52°;
IR (Kbr): 1769, 1670 cm-1;
1H-NMR (DMSO-d6): δ 3,54-3,88 (2H, g, J = 17,5 Hz); 4,59
(2H, s); 5,21 (1H, d, J = 4,76 Hz); 5,32 (1H, d, J = 17,36
Hz); 5,6 (1H, d, J = 17,48 Hz); 7,30 (2H, bs, D2O
austauschbar); 9,60 (1H, d, J = 8,15 Hz, D2O austauschbar).K 2 CO 3 (166 mg, 1.2 mmol) dissolved in water became a stirred solution of an ester of the formula II (500 mg, 1.07 mmol) and tetrahexylammonium chloride (3.9 mg, 0.01 mmol) in CH 2 Cl 2 added at 20 ° C. The reaction was complete after 75 minutes (HPLC monitoring). The pH of the aqueous layer after the separation was adjusted to 2.1 with 10% HCl, where 297 mg of cefixime of the formula I were obtained. Experiments were carried out on this compound of formula I according to the standard procedure, the following results being obtained:
Purity (HPLC) = 98.7%, [α] 25 | D = -79.52 °;
IR (Kbr): 1769, 1670 cm -1 ;
1 H NMR (DMSO-d 6 ): δ 3.54-3.88 (2H, g, J = 17.5 Hz); 4.59 (2H, s); 5.21 (1H, d, J = 4.76 Hz); 5.32 (1H, d, J = 17.36 Hz); 5.6 (1H, d, J = 17.48 Hz); 7.30 (2H, bs, D 2 O interchangeable); 9.60 (1H, d, J = 8.15 Hz, D 2 O interchangeable).
Claims (9)
- - Umsetzung eines Esters der Formel II in einem organischen Lösungsmittel mit einer wäßrigen Lösung einer anorgan ischen Base in Anwesenheit eines Phasentransfer-Kataly sators bei Raumtemperatur über eine Zeitspanne von 30 bis 90 Minuten;
- - Absetzenlassen des erhaltenen Gemisches, bis sich die wäßrige und die organische Schicht getrennt haben;
- - Isolieren von Cefixim mit der erforderlichen Reinheit aus der wäßrigen Schicht durch Ansäuern derselben.
- - Reaction of an ester of formula II in an organic solvent with an aqueous solution of an inorganic base in the presence of a phase transfer catalyst at room temperature over a period of 30 to 90 minutes;
- Allowing the resulting mixture to settle until the aqueous and organic layers have separated;
- Isolate cefixime with the required purity from the aqueous layer by acidifying it.
R = n-Butyl (CH3(CH2)3-),
= n-Pentyl (CH3(CH2)4-),
= n-Hexyl (CH3(CH2)5-),
und X = Cl⁻, Br⁻, I⁻ oder OH⁻
darstellt.8. The method according to claim 1, wherein the phase transfer catalyst quaternary ammonium salts of the general formula R 4 N⁺X⁻, wherein
R = n-butyl (CH 3 (CH 2 ) 3 -),
= n-pentyl (CH 3 (CH 2 ) 4 -),
= n-hexyl (CH 3 (CH 2 ) 5 -),
and X = Cl⁻, Br⁻, I⁻ or OH⁻
represents.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PT102062A PT102062B (en) | 1997-10-08 | 1997-10-08 | PROCESS OF PREPARATION OF AN ANTIBIOTIC CEFALOSPORINA ORAL ACTIVE-CEFIXIME |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE19846449A1 true DE19846449A1 (en) | 1999-04-15 |
Family
ID=20085703
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19846449A Withdrawn DE19846449A1 (en) | 1997-10-08 | 1998-10-08 | Process for the preparation of orally active cephalosporin antibiotic cefixime |
Country Status (4)
| Country | Link |
|---|---|
| DE (1) | DE19846449A1 (en) |
| ES (1) | ES2155349B1 (en) |
| GB (1) | GB2330141A (en) |
| PT (1) | PT102062B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006067806A1 (en) * | 2004-12-21 | 2006-06-29 | Lupin Limited | Process for the preparation of cefixime |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6800755B2 (en) * | 2002-10-24 | 2004-10-05 | Orchid Chemicals And Pharmaceuticals Limited | Process for the preparation of cefixime |
| EP1863822B1 (en) | 2005-03-29 | 2009-10-14 | Hetero Drugs Limited | An improved process for the preparation of cefixime |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9424847D0 (en) * | 1994-12-09 | 1995-02-08 | Smithkline Beecham Plc | Novel process |
-
1997
- 1997-10-08 PT PT102062A patent/PT102062B/en not_active IP Right Cessation
-
1998
- 1998-10-08 ES ES009802177A patent/ES2155349B1/en not_active Expired - Fee Related
- 1998-10-08 DE DE19846449A patent/DE19846449A1/en not_active Withdrawn
- 1998-10-08 GB GB9821967A patent/GB2330141A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006067806A1 (en) * | 2004-12-21 | 2006-06-29 | Lupin Limited | Process for the preparation of cefixime |
| US8008478B2 (en) | 2004-12-21 | 2011-08-30 | Lupin Limited | Process for the preparation of cefixime |
Also Published As
| Publication number | Publication date |
|---|---|
| PT102062B (en) | 2000-08-31 |
| PT102062A (en) | 1998-06-30 |
| ES2155349B1 (en) | 2001-12-01 |
| ES2155349A1 (en) | 2001-05-01 |
| GB2330141A (en) | 1999-04-14 |
| GB9821967D0 (en) | 1998-12-02 |
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