AT381495B - METHOD FOR PRODUCING CEPHALOSPORINE DERIVATIVES - Google Patents
METHOD FOR PRODUCING CEPHALOSPORINE DERIVATIVESInfo
- Publication number
- AT381495B AT381495B AT0105584A AT105584A AT381495B AT 381495 B AT381495 B AT 381495B AT 0105584 A AT0105584 A AT 0105584A AT 105584 A AT105584 A AT 105584A AT 381495 B AT381495 B AT 381495B
- Authority
- AT
- Austria
- Prior art keywords
- formula
- general formula
- compounds
- het
- alcohol
- Prior art date
Links
- HOKIDJSKDBPKTQ-UHFFFAOYSA-N 3-(acetyloxymethyl)-7-[(5-amino-5-carboxypentanoyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical class S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C(NC(=O)CCCC(N)C(O)=O)C12 HOKIDJSKDBPKTQ-UHFFFAOYSA-N 0.000 title 1
- 238000004519 manufacturing process Methods 0.000 title 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 230000002378 acidificating effect Effects 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 7
- -1 D-2-Hydroxy-2-- cephem-4-carboxylic acid Chemical compound 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- OLVCFLKTBJRLHI-AXAPSJFSSA-N cefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](O)C=3C=CC=CC=3)[C@H]2SC1 OLVCFLKTBJRLHI-AXAPSJFSSA-N 0.000 description 4
- 229960003012 cefamandole Drugs 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 238000005809 transesterification reaction Methods 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 230000006198 deformylation Effects 0.000 description 2
- 238000006344 deformylation reaction Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- RRJHESVQVSRQEX-SUYBPPKGSA-N O-formylcefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](OC=O)C=3C=CC=CC=3)[C@H]2SC1 RRJHESVQVSRQEX-SUYBPPKGSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- DYAIAHUQIPBDIP-AXAPSJFSSA-N cefonicid Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)[C@H](O)C=2C=CC=CC=2)CC=1CSC1=NN=NN1CS(O)(=O)=O DYAIAHUQIPBDIP-AXAPSJFSSA-N 0.000 description 1
- 229960004489 cefonicid Drugs 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- LKHYFCSSVZVVNF-UHFFFAOYSA-N ethyl hexanoate;sodium Chemical compound [Na].CCCCCC(=O)OCC LKHYFCSSVZVVNF-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- RPACBEVZENYWOL-XFULWGLBSA-M sodium;(2r)-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate Chemical compound [Na+].C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)[O-])CO1 RPACBEVZENYWOL-XFULWGLBSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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
-
- 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
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Description
<Desc/Clms Page number 1>
Die Erfindung betrifft ein neues Verfahren zur Herstellung von 7- (D-2-Hydroxy-2-phenyl)-acet- amido-3-cephem-4-carbonsäurederivaten der allgemeinen Formel
EMI1.1
worin Rl für Wasserstoff,-O. CO. CH,, S-Het oder unsubstituiertes, substituiertes oder heterocyclisches anelliertes Pyridinium steht, wobei Het einen Heterocyclus bedeutet, durch Deformylierung von Verbindungen der Formel
EMI1.2
worin Rl obige Bedeutung besitzt. Die dabei enthaltenen Verbindungen der Formel (I) und deren
EMI1.3
B. 7- (D-2-Hydroxy-2-- cephem-4-carbonsäure (= Cefonicid).
Beispielsweise steht Het für einen Heterocyclus der Formel
EMI1.4
worin R3 eine niedere Alkylgruppe bedeutet.
Die Herstellung dieser Verbindungen der allgemeinen Formel (I) wird üblicherweise so durchgeführt, dass man die entsprechende 7-Aminocephalosporansäure der allgemeinen Formel
EMI1.5
worin Rl obige Bedeutung besitzt, mit dem an der Hydroxylgruppe der Mandelsäure formylierten (Schutzgruppe) Säurechlorid der Formel
<Desc/Clms Page number 2>
EMI2.1
umsetzt und dadurch zu Verbindungen der allgemeinen Formel (II) gelangt. Um nun die Schutzgruppe (Formylgruppe) zu entfernen, wird üblicherweise in wässeriger, schwach alkalischer Lösung verseift, wie z. B. in der DE-PS Nr. 2018600 beschrieben. Dabei kommt es teilweise zur Bildung von Neben- und Zersetzungsprodukten und meist zu einer Dunkelverfärbung der Reaktionslösung. Ausserdem werden meist lange Reaktionszeiten bei Temperaturen über Raumtemperatur benötigt.
Cephalosporinderivate sind bekannterweise im alkalischen Bereich instabil. Auch im schwach alkalischen Milieu, wie es zur Verseifung des Ameisensäureesters der Formel (II) angewendet wird (PH-Werte : 8 bis 9), sind sie bedeutend instabiler als im schwach sauren Bereich. Das erfindungsgemässe Verfahren, das auf einer schonenden Umesterung des Ameisensäureesters der allgemeinen Formel (II) mit einem aliphatischen Alkohol der allgemeinen Formel HO-R, (V) worin R2 für eine niedere, geradkettige oder verzweigte Alkylgruppe steht, beruht, wird im sauren Milieu unter schonenden Bedingungen durchgeführt, wie das folgende Reaktionsschema zeigt :
EMI2.2
Das erfindungsgemässe Verfahren erlaubt eine schnelle, schonende und nahezu quantitative Herstellung von Verbindungen der Formel (I) aus Verbindungen der Formel (II), wobei durch die schonenden Bedingungen im sauren Milieu praktisch keine Nebenprodukt- und/oder Farbstoffbildung auftritt, was einen erheblichen Vorteil gegenüber der alkalischen Verseifung, wie sie in DE-PS Nr. 2018600 beschrieben wird, darstellt.
Das erfindungsgemässe Verfahren ist dadurch gekennzeichnet, dass man Verbindungen der allgemeinen Formel (II) in einem Alkohol der allgemeinen Formel (V) löst, mit einer Säure oder einem Ionenaustauscher versetzt und unter diesen Bedingungen die Verbindungen der allgemeinen Formel
<Desc/Clms Page number 3>
(I) herstellt.
Die Umsetzung erfolgt üblicherweise im Überschuss des als Reaktionspartner nötigen Alkohols der Formel (V) als Lösungsmittel. Als Alkohole der Formel (V) eignen sich aliphatische Alkohole mit 1 bis 4 C-Atomen, wobei die aliphatische Kette verzweigt sein kann. Bevorzugte Alkohole sind Methanol, Äthanol und Isopropanol, vorzugsweise wird Methanol verwendet.
Als Säure zur Katalyse der Umesterung können starke organische oder Mineralsäuren verwendet werden. Bevorzugte Säure ist konzentrierte Salzsäure. Vorzugsweise wird das Verfahren unter Verwendung eines sauren Ionenaustauschers, beispielsweise von Dowex 50 WX 4, durchgeführt.
Die Temperatur der Umesterung ist nicht kritisch und liegt bevorzugt zwischen -10 und +50 C, vorzugsweise bei Raumtemperatur.
In den folgenden Beispielen, die die Erfindung näher erläutern, ihren Umfang jedoch in keiner Weise einschränken sollen, erfolgen alle Temperaturangaben in Celsiusgraden.
Beispiel 1 : 7- (D-2-Hydroxy-2-phenyl)-acetamido-3- [ (l-methyl-lH-tetrazol-5-yl)-thiomethyl]- - 3-cephem-4-carbonsäure. Natriumsalz (Cefamandol-Na) : 9, 8 g Cefamandolnafat (O-Formylcefamandol-Na) werden in 60 ml Methanol gelöst. Diese Lösung wird bei Raumtemperatur unter gutem Rühren mit 1 ml konzentrierter Salzsäure versetzt. Die Lösung wird dann 40 bis 50 min bei Raumtemperatur stehengelassen, wobei quantitative Entformylierung erfolgt. Die Isolierung des gebildeten Cefamandol kann auf an sich bekannte Weise erfolgen, z. B. wie in DE-PS Nr. 2018600 beschrieben. Dazu wird die Reaktionslösung mit einer Lösung von 3 g Na-Acetat in 30 ml Methanol versetzt und das Na-Salz des Cefamandol durch Fällung mit 250 ml Isopropanol abgeschieden.
Man erhält auf diese Weise 8, 8 g des Natriumsalzes der Titelverbindung in Form eines weissen Pulvers (91% Ausbeute), dessen spektroskopische Daten mit der Literatur übereinstimmen.
Beispiel 2 : 7- (D-2-Hydroxy-2-phenyl)-acetamido-3- [ (l-sulfomethyltetrazol-5-yl)-thiomethyl]- - 3-cephem-4-carbonsäure. Dinatriumsalz (eefonicid)
11, 8 g 7- (D-2-Formyloxy-2-phenylacetamido)-3- (l-sulfomethyl-lH-tetrazol-5-yl-thiomethyl)- - 3-cephem-4-carbonsäure-mono-natriumsalz werden in 100 ml Methanol gelöst und mit 2 ml konzentrierter Hel versetzt. Die Lösung wird 30 min bei 300 gehalten, wobei quantitative Entformylierung eintritt. Der PH-Wert des Reaktionsgemisches wird dann mit 5N NaOH auf 2,5 eingestellt und das Reaktionsgemisch daraufhin im Vakuum auf etwa 50 ml eingeengt, filtriert und dann unter gutem Rühren zu 700 ml Isopropanol getropft.
Der dabei abgeschiedene Feststoff wird abfiltriert, mit Isopropanol gewaschen und im Vakuum getrocknet. Man erhält auf diese Weise 10, 9 g der Titelverbindung mit einem Wassergehalt von etwa 4% (Ausbeute : 93%).
EMI3.1
: 7- (D-2-Hydroxy-2-phenyl)-acetamido-3- [ (l-methyl-lH-tetrazol-5-yD-thiomethyl]-4, 9 g O-Formylcefamandol werden in 30 ml Methanol gelöst. Man gibt 5 g Dowex 50 WX 4 (ein stark saurer Ionenaustauscher in der -Form) zu und rührt 1 h bei 20 , wonach laut DC-Kontrolle die Entformylierung beendet ist. Der Ionenaustauscher wird abfiltriert, mit etwas Methanol nachgewaschen und die vereinigten Filtrate am Rotavapor auf 20 ml eingeengt. Durch Zugabe von 11 ml einer einmolaren Lösung von Natriumäthylhexanoat in Isopropanol wird das Natriumsalz des Cefamandols ausgefällt.
Zur Erhöhung der Ausbeute werden noch 50 ml Isopropanol zugegeben (Ausbeute : 93%).
**WARNUNG** Ende DESC Feld kannt Anfang CLMS uberlappen**.
<Desc / Clms Page number 1>
The invention relates to a new process for the preparation of 7- (D-2-hydroxy-2-phenyl) -acetamido-3-cephem-4-carboxylic acid derivatives of the general formula
EMI1.1
wherein Rl is hydrogen, -O. CO. CH ,, S-Het or unsubstituted, substituted or heterocyclic fused pyridinium, where Het is a heterocycle, by deformylation of compounds of the formula
EMI1.2
where Rl has the above meaning. The compounds of formula (I) contained therein and their
EMI1.3
B. 7- (D-2-Hydroxy-2-- cephem-4-carboxylic acid (= cefonicid).
For example, Het stands for a heterocycle of the formula
EMI1.4
wherein R3 represents a lower alkyl group.
The preparation of these compounds of general formula (I) is usually carried out in such a way that the corresponding 7-aminocephalosporanic acid of the general formula
EMI1.5
wherein Rl has the above meaning, with the (protecting group) acid chloride of the formula formylated on the hydroxyl group of mandelic acid
<Desc / Clms Page number 2>
EMI2.1
reacted and thereby obtained compounds of general formula (II). In order to remove the protective group (formyl group), it is usually saponified in aqueous, weakly alkaline solution, such as. B. described in DE-PS No. 2018600. This sometimes leads to the formation of by-products and decomposition products and usually to a dark discoloration of the reaction solution. In addition, long reaction times at temperatures above room temperature are usually required.
Cephalosporin derivatives are known to be unstable in the alkaline range. Even in a weakly alkaline environment, such as is used to saponify the formic acid ester of the formula (II) (pH values: 8 to 9), they are significantly more unstable than in the weakly acidic range. The process according to the invention, which is based on a gentle transesterification of the formic acid ester of the general formula (II) with an aliphatic alcohol of the general formula HO-R, (V) in which R2 represents a lower, straight-chain or branched alkyl group, is carried out in an acidic environment gentle conditions, as the following reaction scheme shows:
EMI2.2
The process according to the invention allows a rapid, gentle and almost quantitative preparation of compounds of the formula (I) from compounds of the formula (II), with the gentle conditions in the acidic medium virtually no by-product and / or dye formation, which is a considerable advantage compared to the alkaline saponification as described in DE-PS No. 2018600.
The process according to the invention is characterized in that compounds of the general formula (II) are dissolved in an alcohol of the general formula (V), mixed with an acid or an ion exchanger and under these conditions the compounds of the general formula
<Desc / Clms Page number 3>
(I) produces.
The reaction is usually carried out in excess of the alcohol of the formula (V) required as a reactant as a solvent. Suitable alcohols of the formula (V) are aliphatic alcohols having 1 to 4 carbon atoms, it being possible for the aliphatic chain to be branched. Preferred alcohols are methanol, ethanol and isopropanol, preferably methanol is used.
Strong organic or mineral acids can be used as the acid to catalyze the transesterification. The preferred acid is concentrated hydrochloric acid. The process is preferably carried out using an acidic ion exchanger, for example Dowex 50 WX 4.
The temperature of the transesterification is not critical and is preferably between -10 and +50 C, preferably at room temperature.
In the following examples, which explain the invention in more detail but are not intended to restrict its scope in any way, all the temperatures are given in degrees Celsius.
Example 1: 7- (D-2-Hydroxy-2-phenyl) acetamido-3- [(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid. Sodium salt (cefamandol-Na): 9.8 g of cefamandol nafate (O-formyl cefamandol-Na) are dissolved in 60 ml of methanol. This solution is mixed with 1 ml of concentrated hydrochloric acid at room temperature with thorough stirring. The solution is then left to stand at room temperature for 40 to 50 min, quantitative quantification taking place. The cefamandole formed can be isolated in a manner known per se, e.g. B. as described in DE-PS No. 2018600. For this purpose, a solution of 3 g of Na acetate in 30 ml of methanol is added to the reaction solution, and the Na salt of cefamandol is separated off by precipitation with 250 ml of isopropanol.
In this way, 8.8 g of the sodium salt of the title compound are obtained in the form of a white powder (91% yield), the spectroscopic data of which correspond to the literature.
Example 2: 7- (D-2-Hydroxy-2-phenyl) acetamido-3- [(l-sulfomethyltetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid. Disodium salt (eefonicid)
11.8 g of 7- (D-2-formyloxy-2-phenylacetamido) -3- (l-sulfomethyl-lH-tetrazol-5-yl-thiomethyl) - - 3-cephem-4-carboxylic acid monosodium salt are added in Dissolved 100 ml of methanol and mixed with 2 ml of concentrated Hel. The solution is kept at 300 for 30 minutes, with quantitative demolding occurring. The pH of the reaction mixture is then adjusted to 2.5 with 5N NaOH and the reaction mixture is then concentrated in vacuo to about 50 ml, filtered and then added dropwise to 700 ml of isopropanol with good stirring.
The solid which has separated out is filtered off, washed with isopropanol and dried in vacuo. This gives 10.9 g of the title compound with a water content of about 4% (yield: 93%).
EMI3.1
: 7- (D-2-Hydroxy-2-phenyl) acetamido-3- [(1-methyl-1H-tetrazol-5-yD-thiomethyl] -4.9 g of O-formyl cefamandole are dissolved in 30 ml of methanol. 5 g of Dowex 50 WX 4 (a strongly acidic ion exchanger in the form) are added and the mixture is stirred at 20 for 1 h, after which the deformylation has ended, according to the DC control The Rotavapor was concentrated to 20 ml and the sodium salt of cefamandole was precipitated by adding 11 ml of a one-molar solution of sodium ethylhexanoate in isopropanol.
To increase the yield, 50 ml of isopropanol are added (yield: 93%).
** WARNING ** End of DESC field may overlap beginning of CLMS **.
Claims (1)
Priority Applications (22)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT0105584A AT381495B (en) | 1984-03-29 | 1984-03-29 | METHOD FOR PRODUCING CEPHALOSPORINE DERIVATIVES |
| EP85810122A EP0156771A3 (en) | 1984-03-29 | 1985-03-22 | Cephalosporins |
| AU42340/85A AU587974B2 (en) | 1984-03-29 | 1985-03-23 | Process for preparation of cephalosporins |
| HU852157D HU196213B (en) | 1984-03-29 | 1985-03-23 | Process for producing cephalosporin derivatives and pharmaceutical compositions containing them |
| HU88505A HU202537B (en) | 1984-03-29 | 1985-03-23 | Process for producing cefemcarboxylic acid derivatives |
| JP60501842A JPS61501634A (en) | 1984-03-29 | 1985-03-23 | Cephalosporins |
| PCT/EP1985/000122 WO1985004404A1 (en) | 1984-03-29 | 1985-03-23 | Cephalosporins |
| PH32055A PH21445A (en) | 1984-03-29 | 1985-03-26 | Process for producing cephalosporin derivatives of the type cefamandel and cefonicid |
| NZ22513485A NZ225134A (en) | 1984-03-29 | 1985-03-27 | Thiomeandelic acid esters |
| NZ211594A NZ211594A (en) | 1984-03-29 | 1985-03-27 | The preparation of certain cephalosporin derivatives |
| ES541687A ES8706154A1 (en) | 1984-03-29 | 1985-03-28 | Cephalosporins. |
| IL74751A IL74751A (en) | 1984-03-29 | 1985-03-28 | Preparation of cephalosporins |
| ZA852420A ZA852420B (en) | 1984-03-29 | 1985-03-29 | Cephalosporins |
| FI854577A FI81805C (en) | 1984-03-29 | 1985-11-20 | ETT NYTT FOERFARANDE FOER FRAMSTAELLNING AV CEFALOSPORINER SAMT I FOERFARANDET ANVAENDBARA MELLANPRODUKTER. |
| DK552785A DK552785A (en) | 1984-03-29 | 1985-11-28 | PROCEDURE FOR MANUFACTURING CEPHALOSPORINES |
| ES555561A ES8706696A1 (en) | 1984-03-29 | 1986-05-30 | Cephalosporins. |
| ES555562A ES8706697A1 (en) | 1984-03-29 | 1986-05-30 | Cephalosporins. |
| CA000527644A CA1277667C (en) | 1984-03-29 | 1987-01-19 | Thioester acylating agents for the production of cephalosporins |
| IL87602A IL87602A0 (en) | 1984-03-29 | 1988-08-30 | Mandelic acid derivatives and their preparation |
| FI884800A FI82472C (en) | 1984-03-29 | 1988-10-18 | Process for the preparation of cephalosporin |
| FI884801A FI884801A0 (en) | 1984-03-29 | 1988-10-18 | FOERFARANDE FOER FRAMSTAELLNING AV EN FOERENING, VILKEN KAN ANVAENDAS SOM MELLANPRODUKT FOER FRAMSTAELLNING AV KEFALOSPORINER. |
| AU35994/89A AU3599489A (en) | 1984-03-29 | 1989-06-02 | Cephalosporins |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT0105584A AT381495B (en) | 1984-03-29 | 1984-03-29 | METHOD FOR PRODUCING CEPHALOSPORINE DERIVATIVES |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| ATA105584A ATA105584A (en) | 1986-03-15 |
| AT381495B true AT381495B (en) | 1986-10-27 |
Family
ID=3505605
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AT0105584A AT381495B (en) | 1984-03-29 | 1984-03-29 | METHOD FOR PRODUCING CEPHALOSPORINE DERIVATIVES |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPS61501634A (en) |
| AT (1) | AT381495B (en) |
| HU (1) | HU202537B (en) |
| ZA (1) | ZA852420B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4856795B2 (en) * | 2004-07-05 | 2012-01-18 | オーキッド ケミカルズ アンド ファーマシューティカルズ リミテッド | Novel salts in the production of cephalosporin antibiotics. |
-
1984
- 1984-03-29 AT AT0105584A patent/AT381495B/en not_active IP Right Cessation
-
1985
- 1985-03-23 JP JP60501842A patent/JPS61501634A/en active Pending
- 1985-03-23 HU HU88505A patent/HU202537B/en not_active IP Right Cessation
- 1985-03-29 ZA ZA852420A patent/ZA852420B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA852420B (en) | 1986-11-26 |
| HU202537B (en) | 1991-03-28 |
| ATA105584A (en) | 1986-03-15 |
| JPS61501634A (en) | 1986-08-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE2018600B2 (en) | 3-thiadiazolyl mercaptomethyl and tetrazolyl mercaptomethyl cephalosporins and processes for their preparation | |
| CH650503A5 (en) | METHOD FOR PRODUCING (AMINOTHIAZOLYL) ACETIC ACID ESTERS. | |
| AT381495B (en) | METHOD FOR PRODUCING CEPHALOSPORINE DERIVATIVES | |
| DE69233042T2 (en) | Preparation of a cephalosporin antibiotic using the syn isomer of a thiazolyl intermediate | |
| DE2804040C3 (en) | Process for the preparation of cephem compounds | |
| CH615184A5 (en) | ||
| EP0185679B1 (en) | Intermediary products of cephalosporine, preparation process thereof and utilization thereof | |
| CH609700A5 (en) | Process for the preparation of cephalosporin derivatives | |
| DE2451931A1 (en) | 7BETA-ACYLAMIDO-7ALPHA-METHOXYCEPHALOSPORINE AND THE METHOD FOR MANUFACTURING IT | |
| DE2151530C3 (en) | Process for the preparation of 7-aminocephalosporanic acids | |
| DE2602099C3 (en) | Process for the preparation of 7- (4-carboxybutanamido) -cephalosporanic acid derivatives | |
| DE2412598C2 (en) | Process for the production of 7-alkoxycephalosporins or 6-alkoxypenicillins | |
| CH617201A5 (en) | ||
| DD201303A5 (en) | PROCESS FOR THE PREPARATION OF BISTETRAZOLMETHYLTHIOLS | |
| DE3013545C2 (en) | ||
| DE3212613C2 (en) | ||
| DE3721305A1 (en) | 6-TRIFLUORMETHYL-1H-BENZOTRIAZOL-1-YL-DIPHENYLPHOSPHATE AND ITS USE FOR PRODUCING CEPHALOSPORINE DERIVATIVES | |
| CH618702A5 (en) | ||
| DE2841363C2 (en) | ||
| AT363185B (en) | METHOD FOR PRODUCING NEW 3,7-DISUBSTITUTED 3-CEPHEM-4-CARBONIC ACID COMPOUNDS | |
| AT369745B (en) | METHOD FOR PRODUCING CEPHEMIC COMPOUNDS | |
| DE2215048A1 (en) | PROCESS FOR THE MANUFACTURING OF 2-ANGULAR CLAMP ON UP TO (4 ', 4 "-DIALKYLAMINO) BENZHYDRYL ANGLE CLAMP TO -5-AMINOBENZOIC ACID | |
| AT387779B (en) | METHOD FOR PRODUCING A NEW CRYSTALLINE, STABLE FORM OF THE SYN-ISOMER OF (6R, 7R) -7 - ((2- (2-AMINO-4-THIAZOLYL) - (Z) -2- (1-TE T.BUTOXYCARBONYL- 1-METHYLETHOXY) IMINO) ACETAMIDO -3- (1-PYRIDINIUMMETHYL) -3-CEPHEM-4-CARBOXYLATS | |
| AT275034B (en) | Process for the preparation of new derivatives of 7-aminocephalosporanic acid | |
| AT382149B (en) | Process for the preparation of syn isomers of thioacetic esters |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| ELJ | Ceased due to non-payment of the annual fee | ||
| UEP | Publication of translation of european patent specification |