DE1966203B2 - 23-Dioxo-4- (R ', R ") - aminomethylpyrrolidines and process for their preparation - Google Patents
23-Dioxo-4- (R ', R ") - aminomethylpyrrolidines and process for their preparationInfo
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- DE1966203B2 DE1966203B2 DE1966203A DE1966203A DE1966203B2 DE 1966203 B2 DE1966203 B2 DE 1966203B2 DE 1966203 A DE1966203 A DE 1966203A DE 1966203 A DE1966203 A DE 1966203A DE 1966203 B2 DE1966203 B2 DE 1966203B2
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Description
N-HN-H
in der R' und R" Alkyl- oder Aralkylreste darstellen oder zusammen einen Morpholinrest bilden.in which R 'and R "represent alkyl or aralkyl radicals or together form a morpholine residue.
2. Verfahren zur Herstellungder Verbindungen gemäß Anspruch 1, dadurch gekennzeichnet, daß man den 2,3-Dioxo-pyrrolidin-4-carbonsäurebenzylester der Enolformel2. Process for the preparation of the compounds according to Claim 1, characterized in that the 2,3-dioxopyrrolidine-4-carboxylic acid benzyl ester the enol formula
HOHO
LUU- LH,— L„ H5 LUU- LH, - L "H 5
Ν — ΗΝ - Η
einer katalytischen Hydrierung unterwirft, wonach man das ent^.echende 4-Carboxylderivat der For- jo metsubjected to a catalytic hydrogenation, after which the ent ^ .echende 4-carboxyl derivative of the formula jo met
COOH
HOCOOH
HO
J-N- HY-N-H
erhält, das man einer Aminomethylierung nach 4i> Mannich unterwirft und das entsprechende Aminomethylpyrrolidin isoliert.obtained that one aminomethylation after 4i> Mannich submits and the corresponding aminomethylpyrrolidine isolated.
Die Erfindung betrifft 2,3-Dioxo-4-(R',R")-aminomethylpyrrolidine der allgemeinen FormelThe invention relates to 2,3-dioxo-4- (R ', R ") - aminomethylpyrrolidines the general formula
IK)IK)
CH2 NCH 2 N
N HN H
den 2t3-Dioxo-pyrrolidin-4-carbonsäure-benzylester der Enolformelthe 2 t 3-dioxopyrrolidine-4-carboxylic acid benzyl ester of the enol formula
COO—CH,- 0,H5 HO ICOO-CH, -0, H 5 HO I
einer katalytischen Hydrierung unterwirft, wonach man das entsprechende 4-Carboxylderivat der Formelsubjected to a catalytic hydrogenation, after which one the corresponding 4-carboxyl derivative of the formula
JIl HO JIl HO
COOHCOOH
Ν—ΗΝ — Η
erhält, das man einer Aminomethylierung nach Mannich unterwirft und das entsprechende Aminomethyl-pyrrolidin isoliert.obtained, which is subjected to an aminomethylation according to Mannich and the corresponding aminomethyl-pyrrolidine isolated.
Das erfindungsgemäße Verfahren, wie es oben definiert wurde, umfaßt insbesondere eine bemerkenswerte, nicht naheliegende Phase:The method according to the invention, as defined above, comprises in particular a remarkable, not obvious phase:
Die Hydrogenolyse des 2,3-Dioxo-pyrrolidin-4-carbonsäurebenzylesters der Enolformel durch katalytische Hydrierung, die die 3,4-Doppelbindung bestehen läßt, wobei dieser Hydrogenolyse eine Decarboxylierung im Milieu der Aminomethylierung folgt.The hydrogenolysis of the 2,3-dioxopyrrolidine-4-carboxylic acid benzyl ester the enol formula by catalytic hydrogenation, which consist of the 3,4 double bond leaves, this hydrogenolysis being followed by decarboxylation in the aminomethylation environment.
Man beachte, daß im Falle eines in !-Stellung befindlichen Wasserstoffatoms die einfache Eliminierung der Carboxylgruppe, die für die Schaffung einer aktivierten Methylengruppe Mäher alkylierbzr) in der 4-Stellung nützlich ist, bishc nicht durchgeführt werden konnte, ohne die heterocyclische Verkettung zu zerbrechen [vergi. Southwick et coll., J. Org. 21, 1086 (1956)]. Note that in the case of a hydrogen atom in the! Position, the simple elimination of the carboxyl group, which is useful for creating an activated methylene group in the 4-position, could not be carried out without breaking the heterocyclic chain [ forget Southwick et coll., J. Org. 21, 1086 (1956)].
Die beim erfindungsgemäßen Verfahren einzusetzenden Ausgangsstoffe werden gemäß Patent 19 32 504 hergestellt, indem man eine Aminosäure der FormelThe starting materials to be used in the process according to the invention are according to Patent 19 32 504 made by taking an amino acid of the formula
H2N-CH2-CH2-COOHH 2 N-CH 2 -CH 2 -COOH
mit Benzylalkohol in Gegenwart einer Säure der allgemeinen Formel HX umsetzt, in der X ein Halogen-, Schwefelsäure- oder Sulfonsäure-Anion darstellt, das erhaltene Estersalz der allgemeinen Formelwith benzyl alcohol in the presence of an acid of the general formula HX, in which X is a halogen, Sulfuric acid or sulfonic acid anion represents the obtained Ester salt of the general formula
X H1N-CH2-CH2 COO-CH2-Q1H,XH 1 N-CH 2 -CH 2 COO-CH 2 -Q 1 H,
mit einem Oxalsäurealkyl- oder -aralkylester kondensiert, wobei man den gewünschten 2,3-Dioxo-pyrrolidin-,-, 4-carbonsäure-benzylester der Enolformelcondensed with an alkyl or aralkyl oxalate, whereby the desired 2,3-dioxopyrrolidine -, -, 4-carboxylic acid benzyl ester of the enol formula
in der R' und R" Alkyl- oder Aralkylreste darstellen oder zusammen einen Morpholinrest bilden.in which R 'and R "represent alkyl or aralkyl radicals or together form a morpholine radical.
Diese Verbindungen eignen sich zur vorteilhaften Herstellung von neuen Cephalosporinvorprodukten gemäß Patent 19 32 504, die dann zu den neuen Cephalosporinendprodukten gemäß Patent 19 32 505 führen. Wie dort ausgeführt, besitzen diese Cephalosporinderivate interessante antibiotische Eigenschaften.These compounds are suitable for the advantageous production of new cephalosporin precursors according to patent 19 32 504, which then becomes the new cephalosporin end products according to patent 19 32 505 to lead. As stated there, these cephalosporin derivatives have interesting antibiotic properties.
Das erfindungsgemäße Verfahren zur Herstellung der 2,3-Dioxo-4-(R',R")-aminomethyl-pyrrolidine der angegegebenen Formel ist dadurch gekennzeichnet, daß man HOThe process according to the invention for the preparation of the 2,3-dioxo-4- (R ', R ") - aminomethyl-pyrrolidines of the specified Formula is characterized in that one HO
COO-CH2-CH5 COO-CH 2 -CH 5
Ν — ΗΝ - Η
erhält.receives.
Eine bevorzugte Ausführungsform des erfindungsgemäßen Verfahrens kann im einzelnen durch die folgenden Punkte gekennzeichnet werden:A preferred embodiment of the method according to the invention can be characterized in detail by the following points:
Die Hydrogenolyse des J^-Dioxo-pyrrolidin^-carbonsäurebenzylesters der Enolforme! wird in Gegenwart eines Hydrierkatalysators auf der Basis von Palladium oder Platin durchgeführt Die Aminomethylierung des Produktes der Hydrogenolyse wird durch Einwirkung von Formaldehyd und den? Hydrochlorid des gewählten Amins durchgeführt, wobei man in chlorwasserstoffsaurem Milieu arbeitet Als Beispiele für Amine seien Morphoün, Dimethylamin oder Diäthylamin ge- ι ο nanntThe hydrogenolysis of the I ^ -dioxo-pyrrolidin ^ -carboxylic acid benzyl ester the enol form! is carried out in the presence of a hydrogenation catalyst based on palladium or platinum The aminomethylation of the product of hydrogenolysis is caused by the action of formaldehyde and the? Hydrochloride of the chosen amine carried out, working in a hydrochloric acid medium. Examples of amines are Morphoün, dimethylamine or diethylamine ge ι ο called
Das folgende Beispiel erläutert die Erfindung:The following example explains the invention:
C 41,96, H 3,52, N 9,79%, C 41,7, H 3,8, M 9,9%.C 41.96, H 3.52, N 9.79%, C 41.7, H 3.8, M 9.9%.
Soweit bekannt, ist diese Verbindung in der Literatur nicht beschrieben.As far as is known, this connection is in the literature not described.
2. Stufe2nd stage
Hydrochlorid des 2,3-Dioxo-4-morpholino-methylpyrrolidins 2,3-Dioxo-4-morpholino-methylpyrrolidine hydrochloride
mit R'+R" = CH2CH2-O-CH2-CH2 with R '+ R "= CH 2 CH 2 -O-CH 2 -CH 2
Man fügt 2 Tropfen ln-Chlorwasserstoffsäure zu 10 ecm einer Morpholin-hydrochloridlösung, die durch Neutralisation von 8,71 g Morphoün mit konzentrierter Chlorwasserstoffsäure und Zugabe von 50 ecm Wasser hergestellt worden war. Man fügt 2 ecm 30%igen Formaldehyd hinzu und trägt dann 2,83 g 2,3-Dioxo-2 drops of 1N hydrochloric acid are added 10 ecm of a morpholine hydrochloride solution, which by Neutralization of 8.71 g of morphine with concentrated hydrochloric acid and addition of 50 ecm of water had been made. Add 2 ecm of 30% formaldehyde and then carry 2.83 g of 2,3-dioxo
1515th
1. Stufe1st stage
23-Dioxo-pyrrolidin-4-carbonsäure a) Herstellung des Hydrierkatalysators23-dioxo-pyrrolidine-4-carboxylic acid a) Preparation of the hydrogenation catalyst
Man rührt uraer Wasserstoffatmosphäre eine Suspension von 0,8 g Tierkohle in 4 ecm einer wäßrigen 2%igen Palladiumchloridlösung. Nach der Sättigung des Katalysators saugt man ihn unter Luftausschluß ab und spült mehrmals mit wasserfreiem Dimethylformamid.A suspension of 0.8 g of animal charcoal in 4 ecm of an aqueous 2% strength is stirred in a uric hydrogen atmosphere Palladium chloride solution. After the catalyst is saturated, it is suctioned off with exclusion of air and rinsed several times with anhydrous dimethylformamide.
15 b) Hydrierung 15 b) hydrogenation
Man löst 9,32 g 2,3-Dioxo-pyrrolidin-4-carbonsäurebenzylester in 50 ecm wasserfreiem Dimethylformamid, fügt den oben hergestellten Katalysator hinzu. Man setzt das Ganze unter Wasserstoffatmosphäre, rührt dann und kühlt von Zeit zu Zi it, um jegliche spürbare Temperaturerhöhung zu vermeiden. Man filtriert, fügt 500 ecm Isopropyläther zum Filtrat, saugt ab und trocknet.9.32 g of benzyl 2,3-dioxopyrrolidine-4-carboxylate are dissolved in 50 ecm anhydrous dimethylformamide, add the catalyst prepared above. One sets the whole thing under a hydrogen atmosphere, then stirs and cools from time to time to avoid any noticeable increase in temperature to avoid. It is filtered, 500 ecm isopropyl ether is added to the filtrate, suction filtered and dried.
Man erhält 4,618 g(96%) Produkt^ >man so, wie es ist, für die weitere Synthese verwendet Für die Analyse löst ss man es in 6 Volumina Dimethylsulfoxyd und 4 Volumina Methanol. Man filtriert und fügt erneut 4 Volumina Methanol hinzu. Es bildet sich ein weißer Niederschlag, den man absaugt und trocknet Ausbeute bei der Reinigung: 60%.4.618 g (96%) of product are obtained ^> as it is, used for further synthesis For analysis, ss it in 6 volumes of dimethyl sulfoxide and 4 volumes of methanol. It is filtered and another 4 volumes are added Add methanol. A white precipitate forms, which is filtered off with suction and dried Cleaning: 60%.
Das Produkt liegt in Form weißer Kristalle vor, die wegen Decarboxylierung wenig stabil sind. Es ist löslich in Dimethylsulfoxyd und Dimethylformamid, unlöslich in Isopropyläther und Wasser.The product is in the form of white crystals, which are not very stable due to decarboxylation. It is soluble in Dimethyl sulfoxide and dimethyl formamide, insoluble in isopropyl ether and water.
IR-Spektrum (in Nujol): 4> IR spectrum (in Nujol): 4>
Absorption im Bereich von assoziiertem OH/N H Komplexe und starke Absorption im Carboxylbereich: Schulter 1708 cm-' max. 1677 cm-'.Absorption in the area of associated OH / N H complexes and strong absorption in the carboxyl area: Shoulder 1708 cm- 'max. 1677 cm-'.
Analyse C5H5O4N:Analysis C 5 H 5 O 4 N:
Berechnet:
gefunden:Calculated:
found:
pyrrolidin-4-carbonsäure ein. Die Reaktionsmischung wird unter Rühren 30 Stunden lang auf 60 bis 65" C erhitzt Man dampft zur Trockne ein und kristallisiert den Rückstand in Äthanol um. Man erhält 2^86 g Produkt, das direkt für die weitere Synthese brauchbar ist. pyrrolidine-4-carboxylic acid. The reaction mixture is heated to 60 to 65 ° C. for 30 hours while stirring. It is evaporated to dryness and the residue is recrystallized from ethanol. 2 ^ 86 g of product are obtained which can be used directly for further synthesis.
Zwecks Analyse löst man das Produkt in 1 Volumen heißen Wassers und fügt 3 Volumina Äthanol hinzu. Man stellt in Eis, saugt ab und erhält mit einer Ausbeute von 80% ein Produkt, das in Form weißer Kristalle vorliegt, wenig löslich in Äthanol und Äther, löslich in Wasser.For analysis, the product is dissolved in 1 volume of hot water and 3 volumes of ethanol are added. Man puts in ice, sucks off and receives a product in the form of white crystals with a yield of 80%, Slightly soluble in ethanol and ether, soluble in water.
Analyse C9Hi5O3N2CI = 234,7:Analysis C 9 Hi 5 O 3 N 2 CI = 234.7:
Berechnet: C 46,06, H 6,44, N 1134, Cl 15,1!"/O;
gefunden: C 45,8, H 6,4, N 11,8, Cl 15,2%.'Calculated: C 46.06, H 6.44, N 1134, Cl 15.1! "/ O;
found: C 45.8, H 6.4, N 11.8, Cl 15.2%.
IR-Spektrum in Nujol:IR spectrum in Nujol:
Absorptionsbanden bei 3210cm-' und 3,6 bis 4,1 μ Triplett im CarbonylbereichAbsorption bands at 3210 cm- 'and 3.6 to 4.1 μ Triplet in the carbonyl range
1711cm-'1711cm- '
1691 cm-'1691 cm- '
1664 cm-'1664 cm- '
Soweit bekannt, ist diese Verbindung in der Literatur nicht beschrieben.As far as is known, this connection is in the literature not described.
Das Hydrochlorid des 2,3-Dioxo-4-morpholinomethyl-pyrrolidins kann auch ausgehend von 23-Dioxo-pyrrolidin-4-carbonsäure-benzylester ohne Isolierung der zwischendurch auftretenden freien Säure auf folgende Weise erhalten werden:The hydrochloride of 2,3-Dioxo-4-morpholinomethyl-pyrrolidine can also start from 23-dioxopyrrolidine-4-carboxylic acid benzyl ester can be obtained in the following manner without isolating the free acid which occurs in between:
Man trägt 30,33 g 23-Dioxo-pyrrolidin-4-carbonsäure-benzylester in 300 ecm Dioxan mit 10% Wasser ein, erhitzt leicht um das Produkt zu lösen, fügt 3 g Tierkohle und 1 ecm einer wäßrigen 20%igen Palladiumchloridlösung hinzu, man setzt unter Wasserstoffatmosphäre und rührt sehr energisch. In 1 Stunde und 40 Minuten werden 2700 ecm Wasserstoff absorbiert (theoretisches Volumen: 2912 ecm). Man kühlt ab, spült mit Stickstoff und leitet dann 130 ecm der wie folgt zusammengesetzten Mischung ein:30.33 g of 23-dioxopyrrolidine-4-carboxylic acid benzyl ester are carried in 300 ecm of dioxane with 10% water, heated slightly to dissolve the product, add 3 g Animal charcoal and 1 ecm of an aqueous 20% palladium chloride solution are added, and the mixture is set under a hydrogen atmosphere and stirs very vigorously. In 1 hour and 40 minutes, 2700 ecm of hydrogen are absorbed (theoretical Volume: 2912 ecm). It is cooled, flushed with nitrogen and then passed 130 ecm of the compound composed as follows Mixture one:
Morpholin 43,5 gMorpholine 43.5 g
Wasser 100 ecm Konzentrierte Chlorwasserstoffsäure 40 ecm 1 n-Chlorwasserstoffsäure 15 ecmWater 100 ecm Concentrated hydrochloric acid 40 ecm 1 n-hydrochloric acid 15 ecm
Formaldehyd 50 ecmFormaldehyde 50 ecm
Wasser zur Ergänzung auf 500 ecmWater to supplement to 500 ecm
Man erhitzt die Reaktionsmischung auf ungefähr 500C und fängt innerhalb 1 Stunde 2325 ecm Kohlendioxydgas auf. Theoretisch müßte so viel Kohlendioxyd entwickeltHeat the reaction mixture to about 50 0 C intercepts 2325 cc of carbon dioxide gas within 1 hour. Theoretically, so much carbon dioxide should be evolved
-,» werden, wie anfangs in der Reaktion Wasserstoff absorbiert wurde. Man erwartet daher höchstens die Entwicklung von 2700 ecm Kohlendioxydgas. Man rührt leicht einige Minuten, filtriert und dampft im Vakuum zur Trockne ein. Der Rückstand kann so, wie er ist, für die-, »are absorbed, as in the beginning of the reaction, hydrogen became. One therefore expects at most the development of 2700 ecm of carbon dioxide gas. One stirs lightly a few minutes, filtered and evaporated to dryness in vacuo. The residue can be as it is for them
)-, weitere Synthese verwendet werden.) -, further synthesis can be used.
Zwecks Analyse tejgt man das erhaltene Produkt mit Äthanol an, spült mit Äther, trocknet und erhält mit einer Ausbeute von 63,5% ein Produkt, das mit dem oben beschriebenen identisch ist.For the purpose of analysis, the product obtained is mixed with ethanol, rinsed with ether, dried and obtained with a 63.5% yield of a product identical to that described above.
bO Herstellung des Ausgangsmaterials bO Production of the raw material
Stufe ALevel a
p-Toluolsulfonat des jJ-Alaninbenzylesters
In eine Apparatur, die mit einem Wasserabscheider für die azeotrope Entfernung von in der Reaktion gebildetem
Wasser versehen ist, erhitzt man die folgende Mischung 5 Stunden lang am Rückfluß:p-Toluenesulfonate of the jJ-alanine benzyl ester
The following mixture is refluxed for 5 hours in an apparatus equipped with a water separator for the azeotropic removal of water formed in the reaction:
/!-Alanin 89 g/! - alanine 89 g
p-ToluoIsulfonsäure-monohydrat 210gp-Toluene sulfonic acid monohydrate 210g
Benzylalkohol 450 ecmBenzyl alcohol 450 ecm
Tetrachlorkohlenstoff 500 ecmCarbon tetrachloride 500 ecm
Während dieser Zeit wurden ungefähr 45 ecm Wasser abgeschieden. Die Reaktionsflüssigkeit wird anschließend durch Destillation im Vakuum auf ein kleines Volumen eingeengt; man kühlt ab und kristallisiert das gebildete Produkt in Äther. Man stellt in Eis, saugt ab, ι ο trocknet und gewinnt 350 g (entspricht einer quantitativen Ausbeute) Kristalle, F.= 142° C.During this time approximately 45 ecm of water was separated out. The reaction liquid then becomes concentrated to a small volume by distillation in vacuo; one cools down and crystallizes that formed product in ether. It is placed in ice, suctioned off, ι ο dried and recovered 350 g (corresponds to a quantitative Yield) crystals, m.p. = 142 ° C.
Das erhaltene Produkt ist identisch mit dem von Nobuo Yzumiya et colL, Nippon Kagaku Zasshi 78, 662 (1957) beschriebenen.The product obtained is identical to that of Nobuo Yzumiya et colL, Nippon Kagaku Zasshi 78, 662 (1957).
Stufe B
2,3-Dioxo-pyrroIidin-4-carbonsäure-benzylesterLevel B.
2,3-Dioxo-pyrrolidine-4-carboxylic acid benzyl ester
Man trägt 225 g Kalium-tert-butylat in 900 ecm wasserfreies Benzo! ein, fügt 500 ecm Benzylalkohol hinzu, kühlt die Mischung in einem Eis/Niethanol-Bad ab und gibt, ohne 300C zu überschreiten, 351 g p-Toluolsulfonat des /J-Alaninbenzylesters hinzu.One carries 225 g of potassium tert-butoxide in 900 ecm of anhydrous benzo! one adds 500 cc benzyl alcohol, the mixture is cooled in an ice / Niethanol bath and returns without exceeding 30 0 C, 351 g of p-toluene / J-alanine benzyl added.
Andererseits löst man 300 g Oxalsäure-benzylester in 600 ecm heißem Benzol läßt auf Raumtemperatur zurückkommen und neutralisiert die schwache Azidität der Lösung durch Zugabe von 0,4 ecm Triäthylamin. Diese Lösung gibt man zu der oben gebildeten Mischung und hält immer im Kühlbad. Man erwärmt wieder auf Raumtemperatur und erhitzt 5 Stunden lang zum Rückfluß.On the other hand, 300 g of benzyl oxalate are dissolved in 600 ecm of hot benzene and allowed to come to room temperature come back and neutralize the weak acidity of the solution by adding 0.4 ecm of triethylamine. This solution is added to the mixture formed above and is always kept in the cooling bath. One warms up again to room temperature and refluxed for 5 hours.
Man verjagt das Benzol im Vakuum, fügt nacheinander zuerst 21 Wasser, das 15 ecm Essigsäure enthält,dann 1,5 I Isopropyläther und schließlich 110 ecm konzentrierte Chlorwasserstoffsäure hinzu (bis man einen pH von 1 erhält). Man stellt unter Rühren 2>/2 Stunden lang in Eis. Man saugt ab, wäscht mit Wasser, mit Isopropyläther und kristallisiert durch Auflösen in Dimethylformamid und Ausfällen mit Wasser um. Man erhält 1304 g (56%) Produkt, F. = 186° C, löslich in Alkoholen, Äther und Aceton, unlöslich in Benzol und Wasser.The benzene is expelled in a vacuum, first 21 water containing 15 ecm acetic acid is added one after the other, then 1.5 l Isopropyl ether and finally 110 ecm concentrated Add hydrochloric acid (until pH 1 is obtained). Place in ice for 2 1/2 hours with stirring. It is filtered off with suction, washed with water, with isopropyl ether and crystallized by dissolving in dimethylformamide and precipitates with water. 1304 g (56%) are obtained Product, m.p. = 186 ° C, soluble in alcohols, ethers and Acetone, insoluble in benzene and water.
Analyse C,2HuO4N=233,24:Analysis C, 2 HuO 4 N = 233.24:
Berechnet: C 61,8, H 4,76, N 6,01%; gefunden: C 62, H 5,1, N 63%.Calculated: C 61.8, H 4.76, N 6.01%; found: C 62, H 5.1, N 63%.
IR-Spektrum:IR spectrum:
Zwei Maxima im Carbonylgebiet 1729 cm-' und 1693 cm-'Two maxima in the carbonyl region 1729 cm- 'and 1693 cm- '
Absorption im Gebiet von assoziiertem OH/NH Aromatisch monosubstituiert vorhanden.Absorption in the area of associated OH / NH Aromatic monosubstituted present.
Soweit bekannt, ist diese Verbindung in der Literatur nicht beschrieben.As far as is known, this connection is in the literature not described.
VersuchsberichtTest report
Das über die erfindungsgemäßen Produkte erhältliche j>-lactam der L(+)-6 H,7H-cis-7-(p-aminophenylacetamidoJ-S-aminomethyl-ceph-S-em^-carbonsäure (fr^ie Base = Verbindung B) wurde hinsichtlich ihrer antibakteriellen Eigenschaften mit der 7-(a-Aminophenylacetamido)-3-methyl-ceph-3-em-4-car bonsäure, beschrieben in der Patentanmeldung Nr. 6 71 260 in der Südafrikanischen Union, veröffentlicht 1967 und bekannt unter dem Handelsnamen »Cephalexin«, und mit der 7-(D-«-AminophenyIacetamido)-<;ephalosporansäure, beschrieben in der niederländischen Patentanmeldung Nr. 67 14 442, veröffentlicht am 25 April 1968 und bekannt unter dem Handelsnamen »Cephaloglycin«, verglichen.The j> -lactam of L (+) - 6 H, 7H-cis-7- (p-aminophenylacetamidoJ-S-aminomethyl-ceph-S-em ^ -carboxylic acid obtainable via the products according to the invention (for ^ ie base = compound B) was with the 7- (a-aminophenylacetamido) -3-methyl-ceph-3-em-4-car bonsäure, described in Patent Application No. 6 71 260 in the Union of South Africa, published 1967 and known under the trade name "Cephalexin", and with the 7- (D - "- AminophenyIacetamido) - <; ephalosporanic acid, described in Dutch patent application No. 67 14 442, published April 25, 1968 and known under the trade name "Cephaloglycine".
Antibakterielle Aktivität in vitro:Antibacterial activity in vitro:
1) Milieu »Penassay Broth« (DlFCO) bei pH1) "Penassay Broth" environment (DIFCO) at pH
Die Ergebnisse werden ausgedrückt in minimalen Hemmkonzentrationen (y/ml) nach 24The results are expressed in minimum inhibitory concentrations (y / ml) after 24
oder 48 Stunden Inkubationszeit:or 48 hours incubation time:
24 Std. 48 Std. 24 Std. 48 Std. 24 Std. 48 Std.24 hours 48 hours 24 hours 48 hours 24 hours 48 hours
Penicillino-empfindlicher 0,05 2 1 2 2 40More sensitive to penicillino 0.05 2 1 2 2 40
Staphylococcus aureusStaphylococcus aureus
Penicil'iiiio-resistenter 0,4 2 5 5 5 40Penicil'iiiio-resistant 0.4 2 5 5 5 40
Staphylococcus aureusStaphylococcus aureus
2) Selber Stamm wie vorstehend und selbes Milieu, jedoch -,5 3) Selber Stamm wie vorstehend und selbes Milieu, jedoch unter Zusatz von 5% menschlichen Albumins: unter Zusatz von 10% menschlichen Serums:2) Same strain as above and same milieu, however -, 5 3) Same strain as above and same milieu, however with the addition of 5% human albumin: with the addition of 10% human serum:
Penicillino-Penicillino
sensiblermore sensitive
StaphylococcusStaphylococcus
aureusaureus
Penicillino-Penicillino
resistentermore resistant
StaphylococcusStaphylococcus
aureusaureus
24 Std. 48 Std. 24 Std. 48 Std.24 hours 48 hours 24 hours 48 hours
0,20.2
0,40.4
24 Std. 48 Std 24 Std. 48 Std.24 hours 48 hours 24 hours 48 hours
b0 Penicillinosensibler
Staphylococcus
aureus b0 More sensitive to penicillinosis
Staphylococcus
aureus
Penicillinoresistenter
Staphylococcus
aureusMore resistant to penicillin
Staphylococcus
aureus
0,20.2
0.40.4
7 4) Im Milieu »Hodd Hervitt Broth« (DIFCO) bei pH 7,8: 7 4) In the "Hodd Hervitt Broth" environment (DIFCO) at pH 7.8:
haemolyticushaemolyticus
(klinischer Stamm)(clinical strain)
subtilisBacillus
subtilis
bindung BCephalexin comparable cephaloglycin
binding B
LD50 > lg/kg 0,4-1,3 g/kg») 1-1,4 g/kg")LD 50 > lg / kg 0.4-1.3 g / kg ») 1-1.4 g / kg")
*) Merck-lndex, 9. Auflage, Nr. 1932, Seite 248. *·) C A. 73, 1970, 12 672 r*) Merck Index, 9th edition, No. 1932, page 248. * ·) C A. 73, 1970, 12 672 r
Claims (1)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR156898 | 1968-06-27 |
Publications (3)
Publication Number | Publication Date |
---|---|
DE1966203A1 DE1966203A1 (en) | 1972-01-27 |
DE1966203B2 true DE1966203B2 (en) | 1980-02-07 |
DE1966203C3 DE1966203C3 (en) | 1980-10-09 |
Family
ID=8651750
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE19691932498 Withdrawn DE1932498A1 (en) | 1968-06-27 | 1969-06-26 | New cephalosporin derivatives and their manufacturing process |
DE19691966204 Pending DE1966204A1 (en) | 1968-06-27 | 1969-06-26 | New 1,3-thiazine derivatives |
DE1967030A Expired DE1967030C3 (en) | 1968-06-27 | 1969-06-26 | γ-lactams of 6H, 7H-cis-7-amino-3aminomethyl-ceph-3-em-4-carboxylic acids |
DE1966203A Expired DE1966203C3 (en) | 1968-06-27 | 1969-06-26 | 2,3-Dioxo-4- (R ', R ") - aminomethylpyrrolidines and process for their preparation |
Family Applications Before (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE19691932498 Withdrawn DE1932498A1 (en) | 1968-06-27 | 1969-06-26 | New cephalosporin derivatives and their manufacturing process |
DE19691966204 Pending DE1966204A1 (en) | 1968-06-27 | 1969-06-26 | New 1,3-thiazine derivatives |
DE1967030A Expired DE1967030C3 (en) | 1968-06-27 | 1969-06-26 | γ-lactams of 6H, 7H-cis-7-amino-3aminomethyl-ceph-3-em-4-carboxylic acids |
Country Status (14)
Country | Link |
---|---|
JP (2) | JPS4934999B1 (en) |
AT (2) | AT293614B (en) |
BE (1) | BE735127A (en) |
BR (3) | BR6910252D0 (en) |
CH (3) | CH515276A (en) |
DE (4) | DE1932498A1 (en) |
ES (2) | ES368820A1 (en) |
FR (1) | FR1584569A (en) |
GB (5) | GB1271015A (en) |
HU (1) | HU162644B (en) |
IL (1) | IL32379A (en) |
NL (2) | NL142691B (en) |
PL (1) | PL79142B1 (en) |
SU (2) | SU495841A3 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0277215A1 (en) * | 1986-08-19 | 1988-08-10 | Horst Forschner | Do-it-yourself garments and set of components of do-it-yourself garments |
EA013864B1 (en) * | 2008-08-29 | 2010-08-30 | Лимонова, Анастасия Викторовна | Method of enhancement antimicrobal activity of cephalosporin antibiotics |
-
1968
- 1968-06-27 FR FR156898A patent/FR1584569A/fr not_active Expired
-
1969
- 1969-06-11 IL IL32379A patent/IL32379A/en unknown
- 1969-06-13 PL PL1969134161A patent/PL79142B1/en unknown
- 1969-06-24 CH CH968069A patent/CH515276A/en not_active IP Right Cessation
- 1969-06-24 CH CH968169A patent/CH513206A/en not_active IP Right Cessation
- 1969-06-24 CH CH14171A patent/CH522635A/en not_active IP Right Cessation
- 1969-06-25 BE BE735127D patent/BE735127A/xx unknown
- 1969-06-25 HU HURO582A patent/HU162644B/hu unknown
- 1969-06-25 SU SU1343897A patent/SU495841A3/en active
- 1969-06-25 SU SU1340776A patent/SU384232A3/ru active
- 1969-06-26 DE DE19691932498 patent/DE1932498A1/en not_active Withdrawn
- 1969-06-26 DE DE19691966204 patent/DE1966204A1/en active Pending
- 1969-06-26 NL NL696909849A patent/NL142691B/en not_active IP Right Cessation
- 1969-06-26 ES ES368820A patent/ES368820A1/en not_active Expired
- 1969-06-26 DE DE1967030A patent/DE1967030C3/en not_active Expired
- 1969-06-26 NL NL696909850A patent/NL142415B/en not_active IP Right Cessation
- 1969-06-26 DE DE1966203A patent/DE1966203C3/en not_active Expired
- 1969-06-27 AT AT618469A patent/AT293614B/en not_active IP Right Cessation
- 1969-06-27 GB GB47787/71A patent/GB1271015A/en not_active Expired
- 1969-06-27 GB GB47789/71A patent/GB1271017A/en not_active Expired
- 1969-06-27 BR BR210252/69A patent/BR6910252D0/en unknown
- 1969-06-27 GB GB32567/69A patent/GB1271013A/en not_active Expired
- 1969-06-27 GB GB47788/71A patent/GB1271016A/en not_active Expired
- 1969-06-27 JP JP44050288A patent/JPS4934999B1/ja active Pending
- 1969-06-27 GB GB47790/71A patent/GB1271018A/en not_active Expired
- 1969-06-27 AT AT618569A patent/AT293615B/en not_active IP Right Cessation
- 1969-06-27 BR BR210250/69A patent/BR6910250D0/en unknown
- 1969-06-27 BR BR210251/69A patent/BR6910251D0/en unknown
- 1969-06-27 JP JP44050289A patent/JPS5028440B1/ja active Pending
-
1971
- 1971-09-17 ES ES395175A patent/ES395175A2/en not_active Expired
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