DE4033033A1 - Prepn. of carba:penem derivs. as antimicrobials - Google Patents

Prepn. of carba:penem derivs. as antimicrobials

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Publication number
DE4033033A1
DE4033033A1 DE19904033033 DE4033033A DE4033033A1 DE 4033033 A1 DE4033033 A1 DE 4033033A1 DE 19904033033 DE19904033033 DE 19904033033 DE 4033033 A DE4033033 A DE 4033033A DE 4033033 A1 DE4033033 A1 DE 4033033A1
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Prior art keywords
alkyl
alkoxy
cycloalkyl
phenyl
hydrogen
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DE19904033033
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German (de)
Inventor
Karl-Heinz Dr Budt
Rolf Dr Hoerlein
Rudolf Dr Lattrell
Theodor Dr Wollmann
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Hoechst AG
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Hoechst AG
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Priority to DE19904033033 priority Critical patent/DE4033033A1/en
Priority to IL99513A priority patent/IL99513A0/en
Priority to NZ239839A priority patent/NZ239839A/en
Priority to FI914383A priority patent/FI914383A/en
Priority to PT99005A priority patent/PT99005A/en
Priority to AU84575/91A priority patent/AU8457591A/en
Priority to CA002051865A priority patent/CA2051865A1/en
Priority to IE329791A priority patent/IE913297A1/en
Priority to KR1019910016375A priority patent/KR920006359A/en
Priority to NO91913692A priority patent/NO913692L/en
Priority to EP19910115935 priority patent/EP0476649A3/en
Priority to JP3268935A priority patent/JPH04279587A/en
Publication of DE4033033A1 publication Critical patent/DE4033033A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/02—Preparation
    • C07D477/04—Preparation by forming the ring or condensed ring systems

Abstract

Prepn. of carbapenen cpds. of formula (I) comprises reaction of an azetidin-2-one deriv. of formula (II) with a trivalent organophosphorus cpd. of formula (III). In formulae R1, R2 = 1-4C alkyl, 1-4C alkenyl (sic), 1-4C alkoxy, 4-7C cycloalkyl or 3-6C spirocyclyl (sic); R3 = H, 1-4C alkyl or 1-12C alkylthio, both opt. mono- or disubstd. by opt. protected hydroxy, 1-4C alkoxy, 1-4C alkoxy-carbonyl, 1-4C acyloxy, NH2, 1-4C alkylamine, 1-4C acylamino, SH, 1-4C alkylthio or heterocyclylthio; phenyl, phenylthio, heterocyclyl or heterocyclylthio (all opt. mono- or die- ring-substd. by opt. protected hydroxy, COOH, 1-4C alkoxy- carbonyl, allyloxy carbonyl, NH2CO, 1-4C alkylamino-carbonyl, CN, F, Cl or Br); 3-6C cycloalkyl, 3-6C cycloalkylthio, 5-6C oxacycloalkyl (satd. or singly or doubly unsatd.), 3-6C oxocycloalkyl or Q-cycloalkyl, the cycloalkyl gps. being opt. mono- or disubstd. by 1-3C alkyl, 1-3C alkoxy, halo or methylene, and are satd. or contain one or two double bonds; Q = 1,1-bis(1-3C alkoxy), 1-3C alkylimino, 3-6C phenylimino, 3-6C hydroxyimino or 1-3C alkoxyimino; R6, R7 = 1-4C alkyl, allyl, benzyl or phenyl (opt. substd. by 1-3C alkyl or 1-3C alkoxy); R8 = 1-4C alkyl or phenyl (opt. substd. by 1-3C alkyl or 1-3C alkoxy); R4 = H or a carboxy protecting gp. which may be removed by hydrolysis, photolysis, oxidation, redn. or enzymatically; R5 = H or an OH protecting gp.; X = O or S.

Description

Die Erfindung betrifft ein Verfahren zur Herstellung von Carbapenemverbindungen.The invention relates to a process for the preparation of carbapenem compounds.

Carbapenemderivate der Formel I sind wertvolle Verbindungen mit antibiotischen Eigenschaften. Literaturbekannte Syntheseverfahren bedienen sich der Zwischenstufen der Verbindungen der Formeln II und III, deren Herstellung langwierig ist:Carbapenem derivatives of the formula I are valuable compounds with antibiotic Properties. Synthetic processes known from the literature make use of the intermediate stages of the compounds of the formulas II and III, the preparation of which is lengthy:

Eine weitere Verfahrensvariante besteht in der Cyclisierung der Vorstufe IV (Oxalimidcyclisierung):Another process variant is the cyclization of precursor IV (Oxalimide cyclization):

In der Literatur wird als Cyclisierungsreagenz ausschließlich Trimethylphosphit oder Triethylphosphit verwendet. Nachteilig sind die oft sehr niedrigen Ausbeuten aufgrund der notwendigen hohen Reaktionstemperaturen und langen Reaktionszeiten.In the literature, only trimethyl phosphite or is used as the cyclization reagent Triethyl phosphite used. The often very low yields are disadvantageous owing to the necessary high reaction temperatures and long reaction times.

Es wurde nun überraschenderweise gefunden, daß sich diese Nachteile vermeiden lassen, wenn man die Zyklisierung der Vorstufe IV unter Verwendung von Alkylphosphonigsäuredialkylestern ausführt. Diese neuartigen Reagenzien führen im Vergleich mit Alkylphosphiten zu einer Zyklisierung unter wesentlich milderen Reaktionsbedingungen und damit zu wesentlich höheren Ausbeuten an Endprodukt I.It has now surprisingly been found that these disadvantages are avoided if you cyclize precursor IV using Alkylphosphonigsäuredialkylestern executes. These new types of reagents lead to Comparison with alkyl phosphites for a cyclization under much milder ones Reaction conditions and thus significantly higher yields of end product I.

Die Erfindung betrifft daher ein Verfahren zur Herstellung von Carbapenemderivaten der Formel IThe invention therefore relates to a process for the preparation of carbapenem derivatives Formula I.

worin bedeuten:
R(1), R(2) Wasserstoff, (C₁-C₄)-Alkyl, (C₁-C₄)-Alkenyl, (C₁-C₄)-Alkoxy, (C₄-C₇)-Cycloalkyl oder (C₃-C₆)-Spirocyclyl,
R(3) Wasserstoff, (C₁-C₄)-Alkyl, (C₁-C₁₂)-Alkylthio [wobei die Alkylgruppen unsubstituiert sind oder ein- oder zweifach substituiert durch Hydroxy, geschütztes Hydroxy, (C₁-C₄)-Alkoxy, (C₁-C₄)-Alkyloxycarbonyl, (C₁-C₄)Acyloxy, Amino, (C₁-C₄)-Alkylamino, (C₁-C₄)-Acylamino, Thiol, (C₁-C₄)-Alkylthio oder Heterocyclylthio, z. B. Thiazolyl-, Thiadiazolyl-, Pyridylthio], Phenyl, Heterocyclyl, Phenylthio, Heterocyclylthio [wobei die Phenyl- und Heterocyclylringe unsubstituiert oder ein- oder zweifach substituiert sind durch Hydroxy, geschütztes Hydroxy, Carboxy, (C₁-C₄)-Alkoxycarbonyl, Allyloxycarbonyl, Aminocarbonyl, (C₁-C₄)-Alkylaminocarbonyl, Cyano, F, Cl, Br], (C₃-C₆)-Cycloalkyl, (C₃-C₆)-Cycloalkylthio, (C₅-C₆)-Oxacycloalkyl [gesättigt, ein- oder zweifach ungesättigt], (C₃-C₆)-Oxocycloalkyl, (C₃-C₆)-[1,1-bis-(C₁-C₃)- Alkyloxy]-cycloalkyl, (C₃-C₆)-[(C₁-C₃)-Alkylimino]-cycloalkyl, (C₃-C₆)-[Phenylimino]- cycloalkyl, (C₃-C₆)-(Hydroxyimino)-cycloalkyl, (C₃-C₆)-[(C₁-C₃)-Alkyloxyimino]- cycloalkyl, in denen der Cycloalkylrest unsubstituiert oder ein- oder zweifach durch (C₁-C₃)-Alkyl, vorzugsweise Methyl, durch (C₁-C₃)-Alkoxy, vorzugsweise Methoxy, durch Halogen, wie F, Cl, Br, vorzugsweise Chlor, oder durch Methylen subsituiert ist und gesättigt ist oder eine oder zwei Doppelbindungen enthalten kann,
R(4) Wasserstoff oder eine übliche Carboxylschutzgruppe, die durch Hydrolyse, Photolyse, Oxidation, Reduktion oder enzymatisch abgespalten werden kann,
R(5) Wasserstoff oder eine übliche Alkoholschutzgruppe, die durch Hydrolyse, Photolyse, Oxidation, Reduktion oder enzymatisch abgespalten werden kann.in which mean:
R (1), R (2) hydrogen, (C₁-C₄) alkyl, (C₁-C₄) alkenyl, (C₁-C₄) alkoxy, (C₄-C₇) cycloalkyl or (C₃-C₆) -spirocyclyl ,
R (3) hydrogen, (C₁-C₄) alkyl, (C₁-C₁₂) alkylthio [where the alkyl groups are unsubstituted or mono- or disubstituted by hydroxy, protected hydroxy, (C₁-C₄) alkoxy, (C₁- C₄) alkyloxycarbonyl, (C₁-C₄) acyloxy, amino, (C₁-C₄) alkylamino, (C₁-C₄) acylamino, thiol, (C₁-C₄) alkylthio or heterocyclylthio, e.g. B. thiazolyl, thiadiazolyl, pyridylthio], phenyl, heterocyclyl, phenylthio, heterocyclylthio [where the phenyl and heterocyclyl rings are unsubstituted or mono- or disubstituted by hydroxy, protected hydroxy, carboxy, (C₁-C₄) alkoxycarbonyl , Aminocarbonyl, (C₁-C₄) -alkylaminocarbonyl, cyano, F, Cl, Br], (C₃-C₆) -cycloalkyl, (C₃-C₆) -cycloalkylthio, (C₅-C₆) -oxacycloalkyl [saturated, one or two times unsaturated], (C₃-C₆) oxocycloalkyl, (C₃-C₆) - [1,1-bis- (C₁-C₃) alkyloxy] cycloalkyl, (C₃-C₆) - [(C₁-C₃) alkylimino] -cycloalkyl, (C₃-C₆) - [phenylimino] - cycloalkyl, (C₃-C₆) - (hydroxyimino) -cycloalkyl, (C₃-C₆) - [(C₁-C₃) alkyloxyimino] - cycloalkyl, in which the cycloalkyl radical is unsubstituted or is mono- or disubstituted by (C₁-C₃) alkyl, preferably methyl, by (C₁-C₃) alkoxy, preferably methoxy, by halogen, such as F, Cl, Br, preferably chlorine, or by methylene and saturated is or can contain one or two double bonds,
R (4) hydrogen or a customary carboxyl protecting group which can be split off by hydrolysis, photolysis, oxidation, reduction or enzymatically,
R (5) hydrogen or a customary alcohol protecting group which can be split off by hydrolysis, photolysis, oxidation, reduction or enzymatically.

Als besonders bevorzugt kommen die folgenden Substituenten in Betracht:
R(1), R(2) Wasserstoff, (C₁-C₄)-Alkyl, (C₁-C₄)-Alkenyl, (C₁-C₄)-Alkoxy, (C₄-C₇)-Cycloalkyl oder (C₃-C₈)-Spirocyclyl,
R(3) Wasserstoff, (C₁-C₄)-Alkyl, (z. B. Methyl, Ethyl, Hydroxymethyl und Aminomethyl), (C₁-C₄)-Hydroxyalkyl, (C₁-C₃)-Alkylthio (z. B. Methylthio, Ethylthio und Propylthio, Methoxycarbonylmethylthio), Phenyl (z. B. 4- Carboxamidophenyl, geschütztes 3,4-Dihydroxyphenyl, 4-Fluorphenyl oder 4- Cyanophenyl), Heterocyclyl, z. B. Pyridyl, Phenylthio, gesättigtes oder ungesättigtes (C₅-C₆)-Oxacycloalkyl (z. B. Tetrahydrofuryl oder Furyl), (C₄-C₆)- Oxocycloalkyl (z. B. 1-Oxo-cyclobut-3-yl), 3-Hydroxyiminocyclobutyl, 3- Methoxyiminocyclobutyl und 3,3-Dimethoxycyclobutyl,
R(4) eine Carboxylschutzgruppe wie Allyl, p-Nitrobenzyl oder Trimethylsilylethyl,
R(5) Wasserstoff oder eine Alkohol-Schutzgruppe wie Trimethylsilyl, Dimethyl-tert.- butylsilyl, Diphenyl-tert.-butylsilyl, Allyloxycarbonyl, Trichlorethyloxycarbonyl oder 4-Nitrobenzyloxycarbonyl.The following substituents are particularly preferred:
R (1), R (2) hydrogen, (C₁-C₄) alkyl, (C₁-C₄) alkenyl, (C₁-C₄) alkoxy, (C₄-C₇) cycloalkyl or (C₃-C₈) -spirocyclyl ,
R (3) hydrogen, (C₁-C₄) alkyl, (e.g. methyl, ethyl, hydroxymethyl and aminomethyl), (C₁-C₄) hydroxyalkyl, (C₁-C₃) alkylthio (e.g. methylthio, Ethylthio and propylthio, methoxycarbonylmethylthio), phenyl (e.g. 4-carboxamidophenyl, protected 3,4-dihydroxyphenyl, 4-fluorophenyl or 4-cyanophenyl), heterocyclyl, e.g. B. pyridyl, phenylthio, saturated or unsaturated (C₅-C₆) -oxacycloalkyl (e.g. tetrahydrofuryl or furyl), (C₄-C₆) - oxocycloalkyl (e.g. 1-oxo-cyclobut-3-yl), 3 -Hydroxyiminocyclobutyl, 3-methoxyiminocyclobutyl and 3,3-dimethoxycyclobutyl,
R (4) a carboxyl protecting group such as allyl, p-nitrobenzyl or trimethylsilylethyl,
R (5) hydrogen or an alcohol protecting group such as trimethylsilyl, dimethyl-tert-butylsilyl, diphenyl-tert-butylsilyl, allyloxycarbonyl, trichloroethyloxycarbonyl or 4-nitrobenzyloxycarbonyl.

Die Asymmetriezentren C-1, C-5, C-6 und C-8 können sowohl in der R- als auch in der S-Konfiguration vorliegen.The asymmetry centers C-1, C-5, C-6 and C-8 can be found in both the R- and the S configuration available.

Nach dem erfindungsgemäßen Verfahren werden die Verbindungen der Formel I durch Umsetzen einer Verbindung der Formel IVIn the process of the invention, the compounds of the formula I are Reacting a compound of formula IV

worin X Sauerstoff oder Schwefel bedeutet und R(1), R(2), R(3), R(4) und R(5) die obige Bedeutung haben, mit einer dreiwertigen organischen Phosphorverbindung der Formel Vwherein X is oxygen or sulfur and R (1), R (2), R (3), R (4) and R (5) the have the above meaning with a trivalent organic phosphorus compound of formula V

hergestellt, worin bedeuten:
R(6), R(7) (C₁-C₄)-Alkyl, Allyl, Benzyl oder Phenyl, das substituiert sein kann durch (C₁-C₃)-Alkyl oder (C₁-C₃)-Alkoxy, R(6) und R(7) können gleich oder verschieden sein, und
R(8) (C₁-C₄)Alkyl, beispielsweise Methyl, Ethyl oder Trifluormethyl, Phenyl, das substituiert sein kann durch (C₁-C₃)-Alkyl oder (C₁-C₃)-Alkoxy.produced, in which mean:
R (6), R (7) (C₁-C₄) alkyl, allyl, benzyl or phenyl, which can be substituted by (C₁-C₃) alkyl or (C₁-C₃) alkoxy, R (6) and R (7) may be the same or different, and
R (8) (C₁-C₄) alkyl, for example methyl, ethyl or trifluoromethyl, phenyl, which can be substituted by (C₁-C₃) alkyl or (C₁-C₃) alkoxy.

Die Reaktion zwischen einer Verbindung IV und einer Verbindung V kann in einem geeigneten organischen Lösungsmittel durchgeführt werden, beispielsweise in Tetrahydrofuran, Ethylacetat, einem aromatischen Kohlenwasserstoff wie Benzol, Toluol, Xylol oder Mesitylen oder einem halogenierten Kohlenwasserstoff wie Dichlormethan, Trichlormethan oder 1,1,2-Trichlorethan.The reaction between a compound IV and a compound V can be carried out in one suitable organic solvents are carried out, for example in tetrahydrofuran, Ethyl acetate, an aromatic hydrocarbon such as benzene, toluene, xylene or mesitylene or a halogenated hydrocarbon such as dichloromethane, trichloromethane or 1,1,2-trichloroethane.

Die Reaktionstemperatur kann zwischen 50 und 180°C, vorzugsweise zwischen 70 und 165°C variieren.The reaction temperature can be between 50 and 180 ° C, preferably between 70 and Vary 165 ° C.

Die Konzentration der zu cyclisierenden Verbindung IV beträgt zwischen 1 mmol/l und 150 mmol/l, vorzugsweise zwischen 2 mmol/l und 50 mmol/l.The concentration of the compound IV to be cyclized is between 1 mmol / l and 150 mmol / l, preferably between 2 mmol / l and 50 mmol / l.

Die Menge der Verbindung V kann zwischen 2 und 8 Moläquivalenten, vorzugsweise zwischen 2 und 6 Moläquivalenten, bezogen auf IV, betragen.The amount of compound V can be between 2 and 8 molar equivalents, preferably between 2 and 6 molar equivalents, based on IV.

Die als Nebenprodukte gebildeten Alkylphosphonsäuredialkylester und Alkylthiophosphonsäuredialkylester können auf einfache Weise abgetrennt werden.The alkylphosphonic acid dialkyl esters and alkylthiophosphonic acid dialkyl esters formed as by-products can be easily separated.

Die Verbindungen der Formeln IV und V sind bekannt oder können gemäß literaturbekannten Verfahren hergestellt werden.The compounds of the formulas IV and V are known or can be according to literature Processes are made.

Die folgenden Beispiele dienen zur weiteren Erläuterung der Erfindung.The following examples serve to further explain the invention.

Beispiel 1Example 1 (1R,5S,6S)-6-[(1R)-tert.-Butyldimethylsilyloxyethyl)-2-(methoxycarbo-nylmethylthio)-1- methylcarbapen-2-em-3-carbonsäureallylester(1R, 5S, 6S) -6 - [(1R) -tert.-butyldimethylsilyloxyethyl) -2- (methoxycarbonylmethylthio) -1- methylcarbapen-2-em-3-carboxylic acid allyl ester

Eine Lösung von 1,0 g (2 mmol) (3S,4S)-1-Allyloxycarbonylcarbonyl-3-[(1R)-tert-butyldimethylsilylox-yethyl)- 4-[(2R)-1-methoxycarbonylmethylthio-1-oxopropyl]-azetidin-2-on in 50 ml trockenem Xylol wird zum Sieden erhitzt und 1,36 g (10 mmol) Methylphosphonigsäurediethylester werden zugegeben. Nach 15 Minuten wird abgekühlt, die Lösung im Vakuum eingeengt und der Rückstand über Kieselgel, (desaktiviert mit 10% Wasser) mit Toluol : Essigester (10 : 1) chromatographiert. Nach dem Einengen der Produktfraktionen erhält man einen farblosen, kristallinen Feststoff, Ausbeute: 740 mg (78% d. Th.)A solution of 1.0 g (2 mmol) (3S, 4S) -1-allyloxycarbonylcarbonyl-3 - [(1R) -tert-butyldimethylsilyloxyethyl) - 4 - [(2R) -1-methoxycarbonylmethylthio-1-oxopropyl] azetidin-2-one in 50 ml of dry xylene is heated to boiling and 1.36 g (10 mmol)  Diethyl methylphosphonate are added. After 15 minutes it is cooled, the solution was concentrated in vacuo and the residue over silica gel, (deactivated with 10% water) with toluene: ethyl acetate (10: 1). After narrowing the Product fractions are obtained as a colorless, crystalline solid, yield: 740 mg (78% of theory)

Analog wurden die in der Tabelle 1 aufgeführten Verbindungen I aus den in Tabelle 2 aufgeführten Ausgangssubstanzen IV unter den in Tabelle 3 aufgeführten Reaktionsbedingungen erhalten. Analogously, the compounds I listed in Table 1 were obtained from the starting substances IV listed in Table 2 under the reaction conditions listed in Table 3.

Claims (4)

1. Verfahren zum Herstellen einer Carbapenem-Verbindung I worin bedeuten:
R(1), R(2) Wasserstoff, (C₁-C₄)-Alkyl, (C₁-C₄)-Alkenyl, (C₁-C₄)-Alkoxy, (C₄-C₇)-Cycloalkyl oder (C₃-C₆)-Spirocyclyl,
R(3) Wasserstoff, (C₁-C₄)-Alkyl, (C₁-C₁₂)-Alkylthio [wobei die Alkylgruppen unsubstituiert sind oder ein- oder zweifach substituiert durch Hydroxy, geschütztes Hydroxy, (C₁-C₄)-Alkoxy, (C₁-C₄)-Alkyloxycarbonyl, (C₁-C₄)- Acyloxy, Amino, (C₁-C₄)-Alkylamino, (C₁-C₄)-Acylamino, Thiol, (C₁-C₄)- Alkylthio oder Heterocyclylthio], Phenyl, Heterocyclyl, Phenylthio, Heterocyclylthio [wobei die Phenyl- und Heterocyclylringe unsubstituiert oder ein- oder zweifach substituiert sind durch Hydroxy, geschütztes Hydroxy, Carboxy, (C₁-C₄)-Alkoxycarbonyl, Allyloxycarbonyl, Aminocarbonyl, (C₁-C₄)- Alkylaminocarbonyl, Cyano, F, Cl, Br], (C₃-C₆)-Cycloalkyl, (C₃-C₆)- Cycloalkylthio, (C₅-C₆)-Oxacycloalkyl [gesättigt, ein- oder zweifach ungesättigt], (C₃-C₆)-Oxocycloalkyl, (C₃-C₆)-[1,1-bis-(C₁-C₃)-Alkyloxy]- cycloalkyl, (C₃-C₆)-[(C₁-C₃)-Alkylimino]-cycloalkyl, (C₃-C₆)-(Phenylimino)- cycloalkyl, (C₃-C₆)-(Hydroxyimino)-cycloalkyl, (C₃-C₆)-[(C₁-C₃)-Alkyloxyimino]- cycloalkyl, in denen der Cycloalkylrest unsubstituiert oder ein- oder zweifach durch (C₁-C₃)-Alkyl, durch (C₁-C₃)-Alkoxy, durch Halogen, oder durch Methylen substituiert ist und gesättigt ist oder eine oder zwei Doppelbindungen enthalten kann,
R(4) Wasserstoff oder eine übliche Carboxylschutzgruppe, die durch Hydrolyse, Photolyse, Oxidation, Reduktion oder enzymatisch abgespalten werden kann,
R(5) Wasserstoff oder eine Alkohol-Schutzgruppe,
dadurch gekennzeichnet, daß man eine Verbindung der Formel IV worin
X Sauerstoff oder Schwefel bedeutet und
R(1), R(2), R(3), R(4) und R(5) die obige Bedeutung haben,
mit einer dreiwertigen organischen Phosphorverbindung der Formel V umsetzt, worin
R(6) R(7) (C₁-C₄)-Alkyl, Allyl, Benzyl oder Phenyl, das substituiert sein kann durch (C₁-C₃)-Alkyl oder (C₁-C₃)-Alkoxy, R(6) und R(7) können gleich oder verschieden sein, und
R(8) (C₁-C₄)-Alkyl, Phenyl, das substituiert sein kann durch (C₁-C₃)-Alkyl oder (C₁-C₃)-Alkoxy, bedeuten.1. Process for the preparation of a carbapenem compound I in which mean:
R (1), R (2) hydrogen, (C₁-C₄) alkyl, (C₁-C₄) alkenyl, (C₁-C₄) alkoxy, (C₄-C₇) cycloalkyl or (C₃-C₆) -spirocyclyl ,
R (3) hydrogen, (C₁-C₄) alkyl, (C₁-C₁₂) alkylthio [where the alkyl groups are unsubstituted or mono- or disubstituted by hydroxy, protected hydroxy, (C₁-C₄) alkoxy, (C₁- C₄) alkyloxycarbonyl, (C₁-C₄) acyloxy, amino, (C₁-C₄) alkylamino, (C₁-C₄) acylamino, thiol, (C₁-C₄) alkylthio or heterocyclylthio], phenyl, heterocyclyl, phenylthio, Heterocyclylthio [where the phenyl and heterocyclyl rings are unsubstituted or mono- or disubstituted by hydroxy, protected hydroxy, carboxy, (C₁-C₄) alkoxycarbonyl, allyloxycarbonyl, aminocarbonyl, (C₁-C₄) alkylaminocarbonyl, cyano, F, Cl, Br], (C₃-C₆) -cycloalkyl, (C₃-C₆) - cycloalkylthio, (C₅-C₆) -oxacycloalkyl [saturated, mono- or di-unsaturated], (C₃-C₆) -oxocycloalkyl, (C₃-C₆) - [1,1-bis (C₁-C₃) alkyloxy] cycloalkyl, (C₃-C₆) - [(C₁-C₃) alkylimino] cycloalkyl, (C₃-C₆) - (phenylimino) - cycloalkyl, (C₃ -C₆) - (Hydroxyimino) cycloalk yl, (C₃-C₆) - [(C₁-C₃) alkyloxyimino] - cycloalkyl, in which the cycloalkyl radical is unsubstituted or mono- or disubstituted by (C₁-C₃) alkyl, by (C₁-C₃) alkoxy, by halogen , or is substituted by methylene and is saturated or can contain one or two double bonds,
R (4) hydrogen or a customary carboxyl protecting group which can be split off by hydrolysis, photolysis, oxidation, reduction or enzymatically,
R (5) hydrogen or an alcohol protecting group,
characterized in that a compound of formula IV wherein
X means oxygen or sulfur and
R (1), R (2), R (3), R (4) and R (5) have the above meaning,
with a trivalent organic phosphorus compound of formula V implements what
R (6) R (7) (C₁-C₄) alkyl, allyl, benzyl or phenyl, which can be substituted by (C₁-C₃) alkyl or (C₁-C₃) alkoxy, R (6) and R ( 7) can be the same or different, and
R (8) (C₁-C₄) alkyl, phenyl, which may be substituted by (C₁-C₃) alkyl or (C₁-C₃) alkoxy. 2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man die Umsetzung von Verbindung IV mit V in einem organischen Lösungsmittel durchführt.2. The method according to claim 1, characterized in that the implementation of Compound IV with V in an organic solvent. 3. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man die Reaktion zwischen +50°C und +180°C durchführt. 3. The method according to claim 1, characterized in that the reaction between + 50 ° C and + 180 ° C.   4. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß
R(1), R(2) Wasserstoff, (C₁-C₄)-Alkyl, (C₁-C₄)-Alkenyl, (C₁-C₄)-Alkoxy, (C₄-C₇)-Cycloalkyl oder (C₃-C₆)-Spirocyclyl,
R(3) Wasserstoff, (C₁-C₄)-Alkyl, Hydroxy-(C₁-C₄)-Alkyl, (C₁-C₃)-Alkylthio, Phenyl, Heterocyclyl, Phenylthio, gesättigtes oder ungesättigtes (C₅-C₆)- Oxacycloalkyl, (C₄-C₆)-Oxocycloalkyl, 3-Hydroxyiminocyclobutyl, 3- Methoxyiminocyclobutyl und 3,3-Dimethoxycyclobutyl,
R(4) eine Carboxylschutzgruppe ausgewählt aus der Gruppe Allyl, p-Nitrobenzyl oder Trimethylsilylethyl,
R(5) Wasserstoff oder eine Alkohol-Schutzgruppe ausgewählt aus der Gruppe Trimethylsilyl, Dimethyl-tert.butylsilyl, Diphenyl-tert.-butylsilyl, Allyloxycarbonyl, Trichlorethoxycarbonyl oder 4-Nitrobenzyloxycarbonyl) bedeuten.4. The method according to claim 1, characterized in that
R (1), R (2) hydrogen, (C₁-C₄) alkyl, (C₁-C₄) alkenyl, (C₁-C₄) alkoxy, (C₄-C₇) cycloalkyl or (C₃-C₆) -spirocyclyl ,
R (3) hydrogen, (C₁-C₄) alkyl, hydroxy- (C₁-C₄) alkyl, (C₁-C₃) alkylthio, phenyl, heterocyclyl, phenylthio, saturated or unsaturated (C₅-C₆) - oxacycloalkyl, ( C₄-C₆) -oxocycloalkyl, 3-hydroxyiminocyclobutyl, 3-methoxyiminocyclobutyl and 3,3-dimethoxycyclobutyl,
R (4) a carboxyl protecting group selected from the group allyl, p-nitrobenzyl or trimethylsilylethyl,
R (5) is hydrogen or an alcohol protecting group selected from the group trimethylsilyl, dimethyl-tert-butylsilyl, diphenyl-tert-butylsilyl, allyloxycarbonyl, trichloroethoxycarbonyl or 4-nitrobenzyloxycarbonyl).
DE19904033033 1990-09-20 1990-10-18 Prepn. of carba:penem derivs. as antimicrobials Withdrawn DE4033033A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
DE19904033033 DE4033033A1 (en) 1990-10-18 1990-10-18 Prepn. of carba:penem derivs. as antimicrobials
IL99513A IL99513A0 (en) 1990-09-20 1991-09-17 Process for the preparation of carbapenem compounds
NZ239839A NZ239839A (en) 1990-09-20 1991-09-18 Process for the preparation of carbapenem derivatives
FI914383A FI914383A (en) 1990-09-20 1991-09-18 FOERFARANDE FOER FRAMSTAELLNING AV KARBAPENEMFOERENINGAR.
PT99005A PT99005A (en) 1990-09-20 1991-09-19 PROCESS FOR THE PREPARATION OF CARBAPENEM COMPOUNDS
AU84575/91A AU8457591A (en) 1990-09-20 1991-09-19 Process for the preparation of carbapenem compounds
CA002051865A CA2051865A1 (en) 1990-09-20 1991-09-19 Process for the preparation of carbapenem compounds
IE329791A IE913297A1 (en) 1990-09-20 1991-09-19 Process for the preparation of carbapenem compounds
KR1019910016375A KR920006359A (en) 1990-09-20 1991-09-19 Process for preparing carbapenem compound
NO91913692A NO913692L (en) 1990-09-20 1991-09-19 PROCEDURE FOR THE PREPARATION OF CARBAPEN COMPOUNDS.
EP19910115935 EP0476649A3 (en) 1990-09-20 1991-09-19 Process for the preparation of carbapeneme compounds
JP3268935A JPH04279587A (en) 1990-09-20 1991-09-20 Process for producing carbapenem compound

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DE19904033033 DE4033033A1 (en) 1990-10-18 1990-10-18 Prepn. of carba:penem derivs. as antimicrobials

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