DE3914389A1 - Prodn. of penem antibiotics - by reacting 4-acyl:thio-1- oxalyl-2-azetidinone cpds. with phosphonite di:ester - Google Patents

Prodn. of penem antibiotics - by reacting 4-acyl:thio-1- oxalyl-2-azetidinone cpds. with phosphonite di:ester

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Publication number
DE3914389A1
DE3914389A1 DE19893914389 DE3914389A DE3914389A1 DE 3914389 A1 DE3914389 A1 DE 3914389A1 DE 19893914389 DE19893914389 DE 19893914389 DE 3914389 A DE3914389 A DE 3914389A DE 3914389 A1 DE3914389 A1 DE 3914389A1
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Prior art keywords
alkoxy
alkyl
cycloalkyl
phenyl
formula
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DE19893914389
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German (de)
Inventor
Karl-Heinz Dr Budt
Walter Dr Duerckheimer
Gerd Dr Fischer
Rolf Dr Hoerlein
Reiner Dr Kirrstetter
Rudolf Dr Lattrell
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Hoechst AG
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Hoechst AG
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Priority to DE19893914389 priority Critical patent/DE3914389A1/en
Priority to EP90107815A priority patent/EP0399228A1/en
Priority to FI902110A priority patent/FI902110A0/en
Priority to JP2115038A priority patent/JPH02306978A/en
Priority to KR1019900005962A priority patent/KR900016224A/en
Priority to NO901893A priority patent/NO173871C/en
Priority to AU53906/90A priority patent/AU620982B2/en
Priority to CA002015580A priority patent/CA2015580A1/en
Priority to PT93893A priority patent/PT93893A/en
Publication of DE3914389A1 publication Critical patent/DE3914389A1/en
Priority to US07/659,488 priority patent/US5198544A/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/88—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)

Abstract

Prodn. of penem cpds. of formula (I) is effected by reacting a 4-acylthio-1- oxalyl-2-azetidnone of formula (II) with a phosphonite diester of formula (III) where R1 = H, 1-4C alkyl, 1-12C alkoxy, 1-12C alkylthio, OPh, Ph, 3-6C cycloalkyl, 3-6C cycloalkyloxy, 3-6C oxocycloalkyl, gem-di(1-3C)alkoxy (3-6C)cycloalkyl, (1-3C)alkylimino (3-6C)cycloalkyl, arylimino (3-6C)cycloalkyl, hydroxyimino (3-6C)cycloalkyl or (1-3C)alkoxyimino (3-6C)cycloalkyl, where the cycloalkyl gps. contain 0-2 double bonds and are opt. mono- or disubstd. by 1-3C alkyl, 1-3C alkoxy, halogen or CH2; R2 = H or a protecting gp. removable by hydrolysis, photolysis, oxidn., redn. or enzyme treatment; R3 = H, 1-4C alkyl, 2-4C alkenyl, 1-4C alkoxy, 4-7C cycloalkyl, Ph, 2-oxo-1,3-dioxolyl, triazolyl, thiazolyl, NH2, acylamino or alkoxy; X = O or S; R4 and R5 = 1-4C alkyl, allyl, benzyl or phenyl opt. substd. by 1-3C alkyl or 1-3C alkoxy; R6 = 1-4C alkyl or phenyl opt. substd. by 1-3C alkyl or 1-3C alkoxy. N.B., in all exemplified cpds., R3 is protected 1-hydroxyethyl. USE ADVANTAGE - (I) are useful as antibiotics. Compared with similar processes using trialkyl phosphites; the process can be operated at lower temps, gives higher yields and purity, and does not result in isomerisation to the unwanted (5S,6S) isomer.

Description

Die Erfindung betrifft ein Verfahren zur Herstellung von Penemverbindungen.The invention relates to a method for producing Penem connections.

Penemderivate der Formel I sind wertvolle Verbindungen mit antibiotischen Eigenschaften. In einem literaturbekannten Syntheseverfahren für Penemderivate I werden Azetidinonderivate der Formel II mit Trialkylphosphiten intramolekular cyclisiert. Dieses Verfahren liefert jedoch oft nur schlechte Ausbeuten. Überdies ist die Reaktion langsam und erfordert erhöhte Reaktionstemperaturen, z. B. Rückfluß in Toluol. Unter diesen Reaktionsbedingungen tritt häufig eine teilweise Konfigurationsumkehr an C-5 ein, die zu unerwünschten (5S,6S)-Penemen führt.Penem derivatives of the formula I are valuable compounds with antibiotic properties. In a literature known Synthesis methods for penem derivatives I are Azetidinone derivatives of formula II with trialkyl phosphites cyclized intramolecularly. However, this method provides often only poor yields. Moreover, the reaction is slow and requires elevated reaction temperatures, e.g. B. Reflux in toluene. Under these reaction conditions occurs often a partial configuration reversal at C-5 that leads to undesired (5S, 6S) -penemen.

Es wurde nun gefunden, daß sich die beschriebenen Nachteile des bekannten Verfahrens vermeiden lassen, wenn für die Cyclisierungsreaktion Alkylphosphonigsäuredialkylester an Stelle von Trialkylphosphiten verwendet werden. Diese neuartigen Reagentien erlauben niedrigere Reaktionstemperaturen, z. B. Zimmertemperatur, und führen zu kürzeren Reaktionszeiten. Dadurch werden höhere Ausbeuten und reinere Produkte erzielt. Außerdem wird die unerwünschte Isomerierung zu (5S,6S)-Penemen vermieden. Die als Nebenprodukte gebildeten Alkylphosphonsäuredialkylester und Alkylthiophosphonsäuredialkylester können auf einfache Weise abgetrennt werden. It has now been found that the disadvantages described of the known method can be avoided if for the Cyclization reaction of alkylphosphonous dialkyl ester can be used instead of trialkyl phosphites. These novel reagents allow lower Reaction temperatures, e.g. B. room temperature, and lead to shorter response times. This will result in higher yields and purer products. In addition, the undesired isomerization to (5S, 6S) -penemen avoided. The formed as by-products Alkylphosphonic acid dialkyl esters and Alkylthiophosphonic acid dialkyl esters can be easily Be separated.  

Die Erfindung betrifft daher ein Verfahren zur Herstellung von Penemderivaten der Formel I, in denen die bevorzugte Konfiguration (5R,6S) istThe invention therefore relates to a method for manufacturing of penem derivatives of the formula I in which the preferred Configuration (5R, 6S)

und worin
R¹ Wasserstoff, (C₁-C₄)-Alkyl, (C₁-C₁₂)-Alkoxy, (C₁-C₁₂)-Alkylthio, Phenoxy, Phenyl, (C₃-C₆)-Cycloalkyl, (C₃-C₆)-Cycloalkyloxy, (C₃-C₆)-Oxocycloalkyl, (C₃-C₆)-[1,1-bis-(C₁-C₃)- Alkyloxy]-cycloalkyl, (C₃-C₆)-[(C₁-C₃)-Alkylimino]-cycloalkyl, (C₃-C₆)-[Arylimino]cycloalkyl, (C₃-C₆)-Hydroxyiminocycloalkyl, (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, vorzugsweise Chlor, oder durch Methylen substituiert ist und gesättigt ist oder eine oder zwei Doppelbindungen enthalten kann,
R² Wasserstoff oder eine übliche Carboxylschutzgruppe, die durch Hydrolyse, Photolyse, Oxidation, Reduktion oder enzymatisch abgespalten werden kann,
R³ Wasserstoff, (C₁-C₄)-Alkyl, (C₁-C₄)-Alkenyl, (C₁-C₄)-Alkoxy, (C₄-C₇)-Cycloalkyl, Phenyl, 2-oxo-1,3-dioxolyl, Triazolyl, Thiazolyl, Amino, Acylamino oder Alkoxy
bedeutet. and in what
R¹ is hydrogen, (C₁-C₄) alkyl, (C₁-C₁₂) alkoxy, (C₁-C₁₂) alkylthio, phenoxy, phenyl, (C₃-C₆) cycloalkyl, (C₃-C₆) cycloalkyloxy, (C₃- C₆) oxocycloalkyl, (C₃-C₆) - [1,1-bis- (C₁-C₃) alkyloxy] cycloalkyl, (C₃-C₆) - [(C₁-C₃) alkylimino] cycloalkyl, (C₃- C₆) - [Arylimino] cycloalkyl, (C₃-C₆) -hydroxyiminocycloalkyl, (C₃-C₆) - (C₁-C₃-alkyloxyimino) - cycloalkyl in which the cycloalkyl radical is unsubstituted or mono- or disubstituted by C₁-C₃-alkyl, preferably Methyl, is substituted by (C₁-C₃) alkoxy, preferably methoxy, by halogen, preferably chlorine, or by methylene and is saturated or can contain one or two double bonds,
R² is hydrogen or a customary carboxyl protecting group which can be split off by hydrolysis, photolysis, oxidation, reduction or enzymatically,
R³ is hydrogen, (C₁-C₄) alkyl, (C₁-C₄) alkenyl, (C₁-C₄) alkoxy, (C₄-C₇) cycloalkyl, phenyl, 2-oxo-1,3-dioxolyl, triazolyl, thiazolyl , Amino, acylamino or alkoxy
means.

Als besonders bevorzugt kommen die folgenden Substituenten in Betracht:
R¹ Wasserstoff, (C₁-C₄)-Alkyl (z. B. Methyl, Ethyl, Hydroxymethyl und Aminomethyl), (C₁-C₄)-Alkoxy (z. B. Methoxy und Ethoxy), (C₁-C₃)-Alkylthio (z. B. Methylthio, Ethylthio und Propylthio), Phenoxy (z. B. 4-Carboxamidophenoxy oder 4-Cyanophenoxy), Phenyl (z. B. 4-Carboxamidophenyl oder 4-Cyanophenyl), (C₄-C₆)-Oxocycloalkyl (z. B. 1-Oxo-cyclobut-3-yl), 3-Hydroxyiminocyclobutyl, 3-Methoxyiminocyclobutyl und 3,3-Dimethoxycyclobutyl;
R³ 1-Hydroxyethyl (worin die OH-Gruppe frei ist oder geschützt durch Trimethylsilyl, Diphenyl-tert.-butylsilyl, Allyloxycarbonyl, Trichlorethyloxycarbonyl oder 4-Nitrobenzyloxycarbonyl), (C₁-C₃)-Alkoxy (z. B. Methoxy oder Ethoxy), (C₁-C₃)-Alkenyl, z. B. Triazolylethylen oder Thiazolylethylen.The following substituents are particularly preferred:
R¹ is hydrogen, (C₁-C₄) alkyl (e.g. methyl, ethyl, hydroxymethyl and aminomethyl), (C₁-C₄) alkoxy (e.g. methoxy and ethoxy), (C₁-C₃) alkylthio (e.g. E.g. methylthio, ethylthio and propylthio), phenoxy (e.g. 4-carboxamidophenoxy or 4-cyanophenoxy), phenyl (e.g. 4-carboxamidophenyl or 4-cyanophenyl), (C₄-C₆) -oxocycloalkyl (e.g. B. 1-oxo-cyclobut-3-yl), 3-hydroxyiminocyclobutyl, 3-methoxyiminocyclobutyl and 3,3-dimethoxycyclobutyl;
R³ 1-hydroxyethyl (in which the OH group is free or protected by trimethylsilyl, diphenyl-tert-butylsilyl, allyloxycarbonyl, trichloroethyloxycarbonyl or 4-nitrobenzyloxycarbonyl), (C₁-C₃) alkoxy (e.g. methoxy or ethoxy), (C₁-C₃) alkenyl, e.g. B. triazolylethylene or thiazolylethylene.

Die (C₁-C₄)-Alkyl- und (C₁-C₄)-Alkoxy-Gruppen in dem Substituenten R¹ sind entweder unsubstituiert oder ein- oder zweifach substituiert durch Hydroxy, (C₁-C₄)-Alkoxy, (C₁-C₄)-Acyloxy, Amino, (C₁-C₄)-Alkylamino, (C₁-C₄)-Acylamino, Thiol, (C₁-C₄)-Alkylthio oder Heterocyclylthio, z. B. Thiazolyl-, Thiadiozolyl-, Pyridylthio.The (C₁-C₄) alkyl and (C₁-C₄) alkoxy groups in the R¹ substituents are either unsubstituted or mono- or substituted twice by hydroxy, (C₁-C₄) alkoxy, (C₁-C₄) acyloxy, amino, (C₁-C₄) alkylamino, (C₁-C₄) acylamino, thiol, (C₁-C₄) alkylthio or Heterocyclylthio, e.g. B. thiazolyl, thiadiozolyl, Pyridylthio.

Phenylkerne sind ebenfalls unsubstituiert oder ein- oder zweifach substituiert durch Carboxy, (C₁-C₄)-Alkoxycarbonyl, Aminocarbonyl, (C₁-C₄)-Alkylaminocarbonyl, Cyano oder Halogen, vorzugsweise F, Cl, Br. Phenyl nuclei are also unsubstituted or one or substituted twice by carboxy, (C₁-C₄) alkoxycarbonyl, aminocarbonyl, (C₁-C₄) alkylaminocarbonyl, cyano or halogen, preferably F, Cl, Br.  

Die (C₁-C₄)-Alkyl- und (C₁-C₄)-Alkoxy-Gruppen in R³ sind entweder unsubstituiert oder substituiert durch Hydroxy, (C₁-C₄)-Alkoxy, (C₁-C₄)-Acyloxy, Amino, (C₁-C₄)-Alkylamino, (C₁-C₄)-Acylamino, Thiol, (C₁-C₄)-Alkylthiol oder Heterocyclylthio, wobei eine OH-Gruppe frei sein kann oder geschützt durch Trimethylsilyl, Diphenyl-tert.-butylsilyl, (C₁-C₄)-Allyloxycarbonyl, Trichlorethoxycarbonyl oder 4-Nitrobenzyloxycarbonyl.The (C₁-C₄) alkyl and (C₁-C₄) alkoxy groups in R³ are either unsubstituted or substituted by hydroxy, (C₁-C₄) alkoxy, (C₁-C₄) acyloxy, amino, (C₁-C₄) alkylamino, (C₁-C₄) acylamino, thiol, (C₁-C₄) alkylthiol or Heterocyclylthio, where one OH group can be free or protected by trimethylsilyl, diphenyl-tert-butylsilyl, (C₁-C₄) allyloxycarbonyl, trichloroethoxycarbonyl or 4-nitrobenzyloxycarbonyl.

Nach dem erfindungsgemäßen Verfahren werden die Verbindungen der Formel I durch Umsetzen einer Verbindung der Formel IIAccording to the inventive method Compounds of formula I by reacting a compound of formula II

worin
X Sauerstoff oder Schwefel bedeutet und
R¹, R² und R³ die obige Bedeutung haben, mit einer dreiwertigen organischen Phosphorverbindung der Formel IIIwherein
X means oxygen or sulfur and
R¹, R² and R³ have the above meaning, with a trivalent organic phosphorus compound of formula III

hergestellt, worin
R⁶ (C₁-C₄)-Alkyl, beispielsweise Methyl, Ethyl oder Trifluormethyl, Phenyl, das substituiert sein kann durch (C₁-C₃)-Alkyl oder (C₁-C₃)-Alkoxy, und
R⁴ und R⁵ gleich oder verschieden sind und (C₁-C₄)-Alkyl, Allyl, Benzyl oder Phenyl, das substituiert sein kann durch (C₁-C₃)-Alkyl oder (C₁-C₃)-Alkoxy bedeuten.manufactured in which
R⁶ (C₁-C₄) alkyl, for example methyl, ethyl or trifluoromethyl, phenyl, which can be substituted by (C₁-C₃) alkyl or (C₁-C₃) alkoxy, and
R⁴ and R⁵ are the same or different and are (C₁-C₄) alkyl, allyl, benzyl or phenyl, which can be substituted by (C₁-C₃) alkyl or (C₁-C₃) alkoxy.

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

Die Reaktionstemperatur kann zwischen +10°C und 160°C, vorzugsweise zwischen +20°C und +70°C variieren.The reaction temperature can be between + 10 ° C and 160 ° C, preferably vary between + 20 ° C and + 70 ° C.

Die Konzentration der zu cyclisierenden Verbindung II beträgt zwischen 1 mmol/l und 100 mmol/l, vorzugsweise zwischen 2 mmol/l und 20 mmol/l.The concentration of compound II to be cyclized is between 1 mmol / l and 100 mmol / l, preferably between 2 mmol / l and 20 mmol / l.

Die Menge der Verbindung III kann zwischen 2 und 8 Moläquivalenten, vorzugsweise zwischen 2 und 6 Moläquivalenten bezogen auf II betragen.The amount of compound III can range from 2 to 8 Molar equivalents, preferably between 2 and 6 Molecular equivalents based on II.

Die Verbindungen der Formeln II und III sind bekannt oder können gemäß literaturbekannten Verfahren hergestellt werden.The compounds of the formulas II and III are known or can be prepared according to methods known from the literature will.

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

Beispiel 1Example 1 (5R,6S)-6-[(1R)-tert.-Butyldimethylsilyloxyethyl]-2-(4- aminocarbonylphenoxy)penem-3-carbonsäure-(4-nitrobenzyl)- ester(5R, 6S) -6 - [(1R) -tert.-butyldimethylsilyloxyethyl] -2- (4- aminocarbonylphenoxy) penem-3-carboxylic acid- (4-nitrobenzyl) - ester

130 mg (0,2 mmol) (3S,4R)-4-[(Aminocarbonyl)- phenoxythiocarbonylthio]-3-[(1R)-tert.- butyldimethylsilyloxyethyl)]-1-(4-Nitrobenzyloxybarbonyl)- azetidin-2-on wurden bei 55°C in 90 ml CHCl₃ unter Argonatmosphäre gelöst. Dazu gab man binnen 30 Minuten eine Lösung von 90 mg (0,8 mmol) Methylphosphonigsäuredimethylester CH₃P(OCH₃)₂ in 10 ml CHCl₃, rührte nach Beendigung der Zugabe noch 2 Stunden und arbeitete das abgekühlte Gemisch auf. Man extrahierte mit 1 N NaHCO₃-Lösung, 1 N KHSO₄-Lösung und Wasser, trocknete mit Magnesiumsulfat und engte die organische Phase im Vakuum ein. Das Rohprodukt ergab nach Flash-Chromatographie (SiO₂ 70-200 µm + 10% H₂O; zuerst Toluol + Ethylacetat 20 + 1, dann 1 + 1 zur Elution) die Titelverbindung in 83% Ausbeute.130 mg (0.2 mmol) (3S, 4R) -4 - [(aminocarbonyl) - phenoxythiocarbonylthio] -3 - [(1R) -tert.- butyldimethylsilyloxyethyl)] - 1- (4-nitrobenzyloxybarbonyl) - azetidin-2-one were at 55 ° C in 90 ml of CHCl₃ Dissolved argon atmosphere. You added one within 30 minutes Solution of 90 mg (0.8 mmol) Methylphosphonigsäuredimethylester CH₃P (OCH₃) ₂ in 10 ml CHCl₃, stirred after the addition for 2 hours and worked up the cooled mixture. It was extracted with 1 N NaHCO₃ solution, 1 N KHSO₄ solution and water, dried with Magnesium sulfate and narrowed the organic phase in vacuo a. The crude product gave after flash chromatography (SiO₂ 70-200 µm + 10% H₂O; first toluene + ethyl acetate 20 + 1, then 1 + 1 for elution) the title compound in 83% Yield.

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

Tabelle 2 Table 2

Ausgangsverbindungen Output connections

Tabelle 3 Table 3

Reaktionsbedingungen für Cyclisierungsreaktion Reaction conditions for cyclization reaction

Claims (4)

1. Verfahren zum Herstellen einer Penem-Verbindung I in welcher bedeuten:
R¹ Wasserstoff, (C₁-C₄)-Alkyl, (C₁-C₁₂)-Alkoxy, (C₁-C₁₂)-Alkylthio, Phenoxy, Phenyl, (C₃-C₆)-Cycloalkyl, (C₃-C₆)-Cycloalkyloxy, (C₃-C₆)-Oxocycloalkyl, (C₃-C₆)- [1,1-bis-(C₁-C₃)Alkyloxy]-cycloalkyl, (C₃-C₆)-[(C₁-C₃)- Alkylimino]-cycloalkyl, (C₃-C₆)-Aryliminocycloalkyl, (C₃-C₆)Hydroxyiminocycloalkyl, (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,
R² Wasserstoff oder eine übliche Carboxylschutzgruppe, die durch Hydrolyse, Photolyse, Oxidation, Reduktion oder enzymatisch abgespalten werden kann,
R³ Wasserstoff, (C₁-C₄)-Alkyl, (C₁-C₄)-Alkenyl, (C₁-C₄)-Alkoxy, (C₄-C₇)-Cycloalkyl, Phenyl, 2-Oxo-1,3-dioxolyl, Triazolyl, Thiazolyl, Amino, Acylamino oder Alkoxy,
dadurch gekennzeichnet, daß man eine Verbindung der Formel II worin
X Sauerstoff oder Schwefel bedeutet und
R¹, R² und R³ die obige Bedeutung haben, mit einer dreiwertigen organischen Phosphorverbindung der Formel III umsetzt, worin
R⁶ (C₁-C₄)-Alkyl, Phenyl, das substituiert sein kann durch (C₁-C₃)-Alkyl oder (C₁-C₃)Alkoxy, und
R⁴ und R⁵ gleich oder verschieden sind und (C₁-C₄)-Alkyl, Allyl, Benzyl oder Phenyl, das substituiert sein kann durch (C₁-C₃)-Alkyl oder (C₁-C₃)Alkoxy
bedeuten.1. Method for producing a penem compound I in which mean:
R¹ is hydrogen, (C₁-C₄) alkyl, (C₁-C₁₂) alkoxy, (C₁-C₁₂) alkylthio, phenoxy, phenyl, (C₃-C₆) cycloalkyl, (C₃-C₆) cycloalkyloxy, (C₃- C₆) -Oxocycloalkyl, (C₃-C₆) - [1,1-bis- (C₁-C₃) alkyloxy] cycloalkyl, (C₃-C₆) - [(C₁-C₃) - alkylimino] cycloalkyl, (C₃-C₆ ) Aryliminocycloalkyl, (C₃-C₆) hydroxyiminocycloalkyl, (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, is substituted by halogen or by methylene and is saturated or can contain one or two double bonds,
R² is hydrogen or a customary carboxyl protecting group which can be split off by hydrolysis, photolysis, oxidation, reduction or enzymatically,
R³ is hydrogen, (C₁-C₄) alkyl, (C₁-C₄) alkenyl, (C₁-C₄) alkoxy, (C₄-C₇) cycloalkyl, phenyl, 2-oxo-1,3-dioxolyl, triazolyl, thiazolyl , Amino, acylamino or alkoxy,
characterized in that a compound of formula II wherein
X means oxygen or sulfur and
R¹, R² and R³ have the above meaning, with a trivalent organic phosphorus compound of formula III implements what
R⁶ (C₁-C₄) alkyl, phenyl, which may be substituted by (C₁-C₃) alkyl or (C₁-C₃) alkoxy, and
R⁴ and R⁵ are the same or different and (C₁-C₄) alkyl, allyl, benzyl or phenyl, which can be substituted by (C₁-C₃) alkyl or (C₁-C₃) alkoxy
mean. 2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man die Umsetzung von Verbindung II mit III in einem organischen Lösungsmittel durchführt.2. The method according to claim 1, characterized in that one the reaction of compound II with III in one organic solvents. 3. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man die Reaktion zwischen +10°C und +160°C durchführt. 3. The method according to claim 1, characterized in that the reaction is carried out between + 10 ° C and + 160 ° C.   4. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß
R¹ Wasserstoff, (C₁-C₄)-Alkyl, (C₁-C₄)-Alkoxy, (C₁-C₃)- Alkylthio, Phenoxy, Phenyl, (C₄-C₆)-Oxocycloalkyl, 3-Hydroxyiminocyclobutyl, 3-Methoxyiminocyclobutyl, 3,3-Dimethoxycyclobutyl, 3-Methoxy-2-cyclobuten-1-yl, 2-Methoxy-1-cyclobuten-1-yl und 4-Methoxy-3- cyclohexen-1-yl,
R³ 1-Hydroxyethyl (worin die OH-Gruppe frei ist oder geschützt durch Trimethylsilyl, Diphenyl-tert.- butylsilyl, Allyloxycarbonyl, Trichlorethoxycarbonyl oder 4-Nitrobenzyloxycarbonyl), (C₁-C₃)-Alkoxy, (C₁-C₃)-Alkenyl
bedeuten.4. The method according to claim 1, characterized in that
R¹ is hydrogen, (C₁-C₄) alkyl, (C₁-C₄) alkoxy, (C₁-C₃) alkylthio, phenoxy, phenyl, (C₄-C₆) oxocycloalkyl, 3-hydroxyiminocyclobutyl, 3-methoxyiminocyclobutyl, 3.3 -Dimethoxycyclobutyl, 3-methoxy-2-cyclobuten-1-yl, 2-methoxy-1-cyclobuten-1-yl and 4-methoxy-3-cyclohexen-1-yl,
R³ 1-hydroxyethyl (in which the OH group is free or protected by trimethylsilyl, diphenyl tert-butylsilyl, allyloxycarbonyl, trichloroethoxycarbonyl or 4-nitrobenzyloxycarbonyl), (C₁-C₃) alkoxy, (C₁-C₃) alkenyl
mean.
DE19893914389 1989-04-29 1989-04-29 Prodn. of penem antibiotics - by reacting 4-acyl:thio-1- oxalyl-2-azetidinone cpds. with phosphonite di:ester Withdrawn DE3914389A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
DE19893914389 DE3914389A1 (en) 1989-04-29 1989-04-29 Prodn. of penem antibiotics - by reacting 4-acyl:thio-1- oxalyl-2-azetidinone cpds. with phosphonite di:ester
EP90107815A EP0399228A1 (en) 1989-04-29 1990-04-25 Process for the preparation of penem compounds
FI902110A FI902110A0 (en) 1989-04-29 1990-04-26 FOERFARANDE FOER FRAMSTAELLNING AV PENEMFOERENINGAR.
NO901893A NO173871C (en) 1989-04-29 1990-04-27 Procedure for the preparation of penem compounds
KR1019900005962A KR900016224A (en) 1989-04-29 1990-04-27 Process for preparing penem compound
JP2115038A JPH02306978A (en) 1989-04-29 1990-04-27 Preparation of penem compound
AU53906/90A AU620982B2 (en) 1989-04-29 1990-04-27 A process for the preparation of penem compounds
CA002015580A CA2015580A1 (en) 1989-04-29 1990-04-27 Process for the preparation of penem compounds
PT93893A PT93893A (en) 1989-04-29 1990-04-27 PROCESS FOR THE PREPARATION OF PNEMO COMPOUNDS
US07/659,488 US5198544A (en) 1989-04-29 1991-02-25 Process for the preparation of penem compounds

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE19893914389 DE3914389A1 (en) 1989-04-29 1989-04-29 Prodn. of penem antibiotics - by reacting 4-acyl:thio-1- oxalyl-2-azetidinone cpds. with phosphonite di:ester

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DE3914389A1 true DE3914389A1 (en) 1990-11-08

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