CH591505A5 - Heterocycloyloxy-substd. alkanoic acids prodn. - by hydro(geno)lysis of carboxy protected derivs., useful as antibiotic intermediates - Google Patents

Heterocycloyloxy-substd. alkanoic acids prodn. - by hydro(geno)lysis of carboxy protected derivs., useful as antibiotic intermediates

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Publication number
CH591505A5
CH591505A5 CH1617773A CH1617773A CH591505A5 CH 591505 A5 CH591505 A5 CH 591505A5 CH 1617773 A CH1617773 A CH 1617773A CH 1617773 A CH1617773 A CH 1617773A CH 591505 A5 CH591505 A5 CH 591505A5
Authority
CH
Switzerland
Prior art keywords
formula
acid
compound
analogy
benzyl ester
Prior art date
Application number
CH1617773A
Other languages
German (de)
Original Assignee
Hoffmann La Roche
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche
Priority to CH1617773A priority Critical patent/CH591505A5/en
Publication of CH591505A5 publication Critical patent/CH591505A5/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/14—Preparation from compounds containing heterocyclic oxygen
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
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    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
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    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
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    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • 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

Abstract

Prepn. of disubstd. acetic acid derivs. of formula A - COOC(T)H.COOH (II) by catalytic hydrogenation or hydrolysis (T is 2-5C alkyl or alkenyl, cyclopropylmethyl, cyclobutylmethyl or cyclopentyl; A is furyl, tetrahydrofuryl, pyrrolyl, pyrrolidinyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-thiadiazolyl, imidazolyl, pyrazolyl, pyridyl, 1-oxidopyridyl, tetrahydropyranyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, quinolyl or isoquinolyl, which may be substd. by halo, oxo. OH, NH2, 1-3C alkoxy ( -carbonyl), 1-3C alkanoylamino, and/or opt. substd. 1-3C alkyl; B is carboxyl protected by a gp. which can be removed by catalytic hydrogenation or hydrolysis). (I) are intermediates for antibiotics, esp. the penicillins described in CH 580631.

Description

  

  
 



   Die Erfindung betrifft ein Verfahren zur Herstellung von neuen disubstituierten Essigsäurederivaten der Formel
EMI1.1     
 worin T einen   Qs-Alkyl    oder -Alkenylrest oder den Cyclopropylmethyl-, Cyclobutylmethyl- oder Cyclopentylrest und A Furyl, Tetrahydrofuryl, Pyrrolyl, Pyrrolidinyl, Thienyl, Oxazolyl, Isoxazolyl, Thiazolyl, 1,2,3-Thiadiazolyl, Imidazolyl, Pyrazolyl, Pyridyl, 1-Oxidopyridyl, Tetrahydropyranyl, Pyrimidinyl, Pyrazinyl, Benzofuranyl, Indolyl, Chinolyl oder Isochinolyl bedeutet und wobei die Reste A durch Halogen, Oxo, Hydroxy, Amino,   C1¯3-Alkoxy,      Cl-Alkoxycarbonyl,      C13-    Alkanoylamino und/oder gegebenenfalls substituiertes   C1-3-    Alkyl substituiert sein können.



   Als Halogensubstituenten kommen insbesondere Fluor, Chlor und Brom in Betracht.   C1¯3-Alkyl-,    Alkoxy-, Alkoxycarbonyl und Alkanoylaminogruppen sind solche, in denen der Alkylteil 1-3 C-Atome enthält. Eine Alkyl- oder Alkenylgruppe im Substituenten T kann geradkettig oder verzweigt sein. Beispiele von solchen Gruppen sind Äthyl, n-Propyl, Isopropyl, n-Butyl, Isobutyl, n-Pentyl, 3-Methylbutyl, Neopentyl bzw. Vinyl, Allyl, Methallyl, Butenyl und Pentenyl.



   Bevorzugte Gruppen A in der Formel I der erfindungsgemäss erhältlichen Verbindungen sind 3 -Pyridyl, 2-Methyl-4pyridyl, 3-Isoxazolyl, 4-Oxazolyl, 2-Oxo-2-pyrrolidinyl, Pyrazinyl, Tetrahydro-2-furyl, 2-Acetamido-4-thiazolyl, 1,5   Dimethyl-3 -pyrazolyl,    Tetrahydro-4-pyranyl, 1,2,3-Thiadiazol-4-yl, 2-Furyl oder 4-Pyridyl.



   Bevorzugte Gruppen T in der Formel I der erfindungsgemäss erhältlichen Verbindungen sind Alkyl- oder Alkenylgruppen mit 4 bis 5 C-Atomen. Bevorzugte Verbindungen sind ausserdem diejenigen, die in der weiter unten angegebenen Tabelle aufgeführt sind. Besonders bevorzugt ist die Verbindung der Formel I, worin A 2-Furyl und T 2-Methylpropyl bedeutet, d. h. das 1-(2-Furoyloxy)-3-methylbutyl-penicillin, insbesondere die R-Form und dessen Salze.



   Die erfindungsgemäss erhältlichen Säuren der Formel I können in optisch einheitlicher Form oder auch als Racemate eingesetzt werden. Vorzugsweise verwendet man die R-Enantiomeren.



   Die genannten Verbindungen der Formel I werden erfindungsgemäss dadurch hergestellt, dass man in einer Verbindung der Formel
EMI1.2     
 worin B eine durch eine katalytisch oder hydrolytisch abspaltbare Schutzgruppe geschützte Carboxylgruppe darstellt, die Schutzgruppe entweder durch katalytische Hydrierung oder hydrolytisch abspaltet.



   Die geschützte Carboxylgruppe B kann eine leicht spaltbare Estergruppe, beispielsweise die Benzyl- oder die tert. Butylestergruppe, sein. Die Überführung der geschützten Carboxylgruppe B in die freie Carboxylgruppe kann im Falle des Benzylesters durch katalytische Hydrierung mittels eines Edelmetallkatalysators, z. B. Palladium-Kohle, im Falle des tert.-Butylesters durch Behandlung mit Säure, z. B. mit einer Mineralsäure, wie Salzsäure, oder mit Trifluoressigsäure, erfolgen.



   Die Ausgangsverbindungen der Formel II kann man in an sich bekannter Weise dadurch erhalten, dass man die Carboxylgruppe einer Verbindung der Formel
EMI1.3     
 schützt, beispielsweise durch Bildung des Benzylesters oder des tert.-Butylesters, und die erhaltene Verbindung mit einer Verbindung der Formel A-COOH umsetzt, beispielsweise unter Vermittlung von Benzolsulfochlorid.



   Die Verfahrensprodukte sind wertvolle Zwischenprodukte für die Herstellung von Antibiotika, beispielsweise die Penicilline der in der schweizerischen Patentschrift   Nr. 580    631 angeführten Formel I.



   Beispiel 1
55,5 g (R)-2-(2-Furoyloxy)-isocapronsäurebenzylester werden in 400 ml Alkohol nach Zusatz von 5 g Palladiumkohle (Sproz.) bis zur Aufnahme der theoretischen Menge Wasserstoff hydriert. Der Katalysator wird abgesaugt und das Filtrat unter vermindertem Druck bei   40"C    eingedampft. Das zurückbleibende Öl wird in 250 ml 8proz. Natriumbicarbonatlösung gelöst und zweimal mit je 80 ml Äther gewaschen. Die Bicarbonatlösung wird mit konz. Salzsäure auf pH 2 eingestellt und dreimal mit je 100 ml Äthylacetat extrahiert. Die Äthylacetlösungen werden zweimal mit je 50 ml Wasser gewaschen, mit Magnesiumsulfat getrocknet und unter vermindertem Druck   bei 450    eingedampft.

  Die als   Ö1    zurückbleibende (R)2-(2-Furoyloxy)-isocapronsäure wird 2 Stunden bei 0,4 Torr und   40     getrocknet.   [a]D25    =   +7,0     (c = 4,0 in Alkohol).



   Der hierbei als Ausgangsmaterial verwendete (R)-2-(2 Furoyloxy)-isocapronsäurebenzylester ist wie folgt zugänglich:
In einem Dreihalskolben mit Rührer, Thermometer und   Rückflusskühler    mit Calciumchloridrohr werden 264 g (R)-2 Hydroxyisocapronsäure in 1,8 Liter absolutem Dioxan gelöst und nacheinander mit 285 ml Triäthylamin und 236 ml Benzylchlorid versetzt und 20 Stunden unter Rühren in einem Ölbad auf   100"    Innentemperatur erhitzt. Nach dem Abkühlen wird das entstandene Triäthylaminhydrochlorid abfiltriert und mit 500 ml Äthylacetat gewaschen.

  Das Filtrat wird unter vermindertem Druck bei   50     eingedampft, das zurückbleibende Öl in 800 ml Äthylacetat gelöst und zweimal mit je 150 ml 3n Salzsäure, zweimal mit je 100 ml   5proz.    Natriumchloridlösung, zweimal mit je 150 ml   10pro.    Kaliumbicarbonatlösung und zweimal mit je 100 ml Sproz. Natriumchloridlösung gewaschen. Nach jeder dieser Waschungen wird mit 200 ml Äthylacetat nachgewaschen. Die Äthylacetatlösungen werden über Magnesiumsulfat getrocknet und unter vermindertem Druck bei   50     eingedampft. Das so erhaltene Rohprodukt wird bei 0,3 Torr   (112-115 )    destilliert. Man erhält (R)-2-Hydroxyisocapronsäurebenzylester, [a]D25 = +   18,00    (c = 1 in Methanol); nD23 =   ,498.   



   Zu einer Lösung von 23,6 g Furan-2-carbonsäure in 100 ml Pyridin werden bei   25"    unter Rühren innerhalb 20 Minuten 27 ml Benzolsulfochlorid getropft. Anschliessend wird 30 Minuten bei   25     gerührt. Dann werden unter Rühren 44,4 g (R)-2-Hydroxy-isocapronsäurebenzylester zugetropft. Die Lösung wird entweder 2 Stunden auf   60     erwärmt oder 20 Stunden bei   25     gerührt.



   Das Pyridin wird unter vermindertem Druck bei   30-50"    abdestilliert. Der Rückstand wird unter Eiszusatz in 600 ml 3n Salzsäure gelöst und zweimal mit je 250 ml Äthylacetat extrahiert. Die Äthylacetatlösungen werden mit 100 ml 3n Salzsäure, zweimal mit je 100 ml Wasser, zweimal mit je 100 ml   5proz.    Natriumbicarbonatlösung und zweimal mit je 100 ml Wasser gewaschen und mit Magnesiumsulfat getrocknet. Das Äthylacetat wird unter vermindertem Druck bei   40     abdestilliert und das verbleibende   Öl 60    Minuten unter vermindertem Druck bei   60     getrocknet. Man erhält (R)-2-(2 Furoyloxy)-isocapronsäurebenzylester, [a]D25 =   +9,0    (c = 4,0 in Alkohol).

 

   Beispiel 2
Die R-2-(Isonicotinoyloxy)-isocapronsäure, Smp. 138 bis   139 ,    [a]D25 =   +22,3     (c = 3 in Äthanol), wird über ihren   Benzylester in Analogie zu den in Beispiel 1 enthaltenen Angaben erhalten.



   Beispiel 3
14,2 g (S)-Pyroglutaminsäure werden in 60 ml Dimethylformamid suspendiert und mit 15,4 ml Triäthylamin in Lösung gebracht.   Bei 600    gibt man unter Rühren innert 20 Minuten 52 ml einer 5,2molaren Lösung von Phosgen in Toluol zu und nach weiteren 5 Minuten unter starkem Rühren eine auf -40   bis -50"    vorgekühlte Lösung von 22,2 g (R)-2-Hydroxyisocapronsäurebenzylester in 80 ml Pyridin zu. Danach belässt man 16 Stunden bei   2-4"    und dampft unter vermindertem Druck bei trockeneisgekühlter Vorlage ein. Den Rückstand nimmt man in Äther auf und wäscht je dreimal mit in Salzsäure, Wasser,   10pro.    Kaliumbicarbonat und Wasser, trocknet über Natriumsulfat und dampft unter vermindertem Druck ein.

  Der den   (R)-2-[(S)-Pyroglutamoyloxy]-isocapronsäure-    benzylester enthaltende Rückstand wird in   Eisessigfwasser      (95 :5)    mit   5proz.    Palladiumkohle hydriert, bis kein Wasserstoff mehr aufgenommen wird. Dann wird vom Katalysator abfiltriert und unter vermindertem Druck eingedampft. Nach Kristallisation des Rückstandes aus Äthylacetat/Petroläther erhält man 11 g   (R)-2-[(S)-Pyroglutamoyloxy-isocapron-    säure vom Smp.   148-150     (nach Umwandlung bei   80 );    [a]D25 =   +20,4     (c = 1,0 in Methanol).



   Beispiel 4
Die (R)-2-(5-Brom-2-furoyloxy)-isocapronsäure kann über ihren tert.-Butylester in Analogie zu den in Beispiel 14 enthaltenen Angaben erhalten werden.



   Beispiel 5
Die (R)-2-(2,6-Dimethoxyisonicotinoyloxy)-isocapronsäure, Smp.   79-81",    [a]D25 =   +12,2     (c = 2 in Äther), wird über den entsprechenden Benzylester in Analogie zu den in Beispiel 1 enthaltenen Angaben erhalten.



   Beispiel 6
Die (R)-2-(5-Methyl-2-furoyloxy)-isocapronsäure wird über ihren Benzylester in Analogie zu den in Beispiel 1 enthaltenen Angaben erhalten.



   Beispiel 7
Die (R)-2-(2-Benzoylfuroyloxy)-isocapronsäure wird über ihren Benzylester in Analogie zu den in Beispiel 1 enthaltenen Angaben erhalten.



   Beispiel 8
Die   (R)-2-(3-Methyl-5-isoxazolyl-carbonyloxy)-iso-    capronsäure, Smp.   59-62",    [a]D25 =   +13     (c = 2 in Äthanol), wird über ihren Benzylester in Analogie zu den in Beispiel 1 enthaltenen Angaben erhalten.



   Beispiel 9
Die (RS)-2-(3-Furoyloxy)-isocapronsäure, Smp. 85 bis   87 ,    wird über ihren Benzylester in Analogie zu den in Beispiel 1 enthaltenen Angaben die Herstellung des Ausgangsmaterials erhalten.



   Beispiel 10
Die (S)-2-(2-Furoyloxy)-isocapronsäure,   [an25      = -70    (c = 4 in Äthanol), wird über ihren Benzylester in Analogie zu den in Beispiel 1 enthaltenen Angaben erhalten.



   Beispiel 11
Die   (R)-2-[(1,2,3,6-Tetrahydro-2,6-dioxo-4-pyr-      imidinyl)-carbonyloxy]-isocapronsäure,    Smp.   94960,      [a]D25    =   +15,5     (c = 2 in Methanol), wird über ihren Benzylester in Analogie zu den in Beispiel 1 enthaltenen Angaben erhalten.



   Beispiel 12
Die   (R)-2-(1-Methyl-4-imidazolylcarbonyloxy)-iso-    capronsäure wird über ihren Benzylester in Analogie zu den in Beispiel 1 enthaltenen Angaben erhalten.



   Beispiel 13
Die   (R)-2-(4-Isochinolylcarbonyloxy)-isocapronsäure    wird über ihren Benzylester in Analogie zu den in Beispiel 1 enthaltenen Angaben erhalten.



   Beispiel 14
13,0 g 1,2,3-Thiadiazol-4-carbonsäure werden in 100 ml Pyridin suspendiert und bei   25-35"    tropfenweise und unter Rühren innerhalb 20 Minuten mit 12,8 ml Benzolsulfochlorid versetzt. Es wird eine halbe Stunde bei Raumtemperatur weitergerührt, wobei eine klare Lösung entsteht. Unter weiterem Rühren gibt man anschliessend innert 20 Minuten 17,9 g (R)-a-Hydroxyisovaleriansäure-tert.-butylester zu, wobei die Temperatur auf etwa   40     steigt. Nach zweistündigem Rühren bei   60"    wird unter vermindertem Druck eingedampft, in 200 ml Äthylacetat suspendiert und abgenutscht. Der Niederschlag wird mit Äthylacetat zweimal gewaschen, und die vereinigten Filtrate werden dreimal rasch mit eiskalter verd.

  Salzsäure, einmal mit Eiswasser und dreimal mit 10proz.   Kaliumcarbonat-    lösung gewaschen, über Natriumsulfat getrocknet und unter vermindertem Druck eingedampft. Den den (R)-2-(1,2,3   Thiadiazol-4-yl-carbonyloxy) -isocapronsäure-tert.-Butylester    enthaltende Rückstand übergiesst man mit 100 ml Trifluoressigsäure und dampft nach einer halben Stunde unter vermindertem Druck ab, nimmt in Äther auf und extrahiert erschöpfend mit   10proz.    Kaliumbicarbonat. Die vereinigten Bicarbonatauszüge werden auf Kongorot angesäuert und dreimal mit Äthylacetat extrahiert. Nach Waschen, Trocknen und Eindampfen des Lösungsmittels verbleiben 19 g eines kristallisierenden Öls.

  Aus Isopropanol erhält man 12 g (R)-2-(1,2,3 Thiadiazol-4-yl-carbonyloxy)-isocapronsäure vom Smp. 104 bis   105 ,    [a]D25 =   +20,0     (c = 1 in Methanol).



   Beispiel 15
Die (R)-2-(Tetrahydropyran-4-yl-carbonyloxy)-isocapronsäure wird über ihren Benzylester in Analogie zu den in Beispiel 22 enthaltenen Angaben erhalten.



   Beispiel 16
19,2 g 1,5-Dimethylpyrazol-3-carbonsäure werden mit 80 ml Thionylchlorid 20 Minuten am Rückfluss erhitzt und anschliessend unter vermindertem Druck vom überschüssigen Thionylchlorid befreit. Es wird noch zweimal mit Toluol unter vermindertem Druck eingedampft, danach in 100 ml Toluol aufgenommen und bei   0"    unter Rühren zu 22,4 g (R)-a-Hydroxyisocapronsäure-tert. -butylester in 80 ml Pyridin getropft.



  Nach zwei Stunden Rühren bei Raumtemperatur wird unter vermindertem Druck eingedampft, in Äther aufgenommen und mit Wasser und 10proz. Kaliumbicarbonat je dreimal gewaschen. Nach Trocknen und Abdampfen des Lösungsmittels verbleibt ein unter Petroläther kristallisierender Rückstand von 25,5 g; Smp.   69-71".    Dieser den (R)-2-(1,4-Dimethyl   pyrazol-3-ylcarbonyloxy)-isocapronsäure-tert.-butylester    enthaltende Rückstand wird mit 50 ml Trifluoressigsäure 30 Minuten bei Raumtemperatur stehengelassen und nach Abdampfen im Vakuum in Äther gelöst und erschöpfend mit   10pro.   

 

  Kaliumbicarbonat extrahiert. Nach   Ansäuem    der Bicarbonatauszüge auf Kongorot wird mit Äther extrahiert, und der Äther wird nach Waschen und Trocknen- unter vermindertem Druck eingedampft. Der verbleibende Rückstand wird aus Äthyl  acetat umkristallisiert: 16 g (R)-2-(1,5-Dimethylpyrazol-3ylcarbonyloxy)-isocapronsäure; Smp.   155-161",      [am25    =   +13,1     (c= 1,0 in Methanol).



   Beispiel 17
14,4 g 2-Acetamido-4-thiazolcarbonsäure, suspendiert in 200 ml Dimethylformamid, werden mit 11,9 ml Triäthylamin in Lösung gebracht. Bei   160    und starkem Rühren wird langsam mit 38,1 ml einer 2,86molaren Lösung von Phosgen in Toluol versetzt, und danach wird eine auf   ca. 50    vorgekühlte Lösung von 14,6 g (R) -2-Hydroxyisocapronsäure-tert.-butylester in 50 ml Pyridin in einem Guss zugesetzt. Nachdem die Reaktionsmischung Raumtemperatur angenommen hat, wird sie unter vermindertem Druck eingedampft, der Rückstand in Äther aufgenommen und je dreimal mit Wasser und   10proz.   



  Kaliumbicarbonatlösung gewaschen, getrocknet und unter vermindertem Druck wiederum eingedampft. Es verbleiben 26   g kristalline    Masse, welche den (R)-2-(2-Acetamido-4   thiazolcarbonyloxy) -isocapronsäure-tert.-butylester    enthält.



  Diese Masse wird mit 100 ml Trifluoressigsäure 30 Minuten bei Raumtemperatur stehengelassen. Nach Entfernen des Lösungsmittels unter vermindertem Druck nimmt man in Äther auf und extrahiert erschöpfend mit   10pro.    Kaliumbicarbonatlösung. Nach Ansäuern der wässrigen Lösung auf pH 3 wird dreimal mit Äthylacetat extrahiert und der Extrakt nach Waschen mit Wasser und Trocknen über Natriumsulfat unter vermindertem Druck eingedampft. Die (R)-2-(2-Acetamido-4thiazolcarbonyloxy)-isocapronsäure verbleibt dabei als nichtkristallisierendes Harz.



   Beispiel 18
Die   (R)-2-[(RS)-(Tetrahydro-2-furoyloxyj-isocapron-    säure, [a]D25   = -7"    (c = 4 in Äthanol), wird über ihren Benzylester in Analogie zu den in Beispiel 1 enthaltenen Angaben erhalten.



   Beispiel 19
Die (RS)-2-(2-Furoyloxy)-valeriansäure, Smp.   53-56",    wird über ihren Benzylester in Analogie zu den in Beispiel 35 enthaltenen Angaben erhalten.



   Beispiel 20
Die   (RS)-2-(1 ,6-Dihydro-6-oxonicotionyloxy)-isocapron-    säure, Smp.   167-170",    wird über ihren Benzylester in Analogie zu den in Beispiel 35 enthaltenen Angaben erhalten.



   Beispiel 21
Die   (R) -2-(Pyrazinylcarb onyloxy) -isocapronsäure    wird über ihren tert.-Butylester in Analogie zu den in Beispiel 17 enthaltenen Angaben erhalten.



   Beispiel 22
17,8 g Nicotinoylchlorid-hydrochlorid werden in 150 ml Pyridin und 50 ml Dimethylformamid gelöst und unter Rühren langsam bei maximal   15"    mit 22,2 g (R)-2-Hydroxyisovaleriansäurebenzylester [hergestellt durch Umsetzung von (R)-2-Hydroxyisovaleriansäure und Benzylchlorid analog zu den entsprechenden Angaben in Beispiel 1] versetzt. Nach zwei Stunden Rühren bei Raumtemperatur wird unter vermindertem Druck eingedampft. Den Rückstand nimmt man in Äther auf, wäscht dreimal mit Wasser und extrahiert sechsmal mit eiskalter 3n Salzsäure. Die salzsauren Phasen werden sofort in gesättigte Kaliumbicarbonatlösung einlaufengelassen, und die so freigesetzte Base wird dreimal mit Äther extrahiert.



  Nach Waschen und Trocknen wird unter vermindertem Druck eingedampft, wobei man 27 g eines den (R)-2-(Nicotinoyloxy)-isocapronsäurebenzylester enthaltenden Harzes erhält.



  Dieses wird in 200 ml Äthanol mit 2 g Sproz. Palladiumkohle bis zur Aufnahme von 2 Äquivalenten Wasserstoff hydriert.



  Nach Nutschen und Eindampfen wird in 10proz. Kaliumbicarbonat aufgenommen, zweimal mit Äther gewaschen und mit Citronensäure auf pH 3 gestellt. Nach Extraktion mit Äther, Waschen, Trocknen und Eindampfen des Extrakts erhält man ein kristallisierendes Öl. Aus Essigester/Petroläther kristallisieren 14 g (R)-2-(Nicotinoyloxy)-isocapronsäure vom Smp.   101-103 ,    [a]D25 =   +18,8     (c = 1,0 in Methanol).



   Das N-Oxid erhält man aus 26,4 g der Säure in 70 ml Eisessig durch dreistündiges Behandeln mit 11 ml 30proz.



  Wasserstoffperoxid bei   70-80 .    Nach weiterer Zugabe von 8 ml 30proz. Wasserstoffperoxid wird über Nacht bei derselben Temperatur belassen. Unter vermindertem Druck wird vorsichtig eingedampft und zweimal mit je 50 ml Wasser abgedampft, wobei nie bis zur Trockene eingedampft werden darf. Den Rückstand nimmt man in Chloroform auf, wäscht viermal mit Wasser, trocknet und dampft unter vermindertem Druck ein. Aus Äthylacetat kristallisieren 19 g (R)-2-Nicotinoyloxy-isocapronsäure-N-oxid vom Smp.   132134o,      [ai25    =   +20,8     (c = 1,0 in Methanol).



   Beispiel 23
Die (R)-2-(4-Chlorpicolinoyloxy)-isocapronsäure, Smp.



     120-122",    wird über ihren tert.-Butylester in Analogie zu den in Beispiel 17 enthaltenen Angaben erhalten.



   Beispiel 24
Die   (R)-2-(2,6-Dichlorisonicotinoyloxy)-isocapronsäure,    Smp.   79-81"    (Zersetzung), wird über ihren tert.-Butylester in Analogie zu den in Beispiel 16 enthaltenen Angaben erhalten.



   Beispiel 25
Die   (R)-2-(4-Oxazolylcarbonyloxy) -isocapronsäure    wird über ihren Benzylester in Analogie zu den in Beispiel 1 enthaltenen Angaben erhalten.



   Beispiel 26
Die   (R) -2-(2-Methylisonicotinoyloxy)-isocapronsäure    wird über ihren Benzylester in Analogie zu den in Beispiel 22 enthaltenen Angaben erhalten.



   Beispiel 27
Die (R)-2-(3-Isoxazolylcarbonyloxy)-isocapronsäure wird über ihren Benzylester in Analogie zu den in Beispiel 1 enthaltenen Angaben erhalten.



   Beispiel 28
Die   (R)-2-(3 -Indolylcarbonyloxy)-isocapronsäure    wird über ihren Benzylester in Analogie zu den in Beispiel 1 enthaltenen Angaben erhalten.

 

   Beispiel 29
Die (S)-2-(Isonicotionyloxy)-isocapronsäure, Smp. 138 bis   139 ,    [a]D25 =   +22,3     (c = 2 in Äthanol) erhält man über ihren Benzylester in Analogie zu den in Beispiel 1 enthaltenen Angaben.



   Beispiel 30
Die (RS)-2-(2,6-Dimethylisonicotinoyloxy)-isocapronsäure, Smp.   95-96 ,    erhält man über ihren Benzylester in Analogie zu den in Beispiel 35 enthaltenen Angaben.



   Beispiel 31
Die verwendete (R) -2-(Cinchoninoyloxy) -isocapronsäure erhält man über ihren Benzylester in Analogie zu den in Beispiel 1 enthaltenen Angaben.



   Beispiel 32
Die   (R) -2-(7-Chlorcinchoninoyloxy) -isocapronsäure    wird über ihren Benzylester in Analogie zu den in Beispiel 1 enthaltenen Angaben erhalten.  



   Beispiel 33
Die (R)-2-(2-Chlornicotinoyloxy)-isocapronsäure, Smp.



     64-67 ,    [a]D25 =   +17,5     (c = 1 in Methanol) wird über ihren tert.-Butylester in Analogie zu den in Beispiel 16 enthaltenen Angaben über die Herstellung des Ausgangsmaterials erhalten.



   Beispiel 34
Die (R)-2-(Chinaldoyloxy)-isocapronsäure wird über ihren Benzylester in Analogie zu den in Beispiel 22 enthaltenen Angaben erhalten.



   Beispiel 35
Zu einer Lösung von 12,8 g Isonicotinsäure in einem Gemisch von 60 ml Dimethylformamid und 14,8 ml Triäthylamin werden bei   60     unter Rühren innerhalb 15 Minuten 29,5 g (RS)-a-Bromisocapronsäurebenzylester zugetropft. Das Reaktionsgemisch wird 5 Stunden bei   90"    gerührt. Das Triäthylaminhydrobromid wird abgesaugt und das Filtrat unter vermindertem Druck bei   60     eingedampft. Der Rückstand wird in 100 ml Äthylacetat gelöst, filtriert und das Filtrat dreimal mit je 15 ml   1n    Kaliumbicarbonatlösung und zweimal mit je 20 ml Wasser gewaschen. Die Äthylacetatlösung wird mit Magnesiumsulfat getrocknet und unter vermindertem Druck bei   45"    eingedampft. Der RS-2-(Isonicotinoyloxy)-isocapronsäurebenzylester wird als Öl erhalten.



   Zur Reinigung wird dieser Ester in 10 ml Äthylacetat gelöst, mit einer Lösung von 19 g p-Toluolsulfonsäure in 35 ml Äthylacetat vermischt und während 2 Stunden bei   0     kristallisiert. Das (RS)-2- (Isonicotinoyloxy) -isocapronsäurebenzylester-p-toluolsulfonat wird abgesaugt, mit 100 ml Äther gewaschen und unter vermindertem Druck bei   60     getrocknet; Smp.   136".    Das p-Toluolsulfonat wird in 30 ml Wasser gelöst, mit Kaliumcarbonat auf pH 9 gestellt und zweimal mit je 50 ml Äthylacetat extrahiert. Die Äthylacetatlösung wird zweimal mit je 10 ml Wasser gewaschen, mit Magnesiumsulfat getrocknet und unter vermindertem Druck bei   40     eingedampft.

  Das Öl ergibt nach Kristallisation aus tiefsiedendem Petroläther den (RS)-2-(Isonicotinoyloxy)-isocapronsäurebenzylester, Smp.   49-50 .   



   8,2 g   (RS)-2-(Isonicotinoyloxy)-lsocapronsäurebenzyl-    ester werden in 50 ml Alkohol nach Zusatz von 800 mg Palladiumkohle (5proz.) bis zur Aufnahme der theoretischen Menge Wasserstoff hydriert. Der Katalysator wird abfiltriert und das Filtrat unter vermindertem Druck bei   45"    eingedampft. Das Öl wird in überschüssiger Natriumbicarbonatlösung gelöst, dreimal mit je 20 ml Äther extrahiert und die Bicarbonatlösung mit 3n Salzsäure auf pH 2,5 gestellt. Die saure Lösung wird zweimal mit je 70 ml Äthylacetat extrahiert. Nach zweimaligem Waschen mit je 20 ml Sproz. Natriumchloridlösung wird die Äthylacetatlösung mit Magnesiumsulfat getrocknet, unter vermindertem Druck bei   45"    eingedampft und das zurückbleibende Öl aus Äther-Petroläther kristallisiert.

  Man erhält   (RS)-2-(Isonicotinoyloxy)-iso-    capronsäure, Smp.   98-100".   



   Beispiel 36
Die (RS)-2-(Isonicotinoyloxy)-valeriansäure (Smp. 152 bis   153 )    wird über ihren Benzylester in Analogie zu den in Beispiel 35 enthaltenen Angaben erhalten.



   Beispiel 37
Die (R)-2-(Nicotinoyloxy)-isocapronsäure wird über ihren Benzylester in Analogie zu den in Beispiel 22 enthaltenen Angaben erhalten.



   Beispiel 38
Die (R)-2-(2-Thenoyloxy)-isocapronsäure [[a]D25 =    t 13,70    (c = 2 in Äthanol)] wird über ihren tert.-Butylester in
Analogie zu den in Beispiel 16 enthaltenen Angaben erhalten.



   Beispiel 39
Die 2-(2-Pyrrolylcarbonyloxy)-isocapronsäure wird über ihren Benzylester in Analogie zu den in Beispiel 35 enthaltenen Angaben erhalten.



   Beispiel 40
Die (R)-2-(1-Oxido-isonicotinoyloxy)-isocapronsäure [Smp.   168-169 ,    [a]D25 =   +4,2     (c = 2 in Äthanol)] erhält man über ihren Benzylester in Analogie zu den in Beispiel 22 enthaltenen Angaben.



   Beispiel 41
Die   (R) -2-(2,4-Dimethyl-5 -pyrimidinylcarbonyloxy)-    isocapronsäure, eine ölige Substanz, wird über ihren Benzylester in Analogie zu den in Beispiel 1 enthaltenen Angaben erhalten.



   Beispiel 42
Die (R)-2-(5-Pyrimidinylcarbonyloxy)-isocapronsäure, eine ölige Substanz, wird über ihren Benzylester in Analogie zu den in Beispiel 1 enthaltenen Angaben erhalten.



   Beispiel 43
Die (R)-2-(2-Methoxycarbonyl-nicotinoyloxy)-isocapronsäure [Smp.   63-65 ,    [a]D25 =   +27,1     (c = 1 in Me   thanol)]    wird über ihren Benzylester in Analogie zu den in Beispiel 3 enthaltenen Angaben erhalten.

 

   Beispiel 44
Die (R)-2-(5-Methoxymethyl-2-furoyloxy)-isocapronsäure (Smp.   73-74 )    wird über ihren Benzylester in Analogie zu den in Beispiel 1 enthaltenen Angaben erhalten.



   Beispiel 45
Die (R)-2-[(S)-5-Oxotetrahydro-2-furoyloxy]-isocapronsäure [Smp.   115-116 ;      [a]D25    =   +23,4     (c = 0,5 in Dioxan)] erhält man über ihren Benzylester in Analogie zu den in Beispiel 22 enthaltenen Angaben.



   Beispiel 46
Die (R)-2-[(R)-5-Oxotetrahydro-2-furoyloxy]-isocapronsäure, eine ölige Substanz, erhält man über ihren Benzylester in Analogie zu den in Beispiel 22 enthaltenen An gaben. 



  
 



   The invention relates to a process for the preparation of new disubstituted acetic acid derivatives of the formula
EMI1.1
 where T is a Qs-alkyl or alkenyl radical or the cyclopropylmethyl, cyclobutylmethyl or cyclopentyl radical and A is furyl, tetrahydrofuryl, pyrrolyl, pyrrolidinyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-thiadiazolyl, imidazolyl, pyidrazole, 1-oxidopyridyl, tetrahydropyranyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, quinolyl or isoquinolyl and where the radicals A are optionally substituted by halogen, oxo, hydroxy, amino, C1¯3-alkoxy, C1-alkoxycarbonyl, C13-alkanoylamino and / or optionally substituted C1-3 alkyl can be substituted.



   Particularly suitable halogen substituents are fluorine, chlorine and bromine. C1¯3-alkyl, alkoxy, alkoxycarbonyl and alkanoylamino groups are those in which the alkyl part contains 1-3 carbon atoms. An alkyl or alkenyl group in the T substituent can be straight-chain or branched. Examples of such groups are ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, 3-methylbutyl, neopentyl or vinyl, allyl, methallyl, butenyl and pentenyl.



   Preferred groups A in formula I of the compounds available according to the invention are 3-pyridyl, 2-methyl-4-pyridyl, 3-isoxazolyl, 4-oxazolyl, 2-oxo-2-pyrrolidinyl, pyrazinyl, tetrahydro-2-furyl, 2-acetamido- 4-thiazolyl, 1,5-dimethyl-3-pyrazolyl, tetrahydro-4-pyranyl, 1,2,3-thiadiazol-4-yl, 2-furyl or 4-pyridyl.



   Preferred groups T in the formula I of the compounds obtainable according to the invention are alkyl or alkenyl groups having 4 to 5 carbon atoms. Preferred compounds are also those listed in the table given below. Particularly preferred is the compound of the formula I in which A is 2-furyl and T is 2-methylpropyl, d. H. 1- (2-furoyloxy) -3-methylbutyl-penicillin, especially the R-form and its salts.



   The acids of the formula I obtainable according to the invention can be used in optically uniform form or also as racemates. The R enantiomers are preferably used.



   The compounds of the formula I mentioned are prepared according to the invention by converting a compound of the formula
EMI1.2
 where B represents a carboxyl group protected by a catalytically or hydrolytically cleavable protective group, which cleaves the protective group either by catalytic hydrogenation or hydrolytically.



   The protected carboxyl group B can be an easily cleavable ester group, for example the benzyl or tert. Butyl ester group. In the case of the benzyl ester, the protected carboxyl group B can be converted into the free carboxyl group by catalytic hydrogenation using a noble metal catalyst, e.g. B. palladium-carbon, in the case of the tert-butyl ester by treatment with acid, for. B. with a mineral acid such as hydrochloric acid, or with trifluoroacetic acid.



   The starting compounds of the formula II can be obtained in a manner known per se by removing the carboxyl group of a compound of the formula
EMI1.3
 protects, for example by forming the benzyl ester or the tert-butyl ester, and the compound obtained is reacted with a compound of the formula A-COOH, for example with the mediation of benzenesulfonyl chloride.



   The products of the process are valuable intermediate products for the production of antibiotics, for example the penicillins of the formula I listed in Swiss Patent No. 580 631.



   example 1
55.5 g of benzyl (R) -2- (2-furoyloxy) isocaproate are hydrogenated in 400 ml of alcohol after adding 5 g of palladium carbon (sproz.) Until the theoretical amount of hydrogen has been absorbed. The catalyst is filtered off with suction and the filtrate is evaporated under reduced pressure at 40 ° C. The remaining oil is dissolved in 250 ml of 8% sodium bicarbonate solution and washed twice with 80 ml of ether each time. The bicarbonate solution is adjusted to pH 2 with concentrated hydrochloric acid and three times with 100 ml of ethyl acetate each time are extracted The ethyl acetate solutions are washed twice with 50 ml of water each time, dried with magnesium sulphate and evaporated at 450 ° C. under reduced pressure.

  The (R) 2- (2-furoyloxy) -isocaproic acid remaining as oil is dried at 0.4 torr and 40 for 2 hours. [a] D25 = +7.0 (c = 4.0 in alcohol).



   The (R) -2- (2 furoyloxy) -isocaproic acid benzyl ester used here as starting material can be obtained as follows:
In a three-necked flask equipped with a stirrer, thermometer and reflux condenser with calcium chloride tube, 264 g of (R) -2-hydroxyisocaproic acid are dissolved in 1.8 liters of absolute dioxane, and 285 ml of triethylamine and 236 ml of benzyl chloride are added one after the other and heated to 100 "for 20 hours while stirring in an oil bath After cooling, the triethylamine hydrochloride formed is filtered off and washed with 500 ml of ethyl acetate.

  The filtrate is evaporated under reduced pressure at 50, the remaining oil is dissolved in 800 ml of ethyl acetate and twice with 150 ml of 3N hydrochloric acid, twice with 100 ml of 5%. Sodium chloride solution, twice with 150 ml 10pro each. Potassium bicarbonate solution and twice with 100 ml Sproz. Washed sodium chloride solution. After each of these washings, it is rewashed with 200 ml of ethyl acetate. The ethyl acetate solutions are dried over magnesium sulfate and evaporated at 50 under reduced pressure. The crude product thus obtained is distilled at 0.3 torr (112-115). (R) -2-Hydroxyisocaproic acid benzyl ester is obtained, [a] D25 = + 18.00 (c = 1 in methanol); nD23 =. 498.



   To a solution of 23.6 g of furan-2-carboxylic acid in 100 ml of pyridine, 27 ml of benzenesulphonyl chloride are added dropwise at 25 "with stirring over the course of 20 minutes. The mixture is then stirred for 30 minutes at 25. Then, with stirring, 44.4 g of (R) 2-Hydroxy-isocaproic acid benzyl ester is added dropwise in. The solution is either heated to 60 for 2 hours or stirred at 25 for 20 hours.



   The pyridine is distilled off under reduced pressure at 30-50 ". The residue is dissolved in 600 ml of 3N hydrochloric acid with the addition of ice and extracted twice with 250 ml of ethyl acetate each time. The ethyl acetate solutions are mixed with 100 ml of 3N hydrochloric acid, twice with 100 ml of water each time, twice Washed with 100 ml of 5% sodium bicarbonate solution each time and twice with 100 ml of water each time and dried with magnesium sulfate. The ethyl acetate is distilled off under reduced pressure at 40 and the remaining oil is dried for 60 minutes under reduced pressure at 60. This gives (R) -2- Benzyl (2 furoyloxy) isocaproate, [a] D25 = +9.0 (c = 4.0 in alcohol).

 

   Example 2
The R-2- (isonicotinoyloxy) -isocaproic acid, melting point 138 to 139, [a] D25 = +22.3 (c = 3 in ethanol), is obtained via its benzyl ester in analogy to the information given in Example 1.



   Example 3
14.2 g of (S) -pyroglutamic acid are suspended in 60 ml of dimethylformamide and dissolved with 15.4 ml of triethylamine. At 600, 52 ml of a 5.2 molar solution of phosgene in toluene are added within 20 minutes with stirring and, after a further 5 minutes, a solution of 22.2 g (R) -2- precooled to -40 to -50 "is added with vigorous stirring. Hydroxyisocaproic acid benzyl ester in 80 ml of pyridine is then left for 16 hours at 2-4 "and evaporated under reduced pressure from a dry ice-cooled receiver. The residue is taken up in ether and washed three times each with hydrochloric acid, water, 10pro. Potassium bicarbonate and water, dry over sodium sulfate and evaporate under reduced pressure.

  The residue containing the (R) -2 - [(S) -Pyroglutamoyloxy] -isocaproic acid benzyl ester is dissolved in glacial acetic water (95: 5) at 5%. Palladium carbon hydrogenates until no more hydrogen is absorbed. The catalyst is then filtered off and evaporated under reduced pressure. After crystallization of the residue from ethyl acetate / petroleum ether, 11 g of (R) -2 - [(S) -pyroglutamoyloxy-isocaproic acid of melting point 148-150 (after conversion at 80) are obtained; [a] D25 = +20.4 (c = 1.0 in methanol).



   Example 4
The (R) -2- (5-bromo-2-furoyloxy) -isocaproic acid can be obtained via its tert-butyl ester in analogy to the information given in Example 14.



   Example 5
The (R) -2- (2,6-dimethoxyisonicotinoyloxy) -isocaproic acid, m.p. 79-81 ", [a] D25 = +12.2 (c = 2 in ether), is via the corresponding benzyl ester in analogy to the information contained in Example 1 obtained.



   Example 6
The (R) -2- (5-methyl-2-furoyloxy) -isocaproic acid is obtained via its benzyl ester in analogy to the information given in Example 1.



   Example 7
The (R) -2- (2-benzoylfuroyloxy) -isocaproic acid is obtained via its benzyl ester in analogy to the information given in Example 1.



   Example 8
The (R) -2- (3-methyl-5-isoxazolyl-carbonyloxy) -isocaproic acid, m.p. 59-62 ", [a] D25 = +13 (c = 2 in ethanol), is via its benzyl ester in Analogously to the information contained in Example 1 obtained.



   Example 9
The (RS) -2- (3-furoyloxy) -isocaproic acid, melting point 85 to 87, is obtained via its benzyl ester in analogy to the information given in Example 1 for the preparation of the starting material.



   Example 10
The (S) -2- (2-furoyloxy) -isocaproic acid, [an25 = -70 (c = 4 in ethanol), is obtained via its benzyl ester in analogy to the information given in Example 1.



   Example 11
The (R) -2 - [(1,2,3,6-tetrahydro-2,6-dioxo-4-pyr-imidinyl) -carbonyloxy] -isocaproic acid, m.p. 94960, [a] 25 D = +15.5 (c = 2 in methanol) is obtained via its benzyl ester in analogy to the information contained in Example 1.



   Example 12
The (R) -2- (1-methyl-4-imidazolylcarbonyloxy) isocaproic acid is obtained via its benzyl ester in analogy to the information given in Example 1.



   Example 13
The (R) -2- (4-isoquinolylcarbonyloxy) isocaproic acid is obtained via its benzyl ester in analogy to the information given in Example 1.



   Example 14
13.0 g of 1,2,3-thiadiazole-4-carboxylic acid are suspended in 100 ml of pyridine and, at 25-35 ", 12.8 ml of benzenesulfochloride are added dropwise and with stirring over the course of 20 minutes. Stirring is continued for half an hour at room temperature A clear solution is formed. With further stirring, 17.9 g of tert-butyl (R) -a-hydroxyisovaleric acid are then added over the course of 20 minutes, the temperature rising to about 40. After stirring for two hours at 60 ", evaporated under reduced pressure, suspended in 200 ml of ethyl acetate and suction filtered. The precipitate is washed twice with ethyl acetate, and the combined filtrates are washed three times quickly with ice-cold dil.

  Hydrochloric acid, once with ice water and three times with 10 percent. Washed potassium carbonate solution, dried over sodium sulfate and evaporated under reduced pressure. The residue containing the (R) -2- (1,2,3 thiadiazol-4-yl-carbonyloxy) -isocaproic acid tert-butyl ester is poured over with 100 ml of trifluoroacetic acid and evaporated after half an hour under reduced pressure, takes in Ether and extract exhaustively with 10 per cent. Potassium bicarbonate. The combined bicarbonate extracts are acidified to Congo red and extracted three times with ethyl acetate. After washing, drying and evaporating the solvent, 19 g of a crystallizing oil remain.

  From isopropanol, 12 g of (R) -2- (1,2,3 thiadiazol-4-yl-carbonyloxy) -isocaproic acid of melting point 104 to 105, [a] D25 = +20.0 (c = 1 in methanol ).



   Example 15
The (R) -2- (tetrahydropyran-4-yl-carbonyloxy) -isocaproic acid is obtained via its benzyl ester in analogy to the information given in Example 22.



   Example 16
19.2 g of 1,5-dimethylpyrazole-3-carboxylic acid are refluxed with 80 ml of thionyl chloride for 20 minutes and then freed from excess thionyl chloride under reduced pressure. It is evaporated twice more with toluene under reduced pressure, then taken up in 100 ml of toluene and added dropwise at 0 "with stirring to 22.4 g of tert-butyl (R) -a-hydroxyisocaproate in 80 ml of pyridine.



  After two hours of stirring at room temperature, it is evaporated under reduced pressure, taken up in ether and washed with water and 10proz. Potassium bicarbonate washed three times each. After drying and evaporation of the solvent there remains a residue of 25.5 g which crystallizes under petroleum ether; Melting point 69-71 ". This residue containing (R) -2- (1,4-dimethylpyrazol-3-ylcarbonyloxy) -isocaproic acid tert-butyl ester is left to stand with 50 ml of trifluoroacetic acid for 30 minutes at room temperature and, after evaporation, in Vacuum dissolved in ether and exhausted with 10pro.

 

  Potassium bicarbonate extracted. After acidification of the bicarbonate extracts on Congo red, it is extracted with ether and, after washing and drying, the ether is evaporated under reduced pressure. The remaining residue is recrystallized from ethyl acetate: 16 g of (R) -2- (1,5-dimethylpyrazole-3ylcarbonyloxy) isocaproic acid; 155-161 ", [am25 = +13.1 (c = 1.0 in methanol).



   Example 17
14.4 g of 2-acetamido-4-thiazolecarboxylic acid, suspended in 200 ml of dimethylformamide, are brought into solution with 11.9 ml of triethylamine. With 160 and vigorous stirring, 38.1 ml of a 2.86 molar solution of phosgene in toluene are slowly added, and then a solution of 14.6 g of tert-butyl (R) -2-hydroxyisocaproate, which has been precooled to about 50, is added in 50 ml of pyridine added in one pour. After the reaction mixture has assumed room temperature, it is evaporated under reduced pressure, the residue is taken up in ether and each time with water and 10proz.



  Washed potassium bicarbonate solution, dried and again evaporated under reduced pressure. There remain 26 g of crystalline material which contains the tert-butyl (R) -2- (2-acetamido-4-thiazolcarbonyloxy) isocaproate.



  This mass is left to stand with 100 ml of trifluoroacetic acid for 30 minutes at room temperature. After removing the solvent under reduced pressure, it is taken up in ether and extracted exhaustively with 10pro. Potassium bicarbonate solution. After acidifying the aqueous solution to pH 3, it is extracted three times with ethyl acetate and, after washing with water and drying over sodium sulfate, the extract is evaporated under reduced pressure. The (R) -2- (2-acetamido-4thiazolcarbonyloxy) -isocaproic acid remains as a non-crystallizing resin.



   Example 18
The (R) -2 - [(RS) - (tetrahydro-2-furoyloxy-isocaproic acid, [a] D25 = -7 "(c = 4 in ethanol), via its benzyl ester in analogy to that in Example 1 received information.



   Example 19
The (RS) -2- (2-furoyloxy) valeric acid, melting point 53-56 ", is obtained via its benzyl ester in analogy to the information given in Example 35.



   Example 20
The (RS) -2- (1,6-dihydro-6-oxonicotionyloxy) -isocaproic acid, melting point 167-170 ", is obtained via its benzyl ester in analogy to the information given in Example 35.



   Example 21
The (R) -2- (pyrazinylcarbonyloxy) -isocaproic acid is obtained via its tert-butyl ester in analogy to the information given in Example 17.



   Example 22
17.8 g of nicotinoyl chloride hydrochloride are dissolved in 150 ml of pyridine and 50 ml of dimethylformamide and, while stirring, slowly at a maximum of 15 "with 22.2 g of (R) -2-hydroxyisovaleric acid benzyl ester [prepared by reacting (R) -2-hydroxyisovaleric acid and Benzyl chloride analogous to the corresponding information in Example 1]. After two hours of stirring at room temperature, the mixture is evaporated under reduced pressure. The residue is taken up in ether, washed three times with water and extracted six times with ice-cold 3N hydrochloric acid. The hydrochloric acid phases are immediately converted into saturated potassium bicarbonate solution is run in, and the base thus released is extracted three times with ether.



  After washing and drying, the mixture is evaporated under reduced pressure, 27 g of a resin containing benzyl (R) -2- (nicotinoyloxy) isocaproate being obtained.



  This is in 200 ml of ethanol with 2 g of Sproz. Palladium carbon is hydrogenated until 2 equivalents of hydrogen are absorbed.



  After suction filtering and evaporation, in 10proz. Potassium bicarbonate was added, washed twice with ether and adjusted to pH 3 with citric acid. After extraction with ether, washing, drying and evaporation of the extract, a crystallizing oil is obtained. 14 g of (R) -2- (nicotinoyloxy) -isocaproic acid with a melting point of 101-103, [a] 25 D = +18.8 (c = 1.0 in methanol) crystallize from ethyl acetate / petroleum ether.



   The N-oxide is obtained from 26.4 g of the acid in 70 ml of glacial acetic acid by treating with 11 ml of 30% for three hours.



  Hydrogen peroxide at 70-80. After adding 8 ml of 30 percent. Hydrogen peroxide is left at the same temperature overnight. It is carefully evaporated under reduced pressure and evaporated twice with 50 ml of water each time, never evaporating to dryness. The residue is taken up in chloroform, washed four times with water, dried and evaporated under reduced pressure. 19 g of (R) -2-nicotinoyloxy-isocaproic acid-N-oxide of melting point 132134o, [ai25 = +20.8 (c = 1.0 in methanol), crystallize from ethyl acetate.



   Example 23
(R) -2- (4-chloropicolinoyloxy) isocaproic acid, m.p.



     120-122 "is obtained via its tert-butyl ester in analogy to the information contained in Example 17.



   Example 24
The (R) -2- (2,6-dichloroisonicotinoyloxy) isocaproic acid, melting point 79-81 "(decomposition), is obtained via its tert-butyl ester in analogy to the information given in Example 16.



   Example 25
The (R) -2- (4-oxazolylcarbonyloxy) -isocaproic acid is obtained via its benzyl ester in analogy to the information given in Example 1.



   Example 26
The (R) -2- (2-methylisonicotinoyloxy) isocaproic acid is obtained via its benzyl ester in analogy to the information given in Example 22.



   Example 27
The (R) -2- (3-isoxazolylcarbonyloxy) isocaproic acid is obtained via its benzyl ester in analogy to the information given in Example 1.



   Example 28
The (R) -2- (3-indolylcarbonyloxy) -isocaproic acid is obtained via its benzyl ester in analogy to the information given in Example 1.

 

   Example 29
The (S) -2- (isonicotionyloxy) -isocaproic acid, melting point 138 to 139, [a] D25 = +22.3 (c = 2 in ethanol) is obtained via its benzyl ester in analogy to the information given in Example 1.



   Example 30
The (RS) -2- (2,6-dimethylisonicotinoyloxy) -isocaproic acid, melting point 95-96, is obtained via its benzyl ester in analogy to the information given in Example 35.



   Example 31
The (R) -2- (cinchoninoyloxy) -isocaproic acid used is obtained via its benzyl ester in analogy to the information given in Example 1.



   Example 32
The (R) -2- (7-chlorocinchoninoyloxy) -isocaproic acid is obtained via its benzyl ester in analogy to the information given in Example 1.



   Example 33
(R) -2- (2-chloronicotinoyloxy) isocaproic acid, m.p.



     64-67, [a] D25 = +17.5 (c = 1 in methanol) is obtained via its tert-butyl ester in analogy to the information contained in Example 16 on the preparation of the starting material.



   Example 34
The (R) -2- (quinaldoyloxy) -isocaproic acid is obtained via its benzyl ester in analogy to the information given in Example 22.



   Example 35
To a solution of 12.8 g of isonicotinic acid in a mixture of 60 ml of dimethylformamide and 14.8 ml of triethylamine, 29.5 g of benzyl (RS) -a-bromoisocaproate are added dropwise at 60 with stirring over the course of 15 minutes. The reaction mixture is stirred for 5 hours at 90 ". The triethylamine hydrobromide is filtered off with suction and the filtrate is evaporated under reduced pressure at 60. The residue is dissolved in 100 ml of ethyl acetate, filtered and the filtrate with 15 ml of 1N potassium bicarbonate solution each time and 20 ml each time The ethyl acetate solution is dried with magnesium sulfate and evaporated under reduced pressure at 45 ". The benzyl RS-2- (isonicotinoyloxy) isocaproate is obtained as an oil.



   For purification, this ester is dissolved in 10 ml of ethyl acetate, mixed with a solution of 19 g of p-toluenesulfonic acid in 35 ml of ethyl acetate and crystallized at 0 for 2 hours. The (RS) -2- (isonicotinoyloxy) -isocaproic acid benzyl ester-p-toluenesulfonate is filtered off with suction, washed with 100 ml of ether and dried under reduced pressure at 60; Mp. 136 ". The p-toluenesulfonate is dissolved in 30 ml of water, adjusted to pH 9 with potassium carbonate and extracted twice with 50 ml of ethyl acetate each time. The ethyl acetate solution is washed twice with 10 ml of water each time, dried with magnesium sulfate and reduced under reduced pressure 40 evaporated.

  After crystallization from low-boiling petroleum ether, the oil gives benzyl (RS) -2- (isonicotinoyloxy) -isocaproate, mp 49-50.



   8.2 g of (RS) -2- (isonicotinoyloxy) -lsocaproic acid benzyl ester are hydrogenated in 50 ml of alcohol after the addition of 800 mg of palladium carbon (5%) until the theoretical amount of hydrogen is absorbed. The catalyst is filtered off and the filtrate is evaporated under reduced pressure at 45 ". The oil is dissolved in excess sodium bicarbonate solution, extracted three times with 20 ml of ether each time and the bicarbonate solution is adjusted to pH 2.5 with 3N hydrochloric acid. The acidic solution is adjusted twice with 70 ml of ethyl acetate are extracted. After washing twice with 20 ml of sodium chloride solution each time, the ethyl acetate solution is dried with magnesium sulfate, evaporated under reduced pressure at 45 "and the remaining oil is crystallized from ether-petroleum ether.

  (RS) -2- (isonicotinoyloxy) isocaproic acid, melting point 98-100 ", is obtained.



   Example 36
The (RS) -2- (isonicotinoyloxy) valeric acid (melting point 152 to 153) is obtained via its benzyl ester in analogy to the information given in Example 35.



   Example 37
The (R) -2- (nicotinoyloxy) -isocaproic acid is obtained via its benzyl ester in analogy to the information given in Example 22.



   Example 38
The (R) -2- (2-thenoyloxy) -isocaproic acid [[a] D25 = t 13.70 (c = 2 in ethanol)] is converted into a tert-butyl ester in
Analogously to the information contained in Example 16 obtained.



   Example 39
The 2- (2-pyrrolylcarbonyloxy) isocaproic acid is obtained via its benzyl ester in analogy to the information given in Example 35.



   Example 40
The (R) -2- (1-oxido-isonicotinoyloxy) -isocaproic acid [m.p. 168-169, [a] D25 = +4.2 (c = 2 in ethanol)] is obtained via its benzyl ester in analogy to the information given in Example 22.



   Example 41
The (R) -2- (2,4-dimethyl-5-pyrimidinylcarbonyloxy) isocaproic acid, an oily substance, is obtained via its benzyl ester in analogy to the information given in Example 1.



   Example 42
The (R) -2- (5-pyrimidinylcarbonyloxy) -isocaproic acid, an oily substance, is obtained via its benzyl ester in analogy to the information given in Example 1.



   Example 43
(R) -2- (2-methoxycarbonyl-nicotinoyloxy) -isocaproic acid [m.p. 63-65, [a] D25 = +27.1 (c = 1 in methanol)] is obtained via its benzyl ester in analogy to the information contained in Example 3.

 

   Example 44
The (R) -2- (5-methoxymethyl-2-furoyloxy) -isocaproic acid (melting point 73-74) is obtained via its benzyl ester in analogy to the information given in Example 1.



   Example 45
The (R) -2 - [(S) -5-oxotetrahydro-2-furoyloxy] isocaproic acid [m.p. 115-116; [a] D25 = +23.4 (c = 0.5 in dioxane)] is obtained via its benzyl ester in analogy to the information given in Example 22.



   Example 46
The (R) -2 - [(R) -5-oxotetrahydro-2-furoyloxy] isocaproic acid, an oily substance, is obtained via its benzyl ester in analogy to the information contained in Example 22.

Claims (1)

PATENTANSPRUCH PATENT CLAIM Verfahren zur Herstellung von disubstituierten Essigsäure derivaten der Formel EMI4.1 worin T einen C5-Alkyl- oder -Alkenylrest oder den Cyclopropylmethyl- oder Cyclobutylmethylrest oder Cyclopentylrest und A Furyl, Tetrahydrofuryl, Pyrrolyl, Pyrrolidinyl, Thienyl, Oxazolyl, Isoxazolyl, Thiazolyl, 1,2,3-Thiadiazolyl, Imidazolyl, Pyrazolyl, Pyridyl, 1-Oxidopyridyl, Tetrahydropyranyl, Pyrimidinyl, Pyrazinyl, Benzofuranyl, Indolyl, Chinolyl oder Isochinolyl bedeutet und wobei die Reste A durch Halogen, Oxo, Hydroxy, Amino, C13-Alkoxy, C13-Alkoxycarbonyl, Ca¯3¯ Alkanoylamino und/oder gegebenenfalls substituiertes C13- Alkyl substituiert sein können, dadurch gekennzeichnet, Process for the preparation of disubstituted acetic acid derivatives of the formula EMI4.1 where T is a C5-alkyl or alkenyl radical or the cyclopropylmethyl or cyclobutylmethyl radical or cyclopentyl radical and A is furyl, tetrahydrofuryl, pyrrolyl, pyrrolidinyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-thiadiazolyl, imidazolyl, pyidrazolyl, 1-oxidopyridyl, tetrahydropyranyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, quinolyl or isoquinolyl and where the radicals A are substituted by halogen, oxo, hydroxy, amino, C13-alkoxy, C13-alkoxycarbonyl, Cā3¯ alkanoylamino and / or optionally substituted C13 alkyl can be substituted, characterized in that dass man in einer Verbindung der Formel EMI4.2 worin B eine durch eine katalytisch oder hydrolytisch abspaltbare Schutzgruppe geschützte Carboxylgruppe darstellt, die Schutzgruppe entweder durch katalytische Hydrierung oder hydrolytisch abspaltet. that one in a compound of the formula EMI4.2 where B represents a carboxyl group protected by a catalytically or hydrolytically cleavable protective group, which cleaves the protective group either by catalytic hydrogenation or hydrolytically. UNTERANSPRÜCHE 1. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass man eine Verbindung der Formel II verwendet, worin A 3-Pyridyl, 2-Methyl-4-pyAdyl,3-Isoxazolyl, 4-Oxazolyl, 2-Oxo-2-pyrrolidinyl, Pyrazinyl, Tetrahydro-2furyl, 2-Acetamido-4-thiazolyl, 1,5-Dimethyl-3-pyrazolyl, Tetrahydro-4-pyranyl, 1,2,3-Thiadiazol-4-yl, 2-Furyl, oder 4-Pyndyl darstellt. SUBCLAIMS 1. The method according to claim, characterized in that a compound of the formula II is used in which A is 3-pyridyl, 2-methyl-4-pyAdyl, 3-isoxazolyl, 4-oxazolyl, 2-oxo-2-pyrrolidinyl, pyrazinyl, Represents tetrahydro-2-furyl, 2-acetamido-4-thiazolyl, 1,5-dimethyl-3-pyrazolyl, tetrahydro-4-pyranyl, 1,2,3-thiadiazol-4-yl, 2-furyl, or 4-pyndyl. 2. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass man eine Verbindung der Formel II verwendet, worin T eine Alkyl- oder Alkenylgruppe mit 4 oder 5 C-Atomen ist. 2. The method according to claim, characterized in that a compound of the formula II is used in which T is an alkyl or alkenyl group having 4 or 5 carbon atoms. 3. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass man eine Verbindung der Formel II verwendet, worin T Isobutyl ist. 3. The method according to claim, characterized in that a compound of the formula II is used in which T is isobutyl. 4. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass man eine Verbindung der Formel II verwendet, worin A 2-Furyl und T Isobutyl ist. 4. The method according to claim, characterized in that a compound of the formula II is used in which A is 2-furyl and T is isobutyl. 5. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass man eine Verbindung der Formel II mit R-Konfiguration verwendet. 5. The method according to claim, characterized in that a compound of formula II is used with the R configuration.
CH1617773A 1973-11-17 1973-11-17 Heterocycloyloxy-substd. alkanoic acids prodn. - by hydro(geno)lysis of carboxy protected derivs., useful as antibiotic intermediates CH591505A5 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0176217A1 (en) * 1984-08-20 1986-04-02 Unilever Plc Pyroglutamic acid esters, their synthesis and use in topical products

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0176217A1 (en) * 1984-08-20 1986-04-02 Unilever Plc Pyroglutamic acid esters, their synthesis and use in topical products
US4774255A (en) * 1984-08-20 1988-09-27 Lever Brothers Company Pyroglutamic acid esters, their synthesis and use in topical products

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