EP0504351A1 - Method of preparing optically active 4-aryl-2-pyrrolidinones - Google Patents

Method of preparing optically active 4-aryl-2-pyrrolidinones

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Publication number
EP0504351A1
EP0504351A1 EP91917189A EP91917189A EP0504351A1 EP 0504351 A1 EP0504351 A1 EP 0504351A1 EP 91917189 A EP91917189 A EP 91917189A EP 91917189 A EP91917189 A EP 91917189A EP 0504351 A1 EP0504351 A1 EP 0504351A1
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EP
European Patent Office
Prior art keywords
optically active
formula
aryl
pyrrolidinones
compound
Prior art date
Legal status (The legal status 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 status listed.)
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Application number
EP91917189A
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German (de)
French (fr)
Inventor
Johann Mulzer
Ralf Zuhse
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Bayer Pharma AG
Original Assignee
Schering AG
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Publication date
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Publication of EP0504351A1 publication Critical patent/EP0504351A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom

Definitions

  • the invention relates to the process for the preparation of optically active 4-aryl-2-pyrrolidinones and the process for the preparation of the optically active starting compounds which are suitable as intermediates for the preparation of the 4S or 4R enantiomers of 4-aryl-2-pyrrolidinones.
  • the desired (4S) - or (4R) -4-aryl-2-pyrrolidinones can be prepared from the easily accessible optically active starting compounds in a simple synthesis and can be isolated in high optical purity and good yield without expensive separation operations.
  • the recovery of the auxiliary is to be regarded as an additional advantage of the method according to the invention.
  • the invention relates to the process for producing (4S) - or
  • R 1 is hydrogen or a hydrocarbon radical with up to 7 carbon atoms and R 2 C 1-4 alkyl which is optionally interrupted by an oxygen atom, characterized in that an optically active compound of the formula II
  • R 1 has the meaning of R1 or represents an easily removable group
  • R 2 is C 1-4 alkyl
  • Suitable hydrocarbon radicals R 1 are saturated or unsaturated, straight-chain or branched alkyl groups with 1-6 carbon atoms, preferably 1-4 carbon atoms, furthermore C 4-6 cycloalkylalkyl and cycloalkyl groups with 3-7 carbon atoms and the benzyl group and cycloalkyl groups interrupted by an oxygen atom.
  • saturated alkyl groups are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert. Butyl, pentyl, 2,2-dimethylpropyl and hexyl suitable.
  • alkenyl and alkynyl groups 2-propenyl, 2-propionyl.
  • hydrocarbon radical R 1 is a cycloalkyl group, it means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, preferably C 3-5 cycloalkyl groups. Cyclopropylmethyl, cyclopropylethyl and cyclopentylmethyl are to be regarded as preferred for the cycloalkyl-alkyl group.
  • hydrocarbon radical is interrupted by an oxygen atom
  • a further asymmetry center can be present, which can be converted into the antipodes in the usual way.
  • the term “easily removable group” means that the hydroxyl protective group can be easily removed either under the reaction conditions or subsequently in the customary manner.
  • the protecting groups include, for example, the methoxymethyl, methoxyethoxymethyl and also the benzyl group.
  • the commonly used hydrogenation catalysts such as, for example, are suitable as catalysts for the reaction according to the invention Raney nickel or precious metal catalysts such as platinum oxide and palladium / carbon.
  • the reaction takes place at room temperature or with heating to 50 ° C. under normal hydrogen pressure or elevated hydrogen pressure (approx. 50 bar) in an aqueous suspension or in inert solvents such as alcohols, esters or ketones or mixtures thereof.
  • the reaction is generally complete after 1 to 10 hours.
  • the etherification is carried out by reaction with a corresponding tosylate, mesylate or halide in the presence of a base such as alkali metal hydroxides and carbonates and tetrabutylammonium hydrogen sulfate in inert solvents such as dimethyl sulfoxide, dimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride or alcohols at room temperature to the boiling point of the solvent.
  • a base such as alkali metal hydroxides and carbonates and tetrabutylammonium hydrogen sulfate
  • inert solvents such as dimethyl sulfoxide, dimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride or alcohols at room temperature to the boiling point of the solvent.
  • the invention further relates to the compounds of formula II, which are optically active starting compounds, from which the compounds of formula I are obtained with very high optical purity in one reaction step.
  • the invention also relates to the process for the preparation of the compounds of formula II, characterized in that an optically active
  • the addition takes place in the manner of a Michael addition, by forming the enolate amone of compound III with strong bases and adding it to the olefin.
  • the reaction takes place at low temperatures (- 110 ° C to - 40 ° C) in aprotic solvents such as cyclic ethers, for example dioxane or tetrahydrofuran.
  • aprotic solvents such as cyclic ethers, for example dioxane or tetrahydrofuran.
  • the bases are, for example, alkali salts such as
  • the antipode is obtained after the addition of the olefin in good yields and high optical purity after recrystallization.
  • the starting compound of formula III can be prepared by acetylation of (4S) - or (4R) -4-benzyl-2-oxazolidinone by customary methods.
  • the acetylation can for example in the presence of strong bases such as butyllithium, lithium diisopropylamide, NaH and. a. in aprotic solvents such as cyclic ethers or hydrocarbons or in a two-phase system according to the method described by V. Illi Synthesis 1979, 387.
  • the starting compounds of the formula IV can be synthesized, for example, by aldol condensation of the aldehyde with nitromethane (C.B. Gairand, G.R. Lappin 1. Org. Chem. 18, 1 (1953).

Abstract

Procédé stéréosélectif pour la fabrication de (4R)- ou (4S)-4-Aryle-2-pyrrolidinones de formule (I) où R1 représente l'oxygène ou, le cas échéant, un radical d'hydrocarbure interrompu par un atome d'oxygène et ayant jusqu'à 7 atomes de carbone, et où R2 représente un groupe alkyle C1-4. L'invention concerne également des produits intermédiaires et le procédé stéréosélectif pour la fabrication des produits intermédiaires optiquement actifs.Stereoselective process for the manufacture of (4R)- or (4S)-4-Aryl-2-pyrrolidinones of formula (I) where R1 represents oxygen or, where appropriate, a hydrocarbon radical interrupted by an atom of oxygen and having up to 7 carbon atoms, and where R2 represents a C1-4 alkyl group. The invention also relates to intermediate products and the stereoselective process for the manufacture of the optically active intermediate products.

Description

Verfahren zur Herstellung von  Process for the production of
optisch aktiven 4-Aryl-2-pyrrolidinonen  optically active 4-aryl-2-pyrrolidinones
Die Erfindung betrifft das Verfahren zur Herstellung von optisch aktiven 4-Aryl-2-pyrrolidinonen sowie das Verfahren zur Herstellung der optisch aktiven Ausgangsverbindungen, die als Zwischenprodukte zur Herstellung der 4S- oder 4R-Enaπtiomeren von 4-Aryl-2-pyrrolidinonen geeignet sind. The invention relates to the process for the preparation of optically active 4-aryl-2-pyrrolidinones and the process for the preparation of the optically active starting compounds which are suitable as intermediates for the preparation of the 4S or 4R enantiomers of 4-aryl-2-pyrrolidinones.
Es ist aus dem US-Patent 4,012,495 und aus WO 86/02268 bekannt, daß 4- Aryl-2-pyrrolidinone pharmakologisch gut wirksame Verbindungen sind, die sich zur Behandlung neuroleptischer und psychischer Störungen eignen und auch zur topischen Behandlung von Entzündungen eingesetzt werden können. It is known from US Pat. No. 4,012,495 and WO 86/02268 that 4-aryl-2-pyrrolidinones are pharmacologically active compounds which are suitable for the treatment of neuroleptic and psychological disorders and can also be used for the topical treatment of inflammation.
Von den 4-Aryl-2-pyrrolidinonen wurde das 4-(3-Cyclopentyloxy-4-methoxy- phenyl)-2-pyrrolidinon eingehend pharmakologisch untersucht. Mittels eines sehr aufwendigen und im technischen Maßstab nicht nachvollziehbaren Verfahrens wurde diese Verbindung in ihre optischen Antipoden überführt und festgestellt, daß beide Enantiomere pharmakologisch wirksame Verbindungen darstellen. Of the 4-aryl-2-pyrrolidinones, the 4- (3-cyclopentyloxy-4-methoxyphenyl) -2-pyrrolidinone was examined in detail pharmacologically. This compound was converted into its optical antipodes by means of a very complex process which was not comprehensible on an industrial scale and it was found that both enantiomers are pharmacologically active compounds.
Da es wünschenswert ist, daß bei chiralen Arzneimittelwirkstoffen nur jeweils ein Antipode zur Herstellung pharmazeutischer Präparate verwendet wird, bestand die Aufgabe, ein technisch anwendbares Verfahren zur Since it is desirable that only one antipode is used for the production of pharmaceutical preparations in the case of chiral active pharmaceutical ingredients, the object was to develop a technically applicable process for
Herstellung der optisch aktiven 4-Aryl-2-pyrrolidinoneπ zu entwickeln. Development of the optically active 4-aryl-2-pyrrolidinoneπ to develop.
Nach dem erfindungsgemäßen Verfahren sind aus den gut zugänglichen optisch aktiven Ausgangsverbindungen in einer einfachen Synthese die gewünschten (4S)- oder (4R)-4-Aryl-2-pyrrolidinone darstellbar und können in hoher optischer Reinheit und guter Ausbeute ohne aufwendige Trennoperationen isoliert werden. Als zusätzlicher Vorteil des erfindungsgemaßen Verfahrens ist die Rückgewinnung des Auxiliars anzusehen. Die Erfindung betrifft das Verfahren zur Herstellung von (4S)- oder According to the process of the invention, the desired (4S) - or (4R) -4-aryl-2-pyrrolidinones can be prepared from the easily accessible optically active starting compounds in a simple synthesis and can be isolated in high optical purity and good yield without expensive separation operations. The recovery of the auxiliary is to be regarded as an additional advantage of the method according to the invention. The invention relates to the process for producing (4S) - or
(4R)-4-Aryl-2-pyrrolidinσnen der Formel I (4R) -4-aryl-2-pyrrolidinσnen of formula I.
worin wherein
R1 Wasserstoff oder einen gegebenenfalls mit einem Sauerstoffatom unterbrochenen Kohlenwasserstoffrest mit bis zu 7 Kohlenstoffatomen und R2 C1-4-Alkyl ist, dadurch gekennzeichnet, daß man eine optisch aktive Verbindung der Formel II R 1 is hydrogen or a hydrocarbon radical with up to 7 carbon atoms and R 2 C 1-4 alkyl which is optionally interrupted by an oxygen atom, characterized in that an optically active compound of the formula II
y worin y where
R1 die Bedeutung von R1 hat oder eine leicht abspaltbare Gruppe darstellt und R 1 has the meaning of R1 or represents an easily removable group and
R2 C1-4-Alkyl ist R 2 is C 1-4 alkyl
mit Wasserstoff katalytisch reduziert und cyclisiert und gegebenenfalls die leicht abspaltbare Gruppe abspaltet und die so erhaltene Hydroxygruppe verethert. Als Kohlenwasserstoffrest R1 kommen gesättigte oder ungesättigte, gerad- kettige oder verzweigte Alkylgruppen mit 1 - 6 Kohlenstoffatomen, vorzugsweise 1 - 4 Kohlenstoffatomen in Betracht, ferner C4-6-Cycloalkyl- alkyl- und Cycloalkylgruppen mit 3 - 7 Kohlenstoffatomen und die Benzyl- gruppe sowie durch ein Sauerstoffatom unterbrochene Cycloalkylgruppen. catalytically reduced and cyclized with hydrogen and optionally cleaving off the easily cleavable group and etherifying the hydroxyl group thus obtained. Suitable hydrocarbon radicals R 1 are saturated or unsaturated, straight-chain or branched alkyl groups with 1-6 carbon atoms, preferably 1-4 carbon atoms, furthermore C 4-6 cycloalkylalkyl and cycloalkyl groups with 3-7 carbon atoms and the benzyl group and cycloalkyl groups interrupted by an oxygen atom.
Als gesättigte Alkylgruppen sind jeweils beispielsweise Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, sek. Butyl, tert. Butyl, Pentyl, 2,2-Dιmethylpropyl und Hexyl geeignet. As saturated alkyl groups are, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, tert. Butyl, pentyl, 2,2-dimethylpropyl and hexyl suitable.
Als Alkenyl-und Alkinylgruppen seien vorzugsweise genannt: 2-Propenyl, 2-Propιnyl. Bedeutet der Kohlenwasserstoffrest R1 eine Cycloalkylgruppe, so ist Cyclopropyl, Cyclobutyl Cyclopentyl, Cyclohexyl und Cycloheptyl gemeint, vorzugsweise C3-5- Cycloalkylgruppen. Für die Cycloalkyl-alkylgruppe ist Cyclopropylmethyl, Cyclopropylethyl und Cyclopentylmethyl als bevorzugt anzusehen. The following may preferably be mentioned as alkenyl and alkynyl groups: 2-propenyl, 2-propionyl. If the hydrocarbon radical R 1 is a cycloalkyl group, it means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, preferably C 3-5 cycloalkyl groups. Cyclopropylmethyl, cyclopropylethyl and cyclopentylmethyl are to be regarded as preferred for the cycloalkyl-alkyl group.
Ist der Kohlenwasserstoffrest durch ein Sauerstoffatom unterbrochen, so ist insbesondere der Cycloalkylrest gemeint, bei dem eine CH -Gruppe durch ein Sauerstoffatom ersetzt ist, wobei als cyclischer Etherrest beispielsweise 3-Tetrahydrofuranyl und 3-Tetrahydropyranyl genannt seien. If the hydrocarbon radical is interrupted by an oxygen atom, this means in particular the cycloalkyl radical in which a CH group has been replaced by an oxygen atom, 3-tetrahydrofuranyl and 3-tetrahydropyranyl being mentioned as the cyclic ether radical.
Enthält das Molekül einen cyclischen Etherrest, so kann ein weiteres Asymmetriezentrum vorhanden sein, das in üblicher Weise in die Antipoden überführt werden kann. If the molecule contains a cyclic ether residue, a further asymmetry center can be present, which can be converted into the antipodes in the usual way.
Der Ausdruck "leicht abspaltbare Gruppe" bedeutet im Rahmen dieser Erfindung, daß die Hydroxy-Schutzgruppe entweder unter den Reaktionsbedingungen oder anschließend in üblicher Weise leicht abspaltbar ist. Als Schutzgruppen seien beispielsweise die Methoxymethyl-, Methoxy-ethoxymethyl- und auch die Benzylgruppe genannt. In the context of this invention, the term “easily removable group” means that the hydroxyl protective group can be easily removed either under the reaction conditions or subsequently in the customary manner. The protecting groups include, for example, the methoxymethyl, methoxyethoxymethyl and also the benzyl group.
Als Katalysatoren für die erfindungsgemäße Umsetzung eignen sich die üblicherweise verwendeten Hydrierungskatalysatoren wie beispielsweise Raney-Nickel oder Edelmetallkatalysatoren wie Platinoxid und Palladium/ Kohle. Die Reaktion erfolgt bei Raumtemperatur oder unter Erwärmen bis 50 ° C bei Wasserstoffnormaldruck oder erhöhtem Wasserstoffdruck (ca. 50 bar) in einer wässrigen Suspension oder in inerten Loungsmitteln wie Alkoholen, Estern oder Ketonen oder Gemischen derselben. Im allgemeinen ist die Reaktion nach 1 bis 10 Stunden beendet. The commonly used hydrogenation catalysts such as, for example, are suitable as catalysts for the reaction according to the invention Raney nickel or precious metal catalysts such as platinum oxide and palladium / carbon. The reaction takes place at room temperature or with heating to 50 ° C. under normal hydrogen pressure or elevated hydrogen pressure (approx. 50 bar) in an aqueous suspension or in inert solvents such as alcohols, esters or ketones or mixtures thereof. The reaction is generally complete after 1 to 10 hours.
Sollen eventuell vorhandene leicht abspaltbare Gruppen im Verlaufe der erfindungsgemäßen Umsetzung abgespalten werden, so hydriert man If any readily removable groups that may be present are to be split off in the course of the reaction according to the invention, the mixture is hydrogenated
zweckmäs-sigerweise längere Zeit gegebenenfalls unter Druck oder man spaltet die genannten Gruppen in üblicher Weise mit Säure ab. Expediently for a relatively long time, if appropriate under pressure, or the groups mentioned are split off in the customary manner with acid.
Die Veretherung der Hydroxy-Verbindung kann nach den im US-Patent The etherification of the hydroxy compound can be carried out according to the methods described in the US patent
4.012.495 beschriebenen Verfahren durchgeführt werden. Beispielsweise erfolgt die Veretherung durch Umsetzen mit einem entsprechenden Tosylat, Mesylat oder Halogenid in Gegenwart einer Base wie Alkalihydroxiden und -carbonaten und Tetrabutylammoniumhydrogensulfat in inerten Lösungsmitteln wie Dimethylsulfoxid, Dimethylformamid, Acetonitril, Tetrahydrofuran, Methylenchlorid oder Alkoholen bei Raumtemperatur bis zum Siedepunkt des Lösungsmittels. 4,012,495 described procedures are performed. For example, the etherification is carried out by reaction with a corresponding tosylate, mesylate or halide in the presence of a base such as alkali metal hydroxides and carbonates and tetrabutylammonium hydrogen sulfate in inert solvents such as dimethyl sulfoxide, dimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride or alcohols at room temperature to the boiling point of the solvent.
Die Erfindung betrifft ferner die Verbindungen der Formel II, die optisch aktive Ausgangsverbindungen sind, aus denen in einem Reaktionsschritt die Verbindungen der Formel I mit sehr hoher optischer Reinheit erhalten werden. The invention further relates to the compounds of formula II, which are optically active starting compounds, from which the compounds of formula I are obtained with very high optical purity in one reaction step.
Die Erfindung betrifft auch das Verfahren zur Herstellung der Verbindungen der Formel II, dadurch gekennzeichnet, daß man eine optisch aktive The invention also relates to the process for the preparation of the compounds of formula II, characterized in that an optically active
Verbindung der Formel III Compound of formula III
und eine Verbindung der Formel IV and a compound of formula IV
worin R1 und R2 die obige Bedeutung haben, addiert. where R 1 and R 2 have the above meaning added.
Die Addition erfolgt nach Art einer Michael Addition, indem man mit starken Basen das Enolat-Amon der Verbindung III bildet und an das Olefin anlagert. The addition takes place in the manner of a Michael addition, by forming the enolate amone of compound III with strong bases and adding it to the olefin.
Die Umsetzung erfolgt bei tiefen Temperaturen ( - 110°C bis - 40°C ) in aprotischen Losungsmitteln wie cyclischen Ethern, beispielsweise Dioxan oder Tetrahydrofuran. Als Basen sind beispielsweise Alkalisalze wie The reaction takes place at low temperatures (- 110 ° C to - 40 ° C) in aprotic solvents such as cyclic ethers, for example dioxane or tetrahydrofuran. The bases are, for example, alkali salts such as
Natrium-, Kalium- oder Lithiumsalze von Hexamethyldisilazan, Diisopropylarnin oder Tetramethylpiperidin oder Hydride und Alkoholate der genannten Alkalimetalle geeignet. Sodium, potassium or lithium salts of hexamethyldisilazane, diisopropylarnine or tetramethylpiperidine or hydrides and alcoholates of the alkali metals mentioned are suitable.
Je nach der Stellung der Benzylgruppe am Oxazolidinon der Formel III erhalt man nach der Addition des Olefins die Antipode in guten Ausbeuten und hoher optischer Reinheit nach Umkristallisation. Depending on the position of the benzyl group on the oxazolidinone of the formula III, the antipode is obtained after the addition of the olefin in good yields and high optical purity after recrystallization.
Zweckmäßigerweise werden alle hier beschriebenen Umsetzungen unter Appropriately, all implementations described here are under
Schutzgasatmosphäre beispielsweise unter Stickstoff oder Argon vorgenomvorgenommen. Die in den erfindungsgemäßen Verfahren als Ausgangsmaterial verwendeten Verbindungen der Formeln III und IV sind bekannte Verbindungen oder Analoge bekannter Verbindungen, die nach bekannten Methoden stereoselektiv hergestellt werden können. Protective gas atmosphere carried out under nitrogen or argon, for example. The compounds of the formulas III and IV used as starting material in the processes according to the invention are known compounds or analogs of known compounds which can be prepared stereoselectively by known methods.
Die Ausgangsverbindung der Formel III kann durch Acetylierung von (4S)- oder (4R)-4-Benzyl-2-oxazolidinon nach üblichen Methoden dargestellt werden. Die Acetylierung kann beispielsweise in Gegenwart starker Basen wie Butyllithium, Lithiumdiisopropylamid, NaH u. a. in aprotischen Lösungsmitteln wie cyclischen Ethern oder Kohlenwasserstoffen oder im Zweiphasensystem nach der von V. Illi Synthesis 1979, 387 beschriebenen Methode durchgeführt werden. The starting compound of formula III can be prepared by acetylation of (4S) - or (4R) -4-benzyl-2-oxazolidinone by customary methods. The acetylation can for example in the presence of strong bases such as butyllithium, lithium diisopropylamide, NaH and. a. in aprotic solvents such as cyclic ethers or hydrocarbons or in a two-phase system according to the method described by V. Illi Synthesis 1979, 387.
Die Ausgangsverbindungen der Formel IV können beispielsweise durch Aldol- kondensation des Aldehyds mit Nitromethan synthetisiert werden (C.B. Gairand, G.R. Lappin 1. Org . Chem. 18, 1 (1953). The starting compounds of the formula IV can be synthesized, for example, by aldol condensation of the aldehyde with nitromethane (C.B. Gairand, G.R. Lappin 1. Org. Chem. 18, 1 (1953).
Die nachfolgenden Beispiele sollen das erfindungsgemäße Verfahren erläutern. The following examples are intended to explain the process according to the invention.
Herstellung der Ausgangsverbindungen Preparation of the starting compounds
1 ) 2- ( 3-Benzyloxy-4-methoxy-phenyl ) - 1 -nιtro- ( E ) -ethen 1) 2- (3-benzyloxy-4-methoxy-phenyl) -1 -nιtro- (E) -ethene
10g (41.3 mmol) 3-Benzyloxy-4-methoxy-benzaldehyd, 3.2g ( 41.5mmol ,leq ) Ammomumacetat und 12ml Ni-tromethan werden in 50 ml Eisessig gelöst und 12h unter Rückfluß erhitzt. Nach dem Erkalten wird das Gemisch im Vakuum eingeengt, mit wenig Wasser versetzt und mehrmals mit Essigester ausgeschüttelt. Nach dem Trocknen über Natriumsulfat wird das Losungsmittel im Wasserstrahlvakuum entfernt. Der feste Rückstand kann in Essigester/Hexan umkristallisiert werden. Es fallen 8.56g (73%) gold-gelbe plättchenformige Kristalle mit einem Schmelzpunkt von 126°C an. 2) (4S)-3-Acetyl-4-(benzyl)-2-oκazolidinon 10g (41.3 mmol) 3-benzyloxy-4-methoxy-benzaldehyde, 3.2g (41.5mmol, leq) ammonium acetate and 12ml Ni-tromethane are dissolved in 50 ml glacial acetic acid and heated under reflux for 12 hours. After cooling, the mixture is concentrated in vacuo, mixed with a little water and shaken out several times with ethyl acetate. After drying over sodium sulfate, the solvent is removed in a water jet vacuum. The solid residue can be recrystallized from ethyl acetate / hexane. 8.56 g (73%) of gold-yellow platelet-shaped crystals with a melting point of 126 ° C. are obtained. 2) (4S) -3-Acetyl-4- (benzyl) -2-oκazolidinone
10g (56.4 mmol) (4S)-4-Benzyl-2-oxazolidinon werden unter Argona tmo s - pha re in 1 00ml abs . THF gelöst und bei - 78 ° C tropfenweise mit 37ml (59.3mmol, 1.6M in Hexan, 1.05eq) n-Buthyllithium versetzt. Nach 10 Min. werden 4.1 ml ( 4.5 g, 57.5mmol, 1.02eq) Acetylclorid zugepropft. Die Losung wird noch 15min unter Kühlung und anschließend 3h bei Raumtemperatur gerührt. Zur Aufarbeitung wird mit 50ml gesättigter 10g (56.4 mmol) (4S) -4-benzyl-2-oxazolidinone are dissolved under Argona tmo s - pha re in 1 00ml abs. THF dissolved and 37 ml (59.3 mmol, 1.6M in hexane, 1.05 eq) of n-butyllithium added dropwise at -78 ° C. After 10 minutes, 4.1 ml (4.5 g, 57.5 mmol, 1.02 eq) of acetyl chloride are added. The solution is stirred for a further 15 minutes with cooling and then for 3 hours at room temperature. For working up it is saturated with 50ml
Ammoniumchloridlosung versetzt, die organischen Lösungsmittel im Vakuum abdestilliert und der verbleibende Rückstand mit Essigester mehrmals extrahiert. Nach Trocknung über Natriumsulfat und Einengung im Vakuum, kann der zurückbleibende Feststoff in Essigester/Hexan umkristallisiert werden. Es bilden sich 10.3g (83%) farblose Nadeln mit einem Schmelzpunkt von 106°C. Beispiel 1 a) (4S.3 R) und (4S, 3'S)-3-(3 -(3-Benzyloxy-4-methoxy-phenyl)-4 -nitro butansäure)-4-benzyl-2-oxazolidinon Ammonium chloride solution was added, the organic solvents were distilled off in vacuo and the remaining residue was extracted several times with ethyl acetate. After drying over sodium sulfate and concentration in vacuo, the remaining solid can be recrystallized from ethyl acetate / hexane. 10.3 g (83%) of colorless needles with a melting point of 106 ° C. are formed. Example 1 a) (4S.3 R) and (4S, 3'S) -3- (3 - (3-Benzyloxy-4-methoxyphenyl) -4-nitro butanoic acid) -4-benzyl-2-oxazolidinone
Zu einer unter Argonatmosphäre befindlichen Suspension aus 3.1g (16.9mmol) Natriumhexamethyldisilazan in 150ml abs. THF werden bei -78°C 3g To a suspension of 3.1g (16.9mmol) sodium hexamethyldisilazane in 150ml abs. THF become 3g at -78 ° C
(16.9mmol, leq.) (4S)-3-Acetyl-4-benzyl-2-oxazolidinon gelöst in 10ml abs. THF, innerhalb von 10min zugetropft. Der Ansatz wird 30min gerührt und dann mit einer Lösung aus 4.8g ( 16.8mmol.leq) Olefin und 50ml abs. THF innerhalb von 1h versetzt. Die Reaktioπsmischung wird weitere 6h unter Kühlung gerührt und anschließend langsam auf Raumtemperatur erwärmt. Die Reaktion wird mit Zugabe von 50ml gesättigter Ammoniumchloridlösung gestoppt, die orga nischen Lösungsmittel im Vakuum entfernt, die wässrige Phase mit Essigester ausgeschüttelt und erhaltenen organischen Fraktionen über Natrium- sulfat getrocknet. Das vom Solvens befreite Rohprodukt enthält laut ana- lytischer HPLC (0.6% Isopropanol/Hexan, flow  (16.9mmol, leq.) (4S) -3-acetyl-4-benzyl-2-oxazolidinone dissolved in 10ml abs. THF, added dropwise within 10min. The mixture is stirred for 30 minutes and then with a solution of 4.8g (16.8mmol.leq) olefin and 50ml abs. THF shifted within 1h. The reaction mixture is stirred for a further 6 hours with cooling and then slowly warmed to room temperature. The reaction is stopped with the addition of 50 ml of saturated ammonium chloride solution, the organic solvents are removed in vacuo, the aqueous phase is shaken out with ethyl acetate and the organic fractions obtained are dried over sodium sulfate. According to analytical HPLC (0.6% isopropanol / hexane, flow
2ml/min, 5μw-Nucleosil 50, 4*250, UV-Detektion (254nm) die beiden Diastereomere (4S, 3 S) (RT.: 8.45min ) und (4S, 3 R) (RT.: 11.61min ) in einem Verhältnis von 6:94 (de=88%). Durch einmaliges Umkristallisieren aus Essigester/Hexan erhält man 5.5g (65X) einer farblosen, feinkristallinen Substanz mit einem Schmelzpunkt von 153°C, die laut analytischer HPLC ein Diastereomerenverhältnis (4S, 3'S) : (4S, 3 R ) =0.5 :99.5 (de=99%) aufweist.  2ml / min, 5μw-Nucleosil 50, 4 * 250, UV detection (254nm) the two diastereomers (4S, 3 S) (RT .: 8.45min) and (4S, 3 R) (RT .: 11.61min) in a ratio of 6:94 (de = 88%). A single recrystallization from ethyl acetate / hexane gives 5.5 g (65X) of a colorless, finely crystalline substance with a melting point of 153 ° C, which according to analytical HPLC has a diastereomer ratio (4S, 3'S): (4S, 3 R) = 0.5: 99.5 ( de = 99%).
(4S, 3 R)-Oxazolidinon-Derivat = +28.05 (c = 2.3, Chloroform)(4S, 3 R) -oxazolidinone derivative = +28.05 (c = 2.3, chloroform)
(4S, 3 S)-Oxazolidinon-Derivat = + 43.8 (c = 1, Chloroform) Schmelzpunkt: 132° C(4S, 3 S) -oxazolidinone derivative = + 43.8 (c = 1, chloroform) Melting point: 132 ° C
b) (4S)-4-(3-Benzyloxy-4-methoxy-phenyl)-2-pyrrolidιnon b) (4S) -4- (3-benzyloxy-4-methoxy-phenyl) -2-pyrrolidionon
Eine Suspension aus 2g (3.96mmol) des nach a) erhaltenen (4S, 3'R)-Oxazol- idinons und 2ml Raney-Nickel (Aufschlammung in Wasser) werden unter einem Wasserstoffdruck von 2 bar für 6h bei Raumtemperatur geschüttelt. Dann wird der Katalysator abfiltriert, das Lösungsmittel abgezogen und das Rohprodukt einer säulenchromatographischen Reinigung (Methylenchlorid/ Aceton, 7:3) unterzogen. A suspension of 2 g (3.96 mmol) of the (4S, 3'R) -oxazole idinone obtained according to a) and 2 ml of Raney nickel (slurry in water) are shaken under a hydrogen pressure of 2 bar for 6 h at room temperature. The catalyst is then filtered off, the solvent is stripped off and the crude product is subjected to purification by column chromatography (methylene chloride / acetone, 7: 3).
Man isoliert: One isolates:
440mg (4S)-4-(-3-Benzyloxy-4-methoxy-phenyl)-2-pyrrolιdιnon 440mg (4S) -4 - (- 3-Benzyloxy-4-methoxy-phenyl) -2-pyrrolιdιnon
= +28.65 (c=0.5, Chloroform) Schmelzpunkt: 121°C = +28.65 (c = 0.5, chloroform) Melting point: 121 ° C
320mg (4S)-4-(-3-Hydroxy-4-methoxy-phenyl)-2-pyrrolidinon 320mg (4S) -4 - (- 3-Hydroxy-4-methoxyphenyl) -2-pyrrolidinone
= + 36.7 (c=1.8, Chloroform) Schmelzpunkt 145°C = + 36.7 (c = 1.8, chloroform) melting point 145 ° C
470 mg (4S)-4-Benzyl-2-oxazolidinon, Schmelzpunkt 86 °C 470 mg (4S) -4-benzyl-2-oxazolidinone, melting point 86 ° C

Claims

Patentansprüche Claims
1.) Verfahren zur Herstellung von optisch aktiven 4-Aryl-2-pyrrolιdinonen der Formel I 1.) Process for the preparation of optically active 4-aryl-2-pyrrole dinones of the formula I.
worin wherein
R1 Wasserstoff oder einen gegebenenfalls mit einem Sauerstoffatom unterbrochenen Kohlenwasserstoffrest mit bis zu 7 Kohlenstoffatomen und R 1 is hydrogen or a hydrocarbon radical which may be interrupted by an oxygen atom and has up to 7 carbon atoms and
R2 eine C1-4-Alkylgruppe bedeutet, dadurch gekennzeichnet, daß man eine optisch aktive Verbindung der Formel II R 2 represents a C 1-4 alkyl group, characterized in that an optically active compound of the formula II
worin wherein
R1 die Bedeutung von R1 hat oder eine leicht abspaltbare Gruppe ist und R 1 has the meaning of R 1 or is an easily removable group and
R2 eine C1-4-Alkylgruppe bedeutet, mit Wasserstoff katalytisch reduziert und cyclisiert und gegebenenfalls die leicht abspaltbare Gruppe R1) abspaltet und die so erhaltene Hydroκy-Verbindung verethert. R 2 is a C 1-4 alkyl group, catalytically reduced and cyclized with hydrogen and optionally cleaving off the easily removable group R 1) and etherifying the hydroκy compound thus obtained.
2.) Optisch aktive Verbindungen der Formel II 2.) Optically active compounds of the formula II
worinwherein
R1 die Bedeutung von R1 hat oder eine leicht abspaltbare Gruppe darstellt und R 1 has the meaning of R 1 or represents an easily removable group and
R2 C1-4-Alkyl ist. R 2 is C 1-4 alkyl.
3.) Verfahren zur Herstellung der Verbindungen der Formel II, dadurch gekennzeichnet, daß man eine optisch aktive Verbindung der Formel III 3.) Process for the preparation of the compounds of formula II, characterized in that an optically active compound of formula III
und eine Verbindung der Formel IVand a compound of formula IV
worin R1 und R2 die obige Bedeutung haben, addiert. where R 1 and R 2 have the above meaning added.
EP91917189A 1990-10-05 1991-09-27 Method of preparing optically active 4-aryl-2-pyrrolidinones Withdrawn EP0504351A1 (en)

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DE4032055A DE4032055A1 (en) 1990-10-05 1990-10-05 METHOD FOR PRODUCING OPTICALLY ACTIVE 4-ARYL-2-PYRROLIDINONES

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US4193926A (en) * 1974-03-20 1980-03-18 Schering Aktiengesellschaft 4-(Polyalkoxy phenyl)-2-pyrrolidones
DE2413935A1 (en) * 1974-03-20 1975-10-16 Schering Ag 4- (POLYALCOXY-PHENYL) -2-PYRROLIDONE
DE2541855A1 (en) * 1975-09-18 1977-03-31 Schering Ag 4- (POLYALCOXY-PHENYL) -2-PYRROLIDONE II

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