NO771421L - PROCEDURES FOR THE PREPARATION OF TETRAMISOL, LEVAMISOL AND DERIVATIVES THEREOF - Google Patents

PROCEDURES FOR THE PREPARATION OF TETRAMISOL, LEVAMISOL AND DERIVATIVES THEREOF

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Publication number
NO771421L
NO771421L NO771421A NO771421A NO771421L NO 771421 L NO771421 L NO 771421L NO 771421 A NO771421 A NO 771421A NO 771421 A NO771421 A NO 771421A NO 771421 L NO771421 L NO 771421L
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Norway
Prior art keywords
phenyl
imidazolidone
methoxyethyl
formula
alkyl
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NO771421A
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Norwegian (no)
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Sivaraman Raghu
Arthur Kentaro Hoffmann
Balwant Singh
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American Cyanamid Co
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Priority claimed from US05/739,923 external-priority patent/US4087611A/en
Application filed by American Cyanamid Co filed Critical American Cyanamid Co
Publication of NO771421L publication Critical patent/NO771421L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole 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
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/42—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole 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
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole 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
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/38—One oxygen atom with acyl radicals or hetero atoms directly attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D233/70—One oxygen atom

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyrrole Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

"remgangsmåte for fremstilling av tetramisol, levamisol og derivater derav" ."belt process for the preparation of tetramisole, levamisole and derivatives thereof".

Description

Foreliggende oppfinnelse gjelder fremgangsmåte for fremstilling av 1,4-disubstituerte imidazolidin-2-oner og 1,4-disubstituerte imidazolidin-2-tioner med formelen: The present invention relates to a process for the production of 1,4-disubstituted imidazolidin-2-ones and 1,4-disubstituted imidazolidin-2-thiones with the formula:

hvor R er hydrogen, alkyl-C-^-Cg, fenyl, fenyl substituert, med opp til tre grupper bestående av halogensubstituert alkyl-C^-C^, alkyl-C-^-Cg, alkoksy-Cj-Cg eller en del med formelenCOR^hvor R^ where R is hydrogen, alkyl-C-^-Cg, phenyl, phenyl substituted, with up to three groups consisting of halogen-substituted alkyl-C^-C^, alkyl-C-^-Cg, alkoxy-Cj-Cg or a moiety with the formulaCOR^where R^

er hydrogen, alkyl-C-^-C^, alkoksy-C-^-C^, fenoksy-halogenalkyl-C-^-Cg, fenyl, eller fenyl eller fenoksy substituert med opp til fire grupper bestående av alkyl-C^-C^, halogen, trifluormetyl eller alkoksy-C^-Cg; R^er hydrogen eller en del med formelen COR^, hvor R4er alkyl-C^-Cg, alkoksy-C-^-Cg, fenoksy, cykloalkyl-C5-Cl0/ fenyl, eller fenyl eller fenoksy substituert med opp til fire grupper bestående av alkyl-C-^-C^, alkoksy-C^-C^, halogen eller trifluormetyl;R2er fenyl eller fenyl substituert med opp til to grupper bestående av alkyl-C-^-Cg, alkoksy-Cj-C^, halogen eller trifluormetyl og Z er oksygen eller.svovel. is hydrogen, alkyl-C-^-C^, alkoxy-C-^-C^, phenoxy-haloalkyl-C-^-Cg, phenyl, or phenyl or phenoxy substituted with up to four groups consisting of alkyl-C^- C 1 , halogen, trifluoromethyl or alkoxy-C 1 -C 8 ; R^ is hydrogen or a moiety of the formula COR^, where R4 is alkyl-C^-Cg, alkoxy-C-^-Cg, phenoxy, cycloalkyl-C5-Cl0/ phenyl, or phenyl or phenoxy substituted with up to four groups consisting of of alkyl-C-^-C^, alkoxy-C^-C^, halogen or trifluoromethyl; R2 is phenyl or phenyl substituted with up to two groups consisting of alkyl-C-^-C8, alkoxy-Cj-C^, halogen or trifluoromethyl and Z is oxygen or sulfur.

Foreliggende oppfinnelse gjelder en ny fremgangsmåte med bruk av nye mellomprodukter for fremstilling av levamisol. Den omfatter enklere og færre trinn og unngår bruken av kostbare reduseringsmidler. For første gang er det oppnådd en katalytisk, asymmetrisk syntese av levamisol ved reduksjon med et prochiral-mellomprodukt. Alle andre kjente fremgangsmåter foregår via den kostbare oppløsning av tetramisol eller mellomprodukter. Fore liggende oppfinnelse gjør det mulig å fremstille passende syreaddisjonssalter av tetramisol eller levamisol direkte, og er anvendbar for fremstilling av analoger av tetramisol og levamisol. The present invention relates to a new method using new intermediates for the production of levamisole. It involves simpler and fewer steps and avoids the use of expensive reducing agents. For the first time, a catalytic, asymmetric synthesis of levamisole by reduction with a prochiral intermediate has been achieved. All other known methods take place via the expensive dissolution of tetramisole or intermediate products. The present invention makes it possible to prepare suitable acid addition salts of tetramisole or levamisole directly, and is applicable for the preparation of analogues of tetramisole and levamisole.

Det er omtalt mange fremgangsmåter for fremstilling avMany methods for the production of

det anthelmintiske middel tetramisol i litteraturen (Raemakers et al., j.Med. Chem. 9, 545 (1966), Bakelien et al., Aust. J. Chem.. 21, 1557 (1968), T. R. Roy US-patent 3.855.234, M. E. McMenin, US-patent 3.845.070). Disse fremgangsmåter gir tetramisol, en rasemisk forbindélse, som så oppløses slik at dens fysiologisk aktive, venstredreiende enantiomer levamisol oppnås. Ingen av disse fremgangsmåter passer til en direkte syntese av levamisol uten opp-løsning . the anthelmintic agent tetramisole in the literature (Raemakers et al., j. Med. Chem. 9, 545 (1966), Bakelien et al., Aust. J. Chem.. 21, 1557 (1968), T. R. Roy US Patent 3,855 .234, M.E. McMenin, US Patent 3,845,070). These procedures yield tetramisole, a racemic compound, which is then resolved to yield its physiologically active, levorotatory enantiomer levamisole. None of these methods are suitable for a direct synthesis of levamisole without solution.

En fremgangsmåte for fremstilling av levamisol fra l-(2-hydroksyetyl)-4-fenyl-4-imidåzolin-2-tion og tionylklorid er beskrevet i US-patent 3.726.894. Denne forbindelse fremstilles ved hydroboreringsréaksjon på l-vinyl-4-fenyl-4-imidazolin-2-tion, A process for the preparation of levamisole from 1-(2-hydroxyethyl)-4-phenyl-4-imidazolin-2-thione and thionyl chloride is described in US patent 3,726,894. This compound is produced by a hydroboration reaction on 1-vinyl-4-phenyl-4-imidazolin-2-thione,

som oppnås som biprodukt ved rasemisering av fysiologisk inaktiv d-tetramisol til den fysiologisk aktive dl-forbindelsen, tetramisol. which is obtained as a by-product by racemisation of physiologically inactive d-tetramisole to the physiologically active dl-compound, tetramisole.

Foreliggende oppfinnelse overvinner ulempene ved de kjente fremgangsmåtene ved at den er regioselektiv (ingen iso-levamisol kan dannes); alle trinnene gjennomføres med godt utbytte; den omfatter for første gang i levamisolsyntesen et katalytisk reduk-sjonstrinn som kan innføre chiralitet (Egenskapen hos en gjenstand at den ikke er identisk med sitt speilbilde-kalles chiralitet. Et objekt som f.eks. en molekyl som har en gitt konfigurasjon eller konformasjon, kalles chiral når den ikke er identisk med sitt speilbilde; den kalles achiral når den er identisk med sitt speilbilde. J. Org.Chem. vo. 35, nr. 9, sept. 1970) ved å bruke katalytiske mengder av et chiralt reagens som f.eks. rhodiumklorid-komplekset med (+) eller (-), DIOP (se formel (VIII) på side 10). Syntesen ventes til og med å være mer økonomisk enn de aktuelt brukte fremgangsmåter for fremstilling av tetramisol; og den er anvendbar for. syntese av andre analoger. The present invention overcomes the disadvantages of the known methods in that it is regioselective (no iso-levamisole can be formed); all the steps are carried out with good yield; it includes for the first time in the levamisole synthesis a catalytic reduction step that can introduce chirality (The property of an object that it is not identical to its mirror image is called chirality. An object such as a molecule that has a given configuration or conformation, is called chiral when it is not identical to its mirror image; it is called achiral when it is identical to its mirror image. J. Org. Chem. vo. 35, no. 9, Sept. 1970) by using catalytic amounts of a chiral reagent which e.g. the rhodium chloride complex with (+) or (-), DIOP (see formula (VIII) on page 10). The synthesis is even expected to be more economical than the currently used methods for the production of tetramisole; and it is applicable for. synthesis of other analogues.

Fremgangsmåtene ifølge oppfinnelsen illustreres i strøm-ningsdiagrammet nedenfor: The methods according to the invention are illustrated in the flow diagram below:

(R, R^, R2, R3, X og Y er som definert på følgende sider) . (R, R^, R2, R3, X and Y are as defined on the following pages) .

I IN

Et a-substituert keton med formel I, som kan forflyttes ved hjelp av et nukleofilt reagens, omsettes med et amin med formel II eller dets syreaddisjonssalter, slik at det oppnås en forbindelse med formel III. Denne reaksjon kan utføres ved å bruke et overskudd av forbindelsen med formel II, eller i nærvær av et tertiært amin som f.eks. trietylamin, eller i nærvær av en hydroksydkilde som f.eks. natriumkarbonat, ved en temperatur fra ca. 0 til ca. 50°C i et løsningsmiddel (f.eks. alkohol eller halogen-karbon) fra ca. 30 minutter til ca. 3 timer. . Forbindelse III oppløses i et egnet organisk løsnings-middel (f.eks. metanol, kloroform eller metylenklorid), oppvarmes fra ca. 0 til ca. 100°C i nærvær av cyansyre og én egnet hydronium-kilde slik at imidazolinonet med formel IV oppnås. An α-substituted ketone of formula I, which can be displaced by means of a nucleophilic reagent, is reacted with an amine of formula II or its acid addition salts, so that a compound of formula III is obtained. This reaction can be carried out using an excess of the compound of formula II, or in the presence of a tertiary amine such as e.g. triethylamine, or in the presence of a hydroxide source such as e.g. sodium carbonate, at a temperature from approx. 0 to approx. 50°C in a solvent (e.g. alcohol or halogen-carbon) from approx. 30 minutes to approx. 3 hours. . Compound III is dissolved in a suitable organic solvent (e.g. methanol, chloroform or methylene chloride), heated from approx. 0 to approx. 100°C in the presence of cyanic acid and one suitable hydronium source so that the imidazolinone of formula IV is obtained.

To alternative fremgangsmåter for fremstilling av imidazolidonet med formel V kan brukes. I den første av disse to fremgangsmåter hydrogeneres imidazolinonet med formel IV ved ca. 1,05 til 70,3 kg/cm 2 hydrogen i et egnet løsningsmiddel (f.eks. alkohol, hydrokarbon, blandet alkohol-hydrokarbonløsningsmiddel eller eddiksyre) i nærvær av en katalysator (f.eks. palladium på karbon) ved en temperatur fra ca. o til ca. 100°C i ca. 30 minutter eller mer eller reduseres med et egnet reduksjonsmiddel for å gi imidazolidonet med formel V. Alternativt omsettes IV med et acylhalo-genid eller acylanhydrid med formelen. Two alternative methods for preparing the imidazolidone of formula V can be used. In the first of these two methods, the imidazolinone of formula IV is hydrogenated at approx. 1.05 to 70.3 kg/cm 2 of hydrogen in a suitable solvent (e.g. alcohol, hydrocarbon, mixed alcohol-hydrocarbon solvent or acetic acid) in the presence of a catalyst (e.g. palladium on carbon) at a temperature from about. o to approx. 100°C for approx. 30 minutes or more or is reduced with a suitable reducing agent to give the imidazolidone of formula V. Alternatively, IV is reacted with an acyl halide or acyl anhydride of the formula.

hvor Y er hvilken som helst gruppe (f.eks. halogen) som kan forflyttes ved hjelp av et nukleofilt reagens, i nærvær av en hydroksydkilde under tilbakeløpsbehandling med eller uten et hydrokarbon-løsningsmiddel for å gi imidazolinon med formel IVa. Imidazolinonet med formelIVa hydrogeneres under samme betingelser som for IV til V for å gi imidazolidonet med formel IVb. I løpet av hydrogener-ingen av enten IV eller IVa vil hvilke som helst halogener som kan være til stede som del av R, R^- eller R^-gruppene fjernes og erstattes av hydrogen hvis det ikke brukes milde hydrogenerings-betingelser. Imidazolidonet med formelIVb hydrolyseres i nærvær av en hydroksydkilde enten i vann eller alkohol ved en temperatur fra ca. 70 til 100°C for å gi imidazolidonet med formel V. Det finnes generelt i tilfellet IVb med R lik COR^ at COR3~gruppen også hydrolyseres i dette trinn slik at det oppnås V der R er lik hydrogen. wherein Y is any group (eg halogen) which can be displaced by a nucleophilic reagent, in the presence of a hydroxide source under reflux with or without a hydrocarbon solvent to give the imidazolinone of formula IVa. The imidazolinone of formula IVa is hydrogenated under the same conditions as for IV to V to give the imidazolidone of formula IVb. During the hydrogenation of either IV or IVa, any halogens that may be present as part of the R, R^ or R^ groups will be removed and replaced by hydrogen if mild hydrogenation conditions are not used. The imidazolidone of formula IVb is hydrolyzed in the presence of a hydroxide source either in water or alcohol at a temperature from approx. 70 to 100°C to give the imidazolidone of formula V. It is generally found in the case of IVb with R equal to COR^ that the COR3~ group is also hydrolyzed in this step so that V is obtained where R is equal to hydrogen.

Imidazolidonet med formel V oppvarmes i et inert løsnings-middel (f.eks. toluen, xylen eller cykloheksan) ved en temperatur fra ca. 80 til ca. 200°C i nærvær av et reagens (f.eks. fosforpentasulfid) som kan utveksle oksygen med svovel slik at imidazolidintion med formel VI og noe av forbindelsen med formel VII (som fri base) oppnås. Når det gjelder forbindelser med formel V hvor R er hydrogen, påvirker også reaksjon med fosforpentasulfid den frie hydroksylgruppen og forandrer den slik at det dannes en svovel-holdig gruppe som eventuelt også kan inneholde fosfor. Denne for-andrede gruppe er ikke desto mindre i stand til å undergå ring-slutning i slutt-trinnet slik at det dannes forbindelser med formel VII. Når det gjelder forbindelser med formel V hvor R er COR^-delen, skjer det ofte at COR-^-gruppen reagerer med det svovelholdige reagenset (f.eks. fosforpentasulfid) slik at det dannes en CSR^-gruppe. Dette påvirker ikke evnen hos forbindelser med formel VI hvor denne forandring er foregått, til ringdannelse til de nyttige forbindelsene med formel VII. The imidazolidone of formula V is heated in an inert solvent (e.g. toluene, xylene or cyclohexane) at a temperature from approx. 80 to approx. 200°C in the presence of a reagent (e.g. phosphorus pentasulphide) which can exchange oxygen with sulfur so that the imidazolidine thione of formula VI and some of the compound of formula VII (as free base) are obtained. In the case of compounds of formula V where R is hydrogen, reaction with phosphorus pentasulphide also affects the free hydroxyl group and changes it so that a sulphur-containing group is formed which may also contain phosphorus. This altered group is nevertheless capable of undergoing ring closure in the final step so that compounds of formula VII are formed. In the case of compounds of formula V where R is the COR^ moiety, it often happens that the COR-^ group reacts with the sulfur-containing reagent (eg phosphorus pentasulfide) to form a CSR^ group. This does not affect the ability of compounds of formula VI where this change has taken place to form rings to the useful compounds of formula VII.

Imidazolidintionét med formel VI oppvarmes med HY, hvor Y er et farmasøytisk akseptabelt anion (f.eks. klorid, fluorid, jodid, bisulfat og p-toluensulfonat) i et løsningsmiddel ved én temperatur fra ca. 0 til ca. 200°C slik at forbindelsen med formel VII oppnås. Forbindelsen med formel III hvor R er en acylgruppe, kan også fremstilles som følger: The imidazolidine thione of formula VI is heated with HY, where Y is a pharmaceutically acceptable anion (e.g. chloride, fluoride, iodide, bisulfate and p-toluenesulfonate) in a solvent at one temperature from approx. 0 to approx. 200°C so that the compound of formula VII is obtained. The compound of formula III where R is an acyl group can also be prepared as follows:

Forbindelsen med formelIVa undergår homogen reduksjon, The compound of formula IVa undergoes homogeneous reduction,

som vist i det følgende flytskjema, med en chiral katalysator,as shown in the following flow chart, with a chiral catalyst,

som f.eks. forbindelse VIII, når den hydrogeneres ved fra ca.like for example. compound VIII, when hydrogenated at from ca.

1,05 til ca. 105,5 kg/cm 2 hydrogen i et egnet organisk løsnings-middel som f.eks. alkohol eller aromatiske løsningsmidler ved en temperatur fra ca. 70 til ca. 100°C i nærvær av en hydroksydkilde 1.05 to approx. 105.5 kg/cm 2 hydrogen in a suitable organic solvent such as e.g. alcohol or aromatic solvents at a temperature from approx. 70 to approx. 100°C in the presence of a hydroxide source

i vann eller alkohol, til den optisk aktive forbindelsen Vb. Den rasemiske blanding Vb, fra det første flytskjema, eller optisk aktiv Vb fra ""det følgende flytskjema, omdannes til rasemisk VI in water or alcohol, to the optically active compound Vb. The racemic mixture Vb, from the first flowchart, or optically active Vb from ""the following flowchart, is converted to racemic VI

eller optisk aktivVIb, respektive, sammen med noe rasemisk VII og optisk aktiv Vllb, respektive, ved behandling med et reagens som kan erstatte oksygen med svovel i tilbakeløpende hydrokarbonløsnings-midler ved en temperatur fra 80 til ca. 200°C. Som angitt ovenfor kan også andre oksygenfunksjoner som kan være til stede i V eller Vb undergå reaksjon med tieringsmidlet. Forbindelsene med formel or optically active VIb, respectively, together with some racemic VII and optically active Vllb, respectively, by treatment with a reagent capable of replacing oxygen with sulfur in refluxing hydrocarbon solvents at a temperature of from 80 to about 200°C. As indicated above, other oxygen functions which may be present in V or Vb can also undergo reaction with the thiating agent. The compounds with formula

VI og VIb omdannes til rasemisk VII og optisk aktiv Vllb, respektive, ved oppvarmning med HY, hvor Y er et farmasøytisk akseptabelt anion (f.eks. klorid, fluorid, jodid, bisulfat, p-toluensulfonat og lignende) i et egnet løsningsmiddel ved en temperatur fra ca. VI and VIb are converted to racemic VII and optically active Vllb, respectively, by heating with HY, where Y is a pharmaceutically acceptable anion (e.g., chloride, fluoride, iodide, bisulfate, p-toluenesulfonate, and the like) in a suitable solvent at a temperature from approx.

0 til ca. 200°C. 0 to approx. 200°C.

Oppfinnelsen illustreres ved følgende eksempler. The invention is illustrated by the following examples.

Eksempel 1 Example 1

1-( 2- metoksyetyl)- 4- fenyl- 4~ imidazolin- 2- on.1-(2-Methoxyethyl)-4-phenyl-4~imidazolin-2-one.

Fenacylbromid (60 g) i 200 ml metylenklorid tilsettes i løpet av 1 time til 2-metoksyetylamin (52 g) i 100ml metylenklorid og avkjøles med et isbad.Blandingen omrøres i 2 timer ved 0°C. Vann (400 ml) tilsttes og det organiske sjiktet separeres, tørkes over vannfritt natriumsulfat.og konsentreres under aspirator-vakuum (ved romtemperatur). Den viskose oljen (260 g) oppløses i metanol (200 ml), avkjøles til 0°C og eddiksyre (80 ml) og kaliumcyanat (30g) tilsettes. Blandingen tilbakeløpsbehandles i 90 minutter, løsningsmidlet fjernes under redusert trykk og residuet opptas i 600 ml kloroform og vaskes med mettet natriumbikarbonat-løsning. Kloroformsjiktet vaskes, tørkes over natriumsulfat og konsentreres til et halvfast stoff. Utgnidning med eter og filtrering gir titelproduktet som gule krystaller, smp. 152-153°C. Phenacyl bromide (60 g) in 200 ml methylene chloride is added over 1 hour to 2-methoxyethylamine (52 g) in 100 ml methylene chloride and cooled with an ice bath. The mixture is stirred for 2 hours at 0°C. Water (400 ml) is added and the organic layer is separated, dried over anhydrous sodium sulfate and concentrated under aspirator vacuum (at room temperature). The viscous oil (260 g) is dissolved in methanol (200 ml), cooled to 0°C and acetic acid (80 ml) and potassium cyanate (30 g) are added. The mixture is refluxed for 90 minutes, the solvent is removed under reduced pressure and the residue is taken up in 600 ml of chloroform and washed with saturated sodium bicarbonate solution. The chloroform layer is washed, dried over sodium sulfate and concentrated to a semi-solid. Trituration with ether and filtration gives the title product as yellow crystals, m.p. 152-153°C.

Eksempel 2 Example 2

1-( 2- metoksyetyl)- 4- fenyl- 4- imidazdlin- 2- on1-(2- methoxyethyl)- 4- phenyl- 4- imidazdlin- 2- one

Fenacylbromid (199 g) i 400 ml kloroform tilsettes iPhenacyl bromide (199 g) in 400 ml of chloroform is added

løpet av 1/2 time til en blanding av 2-metoksyetylamin (82 g) og trietylamin (152 g) i 200 ml kloroform ved 0°C.Blandingen omrøres i 2 timer ved 0-l0°C. Vann (400 ml) tilsettes og det organiske sjiktet separeres og vaskes med nye 400 ml vann. Kloroformsjiktet avkjøles til 0°C med et isbad, og iseddik (72 g), kaliumcyanat over 1/2 hour to a mixture of 2-methoxyethylamine (82 g) and triethylamine (152 g) in 200 ml of chloroform at 0°C. The mixture is stirred for 2 hours at 0-10°C. Water (400 ml) is added and the organic layer is separated and washed with a new 400 ml of water. The chloroform layer is cooled to 0°C with an ice bath, and glacial acetic acid (72 g), potassium cyanate

(89 g) og metanol (100ml) tilsettes.Blandingen tilbakeløpsbe-handles i 90 minutter, avkjøles og vaskes med mettet natriumbikarbo-natløsning, og det organiske sjiktet tørkes over vannfritt natriumsulfat og konsentreres så til et halvfast stoff.Utgnidning med eter og filtrering gir titelproduktet som gule krystaller, smp, 152-154°C. (89 g) and methanol (100 ml) are added. The mixture is refluxed for 90 minutes, cooled and washed with saturated sodium bicarbonate solution, and the organic layer is dried over anhydrous sodium sulfate and then concentrated to a semi-solid. Trituration with ether and filtration gives the title product as yellow crystals, mp 152-154°C.

Eksempel 3 Example 3

1-( 2- metoksyetyl)- 4- fenyl- 2- imidazolidon1-(2-Methoxyethyl)-4-phenyl-2-imidazolidone

Omtrent 10,9 g 1-(2-metoksyetyl)-4-fenyl-4-imidazolin-2-About 10.9 g of 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-

on og 1 g 10%palladium på karbon i 100ml etanol hydrogeneres. i et "Parr Shaker"-apparat ved 2,1 kg/cm 2 hydrogen i 45 minutter. Katalysatoren frafiltreres, vaskes med etanol og filtratet konsentreres til titelforbindelsen som et voksaktig, hvitt faststoff, on and 1 g of 10% palladium on carbon in 100 ml of ethanol are hydrogenated. in a "Parr Shaker" apparatus at 2.1 kg/cm 2 hydrogen for 45 minutes. The catalyst is filtered off, washed with ethanol and the filtrate is concentrated to the title compound as a waxy white solid,

smp. 82-83°C.m.p. 82-83°C.

Den ovenstående reduksjon kan også utføres med eddiksyre som løsningsmiddel og ved atmosfærisk trykk i begge løsnings-midlene. The above reduction can also be carried out with acetic acid as solvent and at atmospheric pressure in both solvents.

Eksempel 4 Example 4

1-( 2- metoksyetyl)- 4- fenylimidazolidin- 2- tion1-(2-Methoxyethyl)-4-phenylimidazolidin-2-thione

Omtrent lg 1-(2-metoksyetyl)-4-fenyl-2-imidazolidon og 0,4 g fosforpentasulfid tilbakeløpsbehandles i toluen over natten (16 timer). Toluenet avdestilleres under redusert trykk og det resterende halvfaste stoffet oppløses i en løsning av 50 ml kloroform og 30 ml 20%-ig natriumhydroksyd. Det organiske sjiktet separeres, vaskes, tørkes og løsningsmidlet fjernes slik at det oppnås 1 g av en olje. Oljen oppløses i 3 ml aceton og vannfritt hydrogenklorid bobles inn i 2 minutter. Det utfelte tetramisol-hydroklorid avfiltreres og filtratet konsentreres til tørrhet. Filtratet omkrystalliseres fra benzen-cykloheksan for å gi titelforbindelsen som et hvitt faststoff, smp. 76-78°C. About 1g of 1-(2-methoxyethyl)-4-phenyl-2-imidazolidone and 0.4 g of phosphorus pentasulphide are refluxed in toluene overnight (16 hours). The toluene is distilled off under reduced pressure and the remaining semi-solid substance is dissolved in a solution of 50 ml of chloroform and 30 ml of 20% sodium hydroxide. The organic layer is separated, washed, dried and the solvent is removed so that 1 g of an oil is obtained. The oil is dissolved in 3 ml of acetone and anhydrous hydrogen chloride is bubbled in for 2 minutes. The precipitated tetramisole hydrochloride is filtered off and the filtrate is concentrated to dryness. The filtrate is recrystallized from benzene-cyclohexane to give the title compound as a white solid, m.p. 76-78°C.

Eksempel 5Example 5

Fremstilling av tetramisol-hydroklorid fra 1-(2-metoksyetyl)-4-fenylimidazolidin- 2- tion Preparation of tetramisole hydrochloride from 1-(2-methoxyethyl)-4-phenylimidazolidin-2-thione

Omtrent 236 mg 1-(2-metoksyetyl)-4-fenylimidazolidin-2-tion, 5 ml konsentrert saltsyre og 5 ml aceton tilbakeløpsbehand-les sammen i 1 time. Løsningen konsentreres så til tørrhet under redusert trykk og utgnis med 2 ml etanol. Det hvite, faste bunnfallet avfiltreres slik at titelforbindelsen oppnås. Approximately 236 mg of 1-(2-methoxyethyl)-4-phenylimidazolidin-2-thione, 5 ml of concentrated hydrochloric acid and 5 ml of acetone are refluxed together for 1 hour. The solution is then concentrated to dryness under reduced pressure and triturated with 2 ml of ethanol. The white solid precipitate is filtered off to give the title compound.

Eksempel 6Example 6

Fremstilling av tetramisol-hydroklorid fra 1-(2-metoksyetyl)-4-f enyl- 2- imidazolidon Preparation of tetramisole hydrochloride from 1-(2-methoxyethyl)-4-phenyl-2-imidazolidone

Omtrent 4,4 g 1-(2-metoksyetyl)-4-fenyl-2-imidazolidon og 2 g fosforpentasulfid tilbakeløpsbehandles sammen i 200 ml toluen i 20 timer. Toluenet avdestilleres under redusert trykk og residuet opptas i 100 ml kloroform og vaskes med 50 ml 20%-ig natriumhydroksyd. Det organiske sjiktet vaskes med vann, tørkes og løsningsmidlet fjernes for å gi en gul olje. Oljen tilbakeløps-behandles i 1 time i en løsning av 10ml konsentrert saltsyre og 10 ml etanol.Løsningen konsentreres til tørrhet, det gjenværende halvfaste stoffet utgnis med etanol (20 ml), filtreres og tørkes slik at titelforbindelsen oppnås, smp. 260-262°C. About 4.4 g of 1-(2-methoxyethyl)-4-phenyl-2-imidazolidone and 2 g of phosphorus pentasulfide are refluxed together in 200 ml of toluene for 20 hours. The toluene is distilled off under reduced pressure and the residue is taken up in 100 ml of chloroform and washed with 50 ml of 20% sodium hydroxide. The organic layer is washed with water, dried and the solvent removed to give a yellow oil. The oil is refluxed for 1 hour in a solution of 10 ml of concentrated hydrochloric acid and 10 ml of ethanol. The solution is concentrated to dryness, the remaining semi-solid is triturated with ethanol (20 ml), filtered and dried so that the title compound is obtained, m.p. 260-262°C.

Eksempel 7 Example 7

1-( 2- hydroksyetyl)- 4- fenyl- 4- imidazolin- 2- on1-( 2- hydroxyethyl)- 4- phenyl- 4- imidazolin- 2- one

Fenacylbromid (60 g) i metylenklorid (100 ml) tilsettesPhenacyl bromide (60 g) in methylene chloride (100 ml) is added

i løpet av 30 minutter til monoetanolamin (41 g) i metylenklorid (100 ml). over 30 minutes to monoethanolamine (41 g) in methylene chloride (100 ml).

Løsningen avkjøles til 0°C med et isbad, omrøres i 90 minutter. ved 0-5°C og det tilsettes så 400 ml vann. Det organiske sjiktet separeres, tørkes over vannfritt natriumsulfat og konsentreres under redusert trykk ved omtrentlig romtemperatur. Restoljen opp-løses i metanol (150 ml), avkjøles og en løsning av natriumcyanat (24 g) i eddiksyre (30 ml) tilsettes.Blandingen tilbakeløps-behandles i 1 time og avkjøles så. Det hvite, faste bunnfallet frafiltreres, vaskes med vann, metanol og tørkes så slik at titelforbindelsen oppnås, smp. 203-205°C. The solution is cooled to 0°C with an ice bath, stirred for 90 minutes. at 0-5°C and 400 ml of water is then added. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure at about room temperature. The residual oil is dissolved in methanol (150 ml), cooled and a solution of sodium cyanate (24 g) in acetic acid (30 ml) is added. The mixture is refluxed for 1 hour and then cooled. The white solid precipitate is filtered off, washed with water, methanol and then dried to obtain the title compound, m.p. 203-205°C.

Eksempel 8 Example 8

1-( 2- hydroksyetyl)- 4- fenyl- 2- imidazolidon1-(2-Hydroxyethyl)-4-phenyl-2-imidazolidone

En oppslemming av 1-(2-hydroksyetyl)-4-fenyl-4-imidazolin-2-on (10,2 g) og 10% palladium på karbon (lg) i etanol (2.00ml) hydrogeneres i et "parr Shaker"-apparat ved ca. 2,1 kg/cm 2 hydrogen i 3 timer. Katalysatoren frafiltreres så, vaskes med etanol og det kombinerte filtrat og vaskeløsningene konsentreres til en farveløs olje som blir fast ved henstand slik at titelforbindelsen oppnås, smp. 60-63°C. A slurry of 1-(2-hydroxyethyl)-4-phenyl-4-imidazolin-2-one (10.2 g) and 10% palladium on carbon (lg) in ethanol (2.00 ml) is hydrogenated in a "parr Shaker" - device at approx. 2.1 kg/cm 2 hydrogen for 3 hours. The catalyst is then filtered off, washed with ethanol and the combined filtrate and washings concentrated to a colorless oil which solidifies on standing to give the title compound, m.p. 60-63°C.

Eksempel 9Example 9

Fremstilling av tetramisol-hydroklorid fra 1-(2-hydroksyetyl)-4-f enyl- r2- imidazolidon Preparation of tetramisole hydrochloride from 1-(2-hydroxyethyl)-4-phenyl-r2-imidazolidone

En blanding av 1-(2-hydroksyetyl)-4-fenyl-2-imidazolin (4,1 g) og fosforpentasulfid (1,8 g) i toluen (25 ml) tilbakeløps-behandles i 20 timer. Toluenet avdestilleres under redusert trykk og residuet oppløses i en løsning av kloroform (50 ml) og 20%-ig natriumhydroksyd (50 ml). Det organiske sjiktet separeres, vaskes, tørkes over natriumsulfat og konsentreres til en olje. Oljen til-bakeløpsbehandles i en løsning av etanol (10 ml) og.konsentrert saltsyre (20 ml) i 1 time. Løsningen konsentreres til tørrhet, utgnis med etanol (20ml) og filtreres slik at titelforbindelsen oppnås som et hvitt faststoff, smp. 260°C. A mixture of 1-(2-hydroxyethyl)-4-phenyl-2-imidazoline (4.1 g) and phosphorus pentasulfide (1.8 g) in toluene (25 ml) is refluxed for 20 hours. The toluene is distilled off under reduced pressure and the residue is dissolved in a solution of chloroform (50 ml) and 20% sodium hydroxide (50 ml). The organic layer is separated, washed, dried over sodium sulfate and concentrated to an oil. The oil is refluxed in a solution of ethanol (10 ml) and concentrated hydrochloric acid (20 ml) for 1 hour. The solution is concentrated to dryness, triturated with ethanol (20ml) and filtered to give the title compound as a white solid, m.p. 260°C.

Eksempel 10 Example 10

1-( 2- acetoksyetyl)- 4- fenyl- 2- imidazolidon1-(2-acetoxyethyl)-4-phenyl-2-imidazolidone

Omtrent 9,2 g 1-(2-hydroksyetyl)-4-fenyl-2-imidazolidon omrøres med eddiksyreanhydrid (25 ml) og p-toluensulfonsyre (200mg) i 4 timer, i løpet av hvilken tid imidazolidonet oppløses full-stendig. Løsningen (100 ml) fra hvilken et hvitt faststoff ut-felles. Det faste stoffet ekstraheres med metylenklorid (3x100 ml). Det organiske sjiktet separeres, tørkes og løsningsmidlet fjernes for å gi et blekgult faststoff..Omkrystallisasjon fra eter gir titelforbindelsen som et hvitt, krystallinsk faststoff, smp. 88-90°C. About 9.2 g of 1-(2-hydroxyethyl)-4-phenyl-2-imidazolidone is stirred with acetic anhydride (25 ml) and p-toluenesulfonic acid (200 mg) for 4 hours, during which time the imidazolidone is completely dissolved. The solution (100 ml) from which a white solid precipitates. The solid is extracted with methylene chloride (3x100 ml). The organic layer is separated, dried and the solvent removed to give a pale yellow solid..Recrystallization from ether gives the title compound as a white crystalline solid, m.p. 88-90°C.

Eksempel 11 Example 11

Fremstilling av tetramisol-hydroklorid fra 1-(2-acetoksyetyl)-4-feh<y>l-2- imidazolidon Preparation of tetramisole hydrochloride from 1-(2-acetoxyethyl)-4-phe<y>1-2-imidazolidone

Omtrent 5 g.1-(2-acetoksyetyl)-4-fenyl-2-imidazolidon og 1,8 g fosforpentasulfid tilbakeløpsbehandles i 20 ml toluen i 20 timer. Løsningsmidlet avdestilleres under redusert trykk<p>g residuet oppløses i en løsning av kloroform (100 ml) og 20%-ig natriumhydroksyd. (100 ml). Det organiske sjiktet separeres så, vaskes, tørkes over natriumsulfat behandlet med kull, filtreres og konsentreres til en olje. Oljen tilbakeløpsbehandles i en løsning av konsentrert saltsyre (20ml) og etanol (10 ml) i 1 time. Løsningen konsentreres til tørrhet og residuet utgnis med etanol (20 ml) og filtreres så for å gi titelforbindelsen med brun farve, smp. 258-260°C. Approximately 5 g of 1-(2-acetoxyethyl)-4-phenyl-2-imidazolidone and 1.8 g of phosphorus pentasulphide are refluxed in 20 ml of toluene for 20 hours. The solvent is distilled off under reduced pressure and the residue is dissolved in a solution of chloroform (100 ml) and 20% sodium hydroxide. (100ml). The organic layer is then separated, washed, dried over sodium sulfate treated with charcoal, filtered and concentrated to an oil. The oil is refluxed in a solution of concentrated hydrochloric acid (20ml) and ethanol (10ml) for 1 hour. The solution is concentrated to dryness and the residue is triturated with ethanol (20 mL) and then filtered to give the title compound with a brown color, m.p. 258-260°C.

Eksempel 12 Example 12

1-( 2- acetoksyetyl)- 4- fenyl- 4- imidazolin- 2- on1-( 2- acetoxyethyl)- 4- phenyl- 4- imidazolin- 2- one

Omtrent 9 g 2-metyloksazolin og 20g fenacylbromid til-bakeløpsbehandles i 100 ml kloroform i 1 time.Løsningsmidlet konsentreres under redusert trykk og eddiksyre (lo ml), kaliumcyanat (9 g) og metanol (100ml) tilsettes til restoljen og blandingen tilbakeløpsbehandles i 1 time. Metanolen fjernes under redusert trykk og residuet opptas i 200ml metylenklorid og vaskes med mettet natriumbikarbonatløsning. Det organiske sjiktet tørkes og konsentreres til et halvfast stoff. Omkrystallisasjon fra benzen-cykloheksan gir titelforbindelsen, smp. 120-122°C. About 9 g of 2-methyloxazoline and 20 g of phenacyl bromide are refluxed in 100 ml of chloroform for 1 hour. The solvent is concentrated under reduced pressure and acetic acid (10 ml), potassium cyanate (9 g) and methanol (100 ml) are added to the residual oil and the mixture is refluxed for 1 hour. The methanol is removed under reduced pressure and the residue is taken up in 200 ml of methylene chloride and washed with saturated sodium bicarbonate solution. The organic layer is dried and concentrated to a semi-solid. Recrystallization from benzene-cyclohexane gives the title compound, m.p. 120-122°C.

Eksempel 13Example 13

Reduksjon av 1-( 2- acetoksyetyl)- 4- fenyl- 4- imidazolin- 2- onReduction of 1-(2-acetoxyethyl)-4-phenyl-4-imidazolin-2-one

Omtrent 1 g 1-(2-acetoksyetyl)-4-fenyl-4-imidazolin-2-on og 250 mg 10% palladium på karbon i lo ml etanol omrøres i en hydrogenatmosfære.,Etter omtrent tre kvarters forløp frafiltreres katalysatoren og vaskes med 20ml etanol. De kombinerte filtrater konsentreres for å gi titelforbindelsen som et hvitt faststoff, smp. 86-88°C — About 1 g of 1-(2-acetoxyethyl)-4-phenyl-4-imidazolin-2-one and 250 mg of 10% palladium on carbon in 10 ml of ethanol are stirred in a hydrogen atmosphere.,After about three quarters of an hour, the catalyst is filtered off and washed with 20ml of ethanol. The combined filtrates are concentrated to give the title compound as a white solid, m.p. 86-88°C —

Eksempel 14 Example 14

1-( 2- metoksyetyl)- 3- acetyl- 4- fenyl- 4- imidazolin- 2- on1-( 2- methoxyethyl)- 3- acetyl- 4- phenyl- 4- imidazolin- 2- one

Omtrent 21,8 g 1-(2-metoksyetyl)-4-fenyl-4-imidazolin-2-on og 120ml eddiksyreanhydrid tilbakeløpsbehandles i 4 timer. Eddiksyreanhydridet. avdestilleres ved redusert trykk. Det gjenværende halvfaste stoff omkrystalliséres fra eter slik at titelforbindelsen oppnås som et hvitt faststoff, smp. 73-75°C. Approximately 21.8 g of 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one and 120 ml of acetic anhydride are refluxed for 4 hours. The acetic anhydride. is distilled off at reduced pressure. The remaining semi-solid is recrystallized from ether to give the title compound as a white solid, m.p. 73-75°C.

Eksempel 15Example 15

Rasemisk 1-( 2- metoksyetyl)- 3- acetyl- 4- fenyl- 2- imidazolidon Racemic 1-(2- methoxyethyl)- 3- acetyl- 4- phenyl- 2- imidazolidone

Omtrent 3,9 g 1-(2-metoksyetyl)-3-acetyl-4-fenyl-4-imidazolin-2-on og 400mg 10%palladium på karbon i 30ml etanol hydrogeneres i.et "Parr Shaker"-apparat ved 2,1 kg/cm 2 hydrogen. Etter 1 times forløp frafiltreres katalysatoren og vaskes med 50 ml etanol. De kombinerte filtrater konsentreres for å gi titelforbindelsen som en farveløs olje. About 3.9 g of 1-(2-methoxyethyl)-3-acetyl-4-phenyl-4-imidazolin-2-one and 400 mg of 10% palladium on carbon in 30 ml of ethanol are hydrogenated in a "Parr Shaker" apparatus at 2 .1 kg/cm 2 of hydrogen. After 1 hour, the catalyst is filtered off and washed with 50 ml of ethanol. The combined filtrates are concentrated to give the title compound as a colorless oil.

Eksempel 16Example 16

Hydrolyse av 1-(2-metoksyetyl)-3-acetyl-4-fenyl-2-imidazolidon til 1- ( 2- metoksyetyl) - 4- f enyl- 2- imidazolidon Hydrolysis of 1-(2-methoxyethyl)-3-acetyl-4-phenyl-2-imidazolidone to 1-(2-methoxyethyl)-4-phenyl-2-imidazolidone

Omtrent 2,6 g av 3-acetyl-derivatet tilbakeløpsbehandles i 20ml 10%-ig natriumhydroksyd i 1 time. Løsningen avkjøles og ekstraheres så med kloroform (2x20 ml). De kombinerte, kloroform-ekstrakter vaskes, tørkes over natriumsulfat og konsentreres for å gi titelforbindelsen som et faststoff, smp. 81-83°C. Approximately 2.6 g of the 3-acetyl derivative is refluxed in 20 ml of 10% sodium hydroxide for 1 hour. The solution is cooled and then extracted with chloroform (2x20 ml). The combined chloroform extracts are washed, dried over sodium sulfate and concentrated to give the title compound as a solid, m.p. 81-83°C.

Eksempel 17 Example 17

1- ( 2- metoksyetyl) - 3- benzoyl- 4- f enylr- 4- imidazolin- 2- on Omtrent 4,36 g 1-(2-metoksyetyl)-4-fenyl-4-imidazolin-2-on, 3 g trietylamin og 3 g benzoylklorid tilbakeløpsbehandles sammen i 3 timer i kloroform.Løsningen avkjøles, vaskes med vann, 1-( 2- methoxyethyl) - 3- benzoyl- 4- phenylr- 4- imidazolin- 2- one About 4.36 g 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one, 3 g of triethylamine and 3 g of benzoyl chloride are refluxed together for 3 hours in chloroform. The solution is cooled, washed with water,

tørkes og løsningsmidlet fjernes for å gi en olje som er0-benzoylesteren. Esteren tilbakeløpsbehandles i 3 timer i 20 ml xylen. Xylenet fjernes ved redusert trykk. Omkrystallisasjon fra eter gir titelforbindelsen som et blekgult faststoff, smp. 112-117°C. dried and the solvent removed to give an oil which is the 0-benzoyl ester. The ester is refluxed for 3 hours in 20 ml of xylene. The xylene is removed by reduced pressure. Recrystallization from ether gives the title compound as a pale yellow solid, m.p. 112-117°C.

Eksempel 18 Example 18

1- ( 2- metoksyetyl)- 3- benzoyl- 4- fenyl- 4- imidazolin- 2- on1-( 2- methoxyethyl)- 3- benzoyl- 4- phenyl- 4- imidazolin- 2- one

Omtrent 21,8 g 1-(2-metoksyetyl)-4-fenyl-4-imidazolin-2-on, 14,5 g benzoylklorid og 20g tri-n-butylamin tilbakeløps-behandles sammn i 60 ml xylen i 16 timer.Løsningsmidlet avdestilleres under redusert trykk og den gjenværende viskose olje oppløses i 300 ml benzen.Benzenløsningen vaskes med vann About 21.8 g of 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one, 14.5 g of benzoyl chloride and 20 g of tri-n-butylamine are refluxed together in 60 ml of xylene for 16 hours. The solvent is distilled off under reduced pressure and the remaining viscous oil is dissolved in 300 ml of benzene. The benzene solution is washed with water

(2x100 ml), tørkes over natriumsulfat, og løsningsmidlet fjernes for å gi et halvfast stoff. Omkrystallisasjon fra eter gir titelforbindelsen som et blekgult, fast stoff, smp. H4-117°c. (2x100 mL), dried over sodium sulfate, and the solvent removed to give a semi-solid. Recrystallization from ether gives the title compound as a pale yellow solid, m.p. H4-117°c.

Eksempel 19Example 19

Fremstilling av andre 1-(2-metoksyetyl)-3-acyl-4-fenyl-4-imidazolin- 2- oner Preparation of other 1-(2-methoxyethyl)-3-acyl-4-phenyl-4-imidazolin-2-ones

Følgende acylderivater fremstilles ved fremgangsmåter som er identiske med den som er beskrevet for N-benzoylderivatet i eksempel 18: a) 1-(2-metoksyetyl)-3-cykloheksankarbonyl-4-fenyl-4-imidazolin-2- on; b) 1-(2-metoksyetyl)-3-p_-trif luormetylbenzoyl-4-f enyl-4-imidazolin-2-on; c) 1-(2-metoksyetyl)-3-(1-adamantankarbonyl)-4-fenyl-4-imidazolin-2-on; d) 1-(2-metoksyetyl)-3-o-anisoyl-4-fenyl-4-imidazolin-2-on; e) 1-(2-metoksyetyl)-3-(2-klorbenzoyl)-4-fenyl-4-imidazolin-2-on; f) 1-(2-metoksyetyl)-3-(2,4-diklorbenzoyl)-4-fenyl-4-imidazolin-2-on; og g) 1-(2-metoksyetyl)-3-(2-metylbenzoyl)-4-fenyl-4-imidazolin-2-on. The following acyl derivatives are prepared by methods identical to that described for the N-benzoyl derivative in example 18: a) 1-(2-methoxyethyl)-3-cyclohexanecarbonyl-4-phenyl-4-imidazolin-2-one; b) 1-(2-methoxyethyl)-3-p-trifluoromethylbenzoyl-4-phenyl-4-imidazolin-2-one; c) 1-(2-methoxyethyl)-3-(1-adamantanecarbonyl)-4-phenyl-4-imidazolin-2-one; d) 1-(2-methoxyethyl)-3-o-anisoyl-4-phenyl-4-imidazolin-2-one; e) 1-(2-methoxyethyl)-3-(2-chlorobenzoyl)-4-phenyl-4-imidazolin-2-one; f) 1-(2-methoxyethyl)-3-(2,4-dichlorobenzoyl)-4-phenyl-4-imidazolin-2-one; and g) 1-(2-methoxyethyl)-3-(2-methylbenzoyl)-4-phenyl-4-imidazolin-2-one.

Eksempel 20Example 20

Hydrogenering av N-acylderivater av 1-(2-metoksyetyl)-4-fenyl-4-imidazolin-2-on ved bruk av (+)DI0P RhCODCl-katalysator og hydrogen Hydrogenation of N-acyl derivatives of 1-(2-methoxyethyl)-4-phenyl-4-imidazolin-2-one using (+)DI0P RhCODCl catalyst and hydrogen

Hydrogeneringene utføres i et "Parr Shaker"-apparat eller i en høytrykks laboratorieautoklav kledd med gass. produktene ekstraheres med eter eller eter-benzen, konsentreres og hydrolyseres ved tilbakeløpsbehandling i en 10%-ig natriumhydroksyd-løsning. Det rå 1-(2-metoksyetyl)-4-fenyl-2-imidazolidonet som oppnås, ekstraheres med metylenklorid, konsentreres og analyseres på mengden enantiomerer ved hjelp av kjernemagnetisk resonans (Nuclear Magnetic Resonance (NMR)) ved å bruke chiralskiftreagenset tris- [-3-(trifluormetylhydroksymetylen)-d-kamforato ], europium-(III)-derivatet,Eu(tfc)3- Resultatene av hydrogenering-ene er oppsummert i følgende tabell. The hydrogenations are carried out in a "Parr Shaker" apparatus or in a high-pressure laboratory autoclave lined with gas. the products are extracted with ether or ether-benzene, concentrated and hydrolysed by reflux treatment in a 10% sodium hydroxide solution. The crude 1-(2-methoxyethyl)-4-phenyl-2-imidazolidone obtained is extracted with methylene chloride, concentrated and analyzed for the amount of enantiomers by nuclear magnetic resonance (NMR) using the chiral shift reagent tris- [ -3-(trifluoromethylhydroxymethylene)-d-camphorato ], the europium-(III) derivative, Eu(tfc)3- The results of the hydrogenations are summarized in the following table.

Katalysatoren fremstilles fra (-)vinsyre som beskrevet av H.B.Kagan ogT.P.Dang,J.Am.Chem.Soc. 94, 6429 (1972). (+)DIOP-forbindelsen kan også kjøpes fra Strem Chemicals, Inc., Beverly, Mass. The catalyst is prepared from (-)tartaric acid as described by H.B.Kagan and T.P.Dang, J.Am.Chem.Soc. 94, 6429 (1972). The (+)DIOP compound can also be purchased from Strem Chemicals, Inc., Beverly, Mass.

Eksempel 21 Example 21

Optisk aktiv levamisol fra 1-(2-metoksyetyl)-4-fenyl-3-acetyl-4- imidazolin- 2- on Optically active levamisole from 1-(2-methoxyethyl)-4-phenyl-3-acetyl-4-imidazolin-2-one

Omtrent 5,2 g 1-(2-metoksyetyl)-4-acetyl-4-fenyl-4-imidazolin-2-on, 2 50 mg cyklo-oktadien-rhodiumklorid-dimer og 600mg (+)DI0P oppløst under nitrogen i 30 ml etanol og 30 ml benzen hydrogeneres i et "<p>arr Shaker"-apparat ved 40°C og 2,46 kg/cm<2>hydrogen i 11 timer. Løsningen konsentreres til tørrhet under redusert trykk, residuet oppløses i eter (100 ml) og filtreres.Filtratet konsentreres under redusert trykk til en brun olje. Denne olje oppløses i 20 ml etanol, og 40ml 10%-ig natriumhydroksyd tilsettes.Blandingen tilbakeløpsbehandles i 1 time, avkjøles og ekstraheres med metylenklorid (2x50 ml). Det kombinerte organiske sjikt vaskes, tørkes og løsningsmidlet fjernes for å gi optisk aktivt 1-(2-metoksyetyl)-4-fenyl-2-imidazolidon som voksaktig faststoff. Dette materiale beregnes å inneholde 24% overskudd av en enantiomer ved bruk av chiralskiftreagenset Eu(tfc)3som er nevnt About 5.2 g of 1-(2-methoxyethyl)-4-acetyl-4-phenyl-4-imidazolin-2-one, 2 50 mg of cyclo-octadiene-rhodium chloride dimer and 600 mg of (+)DI0P dissolved under nitrogen for 30 ml of ethanol and 30 ml of benzene are hydrogenated in a "<p>arr Shaker" apparatus at 40°C and 2.46 kg/cm<2>hydrogen for 11 hours. The solution is concentrated to dryness under reduced pressure, the residue is dissolved in ether (100 ml) and filtered. The filtrate is concentrated under reduced pressure to a brown oil. This oil is dissolved in 20 ml of ethanol, and 40 ml of 10% sodium hydroxide is added. The mixture is refluxed for 1 hour, cooled and extracted with methylene chloride (2x50 ml). The combined organic layer is washed, dried and the solvent removed to give optically active 1-(2-methoxyethyl)-4-phenyl-2-imidazolidone as a waxy solid. This material is calculated to contain a 24% excess of one enantiomer using the chiral shift reagent Eu(tfc)3 mentioned

i eksempel 20. Det faste stoffet tilbakeløpsbehandles med 2 g fosforpentasulfid i toluen i 20 timer. Toluenet fjernes under redusert trykk, residuet opptas i 100 ml kloroform og 100 ml 20%-ig natriumhydroksyd. Det organiske sjiktet fraskilles, vaskes og konsentreres til en olje. Denne olje opptas i 20 ml konsentrert saltsyre og løsningen tilbakeløpsbehandles i 1 time. Løsningen av-kjøles, filtreres og filtratet gjøres basisk med ammoniumhydroksyd.Blandingen ekstraheres med 2x50 ml metylenklorid. Det kombinerte organiske sjikt vaskes, tørkes og løsningsmidlet fjernes slik at det oppnås en olje som krystalliserer ved henstand. Spektral-egenskapene er identiske med tilsvarende egenskaper for tetramisol og materialet hadde en spesifikk rotasjon lo*]<2>^ = -17,7° (c7 i kloroform) tilsvarende et 21%-ig enantiomeroverskudd av levamisol. in example 20. The solid is refluxed with 2 g of phosphorus pentasulphide in toluene for 20 hours. The toluene is removed under reduced pressure, the residue is taken up in 100 ml of chloroform and 100 ml of 20% sodium hydroxide. The organic layer is separated, washed and concentrated to an oil. This oil is taken up in 20 ml of concentrated hydrochloric acid and the solution refluxed for 1 hour. The solution is cooled, filtered and the filtrate made basic with ammonium hydroxide. The mixture is extracted with 2x50 ml of methylene chloride. The combined organic layer is washed, dried and the solvent removed to give an oil which crystallizes on standing. The spectral properties are identical to corresponding properties for tetramisole and the material had a specific rotation lo*]<2>^ = -17.7° (c7 in chloroform) corresponding to a 21% enantiomeric excess of levamisole.

Eksempel 22Example 22

Optisk aktiv levamisol fra 1-(2-metoksyetyl)-3-benzoyl-4-fenyl-4- imidazolin- 2- on Optically active levamisole from 1-(2-methoxyethyl)-3-benzoyl-4-phenyl-4-imidazolin-2-one

Omtrent 6,4 g 1-(2-metoksyetyl)-3-benzoyl-4-fenyl-4-imidazolin-2-on, 250 mg cyklooktadién-rhodiumklorid-dimer og 550 mg (+)DI0P oppløst i 30 ml etanol og 30 ml benzen hydrogeneres i et "Parr Shaker"-apparat ved 40°C og 3,2 kg/cm hydrogen i 18 timer. Løsningen konsentreres så under redusert trykk og residuet ekstra heres med eter (3x75 ml).Eterekstraktene kombineres og konsentreres til 6,3 g av en olje. Denne olje hydrolyseres ved tilbake-løpsbehandling med 10%-ig natriumhydroksydløsning og det oppnås optisk aktivt 1-(2-metoksyetyl)-4-fenyl-2-imidazolidon som beskrevet i eksempel 21. Dette materiale beregnes å inneholde et 26%-ig overskudd av en enantiomer.Ytterligere omdannelse av dette materiale til levamisol som beskrevet i eksempel 21 gir optisk aktiv levamisol med spesifikk rotasjon ioi]^ CO -17,9 (C 10,kloroform) , tilsvarende et 22%-ig overskudd av levamisol. About 6.4 g of 1-(2-methoxyethyl)-3-benzoyl-4-phenyl-4-imidazolin-2-one, 250 mg of cyclooctadiene rhodium chloride dimer and 550 mg of (+)DI0P dissolved in 30 ml of ethanol and 30 ml of benzene is hydrogenated in a "Parr Shaker" apparatus at 40°C and 3.2 kg/cm hydrogen for 18 hours. The solution is then concentrated under reduced pressure and the residue is further diluted with ether (3x75 ml). The ether extracts are combined and concentrated to 6.3 g of an oil. This oil is hydrolyzed by reflux treatment with a 10% sodium hydroxide solution and optically active 1-(2-methoxyethyl)-4-phenyl-2-imidazolidone is obtained as described in example 21. This material is calculated to contain a 26% excess of an enantiomer. Further conversion of this material to levamisole as described in example 21 gives optically active levamisole with specific rotation ioi]^ CO -17.9 (C 10, chloroform), corresponding to a 22% excess of levamisole.

Eksempel 23 Example 23

1-( 2- butoksyetyl)- 4- fenyl- 4- imidazolin- 2- on1-( 2- butoxyethyl)- 4- phenyl- 4- imidazolin- 2- one

Fenacylbromid (lo g) i 50ml kloroform tilsettes i løpet av 20 minutter til en blanding av 2-butoksyetylamin (6 g) og trietylamin (7 g) i 50 ml kloroform ved 0°C.Blandingen omrøres i 2 timer. Vann (100 ml) tilsettes, det organiske sjiktet separeres, avkjøles til o°C og iseddik (5 ml), kaliumcyanat (5 g) og metanol (20 ml) tilsettes.Blandingen tilbakeløpsbehandles i 90 minutter, avkjøles, vaskes med mettet natriumbikarbonatløsning, tørkes, og løsningsmiddel fjernes slik at titelforbindelsen oppnås. Phenacyl bromide (10 g) in 50 ml chloroform is added over 20 minutes to a mixture of 2-butoxyethylamine (6 g) and triethylamine (7 g) in 50 ml chloroform at 0°C. The mixture is stirred for 2 hours. Water (100 ml) is added, the organic layer is separated, cooled to o°C and glacial acetic acid (5 ml), potassium cyanate (5 g) and methanol (20 ml) are added. The mixture is refluxed for 90 minutes, cooled, washed with saturated sodium bicarbonate solution, dried, and solvent removed to afford the title compound.

Eksempel. 24 Example. 24

1-( 2- butoksyetyl)- 4- fenyl- 2- imidazolidon1-(2-butoxyethyl)-4-phenyl-2-imidazolidone

En løsning av 1-(2-butoksyetyl)-4-fenyl-4-imidazolin-2-on i etanol med 10% palladium på karbon-katalysator reduseres i en hydrogenatmosfære. Etter at den teoretiske mengde hydrogen er absorbert, frafiltreres katalysatoren og filtratet konsentreres for å gi titelforbindelsen. A solution of 1-(2-butoxyethyl)-4-phenyl-4-imidazolin-2-one in ethanol with 10% palladium on carbon catalyst is reduced in a hydrogen atmosphere. After the theoretical amount of hydrogen is absorbed, the catalyst is filtered off and the filtrate is concentrated to give the title compound.

Eksempel 25 Example 25

1-( 2- metoksyetyl)- 4-( 2- klorfenyl)- 4- imidazolin- 2- on1-( 2- methoxyethyl)- 4-( 2- chlorophenyl)- 4- imidazolin- 2- one

Til o-klorfenacylbromid (23,4 g) i 100ml kloroform tilsettes i løpet av 30minutter 2-metoksyetylamin (20 g) i 100 ml kloroform som avkjøles i et isbad.Blandingen omrøres i 1 time ved 0°C. Vann (200 ml) tilsettes og det organiske sjiktet frasepa-reres, avkjøles til 0°C med et isbad og deretter tilsettes iseddik (8 ml), kaliumcyanat (6 g) og metanol.Blandingen tilbakeløpsbe-handles i 90 minutter, avkjøles, vaskes med mettet natriumbikarbo-natløsning, tørkes over vannfritt natriumsulfat og løsningsmiddel fjernes for å gi titelforbindelsen. To o-chlorophenacyl bromide (23.4 g) in 100 ml chloroform, 2-methoxyethylamine (20 g) in 100 ml chloroform, which is cooled in an ice bath, is added over 30 minutes. The mixture is stirred for 1 hour at 0°C. Water (200 ml) is added and the organic layer is separated, cooled to 0°C with an ice bath and then glacial acetic acid (8 ml), potassium cyanate (6 g) and methanol are added. The mixture is refluxed for 90 minutes, cooled, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and solvent removed to give the title compound.

Eksempel 26 Example 26

1-( 2- metoksyetyl)- 4-( substituert fenyl)- 4- imidazolin- 2- oner 1-( 2- methoxyethyl)- 4-( substituted phenyl)- 4- imidazolin- 2-ones

Følgende l-(2-metoksyetyl)-4-(substituert fenyl)-4-imidazolin-2-oner fremstilles på samme måte som beskrevet i eksempel 25: a) 1-(2-metoksyetyl)-4-(2,4-diklorfenyl)-4-imidazolin-2-on og b ) 1- ( 2-metoksyetyl) -4- (p_-trif luormetyl fenyl) -4-imidazolin-2-on. The following 1-(2-methoxyethyl)-4-(substituted phenyl)-4-imidazolin-2-ones are prepared in the same way as described in example 25: a) 1-(2-methoxyethyl)-4-(2,4- dichlorophenyl)-4-imidazolin-2-one and b) 1-(2-methoxyethyl)-4-(p_-trifluoromethyl phenyl)-4-imidazolin-2-one.

Eksempel 2 7Example 2 7

Fremstilling av 1-(2-metoksyetyl)-4-(substituert fenyl)-2-imidazolidon Preparation of 1-(2-methoxyethyl)-4-(substituted phenyl)-2-imidazolidone

En løsning av 1-(2-metoksyetyl)-4-(substituert fenyl)-4-imidazolin-2-on i etanol med 10% palladium på karbon-katalysator reduseres ved fra ca. 1,05 til ca. 70,3 kg/cm<2>hydrogen. Etter at den teoretiske mengde hydrogen er absorbert, frafiltreres katalysatoren og filtratet konsentreres for å gi 1-(2-metoksyetyl)-4-(substituert fenyl)-2-imidazolidonene. Følgende forbindelser ble fremstilt på ovennevnte måte: a) 1-(2-metoksyetyl)-4-(m-trifluormetyl)-2-imidazolidon; b) 1-(2-metoksyetyl)-4-(m-metylfenyl)-2-imidazolidon; c) l-(2-metoksyetyl)-4-(p_-trifluormetylfenyl)-2-imidazolidon; og A solution of 1-(2-methoxyethyl)-4-(substituted phenyl)-4-imidazolin-2-one in ethanol with 10% palladium on carbon catalyst is reduced by from approx. 1.05 to approx. 70.3 kg/cm<2>hydrogen. After the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off and the filtrate is concentrated to give the 1-(2-methoxyethyl)-4-(substituted phenyl)-2-imidazolidones. The following compounds were prepared in the above manner: a) 1-(2-methoxyethyl)-4-(m-trifluoromethyl)-2-imidazolidone; b) 1-(2-methoxyethyl)-4-(m-methylphenyl)-2-imidazolidone; c) 1-(2-methoxyethyl)-4-(p-trifluoromethylphenyl)-2-imidazolidone; and

d) 1-(2-metoksyetyl)-4-(m-metoksyfenyl)-2-imidazolidon.d) 1-(2-methoxyethyl)-4-(m-methoxyphenyl)-2-imidazolidone.

Eksempel 28 Example 28

1-( 2- benzoyloksyetyl)- 4- fenyl- 4- imidazolin- 2- on1-( 2- benzoyloxyethyl)- 4- phenyl- 4- imidazolin- 2- one

Omtrent 15 g 2-fenyloksazolin og 20 g fenacylbromid.til-bakeløpsbehandles i 100 ml kloroform i 1 time. Løsningsmidlet konsentreres under redusert trykk, og eddiksyre (10ml), kaliumcyanat (9 g) og metanol (100 ml) tilsettes og blandingen tilbakeløpsbe-handles i 1 time.Metanolen fjernes under redusert trykk og residuet opptas i 200 ml metylenklorid og vaskes med mettet natriumbi-karbonatløsning. Det organiske sjiktet tørkes og konsentreres for å gi titelforbindelsen. About 15 g of 2-phenyloxazoline and 20 g of phenacyl bromide are refluxed in 100 ml of chloroform for 1 hour. The solvent is concentrated under reduced pressure, and acetic acid (10 ml), potassium cyanate (9 g) and methanol (100 ml) are added and the mixture is refluxed for 1 hour. The methanol is removed under reduced pressure and the residue is taken up in 200 ml of methylene chloride and washed with saturated sodium bicarbonate -carbonate solution. The organic layer is dried and concentrated to give the title compound.

Eksempel 2 9Example 2 9

Fremstilling av andre 1-(2-acyloksyetyl)-4-fenyl-4-imidazolin-2-oner Preparation of other 1-(2-acyloxyethyl)-4-phenyl-4-imidazolin-2-ones

Følgende 1-(2-acyloksyetyl)-4-fenyl-4-imidazolin-2-oner fremstilles ved hjelp av fremgangsmåter som er identiske med den som er beskrevet for benzoyloksy-derivatene i eksempel 28:The following 1-(2-acyloxyethyl)-4-phenyl-4-imidazolin-2-ones are prepared by methods identical to that described for the benzoyloxy derivatives in Example 28:

a) 1-[2-(propionyloksy)etyl]-4-fenyl-4-imidazolin-2-on; b) 1- [2-(p_-metylbenzoyloksy)etyl ]-l- [2-(p_-nitrobenzoyloksy)etyl-4-fenyl-4-imidazolin-2-on; og c) 1- [2-(p_-trifluormetylbenzoyloksy)etyl ]-4-fenyl-4-imidazolin. a) 1-[2-(propionyloxy)ethyl]-4-phenyl-4-imidazolin-2-one; b) 1-[2-(p_-methylbenzoyloxy)ethyl]-1-[2-(p_-nitrobenzoyloxy)ethyl-4-phenyl-4-imidazolin-2-one; and c) 1-[2-(p-trifluoromethylbenzoyloxy)ethyl]-4-phenyl-4-imidazoline.

Eksempel 30Example 30

Fremstilling av 1-( 2- acyloksyetyl)- 4- fenyl- 2- imidazolidoner Preparation of 1-(2-acyloxyethyl)-4-phenyl-2-imidazolidones

Følgende 1-(2-acyloksyetyl)-4-fenyl-2-imidazolidoner fremstilles ved den katalytiske reduksjon av 1-(2-acyloksyetyl)-4-fen'yl-4-imidazolin-2-oner som er identisk med den som er beskrevet for 1-(2-acetoksyetyl)-derivater i eksempel 13: a) 1-[2-benzoyloksyetyl]-4-fenyl-2-imidazolidon; b) 1- [2-(propionyloksy) etyl ]-4-fenyl-2-imidazolidon; The following 1-(2-acyloxyethyl)-4-phenyl-2-imidazolidones are prepared by the catalytic reduction of 1-(2-acyloxyethyl)-4-phenyl-4-imidazolin-2-ones identical to that which is described for 1-(2-acetoxyethyl) derivatives in example 13: a) 1-[2-benzoyloxyethyl]-4-phenyl-2-imidazolidone; b) 1-[2-(propionyloxy)ethyl]-4-phenyl-2-imidazolidone;

c) 1-[2-(p_-metylbenzoyloksy) etyl ]-4-f enyl-2-imidazolin; ogc) 1-[2-(p-methylbenzoyloxy)ethyl]-4-phenyl-2-imidazoline; and

d) 1- [2-(p_-trif luormetylbenzoyloksy) etyl ]-4-fenyl-2-imidazolidon. d) 1-[2-(p_-trifluoromethylbenzoyloxy)ethyl]-4-phenyl-2-imidazolidone.

Eksempel 31Example 31

Følgende aminoketoner med formel A fremstilles ved reaksjonen mellom tilsvarende etanolaminer oppnådd fra deres syreaddisjonssalter og de tilsvarende fenacylbromider som i de tre første setninger i eksempel 2: The following aminoketones of formula A are prepared by the reaction between the corresponding ethanolamines obtained from their acid addition salts and the corresponding phenacyl bromides as in the first three sentences of Example 2:

Det substituerte etanolamin og deres syreaddisjonssalter og fenacylbromid-startmaterialene er fremstilt ifølge kjente litteratur.metoder. The substituted ethanolamine and their acid addition salts and the phenacyl bromide starting materials are prepared according to known literature methods.

Eksempel 3 2Example 3 2

Følgende imidazolinoner med formel B fremstilles fra aminoketoner fremstilt som i eksempel 30ved reaksjonen med kaliumcyanat som i eksemplene 1 og 2: The following imidazolinones of formula B are prepared from aminoketones prepared as in example 30 by the reaction with potassium cyanate as in examples 1 and 2:

Eksempel 33 Example 33

Følgende 3-substituerte imidazolinoner med formel C fremstilles som i eksempel 18 ved å bruke passende karbonylhalogen-ider eller -anhydrider og de tilsvarende 3-H-imidazolinoner: The following 3-substituted imidazolinones of formula C are prepared as in Example 18 using appropriate carbonyl halides or anhydrides and the corresponding 3-H-imidazolinones:

Eksempel 34 Example 34

Følgende 3-substituerte imidazolidoner med formel D fremstilles ved katalytisk hydrogenering av de tilsvarende 3-substituerte imidazolinoner ved å bruke fremgangsmåten fra eksempel 13: The following 3-substituted imidazolidones of formula D are prepared by catalytic hydrogenation of the corresponding 3-substituted imidazolinones using the procedure from Example 13:

Dersom tilsvarende forbindelser med formel C hydrogeneres i nærvær av en homogen hydrogeneringskatalysator som f.eks. tri-strifenylfosfino-klor-rhodium, fremstilles følgende forbindelser med formel D: If corresponding compounds of formula C are hydrogenated in the presence of a homogeneous hydrogenation catalyst such as e.g. tri-striphenylphosphino-chloro-rhodium, the following compounds of formula D are prepared:

Eksempel 3 5 Example 3 5

Følgende imidazolidoner med formel E fremstilles ved hydrogenering av de tilsvarende 3-usubstituerte imidazolinoner ifølge fremgangsmåten fra eksempel 3: The following imidazolidones of formula E are prepared by hydrogenation of the corresponding 3-unsubstituted imidazolinones according to the method from example 3:

Alle ovenstående forbindelser og følgende forbindelser kan fremstilles ved hydrolyse av tilsvarende forbindelser med formel D fra eksempel 34. All the above compounds and the following compounds can be prepared by hydrolysis of corresponding compounds with formula D from example 34.

•ti •ten

Eksempel 36 Example 36

Følgende imidazolidin-2-tioner med formel F fremstilles som i eksempel 4 fra de tilsvarende 3-usubstituerte imidazolidoner som i eksempel 4: The following imidazolidin-2-thiones of formula F are prepared as in example 4 from the corresponding 3-unsubstituted imidazolidones as in example 4:

Claims (10)

1. Optisk aktiv forbindelse, karakterisert ved at den har formelen: 1. Optically active compound, characterized in that it has the formula: hvor R er hydrogen, alkyl-C^ -C^ , fenyl, fenyl substituert med opp til tre grupper bestående av alkyl-C-^ -Cg, substituert halogen-alkyl-C-^-Cg, alkoksy-C^ -Cg og en del med formelen COR^ hvor R^ er hydrogen, alkyl-C-^ -C g, alkoks <y-> C^ -Cg, fenoksy, halogen-C-j^ -Cg-alkyl, fenyl, eller fenyl eller fenoksy substituert med opp til fire grupper bestående av alkyl-C^ -C^ , halogen, trifluormetyl eller alkoksy-C-^-Cg; R^ er hydrogen eller en del med formelen COR^ hvorR^ er alkyl-C^-Cg, alkoksy-c^ -Cg, fenoksy, cykloalkyl-C5 -Cl0 , fenyl, eller fenyl eller fenoksy substituert med opp til fire grupper bestående av alkyl-C^ -Cg, alkoksy-C^ -C^ , halogen eller trifluormetyl; R2 er fenyl eller fenyl substituert med opp til to grupper bestående av alkyl-C-^ -Cg, alkoksy-C^ -C^ , halogen eller trifluormetyl; og Z er oksygen eller svovel.where R is hydrogen, alkyl-C^-C^ , phenyl, phenyl substituted with up to three groups consisting of alkyl-C-^-Cg, substituted halogen-alkyl-C-^-Cg, alkoxy-C^-Cg and a moiety of the formula COR^ wherein R^ is hydrogen, alkyl-C-^ -C g , alkoxy <y-> C^ -C g , phenoxy, halo-C-j^ -C g -alkyl, phenyl, or phenyl or phenoxy substituted with up to four groups consisting of alkyl-C 1 -C 2 , halogen, trifluoromethyl or alkoxy-C 1 -C 8 ; R^ is hydrogen or a moiety of the formula COR^ where R^ is alkyl-C^-Cg, alkoxy-C^-Cg, phenoxy, cycloalkyl-C5-Cl0, phenyl, or phenyl or phenoxy substituted with up to four groups consisting of alkyl-C 1 -C 8 , alkoxy-C 1 -C 6 , halogen or trifluoromethyl; R 2 is phenyl or phenyl substituted with up to two groups consisting of alkyl-C 1 -C 8 , alkoxy-C 1 -C 6 , halogen or trifluoromethyl; and Z is oxygen or sulfur. 2. Forbindelse ifølge krav 1, karakterisert ved at den har formelen: 1-(2-metoksyetyl)-4-fenyl-2-imidazolidon, 1-(2-hydroksyetyl)-4-fenyl-2-imidazolidon, 1-(2-acetoksyetyl)-4-fenyl-2-imidazolidon, 1-(2-metoksyetyl)-4-(3-metoksyfenyl)-2-imidazolidon, 1-(2-metoksyetyl)-4-(3-bromfenyl)-2-imidazolidon, 1- (2-metoksyetyl)-3-acetyl-4-fenyl-2-imidazolidon, 1- (2-metoksy^-etyl)-3-benzoyl-4-fenyl-2-imidazolidon, 1-(2-metoksyetyl)-3-(2-metoksybenzoyl)-4-fenyl-2-imidazolidon, 1-(2-metoksyetyl)-3-(4-trifluormetylbenzoyl)-4-fenyl-2-imidazolidon, 1-(2-metoksyetyl)-3-(1-adamantankarbonyl)-4-fenyl-2-imidazolidon, 1- (2-metoksyetyl)*-3-cykloheksankarbonyl-4-fenyl-2-imidazolidon, 1-(2-butoksyetyl)-4-fenyl-2-imidazolidon, 1-(2-metoksyetyl)-4-(3-trifluormetyl)fenyl-2- imidazolidon, 1-(2-metoksyetyl)-4-(3-metylfenyl)-2-imidazolidon, 1-(2-metoksyetyl)-4-(4-trifluormetylfenyl)-2-imidazolidon, 1-(2- benzoyloksyetyl) -4-fenyl-2-imidazolidon , 1- ( 2-butoksyetyl) -4-fenyl-2-imidazolidon, 1-(2-metoksyetyl)-4-fenylimidazolidon-2-tion, 1-(2-butoksyetyl)-4-fenylimidazolidin-2-tion eller l-(2-fenoksyetyl)-4-fenylimidazolidin-2-tion.2. Compound according to claim 1, characterized in that it has the formula: 1-(2-methoxyethyl)-4-phenyl-2-imidazolidone, 1-(2-hydroxyethyl)-4-phenyl-2-imidazolidone, 1-(2 -acetoxyethyl)-4-phenyl-2-imidazolidone, 1-(2-methoxyethyl)-4-(3-methoxyphenyl)-2-imidazolidone, 1-(2-methoxyethyl)-4-(3-bromophenyl)-2- imidazolidone, 1-(2-methoxyethyl)-3-acetyl-4-phenyl-2-imidazolidone, 1-(2-methoxy^-ethyl)-3-benzoyl-4-phenyl-2-imidazolidone, 1-(2- methoxyethyl)-3-(2-methoxybenzoyl)-4-phenyl-2-imidazolidone, 1-(2-methoxyethyl)-3-(4-trifluoromethylbenzoyl)-4-phenyl-2-imidazolidone, 1-(2-methoxyethyl) -3-(1-adamantanecarbonyl)-4-phenyl-2-imidazolidone, 1-(2-methoxyethyl)*-3-cyclohexanecarbonyl-4-phenyl-2-imidazolidone, 1-(2-butoxyethyl)-4-phenyl- 2-Imidazolidone, 1-(2-Methoxyethyl)-4-(3-trifluoromethyl)phenyl-2- imidazolidone, 1-(2-Methoxyethyl)-4-(3-methylphenyl)-2-imidazolidone, 1-(2- methoxyethyl)-4-(4-trifluoromethylphenyl)-2-imidazolidone, 1-(2-benzoyloxyethyl)-4-phenyl-2-imidazolidone, 1-(2-butoxyethyl)-4-phenyl-2-imidazolidone, 1-( 2-Methoxyethyl)-4-phen ylimidazolidin-2-thione, 1-(2-butoxyethyl)-4-phenylimidazolidin-2-thione or 1-(2-phenoxyethyl)-4-phenylimidazolidin-2-thione. 3. Fremgangsmåte for fremstilling av en optisk aktiv forbindelse med formelen: 3. Method for producing an optically active compound of the formula: hvor R, R2, R^ og Z er som her definert, karakterisert ved at et imidazolinon med formelen: where R, R2, R^ and Z are as defined here, characterized in that an imidazolinone with the formula: hvor R, R^ og R^ er som definert her, reduseres ved hydrogenering i nærvær av en chiral-katalysator i et egnet organisk løsnings-middel ved en temperatur fra ca. 25 til 80°C slik at det oppnås et optisk aktivt imidazolidon med formelen: where R, R^ and R^ are as defined here, is reduced by hydrogenation in the presence of a chiral catalyst in a suitable organic solvent at a temperature from approx. 25 to 80°C so that an optically active imidazolidone with the formula is obtained: hvor R,R2 ogR^ er som ovenfor definert.where R, R2 and R3 are as defined above. 4.F remgangsmåte ifølge krav 3, karakterisert ved at det som egnet organisk løsningsmiddel anvendes alkohol, aromatiske hydrokarboner, ketoner eller etylsyreestere.4. Process according to claim 3, characterized in that alcohol, aromatic hydrocarbons, ketones or ethyl acid esters are used as suitable organic solvents. 5. Fremgangsmåte ifølge krav 3, karakterisert ved at det som chiral-katalysator anvendes (+)2,3-isopropyliden-2,3-di-hydroksy-l,4-bis(difenylfosfino)butan-Rh-CODCl.5. Process according to claim 3, characterized in that (+)2,3-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane-Rh-CODCl is used as chiral catalyst. 6. Fremgangsmåte ifølge krav 3, karakterisert ved at når Z er oksygen omdannes det til svovel ved å hydrolysere en forbindelse med følgende formel: 6. Method according to claim 3, characterized in that when Z is oxygen it is converted to sulfur by hydrolysing a compound with the following formula: hvor R, R^ ogR^ er som ovenfor definert, i nærvær av en hydroksydkilde enten i vann eller alkohol ved en temperatur fra ca. 70 til 100°C for å gi en forbindelse med formel: where R, R^ and R^ are as defined above, in the presence of a hydroxide source either in water or alcohol at a temperature from approx. 70 to 100°C to give a compound of formula: hvor R ogR2 er som ovenfor definert, og tilbakeløpsbehandle nevnte optisk aktive imidazolidon med et reagens som kan erstatte oksygen med svovel i et egnet løsningsmiddel ved en temperatur fra ca. 80 til 200°C.where R and R2 are as defined above, and refluxing said optically active imidazolidone with a reagent which can replace oxygen with sulfur in a suitable solvent at a temperature from approx. 80 to 200°C. 7. Fremgangsmåte ifølge krav 6, karakterisert ved at det som reagens som kan bytte ut oksygen med svovel anvendes fosforpentasulfid eller hydrogensulfid.7. Method according to claim 6, characterized in that phosphorus pentasulphide or hydrogen sulphide is used as a reagent which can replace oxygen with sulphur. 8. Fremgangsmåte for fremstilling av en optisk aktiv forbindelse med formelen: 8. Method for the preparation of an optically active compound of the formula: hvorR2 er som ovenfor definert, Y er et farmasøytisk akseptabelt anion, karakterisert ved at et substituert, optisk aktivt imidazolidintion med formelen: where R2 is as defined above, Y is a pharmaceutically acceptable anion, characterized in that a substituted, optically active imidazolidinion with the formula: hvor R2 er som ovenfor definert og R er alkyl-C-^-Cg, halogensubstituert alkyl-C^ -Cg, fenyl, alkylfenyl-C-^ -Cg, alkoksyfenyl-C^ -Cg eller halogenfenyl, oppvarmes med HY, hvor Y er som ovenfor definert, i et løsningsmiddel ved en temperatur fra o til ca. 200°C og det substituerte, optisk aktive 2,3,5,6-tetrahydroimidazo-[2,1-b Jtiazol syreaddisjonssalt av den frie base utvinnes.where R 2 is as defined above and R is alkyl-C-^-Cg, halogen-substituted alkyl-C^-Cg, phenyl, alkylphenyl-C-^-Cg, alkoxyphenyl-C^-Cg or halophenyl, is heated with HY, where Y is as defined above, in a solvent at a temperature from o to approx. 200°C and the substituted, optically active 2,3,5,6-tetrahydroimidazo-[2,1-b Jthiazole acid addition salt of the free base is recovered. 9. Fremgangsmåte ifølge krav 8, karakterisert ved at det som løsningsmiddel anvendes vann, alkanol-C-^-Cg, keton, eter, hydrokarbon eller halogenert hydrokarbon.9. Method according to claim 8, characterized in that the solvent used is water, alkanol-C-3-C8, ketone, ether, hydrocarbon or halogenated hydrocarbon. 10.F remgangsmåte ifølge krav 8, karakterisert ved at nevnte syreaddisjonssalt nøytraliseres for å skaffe den frie base.10. Process according to claim 8, characterized in that said acid addition salt is neutralized to obtain the free base.
NO771421A 1976-04-26 1977-04-25 PROCEDURES FOR THE PREPARATION OF TETRAMISOL, LEVAMISOL AND DERIVATIVES THEREOF NO771421L (en)

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