DE4035455A1 - Enantiomerentrennung - Google Patents

Enantiomerentrennung

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Publication number
DE4035455A1
DE4035455A1 DE19904035455 DE4035455A DE4035455A1 DE 4035455 A1 DE4035455 A1 DE 4035455A1 DE 19904035455 DE19904035455 DE 19904035455 DE 4035455 A DE4035455 A DE 4035455A DE 4035455 A1 DE4035455 A1 DE 4035455A1
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Prior art keywords
methyl
4c
1h
sulfinyl
pyridinyl
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German (de)
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Bernhard Dr Kohl
Joerg Dr Senn-Bilfinger
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Byk Gulden Lomberg Chemische Fabrik GmbH
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Byk Gulden Lomberg Chemische Fabrik GmbH
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention concerns configurationally homogeneous, enantiomerically pure pyridylmethylsulphinyl-1H-benzimidazoles, a method of preparing them, and new intermediates necessary for the preparation.

Description

Anwendungsgebiet der Erfindung Field of the Invention

Die Erfindung betrifft ein Verfahren zur Auftrennung von chiralen Pyridylme thylsulfinyl-1H-benzimidazolen in ihre Enantiomeren. The invention relates to a method for the separation of chiral Pyridylme thylsulfinyl-1H-benzimidazoles into their enantiomers. Die Enantiomeren werden in der pharmazeutischen Industrie zur Herstellung von Medikamenten verwendet. The enantiomers are used in the pharmaceutical industry for preparing medicaments.

Stand der Technik State of the art

In einer Vielzahl von Patentanmeldungen und Patenten werden Pyridylmethylsulfinyl-1H-benzimidazole beschrieben, die magensäuresekretionshemmende Eigenschaften besitzen. In a number of patent applications and patents pyridylmethylsulfinyl-1H-benzimidazoles are described which possess gastric acid secretion properties. Im Zusammenhang mit der vorliegenden Erfindung seien hier beispielsweise die folgenden Patentanmeldungen und Patente erwähnt: EP-B-5 129, EP-A-1 34 400 (= USP 45 55 518), EP-A-1 27 763 (=USP 45 60 693), EP-B-1 66-287 (=USP 47 58 579), EP-A-1 74 726, EP-A-2 01 575 (=USP 46 86 230), WO89/05 299 und WO89/11 479. - Es ist weiterhin bekannt, daß diese Pyridylmethylsulfinyl-1H- benzimidazole ein Chiralitätszentrum besitzen und daß sie daher in ihre Enantiomeren trennbar sein sollten. In connection with the present invention, the following patent applications and patents are here mentioned, for example: EP-B-5 129, EP-A-1 34 400 (= USP 45 55 518), EP-A-1 27763 (= USP 45 60 693), EP-B-1 66-287 (= USP 47 58 579), EP-A-1 74 726, EP-A-2 01 575 (= USP 46 86 230), WO89 / 05 299 and WO89 / 11 479. - It is also known that these pyridylmethylsulfinyl-1H-benzimidazole have a chiral center and therefore that they should be separated into their enantiomers. Trotz der Vielzahl von Patentanmeldungen auf dem Gebiet der Pyridylmethylsulfinyl-1H-benzimidazole ist bisher jedoch noch kein Verfahren beschrieben worden, mit dessen Hilfe die Pyridylmethylsulfinyl- 1H-benzimidazole in die optischen Antipoden getrennt werden könnten. Despite the large number of patent applications in the field of pyridylmethylsulfinyl-1H-benzimidazole no process has hitherto been described, however, with the aid of which Pyridylmethylsulfinyl- 1H-benzimidazole could be separated into the optical antipodes. Auch die Enantiomeren der Pyridylmethylsulfinyl-1H-benzimidazole sind bisher (mangels eines geeigneten Trennverfahrens) noch nicht isoliert und charakterisiert worden. Also, the enantiomers of the pyridylmethylsulfinyl-1H-benzimidazole are far (in the absence of a suitable separation process) not yet been isolated and characterized.

Beschreibung der Erfindung Description of the Invention

Es wurde nun ein Verfahren gefunden, mit dessen Hilfe die nachstehend näher bezeichneten Pyridylmethylsulfinyl-1H-benzimidazole in ihre optischen Antipoden gespalten werden können. It has now been found a method by which the described in more detail below pyridylmethylsulfinyl-1H-benzimidazole can be resolved into their optical antipodes.

Das Verfahren ist dadurch gekennzeichnet, daß man Verbindungen der Formel I, The method is characterized in that compounds of the formula I,

worin wherein
R1 Wasserstoff, 1-4C-Alkyl oder 1-4C-Alkoxy bedeutet, R1 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
R2 Wasserstoff, Trifluormethyl, 1-4C-Alkyl, 1-4C-Alkoxy, ganz oder überwiegend durch Fluor substituiertes 1-4C-Alkoxy. R2 is hydrogen, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy. Chlordifluormethoxy, 2-Chlor-1,1,2-trifluormethoxy oder gemeinsam mit R3 gewünschtenfalls ganz oder teilweise durch Fluor substituiertes 1-2C-Alkylendioxy oder Chlortrifluorethylendioxy bedeutet, Chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoromethoxy, or together with R3, if desired, completely or partially fluorine-substituted 1-2C-means by alkylenedioxy or chlorotrifluoroethylenedioxy,
R3 Wasserstoff, 1-4C-Alkyl, 1-4C-Alkoxy, ganz oder überwiegend durch Fluor substituiertes 1-4C-Alkoxy, Chlordifluormethoxy, 2-Chlor-1,1,2-trifluorethoxy oder gemeinsam mit R2 gewünschtenfalls ganz oder teilweise durch Fluor substituiertes 1-2C-Alkylendioxy oder Chlortrifluorethylendioxy bedeutet, R3 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or, together with R2, if desired, completely or partially substituted by fluorine substituted 1-2C-alkylenedioxy or chlorotrifluoroethylenedioxy means
R4 Wasserstoff oder 1-4C-Alkyl bedeutet, R4 is hydrogen or 1-4C-alkyl,
R5 Wasserstoff, 1-4C-Alkyl oder 1-4C-Alkoxy bedeutet und R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy and
R6 1-4C-Alkoxy, ganz oder überwiegend durch Fluor substituiertes 1-4C-Alkoxy oder Benzyloxy bedeutet, R6 is 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy or benzyloxy,
oder ihre Salze mit Basen mit konfigurativ einheitlich chiralen Verbindungen der Formel II, or their salts with bases having configuratively uniform chiral compounds of formula II,

Rchi-X (II) RCHI-X (II)

worin Rchi einen konfigurativ einheitlichen, chiralen Rest und X eine Abgangsgruppe darstellt, umsetzt, das erhaltene Isomeren- bzw. Diastereomerengemisch III, wherein RCHI a uniform configuration, chiral radical and X is a leaving group, the diastereomeric mixture of isomers or III obtained,

worin R1, R2, R3, R4, R5 und R6 die oben angegebenen Bedeutungen haben und Rchi einen konfigurativ einheitlichen, chiralen Rest darstellt, trennt und aus den optisch reinen Diastereomeren die konfigurativ einheitlichen, optisch reinen Verbindungen I durch Solvolyse in stark saurem Medium freisetzt. wherein R1, R2, R3, R4, R5 and R6 have the meanings given above and RCHI represents a uniform configuration, chiral radical, separated and the uniform configuration, optically pure compounds I liberated from the optically pure diastereomers by solvolysis in a strongly acidic medium.

1-4C-Alkyl steht für geradkettige oder verzweigte Alkylreste; 1-4C-Alkyl represents straight-chain or branched alkyl radicals; beispielsweise seien der Butyl-, i-Butyl-, sec.-Butyl-, t-Butyl-, Propyl-, Isopropyl-, Ethyl- und insbesondere der Methylrest genannt. for example the butyl, i-butyl, sec-butyl, t-butyl, propyl, isopropyl, ethyl and especially the methyl radical may be mentioned.

1-4C-Alkoxy steht für geradkettige oder verzweigte Alkoxyreste; 1-4C-Alkoxy represents straight-chain or branched alkoxy groups; beispielsweise seien genannt der Butoxy-, i-Butoxy-, sec.-Butoxy-, t-Butoxy-, Propoxy-, Isopropoxy-, Ethoxy- und insbesondere der Methoxyrest. for example, be mentioned are the butoxy, i-butoxy, sec-butoxy, t-butoxy, propoxy, isopropoxy, ethoxy and especially methoxy.

Als ganz oder überwiegend durch Fluor substituiertes 1-4C-Alkoxy seien beispielsweise der 1,2,2,-Trifluorethoxy-, der 2,2,3,3,3-Pentafluorpropoxy-, der Perfluorethoxy- und insbesondere der 1,1,2,2-Tetrafluorethoxy-, der Trifluormethoxy-, der 2,2,2-Trifluorethoxy- und der Difluormethoxyrest genannt. As completely or predominantly fluorine-substituted 1-4C-alkoxy, for example, the 1,2,2, trifluoro-ethoxy, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy and in particular the 1,1,2 called, 2-tetrafluoroethoxy, the trifluoromethoxy, the 2,2,2-trifluoroethoxy and the difluoromethoxy radical.

Wenn R2 und R3 gemeinsam ganz oder teilweise durch Fluor substituiertes 1-2C-Alkylendioxy oder Chlortrifluorethylendioxy bedeuten, so sind die Substituenten R2 oder R3 in Nachbarpositionen am Benzoteil des Benzimidazolringes gebunden. When R2 and R3 together substituted completely or partially fluorine-substituted 1-2C-alkylenedioxy or chlorotrifluoroethylenedioxy mean the substituents R2 or R3 are bonded in neighboring positions on the benzo moiety of the benzimidazole ring.

Als ganz oder teilweise durch Fluor substituiertes 1-2C-Alkylendioxy seien beispielsweise der 1,1-Difluorethylendioxy- (-O-CF₂-CH₂-O-), der 1,1,2,2-Tetrafluorethylendioxy- (-O-CF₂-CF₂-O-) und insbesondere der Difluormethylendioxy- (-O-CF₂-O-) und der 1,1,2-Trifluorethylendioxyrest (-O-CF₂-CHF-O-) genannt. As completely or partially fluorine-substituted 1-2C-alkylenedioxy, for example, the 1,1-Difluorethylendioxy- (-O-CF₂-CH₂-O-), of 1,1,2,2-Tetrafluorethylendioxy- are (-O-CF₂- CF₂-O-) and in particular the Difluormethylendioxy- (-O-CF₂-O-) and 1,1,2-Trifluorethylendioxyrest (-O-CF₂-CHF-O-) called.

Als Verbindungen der Formel II kommen prizipiell alle chiralen, konfigurativ einheitlichen Verbindungen in Frage, die mit der Verbindung I oder ihrem Anion unter Abspaltung der Abgangsgruppe X zu reagieren in der Lage sind und deren Rest Rchi nach der Diastereomerentrennung glatt und ohne unerwünschte Nebenreaktion wieder abgespalten werden kann. Compounds of the formula II prizipiell all chiral, uniform configuration compounds in question, which are to react with the compound I or its anion, with elimination of the leaving group X in the position and whose residual RCHI are cleaved again after the separation of diastereomers smooth and without undesirable secondary reaction can.

Als Abgangsgruppen X kommen insbesondere alle nucleophil ablösbaren Atome oder Gruppen, wie beispielsweise Halogenatome (J, Br oder insbesondere Cl) oder durch Veresterung (z. B. mit Sulfonsäuren) aktivierte Hydroxylgruppen (-O-SO₂-CH₃, -O-SO₂-CF₃ oder -O-SO₂-C₆H₄-p-CH₂) in Frage. Suitable leaving groups X in particular are all nucleophilic releasable atoms or groups such as halogen (I, Br or particularly Cl), or by esterification (eg. B. with sulfonic acids) activated hydroxyl groups (-O-SO₂-CH₃, -O-SO₂-CF₃ or -O-SO₂-C₆H₄-p-CH₂) in question.

Als Reste Rchi kommen alle konfigurativ einheitlichen Reste in Frage, die sich von natürlich vorkommenden oder synthetisch zugänglichen chiralen Verbindungen ableiten lassen und die solvolytisch unter sauren Bedingungen aus den Verbindungen III abgespalten werden können. As radicals RCHI all uniform configuration remains in question, which can be derived from naturally occurring or synthetically accessible chiral compounds and which can be split off by solvolysis under acidic conditions from the compounds III come. Als Reste Rchi seien insbesondere genannt As radicals RCHI be mentioned in particular

  • - Glycosylreste, die sich von Glycopyranosen, Glycofuranosen oder Oligosacchariden ableiten und die gewünschtenfalls mit in der Kohlenhydratchemie üblichen Schutzgruppen teilweise oder vollständig geschützt sind, oder - glucosyl residues derived from glycopyranoses, Glycofuranosen or oligosaccharides and which are optionally protected by conventional protective groups in carbohydrate chemistry partially or completely, or
  • - chirale, über das Sauerstoffatom verknüpfte Terpenalkoholreste, oder - chiral via the oxygen atom linked terpene alcohol radicals, or
  • - andere chirale, über das Sauerstoffatom verknüpfte Alkoholreste, - other chiral, via the oxygen atom linked alcohol residues,

die jeweils an dem als Verknüpfungsglied fungierenden Sauerstoffatom eine Carbonylgruppe oder insbesondere eine Methylengruppe tragen. each carrying on the acting gate oxygen atom or a carbonyl group in particular a methyl group.

Bevorzuge Reste Rchi sind Reste der Formel IV Prefer residues RCHI are radicals of the formula IV

R′-O-CH₂-(IV) R'-O-CH₂- (IV)

worin R′ gemeinsam mit dem Sauerstoffatom, woran es gebunden ist, einen Glycosylrest, einen chiralen Terpenalkoholrest, oder einen sonstigen chiralen Alkoholrest darstellt. wherein R 'represents, together with the oxygen atom to which it is bonded, a glycosyl residue, a chiral terpene alcohol radical, or any other chiral alcohol radical.

Als Glycosylreste R′-O- seien beispielsweise die Reste genannt, die sich von natürlich vorkommenden Mono- oder Disacchariden, wie Arabinose, Fructose, Galactose, Glucose, Lactose, Mannose, Ribose, Xylose, Maltose, Sorbose oder N-Acetyl-D-glucosamin herleiten. As glycosyl R'-O- example, the radicals may be mentioned that from naturally occurring mono- or di-saccharides such as arabinose, fructose, galactose, glucose, lactose, mannose, ribose, xylose, maltose, sorbose or N-acetyl-D- glucosamine derived.

Als chirale Terpenalkoholreste R′-O- seien insbesondere solche Reste genannt, die sich von einem natürlich vorkommenden oder synthetisch leicht zugänglichen Terpenalkohol herleiten. As chiral terpene alcohol R'-O- especially those groups are mentioned, derived from a naturally occurring or synthetically accessible terpene alcohol. Als beispielhafte Terpenalkohole seien hierbei genannt: Isopulegol, Neomenthol, Isomenthol, Menthol, Carveol, Dihydrocarveol, Terpinen-4-ol, Mirtenol, Citronellol, Isoborneol, Borneol, Isopinocampheol und insbesondere Fenchol. Exemplary terpene alcohols are here: isopulegol, Neomenthol, I-menthol, menthol, carveol, dihydrocarveol, terpinene-4-ol, Mirtenol, citronellol, soborneol, borneol, isopinocampheol and especially fenchol.

Als sonstige chirale Alkoholreste R′-O- seien beispielsweise die Reste genannt, die sich von folgenden Alkoholen herleiten: Mandelsäureester, Cinchonidin, Cinchonin, Ephedrin, Serinmethylester, Sitosterol, 3-Hydroxy-2-methyl-propionsäuremethylester und Milchsäureethylester. As other chiral alcohol radicals R'-O- example, the radicals may be mentioned, which are derived from the following alcohols: Mandelsäureester, cinchonidine, cinchonine, ephedrine, serine methyl ester, sitosterol, 3-hydroxy-2-methyl-propionate and lactate.

Ein besonders bevorzugter Rest Rchi ist der Fenchyloxymethylrest. A particularly preferred radical RCHI is the Fenchyloxymethylrest.

Die Umsetzung der Verbindung I mit der Verbindung II erfolgt auf eine dem Fachmann vertraute Weise. The reaction of compound I with the compound II is carried out in a manner familiar to the skilled worker. Zur Erhöhung der Nucleophilie der Verbindungen I ist es zweckmäßig, diese zu deprotonieren, dh von den Salzen der Verbindungen I mit Basen auszugehen. To increase the nucleophilicity of the compounds I, it is convenient to deprotonate this, that is to start from the salts of compounds I with bases. Als Beispiele für basische Salze seien Natrium-, Kalium-, Calcium-, Aluminium-, Magnesium-, Titan-, Ammonium- oder Guanidiniumsalze erwähnt, die beispielsweise durch Umsetzung der Verbindungen I mit den entsprechenden Hydroxiden (z. B. Natriumhydroxid oder Kaliumhydroxid) auf übliche Weise erhalten werden können. Examples of basic salts of sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium or guanidinium salts there may be mentioned, for example, by reacting the compounds I with the corresponding hydroxides (eg., Sodium hydroxide or potassium hydroxide) can be obtained in the usual way.

Die Umsetzung der Verbindungen I mit Verbindungen II wird in inerten, protischen oder aprotischen Lösungsmitteln durchgeführt. The reaction of compounds I with the compounds II is carried out in an inert, protic or aprotic solvents. Als solche eignen sich beispielsweise Methanol, Isopropanol, Dimethylsulfoxid, Aceton, Acetonitril, Dioxan, Dimethylformamid und vorzugsweise N-Methylpyrrolidon. As such, for example, methanol, isopropanol, dimethyl sulfoxide, acetone, acetonitrile, dioxane, dimethylformamide, preferably N-methylpyrrolidone.

Die Umsetzung wird - in Abhängigkeit von der Reaktivität der Verbindung II - vorzugsweise bei Temperaturen zwischen -30°C und +100°C, insbesondere bei Temperaturen zwischen 0°C und 50°C durchgeführt. The reaction is - preferably performed at temperatures between -30 ° C and + 100 ° C, in particular at temperatures between 0 ° C and 50 ° C - depending on the reactivity of the compound II.

Die Trennung des nach der Umsetzung von I mit II erhaltenen Diastereomerengemisches erfolgt in an sich bekannter Weise, beispielsweise durch Chromatographie an geeigneten Säulen oder vorzugsweise durch fraktionierte Kristallisation. The separation of the diastereomer mixture obtained after the reaction of I with II in manner known per se, for example by chromatography on suitable pillars or preferably by fractional crystallization.

Aufgrund der Prototropie im Benzimidazolteil der Verbindungen I (die 5- und 6- Positionen einerseits bzw. die 4- und 7-Positionen andererseits sind zueinander identisch) entstehen bei der Umsetzung mit den Verbindungen II bei entsprechendem Substitutionsmuster im Benzimidazol Isomerengemische. Due to the prototropy in Benzimidazolteil of the compounds I (the 5- and 6 positions on the one hand or the 4- and 7-positions on the other are identical to each other) formed in the reaction with the compounds II with the appropriate substitution pattern in the benzimidazole isomer mixtures. Zweckmäßigerweise werden die Isomeren noch vor Trennung der Diastereomeren voneinander getrennt, beispielsweise durch Säulenchromatographie an geeignetem Trägermaterial (z. B. Kieselgel) und mit geeigneten Elutionsmitteln (z. B. Ethylacetat). Conveniently, the isomers are separated before the separation of the diastereomers from one another, for example by column chromatography on suitable support material (eg. As silica gel) and with suitable eluents (eg., Ethyl acetate).

Die Freisetzung der konformativ einheitlichen Verbindungen I aus den optisch reinen Diastereomeren III erfolgt durch Solvolyse unter stark sauren Bedingungen. The release of the conformationally homogeneous compounds I from the optically pure diastereomers III is carried out by solvolysis under strongly acidic conditions. Als für die Solvolyse geeignete Reagenzien seien beispielsweise starke höherkonzentrierte Säuren (z. B. 60-100%ige Schwefelsäure, konzentrierte Salzsäure, wasserfreie oder wasserhaltige Tetrafluorborsäure, Methansulfonsäure, Trifluormethansulfonsäure, Phosphorsäure oder Perchlorsäure), bevorzugt ca. 90%ige Schwefelsäure genannt. As for the solvolysis are suitable reagents, for example, highly concentrated strong acids (eg. B. 60-100% sulfuric acid, concentrated hydrochloric acid, anhydrous or aqueous tetrafluoroboric acid, methanesulfonic acid, trifluoromethanesulfonic acid, phosphoric acid or perchloric acid), preferably mentioned about 90% sulfuric acid. Die Freisetzung erfolgt vorzugsweise bei Temperaturen zwischen 0° und 40°C. The release is preferably carried out at temperatures between 0 ° and 40 ° C. Bei der auf die Freisetzung folgenden Aufarbeitung wird vorteilhafterweise so verfahren, daß der pH-Wert möglichst rasch erhöht wird, beispielsweise durch Einbringen der stark sauren Lösung in Pufferlösung oder bevorzugt in Lauge. In the following formulations on the release process is advantageously such that the pH value is increased as rapidly as possible, for example by introducing the strong acidic solution in buffer solution, or preferably in solution.

Die Verbindungen der Formel II sind bekannt bzw. sie sind auf eine für den Fachmann vertraute Weise aus bekannten Verbindungen auf analoge Weise zugänglich. The compounds of formula II are known or are accessible in a manner familiar to the skilled person from known compounds in an analogous manner. So können beispielsweise die Verbindungen II, in denen Rchi die Bedeutung der Formel IV hat und X ein Chloratom darstellt, durch Chlormethylierung entsprechender Alkohole [z. For example, the compounds II in which RCHI has the meaning of formula IV and X represents a chlorine atom, by chloromethylation of corresponding alcohols [z. B. in Analogie zu RC Ronald et. B. analogously to RC Ronald et. al., J. Org. Chem. 45 (1980) 2224] hergestellt werden. al., J. Org. Chem. 45 (1980) 2224] are prepared.

Die Verbindungen der Formel III sind neu und ebenfalls Gegenstand der Erfindung. The compounds of formula III are new and also subject of the invention.

Die konfigurativ einheitlichen, optisch reinen Verbindungen der Formel I sind ebenfalls neu und daher auch Gegenstand der Erfindung. The uniform configuration, the optically pure compounds of formula I are also novel and therefore also subject of the invention.

Als beispielhafte, durch das erfindungsgemäße Verfahren herstellbare, optisch reine Verbindungen der Formel I und als dazugehörige erfindungsgemäße Zwischenprodukte III seien anhand der Substituentenbedeutungen in den obenstehenden Formeln I bzw. III die folgenden Verbindungen der nachstehenden Tabelle 1 besonders erwähnt: based on the definitions of substituents in the above formulas I or III the following compounds of Table 1 below particularly mentioned as exemplary, producible by the inventive process, optically pure compounds of formula I and the corresponding intermediates III according to the invention are:

Tabelle 1 Table 1

Besonders bevorzugte, durch das erfindungsgemäße Verfahren herstellbare Verbindungen sind die Verbindungen Particularly preferred, producible by the inventive process are the compounds

(+)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1H-benz imidazol, (+) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1H-benz imidazole;
(-)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1H-benz imidazol, (-) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1H-benz imidazole;
(+)-5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H-benz imidazol, (+) - 5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} -1H-benz imidazole;
(-)-5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H-benz imidazol, (-) - 5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} -1H-benz imidazole;
(+)-2-{[(3-Methyl-4-(2,2,2-trifluorethoxy)-2-pyridinyl]methyl}sulfinyl-1H-benz imidazol, und (+) - 2 - {[(3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl} sulfinyl-1H-benz imidazole, and
(-)-2-{[(3-Methyl-4-(2,2,2-trifluorethoxy)-2-pyridinyl]methyl}sulfinyl-1H-benz imidazol, (-) - 2 - {[(3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl} sulfinyl-1H-benz imidazole;

und ihre Salze mit Basen. and their salts with bases.

Die folgenden Beispiele dienen der näheren Erläuterung der Erfindung. The following examples serve to illustrate the invention. Die Abkürzung h steht für Stunde(n), Schmp. für Schmelzpunkt. The abbreviation h stands for hour (s), mp. For melting point.

Beispiele Examples 1. (+)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1- [(+)-fenchyloxymethyl]-benzimidazol 1. (+) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl] -1- [(+) - fenchyloxymethyl] benzimidazole

Zu einer Lösung von 50 g (0,123 Mol) (±)-5-Difluormethoxy-2-{[(3,4-dimeth oxy-2-pyridinyl)methyl]sulfinyl}-1H-benzimidazol-Na-Salz in 125 ml N-Methylpyrrolidon tropft man bei einer Temperatur von 25-35°C innerhalb einer Stunde 27,5 g (0,136 Mol) (+)-Fenchyl-chlormethylether zu. To a solution of 50 g (0.123 mole) of (±) -5-difluoromethoxy-2 - {[(3,4-dimeth oxy-2-pyridinyl) methyl] sulfinyl} -1H-benzimidazole sodium salt in 125 ml N -methylpyrrolidone is added dropwise at a temperature of 25-35 ° C in one hour 27.5 g (0.136 mol) of (+) - fenchyl chloromethyl ether to. Nach 6 h wird mit 500 ml Wasser verdünnt, der pH-Wert auf 9,0 gestellt und dreimal mit je 100 ml Dichlormethan extrahiert. After 6 hours, the pH is diluted with 500 ml water, set to 9.0 and extracted three times with 100 ml dichloromethane. Die vereinigten organischen Phasen werden mit Wasser gewaschen, getrocknet und im Vakuum vollständig eingeengt. The combined organic phases are washed with water, dried and evaporated to dryness in vacuo. Der ölige Rückstand wird an Kieselgel chromatographiert (Laufmittel: Ethylacetat). The oily residue is chromatographed on silica gel (eluent: ethyl acetate). Man isoliert 25,2 g (74%) eines Diastereomerengemisches aus (+)- und (-)-5-Difluormethoxy- 2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1-[(+)-fenchyloxymethyl]-benzimidazol als blaßgelbes, allmählich kristallisierendes Öl (Rf.-Wert in Ethylacetat ca. 0,85). Are isolated 25.2 g (74%) of a diastereomeric mixture of (+) - and (-) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1 - [( +) - fenchyloxymethyl] benzimidazole as a pale yellow slowly crystallizing oil (Rf. value in ethyl acetate about 0.85). Viermalige Umkristallisation aus Ethylacetat/Diisopropylether liefert die Titelverbindung (9,0 g 71,4%) in Form farbloser Kristalle vom Schmp. 138-139°C {[α] = +155,2° (c=1, Chloroform)}. Four-fold recrystallization from ethyl acetate / diisopropyl ether yields the title compound (9.0 g 71.4%) as colorless crystals, mp. 138-139 ° C {[α] = + 155.2 ° (c = 1, chloroform)}.

2. (+)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1H-benzimidazol 2. (+) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1H-benzimidazole

1,0 g (1,8 mMol) (+)-4-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]- sulfinyl}-1-[(+)-fenchyloxymethyl]-benzimidazol werden portionsweise bei 5-10°C unter Rühren in 7 ml 90%ige Schwefelsäure eingetragen. 1.0 g (1.8 mmol) of (+) - 4-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] - sulfinyl} -1 - [(+) - fenchyloxymethyl] benzimidazole portionwise sodium at 5-10 ° C with stirring in 7 ml of 90% sulfuric acid are added. Nach vollständiger Auflösung wird das Reaktionsgemisch unter Kühlung in 8N Natronlauge eingetropft, der pH auf 7,5 gestellt und mehrmals mit Dichlormethan extrahiert. After complete dissolution, the reaction mixture is added dropwise under cooling in 8N sodium hydroxide solution, the pH adjusted to 7.5 and extracted several times with dichloromethane. Die vereinigten Extrakte werden mit Wasser gewaschen, über Magnesiumsulfat getrocknet und im Vakuum vollständig eingeengt. The combined extracts are washed with water, dried over magnesium sulfate and evaporated to dryness in vacuo. Der rote ölige Rückstand wird über Kieselgel chromatographiert (Dichlormethan/Methanol) und anschließend aus Diisopropylether kristallisiert. The red oily residue is chromatographed on silica gel (dichloromethane / methanol) and then crystallized from diisopropyl ether. Man erhält 0,3 g (44%) der Titelverbindung als farbloses Kristallisat vom Schmp. 147-148°C (Zers.) {[α] = +146,0° (c=0,5, Acetonitril/Methanol 1 : 1)}. This gives 0.3 g (44%) of the title compound as a colorless crystals of mp 147-148 ° C (dec.) {[Α] = + 146.0 ° (c = 0.5, acetonitrile / methanol 1:. 1 )}.

3. (-)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1- [(-)-fenchyloxymethyl]-benzimidazol 3. (-) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1- [(-) - fenchyloxymethyl] benzimidazole

Nach der in Beispiel 1 beschriebenen Arbeitsweise erhält man durch Umsetzung von 28 g (0,069 Mol) (±)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl- methyl]sulfinyl⟩-1H-benzimidazol-Na-Salz mit 16,5 g (0,084 Mol) (-)-Fenchyl chlormethylether in 75 ml N-Methylpyrrolidon nach Chromatographie an Kieselgel (Dichlormethan/Methanol) 11,0 (58%) eines Diastereomerengemisches aus (+)- und (-)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)-methyl]sulfinyl}-1- [(-)-fenchyloxymethyl]-benzimidazol. Mehrmalige Umkristallisation aus Ethylacetat/ Diisopropylether liefert die Titelverbindung in Form farbloser Kristalle (4,0 g, 72%) vom Schmp. 138-139°C {[α] = -152,8° (c=1, Chloroform)}. Following the procedure described in Example 1, is obtained by reaction of 28 g (0.069 mol) of (±) -5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl-methyl] sulfinyl⟩-1H-benzimidazole Na salt with 16.5 g (0.084 mol) of (-) - fenchyl chloromethyl ether in 75 ml of N-methylpyrrolidone, after chromatography on silica gel (dichloromethane / methanol) 11.0 (58%) of a diastereomeric mixture of (+) - and (- ) -5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) -methyl] sulfinyl} -1- [(-) - fenchyloxymethyl]. -benzimidazole Repeated recrystallization from ethyl acetate / diisopropyl ether yields the title compound in the form of colorless crystals (4.0 g, 72%) mp. 138-139 ° C {[α] = -152.8 ° (c = 1, chloroform)}.

4. (-)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1H- benzimidazol benzimidazole {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1H - 4. (-) - 5-difluoromethoxy-2

Nach der in Beispiel 2 beschriebenen Arbeitsweise erhält man aus 1 g (1,8 mMol) (-)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1-[(-)- fenchyloxymethyl]-benzimidazol in 7 ml 90%iger Schwefelsäure 0,25 g (36%) der Titelverbindung vom Schmp. 144-145°C (Zers.) {[α] = -144,4° (c=0,5, Acetonitril/Methanol 1 : 1)}. Following the procedure described in Example 2 Operation is obtained from 1 g (1.8 mmol) of (-) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1 - [( -) - fenchyloxymethyl] benzimidazole dissolved in 7 ml of 90% sulfuric acid, 0.25 g (36%) of the title compound of mp 144-145 ° C (dec) {[α] = -144.4 ° (c = 0,.. , 5, acetonitrile / methanol 1: 1)}.

5. (+)-5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1- [(+)-fenchyloxymethyl]-benzimidazol 5. (+) - 5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} -1- [(+) - fenchyloxymethyl] benzimidazole

Nach der in Beispiel 1 beschriebenen Arbeitsweise erhält man aus (±)-5- Methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H-benzimidazol-Na-Salz (60 mMol) in 80 ml N-Methylpyrrolidon nach Chromatographie an Kieselgel (Ethylacetat) nach mehrmaliger Umkristallisation aus Ethylacetat/Diisopropylether 3,1 g (40%) der Titelverbindung in Form farbloser Kristalle vom Schmp. 161°C (Zers.) {[α] = +103,0° (c=1, Chloroform)}. Following the procedure described in Example 1, is obtained from (±) -5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} -1H-benzimidazole sodium salt ( 60 mmol) (in 80 ml of N-methylpyrrolidone, after chromatography on silica gel, ethyl acetate) after repeated recrystallization from ethyl acetate / diisopropyl ether 3.1 g (40%) of the title compound (colorless crystals of mP. 161 ° C dec.) {[α ] = + 103.0 ° (c = 1, chloroform)}.

6. (+)-5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H- benzimidazol 6. (+) - 5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} -1H-benzimidazole

Nach der in Beispiel 2 beschriebenen Arbeitsweise erhält man aus 0,51 g (1 mMol) (+)-5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}- 1H-[(+)-fenchyloxymethyl]-benzimidzol in 4 ml 90%iger Schwefelsäure 0,15 g (43%) der Titelverbindung als amorphen Feststoff {[α] = +165° (c=0,5, Chloroform)}. Following the procedure described in Example 2 Operation is obtained from 0.51 g (1 mmol) of (+) - 5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} - 1H - [(+) - fenchyloxymethyl] -benzimidzol dissolved in 4 ml of 90% sulfuric acid, 0.15 g (43%) of the title compound {[α] = + 165 ° (c = 0.5, chloroform)} as an amorphous solid.

Gewerbliche Anwendbarkeit commercial Applications

Nach dem erfindungsgemäßen Verfahren können Pyridylmethylsulfinyl-1H-benzimidazole erstmals in ihre optischen Antipoden aufgespalten werden. In the novel process pyridylmethylsulfinyl-1H-benzimidazole can be resolved into their optical antipodes first time. Als besonders überraschend ist hierbei die Tatsache zu werten, daß die Freisetzung der optisch reinen Verbindungen aus den Diastereomeren mit Hilfe hochkonzentrierter Mineralsäuren vorgenommen wird, obwohl bekannt ist, daß es sich bei den Pyridylmethylsulfinyl-1H-benzimidazolen um sehr säurelabile Verbindungen handelt. As particularly surprising the fact here is to be considered that the liberation of the optically pure compounds of the diastereomers is carried out by means of highly concentrated mineral acids, although it is known that it is pyridylmethylsulfinyl-1H-benzimidazoles to is very acid labile compounds with the.

Die erfindungsgemäß hergestellten Verbindungen werden als Wirkstoffe in Arzneimitteln für die Behandlung von Magen- und Darmerkrankungen eingesetzt. The compounds according to the invention are used as active compounds in medicaments for the treatment of gastric and intestinal diseases. Bezüglich der Anwendungsweise und Dosierung der Wirkstoffe wird z. As to the application and dosage of the active ingredients z. B. auf das europäische Patent 1 66 287 verwiesen. As referred to the European patent 1 66,287.

Claims (6)

1. Konfigurativ einheitliche, optisch reine Verbindungen der Formel I worin 1. configuratively uniform, optically pure compounds of formula I wherein
R1 Wasserstoff, 1-4C-Alkyl oder 1-4C-Alkoxy bedeutet, R1 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
R2 Wasserstoff, Trifluormethyl, 1-4C-Alkyl, 1-4C-Alkoxy, ganz oder überwiegend durch Fluor substituiertes 1-4C-Alkoxy. R2 is hydrogen, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy. Chlordifluormethoxy, 2-Chlor-1,1,2-trifluormethoxy oder gemeinsam mit R3 gewünschtenfalls ganz oder teilweise durch Fluor substituiertes 1-2C-Alkylendioxy oder Chlortrifluorethylendioxy bedeutet, Chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoromethoxy, or together with R3, if desired, completely or partially fluorine-substituted 1-2C-means by alkylenedioxy or chlorotrifluoroethylenedioxy,
R3 Wasserstoff, 1-4C-Alkyl, 1-4C-Alkoxy, ganz oder überwiegend durch Fluor substituiertes 1-4C-Alkoxy, Chlordifluormethoxy, 2-Chlor-1,1,2-trifluorethoxy oder gemeinsam mit R2 gewünschtenfalls ganz oder teilweise durch Fluor substituiertes 1-2C-Alkylendioxy oder Chlortrifluorethylendioxy bedeutet, R3 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or, together with R2, if desired, completely or partially substituted by fluorine substituted 1-2C-alkylenedioxy or chlorotrifluoroethylenedioxy means
R4 Wasserstoff oder 1-4C-Alkyl bedeutet, R4 is hydrogen or 1-4C-alkyl,
R5 Wasserstoff, 1-4C-Alkyl oder 1-4C-Alkoxy bedeutet und R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy and
R6 1-4C-Alkoxy, ganz oder überwiegend durch Fluor substituiertes 1-4C-Alkoxy oder Benzyloxy bedeutet, R6 is 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy or benzyloxy,
und ihre Salze mit Basen. and their salts with bases.
2. Verbindung nach Anspruch 1, ausgewählt aus der Gruppe bestehend aus 2. A compound according to claim 1, selected from the group consisting of
(+)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1H-benz imidazol, (+) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1H-benz imidazole;
(-)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1H-benz imidazol, (-) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1H-benz imidazole;
(+)-5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H-benz imidazol, (+) - 5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} -1H-benz imidazole;
(-)-5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H-benz imidazol, (-) - 5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} -1H-benz imidazole;
(+)-2-{[(3-Methyl-4-(2,2,2-trifluorethoxy)-2-pyridinyl]methyl}sulfinyl-1H-benz imidazol, und (+) - 2 - {[(3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl} sulfinyl-1H-benz imidazole, and
(-)-2-{[(3-Methyl-4-(2,2,2-trifluorethoxy)-2-pyridinyl]methyl}sulfinyl-1H-benz imidazol, (-) - 2 - {[(3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl} sulfinyl-1H-benz imidazole;
und ihren Salze mit Basen. and their salts with bases.
3. Verfahren zur Herstellung von konfigurativ einheitlichen, optisch reinen Vebindungen der Formel I nach Anspruch 1 und ihren Salzen, dadurch gekennzeichnet, daß man Racemate von Verbindungen der Formel I, worin R1, R2, R3, R4, R5 und R6 die in Anspruch 1 angegebenen Bedeutungen haben, oder ihre Salze mit Basen, mit konfigurativ einheitlichen, chiralen Verbindungen der Formel II, Rchi-X (II)worin Rchi einen konfigurativ einheitlichen, chiralen Rest und X eine Abgangsgruppe darstellt, umsetzt, das erhaltene Isomeren- bzw. Diastereomerengemisch III, worin R1, R2, R3, R4, R5 und R6 die in Anspruch 1 angegebenen Bedeutungen haben und Rchi einen konfigurativ einheitlichen, chiralen Rest darstellt, trennt und aus den optisch reinen Diastereomeren die konfigurativ einheitlichen, optisch reinen Verbindungen I durch Solvolyse in stark saurem Medium freisetzt und gewünschtenfalls anschließend in die Salze mit Basen überführt. 3. A process for the preparation of uniform configuration, optically pure Vebindungen of the formula I according to claim 1 and their salts, characterized in that racemates of compounds of formula I wherein R1, R2, R3, R4, R5 and R6 are 1 in claim have the meanings indicated, or their salts with bases, with uniform configuration, chiral compounds of formula II, RCHI-X (II) wherein RCHI represents a uniform configuration, chiral radical and X is a leaving group, the isomers and a mixture of diastereomers obtained III wherein R1, R2, R3, R4, R5 and R6 have the meanings given in claim 1 and RCHI represents a uniform configuration, chiral radical, separated and from the optically pure diastereomers, the uniform configuration, optically pure compounds I by solvolysis in a strongly acid medium releases and if desired, then converted into the salts with bases.
4. Verfahren nach Anspruch 3, dadurch gekennzeichnet, daß man eine Verbindung ausgewählt aus der Gruppe bestehend aus 4. The method according to claim 3, characterized in that a compound selected from the group consisting of
(+)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1H-benz imidazol, (+) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1H-benz imidazole;
(-)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1H-benz imidazol, (-) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1H-benz imidazole;
(+)-5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H-benz imidazol, (+) - 5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} -1H-benz imidazole;
(-)-5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H-benz imidazol, (-) - 5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} -1H-benz imidazole;
(+)-2-{[(3-Methyl-4-(2,2,2-trifluorethoxy)-2-pyridinyl]methyl}sulfinyl-1H-benz imidazol, und (+) - 2 - {[(3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl} sulfinyl-1H-benz imidazole, and
(-)-2-{[(3-Methyl-4-(2,2,2-trifluorethoxy)-2-pyridinyl]methyl}sulfinyl-1H-benz imidazol, (-) - 2 - {[(3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl} sulfinyl-1H-benz imidazole;
oder ihr Salz mit Basen herstellt. manufactures or its salt with bases.
5. Zwischenprodukte der Formel III, worin R1, R2, R3, R4, R5 und R6 die in Anspruch 1 angegebenen Bedeutungen haben und Rchi einen konfigurativ einheitlichen, chiralen Rest darstellt. 5. Intermediates of formula III, wherein R1, R2, R3, R4, R5 and R6 have the meanings given in claim 1 and RCHI represents a uniform configuration, chiral radical.
6. Zwischenprodukte nach Anspruch 5, worin Rchi einen Fenchyloxymethylrest darstellt. 6. intermediates according to claim 5, wherein RCHI represents a Fenchyloxymethylrest.
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