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DE4035455A1 - ENANTIOMER SEPARATION - Google Patents

ENANTIOMER SEPARATION

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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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Germany
Prior art keywords
methyl
sulfinyl
pyridinyl
methoxy
alkoxy
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DE19904035455
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German (de)
Inventor
Bernhard Dr Kohl
Joerg Dr Senn-Bilfinger
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Takeda GmbH
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Byk Gulden Lomberg Chemische Fabrik GmbH
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Priority to DE19904035455 priority Critical patent/DE4035455A1/en
Priority to PCT/EP1991/002096 priority patent/WO1992008716A1/en
Priority to AU88406/91A priority patent/AU8840691A/en
Publication of DE4035455A1 publication Critical patent/DE4035455A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic 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
    • C07D401/02—Heterocyclic 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
    • C07D401/12—Heterocyclic 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

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 ErfindungField of application of the invention

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

Stand der TechnikState of the art

In einer Vielzahl von Patentanmeldungen und Patenten werden Pyridylmethylsulfinyl-1H-benzimidazole beschrieben, die magensäuresekretionshemmende Eigenschaften besitzen. 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. 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. Auch die Enantiomeren der Pyridylmethylsulfinyl-1H-benzimidazole sind bisher (mangels eines geeigneten Trennverfahrens) noch nicht isoliert und charakterisiert worden.In a large number of patent applications and patents, pyridylmethylsulfinyl-1H-benzimidazoles described the gastric acid secretion-inhibiting properties have. In connection with the present invention, for example mentions the following patent applications and patents: 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 and WO89 / 11 479. It is also known that these pyridylmethylsulfinyl-1H- Benzimidazoles have a chiral center and that they are therefore in their enantiomers should be separable. Despite the large number of patent applications However, the field of pyridylmethylsulfinyl-1H-benzimidazoles is still so far no method has been described by means of which the pyridylmethylsulfinyl 1H-benzimidazoles could be separated into the optical antipodes. Also the Enantiomers of pyridylmethylsulfinyl-1H-benzimidazoles have so far (lack of a suitable separation process) has not yet been isolated and characterized.

Beschreibung der ErfindungDescription 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.A method has now been found by means of which those described in more detail below Pyridylmethylsulfinyl-1H-benzimidazoles in their optical antipodes can be split.

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

worin
R1 Wasserstoff, 1-4C-Alkyl oder 1-4C-Alkoxy bedeutet,
R2 Wasserstoff, Trifluormethyl, 1-4C-Alkyl, 1-4C-Alkoxy, ganz oder überwiegend durch Fluor substituiertes 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,
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,
R4 Wasserstoff oder 1-4C-Alkyl bedeutet,
R5 Wasserstoff, 1-4C-Alkyl oder 1-4C-Alkoxy bedeutet und
R6 1-4C-Alkoxy, ganz oder überwiegend durch Fluor substituiertes 1-4C-Alkoxy oder Benzyloxy bedeutet,
oder ihre Salze mit Basen mit konfigurativ einheitlich chiralen Verbindungen der Formel II,wherein
R1 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
R2 is hydrogen, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy. Chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoromethoxy or together with R3, if desired, completely or partially means fluorine-substituted 1-2C-alkylenedioxy or chlorotrifluoroethylenedioxy,
R3 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, completely or predominantly substituted by fluorine-1-4C-alkoxy, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or together with R2 if desired in whole or in part by fluorine substituted 1-2C-alkylenedioxy or chlorotrifluoroethylene dioxy means
R4 represents hydrogen or 1-4C-alkyl,
R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy and
R6 denotes 1-4C-alkoxy, completely or predominantly substituted by fluorine-substituted 1-4C-alkoxy or benzyloxy,
or their salts with bases with configuratively uniform chiral compounds of the 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, where Rchi is a configuratively uniform, chiral residue and X is a leaving group represents, implemented, the mixture of isomers or diastereomers obtained III,  

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 configuratively uniform, chiral residue, separates and from the optically pure diastereomers the configuratively uniform, optically pure Releases compounds I by solvolysis in a strongly acidic medium.

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

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

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.Examples of all or predominantly fluorine-substituted 1-4C-alkoxy are the 1,2,2, -trifluoroethoxy-, the 2,2,3,3,3-pentafluoropropoxy-, the Perfluoroethoxy and in particular 1,1,2,2-tetrafluoroethoxy, trifluoromethoxy, the 2,2,2-trifluoroethoxy and the difluoromethoxy radical called.

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 are partially or completely substituted by fluorine-substituted 1-2C-alkylenedioxy or chlorotrifluoroethylene dioxy, the substituents R2 or R3 bound in neighboring positions on the benzo part 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. Examples of all or part of fluorine-substituted 1-2C-alkylenedioxy are the 1,1-difluoroethylene dioxy- (-O-CF₂-CH₂-O-), the 1,1,2,2-tetrafluoroethylene dioxy- (-O-CF₂-CF₂-O-) and especially the difluoromethylene dioxy- (-O-CF₂-O-) and the 1,1,2-trifluoroethylene dioxyrest (-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.In principle, all chiral, configurative compounds come as compounds of the formula II unitary compounds in question, those with compound I or its anion are able to react with separation of the leaving group X and their Rest Rchi smooth after diastereomer separation and without undesirable side reaction can be split off again.

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.All nucleophilically removable atoms or Groups such as halogen atoms (J, Br or especially Cl) or hydroxyl groups activated by esterification (e.g. with sulfonic acids) (-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. Als Reste Rchi seien insbesondere genanntAll configuratively uniform residues that can be considered as residues Rchi of naturally occurring or synthetically accessible chiral compounds can be derived and the solvolytically under acidic conditions from the compounds III can be split off. Rchi may be mentioned in particular as residues

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

die jeweils an dem als Verknüpfungsglied fungierenden Sauerstoffatom eine Carbonylgruppe oder insbesondere eine Methylengruppe tragen.each have a carbonyl group on the oxygen atom functioning as a linking member or especially carry a methylene group.

Bevorzuge Reste Rchi sind Reste der Formel IVPreferred radicals 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 'together with the oxygen atom to which it is attached is a glycosyl radical, a chiral terpene alcohol residue, or another chiral alcohol residue represents.

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 residues R'-O-, for example, the residues are mentioned, which differ from naturally occurring mono- or disaccharides, such as arabinose, fructose, galactose, Glucose, lactose, mannose, ribose, xylose, maltose, sorbose or Derive N-acetyl-D-glucosamine.  

Als chirale Terpenalkoholreste R′-O- seien insbesondere solche Reste genannt, die sich von einem natürlich vorkommenden oder synthetisch leicht zugänglichen Terpenalkohol herleiten. Als beispielhafte Terpenalkohole seien hierbei genannt: Isopulegol, Neomenthol, Isomenthol, Menthol, Carveol, Dihydrocarveol, Terpinen-4-ol, Mirtenol, Citronellol, Isoborneol, Borneol, Isopinocampheol und insbesondere Fenchol.As chiral terpene alcohol residues R′-O-, such residues may be mentioned in particular which are of a naturally occurring or synthetically easily accessible Derive terpene alcohol. Exemplary terpene alcohols are: Isopulegol, neomenthol, isomenthol, menthol, carveol, dihydrocarveol, Terpinen-4-ol, Mirtenol, Citronellol, Isoborneol, 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.Other chiral alcohol residues R′-O- which may be mentioned are, for example, which are derived from the following alcohols: mandelic acid ester, cinchonidine, cinchonine, Ephedrine, serine methyl ester, sitosterol, 3-hydroxy-2-methyl-propionic acid methyl ester and lactic acid ethyl ester.

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

Die Umsetzung der Verbindung I mit der Verbindung II erfolgt auf eine dem Fachmann vertraute Weise. Zur Erhöhung der Nucleophilie der Verbindungen I ist es zweckmäßig, diese zu deprotonieren, d. h. von den Salzen der Verbindungen I mit Basen auszugehen. 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.The reaction of compound I with compound II is carried out by a person skilled in the art familiar way. It is to increase the nucleophilicity of compounds I. expedient to deprotonate them, d. H. of the salts of compounds I with Bases to go out. Examples of basic salts are sodium, potassium, Calcium, aluminum, magnesium, titanium, ammonium or guanidinium salts mentioned, which, for example, by reacting the compounds I with the corresponding ones Hydroxides (e.g. sodium hydroxide or potassium hydroxide) in the usual way can be obtained.

Die Umsetzung der Verbindungen I mit Verbindungen II wird in inerten, protischen oder aprotischen Lösungsmitteln durchgeführt. Als solche eignen sich beispielsweise Methanol, Isopropanol, Dimethylsulfoxid, Aceton, Acetonitril, Dioxan, Dimethylformamid und vorzugsweise N-Methylpyrrolidon.The reaction of the compounds I with compounds II is carried out in inert, protic or aprotic solvents. Suitable as such are, for example Methanol, isopropanol, dimethyl sulfoxide, acetone, acetonitrile, dioxane, Dimethylformamide and 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 - depending on the reactivity of the compound II - preferably at temperatures between -30 ° C and + 100 ° C, especially at temperatures between 0 ° C and 50 ° C.

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 mixture of diastereomers obtained after the reaction of I with II is carried out in a manner known per se, for example by chromatography on suitable columns 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. 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).Due to the prototropy in the benzimidazole part of the compounds I (the 5- and 6- Positions on the one hand and the 4- and 7-positions on the other are mutually related  identical) arise during the reaction with the compounds II with the corresponding Substitution Patterns in Benzimidazole Isomer Mixtures. Conveniently the isomers are separated from one another before the diastereomers are separated, for example by column chromatography on a suitable carrier material (e.g. Silica gel) and with suitable eluents (e.g. ethyl acetate).

Die Freisetzung der konformativ einheitlichen Verbindungen I aus den optisch reinen Diastereomeren III erfolgt durch Solvolyse unter stark sauren Bedingungen. 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. Die Freisetzung erfolgt vorzugsweise bei Temperaturen zwischen 0° und 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.The release of the conformatively uniform compounds I from the optically pure diastereomers III are carried out by solvolysis under strongly acidic conditions. Reagents suitable for solvolysis are, for example, strong ones higher concentrated acids (e.g. 60-100% sulfuric acid, concentrated hydrochloric acid, anhydrous or water-containing tetrafluoroboric acid, methanesulfonic acid, Trifluoromethanesulfonic acid, phosphoric acid or perchloric acid), preferably about 90% Called sulfuric acid. The release takes place preferably at temperatures between 0 ° and 40 ° C. In the workup following the release is advantageously carried out so that the pH increases as quickly as possible is, for example by introducing the strongly acidic solution in buffer solution or preferably in lye.

Die Verbindungen der Formel II sind bekannt bzw. sie sind auf eine für den Fachmann vertraute Weise aus bekannten Verbindungen auf analoge Weise zugänglich. 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. B. in Analogie zu R. C. Ronald et. al., J. Org. Chem. 45 (1980) 2224] hergestellt werden.The compounds of formula II are known or they are based on one for the A person familiar with the art is accessible in an analogous manner from known compounds. For example, the compounds II in which Rchi has the meaning of the formula IV and X represents a chlorine atom, correspondingly by chloromethylation Alcohols [e.g. B. in analogy to R. C. Ronald et. al., J. Org. Chem. 45 (1980) 2224].

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

Die konfigurativ einheitlichen, optisch reinen Verbindungen der Formel I sind ebenfalls neu und daher auch Gegenstand der Erfindung.The configuratively uniform, optically pure compounds of the formula I are also new and therefore also the 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: As an example, optically producible by the method according to the invention pure compounds of the formula I and as associated intermediates III according to the invention be based on the substituent meanings in the above Formulas I and III in particular the following compounds of Table 1 below mentioned:  

Tabelle 1 Table 1

Besonders bevorzugte, durch das erfindungsgemäße Verfahren herstellbare Verbindungen sind die VerbindungenParticularly preferred compounds that can be produced by the method according to the invention are the connections

(+)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1H-benz­ imidazol,
(-)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1H-benz­ imidazol,
(+)-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 imidazol,
(+)-2-{[(3-Methyl-4-(2,2,2-trifluorethoxy)-2-pyridinyl]methyl}sulfinyl-1H-benz­ imidazol, und
(-)-2-{[(3-Methyl-4-(2,2,2-trifluorethoxy)-2-pyridinyl]methyl}sulfinyl-1H-benz­ imidazol,(+) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1H-benz imidazole,
(-) - 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 imidazole,
(-) - 5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} -1H-benz imidazole,
(+) - 2 - {[(3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl} sulfinyl-1H-benz imidazole, and
(-) - 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. Die Abkürzung h steht für Stunde(n), Schmp. für Schmelzpunkt.The following examples serve to explain the invention in more detail. The abbreviation h stands for hour (s), mp for melting point.

BeispieleExamples 1. (+)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1- [(+)-fenchyloxymethyl]-benzimidazol1. (+) - 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. Nach 6 h wird mit 500 ml Wasser verdünnt, der pH-Wert auf 9,0 gestellt und dreimal mit je 100 ml Dichlormethan extrahiert. Die vereinigten organischen Phasen werden mit Wasser gewaschen, getrocknet und im Vakuum vollständig eingeengt. Der ölige Rückstand wird an Kieselgel chromatographiert (Laufmittel: Ethylacetat). 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). 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)}.To a solution of 50 g (0.123 mol) of (±) -5-difluoromethoxy-2 - {[(3,4-dimeth oxy-2-pyridinyl) methyl] sulfinyl} -1H-benzimidazole Na salt in 125 ml of N-methylpyrrolidone one drips at a temperature of 25-35 ° C within an hour 27.5 g (0.136 mol) of (+) - fenchyl chloromethyl ether. After 6 h with 500 ml Diluted water, adjusted the pH to 9.0 and three times with 100 ml dichloromethane extracted. The combined organic phases are with water washed, dried and completely concentrated in vacuo. The oily residue is chromatographed on silica gel (eluent: ethyl acetate). One isolates 25.2 g (74%) of a diastereomer mixture of (+) - and (-) - 5-difluoromethoxy 2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1 - [(+) - fenchyloxymethyl] benzimidazole as a pale yellow, gradually crystallizing oil (Rf. value in ethyl acetate 0.85). Four recrystallizations from ethyl acetate / diisopropyl ether provides the title compound (9.0 g 71.4%) in the form of colorless crystals of M.p. 138-139 ° C {[α] = + 155.2 ° (c = 1, chloroform)}.

2. (+)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1H-benzimidazol2. (+) - 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. Nach vollständiger Auflösung wird das Reaktionsgemisch unter Kühlung in 8N Natronlauge eingetropft, der pH auf 7,5 gestellt und mehrmals mit Dichlormethan extrahiert. Die vereinigten Extrakte werden mit Wasser gewaschen, über Magnesiumsulfat getrocknet und im Vakuum vollständig eingeengt. Der rote ölige Rückstand wird über Kieselgel chromatographiert (Dichlormethan/Methanol) und anschließend aus Diisopropylether kristallisiert. 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)}. 1.0 g (1.8 mmol) (+) - 4-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] - sulfinyl} -1 - [(+) - fenchyloxymethyl] benzimidazole are added in portions at 5-10 ° C entered with stirring in 7 ml of 90% sulfuric acid. After more complete Dissolution, the reaction mixture is dropped in 8N sodium hydroxide solution while cooling, the pH was adjusted to 7.5 and extracted several times with dichloromethane. The combined extracts are washed with water, dried over magnesium sulfate and completely concentrated in vacuo. The red oily residue becomes over Chromatographed silica gel (dichloromethane / methanol) and then out Diisopropyl ether crystallized. 0.3 g (44%) of the title compound are obtained as 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]-benzimidazol3. (-) - 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)}.The procedure described in Example 1 is obtained by implementation of 28 g (0.069 mol) (±) -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 mixture of diastereomers from (+) - and (-) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1- [(-) - fenchyloxymethyl] benzimidazole. Repeated recrystallization from ethyl acetate / Diisopropyl ether provides 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- benzimidazol4. (-) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1H- benzimidazole

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, 1 g (1.8 mmol) is obtained (-) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1 - [(-) - fenchyloxymethyl] benzimidazole in 7 ml 90% sulfuric acid 0.25 g (36%) 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]-benzimidazol5. (+) - 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)}. According to the procedure described in Example 1, (±) -5- Methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} -1H-benzimidazole Na 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 in the form of 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- benzimidazol6. (+) - 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)}. According to the procedure described in Example 2, 0.51 g is obtained (1 mmol) (+) - 5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} - 1H - [(+) - fenchyloxymethyl] benzimidzole in 4 ml of 90% sulfuric acid 0.15 g (43%) of the title compound as an amorphous solid {[α] = + 165 ° (c = 0.5, chloroform)}.  

Gewerbliche AnwendbarkeitIndustrial applicability

Nach dem erfindungsgemäßen Verfahren können Pyridylmethylsulfinyl-1H-benzimidazole erstmals in ihre optischen Antipoden aufgespalten werden. 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.According to the process of the invention, pyridylmethylsulfinyl-1H-benzimidazoles be split into their optical antipodes for the first time. As special What is surprising here is the fact that the release of the optical pure compounds from the diastereomers with the help of highly concentrated Mineral acids is made, although it is known that the Pyridylmethylsulfinyl-1H-benzimidazoles are very acid-labile compounds.

Die erfindungsgemäß hergestellten Verbindungen werden als Wirkstoffe in Arzneimitteln für die Behandlung von Magen- und Darmerkrankungen eingesetzt. Bezüglich der Anwendungsweise und Dosierung der Wirkstoffe wird z. B. auf das europäische Patent 1 66 287 verwiesen.The compounds produced according to the invention are used as active ingredients in medicinal products used for the treatment of gastric and intestinal diseases. In terms of the application and dosage of the active ingredients is such. B. European Patent 1,666,287.

Claims (6)

1. Konfigurativ einheitliche, optisch reine Verbindungen der Formel I worin
R1 Wasserstoff, 1-4C-Alkyl oder 1-4C-Alkoxy bedeutet,
R2 Wasserstoff, Trifluormethyl, 1-4C-Alkyl, 1-4C-Alkoxy, ganz oder überwiegend durch Fluor substituiertes 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,
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,
R4 Wasserstoff oder 1-4C-Alkyl bedeutet,
R5 Wasserstoff, 1-4C-Alkyl oder 1-4C-Alkoxy bedeutet und
R6 1-4C-Alkoxy, ganz oder überwiegend durch Fluor substituiertes 1-4C-Alkoxy oder Benzyloxy bedeutet,
und ihre Salze mit Basen.1. Configuratively uniform, optically pure compounds of the formula I wherein
R1 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy,
R2 is hydrogen, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy. Chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoromethoxy or together with R3, if desired, completely or partially means fluorine-substituted 1-2C-alkylenedioxy or chlorotrifluoroethylenedioxy,
R3 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, completely or predominantly substituted by fluorine-1-4C-alkoxy, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy or together with R2 if desired in whole or in part by fluorine substituted 1-2C-alkylenedioxy or chlorotrifluoroethylene dioxy means
R4 represents hydrogen or 1-4C-alkyl,
R5 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy and
R6 denotes 1-4C-alkoxy, completely or predominantly substituted by fluorine-substituted 1-4C-alkoxy or benzyloxy,
and their salts with bases. 2. Verbindung nach Anspruch 1, ausgewählt aus der Gruppe bestehend aus
(+)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1H-benz­ imidazol,
(-)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1H-benz­ imidazol,
(+)-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 imidazol,
(+)-2-{[(3-Methyl-4-(2,2,2-trifluorethoxy)-2-pyridinyl]methyl}sulfinyl-1H-benz­ imidazol, und
(-)-2-{[(3-Methyl-4-(2,2,2-trifluorethoxy)-2-pyridinyl]methyl}sulfinyl-1H-benz­ imidazol,
und ihren Salze mit Basen.2. A compound according to claim 1 selected from the group consisting of
(+) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1H-benz imidazole,
(-) - 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 imidazole,
(-) - 5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} -1H-benz imidazole,
(+) - 2 - {[(3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl} sulfinyl-1H-benz imidazole, and
(-) - 2 - {[(3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl} sulfinyl-1H-benz imidazole,
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 configuratively uniform, optically pure compounds of the formula I as claimed in claim 1 and their salts, characterized in that racemates of compounds of the formula I in which R1, R2, R3, R4, R5 and R6 are those in claim 1 have the meanings indicated, or their salts with bases, with configuratively uniform, chiral compounds of the formula II, Rchi-X (II) in which Rchi is a configuratively uniform, chiral radical and X is a leaving group, the resulting isomer or diastereomer mixture III , wherein R1, R2, R3, R4, R5 and R6 have the meanings given in claim 1 and Rchi represents a configuratively uniform, chiral radical, separates and from the optically pure diastereomers the configuratively uniform, optically pure compounds I by solvolysis in a strongly acidic medium released 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
(+)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1H-benz­ imidazol,
(-)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1H-benz­ imidazol,
(+)-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 imidazol,
(+)-2-{[(3-Methyl-4-(2,2,2-trifluorethoxy)-2-pyridinyl]methyl}sulfinyl-1H-benz­ imidazol, und
(-)-2-{[(3-Methyl-4-(2,2,2-trifluorethoxy)-2-pyridinyl]methyl}sulfinyl-1H-benz­ imidazol,
oder ihr Salz mit Basen herstellt.4. The method according to claim 3, characterized in that a compound selected from the group consisting of
(+) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1H-benz imidazole,
(-) - 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 imidazole,
(-) - 5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} -1H-benz imidazole,
(+) - 2 - {[(3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl} sulfinyl-1H-benz imidazole, and
(-) - 2 - {[(3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl} sulfinyl-1H-benz imidazole,
or you make 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 configuratively uniform, chiral radical. 6. Zwischenprodukte nach Anspruch 5, worin Rchi einen Fenchyloxymethylrest darstellt.6. Intermediates according to claim 5, wherein Rchi represents a fenchyloxymethyl radical.
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