WO1992008716A1 - Separation of enantiomers - Google Patents

Separation of enantiomers Download PDF

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Publication number
WO1992008716A1
WO1992008716A1 PCT/EP1991/002096 EP9102096W WO9208716A1 WO 1992008716 A1 WO1992008716 A1 WO 1992008716A1 EP 9102096 W EP9102096 W EP 9102096W WO 9208716 A1 WO9208716 A1 WO 9208716A1
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methyl
pyridinyl
benzimidazole
sulfinyl
methoxy
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PCT/EP1991/002096
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German (de)
French (fr)
Inventor
Bernhard Kohl
Jörg Senn-Bilfinger
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Byk Gulden Lomberg Chemische Fabrik Gmbh
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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

Definitions

  • the invention relates to a process for the separation of chiral pyridylmethylsulfinyl-1H-benzimidazoles into their enantiomers.
  • the enantiomers are used in the pharmaceutical industry to manufacture drugs.
  • 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,
  • Chlorotrif1uorethylenedioxy means
  • 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
  • R6 denotes 1-4C-alkoxy, completely or predominantly substituted by fluorine-substituted 1-4C-alkoxy or benzyloxy
  • Rchi - X (II) in which Rchi represents a configuratively uniform, chiral radical and X represents a leaving group, converts the isomer or diastereomer mixture III obtained, wherein R1, R2, R3, R4, R5 and R6 have the meanings given above and Rchi represents a configuratively uniform, chiral radical, separates and releases the configuratively uniform, optically pure compounds I from the optically pure diastereomers by solvolysis in a strongly acidic medium.
  • 1-4C-alkyl represents straight-chain or branched alkyl radicals;
  • the butyl, i-butyl, sec-butyl, t-butyl, propyl, isopropyl, ethyl and especially the methyl radical may be mentioned.
  • 1-4C-Alkoxy stands for straight-chain or branched alkoxy radicals; Examples include the butoxy, i-butoxy, sec.-butoxy, t-butoxy, propoxy, isopropoxy, ethoxy and in particular the methoxy radical.
  • Examples of 1,24-trifluoroethoxy-, 2,2,3,3,3-pentafluoropropoxy-, perfluoroethoxy- and in particular 1,1,2- as completely or predominantly substituted by fluorine-alkoxy include 2-tetrafluoroethoxy, the trifluoromethoxy, the 2,2,2-trifluoroethoxy and the difluoromethoxy radical called.
  • R2 and R3 together mean completely or partially fluorine-substituted 1-2C-alkylenedioxy or chlorotrifluoroethyl endi oxy, the substituents R2 and R3 are bonded in adjacent positions on the benzo part of the benzimidazole ring.
  • fluorine-substituted 1-2C-alkylenedioxy are, for example, the 1,1-difluoroethylene dioxy- (-O-CF 2 -CH 2 -O-), the 1,1,2,2-tetra-fluoroethylene dioxy- ( -O-CF 2 -CF 2 -O-) and in particular the difluoromethylene dioxy (-O-CF 2 -O-) and the 1,1,2-trifluoroethylene dioxy radical (-O-CF 2 -CHF-O-).
  • Suitable compounds of the formula II are in principle all chiral, configuratively uniform compounds which are capable of reacting with the compound I or its anion with elimination of the leaving group X and the rest of which can be split off smoothly after the diastereomer separation and without undesired side reactions .
  • Rchi are all configuratively uniform residues which can be derived from naturally occurring or synthetically accessible chiral compounds and which can be cleaved solvolytically from compounds III under acidic conditions. Rchi may be mentioned in particular as residues
  • glycosyl residues which are derived from glycopyranoses, glycofuranoses or oligosaccharides and which, if desired, are partially or completely protected with protective groups customary in carbohydrate chemistry, or
  • radicals Rchi are radicals of the formula IV
  • glycosyl radicals R'-O- are those which are derived from naturally occurring mono- or disaccharides, such as arabinose, fructose, galactose, glucose, lactose, mannose, ribose, xylose, maltose, sorbose or N-acetyl-D- Derive glucosamine.
  • chiral terpene alcohol radicals R'-O- those radicals may be mentioned which are derived from a naturally occurring or synthetically easily accessible terpene alcohol.
  • terpene alcohols are: isopulegol, neomenthol, isomenthol, menthol, carveol, dihydrocarveol, terpinen-4-ol, mirtenol, citronellol, isoborneol, borneol, isopinocampheol and in particular fenchol.
  • R'-O- are, for example, the residues derived from the following alcohols: almond acid esters, cinchonidine, cinchonine, ephedrine, serine methyl ester, sitosterol, 3-hydroxy-2-methyl-propionic acid methyl ester and lactic acid ethyl ester.
  • a particularly preferred radical Rchi is the fenchyloxymethyl radical.
  • reaction of compound I with compound II is carried out in a manner familiar to the person skilled in the art.
  • it is expedient to deprotonate them i.e. starting from the salts of the compounds I with bases.
  • bases examples of basic salts are sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium or guanidinium salts, for example by reacting the compounds I with the corresponding hydroxides (for example sodium hydroxide or potassium hydroxide) in a customary manner can be obtained.
  • reaction of the compounds I with compounds II is carried out in inert, protic or aprotic solvents.
  • inert, protic or aprotic solvents for example, methanol, isopropanol, dimethyl sulfoxide, acetone, acetonitrile, dioxane, dimethylformamide and preferably N-methylpyrrolidone are suitable.
  • the reaction is preferably carried out at temperatures between -30 ° C and + 100 ° C, in particular at temperatures between 0 ° C and 50 ° C.
  • the diastereomer mixture obtained after the reaction of I with II is separated in a manner known per se, for example by chromatography on suitable columns or preferably by fractional crystallization.
  • the isomers are expediently separated from one another before the diastereomers are separated, for example by column chromatography on a suitable support material (for example silica gel) and with suitable eluents (for example ethyl acetate).
  • the conformatively uniform compounds I are released from the optically pure diastereomers III by solvolysis under strongly acidic conditions.
  • suitable reagents for solvolysis are strong, more highly 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
  • the release is preferably at temperatures between 0 ° and 40 ° C.
  • the procedure is advantageously such that the pH is increased as quickly as possible, for example by introducing the strongly acidic solution in buffer solution or preferably in alkali.
  • the compounds of the formula II are known or can be obtained in an analogous manner from known compounds in a manner familiar to those skilled in the art.
  • the compounds II in which Rchi has the meaning of the formula IV and X represents a chlorine atom can be obtained by chloromethylation of corresponding alcohols [e.g. in analogy to R.C. Ronald et al., J. Org. Chem. 45 (1980) 2224].
  • the compounds of formula III are new and also a subject of the invention.
  • the configuratively uniform, optically pure compounds of the formula I are likewise new and are therefore also an object of the invention.
  • connections are particularly preferred connections which can be produced by the method according to the invention.
  • pyridylmethylsulfinyl-1H-benzimidazoles can be split into their optical antipodes for the first time.
  • the fact that the release of the optically pure compounds from the diastereomers is carried out with the aid of highly concentrated mineral acids is particularly surprising, although it is known that the pyridylmethylsulfinyl-1H-benzimidazoles are very acid-labile compounds.
  • the compounds prepared according to the invention are used as active ingredients in medicaments for the treatment of gastric and intestinal diseases.
  • the active ingredients e.g. refer to European patent 166 287.

Abstract

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

Description

Enantiomerentrennung  Enantiomer separation
Anwendungsgebiet, der Erfindung Field of application, the invention
Die Erfindung betrifft ein Verfahren zur Auftrennung von chiralen Pyridylmethylsulfinyl-lH-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 pyridylmethylsulfinyl-1H-benzimidazoles into their enantiomers. The enantiomers are used in the pharmaceutical industry to manufacture drugs.
Stand der Technik State 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-134400 (= USP 4,555,518), EP-A-127 763 (= USP 4,560,693), EP-B-166287 (= USP 4,758,579), EP-A-174726, EP-A-201 575 (= USP 4,686,230), W089/05299 und W089/11479. - 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. A large number of patent applications and patents describe pyridylmethylsulfinyl-1H-benzimidazoles which have gastric acid secretion-inhibiting properties. The following patent applications and patents may be mentioned here in connection with the present invention: EP-B-5 129, EP-A-134400 (= USP 4,555,518), EP-A-127 763 (= USP 4,560,693), EP-B- 166287 (= USP 4,758,579), EP-A-174726, EP-A-201 575 (= USP 4,686,230), W089 / 05299 and W089 / 11479. - It is also known that these pyridylmethylsulfinyl-1H-benzimidazoles have a chiral center and that they should therefore be separable into their enantiomers. Despite the large number of patent applications in the field of pyridylmethylsulfinyl-1H-benzimidazoles, no process has yet been described by means of which the pyridylmethylsulfinyl-1H-benzimidazoles could be separated into the optical antipodes. The enantiomers of pyridylmethylsulfinyl-1H-benzimidazoles have also not yet been isolated and characterized (in the absence of a suitable separation method).
Beschreibung der Erfindung Description of the invention
Es wurde nun ein Verfahren gefunden, mit dessen Hilfe die nachstehend näher bezeichneten Pyridylmethylsulfinyl-lH-benzimidazole in ihre optischen Antipoden gespaltet werden können. A method has now been found by means of which the pyridylmethylsulfinyl-1H-benzimidazoles described below can be cleaved into their optical antipodes.
Das Verfahren ist dadurch gekennzeichnet, daß man Verbindungen der Formel I,
Figure imgf000004_0001
The process is characterized in that compounds of the formula I
Figure imgf000004_0001
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, Chlordifluormethoxy,  R2 is hydrogen, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy, chlorodifluoromethoxy,
2-Chlor-1,1,2-trifluorethoxy oder gemeinsam mit R3 gewünschtenfalls ganz oder teilweise durch Fluor substituiertes 1-2C-Alkylendioxy oder  2-chloro-1,1,2-trifluoroethoxy or together with R3, if desired, completely or partially substituted by fluorine-substituted 1-2C-alkylenedioxy or
Chlortrif1uorethylendioxy bedeutet,  Chlorotrif1uorethylenedioxy means
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 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 Wasserstoff oder 1-4C-Alkyl bedeutet,  R4 represents 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 denotes 1-4C-alkoxy, completely or predominantly substituted by fluorine-substituted 1-4C-alkoxy or benzyloxy,
oder ihre Salze mit Basen mit konfigurativ einheitlichen chiralen Verbindungen der Formel II, or their salts with bases with configuratively uniform chiral compounds of the formula II,
Rchi - X (II) worin Rchi einen konfigurativ einheitlichen, chiralen Rest und X eine Abgangsgruppe darstellt, umsetzt, das erhaltene Isomeren- bzw. Diastereomerengemisch III,
Figure imgf000005_0001
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. Rchi - X (II) in which Rchi represents a configuratively uniform, chiral radical and X represents a leaving group, converts the isomer or diastereomer mixture III obtained,
Figure imgf000005_0001
wherein R1, R2, R3, R4, R5 and R6 have the meanings given above and Rchi represents a configuratively uniform, chiral radical, separates and releases the configuratively uniform, optically pure compounds I from the optically pure diastereomers 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 Methyl rest genannt. l-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-alkyl represents straight-chain or branched alkyl radicals; For example, the butyl, i-butyl, sec-butyl, t-butyl, propyl, isopropyl, ethyl and especially the methyl radical may be mentioned. 1-4C-Alkoxy stands for straight-chain or branched alkoxy radicals; Examples include the butoxy, i-butoxy, sec.-butoxy, t-butoxy, propoxy, isopropoxy, ethoxy and in particular the methoxy radical.
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 1,24-trifluoroethoxy-, 2,2,3,3,3-pentafluoropropoxy-, perfluoroethoxy- and in particular 1,1,2- as completely or predominantly substituted by fluorine-alkoxy include 2-tetrafluoroethoxy, the 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 Chlortrifluorethyl endi oxy bedeuten, so sind die Substituenten R2 und R3 in Nachbarpositionen am Benzoteil des Benzimidazolringes gebunden. If R2 and R3 together mean completely or partially fluorine-substituted 1-2C-alkylenedioxy or chlorotrifluoroethyl endi oxy, the substituents R2 and R3 are bonded in adjacent positions on the benzo part of the benzimidazole ring.
Als ganz oder teilweise durch Fluor substituiertes 1-2C-Alkylendioxy seien bei spielsweise der 1,1-Difluorethylendioxy- (-O-CF2-CH2-O-), der 1,1,2,2-Tetra-fluorethylendioxy- (-O-CF2-CF2-O-) und insbesondere der Difluormethylendioxy- (-O-CF2-O-) und der 1,1,2-Trifluorethylendioxyrest (-O-CF2-CHF-O-) genannt. Als Verbindungen der Formel II kommen prinzipiell alle chiralen, konfigurativ einheitlichen Verbindungen infrage, 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 Nebenreaktionen wieder abgespalten werden kann. As fully or partially substituted by fluorine-substituted 1-2C-alkylenedioxy are, for example, the 1,1-difluoroethylene dioxy- (-O-CF 2 -CH 2 -O-), the 1,1,2,2-tetra-fluoroethylene dioxy- ( -O-CF 2 -CF 2 -O-) and in particular the difluoromethylene dioxy (-O-CF 2 -O-) and the 1,1,2-trifluoroethylene dioxy radical (-O-CF 2 -CHF-O-). Suitable compounds of the formula II are in principle all chiral, configuratively uniform compounds which are capable of reacting with the compound I or its anion with elimination of the leaving group X and the rest of which can be split off smoothly after the diastereomer separation and without undesired side reactions .
Als Abgangsgruppen X kommen insbesondere alle nucleophil ablösbaren Atome oderAll nucleophilically removable atoms or
Gruppen, wie beispielsweise Halogenatome (J, Br oder insbesondere Cl) oder durch Veresterung (z.B. mit Sulfonsäuren) aktivierte Hydroxylgruppen Groups such as halogen atoms (J, Br or in particular Cl) or hydroxyl groups activated by esterification (e.g. with sulfonic acids)
(-O-SO 2-CH3 , -O-SO 2-CF3 oder -O-SO2 -C 6H4-p-CH3) i n Frage . (-O-SO 2 -CH 3 , -O-SO 2 -CF 3 or -O-SO 2 -C 6 H 4 -p-CH 3 ) in question.
Als Reste Rchi kommen alle konfigurativ einheitlichen Reste infrage, 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 genannt Rchi are all configuratively uniform residues which can be derived from naturally occurring or synthetically accessible chiral compounds and which can be cleaved solvolytically from compounds III under acidic conditions. Rchi may be mentioned in particular as residues
- Glycosylreste, die sich von Glycopyranosen, Glycofuranosen oder Oligosac- chariden ableiten und die gewünschtenfalls mit in der Kohlenhydratchemie üblichen Schutzgruppen teilweise oder vollständig geschützt sind, oderGlycosyl residues which are derived from glycopyranoses, glycofuranoses or oligosaccharides and which, if desired, are partially or completely protected with protective groups customary in carbohydrate chemistry, 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, die jeweils an dem als Verkπüpfungsglied fungierenden Sauerstoffatom eine Car- bonylgruppe oder insbesondere eine Methylengruppe tragen.  - Other chiral alcohol residues linked via the oxygen atom, each of which carries a carbonyl group or in particular a methylene group on the oxygen atom which acts as a linking member.
Bevorzugte Reste Rchi sind Reste der Formel IV Preferred radicals Rchi are radicals of the formula IV
R'-O-CH2- (IV) worin R' gemeinsam mit dem Sauerstoffatom, woran es gebunden ist, einen Glyco- sylrest, einen chiralen Terpenalkoholrest, oder einen sonstigen chiralen Alkoholrest darstellt. R'-O-CH 2 - (IV) wherein R 'together with the oxygen atom to which it is attached represents a glycosyl residue, a chiral terpene alcohol residue, or another chiral alcohol residue.
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. 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. Examples of glycosyl radicals R'-O- are those which are derived from naturally occurring mono- or disaccharides, such as arabinose, fructose, galactose, glucose, lactose, mannose, ribose, xylose, maltose, sorbose or N-acetyl-D- Derive glucosamine. As chiral terpene alcohol radicals R'-O-, those radicals may be mentioned which are derived from a naturally occurring or synthetically easily accessible terpene alcohol. Examples of terpene alcohols are: isopulegol, neomenthol, isomenthol, menthol, carveol, dihydrocarveol, terpinen-4-ol, mirtenol, citronellol, isoborneol, borneol, isopinocampheol and in particular fenchol.
Als sonstige chirale Alkoholreste R'-O- seien beispielsweise die Reste genannt, die sich von folgenden Alkoholen herleiten: Mandel säureester, Cinchonidin, Cinchonin, Ephedrin, Serinmethylester, Sitosterol, 3-Hydroxy-2-methyl-propionsäuremethylester und Milchsäureethylester. Other chiral alcohol residues R'-O- are, for example, the residues derived from the following alcohols: almond acid esters, cinchonidine, cinchonine, ephedrine, serine methyl ester, sitosterol, 3-hydroxy-2-methyl-propionic acid methyl ester and lactic acid ethyl ester.
Ein besonderes 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 in a manner familiar to the person skilled in the art. To increase the nucleophilicity of the compounds I, it is expedient to deprotonate them, i.e. starting from the salts of the compounds I with bases. Examples of basic salts are sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium or guanidinium salts, for example by reacting the compounds I with the corresponding hydroxides (for example sodium hydroxide or potassium hydroxide) in a customary manner can be obtained.
Die Umsetzung der Verbindungen I mit Verbindungen II wird in inerten, protischen oder aproti sehen Lösungsmitteln durchgeführt. Als solche eignen sich beispielsweise Methanol, Isopropanol, Dimethylsulfoxid, Aceton, Acetonitril, Dio- xan, Dimethylformamid und vorzugsweise N-Methylpyrrolidon. The reaction of the compounds I with compounds II is carried out in inert, protic or aprotic solvents. As such, for example, methanol, isopropanol, dimethyl sulfoxide, acetone, acetonitrile, dioxane, dimethylformamide and preferably N-methylpyrrolidone are suitable.
Die Umsetzung wird - in Abhängigkeit von der Reaktivität der Verbindung II - vorzugsweise bei Temperaturen zwischen -30ºC und +100ºC, insbesondere bei Temperaturen zwischen 0ºC und 50ºC durchgeführt. Depending on the reactivity of the compound II, the reaction is preferably carried out at temperatures between -30 ° C and + 100 ° C, in particular 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 Chromatografie an geeigneten Säulen oder vorzugsweise durch fraktionierte Kristallisation. The diastereomer mixture obtained after the reaction of I with II is separated 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). Because of 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 exclusive identical) are formed in the reaction with the compounds II with a corresponding substitution pattern in the benzimidazole isomer mixtures. The isomers are expediently separated from one another before the diastereomers are separated, for example by column chromatography on a suitable support material (for example silica gel) and with suitable eluents (for example 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. 90The conformatively uniform compounds I are released from the optically pure diastereomers III by solvolysis under strongly acidic conditions. Examples of suitable reagents for solvolysis are strong, more highly 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
%-ige Schwefelsäure genannt. Die Freisetzung erfolgt vorzugsweise bei Temperaturen zwischen 0º und 40ºC. 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. % sulfuric acid called. The release is preferably at temperatures between 0 ° and 40 ° C. In the work-up following the release, the procedure is advantageously such that the pH is increased as quickly as possible, for example by introducing the strongly acidic solution in buffer solution or preferably in alkali.
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 the formula II are known or can be obtained in an analogous manner from known compounds in a manner familiar to those skilled in the art. For example, the compounds II in which Rchi has the meaning of the formula IV and X represents a chlorine atom can be obtained by chloromethylation of corresponding alcohols [e.g. 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 likewise new and are therefore also an object 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:
Figure imgf000009_0001
As examples of optically pure compounds of the formula I which can be prepared by the process according to the invention and as associated intermediates III according to the invention, the following compounds of Table 1 below are particularly mentioned on the basis of the substituent meanings in the formulas I and III above:
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000010_0001
Besonders bevorzugte, durch das erfindungsgemäße Verfahren herstellbare Verbin dungen sind die Verbindungen The connections are particularly preferred connections which can be produced by the method according to the invention
(+)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1H-benzimidazol, (+) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1H-benzimidazole,
(-)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1H-benz¬imidazol,  (-) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1H-benzimidazole,
(+)-5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H-benzimidazol,  (+) - 5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} -1H-benzimidazole,
(-)-5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H-benzimidazol,  (-) - 5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} -1H-benzimidazole,
(+)-2-{[3-Methyl-4-(2,2,2-trifluorethoxy)-2-pyridinyl]methyl}sulfinyl-1H-benzimidazol und  (+) - 2 - {[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl} sulfinyl-1H-benzimidazole and
(-)-2-{[3-Methyl-4-(2,2,2-trifluorethoxy)-2-pyridinyl]methyl}sulfinyl-1H-benzimidazol,  (-) - 2 - {[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl} sulfinyl-1H-benzimidazole,
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.
Beispiele Examples
1. (+) -5-Di fl uormethoxy-2-{ [(3,4-dimethoxy-2-pyri dinyl )methyl] sul finyl }-1- [(+) -fechyloxymethyl] -benzimidazol 1. (+) -5-difluoromethoxy-2- {[(3,4-dimethoxy-2-pyridinyl) methyl] sul finyl} -1- [(+) -fechyloxymethyl] benzimidazole
Zu einer Lösung von 50 g (0,123 Mol) (±)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-lH-benzimidazol-Na-Salz in 125 ml N-Methylpyrrolidon tropft man bei einer Temperatur von 25-35ºC innerhalb einer StundeTo a solution of 50 g (0.123 mol) of (±) -5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -lH-benzimidazole Na salt in 125 ml of N- Methylpyrrolidone is added dropwise at a temperature of 25-35 ° C within one hour
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 Titel Verbindung (9,0 g, 71,4 %) in Form farbloser Kristalle vom Schmp. 138-139ºC {[α]D 22 = +155,2 (c=1, Chloroform)}. 27.5 g (0.136 mol) of (+) - fenchyl chloromethyl ether. After 6 h, the mixture is diluted with 500 ml of water, the pH is adjusted to 9.0 and extracted three times with 100 ml of dichloromethane each time. The combined organic phases are washed with water, dried and completely concentrated in vacuo. The oily residue is chromatographed on silica gel (eluent: ethyl acetate). 25.2 g (74%) of a mixture of diastereomers 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 approx. 0.85). Four times recrystallization from ethyl acetate / diisopropyl ether gives the title compound (9.0 g, 71.4%) in the form of colorless crystals of mp. 138-139 ° C {[α] D 22 = +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) (+)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]-sulfinyl}-1-[(+)-fenchyloxymethyl]-benzimidazol werden portionsweise bei 5-10ºC 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 Kiesel gel chromatographiert (Dichlormethan/Methanol) und anschließend aus Diisopropylether kristallisiert. Man erhält 0,3 g (44 %) der TitelVerbindung als farbloses Kristal lisat vom Schmp. 147-148 C (Zers.) {[α]D 22=+146,0 1.0 g (1.8 mmol) (+) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1 - [(+) - fenchyloxymethyl] benzimidazole are added in portions at 7-10 ° C with stirring in 7 ml of 90% sulfuric acid. After complete dissolution, the reaction mixture is dropped in 8N sodium hydroxide solution while cooling, the pH is 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 is chromatographed on silica gel (dichloromethane / methanol) and then crystallized from diisopropyl ether. 0.3 g (44%) of the title compound is obtained as a colorless crystal lisate of mp. 147-148 C (dec.) {[Α] D 22 = + 146.0
(c= 0,5, Acetonitril/Methanol 1:1)}. 3. (-)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1- [(-)-fenchyloxymethyl]-benzimidazol (c = 0.5, acetonitrile / methanol 1: 1)}. 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) (-)-Fenchylchlormethylether in 75 ml N-Methylpyrrolidon nach Chromatographie an Kieselgel (Dichlormethan/Methanol) 11,0 g (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 {[o] = -152,8° (c=1, Chloroform)}. According to the procedure described in Example 1, 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 (-) - fenchylchloromethyl ether in 75 ml of N-methylpyrrolidone after chromatography on silica gel (dichloromethane / methanol) 11.0 g (58%) of a mixture of diastereomers consisting of (+) - and ( -) - 5-Difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1- [(-) - fenchyloxymethyl] benzimidazole. Repeated recrystallization from ethyl acetate / diisopropyl ether gives the title compound in the form of colorless crystals (4.0 g, 72%), mp. 138-139 ° C {[o] = -152.8 ° (c = 1, chloroform)}.
4. (-)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1H- benzimidazol 4. (-) - 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 Titel Verbindung vom Schmp. 144-145 C (Zers.) {[α]D 22 = -144,4º Following the procedure described in Example 2, 1 g (1.8 mmol) of (-) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1 - [( -) - fenchyloxymethyl] benzimidazole in 7 ml of 90% sulfuric acid 0.25 g (36%) of the title compound of mp 144-145 C (dec.) {[α] D 22 = -144.4 °
(c= 0,5, Acetonitril/Methanol 1:1)}.  (c = 0.5, acetonitrile / methanol 1: 1)}.
5. (+)-5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyljsulfinyl}-1- [(+)-fenchyloxymethy1]-benzimidazol 5. (+) - 5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyljsulfinyl} -1- [(+) - fenchyloxymethy1] 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 Titel Verbindung in Form farbloser Kristalle vom Schmp. 161 C (Zers.) {[α]D 22= +103,0 (c=1, Chloroform)}. 6. (+)-5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H- benzimidazol 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 (decomp.) {[Α ] D 22 = +103.0 (c = 1, chloroform)}. 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 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]-benzimidzol in 4 ml 90 %-iger Schwefelsäure (1 mmol) (+) - 5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} -1H - [(+) - fenchyloxymethyl] benzimidzole in 4 ml 90% sulfuric acid
0,15 g (43 %) der Titel Verbindung als amorphen Feststoff {[α]D 22 = +165º 0.15 g (43%) of the title compound as an amorphous solid {[α] D 22 = + 165 °
(c= 0,5, Chloroform)}. (c = 0.5, chloroform)}.
Gewerbliche Anwendbarkeit Industrial applicability
Nach dem erfindungsgemäßen Verfahren können Pyridylmethylsulfinyl-1H-benzimida zole 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 Mineral säuren 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 can be split into their optical antipodes for the first time. The fact that the release of the optically pure compounds from the diastereomers is carried out with the aid of highly concentrated mineral acids is particularly surprising, although it is known that the pyridylmethylsulfinyl-1H-benzimidazoles are very acid-labile compounds.
Die erfindungsgemäß hergestellten Verbindungen werden als Wirkstoffe in Arznei mitteln für die Behandlung von Magen- und Darmerkrankungen eingesetzt. Bezüglich der Anwendungsweise und Dosierung der Wirkstoffe wird z.B. auf das europä ische Patent 166 287 verwiesen. The compounds prepared according to the invention are used as active ingredients in medicaments for the treatment of gastric and intestinal diseases. Regarding the application and dosage of the active ingredients, e.g. refer to European patent 166 287.

Claims

Patentansprüche Claims
1. Konfi gurati v ei nhei tl i che, opti sch reine Verbi ndungen der Formel I 1. Confi gurati ve uni, optically pure compounds of formula I
Figure imgf000016_0001
Figure imgf000016_0001
wori n wori n
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 oderüberwiegend durch Fluor substituiertes 1-4C-Alkoxy, Chlordifluormethoxy,  R2 is hydrogen, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy, chlorodifluoromethoxy,
2-Chlor-1,1,2-trifluorethoxy oder gemeinsam mit R3 gewünschtenfalls ganz oder teilweise durch Fluor substituiertes 1-2C-Alkylendioxy oder  2-chloro-1,1,2-trifluoroethoxy or together with R3, if desired, completely or partially substituted by fluorine-substituted 1-2C-alkylenedioxy or
Chlortrifluorethylendioxy bedeutet,  Chlorotrifluoroethylene dioxy means
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 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 Wasserstoff oder 1-4C-Alkyl bedeutet,  R4 represents 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 denotes 1-4C-alkoxy, completely or predominantly substituted by 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-benzimidazol, (+) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1H-benzimidazole,
(-)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1H-benzimidazol,  (-) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1H-benzimidazole,
(+)-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-benzimidazol, (+) - 5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} -1H-benzimidazole, (-) - 5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} -1H-benzimidazole,
(+)-2-{[3-Methyl-4-(2,2,2-trifluorethoxy)-2-pyridinyl]methyl}sulfinyl-1H-benzimidazol und  (+) - 2 - {[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl} sulfinyl-1H-benzimidazole and
(-)-2-{[3-Methyl-4-(2,2,2-trifluorethoxy)-2-pyridinyl]methyl}sulfinyl-1H-benzimidazol,  (-) - 2 - {[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl} sulfinyl-1H-benzimidazole,
und ihren Salzen mit Basen.  and their salts with bases.
3. Verfahren zur Herstellung von konfigurativ einheitlichen, optisch reinen Verbindungen 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, 3. A process for the preparation of configuratively uniform, optically pure compounds of the formula I according to claim 1 and their salts, characterized in that racemates of compounds of the formula I in which R1, R2, R3, R4 R5 and R6 have the indicated in claim 1 Have meanings, or their salts with bases, with configuratively uniform, chiral compounds of the formula II,
Rchi - X (II) worin Rchi einen konfigurativ einheitlichen, chiralen Rest und X eine Abgangsgruppe darstellt, umsetzt, das erhaltene Isomeren- bzw. Diastereomerengemisch III, Rchi - X (II) in which Rchi represents a configuratively uniform, chiral radical and X represents a leaving group, converts the isomer or diastereomer mixture III obtained,
Figure imgf000017_0001
Figure imgf000017_0001
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. 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 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]sulfiny1}-1H-benzimidazol, (+) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfiny1} -1H-benzimidazole,
(-)-5-Difluormethoxy-2-{[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl}-1H-benzimi dazol, (-) - 5-difluoromethoxy-2 - {[(3,4-dimethoxy-2-pyridinyl) methyl] sulfinyl} -1H-benzimi dazol,
(+)-5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H-benzimidazol,  (+) - 5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} -1H-benzimidazole,
(-)-5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}-1H-benzimidazol,  (-) - 5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} -1H-benzimidazole,
(+)-2-{[3-Methyl-4-(2,2,2-trifluorethoxy)-2-pyridinyl]methyl}sulfinyl-1H-benzimidazol und  (+) - 2 - {[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl} sulfinyl-1H-benzimidazole and
(-)-2-{[3-Methyl-4-(2,2,2-trifluorethoxy)-2-pyridinyl]methyl}sulfinyl-1H-benzimidazol,  (-) - 2 - {[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl} sulfinyl-1H-benzimidazole,
oder ihr Salz mit Basen herstellt. or you make salt with bases.
5. Zwischenprodukte der Formel III, 5. intermediates of formula III,
Figure imgf000018_0001
Figure imgf000018_0001
worin R1, R2, R3, R4, R5 und R6 die in Anspruch 1 angegebenen Bedeutungen haben und Rchi einen konfigurativ einheitlichen, chiralen Rest darstellt. 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 dar stellt. 6. Intermediates according to claim 5, wherein Rchi represents a fenchyloxymethyl radical.
PCT/EP1991/002096 1990-11-08 1991-11-06 Separation of enantiomers WO1992008716A1 (en)

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