MXPA98000160A - A process for the optic purification of derivatives of benzimidazol enriquecidos enantiomericame - Google Patents

Abstract

Process for the optical purification of the simple enantiomers of some 2-sulfinyl-1H-benzimidazole derivatives and other structurally related sulfoxides of the respective enantiomerically enriched preparation of the same

Description

A PROCESS FOR THE OPTICAL PURIFICATION OF BENZIMIDAZOLE DERIVATIVES ENANTIOMICALLY ENRICHED The present invention relates to a process for the optical purification of enantiomerically enriched preparations of some 2- (pyridinylmethylsulfinyl) -l-benzimidazole derivatives as well as another structurally related sulfoxide.

Afft * frntgrjor There are a large number of patents and patent applications that expose different 2- (pyridinylmethylsulfinyl) -1H-benzimidazoles and structurally related sulfoxides. This class of compounds has properties that make the compounds useful as inhibitors of gastric acid secretion. For example the compound (5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) -methyl] sulfinyl] -lH-benzimidazole), which has the generic name omeprazole, and therapeutically acceptable salts thereof are described in EP 5129. Omeprazole and its alkaline salts are effective inhibitors of gastric acid secretion, and are useful as antiulcer agents. Other compounds also effective REF .: 26533 as inhibitors of gastric acid secretion, are the compounds 2- [[[3-methyl-1,4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -lij-benzimidazole that have the generic name lansoprazole, described in EP-A1-174726; 2- [[[4- (3-methoxypropoxy) -3-methyl-2-pyridinyl] methyl] sulfinyl] -lfl-benzimidazole having the generic name pariprazole, described in EP 268956; 2- [[2- (N-isobutyl-N-methylamino) benzyl] sulfinyl] -lH-benzimidazole having the generic name leminoprazole, described in GB 2163747 and 2 - [(4-methoxy-6,7,8, 9-tetrahydro-5H-cyclohepta [b_] pyridin-9-yl) sulfinyl] -1-ü-benzimidazole which is described in EP 434999. These compounds of omeprazole, lansoprazole, pariprazole and leminoprazole all have a stereogenic center at the sulfur and in this way, it exists as two stereoisomers (enantiomers). The compound 2- [(4-methoxy-6,7,8,9-tetrahydro-5H-cyclohepta [b]] pyridin-9-yl) sulfinyl] -1H-benzimidazole has two stereogenic centers, a center at carbon atom of methine adjacent to the sulfur atom and one in the sulfur atom. Thus, this compound exists as four stereoisomers (two pairs of enantiomers). It also indicates that 2- (pyridinylmethylsulfinyl) -lH-benzimidazole includes class of chiral sulfoxides, including omeprazole, have been described in the scientific literature since the late seventies, there is still no efficient asymmetric process reported for the synthesis of simple enantiomers of the same. Simple enantiomers of pharmacologically active compounds have had an interesting increase in recent years because of improved pharmacokinetic and biological properties. Therefore, there is a need for a process that can be used on a large scale for the preparation of simple enantiomers of omeprazole and other optical analogues of pure omeprazole. In general, asymmetric processes for obtaining chiral sulphoxides provide optically active sulfoxides in enantiomerically enriched forms rather than in simple pure enantiomeric forms unless the processes are enzymatic transformations or resolution methods. Therefore, there is also a need for a method that can be used on a large scale for the improvement of optical purity for enantiomerically enriched preparations of optically active omeprazole and other optically active omeprazole analogues. The processes set forth in the prior art for the resolution of different 2- (2-pyridinylmethylsulfinyl) -1H.-substituted benzimidazoles. For example, DE 4035455 and WO 94/27988 describe such resolution processes. These processes include reaction steps wherein a diastereomeric mixture is synthesized from the racemate of the corresponding substituted 2- (2-pyridinylmethylsulfinyl) -lH-benzimidazoles. The diastereomers are then separated and finally the separated diastereomer is converted to the optically pure sulfoxide in a hydrolytic step. These resolution methods involving diastereomeric intermediaries suffer from at least three fundamental disadvantages, namely:. 1) The substituted 2- (2-pyridinylmethylsulfinyl) -lH-benzimidazole, as a racemic intermediate, has to be further processed in a couple of reaction steps before the simple enantiomers can be obtained. 2) The resolution process involves complicated separation steps. 3) There is a great loss of material, highly refined when the unwanted stereoisomer, in the form of the opposite diastereomer, is discarded.

In addition, exposures of the prior art for example enantioselective synthesis of a derivative 2- (2-pyridinylmethylsulfil) -lH-benzimidazole, ie the simple enantiomers of the sulfoxide agent (5,7-dihydro-2- [[[4-methoxy-3]] -methyl-2-pyridinyl) methyl] -sulfil] -5, 5,7,7-tet ramet ilindeno- [5,6-d-imidazol-6- (1H.) -un) see Euro. J. Biochem. 166 (1978) 453-459. This process is based on an enantioselective oxidation of the corresponding prochiral sulphide for said sulfoxide. The authors state that the crude sulfoxide product, which shows an enantiomeric excess (e.e.) of about 30%, can be purified for pure optical sulfoxide f (e.e.) > 95% by several steps of crystallization. However, the yield and the number of crystallization steps are not reported. This proposed method of crystallization is not suitable for the type of substances according to the compounds of formula Ia-Ie in the present application.

BRIEF DESCRIPTION OF THE INVENTION The aim of the present invention is to provide a new process for increasing the optical purity (enantiomeric excess, ee) for enantiomerically enriched preparations of omeprazole, lansoprazole, pariprazole, leminoprazole and 2- [(4-methoxy-6,7,8) , 9-tetrahydro-5H-cyclohepta [b_] pyridin-9-yl) sulfinyl] -1H-benzimidazole. Surprisingly, the racemates of these compounds are precipitated very selectively from a solvent producing the simple enantiomers with improved optical purity. The process of the invention is defined in claim 1 and further the preferred embodiments of the invention are set forth in claims 2-9. The preferred compounds prepared by the new process are defined in claims 10-19.

Detailed description of the invention.

The process of the present invention is characterized by the steps of treating an enantiomerically enriched preparation of optically active omeprazole of the formula the or optically active lansoprazole of the formula Ib, Ib or optically active pariprazole of the formula Ic or optically active leminoprazole of the formula Id Id or optically active 2- [(4-methoxy-6,7,8,9-tetrahydro-5H.-cyclohepta [bj pyridin-9-yl) sulfinyl] -i-benzimidazole of the formula you with a solvent in which the racemate is selectively precipitated. The benzimidazole derivative precipitated as a racemate, or as a racemate together with a small amount of the desired enantiomer is filtered and the simple enantiomer of the benzimidazole derivative, as its (-) -enantiomer or as its (+) - enantiomer, with a Dramatically enriched optical purity is obtained by removing the solvent from the filtrate. The solvent is preferably removed by evaporation. The substituted 2- (2-pyridinylmethylsulfil) -lfl-benzimidazole, to be treated in the process, is preferably omeprazole. The precipitation is carried out in a protic or non-protic solvent. The solvent facilitates crystallization and is necessary for separation. The change of solvent in which the racemate precipitates is not essential for the process. Preferably the solvent is an organic solvent. A suitable organic solvent may be a ketone such as acetone or 2-butanone, or an ester such as ethyl acetate, or an alcohol such as ethanol, or a nitrile such as acetonitrile, or a hydrocarbon such as toluene. The solvent could also be an ether, an amide or any other organic solvent in which the racemate of the compounds according to formula Ia-Ie can be selectively precipitated. The solvent could also be a mixture of different organic solvents or a mixture of water and organic solvents. Preferably the solvent is one selected from acetone, toluene or acetonitrile. The temperature is not important for the process of the invention. However, if the temperature is too high the solubility increases, the selectivity decreases and the compound decomposes. Accordingly, room temperature is preferred, but also temperatures below room temperature are appropriate. Thus, a preferred feature of the process of the invention is that the racemates of the compounds according to formula Ia-Ie surprisingly crystallize very selectively in an organic solvent. A dramatic increase in the enantiomeric excess of the (-) enantiomer or the (+) enantiomer of the present compounds is obtained in the mother liquor (filtrate), even after only one crystallization of the racemate. Therefore, the process becomes highly effective. Consequently, simple enantiomers can be obtained with a very large enantiomeric excess even from optically impure preparations. This means that a high enantioselectivity is not essential for the asymmetric synthesis of said optically active compounds, e.g. ex. the asymmetric oxidation of the corresponding prochiral sulphide. Thus, a broader purpose of synthetic methods can be considered when choosing the most appropriate asymmetric synthetic processes to obtain the compounds according to formula Ia-Ie. For example chemical performance, cost of reagents, reaction time and degree of danger of handling reagents could thus be important factors such as enantioselectivity when making the selection of the synthetic method. The invention is illustrated in more detail by the following examples 1-16. The invention is illustrated in conjunction with an asymmetric synthesis in Examples 7-9.

EXAMPLES The value of the enantiomeric excess in each given example gives an indication of the relative amount of each enantiomer. The value is defined as the difference between the relative percentages of the two enantiomers. For example, when the percentage of the (-) -enantiomer of the sulfoxide is 97.5% and the percentage of the (+) - enantiomer is 2. 5%, the enantiomeric excess for the (-) - enantiomer is 95%.

The enantiomeric composition of each sulfoxide was determined by chiral HPLC on a Chiralpak AD Column or an AGP Chiral Column under the following conditions: Compound of formula la. Column Chiralpak AD 50x4.6 mm Eluent iso-Hexane (100 ml), ethanol (100 ml) and acetic acid (10 ml) Flow 0.5 ml / min Vol. Iny. 50 μl Wavelength 302 nm Retention time for the (-) -enantiomer 4.0 min Retention time for the (+) -enantiomer 5.8 min g m of ffrmuja Ib. Chiral column AGP 100x4.0 mm Eluent sodium phosphate buffer (pH 7.0), 1 = 0.025 (500 ml) and acetonitrile (70 ml) Flow 0.5 ml / min Vol. Iny. 20 μl Wavelength 210 nm Retention time for the (+) -enantiomer 6.2 min Retention time for the (-) -enantiomer 7.2 min Compound of formula le. Column Chiral AGP 100x4.0 mm Eluent sodium phosphate buffer (pH 7.0), 1 = 0.025 (430 ml) and acetonitrile (70 ml) Flow 0.5 ml / min Vol. Iny. 20 μl Wavelength 210 nm Retention time for the (+) -enantiomer 4.1 min Retention time for the (-) -enantiomer 6.8 min Compound of formula Id. Chiralpak column AD 50x4.6 mm Eluent iso-Hexane (200 ml) and ethanol (10 ml) Flow 0.5 ml / min Vol. Iny. 50 μl Wavelength 285 nm Retention time for the (-) -enantiomer 9.0 min Retention time for the (+) - enantiomer 9.8 min Compound of formula le. Column Chiralpak AD 50x4.6 mm Eluent iso-Hexane (150 ml) and 2-propanol (50 ml) Flow 0.4 ml / min Vol. Iny. 50 μl Wavelength, 285 nm Retention time for the (-) -enantiomer of diastereomer A6.9 min Retention time for the (+) -enantiomer of diastereomer A8.1 min Retention time for the (+) -enantiomer of diastereomer B8.8 min Retention time for the (-) -enantiomer of diastereomer B11.0 min The first diastereomer of compound (le) eluted in a straight phase (achiral silica gel, see below) is called diastereomer A and a second as diastereomer B_. up to 98.% of. < -, -5-m? Toxi-2- 1 1 U-matoxi-.? ,? -fl1? tt.U -? - 2. 35 g of a mixture of the enantiomers of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -lft-benzimidazole (60% ee in favor of (-) -enantiomer) as a yellow syrup was dissolved in 20 ml of acetonitrile. Almost immediately the racemate appeared as a solid and after 30 minutes in a refrigerator this white solid was filtered. The solvent of the filtrate was evaporated to yield 1.2 g of the (-) -enantiomer of omeprazole as a yellow syrup with an optical purity of 98.4% e.e.

T1WP1? ? t Maior «ni« ntQ gives the purity? pfcieadede 20% a.a. up to 91.4% «-a. da (-, -5-matoxy-2-? f4-.aat.oxi- ?, g-d.Jm t -2-pyridinyl) - atipaulfinin-1H-hßngi? nidar.o1, (-? - fla. 2. 35 g of a mixture of the enantiomers of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (20% ee in favor of (-) -enantiomer) as a yellow syrup was dissolved in 20 ml of 2-butanone. Almost immediately the racemate appeared as a solid and after one hour in a refrigerator this white solid was filtered. The filtrate solvent was evaporated to yield 0.48 g of the (-) -enantiomer of omeprazole as a yellow syrup with an optical purity of 91.4% e.e. ffi1ffTfrl? ? Tlyfffllft? fll the optical purity from 50% ß.e. pyridinyli- ipa? alfinip-iw- '? py < p-iria «n1 (-) - (Ia) 2. 35 g of a mixture of the enantiomers of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H.-benzimidazole (50% ee in favor of (- ) -enantiomer) as a yellow syrup was dissolved in 20 ml of acetone. Almost immediately the racemate appeared as a solid and after one hour in a refrigerator this white solid was filtered. The filtrate solvent was evaporated to yield 1.0 g of the (-) -enantiomer of omeprazole as a yellow syrup with an optical purity of 97.3% e.e. "fl TTP??> 1f1? TMÍ" * "*" rttt 1 »Bura" optics from 80% e.e. 2-pyridinyl, -metill sulfinill-lH-benr.imi dar. l. 1+) - < Ia) 2. 35 g of a mixture of the enantiomers of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H.-benzimidazole (80% ee in favor of (+ ) -enantiomer) as a yellow syrup was dissolved in 20 ml of ethyl acetate. Almost immediately the racemate appeared as a solid and after one hour in a refrigerator this white solid was filtered. The solvent in the filtrate was evaporated to yield 1.7 g of the (+) - omeprazole enantiomer as a yellow syrup with an optical purity of 95.4% e.e.

Example 5. Improvement of optical purity from 40% e.e. up to 88.7% e.e. of t +) -5-methoxy-2-t 1 1 (4-methoxy-3S-j '»tn-2-pyridinyl) -metill-sulfinyl-lH-benzimidazole. t +) - trust, 2. 35 g of a mixture of the enantiomers of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (40% ee in favor of (+) -enantiomer) as a yellow syrup was dissolved in 20 ml of ethanol. Almost immediately the racemate appeared as a solid and after one hour in a refrigerator this white solid was filtered out. The filtrate solvent was evaporated to yield 1.0 g of the (+) - omeprazole enantiomer as a yellow syrup with an optical purity of 88.7% e.e.

Example 6, Improvement gives optical purity from 30% e.e. up to 97.0% a.a. gives f +? -5-matoxy-2- r T T M-matox -3, 5- trc l, -2-pyridinyl-1-methyl-sulfinyl-lH-benzimidazole. (+) - lla, 2. 35 g of a mixture of the enantiomers of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole (30% ee in favor of (+) -enantiomer) as a yellow syrup was dissolved in 20 ml of toluene. Almost immediately the racemate appeared as a solid and after one hour in a refrigerator this white solid was filtered. The filtrate solvent was evaporated to yield 0.62 g of the (+) - omeprazole enantiomer as a yellow syrup with an optical purity of 97.0% e.e.

Example__7_? Asymmetric synthesis followed by optical purification of. (+) - 5-methoxy-2-rrr (4-methoxy-3,5-dimethyl-2-pyridinyl, -matil.sulfinill-lH-benzimidazole, i +) - (the) A mixture of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -lH-benzimidazole (0.47 g, 1.46 mmol), (3 'S, 2R) - (-) - N - (phenylsul-fonyl) - (3,3-dichlorocamporyl) oxaziridino (0.55 g, 1.46 mmol), triethylamine (0.07 ml, 0.5 mmol) and carbon tetrachloride 20 ml it was stirred for 96 hours at room temperature. After removing the solvent the residue was dissolved in methylene chloride (25 ml). The mixture was extracted with two portions of aqueous solutions of sodium hydroxide (0.1 M, 15 ml). The combined aqueous solutions were neutralized with an aqueous solution of ammonium chloride in the presence of methylene chloride. The phases were separated and the aqueous solution was extracted with two portions of methylene chloride. The combined organic solutions were dried with sodium sulfate and then the solvent was removed. The residue (200 mg, 40% e.e.) was dissolved in 2-butanone (3 mL) and the solid formed was filtered. The solvent in the filtrate was evaporated to yield 0.11 g (22%) of the titled compound with an optical purity of 94% e.e.

^ ItmPl? ? . Asymmetric syntaais followed by optical purification d§ (-, -5-methoxy-2-y? F i4-methoxy-3,5-dimethyl-2- 1. 6 kg (5.0 mol) of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -lH-benzimidazole was dissolved in 5.0 l of ethyl acetate. To the solution was added 31 ml (1.7 mol) of water. To the mixture was added 856 ml (5.0 mol) of (-) -diethyl D-tartrate, -744 ml (2.5 mol) of titanium isopropoxide (IV) and 435 ml (2.5 mol) of diisopropylethylamine at room temperature. The adition of 830 ml (4.5 mol) eumeno hydroperoxide was then made at 30 ° C. After stirring for one hour at 30 ° C the reaction was complete. Chiral and achiral chromatography analyzes showed that the mixture consisted of 71.4% sulfoxide with an enantiomeric excess (e.e.) of 72.9%. The mixture was cooled to 10 ° C and after the addition of 1.71 isooctane, the product was extracted three times with a solution of aqueous ammonia at (12%) with a total volume of 10 1. The combined aqueous phases were neutralized by the addition of 1.5 1 of concentrated acetic acid in the presence of ethyl acetate (3 1 ). The phases were separated and the aqueous phase was extracted with ethyl acetate (3 1). The solvent of the combined organic solutions was removed and at the end of the evaporation was added acetonitrile (1.5 1) to facilitate the removal of the solvent. Acetone (2.5 1) was added to precipitate the omeprazole racemate which was filtered (254 g). HPLC analyzes (achiral and chiral columns) of the filtrate showed that this solution consists of 88% sulfoxide with an optical purity of 96.3% e.e. and in this way the optical purity has been improved from 72.9% e.e. to 96.3% e.e. simply by a racemic omeprazole precipitation. In addition, a content analysis (HPLC) of the filtrate showed that the yield was 0.8 kg (46%). The (-) -enantiomer of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole was not isolated in its neutral form but was also processed for the corresponding sodium salt. optics. (+) - 5-methoxy-2- f T T f 4-methoxy-3,5-dimethyl-2-pyridinyl, -metip sulf inin-1 H-hen imidazole. (+) - (the) 1 . 6 kg (5.0 mol) of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -l-benzimidazole was dissolved in 7. 5 1 of ethyl acetate. To the solution was added 31 ml (1.7 mol) of water. To the mixture was added 856 mol (5.0 mol) of (+) - diethyl L-tartrate, 744 ml (2.5 mol) of titanium isopropoxide (IV) and 436 ml (2.5 mol) diisopropylethylamine at room temperature. The addition of 830 ml (4.5 mol) of eumenal hydroperoxide was then carried out at 30 ° C. After stirring for one hour at 30 ° C the reaction was complete. Chiral and achiral chromatography analyzes showed that the mixture consisted of 75% sulfoxide with an enantiomeric excess (e.e.) of 80%. The mixture was cooled to 10 ° C and after the addition of 1.5 1 of isooctane and ethyl acetate (0.5 1), the product was extracted three times with a solution of aqueous ammonia at (12%) with a total volume of 14. 1. The combined aqueous phases were neutralized by the addition of 1.51 concentrated acetic acid in the presence of ethyl acetate (4 1). The phases were separated and the aqueous phase was extracted with ethyl acetate (4 1). The solvent of the combined organic solutions was removed. Acetone (3.0 1) was added to precipitate the omeprazole racemate which was filtered. HPLC analyzes (achiral and chiral columns) of the filtrate showed that this solution consists of 90% sulfoxide with an optical purity of 95% e.e. and from this the optical purity has been improved from 80% e.e. up to 95% e.e. simply by a racemic omeprazole precipitation. In addition, a content analysis (HPLC) of the filtrate showed that the yield was 1.0 kg (58%). The (+) - enantiomer of 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -lí-benzimidazole was not isolated in its neutral form but was also processed for the corresponding sodium salt. The initial material in the form of enantiomerically enriched preparations for the optical purification of one of the compounds according to formulas Ib, Ic, Id or le was prepared as described in examples 8 and 9.

H * tlFl9 1 ° Memento of the optical purity of two of the stereoisomers of 2- T (4-methoxy-6.7.8.9-tetrahydro-5H-cycloheptafb, Pridon-9-yl. Aulfinill -'Vfl-frt ? tt'i'ftift li fT?), In the following example, the first diastereomer of the titled compound is eluted in straight phase (silica gel) is called diastereomer A. and the second as diastereomer fi. The stereoisomeric composition of the titled compound in a crude mixture such as a syrup (0.25 g) was as follows. The ratio of diastereomers was 4: 3 in favor of diastereomer A. The optical purity of the (-) - enantiomer of diastereomer A. was 76% e.e. and the optical purity of the (+) - enantiomer of diastereomer B was 68% e.e.

Separation of diastereomers. A chromatographic preparation (methanol-methylene chloride 0 to 5%) provided a separation of the two diastereomers. In addition, the (-) - enantiomer of diastereomer A was obtained as a syrup (0.145 g) with an optical purity of 77% ee The (+) - enantiomer of diastereomer B was also obtained as a syrup (0.085 g) with a Optical purity of 68% ee, however, the diastereomer £ was contaminated with ca. 10% diastereomer A.

Optical purification: the optical purity of the (-) - enantiomer of diastereomer A. was improved by the addition of ca. 2 ml of acetonitrile to the enantiomerically enriched preparation of diastereomer A (0.145 g). After stirring overnight, the precipitate formed (almost diastereomeric A. racemic) was filtered and the solvent of the filtrate was removed by film evaporation. In this way, 85 mg of the (-) -enantiomer of diastereomer A. was obtained as a syrup with an optical purity of 88% e.e. The optical purity of the (+) - enantiomer of the diastereomer fi was improved in a similar manner. Thus, by addition of acetonitrile (2 ml) to the enantiomerically enriched preparation of ph diastereomer (0.085 g) followed by stirring overnight resulted in a precipitate which was filtered. From the filtrate, 0.050 g of the (+) - enantiomer of diastereomer B was obtained with an optical purity of 95% e.e.

E p e 11 Improvement of the optical purity of (-) - 2-frr3-methyl-4- (2.2.2-trifluoroethoxy) -2-Pyridinimethyl-sulphonyl-lH-be ^^ imid »zoJ. , (-) - (Ib) t 1. 2 g of a crude mixture of the compound titled with an enantiomeric excess (e.e.) of 55% was treated with acetonitrile (a few mi) and a precipitate was obtained which was removed by filtration. Evaporation of the filtrate gave an oil with improved optical purity. Repeating this procedure a couple of times gave 0.63 g of the desired compound as an oil with an optical purity of 99.5% e.e.

^ ITprlT T? M inriiftn gives the optical lamp of (+1 -2- T T T3-methyl-4- (2.2, 2-trifluoroatoxy) -2-Prididiphenyl-sulfinyl-lH-benzimidazole. (+) - (Ib). 0. 85 g of a crude mixture of the compound titrated with an enantiomeric excess (e.e.) of 46% was treated with acetonitrile (a few mi) and a precipitate was obtained that was removed by filtration. Evaporation of the filtrate gave an oil with improved optical purity. Repeating this procedure a couple of times gave 0.31 g of the desired compound as an oil with an optical purity of 99.6% e.e.

Example 13. Improvement of the optical purity of (-) - 2-rrr4- (3-methoxypropoxy) -3-methyl-2-pyridinyl-1-methyl-1-sulfinyl-1H-benzjmjdazpj. ,. { -) - (T-Q) t 1. 62 g of a crude mixture of the compound titrated with an enantiomeric excess (e.e.) of 90% was treated with acetonitrile (a few ml) and a precipitate was obtained which could be removed by filtration. The concentration of the filtrate gave 1.36 g of the titled compound as an oil with an optical purity of 91.5% e.e. *? Í? TH.? 1 e? Oramiept da. the optical purity of (+) -2-T T T4- (3-methoxypropoxy) -3-methyl-2-pyridinimethyl-1-sulfinyl-1H-benzimidazole. (+) - (him). 1. 63 g of a crude mixture of the compound titled with an enantiomeric excess (e.e.) of 91% was treated with acetonitrile (a few mi) and a precipitate was obtained which could be removed by filtration. The concentration of the filtrate gave 1.1 g of the titled compound as an oil with an optical purity of 96.0% e.e. jamnl 15 Improvement of the optical purity of (-) - 2-T2- (N-i «obtttil« N- ^ .lff ^.?) l-Ma ^ f TVlflff ^^ 11TOff ^ ffÍ ^ ol. (-) - (Id). 1. 6 g of a crude mixture of the compound titrated with an enantiomeric excess (e.e.) of 92% was treated with a small amount of acetonitrile to improve the optical purity. A formed precipitate was removed by filtration. The filtrate solvent was removed by film evaporation and 1.2 g of the desired compound was obtained as an oil. The optical purity of the material was 96% e.e. according to chiral HPLC. gt? ffTTr? f Ma nrami anto gives the pure to optics of (+) -2- T2-4- < I). 3. 0 g of a crude mixture of the titled compound (91% e.e.). contaminated with (-) - diethyl D-tartrate, was dissolved in 40 ml of a mixture of ethyl acetate and hexane (10% EtOAc). A formed precipitate (140 mg) was removed by filtration. The filtrate solvent was removed by film evaporation and the residue was purified by column chromatography (silica gel, EtOAc / hexane 15:85). 0.95 g of the titled compound was obtained showing an optical purity of 96% e.e. according to chiral HPLC.

Claims (19)

1. A process for the optical purification of enantiomerically enriched preparations of one of the compounds according to the formulas la, Ib, le, Id and le the Ib you Id characterized in that an enantiomerically enriched preparation of a compound according to some of the formula Ia-Ie, in favor of its (+) - or (-) - enantiomer was treated with a solvent from which the racemate of said compound is selectively precipitated , wherein the precipitated racemate is filtered followed by the removal of the solvent produced by the simple enantiomer with an improved optical purity of the corresponding compound according to formula Ia-Ie.

2. A process according to claim 1, characterized in that the optical purity of the (-) -enantiomer of the compound according to the formula la is improved.

3. A process according to claim 1, characterized in that the optical purity of the (+) - enantiomer of the compound according to the formula la is improved.

4. A process according to claim 1, characterized in that the solvent is removed by evaporation.

5. A process according to claim 1, characterized in that the enantiomerically enriched preparation is treated with an organic solvent.

6. A process according to claim 1, characterized in that the enantiomerically enriched preparation is treated with a mixture of organic solvents.

7. A process according to claim 1, characterized in that the enantiomerically enriched preparation is treated with a mixture of water and one or more organic solvents.

8. A process according to claim 7, characterized in that the mixture of water and one or more organic solvents contains < 50% water

9. A process according to claim 1, characterized in that the organic solvent is acetone, acetonitrile or toluene.

10. A process according to any of claims 1-9, characterized in that the product prepared is (-) - 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) -methyl] sulfinil ] -lH-benzimidazole.

11. A process according to any of claims 1-9, characterized in that the product prepared is (+) - 5-methoxy-2- [[(4-methoxy-3,5-dimethyl-2-pyridinyl) -methyl] sulfinil ] -lH-benzimidazole.

12. A process according to any of claims 1-9, characterized in that the product prepared is (-) -2- [[[3-methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridinyl] -methyl. ] sulfinyl] -lH-benzimidazole.

13. A process according to any of claims 1-9, characterized in that the product prepared is (+) -2- [[[3-methyl-1-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] -methyl. ] sulfinyl] -lH-benzimidazole.

14. A process according to any of claims 1-9, characterized in that the product prepared is (-) -2- [[[4- (3-methoxypropoxy) -3-methyl-2-pyridinyl] -methyl] sulfinyl] - lH-benzimidazole.

15. A process according to any of claims 1-9, characterized in that the product prepared is (+) -2- [[[4- (3-methoxypropoxy) -3-methyl-2-pyridinyl] -methyl] sulfinyl] - lH-benzimidazole.

16. A process according to any of claims 1-9, characterized in that the product prepared is (-) -2- [2- (N-isobutyl-N-methylamino) benzylsulfinyl] -benzimidazole.

17. A process according to any of claims 1-9, characterized in that the product prepared is (+) -2- [2- (N-isobutyl-N-methylamino) benzylsulfinyl] -benzimidazole.

18. A process according to any of claims 1-9, characterized in that the product prepared is one of the simple enantiomers of the more lipophilic diastereomers of 2- [(4-methoxy-6,7,8,8-tetrahydro-5H- cyclohepta [b] pyridin-9-yl) sulfinyl] -1H-benzimidazole.

19. A process according to any of claims 1-9, characterized in that the product prepared is one of the simple enantiomers of the less lipophilic diastereomers of 2- [(4-methoxy-6,7,8,8-tetrahydro-5H- cyclohepta [b] pyridin-9-yl) sulfinyl] -1H-benzimidazole.