FR2925899A1 - Enantioselective preparation of substituted sulfoxide derivative, useful to treat gastric and duodenal ulcers, comprises coupling sulfinate core with an organometallic compound, where the sulfinate is in the form of diastereoisomer - Google Patents

Abstract

Process for enantioselective preparation of substituted sulfoxide derivative (I), comprises coupling sulfinate core (II), where the sulfinate is in the form of diastereoisomer, with an organometallic compound (III). Process for enantioselective preparation of substituted sulfoxide derivative of formula (A-SO-CH 2-B1) (I), comprises coupling sulfinate core of formula (A-(SO)-OR) (II), where the sulfinate is in the form of diastereoisomer, with an organometallic compound of formula (B1-CH 2-Y1) (III). A : benzimidazole or imidazo-pyridyl core; B1 : pyridyl core; R : chirality inducer group; and Y1 : residue of organolithium or organomagnesium. Independent claims are included for: (1) the sulfinate core compound (II), used as intermediary compound for the synthesis of (I); and (2) the organometallic compound (III) used as intermediary compound for the synthesis of (I). ACTIVITY : Antiulcer; Gastrointestinal-Gen. MECHANISM OF ACTION : Proton pump inhibitors.

Description

The present invention relates to a new process for the enantioselective preparation of substituted derivatives of sulfoxides, and more particularly to a process for the enantioselective preparation of compounds such as the enantiomers of tenatoprazole, omeprazole, and other comparable sulfoxides. Various sulfoxide derivatives, and in particular pyridinyl-methyl-sulfinyl benzimidazoles, which are useful in therapeutics as medicaments having proton pump inhibiting properties, that is to say medicaments which inhibit the secretion of gastric acid and are known in the art, are known. are useful for the treatment of gastric and duodenal ulcers. The first known derivative of the proton pump inhibitor series is omeprazole, or 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] -sulfinyl] 1H- benzimidazole described in EP 005,129, which has inhibitory properties of gastric acid secretion, and is widely used as an anti-ulcer in human therapy. Other structurally similar benzimidazole derivatives are known by their generic names, for example rabeprazole, pantoprazole, lansoprazole, all of which have a structural analogy, and are related to the group of pyridinyl-methyl-sulfinyl-benzimidazoles.

Tenatoprazole, i.e. 5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] imidazo [4,5-b] pyridine, is described. in EP 254,588. It is also considered a proton pump inhibitor and may also be used in the treatment of gastroesophageal reflux disease, gastrointestinal bleeding and dyspepsia. However, tenatoprazole is structurally distinct from the other proton pump inhibitors mentioned above in that it comprises an imidazopyridinyl ring instead of a benzimidazole ring.

All these compounds are sulphoxides having an asymmetry at the level of the sulfur atom and can therefore be in the form of a racemic mixture of two enantiomers. It may be useful to selectively separate them B1686FR in the form of either of the two enantiomers having the R and S, or (+) or H) configurations, the specific properties of which may be substantially different. Thus, patent application WO 2004060891 describes the S enantiomer of tenatoprazole, the pharmacokinetic properties of which are significantly different from those of the R enantiomer. Various methods have been described in the scientific literature to selectively or predominantly prepare one or the other of the enantiomers of these sulphoxides, in particular omeprazole and its S-configuration enantiomer, esomeprazole, as well as its salts such as the sodium or magnesium salt. Thus, patent EP 652,872 describes a process for preparing the magnesium salt of esomeprazole via the ester comprising a chiral acyloxymethyl group, separation of diastereoisomers and solvolysis in an alkaline solution. US Patent 5,776,765 discloses a method using the stereoselective bioreduction of the racemic mixture of the corresponding sulfoxide sulfide, using a microorganism comprising a DMSO reductase, to obtain a strongly enriched mixture of enantiomer (-) relative to the enantiomer (+). H. Kagan et al., Have described an asymmetric sulphide sulfide oxidation system catalyzed by a complex of titanium isopropoxide and optically active diethyl tartrate, using tertbutyl hydroperoxide as oxidant in the presence of water. at a temperature below 0 ° C [see P. Pitchen et al. J. Am. Chem. Soc. 106, pp. 8188-93 (1984)]. S. Zhao, O. Samuel and H. Kagan, Tetrahedron vol.43, pp. 5135-44 (1987) have shown that enantioselectivity can be improved by using cumene hydroperoxide as an oxidant under the same reaction conditions. Various variants of the Kagan method have been developed and for example US Pat. No. 5,948,789 relates to the enantioselective preparation of various sulfoxides, and more particularly to the (-) enantiomer of omeprazole or its sodium salts, by oxidation of the corresponding sulphide ("prochiral" sulphide) with an oxidizing agent in a particular solvent such as toluene and ethyl acetate, in the presence of a base, the reaction being catalyzed by a titanium complex obtained from a titanium compound (1 °), preferably titanium isopropoxide, and a chiral ligand selected from aliphatic diols and aromatic diols, especially L (+) - or D (-) - tartrate diethyl in the presence of water. The addition of a base to the reaction medium makes it possible to improve the enantioselectivity of the oxidation reaction of the sulfide to sulfoxide. The process described in this patent makes it possible to obtain a mixture enriched in one or other of the (-) and (+) enantiomers, according to the ligand used. The above Kagan method and its variants allow enantioselectively obtaining sulfoxides having a benzimidazole type structure, such as omeprazole and its enantiomers. On the other hand, in the case of imidazo-pyridinyl sulfoxides, such as tenatoprazole, the low solubility of sulfides in conventional solvents such as toluene results in a heterogeneous reaction medium accompanied by a loss of selectivity and important formation of sulfone, of the order of 30%. In the series of compounds of the imidazo-pyridinyl type, there is also known from WO 2006/37894, a process for the enantioselective oxidation of a sulphide to sulphoxide which involves a chiral ligand constituted by a beta or gammaamino-cyclic alcohol, and a titanium catalyst. All of these methods, however, have the disadvantage of using metal catalysts, which can remain in the trace state in the final product. It therefore remains desirable to have a process which makes it possible to obtain enantiomers of sulphoxides having an imidazopyridinyl structure or a benzimidazole structure with a satisfactory enantiomeric excess, under good conditions of yield and purity, and which avoids the use of a metal catalyst. The work carried out by the applicant has made it possible to show that enantiomers of sulfoxide derivatives, and in particular tenatoprazole, omeprazole and sulphoxides of similar structure, can be prepared with an excellent enantiomeric excess and a satisfactory yield. by coupling of a chiral alcohol sulfinate and an organometallic compound. The subject of the present invention is therefore a process for the enantioselective preparation of sulphoxide derivatives having an asymmetry at the level of the sulfur atom, providing one or other of the enantiomers with good purity, an excellent enantiomeric excess and a yield. satisfactory. A particularly important object of the invention is a preparation method which substantially enantioselectively provides the enantiomer (-) and enantiomer (+) of tenatoprazole, as well as the enantiomers of omeprazole and other inhibiting sulfoxides of the protons with a benzimidazole or imidazo-pyridinyl structure. The term "substantially enantioselective" as used herein means that the desired enantiomer is obtained selectively or in a predominant amount relative to the other enantiomer. The enantiomeric excess is advantageously greater than 90%, and is preferably greater than 95%. By enantiomeric excess is meant the ratio of the excess of the desired enantiomer to the other enantiomer. Thus the enantiomeric (e.e.) excess of enantiomer S with respect to the R enantiomer can be expressed as: e.e. (S) = 100 x [(S) - (R)] / [(s) + (R)] where ee (S) is the enantiomeric S-enantiomeric excess (in percent), (S) is the concentration of enantiomer S and (R) the concentration of enantiomer R.

In accordance with the invention, enantioselective derivatives of sulfoxides of the following general formula (I) are prepared enantioselectively: A-SO-CH 2 -B (I) wherein A is a benzimidazole or imidazo-pyridyl ring, and B is a pyridyl ring, coupling a chiral sulfinate of general formula (II) hereinafter A- (SO) -OR (II) wherein A is defined as above and R is a chiral inducing group, said sulfinate being in the form of a diastereoisomer, with an organometallic compound of general formula (III) below B-CH2-Y (III) in which B is defined as above and Y represents an organolithium or organomagnesium radical such as MgCl, MgBr or Li. In the general formulas (I) and (II) above, the benzimidazole or imidazo-pyridyl ring represented by A may be substituted by one or more linear or branched alkyl groups of 1 to 6 atoms. of carbon, or linear or branched alkoxy of 1 to 6 carbon atoms, the alkyl and alkoxy groups may be substituted by one or more halogen atoms such as chlorine, bromine or fluorine. In general formulas (I) and (III) above, B may be a pyridyl ring or a pyridyl ring bearing one or more substituents selected from linear or branched alkyl groups of 1 to 6 carbon atoms, linear or branched alkoxy from 1 to 6 carbon atoms, the alkyl and alkoxy groups may be substituted by one or more halogen atoms such as chlorine, bromine or fluorine, or by a methoxy or ethoxy group. In particular, groups A and B are substituted on one or more carbon atoms by a methyl, ethyl, methoxy or fluoromethoxy group and, according to a preferred embodiment, A is a 1H-benzimidazolyl, 5-methoxy-1H-benzimidazolyl or 5-methoxy-imidazo [4,5-b] -pyridyl, and B is 4-methoxy-3,5-dimethyl-2-pyridyl, 3,4-dimethoxy-2-pyridyl or 3-methyl-4 -trifluoroéthoxy-2-pyridyl. For carrying out the process according to the invention, the chiral sulfinate (II) is preferably prepared by carrying out the following successive steps: a) conversion of a thiol of formula A-SH to sulfinyl halide of formula A - (SO) -X, X representing a halogen atom; b) bringing said sulfinyl halide into contact with a compound of formula R-OH and; c) crystallizing the compound obtained in step b) so as to obtain the desired sulfinate.

In one embodiment, the sulfinyl halide prepared in step a) above is a sulfinyl chloride, which can be obtained either by reacting said thiol with chlorine and acetic anhydride, or by reacting said thiol with sulfuryl chloride and an organic acid, for example acetic acid. The chiral moiety R of the sulfinate of formula (II) above is derived from the alcohol R-OH of step b) above. This chiral inducing alcohol may be constituted by any type of alcohol having a chiral center and capable of inducing a second point of chirality in the molecule of the diastereoisomeric sulfinate, so as to obtain a mixture of diastereomers separable by crystallization. Thus the next step of coupling sulfinate (II) and organometallic (III) is carried out with inversion of configuration on sulfur to achieve the desired chiral sulfoxide. The compound of formula R-OH used in step b) above is a chiral alcohol chosen preferably from (+) - menthol, (-) - menthol, 1,2,5,6-diisopropylidene -D- glucose (DAG) or 1,2,5,6-di-O-cyclohexylidene-D-glucose (DCG), with (+) - menthol being particularly preferred. The organometallic compound (III) used for carrying out the process according to the invention is preferably prepared by converting a compound of formula B-CH 2 OH into a compound of formula (V) B-CH 2 X, X being Cl or Br ( Mdcp), then conversion of the compound B-CH2X to a compound of formula (III), B being as defined above. The compound of formula (V) B-CH2X may also be prepared by the method described in patent EP 369,208.

According to one embodiment, the transformation of the compound B-CH2X (V) is carried out by quantitative reduction to obtain the intermediate compound B-CH3 (TMMP, formula (IV)), and the compound B-CH3 is then brought into the presence of butyl lithium to obtain a compound (III) in which Y = Li. According to another embodiment, the transformation of the compound B-CH2X (Mdcp, formula (V)) is carried out by reaction with magnesium, to obtain a compound of formula (III) wherein Y = MgCl or MgBr. The coupling reaction of the sulfinate of formula (II) with the organometallic of formula (III) is carried out under cold conditions, at a temperature below 0 ° C., preferably below -15 ° C. The organometallic is preferably used in excess of sulfinate, the ratio being preferably about 2 to 4 moles of organometallic per mole of sulfinate. The solvent is chosen from those having a crystallization point below the reaction temperature, excluding solvents such as protic solvents that are capable of reacting with the organometallic compound. Tetrahydrofuran is preferably used. The enantiomers of formula (I) obtained can be used in the form of salts, especially of alkali metal or alkaline earth metal salts, and for example in the form of sodium, potassium, lithium, magnesium or calcium salt. These salts can be obtained from the S or R enantiomer of the sulfoxide (I), by salification reaction according to a method common in the art, for example by the action of basic inorganic reagents comprising alkaline or alkaline earth counter-ions. . The (-) or (+) form of the enantiomers obtained can be determined by the optical rotation measurements according to the usual techniques. Thus, for example, the optical rotation angle of (-) - tenatoprazole is levorotatory in dimethylformamide, and its melting point is 130 ° C (decomposition). Although the (-) enantiomers of chiral sulfoxides most often have the S configuration, there is no direct correspondence between the configuration and the rotational power. The (S) and (R) enantiomers of sulfoxides such as tenatoprazole and omeprazole, in the treatment of the pathologies indicated below, can be administered in the usual forms adapted to the chosen mode of administration, for example orally or parenteral, preferably orally or intravenously. For example, formulations of tablets or capsules containing either one of the enantiomers as an active ingredient, or drinkable solutes or emulsions or solutions for parenteral administration containing a tenatoprazole or omeprazole salt with a conventional pharmaceutically acceptable carrier. The enantiomeric salt of the sulfoxide may be chosen for example from sodium, potassium, lithium, magnesium or calcium salts. The S and R enantiomers of the sulfoxides (I) obtained by the process of the present invention can be used in the manufacture of medicaments for the treatment of digestive pathologies, in particular those in which an inhibition of acid secretion must be intense and prolonged, for the treatment of gastroesophageal reflux symptoms and lesions, digestive haemorrhages resistant to other proton pump inhibitors. The dosage is determined by the practitioner according to the condition of the patient and the severity of the condition. It is generally between 10 and 120 mg, preferably between 20 and 80 mg, of enantiomer S or R of the sulfoxide (I) per day. The subject of the invention is also the compound of formula A- (SO) -OR (II), and the compound of formula B-CH 2 -Y (III), in which A and R, B and Y are as defined herein above, useful as synthesis intermediates of the product of formula (1). Examples of enantiomeric preparations are described below to illustrate the present invention. Examples 1 and 2 describe the synthesis of compounds of general formulas (V) and (IV) useful for the synthesis of compound (III) of formula B-CH2-Li. Examples 3 to 6 describe the synthesis of four different sulfinates of general formula (II).

Examples 7 and 8 respectively describe the synthesis of the (S) and (R) enantiomers of tenatoprazole, and Example 9 describes the synthesis of a sulfinate (II) type compound useful for the preparation of esomeprazole obtained according to US Pat. Example 10 Example 1 Preparation of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine (Mdcp) 32.7 g of 3,5-dimethyl-4-methoxy-2-pyridine methanol are solubilized in 45 ml of dichloromethane. 17 ml of thionyl chloride are added to the medium placed under an inert atmosphere and 1.5 h at 0-5 ° C and then transferred to 320 ml cooled to 0-5 ° C. The medium is stirred for 1.5 hours at room temperature. After water and neutralization to pH 7 with 25% aqueous sodium hydroxide, the medium is extracted with 3 times 100 ml of dichloromethane. The dichloromethane phases are dried over sodium sulphate and evaporated to dryness under vacuum. 32.4 g of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine in the form of crystals are obtained after initialization of the crystallization at 5 ° C. and vigorous stirring to avoid caking. Example 2 Preparation of 4-methoxy-2,3,5-trimethylpyridine (TMMP) 150 ml of anhydrous THF and 2.2 g of lithium aluminum hydride are placed in a tricolor under an inert atmosphere. The medium is cooled to 5 ° C - 10 ° C and a solution of 10 g of 2-chloromethyl-3,5-dimethyl-4-methoxy-pyridine in 200 mL of anhydrous THF is added. The medium is warmed to room temperature then brought to light reflux (60 ° C) for 1h30. The reaction medium is diluted with water and then with dichloromethane. After decantation, the organic phase is washed with a saturated aqueous sodium chloride solution, dried and then concentrated under reduced pressure. 6.5 g of 4-methoxy-2,3,5-trimethylpyridine are isolated after distillation of the residue.

Example 3 Preparation of 1,2,5,6-diisopropylidene-D-glucofuranose 5-methoxy-imidazo [4,5-b] pyridine-2-sulfinate (DAG) In a tricolor placed under an inert atmosphere, 15 g of methoxy-imidazo [4,5-b] pyridine-2-thiol are suspended in 150 ml of dichloromethane. 4.5 ml of acetic acid and 13.5 ml of sulfuryl chloride are added to the suspension. The reaction medium is kept under stirring at room temperature for 1 hour and then the solution is concentrated to dryness under reduced pressure. The dried intermediate sulfinyl chloride is diluted with 150 mL of THF and a solution of 10.8 g of 1,2,5,6-diisopropylidene-D-glucofuranose and 19.6 g of pyridine in 50 mL of THF is added to the solution. middle. The reaction medium is stirred for 20 hours at room temperature and then diluted with ethyl acetate. The organic phase is washed with an aqueous solution of sodium hydrogencarbonate and then with an aqueous solution of sodium chloride, dried and concentrated under reduced pressure.

The solid obtained is analyzed by HPLC coupled to a mass detector: demonstration of the expected sulfinate (molecular peak 455) mixed with the usual impurities. Example 4 Preparation of 1,2,5,6-dicyclohexylidene-D-glucofuranose 5-methoxy-imidazo [4,5-b] pyridine-2-sulfinate (DCG) In a tricolor placed under an inert atmosphere, 15 g of -methoxy-imidazo [4,5-b] pyridine-2-thiol are suspended in 150 mL of dichloromethane. 4.5 ml of acetic acid and 13.5 ml of sulfuryl chloride are added to the suspension. The reaction medium is stirred at room temperature for 1 hour and then the solution is concentrated to dryness under reduced pressure. The dried intermediate sulfinyl chloride is diluted with 150 mL of THF and a solution of 14.1 g of 1,2,5,6-dicyclohexylidene-D-glucofuranose and 19.6 g of pyridine in 50 mL of THF is added to the solution. middle. The reaction medium is stirred for 20 hours at room temperature and then diluted with ethyl acetate. The organic phase is washed with an aqueous solution of sodium hydrogencarbonate and then with an aqueous solution of sodium chloride, dried and concentrated under reduced pressure. The solid obtained at this stage is analyzed by HPLC coupled to a mass detector: demonstration of the expected sulfinate (molecular peak 535) mixed with the usual impurities.

EXAMPLE 5 Preparation of (+) -menthyl (R) -5-methoxy-imidazo [4,5-b] pyridine-2-sulfinate In 15 g of 5-methoxy-imidazo [4, 5 g. 5-b] pyridine-2-thiol are suspended in 150 mL of dichloromethane. 4.5 ml of acetic acid and 13.5 ml of sulfuryl chloride are added to the suspension. The reaction medium is stirred at room temperature for 1 hour and then the solution is concentrated to dryness under reduced pressure. The dried intermediate sulfinyl chloride is diluted with 150 mL of THF and a solution of 6.5 g of (+) menthol and 19.6 g of pyridine in 50 mL of THF is added to the medium. The reaction medium is stirred for 20 hours at room temperature and then diluted with ethyl acetate.

The organic phase is washed with an aqueous solution of sodium hydrogencarbonate and then with an aqueous solution of sodium chloride, dried and concentrated under reduced pressure. The solid obtained is re-precipitated with 3 times 100 ml of dichloromethane. After filtration, the dichloromethane phases are washed with an aqueous hydrochloric acid solution, dried and evaporated under reduced pressure. The residue obtained is sublimed under reduced pressure at 50 ° C. for 12 hours and then purified on a heptane / ethyl acetate 80/20 silica column. The product from the silica column is solubilized in 87.2 ml of dichloromethane. After addition of 209.3 ml of cyclohexane, the medium is kept at room temperature for 30 minutes until crystallization begins, and then cooled at 5 ° C. for 24 hours. The precipitate obtained is filtered, dried in an oven and solubilized in 62.4 ml of dichloromethane. After addition of 149.8 ml of cyclohexane, the medium is kept for 30 minutes at room temperature and then cooled at 5 ° C. for 24 hours. 1.2 g of (+) - menthyl (R) -5-methoxy-imidazo [4,5-b] pyridine-2-sulfinate with a diastereomeric excess of 95% are isolated after filtration and drying in an oven at 40 ° C. EXAMPLE 6 Preparation of (-) - menthyl (S) -5-methoxy-imidazo [4,5-b] pyridine-2-sulphinate In 15 g of 5-methoxy-imidazo [4] in a tricolor placed under an inert atmosphere 5-b] pyridine-2-thiol are suspended in 150 mL of dichloromethane. 4.5 ml of acetic acid and 13.5 ml of sulfuryl chloride are added to the suspension. The reaction medium is stirred at room temperature for 1 hour and then the solution is concentrated to dryness under reduced pressure. The dried intermediate sulfinyl chloride is diluted with 150 mL of THF and a solution of 6.5 g of (-) menthol and 19.6 g of pyridine in 50 mL of THF is added to the medium. The reaction medium is stirred for 20 hours at room temperature and then diluted with ethyl acetate. The organic phase is washed with an aqueous solution of sodium hydrogencarbonate and then with an aqueous solution of sodium chloride, dried and concentrated under reduced pressure.

The solid obtained is re-precipitated with 3 times 100 ml of dichloromethane. After filtration, the dichloromethane phases are washed with an aqueous hydrochloric acid solution, dried and evaporated under reduced pressure. The residue obtained is sublimed under reduced pressure at 50 ° C. for 12 hours and then purified on a heptane / ethyl acetate 80/20 silica column.

The product from the silica column is solubilized in 87.2 ml of dichloromethane. After addition of 209.3 ml of cyclohexane, the medium is kept at room temperature for 30 minutes until crystallization begins, and then cooled at 5 ° C. for 24 hours. The precipitate obtained is filtered, dried in an oven and solubilized in 62.4 ml of dichloromethane. After addition of 149.8 ml of cyclohexane, the medium is kept at ambient temperature for 30 minutes and then cooled at 5 ° C. for 24 hours. 1.2 g of (-) - menthyl (S) -5-methoxy-imidazo [4,5-b] pyridine-2-sulfinate with a diastereomeric excess of 95% are isolated after filtration and drying in an oven at 40 ° C. Example 7 Preparation of (S) -5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl} -1H-imidazo [4,5-b] pyridine, or S) -tenatoprazole In a tricolor placed under an inert atmosphere, 16.3 g of 4-methoxy-2,3,5-trimethyl-pyridine (TMMP), prepared according to the procedure described in Example 2, are diluted in 160 ml. mL of THF. The medium is cooled to -15 ° C. and then 55 ml of a 2M solution of butyl lithium in cyclohexane are added while maintaining the temperature. The medium is cooled to -40 ° C. and then a solution of 10 g of (R) -5-methoxy-imidazo [4,5-b] pyridine-2-sulfinate of (+) - menthyl, prepared according to the described procedure. in Example 5, 140 mL of THF is added. The medium is maintained at this temperature for 30 minutes. It is then diluted with a saturated solution of ammonium chloride and then with chloroform. After decantation, the organic phase is washed with a saturated solution of sodium chloride and then extracted with an aqueous sodium hydroxide solution. After decantation, the product precipitates by neutralization of the aqueous sodium hydroxide phase with an aqueous solution of hydrochloric acid. 7.1 g of (S) -5-methoxy-2 - {[4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl} -1H-imidazo [4,5-b] pyridine with excess enantiomeric 95% are obtained by filtration.

Example 8 Preparation of (R) -5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl} -1H-imidazo [4,5-b] pyridine, or ( R) Tenatoprazole In a tricolor placed under an inert atmosphere, 16.3 g of 4-methoxy-2,3,5-trimethylpyridine (TMMP), prepared according to the procedure described in Example 2, are diluted in 160 ml. mL of THF. The medium is cooled to -15 ° C. and then 55 ml of a 2M solution of butyl lithium in cyclohexane are added while maintaining the temperature. The medium is cooled to -40 ° C. and then a solution of 10 g of (-) - menthyl (S) -5-methoxyimidazo [4,5-b] pyridine-2-sulfinate, prepared according to the procedure described in US Pat. Example 6, in 140 mL of THF is added. The medium is maintained at this temperature for 30 minutes. It is then diluted with a saturated solution of ammonium chloride and then with chloroform. After decantation, the organic phase is washed with a saturated solution of sodium chloride and then extracted with an aqueous sodium hydroxide solution. After decantation, the product precipitates by neutralization of the aqueous sodium hydroxide phase with an aqueous solution of hydrochloric acid. 7.1 g of (R) -5-methoxy-2 - {[4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl} -1H-imidazo [4,5-b] pyridine with excess enantiomeric 95% are obtained by filtration.

Example 9 Preparation of (+) - menthyl 5-methoxybenzimidazole-2-sulfinate In a previously inerted tricol, 15 g of 5-methoxybenzimidazole-2-thiol are suspended in 150 ml of dichloromethane. 4.5 ml of acetic acid and 13.5 ml of sulfuryl chloride are added to the suspension. The reaction medium is stirred at room temperature for 1 hour and then the solution is concentrated to dryness under reduced pressure. The dried intermediate sulfinyl chloride is diluted with 150 mL of THF and a solution of 6.5 g of (+) menthol and 19.6 g of pyridine in 50 mL of THF is added to the medium. The reaction medium is stirred for 20 hours at room temperature and then diluted with ethyl acetate. The organic phase is washed with an aqueous solution of sodium hydrogencarbonate and then with an aqueous solution of sodium chloride, dried and concentrated under reduced pressure. The solid obtained at this stage is analyzed by HPLC coupled to a mass detector: demonstration of the expected sulfinate (molecular peak 350) mixed with the usual impurities. EXAMPLE 10 Preparation of (S) -5-methoxy-2 - {[4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl} -1H-benzimidazole (Esomeprazole) The procedure is as in Example 7. replacing (+) - menthyl (R) -5-methoxy-imidazo [4,5-b] pyridine-2-sulfinate with (+) - menthyl 5-methoxy-benzimidazole-2-sulfinate obtained in Example 9 above which is reacted with 4-methoxy-2,3,5-trimethylpyridine under the same reaction conditions.

There is thus obtained (S) -5-methoxy-2 - {[4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl} -1H-benzimidazole with an enantiomeric excess of 94%.

Claims (18)

claims A process for the enantioselective preparation of substituted derivatives of sulfoxides of the following general formula (I): A-SO-CH 2 -B (1) wherein A is a benzimidazole or imidazopyridyl ring, and B is a pyridyl ring, characterized in that it comprises coupling a chiral sulfinate of general formula (II) A- (SO) -OR (II) wherein R is a chirality-inducing group, said sulfinate being in the form of a diastereoisomer, with a organometallic compound of general formula (III) B-CH 2 -Y (III) wherein Y represents an organolithium or organomagnesium radical. 2. Method according to claim 1, characterized in that Y represents -MgCl, -MgBr or -Li. 3. Process according to claim 1, characterized in that A is substituted by one or more linear or branched alkyl groups of 1 to 6 carbon atoms, or linear or branched alkoxy of 1 to 6 carbon atoms, the alkyl and alkoxy groups. may be substituted by one or more halogen atoms. 4. Process according to claim 1, characterized in that B is a pyridyl ring or a pyridyl ring bearing one or more substituents chosen from linear or branched alkyl groups of 1 to 6 carbon atoms, linear or branched alkoxy groups of 1 to 6 carbon atoms, the alkyl and alkoxy groups may be substituted with one or more halogen atoms or with a methoxy or ethoxy group. 5. Process according to any one of the preceding claims, characterized in that A and B are substituted on one or more carbon atoms by a methyl, ethyl, methoxy or fluoromethoxy group. 6. Process according to claim 5, characterized in that A is 1H-benzimidazolyl, 5-methoxy-1H-benzimidazolyl or 5-methoxy-imidazo [4,5-b] pyridyl, and B is a group 4 -methoxy-3,5-dimethyl-2-pyridyl, 3,4-dimethoxy-2-pyridyl or 3-methyl-4-trifluoroethoxy-2-pyridyl. 7. Process according to any one of the preceding claims, characterized in that the chiral sulfinate (II) is prepared by carrying out the following successive stages: a) conversion of a thiol of formula A-SH into sulfinyl halide of formula A- (SO) -X, where X is a halogen atom; b) bringing said sulfinyl halide into contact with a compound of formula R-OH and; c) crystallization of the compound obtained in step b) to obtain the desired sulfinate. 15 8. Process according to claim 7, characterized in that said sulfinyl halide is a sulfinyl chloride. The process according to claim 8, characterized in that said sulfinyl chloride is obtained by reacting said thiol with chlorine and acetic anhydride. The process according to claim 8, characterized in that said sulfinyl chloride is obtained by reacting said thiol with sulfuryl chloride and an organic acid. 25 11. Process according to any one of claims 7 to 10, characterized in that the compound of formula R-OH is chosen from (+) - menthol, (-) - menthol, 1,2,5,6 diisopropylidene-D-glucose (DAG) or 1,2,5,6-di-O-cyclohexylidene-D-glucose (DCG). 30 12. Process according to any one of claims 1 to 6, characterized in that the organometallic compound (I: II) is prepared by conversion of the compound of formula B-CH 2 OH into a compound of formula B-CH 2 X, X being Cl or Br (Mdcp), then conversion of the compound B-CH2X compound of formula (III). 35 13. The method of claim 12, characterized in that the transformation of the compound B-CH2X is carried out by quantitative reduction to obtain the compound B-CH3 (TMMP), and in that the compound B-CH3 is brought into the presence of butyl lithium to obtain a compound (III) in which Y is Li. 14. The method of claim 11, characterized in that the transformation of the compound B-CH2X (Mdcp) is carried out by reaction with magnesium, to obtain a compound of formula (III) wherein Y is MgCl or MgBr. 15. Process according to any one of the preceding claims, characterized in that the enantiomer obtained is salified by the action of basic inorganic reagents comprising alkali or alkaline earth counter-ions. 16. The method of claim 15, characterized in that the salt is a salt of sodium, potassium, lithium, magnesium or calcium. 17. Compound of formula A- (SO) -OR (II), useful as a synthetic intermediate of the product of general formula (I) below. A-SO-CH 2 -B (I) A, B and R being as defined in claim 1. 18. Compound of formula B-CH 2 -Y (III), useful as a synthetic intermediate of the product of general formula (I) below. A-SO-CH 2 -B (I) A, B and Y being as defined in claim 1.