PROCESS FOR PREPARING SULFOXIDE COMPOUNDS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefits of Chinese application No. 2008100450250.5, filed on March 19, 2008, entitled "novel process for preparing sulfoxide compounds," which is explicitly incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention [0002] The present application is generally directed to a process for synthesis of sulfoxide compounds. In particular, the present application is directed to a catalytic oxidation process for enantioselective synthesis of chiral sulfoxide compounds as a single enantiomer or in an enantiomerically enriched form.

2. Description of the Related Art

[0003] Sulfoxide compounds of general formula I having the core structure of 2-[[(2-pyridyl)methylene]sulfinyl]-lH-benzimidazole can be used to inhibit the activity of H ⁺ , K ⁺ /ATPase (also known as proton pump) and therefore to inhibit the secretion of gastric acid. Such compounds have been extensively used to treat peptic ulcer (PU) caused by gastroxia, and the related diseases.

omeprazole: Ri=CH ₃ , R ₂ =OCH ₃ , R ₃ =CH ₃ , R ₄ = R ₆ = Rv=H, R ₅ =OCH ₃ lansoprazole: Ri=H, R ₂ =OCH ₂ CF ₃ , R ₃ =CH ₃ , R ₄ = R ₅ = R ₆ = R ₇ =H pantoprazole: Ri=H, R ₂ =OCH ₃ , R ₃ =OCH ₃ , R ₄ = R ₆ = R ₇ =H, R ₅ =OCHF ₂

[0004] The asymmetrically substituted sulfoxide compounds have a stereogenic center at the sulfur atom. The chirality of the compounds of general formula I is therefore represented by the sulfur atom. [0005] In fact, these compounds have two kinds of single enantiomers, i.e. levo-(-)-isomer and dextro-(+)-isomer, or S -configuration and R-configuration. Earlier studies demonstrate that S-(-)-omeprazole has better clinical effects than the others and therefore

becomes the first commercially available chiral proton pump inhibitor among this kind of compounds.

[0006] Up to now, such compounds have been manufactured in industry by oxidizing the corresponding thioether compounds. For example, a racemic mixture is obtained with a commonly used oxidation process, while a product as a single enantiomer or in an enantiomerically enriched form is obtained with a special oxidation process (e.g. using chiral reagents in the process).

[0007] International patent applications WO 92/08716 and WO 94/27988 disclose a method for separating pyridylmethylsulfinyl-lH-benzimidazole into single enantiomers. The method involves a chemical process to introduce a chiral group into the compounds to produce stereo-discrepancy in the original racemate. The compounds are then separated and purified. After dissociating the introduced chiral group, sulfoxide chiral proton pump inhibitors as single enantiomers are obtained.

[0008] International patent application WO 91/12221 discloses a process for direct resolution of racemic omeprazole into single enantiomers by a cellulose enzyme immobilized on a carrier of silica gel.

[0009] International patent applications WO 96/17076 and WO 96/17077 disclose processes for preparing sulfoxide compounds as single enantiomers by selective oxidation of sulphides and selective reduction of sulfones, respectively. [0010] Chinese patent No. 98124029.1 discloses a process to prepare an anti-peptic ulcer (PU) medicament of optically pure benzimidazoles by inclusion resolution. Chinese patent No. 00113036.6 discloses a process to prepare an optically pure lansoprazole by inclusion resolution. Chinese patent No. 03135164.6 discloses a process for preparing an optically pure neutral S-(-)- and R-(+)-omeprazole. [0011] Chinese patent application No. 200510049387.0 discloses a process for separating omeprazole enantiomers by simulated moving bed chromatography.

[0012] International patent application WO 96/02535 discloses an enantioselective process for oxiding thioethers to sulfoxides in the presence of (+)- or (-)-diethyl tartrate and titanium (IV) isopropoxide. (-)- and (+)-omeprazole, (-)- and (+)-lansoprazole, (-)- and (+)-pantoprazole and (-)- and (+)-rabeprazole are prepared by this process.

[0013] International patent application WO 2004/052881 discloses a process for preparing S-pantoprazole in the presence of (-)- and (+)-tartaric acid derivatives and zirconium (IV) alkoxide or hafnium (IV) alkoxide.

[0014] Chinese patent application No. 200610023955.4 discloses a process for preparing S-(-)-omeprazole with a titanium-comprising catalyst obtained in situ from titanium metal and a chiral diol ligand. Chinese patent application No. 200710010273.4 discloses a

process for preparing S-omeprazole, S-lansoprazole, S-pantoprazole, S-rabeprazole and S-tenatoprazole with a metallic catalyst obtained in situ from titanium (IV) alkoxide or zirconium (IV) alkoxide and a chiral aminoalcohol ligand.

[0015] The enantioselective oxidation process exhibits obvious advantages over the resolution process, in which the utilization ratio of starting materials is low. Therefore, it is quite meaningful to further investigate the enantioselective oxidation process. The differences among the chiral catalytic systems disclosed in the prior art mainly reside in chiral ligands, as shown in the international patent application WO 96/02535 and the Chinese patent application Nos. 200610023955.4 and 200710010273.4. [0016] Though D- or L-tartaric acid diamide compounds belong to chiral diol compounds, a low enantioselectivity (1.6% ee) was reported earlier for the oxidation of thioethers with a complex of titanium (IV) in which the ligand is chiral tartaric acid diamide compounds (P. Pitchen, E. Duiiach, M. N. Deshmukh, H. K. Kagan /. Am. Chem. Soc. 1984, 106, 8188-8193). The prior art neither discloses a process for preparing 2-[[(2-pyridyl)methylene]sulfinyl]-lH-benzimidazole as a single enantiomer with a titanium complex of chiral (-)- or (+)-tartaric acid diamide compounds as a catalyst, nor discloses an enantioselective process for catalytic oxidization of thioethers with (-)- or (+)-tartaric acid di(mono-substituted amide) compounds.

SUMMARY OF THE INVENTION

[0017] In a first aspect, the present application is directed to a process for preparing a chiral sulfoxide compound of general formula I as a single enantiomer or in an enantiomerically enriched form

wherein

R ¹ , R ² and R ³ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkynyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkoxycarbonyl, optionally substituted alkylcarbonyl, optionally

substituted alkylamino, optionally substituted dialkylamino, optionally substituted cycloalkoxy, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, halogen, haloalkyl, cyano, nitro and hydroxy,

R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkynyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkoxycarbonyl, optionally substituted alkylcarbonyl, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted cycloalkoxy, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, halogen, haloalkyl, cyano, nitro and hydroxy, the process comprises the step of oxidation of a thioether of general formula II

wherein R , 1 , τ R-> 2 , τ R-> 3 , τ R-> 4 , τ R-> 5 , τ R"> 6 τ R-) 7 are as defined above,

with a peroxide in an organic solvent and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV and a compound of a transition metal

1

III IV

wherein R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, organic polymer and silica supported carrier.

[0018] In a second aspect, the present application is directed to S-(-)-levo-omeprazole, S-(-)-levo-pantoprazole and S-(-)-levo-lansoprazole prepared by a process for preparing a chiral sulfoxide compound of general formula I as a single enantiomer or in an enantiomerically enriched form

wherein

R ¹ , R ² and R ³ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkynyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkoxycarbonyl, optionally substituted alkylcarbonyl, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted cycloalkoxy, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, halogen, haloalkyl, cyano, nitro and hydroxy,

R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkynyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkoxycarbonyl, optionally substituted alkylcarbonyl, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted cycloalkoxy, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, halogen, haloalkyl, cyano, nitro and hydroxy, the process comprises the step of oxidation of a thioether of general formula II

wherein R , 1 , τ R-> 2 , τ R-> 3 , τ R-> 4 , τ R-> 5 , r R> 6 a „„nd1 τ R-> 7 are as defined above,

with a peroxide in an organic solvent and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV and a compound of a transition metal

1

III IV

wherein R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, organic polymer and silica supported carrier.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0019] In the following description, certain specific details are included to provide a thorough understanding of various disclosed embodiments. One skilled in the relevant art, however, will recognize that embodiments may be practiced without one or more of these specific details, or with other methods, components, materials, etc.

[0020] Unless the context requires otherwise, throughout the specification and claims which follow, the word "comprise" and variations thereof, such as, "comprises" and "comprising" are to be construed in an open, inclusive sense, which is as "including, but not limited to". [0021] Reference throughout this specification to "one embodiment", or "an embodiment", or "another embodiment", or "some embodiments", means that a particularly referred feature, structure, or characteristic described in connection with the embodiment is

included in at least one embodiment. Thus, the appearance of the phrases "in one embodiment", or "in an embodiment", or "in another embodiment", or "in some embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0022] It should be noted that, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the content clearly dictates otherwise. In this application, the use of "or" means "and/or" unless stated otherwise.

[0023] Certain chemical groups named herein are preceded by a shorthand notation indicating the total number of carbon atoms that are to be found in the indicated chemical group. For example, C7-C12 alkyl describes an alkyl group, as defined below, having a total of 7 to 12 carbon atoms, and C ₄ -C ₁₂ cycloalkylalkyl describes a cycloalkylalkyl group, as defined below, having a total of 4 to 12 carbon atoms. The total number of carbons in the shorthand notation does not include carbons that may exist in substituents of the group described. [0024] As used herein, "C _m to C _n " or "C _{m t0 n} " in which "m" and "n" are integers refers to the number of carbon atoms in an alkyl, alkenyl or alkynyl group or the number of carbon atoms in the ring of a cycloalkyl or cycloalkenyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl or ring of the cycloalkenyl can contain from "m" to "n", inclusive, carbon atoms. Thus, for example, a "Ci to C ₄ alkyl" group refers to all alkyl groups having from 1 to 4 carbons, i.e. CH ₃ -, CH ₃ CH ₂ -, CH ₃ CH ₂ CH ₂ -, (CH ₃ ) ₂ CH-, CH ₃ CH ₂ CH ₂ CH ₂ -, CH ₃ CH ₂ CH(CH ₃ )- and (CH ₃ ) ₃ C-. Where no "m" and "n" are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl group, the broadest range described in these definitions is to be assumed.

[0025] Accordingly, as used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated:

[0026] The term "alkyl" as used herein alone or as part of a group means any unbranched or branched, substituted or unsubstituted, saturated hydrocarbon chain redical. The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; e.g., "1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl" where no numerical range is designated). The alkyl group may also be a medium sized alkyl having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 5 carbon atoms. The alkyl group may be designated as "Ci-C ₄ alkyl" or similar designations. By way of example only, "Ci-C ₄ alkyl" indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl,

/sopropyl, w-butyl, iso-butyi, sec-butyl, and £-butyl.

[0027] The alkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is(are) one or more group(s) individually and independently selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted cylcloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryloxy, heterocyclyl, heterocyclooxy, heteroalicyclyl, hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted aryloxy, acyl, thiol, substituted or unsubstituted thioalkoxy, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, acylalkyl, acylamino, acyloxy, aminoacyl, aminoacyloxy, oxyacylamino, keto, thioketo, O-carbamyl, JV-carbamyl, O-thiocarbamyl, λMMocarbamyl, C-amido, iV-amido, 5-sulfonamido, iV-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and substituted or unsubstituted amino, including mono- and di-substituted amino groups and the protected derivatives thereof, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO ₂ -alkyl, -SO ₂ -substituted alkyl, -SO ₂ -aryl and -SO ₂ -heteroaryl.

[0028] Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Wherever a substituent is described as being "optionally substituted" that substitutent may or may not be substituted with one of the above substituents.

[0029] The term "alkenyl" as used herein alone or as part of a group refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, having from two to twelve carbon atoms, preferably one to eight carbon atoms and which is attached to the rest of the molecule by a single bond, e.g., ethenyl, prop- 1 -enyl, but- 1 -enyl, pent- 1 -enyl, penta- 1 ,4-dienyl, and the like.

[0030] The term "alkynyl" as used herein alone or as part of a group refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to twelve carbon atoms, preferably one to eight carbon atoms and which is attached to the rest of the molecule by a single bond, e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0031] The term "alkylene" or "alkylene chain" as used herein alone or as part of a group refers to a straight or branched divalent hydrocarbon chain linking a radical group to the rest of the molecule, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, e.g., methylene, ethylene, propylene, w-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest

of the molecule and to the radical group can be through one carbon or any two carbons within the chain.

[0032] The term "alkenylene" or "alkenylene chain" as used herein alone or as part of a group refers to a straight or branched divalent hydrocarbon chain linking a radical group to the rest of the molecule, consisting solely of carbon and hydrogen, containing at least one double bond and having from two to twelve carbon atoms, e.g., ethenylene, propenylene, w-butenylene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.

[0033] The term "alkynylene" or "alkynylene chain" as used herein alone or as part of a group refers to a straight or branched divalent hydrocarbon chain linking a radical group to the rest of the molecule, consisting solely of carbon and hydrogen, containing at least one triple bond and having from two to twelve carbon atoms, e.g., propynylene, w-butynylene, and the like. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a double bond or a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.

[0034] The term "cycloalkyl" as used herein alone or as part of a group refers to a completely saturated (no double bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion. Cycloalkyl groups of this application may range from C3 to C ₁₀ . In other embodiments, it may range from C3 to C ₆ . A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. When substituted, the substituent(s) may be an alkyl or selected from those indicated above with regard to alkyl group substitution unless otherwise indicated.

[0035] The term "cycloalkenyl" as used herein alone or as part of a group refers to a cycloalkyl group that contains one or more double bonds in the ring although, where there is more than one, they cannot form a fully de localized pi-electron system in the ring (otherwise the group would be "aryl", as defined herein). When composed of two or more rings, the rings may be connetected together in a fused, bridged or spiro-connected fashion. A cycloalkenyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be an alkyl or selected from the groups disclosed above with regard to alkyl group substitution unless otherwise indicated.

[0036] The term "cycloalkynyl" as used herein alone or as part of a group refers to a

cycloalkyl group that contains one or more triple bonds in the ring. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion. A cycloalkynyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be an alkyl or selected from the groups disclosed above with regard to alkyl group substitution unless otherwise indicated.

[0037] The term "carbonyl" as used herein alone or as part of a group refers to the group -(C=O)-.

[0038] The term "alkoxy" as used herein alone or as part of a group refers to the group -O-alkyl, in which the alkyl group is as defined above. Preferred alkoxy groups are methoxy, ethoxy, isopropoxy, ^-butoxy or pentoxy group.

[0039] The term "alkylamino" as used herein alone or as part of a group refers to the group -NH-alkyl, in which the alkyl group is as defined above.

[0040] The term "dialkylamino" herein alone or as part of a group refers to the group -N(alkyl)2, in which the alkyl group is as defined above and may be the same or different. [0041] The term "alkylcarbonyl" as used herein alone or as part of a group refers to an alkyl group, as defined above, bonded to the rest of the molecule through a carbonyl group.

[0042] The term "alkoxycarbonyl" as used herein alone or as part of a group refers to an alkoxy group, as defined above, bonded to the rest of the molecule through a carbonyl group.

[0043] The term "dialkylaminocarbonyl" as used herein alone or as part of a group refers to a dialkylamino group, as defined above, bonded to the rest of the molecule through a carbonyl group.

[0044] The term "alkylaminocarbonyl" as used herein alone or as part of a group refers to an alkylamino group, as defined above, bonded to the rest of the molecule through a carbonyl group. [0045] The term "cycloalkoxy" as used herein alone or as part of a group refers to any non-aromatic hydrocarbon ring, preferably having five to twelve atoms comprising the ring, bonded to the rest of the molecule through an oxygen atom.

[0046] The term "halo" or "halogen" as used herein alone or as part of a group refers to bromo, chloro, fluoro or iodo. [0047] The term "haloalkyl" as used herein alone or as part of a group refers to an alkyl group, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, l-bromomethyl-2-bromoethyl, and the like. The alkyl part of the haloalkyl radical may be optionally substituted as defined above for an alkyl group.

[0048] The term "trihaloalkyl" as used herein alone or as part of a group refers to an

alkyl radical, as defined above, which is substituted by three halo radicals, as defined above, e.g., trifluoromethyl. The alkyl part of the trihaloalkyl radical may be optionally substituted as defined above for an alkyl group.

[0049] The term "haloalkoxy" as used herein alone or as part of a group refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethoxy, difluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, l-fluoromethyl-2-fluoroethoxy, 3-bromo-2-fluoropropoxy, l-bromomethyl-2-bromoethoxy, and the like. The alkyl part of the haloalkoxy radical may be optionally substituted as defined above for an alkyl group. [0050] The term "trihaloalkoxy" as used herein, refers to a radical of an alkoxy group as defined above, which is substituted by three halo radicals, as defined above. The trihaloalkyl part of the trihaloalkoxy group may be optionally substituted as defined above for a trihaloalkyl group.

[0051] The term "heterocyclyl" as used herein alone or as part of a group is intended to mean three-, four-, five-, six-, seven-, and eight- or more membered rings wherein carbon atoms together with from 1 to 3 heteroatoms constitute the ring. A heterocyclyl can optionally contain one or more unsaturated bonds situated in such a way, however, that an aromatic ^/-electron system does not arise. The heteroatoms are independently selected from oxygen, sulfur, or nitrogen. [0052] A heterocyclyl can further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, and the like.

[0053] Heterocyclyl rings can optionally be fused ring systems containing two or more rings wherein at least one atom is shared between two or more rings to form bicyclic or tricyclic structures. In some embodiments, such fused ring systems are formed by a bridging moiety between two atoms of a heterocyclyl.

[0054] Heterocyclyl rings can optionally also be fused to aryl rings, such that the definition includes bicyclic structures. Typically such fused heterocyclyl groups share one bond with an optionally substituted benzene ring. Examples of benzo-fused heterocyclyl groups include, but are not limited to, benzimidazolidinone, tetrahydroquinoline, and methylenedioxybenzene ring structures.

[0055] Examples of "heterocyclyls" include, but are not limited to, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1 ,4-oxathiin, 1,4-oxathiane, tetrahydro- 1 ,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-l,3,5-triazine, tetrahydrothiophene,

tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidine, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, 1,3-oxathiolane, and an azabicyclo system such as azabicyclo[3.2.1]octyl (tropane). Binding to the heterocycle can be at the position of a heteroatom or via a carbon atom of the heterocycle, or, for benzo-fused derivatives, via a carbon of the benzenoid ring.

[0056] The term "aromatic" as used herein refers to an aromatic group which has at least one ring having a conjugated /?/ electron system and includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.

[0057] The term "carbocyclic" as used herein refers to a compound which contains one or more covalently closed ring structures, and the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from heterocyclic rings in which the ring backbone contains at least one atom which is different from carbon. The term "heteroaromatic" as used herein, refers to an aromatic group which contains at least one heterocyclic ring.

[0058] The term "aryl" as used herein alone or as part of a group is intended to mean a carbocyclic aromatic ring or ring system. Moreover, the term "aryl" includes fused ring systems wherein at least two aryl rings, or at least one aryl and at least one C ₃ _ ₈ -cycloalkyl sharing at least one chemical bond. Examples of "aryl" rings include optionally substituted phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl.

[0059] The term "aryl" relates to aromatic, including, for example, benzenoid groups, connected via one of the ring-forming carbon atoms, and optionally carrying one or more substituents selected from heterocyclyl, heteroaryl, halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, Ci_6-alkoxy, Ci_6-alkyl, Ci_6-hydroxyalkyl, Ci_6-aminoalkyl, Ci_6-alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. The aryl group can be substituted at the ortho- and/or para- and/or meta- positions. Representative examples of aryl groups include, but are not limited to, phenyl, 3-halophenyl, 4-halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl, 4-aminophenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl, trifluoromethylphenyl, alkoxyphenyl, 4-morpholin-4-ylphenyl, 4-pyrrolidin-l-ylphenyl, 4-pyrazolylphenyl, 4-triazolylphenyl, and 4-(2-oxopyrrolidin-l-yl)phenyl.

[0060] The term "arylalkyl" or "aralkyl" as used herein alone or as part of a group which can be used synonymously and interchangeably refers to an aryl group covalently bonded to an alkyl group, as defined herein. A "phenylalkyl" is a species of an aralkyl group, and refers

to a phenyl ring covalently bonded to an alkyl group as defined herein. Examples of phenylalkyl groups include, but are not limited to, benzyl, 2-phenylethyl, 1-phenylpropyl, 4-phenylhexyl, 3-phenylamyl and 3-phenyl-2-methylpropyl. Presently preferred phenylalkyl groups are those wherein the phenyl group is covalently bonded to one of the presently preferred alkyl groups. A phenylalkyl group of this invention may be unsubstituted or substituted. Examples of substituted phenylalkyl groups include, but are not limited to, 2-phenyl-l-chloroethyl, 2-(4-methoxyphenyl)ethyl, 4-(2,6-dihydroxyphenyl)hexyl, 2-(5-cyano-3-methoxyphenyl)pentyl, 3-(2,6-dimethylphenyl)propyl, 4-chloro-3-aminobenzyl,

6-(4-methoxyphenyl)-3-carboxy(w-hexyl), 5-(4-aminomethylphenyl)-3-(aminomethyl)pentyl and 5-phenyl-3-oxo-pent-l-yl.

[0061] The term "heteroaryl" as used herein alone or as part of a group is intended to mean a heterocyclic aromatic group where one or more carbon atoms in an aromatic ring have been replaced with one or more heteroatoms selected from the group comprising nitrogen, sulfur, and oxygen. [0062] Furthermore, in the present context, the term "heteroaryl" comprises fused ring systems wherein at least one aryl ring and at least one heteroaryl ring, at least two heteroaryl rings, at least one heteroaryl ring and at least one heterocyclyl ring, or at least one heteroaryl ring and at least one cycloalkyl ring sharing at least one chemical bond.

[0063] The term "heteroaryl" is understood to relate to aromatic, Cs_8 cyclic groups further containing one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom with up to two nitrogen atoms, and their substituted as well as benzo- and pyrido-fused derivatives, for example, connected via one of the ring-forming carbon atoms. Heteroaryl groups can carry one or more substituents selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, Ci_ ₆ -alkoxy, Ci_ ₆ -alkyl, Ci_ ₆ -hydroxyalkyl, Ci_ ₆ -aminoalkyl, Ci_ ₆ -alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. In some embodiments, heteroaryl groups can be five- or six-membered aromatic heterocyclic systems carrying 0, 1, or 2 substituents, which can be independently selected from the list above.

[0064] Representative examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quionoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline, and quinoxaline. In some embodiments, the substituents are halo, hydroxy, cyano, O-Ci_6-alkyl, Ci_6-alkyl, hydroxy-Ci_ ₆ -alkyl, and amino-Ci_ ₆ -alkyl.

[0065] The term "phenyl" as used herein alone or as part of a group refers to a six-membered aryl group. A phenyl group may be unsubstituted or substituted. When substituted the substituent(s) is(are) one or more, preferably one or two, group(s) independently selected from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, -NRR', carboxamide, protected carboxamide, JV-alkylcarboxamide, protected JV-alkylcarboxamide, JV,./V-dialkylcarboxamide, trifluoromethyl, JV-alkylsulfonylamino, JV-(phenylsulfonyl)amino and phenyl (resulting in the formation of a biphenyl group). [0066] Examples of substituted phenyl groups include, but are not limited to, 2-, 3- or

4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2-, 3- or 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected hydroxy derivatives thereof, 2-, 3- or 4-nitrophenyl; 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-methylphenyl, 2,4-dimethylphenyl, 2-, 3- or 4-(iso-propyl)phenyl, 2-, 3- or 4-ethylphenyl, 2-, 3- or 4-(w-propyl)phenyl, 2,6-dimethoxyphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 2-, 3- or 4-(isopropoxy)phenyl, 2-, 3- or 4-(/-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or 4-carboxyphenyl or 2,4-di(protected carboxy)phenyl, 2-, 3-, or 4-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl, 2-, 3- or 4-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl, and 2-, 3- or 4-(N-(methylsulfonylamino))phenyl.

[0067] The term "phenylalkoxy" as used herein alone or as part of a group refers to a "phenylalkyl-O-" group with "phenylalkyl" as defined herein. A phenylalkoxy group of this invention may be substituted or unsubstituted on the phenyl ring, in the alkyl group or both. Examples of phenylalkoxy groups include, but are not limited to, 2-(4-hydroxyphenyl)ethoxy, 4-(4-methoxyphenyl)butoxy, (2i?)-3-phenyl-2-amino-propoxy, (2S)-3-phenyl-2-amino-propoxy, 2-indanoxy, 6-phenyl-l-hexanoxy, cinnamyloxy, 2-phenyl-l-propoxy and

2,2-dimethyl-3-phenyl- 1 -propoxy.

[0068] The term "alkylthio" as used herein alone or as part of a group refers to an "alkyl-S-" group, with alkyl as defined above. Examples of alkylthio group include, but are not limited to, methylthio, ethylthio, w-propylthio, isopropylthio, w-butylthio and ^-butylthio.

[0069] The term "alkylsulfmyl" as used herein alone or as part of a group refers to an "alkyl-SO-" group, with alkyl as defined above. Examples of alkylsulfinyl groups include, but are not limited to, methylsulfmyl, ethylsulfinyl, w-propylsulfmyl, isopropylsulfmyl, w-butylsulfinyl and seobutylsulfinyl. [0070] The term "alkylsulfonyl" as used herein alone or as part of a group refers to an

"alkyl-SO ₂ -" group. Examples of alkylsulfonyl groups include, but are not limited to,

methylsulfonyl, ethylsulfonyl, w-propylsulfonyl, isopropylsulfonyl, w-butylsulfonyl, and /-butylsulfonyl.

[0071] The terms "phenylthio", "phenylsulfϊnyl", and "phenylsulfonyl" as used herein alone or as part of a group refer to a "phenyl-S-", "phenyl-SO-", and "phenyl-SO2-" group, phenyl as defined herein.

[0072] The term "amino" as used herein alone or as part of a group refers to the -NH ₂ radical.

[0073] The term "cyano" as used herein alone or as part of a group refers to the -CN radical. [0074] The term "hydroxy" as used herein alone or as part of a group refers to the -OH radical.

[0075] The term "imino" as used herein alone or as part of a group refers to the =NH substituent.

[0076] The term "nitro" as used herein alone or as part of a group refers to the -NO ₂ radical.

[0077] The term "oxo" as used herein alone or as part of a group refers to the =0 substituent.

[0078] The term "thioxo" as used herein alone or as part of a group refers to the =S substituent. [0079] The term "trifluoromethyl" as used herein alone or as part of a group refers to the -CF ₃ radical.

[0080] The term "optional" or "optionally" as used herein means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. [0081] Unless otherwise indicated, when a substituent is deemed to be "optionally substituted", it is meant that the substituent is a group that may or may not be substituted with one or more group(s) individually and independently selected from morpholinoalkanoate, cycloalkyl, aryl, heteroaryl, heterocyclyl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, JV-carbamyl, O-thiocarbamyl, JV-thiocarbamyl, C-amido, iV-amido, S-sulfonamido, iV-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono- and di-substituted amino groups and the protected derivatives thereof.

[0082] For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and unsubstituted aryl radicals.

[0083] The term "enantiomer" or "enantiomeric" as used herein refers to a molecule

that is nonsuperimposeable on its mirror image and hence optically active where the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction.

[0084] The term "racemic" or "racemate" as used herein refers to a mixture of equal parts of enantiomers which is optically inactive.

[0085] The term "resolution" as used herein refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.

[0086] Optically active (R)- and (S)-isomers and d- and /- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Where, for instance, a particular enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as an amino group, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequently the pure enantiomers can be recovered. In addition, separation of enantiomers and diastereomers is frequently accomplished using chromatography employing chiral stationary phases, optionally in combination with chemical derivatization {e.g., formation of carbamates from amines).

[0087] The term "chiral", "enantiomerically enriched" or "diastereomerically enriched" as used herein, refers to a compound having an enantiomeric excess (ee) or a diastereomeric excess (de) of greater than about 50%, preferably greater than about 70% and more preferably greater than about 90%. In general, enantiomeric or diastereomeric excess of higher than about 90% is particularly preferred, e.g., those compositions with greater than about 95%, greater than about 97% and greater than about 99% ee or de.

[0088] The terms "enantiomeric excess" and "diastereomeric excess" are used interchangeably herein. Compounds with a single stereocenter are referred to as being present in "enantiomeric excess"; those with at least two stereocenters are referred to as being present in "diastereomeric excess".

[0089] The term "enantiomeric excess" is well known in the art and is defined as:

[0090] The term "enantiomeric excess" is related to the older term "optical purity" in that both are measures of the same phenomenon. The value of ee will be a number from 0 to 100,

zero being racemic and 100 being enantiomerically pure. A compound which in the past might have been called 98% optically pure is now more precisely characterized by 96% ee. A 90% ee reflects the presence of 95% of one enantiomer and 5% of the other(s) in the material in question. [0091] The term "transition metal" as used herein refers to any element in the <i-block of the periodic table of the elements. This corresponds to groups 3 (IIIB) to 12 (HB) on the periodic table.

[0092] The term "ligand" in chemistry generally refers to an atom, ion, or molecule that bonds to a central metal, generally involving formal donation of one or more of its electrons. The metal-ligand bonding ranges from covalent to more ionic.

[0093] The term "bidentate ligand" as used herein refers to Lewis bases that donate two pairs ("bi") of electrons to a metal atom. A bidentate ligand is often referred to as a chelating ligand ("chelate" is derived from the Greek word for "claw") because it can "grab" a metal atom in two places.

EMBODIMENTS OF THE INVENTION

[0094] In one aspect, the present application is directed to a process for preparing a chiral sulfoxide compound of general formula I as a single enantiomer or in an enantiomerically enriched form

wherein

R ¹ , R ² and R ³ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkynyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkoxycarbonyl, optionally substituted alkylcarbonyl, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted cycloalkoxy, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, halogen, haloalkyl, cyano, nitro and hydroxy,

R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkynyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkoxycarbonyl, optionally substituted alkylcarbonyl, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted cycloalkoxy, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, halogen, haloalkyl, cyano, nitro and hydroxy, the process comprises the step of oxidation of a thioether of general formula II

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above,

with a peroxide in an organic solvent and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV and a compound of a transition metal

1

III IV

wherein R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, organic polymers and silica supported carriers.

[0095] In some embodiments of the present application, R ¹ , R ² and R ³ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted dialkylamino, optionally substituted heterocyclyl, optionally substituted aryl, optionally

substituted arylalkyl, optionally substituted arylalkoxy, halogen, cyano, nitro and hydroxyl.

[0096] In some embodiments of the present application, R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkoxycarbonyl, optionally substituted alkylcarbonyl, optionally substituted heterocyclyl, halogen, haloalkyl, cyano, nitro and hydroxyl.

[0097] In some preferred embodiments of the present application, R ¹ is hydrogen.

[0098] In some preferred embodiments of the present application, R ¹ is methyl.

[0099] In some preferred embodiments of the present application, R ² is methoxyl.

[0100] In some preferred embodiments of the present application, R ² is trifluoroethoxyl.

[0101] In some preferred embodiments of the present application, R ³ is methyl.

[0102] In some preferred embodiments of the present application, R ³ is methoxyl.

[0103] In some preferred embodiments of the present application, R ⁴ is hydrogen.

[0104] In some preferred embodiments of the present application, R ⁵ is hydrogen. [0105] In some preferred embodiments of the present application, R ⁵ is methoxyl.

[0106] In some preferred embodiments of the present application, R ⁵ is difluoromethoxyl.

[0107] In some preferred embodiments of the present application, R ⁶ is hydrogen.

[0108] In some preferred embodiments of the present application, R ⁷ is hydrogen. [0109] In some embodiments of the present application, R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, organic polymers and silica supported carriers. [0110] In some preferred embodiments of the present application, a chiral bidentate ligand of general formula III is used to prepare a chiral complex with a compound of a transition metal,

III

wherein R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally optionally substituted arylalkyl, organic polymers and

silica supported carriers.

[0111] In some more preferred embodiments of the present application, a chiral bidentate ligand of general formula III is an (R,R)- or (S,S)-isomer in optically pure form, wherein R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted arylalkyl, organic polymers and silica supported carriers.

[0112] In some preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with a peroxide is carried out in an organic solvent and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III of an (R,R)- or (S,S)-isomer in optically pure form and a compound of a transition metal.

[0113] In some preferred embodiments of the present application, a chiral bidentate ligand of general formula IV is used to prepare a chiral complex with a compound of a transition metal,

IV

wherein R ⁹ and R ¹¹ are independently selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, organic polymers and silica supported carriers.

[0114] In some more preferred embodiments of the present application, a chiral bidentate ligand of general formula IV is an (R,R)- or (S,S)-isomer in optically pure form, wherein R ⁹ and R ¹¹ are independently selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted arylalkyl, organic polymers and silica supported carriers.

[0115] In some preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with a peroxide is carried out in an organic solvent and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula IV of an (R,R)- or (S,S)-isomer in optically pure form and a compound of a transition metal. [0116] In some embodiments of the present application, a transition metal that can be used includes, but is not limited to, an atom of Group 4 (IVB) through Group 5 (VB) in the periodic table of the elements.

[0117] In some embodiments of the present application, a transition metal that can be

used includes, but is not limited to, titanium (Ti), zirconium (Zr), hafnium (Hf) and vanadium

(V).

[0118] In some embodiments of the present application, a compound of a transition metal that can be used includes, but is not limited to, an alkoxide of a transition metal and the like.

[0119] In some preferred embodiments of the present application, an alkoxide of a transition metal includes, but is not limited titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) propoxide, titanium (IV) isopropoxide, zirconium (IV) methoxide, zirconium (IV) ethoxide, zirconium (IV) propoxide, zirconium (IV) isopropoxide, hafnium (IV) methoxide, hafnium (IV) ethoxide, hafnium (IV) propoxide, hafnium (IV) isopropoxide, vanadium (V) methoxide, vanadium (V) ethoxide, vanadium (V) propoxide and vanadium (V) isopropoxide.

[0120] In some more preferred embodiments of the present application, a titanium (IV) alkoxide includes, but is not limited to titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) propoxide, and titanium (IV) isopropoxide. [0121] In some even more preferred embodiments of the present application, the compound of the transition metal is titanium (IV) isopropoxide.

[0122] In some preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with a peroxide is carried out in an organic solvent and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV and a compound of a transition metal of Group 4 (IVB) or Group 5 (VB).

[0123] In some preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with a peroxide is carried out in an organic solvent and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV of an (R,R)- or (S,S)-isomer in optically pure form and titanium (IV) alkoxide. [0124] In some preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with a peroxide is carried out in an organic solvent and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV of an (R,R)- or (S,S)-isomer in optically pure form and titanium (IV) isopropoxide.

[0125] According to the nature of the chiral bidentate ligand and the transition metal, the ratio of the chiral bidentate ligand to the transition metal in the chiral complex is preferably 2 : 1 in order to from a sufficiently chelated chiral complex.

[0126] In some embodiments of the present application, the ratio of the chiral complex obtained from a chiral bidentate ligand of general formula III or IV of an (R,R)- or (S,S)-isomer in optically pure form and a compound of a transition metal of Group 4 (IVB) or Group 5 (VB) to the thioether is 0.1-1 : 1 by molar.

[0127] In some preferred embodiments of the present application, the ratio of the

chiral complex obtained from a chiral bidentate ligand of general formula III or IV of an (R,R)- or (S,S)-isomer in optically pure form and a compound of a transition metal of Group 4 (IVB) or Group 5 (VB) to the thioether is 1 : 1 by molar.

[0128] In some preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with a peroxide is carried out in an organic solvent and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV of an (R,R)- or (S,S)-isomer in optically pure form and titanium (IV) alkoxide, wherein, the ratio of the chiral complex to the thioether is 0.1-1 : 1 by molar.

[0129] In some more preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with a peroxide is carried out in an organic solvent and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV of an (R,R)- or (S,S)-isomer in optically pure form and titanium (IV) isopropoxide, wherein, the ratio of the chiral complex to the thioether is 1 : 1 by molar.

[0130] In some embodiments of the present application, an organic solvent that can be used includes, but is not limited to aromatic solvents, halogenated hydrocarbons, ethers and a mixture thereof.

[0131] In some embodiments of the present application, aromatic solvents that can be used include, but are not limited to, benzenes, naphthalenes, phenanthrenes, anthracenes, tetralines, fluorenes, indenes, indanes, and a mixture thereof. [0132] In some embodiments of the present application, aromatic solvents that can be used further include heteroaromatic solvents.

[0133] In some embodiments of the present application, heteroaromatic solvents that can be used include, but are not limited to furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quionoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline, quinoxaline and a mixture thereof.

[0134] In some embodiments of the present application, benzene solvents that can be used include, but are not limited to, benzene, halobenzene, hydroxybenzene, aminobenzene, toluene, methoxybenzene, 4-trifluoromethoxybenzene, cyanobenzene, dimethylbenzene, hydroxymethylbenzene, trifluoromethylbenzene, alkoxybenzene, 4-morpholin-4-ylbenzene, 4-pyrrolidin-l-ylbenzene, 4-pyrazolylbenzene, 4-triazolylbenzene, and

4-(2-oxopyrrolidin- 1 -yl)benzene. [0135] In some preferred embodiments of the present application, the benzene solvent that can be used is toluene.

[0136] In some embodiments of the present application, halogenated hydrocarbons that can be used include, but are not limited to, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, dichlorobutane, diclorodibromomethane, diclorodiiodomethane,

1,1,2,2-tetrachloroethane, 1,1,1-trichloroethane, hexachloroethane, hexachlorocyclohexane, and l,2-dibromo-3-chloropropane.

[0137] In some embodiments of the present application, ethers that can be used include, but are not limited to, anisole, dibenzyl ether, tert-butyi methyl ether, cyclopentyl methyl ether, dibutyl ether, diethyl ether, dihexyl ether, diisopropyl ether, 1,2-dimethoxyethane, 1,4-dioxane,

1,3-dioxolane, diphenyl ether, 2-methyltetrahydrofuran, tetrahydrofuran, tetrahydropyran, diethylene glycol dimethyl ether and a mixture thereof.

[0138] In some preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with a peroxide is carried out in an aromatic solvent and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV and titanium (IV) alkoxide. [0139] In some more preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with a peroxide is carried out in toluene and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV of an (R,R)- or (S,S)-isomer in optically pure form and titanium (IV) isopropoxide.

[0140] In some embodiments of the present application, peroxides that can be used include, but are not limited to, metal peroxides, hydrogen peroxides, peracid salts and organic peroxides.

[0141] In some embodiments of the present application, metal peroxides that can be used include, but are not limited to, alkali metal peroxides such as lithium peroxide, sodium peroxide and potassium peroxide, and alkaline earth metal peroxides such as magnesium peroxide and calcium peroxide.

[0142] In some embodiments of the present application, organic peroxides that can be used include, but are not limited to alkyl peroxides including alkylphenyl peroxides, acyl peroxides, cyclic peroxides, peroxycarbonate/dicarbonates, peroxyketals and peroxyesters.

[0143] In some embodiments of the present application, alkyl peroxides that can be used include, but are not limited to, di(te/t-butylperoxyisopropyl)benzene, dicumyl peroxide, 2,5-dimethyl-2,5-di(te/t-butylperoxy)hexane, di-tert-butyl peroxide, cumyl hydroperoxide, and tert-butyl cumyl peroxide.

[0144] In some preferred embodiments of the present application, the alkyl peroxide is cumyl hydroperoxide. [0145] In some embodiments of the present application, acyl peroxides that can be used include, but are not limited to, dilauroyl peroxide, dibenzoyl peroxide, diisobutyryl

peroxide and di(3,5,5-trimethylhexanoyl) peroxide,

[0146] In some embodiments of the present application, cyclic peroxides that can be used include, but are not limited to, 3,6,9-triethyl-3,6,9-trimethyl-l,4,7-triperoxonane.

[0147] In some embodiments of the present application, peroxycarbonate/dicarbonates that can be used include, but are not limited to, di(4-tert-butylcyclohexyl) peroxydicarbonate, dicetyl peroxydicarbonate, dimyristyl peroxydicarbonate, diisopropyl peroxydicarbonate, te/t-butylperoxy 2-ethylhexyl carbonate, te/t-amylperoxy 2-ethylhexyl carbonate, di(3-methoxy butyl) peroxydicarbonate, te/t-butylperoxy isopropyl carbonate and di(2-ethylhexyl) peroxydicarbonate. [0148] In some embodiments of the present application, peroxyketals that can be used include, but are not limited to, 2,2-di(4,4-di(tert-butylperoxy)cyclohexyl)propane, 1 , 1 -di(/e/t-amylperoxy)cyclohexane, 1 , 1 -di(te/t-butylperoxy)cyclohexane and

1 , 1 -di(te/t-butylperoxy)-3 ,3 ,5-trimethylcyclohexane.

[0149] In some embodiments of the present application, peroxyesters that can be used include, but are not limited to, tert-amyi peroxy-2-ethylhexanoate, tert-amyi peroxypivalate,

2,5-dimethyl-2,5-di(2-ethylhexanoylperoxy)hexane, tert-butyi peroxy-2-ethylhexanoate, tert-butyi peroxyneodecanoate, tert-butyi peroxypivalate, tert-butyi peroxyneoheptanoate, tert-butyi peroxydiethylacetate, tert-butyi peroxy-3,5,5-trimethylhexanoate,

1,1,3,3-tetramethylbutyl peroxy-2-ethylhexanoate, 1,1,3,3-tetramethylbutyl peroxyneodecanoate, tert-butyl peroxy-3,5,5-trimethylhexanoate, cumyl peroxyneodecanoate, di-tert-butyl peroxide, tert-butyi peroxybenzoate and tert-butyi peroxyacetate.

[0150] In some preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with an alkyl peroxide is carried out in an aromatic solvent and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV and titanium (IV) alkoxide.

[0151] In some more preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with cumyl hydroperoxide is carried out in toluene and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV of an (R,R)- or (S,S)-isomer in optically pure form and titanium (IV) isopropoxide.

[0152] In some embodiments of the present application, the ratio of the peroxide to the thioether in the enantioselective oxidation process may be 1-2.5 : 1 by molar.

[0153] In some preferred embodiments of the present application, the ratio of the peroxide to the thioether in the enantioselective oxidation process may be 1-1.5 : 1 by molar. [0154] In some even more preferred embodiments of the present application, the ratio of cumyl hydroperoxide to the thioether in the enantioselective oxidation process may be 1.1 : 1

by molar.

[0155] In some embodiments of the present application, the ratio of water to the thioether in the enantioselective oxidation process may be 0.05-1.2 : 1 by molar.

[0156] In some more preferred embodiments of the present application, the ratio of water to the thioether in the enantioselective oxidation process may be 0.05-0.5 : 1 by molar.

[0157] In some even more preferred embodiments of the present application, the ratio of water to the thioether in the enantioselective oxidation process may be 0.1 : 1 by molar.

[0158] In some preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with cumyl hydroperoxide is carried out in toluene and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV of an (R,R)- or (S,S)-isomer in optically pure form and titanium (IV) isopropoxide, wherein, the ratio of the chiral complex to the thioether is 1 : 1 by molar, the ratio of cumyl hydroperoxide to the thioether is 1.1 : 1 and the ratio of water to the thioether is 0.1 : 1 by molar.

[0159] In some embodiments of the present application, the enantioselective oxidation process is carried out at a temperature in the range of -78 to 55 ⁰ C.

[0160] In some preferred embodiments of the present application, the enantioselective oxidation process is carried out at a temperature in the range of -25 to 45 ⁰ C.

[0161] In some more preferred embodiments of the present application, the enantioselective oxidation process is carried out at a temperature in the range of 0 to 35 ⁰ C. [0162] In some preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with an alkyl peroxide is carried out in an aromatic solvent and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV and a compound of a transition metal of group 4 (IVB) or group 5 (VB) at a temperature in the range of -78 to 55 ⁰ C. [0163] In some more preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with cumyl hydroperoxide is carried out in toluene and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV of an (R,R)- or (S,S)-isomer in optically pure form and titanium (IV) alkoxide at a temperature in the range of -25 to 45 ⁰ C. [0164] In some even more preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with cumyl hydroperoxide is carried out in toluene and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV of an (R,R)- or (S,S)-isomer in optically pure form and titanium (IV) isopropoxide at a temperature in the range of 0 to 35 ⁰ C. [0165] In some embodiments of the present application, the enantioselective oxidation process is carried out over 1 to 72 hours.

[0166] In some preferred embodiments of the present application, the enantioselective oxidation process is carried out over 3 to 48 hours.

[0167] In some preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with an alkyl peroxide is carried out in an aromatic solvent and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV and a compound of a transition metal of group 4 (IVB) or group 5 (VB) at a temperature in the range of -78 to 55 ⁰ C over 1 to 72 hours.

[0168] In some preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with cumyl hydroperoxide is carried out in toluene and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV of an (R,R)- or (S,S)-isomer in optically pure form and titanium (IV) alkoxide at a temperature in the range of -25 to 45 ⁰ C over 1 to 72 hours.

[0169] In some preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with cumyl hydroperoxide is carried out in toluene and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV of an (R,R)- or (S,S)-isomer in optically pure form and titanium (IV) isopropoxide at a temperature in the range of 0 to 35 ⁰ C over 3 to 48 hours.

[0170] In some preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with cumyl hydroperoxide is carried out in toluene and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV of an (R,R)- or (S,S)-isomer in optically pure form and titanium (IV) isopropoxide at a temperature in the range of 0 to 35 ⁰ C over 3 to 48 hours, wherein the ratio of the chiral complex : the peroxide : water : the thioether of general formula II is 0.1-1 : 1-2.5 : 0.05-1.2 : 1 by molar.

[0171] In some more preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with cumyl hydroperoxide is carried out in toluene and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV of an (R,R)- or (S,S)-isomer in optically pure form and titanium (IV) isopropoxide at a temperature in the range of 0 to 35 ⁰ C over 3 to 48 hours, wherein the ratio of the chiral complex : the peroxide : water : the thioether of general formula II is 1 : 1.1 : 0.1 : 1 by molar.

[0172] In some embodiments of the present application, an additive is further present in the step of oxidation of a thioether of general formula II with a peroxide in an organic solvent and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV and a compound of a transition metal. [0173] In some embodiments of the present application, the additives that can be used include, but are not limited to, molecular sieves, silica gels, organic bases and inorganic bases.

[0174] In some embodiments of the present application, the organic bases that can be used include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as, hydrazine, methylamine, trimethylamine, diethylamine, triethylamine, isopropylamine, diisopropylethylamine, tripropylamine, tributylamine, λf,λf-dimethylpropylamine, 4-dimethylaminopyridine, JV,./V-dimethylaniline, JV,./V-diethylaniline, l,5-diazabicyclo[4.3.0]non-5-ene, l,4-diazabicyclo[2.2.2]octane (DABCO), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, pyridine, piperidine, iV-methylpiperidine, iV-ethylpiperidine, polyamine resins and the like.

[0175] In some preferred embodiments of the present application, the organic base is selected from the group consisting of hydrazine, methylamine, trimethylamine, diethylamine, triethylamine, isopropylamine, diisopropylethylamine, tripropylamine, tributylamine, λf,λf-dimethylpropylamine, 4-dimethylaminopyridine, JV,./V-dimethylaniline, JV,./V-diethylaniline, l,5-diazabicyclo[4.3.0]non-5-ene, l,4-diazabicyclo[2.2.2]octane (DABCO), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), piperazine, pyridine, piperidine, JV-methylpiperidine and ./V-ethylpiperidine.

[0176] In some more preferred embodiments of the present application, the organic base is selected from the group consisting of triethylamine and diisopropylethylamine.

[0177] In some embodiments of the present application, inorganic bases that can be used include, but are not limited to, alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate, alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and lithium bicarbonate, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and lithium methoxide, alkali metal thioalkoxides such as sodium thiomethoxide and sodium thioethoxide.

[0178] In some preferred embodiments of the present application, the inorganic base is selected from the group consisting of alkali metal carbonates, alkali metal hydroxides, and alkali metal alkoxides.

[0179] In some more preferred embodiments of the present application, the alkali metal carbonate is selected from the group consisting of sodium carbonate and potassium carbonate.

[0180] In some more preferred embodiments of the present application, the alkali metal hydroxide is selected from the group consisting of sodium hydroxide and potassium hydroxide.

[0181] In some more preferred embodiments of the present application, the alkali metal alkoxide is selected from the group consisting of sodium methoxide, sodium ethoxide and potassium te/t-butoxide.

[0182] In some preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with an alkyl peroxide is carried out in an aromatic solvent and water in the presence of an additive and a chiral complex obtained from a chiral bidentate ligand of general formula III or IV of an (R,R)- or (S,S)-isomer in optically pure form and a compound of titanium (IV) alkoxide.

[0183] In some more preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with an cumyl hydroperoxide is carried out in toluene and water in the presence of an organic base as an additive and a chiral complex obtained from a chiral bidentate ligand of general formula III or IV of an (R,R)- or (S,S)-isomer in optically pure form and titanium (IV) isopropoxide.

[0184] In the step of oxidation of a thioether of general formula II with a peroxide carried out in an organic solvent and water in the presence of an additive and a chiral complex obtained from a chiral bidentate ligand of general formula III or IV of an (R,R)- or (S,S)-isomer in optically pure form and a compound of a transition metal, the ratio of the chiral complex to the thioether is 0.1-1 : 1 by molar, preferably 0.3 : 1 by molar, and the ratio of the additive to the thioether is 0.2-1 : 1 by molar, preferably 0.6 : 1 by molar, with the proviso that, when a molecular sieve or a silica gel is used as an additive, the ratio of the additive to the thioether is 0.2-1 : 1 by weight, preferably 0.3 : 1 by weight. [0185] Therefore, in some preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with an alkyl peroxide is carried out in an aromatic solvent and water in the presence of an additive and a chiral complex obtained from a chiral bidentate ligand of general formula III or IV of an (R,R)- or (S,S)-isomer in optically pure form and a compound of titanium (IV) alkoxide, wherein, the ratio of the chiral complex to the thioether is 0.1-1 : 1 by molar, and the ratio of the additive to the thioether is 0.2-1 : 1 by molar, with the proviso that, when a molecular sieve or a silica gel is used as an additive, the ratio of the additive to the thioether is 0.2-1 : 1 by weight.

[0186] In some more preferred embodiments of the present application, the step of oxidation of a thioether of general formula II with an cumyl hydroperoxide is carried out in toluene and water in the presence of an organic base as an additive and a chiral complex obtained from a chiral bidentate ligand of general formula III or IV of an (R,R)- or (S,S)-isomer in

optically pure form and titanium (IV) isopropoxide, wherein, the ratio of the chiral complex to the thioether is 0.3 : 1 by molar, and the ratio of the organic base to the thioether is 0.6 : 1 by molar.

[0187] In some embodiments of the present application, the resulting solution of chiral sulfoxide compound of general formula I as a single enantiomer or in an enantiomerically enriched form may be extracted by adding a basic aqueous solution and an organic solvent. The pH of the aqueous phase is adjusted with an acid. The resulting aqueous layer is extracted with an organic solvent and the purified product is obtained after recrystallization.

[0188] In another aspect, the present application is directed to S-(-)-levo-omeprazole, S-(-)-levo-pantoprazole and S-(-)-levo-lansoprazole prepared by a process for preparing a chiral sulfoxide compound of general formula I as a single enantiomer or in an enantiomerically enriched form

wherein

R ¹ , R ² and R ³ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkynyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkoxycarbonyl, optionally substituted alkylcarbonyl, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted cycloalkoxy, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, halogen, haloalkyl, cyano, nitro and hydroxy, R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkynyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkoxycarbonyl, optionally substituted alkylcarbonyl, optionally substituted alkylamino, optionally substituted dialkylamino, optionally substituted cycloalkoxy, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted heteroaryl, halogen, haloalkyl, cyano,

nitro and hydroxy, the process comprises the step of oxidation of a thioether of general formula II

whereinR ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above,

with a peroxide in an organic solvent and water in the presence of a chiral complex obtained from a chiral bidentate ligand of general formula III or IV and a compound of a transition metal

1

III IV

wherein R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, organic polymer and silica supported carrier.

[0189] This aspect of the present application is substantially akin to that as described above. Resulting S-(-)-levo-omeprazole, S-(-)-levo-pantoprazole and S-(-)-levo-lansoprazole may be further purified with an appropriate process known in the art.

[0190] The enantioselectivity of the process in the present application is higher and no sulphone by-product is produced in the present process. In addition, the chiral complex of D- or L-tartaric acid diamide compounds can be readily prepared from corresponding chiral tartaric acid diester and has higher chemical stability as compared with chiral tartaric acid diester disclosed in international patent application WO 96/02535. The chiral bidentate ligand of D- or L-tartaric acid diamide compounds used in the present application can be recovered and recycled.

EXAMPLES

[0191] Embodiments of the present application are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the application.

Reagents and Apparatus:

[0192] Molecular Sieves: 4 A, powder, activated, 5 μm, purchase from Aldrich.

Toluene, purity >99.5%, water content <0.03%, purchased from Guangdong Chemical Reagents

Engineering Technology R & D Center, P R China. Triethylamine, purity >99.0%, water content

<0.2%, purchased from Guangdong Chemical Reagents Engineering Technology R & D Center, P R China. N-methyl morpholine, purity >98.0%, purchased from Chengdu Kelong Chemical

Regent Factory, P R China. Pyridine, purity >99.5%, purchased from Guangdong Xilong

Chemical Co., Ltd, P R China. DIPEA, purity >99.0%, purchased from Zhejiang Xinde

Chemical Co., Ltd, P R China. Silica gel H, Chemically Pure, purchased from Qingdao Haiyang

Chemical Co., Ltd, P R China. Tartaric acid diamides, synthesized in the inventor's laboratory following conventional procedures.

[0193] HPLC: Waters 1525 system; Detector: Waters 2487.

Chiral HPLC Conditions:

[0194] Omeprazole: Chiral- AD-H chiral column; eluant: 15% isopropanol/w-hexane; flow rate: 1.0 ml/min; wavelength: 254 nm; retention time: t _R =18.7 min, ts=23.7 min

[0195] Pantoprazole: Chiral-AD-H chiral column; eluant: 15% isopropanol/w-hexane; flow rate: 1.0 ml/min; wavelength: 254 nm; retention time: t _R =33.0 min, ts=42.3 min

[0196] Lansoprazole: Chiral-OD-H chiral column; eluant: 30% isopropanol/w-hexane; flow rate: 1.0 ml/min; wavelength: 254 nm; retention time: t _R =10.2 min, ts=12.1 min

General Method 1: Preparation of Omeprazole without an Additive (Ri=CH ₃ , R ₂ =OCHs, R ₃ =C-H ₃ , R ₄ = R ₆ = R ₇ =H, Rs=OC^H ₃ )

[0197] 5 -Methoxy-2- [ [(4-methoxy-3 ,5 -dimethyl-2-pyridyl)methyl]thio] - 1 H- benzimidazole (0.31 g, 0.95 mmol) was dissolved in toluene (2.5 mL) at 70 ⁰ C under stirring. To the solution was added tartaric acid diamide (1.14 mmol) at 60 ⁰ C. The resulting solution was stirred over 15 minutes and then titanium (IV) tetraisopropoxide (0.16 g, 0.57 mmol) was added thereinto while maintaining the temperature at 60 ⁰ C. The resulting mixture was kept at 60 ⁰ C over 1 hour and then water (4.4 μL, 0.24 mmol) was added thereinto. The resulting solution was kept at 60 ⁰ C over 20 minutes and then cooled to 0 ⁰ C. To the cooled solution was dropwise added cumyl hydroperoxide (0.2 mL, 1.05 mmol). The reaction was kept at 0 ⁰ C over 24 hours.

To the resulting solution was added 10% aqueous sodium hydroxide (50 mL) and then the

solution was shaken several times. The resulting aqueous solution was extracted twice with toluene. The pH of the aqueous layer was adjusted to about 7-8 with glacial acetic acid. The resulting aqueous phase was extracted with dichlormethane. The resulting organic phase was washed twice with saturated aqueous brine, dried over anhydrous sodium sulfate and filtered. The combined organic phase was evaporated to dryness under reduced pressure to give the optically active title compound. The ee of the title compound was measured by HPLC.

Examples 1-10

[0198] Following the procedure as described in General Method 1 and using different bidentate ligands, the title compound of omeprazole was prepared. The results of each reaction using different bidentate ligands were listed in Table 1.

Table 1

Examples Ligands Yields (%) ee (%) Configuration

CONHCH ₂ CH ₃ I-OH

6f H0-| 33 87.6

CONHCH ₂ CH ₃ (D)

CONHCH

9f H0-| ^"0H 95 68.5

CONHCh

* : thiolether : chiral ligand : titanium (IV) tetraisopropoxide : water : oxidant is 1 : 2 : 1 : 0.5 : 1.05 by molar in Examples 1 and 2; f : thiolether : chiral ligand : titanium (IV) tetraisopropoxide : water : oxidant is 1 : 1.2 : 0.6 : 0.25 : 1.1 by molar in Examples 3-10.

General Method 2: Preparation of Omeprazole with an Additive (Ri=CH ₃ , R ₂ =OCH ₃ , R ₃ =CH ₃ , R ₄ = R ₆ = R ₇ =H, R ₅ =OCH ₃ )

[0199] 5 -Methoxy-2- [ [(4-methoxy-3 ,5 -dimethyl-2-pyridyl)methyl]thio] - 1 H- benzimidazole (0.31 g, 0.95 mmol) was dissolved in toluene (2.5 mL) at 70 ⁰ C under stirring. To the solution was added D-tartaric acid di-w-propionamide (0.132 g, 0.57 mmol) at 60 ⁰ C. The resulting solution was stirred over 15 minutes and then titanium (IV) tetraisopropoxide (0.08 g, 0.285 mmol) was added thereinto while maintaining the temperature at 60 ⁰ C. The resulting mixture was kept at 60 ⁰ C over 1 hour and then water (2.2 μL, 0.1 mmol) was added thereinto. The resulting solution was kept at 60 ⁰ C over 20 minutes and then cooled to 30 ⁰ C. To the solution was added an additive (0.285 mmol). The resulting mixture was kept at 30 ⁰ C over 10 minutes and then cooled to 0 ⁰ C. To the cooled solution was dropwise added cumyl hydroperoxide (0.2 mL, 1.05 mmol). The reaction was kept at 0 ⁰ C over 24 hours. To the resulting solution was added 10% aqueous sodium hydroxide (50 mL) and then the solution was shaken several times. The resulting aqueous solution was extracted twice with toluene. The pH of the aqueous layer was adjusted to about 7-8 with glacial acetic acid. The resulting aqueous phase was extracted with dichlormethane. The resulting organic phase was washed twice with saturated aqueous brine, dried over anhydrous sodium sulfate and filtered. The combined organic

phase was evaporated to dryness under reduced pressure to give the optically active title compound. The ee of the title compound was measured by HPLC.

Examples 11-18 [0200] Following the procedure as described in General Method 2 and using different additives, the title compound of omeprazole was prepared. The results of each reaction using different additives were listed in Table 2.

Table 2

Examples Additives Yields (%) ee (%) Configuration

II ¹ molecular sieve 70 90 S

12 ¹ silica gel H 40 86 S

13 triethylamine 70 89.7 S

14 diisopropylethylamine 74 85.1 S

18 ² KHCO ₃ and Bu ₄ NBr 21 72.0 l the ratio of additive to thiolether is 0.3 : 1 by weight.

² the ratio of KHCO ₃ to Bu ₄ NBr is 3 : 1 by weight

General Method 3: Preparation of Omeprazole with an enantioselective and catalytic oxidation process at room temperature (Ri=CH ₃ , R ₂ =OCH ₃ , R ₃ =CH ₃ , R ₄ = R ₆ = R ₇ =H, R ₅ =OCH ₃ ) [0201 ] 5 -Methoxy-2- [ [(4-methoxy-3 ,5 -dimethyl-2-pyridyl)methyl]thio] - 1 H- benzimidazole (0.31 g, 0.95 mmol) was dissolved in toluene (2.5 mL) at 70 ⁰ C under stirring. To the solution was added D-tartaric acid di-w-propionamide (0.132 g, 0.57 mmol) at 60 ⁰ C. The resulting solution was stirred over 15 minutes and then titanium (IV) tetraisopropoxide (0.08 g, 0.285 mmol) was added thereinto while maintaining the temperature at 60 ⁰ C. The resulting

mixture was kept at 60 ⁰ C over 1 hour and then water (2.2 μL, 0.1 mmol) was added thereinto. The resulting solution was kept at 60 ⁰ C over 20 minutes and then cooled to 30 ⁰ C. To the solution was added an additive (0.285 mmol). The resulting solution was stirred for 10 min followed by dropwise adding cumyl hydroperoxide (0.2 mL, 1.05 mmol). The reaction was kept at 30 ⁰ C over 5 hours. To the resulting solution was added 10% aqueous sodium hydroxide (50 mL) and then the solution was shaken several times. The resulting aqueous solution was extracted twice with toluene. The pH of the aqueous layer was adjusted to about 7-8 with glacial acetic acid. The resulting aqueous phase was extracted with dichlormethane. The resulting organic phase was washed twice with saturated aqueous brine, dried over anhydrous sodium sulfate and filtered. The combined organic phase was evaporated to dryness under reduced pressure to give the optically active title compound. The ee of the title compound was measured by HPLC.

Examples 19-22 [0202] Following the procedure as described in General Method 3 and using different bidentate ligands and additives, the title compound of omeprazole was prepared at the reaction temperature of 30 ⁰ C. The results of each reaction using different additives were listed in Table

3.

Table 3

Note: "/" denotes no additive was added

Examples 23-28: Preparation of Omeprazole employing different amount of water (Ri=CH ₃ , R ₂ =OCH ₃ , R ₃ =CH ₃ , R ₄ = R ₆ = Rv=H, R ₅ =OCH ₃ )

[0203] 5 -Methoxy-2- [ [(4-methoxy-3 ,5 -dimethyl-2-pyridyl)methyl]thio] - 1 H- benzimidazole (1.645 g, 5 mmol) and D-tartaric acid di-w-propionamide (0.696 g, 3.000 mmol) was added into a reaction flask together with toluene (15 rnL) and the resulting mixture was stirred at 70 ⁰ C for 15 min. To the solution was added titanium (IV) tetraisopropoxide (0.429 g, 1.500 mmol) at 60 ⁰ C. The resulting mixture was kept at 60 ⁰ C over 1 hour while stirring and then certain amount of water according to the following Table 4 was added thereinto. The resulting solution was kept at 60 ⁰ C over 20 minutes while stirring and then cooled to 30 ⁰ C. To the resulting solution was dropwise added cumyl hydroperoxide (1.0 mL, 5.400 mmol) and the reaction was continued at 30 ⁰ C for 5 h. The resulting product was purified through flash chromatography on silica gel. The yields of the title compoound were determined by NMR. The ee of the title compound was measured by ηPLC. The results of each reaction using different amounts of water are listed below in Table 4.

Table 4

Examples Amounts of Water added (μL) Yields (%) ee (%) Configuration

23 0.0 14.6 45.5 S

24 9.0 36.8 75.0 S

25 10.8 43.3 72.4 S

26 13.5 34.1 71.3 S

27 16.2 36.7 70.6 S

28 18.9 39.8 70.3 S

Examples 29-34: Preparation of Omeprazole employing different amount of base (Ri=Cη ₃ , R ₂ =OCH ₃ , R ₃ =CH ₃ , R ₄ = R ₆ = R ₇ =H, R ₅ =OCH ₃ )

[0204] 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio] -lH- benzimidazole (1.645 g, 5 mmol) and D-tartaric acid di-w-propionamide (0.696 g, 3.000 mmol) was added into a reaction flask together with toluene (15 mL) and the resulting mixture was stirred at 70 ⁰ C for 15 min. To the solution was added titanium (IV) tetraisopropoxide (0.429 g, 1.500 mmol) at 60 ⁰ C. The resulting mixture was kept at 60 ⁰ C over 1 hour while stirring and then water (9.00 μL, 0.500mmol) was added thereinto. The resulting solution was kept at 60 ⁰ C over 20 minutes while stirring and then cooled to 30 ⁰ C. To the resulting solution was added certain amount of triethylamine (TEA) according to the following Table 5 and the reaction was continued at 30 ⁰ C for 30 min. To the solution was added cumyl hydroperoxide (1.0 mL, 5.400 mmol) and the reaction was continued at 30 ⁰ C for 5 h. The resulting product was purified through flash chromatography on silica gel. The yields of the title compoound were determined

by NMR. The ee of the title compound was measured by HPLC. The results of each reaction using different amounts of water are listed below in Table 5.

Table 5

Examples Amounts of TEA added (mL) Yields (%) ee (%) Configuration

29 0.0 36.8 75.0 S

30 0.14 50.0 89.5 S

31 0.28 75.6 90.8 S

32 0.42 75.8 95.7 S

33 0.56 88.5 92.7 S

34 0.70 78.0 91.1 S

Examples 35-37: Preparation of Omeprazole employing different amount of oxidant (Ri=CH ₃ , R ₂ =OCH ₃ , R ₃ =CH ₃ , R ₄ = R ₆ = Rv=H, R ₅ =OCH ₃ )

[0205] 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio] -lH- benzimidazole (1.645 g, 5 mmol) and D-tartaric acid di-w-propionamide (0.696 g, 3.00 mmol) was added into a reaction flask together with toluene (15 mL) and the resulting mixture was stirred at 70 ⁰ C for 15 min. To the solution was added titanium (IV) tetraisopropoxide (0.429 g, 1.500 mmol) at 60 ⁰ C. The resulting mixture was kept at 60 ⁰ C over 1 hour while stirring and then water (9.00 μL, 0.500mmol) was added thereinto. The resulting solution was kept at 60 ⁰ C over 20 minutes while stirring and then cooled to 30 ⁰ C. To the resulting solution was added triethylamine (0.420 mL, 3.00 mmol) and the reaction was continued at 30 ⁰ C for 30 min. To the solution was dropwise added certain amount of cumyl hydroperoxide (CηP) according to the following Table 6 and the reaction was continued at 30 ⁰ C for 5 h. The resulting product was purified through flash chromatography on silica gel. The yields of the title compoound were determined by NMR. The ee of the title compound was measured by ηPLC. The results of each reaction using different amounts of water are listed below in Table 6.

Table 6

Examples Amounts of CηP added (mL) Yields (%) ee (%) Configuration

35 1.0 75. 8 95.7S S

36 1.5 87. 5 90.9S S

37 2. 0 61. 1 70.1S S

Examples 38: Preparation of Omeprazole (Ri=CH ₃ , R ₂ =OCH ₃ , R ₃ =CH ₃ , R ₄ = R ₆ = R ₇ =H, R ₅ =OCH ₃ )

[0206] 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio] -lH- benzimidazole (3.290 g, 10 mmol) and D-tartaric acid di-w-propionamide (0.696 g, 3.000 mmol) was added into a reaction flask together with toluene (25 rnL) and the resulting mixture was stirred at 70 ⁰ C for 15 min. To the solution was added titanium (IV) tetraisopropoxide (0.429 g, 1.500 mmol) at 60 ⁰ C. The resulting mixture was kept at 60 ⁰ C over 1 hour while stirring and then water (9.00 μL, 0.500mmol) was added thereinto. The resulting solution was kept at 60 ⁰ C over 20 minutes while stirring and then cooled to 30 ⁰ C. To the resulting solution was added triethylamine (0.42mL, 3 mmol) and the reaction was continued at 30 ⁰ C for 30 min. To the solution was dropwise cumyl hydroperoxide (CηP, 2.0 mL, 10.80mmol)) and the reaction was continued at 30 ⁰ C for 5 h. The resulting product was purified through flash chromatography on silica gel. The yields of the title compoound were determined by NMR to be 75.0%. The ee of the title compound was measured by ηPLC to be 81.6%.

Example 39: Preparation of S-(-)-levo-omeprazole (Ri=CH ₃ , R ₂ =OCH ₃ , R ₃ =CH ₃ , R ₄ = R ₆ = R ₇ =H, R ₅ =OCH ₃ )

[0207] 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio] -lH- benzimidazole (6.2 g, 19 mmol) was dissolved in toluene (25 mL) at 70 ⁰ C under stirring. To the solution was added D-tartaric acid di-w-propionamide (8.8 g, 38 mmol) at 60 ⁰ C. The resulting solution was stirred over 15 minutes and then titanium (IV) tetraisopropoxide (5.3 g, 19 mmol) was added thereinto while maintaining the temperature at 60 ⁰ C. The resulting mixture was kept at 60 ⁰ C over 1 hour and then water (0.17 mL, 9.5 mmol) was added thereinto. The resulting solution was kept at 60 ⁰ C over 20 minutes and then cooled to 0 ⁰ C. To the cooled solution was dropwise added cumyl hydroperoxide (3.9 mL, 19.95 mmol). The reaction was kept at 0 ⁰ C over 27 hours. To the resulting solution was added 10% aqueous sodium hydroxide (250 mL) and then the solution was shaken several times. The resulting aqueous solution was extracted twice with toluene. The pη of the aqueous layer was adjusted to about 7-8 with glacial acetic acid. The resulting aqueous phase was extracted with dichlormethane. The resulting organic phase was washed twice with saturated aqueous brine, dried over anhydrous sodium sulfate and filtered. The combined organic phase was evaporated to dryness under reduced pressure to give S-(-)-levo-omeprazole (5.2 g, 80%, ee: 93.6%).

Example 40: Preparation of S-(-)-levo-omeprazole at room temperature (Ri=CH ₃ , R ₂ =OCH ₃ ,

[0208] 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio] -lH- benzimidazole (30 g, 90.19 mmol), toluene (242 mL) and D-tartaric acid di-w-propionamide (12.96 g, 54.71 mmol) were added into a reaction flask. The reaction mixture was warmed to 70

⁰ C and stirred for 10 minutes and then cooled to 55-60 ⁰ C. To the resulting solution was added titanium (IV) tetraisopropoxide (7.78 g, 27.36 mmol). The resulting mixture was stirred for 60 minutes and then water (0.16 mL, 9.019 mmol) was added thereinto. The resulting solution was further stirred for 30 minutes and cooled 30 ⁰ C. To the solution was added triethylamine (3.8 mL, 27.36 mmol). The resulting solution was stirred for 30 minutes and then cumyl hydroperoxide (19.4 mL, 107.8 mmol) was added thereinto. The reaction was kept at 30 ⁰ C over 43 hours. To the resulting solution was added 10% aqueous sodium hydroxide. The aqueous phase was separated and extracted twice with toluene. The pH of the aqueous layer was adjusted to about 9 with glacial acetic acid. The resulting aqueous phase was extracted with dichlormethane. The resulting organic phase was washed twice with saturated aqueous brine, dried over anhydrous sodium sulfate and filtered. The combined organic phase was evaporated to dryness under reduced pressure to give S-(-)-levo-omeprazole (29.2 g, 92.7%, ee: 95.2%).

Example 41: Preparation of S-(-)-levo-omeprazole (Ri=CH ₃ , R ₂ =OCH ₃ , R ₃ =CH ₃ , R ₄ = R ₆ = R ₇ =H, R ₅ =OCH ₃ )

[0209] 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio] -lH- benzimidazole (16.45 g, 50 mmol) and D-tartaric acid di-w-propionamide (6.96 g, 30 mmol) was added into a reaction flask together with toluene (150 mL) and the resulting mixture was stirred at 70 ⁰ C for 15 min. To the solution was added titanium (IV) tetraisopropoxide (4.29 g, 15.00 mmol) at 60 ⁰ C. The resulting mixture was kept at 60 ⁰ C over 1 hour while stirring and then water (90.00 μL, 5 mmol) was added thereinto. The resulting solution was kept at 60 ⁰ C over 2.0 hour while stirring and then cooled to 30 ⁰ C. To the resulting solution was added triethylamine (4.2OmL, 30.00 mmol) and the reaction was continued at 30 ⁰ C for 30 min. To the solution was dropwise added (13.5 mL, 75 mmol) cumyl hydroperoxide (CηP) and the reaction was continued at 30 ⁰ C for 24 h. To the resulting solution was added 10% aqueous sodium hydroxide. The aqueous phase was separated and extracted twice with toluene. The pη of the aqueous layer was adjusted to about 8 with glacial acetic acid. The resulting aqueous phase was extracted with dichlormethane. The resulting organic phase was washed twice with saturated aqueous brine, dried over anhydrous sodium sulfate and filtered. The combined organic phase was evaporated to dryness under reduced pressure to give S-(-)-levo-omeprazole (15.00 g, 87%, ee: 95.2%).

Example 42: Preparation of S-(-)-levo-pantoprazole (Ri=H, R ₂ =OCH ₃ , R ₃ =OCH ₃ , R ₄ = R ₆ = R ₇ =H, R ₅ =OCHF ₂ )

[0210] 5 -Difluoromethoxy-2- [[(3 ,4-dimethoxy-2-pyridyl)methyl]thio] - 1 H- benzimidazole (0.363 g, 0.95 mmol) was dissolved in toluene (2.5 mL) at 70 ⁰ C under stirring. To the solution was added D-tartaric acid di-w-propionamide (0.440 g, 1.9 mmol) at 60 ⁰ C. The

resulting solution was stirred over 15 minutes and then titanium (IV) tetraisopropoxide (0.225 g, 0.95 mmol) was added thereinto while maintaining the temperature at 60 ⁰ C. The resulting mixture was stirred over 1 hour and then water (8.5 μL, 0.47 mmol) was added thereinto. The resulting solution was stirred at 60 ⁰ C over 20 minutes and then cooled to 0 ⁰ C. To the cooled solution was dropwise added cumyl hydroperoxide (0.2 mL, 1.08 mmol). The reaction was kept at 0 ⁰ C over 27 hours. To the resulting solution was added 10% aqueous sodium hydroxide (50 mL) and then the solution was shaken several times. The resulting aqueous solution was extracted twice with toluene. The pH of the aqueous layer was adjusted to about 7-8 with glacial acetic acid. The resulting aqueous phase was extracted with dichlormethane. The resulting organic phase was washed twice with saturated aqueous brine, dried over anhydrous sodium sulfate and filtered. The combined organic phase was evaporated to dryness under reduced pressure to give S-(-)-levo-pantoprazole (0.18 g, 50%, ee: 70.0%).

Example 43: Preparation of S-(-)-levo-lansoprazole (Ri=H, R ₂ =OCH ₂ CF ₃ , R ₃ =CH ₃ , R ₄ = R ₅ = R ₆ = R ₇ =H)

[0211] 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thi o]- IH- benzimidazole (0.337 g, 0.95 mmol) was dissolved in toluene (3.0 mL) at 80 ⁰ C under stirring. To the solution was added D-tartaric acid di-w-propionamide (0.440 g, 1.9 mmol) at 60 ⁰ C. The resulting solution was stirred over 15 minutes and then titanium (IV) tetraisopropoxide (0.225 g, 0.95 mmol) was added thereinto while maintaining the temperature at 60 ⁰ C. The resulting mixture was stirred over 1 hour and then water (8.5 μL, 0.47 mmol) was added thereinto. The resulting solution was stirred at 60 ⁰ C over 20 minutes and then cooled to 0 ⁰ C. To the cooled solution was dropwise added cumyl hydroperoxide (0.2 mL, 1.08 mmol). The reaction was kept at 0 ⁰ C over 48 hours. S-(-)-levo-pantoprazole (0.24 g, 44%, ee: 65.0%) was obtained by column chromatography.

[0212] All of the above U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet, are incorporated herein by reference, in their entirety.

[0213] From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.