WO2010118575A1 - Racemic enantiomers resoluting - Google Patents

Abstract

Disclosed are a process for resolution of racemic enantiomers to prepare sulfoxide compounds as a single enantiomer or in an enantiomerically enriched form and salts thereof as a single enantiomer or in an enantiomerically enriched form, and S-(-)-levo-timoprazole, S-(-)-levo-picoprazole, S-(-)-levo-omeprazole, S-(-)-levo-pantoprazole and S-(-)-levo-lansoprazole prepared thereby. Formula (I) timoprazole: R₁= R₂=R₃=R₄=R₅=R₆=R₇=H picoprazole: R₁=R₂=H, R₃=CH₃, R₄=R₇=H, R₅=CO₂CH₃, R₆=CH₃ omeprazole: R₁=CH₃, R₂=OCH₃, R₃=CH₃, R₄=R₆=R₇=H, R₅=OCH₃ lansoprazole: R₁=H, R₂=OCH₂CF₃, R₃=CH₃, R₄=R₅=R₆=R₇=H pantoprazole: R₁=H, R₂=OCH₃, R₃=OCH₃, R₄=R₆=R₇=H, R₅=OCHF₂

Description

RACEMIC ENANTIOMERS RESOLUTING

FIELD OF THE INVENTION

[0001] The present application is generally directed to a process for resolution of racemic enantiomers. In particular, the present application is directed to a process for resolution of racemic enantiomers to prepare sulfoxide compounds as a single enantiomer or in an enantiomerically enriched form and salts thereof as a single enantiomer or in an enantiomerically enriched form.

BACKGROUND OF THE INVENTION

[0002] Sulfoxide compounds of general formula I having the structure of 2-[[(2-pyridyl)methylene]sulfinyl]-lff-benzimidazole or structurally related compounds can be used to inhibit the activity of H⁺, K⁺/ATPase (also known as proton pump) and therefore inhibit the secretion of gastric acid. Such compounds have been extensively used to treat peptic ulcer (PU) caused by gastroxia and the related diseases.

timoprazole: R₁= R₂=R₃=R₄=R₅=R₆=R₇=H picoprazole: Ri=R₂=H, R₃=CH₃, R₄=R₇=H, R₅=CO₂CH₃, R₆=CH₃ omeprazole: Ri=CH₃, R₂=OCH₃, R₃=CH₃, R₄=R₆=R₇=H, R₅=OCH₃ lansoprazole: Ri=H, R₂=OCH₂CF₃, R₃=CH₃, R₄=R₅=R₆=R₇=H pantoprazole: Ri=H, R₂=OCH₃, R₃=OCH₃, R₄=R₆=R₇=H, R₅=OCHF₂

[0003] The asymmetrically substituted sulfoxide compounds have a stereogenic center at the sulfur atom. The chirality of the compounds of general formula I having the inhibition of the secretion of gastric acid is represented by the sulfur atom.

[0004] 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 others and therefore the first commercially available chiral proton pump inhibitor among this kind of compounds is S-(-)-omeprazole. [0005] Up to now, such compounds have been manufactured in industry by oxidizing the corresponding thioether compounds. For example, a racemic mixture is obtained by commonly used oxidation process while a product as a single enantiomer or in an enantiomerically enriched form is obtained by a special oxidation process (e.g. using chiral reagent in the process).

[0006] Jingen DENG et al. in Chinese patent CN 1223262 A disclose a process for preparing an anti-peptic ulcer (PU) medicament as a single enantiomer by resolution of racemic benzimidazole compounds such as (S)-omeprazole, (^-lansoprazole and the like, in which an inclusion complex in an (S)-enantiomerically enriched form is prepared with (S)-binaphthol (BFNOL) and a racemic benzimidazole anti-peptic ulcer (PU) medicament.

HI structure of inclusion complex (III) formed by (S)-omeprazole and (S)-BFNOL

[0007] Jingen DENG et al. in Chinese patent CN 1329003 A disclose a process for preparing (^-lansoprazole as a single enantiomer by resolution of an inclusion complex formed by (S)-binaphthol (BFNOL) and racemic lansoprazole. [0008] The process of DENG et al. in Chinese patent CN 1223262 A comprises disassociating an inclusion complex with column chromatography to give (S)-(-)-omeprazole with an 87% e.e, recrystallizing (S)-(-)-omeprazole and concentrating mother liquor to give a 99% e.e of (S)-(-)-omeprazole. However, as column chromatography using a mixed solvent system of benzene and w-hexane is utilized in the process, the toxicity of benzene is not suitable for the industrialized environmental requirements. [0009] Laura COPPI et al. in international patent application WO 2006/094904 disclose a process for inclusion resolution of racemic omeprazole, in which (S)-BFNOL is used as an inclusion host, a mixture of toluene and w-heptane is used as solvent, and triethylamine is used as an additive to give inclusion complex (III) with a 97% e.e. The inclusion complex (III) is recrystallized upto a 99% e.e and then (S)-BFNOL is dissociated to give (S)-(-)-omeprazole as a single enantiomer. [0010] Tea Hee HA et al. in international patent application WO 2007/013743 disclose a process for preparing esomeprazole as a single enantiomer, in which inclusion complex (III) in an (ιS')-enantiomerically enriched form is prepared with racemic omeprazole and (S)-BINOL as a single enantiomer by adding an organic base in a mixed solvent system of aqueous organic solvent and water. The inclusion complex (III) is recrystallized upto a 99% e.e and then (S)-BINOL is dissociated to give esomeprazole as a single enantiomer.

[0011] All the processes disclosed in the prior art comprise a step of recrystallization to give a higher e.e of an inclusion complex. The inclusion complex is then subjected to dissociation with a base, acidation and extraction to give (S)-(-)-omeprazole or (S)-(-)-esomeprazole as a single enantiomer. However, the yield of recrystallization of an inclusion complex is usually relatively lower. Furthermore, a solvent containing chlorine atoms is used in the extraction carried out after the step of acidation, which, as a result, causes environmental issues.

SUMMARY OF THE INVENTION

[0012] In a first aspect, the present application is directed to a process for resolution of a racemic enantiomer to prepare a compound of general formula I as a single enantiomer or in an enantiomerically enriched form and a salt thereof as a single enantiomer or in an enantiomerically enriched form

wherein

R , R and R are identical or different and each 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 , R⁵, R and R⁷ are identical or different and each 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 alkyl carbonyl, 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 following steps: a) treating a racemic compound of general formula I and a resolving agent as a single enantiomer in a mixture of an alcohol and water with an inorganic base to form an inclusion complex in an enantiomerically enriched form; b) treating the inclusion complex in an enantiomerically enriched form in an organic solvent with a strong inorganic base to form an inorganic salt of a compound of general formula I as a single enantiomer or in an enantiomerically enriched form; and c) treating the inorganic salt of a compound of general formula I as a single enantiomer or in an enantiomerically enriched form in a solvent with an acid to form a compound of general formula I as a single enantiomer or in an enantiomerically enriched form.

[0013] In a second aspect, the present application is directed to a process for resolution of a racemic enantiomer to prepare timoprazole, picoprazole, omeprazole, pantoprazole or lansoprazole as a single enantiomer or in an enantiomerically enriched comprising a) treating a racemic compound of timoprazole, picoprazole, omeprazole, pantoprazole or lansoprazole and a resolving agent as a single enantiomer in a mixture of an alcohol and water with an inorganic base to form an inclusion complex in an enantiomerically enriched form; b) treating the inclusion complex in an enantiomerically enriched form in an organic solvent with a strong inorganic base to form an inorganic salt of a compound of omeprazole as a single enantiomer or in an enantiomerically enriched form; and c) treating the inorganic salt of a compound of timoprazole, picoprazole, omeprazole, pantoprazole or lansoprazole as a single enantiomer or in an enantiomerically enriched form in a solvent with an acid to form a compound of omeprazole as a single enantiomer or in an enantiomerically enriched form.

[0014] In a third aspect, the present application is directed to a sulfoxide compound of general formula I as a single enantiomer or in an enantiomerically enriched form

wherein

R¹, R² and R³ are identical or different and each 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 , R , R and R are identical or different and each 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, prepared by a process for resolution of a racemic enantiomer of general formula I comprising a) treating a racemic compound of general formula I and a resolving agent as a single enantiomer in a mixture of an alcohol and water with an inorganic base to form an inclusion complex in an enantiomerically enriched form; b) treating the inclusion complex in an enantiomerically enriched form in an organic solvent with a strong inorganic base to form an inorganic salt of a compound of general formula I as a single enantiomer or in an enantiomerically enriched form; and c) treating the inorganic salt of a compound of general formula I as a single enantiomer or in an enantiomerically enriched form in a solvent with an acid to form a compound of general formula I as a single enantiomer or in an enantiomerically enriched form.

[0015] In a fourth aspect, the present application is directed to timoprazole, picoprazole, omeprazole, pantoprazole or lansoprazole as a single enantiomer or in an enantiomerically enriched prepared by a process for resolution of a racemic enantiomer of timoprazole, picoprazole, omeprazole, pantoprazole or lansoprazole comprising a) treating a racemic compound of timoprazole, picoprazole, omeprazole, pantoprazole or lansoprazole and a resolving agent as a single enantiomer in a mixture of an alcohol and water with an inorganic base to form an inclusion complex in an enantiomerically enriched form; b) treating the inclusion complex in an enantiomerically enriched form in an organic solvent with a strong inorganic base to form an inorganic salt of a compound of timoprazole, picoprazole, omeprazole, pantoprazole or lansoprazole as a single enantiomer or in an enantiomerically enriched form; and c) treating the inorganic salt of a compound of timoprazole, picoprazole, omeprazole, pantoprazole or lansoprazole as a single enantiomer or in an enantiomerically enriched form in a solvent with an acid to form a compound of omeprazole as a single enantiomer or in an enantiomerically enriched form. DETAILED DESCRIPTION QF THE INVENTION

[0016] 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. [0017] 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".

[0018] Reference throughout this specification to "one embodiment", or "an embodiment", or "in another embodiment", or "some embodiments", or "in some embodiments" means that a particular referent 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. [0019] 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.

[0020] 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 C₄-C₁₂ 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. [0021] As used herein, "C_m to C_n" or "C_{mtO 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 "Cl to C₄ alkyl" group refers to all alkyl groups having from 1 to 4 carbons, that is, CH₃-, CH₃CH₂-, CH₃CH₂CH₂-, (CH₃)₂CH-, CH₃CH₂CH₂CH₂-, CH₃CH₂CH(CH₃)- and (CH₃)₃C-. If 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. Definitions

[0022] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. All patent, applications, published applications and other publications referenced herein are incorporated by reference in their entirety. In the event that there is plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0023] The term "alkyl" as used herein alone or as part of a group means any unbranched or branched, substituted or unsubstituted, saturated hydrocarbon. The alkyl moiety, may be branched, straight chain, or cyclic. 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 size 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 "C₁-C₄ alkyl" or similar designations. By way of example only, "Ci-C₄ 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, wo-propyl, w-butyl, wo-butyl, sec-butyl, and f-butyl.

[0024] 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, 0-carbamyl, Λf-carbamyl, 0-thiocarbamyl, Λf-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-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, -SO₂-alkyl, -SO₂-substituted alkyl, -SO₂-aryl and -SO₂-heteroaryl.

[0025] 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 be substituted with one of the above substituents. [0026] 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-l,4-dienyl, and the like. [0027] 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 the rest of the molecule to a radical group, 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.

[0028] 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 the rest of the molecule to a radical group, 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. [0029] 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 the rest of the molecule to a radical group, 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.

[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 "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 Cm. In other embodiments, it may range from C₃ to Ce. A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. If substituted, the substituent(s) may be an alkyl or selected from those indicated above with regard to substitution of an alkyl group unless otherwise indicated. [0032] 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, if there is more than one, they cannot form a fully delocalized 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.

[0033] 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.

[0034] The term "carbonyl" as used herein alone or as part of a group refers to the group -(CO=).

[0035] The term "alkoxy" as used herein alone or as part of a group refers to any unbranched, or branched, substituted or unsubstituted, saturated or unsaturated ether, with Ci -Ce unbranched, saturated, unsubstituted ethers being preferred, with methoxy being preferred, and also with dimethyl, diethyl, methyl-isobutyl, and methyl-tert-butyl ethers also being preferred.

[0036] The term "alkylamino" as used herein alone or as part of a group refers to the group -NH-alkyl.

[0037] The term "dialkylamino" herein alone or as part of a group refers to the group -N(alkyl)₂, where the alkyl group is the same or different.

[0038] The term "alkylcarbonyl" as used herein alone or as part of a group refers to an alkyl group bonded through a carbonyl group.

[0039] The term "alkoxycarbonyl" as used herein alone or as part of a group refers to an alkoxy group bonded through a carbonyl group.

[0040] The term "dialkylaminocarbonyl" as used herein alone or as part of a group refers to a dialkylamino group bonded through a carbonyl group. [0041] The term "alkylaminocarbonyl" as used herein alone or as part of a group refers to an alkylamino group bonded through a carbonyl group.

[0042] 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.

[0043] The term "halo" or "halogen" as used herein alone or as part of a group refers to bromo, chloro, fluoro or iodo. [0044] The term "haloalkyl" as used herein alone or as part of a group refers to an alkyl radical, 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-fiuoroethyl,

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.

[0045] 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. [0046] 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. [0047] The term "trihaloalkoxy" as used herein, refers to a radical of a trihaloalkyl 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. [0048] 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, and nitrogen.

[0049] 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. [0050] 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. [0051] 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. [0052] Some examples of "heterocyclyls" include, but are not limited to, tetrahydrothiopyran, 4ff-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-l,4-thiazine, 2/7-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, moφholine, 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.

[0053] 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.

[0054] The term "carbocyclic" as used herein, refers to a compound which contains one or more covalently closed ring structures, and that 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.

[0055] 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 C₃_₈-cycloalkyl share at least one chemical bond. Some examples of "aryl" rings include optionally substituted phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl.

[0056] 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 para and/or meta positions. In other embodiments, the aryl group can be substituted at the ortho position. 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-moφholin-4-ylphenyl, 4-pyrrolidin-l-ylphenyl, 4-pyrazolylphenyl, 4-triazolylphenyl, and 4-(2-oxopyrrolidin-l-yl)phenyl. [0057] The term "arylalkyl" or "aralkyl" as used herein alone or as part of a group which are 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 -phenyl ethyl, 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 phenyl alkyl 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. [0058] 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. [0059] 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 share at least one chemical bond.

[0060] The term "heteroaryl" is understood to relate to aromatic, C3_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, alkylsulfϊnyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. In some embodiments, heteroaryl groups can be five- and six-membered aromatic heterocyclic systems carrying 0, 1, or 2 substituents, which can be the same as or different from one another, selected from the list above. [0061] 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.

[0062] 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, Λf-alkylcarboxamide, protected Λf-alkylcarboxamide, Λf Λf-dialkylcarboxamide, trifluoromethyl, Λf-alkylsulfonylamino, Λf-(phenylsulfonyl)amino and phenyl (resulting in the formation of a biphenyl group).

[0063] 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-(f-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-(Λf-(methylsulfonylamino))phenyl. [0064] The term "phenylalkoxy" as used herein alone or as part of a group refers to a "phenylalkyl-O-" group with "phenyl" and "alkyl" 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, (2R)-3-phenyl-2-amino-propoxy, (2ιS")-3-phenyl-2-amino-propoxy, 2-indanoxy, 6-phenyl-l-hexanoxy, cinnamyloxy, 2-phenyl-l-propoxy and 2,2-dimethyl-3 -phenyl- 1-propoxy.

[0065] 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 f-butylthio. [0066] The term "alkylsulfinyl" 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, methylsulfinyl, ethylsulfinyl, w-propylsulfinyl, isopropylsulfinyl, w-butylsulfinyl and sec-butylsulfinyl. [0067] The term "alkylsulfonyl" as used herein alone or as part of a group refers to an "alkyl-SO₂-" group. Examples of alkylsulfonyl groups include, but are not limited to, methylsulfonyl, ethylsulfonyl, w-propylsulfonyl, isopropylsulfonyl, w-butylsulfonyl, and f-butylsulfonyl.

[0068] The terms "phenylthio", "phenylsulfinyl", 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. [0069] The term "amino" as used herein alone or as part of a group refers to the -NH₂ radical. [0070] The term "cyano" as used herein alone or as part of a group refers to the -CN radical. [0071] The term "hydroxy" as used herein alone or as part of a group refers to the -OH radical. [0072] The term "imino" as used herein alone or as part of a group refers to the =NH substituent. [0073] The term "nitro" as used herein alone or as part of a group refers to the -NO₂ radical. [0074] The term "cyano" as used herein alone or as part of a group refers to the -CN substituent. [0075] The term "isocyanato" as used herein alone or as part of a group refers to the -NCO substituent. [0076] The term "thiocyanato" as used herein alone or as part of a group refers to the -CNS substituent. [0077] The term "isothiocyanato" as used herein alone or as part of a group refers to the -NCS substituent.

[0078] The term "O-carboxy" as used herein alone or as part of a group refers to the RC(O)O- substituent in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein. An O-carboxy may be substituted or unsubstituted.

[0079] The term "0-carbamyl" as used herein alone or as part of a group refers to the -OC(=O)NR_AR_B substituent in which R_A and R_B can be the same as R defined with respect to O-carboxy. An 0-carbamyl may be substituted or unsubstituted. [0080] The term 'W-carbamyl" as used herein alone or as part of a group refers to the ROC(=O)NR_A- substituent in which R and R_A can be the same as R defined with respect to O-carboxy. An Λf-carbamyl may be substituted or unsubstituted.

[0081] The term "0-thiocarbamyl" as used herein alone or as part of a group refers to the -OC(=S)-NR_AR_B substituent in which R_A and R_B can be the same as R defined with respect to O-carboxy. An 0-thiocarbamyl may be substituted or unsubstituted.

[0082] The term 'W-thiocarbamyl" as used herein alone or as part of a group refers to the ROC(=S)NR_A- substituent in which R and R_A can be the same as R defined with respect to O-carboxy. An Λf-thiocarbamyl may be substituted or unsubstituted. [0083] The term "C-amido" as used herein alone or as part of a group refers to the -C(=O)NR_AR_B substituent in which R_A and R_B can be the same as R defined with respect to O-carboxy. A C-amido may be substituted or unsubstituted.

[0084] The term 'W-amido" as used herein alone or as part of a group refers to the RC(=O)NR_A- substituent in which R and R_A can be the same as R defined with respect to O-carboxy. An Λf-amido may be substituted or unsubstituted. [0085] The term "oxo" as used herein alone or as part of a group refers to the =0 substituent. [0086] The term "thioxo" as used herein alone or as part of a group refers to the =S substituent. [0087] The term "trifluoromethyl" as used herein alone or as part of a group refers to the -CF₃ radical. [0088] The term "optional" or "optionally" as used herein means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.

[0089] Unless otherwise indicated, when a substituent is deemed to be "optionally substituted", it is meant that the substituent is a group that may 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, 0-carbamyl, Λf-carbamyl, 0-thiocarbamyl, Λf-thiocarbamyl, C-amido, N-amido, S-sulfonamido, Λf-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.

[0090] 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 aryl radicals having no substitution.

[0091] 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.

[0092] The term "racemic" as used herein refers to a mixture of equal parts of enantiomers which is optically inactive.

[0093] The term "resolution" as used herein refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule. [0094] Optically active (R)- and (-)-isomers and d and / isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If, for instance, a particular enantiomer of a compound of the present invention 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 subsequent recovery of the pure enantiomers. 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).

[0095] 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, higher than about 90% enantiomeric or diastereomeric excess is particularly preferred, e.g., those compositions with greater than about 95%, greater than about 97% and greater than about 99% ee or de. [0096] 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". [0097] The term "enantiomeric excess" is well known in the art and is defined as:

[0098] 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.

[0099] The term "inclusion complex" as used herein refers to a complex in which one component (the host) forms a cavity or, in the case of a crystal, a crystal lattice containing spaces in the shape of long tunnels or channels in which molecular entities of a second chemical species (the guest) are located. There is no covalent bonding between guest and host, the attraction being generally due to hydrogen-bonding and van der Waals forces. If the spaces in the host lattice are enclosed on all sides so that the guest species is "trapped" as in a cage, such compounds are known as clathrates or "cage compounds". [0100] The term "host" as used herein refers to a molecular entity that forms complexes with organic or inorganic guests, or a chemical species that can accommodate guests within cavities of its crystal structure. Examples include cryptands and crowns (where there are ion-dipole attractions between heteroatoms and positive ions), hydrogen-bonded molecules that form 'clathrates' {e.g. hydroquinone and water), and host molecules of inclusion compounds {e.g. urea or thiourea). Hydrogen-bonding, Van der Waals forces and hydrophobic interactions bind the guest to the host molecule in clathrates and inclusion compounds. [0101] The term "guest" as used herein refers to an organic or inorganic ion or molecule that occupies a cavity, cleft or pocket within the molecular structure of a host molecular entity and forms a complex with it or that is trapped in a cavity within the crystal structure of a host.

[0102] The term "base" as used herein refers to a chemical species or molecular entity having an available pair of electrons capable of forming a covalent bond with a hydron (proton) (Brønsted base) or with the vacant orbital of some other species (Lewis base). [0103] The term "acid" as used herein refers to a molecular entity or chemical species capable of donating a hydron (proton) (Brønsted acid) or capable of forming a covalent bond with an electron pair

(Lewis acid).

[0104] The term "alcohol" as used herein refers to a compound in which a hydroxy group, -OH, is attached to a saturated carbon atom R3COH.

EMBODIMENTS QF THE INVENTION

[0105] In one aspect, the present application is directed to a process for resolution of a racemic enantiomer to prepare a compound of general formula I as a single enantiomer or in an enantiomerically enriched form and a salt thereof as a single enantiomer or in an enantiomerically enriched form

wherein

R¹, R² and R³ are identical or different and each 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,

R⁴, R⁵, R⁶ and R⁷ are identical or different and each 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 following steps: a) treating a racemic compound of general formula I and a resolving agent as a single enantiomer in a mixture of an alcohol and water with an inorganic base to form an inclusion complex in an enantiomerically enriched form; b) treating the inclusion complex in an enantiomerically enriched form in an organic solvent with a strong inorganic base to form an inorganic salt of a compound of general formula I as a single enantiomer or in an enantiomerically enriched form; and c) treating the inorganic salt of a compound of general formula I as a single enantiomer or in an enantiomerically enriched form in a solvent with an acid to form a compound of general formula I as a single enantiomer or in an enantiomerically enriched form.

[0106] In some embodiments of the present application, the resolving agent as a single enantiomer is binaphthol as a single enantiomer.

[0107] Exemplary binaphthol as a single enantiomer that can be used in the present application includes, but is not limited to, (5)-l,l'-bi(2-naphthol) and (R)-l,l'-bi(2-naphthol). [0108] In some embodiments of the present application, the ratio of the resolving agent to the racemic compound of general formula I used in step a) is about 0.2-1 by mole. In some preferred embodiments of the present application, the ratio of the resolving agent to the racemic compound of general formula I used in step a) is about 0.5-0.7 by mole.

[0109] In some embodiments of the present application, exemplary alcohol that can be used in step a) includes, but is not limited to, methanol, ethanol, w-propanol, isopropanol, w-butanol, seobutanol, zsO-butanol, and a mixture thereof. In some preferred embodiments of the present application, the alcohol that can be used in step a) is ethanol.

[0110] In some embodiments of the present application, the ratio of the alcohol to water used in step a) is about 10-5:5-1 by volume. In some preferred embodiments of the present application, the ratio of the alcohol to water used in step a) is about 10:1 by volume. In some more preferred embodiments of the present application, the ratio of the alcohol to water used in step a) is about 7:3 by volume. In some more preferred embodiments of the present application, the ratio of ethanol to water used in step a) is about 7:3 by volume.

[0111] In some embodiments of the present application, the inorganic base that can be used in step a) includes, but is not limited to, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, and alkali metal alkoxides, alkali metal hydrophosphate, ammonium carbonate and ammonium bicarbonate.

[0112] Exemplary the inorganic base that can be used in step a) includes, but is not limited to, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium alkoxide, potassium alkoxide, sodium hydrophosphate, potassium hydrophosphate, ammonium carbonate and ammonium bicarbonate. In some preferred embodiments of the present application, the inorganic base that can be used in step a) is sodium bicarbonate.

[0113] In some embodiments of the present application, the ratio of the inorganic base to the racemic compound of general formula I used in step a) is about 0.05-1 by mole. In some preferred embodiments of the present application, the ratio of the inorganic base to the racemic compound of general formula I used in step a) is about 0.1-0.2 by mole. In some more preferred embodiments of the present application, the ratio of sodium bicarbonate to the racemic compound of general formula I used in step a) is about 0.1-0.2 by mole.

[0114] In some embodiments of the present application, the base is added in step a) at a temperature in the range of 30^o to 70 °C.

[0115] In some embodiments of the present application, the optical purity of the inclusion complex obtained in step a) is about 94-98%.

[0116] In some embodiments of the present application, the strong inorganic base that can be used in step b) includes, but is not limited, potassium hydroxide and sodium hydroxide. Exemplary strong inorganic base that can be used in step b) includes, but is not limited to alkali metal hydroxide. In some preferred embodiments of the present application, the strong inorganic base used in step b) is sodium hydroxide.

[0117] In some embodiments of the present application, the ratio of the strong inorganic base to the inclusion complex in step b) is about 0.1-2.0 by mole. In some preferred embodiments of the present application, the ratio of the strong inorganic base to the inclusion complex in step b) is about 1-1.5 by mole.

In some more preferred embodiments of the present application, the ratio of potassium hydroxide to the inclusion complex in step b) is about 1-1.5 by mole.

[0118] In some embodiments of the present application, the strong inorganic base is slowly dropwise added in step b) and is stirred at a temperature in the range of 20° to 80 ⁰C. In some embodiments of the present application, the resultatnt solution is cooled to the room temperature and stirred over 3 to 21 hours. In some preferred embodiments of the present application, the resultatnt solution is cooled to the room temperature and stirred over 16 to 21 hours.

[0119] In some embodiments of the present application, the organic solvent that can be used in step b) includes, but is not limited to, an alcohol solvent, a ketone solvent, DMF, DMA, DMSO, a furan solvent and a mixture thereof.

[0120] Exemplary alcohol solvent that can be used in step b) includes, but is not limited to, methanol, ethanol, w-propanol, isopropanol, w-butanol, seobutanol, wo-butanol, and a mixture thereof. In some embodiments of the present application, the alcohol solvent that can be used in step b) is ethanol. [0121] Exemplary ketone solvent that can be used in step b) includes, but is not limited to, acetone, 1-butanone, 2-butanone, cyclohexanone and a mixture thereof.

[0122] Exemplary furan solvent that can be used in step b) includes, but is not limited to, tetrahydro furan (THF), 2-methyltetrahydrofuran, and a mixture thereof.

[0123] In some embodiments of the present application, the volume of the organic solvent in step b) is about 3 to 15 mL per 1 gram of the inclusion complex. [0124] In some embodiments of the present application, the solvent used in step c) is a mixture of water and a water miscible organic solvent. In some preferred embodiments of the present application, the solvent used in step c) is a mixture of water and butanone.

[0125] Exemplary water miscible organic solvent that can be used in step c) includes, but is not limited to, an alcohol and a ketone. Exemplary alcohol that can be used in step c) includes, but is not limited to, methanol, ethanol, w-propanol, isopropanol, w-butanol, sec-butanol, wo-butanol, and a mixture thereof. Exemplary ketone that can be used in step c) includes, but is not limited to, acetone, 1-butanone, diacetone alcohol, γ-butyro lactone, and a mixture thereof.

[0126] In some embodiments of the present application, the ratio of water to the alcohol or ketone used in step c) is about 7-3:3-0.5 by volume. In some preferred embodiments of the present application, the ratio of water to the alcohol or ketone used in step c) is about 5: 1 by volume. In some more preferred embodiments of the present application, the ratio of water to 1-butanone used in step c) is about 5: 1 by volume. In some more preferred embodiments of the present application, the ratio of water to isopropanol used in step c) is about 5: 1 by volume. In some even more preferred embodiments of the present application, the ratio of water to 1-butanone used in step c) is about 5: 1 by volume. [0127] In some embodiments of the present application, the acid used in step c) is an organic or inorganic weak acid.

[0128] Exemplary the organic weak acid that can be used in step c) includes, but is not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene- 1,5-disulfonic acid, naphthalene-2-sulfonic acid, l-hydroxy-2 -naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, /?-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and a mixture thereof. [0129] Exemplary the inorganic weak acid that can be used in step c) includes, but is not limited to, KHSO₄, NaHCO₃, KH₂PO₄, NaH₂PO₄ and a mixture thereof.

[0130] In some embodiment of the present application, KH₂PO₄ is used as an inorganic weak acid in step c).

[0131] In some embodiments of the present application, the pH of the resultant solution is adjusted with an acid to about 7 to 8 in step c). [0132] In another aspect, the present application is directed to a process for resolution of a racemic enantiomer to prepare timoprazole, picoprazole, omeprazole, pantoprazole or lansoprazole as a single enantiomer or in an enantiomerically enriched comprising a) treating a racemic compound of timoprazole, picoprazole, omeprazole, pantoprazole or lansoprazole and a resolving agent as a single enantiomer in a mixture of an alcohol and water with an inorganic base to form an inclusion complex in an enantiomerically enriched form; b) treating the inclusion complex in an enantiomerically enriched form in an organic solvent with a strong inorganic base to form an inorganic salt of a compound of omeprazole as a single enantiomer or in an enantiomerically enriched form; and c) treating the inorganic salt of a compound of timoprazole, picoprazole, omeprazole, pantoprazole or lansoprazole as a single enantiomer or in an enantiomerically enriched form in a solvent with an acid to form a compound of omeprazole as a single enantiomer or in an enantiomerically enriched form.

[0133] This aspect of the present application is substantially akin to that as described above. Therefore, the process in this aspect can be readily carried out by those skilled in the art according to the disclosure of the present application and common knowledge in the art.

[0134] In yet another aspect, the present application is directed to a sulfoxide compound of general formula I as a single enantiomer or in an enantiomerically enriched form

wherein

R , R and R are identical or different and each 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,

R⁴, R⁵, R⁶ and R⁷ are identical or different and each 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, prepared by a process for resolution of a racemic enantiomer of general formula I comprising a) treating a racemic compound of general formula I and a resolving agent as a single enantiomer in a mixture of an alcohol and water with an inorganic base to form an inclusion complex in an enantiomerically enriched form; b) treating the inclusion complex in an enantiomerically enriched form in an organic solvent with a strong inorganic base to form an inorganic salt of a compound of general formula I as a single enantiomer or in an enantiomerically enriched form; and c) treating the inorganic salt of a compound of general formula I as a single enantiomer or in an enantiomerically enriched form in a solvent with an acid to form a compound of general formula I as a single enantiomer or in an enantiomerically enriched form.

[0135] This aspect of the present application is substantially akin to that as described above. Therefore, a sulfoxide compound of general formula I as a single enantiomer or in an enantiomerically enriched form can be readily obtained by those skilled in the art according to the disclosure of the present application and common knowledge in the art.

[0136] In yet another aspect, the present application is directed to timoprazole, picoprazole, omeprazole, pantoprazole or lansoprazole as a single enantiomer or in an enantiomerically prepared by a process a process for resolution of a racemic enantiomer comprising a) treating a racemic compound of timoprazole, picoprazole, omeprazole, pantoprazole or lansoprazole and a resolving agent as a single enantiomer in a mixture of an alcohol and water with an inorganic base to form an inclusion complex in an enantiomerically enriched form; b) treating the inclusion complex in an enantiomerically enriched form in an organic solvent with a strong inorganic base to form an inorganic salt of a compound of timoprazole, picoprazole, omeprazole, pantoprazole or lansoprazole as a single enantiomer or in an enantiomerically enriched form; and c) treating the inorganic salt of a compound of timoprazole, picoprazole, omeprazole, pantoprazole or lansoprazole as a single enantiomer or in an enantiomerically enriched form in a solvent with an acid to form a compound of omeprazole as a single enantiomer or in an enantiomerically enriched form.

[0137] This aspect of the present application is substantially akin to that as described above. Therefore, S-(-)-levo-timoprazole, S-(-)-levo-picoprazole, S-(-)-levo-omeprazole, S-(-)-levo-pantoprazole or

S-(-)-levo-lansoprazole can be readily obtained by those skilled in the art according to the disclosure of the present application and common knowledge in the art.

[0138] The process of the present application avoids the step in the conventional process in which an inclusion complex is recrystallized so that the ee can reach more than 99% and then extracted with an organic solvent. Therefore, the process of the present application can be readily used in the industrial production because the process is easily operated. Moreover, the process of the present application shortens the crystallization time and improves the productivity.

EXAMPLES

[0139] 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.

[0140] The yield of step a) is calculated on the basis of 100% of a single enantiomer.

Reagents and Apparatus:

[0141] Racemic Omeprazole, purchased from India

(S)-BINOL, purity Chiral Assay (HPLC): ee: 99.5% ee (optical purity) Chemical Assay (HPLC): 99.5%, purchased from Lianyungang Chiral Chemical (China) Co., Ltd

Other Reagents: purity>99.0%, purchased from Guangdong Chemical Reagents Engineering Technology R

& D Center, P R China

HPLC: Waters 1525 system; Detector: Waters 2487

Chiral HPLC Conditions: [0142] Omeprazole: Chiral-AD-H chiral column; eluant: 15% isopropanol/n-hexane; flow rate: 1.0 ml/min; wavelength: 254 nm; retention time: t_R=18.7 min, t_s=23.7 min

Pantoprazole: Chiral-AD-H chiral column; eluant: 15% isopropanol/n-hexane; flow rate: 1.0 ml/min; wavelength: 254 nm; retention time: t_R=33.0 min,

min

Lansoprazole: Chiral-OD-H chiral column; eluant: 30% isopropanol/n-hexane; flow rate: 1.0 ml/min; wavelength: 254 nm; retention time: t_R=10.2 min, t_s=12.1 min

Reaction Scheme:

[0143] A reaction scheme to prepare (S)-(-)-omeprazole as a single enantiomer or in an enantiomerically enriched form is descibed as follows. It should be appreciated that other compounds as a single enantiomer or in an enantiomerically enriched form similar to (S)-(-)-omeprazole as a single enantiomer or in an enantiomerically enriched form could be prepared in a process akin to that described below.

racemic omeprazole

(SH-MU '-binaphthalene]-2,2'-diol

in a mixed solvent system of an aqueous adding an inorganic base organic solvent and water

inclusion complex III

in an organic solvent adding an inorganic base

a salt of (SH-)-omeprazole

(SH-)-omeprazole

Reactoion Scheme of Preparation of (S")-(-)-omeprazole General Method: Resolution of Omeprazole

[0144] To a reaction bottle were added (S)-BINOL (2.5 g, 8.74 mmol), EtOH (35 mL) and water (15 mL). The resultant mixture was warmed to 60 ⁰C. After the solution became completely clear, the solution was cooled to 50°-55 ⁰C. To the solution were added NaHCO₃ and racemic omeprazole (5g, 14.49 mmol).

The resulting mixture was cooled to the room temperature under stirring to obtain a solid. The solid was filtered and dried at 40 ⁰C.

Examples 1-13

[0145] Following the procedure as described in General Method and using different inorganic bases, the title compound of racemic omeprazole was prepared. The results of the impacts of different inorganic bases on the resolution effects of omeprazole were listed in Table 1.

Table 1 Impacts of Different Inorganic Bases On Resolution Effects of Omeprazole

Solvent Inorganic Crystallization Crystallization

Yield* Ee

Examples (by volume, bases Temperature Time (% ) (% ) v/v) (by mole) (⁰O (hour)

EtOH/H₂O NaHCO₃

1 81.8 94.3 25 4

(7:3) (0.25)

EtOH/H₂O KHCO₃

2 81.4 87.5 21 4

(7:3) (0.25)

EtOH/H₂O Na₂HPO₄

3 93.6 92.0 25 15

(7:3) (0.25)

EtOH/H₂O Na₂CO₃

4 70.0 88.4 25 15

(7:3) (0.25)

EtOH/H₂O NH₄HCO₃

5 76.6 96.6 25 3.5

(7:3) (0.25)

EtOH/H₂O KOH

6 80.1 88.0 25 3.5

(7:3) (0.25)

EtOH/H₂O NaOH

7 79.2 79.3 25 3.5

(7:3) (0.25) Solvent Inorganic Crystallization Crystallization

Yield* Ee

Examples (by volume, bases Temperature Time (% ) (% ) v/v) (by mole) (⁰C) (hour)

EtOH/H₂O NH₄HCO₃

8 83.8 91.4 25 4

(7:3) (0.5)

EtOH/H₂O NH₄HCO₃

9 87.9 95.7 25 4

(7:3) (0.1)

EtOH/H₂O Na₂HPO₄

10 93.0 88.6 25 4

(7:3) (0.1)

EtOH/H₂O NaHCO₃

11 84.9 97.1 25 4

(7:3) (0.1)

NaHCO₃

12 EtOH 94.1 10.7 25 4

(0.2)

NaHCO₃

13 H₂O 157.5 0 25 4 (0.1)

* Yield is calculated on the basis of 100% of single enantiomer Example 14

[0146] To a reaction bottle were added the above obtained omeprazole inclusion complex (3.83 g, 6.07 mmol, ee: 91.4%) and EtOH (26.8 mL). To the reaction bottle was slowly dropwise added a solution of KOH (0.34 g, 6.07 mmol) in EtOH (17.6 mL). The reaction solution became turbid. The turbid solution was heated to 50 ⁰C and became completely clear. The clear solution was cooled to the room temperature under stirring and then was stirred for further 3 hours. The resultant solution was filtered to obtain a white-like solid (potassium omeprazole confirmed by NMR). The obtained solid was dissolved in water (50 mL). To the resultant solution was added IPA (1 mL). The pH of the solution was adjusted to 8 with HAc (IN). The solution was warmed at 18 ⁰C over 4.5 hours and then was filtered to give a white-like solid (1.4 g). The solid was dried to give a final product (0.5 g). Yeild: 23.9% (two steps). Ee: 99.8%. Example 15 [0147] To a reaction bottle were added the above obtained omeprazole inclusion complex (3.72 g, 5.895 mmol, ee: 87.5%) and EtOH (26.0 mL). To the reaction bottle was slowly dropwise added a solution of KOH (0.396 g, 7.074 mmol) in EtOH (17.1 mL). The reaction solution became turbid. The turbid solution was heated to 75 ⁰C and became completely clear. The clear solution was cooled to the room temperature under stirring and then was stirred for further 17 hours. The resultant solution was filtered to obtain a white solid (2.1 g). The obtained solid was dissolved in a mixture of water (21 mL) and butanone (4.2 mL). To the resultant solution was added KH₂PO₄ (0.746 g, 5.482 mmol) in an ice bath under stirring. The solution was stirred for further 4 hours and then was filtered to give a solid (3.3 g). The solid was dried to give a final product (1.4 g). Yeild: 69.0% (two steps). Ee: 100%. Content (HPLC): 99.0%. Example 16 [0148] To a reaction bottle were added the above obtained omeprazole inclusion complex (4.28 g, 6.783 mmol, ee: 92.0%) and EtOH (29.9 mL). To the reaction bottle was slowly dropwise added a solution of KOH (0.456 g, 8.14 mmol) in EtOH (19.7 mL). The reaction solution became turbid. The turbid solution was heated to 80 ⁰C and became completely clear. The clear solution was cooled to the room temperature under stirring and then was stirred for further 17 hours. The resultant solution was filtered. To the filtrate was added a small amount of potassium salt as a crystal seed. The filtrate was stirred for further 5 hours at the room temperature and then was filtered to obtain a white solid (1.66 g). The obtained solid was dissolved in a mixture of water (16.6 mL) and butanone (3.3 mL). To the resultant solution was added KH₂PO₄ (0.59 g, 4.335 mmol) in an ice bath under stirring. The solution was warmed at 22 ⁰C and stirred for further 14 hours and then was filtered to give a offwhite solid (1.0 g). The solid was dried to give a final product (0.765 g). Yeild: 36.5% (two steps). Ee: 100%. Content (HPLC): 98.3%. Example 17

[0149] To a reaction bottle were added the above obtained omeprazole inclusion complex (3.74 g, 5.927 mmol, ee: 94.3%) and EtOH (26.1 mL). To the reaction bottle was slowly dropwise added a solution of KOH (0.398 g, 7.113 mmol) in EtOH (17.2 mL). The reaction solution became turbid. The turbid solution was heated to 70 ⁰C and became completely clear. The clear solution was cooled to the room temperature under stirring and then was stirred for further 20 hours. The resultant solution was filtered to obtain a white solid (2.46 g). The obtained solid was dissolved in a mixture of water (22.7 mL) and butanone (4.5 mL). To the resultant solution was added KH₂PO₄ (0.807 g, 5.93 mmol) in an ice bath under stirring. The solution was stirred for further 4 hours and then was filtered to give a white solid (3.9 g). The solid was dried to give a final product (1.179 g). Yeild: 57.7% (two steps). Ee: 100%. Content (HPLC): 98.9%. Example 18

[0150] To a reaction bottle were added the above obtained omeprazole inclusion complex (3.88 g, 6.149 mmol, ee: 97.1%) and EtOH (27.1 mL). To the reaction bottle was slowly dropwise added a solution of KOH (0.413 g, 7.379 mmol) in EtOH (17.8 mL). The reaction solution became turbid. The turbid solution was heated to 70 ⁰C and became completely clear. The clear solution was cooled to the room temperature under stirring and then was stirred for further 21 hours. The resultant solution was filtered to obtain a white solid (2.08 g). The obtained solid was dissolved in a mixture of water (20.8 mL) and butanone (4.2 mL). To the resultant solution was added KH₂PO₄ (0.739 g, 5.43 mmol) in an ice bath under stirring. The solution was stirred for further 4 hours and then was filtered to give a white solid (3.7 g). The solid was dried to give a final product (1.187 g). Yeild: 56.0% (two steps). Ee: 100%. Content (HPLC): 99.2%. Example 19

[0151] To a reaction bottle were added (S)-BINOL (9.948 g, 0.0348 mol), EtOH (140 mL) and water (60 mL). The resultant mixture was warmed to 60 ⁰C. After the solution became completely clear, the solution was cooled to 50°-55 ⁰C. To the solution were added NaHCO₃ (1.218 g, 0.0145 mol) and racemic omeprazole (20 g, 0.058 mol). The resulting mixture was cooled to the room temperature under stirring to obtain a yellow white solid (35 g). The solid was filtered and dried at 40 ⁰C (15.309 g, 83.7% yield, Ee:

[0152] To a reaction bottle were added the above obtained omeprazole inclusion complex (15.309 g, 0.0243 mol, ee: 98.0%) and EtOH (107 mL). To the reaction bottle was slowly dropwise added a solution of KOH (1.63 g, 0.0291 mol) in EtOH (70.4 mL). The reaction solution became turbid. The turbid solution was heated to 75 ⁰C and became completely clear. The clear solution was cooled to the room temperature under stirring and then was stirred for further 16.5 hours. The resultant solution was filtered to obtain a white solid (10.84 g, 116.7%, yield). The obtained solid was dissolved in a mixture of water (92.9 mL) and butanone (18.6 mL). To the resultant solution was added KH₂PO₄ (3.3 g, 0.0242 mol) in an ice bath under stirring. The solution was kept warm and stirred for further 4 hours and then was filtered to give a white solid (13.5 g). The solid was dried to give a final product (6.383 g). Yeild: 76.3% (two steps). Ee: 100%. Content (HPLC): 98.3%. Example 20 [0153] To a reaction bottle were added (S)-BINOL (9.948 g, 0.0348 mol), EtOH (140 mL) and water (60 mL). The resultant mixture was warmed to 60 ⁰C. After the solution became completely clear, the solution was cooled to 50°-55 ⁰C. To the solution were added NaHCO₃ (0.487 g, 0.0058 mol) and racemic omeprazole (20 g, 0.058 mol). The resulting mixture was cooled to the room temperature under stirring to obtain a yellow white solid (49 g). The solid was filtered and dried at 40 ⁰C (16.51 g, 90.3% yield, Ee: 95.8%). [0154] To a reaction bottle were added the above obtained omeprazole inclusion complex (16.51 g, 0.0262 mol, ee: 95.8%) and EtOH (115 mL). To the reaction bottle was slowly dropwise added a solution of KOH (1.76 g, 0.0314 mol) in EtOH (76 mL). The reaction solution became turbid. The turbid solution was heated to 55°-60 ⁰C and became completely clear. The clear solution was cooled to the room temperature under stirring and then was stirred for further 16 hours. The resultant solution was filtered to obtain a white solid (11.3 g). The obtained solid (11.3 g) was dissolved in EtOH (40 mL). The solution was heated to 75 ⁰C and became completely clear. The clear solution then was cooled to the room temperature and was stirred over 3.5 hours at the room temperature. The resultant solution was filtered to obtain a white solid (10.78 g). The obtained solid was dissolved in a mixture of water (80 mL) and butanone (16 mL). To the resultant solution was added KH₂PO₄ in an ice bath to adjust the pH of the solution to 7. The solution was kept warm and stirred over 4 hours and then was filtered to give a white solid (13.6 g). The solid was dried to give a final product (6.035 g). Yeild: 66.9% (two steps). Ee: 100%. Content (HPLC): 99.8%. Example 21

[0155] The ethanol mother liquor of Example 18 was condensed to a volume of about 18 mL. To the condensed solution was added water (18 mL). The resultant mixture was stirred over 4 hours at the room temperature and then was filtered to give a light yellow solid. The solid was dried at 40 ⁰C to give a final product (1.45 g, 82.5% yield, Ee: 100%).

[0156] Similarly, it would be contemplated that other compounds such as timoprazole (Ri=R₂=R₃=R₄=R₅=R₆=R₇=H), picoprazole (Ri=R₂=H, R₃=CH₃, R₄=R₇=H, R₅=CO₂CH₃, R₆=CH₃), lansoprazole (Ri=H, R₂=OCH₂CF₃, R₃=CH₃, R₄=R₅=R₆=R₇=H), and pantoprazole (Ri=H, R₂=OCH₃, R₃=OCH₃, R₄=R₆=R₇=H, R₅=OCHF₂) as a single enantiomer or in an enantiomerically enriched form can be prepared according to the process disclosed in the present application and common knowledge of a person having ordinary skill in the art. For example, S-(-)-levo-lansoprazole may be prepared in accordance with the following steps a) treating racemic lansoprazole and (ιS")-l,l '-bi(2-naphthol) (wherein the ration of (ιS")-l,l '-bi(2-naphthol) to lansoprazole is about 0.5-0.7 by mole) in a mixture of an ethanol and water (wherein the ratio of ethanol to water is about 7:3 by volume) with sodium carbonate (wherein the ratio of sodium carbonate to lansoprazole is about 0.1-0.2 by mole) to form an inclusion complex in an enantiomerically enriched form; b) treating the inclusion complex in an enantiomerically enriched form in ethanol with potassium hydroxide to form an inorganic salt of lansoprazole (wherein the ratio of potassium hydroxide to the inclusion is about 1-1.5 by mole) as a single enantiomer or in an enantiomerically enriched form; and c) treating the inorganic salt of lansoprazole as a single enantiomer or in an enantiomerically enriched form in a mixture of water and butanone (wherein the ratio of water to butanone is about 5: 1 by volume) with KH₂PCMo form S-(-)-levo-lansoprazole

[0157] 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.

[0158] 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.

Claims

WHAT IS CLAIMED IS:

1. A process for resolution of a racemic enantiomer to prepare a compound of general formula I as a single enantiomer or in an enantiomerically enriched form and a salt thereof as a single enantiomer or in an enantiomerically enriched form

wherein

R¹, R² and R³ are identical or different and each 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 alkoxy carbonyl, 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 , R , R and R are identical or different and each 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 following steps: a) treating a racemic compound of general formula I and a resolving agent as a single enantiomer in a mixture of an alcohol and water with an inorganic base to form an inclusion complex in an enantiomerically enriched form; b) treating the inclusion complex in an enantiomerically enriched form in an organic solvent with a strong inorganic base to form an inorganic salt of a compound of general formula I as a single enantiomer or in an enantiomerically enriched form; and c) treating the inorganic salt of a compound of general formula I as a single enantiomer or in an enantiomerically enriched form in a solvent with an acid to form a compound of general formula I as a single enantiomer or in an enantiomerically enriched form.

2. A process of claim 1, wherein the resolving agent as a single enantiomer is binaphthol as a single enantiomer.

3. A process of claim 2, wherein the binaphthol as a single enantiomer is selected from the group consisting of (5)-l,l '-bi(2-naphthol) and (/?)-l,l '-bi(2-naphthol).

4. A process of claim 1, wherein the alcohol used in step a) is selected from the group consisting of methanol, ethanol, w-propanol, isopropanol, w-butanol, seobutanol, wo-butanol, and a mixture thereof, and preferably the alcohol used in step a) is ethanol.

5. A process of claim 1, wherein the inorganic base used in step a) is selected from the group consisting of alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal alkoxides, alkali metal hydrophosphates, ammonium carbonate and ammonium bicarbonate.

6. A process of claim 1, wherein the inorganic base used in step a) is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium alkoxide, potassium alkoxide, sodium hydrophosphate, potassium hydrophosphate, ammonium carbonate and ammonium bicarbonate, and preferably the inorganic base used in step a) is sodium bicarbonate.

7. A process of claim 1, wherein the strong inorganic base used in step b) is selected from the group consisiting of potassium hydroxide, sodium hydroxide, and preferably the inorganic base used in step b) is sodium hydroxide.

8. A process of claim 1, wherein the organic solvent used in step b) is selected from the group consisiting of an alcohol solvent, a ketone solvent, DMF, DMA, DMSO, a furan solvent and a mixture thereof.

9. A process of claim 8, wherein the alcohol solvent is selected from the group consisting of methanol, ethanol, w-propanol, isopropanol, w-butanol, sec-butanol, wo-butanol, and a mixture thereof, and preferably the alcohol solvent is ethanol.

10. A process of claim 8, wherein the ketone solvent is selected from the group consisting of acetone, butanone, and a mixture thereof.

11. A process of claim 8, wherein the furan solvent is selected from the group consisting of tetrahydro furan (THF), and a mixture thereof.

12. A process of claim 1, wherein the solvent used in step c) is a mixture of water and a water miscible organic solvent.

13. A process of claim 12, wherein water miscible organic solvent is selected from the group consisting of an alcohol and a ketone.

14. A process of claim 13, wherein the alcohol is selected from the group consisting of methanol, ethanol, w-propanol, isopropanol, w-butanol, seobutanol, wo-butanol, and a mixture thereof.

15. A process of claim 13, wherein the ketone is selected from the group consisting of acetone, 1-butanone, diacetone alcohol, γ-butyro lactone, and a mixture thereof.

16. A process of claim 1, wherein the acid used in step c) is an organic or inorganic weak acid, and preferably the acid used in step c) is KH₂PO₄.

17. A process of claim 14, wherein the organic weak acid is selected from the group consisting of acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene- 1, 5 -disulfonic acid, naphthalene-2-sulfonic acid, l-hydroxy-2 -naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, /?-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and a mixture thereof.

18. A process of claim 14, the inorganic weak acid is selected from the group consisting OfKHSO₄, NaHCO₃, KH₂PO₄, NaH₂PO₄ and a mixture thereof.

19. A process of claim 1, wherein the ratio of the resolving agent to the racemic compound of general formula I used in step a) is about 0.2-1 by mole, preferably about 0.5-0.7 by mole.

20. A process of claim 1, wherein the ratio of the inorganic base to the racemic compound of general formula I used in step a) is about 0.05-1 by mole, preferably about 0.1-0.2 by mole.

21. A process of claim 1, wherein the ratio of the alcohol to water used in step a) is about 10: 1 by volume, preferably about 7:3 by volume.

22. A process of claim 1, wherein the ratio of the strong inorganic base to the inclusion complex in step b) is about 0.1-2.0 by mole, preferably about 1-1.5 by mole.

23. A process of claim 12, wherein the ratio of water to the water miscible organic solvent is about 7:3 by volume, preferably about 5: 1 by volume.

24. A process of claim 1, wherein R , R and R are identical or different and each 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.

25. A process of claim 1, wherein R⁴, R⁵, R⁶ and R⁷ are identical or different and each 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.

26. A process of any one of claims 1-25, wherein Ri= R₂=R₃=R₄=R₅=R₆ ⁼R₇ ⁼H.

27. A process of any one of claims 1-25, wherein Ri=R₂=H, R₃=CH₃, R₄=R₇=H,

R₅=CO₂CH₃, R₆=CH₃.

28. A process of any one of claims 1-25, wherein Ri=CH₃, R₂=OCH₃, R₃=CH₃, R₄= R₆= R₇=H, and R₅=OCH₃.

29. A process of any one of claims 1-25, wherein Ri=H, R₂=OCH₂CF₃, R₃=CH₃, and R₄= R₅= R₆= R₇=H.

30. A process of any one of claims 1-25, wherein Ri=H, R₂=OCH₃, R₃=OCH₃, and R₄= R₆= R₇=H, R₅=OCHF₂.

31. S-(-)-levo-timoprazole prepared by a process of any one of claims 1-25.

32. S-(-)-levo-picoprazole prepared by a process of any one of claims 1-25.

33. S-(-)-levo-omeprazole prepared by a process of any one of claims 1-25.

34. S-(-)-levo-pantoprazole prepared by a process of any one of claims 1-25.

35. ιS"-(-)-levo-lansoprazole prepared by a process of any one of claims 1-25.