CN1665805A - A method for preparing optically pure or optically concentrated sulfoxide compounds including amorphous esomeprazole and salts thereof - Google Patents

Abstract

A process of preparation of optically pure or optically enriched isomers of omeprazole and structurally related sulfoxides is provided. Also provided are an amorphous form of esomeprazole, as well a pharmaceutical composition containing it and a method of using it for treatment of gastric disorders.

Description

A process for the preparation of optically pure or optically concentrated sulfoxide compounds including amorphous esomeprazole and salts thereof

Cross References to Related Applications

This application claims priority to Indian Patent Application 489/MAS/2002 filed on June 27, 2002 (filing date) and Indian Patent Application 493/MAS/2002 filed on June 28, 2002, both patents The contents of the literature are hereby incorporated by reference in their entirety.

technical field

The present invention relates to a process for the preparation of single enantiomers of organic sulfoxides such as omeprazole and compounds of related structure, as well as salts and hydrates thereof. Also provided are specific salts of the resulting enantiomerically pure or enantiomerically enriched sulfoxides and methods of their use.

Background technique

Omeprazole and structurally similar sulfoxide compounds are known inhibitors of gastric acid secretion and are used as antiulcer agents. The sulfur atom of the sulfoxide group in the asymmetric substitution sulfoxide is chiral. Therefore, omeprazole and related sulfoxides exhibit optical isomerism at the sulfur atom of the sulfoxide. Omeprazole actually exists as a pair of enantiomers; the S(-) enantiomer is called esomeprazole.

Certain analytical and preparative methods for the separation of the enantiomers of omeprazole are known in the art. For example, the reaction of the 6-methoxy analogue of omeprazole with R-mandelic acid in chloroform produces a mixture of diastereomeric forms that can be separated by reverse phase chromatography. The preparation of single enantiomers or enantiomerically enriched omeprazoles by asymmetric oxidation of pro-chiral sulfides is also known. If salts of sulfoxides are desired, they can be obtained, for example, by reaction with corresponding bases or alkaline earth bases.

However, there is also a need for new methods of preparing substantially optically pure or optically concentrated sulfoxide compounds as well as isomers of previously obtained compounds, their salts, and their hydrates.

Summary of the invention

One aspect of the present invention provides a method for the enantioselective preparation of a single enantiomer of a sulfoxide compound and pharmaceutically acceptable salts and hydrates thereof. Sulfoxide compounds suitable as substrates for this method of the invention include, for example, such pharmaceutically acceptable compounds as omeprazole, lansoprazole, pantoprazole, pariprazole, and leminoprazole. Thus, in this aspect there is provided a process for the preparation of a substantially optically pure or optically concentrated sulfoxide compound comprising

a) providing a starting material located in an organic solvent, said starting material being a mixture of optical isomers of a compound containing a sulfoxide group of the following structure or a salt thereof,

The different optical isomers have R and S configurations on the sulfur atom of the sulfoxide group;

b) reacting the mixture of optical isomers with i) a complexing agent comprising a transition metal, and ii) a chelating agent in an organic solvent, whereby each optical isomer forms a transition with it on the sulfoxide group metal complexes;

c) reacting a mixture of transition metal complexes with an organic acid or salt thereof capable of forming an addition product with the transition metal complex; wherein at least one of said chelating agent or organic acid comprises a chiral center and in substantially enantiomerically pure form with respect to the chiral center; whereby each transition metal complex of the optical isomer forms an adduct with an organic acid or a salt thereof, the different adducts having at least A physical property different from other adducts;

d) separating the adducts from each other on the basis of said at least one different physical property; treating the separated adducts with an external acid or base to treat said adducts on said sulfoxide group Transition metal complexes are decomposed to obtain an optical isomer of the sulfoxide compound in substantially optically pure or optically concentrated form; wherein R' is

or

R" is

and X is

或

or

wherein R ₁ , R ₂ , R ₃ , and R ₄ , which may be the same or different, are independently hydrogen, alkyl, alkoxy, halogen, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolyl, or trifluoroalkyl;

R ₅ , R ₆ , and R ₇ , which may be the same or different, are each independently hydrogen, alkyl, haloalkyl, alkylthio, haloalkylthio, alkoxy, haloalkoxy, alkoxyalkoxy, di Alkylamino, piperdino, morpholino, halogen, phenylalkyl or phenylalkoxy;

R ₈ is hydrogen or lower alkyl;

R ₉ and R ₁₀ , which may be the same or different, are each independently hydrogen, halogen, alkyl or alkoxy.

In a more preferred embodiment, the organic acid or salt thereof is added in step c) while stirring at ambient temperature for about 15 minutes to about 5 hours.

In a more preferred embodiment, the present invention provides specific processes for the preparation of omeprazole and salts thereof in substantially enantiomerically pure or enantiomerically enriched form. In other preferred aspects, the present invention also provides an amorphous form of esomeprazole, a pharmaceutical composition containing the amorphous form, and related treatment methods.

Brief description of the drawings

Figure 1 shows the X-ray powder diffraction pattern of amorphous esomeprazole.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

In order to describe the present invention, some terms are defined as follows. A "compound" is a chemical substance comprising one or more molecules of the same structure. A "compound" is not a mixture. A "composition" may include a single compound or a mixture of compounds. A "pharmaceutical composition" is any composition that is or may be useful in producing a pharmacological response in a subject using such a pharmaceutical composition.

The term "solvent" as used herein refers to a single compound or a mixture of compounds. The term "organic solvent" refers to solvents generally understood in the art, including solvents which are preferably non-polar or hydrophobic and substantially soluble. Non-limiting examples of organic solvents include chlorinated alkanes such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; ketones and alkyl ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketones, and diethyl ketone; esters of organic acids, such as ethyl acetate; and nitriles, such as acetonitrile. The term "aqueous solvent" refers to a solvent comprising water. Thus, the term "aqueous/organic solvent" refers to a mixture of water and an organic solvent (group of organic solvents) that is either predominantly organic or predominantly aqueous; for example, may be about 99.1% organic to about Any mixture ranging from 0.1% water to about 99.1% water to about 0.1% organic solvent, and preferably about 95% organic solvent to about 5% water. As used herein, an "external" acid or base is distinct from an acid or base already present in the reaction mixture, and refers to an acid or base that is added to the reaction independently during the indicated step.

In describing the compounds of the present invention, certain nomenclature and terminology are used throughout to designate various groups, substituents, and the like. In this regard, the description " _Cx - _Cy " refers to a chain or carbocyclic skeleton comprising carbon atoms comprising x to y atoms, including X and Y. Designated ranges of carbon atoms shall refer independently to the number of carbon atoms in the chain or cyclic backbone or the portion of larger substituents in which the chain or backbone is contained. Unless otherwise stated, the designated group or substituent terminal moiety is described first, followed by the functional group or molecular part that is more closely attached to the remainder of the molecule. In one non-limiting example, "carboxyalkyl" refers to a group having a terminal carboxyl group and a point of attachment to the remainder of the molecule. By exception, "alkylhydroxyl" refers to an alkyl group having a terminal or pendant-attached hydroxyl group.

Whether used alone or as part of another group, the term "alkyl" is a group or substituent that includes a chain of carbon atoms. An "alkyl" group or substituent may include a chain of carbon atoms only, or may include a chain of carbon atoms terminated with a non-alkyl functionality, or may include a chain of carbon atoms attached to the molecule through a non-alkyl functionality. A chain of carbon atoms on the remainder. The chain of carbon atoms of the alkyl groups described and claimed herein may be saturated or unsaturated, straight or branched, substituted or unsubstituted. In a preferred embodiment, the alkyl group is a C ₁ -C ₁₆ alkyl group, more preferably the alkyl group is a C ₁ -C ₆ alkyl group.

In one non-limiting example, groups comprising carbon chains of the structure -CH ₂ CH ₂ CH ₃ , -CHCHCH ₃ , and -CH(CH ₃ )CH ₂ CH ₃ are all "alkyl groups" as defined herein. ". In other non-limiting examples, those comprising the structures _-CH2CF2CH3 , _{-CHCHCFH2 , -CH2} - _CH (OH _{) CH2CH3} , and _-CH ( _CH3 ) _CH2CH2COOH Carbon chain radicals are all "alkyl" as defined herein. "Haloalkyl" refers to a group in which one or more hydrogen atoms attached to the carbon atoms of the chain are replaced by one or more halo (which refers to fluorine, chlorine, bromine, or iodine).

The term "alkoxy" refers to an oxyether group comprising an alkyl group as previously defined and an oxygen linking the "alkoxy" to the rest of the molecule. In a preferred embodiment, the alkoxy is a C ₁ -C ₁₆ alkoxy, more preferably a C ₁ -C ₆ alkoxy. The alkyl and alkoxy groups of the compounds described herein may be independently substituted by one or more substituents, which are non-limitingly mono-, di-, tri-, or per-halogenated, including Substituted by chlorine, fluorine, bromine and iodine; lower alkyl, such as C ₁ -C ₆ alkyl, specifically including methyl, ethyl, and propyl; lower alkoxy, such as C ₁ -C ₆ alkoxy, Specifically include methoxy, ethoxy, and propoxy; hydroxyl; amino, including mono-(C ₁ -C ₆ alkyl)amino, such as specifically methylamino, ethylamino, propylamino, etc. etc., and di-(C ₁ -C ₆ alkyl)amino, such as specifically dimethylamino, diethylamino, methylethylamino, dipropylamino, ethylpropylamino and the like; aryl hydroxyaryl; hydroxyalkyl; alkoxyaryl; heteroaryl, specifically including pyridyl; heterocyclyl, cyano; mercapto; nitro; and C ₁ -C ₈ acyloxy. This group can have a general definition or a more specific definition, as required. For example, a group comprising a carbon chain with one carbon-carbon double bond may be described as an alkyl or alkenyl group as appropriate. In another non-limiting example, a group comprising a carbon chain with a chlorine substituent may be described as an alkyl or haloalkyl as appropriate. As defined, the term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms attached to a carbon atom of the chain has been replaced by one or more halogens. "Alkoxyalkoxy" means lower alkoxy-substituted lower alkoxy as defined C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy, e.g. methoxymethoxy .

Whether used alone or as part of a substituent, the term "acyl" refers to an organic radical obtained by removing a hydroxyl group from an organic acid. "C _x -C _y acyl" refers to an acyl group derived from an organic acid comprising a carbon chain having from x to y carbon atoms. The acyl group may be a C ₁ -C ₆ acyl group, non-limiting examples of which are acetyl, propionyl or benzoyl. The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine. Mono-, di-, tri-, and per-halo-alkyl are alkyl groups obtained by independently replacing a hydrogen atom with a halogen.

"Aryl", whether used alone or as part of a substituent, is a carbocyclic aryl group, examples of which include, but are not limited to, phenyl, 1- or 2-naphthyl, and the like. The "aryl" of the compounds described herein can be independently replaced by substituents for 1 to 3 hydrogen atoms on the carbocyclic aromatic skeleton, said substituents include, but are not limited to, halogen, -OH, -CN , mercapto, nitro, amino, substituted amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylamino, halo C ₁ -C ₆ alkyl, formyl, C ₁ -C ₆ acyl, C ₁ -C ₆ alkoxyacyl, and C ₁ -C ₆ amido. Examples of aryl include, but are not limited to, phenyl, naphthyl, diphenyl, fluorophenyl, methoxyethylphenyl, difluorophenyl, benzyl, benzoyloxyphenyl, ethoxycarbonyl Phenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, tolyl, xylyl, and dimethylcarbamoylphenyl base.

Whenever the term "alkyl", "acyl", or "aryl" or any of its prefixed radicals (e.g., aralkyl, dialkylamino) appears in the description of a substituent, it should be construed to include the above Groups used in the definitions of "alkyl", "acyl", and "aryl". "Heteroaryl", whether used alone or as part of a substituent, means a cyclic aromatic radical having 5 to 10 ring atoms, one of said ring atoms being selected from the group consisting of S, O, and N; 0-2 ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon. The group is attached to the remainder of the molecule through any ring atom, for example, pyridyl, pyrazinyl, pyrimidinyl, pyrrocarbonyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazole group, thiadiazolyl, triazolyl, oxadiazolyl, thienyl, furyl, quinolinyl, isoquinolyl, etc. Said heteroaryl may be substituted by independently replacing 1 to 3 hydrogen atoms on the carbocyclic aromatic backbone with substituents including, but not limited to, halogen, -OH, -CN, mercapto , nitro, amino, substituted amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylamino, halogenated C ₁ -C ₆ alkyl, formyl, C ₁ -C ₆ acyl, C ₁ -C ₆ alkoxyacyl, and C ₁ -C ₆ amido. Phenylalkyl refers to phenyl attached to the parent molecule through an alkyl substituent (alkyl as defined herein), eg benzyl, 2-phenylethyl, 3-phenylpropyl. Phenylalkoxy refers to phenyl attached to the parent molecule through an alkoxy substituent (alkoxy as defined), eg, benzoyl, 3-bromo-benzoyl, 4-benzyl Oxybenzoyl, 4-hydroxybenzoyl, 3,5-dibromobenzoyl. Alkylcarbonyl refers to an alkyl group as defined (R ₁ R ₂ C(O)) attached to the parent molecule through a carbonyl group, eg methylcarbonyl. Alkoxycarbonyl refers to an alkoxy group attached to the parent molecule through a carbonyl group, eg tert-butoxycarbonyl.

Unless otherwise specified, any substituent or variable at a particular position on a molecule is defined independently of its definition elsewhere in the molecule. It should be apparent that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and readily synthesized using techniques well known in the art and methods described herein. The term "saturated" as used in reference to heterocyclic or carbocyclic skeletons is used to describe a skeleton that has no double or triple bonds between the skeleton atoms.

The term "subject" includes, without limitation, any animal or artificially modified animal. For particular embodiments, the subject is a human. The terms "drug resistance" or "drug resistance" refer to the property of microorganisms that survive in the presence of currently available antimicrobial agents, such as antibiotics, at their usual effective concentrations. The term "pharmaceutically acceptable" defines a non-toxic substance generally suitable for human or animal medicine.

The present invention relates to a process for the preparation of substantially optically pure or optically concentrated sulfoxide compounds, ie by the process of the present invention. Intermediates in the process of the invention are also part of the invention, as are their salts and hydrates.

In one embodiment of the method aspects of the invention, the starting material is a salt of formula (I):

wherein M is an alkali or alkaline earth metal; M is preferably sodium. In one variation, R ₁ , R ₂ , R ₃ , and R ₄ are hydrogen. In another variant, R ₆ may be O(CH ₂ ) ₃ OCH ₃ or OCH ₂ CF ₃ , especially wherein R ₅ is hydrogen and R ₇ is methyl. In another variation, R ₁ , R ₃ , and R ₄ are hydrogen; R ₂ and R ₆ are methoxy; and R ₅ and R ₇ are methyl, and in yet another embodiment, R ₁ , _R3 , _R4 , and _R5 are hydrogen; _R2 is difluoromethoxy; and _R6 and _R7 are methoxy. Suitable specific starting materials include omeprazole, lansoprazole, pantoprazole, and rabeprazole:

Pantoprazole

Omeprazole

                          

Lansoprazole

The method of the invention will be illustrated using the compound of formula (I) as an example. First, a racemic mixture of sulfoxides in an organic solvent is provided (e.g. with Both R and S configurations exist on the sulfur atom of the sulfoxide group as indicated by the bond). This can be done, for example, by suspending or dissolving a compound of formula (I) in a solvent. Suitable organic solvents are preferably polar solvents, such as esters of organic acids, nitriles, and ketones, mixtures thereof, and the like. Said organic solvent is more preferably an alkyl ketone, such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone, or a mixture thereof; more preferably acetone. However, other solvents are also suitable and can be used in the described process. Thus, ethyl acetate, and acetonitrile, and mixtures are also suitable.

The suspension or solution of the starting sulfoxide (I) is then treated with a complexing agent whose molecule contains a transition metal, and a chelating agent to obtain a transition metal complex of formula (II):

键所示的那样，式(I)化合物的两种光学异构体形成了所说的过渡金属络合物。虽然本发明不是以任何特定理论为基础，但是相信配位剂的过渡金属在其电子结构中包含空d-轨道，因此使得可以与亚砜硫原子的电子对进行供体-受体相互作用。适宜配位剂的实例包括Ti(IV)醇化物，如异丙醇盐、甲醇盐、和叔-丁醇盐；更优选的配位剂是Ti(IV)异丙醇盐。认为螯合剂可以促进配位和络合物形成。更优选的螯合剂是酒石酸二乙酯。络合作用优选地是在存在有机碱的情况下进行的，所说的有机碱更优选地是有机胺，如二异丙基乙基胺、三乙胺、或其混合物。When referring to formula (II), L represents a molecular moiety including complexing and chelating agents, and the * symbol indicates the presence of chirality. like

As indicated by the bond, the two optical isomers of the compound of formula (I) form said transition metal complex. While the present invention is not based on any particular theory, it is believed that the transition metal of the complexing agent contains an empty d-orbital in its electronic structure, thus allowing a donor-acceptor interaction with the electron pair of the sulfoxide sulfur atom. Examples of suitable complexing agents include Ti(IV) alcoholates such as isopropoxide, methoxide, and t-butoxide; a more preferred complexing agent is Ti(IV) isopropoxide. Chelating agents are believed to facilitate coordination and complex formation. A more preferred chelating agent is diethyl tartrate. Complexation is preferably carried out in the presence of an organic base, more preferably an organic amine, such as diisopropylethylamine, triethylamine, or mixtures thereof.

The transition metal complex mixture of formula (II) is then treated with acid A to give adduct (III):

The adduct (III) is essentially an acid addition salt of the transition metal complex (II). Preferred acids include mandelic acid, camphorsulfonic acid and derivatives, and tartaric acid; more preferred is mandelic acid. Adduct (III) is a mixture of adducts (IIIA) and (IIIB) with the R and S configurations at the sulfur atom of the sulfoxide:

The purpose of the above steps is to introduce at least one additional chiral center into the molecule in substantially optically pure form. To this end, for such optical centers, the moiety L or the acid L or the moiety L and the acid L having at least one chiral center in the structure is introduced in substantially optically pure or optically concentrated form. Preferably both moiety L and acid A contain a chiral center(s) and are introduced in substantially optically pure or optically condensed form. Moiety L preferably contains at least one chiral center; such a chiral center is more preferably introduced into moiety L by a chelating agent. For example, using diethyl tartrate as a chelating agent, the D- or L-isomer can be used to introduce chirality into moiety L. Because of the presence of this type of optical center, the adduct (III) has diastereomeric properties. As is well known to those skilled in the art, in contrast to enantiomers, diastereoisomers have different physical properties, e.g., solubility, thus making it possible to combine diastereomerically-related adducts (IIIA) and (IIIB) separate. For example, one of the adducts (IIIA) or (IIIB) may have lower solubility in the organic solvent chosen for the process. The choice of making adducts (i.e., adducts prepared from starting materials with the R or S configuration on the sulfur atom of the sulfoxide) less soluble can be achieved through the addition of moiety L and/or acid A chiral centers The optical configuration (multiple chiral centers) is selected to proceed. In order to separate the adducts, the amount of solvent can be chosen, for example, in such a way that one of the adducts precipitates out of solution while the more soluble adduct remains substantially soluble. The less soluble adducts (eg, (adduct (IIIA)) are filtered off.

In this step of the process, subsequent reactions can be carried out separately with the respective adducts without affecting the configuration at the sulfoxide sulfur atom. To obtain the sulfoxide compound itself, the acid addition salt of the individual adducts and the sulfoxide/transition metal complex are removed in essentially optically pure form. This can be done, for example, by treatment with an external acid or base:

In a preferred variant, the precipitated adduct (eg adduct (IIIA)) is suspended or dissolved in a chlorinated solvent in the presence of an aqueous organic or inorganic base (eg aqueous sodium bicarbonate) , the free species of sulfoxide (compound of formula (IVA)) is obtained with the desired configuration at the sulfur atom. Preferred chlorinated solvents in this mixture include chloroform, dichloromethane, dichloroethane, or carbon tetrachloride.

If desired, the free species (IVA) can be converted into the desired salt (e.g. alkali or alkaline earth salt (V)) by methods well known to those skilled in the art, e.g. by treatment with the corresponding base conversion of:

wherein M is a metal and MB is a metal base such as sodium hydroxide, potassium hydroxide, and the like. Any of the adducts can be converted into a salt form of the sulfoxide, for example, an alkali or alkaline earth salt of one of the optical isomers of the sulfoxide compound in substantially optically pure or optically concentrated form, such as magnesium, sodium , or potassium salt, also including any hydrate.

The more soluble adduct (IIIB) can be converted into its own free species (IVB), which can be used in enantiomerically pure form,

Alternatively, if only one optical isomer is desired, it can be racemized in any manner known to those skilled in the art to obtain the starting sulfoxide (I). Racemization makes it possible to increase the availability of the material, since the racemized product can be reused in the process.

A preferred embodiment of the process of the present invention relates to the preparation of the (S) enantiomer of omeprazole known as esomeprazole and salts thereof. The flow chart illustrates the preferred method considered by the inventors of the present invention:

Thus, according to a particular variant of the process of the invention, the sodium salt of omeprazole (1) is suspended in acetone or other ketone solvents. The starting salt (2) can be purchased from commercial sources if available. Alternatively, free omeprazole can be treated with sodium hydroxide in a suitable solvent to obtain the sodium salt omeprazole (2) of omeprazole, said suitable solvent is preferably alcohol, such as methanol or isopropanol. A suspension of racemic omeprazole sodium salt is treated with titanium(IV) isopropoxide, diethyl D-tartrate in the presence of an organic base. Preferred bases are diisopropylethylamine and triethylamine. Titanium isopropoxide is a complexing agent, and diethyl tartrate is a chelating agent. The resulting titanium complex (3) was then treated with L(+) mandelic acid to give mandelate salts (4A) and (4B). Salt (4A) was obtained from the omeprazole enantiomer having the S configuration at the sulfur atom of the sulfoxide. Salt (4B) was obtained from the enantiomer with the R configuration. Salts (4A) and (4B) are diastereomerically related and thus have different physical properties. The present inventors found that when D diethyl tartrate and L(+) mandelic acid were used in the process, salt (4A) had lower solubility in ketones, especially acetone. The amount of solvent is chosen in such a way that the less soluble salt (4A) completely precipitates and the more soluble salt (4B) dissolves. Interestingly, the inventors found that if the enantiomer derived from the R-configured isomer of omeprazole was more desired, L diethyl tartrate and D(-) almonds could be used in the process Acids, salts derived from such R-configuration isomers have lower solubility in ketone solvents. In this preferred variation, the reaction mixture is stirred at room temperature for at least about 15 minutes up to about 5 hours after the addition of mandelic acid. Salt (4A) precipitates out while salt (4B) remains in solution. The isolated solid salt (4A) was filtered off and suspended in a mixture of aqueous base and chlorinated solvent. A preferred aqueous base is a dilute solution of sodium bicarbonate. Preferred chlorinated solvents include chloroform, methylene chloride, and carbon tetrachloride. Under basic conditions, the salt (4A) was converted to the S-enantiomer of omeprazole (5A). The organic layer of the biphasic reaction mixture containing free esomeprazole was separated. Compound (5A) (esomeprazole, free form) can be isolated by any means known to those skilled in the art.

In one variant, the organic solvent is removed, for example by vacuum distillation, and the residue of compound (5A) is then reprecipitated with a mixture of water and a ketone solvent, preferably acetone. In one non-limiting example, the esomeprazole residue is combined with a water/acetone mixture (approximately 1:2 by volume) and stirred to dissolve the residue. The solution was cooled to 5-10°C and maintained at this temperature until the esomeprazole solid material separated. The material was filtered and dried at 25-30°C to constant weight. The solid esomeprazole prepared in this way is then dried at a temperature of about 25 to about 30° C., preferably under reduced pressure, more preferably under rotation (for example, at about 750 mm/Hg at Buchi rotavapor flask). It is believed that this drying method provides an unsolvated free-flowing solid. The esomeprazole solid obtained in this way was found to be amorphous. Figure 1 shows the X-ray diffraction pattern of this esomeprazole solid. The X-ray powder diffraction pattern of Figure 1 was obtained with a Bruker Axs, D8 advance powder X-ray diffractometer using a CuKα-1 radiation source. No significant peaks were observed, which is characteristic of amorphous material. Therefore, in another preferred aspect, the present invention also provides amorphous esomeprazole. If desired, the amorphous esomeprazole can then be converted into pharmaceutically acceptable salts such as magnesium, sodium, or potassium salts and hydrates thereof.

In another variation, the free compound (5A) can be converted into a salt (6A). For example, the solvent can be removed and the residue of compound (5A) treated with an alkali metal base in a manner well known to those skilled in the art. The residue can also be treated with a free alkaline earth metal, preferably in an alcoholic solvent, to obtain the desired metal salt. In one non-limiting example, the magnesium salt of esomeprazole, believed to be in the trihydrate form, can be obtained as described below. Magnesium metal was suspended in methanol in the presence of dichloromethane; the mass was cooled to 5-10°C, and compound (5A) was added thereto. After completion of the salt formation, the reaction mixture is mixed with a large amount of water and the mixture is stirred until the solid of esomeprazole magnesium salt (compound (6A) when M is magnesium) separates from the liquid phase. The solid material was filtered off, redissolved in methanol and filtered again to remove unreacted magnesium metal. The solvent was removed and the residue was crystallized from acetone at 5-10°C to give esomeprazole magnesium trihydrate.

Referring again to the scheme, the adduct (4B) remains in solution. Adduct (4B) can be converted to the R enantiomer of omeprazole, if desired, in the same manner as for adduct (4A). Thereafter, the R enantiomer can be racemized to omeprazole (1), which can then be reused in the process.

The above method, or a portion thereof, may be repeated to improve the optical purity of the sulfoxide product. This method can be used to prepare sulfoxide products, such as the magnesium salt trihydrate salt of the S enantiomer of omeprazole, which are optically pure and have an enantiomeric excess greater than about 97%, preferably is greater than about 98%, more preferably, greater than about 98.5%, and, still more preferably, greater than about 99%. As noted earlier, the main product of the method can be altered by the nature of the reagents. For example, in a specific variant, to obtain esomeprazole, it is preferred to use D-diethyl tartrate and L-mandelic acid; whereas L-diethyl tartrate and D-mandelic acid are used to obtain the R enantiomer of omeprazole isomer. Examples of single or enantiomerically enriched sulfoxide salts and hydrates that can be synthesized by the method of the present invention are the R(-) enantiomer of omeprazole, its pharmaceutically acceptable salts and their hydrates; the S(+) enantiomer of omeprazole, its salts and their hydrates; the magnesium salt of the S(+) enantiomer of omeprazole and its hydrates; Omeprazole S(+) enantiomer sodium salt and its hydrate; Omeprazole S(+) enantiomer potassium salt and its hydrate; Omeprazole R(-) Magnesium salt of the enantiomer; Sodium salt of the R(-) enantiomer of omeprazole and its hydrate; Potassium salt of the R(-) enantiomer of omeprazole and its hydrate ; and the magnesium salt trihydrate of the R(-) enantiomer of omeprazole, and the like.

Also provided are pharmaceutical compositions of one or more compounds obtained by the methods of the invention. In particular, in a variant, there is also provided a pharmaceutical composition comprising amorphous esomeprazole as prepared above. In addition to the active compound, the pharmaceutical composition also contains one or more pharmaceutically acceptable excipients, which generally lack pharmaceutical activity, but possess various useful properties, for example, they can enhance stability, sterility, bioavailability, and ease of preparation of the pharmaceutical composition. The excipient may be solid, semi-solid, or liquid, and may be prepared with large quantities of the compound, but ultimately it is in the form of a unit dosage formulation (i.e., a physically discrete unit containing a specific quantity of active ingredient) such as a tablet or capsule. . The pharmaceutical compositions of the invention may contain one or more active compounds in addition to the compounds of the invention.

In general, the compounds of this invention are prepared by uniformly admixing the active ingredient with liquid or solid carriers, and then shaping the product into the desired form. The pharmaceutical composition may be in suspension, solution, elixir, aerosol, or solid dosage form. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms using solid pharmaceutical carriers.

A more preferred oral solid formulation is a tablet. Tablets may be prepared by direct compression, wet granulation, or molding of the amorphous form of esomeprazole together with carriers or other excipients by methods well known to those skilled in the art. It may be obtained by compressing in a suitable machine the active ingredient in free-flowing form, e.g. in powder or granule form, optionally mixed with a binder, lubricant, inert diluent, surfactant or disintegrant. Prepare compressed tablets. Molded tablets may be made by preparing in a suitable machine a mixture of the powdered compound moistened with a suitable inert liquid diluent in the case of oral solid dosage forms (eg, powders, capsules, and tablets). Tablets may be coated, if desired, using standard techniques. The amorphous form of esomeprazole described herein can be prepared as a typical disintegrating tablet, or as a controlled or extended release dosage form. Examples of suitable controlled release formulation carriers are disclosed in US 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, the contents of which are hereby incorporated by reference in their entirety.

The pharmaceutical composition of the present invention can be a variety of preparations suitable for various administration methods, and said various administration methods include, without limitation, inhalation, oral, rectal, parenteral (including subcutaneous, intradermal, intramuscular) Intravenous, intravenous), implant, intravaginal and transdermal administration. The most suitable route of administration in any given case will depend on the duration of the condition in the subject, the length of treatment desired, the nature and severity of the condition being treated, and the particular formulation used. The formulations may be presented in bulk or unit dosage form and may be prepared by methods well known in the art of formulation for which they are given.

The amount of active ingredient contained in a unit dosage form depends on the type of formulation in which the active ingredient is present. Pharmaceutical compositions generally comprise from about 0.1% to about 99% by weight of active ingredient, preferably from about 1% to 50% by weight for oral administration, preferably from about 0.2% to 50% by weight for parenteral administration. About 20% by weight.

Formulations suitable for oral administration include capsules (hard and soft capsules), cachets, lozenges, syrups, suppositories, and tablets, each containing a predetermined amount of the active compound; powders or granules; aqueous or Solutions or suspensions in non-aqueous liquids; or oil-in-water or water-in-oil emulsions. Such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and a suitable carrier or carriers. The amount of active ingredient per unit dose of solid preparation is preferably about 5 mg to 60 mg, especially about 8 to 10 mg, about 16 to 20 mg, and about 32 to 40 mg. For liquid oral dosage forms, the preferred amount is from about 2% to about 20% by weight. Suitable carriers include, without limitation, fillers, binders, lubricants, inert diluents, surface active/dispersing agents, flavoring agents, antioxidants, bulking and granulating agents, absorbents, preservatives, emulsifying agents agents, suspending and wetting agents, glidants, disintegrants, buffers and pH-regulators, and colorants. Examples of carriers include celluloses, modified celluloses, cyclodextrins, starches, oils, polyols, sugar alcohols and sugars, and the like. For liquid formulations, sugars, sugar alcohols, ethanol, water, glycerin, and polyethylene glycol are particularly suitable, and they can also be used in solid formulations. In particular cyclodextrins can be used to increase bioavailability. Formulations for oral administration may optionally contain enteric coatings known in the art to prevent breakdown of the formulation in the stomach and to provide release of the drug in the small intestine.

Formulations suitable for buccal or sublingual administration include lozenges containing the active compound in a flavored base, usually sucrose and acacia or tragacanth (although others are suitable), and pastilles containing the compound in an inert base such as gelatin and glycerin or sucrose and acacia.

Formulations of the present invention suitable for parenteral administration include sterile aqueous or non-aqueous injection solutions of the active compound which are preferably isotonic with the blood of the recipient to whom it is applied. The amount of active ingredient is preferably a concentration of about 0.1% to 10% by weight. These formulations may contain, among other ingredients, antioxidants, buffers, bacteriostatic agents, and solutes to render the formulation isotonic with the blood of the recipient to whom it is used. Aqueous and non-aqueous sterile suspensions may contain suspending agents and thickening agents, among other substances. The formulations may be presented in unit-dose or multi-dose containers, such as sealed capsules and vials, and may be stored in a freeze-dried or lyophilized form requiring only the addition of a sterile liquid carrier, such as physiological saline or water for injection, prior to use. In freeze-dried condition. Immediate injectable solutions and suspensions can be prepared from sterile powders, granules and tablets as previously described.

Formulations suitable for rectal administration are preferably presented as unit dose suppositories. They can be prepared by mixing the active compound with one or more conventional solid carriers, such as cocoa butter, and shaping the resulting mixture.

Formulations suitable for transdermal delivery include ointments, creams, lotions and oils and contain well known pharmaceutically and cosmetically appropriate ingredients. Bases for such formulations include, for example, alcohols, lanolin, petrolatum, paraffins, polyethylene glycols, emulsifiers, penetration enhancers, and oily bases such as oils. Skin patches, which generally comprise a fabric or paper matrix impregnated with an appropriate dose of the transdermal formulation, may also be used. Formulations suitable for transdermal administration can also be delivered by iontophoresis and generally take the form of buffered or unbuffered aqueous solutions of the active compound.

In another aspect, the present invention also provides a method of treatment with the compounds and pharmaceutical compositions described herein. The compounds and compositions of the invention may be administered to a subject in an amount effective to reduce gastric secretion in the subject. In addition, the compounds and compositions of the present invention can also be administered to a subject in an amount effective to reduce gastric acid secretion in said subject to treat conditions caused by gastric acid secretion.

The compounds and compositions described herein are useful in the treatment of a variety of specific disorders or conditions involving gastric acid secretion as well as other conditions known to be amenable to treatment with the described sulfoxide compounds. For example, certain compounds are useful in the treatment of bradyphremia, elevated intraocular pressure, schizophrenia, infections (especially caused by Gram-negative bacteria, microaerophilic bacteria, Campylobacter pylori), and inflammation (especially those involving lysosomal enzymes), ulcers (including those caused by H. , Zollinger-Ellison syndrome, endocrine adenomas, generalized mastocytosis), gastritis, duodenitis, dyspepsia, acute gastrointestinal bleeding (especially upper GI tract) , administered to patients on NSAID therapy or in intensive care to reduce or prevent gastric acid aspiration and stress ulcers, psoriasis and lysosomal enzyme problems, and infections such as those caused by Helicobacter pylori.

Although it is possible to prevent gastric acid secretion with the compounds and compositions of the invention by establishing dosage levels effective therefor, such treatment should only be used in exceptional circumstances, since it is intended to relieve or eliminate most of the effects of the compounds of the invention. In the case of treatment, gastric acid secretion should not be completely eliminated, but only reduced in amount or duration. In general, treatment to alleviate, eliminate, or prevent a given condition can be determined according to factors ascertainable by a skilled practitioner, as discussed in the Determining an Effective Dose section below.

A subject refers to a human or an animal, preferably a human. Animals contemplated by the present invention include any animal that can be safely treated with the compounds of the present invention, preferably mammals such as bovines, sheep, goats, horses, felines, canines, rodents, lagomorphs , and other farmland mammals and zoo animals or household pets.

A therapeutically effective amount (ie, dosage) of an active compound depends on the route of administration, the condition being treated, its severity and duration, and the state and age of the subject. A skilled physician will monitor the subject's progress and will adjust dosage accordingly according to whether the goal of eliminating, alleviating or preventing a given condition is achieved. In general, the starting dose can be lower, but it is necessary to start at least at the lower end of the effective range, and in the case of severe ulcers the dose can be increased and the active substance can be administered as a maintenance therapy. The dose of active compound can be adjusted towards the high end of this effective range, or if desired, towards the higher end, but proportionality to the patient's weight must always be considered. Depending on the solubility of the particular formulation of the active compound to be administered, the daily dose may be administered in divided doses or in several unit doses. The active compound can be administered therapeutically, ie palliative therapy, or it can be administered prophylactically and can be safely maintained over a long period of time. Those of ordinary skill in the art will take such factors into consideration when determining dosage. Oral and parenteral dosages will generally range from about 5 to about 350 to 400 mg active ingredient per day, preferably from about 8 mg to about 60 mg, most preferably from about 10 mg to about 40 mg active ingredient.

The examples given below are for illustration rather than limiting the scope of the present invention.

Reference example

Preparation of Omeprazole Sodium

Sodium hydroxide flakes (12.8 g) were dissolved in methanol (100 ml) and stirred until completely dissolved. Isopropanol (900ml) was added and the reaction mixture was cooled to 25-30°C. The solution was filtered through a hi-flow bedded funnel and washed with isopropanol (100ml). To the clear filtrate was added omeprazole (100 g) at room temperature and stirred for 1-2 hours. The isolated product was filtered off and washed with isopropanol (200ml) then petroleum ether (200ml) and dried at atmospheric temperature to give the sodium salt of omeprazole. Weight: ~100 grams.

Example 1

Preparation of Esomeprazole Titanium Mandelate Complex Salt

Omeprazole sodium (100 g) was suspended in acetone (1.2 liters), and D-diethyl tartrate (56.0 g), titanium isopropoxide (IV ) (40.0 grams) and triethylamine (82.0 grams). L(+) mandelic acid (41.5 g) was then added thereto and it was stirred for a further 15-30 minutes. The solid material was separated filtered and washed with acetone (500ml) to give the title compound. This product has the following properties. Weight: 80.0 g; Chiral purity: 99.78%.

Example 2

(-)-5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridylmethyl]sulfinyl

Preparation of base]-1H-benzimidazole

The esomeprazole titanium mandelate complex salt (75.0 grams) obtained in Example 1 was suspended in the mixture of dichloromethane (375ml) and 5% sodium bicarbonate solution (375ml), and it was stirred for 15 -30 minutes. The dichloromethane layer was separated from the resulting solution, and the solvent was completely distilled to give the title compound as a residue. The characteristics of the product thus obtained are as follows. Weight: 37.0g. Chiral purity: 99.85%.

Example 3

(-)5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridyl]methyl]sulfinyl

Preparation of ]-1H-benzimidazole magnesium salt trihydrate

Magnesium metal (1.33g) and dichloromethane (3.7ml) were added to methanol (111ml) and stirred for 1-2 hours. This substance was cooled to 5-10°C, and esomeprazole (37.0 g) obtained in Example 2 and methanol (111.0 ml) were added thereto while stirring it for 15-30 minutes. The reaction mass was decomposed in water (666ml) at 5-10°C for 45-60 minutes, then stirred for a further 30-45 minutes to separate the solid. The solid material was filtered and washed with water (222ml). The compound thus obtained was dissolved in methanol (222ml) and the solution was filtered to separate off any excess magnesium. The solvent was removed from the filtrate to give a residue. The residue was crystallized in acetone (278ml) at 0-5°C to give optically pure esomeprazole magnesium salt trihydrate. The resulting product had the following properties. Weight: 11.5g. Chiral purity: ~100%. Optical rotation: -125° (c=0.5% methanol)

The (-) enantiomer of omeprazole magnesium salt dihydrate was prepared as described above using a controlled drying procedure.

Example 4

(-)-5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridyl]methyl]sulfinyl

Preparation of trihydrate of sodium salt of base]-1H-benzimidazole

Sodium hydroxide flakes (4.5 g) were added to methanol (50 ml) and stirred for 15-30 minutes. The substance was cooled to 5-10°C, and esomeprazole (25.0 g) obtained in Example 2 and methanol (100.0 ml) were added thereto while stirring it for 30-60 minutes. The solvent was completely removed from the reaction solution. Diisopropyl ether (150ml) was added to the residue and it was stirred for a further 30-60 minutes. The material was cooled to 0-5°C and stirred for 30-60 minutes to separate the solid material. The solid material was filtered off and dried under vacuum at a temperature of 60-70°C to obtain optically pure esomeprazole sodium salt trihydrate. The characteristics of this product are as follows. Weight: 14.5g. Chiral purity: 99.53 Optical rotation: +42° (c=0.5% water)

The sodium salt dihydrate of the S(-) enantiomer of omeprazole was prepared similarly to the above procedure using a controlled drying procedure.

Example 5

(-)-5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridyl]methyl]sulfinyl

Preparation of base]-1H-benzimidazole potassium salt

Potassium hydroxide flakes (6.3 g) were added to methanol (50 ml) and stirred for 15-30 minutes. The substance was cooled to 5-10°C, and esomeprazole (25.0 g) obtained by the method of Example 2 and methanol (100.0 ml) were added thereto while stirring it for 30-60 minutes. The solvent was completely removed from the reaction solution. Diisopropyl ether (150ml) was added to the residue and it was stirred for a further 30-60 minutes. The material was cooled to 0-5°C and stirred for 30-60 minutes to separate the solid material. The solid material was filtered off and dried under vacuum at a temperature of 60-70°C to obtain optically pure esomeprazole sodium salt trihydrate. The characteristics of this product are as follows. Weight: 12.0g. Chiral purity: 100%, optical rotation: +28.0° (c=1% water).

The sodium salt dihydrate of the S(-) enantiomer of omeprazole was prepared in the manner described above using a controlled drying procedure.

Example 6

(-)-5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridyl]methyl]sulfinyl

Base]-1H-benzimidazole (solid form) preparation

Esomeprazole (20.0 g, obtained according to Example-2) was dissolved in a mixture of acetone (100 ml) and water (200 ml), and it was stirred for 15-30 minutes. The pH of the material was adjusted to 12-13 with caustic while it was stirred for 30-60 minutes. The reaction solution was subjected to carbon treatment at atmospheric temperature. The pH was readjusted to 7-8 with acetic acid, then the reaction was cooled to 5-10°C and stirred for 1-2 hours to allow the solid material to crystallize. The solid material was filtered off, washed with water (100 ml), then dried under vacuum at a temperature of 25-30° C. to constant weight. The characteristics of the product thus obtained are as follows: Weight: 7.0 g. Chiral purity: 99.94%

Example 7

Preparation of Titanium Mandelate Complex Salt of R(+) Enantiomer of Omeprazole

Omeprazole sodium (10 g) was suspended in acetone (120 ml), and then at a temperature of 35-40° C., L-diethyl tartrate (5.6 g), titanium (IV) isopropoxide were added successively thereto (4.0 g) and triethylamine (8.2 g). D(-)mandelic acid (4.2 g) was then added thereto and stirred for 15-30 minutes. The solid which separated was filtered off and washed with acetone (50ml) to give the title compound. The characteristics of the product thus obtained are as follows. Weight: 7.50g. Chiral purity: 98.01% (R isomer)

The (+) enantiomer of omeprazole and its salts, including magnesium, sodium and potassium salts, were prepared in a manner similar to that described in the previous examples.

Unless stated to the contrary, any use of terms herein such as "comprises," "comprises," "containing," "having," etc., means "including without limitation" and should not be construed as including The general statement which follows it is limited to the specific or similar clause or substance which immediately follows. Unless the context indicates otherwise, all exemplary values are assumed, do not relate to actual entities and are used for illustration only. Most of the foregoing alternative embodiments are not mutually exclusive, but can be implemented in various combinations. Because these and other variations and combinations of features discussed above can be utilized without departing from the invention as defined by the appended claims, they are to be considered in an illustrative rather than limiting manner The above description about the embodiment.

Claims (63)

1. A method for preparing substantially optically pure or optically concentrated sulfoxide compounds, said method comprising a) providing a starting material located in an organic solvent, said starting material being a mixture of optical isomers of a compound containing a sulfoxide group of the following structure or a salt thereof, said different optical isomers have R and S configurations at the sulfur atom of the sulfoxide group; b) reacting a mixture of said optical isomers with i) a complexing agent containing a transition metal, and ii) a chelating agent in said organic solvent, whereby each of said optical isomers isomer forms a transition metal complex with it on said sulfoxide group; c) reacting the mixture of said transition metal complex with an organic acid or a salt thereof capable of forming an addition product with said transition metal complex; wherein at least one of said chelating agent and said organic acid contains a chiral center and is substantially enantiomerically pure with respect to that chiral center; whereby said transition metal complexes of said optical isomers each form a compound with said organic acid or salt thereof adducts, said different adducts having at least one physical property different from the other adducts; d) separating said adduct from other adducts based on said at least one different physical property; treating said isolated adduct with an external acid or base to decompose said transition metal complex on said sulfoxide group to obtain a substantially optically pure or optically one of said optical isomers of said sulfoxide compound in concentrated form; where R' is R" is and X is wherein R ₁ , R ₂ , R ₃ , and R ₄ , which may be the same or different, are independently hydrogen, alkyl, alkoxy, halogen, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolyl, or trifluoroalkyl; R ₅ , R ₆ , and R ₇ , which may be the same or different, are each independently hydrogen, alkyl, haloalkyl, alkylthio, haloalkylthio, alkoxy, haloalkoxy, alkoxyalkoxy, di Alkylamino, piperdino, morpholino, halogen, phenylalkyl or phenylalkoxy; R ₈ is hydrogen or lower alkyl; R ₉ and R ₁₀ , which may be the same or different, are each independently hydrogen, halogen, alkyl or alkoxy. 2. The method of claim 1, wherein said starting material is a salt of the following structure: wherein M is an alkali metal. 3. The method of claim 2, wherein M is sodium. 4. The method of claim 2, wherein _R1 , _R2 , _R3 , and _R4 are hydrogen. 5. The method of claim 4, wherein _R5 is hydrogen and _R7 is methyl. 6. The method _of claim 5, wherein _R6 is -O( _CH2 ) _3OCH3 . 7. _The method of claim 5, wherein _R6 is _-OCH2CF3 . 8. The method of claim 2, wherein _R1 , _R3 , and _R4 are hydrogen; _R2 and _R6 are methoxy; and _R5 and _R7 are methyl. 9. The method of claim 2, wherein _R1 , _R3 , _R4 , and _R5 are hydrogen; _R2 is difluoromethoxy; and _R6 and _R7 are methoxy. 10. The method of claim 2, wherein said step of providing a starting material comprises suspending said salt in said organic solvent. 11. The method of claim 10, wherein said step of forming a transition metal complex further comprises mixing said starting material with said complexing agent and said chelating agent in the presence of an organic base react in case. 12. The method of claim 1, wherein said at least one different physical property is the solubility of said adduct in said organic solvent. 13. The method of claim 12, wherein said step of isolating said adduct comprises adducting the less water soluble adduct under conditions such that the more soluble adduct remains in the solvent. matter precipitation. 14. The method of claim 13, wherein said step of treating said less water soluble adduct comprises suspending said less soluble adduct in acidic or basic conditions in aqueous/organic solvent mixtures. 15. The method of claim 14, wherein said step of treating said less soluble adduct comprises reacting with sodium bicarbonate. 16. The method of claim 12, further comprising decomposing said transition metal complex of said more water-soluble adduct to obtain said transition metal complex different from said less water-soluble adduct. The second optical isomer of the first isomer of said sulfoxide compound. 17. The method of claim 16, further comprising racemizing said second optical isomer to obtain a mixture of different isomers having R and S configurations at the sulfoxide sulfur atom. 18. The method of claim 1, wherein said organic solvent is a ketone, an ester of an organic acid, a nitrile, or a mixture thereof. 19. The method of claim 1, wherein said organic solvent is acetone, ethyl acetate, acetonitrile, or a mixture thereof. 20. The method of claim 1, wherein said chelating agent is diethyl tartrate. 21. The method of claim 11, wherein said organic base is an organic amine base. 22. The method of claim 21, wherein said organic amine base is diisopropylethylamine, triethylamine, or a mixture thereof. 23. The method of claim 1, wherein said complexing agent is titanium (IV) isopropoxide. 24. The method of claim 1, wherein said organic acid is L-mandelic acid. 25. The method of claim 1, wherein said organic acid is D-mandelic acid. 26. The method of claim 10, wherein said organic solvent is an alkyl ketone. 27. The method of claim 26, wherein said alkyl ketone solvent is selected from the group consisting of acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone, or mixtures thereof. 28. The method of claim 26, wherein said alkyl ketone solvent is acetone. 29. The method of claim 1, wherein the organic acid or salt is added while stirring at about ambient temperature for about 15 minutes to about 5 hours. 30. The method of claim 14, wherein said aqueous/organic solvent mixture comprises an organic solvent selected from the group consisting of chloroform, methylene chloride, ethylene dichloride, carbon tetrachloride, or mixtures thereof. 31. The method of claim 30, wherein said aqueous/organic solvent mixture comprises dichloromethane. 32. The method of claim 1, wherein said separating step comprises filtering. 33. The method of claim 1, further comprising converting the optical isomer from one of the adducts into its salt form. 34. The method of claim 33, wherein the salt of one of said optical isomers of said sulfoxide compound in substantially optically pure or optically concentrated form is an alkali or alkaline earth salt. 35. The method of claim 33, wherein the salt of one of said optical isomers of said sulfoxide compound in substantially optically pure or optically concentrated form is a magnesium, sodium, or potassium salt, or a hydrate thereof . 36. The method of claim 1, wherein said starting material is omeprazole. 37. The method of claim 36, wherein said chiral organic acid is L-mandelic acid. 38. The method of claim 37, wherein said chelating agent is diethyl D-tartrate. 39. The method of claim 36, wherein said chiral organic acid is D-mandelic acid. 40. The method of claim 37, wherein said chelating agent is diethyl L-tartrate. 41. The method of claim 36, wherein said product is the R enantiomer of omeprazole. 42. The method of claim 36, wherein said product is the S enantiomer of omeprazole. 43. The method of claim 41, wherein said R enantiomer of omeprazole has an optical purity greater than about 99.7%. 44. A method for separating the enantiomers of omeprazole, said method comprising: Provide a suspension of omeprazole salt in an alkyl ketone solvent; Said omeprazole salt is reacted with titanium isopropoxide (IV) and D-diethyl tartrate in the presence of an organic base; reacting the product of said reaction with L-mandelic acid; maintaining the reaction mixture until solid material separates; Wherein said solid substance is the mandelate of the titanium complex of the S enantiomer of omeprazole. 45. The method of claim 44, further comprising filtering said solid material. 46. The method of claim 45, which comprises reacting said salt of mandelate with an aqueous base to obtain a residue which is free form esomeprazole. 47. The method of claim 45, further comprising reprecipitating said residue from a mixture of water and acetone to obtain free esomeprazole as an amorphous solid. 48. The method as claimed in claim 45, which also comprises reacting said free type omeprazole and magnesium metal in an alcoholic solvent in the presence of dichloromethane, thereby obtaining esomeprazole magnesium salt residue. 49. Esomeprazole magnesium salt prepared by the method of claim 48. 50. The method of claim 48, further comprising dissolving said esomeprazole magnesium salt residue in acetone and reducing the temperature of said acetone solution so that the magnesium salt of esomeprazole is Precipitate out. 51. The magnesium salt of esomeprazole prepared by the process of claim 50. 52. The method of claim 48, wherein said alcoholic solvent is methanol. 53. The method of claim 45, wherein said ketone is acetone. 54. The method of claim 45, wherein said organic base is diisopropylethylamine, triethylamine, or a mixture thereof. 55. The method of claim 46, wherein said aqueous base is aqueous sodium bicarbonate. 56. The method of claim 55, wherein said sodium bicarbonate is present in said solution at a concentration of about 5% by weight. 57. A compound which is amorphous esomeprazole prepared by the method of claim 47. 58. A pharmaceutical composition comprising i) amorphous esomeprazole prepared by the method of claim 47; and ii) one or more pharmaceutically acceptable excipients. 59. The pharmaceutical composition according to claim 58, which is a solid dosage form for oral administration. 60. The pharmaceutical composition of claim 59, wherein said solid dosage form is a tablet. 61. A method of preventing or treating undesired gastric acid secretion or gastric ulcer, comprising administering to a subject in need thereof a pharmaceutical combination comprising an effective amount of amorphous esomeprazole prepared by the method of claim 47 thing. 62. The method of claim 61, wherein said pharmaceutical composition is intended for oral administration. 63. The method of claim 62, wherein said pharmaceutical composition is a suspension, solution, powder, tablet, or capsule.

Images