TW200906404A - Transition metal mediated oxidation of hetero atoms in organic molecules coordinated to transition metals - Google Patents

Abstract

The present invention is directed to a process for the catalytic oxidation of the thioether 5-methoxy-2-((4-methoxy-3, 5-dimethyl-2-pyridinyl)methyl) methylthio)-1H- benzimidazole to its sulfoxide: 5-methoxy-2-((4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl) methylsulfinyl)-1H-benzimidazole comprising: reacting the thioether with: 1) a transition metal catalyst; and, 2) an oxygen source; wherein the thioether is oxidized to a sulfoxide and wherein one of either the R and S enantiomers is formed to an enantiomeric excess.

Description

200906404 IX. INSTRUCTIONS: [Technical field to which the invention pertains] The present invention is directed to a sulfur mystery 5-mercapto-2-((4-anthoxy_3,5-diindenyl 2 ° ratio) Methylthio)-1Η- abbreviated imidazole to its sub-milling: 5_decyloxy-2·((4-methoxy-3,5-dimethyl-2-pyridinyl)indenyl) A method of direct or catalytic oxidation of a sulfinyl) hydrazine imidazole, the method comprising: reacting a thioether with a .1) transition metal compound; and 2) an oxygen source; wherein the thioether is /K.. Oxidation to sulfoxide and wherein any of the R and S enantiomers is formed as an enantiomeric excess. The present invention is also a pharmaceutical dosage form containing sulfoxide for the treatment of a medical condition in a patient in need of such a benzoquinone-flavored beta-active agent. The present invention is directed to a kit for administration of a drug active agent, which comprises: a) a pharmaceutically active agent such as a dosage form selected from the group consisting of pills, troches, capsules, liquids and powders; Information guide describing the dosage form and how to use the dosage form; c) packaging for holding a) and b). [Prior Art]

Useful organic compounds contain heteroatoms, for example, oxygen atoms, deuterium atoms, selenium atoms, deuterium atoms, E as early as from deuterium nitrogen atoms, phosphorus atoms, arsenic atoms, and antimony atoms. Some of the most heterogeneous; interstitial insertion of a hetero atom to obtain a hydrogen bond ,, for example, an oxygen atom inserted into one of the carbon: one of the bonds produces methanol (4). This substitution produces a rich and varied anion of the carbon: compound. When a hetero atom is not an oxygen shoulder, for example, a sulfur atom, ', . 屌 a 碲 atom, a nitrogen atom, a phosphonium scorpion, an eyebrow, and a recorded atom, m μ + "the unshared electron on the original hetero atom 12669 】.doc 200906404 The formation of a coordination bond to an oxygen atom to cause a related oxidation product. In the case of an organic amine, the 'related oxidation product is an amine N-oxide; similarly, a phosphine oxide is derived from a phosphine. In this case, the two unshared electron pairs present on the sulfur atom of the thioether will participate in this oxidation reaction in a stepwise manner to first form an anthracene and then form a sulfone. Frequently the 'related oxidation product is obtained as a result of oxidation. Structural properties. When oxidized to form the N-oxide RaRbRcNO, the formula triamine exhibits the same stereochemical type as the carbon compound, wherein a given carbon atom in the structure is replaced by four different Upon substitution by a radical, an optical isomer, that is, an enantiomer isomer. Although it is possible to speculate that an asymmetric third amine can exist as an optical isomer, via nitrogen The well-known structural interconversion of umbrellation quickly raises this stereochemistry problem (the term asymmetry is used herein inclusive to cover more specific terms desymmetry and asymmetry). For unshared electrons on sulfur For organic sulfur compounds which are stable in the form of nitrogen, this is not the case, and the organosulfur compounds do not undergo interconversion between the enantiomers. Therefore, the first oxidation of asymmetric thioethers (for example, RaRbs) The reaction results in a sulfur oxide in the form of an enantiomer, since the unshared electron pair of sulfur is stereochemically significant, that is, the molecule rapidly undergoes an unshared electron pair on the nitrogen atom of the amine. In the sense of a typical umbrella, it is not stereochemically unstable. Further oxidation of sulfoxide to hydrazine destroys optical isomerism because the sulfur atom now has two equivalent substituents, two oxygens of the sulfone. Atoms Many N-oxide compounds (Aachen and its similar compounds) have significant use in their steric chemistry. For example, The third group of oxides is an excellent oxidation inhibitor in the polymer. When the thermoplastic compound is treated at such high temperatures as those occurring in extrusion (where the polydioxide must be melted), the I third amine When one of the substituents is a methyl group, the first N-oxide can be reacted with the (tetra) 1 to effect the localized + substituted pyrosidation: which acts to prevent thermal degradation of the polymer. , it has been found that many drugs are in the form of enantiomers or intermediates.

There is, and one optical isomer is more pharmaceutically active than other isomers. As long as some of the enantiomeric forms of these compounds are biologically inert, they pose economic problems only in the manufacture of the active ingredients. However, it has been occasionally found that while one enantiomeric isomer of a pharmaceutically active compound is beneficial, the other or other enantiomeric isomers may be deleterious. & causes stereochemical control problems in order to separate the desired active form of the molecule. Conversion of amines in the synthesis of many drugs or by free radical oxidation (such as 'use of oxygen-forming bubbles via liquid reaction media or using peroxides' such as 'hydrogen peroxide or peracetic acid') to convert active ingredients, bismuth, sulphur The complexation of bonds and analogs to their associated oxides just raises these types of problems, thereby introducing an optically isomeric center into the converted molecule, ie, the opposite of the enantiomer in the palm A more active enantiomer compared to other enantiomers. Coordination complexes of transition metals can be broadly characterized as positional isomerism (ie, the same atomic set but different Key sets) or stereoisomerism (ie, the same atom and bond set but different symmetry) of various isomeric forms exist. 126691.doc 200906404. Widely, positional isomerism in coordination complexes The types are: 1) When the coordination ligand can be bonded to the transition metal via more than one atom, the bond isomerism exists, example: a complex of 0N0 (N〇2), when passed through the mouse atomic bond When it is connected, the complex is correct. a complex, and when bonded via an oxygen atom, the complex is a nitroso compound; 2) when different central metal ions can be exchanged between different sets of ligands, there is coordination isomerism, for example, ( Cr(NH3)6)(c〇(cN)6) for (Co(NH3)6)(Cr(CN)6); 3) Although the group bonded to the central metal ion can be substituted to the ligand molecule At different positions, there is a heterogeneity of the ligand, for example, (c〇(l,2_diaminopropyl) 3) + 3 pairs (C〇(l,3-diaminepropane)3) + 3 ; 4) Solvent isomerism (or more specifically for h2〇, hydration isomerism) when the solvent is coordinated as opposed to a portion having a crystal structure in hydrated water, for example, (Cr(H20) 6) Cl3#(Cr(H2〇)5C1) cl2_H2〇; 5) When the substance is exchanged between the coordination layer and the simple ion, there is ionization isomerization 2, for example, (Pt(NH3)4(OH)2 S0^Pt(NH3)4S〇4)(〇H)2; and 6) When the molecular weights are different but the empirical weight is the same, there is polymerizable isomerism, such as '(Pt(NH3)2Cl2)4(Pt(NH3) 4) (PtCl4). Stereoisomerism exists widely in two main categories: 1) by square plane Geometrical isomerism exemplified by cis-trans isomerism in a compound or octahedral complex; and 2) optical isomerism. Optical isomerism due to optical isomerism present in transition metal complexes Similar to the optical isomerism observed in carbon compounds. The simplified view of transition metal 126691.doc 200906404 to optical isomerism in f-shell is 'there is no central metal ion passing through the transition metal compound or complex a symmetry center or a plane of symmetry and ions, compounds or molecules may be present in two or more forms, the two or more forms having equivalent chemical formulas and molecular weights but wherein different forms of the molecules are not bondable by surrounding molecules Rotating substituent groups and interchanging. Thus, the molecule is present in the so-called enantiomeric isomer, or if two or more asymmetric centers are present in the molecule, the molecule is present in the diastereomeric isomer. The terms desymmetry and asymmetry have gained specific specific meaning in the field of stereochemistry; as used herein, the term asymmetry will be used herein generally and the reference to the context will be appropriately more specifically described as desymmetric or not. Symmetrical chemical structures. Asymmetric complexes of transition metals have been found to be useful in the synthesis or preparation of enantiomeric organic compounds by more or less standard chemical reactions or reactions catalyzed by homogeneous or heterogeneous catalysts. SUMMARY OF THE INVENTION The present invention is directed to thioether 5-methoxy-2-((4-methoxy-3,5-diindenyl-2-yl)pyridyl)methyl)methylthio)-lH_ Benzimidazole to its sulfoxide: 5_decyloxy_2_((4-methoxy-3,5-diindenyl-2-pyridyl)methyl)methanesulfinyl)_111_cyanimidazole a method of direct or catalytic oxidation reaction comprising: reacting a thioether with a .1) transition metal compound; and 2) an oxygen source; wherein the sulfur is oxidized to a sulfoxide and wherein the R and S enantiomers Either one is formed as an enantiomeric excess. The present invention is also directed to a pharmaceutical preparation comprising: (a) an alkaline reaction core comprising: an acid labile pharmaceutically active substance and 126691.doc • 10· 200906404 an alkaline reaction compound different from the active substance, acid An alkaline salt of an unstable pharmaceutically active substance, or an alkaline salt of an acid labile pharmaceutically active substance and an alkaline reaction compound different from the active substance; (b) rapidly dissolved in water disposed on the core region Or a disintegrating inert sub-coating comprising one or more layers' or the layers comprising a material selected from the group consisting of a tablet excipient, a film forming compound, and a basic compound; and (c An enteric layer surrounding the sub-coating, wherein the sub-coating isolates the alkaline reaction core from the casing layer to enhance stability of the formulation, and wherein the acid labile pharmaceutically active substance is a benzoimidazole compound and Manufactured by a method wherein the sulfoxide: 5·methoxy-2-((4-methoxy-3-3,5-dimethyl-2-pyridyl)methyl)methanesulfinyl)-1H- Benzimidazole is catalytically converted from the following steps趟5_Methoxy-2-((4-methoxy-3,5-dimethyl-2·吼) thiol)methylthio)-1Η-benzoquinone saliva: 1} a transition metal catalyst; and an oxygen source reaction; the sulphur mystery is oxidized to an anthracene and wherein either of the R and S enantiomers is formed as an enantiomeric excess. [Embodiment] / 语||Pharmaceutically acceptable" is used herein to refer to the application in the correct treatment judgment 11 for contact with human and animal tissues, commensurate with a reasonable benefit/risk ratio, without excessive toxicity, A compound, material, composition, and/or dosage form of a stimulus, an allergic reaction, or other problem or complication. As used herein, '"pharmaceutically acceptable salt" refers to the organism of the disclosed compound. The parent compound is modified by making an acidic or basic salt of the parent compound. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of base f groups such as amines. And an organic or salt of an acidic group (such as 126691.doc 200906404, a few acids). Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or grade 4 of parent compounds formed from non-toxic inorganic or organic acids. For example, the indium π & * temple knows that no parent salt includes non-toxic salts derived from inorganic acids, such as hydrochloride, hydrogen sulphate, sulfate, and amine acid , acid salt and citrate; and own Acid-prepared salts, such as acetic acid:, propionate, succinate, glycolate, stearate, lactate, tartrate, succulent acid , diperate, butyl succinate, (d) cis-butane citrate, phenyl acetate, glutamate, benzoate, salicylate, p-aminobenzoate, 2 _Ethyl oxybenzoate, fumarate, tosylate, methanesulfonate ethane disulfonate, oxalate and isethionate. Acceptable salts can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be obtained by allowing the free acid or base forms of such compounds in water or in an organic solvent or in two The mixture is prepared by reacting with a stoichiometric amount of a suitable base or acid; typically, a non-aqueous medium similar to diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred. In Remington, s Pharmaceutical (6) A list of suitable salts is found in the 17th edition (Mack Publishing Company, Easton, pa.), pp. 1418, 1985. The disclosures of which are hereby incorporated by reference. The present invention is hereby incorporated herein by reference in its entirety in its entirety in its entirety in the intent in It is intended to cover the currently claimed compounds, the methods of delivery thereof, and the conjugates thereof. "prodrugs" are intended to include 126691.doc -12· 200906404 when the drug is administered to a mammalian subject in vivo Any covalently bonded carrier in which the active parent drug of the present invention is released. The prodrug of the present invention is prepared by modifying the functional group present in the compound in such a manner that it is decomposed into a parent compound in a conventional operation or in a living body. The present invention is directed to a compound of the present invention in which a group, an amine group or a sulfhydryl group is bonded to any group such that the prodrug of the present invention is decomposed when administered to a mammalian subject to form a self-field, respectively. By a radical, a free amine group or a free sulfhydryl group. Examples of prodrugs include, but are not limited to, various salts of benzoquinone-flavored saliva compounds including, but not limited to, sodium and potassium salts, acetates of alcohols and amine functional groups in the compounds of the present invention. , formate and benzoate derivatives. Moreover, for the purposes of the present invention, the term prodrug, including the active agent, is devoid of all physical forms, including crystalline and amorphous. "stabilizing compounds" and "Justing the gentleman's sister, ', ° is intended to indicate that it is sufficiently stable to withstand the segregation of the self-reactive mixture into a compound that can be deducted from the bell and formulated into an effective therapeutic agent. Effective Quantity "Accounting for White Crocker, L% to include a compound of the present invention which is effective in alleviating the need for H2 antagonists or the active agents of the present invention. Amount or combination of claimed compounds. For the purposes of this month, the term "coordination compound" means by means of a metal ion (l suspension as a transition metal) and is called a "coordination" A metal ion or a combination of molecules forms a compound of the temple. The ligand can be positively charged or negatively charged or the ligand can be water or a shame knife. The most common metal ions are transitions that form highly stable compounds, such as the cobalt ion, the ionic ion, the iron cone, the ion, and the sulphide. The total number of bonds that bond metal 126691.doc 200906404 to a ligand is referred to as its "coordination number". The coordination number is usually 2, 4, or 6, but usually depends on the type of ligand involved. It is stated that all ligands have an electron pair on the coordination atom that can be contributed to or shared with the metal ion. The metal ion acts as a Lewis acid (electron acceptor) and the ligand acts as a Lewis base (electron donor) The charge on the miscellaneous ion is the sum of the metal ion and the charge on the ligand. These coordinating compounds may participate in a direct reaction such as an oxidation reaction or a reduction reaction, or they may act as a catalyst to catalyze an oxidation reaction or a reduction reaction. The chemical reaction or conversion occurring by means of the transition metal compounds described herein can occur as a direct reaction including, but not limited to, oxidation, reduction, metathesis, exchange, addition, elimination or rearrangement; It can occur as a catalytic reaction, wherein the transition metal compounds described herein act as catalysts homogeneously or heterogeneously. In this context or in the scope of the accompanying claims Where the term "compound" is used, the term is intended to encompass the use of a compound as a stoichiometric reactant or as a catalyst to achieve a defined chemical conversion. As used herein, 5 Slang. Directly means to participate in a chemical reaction or conversion on the basis of a chemical clock | which is based on the Ten Commandments. As used herein, the word " reminder,,, ym 匕 or its various grammatical variations means participation on a non-stoichiometric basis Chemical anti-α should be used as used herein, and the phrase milk source includes, but is not limited to, a group consisting of over-flattened hydrogen, dimethyl dioxirane, and molecular oxygen. The term "main" of the present invention refers to all mammals, including all mammals, animals such as goats and sheep. The field is moving: and the combinations of the compounds and the (4) nutrient compounds are preferably the synergistic group A + and the pigs. . D ° when in combination administration 126691.doc -14- 200906404 The effect of the compound is greater than the additive effect of the compound when administered as a single agent, as for example, by Chou and Talalay, Adv. Enzyme, 1984 The synergy described in Regul. Vol. 22, pp. 27-55 occurs. In general, the synergistic effect is most clearly manifested at the suboptimal concentration of the compound. Efficacy may be based on lower cytotoxicity, increased H2 antagonism, or some other effective effect on a combination compared to individual components.

S-5-methoxy-2-((4-methoxy-3,5-dimercapto-2-pyridyl)methyl)methanesulfinyl)-1H-benzoimidazole is a known medicine An active agent, which is generally known as sO--M--E--P--R--A- _Ζ· _〇· _L_ _E and is included by Astra Zeneca to include P_-R· + _L_ ·〇· _s_ Several trademarks of Ε__c are for sale. Methods of making such compounds are well known in the art. Astra Zeneca is hereby incorporated by reference in its entirety in its entirety by reference in its entirety in its entirety in its entirety in the the the the the the the the the A benzoimidazole compound according to the present invention may be used in combination with other pharmaceutically active agents. These other pharmaceutically active agents include, but are not limited to, anti- and steroid anti-inflammatory agents. It has been found that the coordination of an organic precursor to a transition metal ion to form an asymmetric or palmitic coordination complex provides a red compound, specifically a pharmaceutical precursor anti-stereochemistry in which subsequent coordination can be controlled. Methods. In addition, it has been found that the four-way reaction is asymmetrical or palm-like complex and the transitional gold or the palm transition metal complex* is implemented in a non-aligned manner: "Two methods At least one of 126691.doc 15- 200906404

The complex metal complex reacts with the organic precursor to form a complex, followed by a coordinated organic precursor ligand, which is asymmetrical when it is self-symmetric or palm-to-palm When the metal complex is separated, it is palmar. When such asymmetric or palm-like complexes are combined with a substrate that can react to form an enantiomer, the reaction of the coordinating ligand that can be a precursor of the drug results in more or less The product of controlled stereochemistry f, i.e., some of the desired compounds can be produced in excess of the enantiomer. As used herein, the term enantiomeric excess refers to the synthesis result obtained from the reaction in which various two or more enantiomeric compounds as reaction products of a given reaction are One of the various reaction products is present in the mixture in weight percent, by volume percent, or by moles over the other. As used herein, the term palmity is used in its generally accepted meaning. The present invention also provides means for recovering such chemically modified coordinating species after the chemically modified coordinating species have been reacted. Thus, the present invention provides a method for directly or catalytically oxidizing a thioether, the method comprising: reacting: 126691.doc -16· 200906404 ' wherein R1 and R2 are hexavalent organic radicals;

a) a separate b) transition metal catalyst having a thioether carbon atom of the formula RiSR2; and c) an oxygen source whereby the thioether is oxidized to a sub-machine radical, which contains a carbon atom R, a ruthenium atom having from six to twenty carbon atoms, the atom being optionally selected from the group consisting of ruthenium, S, Se, Te, N, P,

The As and Sb groups are grouped with _ or a plurality of heterogeneous cuts, and the hydrogen atoms may be replaced by i groups of a group consisting of free chaotic and chlorine m. The present invention further provides a process wherein a transition metal compound or catalyst is a coordination complex of the transition metal (as used herein, the phrase transition metal catalyst and transition metal coordination complex are used interchangeably and The word changes to indicate the transition metal catalyst). The invention further provides the method of claim 2, wherein the coordination complex of the transition metal comprises one or more ligands selected from the group consisting of: monodentate, bidentate, tridentate Or polydentate amines, diamines, polyamines, phosphines, diphosphines and polylin. More particularly, the invention provides a method wherein the ligand is 2(s), 3(S)-bis(diphenylphosphino)butane. More particularly, the invention provides a method wherein the complex additionally comprises a cyclopentadienyl group. More particularly, the present invention provides a process wherein the thioether is 5-methoxy-2-((4-methoxy.3,5-dimethyl-2-acridinyl)methyl)methyl Thio))-1H-benzimidazole and wherein the subhard is 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-.by dimethyl)methyl) Sulfhydryl)-1Η-benzimidazole. The method of the present invention relates to the preparation of a transition metal complex metal complex, the 12669 l.doc • 17· 200906404 transition metal complex is a ligand-unsaturated and further with at least one additional coordination of a ligand, a base The material is coordinated with the seat. The transition metal complex is preferably asymmetric or palm-shaped after forming a coordination complex with the substrate ligand. The coordinated substrate ligand is then chemically modified while being coordinated to the transition metal complex such that the substrate ligand takes better stereochemistry when it is reacted while being coordinated. Preferably, the reaction is an oxidation reaction. The chemically modified coordination of the substrate ligand is separated from the transition metal complex by reaction. A transition metal compound or complex can be reused in the catalytic cycle. The chemically modified substrate ligand is isolated and used in the preferred embodiment as a drug. Almost all transition metals in the third, fourth and fifth cycles of the halogen periodic table form coordination complexes and, where appropriate, most of these metals can act as homogeneous catalysts or heterogeneous catalysts. The highest level of stereochemistry and kinetic control is often achieved under conditions that are typically characterized by homogeneous catalysis. In the simplest definition of a catalyst, a catalyst is a substance that changes the rate of reaction of a chemical reaction without participating in the overall reaction. > With all simple definitions, this oversimplifies what actually happens on a microscopic scale, so that a substance that can be characterized as a catalyst at an abstraction level actually participates in the reaction at a finer resolution level. Such materials which exit the reaction sequence in the form they enter into the reaction sequence are formally a catalyst, but which have undergone a series of chemical changes or conversions between the two ends of the process. As used herein, 乂 节 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , The pharmaceutical precursor) is recycled and reused to effect a conversion (eg, 'oxidation, reduction, addition, or elimination of reactions>). Thus the terminology is adjusted to include (but is not limited to) Chemical reactions and catalytic reactions (like catalytic reactions and heterogeneous catalytic reactions). The term transition metal includes chemical elements having an atomic number from 21 to 30, from 39 to 48, from 57 to 80, and from 89 to 103 (inclusive). This range includes lanthanum elements 57 to 71 and lanthanum elements 89 to 103, respectively. More specifically, the transition metal used to carry out the method of the present invention is a transition metal of Groups VIb and viii of the Periodic Table of the Elements, having atomic numbers 24, 42, 74, 26, 27, 28, 44, 45, 46, 76, Elements of 77 and 78. More specifically, the elements used to carry out the method of the present invention have atomic numbers 24, 74, 44, 45, 46, 77 and 78, i.e., Cr, w, RU, Rh, Pd, lr and Pt. These transition metals are used as their coordination complexes, that is, as their ionic form as a reaction product of a transition metal salt, which is usually a halide, that is, a coordination ligand (pair) a fluoride, chloride, bromide or iodide of a palm or a non-pivoted coordination ligand, the coordination of which is a monodentate, bidentate or polydentate amine, Amine, polyamine, phosphine, diphosphine, polyphosphine. The coordinating complexes of such coordinating complexes may or may not be further mono-, bi-, tri- or polydentate with or without the coordinator of the same or other ligands for palm or non-pivoting coordination. , polyamines, scales, diphosphines, polyphosphines. Income, the match

Reacting with reagents to oxidize, molecular substances, organic ligands or medical precursors, organic ligands or pharmaceutical precursors in the coordination, reduction, addition chemical moiety to coordination of organic 126691.doc -19- 200906404 or The drug, such as a body or a self-coordinating organic or pharmaceutical precursor, eliminates the chemical moiety. Since most of the coordination complexes of transition metals involve the formation of a bond between the coordinating substance or the ligand and the transition metal, when the coordination substance (hereinafter a ligand) has at least one unshared electron pair and is coordinated This bond is most easily formed when the transition metal has an idle outer rail domain (typically the valence d, s or ρ rail domain). A ligand having at least one unshared electron pair is typically incorporated with a heteroatom selected from the group consisting of N, P, As, Sb, 0, S, Se or Te, although 7 Γ electrons of the alkene, alkyne and aromatic molecules You can also participate in this type of bond to act as a ligand. Typically such heteroatoms are trajectories of unshared electron pairs and are therefore not fully oxidized in terms of the available oxidation state of the heteroatoms. In the preparation of a coordinating unsaturated coordination complex containing a transition metal ion of an amine and/or a phosphine ligand, 'the oxidation state of the transition metal is changed by oxidizing the complex or reducing the complex to cause coordination. Unsaturation can be useful. An oxidizing agent such as those listed below for use in the reaction of the substrate ligand can be used to oxidize the complex. A reducing agent may be used to lower the oxidation state, and it is preferred that the reducing agent be hydrazine. These techniques are conventional in the art. Several different reactants can be used to affect the chemical structural changes of the coordinating ligand or organic precursor. For example, an acid halide having the following general chemical formula:

RdC(0)X wherein Rd is a monovalent organic radical, C(O) is a carbonyl functional group associated with an organic carboxylic acid, and X is a dentate selected from the group consisting of fluorine, chlorine, bromine and iodine. Gas and bromine are preferred, and gas is especially preferred. Another example of the reaction of a ligated molecule may involve the use of an acid acid having the following general formula: 126691.doc -20-200906404:

RdC(〇) Re is associated with a different carbonyl. Among them, Rd is a valence organic radical, c(〇) is a functional group with an organic tickic acid, and K is the same or different monovalent organic radical, in Rd. The = position can be oxidized by various reactive oxygen species f, such as = oxygen: oxygen, hydrogen peroxide, and molecular species containing reactive oxygen. Often organic acids with a general chemical formula: phase L is known as a valence organic radical or ammonia, and C (〇) is a functional group with an organic tickic acid. Many of the so-called peroxyacids are commercially available (as a non-limiting list) for acetamidine cH3c (〇) 〇 2H, peroxygen scavenging ^ (free radicals) (10), peroxyformic acid hc (〇) 〇2h, trichloro@, (ntrrM〇r〇PeraCetiC acid)ccl3C^〇2H^3-ai,^ f : (strain oxybenzoic acid). Inorganic peroxyacids are also known and can be used Η: for example, 'peroxidic monosulfate H2S〇3 (〇2) and disulfate H2(S03)2〇2. The molecular oxygen reaction can be carried out in the presence of atmospheric oxygen. "Milk gas 2 bubbles" can be produced in the reaction medium or pure oxygen (commercially available as a pressurized gas or as an ultra-cold liquid) can be used. Hydrogen peroxide source instead of introducing atmospheric oxygen into the reaction medium can be dissolved or Water containing 12669l.doc -21 - 200906404 Any source of deuterated 11 (including those containing 3 to 100 percent hydrogen peroxide) Preferably, the hydrogen peroxide is between about 20 weight percent and 7 weight percent: Preferably, between 45 and 8% by weight of the live, & amp 虱 虱. Due to the presence of the solvent in the process, the more concentrated oxidized chlorine can be used without the difficulty of stirring the reaction mixture.

〇 k Hydrogen peroxide should be at least stoichiometric. The range is usually between about 1 mole of hydrogen peroxide to 5 moles of hydrogen peroxide per mole of primary amine, more preferably between about 1 mole of amine per mole of hydrogen peroxide to 15 moles of hydrogen peroxide. Preferably, the high f is about 1. G5 h. 3 mole peroxygen per mole of the compound to be oxidized: 虱, and particularly preferably the amount of the compound to be oxidized per mole of about I. 〗 〖I] hydrogen. Any of the four hydrogen peroxides in the reverse (4) may be destroyed by the addition of reduction #1 (e.g., sodium sulfite, sodium thiosulfate, and/or sodium thiosulfite). In addition, enzymes known in the art have been shown. : Enzymes from the trademark Catazyme of Novo Nordisk, including $50 L), can be effectively used to destroy any excess hydrogen peroxide remaining. Molecularly Reactive Oxygen Source The reactive oxygen source used in the oxygenation or oxidation reaction disclosed herein is dimethyl bis(E): (10) (9), which consists of two oxygen atoms and - carbon atoms. A three-membered ring and substituted by two methyl groups on a ring carbon atom. Despite its highly reactive nature, dimethyl bisphenol is chemically surprisingly selective in its ability to act as a selective electrophilic oxygen transfer reagent. DMD can be used in epoxidation reactions and is especially useful in the selective epoxidation of organic transition metal complexes such as polyene complexes. Should also be used to change the functionality of the hydroquinone by inserting an oxygen atom into the hydrogen bond of the stone. One of the particular advantages of using DMD as an oxygen source is that the genus (CH3)2C (〇) is the only product after completion of oxygen transfer, thereby simplifying the subsequent work (work_up) due to the volatility of acetone. Solvent Selection When the reaction product needs to be separated by azeotropic distillation, the organic solvent used in the present invention may be any organic liquid, and the organic hetero compound and its related oxidation product are soluble in the organic liquid at the reaction temperature and the organic liquid It may or may not form an azeotrope with water. However, to avoid the risk of explosion, the solvent can be substantially inert. In a preferred embodiment of the invention, the solvent is capable of maintaining the reaction mixture as flowing and agitable without reducing the solids content of the reaction mixture to about 15% by weight or less, preferably to about 30 weight percent. The amount below % is used. Good results can be achieved at a solids content of about 50% by weight. / ·> k'f Based on cost and availability and utility, the preferred solvent for use in the process is a lower alkyl alcohol, such as (from: 丨 to an alcohol, and especially containing - or a plurality of hydroxyl groups C1 to C4 alcohol. Exemplary alcohols include: methanol, ethanol, propanol, 2. propanol, 1-butanol, 2-butanol, pentyl alcohol, 2-pentanol, % pentanol, tert-butyl alcohol, 1 -hexanol, 2-hexanol, 3-hexanol, 2-methyl+propanol, amyl alcohol, 2-methyl-1-butanol 2-methyl-2-propanol decyl-1 butanol , 3-methyl-2-butanol, neopentyl alcohol, 2,3·dimethyl-2-butanol 3'3-dimercaptobutanol, hexyl alcohol, 2-hexanol, 3· Alcohols and the like and various mixtures thereof. Particularly preferred solvents include hydrazine-propyl alcohol, dimethyl ketone, 1-butanol and 2-butanol. The cycloaliphatic or aromatic solvent may contain another solvent as needed. Such as, aliphatic, 126691.doc •23·200906404 family hydrocarbons (such as hexane, isohexane, heptane, 2-ethylhexane, octane, isooctane, cyclohexane, cyclooctane, toluene or Analogs), or halogenated hydrocarbons (such as gas benzene, dichlorobenzene, bromobenzene, gaseous toluene, 2 , 4-dichlorotoluene and the like). The ester solvent can also be used as a cosolvent, and exemplary ester solvents include: methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, second butyl vinegar, Tert-butyl acetate, isobutyl acetate, amyl acetate and the corresponding propionic acid vinegar, butyrate and valerate. When an optional co-solvent is used, the amount is usually limited to up to about 25 weight by weight of the polar solvent. The amount of % (for example, 1 weight / 〇 to 25 weight 〇 / 〇). The use of a non-polar solvent reduces the solubility of the tertiary amine and / or amine oxide in the reaction mixture.

The method also includes the use of an accelerator for the oxidation of the heteroatoms (especially when the heteroatom is a nitrogen atom). Preferred promoters include lower organic acids which are capable of being removed from the reaction mixture by distillation upon completion of the oxidation. Preferred acids include: formic acid, acetic acid and propionic acid, with acetic acid being especially preferred. Other organic carboxylic acids such as diethylenetriamine pentaacetic acid or ethylenediaminetetracarboxylic acid are also useful. Other accelerators & include: carbonated, heavy carbonic acid and aminocarboxylic acid recordings and mixtures of accelerators. Carbon dioxide and aluminum are also effective promoters. The amount of promoter can vary over a wide range of factors. The amount of promoter in the reaction mixture is required to be such that the reaction proceeds at a rate that is faster than the rate achieved without the addition of the promoter. At least a catalytic amount of accelerator should be present in the shifter's. The usable concentration of the accelerator is: based on the weight of the heteroatom compound precursor. Tear to a difficult number, number. A preferred concentration is from about Ο. to about 1 weight percent. A better degree of indifference is: 〇·(Η to 0.8% by weight. When carbon dioxide is added as a promoter, it can be added as a blanket on the reaction mixture, or more preferably, carbon dioxide, 126691.doc -24-200906404 It can be dissolved in aqueous hydrogen peroxide and/or solvent.

Depending on the substrate, the reaction can be carried out over a wide temperature range. The temperature should be sufficient to allow the reaction to proceed at a reasonable rate, but not so high as to cause decomposition of the reactants or products. The usable temperature range is from about _3 (rc to 14{rc. More preferably, the temperature range is from about -20 ° C to 140 ° C. Further preferably, the temperature range is from about 45 C > c to 130 ° C. For oxidation of nitrogen-containing substances In terms of reaction, optimally, the reaction is carried out at a temperature of from about 45 ° C to 110 ° C. In this temperature range, the reaction is very fast and is normally completed in less than about 30 hours, usually less than about 2 hours. Good results have been achieved from about 55 ° C to (iv). For the oxidation reaction of sulfur-containing f, a temperature range of -30 ° C to 30 ° C is preferred. In one embodiment, by adding aqueous peroxidation The method of the present invention is carried out by hydrogen to a tertiary amine solution in a solvent containing a promoter. The organic solvent is usually present throughout the reaction, even if it is present at any point during the reaction, and the amount of the component is + The initial period can be minimized and then gradually added during the reaction to keep the reaction mixture flowing and can be dropped. Or 'the organic solvent can be completely added at the beginning of the reaction, or can be added after the reaction process.' The limitation is that it exists for the use of water-containing hydrogen peroxide The solvent for removing water. Hydrogen peroxide is preferably added in a row such that the temperature is preferably maintained within the range as previously discussed. * The portion may become necessary to maintain the temperature within the desired range. Peroxidation / Addition The rate is preferably such that no large accumulation of unreacted gas occurs at any given time. The reaction temperature is maintained within the temperature range, straight:: The reaction is substantially completed, usually within less than about fifty hours (four), 126691 .doc -25- 200906404 is usually less than about forty hours. When the reaction is completed, the relevant oxide can be recovered immediately by removing the organic solvent and water as azeotrope. Alternatively, the azeotrope can be During the reaction, it is added to the anti-bank ice (4) and (4). It is better to add enough organic solvent in the vacuum (usually at least 25 mm Hg) to ensure that the water is completely removed from the K-hydrogen. /, mixture, when the relevant oxygen is a secondary amine oxide, the relevant oxide is thus recovered as a solid in the form of a dihydrate, a monohydrate and / or an anhydrate. r can be used as collected Back The related oxide may be dissolved in the organic compound by the recovery of the relevant oxide at a higher temperature and at a lower temperature from the organic matter of the sputum. _ Qiao 馎 d recrystallization recovery related The oxide is modified one or more times to improve the purity of the relevant oxide. By using an organic solvent such as ethyl acetate, which is at least partially soluble, the recrystallization can also be used to reduce The small water recovers the water content of the relevant oxide (if needed). For example, if the amine oxide is recovered as a dihydrate, and it is desirable to convert the dihydrate to an oxide containing a smaller amount of water, such as 'conversion When the mixture of the dihydrate, the monohydrate and the anhydrous oxide (4) is converted into a monohydrate or anhydrous form, the amine oxide can be recrystallized from the organic solvent until the desired degree of dehydration is achieved. Although the initial salts used as transition metals for the synthesis or preparation of precursors for asymmetric or palmotropic transition metal complexes will typically involve classical counterions or anions (such as sulfates, phosphates, dentates (fluoride) , chloride, desert or moth), nitrate, sulphate and the like), but in terms of the ability to subsequently react and isolate products, 'utilize mismatched non-oxidative properties 126691.doc -26 - 200906404 anions It is generally more convenient for these mis-aligned non-oxidizing anions to be exemplified by (SbF6) 1, (AsFJ1, (PF6)·1 or (BF4)-i; in some cases 'organic analogues of such anions It may be a preferred choice, for example, (Βββ5)4,1. These preferred salt forms for asymmetric or palmitic transition metal complexes are readily available by the usual use of the following sodium, potassium or ammonium anions Prepared by the conventional anion exchange technique of salt: Na(SbF6),

Na(AsF6), Na(PF6), Na(BF4), K(SbF6), K(AsF6), K(PF6), K(BF4), NH4(SbF6), NH4(AsF6), NH4(PF6) or NH4 (BF4). The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, along with synthetic methods known in the art of synthetic organic chemistry, or variations as known to those skilled in the art. Preferred methods include, but are not limited to, the methods described below. All references cited herein are hereby incorporated by reference in their entirety. The novel compounds of the present invention can be prepared using the reactions and techniques described in this section. The reaction is carried out in a solvent suitable for the reagents and materials used and is suitable for the conversion being achieved. Further, in the description of the synthesis method described below, 'should understand' that all of the proposed reaction conditions including solvent selection, reaction atmosphere, reaction temperature, duration of experiment, and treatment procedure are selected as standard conditions for the reaction, familiar with this. The technician should be easy to understand. Those skilled in the art of organic synthesis should understand that the functionality present on various parts of the molecule must be compatible with the proposed reagents and reactions. Such constraints on the substituents that are compatible with the reaction conditions will be readily apparent to those skilled in the art, and 126691.doc -27-200906404 then an alternative method must be used. Skilled artisans will appreciate that pharmaceutical compositions containing active agents such as proton pumps and antagonists are well known in the art. Some examples of such compositions and methods for their manufacture are shown, for example, in the following patents: U.S. Patent No. 5,626,8,75, filed on April 27, 1995, to the name of Esteve Quimica, SA US Patent No. 6,077,541 to Andrx Corporation, entitled "Pharmaceutical formulations containing a non-steroidal anti-inflammatory drug and a proton pump inhibitor", and issued to Andrx Corporation, on June 18, 1999. 6, 869, 615; titled "5-11161:11(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl)methylsulfinyl)-ΙΗ-benzimidazole formulation" and awarded to Andrx Corporation 6,855,336; entitled "5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridinyl) methyl)methylsulfinyl)-1 H-benzimidazole formulation" and issued to Andrx Corporation 6,780,435; entitled '' 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridinyl) methyl)methylsulfinyl)-1 H-benzimidazole formulation" and issued to Andrx Corporation 6,733,778; entitled "5-methoxy-2- ((4-methoxy-3,5-d Imethyl-2-pyridinyl)methyl) methy lsulfinyl) -1 H-benzimidazole formulation" and issued to Andrx Corporation 6,602,522; entitled "Pharmaceutical formulation for acid-labile compounds" and issued to Andrx Corporation 6,544,556; entitled " Pharmaceutical formulations containing a non-steroidal anti-inflammatory drug and a proton pump inhibitor" and awarded 126691.doc -28- 200906404

Andrx Corporation 6,174,548; entitled "5-11161; 11-methoxy-3,5-dimethyl-2-pyridinyl methyl)methylsulfinyl)-ΙΗ-benzimidazole Formulation" and awarded to Andrx Corporation 6,174,548; entitled "5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridinyl) methyl)methylsulfinyl)-1H-benzimidazole Formulation" and issued to Andrx Corporation 6,096,340; titled &quot ; 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridinyl) methyl)methylsulfinyl)-lH-benzimidazole Formulations" and awarded to Andrx Corporation 6,077,541; Seth Pawan on August 3, 1998 U.S. Patent No. 6,207,198 to Schwarz Pharma; entitled "Pharmaceutical Compositions Containing An Acid labile Ο- -M- -E- _P- -R- -A- -Z- -0 - L- - U.S. Patent No. 6,248,355 to E. and U.S. Patent No. 6, 248, 355, to U.S. Pat. The full text is like a comprehensive explanation. The present invention will be further described in the following description of the exemplary embodiments of the present invention, which are set forth to illustrate the invention and are not intended to limit the invention. The solution is expressed in volumetric relationship. The NMR chemical shifts are recorded in parts per million (6). The abbreviations used in the examples are defined as follows: "°C" for Celsius, "eq" for equivalents, "g" for grams, "h" For hours, "mg" for mg, "mL" for ML, "mmol" for 135691.doc -29- 200906404 Moer for Mohr, "mm" for minutes, "HpLC" for high pressure fluid Phase tomography, "η" for room temperature ' NMR " for nuclear magnetic resonance analysis, "tic" for thin layer chromatography, "atm, for the atmosphere, and "Ava (4) (four)", double (beta), R", and "s" are stereochemical representations that are familiar to those skilled in the art. Example 1 Preparation of a material for cyclopentaphosphoric acid complex

RuC13 3H20 is available from a variety of fine chemical supply companies including, for example, Aidrich* Degussa. Commercially known as (S,S)-CHIRAPHOS 2(S), 3(S)-bis(diphenylphosphino) Ding Hyun, hereinafter abbreviated as "chirpp") available from streni Chemicals and without further Used in the case of purification. For the needle complex (CpRu(LL')Cl, the phosphine ligand dppm is prepared according to the method described in Schenk et al., Inoi. Chem. (1997), Vol. 36, p. 2372, footnote 16. 1-bis-diphenylphosphinomethane), dppe (l,2-bis-diphenylphosphinoethane) and dpme(2-(dimethylphosphino)ethyl)diphenylphosphine' Cp Cyclopentadienyl or cyclopentadienyl (CyCi〇pentadienylide) and LL' is (pph3)2, dppm; dppe; CO; PPh3, dpme or chirp. Sulfur can be alkylated by the corresponding thiol Prepared for action, or in some cases it can be from Aldrich. For example, Adam et al., Chem. Ber. (1991) Vol. 124, p. 2377 or Murray et al., j. 〇rg chem. (1985) 50th The volume of 0.08 Μ to 0.12 Μ 126691.doc -30- 200906404 acetone solution of freshly prepared dimercapto dioxirane is described in Volume 2817. Preparation of hydrazine sulfide complex when LL' is a carbonyl group ( For CO) or triphenylphosphine (PPh3), 0.25 mmol (CpRu(LL)Cl and 0.30 mmol of NH4 (PF6) and 1.0 mmol of the appropriate thioether are suspended in methanol CH3OH and heated to 60 ° C lasts 3 hours or six hours. Moves under vacuum The volatiles were removed and the residue was extracted with a portion of dichloromethane (EtOAc). After filtration, the product was precipitated by partial evaporation and diethyl ether (CH3). The thioether used was: CH3SC6H5, [CH3S-i-C3H7, CH3SCH2C6H5 and 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-(pyridyl)methyl)methylthio)-1Η- Benzimidazole (pyrmetazole); the complex prepared is (CpRu(chirp)(CH3SC6H5))(PF6), (CpRU(chirP)(CH3S-i-C3H7))(PF6), (CpRu(chirp)(CH3SCH2C6H5))(PF6) and (匚?1111((:1^印)(5-methoxy-2-((4-methoxy-3,5-dimethyl-2) - acridinyl)methyl)methylthio)-111-benzimidazole)) (?[6). Although the conversion of thiol-substituted thioethers is essentially quantitative, it is highly space-dependent. The substrate is less complete, and attempts to drive the reaction using a larger excess of dimethyl bis-epoxyethyl ketone are added to the decomposition. The reaction is replaced by a mismatched sulphur in the thioether. The base aspect becomes more space-demanding, and other sources of oxygen may therefore be more suitable. Example 2 Oxidation of a thioether complex to produce a sulfoxide complex to any of the thioether complexes formed in Example 1 (0.12 mmol) in acetone (10 mL) at 0 ° The solution of C was slowly added in four (4) times excess of an acetone solution of dimethyldioxirane cooled to -30 °C. After 45 minutes 126691.doc 31 - 200906404, remove all volatiles under vacuum. The yield is almost quantitative and the ratio of diastereomers is determined from the NMR spectrum of the crude reaction mixture. When the self-aligned transition metal cation is precipitated, the resulting methyl hydrazine exhibits a selectivity to the 8 enantiomeric form 'this selectivity is 73% for the oxidation of the mis-linked methyl phenyl sulfide, to It is used for 93% of mismatched methyl isopropyl sulfide to vary between greater than 99% of mismatched methylbenzylidene sulfide. Example 3 Recovery of a miscible sapphire produced by oxidation of a miscible thioether to heat the hydrazine complex (〇1〇 millimole) and sodium iodide (Nal) (0.50 mmol) under a jet (reflow) Ear) and acetone (5 nL) lasted 15 hours. The mixture was then evaporated to dryness. The residue was extracted with methylene chloride (2 mL) and the residue was chromatographed on a short 10 cm silica column. First, the iodinated complex CPRu(chirp)I' is dissolved and then acetone is used as a dissolving agent to dissolve the subhard. The evaporation of C_ leaves ferrous iron. When the sulfur is determined to be 5-methoxy-2-((4-methoxy-3,5-diindenyl-2_0-pyridyl)methyl)phosphonium)_iH_benzimidazole, the recovered飒 is 5-methoxy-2_((4·曱oxy_3,5-didecyl-specific) methyl) 曱 醯 26 醯 ) _ 幷 幷 幷 嗤 嗤, which is generally or generally known It is 5-methoxy-2-((4-methoxy-3-3,5-dimethyl-2-indolyl) methyl) sulfinyl)-1Η-benzimidazole. This method produces an excess of enantiomers (mainly in the form of S) of 5-nonyloxy-2_((4-methoxy-3-3,5-dimethyl-2-pyridyl)indolyl)sulfin Sulfhydryl)_1H_benzimidazole. Example 4 Preparation of a pharmaceutical dosage form using a benzoquinone compound prepared according to Example 3 'Disperse 436 g S-5-methoxy·2·(3·曱0126.doc 32-200906404 based on 3440 g of deionized water) Miao-methyl~biteryl)methyl)methyl sulfonate) _ιη·benzoquinone, 444 g of propylmethylcellulose and 118 g of talc. (4) g, powder balls (according to the composition of the United States Pharmacopoeia) were introduced into a fluidized bed apparatus, and after the previously obtained dispersion was sprayed onto the ball, the balls were dried before the second layer was applied. In 2365 g of deionized water, 355 g of bis-methylcellulose, 43 g of talc, and 43 g of titanium dioxide were dispersed, and the resulting aqueous dispersion was sprayed onto the sphere obtained in the previous step. After spraying, the balls are dried before the third casing layer is applied. Disperse 1950 g of methacrylic acid copolymer (United States Pharmacopoeia 'type c aqueous dispersion), 98 g of triethyl gluconate and 98 g of talc %' in 1' g of deionized water and spray the resulting aqueous dispersion onto The ball obtained in the previous step. After coating the final casing layer, the balls (pellets) are dried. Example 5 Preparation of a pharmaceutical dosage form using a benzoimidazole compound prepared according to Example 3 by placing a sugar sphere in a fluid bed coater and spraying containing 5-methoxy-2-((4-methoxy) _3,5_Dimercapto-2-pyridyl)methyl)methanesulfinyl group> 1H-benzimidazole suspension on sugar spheres to form 5-methoxymethoxy_3,5 Active pellets of _dimethyl-2~~pyridyl)methyl)methanesulfinyl)-1Η-benzimidazole. The formulation used to make the active pellets has the following composition: polyvinylpyrrolidone, usp (piasd〇ne K9〇) 4 5 g sodium lauryl sulfate, NF 1 〇 6 g anhydrous lactose, NF 427.7 g disodium phosphate , NF 51.3g 126691.doc -33· 200906404 s-5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridyl)methyl)methylsulfinyl )-1Η-benzimidazole, USP (micron size) 427.7 g pure water, USP 3336.0 g Polyvinyl pyrrolidone, anhydrous lactose, monosodium phosphate and pure water were mixed using a mechanical mixer until the material dissolved. Next, sodium lauryl sulfate was added to the mixture with gentle agitation to avoid the formation of additional foam until the sodium lauryl sulfate was completely dissolved. At that time, micron-sized s_methoxy-2-((4-methoxy-3,5-dimethyl-2·β than dimethyl)methyl)methyl sulfhydryl)-1Η-benzene Indazole is added to the mixture and stirring is continued until micronized s-5-methoxy-2-((4-methoxy-3-3,5.dimethyl-2-pyridyl)methyl ) sulfinyl)-lH_benzimidazole is completely dispersed. 2500.0 g of non-pareil sugar spheres (USPXII) (1 8/2 inch mesh) were placed in a fluid bed coater at 35. (: to 45. The product temperature of 〇, the atomization pressure of 15 bar to 3 mbar and the pumping rate of 2 ml/min to 50 ml/min are coated with s-5-methoxy-2-(( 4-Methoxy-3,5-dimethylpyridinyl)methyl) a suspension of stilbene-1 Η-benzoquinone saliva starting at a low pumping rate to avoid cohesion and avoid cohesion Formally increasing the pumping rate. After the coating is completed, the pellets are dried at a temperature of 5 (TC until the loss of drying is less than 2.5 wt%. The sieves are then sieved through #14 mesh and coated by the following casing formulations : hydroxypropyl methylcellulose terephthalate (phthalate), NF 258.1 g cetyl alcohol, NF 12.9 g talc, USP 129.0 g isopropyl alcohol, USP* 1663.0 g acetone, NF* 1663.0 g 126691 .doc -34- 200906404 Evaporation of hydroxypropyl methylcellulose terephthalate and cetyl alcohol during processing with isopropyl alcohol and propylene_mixed until all materials are dissolved. The talc powder is dispersed in the solution while mixing. The kilogram of active pellets are placed in a body bed coater, and all casing mixtures are coated using the coating conditions used to form the active pellets. The coated pellets are then placed in a hard gelatin capsule of the number "2··, which contains 8_5_methoxy-2-((4-methoxyl_3,5·2) Methyl-2_〇pyridinyl)methyl)methanesulfinyl)-1H-benzoquinone. Sitting pellets. Example 6 Preparation of a pharmaceutical dosage form using a benzoimidazole compound prepared according to Example 3 A pharmaceutical composition according to the present invention in the form of a micro-tablet contained in a gelatin capsule having the following composition expressed in mg was prepared. Core composition per capsule micro-tablet (by 16 tablets) s_5_decyloxy-2-((4-methoxy_3 5-didecyl-2-pyridyl)methyl) fluorene )-1Η-benzoimidazole 1 250 (20.00) propyl propyl fluorenyl cellulose 〇 · 625 (1 〇〇〇) lactose 11.875 (190.00) stearin bismuth succinate 〇.15 〇 (2.40) Cross-linked polyvinylpyrrolidone 〇·75〇 (12.00) Water 7.500 (120,00) Intermediate layer composition per capsule micro-tablet (by 16 tablets) 126691.doc •35· 200906404 Talc 0.375 (6.00) Titanium dioxide 0.150 (2.40) Hydroxypropylmethylcellulose 0.750 (12.00) Water 5.000 (80.00) Composition of the casing layer Each capsule microinner (by 16 tablets) Methacrylic acid copolymer, 1.375 (22.00) Type C Triethyl Lemon Acidate 0.206 (3.30) Talc 0.275 (4.40) Water 3.750 (60.00) First, by dissolving hydroxypropyl fluorenyl cellulose in water followed by s-5-methoxy-2-((4-A) The core was prepared by homogenizing the resulting suspension with oxy-3,5-dimethyl-2-"methylidene)methyl)methanesulfonyl)-1H-benzimidazole. The thus obtained s-5-methoxy-2-((4-methoxy_3,5-dimethyl-2-pyridyl)methyl)methyl hydrazino)-1H-benzimidazole The suspension is sprayed onto a lactose core having a particle size of 250 ηηχ.Γη in a suitable fluid bed granulator, such as a granulator sold by the company Glatt, 〇 〇 111, etc. Any type of fluidized bed granulator conventionally used in this type of step can be used in the present invention. After spraying all of the suspension, the core is dried in a conventional manner using, for example, a fluidized bed, and the product temperature is preferably maintained below 450 °C. Sodium stearyl fumarate and cross-linked polyvinylpyrrolidone are then added to the dried core, followed by mixing. Thereafter, compression of the obtained mixture is carried out to obtain a micro-tablet having a diameter of about 2.5 mm (generally comprising a diameter between 2 mm and 4 mm); or, compression of the obtained mixture is carried out to obtain a tablet of a conventional size. The troches and lozenges can be 126691.doc -36- 200906404 containing, for example, 20 mg and 4 mg of an effective amount of the active agent. An intermediate layer prepared by dissolving propylmethylcellulose in water followed by addition of vermiculite and titanium oxide followed by homogenization by spraying is deposited on the micro-key. This can be done in any suitable coating equipment (e.g., a G丨att coater with a Wurster type column) that allows for the acquisition of a f gauge film. Example 7 Preparation of a pharmaceutical dosage form using a benzoquinone miso compound prepared according to Example 3 A pharmaceutical composition according to the present invention in the form of a micro-tablet contained in a gelatin capsule having the following composition expressed in mg was prepared. Uncoated pellets lactose powder 253 g I anhydrous lactose 167 g hydroxypropyl cellulose 25 g S-5-decyloxy-2-((4-decyloxy-3,5-dimethyl-2 -pyridyl)methyl)methylammonium)-1Η-benzoimidazole 50 g sodium lauryl sulfate 5 g II disodium hydrogen phosphate 1.5 g sodium dihydrogen phosphate 0.1 g distilled water 125 g premixed and dried in a mixer Ingredient (I). A granulating liquid (II) containing the suspended active compound is added, and the lumps are wet-mixed to a suitable consistency. The wet mass is extruded through an extruder and spheronized into pellets. These pellets are dried and classified into a suitable particle size range. Coated pellets 126691.doc -37· 200906404 Uncoated pellets 500 g ΠΙHydroxypropylmethylcellulose 20 g Distilled water 400 g Polymer solution sprayed in a fluidized bed apparatus On uncoated pellets. The spray is placed on the fluidized bed. Coated coated pellets coated with sub-coating 500 g iv hydroxypropyl methylcellulose terephthalate 57 g cetyl alcohol 3 g propyl I 540 g ethanol 231 g in a fluidized bed apparatus The polymer solution (IV) was sprayed onto the coated sub-powder using a spray placed on the bed. After drying to 〇.5% water containing mash, the coated casing pellets were sorted and filled in hard gelatin capsules in an amount corresponding to 284 mg of 25 Active Compound 1. Pack 30 capsules together with a desiccant in a tight container. Example 8 Preparation of a pharmaceutical dosage form using a benzoimidazole compound prepared according to Example 3 A pharmaceutical composition according to the present invention in the form of a micro-tablet contained in a gelatin capsule having the following composition expressed in mg was prepared. Uncoated pellets S 5 -decyloxy-2-((4-methoxy_3,5-diindenyl 2_πΛπ-decyl)methyl)-methyl sulphate-branched)-1Η-benzoquinone Salinated salt 339 g Mannitol powder 2 422 g 126691.doc •38- 200906404 I anhydrous lactose 120 g Hydroxypropyl cellulose 90 g Microcrystalline cellulose 60 g Sodium lauryl sulfate 7 g Distilled distilled water 650 g In addition to the mixture I In addition to the sodium salt of the s-benzimidazole compound added, it was prepared as described in the previous example (Example 7). 5" He is coated with a sub-coated pellet

Uncoated pellets 500 g Hydroxypropyl methylcellulose 20 g ΙΠ Potassium hydroxide/magnesium carbonate 4 g Steamed water 4 0 0 g Coated coated pellets from the following: III 5 00 g Hydroxypropyl methylcellulose 2 〇g IV distilled water 400 g Two sub-coats III and IV were applied to the uncoated pellets in a fluid bed apparatus in a sequential order as previously described. Coated coated pellets coated with sub-coating 5 〇〇g hydroxypropyl methylcellulose terephthalate 57 g V cetyl alcohol 3 g acetone 540 g ethanol 231 g as in Example 7 The preparation of the coated casing pellets is carried out as described. 126691.doc -39.200906404 Example 9 Preparation of a pharmaceutical dosage form using a benzoimidazole compound prepared according to Example 3 This example provides a unit dosage composition in accordance with the present invention. Tablet core S-5-methoxy-2-((4-methoxy-3-3,5-didecylpyridinyl) indenyl)methyl hydrazino)-1Η-benzoquinone miso, 15 mg Lactose 119 mg Hydroxypropylcellulose (low substitution) 5 mg Hydroxypropylcellulose 1 mg (low substitution) Talc 5 mg

Mg(OH)2 15 mg Total 1 60 0 g First, a tablet core having the above composition and each weighing 16 〇 mg was prepared by a known technique. Separation layer (inner) Hydroxypropyl cellulose 2 mg Synthetic hydrotalcite 0.3 mg [Al203.6Mg0.C02.12H20] Separation layer (external) Separation of two by propyl cellulose 2 mg by known coating techniques The layer is applied to the core. Enteric layer hydroxypropyl methylcellulose terephthalate 7 mg cetyl alcohol 0.5 mg The casing coating solution was sprayed onto the layer by two separate coatings 126691.doc •40-200906404 by known casing coating techniques On the core of the cloth. The following examples are merely illustrative of the invention, and are intended to illustrate only certain features of the invention. Selected embodiment. Accordingly, the Applicant intends that the scope of the appended claims is not limited to the selection of examples to illustrate the features of the invention. As the scope of the patent application, the phrase "including" and its grammatical changes are logically defined and different degrees of phrases, such as (but not limited to) "essentially by .... ...... 'Composition " and '1 consists of.". Where necessary, the scope=special range includes all sub-ranges between them. These ranges can be seen by the ar ush group or by The different pairs of digitally restricted groups are completely bounded by their lower bounds; one by one, one by one, and thus from the lower end to the upper end of the endpoint with a single technique & (4) " increase and / or decrease. I hope to have the same in this technology: :: practitioners can understand the changes in these areas, and in the absence of speciality, their changes should be covered in scope. ❹ 转 为 ( 四 四 ( 四 四 四 四 四 请 请 请 请 请 请 请 请 请 请 请 请 请 请 专利 专利 专利 专利 专利 精确 精确 精确 精确 精确 精确 精确(4) (4) (and ^== cover. The description in this article is generally incorporated by reference in this document. Therefore, it is like 126691.doc • 41 -

Claims (1)

200906404 X. Patent application scope: 1. One kind of thioether 5-methoxy-2-((4-methoxy-3,5-dimercapto-2.pyridyl)methyl) sulfonium sulfide -1H-benzoquinone is oxidized directly or catalytically to its hydrazine: 5- methoxy-2-((4-methoxy·3,5·dimethyl-2-0-butyl) a method of treating a methyl group with a -1H-benzoquinone-flavored beta, the method comprising: a) reacting the thioether with: 1) a transition metal compound; and 2) an oxygen source; wherein the thioether is Oxidation to sulfoxide, and wherein one of the r and S enantiomers is formed as an enantiomeric excess. The method of claim 1, wherein the transition metal catalyst is a coordination complex of the transition metal formed by the combination of a metal ion and a non-metal ion or a molecule. The method of claim 2, wherein the coordination complex of the transition metal comprises a compound selected from the group consisting of monodentate, bidentate, tridentate or polydentate amines, diamines, polyamines, phosphines 'diphosphines and polyphosphides One or more of the ligands that make up the group. 4. The method of claim 3 wherein the ligand is 2(S), 3(S)_bis(diphenylphosphino)butane. The method of claim 4, wherein the complex further comprises a cyclopentane group. 6 _ The method of claim 5, wherein the metal ion is a transition metal. 7. The method of claim 6, wherein the transition metal is selected from the group consisting of Ru, Rh, pd, Ir, and Pt. 8. The method of claim 7, wherein the transition metal is RU. 9. The method of claim 1, wherein the source of oxygen is selected from the group consisting of peroxyacids, peroxygen gas, dinonyl dioxirane, and molecular oxygen. The method of claim 9, wherein the source of oxygen is selected from the group consisting of peroxyacids and dimethyldioxirane. A method of claim i, wherein the sulfoxide s_5_methoxymethoxy-3'5-dimethylpyridyl)methyl) sulfinyl)-1Η-benzoimidazole An excess of 60% of the enantiomer greater than the combined amount of the enantiomers is produced in excess. 12. The method of claim u, wherein the sulfoxide s_5_methoxy·2_((4-methoxy-3,5·dimethyl-2_π-pyridyl)methyl)methanesulfinyl The hydrazine imidazole is produced in excess of 75% of the enantiomer of the combined amount of the enantiomers. 13. The method of claim 12, wherein the sulfoxide s_5_methoxymethoxy-3,5-dimercapto-2_npyridyl)methyl)methylsulfinyl)_1H_benzoquinone π m The lanthanide is produced in excess of greater than 90% of the enantiomer of the combined amount of the enantiomers. 14. The method of claim 13, wherein the sulfoxide s_5_methoxymethoxy-3,5-diindenyl-2-azino)indolyl)sulfinyl)-1Η- awkward The miso is produced in an excess of greater than 95% of the enantiomer of the combined amount of the enantiomers. The method of claim 14, wherein the sulfoxide S-5-methoxy-2-((4-methoxy-3,5-dimethyl-2-acridinyl)methyl)carbamate The sulfonyl)-1Η-benzoquinone oxime is produced in excess of 98% of the enantiomer of the combined amount of the enantiomers. 16_ The method of claim ^, wherein the sub Sulfone S_5·methoxy-2-((4_methoxydimethyl-2-β)) methyl) 甲 醯 醯 兴 - - - - - - 唆 唆 唆 唆 唆 唆 唆 唆 唆 唆 唆 唆 唆 唆 唆 唆 唆 唆 唆 唆 唆 唆 唆 唆 唆 唆 唆The 99% enantiomer of the combined amount of the enantiomers is produced in excess. 17. The method of claim 1, wherein the transition metal catalyst is an asymmetric coordination complex of the transition metal. 18. The method of claim 17, wherein the coordination complex of the transition metal comprises a compound selected from the group consisting of monodentate, bidentate, tridentate or polydentate amines, diamines, polyamine phosphines, monophosphines, and multiples. One or more ligands of the group. 19. The method of claim 18, wherein the ligand is 2 (s), 3 bis(diphenylphosphino) butadiene. 20) The method of claim 9, wherein the complex further comprises a cyclopentadienyl group. 21. The method of claim 2, wherein the transition metal is selected from the group consisting of w, Ru, Rh, Pd, A group of IrAPt. The method of claim 1, wherein one or more of the steps of the reaction occur in a solvent of a group consisting of a free organic solvent and an inorganic solvent. The method of claim 22, wherein the organic solvent is selected from the group consisting of halogenated aliphatic hydrocarbons, including four gasified carbon, chloroform, and digas; _' including propylene and methyl ethyl Ketones; alcohols, including ethanol, propane, butanol, and pentanol; S means 'including acetic acid, non-base solvent and aromatic solvent. 24.:: The composition of matter 1 comprises: by arranging 5·methoxy·2_((4·methoxy·3,5.dimethyl)methyl)methylthio) according to the method comprising the following steps: -1Η-Benzene 幷 峰 拙 拙 备 # # 亚 之 之 之 之 之 之 之 催化 催化 催化 催化 催化 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 Continued 126691.doc 200906404 Brewing base)-1 Η-benzoquinone π m嗤 or its prodrug: am (4) and: (10) a metal catalyst; and 2) an oxygen source reaction; wherein the thioether is oxidized to a subhard, One of the R and S enantiomers is formed as an enantiomeric excess. 25. The composition of claim 24, 兮π in j1, the S enantiomer of the dried submicron is present in an amount from about 55% to about 99%. • 26. The composition of claim 24, wherein the s enantiomer of the sulfoxide 5 ΖΗ 4 » η /, the sulfoxide is present in an amount of from about 55% to about 95%. f ' 27. The composition of claim 24, wherein the s enantiomer of the sulphate, Y sulfoxide, is present in an amount of from about 55% to about 90%. 28. The composition of claim 24, wherein the S enantiomer of the arsenic-l/, sulfoxide is about 55°/. It is present in an amount of about 85%. 29_ - a pharmaceutical dosage form comprising 5-methoxy-2-((4-methoxy-3,5•dimethyl-2-acridinyl)indolyl)sulfinyl)_1H_benzoquinone One of the imidazoles is a quantitative racemic mixture wherein the 8 enantiomer is present in an amount from about 50% to about 80% by weight of the combined weight of the enantiomers. U 30. The pharmaceutical dosage form of claim 29, wherein the s enantiomer of the active agent is a crystalline form. 31. A pharmaceutical dosage form comprising 5-methoxy-2-((4-methoxy-3,5-diamidino-2-pyridinyl)indolyl)sulfinyl)_1H_phenylhydrazine A racemic mixture of one of the imidazoles, wherein the S enantiomer is present in an amount from about 50% to about 99% by weight of the combined weight of the enantiomers, and wherein the remaining solvent is greater than 100 ppm. 32. The pharmaceutical dosage form of claim 3, wherein the amount of residual solvent is greater than 2〇 126691.doc 200906404 ppm. 33. A stable oral pharmaceutical preparation containing an acid labile benzoimidazole compound methoxy-2-((4-methoxy-3-3,5-dimethyl-2-pyridyl) alumina)甲亚#酿基)·1Η-benzoquinone. Sitting, comprising: a core formed by an inert core, the acid labile benzoimidazole compound, a non-inert inert water-soluble polymer, and a non-intestinal pharmaceutically acceptable bismuth; (b) An inert, non-alkaline coating on the core formed from a non-alkaline water-soluble steep polymer and a non-alkaline pharmaceutical excipient; (C) an outer layer disposed on the prior coating, the outer layer comprising a casing coating and Wherein the acid labile benzoimidazole compound is prepared according to the following method, wherein the thioether 5-methoxy-2_((4-methoxy-3,5-dimethyl-2) is obtained by the following procedure Pyridyl)methyl)methylthio)_1H_ abbreviated imidazole is catalytically converted to its hydrazine: 5-methoxymethoxy-3,5-monomethylpyridinyl)methyl)methylsulfinyl _1H_benzoquinone ° sits: a) makes the consideration: D transition metal catalyst; and 2) oxygen source reaction; wherein the thioether is oxidized to sub-grinding, and in the ampule and the enantiomer One is formed as an enantiomeric excess. 34. One for 5-methoxylated methoxy_3,5-dimethyl_2_. a pharmaceutical capsule for oral administration of a methyl group, which is composed of a capsule and more than one of the pellets, wherein the pellet consists of the following Composition: (a) inert core; 126691.doc 200906404 (b) a drug layer surrounding the inert core, the drug layer consisting of 2% by weight to 7% by weight of 5-methoxy-2-((4-A) Oxy-3,5-dimethyl-2-pyridyl)methyl)methyl sulfhydryl)-1Η-benzimidazole, 0.1 wt0/〇 to 5 wt% surfactant, 20 wt% to 70 Wt% filler, 1 wt% to 2 〇wt. /. The pharmaceutical composition may comprise an alkaline agent and a binder composition of wtj wt% to 5 wt%; and (c) a coating surrounding the drug layer, the coating consisting essentially of an enteric agent and an inert treatment aid, wherein The coating is based on the 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridyl)methyl)sulfonium)-1H-benzoquinone The drug layer of imidazole and the coating layer are directly coated to the 5-methoxy-2-((4-methoxy-3-, 5-dimethyl-2-pyridyl group) without a separation layer a methyl sulfinyl group, a drug layer of succinimide, and wherein the smectic imidazole compound is prepared according to the following method, wherein §Hia hard: 5-methoxy-2_((4_) Methoxy·3 5-dimethyl-2~~pyridyl)methyl)methanesulfinyl)-1Η-phenylimidazole is catalytically converted from the thioether 5-methoxyl by the following procedure. 2-((4-methoxy-3,5-dimethyl-2.oxaridinyl)indenyl)methylthio)·ιη_benzoquinone a) a thioether with: D transition metal catalyst; 2) an oxygen source reaction; wherein the thioether is oxidized to a sub-milling' and wherein one of the enantiomers is formed as an enantiomer Excessive structure. 3 5. A stable pharmaceutical composition comprising: (a) an acid labile 5-oxooxy_2«4 pyridyl) fluorenyl) sulfinyl)_1H-decyloxy-3 ,5-Dimethyl_2_-nuclear imidazole active ingredient core 126691.doc 200906404 heart 'this core is composed of a compressed nucleus and the active ingredient, and the 5_methoxy_ 2_((4_methoxy_3,5-dimethyl-2-oxaridinyl)indolyl) sulfinyl)_1H•benzimidazole active ingredient is not in the form of an experimental salt; (b) intermediate a layer comprising: selected from the group consisting of sugars, polyethylene glycols, polyvinylpyrrole bites, poly(ethylene glycol), hydroxypropyl cellulose, fluorenyl cellulose, μ propyl methyl cellulose, and At least one polymer of a mixture of the mixture; and (C) an enteric layer which is free of a basic reaction compound, and wherein the benzoimidazole compound is prepared according to the following method: "The sulfoxide: 5-methoxyl _2_((4_曱oxy_3,5-dimethyl as a ratio. base) methyl) sulfinyl)-1Η-benzoimidazole is catalytically converted from thioether by the following steps 5- Methoxy-2-(( 4-methoxy-3,5-dimethyl-2-pyridyl)methyl)methylthio)-1Η-benzoimidazole: a) the thioether with: 1) a transition metal catalyst; and 2) An oxygen source reaction; wherein the thioether is oxidized to a sulfoxide, and wherein one of the amp and the s enantiomer is formed as an enantiomeric excess. 3 6. A pharmaceutical preparation comprising: (a) an alkaline reaction core comprising: an acid labile pharmaceutically active substance and an alkali reaction compound different from the active substance, a base of an acid labile pharmaceutically active substance Salt, or an alkaline salt of an acid labile pharmaceutically active substance and an alkaline reaction compound different from the active substance; (b) an inert layer rapidly dissolving or disintegrating in water disposed on the core region 126691.doc 200906404 a sub-coating comprising one or more layers, the layer or layers comprising a material selected from the group consisting of a tablet excipient, a film forming compound, and a basic compound; and 0) surrounding the sub-layer a coating layer of the coating, wherein the sub-coating separates the alkaline reaction core from the casing layer to enhance the stability of the preparation (wherein the acid-labile pharmaceutically active substance is a benzoimidazole compound and Manufactured according to the following method, wherein the hydrazine: 5 • methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridyl)methyl)methanesulfonate) 1 Η幷啼β siting by making sulphur mystery with 1) transition metal catalyst And 2) the oxygen source reacts and is catalytically converted from the thioether 5-methoxymethoxy-3,5-dimethyl-2-pyridinyl) fluorenyl) thiol) _ benzoquinone Imidazole; wherein the thioether is oxidized to a sulfoxide, and wherein one of the R&s enantiomers is formed as an enantiomeric excess. 37. 38. A kit for administration of a pharmaceutically active agent, comprising: a) a pharmaceutically active agent as claimed in claim 24 as a dosage form selected from the group consisting of pills, troches, capsules, and powders; b) Formulations and information on how to use the dosage form; c) Packaging for holding a) and b). A composition comprising: a) a transition metal selected from the group consisting of Cr, W, Ru, Rh, Pd, lr, and Pt; & b) selecting a bidentate, tridentate or polydentate amine, a diamine a palmitic ligand of a group consisting of a polyamine, a phosphine, a diphosphine, and a polyphosphine; and c) a sulfur scale as claimed in claim 1. 126691.doc 200906404 39: = : 38 composition comprising a limpid compound obtained by oxidizing the sulphur puzzle. 40. The method of claim 2, wherein the organic solvent is selected from the following Group of two: the functionalized aliphatic hydrocarbons 'including four gasified carbon, chloroform, and dichloro-aromatic aromatic hydrocarbons' include alkyl aromatic solvents, toothed hydrocarbons, such as gas benzene, monochlorobenzene, desert benzene, Chlorotoluene, 2,4-di-toluene; propylene and methyl ethyl ketone; alcohol, including methanol, ethanol, 1-propanol, 2-propanol, butanol, 2-butanol, 1- Pentanol, 2-pentanol, 3-pentanol, tert-butyl alcohol, 丨-hexanol, 2-hexanol, 3-hexanol, 2-hydrazino-propanol, 2-methyl·2- Propanol, third amyl alcohol, 2-methyl-hydrazine-butanol, 3-methyl-1-butanol, 3-mercapto-2-butanol, neopentyl alcohol, 2,3-dimethyl _2_butanol, 3,3-dimethyl-2-butanol, hexyl alcohol, 2-hexanol, 3-hexanol; vinegar' includes ethyl acetate, moderately polar non-hydroxyl solvent, aliphatic, cycloaliphatic a family or aromatic hydrocarbon such as 'hexa burn, dispirited, gypsum, 2-ethylhexane, octane, isooctane, cyclohexane, cyclooctane, toluene, and ester solvents, including decyl acetate, Ethyl acetate, isopropyl acetate, butyl acetate, second butyl acetate, third butyl acetate, isobutyl acetate, amyl acetate and corresponding Propionate, butyrate and valerate, and mixtures thereof. 126691.doc -9- 200906404 VII. Designated representative 圊: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: VIII. If there is a chemical formula in this case, please reveal the best Chemical formula showing the characteristics of the invention: (none) 126691.doc 200906404 Mingming Patent Specification p Chinese Manual Replacement Page (June 97) (Please do not change the format, order and bold text of this manual, please do not fill in the ※ part) ※Application number: 096148286 ※Application date: 96.12. 17 糸1?<:Classification: B01J; C07C; A61K I. Name of the invention: (Chinese/English) Transition metal-mediated oxidation reaction of heteroatoms in organic molecules coordinated to transition metals. TRANSITION METAL MEDIATED OXIDATION OF HETERO ATOMS IN ORGANIC MOLECULES COORDINATED TO TRANSITION METALS II. Applicant: (1 in total) Name or Name: (Chinese/English) US Patty Carters Pharmaceutical Company PRAKTIKATALYST PHARMA, LLC Representative: (Chinese / English) Kenneth S Wylock Lock WHEELOCK, KENNETH S. Residence or Sales Office Address: (Chinese/English) 25 Julianna Road, Pittsfield, Massachusetts, USA 25 JULIANA DRIVE, PITTSFIELD, ΜΑ 01201, USA Nationality: (Chinese / English) United States USA 126691.doc