CN104203938A - Process for the preparation of 2-pyridinylmethylsulfinyl benzimidazoles, their analogs and optically active enantiomers - Google Patents

Abstract

The present invention provides a commercial method for preparing high-purity 2-pyridylmethylsulfinylbenzimidazoles, their analogs and optically active enantiomers, or pharmaceutically acceptable salts, hydrates or solvates thereof. Feasible, cost-effective and energy-efficient process by using reactors such as plug flow reactors, microreactors, microflow flow reactors, tubular flow reactors, coil flow reactors, laminar flow reactors , packed bed reactor, fluidized bed reactor or fixed bed reactor.

Description

Process for the preparation of 2-pyridylmethylsulfinylbenzimidazoles, their analogs and optically active enantiomers

field of invention

The present invention discloses a commercial method for preparing high-purity 2-pyridylmethylsulfinylbenzimidazoles, their analogs and optically active enantiomers, or pharmaceutically acceptable salts, hydrates or solvates thereof. Feasible, cost-effective and energy-efficient method by using reactors such as plug flow reactors, microreactors, microfluidic flow reactors (microfluidic flow reactors), tubular flow reactors, coil flow reactors, Laminar flow reactor, packed bed reactor, fluidized bed reactor or fixed bed reactor.

Background of the invention

A naturally occurring benzimidazole (a heterocyclic aromatic organic compound formed by the fusion of benzene and imidazole) is N-ribosyl-dimethylbenzimidazole, which acts as an axial ligand for cobalt in vitamin B-12 body.

Benzimidazole derivatives, especially pyridylmethylsulfinyl benzimidazole compounds are known to have H ⁺ /K ⁺ -ATPase inhibitory action and are therefore of considerable importance in the treatment of diseases associated with increased gastric acid secretion, or Used as an antiulcer agent. Such pyridylmethylsulfinyl substituted benzimidazole compounds or pharmaceutically acceptable salts thereof are known for example from EP0005129, EP174726, EP166287, EP268956 and EP254588 as given in formula I below:

Omeprazole: R ₁ =CH ₃ , R ₂ =OCH ₃ , R ₃ =CH ₃ , R ₄ =R ₆ =R ₇ =H, R ₅ =OCH ₃ , R ₈ =H, A=C

Lansoprazole: R ₁ =H, R ₂ =OCH ₂ CF ₃ , R ₃ =CH ₃ , R ₄ =R5=R 6 =R ₇ =H, _{R 8 =} H, A=C

Pantoprazole: R ₁ =H, R ₂ =OCH ₃ , R ₃ =OCH ₃ , R ₄ =R ₆ =R ₇ =H, R ₅ =OCHF ₂ , R ₈ =H, A=C

Rabeprazole: R ₁ =H, R ₂ =O(CH ₂ ) ₃ OCH ₃ , R _{3 =} CH ₃ , R ₄ =R 5 =R ₆ =R ₇ =H, R ₈ =H, A=C

Tenatoprazole: R ₁ =CH ₃ , R ₂ =OCH ₃ , R ₃ =CH ₃ , R ₄ ≠H, R ₆ =R ₇ =H, R ₅ =OCH ₃ , R ₈ =H, A=N

Ilaprazole: R ₁ =H, R ₂ =OCH ₃ , R ₃ -CH ₃ , R ₄ =H, R ₅ =1-aza,2,4-cyclopentadiene, R ₆ = _R7 =H, _R8 =H, A=C

Compounds known by the generic names omeprazole and esomeprazole (5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl )methyl]sulfinyl]-lH-benzimidazole) and its optically active analog S-(5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2 -pyridyl)methyl]sulfinyl]-1H-benzimidazole) are listed in the U.S. under the trade names Prilosec and Nexium, respectively, for the treatment of duodenal ulcer, gastric ulcer and GERD; erosive esophagitis Healing maintenance; and long-term treatment of pathological hypersecretory conditions. Omeprazole is disclosed in US 4,738,974 and esomeprazole is disclosed in WO94/27988.

Rabeprazole is another compound of the same class, chemically known as 2-[[[(4-(3-methoxypropoxy)-2-methyl-2-pyridyl]methyl]ylidene Sulfuryl-1H-benzimidazole. It is reported in US5,045,552 and is marketed in the United States under the trade name Aciphex as the sodium salt for the healing of erosive or ulcerative GERD, the healing maintenance of GERD and the management of symptomatic GERD. treat.

Pantoprazole is the active ingredient of a drug product sold under the trade name Protonix by Wyeth-pharms Inc in the United States as the sodium salt and protected by US 4,758,579. The chemical name of pantoprazole is (5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-lH-benzo Imidazole. Pantoprazole is indicated for short-term treatment of erosive esophagitis associated with gastroesophageal reflux disease (GERD), healing maintenance of erosive esophagitis and pathological hypersecretory disorders including Zollinger-Ellison syndrome.

Lansoprazole is known as 2-[[[3-methyl-4(2,2,2,-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-lH-benzene Another compound of imidazole and reported in US 4,628,098. It is marketed under the brand name Prevacid(R) for short-term treatment of duodenal ulcers, eradication of Helicobacter pylori (H. Pylori) to prevent recurrence of duodenal ulcers, and maintenance of healed duodenal ulcers .

Tentoprazole is known as 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridylmethyl)sulfinyl)-lH-imidazo(4, 5-b) Pyridine, and reported in US 4,808,596 and marketed under the trade name Ulsacare. Tentoprazole is also a proton pump inhibitor indicated for the treatment of reflux esophagitis and peptic ulcer.

Ilaprazole is another drug known as 2-[(4-methoxy-3-methylpyridin-2-yl)methylsulfinyl]-6-pyrrol-1-yl-1H-benzimidazole A compound protected by US 5,703,097. It is used to treat indigestion, peptic ulcer disease (PUD), gastroesophageal reflux disease (GORD/GERD), and duodenal ulcer.

The preparation of 2-[(pyridyl)methyl]sulfinyl-substituted benzimidazoles of formula (I) by oxidation of compounds of formula II is well known and described in U.S. Pat. discuss.

Various methods of carrying out this oxidation using different oxidizing agents are reported in the literature of the prior art.

For example, CA 1,263,119 describes the use of hydrogen peroxide over vanadium catalysts such as vanadium pentoxide, sodium vanadate and vanadium acetylacetonate. CA 1,127,158 similarly describes the use of peracids, peresters, ozone, etc. EP 533,264 describes the use of magnesium monoperoxyphthalate as oxidizing agent. WO 91/18895 describes the use of m-chloroperoxy benzoic acid as oxidizing agent. GB 2,069,492 generally describes the use of m-chloroperoxybenzoic acid, together with other peroxyacids, for the oxidation of substituted (phenylthiomethyl)pyridines.

US 5,374,730 relates to omeprazole and lansoprazole, in particular two novel synthetic methods for their preparation. According to this method, sulfinyl compounds are prepared from the corresponding acetamide sulfide compounds as follows, using hydrogen peroxide as the oxidizing agent to form the amide sulfinyl compound, followed by alkaline hydrolysis to form the sulfinyl carboxylate or salt, and decarboxylation.

US 6,313,303 discloses a process for the preparation of rabeprazole, lansoprazole and other related compounds by using N-halosuccinamide, 1,3-dihalo-5, 5-Dimethylhydantoin or dichloroisocyanurate to oxidize thioether precursor compounds.

Similarly, EP 484,265 discloses a process for the preparation of omeprazole (Examples 32 and 33) in a suitable organic solvent containing 50% _H2O2 at lower _temperatures over a catalyst ( Such as (P(W ₃ O ₁₀ ) ₄ .xH ₂ O), ammonium molybdate (molecular formula is (NH ₄ ) ₂ MoO ₄ ), sodium tungstate (molecular formula is Na ₂ WO ₄ ), phosphomolybdic acid (molecular formula is H In the presence of ₃ (P(Mo ₃ O ₁₀ ) _4. xH ₂ O) and silicotungstic acid (molecular formula is H ₄ (Si(W ₃ O ₁₀ ) ₄ .xH ₂ O), 2-(((3, 5-Dimethyl-4-methoxy-2-pyridyl)methyl)sulfinyl)-5-methoxy-1H-benzimidazole oxidation. In this oxidation method the use of base is necessary The problem with this method is that the operations to isolate the product are tedious and more expensive. The use of organic solvents such as dichloromethane and ethyl acetate and the subsequent washing with said same solvents at -15°C are very tedious operations.

WO2012/004802 discloses a continuous micromixer based method for the synthesis of sulfoxide compounds with a reaction time of less than or equal to 1 minute and a selectivity >95% for sulfoxide compounds. However, this method has several disadvantages related to (i) choice of oxidant (ii) selectivity (iii) use of solvent, (iv) design of micromixer, etc. WO'802 mentions the reaction of imidazo[4,5-b]pyridine compounds to obtain sulfoxides using an oxidizing agent dissolved in _a solvent, where conventionally used oxidizing agents such as _H2O2 , sodium hypochlorite yield only 2 to 3% conversion rate, which is highly undesirable on a commercial scale. The only oxidizing agents that give conversions greater than 82% are expensive reagents whose use is frustrating and uneconomical on a commercial scale. Further, although applicants claim >95% selectivity, actual examples show selectivity less than 93%.

However, it has been reported in the literature that due to overoxidation of the thioether compounds of the formula (II), the respective sulfone compounds of the formula (III) are also formed, since the reaction does not stop at the sulfoxide formation stage, but proceeds further with side reaction, which reoxidizes part of the formed sulfoxide to sulfone. When sulfones are formed, there is a problem not only in that the yield of the target sulfoxide is lowered but also in that it is difficult to separate and purify them because the physicochemical properties between the two compounds are very similar.

Therefore, there is a need in the art to develop an industrially feasible, cost-effective, economical and simple method for the preparation of 2-[(pyridyl)methyl]sulfinyl substituted compounds in high purity and high yield that can control sulfone impurities as well as other impurities. There is a demand for methods for the benzimidazoles, their analogs, and optically active enantiomers or their pharmaceutically acceptable salts, hydrates or solvates.

Accordingly, as an alternative to the prior art methods, for 2-[(pyridyl)methyl]sulfinyl substituted benzimidazoles, their analogs and optically active enantiomers or pharmaceutically acceptable salts thereof , hydrate or solvate synthesis, new and improved conditions have been developed and optimized in the present invention by using reactors such as plug flow reactors, microreactors, microflow flow reactors, tubular flow reactors reactor, coil flow reactor, laminar flow reactor, packed bed reactor, fluidized bed reactor or fixed bed reactor.

Chemical reactors are vessels in which chemical reactions take place; their performance determines the reliability and applicability of the method, its environmental safety, energy consumption and required raw materials. Among all known chemical reactors, continuous flow reactors are very suitable for reactions where high yield and high purity are expected, the best applied continuous flow reactors are plug flow reactors, microreactors wait. Plug flow reactors are tubular reactors, which are basically continuous reactors in which there are no moving parts other than the pumps that transport the reactants. To achieve efficient mixing of the reactants, static mixing elements such as glass beads are incorporated into the interior of the tubular reactor, providing the ideal conditions for radial mixing and near-plug flow necessary to carry out the reaction. In a plug flow reactor, the flow of reactants pumped into the reactor is laminar and the properties of the reaction medium, i.e. pressure, temperature, reactant and product concentrations, are the same throughout the cross-section of the flow . Additionally, all elemental volumes of the reaction medium remain in the reactor for the same period of time, and the changes in concentration, temperature and pressure over time are the same for each elemental volume. Plug flow reactors typically operate under adiabatic and non-isothermal conditions. Therefore, plug flow reactors are more efficient than stirred tank reactors from the viewpoint of kinetic parameters of chemical reactions under isothermal conditions.

Microreactors have been defined as "microsystems fabricated at least in part by methods of microtechnology and precision engineering. Fluidic channels range from about 1 um (nanoreactors) to about 1 mm (microreactors)". See Microreactors, Ehrfeld, Hessel & Lowe 2000, the entire disclosure of which is hereby incorporated by reference. Typical microreactors consist of miniaturized channels, often embedded in planes called "chips." These planes may be glass plates or metal plates such as stainless steel or Hastelloy plates. Microreactors have proven to be invaluable tools in organic chemistry due to their efficient heat transfer, optimal mixing, and efficient reaction control with sufficient flexibility in their operating conditions. The continuous mode of operation in microreactors offers several benefits over batch processes, such as simplified handling, shortened reaction times, precise process control, higher reproducibility and in some cases even improved reaction options sex. Immediate separation of the product from the reaction mixture eliminates possible by-products that may arise from secondary reactions. The continuous mode could also provide an alternative to large reactors, which are costly and take up expensive laboratory or chemical plant space. In addition to the benefits above, microreactors offer their own unique advantages over traditional continuous processing systems, including efficient heat transfer and small reaction volumes, which enable safer handling of exothermic reactions, involving explosive and toxic materials reactions, increased precision in response control and other hazardous reactions that are often difficult to scale up. Microreactors are particularly useful for rapid optimization, screening of different reaction conditions, catalysts, ligands, bases, and solvents; mechanistic research; cost-effective industrial scale-up; and rapid screening of new drugs. Furthermore, by using this concept, microreactors can be operated to produce large quantities of desired end products, where multiple microreactors are operated continuously and in series and/or in parallel to mimic large flow reactors, improving The production capacity of the factory.

The present invention provides benzimidazoles substituted by 2-[(pyridyl)methyl]sulfinyl, their analogs and optically active enantiomers, or pharmaceutically acceptable salts, hydrates or solvates thereof An improved method using reactors such as plug flow reactors, microreactors, microflow flow reactors, tubular flow reactors, coil flow reactors, laminar flow reactors, packed bed reactors, fluidized bed reactor or fixed bed reactor. Compared with conventional methods, this method has obvious advantages in terms of cycle time, energy consumption, yield and product purity.

Invention purpose and overview

The main purpose of the present invention is to provide benzimidazoles, their analogs and optically active enantiomers or their pharmaceutically acceptable salts and hydrates which are substituted by 2-[(pyridyl)methyl]sulfinyl Or the method of solvates, which uses reactors such as plug flow reactors, microreactors, microflow flow reactors, tubular flow reactors, coil flow reactors, laminar flow reactors, packed bed reactors, Fluidized bed reactor or fixed bed reactor, this method alleviates the disadvantages of the prior art methods.

Another object of the present invention is to provide 2-[(pyridyl)methyl]sulfinyl substituted benzimidazoles, their analogs and optically active enantiomers or their pharmaceutically acceptable salts, hydrated A cost-effective and industrially feasible process for compounds or solvates, wherein the process provides the desired product in high yield and high purity in a consistent and reproducible manner by reducing the formation of impurities, preferably sulfone impurities.

According to an embodiment, the present invention provides a method for preparing 2-[(pyridyl)methyl]sulfinyl substituted benzimidazoles of formula I, their analogs and optically active enantiomers or pharmaceutically acceptable salt, hydrate or solvate method,

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are the same or different, and are selected from hydrogen, C _1-7 alkyl, C _1-7 alkoxy, optionally composed of halogen , 1-aza-2,4-cyclopentadiene, R ₈ is a hydrogen or nitrogen protecting group, and A is carbon or nitrogen.

The method includes the following steps:

(a) benzimidazole substituted by 2-[(pyridyl)methyl]sulfinyl of formula II or its

Dissolving their analogs, optionally in a solvent, to prepare solution A;

wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , A are as defined above;

(b) preparing solution B by dissolving the oxidizing agent, optionally in a solvent;

(c) Make solution A and solution B in a reactor, such as plug flow reactor, microreactor, microflow flow reactor, tubular flow reactor, coil flow reactor, laminar flow reactor, packed bed reactor , a fluidized bed reactor or a fixed bed reactor, to obtain 2-[(pyridyl)methyl]sulfinyl substituted benzimidazoles of formula I, their analogs and optically active enantiomers; and

(d) optionally converting 2-[(pyridyl)methyl]sulfinyl-substituted benzimidazoles of formula I, their analogs and optically active enantiomers into their pharmaceutically acceptable salts, Hydrate or solvate.

Detailed description of the invention

While the specification concludes with what is particularly pointed out and distinctly claimed, which is regarded as the invention, it is contemplated that a reading of the following detailed description of the invention, together with a study of the included examples, will more readily understanding of the present invention.

The present invention provides benzimidazoles substituted by 2-[(pyridyl)methyl]sulfinyl, their analogs and optically active enantiomers, or pharmaceutically acceptable salts, hydrates or solvates thereof commercially viable and economical method. The method uses reactors such as plug flow reactors, microreactors, microflow flow reactors, tubular flow reactors, coil flow reactors, laminar flow reactors, packed bed reactors, fluidized bed reactors or fixed bed reactors to produce high yields and high purity of the desired product with enhanced in-process control of impurities, especially sulfone impurities, and shorter reaction times.

For the preparation of 2-[(pyridyl]methyl]sulfinyl substituted benzimidazoles of formula I, their analogs or their optically active enantiomers or their pharmaceutically acceptable salts, hydrates or solvents compound according to the method of the invention,

Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are the same or different, and are selected from hydrogen, C _1-7 alkyl, C _1-7 alkoxy, optionally composed of halogen , 1-aza-2,4-cyclopentadiene is substituted, R ₈ is a hydrogen or nitrogen protecting group, A is carbon or nitrogen,

The method includes the following steps:

(a) Solution A is prepared by dissolving 2-[(pyridyl)methyl]sulfinyl substituted benzimidazoles of formula II or their analogs, optionally in a solvent;

wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , A are as defined above;

(b) preparing solution B by dissolving the oxidizing agent, optionally in a solvent;

(c) Make solution A and solution B in a reactor, such as plug flow reactor, microreactor, microflow flow reactor, tubular flow reactor, coil flow reactor, laminar flow reactor, packed bed reactor , a fluidized bed reactor or a fixed bed reactor, to obtain 2-[(pyridyl)methyl]sulfinyl substituted benzimidazoles of formula I, their analogs and optically active enantiomers; and

(d) optionally converting 2-[(pyridyl)methyl]sulfinyl-substituted benzimidazoles of formula I, their analogs and optically active enantiomers into their pharmaceutically acceptable salts, Hydrate or solvate.

According to the invention, the preparation of solution A is optionally carried out in a solvent depending on the type of reactor chosen for the oxidation reaction, such as a microreactor. The solvent used to prepare solution A is selected from: alcohols, such as methanol, ethanol, propanol, butanol, ethylene glycol, etc.; aromatic hydrocarbons, such as toluene, xylene, etc.; ethers, such as diisopropyl ether, tert-butyl methyl ether , tetrahydrofuran, dioxane (dioxane), ethylene glycol dimethyl ether (monoglyme), diglyme, etc.; esters, such as ethyl acetate, methyl acetate, etc.; halogenated hydrocarbons, such as methylene chloride, chloroform , dichloroethane, etc.; ketones, such as acetone, methyl ethyl ketone, ethyl isobutyl ketone, etc.; nitriles, such as acetonitrile, propionitrile, etc.; aprotic polar solvents, such as N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, etc.; water; or a mixture thereof.

According to the invention, the preparation of solution A is optionally carried out in the presence of a base selected from organic or inorganic bases. The organic base is selected from: amines, such as triethylamine, diisopropylamine, diisopropylethylamine, piperidine, etc.; alkali metal alkoxides, such as sodium methylate, potassium methylate, etc. The inorganic base is selected from ammonia, alkali and alkaline earth metal carbonates, bicarbonates, hydroxides, hydrides, etc., wherein the alkali metal and alkaline earth metal is selected from lithium, sodium, potassium, magnesium, calcium, barium, and the like.

According to the present invention, the oxidizing agent in solution B is selected from hydrogen peroxide, alkyl hydroperoxide, aryl alkyl hydroperoxide, alkali metal or alkaline earth metal hypohalite, wherein alkali metal or alkaline earth metal is selected from sodium , lithium, potassium, magnesium, calcium, and halite is selected from fluorite, chlorite, bromite, and the like. The solvent is selected from alcohols, such as methanol, ethanol, propanol, butanol, ethylene glycol, etc.; aromatic hydrocarbons, such as toluene, xylene, etc.; ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane (dioxane ), ethylene glycol dimethyl ether (monoglyme), diglyme, etc.; esters, such as ethyl acetate, methyl acetate, etc.; halogenated hydrocarbons, such as methylene chloride, chloroform, dichloroethane, etc.; ketones , such as acetone, methyl ethyl ketone, ethyl isobutyl ketone, etc.; nitriles, such as acetonitrile, propionitrile, etc.; aprotic polar solvents, such as N,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphine amides, etc.; water; or mixtures thereof.

According to the invention, the preparation of solution B is optionally carried out in the presence of a base selected from organic or inorganic bases. The organic base is selected from: amines, such as triethylamine, diisopropylamine, diisopropylethylamine, piperidine, etc.; alkali metal alkoxides, such as sodium methylate, potassium methylate, etc. The inorganic base is selected from ammonia, alkali metal or alkaline earth metal carbonate, bicarbonate, hydroxide, hydride, etc., wherein the alkali metal and alkaline earth metal are selected from lithium, sodium, potassium, magnesium, calcium, barium, etc.

According to the invention, the oxidation reaction is carried out in continuous mode, wherein the reactor carries a flowing stream, the reactants are continuously fed into the reactor and a continuous product stream occurs.

According to the invention, the oxidation reaction is optionally carried out in the presence of a metal catalyst. Preferably, the metal of the metal catalyst is selected from rhenium, vanadium, molybdenum, tungsten, cerium and yettribium.

According to the invention, the oxidation reaction is optionally carried out under an inert atmosphere or under a flow of an inert gas. Examples of inert gases include nitrogen, helium, neon, argon, and the like.

According to the present invention, for the asymmetric oxidation of compounds of formula II or their analogs, solution A is prepared by mixing a chiral transition metal complex with a compound of formula II or their analogs, wherein the chiral Transition metal complexes are prepared from transition metal compounds and chiral ligands. The transition metal is selected from titanium, vanadium, molybdenum and tungsten, etc., preferably compounds of titanium, vanadium and tungsten. Preferred transition metal compounds are titanium(IV) isopropoxide, titanium(IV) propoxide, titanium(IV) ethoxide, titanium(IV) methoxide, vanadium oxy triproxide or vanadium oxytripropoxide wait. The chiral ligands used here are selected from branched or unbranched alkyl diols or aromatic diols. Preferred chiral diols are esters of tartaric acid, especially (+)-L-diethyl tartrate or (-)-D-diethyl tartrate, (+)-L-dimethyl tartrate, (-)- D-dimethyl tartrate, etc.

The asymmetric oxidation is optionally carried out in the presence of a catalyst. The preferred catalyst used in this process is water.

According to the present invention, the reaction of solution A and solution B produced by steps (a) and (b) is carried out in reactors such as plug flow reactors, microreactors, microflow flow reactors, tubular flow reactors, coils, etc. Type flow reactor, laminar flow reactor, packed bed reactor, fluidized bed reactor or fixed bed reactor. The reaction is carried out at a temperature of -20 to 100°C by feeding in two streams simultaneously. The flow rates of the solution A stream and the solution B stream are controlled based on the reactor design.

The residence time necessary in the process according to the invention depends on various parameters, such as the temperature or reactivity of the starting materials, the flow rate and the like. The term "residence time" refers to the internal volume of the reaction zone within a plug flow reactor occupied by the reactant fluid flowing through the space of the reaction zone at the temperature and pressure employed. The residence time can be, for example, from about 1.2 minutes to about 10 minutes.

According to the present invention, the plug flow reactors used herein are designed in such a way that multiple entry points for feeding reactants/reagents are available while the reaction is in progress.

After the reaction is complete, suitable separation/solvent extraction/isolation, filtration and/or purification steps are carried out to isolate the desired sulfoxide compound, such as the produced 2-[(pyridyl)methyl ] The sulfinyl-substituted benzimidazole is subjected to washing, charcoal treatment, filtration steps, and the like. Optionally, the final product is purified, for example by a suitable recrystallization step.

According to the present invention, optionally, the 2-[(pyridyl)methyl]sulfinyl substituted benzimidazoles, their analogs and optically active enantiomers of formula I obtained in step (c) are prepared according to the existing Conversion to the desired pharmaceutically acceptable salt, hydrate or solvate thereof is carried out by methods well known in the technical literature.

Important advantages achieved by the present invention are high yields, high purity, consistency, absence or minimal formation of sulfones and/or unknown impurities compared to prior art batch processes.

In reactors such as plug flow reactors, microreactors, microflow flow reactors, tubular flow reactors, coil flow reactors, laminar flow reactors, packed bed reactors, fluidized bed reactors or fixed bed reactors These clearly identified advantages of reactions in vessels result from the minimized residence time and continuous flow nature of the reaction, thereby reducing the contact time between the desired product and the oxidizing agent.

The invention is further described in more detail as shown in the non-limiting examples. It should be understood that variations and modifications of the method are possible within the scope of the invention broadly disclosed herein.

Example

Example 1

Preparation of 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfite in a microreactor Acyl]-lH-benzimidazole sodium sesquihydrate (pantoprazole sodium sesquihydrate)

Preparation of solution A: Dissolve 16.4g of sodium hydroxide in 200ml of water at 25-30°C, add 200ml of acetonitrile and 100g of 5-difluoromethoxy-2-[(3,4-dimethyl Oxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole to obtain solution A.

Preparation of solution B: 6.87 g of sodium hydroxide was dissolved in 62.5 ml of water at 25-30° C., and added to 307.68 g of sodium hypochlorite solution (4%) to obtain solution B.

Solutions A and B prepared above were cooled to -5-0°C. The temperature of the microreactor was set at -5-0°C. Solution A at a flow rate of 30 ml/min and solution B at a flow rate of 22 ml/min were simultaneously fed into the microreactor channels at -5-0°C. After the reaction was complete, the resulting reactant was treated with an aqueous solution of sodium thiosulfate (8.0 g of sodium thiosulfate in 20 mL of water) and then washed with 100 mL of dichloromethane. The pH of the reaction was adjusted to 8.0-8.5 by adding acetic acid at 25-30°C. The reaction was extracted with dichloromethane. Subsequently, the organic layer was treated with a solution of 9.8 g of sodium hydroxide in 10 ml of water at 25-30°C. The organic solvent was distilled off under vacuum at 40-45°C. To the resulting reaction was added 300 ml of acetonitrile and 5.4 ml of water at 25-30°C. The reaction was then stirred at 25-30°C for 30 minutes. The reaction was maintained at 25-30°C for 8-10 hours. The reaction was then cooled to 10-15°C to obtain a solid which was filtered and dried under vacuum to obtain the title compound.

HPLC purity: 99.81%

Sulfone impurity: 0.02%

Example 2

Preparation of 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl] in a plug flow reactor Sulfuryl]-1H-benzimidazole-1-sodium sesquihydrate (pantoprazole sodium sesquihydrate)

Preparation of solution A: Dissolve 16.4 g of sodium hydroxide in 200 ml of water at 25-30°C and add it to 100 g of 5-(difluoromethoxy)-2- [[(3,4-Dimethoxy-2-pyridyl)methyl]thio]-1H-benzimidazole in 200 ml of acetonitrile to obtain solution A.

Preparation of solution B: 7.17 g of sodium hydroxide was dissolved in 65 ml of water at 25-30° C., and added to 708.8 g of sodium hypochlorite solution (4%) to obtain solution B.

Solutions A and B prepared above were cooled to -5 to 0°C. The temperature of the plug flow reactor was set at -5 to -10°C. Solution A at a flow rate of 22 ml/min and solution B at a flow rate of 32 ml/min were simultaneously fed to the plug flow reactor at -5 to -10°C. After the reaction was complete, the resulting reactant was treated with an aqueous solution of sodium thiosulfate (8.0 g of sodium thiosulfate in 20 mL of water), and then washed with 100 mL of dichloromethane. The pH of the reaction was adjusted to 8.0-8.5 by adding acetic acid at 25-30°C. The reaction was extracted with dichloromethane. Subsequently, the organic layer was treated with a solution of 9.0 g of sodium hydroxide in 9.0 ml of water at 25-30°C. The organic solvent was distilled off under vacuum at 40-45°C. To the resulting reaction mass, 200 ml of acetonitrile and 5.0 ml of water were added at 25-30°C. The reaction was then stirred at 25-30°C for 30 minutes. The reaction was maintained at 25-30°C for 8-10 hours. The reaction was then cooled to 10-15°C to obtain a solid which was filtered and dried under vacuum to obtain the title compound.

HPLC purity: 99.9%

Sulfone impurity: 0.03%

Example 3

Preparation of 2-[[[(4-(3-methoxypropoxy)-2-methyl-2-pyridyl]methyl]sulfite in a microreactor Acyl-lH-benzimidazole sodium (rabeprazole sodium)

Phase 1: Preparation of Rabeprazole

Solution preparation: Dissolve 11.5 g of sodium hydroxide in 200 ml of water at 20-30°C and add it to 100 g of 2-[[[(4-(3-methoxy Propyloxy)-2-methyl-2-pyridyl]methyl]sulfinyl-lH-benzimidazole in 500 ml of methanol to obtain solution A.

Preparation of solution B: 7.25 g of sodium hydroxide was dissolved in 100 ml of water at 25-30° C., and added to 287.92 g of sodium hypochlorite solution to obtain solution B.

Solutions A and B prepared above were cooled to -5-0°C. The temperature of the microreactor was set at -2-3°C. Solution A at a flow rate of 30 ml/min and solution B at a flow rate of 12.2 ml/min were simultaneously fed to the microreactor channels at -2-3°C. After the reaction was complete, the resulting reaction was treated with an aqueous solution of sodium thiosulfate (14.0 g of sodium thiosulfate in 100 mL of water), followed by the addition of dichloromethane. The layers were separated and the pH of the aqueous layer was adjusted to 8.8-9.2 by the addition of acetic acid at 10-15°C. The reaction was extracted with 200 mL of dichloromethane. Subsequently, the organic layer was treated with a solution of 11.64 g of sodium hydroxide in 600 ml of water at 25-30° C. and stirred. The aqueous layer was washed with dichloromethane. To the obtained aqueous layer was added 200 ml of acetonitrile at 25-30°C. The reactant was then cooled to 0-5°C, and the pH of the reactant was adjusted to 8.5-8.7 with 30% aqueous acetic acid. The reaction was then stirred at 0-5°C for 10-12 hours. The solid obtained was filtered and sucked dry.

HPLC purity: 99.8%

Sulfone impurity: 0.02%

Stage 2: Preparation of Rabeprazole Sodium

The wet feed from stage 1 was added to a solution of 11.01 g of sodium hydroxide in 500 ml of water at 25-30°C. Subsequently, the reaction was stirred for about 1 hour and washed with dichloromethane. The aqueous layer was then spray dried to obtain the title compound.

Example 4

Preparation of 2-[[[(4-(3-methoxypropoxy)-2-methyl-2-pyridyl]methyl]methoxymethylene in a plug flow reactor Sulfonyl-lH-benzimidazole sodium (rabeprazole sodium)

Phase 1: Preparation of Rabeprazole

Preparation of solution A: Dissolve 11.5g of sodium hydroxide in 200ml of water at 20-30°C and add it to 100g of 2[[[(4-(3-methoxy Propyloxy)-2-methyl-2-pyridyl]methyl]sulfonyl-1H-benzimidazole in 500 ml of methanol to obtain solution A.

Preparation of solution B: 7.25 g of sodium hydroxide was dissolved in 100 ml of water at 25-30° C., and added to 650 g of sodium hypochlorite (4%) to obtain solution B.

Solutions A and B prepared above were cooled to -5 to 0°C. The temperature of the plug flow reactor was set at -2 to -5°C. Solution A at a flow rate of 31 ml/min and solution B at a flow rate of 30 ml/min were simultaneously fed to the plug flow reactor at -2 to -5°C. After the reaction was complete, the resulting reaction was continuously quenched with an aqueous solution of sodium thiosulfate (8.0 g of sodium thiosulfate in 20 mL of water), followed by the addition of dichloromethane. The layers were separated, and the pH of the aqueous layer was adjusted to 8.8-9.2 by adding acetic acid at 10-15°C. The reaction was extracted with 200 mL of dichloromethane. The organic layer was treated with a solution of 11.64 g of sodium hydroxide in 600 ml of water at 25-30°C with stirring. The aqueous layer was washed with dichloromethane. To the formed aqueous layer was added 200 ml of acetonitrile at 25-30°C. The reactant was then cooled to 0-5°C, and the pH of the reactant was adjusted to 8.5-8.7 with 30% aqueous acetic acid. The reaction was then stirred at 0-5°C for 10-12 hours. The solid obtained was filtered and sucked dry.

Stage 2: Preparation of Rabeprazole Sodium

The wet feed from stage 1 was added to a solution of 11.01 g of sodium hydroxide in 500 ml of water at 25-30°C. Subsequently, the reaction was stirred for about 1 hour and washed with dichloromethane. The aqueous layer was then spray dried to obtain the title compound.

HPLC purity: 99.9%

Sulfone impurity: 0.02%

Example 5

Preparation of S-(5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl] in a microreactor Sulfuryl]-lH-benzimidazole) (esomeprazole potassium)

Preparation of Solution A: Under stirring, 100 g of (5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl] -lH-benzimidazole) in 400 ml of toluene was heated to 50-55°C. To the resulting solution were added 25.9 g of titanium isopropoxide and 37.6 g of (-)diethyl tartrate. The reaction was then stirred at 50-55°C for 15 minutes and 0.82 g of water was added, after which the reaction was stirred again for 1 hour. The reaction was then cooled to 25-30°C and 11.8 g of diisopropylethylamine was added to obtain solution A.

Preparation of solution B: 59.8 g of cumene hydroperoxide was dissolved in 200 ml of toluene to obtain solution B.

The temperature of the microreactor was set to 25°C. Solution A at a flow rate of 20 ml/min and solution B at a flow rate of 9.1 ml/min were simultaneously fed into the microreactor channels at -25-30°C. After the reaction was complete, the resulting reaction mass was cooled to 0-5°C and treated with a solution of 40 g potassium hydroxide in 100 ml methanol. The reaction was then stirred for 1 hour. The reaction was filtered and blotted dry. 500 ml of water were added to the wet mass at 25-30°C and the resulting reaction was stirred for 15 minutes. The layers were separated, and 500 mL of dichloromethane was added to the aqueous layer, and the pH was adjusted to 7.5-8.0 with 10% aqueous acetic acid. The layers were separated, and the organic layer was washed with water and brine solution. The solvent was distilled off under vacuum at 35-40°C. Take the semi-solid material into methyl ethyl ketone and cool to 0-5°C. A solution of 20 g of potassium hydroxide in 100 ml of methanol was added to the reaction mass and the temperature was raised to 25-30°C. The reaction was then stirred for 1 hour and the solid was filtered and dried under vacuum at 35-40°C to obtain the title compound.

HPLC purity: NLT99%

Sulfone impurity: 0.17%

Example 6

Preparation of S-(5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methanol in a plug flow reactor base] sulfinyl] -lH-benzimidazole) (esomeprazole potassium)

Solution A: 62.59 g of (-)diethyl tartrate were added to 60.4 g of titanium isopropoxide at 20-25°C. The solution was then stirred for 15 minutes and the temperature of the reaction was raised to 55-58°C. The reaction was stirred again for 30-45 minutes. To the resulting mass was added 100 g of (5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-lH- benzimidazole), stirred for 30 minutes and added 2.1 g of water to obtain solution A.

Solution B: Take 89 g of cumene hydroperoxide (70% solution) as solution B.

The temperature of the circulating water of the plug flow reactor was set at 35-38°C. Solution A was fed simultaneously to the plug flow feed point at a flow rate of 15.0 g/min at 55-58°C and Solution B at a flow rate of 4.0 ml/min at 25-30°C. The reactants formed by the plug flow reactor were placed directly into a solution of 30.7 g of triethylamine in 500 ml of toluene and 400 ml of water at 0-5°C. The organic layer was separated and washed with water, then brine solution, and cooled to 10-15 °C. To the formed organic layer was added a solution of potassium hydroxide in methanol at 10-15°C over 10-15 minutes. The temperature of the reaction was raised to 20-25°C. Pure esoprazole potassium crystals were added to the reaction as seed crystals. The reaction was then stirred at 20-25°C for 8 hours. The reaction was filtered and blotted dry. 500 ml of water was added to the wet mass at 20-25°C and the resulting reaction was stirred. 500 ml of water was added to the reactant, and the pH of the reactant was adjusted to 7.5-8.0 with 5% aqueous acetic acid. 500 mL of dichloromethane was added to the reaction. The layers were separated and the organic layer was washed with water. The solvent was distilled off under vacuum. Take the semi-solid material into methyl ethyl ketone and cool to 10-15°C. A solution of 30 g potassium hydroxide in 100 ml methanol was added to the reaction mass and the temperature was raised to 20-25°C. The reaction was then stirred for 2-3 hours and the solid was filtered and dried under vacuum at 45-50 °C to obtain the title compound.

HPLC purity: NLT99%

Sulfone impurity: 0.12%

Example 7

Preparation of 2-(((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl) in a plug flow reactor Sulfuryl)-1H-benzimidazole (lansoprazole)

Preparation of solution A: Dissolve 17.0 g of sodium hydroxide in 70 ml of water at 25-30° C., add it to 100 g of 2-(((3-methyl-4-(2, A solution of 2,2-trifluoroethoxy)pyridin-2-yl)methyl)sulfonyl)-1H-benzimidazole in a solvent mixture of 400 ml acetonitrile and 300 ml methanol to obtain solution A.

Preparation of solution B: take sodium hypochlorite solution (6.0% w/w) as solution B.

Solutions A and B prepared above were cooled to 0 to 5°C. The temperature of the plug flow reactor was set at 0 to -5°C. Solution A was fed simultaneously to the plug flow reactor at a flow rate of 21 ml/min and solution B at a flow rate of 12 ml/min at -5 to 0°C. After the reaction was complete, the resulting reaction mass was treated with an aqueous solution of sodium thiosulfate (20.0 g sodium thiosulfate in 50 mL water), followed by the addition of 400 mL water. The pH of the reaction was adjusted to 8.5-9 by adding acetic acid at 20-30°C. The precipitated solid material was filtered, washed with water and dried to obtain the title compound.

HPLC purity: 99.6%

Sulfone impurity: 0.01%

Claims (34)

1. A 2-[(pyridyl] methyl] sulfinyl substituted benzimidazole for the preparation of formula I, their analogs or their optically active enantiomers or pharmaceutically acceptable salts thereof, Hydrate or solvate method, Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are the same or different, and are selected from hydrogen, C _1-7 alkyl, C _1-7 alkoxy, optionally composed of halogen , 1-aza-2,4-cyclopentadiene is substituted, R ₈ is a hydrogen or nitrogen protecting group, A is carbon or nitrogen, The method includes the following steps: (a) benzimidazole substituted by 2-[(pyridyl)methyl]sulfinyl of formula II or its Dissolving their analogs, optionally in a solvent, to prepare Solution A; wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , A are as defined above, (b) preparing solution B by dissolving the oxidizing agent, optionally in a solvent; (c) make solution A and solution B in a process selected from plug flow reactor, microreactor, microflow flow reactor, tubular flow reactor, coil flow reactor, laminar flow reactor, packed bed reactor, flow reactor, React in the reactor of fluidized bed reactor and fixed bed reactor, obtain the 2-[(pyridyl) methyl] sulfinyl substituted benzimidazole of formula I, their analogue and optically active enantiomer; and (d) optionally converting 2-[(pyridyl)methyl]sulfinyl-substituted benzimidazoles of formula I, their analogs and optically active enantiomers into their pharmaceutically acceptable salts, Hydrates and solvates. 2. A 2-[(pyridyl] methyl] sulfinyl substituted benzimidazole for the preparation of formula I, their analogs or their optically active enantiomers or their pharmaceutically acceptable salts, hydrate and solvate method, Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are the same or different, and are selected from hydrogen, C _1-7 alkyl, C _1-7 alkoxy, optionally composed of halogen , 1-aza-2,4-cyclopentadiene is substituted, R ₈ is a hydrogen or nitrogen protecting group, A is carbon or nitrogen, The method includes the following steps: (a) Solution A is prepared by dissolving 2-[(pyridyl)methyl]sulfinyl substituted benzimidazoles of formula II or their analogs, optionally in a solvent; wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , A are as defined above, (b) preparing solution B by dissolving the oxidizing agent, optionally in a solvent; (c) react solution A and solution B in a plug flow reactor to obtain 2-[(pyridyl)methyl]sulfinyl substituted benzimidazoles of formula I, their analogs and optically active enantiomers body; and (d) optionally converting 2-[(pyridyl)methyl]sulfinyl-substituted benzimidazoles of formula I, their analogs and optically active enantiomers into their pharmaceutically acceptable salts, Hydrates and solvates. 3. A 2-[(pyridyl] methyl] sulfinyl substituted benzimidazole for the preparation of formula I, their analogs or their optically active enantiomers or their pharmaceutically acceptable salts, hydrate or solvate method, Wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , and R ₇ are the same or different, and are selected from hydrogen, C _1-7 alkyl, C _1-7 alkoxy, optionally composed of halogen , 1-aza-2,4-cyclopentadiene is substituted, R ₈ is a hydrogen or nitrogen protecting group, A is carbon or nitrogen, The method includes the following steps: (a) Prepare solution A by dissolving 2-[(pyridyl)methyl]sulfinyl substituted benzimidazoles of formula II or their analogs in a solvent; wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , A are as defined above, (b) preparing solution B by dissolving the oxidizing agent, optionally in a solvent; (c) Reaction of solution A and solution B in a microreactor to obtain 2-[(pyridyl)methyl]sulfinyl substituted benzimidazoles of formula I, their analogs and optically active enantiomers ;and (d) optionally converting 2-[(pyridyl)methyl]sulfinyl-substituted benzimidazoles of formula I, their analogs and optically active enantiomers into their pharmaceutically acceptable salts, Hydrates and solvates. 4. The method according to claim 1, 2 or 3, wherein the reaction of solution A and solution B is carried out in continuous mode. 5. The method according to claim 1, 2 or 3, wherein the solvent used to prepare solution A in step 1(a), 2(a) or 3(a) is selected from alcohols, aromatic hydrocarbons, ethers, esters , halogenated hydrocarbons, ketones, nitriles, aprotic polar solvents, water and mixtures thereof. 6. The method according to claim 5, wherein the solvent used is selected from the group consisting of methanol, ethanol, propanol, butanol, ethylene glycol, toluene, xylene, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxin Alkanes, ethylene glycol dimethyl ether, diglyme, ethyl acetate, methyl acetate, dichloromethane, chloroform, dichloroethane, acetone, methyl ethyl ketone, ethyl isobutyl ketone, acetonitrile, propionitrile , N,N-dimethylformamide, dimethylsulfoxide and hexamethylphosphoramide. 7. The method of claim 1 , 2 or 3, wherein the preparation of solution A in step 1(a), 2(a) or 3(a) is optionally carried out in the presence of a base. 8. The method according to claim 7, wherein the base is selected from organic bases and inorganic bases. 9. The method of claim 8, wherein the organic base is selected from amines and alkali metal alkoxides. 10. The method of claim 9, wherein the amine is selected from the group consisting of triethylamine, diisopropylamine, diisopropylethylamine and piperidine. 11. The method of claim 9, wherein the alkali metal alkoxide is selected from sodium methoxide and potassium methoxide. 12. The method of claim 8, wherein the inorganic base is selected from the group consisting of ammonia, alkali and alkaline earth metal carbonates, bicarbonates, hydroxides and hydrides. 13. The method of claim 12, wherein the alkali and alkaline earth metals are selected from the group consisting of lithium, sodium, potassium, magnesium, calcium and barium. 14. The method according to claim 1, 2 or 3, wherein the oxidizing agent in solution B is selected from the group consisting of hydrogen peroxide, alkyl hydroperoxides, arylalkyl hydroperoxides, alkali metals and alkaline earth metals Halogen salts. 15. The method of claim 14, wherein the alkali and alkaline earth metals are selected from the group consisting of sodium, lithium, potassium, magnesium and calcium. 16. The method of claim 14, wherein the halite is selected from the group consisting of fluorite, chlorite and bromite. 17. The method according to claim 1, 2 or 3, wherein the solvent used to prepare solution B in step 1 (b), 2 (b) or 3 (b) is selected from alcohols, aromatic hydrocarbons, ethers, esters, Halogenated hydrocarbons, ketones, nitriles, aprotic polar solvents, water and mixtures thereof. 18. The method according to claim 17, wherein the solvent used is selected from methanol, ethanol, propanol, butanol, ethylene glycol, toluene, xylene, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxin Alkanes, ethylene glycol dimethyl ether, diglyme, ethyl acetate, methyl acetate, dichloromethane, chloroform, dichloroethane, acetone, methyl ethyl ketone, ethyl isobutyl ketone, acetonitrile, propionitrile , N,N-dimethylformamide, dimethylsulfoxide and hexamethylphosphoramide. 19. The method of claim 1, 2 or 3, wherein the preparation of solution B in step 1(b), 2(b) or 3(b) is optionally carried out in the presence of a base. 20. The method of claim 19, wherein the base is selected from organic bases and inorganic bases. 21. The method of claim 19, wherein the organic base is selected from amines and alkali metal alkoxides. 22. The method of claim 21, wherein the amine is selected from the group consisting of triethylamine, diisopropylamine, diisopropylethylamine and piperidine. 23. The method of claim 21, wherein the alkali metal alkoxide is selected from sodium methoxide and potassium methoxide. 24. The method of claim 20, wherein the inorganic base is selected from the group consisting of ammonia, carbonates, bicarbonates, hydroxides and hydrides of alkali and alkaline earth metals. 25. The method of claim 24, wherein the alkali and alkaline earth metals are selected from the group consisting of lithium, sodium, potassium, magnesium, calcium and barium. 26. The method of claim 1 , 2 or 3, wherein the reaction in step 1(c), 2(c) or 3(c) is optionally carried out in the presence of a metal catalyst. 27. The method of claim 26, wherein the metal of the metal catalyst is selected from the group consisting of rhenium, vanadium, molybdenum, tungsten, cerium and yttrium. 28. The method of claim 1, 2 or 3, wherein the oxidation of the compound of formula II to the compound of formula I is asymmetric. 29. The method according to claim 28, wherein the preparation of solution A in said step 1(a), 2(a) or 3(a) is by mixing a chiral transition metal complex with a compound of formula II performed, optionally in a solvent. 30. The method of claim 29, wherein the chiral transition metal complex is prepared from a transition metal compound and a chiral ligand. 31. The method according to claim 30, wherein the transition metal compound is selected from the group consisting of titanium(IV) isopropoxide, titanium(IV) propoxide, titanium(IV) ethoxide, titanium(IV) methoxide, tripropanol oxide Vanadium and vanadium oxide triisopropoxide. 32. The method according to claim 30, wherein the chiral ligand is selected from the group consisting of (+)-L-diethyl tartrate, (-)-D-diethyl tartrate, (+)-L-diethyl tartrate methyl ester and (-)-D-dimethyltartrate. 33. The method of claim 28, wherein the asymmetric oxidation is performed in the presence of a catalyst. 34. The method according to claim 33, wherein the catalyst/catalyst used is water.