WO2009145368A1

WO2009145368A1 - Improved preparing method of (s)-omeprazole from omeprazole racemate using optical resolution agent

Info

Publication number: WO2009145368A1
Application number: PCT/KR2008/002961
Authority: WO
Inventors: Jae-Sun Kim; Jin Young Lee; Sun Ho Kim; Nam Ho Kim; Nam Kyu Lee; Eun Ju Park; Do Seung Kum
Original assignee: Sk Chemicals Co., Ltd.
Priority date: 2008-05-27
Filing date: 2008-05-27
Publication date: 2009-12-03

Abstract

The present invention relates to an improved preparing method of (S)-omeprazole from omeprazole racemate. In an exemplary embodiment, the preparing method according to the present invention comprises the steps of: a) reacting omeprazole racemate with optically active diethyl-D-tartrate and a titanium compound in an alcohol solvent to prepare an omeprazole racemic complex; b) reacting the omeprazole racemic complex with 1.5-3.0 molar equivalents of (S)-(+)-mandelic acid as optical resolution agent to prepare an optically active (S)-omeprazole complex; and c) dissociating the optically active (S)-omeprazole complex with a basic solution to prepare an (S)-omeprazole free base or reacting the (S)- omeprazole free base with a metal salt to transfer to a metal salt or a metal salt hydrate of (S)- omeprazole. With optical purity of 99.0 %ee or better, the (S)-omeprazole, the metal salt thereof or the hydrate thereof prepared in accordance with the present invention is useful as a medicinal material.

Description

[DESCRIPTION] [Invention Title]

IMPROVED PREPARING METHOD OF (S)-OMEPRAZOLE FROM OMEPRAZOLE RACEMATE USING OPTICAL RESOLUTION AGENT

[Technical Field]

The present invention relates to an improved preparing method of (S)- omeprazole from omeprazole racemate. More particularly, the preparation method comprises the steps of: a) binding the chiral sulfur of omeprazole racemate with optically active diethyl-D-tartrate and titanium ion as ligand in an alcohol solvent to prepare an omeprazole racemic complex; b) reacting the omeprazole racemic complex with 1.5-3.0 molar equivalents of (S)-(+)-mandelic acid as optical resolution agent to prepare an optically active (S)-omeprazole complex; and c) reacting the optically active (S)-omeprazole complex with a basic solution to prepare an (S)- omeprazole free base or reacting the (S)-omeprazole with a metal salt to prepare a metal salt or a metal salt hydrate of (S)-omeprazole. The (S)-omeprazole, the metal salt or the metal salt hydrate thereof prepared by the present invention has an optical purity of 99.0 %ee or better, and thus, is useful as a medicinal material. [Background Art]

(S)-Omeprazole is a chiral compound represented by the following Chemical Formula 1, having chiral sulfur in the asymmetrically substituted sulfoxide group: [Chemical Formula 1]

In general, optically pure isomers of chiral drug compounds provide superior therapeutic effects over racemates. Often, different pharmacological characteristics are derived from different stereostructure of the isomers or different salt type thereof. (S)-Omeprazole is known to have less side effects than omeprazole racemate because it affects the liver metabolism less. With superior therapeutic effect for gastric ulcer, duodenal ulcer, reflux esophagitis, and the like, it has been placed in a commercial market as an anti-ulcer agent under the name Nexium™.

In order to maximize the therapeutic effect of (S)-omeprazole, it is required to improve the optical purity of (S)-omeprazole. To this end, it is important to prepare optically pure left-handed isomer (S)-omeprazole practically without the right-handed counterpart. WO 94/27988 discloses a method of preparing a diastereomeric mixture of omeprazole racemate in chloroform solvent using (K)-mandelic acid and preparing (S)-omeprazole by separating the same through reversed phase chromatography.

U.S. Patent Nos. 5,693,818 and 6,369,085 disclose also disclose a method of isolating and preparing (S)-omeprazole from omeprazole racemate in basic aqueous solution using (R)-mandelic acid.

Various advancements of the aforesaid preparation method of (S)-omeprazole have been presented in patents [WO 96/02535, WO 97/02261, WO 2004/02982, WO 2003/089408, WO 2004/077869, WO 2005/105786, WO 2005/116001, U.S. Patent No. 5,948,789, Chinese Patent No. 1,087,739, and Korean Patent No. 641,534] and literatures Q. Deng et al, Tetrahedron: Asymmetry, 11, 1729-1732, 2000; and H. Cotton et al., Tetrahedron: Asymmetry, 11, 3819-3825, 2000]. These conventional techniques are largely classified into the following two methods: 1) a method of preparing (S)- omeprazole from optical resolution of omeprazole racemate or a derivative thereof using an optical resolution agent, and 2) a method of preparing (S)-omeprazole through catalytic asymmetric oxidation during the process of preparing sulfoxide from the sulfide precursor. The latter method of preparing (S)-omeprazole through asymmetric oxidation has been technically advanced enough for commercialization in spite of the disadvantages that the preparation process is complicated, fastidious reaction conditions and various reagents are required, and a series of post-treatment and purification processes are required to attain a pharmaceutically required optical purity [U.S. Patent No. 6,369,085]. In contrast, the former method of preparing (S)- omeprazole through optical resolution using an optical resolution agent has not reached the stage of commercialization although it is industrially highly promising because of relatively simple processes.

Typical examples of the method of preparing (S)-omeprazole through optical resolution using an optical resolution agent are as follows. In the first method, an inclusion complex of (S)-omeprazole and (S)-(-)-BINOL is prepared from omeprazole racemate using (S)-(-)-BINOL as optical resolution agent. Then, (S)-(-)-BINOL is removed to obtain (S)-omeprazole [Chinese Patent No. 1,087,739 and Korean Patent No. 641,534]. However, this method has the following disadvantages: 1) to attain good optical purity, the relatively expensive optical resolution agent (S)-(-)-BINOL should be used in an amount of 0.5-1.0 molar equivalent based on 1 mol of omeprazole, 2) the solvent with a high risk of toxicity such as benzene should be used in excess, 3) discoloration is required because the resultant inclusion complex and reaction solution are severely colored dark purple, 4) a chromatography process, which is inapplicable in large-scale production, is used in order to remove (S)-(-)-BINOL from the (S)-omeprazole inclusion complex, and 5) despite the foregoing, the optical purity of the (S)-omeprazole inclusion complex is as low as 90-98 %ee (enantiomeric excess). In the second method, a sodium salt of omeprazole racemate is prepared into an omeprazole racemic complex in acetone solvent using optically active diethyl-D- tartrate, titanium tetraisopropoxide and triethylamine. Then, an optically active (S)-omeprazole complex is prepared using (S)-(+)-mandelic acid as optical resolution agent, and (S)-(+)-mandelic acid is removed therefrom to prepare (S)-omeprazole free base [U.S. Patent Publication No. 2004/0077869]. However, when (S)- omeprazole free base was actually prepared according the method, the optical purity was very low as 70-80 %ee.

[Disclosure] The present invention is an improvement of the preparation process of U.S.

Patent Publication No. 2004/0077869 using (S)-(+)-mandelic acid as optical resolution agent. By carrying out the preparation of an omeprazole racemic complex in alcohol solvent and controlling the equivalent amounts of the optical resolution agent (S)-(+)-mandelic acid and other components, the present invention provides ('^-omeprazole, a metal salt thereof or a metal salt hydrate thereof with optical purity of 99.0 %ee or better.

Accordingly, an object of the present invention is to provide an improved preparing method of (S)-omeprazole from omeprazole racemate using an optical resolution agent.

[Best Mode]

The present invention is characterized by a preparing method of (S)- omeprazole, a metal salt thereof or a hydrate thereof from omeprazole racemate, which comprises the steps of: a) reacting omeprazole racemate, optically active diethyl-D-tartrate and a titanium compound in an alcohol solvent to prepare an omeprazole racemic complex; b) reacting the omeprazole racemic complex with 1.5-3.0 molar equivalents of

(S)-(+)-mandelic acid as optical resolution agent to prepare an optically active (S)- omeprazole complex; and c) dissociating the optically active (S)-omeprazole complex in basic solution to prepare (S)-omeprazole free base or reacting the (S)-omeprazole free base with a metal salt to prepare a metal salt or a metal salt hydrate of (S)-omeprazole.

Hereinafter, the present invention is described in more detail.

The present invention is an improvement of the preparation process of U.S. Patent Publication No. 2004/0077869. By specifically controlling the reaction conditions of each step, the present invention provides (S)-omeprazole, a metal salt thereof or a metal salt hydrate thereof with optical purity of 99.0 %ee or better.

The respective steps of the preparing method according to the present invention will be described in detail. In the first step, an omeprazole racemic complex is prepared.

In the present invention, omeprazole racemate, optically active diethyl-D- tartrate and a titanium compound are reacted in an alcohol solvent to prepare an omeprazole racemic complex.

The omeprazole racemate used as starting material in the present invention includes a free base of omeprazole racemate, a metal salt thereof and a metal salt hydrate, and is not specially limited. The metal salt refers to an alkali metal salt or an alkaline earth metal salt of omeprazole racemate. Specifically, a sodium salt, a potassium salt, a magnesium salt, or the like may be included. The metal salt hydrate of omeprazole refers to a metal salt of omeprazole hydrated with water. The metal salt or the metal salt hydrate may be prepared by the methods well known in the related art.

As the ligand for the preparation of the omeprazole racemic complex, the present invention uses optically active diethyl-D-tartrate and a titanium compound. The titanium compound may be any organic compound containing a titanium(IV) ion. Specific examples include titanium tetra(Ci-C6 alkoxide) such as titanium tetra(methoxide), titanium tetra(ethoxide), titanium tetra(isopropoxide)_/ etc. Typically, titanium tetra(isopropoxide) may be used. More preferably, the omeprazole racemic complex is prepared in the presence of a base. The base may be an organic amine base. More specifically, Ci-C₁O alkylamine, alkylammonium, pyridine, or the like may be used. Typically, triethylamine may be used.

The preparation of the omeprazole racemic complex is performed at 30-50 ⁰C, preferably at 35-45 ⁰C, more preferably at 40 ⁰C.

The reaction solvent may be a O-C7 low alcohol. Specific examples may include methanol, ethanol, n-propanol, isopropanol, n-butanol, f-butanol, n-pentanol, isopentanol, n-hexanol, cyclohexanol, and the like. Preferably, ethanol or n- propanol is used. More preferably, n-propanol is used. And, if necessary, a mixture solvent comprising the aforesaid alcohol solvent as main solvent and an adequate cosolvent may be used. The cosolvent mixed with the main solvent may be selected from water, C3-C10 ketone, C₁-Qo alcohol, C2-Q0 ether, C₂-C₁O amide, C₁- C₁O sulfoxide, C₂-C₁O ester, C₁-C₁O hydrocarbon, C₁-C₁O chlorohydrocarbon and C₂-C₁O nitrile. Preferred ketone solvent may include acetone and methyl ethyl ketone. Preferred alcohol solvent may include C1-C7 saturated alcohol. Preferred ether solvent may include diethyl ether and tetrahydrofuran (THF). Preferred amide solvent may include N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC) and N,N'-dimethylpropyleneurea (DMPU). Preferred ester solvent may include an acetate solvent such as ethyl acetate (EtOAc). Preferred hydrocarbon solvent may include a C5-C10 hydrocarbon such as pentane, hexane and toluene. Preferred chlorohydrocarbon solvent may include chloroform, dichloromethane, 1,2- dichloroethane and 1,1,1-trichloroethane. Preferred nitrile solvent may include a C2-C7 nitrile such as acetonitrile. More specific examples of the cosolvent that may be used in the present invention may be selected from water, acetone, acetonitrile, dimethyl sulfoxide, dimethylacetamide, methyl ethyl ketone, tetrahydrofuran, ethyl acetate, dichloromethane, dimethylformamide, toluene, methanol, ethanol, f-butanol and N,N'-dimethylpropyleneurea. The maximum amount of the cosolvent mixed with the alcohol as main solvent may be up to 50 vol%, in general, relative to the alcohol as main solvent, although variable depending on the particular cosolvent. When the cosolvent is used in excess of 50 vol% relative to the alcohol as main solvent, optical purity may decrease significantly.

The solvent is used in an amount of 5-20 mL, preferably 10-15 mL, based on 1 g of the omeprazole racemate whether the alcohol solvent is used alone or in combination with the cosolvent.

The ligand or the diethyl-D-tartrate is used in an amount of 0.5-1.5 molar equivalents, preferably 0.8-1.2 molar equivalents, more preferably 0.95-1.05 molar equivalents, and most preferably 1.0 molar equivalent, based on 1 mol of the omeprazole racemate.

The other ligand or the titanium compound is used in an amount of 0.25-1.0 molar equivalent, preferably 0.4-0.6 molar equivalent, more preferably 0.45-0.55 molar equivalent, and most preferably 0.50 molar equivalent, based on 1 mol of the omeprazole racemate.

The organic amine base is used in an amount of 1.0-5.0 molar equivalents, preferably 2.5-3.5 molar equivalents, more preferably 2.9-3.1 molar equivalents, and most preferably 3.0 molar equivalents, based on 1 mol of the omeprazole racemate.

In the second step, the omeprazole racemic complex is reacted with 1.5-3.0 molar equivalents of (S)-(+)-mandelic acid as optical resolution agent to prepare an optically active (S)-omeprazole complex. In the present invention, the omeprazole racemic complex is reacted with the optical resolution agent (S)-(+)-mandelic acid to prepare an optically active (S)- omeprazole complex as solid precipitate.

The (S)-(+)-mandelic acid, which is used in the present invention as optical resolution agent, is used in an amount of 1.5-3.0 molar equivalents, preferably 1.5-1.9 molar equivalents, more preferably 1.5-1.7 molar equivalents, and most preferably 1.5 molar equivalents, based on 1 mol of the omeprazole racemate. The reason why the most preferred amount of the (S)-(+)-mandelic acid is selected as 1.5 molar equivalents is as follows. The inventors of the present invention have performed NMR structural analysis on the solid precipitate of the optically active (S)- omeprazole complex prepared by the present invention. As a result, it was confirmed that the (S)-omeprazole, the diethyl-D-tartrate and the (S)-(+)-mandelic acid were bound at a proportion of 1 : 1 : 3 based on molar equivalents. The reason why the (S)-(+)-mandelic acid is used in an amount of 1.5 molar equivalents is because only half of the omeprazole racemate is (S)-omeprazole. That is, the proportion of the (S)-omeprazole in the optically active (S)-omeprazole complex to the (S)-(+)-mandelic acid is the same as 1 : 3. Actually, according to experiments, when the (S)-(+)-mandelic acid was used in an amount less than 1.5 molar equivalents, optical purity was below the commercially available degree and the yield was significantly low. When the (S)-(+)-mandelic acid was used in an amount more than 1.5 molar equivalents, the optical purity and the yield were maintained without apparent change. But, excessive use more than is required is economically undesirable. Thus, the inventors of the present invention have selected the commercially most favorable amount of the (S)-(+)-mandelic acid as 1.5 molar equivalents. That is, it is the most reasonable to use 1.5 molar equivalents of (S)- (+)-mandelic acid based on 1 mol of the omeprazole racemate.

U.S. Patent Publication No. 2004/0077869 states that optically active (S)- omeprazole complex was obtained with good optical purity by using 1.0 molar equivalent of (S)-(+)-mandelic acid based on 1 mol of omeprazole racemate. However, when the inventors of the present invention performed experiments under the same conditions, the optical purity was lower than 80 %ee (Comparative

Example 1). The reaction temperature is from 30 ⁰C to 50⁰C, preferably from 35⁰C to 45 ⁰C, and more preferably 40⁰C. The reaction time refers to the time from the addition of the (S)-(+)-mandelic acid until the formation of the optically active (S)-omeprazole complex as solid precipitate. The reaction temperature is preferably from 2 to 4 hours, although it may be different depending on the main solvent and the cosolvent.

Thus prepared optically active (S)-omeprazole complex is allowed to stand for sufficient time so that it may be precipitated as solid precipitate. Then, it is collected by filtering and dried in vacuum. More specifically, the optically active

(S)-omeprazole complex obtained as solid precipitate is filtered by the conventional method and washed with the main solvent or the cosolvent used for the preparation. Then, after further washing with a hydrocarbon based organic solvent or an ether based organic solvent, drying is performed in vacuum at adequate temperature. The filtering of the solid complex precipitate is performed by the conventional method. The hydrocarbon based organic solvent used for the washing may include a C5-C10 hydrocarbon such as pentane, hexane, etc. Hexane is preferred. And, the ether based organic solvent may be diethyl ether, dimethyl ether, petroleum ether, etc. Diethyl ether is preferred. The optically active (S)-omeprazole complex obtained as solid precipitate is dried at room temperature to 50 ⁰C, preferably at 25- 35 ⁰Q for 12-24 hours. Thus obtained optically active (S)-omeprazole complex is a solid compound with optical purity of 99.0 %ee or better.

The filtrate discharged during the filtering contains other isomers such as optically active (R)-omeprazole complex. Therefore, it can be transferred into omeprazole racemate using a base or through racemization for reuse in the preparation process of optically active (S)-omeprazole complex. Accordingly, the present invention also provides a method of re-circulating the filtrate discharged during the filtering process into the preparation process of optically active (S)- omeprazole complex. In the third step, the optically active (S)-omeprazole complex is dissociated using a basic solution to prepare (S)-omeprazole free base or the (S)-omeprazole free base is transferred to a metal salt or a metal salt hydrate.

In the present invention, the optically active (S)-omeprazole complex obtained as solid precipitate is dissociated using a basic solution to prepare (S)- omeprazole. More specifically, the optically active (S)-omeprazole complex is mixed with an aqueous solution of an organic base or an inorganic base in a chlorohydrocarbon solvent or an ester solvent to dissociate it into (S)-omeprazole free base. Then, the (S)-omeprazole free base is extracted and the filtrate is dried in vacuum according to the conventional method.

Here, the chlorohydrocarbon solvent used as reaction solvent may be the same as defined above. Chloroform, dichloromethane, 1,2-dichloroethane or 1,1,1- trichloroethane may be used. More preferably, dichloromethane is used. Also, the ester solvent may be the same as defined above. An acetate solvent such as ethyl acetate is used. The organic base may be the organic amine base defined above. More specifically, Ci-Cio alkylamine, alkylammonium, pyridine, etc. may be used. Typically, triethylamine is used. The inorganic base is an alkali metal- or alkaline earth metal-containing compound, including halide, hydroxide, oxide, etc. Preferably, sodium hydroxide is used.

The filtrate discharged during the filtering contains diethyl-D-tartrate and (S)- (+)-mandelic acid. The organic compounds other than the (S)-(+)-mandelic acid can be removed by extraction using an organic solvent under a basic aqueous solution condition. Then, the (S)-(+)-mandelic acid may be formed as solid precipitate under an acidic aqueous solution condition for reuse in the preparation process of optically active (S)-omeprazole complex. Accordingly, the present invention also provides a method of re-circulating the filtrate discharged during the filtering process into the preparation process of optically active (S)-omeprazole complex.

Further, the (S)-omeprazole free base may be reacted with a metal salt or water by ihe conventional method to prepare a metal salt or a hydrate of (S)- omeprazole. The metal salt may be an alkali metal- or an alkaline earth metal- containing compound, including halide, hydroxide, oxide, etc. Specific examples include sodium hydroxide, potassium hydroxide, magnesium hydroxide, and the like. The metal salt hydrate of (S)-omeprazole may be prepared by hydrating the metal salt of (S)-omeprazole with water.

The (S)-omeprazole, the metal salt thereof or the metal salt hydrate thereof prepared by the aforesaid preparation process has optical purity of 99.0 %ee or better and has white or creamy white color.

The preparation process according to the present invention can be summarized by the following Scheme 1.

[Scheme Λ ]

, base;

acid

Aqueous basic solution

Raσernκβtion and organic solvent

Mela Insolvent

In Scheme 1, L stands for a ligand.

[Mode for Invention]

The following examples further illustrate the present invention but are not intended to limit the scope of the present invention. Optical purity of the compounds synthesized in the examples was measured by chiral HPLC under the following conditions:

- Column: Chiral-AGP 100x4.0 mm, 5.0 urn

- Flow rate: 0.5 mL/min

- Detection wavelength: 210 nm

- Eluent: sodium hydrogen phosphate buffer (0.2 M, pH 7)/acetonitrile (88/12, v/v)

- Sample: dissolved in acetonitrile/ water (50/50, v/v) mixture solution to 0.025 mg/mL

Example 1: Preparation of sodium salt of omeprazole racemate

128.0 g of sodium hydroxide was completely dissolved in 1.0 L of methanol by stirring at room temperature. After adding 9.0 L of isopropanol, stirring was performed at room temperature for 10 minutes. The resulting solution was filtered once through filter paper. After adding 1.0 kg of omeprazole racemate, stirring was performed at room temperature for 2 hours. The produced solid precipitate was collected by filtering, washed with 2.0 L of isopropanol and 1.0 L of ethyl ether, and dried in vacuum at room temperature for 2 days. 0.98 kg of sodium salt of omeprazole racemate was obtained (theoretical yield: 92.8%).

Example 2: Preparation of optically active (S)-omeprazole complex 36.7 g (100 mmol) of the sodium salt of omeprazole racemate was added to 500 mL of ethanol and stirred at 40 ⁰C. After sequentially adding 20.6 g of diethyl- D-tartrate (100 mmol, 1.0 molar equivalent), 14.2 g of titanium(IV) tetraisopropoxide (50 mmol, 0.5 molar equivalent) and 30.2 g of triethylamine (300 mmol, 3.0 molar equivalents), stirring was performed at 40 ⁰C for 10 minutes. Before the solid precipitate was formed, 22.8 g of (S)-(+)-mandelic acid (150 mmol, 1.5 molar equivalents) was added and stirring was performed at 40 ⁰C for 3 hours. The produced solid precipitate was collected by filtering, washed with 50 mL of ethanol, and dried in vacuum at room temperature. 22.17 g of complex comprising optically active (S)-omeprazole, titanium, diethyl-D-tartrate and (S)-(+)-mandelic acid was obtained. Optical purity: 99.70 %ee

Example 3: Preparation of optically active (S)-omeprazole free base

22.1 g of the optically active (S)-omeprazole complex was added to 221 mL of a 1:1 mixture solution of dichloromethane and 5% sodium bicarbonate aqueous solution and stirred at room temperature for 30 minutes. The organic layer was extracted, washed twice with 22 mL of distilled water, and evaporated under reduced pressure. 12.0 g of (S)-omeprazole free base (theoretical yield (2 steps): 69.5%) was obtained.

Optical purity: 99.72 %ee

Example 4: Preparation of potassium salt of optically active (S)-omeprazole 12.0 g of the optically active (S)-omeprazole free base obtained in Example 3 was added to a potassium hydroxide/ methanol solution (3.84 g of potassium hydroxide in 120 mL of methanol) and stirred at room temperature for 1 hour. The produced solid precipitate was collected by filtering, washed with 12 mL of methanol, and dried in vacuum at 35 ⁰C. 12.8 g of potassium salt of optically active (S)-omeprazole (theoretical yield: 96.0%) was obtained. Optical purity: 99.84 %ee, theoretical yield (3 steps): 66.8%

Example 5: Preparation of optically active (S)-omeprazole complex

36.7 g (100 mmol) of sodium salt of omeprazole racemate was added to 500 mL of n-propanol and stirred at 40 ⁰C. After sequentially adding 20.6 g of diethyl- D-tartrate (100 mmol, 1.0 molar equivalent), 14.2 g of titanium(IV) tetraisopropoxide (50 mmol, 0.5 molar equivalent) and 30.2 g of triethylamine (300 mmol, 3.0 molar equivalents), stirring was performed at 40 ⁰C for 10 minutes. Before the solid precipitate was formed, 22.8 g of (S)-(+)-mandelic acid (150 mmol, 1.5 molar equivalents) was added and stirring was performed at 40 ⁰C for 3 hours. The produced solid precipitate was collected by filtering, washed with 50 mL of 1- propanol, and dried in vacuum at room temperature. 44.34 g of optically active (S)- omeprazole complex was obtained. Optical purity: 99.61 %ee

Example 6: Preparation of optically active (S)-omeprazole free base

44.30 g of the optically active (S)-omeprazole complex obtained in Example 5 was added to 440 mL of a 1:1 mixture solution of dichloromethane and 5% sodium bicarbonate aqueous solution and stirred at room temperature for 30 minutes. The organic layer was extracted, washed twice with 44 mL of distilled water, and evaporated under reduced pressure. 17.0 g of (S)-omeprazole free base (theoretical yield (2 steps): 98.5%) was obtained. Optical purity: 99.69 %ee

Example 7: Preparation of potassium salt of optically active (S)-omeprazole 17.0 g of the optically active (S)-omeprazole free base obtained in Example 6 was added to a potassium hydroxide/ methanol solution (5.45 g of potassium hydroxide in 170 mL of methanol) and stirred at room temperature for 1 hour. The produced solid precipitate was collected by filtering, washed with 17 mL of methanol, and dried in vacuum at 35 ⁰C. 17.3 g of potassium salt of optically active (S)-omeprazole (theoretical yield: 92.0%) was obtained. Optical purity: 99.89 %ee, theoretical yield (3 steps): 90.6%

Example 8: Preparation of optically active (S)-omeprazole complex

367 g (1.0 mol) of sodium salt of omeprazole racemate was added to 5 L of 1- propanol and stirred at 40 ⁰C. After sequentially adding 206 g of diethyl-D-tartrate (1.0 mol, 1.0 molar equivalent), 142 g of titanium(IV) tetraisopropoxide (0.5 mol, 0.5 molar equivalent) and 302 g of triethylamine (3.0 mol, 3.0 molar equivalents), stirring was performed at 40 ⁰C for 10 minutes. Before the solid precipitate was formed, 228 g of (S)-(+)-mandelic acid (1.5 mol, 1.5 molar equivalents) was added and stirring was performed at 40 ⁰C for 3 hours. The produced solid precipitate was collected by filtering, washed with 500 mL of 1-propanol, and dried in vacuum at room temperature. 370 g of complex comprising optically active (S)-omeprazole, titanium, diethyl-D-tartrate and (S)-(+)-mandelic acid was obtained. Optical purity: 98.55 %ee

Example 9: Preparation of optically active (S)-omeprazole free base

367 g of the optically active (S)-omeprazole complex obtained in Example 8 was added to 3.67 L of a 1:1 (v/v) mixture solution of dichloromethane and 5% sodium bicarbonate aqueous solution and stirred at room temperature for 30 minutes. The organic layer was extracted, washed twice with 367 mL of distilled water, and evaporated under reduced pressure. 170 g of (S)-omeprazole free was obtained.

Optical purity: 99.01 %ee

Example 10: Preparation of potassium salt of optically active (S)-omeprazole 170 g of the optically active (S)-omeprazole free base obtained in Example 9 was added to a potassium hydroxide/ methanol solution (54.5 g of potassium hydroxide in 1.7 L of methanol) and stirred at room temperature for 1 hour. The produced solid precipitate was collected by filtering, washed with 170 mL of methanol, and dried in vacuum at 35 ⁰C. 145.5 g of potassium salt of optically active (S)-omeprazole was obtained.

Optical purity: 99.93 %ee, theoretical yield (3 steps): 75.9%

Examples 11-22: Preparation of optically active (S)-omeprazole complex Optically active (S)-omeprazole complex was prepared using 1.84 g of sodium salt of omeprazole racemate in the same manner of Example 5, except that 500 mL of n-propanol was used as reaction solvent and the amount of the optical resolution agent (S)-(+)-mandelic acid was varied as shown in the following Table 1. The result is also given in Table 1.

[Table 1]

As seen in Table 1, the optical purity and yield of the optically active (S)- omeprazole complex varied a lot depending on the amount of the optical resolution agent (S)-(+)-mandelic acid. When the amount of the (S)-(+)-mandelic acid was less than 1.2 molar equivalents, the optical purity was below the commercially available level and the yield was also significantly low. When the amount was 1.2 molar equivalents or more, the optical purity and yield were maintained without apparent change. Particularly, the optical purity was maintained at 99 %ee or higher when the amount was 1.5 molar equivalents or more. However, because excessive use of the expensive optical resolution agent is economically undesirable, it is recommended to determine the amount adequately.

Examples 23-31: Preparation of optically active (S)-omeprazole complex

Optically active (S)-omeprazole complex was prepared using 36.7 g of sodium salt of omeprazole racemate in the same manner of Example 2, except that 1. 5 molar equivalents of (S)-(+)-mandelic acid was used as an optical resolution agent and 500 mL of various reaction solvent was used as shown in the following Table 2. The result is also given in Table 2.

[Table 2]

As seen in Table 2, the optical purity the optically active (S)-omeprazole complex varied a lot depending on the selection of the reaction solvent. When an alcohol solvent, particularly ethanol or n-propanol, was used, the optical purity was 99 %ee or higher. When acetone was used, the optical purity increased significantly when 1.5 molar equivalents of (S)-(+)-mandelic acid were used as proposed by the present invention. But, the optical purity was lower than when ethanol or n-propanol was used, below the commercially available level.

Example 32: Preparation of sodium salt of (S)-omeprazole

3.45 g of optically active (S)-omeprazole free base was added to 0.60 g of sodium hydroxide dissolved in 34.5 mL of methanol and stirred at room temperature for 30 minutes. The produced solid precipitate was filtered and dried in vacuum at 35 ⁰C. 3.50 g of optically active sodium salt of (S)-omeprazole (theoretical yield: 95.0%) was obtained. Optical purity: 99.93 %ee

Example 33: Preparation of potassium salt of (S)-omeprazole

3.45 g of optically active (S)-omeprazole free base was added to 0.80 g of potassium hydroxide dissolved in 34.5 mL of methanol and stirred at room temperature for 30 minutes. The produced solid precipitate was filtered and dried in vacuum at 35 ⁰C. 3.61 g of optically active potassium salt of (S)-omeprazole (theoretical yield: 94.1%) was obtained. Optical purity: 99.96 %ee

Example 34: Preparation of magnesium salt of (S)-omeprazole

3.45 g of optically active (S)-omeprazole free base was added to 1.9 g of magnesium chloride dissolved in 69 mL of 1:1 mixture of methanol and water, and stirred at room temperature for 30 minutes. The produced solid precipitate was filtered and dried in vacuum at 35 ⁰C. 3.30 g of optically active magnesium salt of

(S)-omeprazole (theoretical yield: 90.0%) was obtained. Optical purity: 99.86 %ee

Example 35: Preparation of magnesium dihydrate of (S)-omeprazole 4.0 g of potassium salt of optically active (S)-omeprazole was dissolved in 8.0 mL of water. After adding 2.0 g of magnesium chloride, stirring was performed at room temperature for 2 hours. The produced solid precipitate was filtered, washed with 10 mL of methanol, and dried in vacuum at 35 ⁰C. 3.1 g of magnesium dihydrate of optically active (S)-omeprazole was obtained. Optical purity: 99.81 %ee

Example 36: Preparation of magnesium trihydrate of (S)-omeprazole 4.0 g of potassium salt of optically active (S)-omeprazole was dissolved in 8.0 mL of water. After adding 2.0 g of magnesium chloride, stirring was performed at room temperature for 2 hours. The produced solid precipitate was filtered, and stirred at 40 ⁰C for 3 hours after adding 30 mL of water. The produced solid precipitate was filtered, washed with 10 mL of methanol, and dried in vacuum at 35 ⁰C. 2.1 g of magnesium trihydrate of optically active (S)-omeprazole was obtained.

Optical purity: 99.88%ee Comparative Example 1: Preparation of optically active (S)-omeprazole complex (cf . U.S. Patent Publication No. 2004-77869)

10 g of sodium salt of omeprazole racemate was dissolved in 120 mL of acetone and stirred at 40 ⁰C. After sequentially adding 5.6 g of diethyl-D-tartrate

(1.0 molar equivalent), 4.0 g of titanium(IV) tetraisopropoxide (0.5 molar equivalent) and 8.2 g of triethylamine (3.0 molar equivalents), stirring was performed at 40 ⁰C for 10 minutes. 4.2 g of (S)-(+)-mandelic acid (1.0 molar equivalent) was added and stirring was performed at 40 ⁰C for 2 hours. The produced solid precipitate was collected by filtering, washed twice with 50 mL of acetone, and dried in vacuum at room temperature. 6.48 g of complex comprising optically active (S)-omeprazole, titanium, diethyl-D-tartrate and (S)-(+)-mandelic acid was obtained.

Optical purity: 70.45 %ee

[Industrial Applicability]

The present invention provides an improved preparation method of (S)- omeprazole, a metal salt thereof or a metal salt hydrate thereof from omeprazole racemate using (S)-(+)-mandelic acid as optical resolution agent. By carrying out the preparation of an omeprazole racemic complex in alcohol solvent and optimizing the equivalent amounts of the optical resolution agent (S)-

(+)-mandelic acid and other components, the present invention drastically improved the preparation of (S)-omeprazole, a metal salt thereof or a metal salt hydrate thereof with optical purity of 99.0 %ee or better.

Accordingly, the preparation process according to the present invention is applicable to large-scale production of optically active (S)-omeprazole.

Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.

Claims

[CLAIMS] [Claim 1]

A preparing method of (S)-omeprazole, a metal salt or a hydrate thereof from omeprazole racemate comprising the steps of: a) reacting omeprazole racemate with optically active diethyl-D-tartrate and a titanium compound in an alcohol solvent to prepare an omeprazole racemic complex; b) reacting the omeprazole racemic complex with 1.5-3.0 molar equivalents of (S)-(+)-mandelic acid as optical resolution agent to prepare an optically active (S)- omeprazole complex; and c) dissociating the optically active (S)-omeprazole complex with a basic solution to prepare an (S)-omeprazole free base or reacting the (S)-omeprazole free base with a metal salt to prepare a metal salt or a metal salt hydrate of (S)- omeprazole.

[Claim 2]

The method as claimed in claim 1, wherein the omeprazole racemate of the step a) is omeprazole racemate free base, a metal salt thereof or a metal salt hydrate thereof.

[Claim 3]

The method as claimed in claim I₁ wherein the omeprazole racemate of the step a) is a sodium salt of omeprazole racemate.

[Claim 4]

The method as claimed in claim 1, wherein the titanium compound of the step a) is titanium tetra(Gι-C₆alkoxide).

[Claim 5]

The method as claimed in claim 1, wherein the titanium compound of the step a) is titanium tetra(isopropoxide).

[Claim 6]

The method as claimed in claim 1, wherein the reaction for the preparation of the omeprazole racemic complex in the step a) is performed in the presence of an organic amine base.

[Claim 7]

The method as claimed in claim 6, wherein the organic amine base is triethylamine.

[Claim 8]

The method as claimed in claim 1, wherein the reaction for the preparation of the omeprazole racemic complex in the step a) is performed at 30-50⁰C.

[Claim 9]

The method as claimed in claim 8, wherein the reaction for the preparation of the omeprazole racemic complex in the step a) is performed at 35-45 ⁰C.

[Claim 10] The method as claimed in claim 9, wherein the reaction for the preparation of the omeprazole racemic complex in the step a) is performed at 40⁰C.

[Claim 11] The method as claimed in claim 1, wherein the alcohol solvent of the step a) is a C₁-O low alcohol.

[Claim 12]

The method as claimed in claim 11, wherein the alcohol solvent of the step a) is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, f-butanol, n- pentanol, isopentanol, n-hexanol, cyclohexanol and a mixture thereof.

[Claim 13] The method as claimed in claim 12, wherein the alcohol solvent of the step a) is ethanol or n-propanol.

[Claim 14]

The method as claimed in claim 13, wherein the alcohol solvent of the step a) is n-propanol.

[Claim 15]

The method as claimed in claim 1, wherein the solvent for the reaction for the preparation of the omeprazole racemic complex in the step a) is a single alcohol solvent or a mixture solvent of an alcohol solvent and a cosolvent selected from water, C3-C10 ketone, Ci-C₁O alcohol, C2-C10 ether, C2-C10 amide, C1-C10 sulfoxide, C2- Cio ester, C1-C10 hydrocarbon, C1-C10 chlorohydrocarbon and C2-C10 nitrile.

[Claim 16]

The method as claimed in claim 15, wherein the cosolvent is used in an amount of less than 50 vol% relative to the alcohol solvent.

[Claim 17]

The method as claimed in claim 1 or 15, wherein the solvent is used in an amount from 5 mL to 20 mL based on 1 g of the omeprazole racemate.

[Claim 18] The method as claimed in claim 17, wherein the solvent is used in an amount from 10 mL to 15 mL based on 1 g of the omeprazole racemate.

[Claim 19] The method as claimed in claim 1, wherein the optically active diethyl-D- tartrate is used in an amount from 0.5 to 1.5 molar equivalents based on 1 mol of the omeprazole racemate.

[Claim 20]

The method as claimed in claim 19, wherein the optically active diethyl-D- tartrate is used in an amount from 0.8 to 1.2 molar equivalents based on 1 mol of the omeprazole racemate.

[Claim 21]

The method as claimed in claim 20, wherein the optically active diethyl-D- tartrate is used in an amount from 0.95 to 1.05 molar equivalents based on 1 mol of the omeprazole racemate.

[Claim 22]

The method as claimed in claim 20, wherein the optically active diethyl-D- tartrate is used in an amount of 1.0 molar equivalent based on 1 mol of the omeprazole racemate.

[Claim 23]

The method as claimed in claim 1, wherein the titanium compound is used in an amount from 0.25 to 1.0 molar equivalent based on 1 mol of the omeprazole racemate.

[Claim 24]

The method as claimed in claim 23, wherein the titanium compound is used in an amount from 0.4 to 0.6 molar equivalent based on 1 mol of the omeprazole racemate.

[Claim 25]

The method as claimed in claim 24, wherein the titanium compound is used in an amount from 0.45 to 0.55 molar equivalent based on 1 mol of the omeprazole racemate.

[Claim 26]

The method as claimed in claim 25, wherein the titanium compound is used in an amount of 0.50 molar equivalent based on 1 mol of the omeprazole racemate.

[Claim 27]

The method as claimed in claim 6, wherein the organic amine base is used in an amount from 1.0 to 5.0 molar equivalents based on 1 mol of the omeprazole racemate.

[Claim 28]

The method as claimed in claim 27, wherein the organic amine base is used in an amount from 2.5 to 3.5 molar equivalents based on 1 mol of the omeprazole racemate.

[Claim 29]

The method as claimed in claim 28, wherein the organic amine base is used in an amount from 2.9 to 3.1 molar equivalents based on 1 mol of the omeprazole racemate.

[Claim 30] The method as claimed in claim 29, wherein the organic amine base is used in an amount of 3.0 molar equivalents based on 1 mol of the omeprazole racemate.

[Claim 31]

The method as claimed in claim 1, wherein the (S)-(+)-mandelic acid is used in an amount from 1.5 molar to 1.9 molar equivalents based on 1 mol of the omeprazole racemate.

[Claim 32] The method as claimed in claim 31, wherein the (S)-(+)-mandelic acid is used in an amount from 1.5 to 1.7 molar equivalents based on 1 mol of the omeprazole racemate.

[Claim 33] The method as claimed in claim 32, wherein the (S)-(+)-mandelic acid is used in an amount of 1.5 molar equivalents based on 1 mol of the omeprazole racemate.

[Claim 34] The method as claimed in claim 1, wherein the reaction for the preparation of the optically active (S)-omeprazole complex in the step b) is performed for 2-4 hours.

[Claim 35]

The method as claimed in claim 1, wherein the reaction for the preparation of the optically active (S)-omeprazole complex in the step b) is performed at 30-50⁰C.

[Claim 36]

The method as claimed in claim 35, wherein the reaction for the preparation of the optically active (S)-omeprazole complex in the step b) is performed at 35-45 ⁰C.

[Claim 37]

The method as claimed in claim 36, wherein the reaction for the preparation of the optically active (S)-omeprazole complex in the step b) is performed at 40 ⁰C.

[Claim 38]

The method as claimed in claim 1, which further comprises a step of, after obtaining the optically active (S)-omeprazole complex by filtering as solid precipitate in the step b), drying the same at room temperature to 50 ⁰C.

[Claim 39]

The method as claimed in claim 38, wherein the drying is performed at 25-35 ⁰C.

[Claim 40]

The method as claimed in claim 38 or 39, wherein the drying is performed for 12-24 hours.

[Claim 41]

The method as claimed in claim 1 or 38, wherein the optically active (S)- omeprazole complex obtained in the step b) has an optical purity of 99.0 %ee or better.

[Claim 42]

The method as claimed in claim 38, wherein the filtrate discharged during the filtering step is used again in the step a) of the preparing method of the omeprazole racemic complex.

[Claim 43]

The method as claimed in claim 1, wherein the reaction for the preparation of the (S)-omeprazole free base in the step c) is performed using a solvent selected from a C₁-CiO chlorohydrocarbon and a C2-C10 alkylester.

[Claim 44]

The method as claimed in claim 43, wherein the reaction for the preparation of the (S)-omeprazole free base in the step c) is performed using a solvent selected from chloroform, dichloromethane, 1,2-dichloroethane and 1,1,1-trichloroethane.

[Claim 45]

The method as claimed in claim 44, wherein the reaction for the preparation of the (S)-omeprazole free base in the step c) is performed using dichloromethane as a solvent.

[Claim 46] The method as claimed in claim 43, wherein the reaction for the preparation of the (S)-omeprazole free base in the step c) is performed using ethyl acetate as a solvent.

[Claim 47]

The method as claimed in claim 1, wherein the metal salt of the step c) is selected from halide, hydroxide and oxide of an alkali metal or an alkaline earth metal.

[Claim 48]

The method as claimed in claim 47, wherein the metal salt of the step c) is selected from sodium hydroxide, potassium hydroxide, magnesium hydroxide and magnesium chloride.

[Claim 49]

The method as claimed in claim 1, wherein the preparation of the omeprazole racemic complex in the step a) is performed by reacting omeprazole racemate, optically active diethyl-D-tartrate and a titanium tetraisopropoxide in a n- isopropanol solvent and in the presence of a triethylamine base.

[Claim 50]

The method as claimed in claim 1 or 49, wherein the (S)-omeprazole, the metal salt thereof or the hydrate thereof has an optical purity of 99.0 %ee or better.