KR101303813B1 - Improved preparing method of (S)-omeprazole from omeprazole racemate using optical resolution agent - Google Patents

Abstract

The present invention relates to an improved process for the preparation of esomeprazole from racemic omeprazole. As an example of the preparation method of the present invention, a) a racemic omeprazole complex is prepared by binding an optically active diethyl-D-tartrate and titanium ions with a ligand to an asymmetric sulfur element in the racemic omeprazole in an alcohol solvent. (B) preparing an optically active esomeprazole complex by reacting the racemic omeprazole complex with an optical splitting agent of 1.5 to 3.0 molar equivalents of (S)-(+)-mandelic acid; c) A process of preparing an eomeprazole free base by reacting an optically active esomeprazole complex with a base solution, or by converting the esomeprazole free base into a metal salt or metal salt hydrate of esomeprazole by reacting with a metal salt. It is made, including. Esomeprazole or a metal salt thereof or a metal salt hydrate thereof prepared by the method of the present invention has high optical purity of 99.0% ee or more and is useful as a pharmaceutical raw material.

Someprazole, racemic omeprazole, racemic omeprazole complex, optically active esomeprazole complex, optical isomer, optical separation

Description

Improved preparation method of (S) -omeprazole from omeprazole racemate using optical resolution agent}

The present invention relates to an improved process for the preparation of esomeprazole from racemic omeprazole, and more particularly to a) asymmetric sulfur compounds in racemic omeprazole in alcoholic solvents with optically active diethyl-D-tartrate and titanium. Preparing a racemic omeprazole complex by binding ions with a ligand; b) reacting the racemic omeprazole complex with an optical splitting agent of 1.5 to 3.0 molar equivalents of (S)-(+)-mandelic acid A process for preparing an omeprazole complex, c) preparing an omeprazole free base by reacting the optically active esomeprazole complex with a base solution, or preparing a metal salt or metal salt hydrate of esomeprazole by reacting the esomeprazole with a metal salt. S made by the optical separation method of the present invention, including the process of Omeprazole or a metal salt thereof or a metal salt hydrate thereof has high optical purity of 99.0% ee or more and is useful as a pharmaceutical raw material.

Eomeprazole ((S) -omeprazole) is a chiral compound in which an asymmetric sulfur element (chiral silfur) of an asymmetrically substituted sulfoxide group, as represented by the following formula (1), is present.

In general, the therapeutic effect as a drug for chiral compounds is better than pure isomeric compounds rather than isomeric mixtures, and may also have different pharmacological properties depending on the steric configuration of the isomeric compounds or their salt forms. Esomeprazole is known to have less side effects due to its lesser effect on liver metabolism than racemic omeprazole racemate. It is commercially available as an ulcer treatment agent under the trade name).

In order to maximize the therapeutic effect of esomeprazole drugs, the optical purity of esomeprazole should be high, and in order to do so, it is important to prepare optically pure lecithin optical actives corresponding to esomeprazole so that the enantiomer of priority is not substantially contained. Do.

International Patent Publication No. WO94 / 27988 discloses a process for preparing diasomeromer mixtures using (R) -mandelic acid in a chloroform solvent and separating them by reverse phase chromatography to prepare esomeprazole.

U.S. Patent Nos. 5,693,818 and 6,369,085 disclose a process for the separate preparation of esomeprazole in racemic omeprazole in basic aqueous solution using (R) -mandelic acid in the same manner.

In addition, various methods of improving the manufacturing method of the above-mentioned omeprazole are disclosed in the patent [International Patent Publication WO96 / 02535, WO97 / 02261, WO2004 / 02982, WO2003 / 089408, WO2004 / 077869, WO2005 / 105786 WO 2005/116001, US Patent No. 5,948,789, Chinese Patent No. 1,087,739, Korean Patent No. 641,534 and J. Pat. 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 divided into the following two methods, 1) a method for producing eomeprazole by the optical splitting method of the racemic omeprazole or derivatives thereof, and 2) from the corresponding precursor sulfide It is a method for preparing esomeprazole by catalytic asymmetric oxidation in the process for preparing sulfoxide. As the second method, a method for preparing esomeprazole by asymmetric oxidation method requires a complicated and sophisticated reaction condition and a large number of reagents, and in order to obtain sufficient optical purity that is pharmaceutically required, Although it is well known that there are disadvantages such as having to perform a post-treatment process and a purification process, sufficient technical progress has been made to make it practical [US Patent No. 6,369,085]. On the other hand, the method of preparing esomeprazole by the optical splitting method using an optical splitting agent as the first method has not reached the level of technology that can be put to practical use even though the manufacturing process is relatively simple and the industrial usefulness is large. to be.

Representative examples of preparing esomeprazole by an optical splitting method using an optical splitting agent are the following two methods.

The first method produces an inclusion complex of esomeprazole and (S)-(-)-binol from racemic omeprazole using an optical splitting agent of (S)-(-)-binol. To (S)-(-)-binol to remove the method of preparing eomeprazole (China Patent No. 1,087,739, Korean Patent No. 641,534). However, the first method requires 1) using a relatively expensive (S)-(-)-binol optical splitting agent in an amount of 0.5 to 1.0 molar equivalents relative to 1 molar equivalent of omeprazole in order to obtain the best optical purity. ) Excessive use of solvents such as benzene, which has a high toxic potential, 3) The obtained inclusion complex and reaction solution should be severely colored in black purple to perform decolorization process, and 4) from the inclusion complex of Someprazole. Chromatography is not suitable for mass production to remove)-(-)-binol. 5) Nevertheless, the optical purity of the inclusion complex composition of esomeprazole is 90-98% ee (in excess of enantiomer, It has a problem of being low at enantiomeric excess level.

In the second method, the sodium salt of racemic omeprazole was formed in acetone solvent using optically active diethyl-D-tartrate, titanium tetraisopropoxide, and triethylamine to form a racemic omeprazole complex (S). Method for preparing an optically active esomeprazole complex using an optical splitting agent of-(+)-mandelic acid, and removing the (S)-(+)-mandelic acid therefrom to prepare an esomeprazole free base. US Patent Publication No. 2004/0077869. However, the second method is actually unsuitable for use as a raw material for medicines because the optical purity of the eomeprazole free base is very low as 70 to 80% ee as a result of the actual performance according to the embodiment.

The present invention is an improved invention that improves the manufacturing method of US Patent Publication No. 2004/0077869 using an optical splitting agent of (S)-(+)-mandelic acid. In the present invention, the process for preparing the racemic omeprazole complex is carried out in an alcohol solvent, and by adjusting the equivalent weight of the component used, such as an optical splitting agent of (S)-(+)-mandelic acid, esomeprazole or a metal salt thereof or a salt thereof The optical purity of the metal salt hydrate is increased to 99.0% ee or more, and a significant effect is obtained.

It is therefore an object of the present invention to provide an improved process for the preparation of esomeprazole from racemic omeprazole using an optical splitting agent.

The present invention

a) a process of reacting a racemic omeprazole compound, an optically active diethyl-D-tartrate and a titanium compound in an alcohol solvent to prepare a racemic omeprazole complex;

b) reacting the racemic omeprazole complex with an optical splitting agent of (S)-(+)-mandelic acid in an amount of 1.5 to 3.0 molar equivalents to produce an optically active esomeprazole complex; And

c) freeing the optically active esomeprazole complex with a base solution to prepare an eomeprazole free base or reacting the eomeprazole free base with a metal salt to produce a metal salt or metal salt hydrate of esomeprazole Process of doing;

It is characterized by a method for producing esomeprazole or a metal salt thereof or a hydrate thereof from a racemic omeprazole comprising a.

Hereinafter, the present invention will be described in detail.

The present invention is an improved invention that improves the manufacturing method of US Patent Publication No. 2004/0077869, which is 99% ee the optical purity of esomeprazole, its metal salt or its metal salt hydrate finally prepared by specifically controlling the reaction conditions for each process The effect which markedly improved is obtained above.

The manufacturing method according to the present invention will be described in detail by subdividing each step as follows.

The first step is to prepare the racemic omeprazole complex.

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

The racemic omeprazole compound used as the starting material of the present invention includes both racemic omeprazole free base or a metal salt thereof or a metal salt hydrate thereof, and there is no particular limitation on the selection thereof. In this case, the metal salt refers to a salt of racemic omeprazole and an alkali metal or alkaline earth metal, and specifically, may include sodium salt, potassium salt, magnesium salt, and the like. The metal salt hydrate of omeprazole refers to one prepared by hydrating water with respect to the metal salt of omeprazole. The method for preparing a metal salt or metal salt hydrate corresponds to known methods well known in the art, and modifications may be made within the known method limits.

As ligands for preparing racemic omeprazole complexes, optically active diethyl-D-tartrate and titanium compounds are used in the present invention. The titanium compound used as the ligand may be applied to all organic compounds including titanium (IV) ions, and more specifically, titanium tetra (methoxide), titanium tetra (ethoxide), and titanium tetra (isopropoxide). Titanium tetra (C ₁ -C ₆ alkoxide) such as) may be used, and typically titanium tetra (isopropoxide) is used.

The reaction for preparing racemic omeprazole complex is more preferably performed in the presence of a base, and an organic amine base may be used as the base, and more specifically, may include alkylamine, alkylammonium, pyridine and the like having 1 to 10 carbon atoms. Typically, triethylamine is used.

The reaction temperature for preparing the racemic omeprazole complex is 30 ° C to 50 ° C, preferably 35 ° C to 45 ° C, and more preferably 40 ° C.

In this case, a lower alcohol solvent having 1 to 7 carbon atoms is used as the alcohol solvent to be selectively used. Specifically, methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, n-pentanol, Isopentanol, n-hexanol, cyclohexanol, etc. may be included, Preferably, ethanol and n-propanol are used, More preferably, n-propanol is used. If necessary, the alcoholic solvent may be used as a main solvent, and a suitable solvent may be used as a mixed solvent. The cosolvent to be mixed and used in the main solvent includes water, a C 3-10 ketone, a C 1-10 alcohol, a C 2-10 ether, a C 2-10 amide, a C 1-10 sulfoxide and a C 2 It is selected from esters of 10 to 10, hydrocarbons of 1 to 10 carbon atoms, chlorohydrocarbons of 1 to 10 carbon atoms and nitriles of 2 to 10 carbon atoms. Preferred ketone solvents may include acetone and methylethylketone. Preferred alcohol solvents may include C ₁ to C ₇ saturated alcohols. Preferred ether solvents may include diethyl ether and tetrahydrofuran (THF). Preferred amide solvents may include N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC) and N, N'-dimethylpropyleneurea (DMPU). Preferred ester solvents may include acetate solvents such as ethyl acetate (EtOAc). Preferred hydrocarbon solvents may include C _{5 to} C ₁₀ hydrocarbons such as pentane, hexane and toluene. Preferred chlorohydrocarbon solvents may include chloroform, dichloromethane, 1,2-dichloroethane and 1,1,1-trichloroethane. Preferred nitrile solvents may include C ₂ -C ₇ nitriles such as acetonitrile. Specific examples of the cosolvent that can be used in the present invention include water, acetone, acetonitrile, dimethyl sulfoxide, dimethylacetamide, methyl ethyl ketone, tetrahydrofuran, ethyl acetate, dichloromethane, dimethylformamide, toluene, Methanol, ethanol, t-butanol and N, N'-dimethylpropyleneurea. In addition, the maximum amount of the co-solvent to be mixed with the alcohol main solvent may vary depending on the specific co-solvent used, but can be mixed and used within the range of less than 50% by volume with respect to the alcohol main solvent. If the co-solvent is used in a relatively excessive amount of more than 50% by volume with respect to the alcohol main solvent may have a problem that the optical purity is significantly lowered.

The solvent may be used in a volume ratio of 5 mL to 20 mL based on 1 g of the racemate omeprazole compound even if an alcohol solvent alone or a mixed solvent of an alcoholic main solvent and a cosolvent is used. It is used in the volume ratio of mL.

The diethyl-D-tartrate used as the ligand is used in the amount of 0.5 to 1.5 molar equivalents, preferably 0.8 to 1.2 molar equivalents, more preferably based on 1 molar equivalent of the racemic omeprazole compound. Is used from 0.95 molar equivalents to 1.05 molar equivalents, most preferably 1.0 molar equivalent.

The titanium compound to be used as another ligand uses from 0.25 molar equivalents to 1.0 molar equivalents based on 1 molar equivalent of racemic omeprazole compound, preferably from 0.4 molar equivalents to 0.6 molar equivalents, more preferably 0.45 molar equivalents. Equivalent to 0.55 molar equivalents, most preferably 0.50 molar equivalents are used.

The organic amine base is used in the range of 1.0 molar equivalent to 5.0 molar equivalent, based on 1 molar equivalent of the racemic omeprazole compound, preferably 2.5 molar equivalent to 3.5 molar equivalent, more preferably 2.9 molar equivalent to 3.1 molar equivalent Most preferably 3.0 molar equivalents.

The second process is to prepare the optically active esomeprazole complex by reacting the racemic omeprazole complex with an optical splitting agent of 1.5 to 3.0 molar equivalents of (S)-(+)-mandelic acid.

In the present invention, the optically active esomeprazole complex is prepared as a solid precipitate by reacting the racemic omeprazole complex with (S)-(+)-mandelic acid with an optical splitting agent.

The (S)-(+)-mandelic acid used as the optical splitting agent in the present invention uses 1.5 molar equivalents to 3.0 molar equivalents based on 1 molar equivalent of the racemic omeprazole compound, preferably 1.5 molar equivalents to 1.9 molar equivalents. Equivalents, more preferably 1.5 molar equivalents to 1.7 molar equivalents, most preferably 1.5 molar equivalents are used. The reason for choosing the most preferable amount of (S)-(+)-mandelic acid at 1.5 molar equivalent is as follows. The present inventors have analyzed the structure of the complex through nuclear magnetic resonance (NMR) analysis of the solid precipitate of the optically active esomeprazole complex prepared through this process, and found that esomeprazole, diethyl-D-tartrate, and (S It was confirmed that)-(+)-mandelic acid was bound in a ratio of 1: 1: 3 in molar equivalent ratio, respectively. Since only half of 1 molar equivalent of the racemic omeprazole compound in the above reaction is esomeprazole, the use of 1.5 molar equivalents of (S)-(+)-mandelic acid in this reaction is useful for the use of esomeprazole and (S)-( +)-Same as the ratio of mandelic acid (1: 3). Indeed, as confirmed by the examples, the use of (S)-(+)-mandelic acid in less than 1.5 molar equivalents results in a lower optical purity than the commercially available range, and a significantly lower yield. It can be seen that the use of more than the molar equivalent is maintained without significant change in the optical purity and yield, but when used in excess of the appropriate amount is economically unreasonable. The inventors thus select 1.5 molar equivalents of (S)-(+)-mandelic acid as the commercially most favorable reaction conditions. That is, it is most reasonable to use 1.5 molar equivalents of (S)-(+)-mandelic acid based on 1 molar equivalent of racemic omeprazole compound.

On the other hand, US Patent Publication No. 2004/0077869, on the other hand, 1.0 molar equivalent of (S)-(+)-mandelic acid was obtained with respect to 1 molar equivalent of racemic omeprazole compound to obtain an optically active esomeprazole complex with high optical purity. However, in the comparative example, the present inventors showed the optical purity of less than 80% ee when the present inventors performed the same conditions.

The reaction temperature is 30 ° C to 50 ° C, preferably 35 ° C to 45 ° C, and more preferably 40 ° C. The reaction time is the time required for the formation of the solid precipitate by the formation of the optically active esomeprazole complex after the addition of (S)-(+)-mandelic acid, which may vary depending on the main solvent and the cosolvent used. Preferably 2 hours to 4 hours is sufficient.

The optically active esomeprazole complex prepared through the above procedure is allowed to stand for sufficient time to precipitate as a solid precipitate, which is then recovered by filtration and vacuum dried. More specifically, when the optically active esomeprazole complex is formed as a solid precipitate, it is filtered and washed with a main solvent or a cosolvent used according to a conventional method, followed by further washing with a hydrocarbon organic solvent or an ether organic solvent. And then vacuum drying at a suitable temperature. In this step, the solid precipitated composite is filtered according to a conventional method. The hydrocarbon organic solvent used as the washing solvent in the process may include C ₅ -C ₁₀ hydrocarbons such as pentane, hexane, and the like, preferably hexane, and diethyl ether and dimethyl ether as ether organic solvents. , Petroleum ether and the like are used, preferably diethyl ether is used. The optically active esomeprazole composite obtained as a solid precipitate is dried at room temperature to 50 ° C, preferably at 25 ° C to 35 ° C for 12 to 24 hours. The optically active esomeprazole composite thus obtained is a solid compound having an optical purity of 99.0% ee or more.

In addition, since the filtrate discharged through the filtration contains an isomeric compound having a different orientation, such as an optically active alomeprazole complex, preparation of the optically active esomeprazole complex by converting to racemic omeprazole by vitrification and racemization using a base. It can also be reused in the process. Therefore, the present invention also includes a method for recycling the filtrate discharged from the filtration process to the manufacturing process of the optically active someprazole complex in the scope of rights.

The third step is to liberate the optically active esomeprazole complex with a base solution to prepare an eomeprazole free base, or to convert the esomeprazole freebase into a metal salt or metal salt hydrate.

In the present invention, the optically active esomeprazole complex obtained as a solid precipitate is liberated with a base solution to prepare esomeprazole. More specifically, the optically active esomeprazole complex is mixed with an organic base or an inorganic base aqueous solution in a chlorohydrocarbon solvent or an ester solvent and liberated with esomeprazole free base, which is then extracted according to a conventional method to vacuum dry the filtrate. It includes the process of doing.

In this case, the chlorohydrocarbon solvent selected as the reaction solvent may include chloroform, dichloromethane, 1,2-dichloroethane and 1,1,1-trichloroethane, and more preferably dichloromethane. . The ester solvent is also defined above using an acetate solvent such as ethyl acetate. The organic base may use the organic amine base defined above, and more specifically, may include alkylamine, alkylammonium, pyridine and the like having 1 to 10 carbon atoms, and triethylamine is typically used. The inorganic base is an alkali metal or alkaline earth metal-containing compound, and may include halides, hydroxides, oxides, and the like, preferably sodium hydroxide.

In addition, since the filtrate discharged through the filtration contains diethyl-D-tartrate and (S)-(+)-mandelic acid, and the like (S)- After removing the organic compound except for (+)-mandelic acid, a solid precipitate of (S)-(+)-mandelic acid may be formed under acid aqueous solution, and may be reused in the preparation of the optically active esomeprazole complex. Therefore, the present invention also includes a method for recycling the filtrate discharged from the filtration process to the manufacturing process of the ESOMEPrazole complex as a scope of rights.

In addition, the present invention may be prepared as a metal salt or hydrate of esomeprazole by reacting the free esomeprazole free base with a metal salt or water according to a conventional method. The metal salt used at this time is an alkali metal or alkaline earth metal-containing compound, and may include halides, hydroxides, oxides, and the like, and specifically, sodium hydroxide, potassium hydroxide, magnesium hydroxide, and the like. The metal salt hydrate of esomeprazole can be prepared by hydrating water with respect to the metal salt of esomeprazole.

The optical purity of esomeprazole, or a metal salt thereof, or a metal salt hydrate thereof prepared by the above method is 99.0% ee or more, and has a white or light white color.

When the previous step according to the present invention represented by the reaction scheme shown in Scheme 1.

In Scheme 1, L represents a ligand.

Such a present invention will be described in more detail based on the following examples, but the present invention is not limited thereto.

In addition, the optical purity of the compounds synthesized in the Examples according to the present invention was measured by chiral HPLC, HPLC conditions used for separation are as follows:

Column: Chiral-AGP 100 × 4.0mm, 5.0um

Flow rate: 0.5 ml / min

Detection wavelength: 210 nm

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

Sample: dissolved in 0.025 mg / ml of acetonitrile / water (50/50, v / v)

Example 1 Preparation of Racemic Omeprazole Sodium Salt

128.0 g of sodium hydroxide was added to 1.0 L of methanol, and the mixture was stirred at room temperature to completely dissolve. 9.0 L of isopropanol was added to the solution and stirred for 10 minutes at room temperature. 1.0 kg of racemic omeprazole was added to the solution which was once filtered using a filter paper, and the mixed solution was stirred at room temperature for 2 hours. The resulting solid precipitate was collected by filtration, washed with 2.0 L of isopropanol and 1.0 L of ethyl ether, followed by vacuum drying at room temperature for 2 days to obtain 0.98 kg of racemic omeprazole sodium salt (theoretical yield 92.8%).

Example 2 Preparation of Optically Active Esomeprazole Complex

36.7 g (100 mmol) of racemic omeprazole sodium salt was added to 500 mL of ethanol, and the mixture was stirred at 40 ° C. To this solution 20.6 g (100 mmol, 1.0 molar equivalent) of diethyl-D-tartrate, 14.2 g (50 mmol, 0.5 molar equivalent) of titanium (IV) tetraisopropoxide, and 30.2 g (300 molar equivalents) of triethylamine mmol, 3.0 molar equivalents) was added sequentially and stirred at 40 ° C. for 10 minutes. Before the solid precipitate was formed, 22.8 g (150 mmol, 1.5 molar equivalents) of (S)-(+)-mandelic acid was added thereto and stirred at 40 ° C. for 3 hours. The resulting solid precipitate was collected by filtration, washed with 50 mL of ethanol and dried in vacuo at room temperature to produce a complex of optically active esomeprazole with titanium, diethyl-D-tartrate and (S)-(+)-mandelic acid. 22.17 g was obtained.

Optical purity: 99.70% ee

Example 3 Preparation of Optically Active Esomeprazole Free Base

22.1 g of optically active esomeprazole complex was added to 221 mL of a 1: 1 mixed solution of dichloromethane and 5% aqueous sodium bicarbonate 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 esomeprazole freebase (theoretical yield, 2 steps; 69.5%) was obtained.

Optical purity: 99.72% ee

Example 4 Preparation of Optically Active Esomeprazole Potassium Salt

12.0 g of the optically active esomeprazole free base obtained in Example 3 was added to a potassium hydroxide / methanol solution (3.84 g of potassium hydroxide, 120 mL of methanol) and stirred at room temperature for 1 hour. The resulting solid precipitate was collected by filtration, washed with 12 mL of methanol and dried in vacuo at 35 ° C. to give 12.8 g (theoretical yield, 96.0%) of optically active esomeprazole potassium salt.

Optical purity: 99.84% ee, theoretical yield, 3 steps; 66.8%

Example 5 Preparation of Optically Active Esomeprazole Composites

36.7 g (100 mmol) of racemic omeprazole sodium salt were added to 500 ml of n-propanol, and the mixture was heated to 40 ° C. and stirred. To this solution 20.6 g (100 mmol, 1.0 molar equivalent) of diethyl-D-tartrate, 14.2 g (50 mmol, 0.5 molar equivalent) of titanium (IV) tetraisopropoxide, and 30.2 g (300 molar equivalents) of triethylamine mmol, 3.0 molar equivalents) was added sequentially and stirred at 40 ° C. for 10 minutes. Before the solid precipitate was formed, 22.8 g (150 mmol, 1.5 molar equivalents) of (S)-(+)-mandelic acid was added thereto and stirred at 40 ° C. for 3 hours. The resulting solid precipitate was collected by filtration, washed with 50 mL of 1-propanol and dried in vacuo at room temperature to give 44.34 g of an optically active esomeprazole complex.

Optical purity: 99.61% ee

Example 6 Preparation of Optically Active Esomeprazole Free Base

44.30 g of the optically active esomeprazole complex obtained in Example 5 was added to 440 mL of a 1: 1 mixed 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 esomeprazole freebase (theoretical yield, 2 steps; 98.5%) was obtained.

Optical Purity: 99.69% ee

Example 7 Preparation of Optically Active Esomeprazole Potassium Salt

17.0 g of the optically active esomeprazole free base obtained in Example 6 was added to a potassium hydroxide / methanol solution (5.45 g of potassium hydroxide, 170 mL of methanol) and stirred at room temperature for 1 hour. The resulting solid precipitate was collected by filtration, washed with 17 mL of methanol and dried in vacuo at 35 ° C. to give 17.3 g (theoretical yield, 92.0%) of the optically active esomeprazole potassium salt.

Optical purity: 99.89% ee, theoretical yield, 3 steps; 90.6%

Example 8. Preparation of Optically Active Esomeprazole Complex

367 g (1.0 mol) of racemic omeprazole sodium salt was added to 5 L of 1-propanol, and the temperature was raised to 40 ° C and stirred. To this solution 206 g (1.0 mol, 1.0 mol equivalent) of diethyl-D-tartrate, 142 g (0.5 mol, 0.5 mol equivalent) of titanium (IV) tetraisopropoxide, 302 g (3.0 mol of triethylamine) , 3.0 molar equivalents) was added sequentially and stirred at 40 ° C. for 10 minutes. Before the solid precipitate was formed, 228 g (1.5 mol, 1.5 mol equivalent) of (S)-(+)-mandelic acid was added thereto and stirred at 40 ° C. for 3 hours. The resulting solid precipitate was collected by filtration, washed with 500 mL of 1-propanol and dried in vacuo at room temperature to provide optically active esomeprazole with titanium, diethyl-D-tartrate and (S)-(+)-mandelic acid. 370 g of was obtained.

Optical purity: 98.55% ee

Example 9 Preparation of Optically Active Esomeprazole Free Base

367 g of the optically active esomeprazole complex obtained in Example 8 was added to 3.67 L of a 1: 1 (volume ratio) mixed solution of dichloromethane and 5% aqueous sodium bicarbonate 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 eomeprazole free base was obtained.

Optical purity: 99.01% ee

Example 10 Preparation of Optically Active Esomeprazole Potassium Salt

170 g of the optically active esomeprazole free base obtained in Example 9 was added to a potassium hydroxide / methanol solution (54.5 g of potassium hydroxide, 1.7 L of methanol) and stirred at room temperature for 1 hour. The resulting solid precipitate was collected by filtration, washed with 170 mL of methanol and dried in vacuo at 35 ° C. to obtain 145.5 g of optically active esomeprazole potassium salt.

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

Examples 11-22. Preparation of Optically Active Esomeprazole Complex

An optically active esomeprazole complex was prepared using 1.84 g of racemic omeprazole sodium salt by the method of Example 5, except that 500 mL of n-propanol as a reaction solvent and (S)-as an optical activator, as shown in Table 1 below. The reaction was carried out under different conditions of use of (+)-mandelic acid. The results are shown in Table 1 below.

Example Reaction solvent (S)-(+)-mandelic acid
(Molar equivalent) Yield (g) Optical purity (% ee) 11 n-propanol 1.0 0.66 5.3 12 n-propanol 1.1 0.23 40.3 13 n-propanol 1.2 0.29 96.7 14 n-propanol 1.3 0.73 97.3 15 n-propanol 1.4 0.85 98.2 16 n-propanol 1.5 1.70 99.8 17 n-propanol 1.6 1.69 99.4 18 n-propanol 1.7 1.59 99.8 19 n-propanol 1.8 1.67 99.7 20 n-propanol 1.9 1.85 99.8 21 n-propanol 2.0 1.07 99.7 22 n-propanol 3.0 1.44 99.6

According to the results of Table 1, the optical purity and yield of the composite prepared according to the amount of the optical active agent (S)-(+)-mandelic acid used in the preparation process of the optically active esomeprazole complex of the present invention is greatly changed. Could confirm. When the (S)-(+)-mandelic acid is used in less than 1.2 molar equivalents, the optical purity is lower than the commercially available range, and the yield is significantly lowered. When using more than 1.2 molar equivalents, the optical purity It can be seen that the yield remains unchanged. In particular, when using 1.5 mol equivalent or more, it can be seen that the optical purity is maintained at 99% ee or more. However, the use of an expensive optical active agent in an excessive amount may be a problem in economical efficiency, so it is preferable to use it within an appropriate amount range.

Examples 23-31. Preparation of Optically Active Esomeprazole Complex

36.7 g of racemic omeprazole sodium salt was prepared by the method of Example 2, except that (S)-(+)-mandelic acid was racemic as an optical activator as shown in Table 2 below. The reaction was carried out using 1.5 molar equivalents based on omeprazole sodium salt and 500 mL of various reaction solvents. The results are shown in Table 2 below.

Example Reaction solvent (S)-(+)-mandelic acid (molar equivalents) Optical purity (% ee) 23 Diethyl ether 1.50 56.1 24 Ethyl acetate 1.50 73.3 25 Acetone 1.50 89.7 26 Methanol 1.50 79.8 27 ethanol 1.50 99.8 28 n-propanol 1.50 99.8 29 Isopropanol 1.50 79.0 30 n-butanol 1.50 94.7 31 t-butanol 1.50 73.3

According to the results of Table 2, the optically active esomeprazole complex manufacturing process of the present invention was confirmed that the optical purity of the prepared composite is significantly changed depending on the choice of the reaction solvent. As suggested by the present invention, the optical purity of the complex was higher than 99% ee under the conditions using an alcohol solvent, in particular ethanol and n-propanol. In addition, even if acetone is used, the optical purity is significantly increased by using 1.5 molar equivalents of (S)-(+)-mandelic acid as suggested by the present invention, but the optical purity in comparison with ethanol or n-propanol is used. It was found to be low commercially unsuitable.

Example 32. Preparation of Eomeprazole Sodium Salt

3.45 g of optically active esomeprazole free base was added to 34.5 mL of methanol in which 0.60 g of sodium hydroxide was dissolved, and stirred for 30 minutes at room temperature. The resulting solid precipitate was filtered and dried in vacuo at 35 ° C. to give 3.50 g (theoretical yield, 95.0%) of the optically active esomeprazole sodium salt.

Optical purity: 99.93% ee

Example 33. Preparation of Eomeprazole Potassium Salt

3.45 g of optically active esomeprazole free base was added to 34.5 mL of methanol in which 0.80 g of potassium hydroxide was dissolved, and stirred for 30 minutes at room temperature. The resulting solid precipitate was filtered and dried in vacuo at 35 ° C. to give 3.61 g (theoretical yield, 94.1%) of the optically active esomeprazole potassium salt.

Optical purity: 99.96% ee

Example 34 Preparation of Eomeprazole Magnesium Salt

3.45 g of optically active eomeprazole free base was added to 69 mL of a 1: 1 mixed solution of methanol and water in which 1.9 g of magnesium chloride was dissolved, and stirred at room temperature for 30 minutes. The resulting solid precipitate was filtered and dried in vacuo at 35 ° C. to give 3.30 g (theoretical yield, 90.0%) of the optically active esomeprazole magnesium salt.

Optical purity: 99.86% ee

Example 35. Preparation of Eomeprazole Magnesium Dihydrate

4.0 g of optically active esomeprazole potassium salt is dissolved in 8.0 ml of water, and then dissolved in 2.0 g of magnesium chloride, followed by stirring at room temperature for 2 hours. The solid precipitate was filtered off, washed with 10 ml of methanol and dried in vacuo at 35 ° C. to obtain 3.1 g of optically active esomeprazole magnesium dihydrate.

Optical purity: 99.81% ee

Example 36 Preparation of Eomeprazole Magnesium Trihydrate

4.0 g of optically active esomeprazole potassium salt was dissolved in 8.0 ml of water, and then 2.0 g of magnesium chloride was added thereto, followed by stirring at room temperature for 2 hours. The solid precipitate was filtered and 30 ml of water was added and stirred at 40 ° C. for 3 hours. The obtained solid precipitate was filtered, washed with 10 ml of methanol and dried in vacuo at 35 ° C. to obtain 2.1 g of optically active esomeprazole magnesium trihydrate.

Optical Purity: 99.88% ee

Comparative Example 1. Preparation of optically active someprazole complex (see US Patent Publication No. 2004-77869)

10 g of racemate omeprazole sodium salt was added to 120 mL of acetone, and then heated to 40 ° C. and stirred. To the solution was added 5.6 g (1.0 molar equivalent) of diethyl-D-tartrate, 4.0 g (0.5 molar equivalent) of titanium (IV) tetraisopropoxide, and 8.2 g (3.0 molar equivalent) of triethylamine. Stir at 10 ° C. for 10 minutes. 4.2 g (1.0 molar equivalent) of (S)-(+)-mandelic acid was added thereto and stirred at 40 ° C. for 2 hours. The resulting solid precipitate was collected by filtration, washed twice with 50 mL of acetone and then vacuum dried at room temperature, followed by optically active esomeprazole and titanium, diethyl-D-tartrate and (S)-(+)-mandelic acid. 6.48 g of was obtained.

Optical purity: 70.45% ee

The present invention is an improved invention that improves the process for preparing esomeprazole, its metal salt or metal salt hydrate thereof from racemic omeprazole using conventional optical splitting agents of (S)-(+)-mandelic acid.

The present invention is carried out the process of preparing the racemic omeprazole complex in an alcohol solvent, and by controlling the optimum equivalent weight of the component used, such as (S)-(+)-mandelic acid optical splitting agent, optically active esomeprazole or The optical purity of the metal salt or its hydrate is increased to 99.0% ee or more to obtain a significant effect.

Therefore, the preparation method of the present invention is useful as a mass production method of optically active omeprazole used as a pharmaceutical raw material.

Claims (50)

a) reacting a racemic omeprazole compound, an optically active diethyl-D-tartrate and a titanium compound in an alcohol solvent to prepare a racemic omeprazole complex; b) reacting the racemic omeprazole complex with an optical splitting agent of 1.5 to 3.0 molar equivalents of (S)-(+)-mandelic acid to prepare an optically active esomeprazole complex; And c) freeing the optically active esomeprazole complex with a base solution to prepare an eomeprazole free base or reacting the eomeprazole free base with a metal salt to produce a metal salt or metal salt hydrate of esomeprazole Process of doing; A method for producing esomeprazole or a metal salt thereof or a hydrate thereof from a racemic omeprazole, comprising the same. The method according to claim 1, wherein the a) racemic omeprazole compound is a racemic omeprazole free base or a metal salt thereof or a metal salt hydrate thereof. The method of claim 2 wherein the a) racemic omeprazole compound is a racemic omeprazole sodium salt. The method of claim 1, wherein the a) titanium compound is titanium tetra (C ₁ -C ₆ alkoxide). The method of claim 1, wherein the a) titanium compound is titanium tetra (isopropoxide). The method of claim 1, wherein a) the reaction for preparing the racemic omeprazole complex is performed in the presence of an organic amine base. 7. The method of claim 6, wherein said organic amine base is triethylamine. The method of claim 1, wherein the a) reaction temperature for preparing the racemic omeprazole complex is in the range of 30 ° C to 50 ° C. The method according to claim 8, wherein the a) reaction temperature for preparing the racemic omeprazole complex is in the range of 35 ° C to 45 ° C. The method according to claim 9, wherein the a) reaction temperature for preparing the racemic omeprazole complex is 40 ° C. The method of claim 1, wherein the a) alcohol solvent is characterized in that the lower alcohol solvent having 1 to 7 carbon atoms. 12. The method of claim 11, wherein a) the alcohol solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, n-pentanol, isopentanol, n-hexanol, and cyclohexanol Characterized in that it is a single or mixed solvent. 13. The method of claim 12, wherein a) the alcohol solvent is ethanol or n-propanol. The method of claim 13 wherein a) the alcohol solvent is n-propanol. The reaction solvent according to claim 1, wherein the a) preparation of the racemic omeprazole complex is an alcohol solvent alone or an alcohol solvent and water, a ketone having 3 to 10 carbon atoms, an alcohol having 1 to 10 carbon atoms, and an ether having 2 to 10 carbon atoms. , A mixture of cosolvents selected from amides of 2 to 10 carbon atoms, sulfoxides of 1 to 10 carbon atoms, esters of 2 to 10 carbon atoms, hydrocarbons of 1 to 10 carbon atoms, chlorohydrocarbons of 1 to 10 carbon atoms, and nitriles of 2 to 10 carbon atoms. And a solvent. The method of claim 15, wherein the cosolvent is used in the range of less than 50% by volume with respect to the alcohol solvent. The method of claim 1 or 15, wherein the solvent is used in the range of 5 mL to 20 mL based on 1 g of the racemic omeprazole compound. The method of claim 17, wherein the solvent is used in the range of 10 mL to 15 mL based on 1 g of the racemic omeprazole compound. The method of claim 1, wherein the optically active diethyl-D-tartrate is used in the range of 0.5 molar equivalents to 1.5 molar equivalents based on 1 molar equivalent of the racemic omeprazole compound. The method of claim 19, wherein the optically active diethyl-D-tartrate is used in the range of 0.8 to 1.2 molar equivalents based on 1 molar equivalent of the racemic omeprazole compound. The method of claim 20, wherein the optically active diethyl-D-tartrate is used in the range of 0.95 molar equivalents to 1.05 molar equivalents based on 1 molar equivalent of racemic omeprazole compound. The method of claim 20, wherein the optically active diethyl-D-tartrate is used in an amount of 1.0 molar equivalent based on 1 molar equivalent of the racemic omeprazole compound. The method of claim 1, wherein the titanium compound is used in the range of 0.25 molar equivalents to 1.0 molar equivalents based on 1 molar equivalent of racemic omeprazole compound. The method of claim 23, wherein the titanium compound is used in the range of 0.4 to 0.6 molar equivalents based on 1 molar equivalent of the racemic omeprazole compound. The method of claim 24, wherein the titanium compound is used in the range of 0.45 molar equivalents to 0.55 molar equivalents based on 1 molar equivalent of racemic omeprazole compound. 26. The method of claim 25, wherein the titanium compound is used at 0.50 molar equivalents based on 1 molar equivalent of the racemic omeprazole compound. The method of claim 6, wherein the organic amine base is used in the range of 1.0 molar equivalent to 5.0 molar equivalent based on 1 molar equivalent of the racemic omeprazole compound. The method of claim 27, wherein the organic amine base is used in the range of 2.5 to 3.5 molar equivalents based on 1 molar equivalent of the racemic omeprazole compound. The method according to claim 28, wherein the organic amine base is used in the range of 2.9 molar equivalents to 3.1 molar equivalents based on 1 molar equivalent of racemic omeprazole compound. 30. The method of claim 29, wherein the organic amine base is used at 3.0 molar equivalents based on 1 molar equivalent of racemic omeprazole compound. The method of claim 1, wherein the (S)-(+)-mandelic acid is used in the range of 1.5 molar equivalents to 1.9 molar equivalents based on 1 molar equivalent of the racemic omeprazole compound. 32. The method of claim 31, wherein the (S)-(+)-mandelic acid is used in the range of 1.5 molar equivalents to 1.7 molar equivalents based on 1 molar equivalent of racemic omeprazole compound. 33. The method of claim 32, wherein the (S)-(+)-mandelic acid is used in an amount of 1.5 molar equivalents based on 1 molar equivalent of the racemic omeprazole compound. The method of claim 1, wherein b) the reaction time for preparing the optically active esomeprazole complex is 2 hours to 4 hours. The method of claim 1, wherein b) the reaction temperature of the preparation of the optically active eomeprazole complex is 30 ℃ to 50 ℃. 36. The method of claim 35, wherein b) the reaction temperature of the preparation of the optically active esomeprazole complex is 35 ℃ to 45 ℃. The method of claim 36, wherein b) the reaction temperature of the preparation of the optically active eomeprazole complex is 40 ℃. The method of claim 1, wherein the step b) is obtained by filtration of the optically active esomeprazole complex as a solid precipitate, followed by drying at room temperature to 50 ° C. The method of claim 38, wherein the drying temperature is 25 ℃ to 35 ℃. 40. The method of claim 38 or 39, wherein the drying is performed for 12 to 24 hours. 39. The method according to claim 1 or 38, wherein the optical purity of said optically active esomeprazole complex is at least 99.0% ee. The method of claim 38, wherein the filtrate discharged by filtration is a) characterized in that for reuse in the manufacturing process of the racemic omeprazole complex. The method of claim 1, wherein c) the preparation of esomeprazole free base is performed under solvent conditions selected from chlorohydrocarbons having 1 to 10 carbon atoms and alkyl esters having 2 to 10 carbon atoms. 45. The method of claim 43, wherein c) the preparation of esomeprazole free base is performed under solvent conditions selected from chloroform, dichloromethane, 1,2-dichloroethane and 1,1,1-trichloroethane. . 45. The method of claim 44, wherein c) preparation of esomeprazole free base is carried out under solvent conditions of dichloromethane. 45. The method of claim 43, wherein c) preparation of esomeprazole free base is performed under conditions using a solvent of ethyl acetate. The method of claim 1, wherein c) the metal salt is selected from halides, hydroxides and oxides of alkali or alkaline earth metals. 48. The method of claim 47, wherein c) the metal salt is selected from sodium hydroxide, potassium hydroxide, magnesium hydroxide and magnesium chloride. According to claim 1, wherein a) the process for preparing the racemic omeprazole complex is a racemic omeprazole compound, optically active diethyl-D- tartrate and titanium tetraisopropoxide in the presence of a base of n-isopropanol solvent and triethylamine Method for producing by reacting. 50. The method of claim 1 or 49, wherein the optical purity of esomeprazole or a metal salt thereof or a hydrate thereof is at least 99.0% ee.