CN104530003A - Preparation method of salt of pyridylmethylsulfinyl-1H-benzimidazole compound - Google Patents

Abstract

The invention relates to a method for preparing (5-methoxy-2- [ (S) - [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] sulfonyl ] -1H-benzimidazole sodium salt, which comprises the steps of mixing esomeprazole and sodium hydroxide solid in a single non-alcohol solvent, and crystallizing.

Description

Preparation method of salt of pyridylmethylsulfinyl-1H-benzimidazole compound

technical field

The invention relates to the field of medicinal chemistry, in particular to the preparation of (5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfonyl ]-1H-benzimidazole esomeprazole sodium method.

Background technique

Esomeprazole, its structure is shown in formula (I), and its chemical name is 5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2 -pyridyl) methyl] sulfinyl] -1H-benzimidazole, esomeprazole injection exists in the form of sodium salt, the chemical structure of esomeprazole sodium is as shown in formula (Ia):

Example 11 of PCT application WO 1996/025235, prepared by reacting esomeprazole with sodium hydroxide in a mixture of methyl isobutyl ketone (MIK)/acetonitrile from which esomeprazole sodium was precipitated Esomeprazole Sodium.

Example 41 of PCT application WO 2007/012650, prepared by reacting esomeprazole with sodium hydroxide in a mixture of methyl isobutyl ketone/isopropanol from which esomeprazole sodium was precipitated Esomeprazole sodium with deutered methoxy groups.

In Examples 1.1 to 1.3 of International Patent Application WO 2006/001753, different solid forms were prepared by reacting esomeprazole with sodium hydroxide in mixtures of toluene/methanol, toluene/ethanol and toluene/isopropanol, respectively esomeprazole sodium.

Example 15 of PCT application WO 2008/149204 describes the preparation of esomeprazole sodium by dissolving esomeprazole in aqueous sodium hydroxide solution, extracting with dichloromethane, distilling off the solvent, followed by addition of ethanol Distillation, adding ethyl acetate distillation, and finally crystallization from ethyl acetate. Example 16 describes the preparation of esomeprazole sodium using sodium ethoxide as base and ethyl acetate as solvent.

Chinese patent application CN 201180008960 summarizes various shortcomings and deficiencies of other prior art, and its technical solution for solving technical problems includes: a) mixing esomeprazole and (C3-C8)-ketone or its mixture, sodium alkoxide and (C1-C5)-alcohol; or mixed esomeprazole sodium with (C3-C8)-ketone or mixture thereof, and (C1-C5)-alcohol; and b) recovering the formed esomeprazole from the reaction medium by filtration Meprazole sodium. The advantage of this method is the excessive oxide impurity sulfone, and its structure is low as the content of the compound shown in formula (II), but this method adopts more than two kinds of mixed solvents, and productive rate is only 51%-78%, and wherein productive rate is 78% %Adopt the mixed solvent of four kinds of solvents, and the crystallization time of this method is long, needs overnight,

Definition of Terms

The term "the compound shown in (II)" refers to 5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfonate Acyl]-1H-benzimidazole.

The term "esomeprazole" refers to 5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl ]-1H-benzimidazole, esomeprazole of the present invention can be prepared by the method disclosed in the known prior art, and can also be prepared by Example 2 of the present invention.

In the following, whether or not the word "about" or "approximately" is used, all figures disclosed herein are approximate. The value of each figure may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15% or 20%.

Contents of the invention

A kind of preparation method of esomeprazole sodium salt is provided here, and described method yield is high and over-oxidizes impurity sulfone, and its structure is as shown in formula (II), and content is low, and aftertreatment process is simple, and crystallization time short,

A preparation method of esomeprazole sodium, which comprises: mixing esomeprazole and sodium hydroxide solid in a single non-alcoholic solvent, and crystallizing.

In some embodiments, the single non-alcoholic solvent is selected from one of ketone solvents, ester solvents, halogenated hydrocarbon solvents or aromatic hydrocarbon solvents, and the ketone solvent is selected from such as acetone, 2-butanol Ketone or 4-methyl-2-pentanone, the ester solvent is selected from such as ethyl acetate, isopropyl acetate, n-butyl acetate or tert-butyl acetate, and the halogenated hydrocarbon solvent is selected from such as di Chloromethane (DCM), chloroform, carbon tetrachloride, described aromatic solvent is selected from such as benzene, toluene, xylene; In one embodiment, described single non-alcoholic solvent is acetone; In another implementation In scheme, described single non-alcoholic solvent is ethyl acetate; In some embodiments, described single non-alcoholic solvent is dichloromethane; In a certain embodiment, described single non-alcoholic solvent The solvent is toluene.

In one embodiment, the preparation method of the esomeprazole sodium salt comprises: adding esomeprazole to acetone, stirring evenly, adding solid sodium hydroxide, heating to reflux, and stirring for about 4.0 hours After cooling down to about 25°C, crystallize, filter, wash with acetone, and dry.

In some embodiments, esomeprazole is added to toluene, after stirring evenly, solid sodium hydroxide is added, the temperature is raised to about 65°C, the temperature is kept and stirred for about 6.0 hours, the temperature is lowered to about 30°C, and the crystallization is about 4.0 hours, Filter, wash with toluene, and dry.

In some embodiments, esomeprazole is added to dichloromethane, after stirring evenly, solid sodium hydroxide is added, the temperature is raised to reflux, the temperature is kept and stirred for about 4.0 hours, the temperature is lowered to about 25°C, and the crystallization is about 4.0 hours, Filter, wash with dichloromethane, and dry.

In some embodiments, esomeprazole is added to ethyl acetate, after stirring evenly, solid sodium hydroxide is added, the temperature is raised to about 65°C, the temperature is kept and stirred for about 6.0 hours, the temperature is lowered to about 30°C, and the crystallization is about 4.0 After hours, filter, wash with ethyl acetate and dry.

In some embodiments, the preparation method of esomeprazole sodium salt comprises: esomeprazole and sodium hydroxide solid are selected from acetone, toluene, dichloromethane, ethyl acetate in a single non-alcohol Mix with similar solvents, heat the obtained mixture to 40°C to 70°C, keep stirring for 30 minutes to 12 hours, then lower the temperature to about 35°C to -5°C, crystallize and filter.

In the above embodiments, per gram of esomeprazole, the amount of the single non-alcoholic solvent is about 6ml to about 10ml, and in some embodiments, it is 8ml/g.

In the above embodiments, the sodium hydroxide solid is 1.0 to 2.0 equivalents relative to esomeprazole, and in some embodiments is 1.2 equivalents.

In the above embodiment, the time required for the crystallization is within 12 hours, preferably within 6 hours, more preferably within 4 hours.

The raw material esomeprazole that is used to prepare esomeprazole sodium can be prepared by methods disclosed in the prior art, such as WO 2006040635, CN95194956, etc., and can also be prepared by the method of the present invention, usually as raw material esomeprazole The over-oxidation impurity of azole, the content of the compound represented by formula (II), its HPLC purity (peak area) is above 0.5%.

In the preparation method provided by the present invention, post-treatment only needs to be filtered and washed. The whole salt-forming process uses a single non-alcoholic solvent, the solvent can be recycled, and the total yield of the two-step reaction of oxidation and salt formation is increased to 85%. More than %, the HPLC purity (peak area) of product is more than 99%, excessive oxidation impurity, its HPLC purity (peak area) of the content of compound shown in formula (II) is below 0.3%, preferably below 0.15%, more preferably 0.1% the following.

Detailed ways

In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.

The reagents used in the present invention can be purchased from the market or can be prepared by the methods described in the present invention.

In the present invention, mmol means millimole, h means hour, g means gram, and ml means milliliter.

Example 1 Preparation of 5-methoxy-2-{(S)-[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl}-1H-benzimidazole

In the reaction flask, add water (36ml), NaOH solid (15g), cool down to about 30 ℃, after the solution is clarified, add methanol (70.0ml) and 2-mercapto-5-methoxybenzimidazole (30g ), 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride (36.2g) was dissolved in methanol (18.0ml) and water (55.0ml), and the temperature was raised to about 35°C , the methanol-water solution of 2-chloromethyl-3,5-dimethyl-4-methoxypyridine hydrochloride was slowly added dropwise to the methanol-water solution of 2-mercapto-5-methoxybenzimidazole, After 2 hours, the reaction was detected by HPLC. After the reaction was complete, the temperature was lowered, stirred and crystallized for 2 hours, suction filtered, the filter cake was washed with tap water until neutral, and dried in vacuum. When the moisture content was lower than 0.2%, the drying was completed to obtain intermediate 5 -Methoxy-2-{(S)-[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl}-1H-benzimidazole (52.2g), yield 95.1%

Example 2 5-methoxy-2-{(S)-[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl-sulfoxide}-1H-benzimidazole preparation of

Add 5-methoxy-2-{(S)-[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl}-1H-benzene to the four-necked flask at room temperature And imidazole (60g), toluene (210ml), D-diethyl tartrate (22.5g), after stirring evenly, add tetraisopropyl titanate (15.54g), heat up to 60°C, keep stirring for half an hour, add water, Continue to insulate and stir for half an hour, lower the temperature to room temperature, then add diisopropylethylamine (7.05g), then slowly add dropwise the toluene solution of cumene hydroperoxide (33.24g), control the dropping time for about 1 hour, drop After the addition was completed, the temperature was controlled and stirred to react. After the reaction was completed, NaOH solution was added to the system to quench the reaction, the organic phase was removed, the aqueous phase was adjusted to pH about 7.5 with acetic acid, extracted three times with ethyl acetate, and the oily substance 5- Methoxy-2-{(S)-[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl-sulfoxide}-1H-benzimidazole (Esomela azole), 60g, the HPLC purity of the gained oil is 95.113%, and the content of the compound shown in formula (II) is 0.513%, and the gained oil is directly used in the next step to form a salt.

Example 3 5-methoxy-2-{(S)-[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl-sulfoxide}-1H-benzimidazole Sodium preparation

Add 5-methoxy-2-{(S)-[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl}-1H-benzene to the four-necked flask at room temperature And imidazole (60g), toluene (210ml), D-diethyl tartrate (22.5g), stir evenly, add tetraisopropyl titanate (15.54g), heat up to 65°C, keep stirring for half an hour, add water, Continue to keep warm and stir for half an hour, cool down to room temperature, then add diisopropylethylamine (7.05g), stir for 10 minutes, cool down the system to 0°C, slowly add dropwise a toluene solution of cumene hydroperoxide (33.24g) , control the dropping time for about 1 hour. After the dropping is complete, control the temperature and stir the reaction. After the reaction is completed, add NaOH solution to the system to quench the reaction, remove the organic phase, and adjust the water phase to a pH of about 7.5 with acetic acid. Ethyl acetate (160ml x 3) extraction, combined organic phase, the organic phase was directly used for the next reaction.

Add solid NaOH (8.0 g) to the above solution, raise the temperature to 55°C, keep stirring for 6.0 hours, a large amount of solids appear, cool down to 30°C, crystallize for 4.0 hours, filter, wash with ethyl acetate, and dry under vacuum at 45°C , to obtain esomeprazole sodium salt (57.38g), yield 85.0%, HPLC purity 99.589%, compound content (peak area) represented by formula (II) 0.06%.

Example 4 5-methoxy-2-{(S)-[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl-sulfoxide}-1H-benzimidazole Preparation of sodium (esomeprazole sodium)

Add the product (60g) prepared according to the steps described in Example 2 into toluene (480ml), stir evenly, add NaOH solid (8.0g), heat up to 65°C, keep stirring for 6.0 hours, a large amount of solids appear, cool to 30 DEG C, crystallize 4.0 hours, filter, wash with toluene, vacuum-dry at 45 DEG C, obtain title compound (55.4g), yield 82.69%, HPLC purity 99.849%, the compound content (peak area) shown in formula (II) )0.017%.

Example 5 5-methoxy-2-{(S)-[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl-sulfoxide}-1H-benzimidazole Sodium preparation

Add 60 g of the product prepared according to the method described in Example 2 into dichloromethane (480 ml), stir evenly, add NaOH solid (8.0 g), heat up to reflux, keep stirring for 4.0 hours, a large amount of solids appear, cool to 25 °C, crystallized for 4.0 hours, filtered, washed with DCM, and dried in vacuo at 45 °C to obtain the title compound (55.4 g), with a yield of 82.68%, an HPLC purity of 99.628%, and a content of the compound represented by formula (II) of 0.106%.

Example 6 5-methoxy-2-{(S)-[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl-sulfoxide}-1H-benzimidazole Sodium preparation

The 5-methoxyl-2-{(S)-[(4-methoxyl-3,5-dimethyl-2-pyridyl)-methyl-methoxyl) prepared according to the method described in Example 2 Add sulfone}-1H-benzimidazole oil (esomeprazole) (60g) into acetone (480ml), stir well, add NaOH solid (8.0g), heat up to reflux, keep stirring for 4.0 hours, a large amount of solid appears , cooled to 25°C, crystallized, filtered, washed with acetone, and dried in vacuum at 45°C to obtain 5-methoxy-2-{(S)-[(4-methoxy-3,5-dimethyl -2-pyridyl)-methyl-sulfoxide}-1H-benzimidazole sodium (58.17g), yield 86.7%, HPLC purity (peak area) 99.368%, compound content (peak area) shown in formula (II) area) 0.018%.

Example 7 5-methoxy-2-{(S)-[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl-sulfoxide}-1H-benzimidazole The preparation of sodium (comparative example 1)

Add the product (60g) prepared according to the method described in Example 2 into dichloromethane (480ml), stir evenly, add 30% methanol solution of sodium methoxide (200mmol), heat up to reflux, after the reaction is complete, cool down At about 25°C, no solid was precipitated. After vacuum distillation to dryness, an oil was obtained with a yield of 66.2% and an HPLC purity (peak area) of 89.3%.

Example 8 5-methoxy-2-{(S)-[(4-methoxy-3,5-dimethyl-2-pyridyl)-methyl-sulfoxide}-1H-benzimidazole The preparation of sodium (comparative example 2)

Add the product (60g) prepared according to the method described in Example 2 into dichloromethane (480ml), stir evenly, add 50% aqueous sodium hydroxide solution (200mmol), heat up to reflux, after the reaction is complete, depressurize After distilling with water, centrifuge again to obtain a light yellow solid with a yield of 65%.

Embodiment 9 HPLC detection condition

Liquid Chromatography Conditions

Phosphate buffer: Measure 70ml (10.92g) of 1mol/L sodium dihydrogen phosphate dihydrate and 20ml of 0.5mol/L disodium hydrogenphosphate (1.42g), add water to dilute to 1000ml. Take 250ml of the above solution, add water to dilute to 1000ml, filter, degas, and obtain;

Phase A: phosphate buffer: methanol (92.5:7.5); phase B: acetonitrile;

Chromatographic column: Agilent Poroshell 120EC-C18 (50mm×4.6mm, 2.7μm);

Flow rate: 1.0ml·min ^-1 ;

Column temperature: 30°C;

Wavelength: 280nm

Gradient elution program:

The method of the present invention has been described through preferred embodiments, and relevant persons can obviously make changes or appropriate changes and combinations to the methods and applications described herein within the content, spirit and scope of the present invention to realize and apply the technology of the present invention . Those skilled in the art can refer to the content of this article to appropriately improve the process parameters to achieve. In particular, it should be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims (10)

1. a preparation method of esomeprazole sodium, which comprises: esomeprazole and sodium hydroxide solid are mixed in a single non-alcoholic solvent, crystallization. 2. the method for claim 1, described single non-alcoholic solvent is selected from the one in ketone solvent, ester solvent, halogenated hydrocarbon solvent or aromatic hydrocarbon solvent, and described ketone solvent is selected from Such as acetone, 2-butanone or 4-methyl-2-pentanone, the ester solvent is selected from such as ethyl acetate, isopropyl acetate, n-butyl acetate or tert-butyl acetate, the halogenated hydrocarbon The class solvent is selected from such as dichloromethane, chloroform or carbon tetrachloride, and the aromatic hydrocarbon class solvent is selected from such as benzene, toluene or xylene. 3. the method for claim 2, described single non-alcoholic solvent is acetone, ethyl acetate, methylene dichloride or toluene. 4. method as claimed in claim 1, it further comprises: esomeprazole and sodium hydroxide solid are selected from acetone, toluene, methylene dichloride, the single non-alcoholic solvent mixing of ethyl acetate, will obtain The mixture was heated to 40°C to 70°C, kept stirring for 30 minutes to 12 hours, then the temperature was lowered to about 35°C to -5°C, crystallized and filtered. 5. The method as claimed in claim 1, the required single non-alcoholic solvent consumption is about 6ml to about 10ml per gram of esomeprazole. 6. The method according to claim 5, for every gram of esomeprazole, the required single non-alcoholic solvent consumption is about 8ml/g. 7. the method for claim 1, described sodium hydroxide solid is 1.0 equivalent to 2.0 equivalents with respect to esomeprazole, or is 1.2 equivalents. 8. The method according to any one of claims 1-7, wherein the time required for the crystallization is within 12 hours, preferably within 6 hours, more preferably within 4 hours. 9. The method as claimed in claim 1, comprising: adding esomeprazole ((60g) in toluene (480ml), adding NaOH solid (8.0g) after stirring evenly, warming up to 65°C, and stirring for 6.0 After hours, a large amount of solid appeared, cooled to 30°C, crystallized for 4.0 hours, filtered, washed with toluene, and dried under vacuum at 45°C. 10. the method for claim 1, it comprises: esomeprazole ((60g) is added in acetone (480ml), stirs, adds NaOH solid (8.0g), warming up to reflux, insulated and stirred for 4.0 hours, A large amount of solid appeared, cooled to 25°C, crystallized, filtered, washed with acetone, and dried under vacuum at 45°C.