Preparation method of omeprazole

Abstract

The invention belongs to the technical field of medicine and chemical production, and particularly relates to a preparation method of omeprazole. The preparation method comprises the following steps: adding omeprazole thioether, polyaniline and cobalt salt into toluene, dropwise adding a hydrogen peroxide solution, and after dropwise adding, carrying out heat preservation and stirring, cooling and crystallizing, filtering, washing and drying to obtain an omeprazole solid. The polyaniline is used as the catalyst, the cobalt salt is used as the cocatalyst, the catalyst is high in stability and high in catalytic capacity, the yield of the synthesis method is high, and over-oxidized sulfone impurities cannot be generated. The catalyst is not inactivated after being recycled for multiple times, so that the catalyst cost can be greatly reduced, and the production cost of the product is reduced. The method does not need to separate the catalyst, can be recycled by using the mother liquor, and can be developed into a continuous synthesis process.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine and chemical production, and particularly relates to a method for preparing omeprazole. Background Art

[0002] Omeprazole is a clinical drug for the treatment of digestive system diseases such as chronic atrophic gastritis and gastric ulcers. It mainly binds to hydrogen ions in gastric mucosal cells to regulate the pH of gastric juice, effectively inhibit excessive gastric acid secretion, relieve the irritation of gastric acid on gastric mucosa, and repair gastric mucosa. As a traditional drug for the treatment of digestive system diseases, omeprazole still has an indispensable position in the medical field.

[0003] In the traditional synthesis process of omeprazole, the last step is mostly the oxidation step of omeprazole sulfide, so the yield of this step greatly affects the process cost, and omeprazole is unstable in nature and is easily over-oxidized in the solvent to produce sulfone impurities, which is extremely demanding on the reaction conditions. At present, most processes are carried out at a temperature of -20 ° C, which has high requirements for production equipment. In addition, if the temperature is not controlled during the oxidation process of omeprazole sulfide, other impurities will be produced, which will increase the impurity removal process and production costs. It can be seen that optimizing the oxidation process of omeprazole sulfide, simplifying the operation and reducing the production cost are key technical issues that need to be solved in this field. Summary of the invention

[0004] In order to solve the above technical problems, the object of the present invention is to provide a method for preparing omeprazole from omeprazole thioether.

[0005] In order to achieve the above-mentioned invention object, the technical solution provided by the present invention is: A method for preparing omeprazole comprises the following steps: adding omeprazole sulfide, polyaniline and cobalt salt into toluene, then dripping hydrogen peroxide solution, and after the dripping is completed, heat-insulating and stirring, cooling and crystallizing, filtering, washing and drying to obtain omeprazole solid; The cobalt salt is selected from any one of cobalt trifluoromethanesulfonate, cobalt bis(dimethylglyoxime)pyridine chloride, bis(pentamethylcyclopentadienyl)cobalt hexafluorophosphate, tri(ethylenediamine)cobalt chloride, pentaamminechlorocobalt chloride, cobalt acetylacetonate, cobalt bis(dimethylglyoxime)pyridine chloride, and tris(2,2'-bipyridine)tris(trifluoromethanesulfonyl imide)cobalt.

[0006] Furthermore, the cobalt salt is tris(2,2'-bipyridine)tris(trifluoromethanesulfonyl imide)cobalt, and the unique ligand contained in the cobalt salt has high selectivity for the oxidation of omeprazole thioether and does not produce excessively oxidized impurities.

[0007] Furthermore, the preparation method of polyaniline comprises the following steps: dissolving 0.05 mol of aniline in 50 mL of 1M hydrochloric acid aqueous solution, dropping 2 mL of 30% by mass hydrogen peroxide aqueous solution for oxidative polymerization, stirring for 10 minutes, standing the mixture at room temperature for 24 hours, and then neutralizing with 1M sodium hydroxide aqueous solution to pH = 7. The precipitate is collected by centrifugation, washed three times with deionized water and ethanol respectively, and then vacuum dried at 70°C for 6 hours to obtain polyaniline.

[0008] Furthermore, the mass of the cobalt salt is 1-5% of the mass of omeprazole sulfide, preferably 2%. Using this dosage of the cobalt salt catalyst, the yield of the product is the highest.

[0009] Furthermore, the mass of the polyaniline is 6-14% of the mass of the omeprazole sulfide, preferably 10%. Using this dosage of the polyaniline catalyst can maximize the yield of the product.

[0010] Furthermore, the mass of the toluene is 3 to 8 times the mass of the omeprazole sulfide, preferably 5 times. Using this dose of toluene, omeprazole can be cooled and crystallized.

[0011] Furthermore, the temperature of the dropwise addition of the hydrogen peroxide solution is between -10°C and 15°C, preferably 5°C, at which the oxidation yield is the highest and most economical.

[0012] Furthermore, the mass fraction of hydrogen peroxide in the hydrogen peroxide solution is 30%.

[0013] Furthermore, the mass of the hydrogen peroxide solution is 20-60% of the mass of omeprazole sulfide, preferably 40%.

[0014] Furthermore, after the dropwise addition is completed, the mixture is kept warm and stirred, cooled and crystallized, filtered, washed and dried, specifically including: keeping warm and stirring for 0.5 hours after the dropwise addition is completed, cooling to 0°C and stirring and crystallizing for 1 hour after the reaction is completed, filtering with suction, rinsing the filter cake with 0°C toluene, and vacuum drying at 50°C.

[0015] Compared with the prior art, the present invention has the following beneficial effects: The method of the present invention uses cobalt salt as a co-catalyst. Cobalt salt has good coordination ability, and cobalt ions can chelate with a variety of ligands to obtain specific functions, and the complex can be directly obtained by purchase; polyaniline can also be synthesized from commercially available raw materials by known methods (ACS Sustain. Chem. Eng. 2022, 10, 7658-7663). The synthesis of polyaniline catalyst is simple, and the abundant nitrogen atoms can be fully utilized to produce coordination effects with metal ions, and the abundant electron clouds around nitrogen atoms can be used to interact with metal ions to enhance the catalytic ability of metal ions. At the same time, the reduction unit and oxidation unit of polyaniline are used to make the catalyst more stable, so that the catalytic system can be recycled many times without deactivation.

[0016] The synthesis method of the present invention has a high yield and does not produce over-oxidized sulfone impurities. The catalyst is recycled for multiple times without deactivation, which can greatly reduce the catalyst cost, thereby reducing the production cost of the product. The method does not require separation of the catalyst, and the mother liquor can be recycled and applied, and can be developed into a continuous synthesis process. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 It is the liquid chromatogram of the product of Example 1. DETAILED DESCRIPTION

[0018] The following examples illustrate the present invention in more detail but are not intended to further limit the present invention.

[0019] In the present invention, omeprazole is prepared from omeprazole sulfide as a raw material through catalytic oxidation and optimization of key parameters including the amount of polyaniline, the amount of cobalt salt, the amount of hydrogen peroxide, the reaction temperature, etc. Compared with the prior art, the operation is simpler and the production cost is greatly reduced.

[0020] The polyaniline involved in the embodiment is synthesized according to the method reported by Meng et al. (ACS Sustain. Chem. Eng. 2022, 10, 7658−7663). The specific preparation method is as follows: 0.05 mol of aniline is dissolved in 50 mL of 1 M hydrochloric acid aqueous solution, 2 mL of 30% by mass hydrogen peroxide aqueous solution is added dropwise for oxidative polymerization, and after stirring for 10 minutes, the mixture is allowed to stand at room temperature for 24 hours, and then neutralized with 1 M sodium hydroxide aqueous solution to pH = 7. The precipitate is collected by centrifugation, washed three times with deionized water and ethanol respectively, and then vacuum dried at 70 ° C for 6 hours to obtain polyaniline.

[0021] Example 1 A method for preparing omeprazole comprises the following steps: In a 250 mL round-bottom flask, 10.0 g of omeprazole sulfide, 1.0 g of polyaniline, 0.2 g of tris(2,2'-bipyridine)tris(trifluoromethanesulfonylimide)cobalt, and 80.0 g of toluene were added. The mixture was cooled to 5°C under mechanical stirring (300 rpm). 4.0 g of 30% hydrogen peroxide solution was added dropwise at 5°C.

[0022] After the dropwise addition, the mixture was stirred for 0.5 hours. After the reaction was completed, the mixture was cooled to 0°C and stirred for crystallization for 1 hour. The mixture was filtered and the filter cake was washed with 0°C toluene and dried under vacuum at 50°C to obtain the product omeprazole. The yield was 85%. The liquid chromatography results were as follows: Figure 1 As shown, no sulfone impurities were produced due to over-oxidation.

[0023] In the above experiments, the sources and purity of the drugs used are as follows: Aniline (CAS No.: 62-53-3), purchased from Sinopharm Group, concentration 99.5%; Hydrochloric acid (CAS No. 7647-01-0), purchased from Sinopharm Group, concentration 36%~38%; Sodium hydroxide (CAS No.: 1310-73-2), purchased from Anaiji, purity 97%; Omeprazole sulfide (CAS No.: 73590-85-9), purchased from Anaiji, purity 98%; Tris(2,2'-bipyridyl)tris(trifluoromethanesulfonyl imide)cobalt (CAS No. 1353745-91-1), purchased from Aladdin, purity 99%; Hydrogen peroxide solution (CAS No.: 7722-84-1), purchased from Anaiji, purity 30%; Toluene (CAS No.: 108-88-3) was purchased from Sinopharm Group with a purity of 99.5%.

[0024] Example 2 The preparation method of omeprazole only changes the type of cobalt salt, and the other conditions are the same as in Example 1. The effects of using different cobalt salt catalysts are studied, and the results are shown in Table 1: Table 1 Comparison of the effects of different cobalt salt catalysts

[0025] From the above results, it can be seen that the addition of cobalt salt can greatly improve the yield of omeprazole, and the type of ligand also affects the yield of omeprazole. Among them, cobalt salts with large steric hindrance ligands have the best effect, such as tris(2,2'-bipyridine)tris(trifluoromethanesulfonylimide)cobalt and bis(pentamethylcyclopentadienyl)cobalt hexafluorophosphate in Example 1.

[0026] Example 3 The preparation method of omeprazole only changes the amount of cobalt salt used, and the other conditions are the same as Example 1. The effects of using different amounts of cobalt salt are studied, and the results are shown in Table 2.

[0027] Table 2 Comparison of the effects of different cobalt salt dosages

[0028] From the above results, it can be seen that when the dosage of cobalt salt is 2% (Example 1), the yield of omeprazole is the highest (No. 2).

[0029] Example 4 The preparation method of omeprazole only changes the amount of polyaniline, and the other conditions are the same as in Example 1. The effect of using different amounts of polyaniline was studied, and the results are shown in Table 3.

[0030] Table 3 Comparison of the effect of polyaniline dosage

[0031] From the above results, it can be seen that when the dosage of polyaniline is 10% (Example 1), the yield of omeprazole is the highest (No. 3).

[0032] Example 5 The preparation method of omeprazole, only the amount of toluene was changed, and the other conditions were the same as Example 1, and the influence of using different amounts of toluene was studied. The results are shown in Table 4.

[0033] Table 4 Comparison of the effects of toluene dosage

[0034] From the above results, it can be seen that when the amount of toluene is 5 times (Example 1), the yield of omeprazole is the highest, and even if the amount is increased, the yield remains basically stable (No. 3).

[0035] Example 6 The preparation method of omeprazole only changes the dropping temperature of hydrogen peroxide, and the other conditions are the same as those in Example 1. The influence of different dropping temperatures was studied, and the results are shown in Table 5.

[0036] Table 5 Comparison of the effects of hydrogen peroxide dropping temperature

[0037] From the above results, it can be seen that when the dropping temperature of hydrogen peroxide is 5°C (Example 1), the yield of omeprazole is the highest (No. 4).

[0038] Example 7 The preparation method of omeprazole, only the amount of hydrogen peroxide solution was changed, and other conditions were the same as Example 1, and the effects of using different amounts of hydrogen peroxide solution were studied. The results are shown in Table 6.

[0039] Table 6 Comparison of the effects of the amount of hydrogen peroxide solution

[0040] It can be seen from the above results that when the dosage of hydrogen peroxide solution is 40% (Example 1), the yield of omeprazole is the highest, and even if the basic dosage is increased, the yield remains basically stable (No. 3).

[0041] Example 8 The preparation method of omeprazole, after the reaction of Example 1 is completed, an equal amount (10.0 g) of omeprazole sulfide is added to the filtered mother liquor, and the reaction process of Example 1 is repeated again (without adding additional catalyst), and the reaction is cycled again after the reaction is completed. The results of multiple cycle reactions are shown in Table 7.

[0042] Table 7 Comparison of catalyst circulation effect test

[0043] As shown in the above results, the catalyst system can be recycled at least 6 times without deactivation, and only the mother liquor needs to be reused without any other treatment, which means that this catalytic system can be developed into a continuous synthesis process and has prospects for industrial application.

[0044] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Any technician familiar with the profession, without departing from the scope of the technical solution of the present invention, according to the technical essence of the present invention, any simple modification, equivalent replacement and improvement made to the above embodiment still falls within the protection scope of the technical solution of the present invention.

Claims

1. A method for preparing omeprazole, characterized in that: The following steps are involved: Add omeprazole sulfide, polyaniline and cobalt salt to toluene, then drop hydrogen peroxide solution, keep warm and stir after the dropwise addition is completed, cool and crystallize, filter, wash and dry to obtain omeprazole solid; the cobalt salt is selected from any one of cobalt trifluoromethanesulfonate, chlorobis(dimethylglyoxime)pyridine cobalt, bis(pentamethylcyclopentadienyl)cobalt hexafluorophosphate, tri(ethylenediamine)cobalt chloride, pentaamminechlorocobalt chloride, cobalt acetylacetonate, chlorobis(dimethylglyoxime)pyridine cobalt, tri(2,2'-bipyridine)tris(trifluoromethanesulfonylimide)cobalt; The mass of the polyaniline is 10% of the mass of omeprazole sulfide.

2. A method for preparing omeprazole according to claim 1, characterized in that, The preparation method of the polyaniline is as follows: 0.05 mol of aniline is dissolved in 50 mL of 1 M hydrochloric acid aqueous solution, 2 mL of 30% by mass hydrogen peroxide solution is added dropwise for oxidative polymerization, and after stirring for 10 minutes, the mixture is allowed to stand at room temperature for 24 hours, and then neutralized with 1 M sodium hydroxide aqueous solution to pH = 7. The precipitate is collected by centrifugation, washed three times with deionized water and ethanol respectively, and then vacuum dried at 70°C for 6 hours to obtain polyaniline.

3. A method for preparing omeprazole according to claim 1, characterized in that, The cobalt salt is tris(2,2'-bipyridine)tris(trifluoromethanesulfonyl imide)cobalt.

4. The method for preparing omeprazole according to claim 1, wherein: The mass of the cobalt salt is 1-5% of the mass of omeprazole sulfide.

5. The method for preparing omeprazole according to claim 1, wherein: The mass of the toluene is 3 to 8 times the mass of omeprazole sulfide.

6. The method for preparing omeprazole according to claim 1, wherein: The temperature of the dropwise addition of the hydrogen peroxide solution is between -10°C and 15°C.

7. The method for preparing omeprazole according to claim 1, characterized in that: The mass fraction of the hydrogen peroxide solution is 30%.

8. The method for preparing omeprazole according to claim 7, characterized in that: The mass of the hydrogen peroxide solution is 20-60% of the mass of omeprazole sulfide.

9. The method for preparing omeprazole according to claim 1, characterized in that: After the dropwise addition is completed, the mixture is kept warm and stirred, cooled and crystallized, filtered, washed and dried, specifically comprising: keeping warm and stirring for 0.5 hours after the dropwise addition is completed, cooling to 0°C and stirring and crystallizing for 1 hour after the reaction is completed, filtering with suction, rinsing the filter cake with 0°C toluene, and vacuum drying at 50°C.

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