Method for preparing ilaprazole sodium by continuous flow method

Abstract

The invention belongs to the technical field of medicine and chemical production, and particularly relates to a method for preparing ilaprazole sodium by a continuous flow method. The preparation method comprises the following steps: (1) adding ilaprazole thioether, a sodium hydroxide solution and an iron catalyst into acetone to obtain ilaprazole thioether alkali liquor; (2) respectively introducing the ilaprazole thioether alkali liquor and oxygen into the tubular reactor through a flow meter for reaction; and (3) evaporating the organic phase obtained in the step (2) to dryness, adding ethyl acetate, pulping, filtering and drying to obtain the ilaprazole sodium solid. A continuous flow reaction process is adopted to replace a traditional kettle type process, oxygen is adopted as an oxidizing agent for oxidation reaction, conditions are mild, process parameters are easy to control and adjust, the safety is improved, the reaction time is greatly shortened, the reaction heat transfer effect is good, the whole experimental operation is simpler and more convenient, and the method is suitable for industrial continuous production.

Description

Technical Field

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

[0002] As a next-generation proton pump inhibitor, the development of ilaprazole sodium's synthesis technology is closely tied to clinical application needs. Due to its potent acid-suppressing activity and long half-life, ilaprazole sodium has become an important treatment for gastric acid-related diseases. However, optimizing its synthesis process remains a core challenge in R&D, primarily involving intermediate preparation, environmental friendliness, and crystal stability.

[0003] The low yield of the thioether oxidation step directly affects the cost of the synthesis process. Existing literature reports that current methods for ilaprazole thioether oxidation mainly use meta-chloroperbenzoic acid or sodium hypochlorite as oxidants. However, the poor solubility of meta-chloroperbenzoic acid limits the choice of reaction solvent. Furthermore, meta-chloroperbenzoic acid poses an explosion risk at high purity levels, while oxidation with sodium hypochlorite produces difficult-to-remove process impurities, significantly increasing the cost of impurity removal.

[0004] Oxygen as an oxidant offers significant advantages in chemical synthesis, particularly in green chemistry and industrial production. Its core advantages lie in its environmental friendliness, affordability, high selectivity, and industrial friendliness. Developing an oxidation process using oxygen as an oxidant is a key technical challenge urgently needed in this field. Summary of the Invention

[0005] To solve the above technical problems, the present invention aims to provide a method for preparing ilaprazole sodium by a continuous flow process.

[0006] In order to achieve the above-mentioned object of the invention, the technical solution provided by the present invention is: A method for preparing ilaprazole sodium comprises the following steps: (1) Adding ilaprazole sulfide, sodium hydroxide solution and iron catalyst to acetone to obtain ilaprazole sulfide alkali solution; (2) Ilaprazole sulfide alkali solution and oxygen were introduced into the tubular reactor through flow meters respectively. The reaction liquid in the tubular reactor was reacted at 40-60°C and 0.6-1.4 MPa, and the discharged liquid was collected; (3) The discharge liquid of step (2) was evaporated to dryness, and the resulting residue was added to ethyl acetate, slurried, filtered, and dried to obtain ilaprazole sodium; The iron catalyst is selected from any one of ferric chloride, ferric stearate, ferric acetate, ferrocene, tricarbonylcyclooctatetraenyl iron, ferric acetylacetonate, and dinonylcarbonyl iron.

[0007] Further, the iron catalyst is tricarbonyl(cyclooctatetraene)iron. The carbonyl groups in tricarbonyl(cyclooctatetraene)iron act as strong-field ligands to interact with metal atoms, reducing the electron density of the metal atoms and enhancing their interaction ability with oxygen. At the same time, the cyclic structure of cyclooctatetraene has steric hindrance to the substrate, so selective catalytic oxidation can be carried out.

[0008] Further, the mass of the iron catalyst is 0.1 - 0.5% of the mass of ilaprazole sulfide; more specifically, the mass of the iron catalyst is 0.2% of the mass of ilaprazole sulfide. Using the iron catalyst in this dosage, the product yield is the highest.

[0009] Further, the mass of the acetone is 8 times the mass of ilaprazole sulfide, the sodium hydroxide solution is 30% aqueous sodium hydroxide solution, and the mass of the sodium hydroxide solution is 2 times the mass of ilaprazole sulfide.

[0010] Further, the reaction temperature is 50 °C, and the oxidation yield is the highest at this temperature.

[0011] Further, the reaction pressure is 1.2 MPa, and the oxidation effect is the best under this pressure.

[0012] Further, the flow rate of the ilaprazole sulfide alkaline solution is 4 - 8 mL / min.

[0013] More specifically, the flow rate of the ilaprazole sulfide alkaline solution is 7 mL / min, and the oxidation yield is the highest at this flow rate.

[0014] Further, the oxygen flow rate is 300 - 700 SCCM.

[0015] More specifically, the oxygen flow rate is 500 SCCM, and the oxidation yield is the highest at this flow rate without causing waste of oxygen.

[0016] Further, the residence time of the reaction solution in the reactor is 4 - 7 min.

[0017] Further, step (3) specifically includes: evaporating the exclusion liquid to dryness and then adding it to ethyl acetate. The mass of the ethyl acetate is equal to that of the acetone in step (1), pulping for one hour, filtering, and drying the solid in vacuo at 50 °C.

[0018] Compared with the prior art, the present invention has the following beneficial effects: The present invention uses a continuous flow reaction process to replace the traditional batch process, uses oxygen as the oxidant for the oxidation reaction, has mild conditions, easy control and adjustment of process parameters, improved safety, greatly shortens the reaction time, has good heat transfer effect during the reaction, and the whole experimental operation is more convenient, which is suitable for industrial continuous production. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 This is a liquid chromatogram of the ilaprazole sodium solid obtained in Example 1 of the present invention. DETAILED DESCRIPTION

[0020] The following examples illustrate the present invention in more detail, but are not intended to further limit the present invention.

[0021] In the present invention, ilaprazole sodium is prepared from ilaprazole sulfide as a raw material through catalytic oxidation in a tubular reactor and optimization of key parameters, including the amount of iron catalyst, reaction temperature, and the flow rates of each component. Compared with the existing technology, the reaction time is greatly reduced, making it more suitable for industrial production.

[0022] Example 1 The preparation method of ilaprazole sodium comprises the following steps: (1) Add 50.0 g of ilaprazole sulfide to 400 g of acetone, stir until dissolved, then add 100 g of 30% sodium hydroxide solution and 100 mg of tricarbonyl cyclooctatetraenyl iron to obtain ilaprazole sulfide alkaline solution; (2) Ilaprazole sulfide alkali solution and oxygen were introduced into a tubular reactor through flow meters for reaction. The reaction temperature was 50 °C, the reaction pressure was 1.2 MPa, the flow rate of ilaprazole sulfide alkali solution was 7 mL / min, the flow rate of oxygen was 500 SCCM, the residence time of the reaction solution in the reactor was 5 min, and the effluent was collected. (3) After the discharge liquid of step (2) was evaporated to dryness, 400 g of ethyl acetate was added, and the mixture was beaten for one hour. After filtration, the mixture was vacuum dried at 50 ° C to obtain solid ilaprazole sodium with a yield of 92.1% and a purity of 99.5%. The liquid chromatogram was as follows Figure 1 shown.

[0023] In the above experiments, the sources and purity of the drugs used are as follows: Acetone (CAS No.: 67-64-1) was purchased from Sinopharm Group with a concentration of 99.5%; Ilaprazole sulfide (CAS No. 172152-35-1) was purchased from Aladdin, with a concentration of 95%; Sodium hydroxide (CAS No. 1310-58-3) was purchased from Aladdin with a purity of 95%; Tricarbonylcyclooctatetraenyl iron (CAS No. 12093-05-9) was purchased from Aladdin with a purity of 96%; Ethyl acetate (CAS No. 141-78-6) was purchased from Aladdin with a purity of 99.5%.

[0024] Example 2 The preparation method of ilaprazole sodium, only changing the type of iron catalyst, with other conditions the same as in Example 1. The effects of using different iron catalysts were studied, and the results are shown in Table 1 as follows: Table 1. Comparison table of the effects of different iron catalysts

[0025] From the above results, it can be seen that the addition of the iron catalyst makes the reaction proceed faster. When using the iron cyclooctatetraene tricarbonyl in Example 1, the yield of ilaprazole sodium is the highest (No. 5). This is because the carbonyl group, as a strong-field ligand, interacts with the metal atom, reducing the electron cloud density of the central atom and enhancing its interaction ability with oxygen.

[0026] Example 3 The preparation method of ilaprazole sodium, only changing the dosage of the iron catalyst, with other conditions the same as in Example 1. The effects of using different dosages of the iron catalyst were studied, and the results are shown in Table 2 as follows.

[0027] Table 2. Comparison table for testing the effects of different dosages of iron catalyst

[0028] From the above results, it can be seen that when the dosage of the iron catalyst is 0.2% in Example 1, the yield of ilaprazole sodium is the highest (No. 2).

[0029] Example 4 The preparation method of ilaprazole sodium, only changing the reaction temperature, with other conditions the same as in Example 1. The influence of temperature on the reaction was studied, and the results are shown in Table 3 as follows.

[0030] Table 3. Comparison table for testing the influence effect of reaction temperature

[0031] From the above results, it can be seen that when the reaction temperature is 50 °C in Example 1, the yield of ilaprazole sodium is the highest (No. 3).

[0032] Example 5 The preparation method of ilaprazole sodium, only changing the reaction pressure, with other conditions the same as in Example 1. The influence of pressure on the reaction was studied, and the results are shown in Table 4 as follows.

[0033] Table 4. Comparison table for testing the influence effect of reaction pressure

[0034] From the above results, it can be seen that when the reaction pressure is 1.2 MPa in Example 1, the yield of ilaprazole sodium is the highest (No. 4).

[0035] Example 6 The preparation method of ilaprazole sodium, only changing the flow rate of ilaprazole thioether alkaline solution, with other conditions the same as in Example 1. The influence of different flow rates of ilaprazole thioether alkaline solution on the reaction was studied, and the results are shown in Table 5.

[0036] Table 5. Comparison table for testing the influence effect of the flow rate of ilaprazole thioether alkaline solution

[0037] From the above results, it can be seen that when the flow rate of ilaprazole thioether alkaline solution is 7 mL / min in Example 1, the yield of ilaprazole sodium is the highest (No. 4).

[0038] Example 7 The preparation method of ilaprazole sodium, only changing the oxygen flow rate, with other conditions the same as in Example 1. The influence of different oxygen flow rates on the reaction was studied, and the results are shown in Table 6.

[0039] Table 6. Comparison table for testing the influence effect of the oxygen flow rate

[0040] From the above results, it can be seen that when the flow rate of ilaprazole thioether alkaline solution is 7 mL / min in Example 1, the yield of ilaprazole sodium is the highest (No. 3).

[0041] The above are only the preferred embodiments of the present invention, and do not impose any form of limitation on the present invention. Any person skilled in the art, without departing from the scope of the technical solution of the present invention, based on the technical essence of the present invention, any simple modification, equivalent replacement and improvement made to the above embodiments, etc., still fall within the protection scope of the technical solution of the present invention.

Claims

1. A method for preparing ilaprazole sodium by a continuous flow method, characterized in that, It includes the following steps: (1) Add ilaprazole thioether, sodium hydroxide solution and an iron catalyst to acetone to obtain an ilaprazole thioether alkaline solution; (2) Pass the ilaprazole thioether alkaline solution and oxygen through a flowmeter into a tubular reactor respectively. The reaction solution in the tubular reactor reacts at 40 - 60 °C and 0.6 - 1.4 MPa, and collect the discharged liquid; (3) Evaporate the discharged liquid obtained in step (2) to dryness, add the obtained residue to ethyl acetate, carry out pulping, filtration and drying to obtain ilaprazole sodium; The iron catalyst is selected from any one of ferric chloride, iron stearate, iron acetate, ferrocene, tricarbonylcyclooctatetraenyliron, iron acetylacetonate, iron dinonylcarbonyl; 2. The method according to claim 1, characterized in that In step (1), the iron catalyst is tricarbonylcyclooctatetraenyliron; 3. The method according to claim 1, characterized in that, In step (1), the mass of the iron catalyst is 0.1 - 0.5% of the mass of ilaprazole thioether; 4. The method according to claim 1, characterized in that, In step (1), the mass of the acetone is 8 times the mass of ilaprazole thioether, the sodium hydroxide solution is 30% aqueous sodium hydroxide solution, and the mass of the sodium hydroxide solution is 2 times the mass of ilaprazole thioether; 5. The method according to claim 1, wherein In step (2), the reaction temperature of the tubular reactor is 50 °C and the reaction pressure is 1.2 MPa; 6. The method according to claim 1, characterized in that In step (2), the flow rate of the ilaprazole thioether alkaline solution is 4 - 8 mL / min; 7. The method according to claim 6, characterized in that, In step (2), the flow rate of the ilaprazole thioether alkaline solution is 7 mL / min; 8. The method according to claim 1, wherein In step (2), the oxygen flow rate is 300 - 700 SCCM, and the residence time of the reaction solution in the reactor is 4 - 7 min; 9. The method according to claim 8, wherein In step (2), the oxygen flow rate is 500 SCCM; 10. The method according to claim 1, wherein In step (3), step (3) specifically includes: evaporate the excluded liquid to dryness and then add it to ethyl acetate. The mass of the ethyl acetate is equal to that of the acetone in step (1), carry out pulping for one hour, filter, and vacuum dry the solid at 50 °C.

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