A method for preparing esomeprazole sodium by continuous flow process

Abstract

The application belongs to the technical field of medicine and chemical industry, and particularly relates to a method for preparing esilprazole sodium by a continuous flow method. The preparation method comprises the following steps: (1) adding esilprazole sulfide, a sodium hydroxide solution and an iron catalyst into acetone to obtain an esilprazole sulfide alkali liquor; (2) respectively feeding the esilprazole sulfide alkali liquor and oxygen through flowmeters into a tubular reactor to perform a reaction; and (3) adding ethyl acetate into the organic phase obtained in the step (2) after being evaporated to dryness, and then performing beating, filtering and drying to obtain esilprazole sodium solid. The continuous flow reaction process is used to replace the traditional kettle process, and oxygen is used as an oxidizing agent to perform an oxidation reaction, so that the conditions are mild, the 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 more simple, 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] In order to solve the above technical problems, the purpose of the present invention is 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:

[0007] A method for preparing ilaprazole sodium comprises the following steps:

[0008] (1) Adding ilaprazole sulfide, sodium hydroxide solution and iron catalyst to acetone to obtain ilaprazole sulfide alkali solution;

[0009] (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;

[0010] (3) The discharge liquid of step (2) was evaporated to dryness, and the resulting residue was added to ethyl acetate, beaten, filtered, and dried to obtain ilaprazole sodium;

[0011] The iron catalyst is selected from any one of ferric chloride, ferric stearate, ferric acetate, ferrocene, tricarbonylcyclooctatetraenyl iron, ferric acetylacetonate, and dinonylcarbonyl iron.

[0012] Furthermore, the iron catalyst is tricarbonylcyclooctatetraenyl iron. The carbonyl group in the tricarbonylcyclooctatetraenyl iron acts as a strong-field ligand to interact with the metal atoms, reducing the electron density of the metal atoms and enhancing their interaction ability with oxygen. At the same time, the ring structure of cyclooctatetraenyl has a steric hindrance to the substrate, thereby enabling selective catalytic oxidation.

[0013] Furthermore, the mass of the iron catalyst is 0.1 to 0.5% of the mass of ilaprazole sulfide; furthermore, the mass of the iron catalyst is 0.2% of the mass of ilaprazole sulfide. Using this dosage of iron catalyst, the product yield is the highest.

[0014] Furthermore, the mass of the acetone is 8 times the mass of ilaprazole sulfide, the sodium hydroxide solution is a 30% sodium hydroxide aqueous solution, and the mass of the sodium hydroxide solution is 2 times the mass of ilaprazole sulfide.

[0015] Furthermore, the reaction temperature is 50° C., at which the oxidation yield is the highest.

[0016] Furthermore, the reaction pressure is 1.2 MPa, and the oxidation effect is best under pressure.

[0017] Furthermore, the flow rate of the ilaprazole sulfide alkali solution is 4 to 8 mL / min.

[0018] Furthermore, the flow rate of the ilaprazole sulfide alkaline solution is 7 mL / min, at which the oxidation yield is the highest.

[0019] Furthermore, the oxygen flow rate is 300-700 SCCM.

[0020] Furthermore, the oxygen flow rate is 500 SCCM, at which the oxidation yield is the highest and no oxygen is wasted.

[0021] Furthermore, the residence time of the reaction liquid in the reactor is 4 to 7 minutes.

[0022] Furthermore, step (3) specifically includes: evaporating the drained liquid to dryness and adding it to ethyl acetate, the mass of which is equal to that of the acetone in step (1), beating for one hour, filtering, and vacuum drying the solid at 50°C.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The application adopts a continuous flow reaction process to replace a traditional tank type process, adopts oxygen as an oxidizing agent to perform an oxidation reaction, conditions are mild, process parameters are easy to control and adjust, safety is improved, reaction time is greatly shortened, reaction heat transfer effect is good, and the whole experimental operation is more simple, and the application is suitable for industrial continuous production. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 A liquid chromatogram of the obtained esiloprazole sodium solid in Example 1 of the application. DETAILED DESCRIPTION

[0026] The following examples are used to further illustrate the application, but are not further limitations of the application.

[0027] In the application, esiloprazole sodium is prepared from esiloprazole sulfide as a raw material, through a tubular reactor catalytic oxidation and optimization of key parameters, including iron catalyst dosage, reaction temperature, flow rate of each component, etc., compared with the prior art, the reaction time is greatly reduced, and the application is more suitable for industrial production.

[0028] Example 1

[0029] The preparation method of esiloprazole sodium comprises the following steps:

[0030] (1). 50.0 g of esiloprazole sulfide is added to 400 g of acetone, stirred until dissolved, then 100 g of 30% sodium hydroxide solution and 100 mg of tricarbonyl cyclooctatetraenyl iron are added to obtain esiloprazole sulfide lye;

[0031] (2). The esiloprazole sulfide lye and oxygen are respectively passed through flow meters into a tubular reactor for reaction, wherein the reaction temperature is 50 ℃, the reaction pressure is 1.2 MPa, the flow rate of the esiloprazole sulfide lye is 7 mL / min, the flow rate of the oxygen is 500 SCCM, the residence time of the reaction liquid in the reactor is 5 min, and the discharged liquid is collected;

[0032] (3). After the discharged liquid of step (2) is evaporated, 400 g of ethyl acetate is added, and the slurry is stirred for one hour, then filtered and vacuum dried at 50 ℃ to obtain esiloprazole sodium solid, the yield is 92.1%, the purity is 99.5%, and the liquid chromatogram is as shown in Figure 1 .

[0033] In the above experiment, the sources and purities of the used drugs are as follows:

[0034] Acetone (CAS number: 67-64-1) is purchased from the National Pharmaceutical Group, with a concentration of 99.5%;

[0035] Esiloprazole sulfide (CAS number: 172152-35-1) is purchased from Aladdin, with a concentration of 95%.

[0036] Sodium hydroxide (CAS No. 1310-58-3) was purchased from Aladdin with a purity of 95%;

[0037] Tricarbonylcyclooctatetraenyl iron (CAS No. 12093-05-9) was purchased from Aladdin with a purity of 96%;

[0038] Ethyl acetate (CAS No. 141-78-6) was purchased from Aladdin with a purity of 99.5%.

[0039] Example 2

[0040] The preparation method of ilaprazole sodium was carried out by changing only the type of iron catalyst, and other conditions were the same as those in Example 1. The effects of using different iron catalysts were studied, and the results are shown in Table 1:

[0041] Table 1. Comparison of the effects of different iron catalysts

[0042]

[0043] The above results indicate that the addition of an iron catalyst accelerates the reaction. When tricarbonylcyclooctatetraenyl iron from Example 1 was used, the yield of ilaprazole sodium was the highest (No. 5). This is because the carbonyl group acts as a strong-field ligand, interacting with the metal atom, reducing the electron cloud density of the central atom and enhancing its ability to interact with oxygen.

[0044] Example 3

[0045] The preparation method of ilaprazole sodium was the same as Example 1 except that only the amount of the iron catalyst was changed. The effects of using different amounts of the iron catalyst were studied, and the results are shown in Table 2.

[0046] Table 2. Comparison of the effects of different iron catalyst dosages

[0047]

[0048] From the above results, it can be seen that when the amount of iron catalyst is 0.2% as in Example 1, the yield of ilaprazole sodium is the highest (No. 2).

[0049] Example 4

[0050] The preparation method of ilaprazole sodium was the same as Example 1 except that the reaction temperature was changed. The effect of temperature on the reaction was studied, and the results are shown in Table 3.

[0051] Table 3. Comparison of reaction temperature effect test

[0052]

[0053] From the above results, it can be seen that when the reaction temperature is 50°C as in Example 1, the yield of ilaprazole sodium is the highest (No. 3).

[0054] Example 5

[0055] The preparation method of ilaprazole sodium was the same as Example 1 except that only the reaction pressure was changed. The effect of pressure on the reaction was studied, and the results are shown in Table 4.

[0056] Table 4. Comparison of reaction pressure effect test

[0057]

[0058] From the above results, it can be seen that when the reaction pressure is 1.2 MPa as in Example 1, the yield of ilaprazole sodium is the highest (No. 4).

[0059] Example 6

[0060] The preparation method of ilaprazole sodium was carried out by changing the flow rate of ilaprazole sulfide alkali solution, while other conditions were the same as those in Example 1. The effect of different flow rates of ilaprazole sulfide alkali solution on the reaction was studied, and the results are shown in Table 5.

[0061] Table 5. Comparison of the effects of ilaprazole sulfide alkali flow rate

[0062]

[0063] From the above results, it can be seen that when the flow rate of ilaprazole sulfide alkali solution is 7 mL / min as in Example 1, the yield of ilaprazole sodium is the highest (No. 4).

[0064] Example 7

[0065] The preparation method of ilaprazole sodium was the same as Example 1 except that only the oxygen flow rate was changed. The effects of different oxygen flow rates on the reaction were studied, and the results are shown in Table 6.

[0066] Table 6. Comparison of oxygen flow rate effect test results

[0067]

[0068] From the above results, it can be seen that when the flow rate of ilaprazole sulfide alkali solution is 7 mL / min as in Example 1, the yield of ilaprazole sodium is the highest (No. 3).

[0069] The above description is only a preferred embodiment of the present invention and does not constitute any form of limitation to the present invention. Any simple modification, equivalent replacement and improvement made by any technician familiar with the profession to the above embodiment without departing from the scope of the technical solution of the present invention and based on the technical essence of the present invention shall still fall within the scope of protection of the technical solution of the present invention.

Claims

1. A method for preparing ilaprazole sodium by a continuous flow process, characterized in that: The following steps are involved: (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 are introduced into a tubular reactor through flow meters, respectively. The reaction liquid in the tubular reactor is reacted at 40-60°C and 0.6-1.4 MPa, and the discharged liquid is collected; (3) evaporating the discharge liquid of step (2) to dryness, adding the obtained residue to ethyl acetate, beating, filtering, and drying to obtain ilaprazole sodium; The iron catalyst is tricarbonylcyclooctatetraenyl iron.

2. The method according to claim 1, characterized in that In step (1), the mass of the iron catalyst is 0.1 to 0.5% of the mass of ilaprazole sulfide.

3. The method according to claim 1, characterized in that In step (1), the mass of the acetone is 8 times the mass of ilaprazole sulfide, the sodium hydroxide solution is a 30% sodium hydroxide aqueous solution, and the mass of the sodium hydroxide solution is 2 times the mass of ilaprazole sulfide.

4. 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.

5. The method according to claim 1, wherein In step (2), the flow rate of the ilaprazole sulfide alkali solution is 4 to 8 mL / min.

6. The method according to claim 5, wherein In step (2), the flow rate of the ilaprazole sulfide alkali solution is 7 mL / min.

7. 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 liquid in the reactor is 4-7 min.

8. The method according to claim 7, wherein: In step (2), the oxygen flow rate is 500 SCCM.

9. The method according to claim 1, wherein In step (3), step (3) specifically includes: evaporating the excluded liquid to dryness and adding it to ethyl acetate, the mass of which is equal to that of the acetone described in step (1), beating for one hour, filtering, and vacuum drying the solid at 50°C.

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