CN106045975A - A preparing method for high-purity ilaprazole sodium - Google Patents

Abstract

The invention provides a kind of preparation method of high-purity ilaprazole sodium, comprising the following steps: 1) 5-(1H-pyrrole-1-yl)-2-[[(4-methoxy-3-methyl Base)-2-pyridyl]-methyl]-sulfinyl-1H-benzimidazole crude product is dissolved in an organic solvent, added an inorganic base to form a salt, and filtered to obtain 5-(1H-pyrrole-1-yl)- 2‑[[(4‑methoxy‑3‑methyl)‑2‑pyridyl]‑methyl]‑sulfinyl‑1H‑benzimidazolium salt (A); 2) A is dissolved in an organic solvent, Use acid to adjust the pH to weak alkaline to prepare high-purity 5-(1H-pyrrole-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl ]-sulfinyl-1H-benzimidazole (B); 3) reacting the prepared B with a sodium-containing compound in an aqueous solvent to prepare ilaprazole sodium.

Description

A kind of preparation method of high-purity ilaprazole sodium

technical field

The invention relates to the field of medicine preparation, in particular to a method for refining ilaprazole sodium.

Background technique

5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl]-sulfinic acid is described in Chinese patent CN94191913.7 The synthetic method of acyl-1H-benzimidazole, the synthetic method uses chloroform as a solvent, m-chloroperoxybenzoic acid as an oxidizing agent to oxidize 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy -3-methyl)-2-pyridyl]-methyl]-mercapto-1H-benzimidazole to prepare 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3- Methyl)-2-pyridyl]-methyl]-sulfinyl-1H-benzimidazole. The synthetic route is as follows:

However, this route is prone to peroxidative side reactions in the middle of the oxidation process, resulting in the formation of peroxysulfonyl compounds that are difficult to remove. In the current technology, there is no preparation method that can effectively remove impurities and obtain high-purity ilaprazole sodium salt.

Contents of the invention

The present invention provides a refined 5-(1H-pyrrol-1-yl)-2-[[(4-methoxyl-3-methyl)-2 -pyridyl]-methyl]-sulfinyl-1H-benzimidazole sodium (ilaprazole sodium) method.

To achieve the above object, the present invention adopts the following technical solutions, including steps:

(1) 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl]-sulfinyl-1H-benzene The crude imidazole was dissolved in organic solvent A, added with inorganic base to form a salt, and filtered to obtain 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2- Pyridyl]-methyl]-sulfinyl-1H-benzimidazolium salt;

(2) 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl]-sulfinyl-1H-benzene Dissolve imidazolium salt in organic solvent B, adjust the pH to weak alkalinity with pH regulator acid, and obtain high-purity 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3- Methyl)-2-pyridyl]-methyl]-sulfinyl-1H-benzimidazole;

(3) The obtained high-purity 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl]-sulfinic acid Acyl-1H-benzimidazole reacts with a sodium-containing compound in an aqueous solvent to prepare ilaprazole sodium.

Concrete synthetic route is as follows:

The organic solvent A used in the above-mentioned step (1) comprises methyl alcohol, ethanol, Virahol, xylene, toluene, tetrahydrofuran, 1,2-dichloroethane, acetone, ether, dichloromethane, acetonitrile, dimethyl ethylene One or more of sulfone and N,N-dimethylacetamide. Methanol and ethanol are preferred.

The reaction temperature range in the above step (1) is 0-100°C. The room temperature of 25°C is preferred.

The inorganic base used in the above step (1) includes one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide. Sodium hydroxide and potassium hydroxide are preferred.

The organic solvent B used in the above-mentioned step (2) comprises methyl alcohol, ethanol, Virahol, xylene, toluene, THF, 1,2-dichloroethane, acetone, ether, dichloromethane, acetonitrile, dimethyl ethylene One or more of sulfone and N,N-dimethylacetamide. Ethanol is preferred.

The reaction temperature range in the above step (2) is 0-100°C. 25°C is preferred.

Adjust pH to 7.5-9.5 in the above-mentioned step (2), optimally is 9.0; The acid of pH adjuster can be benzoic acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, chloroacetic acid, isooctanoic acid, butyric acid, methanesulfonic acid One or more of them, preferably acetic acid ethanol solution. In this reaction, the adjustment and adjustment rate of pH are very important. If the pH value after acid adjustment is too high, some ilaprazole sodium salts will be precipitated and the product yield will be reduced; and if the pH value is too low, degradation products will be generated. Impurities are formed. Compared with other acids, acetic acid will not destroy ilaprazole due to low local pH value during the process of pH adjustment.

The refining method of the present invention can effectively remove the peroxysulfonyl compound produced by the side reaction, so that the prepared 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl )-2-pyridyl]-methyl]-sulfinyl-1H-benzimidazole has high product purity; the refining process is simple and easy, and the yield is high; it is environmentally friendly and has no pollution to the environment.

Specifically, the invention patent has the following advantages:

1. High product quality. The purity of the product is greater than 99.5%, which can effectively remove 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl]-sulfinic acid 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl] produced during the preparation of acyl-1H-benzimidazole -Sulfonyl-1H-benzimidazole and other impurities.

2. The reaction conditions are mild and the operation is simple. In the refining process, the temperature required for the reaction is room temperature, and the process operation is simple.

3. Green and environmental protection. The refining process does not use highly toxic reagents, and the reagents used have little environmental pollution and are easy to handle.

Therefore, the patent of the present invention can effectively improve 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl]-sulfinic acid The quality of acyl-1H-benzimidazole has practical application significance.

specific embodiment

Example 1: 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl]-sulfinyl-1H-benzene Preparation of imidazole potassium salt

Add methanol (110mL) and potassium hydroxide (3.1g) to a 250mL three-necked flask, stir to dissolve and clarify, then add 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3- Methyl)-2-pyridyl]-methyl]-sulfinyl-1H-benzimidazole (20 g), and the mixture was stirred at 25° C. for 18 hours. The mixture was filtered, the filter cake was washed with methanol (20mL*2), and the collected solid was dried at 40°C for 4 hours to obtain 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3 -Methyl)-2-pyridyl]-methyl]-sulfinyl-1H-benzimidazole potassium salt (20.0 g), yield: 90%.

Example 2: 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl]-sulfinyl-1H-benzene Preparation of imidazole sodium salt

Add organic solvent A (110mL) and sodium hydroxide (2.2g) to a 250mL three-necked flask, stir to dissolve and clarify, then add 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy- 3-methyl)-2-pyridyl]-methyl]-sulfinyl-1H-benzimidazole (20 g), and the mixture was stirred at a specific temperature for 18 hours. The mixture was filtered, the filter cake was washed with methanol (20mL*2), and the collected solid was dried at 40°C for 4 hours to obtain 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3 -methyl)-2-pyridyl]-methyl]-sulfinyl-1H-benzimidazole sodium salt, specifically as shown in Table 1:

Table 1: Comparison of experimental results of organic solvent A and reaction temperature

serial number Organic solvent A Reaction temperature (°C) Product yield (%) 1 Methanol 25 92 2 ethanol 25 91.3 3 Dimethyl sulfoxide 40 61

As shown in the table above, the organic solvent A is preferably methanol or ethanol, and the reaction temperature is preferably 25°C.

Example 3: 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl]-sulfinyl-1H-benzene Preparation of imidazole

Add ethanol (200mL) to a 500mL three-necked flask, 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl] -Sulfinyl-1H-benzimidazole potassium salt (10g), add 10% acetic acid ethanol solution dropwise at 25°C to adjust the pH value to 9.0, let stand for 30 minutes and filter, filter cake with ethanol aqueous solution (50%, 30mL* 2) 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl] after washing and drying at 30°C -Sulfinyl-1H-benzimidazole (7.4 g, white solid), yield: 82%, purity: 99.2%.

Example 4: 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl]-sulfinyl-1H-benzene Preparation of imidazole

In a 500mL three-necked flask, organic solvent B (200mL), 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl Base]-sulfinyl-1H-benzimidazole potassium salt (10g), drop a pH regulator at 25°C, adjust the pH value to 9.0, filter after standing for 30 minutes, filter cake with ethanol aqueous solution (50%, 30mL *2) 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl after washing and drying at 30°C ]-sulfinyl-1H-benzimidazole, specifically as shown in Table 2:

Table 2: Comparison of experimental results of organic solvent B and pH regulator

serial number Organic solvent B pH regulator Product yield (%) Product yield (%) 1 ethanol 10% acetic acid ethanol solution 82 99.2 2 ethanol 10% sulfuric acid ethanol solution 78 93.1 3 ethanol 10% ethanol hydrochloric acid solution 68 92.5 4 Methanol 10% acetic acid ethanol solution 75 99.0 5 Acetonitrile 10% acetic acid ethanol solution 72 98.5

As shown in the table above, the organic solvent B is preferably ethanol, and the pH regulator is preferably acetic acid ethanol solution.

Embodiment 5: the influence of pH regulation on experimental result

Add ethanol (200mL) to a 500mL three-necked flask, 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl] -Sulphinyl-1H-benzimidazole sodium salt (10g), add 10% acetic acid ethanol solution dropwise at room temperature to adjust the pH value, then let it stand for 30 minutes and filter, and filter the cake with ethanol aqueous solution (50%, 30mL*2) After washing, the 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl]-ylidene Sulfonyl-1H-benzimidazole (7.3g, white solid), specifically as shown in Table 3:

Table 3: Comparison of adjusted pH value and experimental results

Conclusion: From the results in the table above, it can be seen that when the adjusted pH is as low as 6.5, the product yield and product purity are low; when the adjusted pH is as high as 10.5, the product yield should drop significantly. And when the pH after adjustment is 7.5-9.5, the yield of the product and the purity of the product are all in a better range, meeting the production requirements.

Embodiment 6 Preparation of ilaprazole sodium salt

Take the product prepared in the above-mentioned Example 4: 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl]- Add 10.0g (0.0273mol) of sulfinyl-1H-benzimidazole to 50ml of methanol, add 1.09g (0.0273mol) of sodium hydroxide, stir at room temperature for 2 hours, concentrate, add n-butanol, add isopropyl ether to crystallize at room temperature , the obtained product was dried under reduced pressure at 60° C. to obtain white crystals, i.e. ilaprazole sodium 9.5 g, yield: 90%, content: 99.8%.

Example 7 Preparation of ilaprazole sodium salt

Take the product prepared in Example 5 above: 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl]- Add 10.0 g (0.0273 mol) of sulfinyl-1H-benzimidazole to 50 ml of methanol, heat up to 50 ° C, add 4.92 g (0.0273 mol) of methanol solution containing 30% (weight) sodium methoxide, stir for 2 hours, and cool to 0°C, filtered, and the obtained product was dried under reduced pressure at 60°C to obtain white crystals, i.e. ilaprazole sodium 9.33g, yield: 88%, content: 99.9%.

Claims (10)

1. a preparation method of high-purity ilaprazole sodium, comprising the steps of: 1) 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl]-sulfinyl-1H-benzo Crude imidazole was dissolved in organic solvent A, added with inorganic base to form a salt, and filtered to obtain 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridine Base]-methyl]-sulfinyl-1H-benzimidazolium salt; 2) 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl]-sulfinyl-1H-benzo Dissolve imidazolium salt in organic solvent B, use pH adjuster, adjust pH to weak alkaline with acid, and obtain high-purity 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3- Methyl)-2-pyridyl]-methyl]-sulfinyl-1H-benzimidazole; 3) The high-purity 5-(1H-pyrrol-1-yl)-2-[[(4-methoxy-3-methyl)-2-pyridyl]-methyl]-sulfinyl -1H-benzimidazole reacts with a sodium-containing compound in an aqueous solvent to prepare ilaprazole sodium. 2. preparation method according to claim 1, is characterized in that, the organic solvent A used in described step 1) comprises methanol, ethanol, Virahol, xylene, toluene, tetrahydrofuran, 1,2-dichloro One or more of ethane, acetone, ether, dichloromethane, acetonitrile, dimethylsulfoxide, N,N-dimethylacetamide. 3. The preparation method according to claim 2, wherein the organic solvent A used in the step 1) is selected from one or both of methanol and ethanol. 4. The preparation method according to claim 3, wherein the inorganic base used in the step 1) is selected from one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide. 5. preparation method according to claim 4 is characterized in that, the inorganic base used in the described step 1) is sodium hydroxide. 6. preparation method according to claim 5, is characterized in that, the organic solvent B used in described step 2) comprises methanol, ethanol, Virahol, xylene, toluene, tetrahydrofuran, 1,2-dichloro One or more of ethane, acetone, ether, dichloromethane, acetonitrile, dimethylsulfoxide, N,N-dimethylacetamide. 7. The preparation method according to claim 6, characterized in that, the organic solvent B used in the step 2) is ethanol. 8. The preparation method according to claim 7, characterized in that the pH is adjusted to 7.5-9.5 in the step 2). 9. preparation method according to claim 8, it is characterized in that, described step 2) the acid of pH regulator can be used benzoic acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, chloroacetic acid, isooctanoic acid, butyric acid, One or more of methanesulfonic acid. 10. The preparation method according to claim 9, characterized in that, the acid of the pH regulator in the step 2) is acetic acid.