A preparation method for degrading impurities from esomeprazole magnesium

Abstract

The invention discloses a method for preparing esomeprazole magnesium degradation impurities, comprising: oxidizing 3,5-dimethyl-2-hydroxymethyl-4-pyridone to obtain 3,5-dimethyl-2-carboxyl-4-pyridone; in the presence of an inorganic base, condensing 3,5-dimethyl-2-carboxyl-4-pyridone and 2-chloro-5-methoxybenzimidazole; adjusting the pH of the reaction solution to 6-7; filtering; drying the wet product to obtain a crude esomeprazole magnesium degradation impurity product; and recrystallizing the crude product from an alcohol-water mixed solution to obtain a refined esomeprazole magnesium degradation impurity product. The method first performs site-specific oxidation of the 2-position alcoholic hydroxyl group of 3,5-dimethyl-2-hydroxymethyl-4-pyridone to a 2-position aldehyde group, and then site-specifically oxidizing the 2-position aldehyde group to a 2-position carboxyl group. The two-step oxidation process does not affect the C=C double bond in the pyridone. The method of the present invention is used to prepare esomeprazole magnesium by degrading impurities, with a total yield of more than 60% and a purity of more than 99%.

Description

Technical Field

[0001] The invention belongs to the field of raw material medicine preparation and relates to a preparation method of esomeprazole magnesium by degradation of impurities. Background Art

[0002] Esomeprazole is a proton pump inhibitor that inhibits H + / K + -ATPase to reduce gastric acid secretion and prevent the formation of gastric acid, for the initial and long-term treatment of gastroesophageal reflux disease (GORD) including erosive reflux esophagitis (including erosive esophagitis).

[0003] Esomeprazole magnesium is the magnesium salt of esomeprazole. Astra Corporation states in CN1110477A that the sodium and magnesium salts are the most effective esomeprazole salts. Lin Qing, in "Preparation, Characterization, and Interconversion of Esomeprazole Magnesium Polymorphs," demonstrates that esomeprazole magnesium trihydrate is the most stable of the magnesium salts. Its chemical name is bis-(S)-5-methoxy-2-(((4-methoxy-3,5-dimethyl-2-pyridyl)methyl)sulfinyl)-1H-benzimidazole magnesium trihydrate, CAS: 161973-10-0.

[0004] In order to ensure the safety and effectiveness of drugs, it is necessary to study, detect and monitor the relevant substances in the drugs. The relevant substances are mainly process by-products and degradation products. The impurity spectrum of drugs changes during storage. Figure 1 As shown, esomeprazole or its salt will degrade to produce impurities with a structure as shown in Formula V, whose molecular formula is C 16 H 15 N3O4, molecular weight is 313.31, chemical name: 1,4-dihydro-1-(6-methoxy-1H-benzimidazol-2-yl)-3,5-dimethyl-4-oxo-2-pyridinecarboxylic acid.

[0005]

[0006] Currently, this degradation impurity is mainly obtained by preparative liquid phase separation of omeprazole degradation products, such as EP2189456A1, J. Pharmaceut. Biomed. 118 (2016) 370-379, but this method has low production capacity and high cost. Therefore, the targeted synthesis of this impurity is of great significance.

[0007] Chinese patent application CN112321562A reports a method for preparing the degradation impurity, wherein omeprazole sodium bicarbonate dry suspension is destroyed at high temperature under alkaline conditions to obtain a small amount of the impurity, which is then subjected to gradient elution to obtain a pure product of the degradation impurity.

[0008] The preparation method is complicated, the amount of impurities obtained by alkali destruction is small, the gradient elution procedure is complicated, and the practical application value is low.

[0009]

[0010] Similarly, Chinese patent application CN114409631A reports a method for preparing this degradation impurity. The method involves dissolving esomeprazole in an organic solvent, adding an appropriate amount of hydrochloric acid to accelerate its degradation, and finally isolating the intermediate 8-(or 9)methoxy-1,3-dimethyl-12-thiopyrido[1,2:3,4]-imidazo[1,2-a]benzimidazol-2(1,2H)-one. This intermediate is then subjected to alkaline decomposition to obtain the pure degradation impurity. This preparation method is relatively inefficient, resulting in poorly purified impurities from acid-base destruction, poor separation efficiency from preparative columns, and low practical application value.

[0011] Summary of the Invention

[0012] The present invention aims to abandon the traditional acid-base destruction method and use chemical synthesis to prepare high-purity esomeprazole magnesium degradation impurities (Compound V). The method has mild reaction conditions and uses a two-step special oxidation reagent to oxidize the alcohol group and the aldehyde group without affecting the double bond in the structural formula, thereby improving the purity and yield of the product and enabling the esomeprazole magnesium degradation impurities to be used as reference substances in impurity detection.

[0013] The purpose of the present invention is achieved through the following technical solutions:

[0014] A method for preparing esomeprazole magnesium by degradation of impurities, the synthetic route of the method is as follows:

[0015]

[0016] The method comprises the following steps: 3,5-dimethyl-2-hydroxymethyl-4-pyridone (Compound I) is oxidized to obtain 3,5-dimethyl-2-carboxyl-4-pyridone (Compound III); in the presence of an inorganic base, 3,5-dimethyl-2-carboxyl-4-pyridone and 2-chloro-5-methoxybenzimidazole (Compound IV) undergo a condensation reaction, the pH of the reaction solution is adjusted to 6-7, and a wet product is obtained by filtration. The wet product is dried to obtain a crude product of esomeprazole magnesium degradation impurities having a structure shown in Formula V, and the crude product is recrystallized from an alcohol-water mixed solution to obtain a refined product of esomeprazole magnesium degradation impurities.

[0017] Specifically, the method for preparing esomeprazole magnesium by degrading impurities according to the present invention comprises the following steps:

[0018] Step (1), using 3,5-dimethyl-2-hydroxymethyl-4-pyridone as a starting material, in the presence of an oxidant, undergoing an oxidation reaction to obtain 3,5-dimethyl-2-aldehyde-4-pyridone (Compound II);

[0019] Step (2), 3,5-dimethyl-2-aldehyde-4-pyridone (Compound II) and an oxidant are further oxidized to obtain 3,5-dimethyl-2-carboxyl-4-pyridone;

[0020] Step (3), in the presence of an inorganic base, condensing 3,5-dimethyl-2-carboxyl-4-pyridone with 2-chloro-5-methoxybenzimidazole, adjusting the pH of the reaction solution to 6-7, filtering to obtain a wet product, and drying the wet product under reduced pressure to obtain a crude product of degraded impurities of esomeprazole magnesium;

[0021] Step (4), the crude product of esomeprazole magnesium degraded impurities is recrystallized from a mixed solution of alcohol and water to obtain a refined product of compound V.

[0022] In step (1), the reaction solvent is dichloromethane, toluene, chloroform, etc., preferably dichloromethane.

[0023] The molar ratio of the 3,5-dimethyl-2-hydroxymethyl-4-pyridone (Compound I) to the oxidant is 1:1 to 1:2.5, preferably 1:2.

[0024] The oxidant is pyridinium chlorochromate (PCC), manganese dioxide, or dicyclohexylcarbodiimide (DCC). Manganese dioxide can specifically oxidize the 2-hydroxyl group of 3,5-dimethyl-2-hydroxymethyl-4-pyridone to the 2-aldehyde group. However, as it is a heavy metal oxidant, post-processing is cumbersome and generates solid waste. Therefore, the oxidant is preferably pyridinium chlorochromate.

[0025] The temperature of the oxidation reaction is 10-40°C, preferably 20-30°C.

[0026] Specifically, after the reaction is completed, a saturated aqueous sodium sulfite solution is added dropwise to the reaction solution, stirred, separated, and the organic phase is collected. The organic phase is washed with saturated brine and dried over anhydrous sodium sulfate, and then distilled until a large amount of solid is precipitated. The wet product is filtered to obtain a product, which is dried to obtain 3,5-dimethyl-2-aldehyde-4-pyridone.

[0027] In step (2), the reaction solvent is dichloromethane, DMSO, toluene, tetrahydrofuran, etc. or a mixed solvent of one of dichloromethane, DMSO, toluene, tetrahydrofuran and water, and the mass ratio of one of dichloromethane, DMSO, toluene, tetrahydrofuran and water is 1:6 to 1:6.5, preferably tetrahydrofuran or a mixed solvent of tetrahydrofuran and water.

[0028] The molar ratio of the 3,5-dimethyl-2-formyl-4-pyridone to the oxidant is 1:1 to 1:3, preferably 1:3.

[0029] The oxidant is Tollens reagent (ammonia solution of silver nitrate) or Fehling's reagent (sodium potassium tartrate solution of copper sulfate, with Cu 2+ Fehling's reagent is preferred.

[0030] When Fehling's reagent is used as the oxidant, specifically: 3,5-dimethyl-2-formyl-4-pyridone is dissolved in a reaction solvent, Fehling's reagent is added dropwise under stirring, and the temperature is increased to carry out an oxidation reaction.

[0031] The temperature of the oxidation reaction is 30-60°C, preferably 40-50°C.

[0032] Specifically, after the reaction is completed, activated carbon is added to the reaction solution, the mixture is stirred and then filtered, the filtrate is collected, the solvent is distilled off under reduced pressure, and then dried under reduced pressure to obtain 3,5-dimethyl-2-carboxyl-4-pyridone; wherein the mass ratio of activated carbon to 3,5-dimethyl-2-aldehyde-4-pyridone is 1:100 to 3:100.

[0033] In step (3), the reaction solvent is acetone, toluene, DMF, etc. or a mixed solvent of one of acetone, toluene, DMF and water, and the mass ratio of one of acetone, toluene, DMF and water is 6:1 to 8:1. Preferably, the reaction solvent is acetone or a mixed solvent of acetone and water.

[0034] The molar ratio of 3,5-dimethyl-2-carboxyl-4-pyridone to 2-chloro-5-methoxybenzimidazole is 1:1 to 1.5, preferably 1:1.5.

[0035] The inorganic base is sodium hydroxide, potassium hydroxide, potassium tert-butoxide, etc., preferably sodium hydroxide.

[0036] The molar ratio of the 3,5-dimethyl-2-carboxyl-4-pyridone to the inorganic base is 1:1.0-3.0, preferably 1:2.5.

[0037] Preferably, in order to precipitate more esomeprazole magnesium degradation impurities from the reaction solution, after the reaction is completed, the pH of the reaction solution is adjusted to 6-7, and then the temperature is lowered to 0-5°C.

[0038] Preferably, glacial acetic acid is used to adjust the pH of the reaction solution to 6-7.

[0039] In step (4), the recrystallization is as follows: the crude product of esomeprazole magnesium degradation impurities is mixed with an alcohol-water mixed solution, the temperature is raised to 55±5°C, stirred until dissolved, and then cooled to 10-15°C for recrystallization, filtered, and the solid is dried at 40-60°C to obtain a refined product of esomeprazole magnesium degradation impurities. The mass ratio of the crude product of esomeprazole magnesium degradation impurities to the alcohol-water mixed solution is 1:6-1:8, preferably 1:7.5; the alcohol-water mixed solution is prepared by mixing anhydrous ethanol and water in a mass ratio of 3:1-1.5:1, preferably 2:1.

[0040] Beneficial effects of the present invention:

[0041] The preparation method of the present invention is simple. First, a highly selective oxidant is used to site-specifically oxidize the 2-position alcoholic hydroxyl group of 3,5-dimethyl-2-hydroxymethyl-4-pyridone to a 2-position aldehyde group. Then, a highly selective oxidant is used to site-specifically oxidize the 2-position aldehyde group to a 2-position carboxyl group. The two-step oxidation process does not affect the C=C double bond in the pyridone, thereby avoiding the ring opening of the pyridone. Finally, a crude product is obtained through a condensation reaction, and an ethanol aqueous solution is used as a recrystallization solvent. The purity of the product is further improved through recrystallization.

[0042] The method of the present invention is used to prepare the degradation impurities of esomeprazole magnesium, with a total yield of more than 60% and a purity of more than 99%. The prepared impurities can be used as a reference substance in the detection of the degradation impurities of esomeprazole magnesium. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 This is the degradation mechanism diagram of esomeprazole magnesium impurities.

[0044] Figure 2 This is the UV scanning spectrum of degradation impurities of esomeprazole magnesium. DETAILED DESCRIPTION

[0045] The technical solution of the present invention is further described below in conjunction with specific implementation methods, but is not limited to the essence of the present invention.

[0046] Example 1

[0047] Preparation of 3,5-dimethyl-2-formyl-4-pyridone (Compound II)

[0048]

[0049] 15.3 g (0.1 mol) of 3,5-dimethyl-2-hydroxymethyl-4-pyridone (Compound I) was added to a 500 mL reaction flask, and 150 mL of dichloromethane was added. The temperature was lowered to -5 to 0°C, and a dichloromethane solution of PCC (43.1 g (0.2 mol) PCC, 50 mL of dichloromethane) was added dropwise with stirring. The temperature was raised to 20 to 30°C, and the reaction was kept warm until the reaction was completed as detected by TLC. 100 mL of saturated aqueous sodium sulfite solution was added dropwise to the reaction solution, and after stirring for 30 minutes, the liquids were separated, and the dichloromethane phase was collected. The solution was first washed with 100 mL of saturated brine and then dried over anhydrous sodium sulfate. The dichloromethane phase was distilled until a large amount of solid was precipitated. The wet product was filtered and dried to obtain 13.9 g of Compound II with a yield of 92.0%.

[0050] Preparation of 3,5-dimethyl-2-carboxy-4-pyridone (Compound III)

[0051]

[0052] In a 250 mL reaction flask, add 7.6 g (0.05 mol) of compound II, add 150 mL of tetrahydrofuran, and add 950 mL of Fehling's reagent (in the form of Cu 2+ The reaction mixture was stirred for 2 h, the molar ratio of the oxidant to the compound II was 3:1), the temperature was raised to 40-50°C, and the reaction was kept warm until the reaction was completed by TLC. 0.2 g of activated carbon was added to the reaction solution, and the mixture was stirred and filtered. The filter cake was discarded, and the filtrate was collected. The solvent was distilled from the filtrate under reduced pressure to dryness to obtain a wet product of compound III, which was then dried under reduced pressure to obtain about 7.9 g of compound III with a yield of 95.0%.

[0053] Preparation of crude compound V

[0054]

[0055] 6.7 g (0.04 mol) of compound III was added to a 250 mL four-necked flask, and 70 g of acetone was added. A sodium hydroxide aqueous solution (4 g (0.1 mol) of sodium hydroxide, 10 g of drinking water) was added with stirring. After the addition was completed, the mixture was stirred for 30 min. 11 g (0.06 mol) of compound IV was added to the system, and the condensation reaction was carried out at a temperature of 30-40 ° C. When TLC detection showed that the reaction was complete, glacial acetic acid was added dropwise to a pH value of 6. After continuing to stir for 1 h, the temperature was lowered to 0-5 ° C. and 14.8 g of wet compound V was obtained by filtration. After drying under reduced pressure at 40 ° C, 11.2 g of a crude product was obtained with a purity of 88.70% and a yield of 79.3%.

[0056] recrystallization

[0057] 11.2 g of the obtained crude compound V was added to a 250 mL single-necked flask, and a total of 84 g of ethanol-water solution (56 g of ethanol and 28 g of drinking water) was added. The temperature was raised to 50-60° C. and stirred until dissolved. The temperature was slowly lowered to 10-15° C. and crystallized for 2 h. The light yellow solid was filtered and dried under reduced pressure at 50° C. to obtain 8.8 g of refined compound V with a purity of 99.91%. The yield of this step was 88.5%, and the total yield of refined compounds I to compound V was 61.3%.

[0058] ESI-MS: m / z 314.46[M+H] + The hydrogen spectrum of compound V is shown in Table 1; the UV scanning spectrum of compound V is shown in Figure 2 , with maximum absorption at 303.50nm and 200.50nm.

[0059]

[0060] Table 1. Proton spectrum data of compound V

[0061] Chemical shift (ppm) Proton type Peak shape Attribution H number 1.82 <![CDATA[2CH3]]> S peak Hydrogen at positions 8 and 9 3.78 <![CDATA[CH3]]> S peak Hydrogen at position 20 6.83 ArH dd peak Hydrogen at position 17 7.06 ArH d peak Hydrogen at position 15 7.43 ArH d peak Hydrogen at position 18 7.81 ArH S peak 5-Hydrogen 8.32 <![CDATA[NH4 + ]]> br peak 1 hydrogen

[0062] Example 2

[0063] The crude compound V (88.70% purity) was added to a 250 mL single-necked flask. An ethanol solution was added at a mass ratio of 1:7.5 between the crude compound V and the ethanol solution (see Table 2 for the mass ratio of ethanol to drinking water). The temperature was raised to 50-60°C and stirred until the solution became clear. The temperature was slowly lowered to 10-15°C and crystallized for 2 hours. The solid was filtered to obtain a pale yellow solid, which was then dried under reduced pressure at 50°C. The purity and yield of the refined compound V are shown in Table 2. Taking all factors into consideration, an ethanol solution composed of anhydrous ethanol and water in a mass ratio of 3:1 to 1.5:1 was the preferred recrystallization solvent, and an ethanol solution in a mass ratio of 2:1 was particularly preferred.

[0064] Table 2. Effect of the mass ratio of ethanol to water in ethanol-water solution on recrystallization

[0065] Serial number <![CDATA[m 乙醇 :m 水 ]]> Purity of Compound V Yield of compound V 1 1:1 99.80％ 92.7％ 2 2:1 99.91％ 88.5％ 3 3:1 99.92％ 81.2％ 4 4:1 99.94％ 76.9％

Claims

1. A method for preparing esomeprazole magnesium by degrading impurities, characterized in that: The synthetic route is as follows: The steps include: Step (1), using 3,5-dimethyl-2-hydroxymethyl-4-pyridone as a starting material, and subjecting it to an oxidation reaction in the presence of an oxidant to obtain 3,5-dimethyl-2-aldehyde-4-pyridone; the oxidant is pyridinium chlorochromate; Step (2), 3,5-dimethyl-2-aldehyde-4-pyridone and an oxidant undergo an oxidation reaction to obtain 3,5-dimethyl-2-carboxyl-4-pyridone; the oxidant is Tollens reagent or Fehling's reagent; Step (3), in the presence of an inorganic base, condensing 3,5-dimethyl-2-carboxyl-4-pyridone with 2-chloro-5-methoxybenzimidazole, adjusting the pH of the reaction solution to 6-7, filtering to obtain a wet product, and drying the wet product under reduced pressure to obtain a crude product of degraded impurities of esomeprazole magnesium; Step (4), the crude product of esomeprazole magnesium degradation impurities is recrystallized from an alcohol-water mixed solution to obtain a refined product of esomeprazole magnesium degradation impurities.

2. The method for preparing esomeprazole magnesium by degradation of impurities according to claim 1, wherein: In step (1), the reaction solvent is dichloromethane, toluene, or chloroform; in step (2), the reaction solvent is dichloromethane, DMSO, toluene, tetrahydrofuran, or a mixed solvent of one of dichloromethane, DMSO, toluene, or tetrahydrofuran and water, and the mass ratio of one of dichloromethane, DMSO, toluene, or tetrahydrofuran to water is 1:6 to 1:6.

5.

3. The method for preparing esomeprazole magnesium by degradation of impurities according to claim 2, wherein: In step (1), the reaction solvent is dichloromethane; in step (2), the reaction solvent is tetrahydrofuran or a mixed solvent of tetrahydrofuran and water.

4. The method for preparing esomeprazole magnesium by degradation of impurities according to claim 1, wherein: In step (1), the molar ratio of the 3,5-dimethyl-2-hydroxymethyl-4-pyridone to the oxidant is 1:1 to 1:2.5; in step (2), the molar ratio of the 3,5-dimethyl-2-aldehyde-4-pyridone to the oxidant is 1:1 to 1:

3.

5. The method for preparing esomeprazole magnesium by degradation of impurities according to claim 4, wherein: In step (1), the molar ratio of the 3,5-dimethyl-2-hydroxymethyl-4-pyridone to the oxidant is 1:2; in step (2), the molar ratio of the 3,5-dimethyl-2-aldehyde-4-pyridone to the oxidant is 1:

3.

6. The method for preparing esomeprazole magnesium by degrading impurities according to claim 1, wherein: In step (1), the temperature of the oxidation reaction is 10-40°C; in step (2), the temperature of the oxidation reaction is 30-60°C.

7. The method for preparing esomeprazole magnesium by degrading impurities according to claim 6, wherein: In step (1), the temperature of the oxidation reaction is 20-30°C; in step (2), the temperature of the oxidation reaction is 40-50°C.

8. The method for preparing esomeprazole magnesium by degrading impurities according to claim 1, wherein: In step (2), after the reaction is completed, activated carbon is added to the reaction solution, the mixture is stirred and then filtered, the filtrate is collected, the solvent is distilled off under reduced pressure, and then dried under reduced pressure to obtain 3,5-dimethyl-2-carboxyl-4-pyridone; wherein the mass ratio of activated carbon to 3,5-dimethyl-2-aldehyde-4-pyridone is 1:100 to 3:

100.

9. The method for preparing esomeprazole magnesium by degrading impurities according to claim 1, wherein: In step (3), the reaction solvent is acetone, toluene, DMF or a mixed solvent of one of acetone, toluene, DMF and water, and the mass ratio of one of acetone, toluene, DMF and water is 6:1 to 8:

1.

10. The method for preparing esomeprazole magnesium by degrading impurities according to claim 9, characterized in that: In step (3), the reaction solvent is acetone or a mixed solvent of acetone and water.

11. The method for preparing esomeprazole magnesium by degrading impurities according to claim 1, wherein: In step (3), the molar ratio of 3,5-dimethyl-2-carboxyl-4-pyridone to 2-chloro-5-methoxybenzimidazole is 1:1 to 1.5; The inorganic base is sodium hydroxide, potassium hydroxide, or potassium tert-butoxide; The molar ratio of the 3,5-dimethyl-2-carboxyl-4-pyridone to the inorganic base is 1:1.0-3.

0.

12. The method for preparing esomeprazole magnesium by degrading impurities according to claim 11, characterized in that: In step (3), the molar ratio of 3,5-dimethyl-2-carboxyl-4-pyridone to 2-chloro-5-methoxybenzimidazole is 1:1.

5.

13. The method for preparing esomeprazole magnesium by degrading impurities according to claim 11, characterized in that: In step (3), the inorganic base is sodium hydroxide.

14. The method for preparing esomeprazole magnesium by degrading impurities according to claim 11, characterized in that: In step (3), the molar ratio of 3,5-dimethyl-2-carboxyl-4-pyridone to the inorganic base is 1:2.

5.

15. The method for preparing esomeprazole magnesium by degrading impurities according to claim 1, characterized in that: In step (4), the recrystallization comprises the following steps: mixing the crude product of esomeprazole magnesium degradation impurities with an alcohol-water mixed solution, heating the mixture to 55±5°C, stirring until the mixture is clear, then cooling the mixture to 10-15°C for recrystallization, filtering, and drying the solid at 40-60°C to obtain a refined product of esomeprazole magnesium degradation impurities; wherein the mass ratio of the crude product of esomeprazole magnesium degradation impurities to the alcohol-water mixed solution is 1:6-1:8; and the alcohol-water mixed solution is prepared by mixing anhydrous ethanol and water in a mass ratio of 3:1-1.5:

1.

16. The method for preparing esomeprazole magnesium by degrading impurities according to claim 15, characterized in that: In step (4), the mass ratio of the crude product of esomeprazole magnesium degradation impurities to the alcohol-water mixed solution is 1:7.

5.

17. The method for preparing esomeprazole magnesium by degrading impurities according to claim 15, characterized in that: In step (4), the alcohol-water mixed solution is prepared by mixing anhydrous ethanol and water in a mass ratio of 2:1.

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