CN116947812A - Preparation method of Esomeprazole magnesium degradation impurity - Google Patents

Preparation method of Esomeprazole magnesium degradation impurity Download PDF

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CN116947812A
CN116947812A CN202310788699.1A CN202310788699A CN116947812A CN 116947812 A CN116947812 A CN 116947812A CN 202310788699 A CN202310788699 A CN 202310788699A CN 116947812 A CN116947812 A CN 116947812A
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pyridone
dimethyl
degradation impurity
esomeprazole magnesium
reaction
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史凌云
李维思
刘垚
柳贞
张根元
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Jiangsu Zhongbang Pharmaceutical Co ltd
Nanjing Red Sun Pharmaceutical Research Institute Co ltd
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Jiangsu Zhongbang Pharmaceutical Co ltd
Nanjing Red Sun Pharmaceutical Research Institute Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

The invention discloses a preparation method of an esomeprazole magnesium degradation impurity, which comprises the following steps: oxidizing 3, 5-dimethyl-2-hydroxymethyl-4-pyridone to obtain 3, 5-dimethyl-2-carboxyl-4-pyridone; in the presence of inorganic alkali, 3, 5-dimethyl-2-carboxyl-4-pyridone and 2-chloro-5-methoxybenzimidazole undergo a condensation reaction, the pH value of the reaction solution is regulated to 6-7, the reaction solution is filtered, wet products are dried to obtain crude products of degradation impurities of the esomeprazole magnesium, and the crude products are recrystallized by an alcohol-water mixed solution to obtain refined products of degradation impurities of the esomeprazole magnesium. The invention firstly oxidizes the 2-position alcohol hydroxyl of 3, 5-dimethyl-2-hydroxymethyl-4-pyridone into 2-position aldehyde group at fixed point, and then oxidizes the 2-position aldehyde group into 2-position carboxyl, and the two-step oxidization process does not affect the C=C double bond in the pyridone. The method for preparing the magnesium degradation impurity of the esomeprazole has the advantages that the total yield can reach more than 60 percent, and the purity can reach more than 99 percent.

Description

Preparation method of Esomeprazole magnesium degradation impurity
Technical Field
The invention belongs to the field of preparation of bulk drugs, and relates to a preparation method of magnesium degradation impurities of esomeprazole.
Background
Esomeprazole is a proton pump inhibitor by inhibiting H in cells of the stomach wall + /K + Atpase to reduce gastric acid secretion, prevent the formation of gastric acid, for the initiation and long-term treatment of gastroesophageal reflux disease (GORD) including erosive reflux esophagitis, including erosive esophagitis.
The magnesium salt of esomeprazole is the magnesium salt of esomeprazole, and the company of astorab indicates in CN1110477a that the sodium and magnesium salts are the best-performing esomeprazole salts. Lin Qing in Esomeprazole magnesium polymorphic form preparation, characterization and interconversion, it is shown that Esomeprazole magnesium trihydrate is the most stable compound of Esomeprazole magnesium salts, its chemical name is bis- (S) -5-methoxy-2- (((4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl) sulfinyl) -1H-benzimidazole magnesium trihydrate, CAS:161973-10-0.
In order to ensure the safety and effectiveness of the medicament, the related substances in the medicament need to be researched, detected and monitored. The related substances are mainly process byproducts and degradation products, and the impurity spectrum is changed in the process of placing the medicine. As shown in FIG. 1, esomeprazole or its salt can be degraded to produce impurities of formula V, with formula C 16 H 15 N 3 O 4 Molecular weight 313.31, chemical name: 1, 4-dihydro-1- (6-methoxy-1H-benzoimidazol-2-yl) -3, 5-dimethyl-4-oxo-2-pyridinecarboxylic acid.
At present, the degradation impurity is mainly obtained by preparing omeprazole degradation products through liquid phase separation, such as EP2189456Al, J.Ph armacet.biomed.118 (2016) 370-379, but the method has low productivity and high cost. Therefore, the method has important significance for the directional synthesis of the impurity.
Chinese patent application CN112321562A reports the preparation method of the degraded impurity, wherein omeprazole sodium bicarbonate dry suspension is destroyed at high temperature under alkaline condition to obtain a small amount of the impurity, and then gradient elution is carried out to obtain the pure product of the degraded impurity.
The preparation method is complex, the amount of impurities obtained by alkali damage is small, the gradient elution procedure is complex, and the practical application value is low.
Similarly, chinese patent application CN114409631a reports a preparation method of the degradation impurity, in which esomeprazole is dissolved in an organic solvent, and then added with a proper amount of hydrochloric acid to accelerate degradation, and finally separated to obtain an intermediate 8- (or 9) methoxy-1, 3-dimethyl-12-thiopyrido [1,2:3,4] -imidazo [1,2-a ] benzimidazol-2 (1,2H) -one, and then subjected to alkaline decomposition to obtain the degradation impurity pure product. The preparation method is low in preparation mode, impurities obtained by acid and alkali damage are poor, the separation effect of the preparation column is poor, and the practical application value is low.
Disclosure of Invention
The invention aims to eliminate the traditional acid-base damage method, and prepare the high-purity esomeprazole magnesium degradation impurity (compound V) by chemical synthesis.
The invention aims at realizing the following technical scheme:
the preparation method of the Esomeprazole magnesium degradation impurity comprises the following synthetic route:
comprising the following steps: oxidizing 3, 5-dimethyl-2-hydroxymethyl-4-pyridone (compound I) to obtain 3, 5-dimethyl-2-carboxyl-4-pyridone (compound III); in the presence of inorganic alkali, 3, 5-dimethyl-2-carboxyl-4-pyridone and 2-chloro-5-methoxybenzimidazole (compound IV) undergo condensation reaction, the pH value of the reaction solution is regulated to be 6-7, a wet product is obtained after filtration, the wet product is dried to obtain a crude product of the degradation impurity of the esomeprazole magnesium with the structure shown in a formula V, and the crude product is recrystallized by an alcohol-water mixed solution to obtain a refined product of the degradation impurity of the esomeprazole magnesium.
Specifically, the method for preparing the magnesium degradation impurity of the esomeprazole comprises the following steps of:
step (1), 3, 5-dimethyl-2-hydroxymethyl-4-pyridone is taken as an initial raw material, and 3, 5-dimethyl-2-aldehyde-4-pyridone (compound II) is obtained through oxidation reaction under the action of an oxidant;
step (2), 3, 5-dimethyl-2-aldehyde-4-pyridone (compound II) and an oxidant are subjected to further oxidation reaction to obtain 3, 5-dimethyl-2-carboxyl-4-pyridone;
step (3), in the presence of inorganic alkali, 3, 5-dimethyl-2-carboxyl-4-pyridone and 2-chloro-5-methoxybenzimidazole undergo a condensation reaction, after the reaction is finished, the pH value of the reaction solution is regulated to 6-7, a wet product is obtained by filtration, and the wet product is dried under reduced pressure to obtain crude product of the degradation impurity of the esomeprazole magnesium;
and (4) recrystallizing the crude product of the magnesium degradation impurity of the esomeprazole by using an alcohol-water mixed solution to obtain a refined product of the compound V.
In the step (1), the reaction solvent is dichloromethane, toluene, chloroform, etc., preferably dichloromethane.
The molar ratio of the 3, 5-dimethyl-2-hydroxymethyl-4-pyridone (compound I) to the oxidant is 1:1-1:2.5, preferably 1:2.
The oxidant is pyridinium chlorochromate (PCC), manganese dioxide or Dicyclohexylcarbodiimide (DCC). Manganese dioxide can oxidize the 2-hydroxyl of 3, 5-dimethyl-2-hydroxymethyl-4-pyridone into 2-aldehyde group at fixed point, but the manganese dioxide belongs to heavy metal oxidant, the post-treatment is complex, and solid waste is generated. Thus, the oxidizing agent is preferably pyridinium chlorochromate.
The temperature of the oxidation reaction is 10-40 ℃, preferably 20-30 ℃.
Specifically, after the reaction is finished, a saturated sodium sulfite aqueous solution is dropwise added into the reaction solution, stirring and liquid separation are carried out, an organic phase is collected, the organic phase is sequentially washed by saturated saline water and dried by anhydrous sodium sulfate, then a large amount of solid is separated out by distillation, a wet product is obtained by filtration, and 3, 5-dimethyl-2-aldehyde-4-pyridone is obtained by drying.
In the step (2), the reaction solvent is dichloromethane, DMSO, toluene, tetrahydrofuran or the like or a mixed solvent of one of dichloromethane, DMSO, toluene and tetrahydrofuran and water, wherein the mass ratio of the one of dichloromethane, DMSO, toluene and tetrahydrofuran to water is 1:6-1:6.5, and preferably tetrahydrofuran or the mixed solvent of tetrahydrofuran and water.
The molar ratio of the 3, 5-dimethyl-2-aldehyde-4-pyridone to the oxidant is 1:1-1:3, preferably 1:3.
The oxidant is Tollens reagent (ammonia water solution of silver nitrate) or Filin reagent (sodium potassium tartrate solution of copper sulfate, cu 2+ Meter), preferably a filin reagent.
When a filin reagent is used as an oxidant, the following steps are specifically: 3, 5-dimethyl-2-aldehyde-4-pyridone is dissolved in a reaction solvent, a filin reagent is added dropwise under stirring, and the temperature is raised to perform oxidation reaction.
The temperature of the oxidation reaction is 30-60 ℃, preferably 40-50 ℃.
Specifically, after the reaction is finished, adding active carbon into the reaction solution, stirring, filtering, collecting filtrate, distilling under reduced pressure to remove solvent, and drying under reduced pressure to obtain 3, 5-dimethyl-2-carboxyl-4-pyridone; wherein the mass ratio of the active carbon to the 3, 5-dimethyl-2-aldehyde-4-pyridone is 1:100-3:100.
In the step (3), the reaction solvent is acetone, toluene, DMF or a mixed solvent of acetone, toluene, DMF or the like and water, the mass ratio of the acetone, toluene, DMF or the like to the water is 6:1-8:1, and preferably, the reaction solvent is acetone or the mixed solvent of acetone and water.
The molar ratio of the 3, 5-dimethyl-2-carboxyl-4-pyridone to the 2-chloro-5-methoxybenzimidazole is 1:1-1.5, preferably 1:1.5.
The inorganic base is sodium hydroxide, potassium tert-butoxide, etc., preferably sodium hydroxide.
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.
Preferably, in order to separate out more magnesium esomeprazole 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 reduced to 0-5 ℃.
Preferably, glacial acetic acid is used to adjust the pH of the reaction solution to 6-7.
In step (4), the recrystallization: mixing the crude product of the degradation impurity of the esomeprazole magnesium with the alcohol-water mixed solution, heating to 55+/-5 ℃, stirring until the solution is clear, cooling to 10-15 ℃ for recrystallization, filtering, and drying the solid at 40-60 ℃ to obtain the refined product of the degradation impurity of the esomeprazole magnesium. Wherein the mass ratio of the crude product of the degradation impurity of the esomeprazole magnesium to the alcohol-water mixed solution is 1:6-1:8, and is preferably 1:7.5; the alcohol-water mixed solution is prepared from absolute ethyl alcohol and water according to a mass ratio of 3:1-1.5:1, preferably 2:1.
The invention has the beneficial effects that:
the preparation method is simple, firstly, the 2-alcoholic hydroxyl group of 3, 5-dimethyl-2-hydroxymethyl-4-pyridone is oxidized into the 2-aldehyde group at fixed point by adopting a strong-selectivity oxidant, then the 2-aldehyde group is oxidized into the 2-carboxyl group at fixed point by adopting a strong-selectivity oxidant, the C=C double bond in the pyridone is not influenced in the two-step oxidation process, and the ring opening of the pyridone is avoided; finally, the crude product is obtained through condensation reaction, and the ethanol aqueous solution is used as a recrystallization solvent, and the product purity is further improved through recrystallization.
The total yield of the Esomeprazole magnesium degradation impurity prepared by the method can reach more than 60%, the purity can reach more than 99%, and the prepared impurity can be used as a reference substance in the detection of the Esomeprazole magnesium degradation impurity.
Drawings
Fig. 1 is a diagram of the degradation mechanism of magnesium impurities of esomeprazole.
Fig. 2 is a UV scan of the magnesium degradation impurity of esomeprazole.
Detailed Description
The following describes the technical scheme of the invention in conjunction with specific implementation method, but is not limited to the essence of the invention.
Example 1
Preparation of 3, 5-dimethyl-2-aldehyde-4-pyridone (Compound II)
15.3g (0.1 mol) of 3, 5-dimethyl-2-hydroxymethyl-4-pyridone (compound I) is added into a 500mL reaction bottle, 150mL of dichloromethane is added, the temperature is reduced to-5-0 ℃, a dichloromethane solution of PCC (43.1 g (0.2 mol) of PCC and 50mL of dichloromethane) is dropwise added under stirring, the temperature is raised to 20-30 ℃, and the temperature is kept until the TLC detection reaction is completed; 100mL of saturated aqueous sodium sulfite solution was added dropwise to the reaction solution, the mixture was stirred for 30 minutes, the mixture was separated, and a methylene chloride phase was collected, washed with 100mL of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the methylene chloride phase was distilled until a large amount of solid was separated out, and the resultant was filtered to obtain a wet product, and dried to obtain 13.9g of Compound II in a yield of 92.0%.
Preparation of 3, 5-dimethyl-2-carboxy-4-pyridone (Compound III)
Into a 250mL reaction flask was added 7.6g (0.05 mol) of Compound II, 150mL of tetrahydrofuran was added, and 950mL of Filin reagent (in Cu) was added dropwise with stirring 2+ Based on the oxidizing agent and the compoundThe molar ratio of II is 3:1), heating to 40-50 ℃, preserving heat, reacting until TLC detection reaction is finished, adding 0.2g of active carbon into the reaction liquid, stirring, filtering, discarding filter cakes, collecting filtrate, distilling the filtrate under reduced pressure until the solvent is dry, obtaining a wet product of the compound III, and drying under reduced pressure to obtain about 7.9g of the compound III with the yield of 95.0%.
Preparation of crude Compound V
6.7g (0.04 mol) of compound III is added into a 250mL four-neck flask, 70g of acetone is added, sodium hydroxide aqueous solution (4 g (0.1 mol) of sodium hydroxide and 10g of drinking water) is added under stirring, after the addition is finished, stirring is carried out for 30min, 11g (0.06 mol) of compound IV is added into the system, condensation reaction is carried out at the temperature of 30-40 ℃ until TLC detection shows that the reaction is finished, glacial acetic acid is dropwise added until the pH value of the system is 6, stirring is continued for 1h, cooling is carried out to 0-5 ℃, 14.8g of wet product of the compound V is obtained after filtering, 11.2g of crude product is obtained after drying under reduced pressure at the temperature of 40 ℃, the purity is 88.70%, and the yield is 79.3%.
Recrystallizing
Adding 11.2g of the obtained crude product of the compound V into a 250mL single-neck flask, adding 84g (56 g of ethanol and 28g of drinking water) of ethanol aqueous solution, heating to 50-60 ℃, stirring to dissolve, slowly cooling to 10-15 ℃, crystallizing for 2h, filtering to obtain a pale yellow solid, drying at 50 ℃ under reduced pressure to obtain 8.8g of refined product of the compound V, wherein the purity is 99.91%, the step yield is 88.5%, and the total yield of the compound I to the refined product of the compound V is 61.3%.
ESI-MS:m/z 314.46[M+H] + . The hydrogen spectrum assignment of compound V is shown in Table 1; the UV scan pattern of compound V is shown in FIG. 2, with maximum absorption at 303.50nm and 200.50 nm.
TABLE 1 Hydrogen profile data for Compound V
Chemical shift (ppm) Proton type Peak type Home H number
1.82 2CH 3 s peak 8. Hydrogen at 9 position
3.78 CH 3 s peak Hydrogen at 20 position
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 18 position
7.81 ArH s peak Hydrogen at 5 position
8.32 NH 4 + br peak Hydrogen at 1 position
Example 2
Adding the crude product (purity 88.70%) of the compound V into a 250mL single-neck flask, adding an ethanol water solution (the mass ratio of ethanol to drinking water is shown in table 2) according to the mass ratio of the crude product of the compound V to the ethanol solution of 1:7.5, heating to 50-60 ℃, stirring until the mixture is clear, slowly cooling to 10-15 ℃, crystallizing for 2h, filtering to obtain a light yellow solid, and drying under reduced pressure at 50 ℃, wherein the purity and yield of the refined product of the compound V are shown in table 2. In comprehensive consideration, the ethanol aqueous solution prepared by anhydrous ethanol and water according to the mass ratio of 3:1-1.5:1 is a preferred scheme of a recrystallization solvent, and particularly the ethanol aqueous solution prepared by the mass ratio of 2:1 is the preferred scheme of the recrystallization solvent.
TABLE 2 influence of mass ratio of ethanol and water in aqueous ethanol solution on recrystallization
Sequence number m Ethanol :m Water and its preparation method 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 (10)

1. A preparation method of an esomeprazole magnesium degradation impurity is characterized by comprising the following steps: the synthetic route is as follows:
comprising the following steps: oxidizing 3, 5-dimethyl-2-hydroxymethyl-4-pyridone to obtain 3, 5-dimethyl-2-carboxyl-4-pyridone; in the presence of inorganic alkali, 3, 5-dimethyl-2-carboxyl-4-pyridone and 2-chloro-5-methoxybenzimidazole undergo a condensation reaction, the pH value of the reaction solution is regulated to 6-7, a wet product is obtained by filtration, the wet product is dried to obtain a crude product of the degradation impurity of the esomeprazole magnesium with the structure shown in formula V, and the crude product is recrystallized by an alcohol-water mixed solution to obtain a refined product of the degradation impurity of the esomeprazole magnesium.
2. The preparation method of the esomeprazole magnesium degradation impurity according to claim 1, characterized in that: the method comprises the following steps:
step (1), 3, 5-dimethyl-2-hydroxymethyl-4-pyridone is taken as an initial raw material, and 3, 5-dimethyl-2-aldehyde-4-pyridone is obtained through oxidation reaction under the action of an oxidant; the oxidant is pyridinium chlorochromate, manganese dioxide or dicyclohexylcarbodiimide;
step (2), carrying out an oxidation reaction on the 3, 5-dimethyl-2-aldehyde-4-pyridone and an oxidant to obtain 3, 5-dimethyl-2-carboxyl-4-pyridone; the oxidant is a Tollens reagent or a Filin reagent;
step (3), in the presence of inorganic alkali, 3, 5-dimethyl-2-carboxyl-4-pyridone and 2-chloro-5-methoxybenzimidazole undergo a condensation reaction, after the reaction is finished, the pH value of the reaction solution is regulated to 6-7, a wet product is obtained by filtration, and the wet product is dried under reduced pressure to obtain crude product of the degradation impurity of the esomeprazole magnesium;
and (4) recrystallizing the crude product of the magnesium degradation impurity of the esomeprazole by using an alcohol-water mixed solution to obtain a refined product of the compound V.
3. The preparation method of the esomeprazole magnesium degradation impurity according to claim 2, characterized in that: in the step (1), the reaction solvent is dichloromethane, toluene, chloroform, preferably dichloromethane; in the step (2), the reaction solvent is dichloromethane, DMSO, toluene, tetrahydrofuran or a mixed solvent of one of dichloromethane, DMSO, toluene and tetrahydrofuran and water, and the mass ratio of one of dichloromethane, DMSO, toluene and tetrahydrofuran to water is 1:6-1:6.5, preferably tetrahydrofuran or a mixed solvent of tetrahydrofuran and water.
4. The preparation method of the esomeprazole magnesium degradation impurity according to claim 2, characterized in that: in the step (1), the molar ratio of the 3, 5-dimethyl-2-hydroxymethyl-4-pyridone to the oxidant is 1:1-1:2.5, preferably 1:2; in the step (2), the molar ratio of the 3, 5-dimethyl-2-aldehyde-4-pyridone to the oxidant is 1:1-1:3, preferably 1:3.
5. The preparation method of the esomeprazole magnesium degradation impurity according to claim 2, characterized in that: in the step (1), the oxidant is pyridinium chlorochromate; in the step (2), the oxidant is a filin reagent.
6. The preparation method of the esomeprazole magnesium degradation impurity according to claim 2, characterized in that: in the step (1), the temperature of the oxidation reaction is 10-40 ℃, preferably 20-30 ℃; in the step (2), the temperature of the oxidation reaction is 30 to 60 ℃, preferably 40 to 50 ℃.
7. The preparation method of the esomeprazole magnesium degradation impurity according to claim 2, characterized in that: in the step (2), after the reaction is finished, adding active carbon into the reaction liquid, stirring, filtering, collecting filtrate, distilling under reduced pressure to remove solvent, and drying under reduced pressure to obtain 3, 5-dimethyl-2-carboxyl-4-pyridone; wherein the mass ratio of the active carbon to the 3, 5-dimethyl-2-aldehyde-4-pyridone is 1:100-3:100.
8. The preparation method of the esomeprazole magnesium degradation impurity according to claim 2, characterized in that: in the step (3), the reaction solvent is acetone, toluene, DMF or a mixed solvent of acetone, toluene and DMF and water, and the mass ratio of the acetone, the toluene and the DMF to the water is 6:1-8:1; preferably, the reaction solvent is acetone or a mixed solvent of acetone and water.
9. The preparation method of the esomeprazole magnesium degradation impurity according to claim 2, characterized in that: in the step (3), the molar ratio of the 3, 5-dimethyl-2-carboxyl-4-pyridone to the 2-chloro-5-methoxybenzimidazole is 1:1-1.5, preferably 1:1.5;
the inorganic base is sodium hydroxide, potassium hydroxide and potassium tert-butoxide, preferably sodium hydroxide;
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.
10. The preparation method of the esomeprazole magnesium degradation impurity according to claim 2, characterized in that: in step (4), the recrystallization: mixing the crude product of the degradation impurity of the esomeprazole magnesium with an alcohol-water mixed solution, heating to 55+/-5 ℃, stirring until the solution is clear, cooling to 10-15 ℃ for recrystallization, filtering, and drying the solid at 40-60 ℃ to obtain a refined product of the degradation impurity of the esomeprazole magnesium; wherein the mass ratio of the crude product of the degradation impurity of the esomeprazole magnesium to the alcohol-water mixed solution is 1:6-1:8, and is preferably 1:7.5; the alcohol-water mixed solution is prepared from absolute ethyl alcohol and water according to a mass ratio of 3:1-1.5:1, preferably 2:1.
CN202310788699.1A 2023-06-30 2023-06-30 Preparation method of Esomeprazole magnesium degradation impurity Pending CN116947812A (en)

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