CN111635393A - Preparation method of esomeprazole sodium - Google Patents
Preparation method of esomeprazole sodium Download PDFInfo
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- CN111635393A CN111635393A CN202010595218.1A CN202010595218A CN111635393A CN 111635393 A CN111635393 A CN 111635393A CN 202010595218 A CN202010595218 A CN 202010595218A CN 111635393 A CN111635393 A CN 111635393A
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- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
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- C07B2200/07—Optical isomers
Abstract
The invention provides a preparation method of esomeprazole sodium, and particularly provides a preparation method of optically pure esomeprazole sodium, which comprises the step of preparing the esomeprazole sodium by using 2-mercapto-5-methoxy-1H-benzimidazole and 2-chloromethyl-4-methoxy-3, 5-dimethylpyridine hydrochloride as starting raw materials. The method has good selectivity, can obtain almost optically pure products, and is suitable for industrial production of the esomeprazole sodium.
Description
Technical Field
The invention relates to the field of organic synthesis, and particularly provides a preparation method of optically pure esomeprazole.
Background
Esomeprazole is the s-optical isomer of omeprazole, the first global isomer proton pump inhibitor, which reduces gastric acid secretion by specifically inhibiting parietal cell proton pump. A large number of clinical experiments and pharmaceutical researches prove that the gastric pH-resistant inhibitor has longer time for maintaining the pH in the stomach to be more than 4, higher acid inhibition efficiency, better curative effect than the first two generations of proton pump inhibitors and small individual difference. As a new generation of proton pump inhibitors, it has been widely used in clinical treatment of many acid-related diseases. Therefore, how to obtain the esomeprazole sodium by a simple and feasible method and ensure the safety of the esomeprazole sodium by precisely controlling the quality is a very important topic.
In conclusion, a preparation method of esomeprazole sodium with high yield and good optical selectivity is not available in the field.
Disclosure of Invention
The invention aims to provide a preparation method of esomeprazole sodium, which is high in yield and good in optical selectivity.
In a first aspect of the present invention, there is provided a process for the preparation of esomeprazole sodium, the process comprising the steps of:
(1) reacting 2-mercapto-5-methoxy-1H-benzimidazole with 2-chloromethyl-4-methoxy-3, 5-dimethylpyridine hydrochloride in an inert solvent to obtain 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] thio ] -1H-benzimidazole;
(2) in an inert solvent, in an organic base and H2In the presence of O, using diethyl D-tartrate, tetraisopropyl titanate, hydroxy-cumyl peroxide and 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl group]Sulfur]And (3) reacting the-1H-benzimidazole, and then reacting with sodium hydroxide to obtain the esomeprazole sodium.
In another preferred embodiment, in the step (1), the inert solvent is selected from the group consisting of: methanol, ethanol, tetrahydrofuran, water, or combinations thereof.
In another preferred embodiment, in the step (1), the method is performed in the presence of a base; preferably, the base is selected from the group consisting of: sodium hydroxide, potassium hydroxide, sodium carbonate, or a combination thereof.
In another preferred embodiment, in the step (1), the molar ratio of the 2-mercapto-5-methoxy-1H-benzimidazole to the base is 1: 1-3.
In another preferred embodiment, in the step (2), the inert solvent is selected from the group consisting of: 1, 2-dichloroethane, toluene, chloroform, carbon tetrachloride, or a combination thereof; preferably a mixed solvent of 1, 2-dichloroethane and toluene; more preferably a mixed solvent of 1, 2-dichloroethane and toluene in a volume ratio of 1: 2-6.
In another preferred embodiment, in said step (2), said 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl ] is used]Sulfur]-1H-benzimidazole and H2The molar ratio of O is 1: 0.5-2; preferably 1: 0.8-1.2.
In another preferred embodiment, the organic base is selected from the group consisting of: diisopropylethylamine, triethylamine, diethylamine, DBU, or a combination thereof.
In another preferred embodiment, in said step (2), said 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl ] is used]Sulfur]-1H-benzimidazole and H2The molar ratio of O is 1: 0.5-2; preferably 1: 0.8-1.2.
In another preferred embodiment, in the step (2), the molar ratio of the 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] thio ] -1H-benzimidazole to the diethyl D-tartrate and the tetraisopropyl titanate is 1: 0.02-0.4; 0.05-0.5; preferably 1: 0.05-0.2; 0.1-0.3.
In another preferred embodiment, in the step (2), the molar ratio of the 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] thio ] -1H-benzimidazole to the sodium hydroxide is 1: 1-5, preferably 1: 2-3.
In another preferred embodiment, in said step (2), said 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl ] thio ] -1H-benzimidazole and dicumyl hydroperoxide are in a molar ratio of 0.5-0.8: 0.8-1.2.
In a second aspect of the present invention, there is provided a process for preparing S-omeprazole sodium, which comprises the steps of:
(2) in an inert solvent, in H2In the presence of O, using diethyl D-tartrate, tetraisopropyl titanate, hydroxy-cumyl peroxide and 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl group]Sulfur]And (3) reacting the-1H-benzimidazole, and then reacting with sodium hydroxide to obtain the esomeprazole sodium.
In another preferred embodiment, the method further comprises the steps of: after the reaction is finished, refining the obtained esomeprazole sodium, wherein the refining comprises the following steps:
(3) dissolving the product with methanol, adding sodium hydroxide and active carbon, and stirring to obtain a first post-treatment mixture;
(4) filtering the first post-treatment mixture, spin-drying the filtrate, and refluxing with acetone to obtain a second post-treatment mixture;
(5) and filtering the second post-treatment mixture to obtain white solid esomeprazole sodium.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
EXAMPLE 1 preparation of S-omeprazole sodium
The basic scheme is shown as follows:
step preparation of 15-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl ] thio ] -1H-benzimidazole
2-mercapto-5-methoxy-1H-benzimidazole (62g, 0.34mol) and methanol (210mL) were added to the reaction vessel and dissolved with stirring. 100ml of an aqueous solution of sodium hydroxide (28g, 0.7mol) was added, and 210ml of a methanol solution of 2-chloromethyl-4-methoxy-3, 5-dimethylpyridine hydrochloride (70g, 0.32mol) was added dropwise to the reaction tank over 10 min. After the dropwise addition is finished, stirring and reacting for 3-5 hours at the temperature of 0-30 ℃.
After the reaction is finished, the temperature of the reaction solution is controlled to be 89-92 ℃ and the reaction solution is distilled to be dry. After completion of the distillation, 200mL of methylene chloride was added and dissolved with stirring, and then 100mL of purified water was added and washed. The dichloromethane layer is distilled to be dry, 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] thio ] -1H-benzimidazole crude product is obtained after the distillation is finished, and the product is directly used in the next step.
Step 2 preparation of esomeprazole sodium
Reacting 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl group]Sulfur]Adding a mixed solvent of 60g (0.182mol) of-1H-benzimidazole, 50ml of 1, 2-dichloroethane and 200ml of toluene into a reaction tank, stirring, heating to 70-80 ℃, dissolving, cooling to 40-50 ℃, adding 3.75g (0.0182mol) of diethyl D-tartrate, 10.35g (0.0364mol) of tetraisopropyl titanate, 2.352g (0.0182mol) of diisopropylethylamine and H2O3.3 mL, 40mL of cumyl hydroperoxide is added dropwise and the temperature is kept at 40-50 ℃ for 4 h. Then 20g (0.5mol) of sodium hydroxide solution in methanol (80ml) is added into the reaction kettle, the mixture is continuously stirred overnight, and the crude product is obtained after suction filtration and drying.
The crude product was dissolved in 400mL of methanol, followed by addition of 4.5g (0.113mol) of sodium hydroxide and stirring at room temperature for 2 hours, and activated carbon was decolorized with stirring for 30 minutes. Filtering, adding 200mL of acetone after spin drying of the filtrate, stirring and refluxing for 30 minutes, cooling to room temperature, filtering, leaching with acetone, and vacuum drying at 35 ℃ for 3 hours to obtain 64.20g of white solid with the yield of 96.0%.
The product has an ee value > 99% as determined by manual HPLC.
EXAMPLE 2 preparation of S-omeprazole sodium
The basic scheme is shown as follows:
step preparation of 15-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl ] thio ] -1H-benzimidazole
2-mercapto-5-methoxy-1H-benzimidazole (62g, 0.34mol) and methanol (210mL) were added to the reaction vessel and dissolved with stirring. 100ml of an aqueous solution of sodium hydroxide (28g, 0.7mol) was added, and 210ml of a methanol solution of 2-chloromethyl-4-methoxy-3, 5-dimethylpyridine hydrochloride (70g, 0.39mol) was added dropwise to the reaction tank over 10 min. After the dropwise addition is finished, stirring and reacting for 3-5 hours at the temperature of 0-30 ℃.
After the reaction is finished, the temperature of the reaction solution is controlled to be 89-92 ℃ and the reaction solution is distilled to be dry. After completion of the distillation, 200mL of methylene chloride was added and dissolved with stirring, and then 100mL of purified water was added and washed. The dichloromethane layer is distilled to be dry, 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] thio ] -1H-benzimidazole crude product is obtained after the distillation is finished, and the product is directly used in the next step.
Step 2 preparation of esomeprazole sodium
Reacting 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl group]Sulfur]Adding a mixed solvent of 60g (0.182mol) of-1H-benzimidazole, 30ml of 1, 2-dichloroethane and 220ml of toluene into a reaction tank, stirring, heating to 70-80 ℃, dissolving, cooling to 40-50 ℃, adding 3.75g (0.0182mol) of diethyl D-tartrate, 10.35g (0.0364mol) of tetraisopropyl titanate, 2.352g (0.0182mol) of diisopropylethylamine and H2O3.3 mL, 40mL of cumyl hydroperoxide is added dropwise at 40-50 DEG CAnd keeping the temperature for 4 hours. Then 20g (0.5mol) of sodium hydroxide solution in methanol (80m1) is added into the reaction kettle, the mixture is stirred continuously overnight, and the crude product is obtained after suction filtration and drying.
The crude product was dissolved in 400mL of methanol, followed by addition of 4.5g (0.113mol) of sodium hydroxide and stirring at room temperature for 2 hours, and activated carbon was decolorized with stirring for 30 minutes. Filtering, adding 200mL of acetone after spin drying of the filtrate, stirring and refluxing for 30 minutes, cooling to room temperature, filtering, leaching with acetone, and vacuum drying at 35 ℃ for 3 hours to obtain 61.52g of white solid with the yield of 96.0%.
The product was determined by manual HPLC with an ee value of 98%.
EXAMPLE 3 preparation of S-omeprazole sodium
The basic scheme is shown as follows:
step preparation of 15-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl ] thio ] -1H-benzimidazole
2-mercapto-5-methoxy-1H-benzimidazole (62g, 0.34mol) and methanol (210mL) were added to the reaction vessel and dissolved with stirring. 100ml of an aqueous solution of sodium hydroxide (28g, 0.7mol) was added, and 210ml of a methanol solution of 2-chloromethyl-4-methoxy-3, 5-dimethylpyridine hydrochloride (70g, 0.39mol) was added dropwise to the reaction tank over 10 min. After the dropwise addition is finished, stirring and reacting for 3-5 hours at the temperature of 0-30 ℃.
After the reaction is finished, the temperature of the reaction solution is controlled to be 89-92 ℃ and the reaction solution is distilled to be dry. After completion of the distillation, 200mL of methylene chloride was added and dissolved with stirring, and then 100mL of purified water was added and washed. The dichloromethane layer is distilled to be dry, 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] thio ] -1H-benzimidazole crude product is obtained after the distillation is finished, and the product is directly used in the next step.
Step 2 preparation of esomeprazole sodium
Reacting 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl group]Sulfur]A mixed solvent of 60g (0.182mol) of (E) -1H-benzimidazole, 80ml of 1, 2-dichloroethane and 170ml of toluene is added into a reaction tank, stirred and heated to 7 DEGDissolving at 0-80 deg.C, cooling to 40-50 deg.C, adding 3.75g (0.0182mol) of diethyl D-tartrate, 10.35g (0.0364mol) of tetraisopropyl titanate, 2.352g (0.0182mol) of diisopropylethylamine, and H2O3.3 mL, 40mL of cumyl hydroperoxide is added dropwise and the temperature is kept at 40-50 ℃ for 4 h. Then 20g (0.5mol) of sodium hydroxide solution in methanol (80ml) is added into the reaction kettle, the mixture is continuously stirred overnight, and the crude product is obtained after suction filtration and drying.
The crude product was dissolved in 400mL of methanol, followed by addition of 4.5g (0.113mol) of sodium hydroxide and stirring at room temperature for 2 hours, and activated carbon was decolorized with stirring for 30 minutes. Filtering, adding 200mL of acetone after spin drying of the filtrate, stirring and refluxing for 30 minutes, cooling to room temperature, filtering, leaching with acetone, and vacuum drying at 35 ℃ for 3 hours to obtain 59.60g of white solid with the yield of 89.1%.
The product was determined by manual HPLC with an ee value of 98%.
The results of examples 1 to 3 show that the solvent selection of the reaction system has a certain influence on the yield, and that the reaction can achieve a yield of about 90% in the case of using a mixed solvent system of 1, 2-dichloroethane and toluene, and about 96% in the case of an optimized mixed solvent system.
EXAMPLE 4 preparation of S-omeprazole sodium
The basic scheme is shown as follows:
step preparation of 15-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl ] thio ] -1H-benzimidazole
2-mercapto-5-methoxy-1H-benzimidazole (62g, 0.34mol) and methanol (210mL) were added to the reaction vessel and dissolved with stirring. 100ml of an aqueous solution of sodium hydroxide (28g, 0.7mol) was added, and 210ml of a methanol solution of 2-chloromethyl-4-methoxy-3, 5-dimethylpyridine hydrochloride (70g, 0.32mol) was added dropwise to the reaction tank over 10 min. After the dropwise addition is finished, stirring and reacting for 3-5 hours at the temperature of 0-30 ℃.
After the reaction is finished, the temperature of the reaction solution is controlled to be 89-92 ℃ and the reaction solution is distilled to be dry. After completion of the distillation, 200mL of methylene chloride was added and dissolved with stirring, and then 100mL of purified water was added and washed. The dichloromethane layer is distilled to be dry, 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] thio ] -1H-benzimidazole crude product is obtained after the distillation is finished, and the product is directly used in the next step.
Step 2 preparation of esomeprazole sodium
Reacting 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl group]Sulfur]Adding a mixed solvent of 60g (0.182mol) of-1H-benzimidazole, 50ml of 1, 2-dichloroethane and 200ml of toluene into a reaction tank, stirring, heating to 70-80 ℃, dissolving, cooling to 40-50 ℃, adding 3.75g (0.0182mol) of diethyl D-tartrate, 10.35g (0.0364mol) of tetraisopropyl titanate, 2.352g (0.0182mol) of diisopropylethylamine and H2O1 mL, 40mL of cumyl hydroperoxide is added dropwise and the temperature is kept at 40-50 ℃ for 4 h. Then 20g (0.5mol) of sodium hydroxide solution in methanol (80ml) is added into the reaction kettle, the mixture is continuously stirred overnight, and the crude product is obtained after suction filtration and drying.
The crude product was dissolved in 400mL of methanol, followed by addition of 4.5g (0.113mol) of sodium hydroxide and stirring at room temperature for 2 hours, and activated carbon was decolorized with stirring for 30 minutes. Filtering, adding 200mL of acetone after spin drying of the filtrate, stirring and refluxing for 30 minutes, cooling to room temperature, filtering, leaching with acetone, and vacuum drying at 35 ℃ for 3 hours to obtain 65.1g of white solid with the yield of 97.4%.
The product was determined by manual HPLC with an ee value of 70%.
The results show that the selectivity of the reaction decreases significantly when the amount of water used in the chiral oxidation step is reduced.
EXAMPLE 5 preparation of S-omeprazole sodium
The basic scheme is shown as follows:
step preparation of 15-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl ] thio ] -1H-benzimidazole
2-mercapto-5-methoxy-1H-benzimidazole (62g, 0.34mol) and methanol (210mL) were added to the reaction vessel and dissolved with stirring. 100ml of an aqueous solution of sodium hydroxide (28g, 0.7mol) was added, and 210ml of a methanol solution of 2-chloromethyl-4-methoxy-3, 5-dimethylpyridine hydrochloride (70g, 0.32mol) was added dropwise to the reaction tank over 10 min. After the dropwise addition is finished, stirring and reacting for 3-5 hours at the temperature of 0-30 ℃.
After the reaction is finished, the temperature of the reaction solution is controlled to be 89-92 ℃ and the reaction solution is distilled to be dry. After completion of the distillation, 200mL of methylene chloride was added and dissolved with stirring, and then 100mL of purified water was added and washed. The dichloromethane layer is distilled to be dry, 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] thio ] -1H-benzimidazole crude product is obtained after the distillation is finished, and the product is directly used in the next step.
Step 2 preparation of esomeprazole sodium
Reacting 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl group]Sulfur]Adding a mixed solvent of 60g (0.182mol) of-1H-benzimidazole, 50ml of 1, 2-dichloroethane and 200ml of toluene into a reaction tank, stirring, heating to 70-80 ℃, dissolving, cooling to 40-50 ℃, adding 3.75g (0.0182mol) of diethyl D-tartrate, 10.35g (0.0364mol) of tetraisopropyl titanate, 2.77g (0.0182mol) of DBU, and H2O3.3 mL, 40mL of cumyl hydroperoxide is added dropwise and the temperature is kept at 40-50 ℃ for 4 h. Then 20g (0.5mol) of sodium hydroxide solution in methanol (80m1) is added into the reaction kettle, the mixture is stirred continuously overnight, and the crude product is obtained after suction filtration and drying.
The crude product was dissolved in 400mL of methanol, followed by addition of 4.5g (0.113mol) of sodium hydroxide and stirring at room temperature for 2 hours, and activated carbon was decolorized with stirring for 30 minutes. Filtering, after spin-drying the filtrate, adding 200mL of acetone, stirring and refluxing for 30 minutes, cooling to room temperature, filtering, leaching with acetone, and vacuum-drying at 35 ℃ for 3 hours to obtain 63.92g of white solid with the yield of 95.6%.
The product was determined by manual HPLC with an ee value of 88%.
The results show that the ee value of the product is improved when diisopropylethylamine is used as the base for the reaction compared to when other organic bases (e.g. DBU in example 5) are used.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A preparation method of esomeprazole sodium is characterized by comprising the following steps:
(1) reacting 2-mercapto-5-methoxy-1H-benzimidazole with 2-chloromethyl-4-methoxy-3, 5-dimethylpyridine hydrochloride in an inert solvent to obtain 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl ] thio ] -1H-benzimidazole;
(2) in an inert solvent, in an organic base and H2In the presence of O, using diethyl D-tartrate, tetraisopropyl titanate, hydroxy-cumyl peroxide and 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl group]Sulfur]And (3) reacting the-1H-benzimidazole, and then reacting with sodium hydroxide to obtain the esomeprazole sodium.
2. The method of claim 1, wherein in step (1), the inert solvent is selected from the group consisting of: methanol, ethanol, tetrahydrofuran, water, or combinations thereof.
3. The process of claim 1, wherein in step (1), the process is carried out in the presence of a base; preferably, the base is selected from the group consisting of: sodium hydroxide, potassium hydroxide, sodium carbonate, or a combination thereof.
4. The method of claim 1, wherein in step (1), the molar ratio of 2-mercapto-5-methoxy-1H-benzimidazole to base is 1: 1-3.
5. The method of claim 1, wherein in step (2), the inert solvent is selected from the group consisting of: 1, 2-dichloroethane, toluene, chloroform, carbon tetrachloride, or a combination thereof; preferably a mixed solvent of 1, 2-dichloroethane and toluene; more preferably a mixed solvent of 1, 2-dichloroethane and toluene in a volume ratio of 1: 2-6.
6. The method of claim 1, wherein in said step (2), said 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl group]Sulfur]-1H-benzimidazole and H2The molar ratio of O is 1: 0.5-2; preferably 1: 0.8-1.2.
7. The method of claim 1, wherein the organic base is selected from the group consisting of: diisopropylethylamine, triethylamine, diethylamine, DBU, or a combination thereof.
8. The method of claim 1, wherein in step (2), the molar ratio of 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl ] thio ] -1H-benzimidazole to sodium hydroxide is 1: 1-5, preferably 1: 2-3.
9. A preparation method of S-omeprazole sodium is characterized by comprising the following steps:
(2) in an inert solvent, in H2In the presence of O, using diethyl D-tartrate, tetraisopropyl titanate, hydroxy-cumyl peroxide and 5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methyl group]Sulfur]And (3) reacting the-1H-benzimidazole, and then reacting with sodium hydroxide to obtain the esomeprazole sodium.
10. The method of claim 1, wherein said method further comprises the steps of: after the reaction is finished, refining the obtained esomeprazole sodium, wherein the refining comprises the following steps:
(3) dissolving the product with methanol, adding sodium hydroxide and active carbon, and stirring to obtain a first post-treatment mixture;
(4) filtering the first post-treatment mixture, spin-drying the filtrate, and refluxing with acetone to obtain a second post-treatment mixture;
(5) and filtering the second post-treatment mixture to obtain white solid esomeprazole sodium.
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| CN110483345A (en) * | 2019-07-19 | 2019-11-22 | 华东师范大学 | Sulfoxide, sulphones and its method for selective synthesis and application |
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