CN111635393A - A kind of preparation method of esomeprazole sodium - Google Patents

Abstract

The invention provides a preparation method of esomeprazole sodium, specifically, the invention provides a preparation method of optically pure esomeprazole sodium, which comprises using 2-mercapto-5-methyl Oxygen-1H-benzimidazole and 2-chloromethyl-4-methoxy-3,5-lutidine hydrochloride are used as starting materials to prepare esomeprazole sodium. The method of the invention has good selectivity, can obtain almost optically pure products, and is suitable for industrial production of esomeprazole sodium.

Description

A kind of preparation method of esomeprazole sodium

technical field

The invention relates to the field of organic synthesis, in particular, the invention provides a preparation method of optically pure esomeprazole.

Background technique

Esomeprazole, the s-optical isomer of omeprazole, is the world's first isomer proton pump inhibitor, which reduces gastric acid secretion by specifically inhibiting the proton pump of gastric parietal cells. A large number of clinical experiments and drug studies have confirmed that it maintains gastric pH>4 for a longer time, has a higher acid-suppressing efficiency, and has a better curative effect than the previous two generations of proton pump inhibitors, with small individual differences. 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 esomeprazole sodium by a simple and feasible method, and ensure the safety of esomeprazole sodium through precise quality control, is a very important issue.

To sum up, there is still a lack of a method for preparing esomeprazole sodium with high yield and good optical selectivity in the art.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a method for preparing esomeprazole sodium with high yield and good optical selectivity.

A first aspect of the present invention provides a preparation method of esomeprazole sodium, the method comprising the steps:

(1) In an inert solvent, react with 2-mercapto-5-methoxy-1H-benzimidazole and 2-chloromethyl-4-methoxy-3,5-lutidine hydrochloride , to obtain 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1H-benzimidazole;

(2) In an inert solvent, in the presence of an organic base and H ₂ O, with D-diethyl tartrate, tetraisopropyl titanate, hydroxycumene peroxide and 5-methoxy-2-[[ (4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfur]-1H-benzimidazole was reacted with sodium hydroxide to obtain esomeprazole sodium.

In another preferred example, in the step (1), the inert solvent is selected from the group consisting of methanol, ethanol, tetrahydrofuran, water, or a combination thereof.

In another preferred example, in the step (1), the method is carried out in the presence of an alkali; preferably, the alkali is selected from the following group: sodium hydroxide, potassium hydroxide, sodium carbonate, or its combination.

In another preferred example, 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 example, in the step (2), the inert solvent is selected from the following group: 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 with a volume ratio of 1,2-dichloroethane and toluene of 1:2-6.

In another preferred example, in the step (2), the 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl The molar ratio of [yl]sulfur]-1H-benzimidazole to _H2O 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 example, in the step (2), the 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl The molar ratio of [yl]sulfur]-1H-benzimidazole to _H2O is 1:0.5-2; preferably 1:0.8-1.2.

In another preferred example, in the step (2), the 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl The molar ratio of [methyl]sulfur]-1H-benzimidazole to D-diethyl tartrate and 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 example, in the step (2), the 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl The molar ratio of [yl]sulfur]-1H-benzimidazole and sodium hydroxide is 1:1-5, preferably 1:2-3.

In another preferred example, in the step (2), the 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl The molar ratio of [yl]sulfur]-1H-benzimidazole to hydroxycumene peroxide is 0.5-0.8:0.8-1.2.

The second aspect of the present invention provides a kind of preparation method of S-omeprazole sodium, it is characterized in that, comprises the steps:

(2) In an inert solvent, in the presence of _H2O , with D-diethyl tartrate, tetraisopropyl titanate, hydroxycumene peroxide and 5-methoxy-2-[[(4- Methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfur]-1H-benzimidazole was reacted with sodium hydroxide to give esomeprazole sodium.

In another preferred embodiment, the method further comprises the steps of: after the reaction finishes, refining the obtained esomeprazole sodium, and the refining comprises the steps:

(3) dissolve the product with methanol, add sodium hydroxide and gac and stir to obtain the first aftertreatment mixture;

(4) the first post-treatment mixture is filtered and the filtrate is spin-dried, and then refluxed with acetone to obtain the second post-treatment mixture;

(5) The second post-processing mixture is filtered to obtain esomeprazole sodium as a white solid.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, it is not repeated here.

Detailed ways

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

The preparation of embodiment 1S-omeprazole sodium

The basic process is as follows:

Step 1 Preparation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1H-benzimidazole

2-mercapto-5-methoxy-1H-benzimidazole (62 g, 0.34 mol) and methanol (210 mL) were added to the reaction tank, and the mixture was stirred and dissolved. A solution of sodium hydroxide (28 g, 0.7 mol) in 100 ml of water was added, followed by 210 ml of 2-chloromethyl-4-methoxy-3,5-lutidine hydrochloride (70 g, 0.32 mol) in 10 min The methanol solution was added dropwise to the reaction tank. After the dropwise addition, the stirring reaction was continued at 0 to 30° C. for 3 to 5 hours.

After the reaction was completed, the temperature of the reaction solution was controlled at 89-92° C. and distilled to dryness. After distillation, 200 mL of dichloromethane was added and stirred to dissolve, and then 100 mL of purified water was added to wash. The dichloromethane layer was distilled to dryness, and the distillation was completed to obtain 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfur]-1H-benzene The crude imidazole was used directly in the next step.

Step 2 Preparation of Esomeprazole Sodium

5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1H-benzimidazole 60g (0.182mol) and 1, A mixed solvent of 50ml of 2-dichloroethane and 200ml of toluene was added to the reaction tank, stirred, heated to 70-80°C to dissolve, cooled to 40-50°C, added 3.75g (0.0182mol) of D-diethyl tartrate, titanium 10.35 g (0.0364 mol) of tetraisopropyl acid, 2.352 g (0.0182 mol) of diisopropylethylamine, 3.3 mL of H ₂ O, 40 mL of cumene peroxide were added dropwise, and the mixture was incubated at 40-50° C. for 4 h. Then add the methanol (80ml) solution of sodium hydroxide 20g (0.5mol), add the reaction kettle, continue to stir overnight, and dry with suction to obtain the crude product.

The crude product was dissolved in 400 mL of methanol, then 4.5 g (0.113 mol) of sodium hydroxide was added and stirred at room temperature for 2 hours, and activated carbon was stirred for 30 minutes for decolorization. Filtration, after the filtrate was spin-dried, 200 mL of acetone was added, stirred and refluxed for 30 minutes, cooled to room temperature for filtration, rinsed with acetone, and dried under vacuum at 35° C. for 3 hours to obtain 64.20 g of a white solid with a yield of 96.0%.

The product was determined by chiral HPLC with ee >99%.

The preparation of embodiment 2S-omeprazole sodium

The basic process is as follows:

Step 1 Preparation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1H-benzimidazole

2-mercapto-5-methoxy-1H-benzimidazole (62 g, 0.34 mol) and methanol (210 mL) were added to the reaction tank, and the mixture was stirred and dissolved. A solution of sodium hydroxide (28 g, 0.7 mol) in 100 ml of water was added, followed by 210 ml of 2-chloromethyl-4-methoxy-3,5-lutidine hydrochloride (70 g, 0.39 mol) in 10 min The methanol solution was added dropwise to the reaction tank. After the dropwise addition, the stirring reaction was continued at 0 to 30° C. for 3 to 5 hours.

After the reaction was completed, the temperature of the reaction solution was controlled at 89-92° C. and distilled to dryness. After distillation, 200 mL of dichloromethane was added and stirred to dissolve, and then 100 mL of purified water was added to wash. The dichloromethane layer was distilled to dryness, and the distillation was completed to obtain 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfur]-1H-benzene The crude imidazole was used directly in the next step.

Step 2 Preparation of Esomeprazole Sodium

5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1H-benzimidazole 60g (0.182mol) and 1, A mixed solvent of 30ml of 2-dichloroethane and 220ml of toluene was added to the reaction tank, stirred, heated to 70-80°C to dissolve and then cooled to 40-50°C, added 3.75g (0.0182mol) of D-diethyl tartrate, titanium 10.35 g (0.0364 mol) of tetraisopropyl acid, 2.352 g (0.0182 mol) of diisopropylethylamine, 3.3 mL of H ₂ O, 40 mL of cumene peroxide were added dropwise, and the mixture was incubated at 40-50° C. for 4 h. Then add sodium hydroxide 20g (0.5mol) methanol (80ml) solution, add the reaction kettle, continue to stir overnight, suction filtration and drying to obtain the crude product.

The crude product was dissolved in 400 mL of methanol, then 4.5 g (0.113 mol) of sodium hydroxide was added and stirred at room temperature for 2 hours, and activated carbon was stirred for 30 minutes for decolorization. After filtration, the filtrate was spin-dried, 200 mL of acetone was added, stirred and refluxed for 30 minutes, cooled to room temperature for filtration, rinsed with acetone, and dried under vacuum at 35°C for 3 hours to obtain 61.52 g of a white solid with a yield of 96.0%.

The product was determined by chiral HPLC with ee = 98%.

Example 3 Preparation of S-omeprazole sodium

The basic process is as follows:

Step 1 Preparation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1H-benzimidazole

2-mercapto-5-methoxy-1H-benzimidazole (62 g, 0.34 mol) and methanol (210 mL) were added to the reaction tank, and the mixture was stirred and dissolved. A solution of sodium hydroxide (28 g, 0.7 mol) in 100 ml of water was added, followed by 210 ml of 2-chloromethyl-4-methoxy-3,5-lutidine hydrochloride (70 g, 0.39 mol) in 10 min The methanol solution was added dropwise to the reaction tank. After the dropwise addition, the stirring reaction was continued at 0 to 30° C. for 3 to 5 hours.

After the reaction was completed, the temperature of the reaction solution was controlled at 89-92° C. and distilled to dryness. After distillation, 200 mL of dichloromethane was added and stirred to dissolve, and then 100 mL of purified water was added to wash. The dichloromethane layer was distilled to dryness, and the distillation was completed to obtain 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfur]-1H-benzene The crude imidazole was used directly in the next step.

Step 2 Preparation of Esomeprazole Sodium

5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1H-benzimidazole 60g (0.182mol) and 1, A mixed solvent of 80ml of 2-dichloroethane and 170ml of toluene was added to the reaction tank, stirred, heated to 70-80°C to dissolve, cooled to 40-50°C, added D-diethyl tartrate 3.75g (0.0182mol), titanium 10.35 g (0.0364 mol) of tetraisopropyl acid, 2.352 g (0.0182 mol) of diisopropylethylamine, 3.3 mL of H ₂ O, 40 mL of cumene peroxide were added dropwise, and the mixture was incubated at 40-50° C. for 4 h. Then add the methanol (80ml) solution of sodium hydroxide 20g (0.5mol), add the reaction kettle, continue to stir overnight, and dry with suction to obtain the crude product.

The crude product was dissolved in 400 mL of methanol, then 4.5 g (0.113 mol) of sodium hydroxide was added and stirred at room temperature for 2 hours, and activated carbon was stirred for 30 minutes for decolorization. Filtration, after the filtrate was spin-dried, added 200 mL of acetone, stirred and refluxed for 30 minutes, cooled to room temperature for filtration, rinsed with acetone, and vacuum-dried at 35°C for 3 hours to obtain 59.60 g of a white solid with a yield of 89.1%.

The product was determined by chiral HPLC with ee = 98%.

The results of Examples 1-3 show that the solvent selection of the reaction system has a certain influence on the yield. When a mixed solvent system of 1,2-dichloroethane and toluene is used, the reaction can achieve a yield of about 90%. In the optimized mixed solvent system, a yield of about 96% can be obtained.

Example 4 Preparation of S-omeprazole sodium

The basic process is as follows:

Step 1 Preparation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1H-benzimidazole

2-mercapto-5-methoxy-1H-benzimidazole (62 g, 0.34 mol) and methanol (210 mL) were added to the reaction tank, and the mixture was stirred and dissolved. A solution of sodium hydroxide (28 g, 0.7 mol) in 100 ml of water was added, followed by 210 ml of 2-chloromethyl-4-methoxy-3,5-lutidine hydrochloride (70 g, 0.32 mol) in 10 min The methanol solution was added dropwise to the reaction tank. After the dropwise addition, the stirring reaction was continued at 0 to 30° C. for 3 to 5 hours.

After the reaction was completed, the temperature of the reaction solution was controlled at 89-92° C. and distilled to dryness. After distillation, 200 mL of dichloromethane was added and stirred to dissolve, and then 100 mL of purified water was added to wash. The dichloromethane layer was distilled to dryness, and the distillation was completed to obtain 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfur]-1H-benzene The crude imidazole was used directly in the next step.

Step 2 Preparation of Esomeprazole Sodium

5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1H-benzimidazole 60g (0.182mol) and 1, A mixed solvent of 50ml of 2-dichloroethane and 200ml of toluene was added to the reaction tank, stirred, heated to 70-80°C to dissolve, cooled to 40-50°C, added 3.75g (0.0182mol) of D-diethyl tartrate, titanium 10.35 g (0.0364 mol) of tetraisopropyl acid, 2.352 g (0.0182 mol) of diisopropylethylamine, 1 mL of H ₂ O, 40 mL of hydroxycumene peroxide was added dropwise, and the mixture was incubated at 40-50° C. for 4 h. Then add the methanol (80ml) solution of sodium hydroxide 20g (0.5mol), add the reaction kettle, continue to stir overnight, and dry with suction to obtain the crude product.

The crude product was dissolved in 400 mL of methanol, then 4.5 g (0.113 mol) of sodium hydroxide was added and stirred at room temperature for 2 hours, and activated carbon was stirred for 30 minutes for decolorization. Filtration, after the filtrate was spin-dried, 200 mL of acetone was added, stirred and refluxed for 30 minutes, cooled to room temperature for filtration, rinsed with acetone, and dried under vacuum at 35°C for 3 hours to obtain 65.1 g of white solid with a yield of 97.4%.

The product was determined by chiral HPLC with ee = 70%.

The results show that when the amount of water in the chiral oxidation step is reduced, the selectivity of the reaction is significantly reduced.

Example 5 Preparation of S-omeprazole sodium

The basic process is as follows:

Step 1 Preparation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1H-benzimidazole

2-mercapto-5-methoxy-1H-benzimidazole (62 g, 0.34 mol) and methanol (210 mL) were added to the reaction tank, and the mixture was stirred and dissolved. A solution of sodium hydroxide (28 g, 0.7 mol) in 100 ml of water was added, followed by 210 ml of 2-chloromethyl-4-methoxy-3,5-lutidine hydrochloride (70 g, 0.32 mol) in 10 min The methanol solution was added dropwise to the reaction tank. After the dropwise addition, the stirring reaction was continued at 0 to 30° C. for 3 to 5 hours.

After the reaction was completed, the temperature of the reaction solution was controlled at 89-92° C. and distilled to dryness. After distillation, 200 mL of dichloromethane was added and stirred to dissolve, and then 100 mL of purified water was added to wash. The dichloromethane layer was distilled to dryness, and the distillation was completed to obtain 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfur]-1H-benzene The crude imidazole was used directly in the next step.

Step 2 Preparation of Esomeprazole Sodium

5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-1H-benzimidazole 60g (0.182mol) and 1, A mixed solvent of 50ml of 2-dichloroethane and 200ml of toluene was added to the reaction tank, stirred, heated to 70-80°C to dissolve, cooled to 40-50°C, added 3.75g (0.0182mol) of D-diethyl tartrate, titanium Tetraisopropyl acid 10.35 g (0.0364 mol), DBU 2.77 g (0.0182 mol), H ₂ O 3.3 mL, 40 mL of cumene peroxide was added dropwise, and the mixture was incubated at 40-50° C. for 4 h. Then add sodium hydroxide 20g (0.5mol) methanol (80ml) solution, add the reaction kettle, continue to stir overnight, suction filtration and drying to obtain the crude product.

The crude product was dissolved in 400 mL of methanol, then 4.5 g (0.113 mol) of sodium hydroxide was added and stirred at room temperature for 2 hours, and activated carbon was stirred for 30 minutes for decolorization. Filtration, after the filtrate was spin-dried, 200 mL of acetone was added, stirred and refluxed for 30 minutes, cooled to room temperature for filtration, rinsed with acetone, and dried under vacuum at 35°C for 3 hours to obtain 63.92 g of white solid with a yield of 95.6%.

The product was determined by chiral HPLC with ee = 88%.

The results show that when diisopropylethylamine is used as the base of the reaction, the ee value of the product is improved compared with other organic bases (such as DBU of Example 5).

All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

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.