Preparation method of digestive drug intermediate

Abstract

The invention discloses a preparation method of a digestive drug intermediate, 5-difluoromethoxy-2-mercapto-1H-benzimidazole (II) and 2-chloromethyl-3, 4-dimethoxypyridine hydrochloride (III) react to prepare an intermediate I. The product obtained by the preparation method provided by the invention is high in yield and purity, and the pollution of three wastes is low. And the preparation process is simple to operate, mild in reaction condition, favorable for saving the production cost and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing a digestive drug intermediate. Background Art

[0002] Pantoprazole Sodium, chemical name is 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole sodium sesquihydrate, and its structural formula is:

[0003]

[0004] Pantoprazole sodium is the third generation proton pump inhibitor after omeprazole and lansoprazole. Pantoprazole sodium is a proton pump inhibitor of gastric parietal cells. It is relatively stable under neutral and weakly alkaline conditions and rapidly activated under acidic conditions. Its pH-dependent activation characteristics make it more selective for H+ and K+-ATPase. This product can specifically inhibit the H+ and K+-ATPase on the secretory microtubules and tubular vesicles in the cytoplasm of the parietal cells, causing irreversible inhibition of the enzyme, thereby effectively inhibiting the secretion of gastric acid. Since H+ and K+-ATPase are the last process of acid secretion of parietal cells, this product has a strong acid inhibition ability. It can not only non-competitively inhibit gastric acid secretion caused by gastrin, histamine, and choline, but also inhibit part of the basic gastric acid secretion that is not affected by choline or cardiac receptor blockers. When used in combination with other drugs, this product has the advantage of small drug interactions. This product is metabolized by the I system of the cytochrome P450 enzyme system in hepatocytes, and can also be metabolized by the II system. When used with other drugs that are metabolized by the P450 enzyme system, the metabolic pathway of this product can be carried out through the II enzyme system, which makes it less likely to have competitive effects on the drug-metabolizing enzyme system and reduce the interaction between drugs in the body. It has no mutagenic, carcinogenic and teratogenic effects.

[0005] The synthesis route of pantoprazole sodium reported in the current patent literature uses 5-difluoromethoxy-2-mercapto-1H-benzimidazole and 2-chloromethyl-3,4-dimethoxypyridine hydrochloride as starting materials, and prepares pantoprazole sodium through condensation, oxidation, and salt-forming reactions. Among them, thioether is an important intermediate for the synthesis of pantoprazole sodium and is also the key to the production cost of pantoprazole sodium. Therefore, the intermediate thioether plays an important role.

[0006] Chinese patent CN103232438A discloses a method for preparing pantoprazole intermediate sulfide: the process uses water as a reaction solvent, obtains a crude sulfide after reaction, crystallization, filtration and drying, and then the crude product is refined in isopropanol to obtain a refined sulfide. However, the process takes a long time for reaction and refining crystallization, and the purity of the obtained crude product is not high. A further refining step is required to meet the requirements, and the yield is only 90%. Therefore, the cost is high and it is not suitable for large-scale production.

[0007] The literature J.Med.Chem.1992,35,1049-1057 reported that ethanol was used as the solvent, the reaction was carried out at 50°C for 2 hours, and then the reaction was concentrated, extracted with dichloromethane, washed with sodium hydroxide aqueous solution, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product with a yield of 92%. The process operation is particularly cumbersome, and the purity of the obtained crude product is not high.

[0008] In order to solve the problems existing in the prior art, the present invention provides a new preparation method, which has simple operation in the post-reaction treatment process, high product yield and purity, low cost and is very suitable for industrial production. Summary of the invention

[0009] The present invention aims to provide a method for preparing a digestive drug intermediate in view of the deficiencies in the prior art. The method has mild reaction conditions, simple operation, significantly improved product yield and purity, low production cost, and is suitable for industrial production.

[0010] A method for preparing a digestive drug intermediate comprises the following steps:

[0011] After 5-difluoromethoxy-2-mercapto-1H-benzimidazole (Ⅱ) reacts with 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (Ⅲ), a solvent is first added for crystallization, and then an acid solution is used to adjust the pH for crystallization, and pantoprazole sodium thioether intermediate (Ⅰ) is prepared through post-treatment.

[0012] Its synthetic route is as follows:

[0013]

[0014] Preferably, the acid is hydrochloric acid, sulfuric acid, acetic acid or phosphoric acid, more preferably hydrochloric acid.

[0015] Preferably, the molar ratio of 5-difluoromethoxy-2-mercapto-1H-benzimidazole (II) to 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (III) is 1-1.1:1.

[0016] Preferably, the pH is 9.5-13, and more preferably, the pH is 10.5-12.

[0017] Preferably, the solvent is water.

[0018] Preferably, the reaction conditions of 5-difluoromethoxy-2-mercapto-1H-benzimidazole (II) and 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (III) are organic solvent and base.

[0019] Preferably, the organic solvent is anhydrous ethanol.

[0020] Preferably, the base is sodium hydroxide, and the molar ratio of the sodium hydroxide to 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (III) is 2-3:1.

[0021] Preferably, the post-treatment is filtering, washing and drying.

[0022] Preferably, the specific reaction steps of the present invention are as follows: adding anhydrous ethanol, 5-difluoromethoxy-2-mercapto-1H-benzimidazole (II), sodium hydroxide aqueous solution, and 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (III) into a reactor; after the reaction is completed, adding water for crystallization, then adjusting the pH with hydrochloric acid solution for crystallization, filtering, washing with water, and vacuum drying to obtain pantoprazole sodium intermediate sulfide (I).

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] 1. By improving the existing technical process, the product yield and quality are improved;

[0025] 2. The preparation method of the present invention is simple, the reaction conditions are mild, the production cost is low, and it is suitable for industrial production. DETAILED DESCRIPTION

[0026] The content of the invention of the present invention is further described in detail below through specific embodiments, but the content of the present invention is not limited thereto.

[0027] Example 1: Preparation of Pantoprazole Sodium Intermediate Thioether (I)

[0028] Add 2.5L of anhydrous ethanol and 500g of 5-difluoromethoxy-2-mercapto-1H-benzimidazole (II) into the reactor, add sodium hydroxide solution (223g of sodium hydroxide dissolved in 2.5L of water) dropwise at 25°C within 1h, and then continue to add 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (III) solution (500g of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (III) dissolved in 2.5L of purified water) dropwise within 1h. After the addition is complete, stir the reaction for 1h. Then, 10 L of water was added to the system, and the pH of the solution was adjusted to 11.5 with 2 mol / L hydrochloric acid. The temperature was lowered to 0-10°C for crystallization for 1 h, filtered, the filter cake was rinsed with 5 L of water, and vacuum dried at 40°C to obtain 841.19 g of solid. The yield of pantoprazole sulfide (IV) (water content: 98.0%), water content: 4.5%, and purity: 99.38%.

[0029] Example 2: Preparation of Pantoprazole Sodium Intermediate Thioether (I)

[0030] Add 2.5L of anhydrous ethanol and 482.44g of 5-difluoromethoxy-2-mercapto-1H-benzimidazole (II) into the reactor, add sodium hydroxide solution (178.50g of sodium hydroxide dissolved in 2.5L of water) dropwise at 25°C within 1h, and then continue to add 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (III) solution (500g of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (III) dissolved in 2.5L of purified water) dropwise within 1h. After the addition is complete, stir the reaction for 1h. Then, 10 L of water was added to the system, and the pH of the solution was adjusted to 10.5 with acetic acid. The temperature was lowered to 0-10° C. for crystallization for 1 h, filtered, the filter cake was rinsed with 5 L of water, and vacuum dried at 40° C. to obtain 846.37 g of solid. The yield of pantoprazole sulfide (IV) (water content: 98.5%), water content: 4.6%, and purity: 99.25%.

[0031] Example 3: Preparation of Pantoprazole Sodium Intermediate Thioether (I)

[0032] Add 2.5L of anhydrous ethanol and 530.68g of 5-difluoromethoxy-2-mercapto-1H-benzimidazole (II) to the reactor, add sodium hydroxide solution (267.76g of sodium hydroxide dissolved in 2.5L of water) dropwise at 25°C within 1h, then continue to add 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (III) solution (500g of 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (III) dissolved in 2.5L of purified water) dropwise within 1h, stir and react for 1h. Then add 10L of water to the system, adjust the pH of the feed solution to 12 with phosphoric acid, cool to 0-10°C for crystallization for 1h, filter, rinse the filter cake with 5L of water, and vacuum dry at 40°C to obtain 835.18g of solid, pantoprazole sulfide (IV) yield (water dry): 97.3%, water: 4.5%, purity: 99.44%.

Claims

1. A method for preparing a digestive drug intermediate, characterized in that: It includes the following steps: After 5-difluoromethoxy-2-mercapto-1H-benzimidazole (II) reacts with 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (III), a solvent is first added for crystallization, and then an acid solution is used to adjust the pH for crystallization. After post-treatment, pantoprazole sodium sulfide intermediate (I) is prepared. The synthetic route is as follows:

2. The preparation method according to claim 1, characterized in that The acid is hydrochloric acid, acetic acid or phosphoric acid, preferably hydrochloric acid.

3. The preparation method according to claim 1, characterized in that: The molar ratio of the 5-difluoromethoxy-2-mercapto-1H-benzimidazole (II) to the 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (III) is 1-1.1:

1.

4. The preparation method according to claim 1, characterized in that: The pH is 9.5-13.

5. The preparation method according to claim 4, characterized in that: The pH is 10.5-12.

6. The preparation method according to claim 1, characterized in that: The solvent is water.

7. The preparation method according to claim 1, characterized in that: The reaction conditions of 5-difluoromethoxy-2-mercapto-1H-benzimidazole (II) and 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (III) are organic solvent and base.

8. The preparation method as claimed in claim 7, characterized in that The organic solvent is anhydrous ethanol.

9. The preparation method as claimed in claim 7, characterized in that The base is sodium hydroxide, and the molar ratio of the sodium hydroxide to 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (III) is 2-3:

1.

10. The preparation method according to claim 1, characterized in that: The post-treatment is filtering, washing and drying; the preferred specific reaction steps are as follows: adding anhydrous ethanol, 5-difluoromethoxy-2-mercapto-1H-benzimidazole (II), sodium hydroxide aqueous solution and 2-chloromethyl-3,4-dimethoxypyridine hydrochloride (III) into a reactor; after the reaction is completed, adding water for crystallization, then adjusting the pH with hydrochloric acid solution for crystallization, filtering, washing with water and vacuum drying to obtain pantoprazole sodium intermediate sulfide (I).

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