Preparation method of ilaprazole

A technology of ilaprazole and mercaptobenzimidazole, which is applied in the field of preparation of ilaprazole, can solve the problems of high production cost, complicated operation, and many impurities, and achieve the reduction of production power cost, mild reaction conditions, and optimized reaction The effect of the operation

Active Publication Date: 2013-05-01
LIVZON PHARM GRP INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] 1), the reaction time of the intermediate thioether is too long, the operation is more complicated, and the yield is low
[0014] 2), using chloroform and ether as solvents, which are highly toxic and pollute the environment
[0015] 3) Using m-chloroperoxybenzoic acid as the oxidizing agent is expensive, the production cost is high, the process stability is poor, and the reaction conditions are relatively harsh. It needs to be carried out at a low temperature of -30~-40°C
[0016] 4) The oxidation process will also be accompanied by the occurrence of peroxidation reaction, resulting in the production of impurity peroxide sulfonylate, the product quality is low, or in order to remove this impurity, it needs to be further refined and removed, resulting in a further increase in cost
This preparation method uses oxidizing agent to be hydrogen peroxide, and this method is used for preparing omeprazole better, and if it is used for preparing pantoprazole, lansoprazole, its quality is relatively poor, does not see it has Aipu in addition The preparation example of omeprazole, the yield of ilaprazole obtained according to the example method of preparing omeprazole is only 45%; In addition, the reaction is not well controlled, and there are many impurities

Method used

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  • Preparation method of ilaprazole
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  • Preparation method of ilaprazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Embodiment 1 prepares ilaprazole intermediate thioether

[0055] Experiment A

[0056] Operate with reference to Example 1 of Chinese Patent CN94191913.7.

[0057] At room temperature, 2g of 5-(1H-pyrrol-1-yl)-2-mercaptobenzimidazole was dissolved in 0.74g of sodium hydroxide and 100ml of methanol solution, and 3-methyl-4- Methoxy-2-chloromethylpyridine hydrochloride 1.9g, then reacted at 50-60°C for 3 hours, and filtered to remove inorganic substances. The solvent was evaporated under reduced pressure and crystallized from diethyl ether. A light yellow solid was obtained, which was dried to obtain the thioether intermediate of ilaprazole. The yield is 80.5%, and the purity is 98.0% (see accompanying drawing 1).

[0058] The purity detection of the product adopts HPLC method.

[0059] Experiment B

[0060] Operate with reference to Example 22 of Chinese Patent CN200610022315.3.

[0061] At room temperature, 0.66g (2.18mmol) of 5-amino-2[(4-methoxy-3-methyl-2-pyri...

Embodiment 2

[0067] Embodiment 2 prepares ilaprazole intermediate sulfide

[0068] At room temperature, sequentially add 5-(1H-pyrrol-1-yl)-2-mercaptobenzimidazole (85.9g, 0.40mol), sodium hydroxide (31.9g, 0.80mol), organic solvent A (2121ml), ice Stir in a water bath, slowly add 3-methyl-4-methoxy-2-chloromethylpyridine hydrochloride (84.0g, 0.41mol), potassium iodide (3.3g, 0.02mol), slowly heat up to reflux, and react After about 1 hour, the reaction progress was monitored by TLC. After the reaction was complete, part of the solvent was evaporated under reduced pressure, and then purified water was added to obtain a white solid, which was dried to obtain ilaprazole intermediate thioether. (Purity measured by HPLC).

[0069] Organic solvent A

[0070] As can be seen from the above table, the selection of the organic solvent in this step has a great impact on the yield and purity of ilaprazole intermediate thioether, wherein acetone is the optimal choice.

Embodiment 3

[0071] Embodiment 3 prepares ilaprazole intermediate thioether

[0072] At room temperature, 5-(1H-pyrrol-1-yl)-2-mercaptobenzimidazole (85.9g, 0.40mol), inorganic base (31.9g, 0.80mol), acetone (2121ml) were added successively, stirred in an ice-water bath, Slowly add 3-methyl-4-methoxy-2-chloromethylpyridine hydrochloride (84.0g, 0.41mol), potassium iodide (3.3g, 0.02mol), slowly raise the temperature to reflux, and react for about 1h , TLC monitoring of the reaction process, after the reaction is complete, part of the solvent was evaporated under reduced pressure, and then purified water was added to obtain a white solid, which was dried to obtain ilaprazole intermediate thioether. (Purity measured by HPLC).

[0073] Inorganic base

[0074] potassium carbonate

[0075] As can be seen from the above table, the selection of the inorganic base in this step has a great impact on the yield and purity of ilaprazole intermediate sulfide, wherein sodium hydroxi...

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Abstract

The invention provides a preparation method of ilaprazole. According to the method, ilaprazole is prepared through a thioether intermediate; obtained ilaprazole is high in quality and has no overoxidation impurities; the method is simple and easy, high in yield, low in cost, environment-friendly, and suitable for industrial production, and has no need for special equipment; and no toxic chloroform solvent is used.

Description

technical field [0001] The invention relates to a preparation method of ilaprazole. Background technique [0002] Ilaprazole (Formula I) is a new generation of proton pump inhibitors (PPI). In 2001, Livzon Pharmaceutical Group obtained the patent right to use Ilaprazole from Ilyang Pharmaceutical Co., Ltd. in Korea, and in 2008 Livzon Pharmaceutical Group was the first to go public globally. [0003] [0004] Ilaprazole [0005] Ilaprazole is an irreversible proton pump inhibitor, and its structure belongs to the benzimidazole class. After oral administration, ilaprazole selectively enters the parietal cells of the stomach and is transformed into an active metabolite of sulfenamide, which interacts with the sulfhydryl group on the H+, K+-ATPase to form a covalent combination of disulfide bonds, irreversibly inhibiting H+, K+- ATPase, which produces the effect of inhibiting gastric acid secretion. [0006] The first-generation proton pump inhibitors PPIs (omeprazole, p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14
Inventor 周月广曾创叶剑轩涂增清陈剑陈海龙黄滔侯雪梅肖鸿汪伟明李菁
Owner LIVZON PHARM GRP INC
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