Preparation method of ilaprazole degradation impurity A
The problem of efficient preparation of impurity A in ipramazole degradation was solved by using a reaction catalyzed by a carbocation scavenger and Lewis acid, and by recrystallization. This method achieved high purity and stability, meeting the requirements of drug quality control.
Patent Information
- Application Number
- CN202310881703.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-07-18
- Publication Date
- 2025-01-21
AI Technical Summary
Existing technologies make it difficult to efficiently prepare high-purity ipramazole degradation impurity A, and it is easily degraded in acidic environments, affecting drug safety and quality control.
The reaction of ipramazole with the organic solvent chloroform was catalyzed at low temperature using carbocation scavenger anisole and Lewis acid copper trifluoromethanesulfonate. Subsequently, the ipramazole degradation impurity A was purified by recrystallization in a mixed solvent of n-butanol and acetonitrile.
A high-yield and high-purity preparation of ipramazole degradation impurity A was achieved, ensuring drug stability and quality control, and is suitable for toxicological studies in drug development and production processes.
Abstract
Description
Technical Field
[0001] The present invention belongs to the field of drug preparation, and in particular, relates to a method for preparing an ilaprazole degradation impurity A. Background Art
[0002] Ilaprazole, structural formula: ; It is a new generation of proton pump inhibitor (PPI). In 2001, Livzon Pharmaceutical Group purchased the patent rights of ilaprazole from Ilyang Pharmaceutical Co., Ltd. of South Korea, and in 2008, Livzon Pharmaceutical Group was the first to launch it globally.
[0003] Ilaprazole is an irreversible proton pump inhibitor, and its structure belongs to the benzimidazole class. After oral administration, ilaprazole selectively enters the gastric parietal cells and is converted into a sulfonamide active metabolite, which reacts with the hydrophobic groups on H+ and K+-ATPase to form a covalent disulfide bond, irreversibly inhibiting H+ and K+-ATPase and inhibiting gastric acid secretion.
[0004] The first generation of proton pump inhibitors (PPIs) (omeprazole, pantoprazole and lansoprazole) are now widely used in clinical practice because of their low cost. However, they rely on hepatic cytochrome P450 isoenzymes (CYP2C19 and CYP3A4) for metabolism and clearance, and have significant interactions with other drugs that are metabolized and cleared by this isoenzyme. In addition, the instability of acid suppression, the concentration and enzyme activity required for its effect, and the short half-life have limited clinical application; the onset of action is slow, the cure rate and remission rate are unstable, and some patients even develop omeprazole resistance or failure. It can be seen that the efficacy of the first generation of PPIs is greatly affected by metabolism, resulting in significant individual differences in efficacy.
[0005] Ilaprazole is a second-generation proton pump inhibitor that basically overcomes the above shortcomings. Its characteristics are as follows: 1. It has a faster onset of action, better acid suppression effect, and can suppress acid for 24 hours. The inhibitory activity of ilaprazole on proton pumps is 16 times that of omeprazole and 2 times that of rabeprazole. 2. It is less dependent on the metabolism of CYP2C19 enzyme in the liver P450 enzyme series, with small individual differences and less interaction with other drugs. 3. It has advantages in pharmacokinetics, such as the higher dissociation constant of ilaprazole, so it can accumulate faster in parietal cells and exert its effect faster and better. 4. The half-life of ilaprazole is 3.0 to 4.0 hours, which is the longest among all PPIs, and therefore the effect is the most lasting.
[0006] Ilaprazole has a prominent disadvantage, which is poor thermal stability. It is more susceptible to degradation in an acidic environment. The main degradation component is the degradation impurity A of Ilaprazole, whose structural formula is: ; The chemical name is 1-methyl-8-(1H-pyrrole-1-yl)-12-thiobenzo[4',5']imidazo[2',1':2,3]imidazo[1,5-a]pyridine-2(12H)-one. In the process of drug development and production, a large amount of this degradation impurity needs to be prepared for toxicological research. In the production of raw materials, preparation process, and storage process of ilaprazole, ilaprazole degradation impurity A must be tracked and monitored to ensure the safety and effectiveness of the drug. Therefore, a stable and high-purity method for preparing ilaprazole degradation impurity A is needed. Summary of the invention
[0007] The object of the present invention is to provide a method for preparing ilaprazole with high quality and high yield by degradation of impurities. The specific reaction formula is as follows: .
[0008] Specifically, the technical solution of the present invention is a method for preparing ilaprazole degradation impurity A. The method comprises the following steps: Step 1: The pure ilaprazole (content greater than 99%) is cyclized in an organic solvent under the action of a carbocation scavenger and the catalysis of a Lewis acid to generate ilaprazole degradation impurity A.
[0009] Step 2: The ilaprazole degradation impurity A obtained in step 1 is recrystallized in a mixed solvent of n-butanol and acetonitrile to obtain a pure product of ilaprazole degradation impurity A.
[0010] In the above step 1, the carbocation eliminator is anisole; In the above step 1, the solvent is chloroform; In the above step 1, the Lewis acid is copper trifluoromethanesulfonate; In the above step 1, the optimal reaction temperature is 0-10°C; In the above step 2, the ratio of n-butanol to acetonitrile is 1:1; The invention provides a convenient method for preparing high-purity ilaprazole degradation impurity A, and the method is stable and easy to operate. Specific embodiments
[0011] 1. Preparation of Ilaprazole Degradation Impurity A In a 250ml three-necked flask, add 5g of pure ilaprazole (content greater than 99%), 40ml of chloroform and 5ml of anisole, cool the reaction solution to 0-10°C while stirring, then add 0.8g of copper trifluoromethanesulfonate and stir at 0-10°C for 2 hours. After the reaction is completed, add 50ml of water to the reaction solution and stir to separate the layers. The chloroform layer is evaporated to dryness under reduced pressure and rotary evaporated. Add 20ml of ethanol and stir at room temperature for crystallization for 1 hour. Filter with suction, wash the filter cake with 5ml of ethanol, and dry the obtained solid at 45-55°C under normal pressure for 4 hours to obtain 3.8g of ilaprazole degradation impurity A solid.
[0012] 2. Purification of Ilaprazole Degradation Impurity A In a 250ml three-necked flask, add 3.8g of ilaprazole degradation impurity A primary product, 15ml of n-butanol and 15ml of acetonitrile, stir, and reflux for 0.5 hours. Naturally cool to room temperature, stir and crystallize for 1 hour, filter by suction, wash the filter cake with 5ml of ethanol, and dry the obtained solid at 45-55℃ under normal pressure for 4 hours to obtain 2.5g of ilaprazole degradation impurity A solid pure product, with a content of more than 99.6%.
Claims
1. A method for preparing ilaprazole degradation impurity A, the preparation method comprising the following steps: (1) cyclizing the pure ilaprazole in an organic solvent under the action of a carbocation scavenger and the catalysis of a Lewis acid to generate ilaprazole degradation impurity A; (2) The ilaprazole degradation impurity A obtained in step 1 is recrystallized in a mixed solvent of n-butanol and acetonitrile to obtain a pure product of ilaprazole degradation impurity A.
2. In the preparation method according to claim 1, the carbocation eliminating agent described in the above-mentioned step 1 is anisole.
3. In the preparation method according to claim 1, the solvent in the above step 1 is chloroform.
4. In the preparation method according to claim 1, in the above step 1, the Lewis acid is copper trifluoromethanesulfonate.
5. In the preparation method according to claim 1, the optimal reaction temperature in the above step 1 is 0-10°C.
6. In the preparation method according to claim 1, in the above step 2, the ratio of n-butanol to acetonitrile is 1:1.