Preparation method of ilaprazole

A technology of ilaprazole and mercaptobenzimidazole, applied in the field of medicine

Inactive Publication Date: 2015-05-27
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Although this method has some improvements, it still has some defects, mainly in the following aspects: 1. The reaction produces a large amount of reddish-brown by-product solid, which has poor solubility and wraps Some products are difficult to separate and purify
2. The highest yield of the patent announcement is 85%, but according to the patented method and repeated experiments, the highest yield is only 46%, and the yield is still very low
3. The whole operation process is complicated and the procedure is cumbersome, which is not conducive to industrial production
The surfactants and phase transfer catalysts used are difficult to remove and affect product quality
This method is less effective for ilaprazole, the yield is 56%, and the purity is only 85.4%
[0017] Chinese patent CN200810044803.1 discloses a preparation method of a benzimidazole proton pump inhibitor drug, using polymetallic oxygen salt as a catalyst, and using 30% H 2O2 is an oxidizing agent, which can be oxidized to obtain benzimidazole proton pump inhibitor drugs (omeprazole, pantoprazole, lansoprazole), the patent There is no preparation example of ilaprazole and no purification method of the product
Obviously the yield is still low and unsatisfactory

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Example 1 Preparation of 2-nitro-4-(1H-pyrrol-1-yl)aniline (formula VI):

[0067] 120 g (0.784 mol) of 2-nitro-1,4-phenylenediamine (Formula VII), add 12 mL of glacial acetic acid, 1200 mL of water, and 1200 mL of dichloromethane, raise the temperature to reflux, and dissolve all the raw materials, add 2,5 - 232.8 mL (1.960 mol) of dimethoxytetrahydrofuran, refluxed for 6 h, and TLC monitored the completion of the reaction. The reaction liquid was cooled, and the pH was adjusted to 7-8 with 5% sodium hydroxide solution. A large amount of solids were precipitated, and the filtrate was separated by suction filtration. The dichloromethane layer was washed with saturated brine, and dried over sodium sulfate. The aqueous layer was extracted with 1200 mL of dichloromethane. Add 1000 mL of dichloromethane to the filter cake, stir, and filter with suction. The organic phases were combined, washed with saturated brine, and dried over sodium sulfate. The desiccant was filtered...

Embodiment 2

[0068] Example 2 Preparation of 4-(1H-pyrrol-1-yl)-1,2-phenylenediamine (Formula V):

[0069] 2-nitro-4-(1H-pyrrol-1-yl)aniline (formula VI) 120.0 g (0.591 mol) and SnCl 2 2H 2 O 348 g (1.182 mol) was added to 1200 mL of ethanol, heated to reflux for 1 h, and the reaction was complete as monitored by TLC. Ethanol was recovered by distillation under reduced pressure, 1200 mL of water was added to the residue, the pH was adjusted to 9 with 5% NaOH under stirring, 1200 mL of dichloromethane was added, stirred, suction filtered, separated, the aqueous layer was extracted once with dichloromethane, The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The desiccant was filtered off and concentrated to obtain 93.2 g of 4-(1H-pyrrol-1-yl)-1,2-phenylenediamine (Formula V), yield: 91.1%. Mp: 75.2-76.1°C; 1 H NMR (DMSO-d 6 , 300MHz): 6.97-6.96(t, 2H), 6.75-6.72(m, 3H), 6.30-6.27(t, 2H), 3.43(s, 4H); ESI-MS m / z: 174.1 [M+H ] + .

Embodiment 3

[0070] Example 3 Preparation of 4-(1H-pyrrol-1-yl)-1,2-phenylenediamine (Formula V):

[0071] 2-Nitro-4-(1H-pyrrol-1-yl)aniline (Formula VI) 10.0 g (0.049 mol), sodium hydrosulfite 25.5 g (0.147 mol), add 100 mL of ethanol and 100 ml of water, heat to reflux 4 h, TLC monitors that the reaction is not complete, add 8.5 g (0.049 mol) of hydrosulfite, reflux for 2 h, and TLC monitors that the reaction is complete. Ethanol was distilled off under reduced pressure, and the aqueous layer was extracted three times with 100 mL of dichloromethane, combined, and dried over magnesium sulfate. The desiccant was filtered off and concentrated to obtain 7.1 g of 4-(1H-pyrrol-1-yl)-1,2-phenylenediamine (Formula V), yield: 84.2%.

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Abstract

The invention belongs to the technical field of medicines and provides a preparation method of ilaprazole. The method comprises the following steps: by taking 2-nitry-1, 4-phenylenediamine as an initial raw material, preparing an important intermediate 5-(1H-pyrrole-1-yl)-2-mercapto benzimidazole through the route; and then abutting and oxidizing to obtain ilaprazole. The invention not only provides a novel synthetic route, but also provides a novel method for purifying ilaprazole. The synthetic route is relatively high in yield, simple to operate without special preparation and easy for industrial production. The purification method is simple to operate, and products are obtained by primary treatment without repeated purification, so that a lot of manpower and material resources and time are saved, and moreover, the product is high in purity and good in quality.

Description

Technical field: [0001] The invention belongs to the technical field of medicine, and relates to a preparation method of ilaprazole, in particular to a synthesis and purification method of ilaprazole. Background technique: [0002] Ilaprazole (Ilaprazole) is a new generation of proton pump inhibitors (PPI), and its chemical structure belongs to benzimidazole derivatives. The drug was developed by Korea Ilyang Pharmaceutical Co., Ltd., and was first marketed by Livzon Group. [0003] [0004] Ilaprazole is an irreversible proton pump inhibitor. After oral absorption, it is metabolized into its active product, sulfenamide, and H + / K + -ATPase sulfhydryl coupling forms an irreversible covalent disulfide bond, blocking the enzyme's H + / K + transport mechanism, thereby inhibiting acid secretion. [0005] As a second-generation proton pump inhibitor, ilaprazole has many advantages over the first-generation proton pump inhibitors (PPIs) represented by omeprazole. 1. In...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14
CPCC07D401/14
Inventor 赵冬梅程卯生张如亮宋帅葛军罗江胜
Owner SHENYANG PHARMA UNIVERSITY
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