Preparation methods of optically pure rabeprazole and sodium salt thereof

A technology of rabeprazole sodium and rabeprazole, which is applied in the field of preparation and purification of high-purity chiral rabeprazole and its sodium salt, can solve the problems of difficulty in determining the amount of NaOH, lower yield, etc., and achieve the benefit of Effects of chemical purity, low cost, and improved optical purity

Active Publication Date: 2015-03-18
燃点(南京)生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Simultaneously, when preparing rabeprazole sodium with NaOH solution, it is difficult to determine the amount of NaOH that actually adds, and when water is excessive or insufficient in the mixed solution, all can cause yield to reduce

Method used

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  • Preparation methods of optically pure rabeprazole and sodium salt thereof
  • Preparation methods of optically pure rabeprazole and sodium salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Embodiment 1: the purification of R-(+)-rabeprazole

[0034] Add 9g of crude R-(+)-rabeprazole with 95% purity and 100mL of toluene, stir to dissolve, and extract the mixture with 12.5% ​​ammonia water three times (50mL×3), and combine the aqueous phases. Take the aqueous phase, add 80 mL of methyl isobutyl ketone, and adjust the pH to 9.0 with 80% acetic acid. The liquid was separated, and the aqueous phase was extracted twice with methyl isobutyl ketone (50mL×2). Combine the organic phases with pH 10.5 K 3 PO 4 -K 2 HPO 4 Wash once with 25 mL of buffer solution. Take the organic layer, lower the temperature, let stand, and precipitate the solid. Suction filtration, washing with methyl isobutyl ketone, and drying gave 7.5 g of a white solid with a chemical purity of 99.93% (achiral analysis) and an ee value of 99.98% (chiral analysis).

Embodiment 2

[0035] Embodiment 2: the purification of S-(-)-rabeprazole

[0036] Add 9 g of crude S-(-)-rabeprazole with 70% purity and 100 mL of toluene, stir to dissolve, and extract the mixture three times with 12.5% ​​ammonia water (50 mL×3), and combine the aqueous phases. Take the water phase, add 80 mL of methyl isobutyl ketone, and adjust the pH to 9.5 with 80% acetic acid. The liquid was separated, and the aqueous phase was extracted twice with methyl isobutyl ketone (50mL×2). Combine the organic phases and wash with Na at pH 10.5 2 CO 3 -NaHCO 3 Wash once with 25 mL of buffer solution. Take the organic layer, lower the temperature, let stand, and precipitate the solid. Suction filtration, washing with methyl isobutyl ketone, and drying gave 5.9 g of a white solid with a chemical purity of 99.91% (achiral analysis) and an ee value of 99.95% (chiral analysis).

Embodiment 3

[0037] Embodiment 3: the preparation of R-(+)-rabeprazole

[0038] Add 2-[4-(3-methoxypropoxy-3-methyl-2-pyridyl)methylthio]-1H-benzimidazole 20.0g, toluene 200mL, L-(+)-tartaric acid di Ethyl ester 6.2mL, titanium tetraisopropoxide 5.2mL, water 0.14mL. After the addition was complete, the reaction was stirred at 54°C for 1h. Cool down to below 20°C, add 3.1 mL of N,N-diisopropylethylamine and 10.2 mL of cumene hydroperoxide. After addition, the reaction was stirred at 20°C for 2h. After the reaction was completed, the reaction solution was extracted three times with 12.5% ​​ammonia water (50 mL×3), and the aqueous phase was combined. Take the water phase, add 120 mL of methyl isobutyl ketone, and adjust the pH to 9.5 with 80% acetic acid. The liquid was separated, and the aqueous phase was extracted twice with methyl isobutyl ketone (50mL×2). Combine the organic phases, lower the temperature, let stand, and precipitate the solid. Suction filtration, washing with methyl ...

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Abstract

The invention discloses preparation methods of optically pure rabeprazole and a sodium salt thereof. The preparation method of optically pure rabeprazole specifically comprises the steps of dissolving an S-(-)-rabeprazole or R-(+)-rabeprazole crude product in an organic solvent, extracting by using ammonium hydroxide, removing an organic layer, adjusting a pH value of the ammonium hydroxide extract to be 8.5-10.5 by using acetic acid, extracting by using a ketone type solvent, washing the obtained organic layer by using a buffering solution with the pH value of 9-11, and cooling and crystallizing to obtain optically pure rabeprazole. According to the preparation method of optically pure rabeprazole, the chiral rabeprazole solids can be obtained at lower temperature without being subjected to high-temperature concentration; the obtained chiral rabeprazole has good crystal form, high chemical purity and high chiral purity.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation and purification method of high-purity chiral rabeprazole and its sodium salt. Background technique [0002] Rabeprazole, a second-generation proton pump inhibitor, was developed by Eisai of Japan and launched in 1991. It is clinically used to treat digestive system diseases such as duodenal ulcer, gastric ulcer, and reflux esophagitis. Rabeprazole is a partially reversible H + / K + -ATPase inhibitors that act on H + / K + - The 4 parts of ATPase, due to the increase in the number of binding targets, has a faster, longer-lasting and stronger acid-suppressing effect than other drugs. Its dissociation constant is larger than that of the first-generation PPI, and the pH range of activation is significantly larger, so it can accumulate faster in the parietal cells, and the onset of effect and the speed of relief of symptoms are faster than the first-generation PPI....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 秦勇赵维金春陈建芳苏晋沈国梁周自桂刘仙仙
Owner 燃点(南京)生物医药科技有限公司
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