Method for synthesizing and purifying dexlansoprazole

A technology of dexlansoprazole and an oxidizing agent, which is applied in organic chemistry and other fields, can solve the problems of poor product stability, complicated process, waste of resources and energy, etc., and achieve the effect of simple and easy-to-control preparation process, high purity and low cost

Active Publication Date: 2012-09-12
南京博德生物制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this preparation method meets the needs of industrial production to a certain extent, it still has the defects of complex process, low overall yield and purity, and poor product stability, resulting in waste of resources and energy.

Method used

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  • Method for synthesizing and purifying dexlansoprazole
  • Method for synthesizing and purifying dexlansoprazole
  • Method for synthesizing and purifying dexlansoprazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] The preparation method of embodiment 1 dexlansoprazole

[0027]

[0028] 2.70kg of the compound shown in formula I (Cas No.: 103577-40-8, purchased from Zhejiang Xinsanhe Pharmaceutical Chemical Co., Ltd.) and 1.50L of L-diethyl tartrate were suspended in 10L of toluene, Add catalytic amount of purified water dropwise, stir mechanically evenly, then add 1.5L of tetraisopropyl titanate, at this time the solution turns into a tea-red clear liquid, keep the temperature at 50-55°C and stir for 1 hour, then add 1.3L after cooling to room temperature Put the diisopropylethylamine in the cooling bath to lower the temperature. When the internal temperature drops to -5~0℃, slowly add 3.5L of cumene hydroperoxide dropwise, keep the temperature constant, and continue to stir for 1h. TLC monitoring (CH 2 Cl 2 : MeOH=25: 1, the same below) the reaction is completed, and the dexlansoprazole shown in the formula II is obtained.

[0029] Slowly pour the above reaction liquid int...

Embodiment 2

[0031] The preparation method of embodiment 2 dexlansoprazole

[0032]

[0033] Suspend 2.0 kg of the compound represented by formula I and 1.50 L of L-diethyl tartrate in 12 L of methanol, dropwise add a catalytic amount of purified water, and stir mechanically, then add 1.5 L of tetraisopropyl titanate, At this time, the solution turns into a tea-red clear liquid, keep the temperature at 40-45°C and stir for 1 hour, add 1.0L triethylamine after cooling to room temperature, put it in a cooling bath to cool down, and when the internal temperature drops to -10--5°C, Start to slowly add 3.5L cumene hydroperoxide dropwise, keep the temperature constant, continue to stir for 1h, and TLC monitors the completion of the reaction to obtain the dexlansoprazole shown in formula II.

[0034] Slowly pour the above reaction liquid into 30L of petroleum ether, a large amount of white milky matter is formed, let it stand for 0.5~1h, after the stratification is complete, separate the bro...

Embodiment 3

[0036] The preparation method of embodiment 3 dexlansoprazole

[0037]

[0038] Suspend 3.0 kg of the compound represented by formula I and 2.0 L of L-diethyl tartrate in 12 L of toluene, add a catalytic amount of purified water dropwise, and stir mechanically, then add 2.0 L of tetraisopropyl titanate At this time, the solution turns into a tea-red clear liquid. Keep the temperature at 60-70°C and stir for 1 hour. After cooling to room temperature, add 1.5L diisopropylethylamine, put it in a cooling bath to cool down, and wait until the internal temperature drops to -15-15°C. At -10°C, start to slowly add 4.0L cumene hydroperoxide dropwise, keep the temperature constant, continue to stir for 1h, and monitor the completion of the reaction by TLC to obtain dexlansoprazole shown in formula II.

[0039] Slowly pour the above reaction liquid into 43L of n-heptane, a large amount of white milky substance is formed, let it stand for 1.5h, wait for the stratification to complete...

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Abstract

The invention mainly relates to an improved method for synthesizing dexlansoprazole by utilizing a Sharpless asymmetric oxidation method and an optimized method for purifying dexlansoprazole. According to the method, the total yield is above 40% and the purity of the product and the enantiomeric excess (e.e.) are both above 99.5%. The preparation method is simple, is low in cost and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing and purifying dexlansoprazole. Background technique [0002] Lansoprazole (Lansoprazole, Cas No.: 103577-45-3) is a benzimidazole derivative with gastric acid secretion inhibitory effect developed by Japan's Takeda Pharmaceutical Company in the late 1980s. In 1986, it was developed by Nohara Akira et al. It was first synthesized, and clinical experiments proved that the compound has the characteristics of anti-ulcer activity, control of gastric acid secretion, protection of gastric mucosa, and low toxicity. It was first listed in Japan in 1992. The chemical name of lansoprazole is 2-[3-methyl-4-(2,2,2-trifluoroethyl)-2-pyridyl]-methylsulfinyl-1H-benzimidazole, which has The chemical structure shown in the formula (Lansoprazole). [0003] [0004] Akira et al first disclosed the chemical structure and preparation method of lansoprazole in US4628098, and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
Inventor 闵涛车晓明晁阳叶海顾传虎胡玉琴
Owner 南京博德生物制药有限公司
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