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Preparation method of dexlansoprazole

A technology of dexlansoprazole and trifluoroethanol, applied in the field of pharmaceutical synthesis, can solve the problems of large sulfone-type impurities, high cost and low purity of the product, and achieve the effects of shortening the process cycle, improving the yield and simplifying the process flow

Inactive Publication Date: 2018-05-29
JIANGSU HANSOH PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] (1) In the process of asymmetric oxidation, impurities such as sulfone impurities and N-oxides will be produced. These impurities are difficult to remove by conventional purification methods such as recrystallization. Therefore, this method needs to be removed by chromatography. However, this method for removing impurities cost too high
[0013] (2) In order to precisely control the oxidation in the asymmetric oxidation process, transition metals such as vanadium need to be used as catalysts to suppress the generation of impurities, but this can only hinder the generation of N-oxides, and cannot reduce the sulfone type in the product. The content of impurities, and these transition metals will bring toxicity to the active components
However, there are problems in this method that the raw materials cannot be completely reacted, and the resulting product has large sulfone-type impurities and low purity. It is difficult to obtain qualified samples without column chromatography purification.

Method used

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  • Preparation method of dexlansoprazole
  • Preparation method of dexlansoprazole
  • Preparation method of dexlansoprazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039]

[0040]Add dimethyl sulfoxide (DMSO)) 4L, trifluoroethanol 2.6kg, sodium trifluoroethoxide 2.5kg, R-2-(((4-chloro-3-methyl-2-pyridyl) Methyl)sulfinyl)benzimidazole 800g, heated to 90-100°C, reacted for 3-4 hours, HPLC detection formula (I) compound content was 0.04%, sulfone type impurity content 0.23%; the reaction solution was cooled to At room temperature, add 24L of 5% sodium chloride aqueous solution dropwise, lower to 0-10°C and stir for 0.5-1 hour, filter, dissolve the obtained solid in 24L of ammonia water, wash with dichloromethane (8L×3), stir for 15-20 Minutes, separate the liquid, adjust the pH of the ammonia water layer to 8-9 with glacial acetic acid (temperature control 0-10°C during the period), stir for 0.5-1 hour, filter, dissolve the obtained solid in 8L of acetonitrile, add 32L of water dropwise, and stir for 2-3 hours , filtered, the obtained solid was dissolved in 8L of acetonitrile again, 32L of water was added dropwise, stirred for 2-3 hours,...

Embodiment 2

[0043]

[0044] Add 1 L of N-methylpyrrolidone (NMP), 650 g of trifluoroethanol, 625 g of sodium trifluoroethoxide, R-2-(((4-chloro-3-methyl-2-pyridyl) methyl ) sulfinyl)benzimidazole 200g, heated to 90-100°C, reacted for 3-4 hours, HPLC detected that the compound content of formula (I) was 0.05%, and the content of sulfone-type impurities was 0.3%; the reaction solution was cooled to room temperature, Add 6L of 5% aqueous sodium chloride solution dropwise, drop to 0-10°C and stir for 0.5-1 hour, filter, dissolve the obtained solid in 6L of ammonia water, wash with dichloromethane (2L×3), stir for 15-20 minutes each time, Separate the liquid, adjust the pH of the aqueous ammonia layer to 8-9 with glacial acetic acid (control the temperature at 0-10°C during the period), stir for 0.5-1 hour, filter, dissolve the obtained solid in 2L of acetonitrile, add 8L of water dropwise, stir for 2-3 hours, and filter , the obtained solid was dissolved in 2L of acetonitrile again, 8L of ...

Embodiment 3

[0047]

[0048] Add N,N-dimethylformamide (DMF) 800ml, sodium trifluoroethoxide 500g, R-2-(((4-chloro-3-methyl-2-pyridyl)methyl) Sulfinyl)benzimidazole 160g, heated to 90-100°C, reacted for 3-4 hours, HPLC detection formula (I) compound content was 0.04%, sulfone impurity content 0.2%; the reaction solution was cooled to room temperature, drop Add 4.8L of 5% sodium chloride aqueous solution, lower to 0-10°C and stir for 0.5-1 hour, filter, dissolve the obtained solid in 4.8L of ammonia water, wash with dichloromethane (1.6L×3), stir for 15-20 Minutes, liquid separation, the ammonia water layer was adjusted to pH 8-9 with glacial acetic acid (temperature control 0-10°C during the period), stirred for 0.5-1 hour, filtered, the obtained solid was dissolved in 1.6L of acetonitrile, 6.4L of water was added dropwise, and stirred for 2- After 3 hours, filter, the obtained solid was dissolved in 1.6L of acetonitrile again, 6.4L of water was added dropwise, stirred for 2-3 hours, fi...

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Abstract

The invention relates to a preparation method of dexlansoprazole. The method includes: preparation of the formula (I) compound into dexlansoprazole by substitution in the presence of a trifluoroethanol metal salt. The method has a simple process, and can acquire high yield and high purity dexlansoprazole without column chromatography, and is very suitable for industrial mass production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a preparation method of dexlansoprazole. Background technique [0002] Dexlansoprazole is a new gastroesophageal reflux disease drug superior to lansoprazole, and its structural formula is as follows. [0003] [0004] FDA approves Takeda Pharmaceutical North America's dexlansoprazole controlled-release capsules (dexlansoprazole, Kapidex) for the treatment of heartburn caused by non-erosive gastroesophageal reflux (GERD), erosive esophagitis (EE) and EE maintenance treatment was administered once a day. This product is the first dual-release controlled-release (DDR) proton pump inhibitor on the market, with a formulation specification of 30mg or 60mg per capsule. [0005] Proton pump inhibitors reduce gastric acid production by inhibiting H' / K'-ATP. This product contains 2 types of enteric-coated granules, and there are 2 unique peaks in the temporary curve of the drug. The fi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 仇伟强盛志辉傅小勤陈安丰周炳城
Owner JIANGSU HANSOH PHARMA CO LTD
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