Preparation method for dexlansoprazole

A technology of dexlansoprazole and benzimidazole, which is applied in the field of preparation of dexlansoprazole, can solve problems such as increased by-products, slow reaction speed, impact on final product yield and purity, and achieves guaranteed product yield , improve product quality, shorten the effect of response time

Inactive Publication Date: 2017-03-29
石家庄市度智医药科技有限公司
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  • Abstract
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  • Application Information

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Problems solved by technology

The reaction type of this step is a nucleophilic substitution reaction, and the reaction speed is slow. With the increase of the reaction temperatu

Method used

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  • Preparation method for dexlansoprazole
  • Preparation method for dexlansoprazole
  • Preparation method for dexlansoprazole

Examples

Experimental program
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Embodiment 1

[0028] A preparation method of dexlansoprazole, comprising the following steps:

[0029] (1) Preparation of 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine

[0030] At room temperature, 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine (250g, 1.13mol) in dioxane (2.5L) was added Sulfoxide (0.11 L, 1.47 mol). The mixture was stirred and reacted at 50 °C for 3 h, then cooled to room temperature. Dilute with dichloromethane and wash successively with saturated sodium bicarbonate solution and brine solution. Dry over anhydrous magnesium sulfate, filter, and evaporate the solvent under reduced pressure to obtain 245 g of 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine with a yield of 90.5%. 1 H-NMR (CDCl 3 , 300MHz) δ8.34(d, J=5.6Hz, 1H), 6.67(d, J=5.6Hz, 1H), 4.68(s, 2H), 4.38(q, J=7.8Hz, 2H), 2.31( s, 3H).

[0031] (2) Preparation of 2-[[2-(3-methyl-4-(2,2,2-trifluoroethoxy)pyridyl)methyl]-sulfanyl]-1H-benzimidazole

[0032] 2-Chloromethyl-3-me...

example 1

[0034] Example 1. Under nitrogen protection, 2-[[2-(3-methyl-4-(2,2,2-trifluoroethoxy)pyridyl)methyl]-sulfanyl]-1H-benzimidazole (50.0g, 0.142mol), toluene (250mL) and L-(+)-diethyl tartrate (5.5mL, 0.038mol) were mixed and stirred at 50°C-55°C for 30 minutes. Under nitrogen protection, titanium tetraisopropoxide (4.15 mL, 0.0143 mol) was added, and the mixture was stirred at 50°C-55°C for 1 hour. Diisopropylethylamine (8.13 mL, 0.048 mol) was added under cooling, 82% cumene peroxide (76.5 mL, 0.425 mol) was added dropwise at 0° C. to 10° C., and the mixture was incubated and stirred for 3.5 hours.

[0035] The reaction solution was detected by HPLC (CHIRALCEL OD, mobile phase: n-hexane / ethanol=90 / 10, flow rate: 1.0 mL / min, detection wavelength: 285 nm): sulfide 1.26%, sulfone 1.01%. No other related substances were detected. Enantiomer detection: 98.0% ee.

example 2

[0036] Example 2. Under nitrogen protection, 2-[[2-(3-methyl-4-(2,2,2-trifluoroethoxy)pyridyl)methyl]-sulfanyl]-1H-benzimidazole (4.5kg, 12.7mol), toluene (22L) and L-(+)-diethyl tartrate (958mL, 5.6mol) were mixed. Under the protection of nitrogen, titanium tetraisopropoxide (7.47 L, 2.53 mol) was added at 50° C. to 60° C., and the mixture was kept stirring for 30 minutes. Diisopropylethylamine (0.733 L, 4.44 mol) was added at room temperature, and 82% cumene peroxide (6.88 L, 37.5 mol) was added dropwise at -5°C to 5°C, and kept stirring for 1.5 hours. In the above reaction solution, add 30% sodium thiosulfate aqueous solution to decompose excess cumene peroxide. Separate the organic phase, add water (4.5 L), petroleum ether (60-90° C.) (13.5 L), tert-butyl methyl ether (18 L) and petroleum ether (27 L) in sequence, and stir to crystallize. Filter and wash with tert-butyl methyl ether-toluene (4:1) (4L) to obtain dexlansoprazole.

[0037] Use HPLC to detect crystallizatio...

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Abstract

The invention discloses a preparation method for dexlansoprazole, belonging to the field of organic synthesis. The method comprises the following steps: (1) carrying out reaction on 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoro ethyoxyl) pyridine and thionyl chloride, and compounding 2-chloromethyl-3-methyl-4-(2,2,2-trifluoro ethyoxyl) pyridine; (2) putting 2-chloromethyl-3-methyl-4-(2,2,2-trifluoro ethyoxyl) pyridine acquired in the step (1) and 2-sulfydryl-1H-benzimidazole into an aqueous liquid, and then adding a phase transfer catalyst and sodium hydroxide, thereby acquiring 2-[[3-methyl-4-(2,2,2-trifluoro ethyoxyl) pyridine-2-group] methylmercapto]-1H-benzimidazole; (3) taking L-ethyl tartrate as a chiral assistant agent, titanium isopropoxide and diisopropylethylamine as a catalyst and cumyl hydroperoxide as an oxidizing agent and reacting with 2-[[3-methyl-4-(2,2,2-trifluoro ethyoxyl) pyridine-2-group] methylmercapto]-1H-benzimidazole acquired in the step (2) at low temperature, thereby acquiring dexlansoprazole. The preparation method for dexlansoprazole disclosed by the invention is simple and efficient, is capable of obviously shortening the reaction time under the condition of guaranteeing the product yield and is capable of improving the product quality.

Description

technical field [0001] The invention relates to a preparation method of dexlansoprazole, which belongs to the field of organic synthesis. Background technique [0002] Dexlansoprazole, English name: (R)-(+)-Lansoprazole (dexlansoprazole), chemical name: (R)-(+)-2-[[3-methyl-4-(2,2,2 -trifluoroethoxy)pyridin-2-yl]methylsulfinyl]-1H-benzimidazole, which has a chiral sulfur atom in the molecule and is an enantiomer of the proton pump inhibitor lansoprazole, Also known as dexlansoprazole, it is used to treat heartburn and different degrees of erosive esophagitis associated with non-erosive gastroesophageal reflux disease. It is a new drug for the treatment of esophagitis developed by Takeda Pharmaceutical Company of Japan, the United States FDA approved the listing on January 30, 2009. [0003] Dexlansoprazole is a benzimidazole proton pump inhibitor. acts specifically and noncompetitively on H + / K + -ATPase, treatment of peptic ulcer. Most proton pump inhibitors are fat-...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12
Inventor 方瑜杜玉民
Owner 石家庄市度智医药科技有限公司
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