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Preparation method of (R)-lansoprazole

A technology of dexlansoprazole and dexlansoprazole, which is applied in the field of preparation of dexlansoprazole, can solve problems such as high price of resolving agent, unfavorable large-scale production, serious environmental pollution, etc., and achieve material cost The effect of reducing energy consumption, convenient post-processing, and simple process

Inactive Publication Date: 2017-09-08
长沙康普大药房有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The existing synthetic route has the following disadvantages: (1) The synthesis cost is high, the harm to the human body is great, and the environmental pollution is serious; (2) The price of the resolving agent is relatively expensive, and it needs to undergo multiple encapsulation and splitting to obtain Optically pure products have low yields; (3) dangerous and highly toxic reagents are used, which require high equipment and are not conducive to large-scale production

Method used

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  • Preparation method of (R)-lansoprazole
  • Preparation method of (R)-lansoprazole
  • Preparation method of (R)-lansoprazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] (1) Preparation of (IV)

[0036]

[0037]Add sodium hydroxide (20.0 g, 0.5 mol) into ethanol (95%, 0.5 L ), stir and dissolve, then add compound Ⅱ (34.1 g, 0.23 mol) and compound Ⅲ (62.7 g, 0.23 mol) in turn, at room temperature The reaction was stirred for 2 h. About 400mL of ethanol was distilled off, water (0.46 L ) was added to the residue, stirred at room temperature for 1 hour, then suction filtered, and the filter cake was washed with water (300mL×3). The obtained solid was beaten and washed with ethyl acetate (300ml) for 1 h, then suction filtered, and the filter cake was dried at 45°C to obtain white powdery solid IV (76.32g), with a yield of 95%.

[0038] (2) Preparation of (I)

[0039]

[0040] Compound IV (60 g, 169.8 mmol), toluene (700 ml), D-(-)-C)-diethyl tartrate (70.1 g, 340.4 mmol), titanium tetraisopropoxide (48.4 g, 170.4mmol) and water (1.53 g, 84.8mmol) were sequentially added to the three-necked flask, stirred and heated to reflux for 1h...

Embodiment 2

[0043] Embodiment 2: the difference with embodiment 1 is that the preparation of (I) adopts sodium methylate and methyl alcohol.

[0044] Add sodium methoxide (27.0g, 0.5mol) into methanol (95%, 0.5L), stir to dissolve, add compound II (34.1g, 0.23mol) and compound III (62.7 g, 0.23mol) in turn, and stir at room temperature React for 2 h. About 400mL of methanol was distilled off, water (0.46 L ) was added to the residue, stirred at room temperature for 1 hour, then suction filtered, and the filter cake was washed with water (300mL×3). The obtained solid was beaten and washed with ethyl acetate (300ml) for 1 h, then suction filtered, and the filter cake was dried at 45°C to obtain white powdery solid IV (74.23g), with a yield of 92.4%.

Embodiment 3

[0045] Embodiment 3: the difference with embodiment 1 is that (I) refining used solvent is different.

[0046] Under nitrogen protection, compound IV (25g, 70.8mmol) was thrown into toluene (100ml), and L-diethyl tartrate (12.1ml, 70.8mmol) and vanadyl acetylacetonate (9.42g, 35.4mmol) were added successively under stirring. ), and stirred for 1 h at 50-55 °C. After cooling, add triethylamine (7.3mL, 53mmol), slowly add cumene hydroperoxide (85%, 18.4ml, 106.2mmol) under stirring, react at room temperature for 8 h, evaporate the solvent under reduced pressure, and obtain an off-white solid Throw it into acetonitrile (180ml), stir for 15min, then filter with suction, and repeat the above operation once for the filtrate (the volume of acetonitrile used is 90ml). The solvent is evaporated under reduced pressure to obtain compound I1 (51.2g, 81.5%) as a white solid.

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Abstract

The invention provides a preparation method of (R)-lansoprazole. Through a condensation reaction and an asymmetric oxidation reaction of thioether, the (R)-lansoprazole is prepared. The preparation method comprises refining a (R)-lansoprazole finished product. In the first reaction step, cheap sodium hydroxide replaces sodium methylate, a reaction temperature is reduced to the room temperature from a return temperature, ethanol is used as a solvent and a high yield of 99.5% is realized. In the second asymmetric oxidation step, a yield is 80% or more. The preparation method has simple processes, is free of multiple complex extraction and separation processes and is suitable for industrial production. In the third step, through reaction condition optimization, a reaction conversion rate is greater than 85% and enantioselectivity is greater than 97%. Through purification, the product quality satisfies the FDA same-type product standards, optical purity and chemical purity are greater than 99.5%, the content of thioether is less than 0.1% and sulphone content is less than 0.1%. The preparation method has stable processes and an industrialization prospect.

Description

technical field [0001] The invention belongs to the field of chemical medicine synthesis and specifically designs a preparation method of D-lansoprazole. Background technique [0002] Lansoprazole (Lansoprazole), chemical name: 2-({[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl}sulfinyl) -1H-benzimidazole, a benzimidazole derivative with anti-acid effect developed by Takeda Corporation in December 1991. As a new type of proton pump inhibitor, lansoprazole is an upgraded product of omeprazole, its bioavailability is more than 30% higher than that of omeprazole, and its lipophilicity is also stronger than that of omeprazole. Under acidic conditions, it can quickly pass through the parietal cell membrane and convert into sulfenic acid and sulfenyl derivatives to exert its medicinal effect, and its antibacterial activity against HP is four times higher than that of omeprazole. Lansoprazole acts on the H+-K+-ATPase of gastric parietal cells, so that the H+ of parietal cel...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12C07B2200/07
Inventor 何雄肖利辉贺莲张静
Owner 长沙康普大药房有限责任公司
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