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Improvement method for preparing 6-fluorin-3,4-dihydro-2H-1-benzopyranyl-2-epoxy ethane

A technology of benzopyran and ethylene oxide, which is applied in the field of key intermediates for the preparation of nebivolol, can solve the problems of strong corrosion of halogenated hydrogen acids, unfavorable large-scale application, harsh reaction conditions, etc., and achieve environmental friendliness , Conducive to industrial large-scale production, the effect of reaction yield and purity improvement

Active Publication Date: 2011-07-20
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] The main shortcoming of the method that CN101522656 introduces is that the used raw material of preparation compound (II) is difficult to obtain, and reaction condition is harsh, and operation is complicated, and the halogenated hydrogen acid used in the reaction process is highly corrosive, is unfavorable for large-scale application in industry

Method used

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  • Improvement method for preparing 6-fluorin-3,4-dihydro-2H-1-benzopyranyl-2-epoxy ethane
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  • Improvement method for preparing 6-fluorin-3,4-dihydro-2H-1-benzopyranyl-2-epoxy ethane

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Effect test

Embodiment 1

[0048] Preparation of 2-chloro-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl) ethyl ketone

[0049] In a 500ml four-neck flask equipped with a mechanical stirrer, a thermometer, and a constant pressure dropping funnel, add 150ml of dry tetrahydrofuran, protect it with nitrogen, and add 24.4g of 6-fluoro-3,4-dihydro-2H-benzo Ethyl pyran-2-carboxylate, then add 40.4 g of bromochloromethane, cool down to -50°C, add 130 ml of 2.5 mol / L n-butyllithium n-hexane solution dropwise, after the addition is complete, react for 3 hours, use saturated 100 milliliters of ammonium chloride solution was quenched, after the solvent was distilled off under reduced pressure, 100 milliliters of toluene was added to extract three times, the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain 22.1 grams of product with a yield of 89% (HPLC 95% purity).

Embodiment 2

[0051] Preparation of 2-chloro-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl) ethyl ketone

[0052] In a 500ml four-neck flask equipped with a mechanical stirrer, a thermometer, and a constant pressure dropping funnel, add 150ml of dry tetrahydrofuran, protect it with nitrogen, and add 24.4g of 6-fluoro-3,4-dihydro-2H-benzo Ethyl pyran-2-carboxylate, then add 40.0 g of iodochloromethane, cool down to -60°C, add 108 ml of 2.5 mol / L n-butyllithium n-hexane solution dropwise, after the dropwise addition, react for 3 hours, use 100 milliliters of saturated ammonium chloride solution was quenched, after the solvent was distilled off under reduced pressure, 100 milliliters of toluene was added to extract three times, the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain 23 grams of product, yield 92% ( HPLC purity 96%).

Embodiment 3

[0054] Preparation of 2-bromo-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)ethyl ketone

[0055] In a 500ml four-neck flask equipped with a mechanical stirrer, a thermometer, and a constant pressure dropping funnel, add 150ml of dry tetrahydrofuran, protect it with nitrogen, and add 24.4g of 6-fluoro-3,4-dihydro-2H-benzo Ethyl pyran-2-carboxylate, then add 27.6 g of iodobromomethane, cool down to -70°C, add 65 ml of 2.5 mol / L n-butyllithium n-hexane solution dropwise, after the addition is complete, react for 3 hours, use saturated 100 milliliters of ammonium chloride solution was quenched, after the solvent was evaporated under reduced pressure, 100 milliliters of toluene was added to extract three times, the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain 26.4 grams of product, yield 89% (HPLC The purity is 96%).

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Abstract

The invention relates to an improvement method for preparing a nebivolol key intermediate, namely 6-fluorin-3,4-dihydro-2H-1-benzopyranyl-2-epoxy ethane. The method comprises the following steps of: (a) condensing a compound (IV) and dihalogenated methane in the presence of an organic metal lithium compound to obtain a compound (II); (b) reducing the compound (II) to obtain a compound (III); and (c) performing cyclization on the compound (III) under alkaline condition to obtain a compound (I). The scheme of the invention has the advantages of readily available raw materials, easiness in operating, greatly increased reaction yield and purity and high contribution to industrial mass production.

Description

technical field [0001] The invention relates to an improved method for preparing a key intermediate of nebivolol, namely 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-oxirane. Background technique [0002] Nebivolol is a racemate composed of equal amounts of formula (IA) and equal amount of formula (IB). [0003] [0004] It is a new generation of antihypertensive drugs, a third-generation beta-blocker with strong selectivity, and its strength is 290 times that of the receptor, while bisoprolol is 26 times and atenolol is 15 times, Propranolol was 1.9 times. In December 2007, the FDA announced the approval of Nebivolol of Mylan Bertek Pharmaceuticals in the United States. [0005] 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-oxirane is a key intermediate in the synthesis of the drug, which is almost always used in the reported synthetic routes, Its synthesis method has attracted much attention. [0006] US Patent No. 4,654,362 describes a synthesis method of 6-fluoro-3,4-dihydro-2...

Claims

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Application Information

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IPC IPC(8): C07D407/04
Inventor 李东伟甘立新李克春
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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