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Method for preparing darifenacin intermediate 5-(2-bromoethyl)-2,3-dihydro-1-benzofuran

A technology of benzofuran and dihydrobenzene, which is applied in the field of preparation of darfinazine intermediate 5--2, can solve the problems of unsuitable for industrialization, high cost, low yield, etc.

Inactive Publication Date: 2010-10-13
ZHEJIANG MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] In order to solve the shortcomings of 5-(2-bromoethyl)-2,3-dihydro-1-benzofuran preparation method, dangerous and expensive reagents are needed, the yield is low, the cost is high, and it is not suitable for industrialization, The invention provides a new preparation method, the method is simple and convenient, the raw materials are easy to obtain, and the yield is high, which is suitable for industrial production

Method used

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  • Method for preparing darifenacin intermediate 5-(2-bromoethyl)-2,3-dihydro-1-benzofuran
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  • Method for preparing darifenacin intermediate 5-(2-bromoethyl)-2,3-dihydro-1-benzofuran

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example 1

[0025] Example 1. Synthesis of 5-(2-bromoethyl)-2,3-dihydro-1-benzofuran

[0026] 250 ml of tetrahydrofuran, 52.9 g of sodium borohydride, and 71.2 g of 2,3-dihydrobenzofuran-5-acetic acid in 150 ml of THF were added to the reaction flask at 5-10°C. Stir in an ice bath, and when the temperature is lower than 20°C, slowly add 37.3ml of concentrated sulfuric acid dropwise, and stir at room temperature for 2 hours after the drop is completed. After the reaction is completed, add methanol to quench the reaction solution. 300ml, 300ml of 10% NaOH were left to separate and the organic layer was washed with water. Continuously extract the aqueous layer with dichloromethane, combine the organic layers, dry over anhydrous magnesium sulfate, concentrate the organic layer to dryness under reduced pressure, add DMF150ml and stir to dissolve. In an ice bath, slowly add 120 g of phosphorus tribromide dropwise at a temperature of 25 ° C, and react for 1 hour at 45 ~ 50 ° C. After the end, i...

example 2

[0027] Example 2.2, Synthesis of 3-dihydrobenzofuran-5-ethanol

[0028] 250 ml of 1,4-dioxane, 80.7 g of potassium borohydride, and 71.2 g of 2,3-dihydrobenzofuran-5-acetic acid in 150 ml of THF were added to the reaction flask at 5-10°C. Stir in an ice bath, and when the temperature is lower than 20°C, slowly add 127g of iodine in 200ml THF solution dropwise, stir at room temperature for 2 hours after dropping, and react at 60°C for 2 hours, after the reaction is completed, add dilute hydrochloric acid to quench, and the reaction solution is concentrated to dryness , add 100ml of water, 300ml of dichloromethane, 300ml of 20% NaOH and let stand to separate the layers, and the organic layer is washed with water. The aqueous layer was continuously extracted with dichloromethane, the organic layers were combined, dried over anhydrous magnesium sulfate, and the organic layer was concentrated to dryness under reduced pressure to obtain 64.3 g of a white solid. Yield 98%.

example 3

[0029] Example 3.2, Synthesis of 3-dihydrobenzofuran-5-ethanol

[0030] 250 ml of diethylene glycol dimethyl ether, 75.4 g of potassium borohydride, and 71.2 g of 2,3-dihydrobenzofuran-5-acetic acid in 150 ml of THF were added to the reaction flask at 5-10°C. Stir in an ice bath, and when the temperature is lower than 20°C, slowly add 37.3ml of concentrated sulfuric acid dropwise, stir at room temperature for 2 hours after dropping, and react at 5°C for 2 hours. Add 100ml of water, 300ml of dichloromethane, and 300ml of 20% NaOH to separate the layers, and wash the organic layer with water. The aqueous layer was continuously extracted with dichloromethane, the organic layers were combined, dried over anhydrous magnesium sulfate, and the organic layer was concentrated to dryness under reduced pressure to obtain 64.9 g of a white solid. Yield 99%.

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Abstract

The invention provides a method for preparing darifenacin intermediate 5-(2-bromoethyl)-2,3-dihydro-1-benzofuran. The method comprises the following steps of: directly reducing 2,3-dihydro benzofuran-5-acetic acid serving as a raw material into 2,3-dihydro benzofuran-5-ethanol in the presence of an ether solvent; and performing bromination on the 2,3-dihydro benzofuran-5-ethanol to obtain 5-(2-bromoethyl)-2,3-dihydro-1-benzofuran. The method has the advantages of simple and convenient operation, readily available raw material, high yield, low production cost and suitability for industrial production.

Description

technical field [0001] The invention relates to a method for preparing dalfenacin intermediate 5-(2-bromoethyl)-2,3-dihydro-1-benzofuran, which belongs to the fields of chemical industry and chemical medicine. technical background [0002] Darifenacin (DariFenacin), (S)-2-[1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl]-2,2- Diphenylacetamide, a selective muscarinic antagonist developed by Pfizer of the United States, is mainly used for the treatment of urinary incontinence, and was successfully purchased by Novartis for US$225 million. It was approved by the FDA on December 22, 2004 Approved in the U.S. as Enablex The product name is listed. Its structural formula is as follows: [0003] [0004] There are many synthetic documents of darfenazine, such as U.S. Patent US5096890 and European Patent EP0388054, all adopt 5-(2-bromoethyl)-2,3-dihydro-1-benzofuran as the key intermediate, which is synthesized The method is: 2,3-dihydrobenzofuran is used as raw mate...

Claims

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Application Information

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IPC IPC(8): C07D307/79
Inventor 陈为人刘雄
Owner ZHEJIANG MENOVO PHARMA
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