Preparation of darifenacin intermediate 5-(halogenated ethyl)-2,3-dihydrobenzofuran

A technology of haloethyl and dihydrobenzene, which is applied in the field of chemical synthesis, can solve the problems of needing dangerous reagents, difficulty in industrialization, and high cost, and achieve the effect of novel process route, low production cost, and no three wastes

Inactive Publication Date: 2008-10-08
BEIJING CHEMSUN PHARMA TECH
View PDF6 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In view of this, in order to solve the shortcomings of the existing 5-(haloethyl)-2,3-dihydrobenzofuran preparation method with long steps, dangerous reagents, high cost and difficult industrialization

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation of darifenacin intermediate 5-(halogenated ethyl)-2,3-dihydrobenzofuran
  • Preparation of darifenacin intermediate 5-(halogenated ethyl)-2,3-dihydrobenzofuran
  • Preparation of darifenacin intermediate 5-(halogenated ethyl)-2,3-dihydrobenzofuran

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] (1) Synthesis of 5-bromo-2,3-dihydrobenzofuran

[0030] Dissolve 6 grams of 2,3-dihydrobenzofuran in 250 milliliters of dichloromethane, at room temperature, add dropwise a solution of 48 grams of liquid bromine in 50 milliliters of dichloromethane within 45 minutes, keep stirring for 30 minutes after adding, The reaction was quenched by adding 50 ml of sodium bisulfite aqueous solution, and the layers were separated. The organic layer was washed with 100 ml of water, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 5-bromo-2,3-dihydrobenzofuran as a yellow solid. The melting point is 51-52°C.

[0031] (2) Synthesis of 2,3-dihydrobenzofuran-5-ethanol

[0032] 1.7 g (70 mmol) of magnesium chips and 20 ml of tetrahydrofuran were heated to reflux, 5 drops of 1,2-dibromoethane were added, and 12.4 g (62.3 mmol) of 5-bromo-2,3-dihydro 40 ml of tetrahydrofuran solution of benzofuran, keep refluxing until the magnesium chips basically disappear. Co...

Embodiment 2

[0043] Step (1), step (3) are the same as embodiment 1, the difference is:

[0044] Step (2): Synthesis of 2,3-dihydrobenzofuran-5-ethanol

[0045]1.7 g (70 mmol) of magnesium chips and 30 ml of anhydrous ether were heated to reflux, 5 drops of 1,2-dibromoethane were added, and 12.4 g (62.3 mmol) of 5-bromo-2,3- 40 milliliters of tetrahydrofuran solution of dihydrobenzofuran, then keep reflux until the magnesium chips disappear substantially. Cool, keep the temperature not exceeding 0°C, feed ethylene oxide, keep feeding for 30 minutes, then heat to reflux for 6 hours, cool to 25°C, inject the reaction solution into 75 ml of saturated ammonium chloride aqueous solution. The organic layer was separated, and the aqueous layer was extracted twice with a small amount of ether. The organic layers were combined, dried, filtered, and the filtrate was concentrated under reduced pressure to obtain 10.2 g of yellow oily 2,3-dihydrobenzofuran-5-ethanol.

Embodiment 3

[0047] Step (1), step (2) are the same as embodiment 1, the difference is:

[0048] Step (3): 5-(Chloroethyl)-2,3-dihydrobenzofuran

[0049] Add 0.612 g of 2,3-dihydrobenzofuran-5-ethanol dropwise to 10 ml of thionyl chloride solution, heat to reflux for 3 hours, recover excess thionyl chloride, cool to room temperature, add 20 ml of dichloromethane Methane, 20 milliliters of 10% sodium carbonate solution was added dropwise, the layers were separated, the aqueous layer was extracted with 20 milliliters × 2 of dichloromethane, the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain an oil, which was solidified on standing. Obtained 0.32 g of 5-(chloroethyl)-2,3-dihydrobenzofuran with a melting point of 49-50° C. (see figure 2 ).

[0050] The corresponding data of the 1HNMR spectrum of 5-(2-bromoethyl)-2,3-dihydrobenzofuran in this example are as follows: 1HNMR (CDCl3), δ=7.04 (s, 1H); 6.95-6.93 (d, 1H); 6.7...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
Melting pointaaaaaaaaaa
Login to view more

Abstract

The invention discloses a method to synthesize darifenacin intermediate compound with formula (I). Darifenacin is an effective for muscarine M3 receptor antagonist and can be used to cure overactive bladder diseases such as uroclepsia, urgency of urination and frequent micturition. The method takes 2,3-dihydrobenzofuran as material to produce 5-bromine-2,3-dihydrobenzofuran through bromination and then to prepare 2,3-dihydrobenzofuran-5-ethanol through grignard reaction and the introduction of ethylene oxide; finally the target compound (I) is obtained through halogenation. The method is novel in process route, with short process, simple operation, high yield, low cost and little waste(liquid, gas and solid); therefore the method is of great practical value and social economic value.

Description

technical field [0001] The invention relates to a chemical synthesis method, in particular to a preparation method of darfinacin intermediate 5-(haloethyl)-2,3-dihydrobenzofuran. technical background [0002] Darifenacin ((S)-[1-[2-(2,3-dihydro-5-benzofuranyl)ethyl]-α,α-diphenyl]-3-Pyrrolidineacetamide) is a potent muscarinic M3 receptor blockers can selectively block the M3 receptors that regulate the contractility of the detrusor muscle, and do not affect the central and cardiovascular system M1 and M2 receptors. Swiss Novartis purchased this product from Pfizer in 2003. In December 2003, the US FDA approved this product for overactive bladder; in December 2004, darfinacine hydrobromide sustained-release tablets were approved for the treatment of urinary incontinence, urgency and frequency and other overactive bladder syndrome (OAB). The M3 effect of darfinacine is unique among all OAB treatment drugs. The sustained-release tablets can reduce the incidence of central ne...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): C07D307/79
Inventor 费久佳叶太平韩彦召高全宝王丽君
Owner BEIJING CHEMSUN PHARMA TECH
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap