Preparation method of 5-cyanogen-1-(4-fluobenzene)-1,3-dihydrogenated-isobenzofuranone

A technology of fluorophenyl and dihydrogenation, which is applied in the direction of organic chemistry, can solve the problems of low yield, large amount of sodium borohydride, and low total yield, and achieve the effects of easy control of the reaction, simple process, and low cost

Inactive Publication Date: 2014-01-01
SOUTHEAST UNIV
View PDF17 Cites 6 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, the main drawback of this method is
[0008] 1. For industrial production, anhydrous tetrahydrofuran has a high cost and is difficult to recycle;
[0009] 2. Different solvents are used in different reaction steps, which makes it more cumbersome in industrial production;
[0010] 3. A large amount of sodium borohydride is needed in the reaction process, which makes the reaction dangerous;
[0011] 4. Lower yield
[0026] Although the synthesis method is relatively simple to operate, it requires a large amount of sodium borohydride, the operation has certain risks, and the total yield is low

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 method of 5-cyanogen-1-(4-fluobenzene)-1,3-dihydrogenated-isobenzofuranone
  • Preparation method of 5-cyanogen-1-(4-fluobenzene)-1,3-dihydrogenated-isobenzofuranone
  • Preparation method of 5-cyanogen-1-(4-fluobenzene)-1,3-dihydrogenated-isobenzofuranone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] The preparation of 5-cyano-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran includes the following steps:

[0048] (1) Synthesis of p-fluorobenzoyl hydrazide

[0049] The reaction equation is:

[0050]

[0051] Ethyl p-fluorobenzoate (115 g, 683.8 mmol) was added to 1500 ml of ethanol solution, stirred until the solution was clear, 1.7 mol of hydrazine hydrate was added dropwise to the solution, and the reaction was refluxed at 90°C for 1 hour. TLC monitoring showed that after the reaction was completed, it was allowed to stand overnight, and 95 g of solid was precipitated, namely p-fluorobenzoyl hydrazide (compound 2), with a yield of 89.7%.

[0052] 1 H-NMR(300M,CDCl 3 ): 8.12 (m, 2H), 7.42 (t, 2H), 8.0 (s, 1H), 2.0 (s, 2H).

[0053] (2) Synthesis of 4-fluoro-[(5-bromo-2-hydroxyphenyl)methylene]hydrazide benzoic acid

[0054] The reaction equation is:

[0055]

[0056] 5-Bromo-2-hydroxybenzaldehyde (21g, 100mmol) was dissolved in 50ml of acetic acid aqueous solution with pH 3.5, p-f...

Embodiment 2

[0076] The preparation of 5-cyano-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran includes the following steps:

[0077] (1) Synthesis of p-fluorobenzoyl hydrazide

[0078] 0.5 mol of methyl p-fluorobenzoate was added to 1500 ml of ethanol solution, stirred until the solution was clear, 0.5 mol of hydrazine hydrate was added dropwise to the solution, and the reaction was refluxed at 100°C for 1.5 hours. According to TLC monitoring, after the reaction was completed, it was allowed to stand overnight, and a solid was precipitated to obtain 0.45 mol of p-fluorobenzoyl hydrazide with a yield of 90.0%.

[0079] (2) Synthesis of 4-fluoro-[(5-bromo-2-hydroxyphenyl)methylene]hydrazide benzoic acid

[0080] Dissolve 0.2mol of 5-bromo-2-hydroxybenzaldehyde in 50ml aqueous acetic acid with pH 3.0, add 0.2mol of p-fluorobenzoyl hydrazide, and react for 10 minutes at 40°C. After the reaction is completed, pour the reaction solution into cold water to precipitate Yellow-white solid, filtered and wash...

Embodiment 3

[0088] The preparation of 5-cyano-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran includes the following steps:

[0089] (1) Synthesis of p-fluorobenzoyl hydrazide

[0090] Add 0.5 mol of ethyl p-fluorobenzoate to 1500 ml of ethanol solution, stir until the solution is clear, add 2.5 mol of hydrazine hydrate to the solution dropwise, and react under reflux at 80°C for 1 hour. According to TLC monitoring, after the reaction was completed, it was allowed to stand overnight, and a solid was precipitated to obtain 0.46 mol of p-fluorobenzoyl hydrazide with a yield of 92.0%.

[0091] (2) Synthesis of 4-fluoro-[(5-bromo-2-hydroxyphenyl)methylene]hydrazide benzoic acid

[0092] Dissolve 0.4 mol of 5-bromo-2-hydroxybenzaldehyde in 50 ml of acetic acid with a pH of 4.0, add 0.2 mol of p-fluorobenzoyl hydrazide, and react at 30°C for 20 minutes. After the reaction is completed, pour the reaction solution into cold water to precipitate The yellow-white solid was filtered and washed with n-hexane t...

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

No PUM Login to view more

Abstract

The invention provides a preparation method of 5-cyanogen-1-(4-fluobenzene)-1,3-dihydrogenated-isobenzofuranone. The preparation method comprises the following steps: reducing fluorobenzoic acid ester through hydrazine hydrate to obtain fluorobenzene formylhydrazine; enabling the fluorobenzene formylhydrazine to react with 5-bromine-2-hydroxybenzaldehyde under acidic conditions to obtain 4-fluorine-[(5-bromine-2- hydroxy phenyl) methene] hydrazide benzoic acid; oxidizing the 4-fluorine-[(5-bromine-2- hydroxy phenyl) methene] hydrazide benzoic acid through an oxidizing agent to obtain 5-bromine-2-(4-fluorine benzoyl)-benzaldehyde; reducing the 5-bromine-2-(4-fluorine benzoyl)-benzaldehyde through a reducing agent to obtain 4-bromine-Alpha 1-(4-fluorine phenyl)-1,2-xylyl alcohol; performing condensation reaction on the 4-bromine-Alpha 1-(4-fluorine phenyl)-1,2-xylyl alcohol by using toluenesulfonic acid as a catalyst to obtain 1-(4-fluobenzene)-5-bromine-1,3-dihydro- isobenzofuranone; enabling the 1-(4-fluobenzene)-5-bromine-1,3-dihydro- isobenzofuranone to react with copper cyanide to obtain the product. The method is low in cost, simple in technology, easy-operated in reaction, high in yield and suitable for industrialized production.

Description

Technical field [0001] The invention belongs to the field of organic chemistry, and particularly relates to a preparation method of escitalopram intermediate 5-cyano-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran. Background technique [0002] Escitalopram (Escitalopram) is also known as Lexap, and its chemical name is (+)-(s)-1-[3-(dimethylamino)-propyl]-1-(4-fluorophenyl)- 1,3-Dihydroisobenzofuran-5-carbonitrile is the S-isomer of the racemate citalopram. Escitalopram was developed by the Danish company Lundbeck and was first listed in Switzerland on March 15, 2002. This product is used to treat depression and can increase the reuptake of serotonin in the central nervous system. Compared with citalopram, this product has a stronger selection of serotonin, and has a quick onset and high safety. [0003] 5-cyano-1-(4-fluorophenyl)-1,3-dihydro-isobenzofuran is an important intermediate for the synthesis of citalopram. In the prior art, the synthesis methods of 5-cyano-1-(4-fluoroph...

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
Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/87
CPCC07D307/87
Inventor 吉民张蕊王鹏
Owner SOUTHEAST UNIV
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