Method for synthesizing optical enantiomer 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxylic acid and 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxylate

A technology of benzopyran and synthesis method, applied in the direction of organic chemistry, etc., can solve problems such as low yield, large reaction pollution, unreasonable synthesis method, etc.

Inactive Publication Date: 2005-06-22
TECHNICAL INST OF PHYSICS & CHEMISTRY - CHINESE ACAD OF SCI
View PDF2 Cites 13 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] One of the purposes of the present invention is to overcome the unreasonable synthesis method existing in the prior art, the reaction pollution is large, the cost of enantiomer resolution is high, the yield is low, the mass production of the product is difficult, and the raw materials cannot be localized, etc., and provide Two (R)-(-)-6-fluoro-3,4-dihydro-2H-1-benzopyrans, which are mild in reaction conditions, easy to operate, reasonable in sequence and low in synthesis cost, are suitable for industrial mass production. -2-carboxylic acid [where (R)-(-)-1], and (S)-(+)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2- The synthetic method of carboxylic acid [(S)-(+)-1 in the formula]

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
  • Method for synthesizing optical enantiomer 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxylic acid and 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxylate
  • Method for synthesizing optical enantiomer 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxylic acid and 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxylate
  • Method for synthesizing optical enantiomer 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxylic acid and 6-fluoro-3, 4-dihydro-2H-1-benzopyran-2-carboxylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1. Prepare (±)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid [in the formula (±)-1] and (±) according to synthetic method one -6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate [where (±)-1b]

[0047] 1.1 p-Fluoroanisole

[0048] Dissolve p-fluorophenol (25.6g, 0.05mol) in 500ml of 5wt% NaOH aqueous solution, add dimethyl sulfate (32g, 0.254mol) dropwise, heat to 70°C, stir for 5 hours and stop, wait until the system is cooled to room temperature Then, it was extracted with ethyl acetate 20ml×3, the ethyl acetate layer was collected, dried with anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation to obtain a light yellow viscous liquid, which was distilled under reduced pressure to collect 38-40℃ / The 5mmHg fraction yielded p-fluoroanisole (6.2g, 98%).

[0049] 1.2 4-(5-Fluoro-2-hydroxy)phenyl-4one-2,3-butenoic acid

[0050] Feed with maleic anhydride (4g, 0.04mol), aluminum trichloride catalyst (15g, 0.112mol), p-fluoroani...

Embodiment 2

[0060] 1.1 p-Fluoroanisole

[0061] Dissolve p-fluorophenol (51.2g, 0.1mol) in 5wt% Na 2 CO 3 Add dimethyl sulfate (64g, 0.508mol) dropwise to 1000ml of aqueous solution, heat to 75°C, stir for 5 hours and then stop. After the system is cooled to room temperature, extract with 40ml×3 ethyl acetate and collect the ethyl acetate layer. After drying with anhydrous sodium sulfate, filtering, and rotary evaporation to remove the solvent, a light yellow viscous liquid was obtained, which was distilled under reduced pressure to collect the fraction of 38~40℃ / 5mmHg to obtain p-fluoroanisole (12.4g, 98%) .

[0062] 1.2 4-(5-Fluoro-2-hydroxy)phenyl-4one-2,3-butenoic acid

[0063] Feed with maleic anhydride (8g, 0.08mol), catalyst aluminum trichloride (30g, 0.224mol), p-fluoroanisole (5.0g, 0.04mol), dissolve in 55ml of dichloromethane, and heat to 60°C, The reaction is carried out for 2 hours. After the reaction is completed, a mixed solution of ice water and hydrochloric acid is added to t...

Embodiment 3

[0073] Prepare (±)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid [in the formula (±)-1] and (±)-6-fluoro -3,4-Dihydro-2H-1-benzopyran-2-carboxylate [where (±)-1b]

[0074] 1.1 p-Fluoroanisole

[0075] The preparation of p-fluoroanisole is the same as in Example 1.

[0076] 1.2 5-Fluoro-2-hydroxy-acetophenone

[0077] 4-Fluoroanisole (0.1mol), CS 2 100ml, catalyst aluminum trichloride (0.25mol), slowly add acetic anhydride (0.12mol) while stirring, the reaction temperature is 75℃, after the reaction is over, add appropriate amount of hydrochloric acid and crushed ice to the system, stir vigorously, divide The organic layer was separated, the aqueous layer was extracted with ethyl acetate (3×25 ml), the organic layers were combined and washed with water, and finally the organic layer was washed with Na 2 SO 4 After drying and removing the solvent, the product 5-fluoro-2-hydroxy-acetophenone is obtained. Mp 55~56℃.

[0078] 1.3(a) 5-Fluoro-2-hydroxy-acetophenone (0.1mol), di...

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 the method for synthesizing destination substance of (+-)-6-fluoine-3,4-dihydrogen-2H-1-benzopyrans-2-carboxylic acid through two paths, the (+-)-6-fluoine-3,4-dihydrogen-2H-1-benzopyrans-2-carboxylic acid and C1-C10 alcohols are subject to esterification reaction so as to synthesize the corresponding racemic ester. Then chemical dismantling is conducted to (+-)-6-fluoine-3,4-dihydrogen-2H-1-benzopyrans-2-carboxylic acid, in order to obtain prepare optical purity of (R)-(-)-6-fluoine-3,4-dihydrogen-2H-1-benzopyrans-2-carboxylic acid and (S)-(+)-6-fluoine-3,4-dihydrogen-2H-1-benzopyrans-2-carboxylic acid.

Description

Technical field [0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to optically pure (R)-(-)-6-fluoro-3,4-dihydro-2H-1-phenylpyridine intermediates of β-adrenal antagonist antihypertensive drugs Pyran-2-carboxylic acid [where (R)-(-)-1] and (S)-(+)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2 -Synthesis method of carboxylic acid [in the formula (S)-(+)-1] and their racemic carboxylic acid esters. Background technique [0002] The optical enantiomer (R)-(-)-6-fluoro-3,4-dihydro-2H-1-chroman-2-carboxylic acid [where (R)-(-)-1] and (S)-(+)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid [where (S)-(+)-1] is a drug synthesis The intermediate is mainly used in the synthesis of β-adrenal antagonist antihypertensive drugs. [0003] About (R)-(-)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid [where (R)-(-)-1] and (S) -(+)-6-Fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid [where (S)-(+)-1] and their ethyl carboxylate Synthesis...

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): C07D311/66
Inventor 王乃兴杨运旭
Owner TECHNICAL INST OF PHYSICS & CHEMISTRY - CHINESE ACAD OF SCI
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