Preparation method for canagliflozin intermediate

A technology of intermediates and synthetic methods, which is applied in the field of preparation of canagliflozin intermediates, can solve problems such as unsuitability for industrial production, high toxicity, inflammability and explosion, and achieve low anhydrous requirements, high selectivity, and Dealing with Easy Effects

Inactive Publication Date: 2020-02-28
TAIZHOU UNIV
View PDF8 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This invention uses highly toxic, flammable, explosive, and foul-smelling phosphorus pentasulfide as the key raw material for the reaction, and it needs to be reacted under microwave conditions, which is not suitable for industrial production.

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 for canagliflozin intermediate
  • Preparation method for canagliflozin intermediate
  • Preparation method for canagliflozin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1: a kind of preparation method of canagliflozin intermediate comprises the following steps:

[0032] Step 1: Preparation of 2-(4-fluorophenyl)-5-methylthiophene

[0033] Get 2-bromo-5-methylthiophene (20mmol) and dissolve in the mixed solvent of ethanol (30ml) and water (10ml), add tris(dibenzylideneacetone) dipalladium (0.3mmol), tricyclohexylphosphine successively (1mmol), potassium carbonate (20mmol) and 4-fluorophenylboronic acid (10mmol), stirred at 85°C for 12h, cooled to room temperature, added ethyl acetate (20ml × 3) for extraction, dried over anhydrous magnesium sulfate, collected the filtrate and Concentration gave a crude product, which was recrystallized from ethanol (10ml) to give 2-(4-fluorophenyl)-5-methylthiophene (89% yield).

[0034]Step 2: Preparation of 2-bromomethyl-5-(4-fluorophenyl)thiophene

[0035] Put 2-(4-fluorophenyl)-5-methylthiophene (20mmol), 2,2-azobisisobutyronitrile (4mmol), N-bromosuccinimide (22mmol) and 20ml chloroform...

Embodiment 2

[0039] Step 1: Preparation of 2-(4-fluorophenyl)-5-methylthiophene

[0040] Take 2-bromo-5-methylthiophene (20mmol) and dissolve it in dimethylformamide (20ml) solvent, add tris(dibenzylideneacetone)dipalladium (0.3mmol), tricyclohexylphosphine (1mmol) successively , potassium carbonate (20mmol) and 4-fluorophenylboronic acid (10mmol), stirred and reacted at 90°C for 10h, cooled to room temperature, added ethyl acetate (20ml×3) for extraction, dried over anhydrous magnesium sulfate, collected the filtrate and concentrated to obtain The crude product was recrystallized from ethanol (10ml) to obtain 2-(4-fluorophenyl)-5-methylthiophene (90% yield).

[0041] Step 2: Preparation of 2-bromomethyl-5-(4-fluorophenyl)thiophene

[0042] Put 2-(4-fluorophenyl)-5-methylthiophene (20mmol), 2,2-azobisisobutyronitrile (4mmol), N-bromosuccinimide (26mmol) and 20ml chloroform into 50ml dry three-necked flask, reflux for 3h. Dilute with petroleum ether (75ml), filter out the solid, wash the...

Embodiment 3

[0046] Step 1: Preparation of 2-(4-fluorophenyl)-5-methylthiophene

[0047] Take 2-bromo-5-methylthiophene (20mmol) and dissolve in dimethylformamide (20ml) solvent, add tris(dibenzylideneacetone) dipalladium (0.2mmol), tricyclohexylphosphine (0.4mmol) ), potassium carbonate (20mmol) and 4-fluorophenylboronic acid (15mmol), stirred and reacted at 100°C for 8h, cooled to room temperature, added ethyl acetate (20ml×3) for extraction, dried over anhydrous magnesium sulfate, collected the filtrate and concentrated, The crude product was obtained and recrystallized from ethanol (10ml) to obtain 2-(4-fluorophenyl)-5-methylthiophene (yield 85%).

[0048] Step 2: Preparation of 2-bromomethyl-5-(4-fluorophenyl)thiophene

[0049] Put 2-(4-fluorophenyl)-5-methylthiophene (20mmol), 2,2-azobisisobutyronitrile (6mmol), N-bromosuccinimide (22mmol) and 20ml chloroform into 50ml dry three-neck flask, reflux for 5h. Dilute with petroleum ether (75ml), filter out the solid, wash the filtrate ...

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 relates to a preparation method for a canagliflozin intermediate. The canagliflozin key intermediate, namely 2-(4-fluorophenyl)-5-[(5-bromo-2-methylphenyl)methyl]thiophene is obtained through a three-step reaction of coupling, N-halogenated succinimide halogenation and p-bromotoluene alkylation by using easily-available 2-bromo-5-methylthiophene as a starting raw material. The preparation method provided by the invention has the characteristics of easily-available raw materials, short production steps, simple operation, stable process, high yield and good product quality.

Description

technical field [0001] The invention relates to a preparation method of a canagliflozin intermediate, belonging to the field of drug synthesis. Background technique [0002] Canagliflozin was approved by the FDA in March 2013, becoming the first ggliflozin hypoglycemic drug to be marketed in the United States. Canagliflozin is a new type of sodium-dependent glucose transporter inhibitor jointly developed by Mitsubishi Tanabe and Johnson & Johnson for the treatment of adult type 2 diabetes. Its trade name is Invokana. The pharmacological effect of canagliflozin is to prevent the glucose in the renal tubules from being reabsorbed into the blood smoothly by inhibiting SGLT2, thereby increasing the glucose content in the urine and causing a drop in blood sugar, which can effectively control the blood sugar content in the human body , the drug achieved great success in the U.S. market after it was launched. [0003] Synthesis of canagliflozin, 2-(4-fluorophenyl)-5-[(5-bromo-2-m...

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): C07D333/12
CPCC07D333/12
Inventor 郑人华郭海昌蒋华江
Owner TAIZHOU 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